# bib

id: cord-296562-3h2oqb9k
title: Preemptive interleukin-6 blockade in patients with COVID-19
author: Guillén, Lucía
date: 2020-10-08
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url: https://doi.org/10.1038/s41598-020-74001-3
doi: 10.1038/s41598-020-74001-3
summary:
  In contrast to other respiratory viral infections like influenza, a major pathogenic mechanism implicated in severe clinical manifestations of COVID-19 is an aberrant host immune response resulting in an excessive cytokine and chemokine release known as "cytokine storm" or "cytokine release syndrome" 2,3 . In a sensitivity analysis including only the 55 patients with confirmed SARS-CoV-2 infection by RT-PCR, the significant variables in the adjusted multivariate model were a NLR > 2.55 (OR 5.26; 95% CI 1.02-25), higher Charlson comorbidity index (OR 1.56; 95% CI 1.04-2.34) per unit, and higher SOFA score (OR 5.05; 95% CI 1.10-23.24) (Supplementary Table 2 ). This biomarker reflects excessive inflammation and dysregulation of immune cells that play a central role in severity of disease in viral infections 23 , and has been associated with mortality in patients hospitalized with COVID-19 24 . www.nature.com/scientificreports/ four comorbidities are included in the Charlson index, and have been associated with higher disease severity in patients with COVID-19 31 .

abstract:
  Excessive interleukin-6 signaling is a key factor contributing to the cytokine release syndrome implicated in clinical manifestations of COVID-19. Preliminary results suggest that tocilizumab, a humanized monoclonal anti-interleukin-6 receptor antibody, may be beneficial in severely ill patients, but no data are available on earlier stages of disease. An anticipated blockade of interleukin-6 might hypothetically prevent the catastrophic consequences of the overt cytokine storm. We evaluated early-given tocilizumab in patients hospitalized with COVID-19, and identified outcome predictors. Consecutive patients with initial Sequential-Organ-Failure-Assessment (SOFA) score < 3 fulfilling pre-defined criteria were treated with tocilizumab. Serial plasma biomarkers and nasopharyngeal swabs were collected. Of 193 patients admitted with COVID-19, 64 met the inclusion criteria. After tocilizumab, 49 (76.6%) had an early favorable response. Adjusted predictors of response were gender, SOFA score, neutrophil/lymphocyte ratio, Charlson comorbidity index and systolic blood pressure. At week-4, 56.1% of responders and 30% of non-responders had cleared the SARS-CoV-2 from nasopharynx. Temporal profiles of interleukin-6, C-reactive protein, neutrophil/lymphocyte ratio, NT-ProBNP, D-dimer, and cardiac-troponin-I differed according to tocilizumab response and discriminated final in-hospital outcome. No deaths or disease recurrences were observed. Preemptive therapy with tocilizumab was safe and associated with favorable outcomes in most patients. Biological and clinical markers predicted outcomes.


id: cord-296867-6o4scan1
author: Hisada, Shohei
date: 2020-10-29
txt: ./txt/cord-296867-6o4scan1.txt
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url: https://www.ncbi.nlm.nih.gov/pubmed/33122686/
doi: 10.1038/s41598-020-75771-6
summary:
  title: Surveillance of early stage COVID-19 clusters using search query logs and mobile device-based location information In contrast, we utilized web search query logs per user to detect WSSCI and gather their location histories to identify locations they visited or passed through, resulting in COVID-19 cluster detection. In the Kitami area (Fig. 3a) , the WSSCI has a maximum cross-correlation of 0.766, determined 2 days after the change in the number of new patients. This study attempted to detect early clusters by identifying people who suspected their own COVID-19 infection using web search query logs and by extracting their location information. We utilized web search query log data and location information provided by Yahoo Japan Corporation 17 as signals for syndromic surveillance. Syndromic surveillance using search query logs and user location information from smartphones against COVID-19 clusters in Japan

title:
  Surveillance of early stage COVID-19 clusters using search query logs and mobile device-based location information

abstract:
  Two clusters of the coronavirus disease 2019 (COVID-19) were confirmed in Hokkaido, Japan, in February 2020. To identify these clusters, this study employed web search query logs of multiple devices and user location information from location-aware mobile devices. We anonymously identified users who used a web search engine (i.e., Yahoo! JAPAN) to search for COVID-19 or its symptoms. We regarded them as web searchers who were suspicious of their own COVID-19 infection (WSSCI). We extracted the location of WSSCI via a mobile operating system application and compared the spatio-temporal distribution of WSSCI with the actual location of the two known clusters. In the early stage of cluster development, we confirmed several WSSCI. Our approach was accurate in this stage and became biased after a public announcement of the cluster development. When other cluster-related resources, such as detailed population statistics, are not available, the proposed metric can capture hints of emerging clusters.


id: cord-299605-j1ewxk4q
author: Lin, Jing-wen
date: 2017-02-03
txt: ./txt/cord-299605-j1ewxk4q.txt
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url: https://www.ncbi.nlm.nih.gov/pubmed/28155887/
doi: 10.1038/srep41722
summary:
  c. chabaudi, AS and CB, that differ in virulence in C57BL/6 mice, we performed high-resolution comparative whole-blood transcriptomic analysis throughout the acute phase of the blood-stage infection, and identified several transcriptomic signatures associated with severe malarial pathology before the onset of pathology or disease. Spearman''s rank correlation coefficient (r s ) analysis of unfiltered transcripts normalised across the median of all samples, revealed high levels of similarity amongst naïve and 2, 4 dpi samples in both AS and CB infections (Fig. 2ai ,ii, r s ranging from 0.73 to 0.88), while from 6 dpi onwards the whole blood transcriptomes diverge significantly from the earlier time points (r s ranging from 0.08 to − 0.59 compared to naïve controls). Importantly, in 4 of the CB infected mice that had reached humane end points at 9 dpi, these 5 genes showed an even higher level of up-regulation compared to naïve controls (Fig. 3c) , indicating possible lung pathology in these 4 CB infected mice.

title:
  Signatures of malaria-associated pathology revealed by high-resolution whole-blood transcriptomics in a rodent model of malaria

abstract:
  The influence of parasite genetic factors on immune responses and development of severe pathology of malaria is largely unknown. In this study, we performed genome-wide transcriptomic profiling of mouse whole blood during blood-stage infections of two strains of the rodent malaria parasite Plasmodium chabaudi that differ in virulence. We identified several transcriptomic signatures associated with the virulent infection, including signatures for platelet aggregation, stronger and prolonged anemia and lung inflammation. The first two signatures were detected prior to pathology. The anemia signature indicated deregulation of host erythropoiesis, and the lung inflammation signature was linked to increased neutrophil infiltration, more cell death and greater parasite sequestration in the lungs. This comparative whole-blood transcriptomics profiling of virulent and avirulent malaria shows the validity of this approach to inform severity of the infection and provide insight into pathogenic mechanisms.


id: cord-301016-9t7v7ipt
title: The heptad repeat region is a major selection target in MERS-CoV and related coronaviruses
author: Forni, Diego
date: 2015-09-25
url: https://doi.org/10.1038/srep14480
doi: 10.1038/srep14480
abstract:
  Middle East respiratory syndrome coronavirus (MERS-CoV) originated in bats and spread to humans via zoonotic transmission from camels. We analyzed the evolution of the spike (S) gene in betacoronaviruses (betaCoVs) isolated from different mammals, in bat coronavirus populations, as well as in MERS-CoV strains from the current outbreak. Results indicated several positively selected sites located in the region comprising the two heptad repeats (HR1 and HR2) and their linker. Two sites (R652 and V1060) were positively selected in the betaCoVs phylogeny and correspond to mutations associated with expanded host range in other coronaviruses. During the most recent evolution of MERS-CoV, adaptive mutations in the HR1 (Q/R/H1020) arose in camels or in a previous host and spread to humans. We determined that different residues at position 1020 establish distinct inter- and intra-helical interactions and affect the stability of the six-helix bundle formed by the HRs. A similar effect on stability was observed for a nearby mutation (T1015N) that increases MERS-CoV infection efficiency in vitro. Data herein indicate that the heptad repeat region was a major target of adaptive evolution in MERS-CoV-related viruses; these results are relevant for the design of fusion inhibitor peptides with antiviral function.


id: cord-302080-fegcf1fu
author: Oliveira-de-Souza, Deivide
date: 2020-07-09
url: https://doi.org/10.1038/s41598-020-68255-0
doi: 10.1038/s41598-020-68255-0
title:
  Aging increases the systemic molecular degree of inflammatory perturbation in patients with tuberculosis

abstract:
  Tuberculosis (TB) is a chronic infection that can affect individuals of all ages. The description of determinants of immunopathogenesis in TB is of tremendous interest due to the perspective of finding a reliable host-directed therapy to reduce disease burden. The association between specific biomarker profiles related to inflammation and the diverse clinical disease presentations in TB has been extensively studied in adults. However, relatively scarce data on profiling the inflammatory responses in pediatric TB are available. Here, we employed the molecular degree of perturbation (MDP) score adapted to plasma biomarkers in two distinct databanks from studies that examined either adults or children presenting with pulmonary or extrapulmonary disease. We used multidimensional statistical analyses to characterize the impact of age on the overall changes in the systemic inflammation profiles in subpopulation of TB patients. Our findings indicate that TB results in significant increases in molecular perturbation, with the highest values being detected in adult patients. Furthermore, there were unique differences in the biomarker perturbation patterns and the overall degree of inflammation according to disease site and age. Importantly, the molecular degree of perturbation was not influenced by sex. Our results revealed that aging is an important determinant of the differences in quality and magnitude of systemic inflammatory perturbation in distinct clinical forms of TB.


id: cord-302459-grs2x26l
title: A Plasma Biomarker Panel of Four MicroRNAs for the Diagnosis of Prostate Cancer
author: Matin, Farhana
date: 2018-04-27
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url: https://doi.org/10.1038/s41598-018-24424-w
doi: 10.1038/s41598-018-24424-w
summary:
  In this study we profiled 372 cancer-associated miRNAs in plasma collected before (~60% patients) and after/during commencement of treatment (~40% patients), from age-matched prostate cancer patients and healthy controls, and observed elevated levels of 4 miRNAs miR-4289, miR-326, miR-152-3p and miR-98-5p, which were validated in an independent cohort. Analysis of published miRNA transcriptomic data from clinical samples in the TCGA dataset demonstrated low expression of miR-152-3p in tumour compared to adjacent non-malignant tissues (p = 0.001) (Wilcoxon test, p ≤ 0.05) (Fig. 4) Figure S3) . Similarly, other groups have assessed the diagnostic performance of plasma or serum miRNAs in patients with localised or metastatic prostate cancer, BPH and healthy controls, and in most instances the specificity and sensitivity of the miRNA biomarkers have outperformed the accuracy of the PSA test 23, 28, 29 .

abstract:
  Prostate cancer is diagnosed in over 1 million men every year globally, yet current diagnostic modalities are inadequate for identification of significant cancer and more reliable early diagnostic biomarkers are necessary for improved clinical management of prostate cancer patients. MicroRNAs (miRNAs) modulate important cellular processes/pathways contributing to cancer and are stably present in body fluids. In this study we profiled 372 cancer-associated miRNAs in plasma collected before (~60% patients) and after/during commencement of treatment (~40% patients), from age-matched prostate cancer patients and healthy controls, and observed elevated levels of 4 miRNAs - miR-4289, miR-326, miR-152-3p and miR-98-5p, which were validated in an independent cohort. The miRNA panel was able to differentiate between prostate cancer patients and controls (AUC = 0.88). Analysis of published miRNA transcriptomic data from clinical samples demonstrated low expression of miR-152-3p in tumour compared to adjacent non-malignant tissues. Overexpression of miR-152-3p increased proliferation and migration of prostate cancer cells, suggesting a role for this miRNA in prostate cancer pathogenesis, a concept that was supported by pathway analysis of predicted miR-152-3p target genes. In summary, a four miRNA panel, including miR-152-3p which likely targets genes with key roles in prostate cancer pathogenesis, has the potential to improve early prostate cancer diagnosis.


id: cord-303601-o8uk6if2
title: Modeling, state estimation, and optimal control for the US COVID-19 outbreak
author: Tsay, Calvin
date: 2020-07-01
txt: ./txt/cord-303601-o8uk6if2.txt
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url: https://doi.org/10.1038/s41598-020-67459-8
doi: 10.1038/s41598-020-67459-8
summary:
  This includes modeling the dynamics of affected populations, estimating the model parameters and hidden states from data, and an optimal control strategy for sequencing social distancing and testing events such that the number of infections is minimized. Figure 2 shows the predicted values obtained by solving the parameter estimation problem and the historical data by country, retrieved by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (https ://githu b.com/CSSEG ISand Data/COVID -19; accessed April 16, 2020). For the estimated parameter values as described previously, we simulate the results of implementing two different simplistic control policies: (i) continuing with strict social distancing, quarantining, and testing, policies that result from continuing to lower the asymptomatic ( α a ) and infected ( α i ) exposures shown in Fig. 2 ; and (ii) a relaxed policy with more lenient measures and reduced testing, in this case the values of α a and α i are increased to 0.2 and 0.02, respectively, while κ is decreased to 0.2.

abstract:
  The novel coronavirus SARS-CoV-2 and resulting COVID-19 disease have had an unprecedented spread and continue to cause an increasing number of fatalities worldwide. While vaccines are still under development, social distancing, extensive testing, and quarantining of confirmed infected subjects remain the most effective measures to contain the pandemic. These measures carry a significant socioeconomic cost. In this work, we introduce a novel optimization-based decision-making framework for managing the COVID-19 outbreak in the US. This includes modeling the dynamics of affected populations, estimating the model parameters and hidden states from data, and an optimal control strategy for sequencing social distancing and testing events such that the number of infections is minimized. The analysis of our extensive computational efforts reveals that social distancing and quarantining are most effective when implemented early, with quarantining of confirmed infected subjects having a much higher impact. Further, we find that “on-off” policies alternating between strict social distancing and relaxing such restrictions can be effective at “flattening” the curve while likely minimizing social and economic cost.


id: cord-304040-64obh7i3
author: Sande, Charles J.
date: 2018-09-14
url: https://doi.org/10.1038/s41598-018-32072-3
doi: 10.1038/s41598-018-32072-3
title:
  Untargeted analysis of the airway proteomes of children with respiratory infections using mass spectrometry based proteomics

abstract:
  The upper airway – which consists mainly of the naso- and oro-pharynx - is the first point of contact between the respiratory system and microbial organisms that are ubiquitous in the environment. It has evolved highly specialised functions to address these constant threats whilst facilitating seamless respiratory exchange with the lower respiratory tract. Dysregulation of its critical homeostatic and defence functions can lead to ingress of pathogens into the lower respiratory tract, potentially leading to serious illness. Systems-wide proteomic tools may facilitate a better understanding of mechanisms in the upper airways in health and disease. In this study, we aimed to develop a mass spectrometry based proteomics method for characterizing the upper airways proteome. Naso- and oropharyngeal swab samples used in all our experiments had been eluted in the Universal Transport Media (UTM) containing significantly high levels of bovine serum albumin. Our proteomic experiments tested the optimal approach to characterize airway proteome on swab samples eluted in UTM based on the number of proteins identified without BSA depletion (Total proteome: Protocol A) and with its depletion using a commercial kit; Allprep, Qiagen (cellular proteome: Protocol B, Ci, and Cii). Observations and lessons drawn from protocol A, fed into the design and implementation of protocol B, and from B to protocol Ci and finally Cii. Label free proteome quantification was used in Protocol A (n = 6) and B (n = 4) while commercial TMT 10plex reagents were used for protocols Ci and ii (n = 83). Protocols Ci and ii were carried out under similar conditions except for the elution gradient: 3 h and 6 h respectively. Swab samples tested in this study were from infants and children with and without upper respiratory tract infections from Kilifi County Hospital on the Kenyan Coast. Protocol A had the least number of proteins identified (215) while B produced the highest number of protein identifications (2396). When Protocol B was modified through sample multiplexing with TMT to enable higher throughput (Protocol Ci), the number of protein identified reduced to 1432. Modification of protocol Ci by increasing the peptide elution time generated Protocol Cii that substantially increased the number of proteins identified to 1875. The coefficient of variation among the TMT runs in Protocol Cii was <20%. There was substantial overlap in the identity of proteins using the four protocols. Our method was were able to identify marker proteins characteristically expressed in the upper airway. We found high expression levels of signature nasopharyngeal and oral proteins, including BPIFA1/2 and AMY1A, as well as a high abundance of proteins related to innate and adaptive immune function in the upper airway. We have developed a sensitive systems-level proteomic assay for the systematic quantification of naso-oro-pharyngeal proteins. The assay will advance mechanistic studies of respiratory pathology, by providing an untargeted and hypothesis-free approach of examining the airway proteome.


id: cord-305031-9ze0097w
author: Büchel, Beda
date: 2020-10-29
txt: ./txt/cord-305031-9ze0097w.txt
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url: https://www.ncbi.nlm.nih.gov/pubmed/33122669/
doi: 10.1038/s41598-020-75538-z
summary:
  We cannot consider delay changes for freight traffic, as its volume was strongly affected by the Rastatt disruption; and more generally, freight traffic does not stop at stations thus having a ill-defined delay; and Scientific Reports | (2020) 10:18584 | https://doi.org/10.1038/s41598-020-75538-z www.nature.com/scientificreports/ despite its buffer times are typically large, its performance is often erratic. We now discuss how a state-of-the-art simulation model, OnTime, based on typical delay propagation theory 39 (the Methods section describes its assumptions and functioning, and its calibration for the test case) can partially replicate the degree by which the delay performance of passenger trains improved in the area of Basel, and decreased in the area of Schaffhausen. Newly designed statistical tests were applied to delay analysis in railway networks, performed at different percentile levels, over multiple time scales, and two specific factors (reduced entrance delay for passenger trains and rerouted freight trains).

title:
  Empirical dynamics of railway delay propagation identified during the large-scale Rastatt disruption

abstract:
  Transport networks are becoming increasingly large and interconnected. This interconnectivity is a key enabler of accessibility; on the other hand, it results in vulnerability, i.e. reduced performance, in case any specific part is subject to disruptions. We analyse how railway systems are vulnerable to delay, and how delays propagate in railway networks, studying real-life delay propagation phenomena on empirical data, determining real-life impact and delay propagation for the uncommon case of railway disruptions. We take a unique approach by looking at the same system, in two different operating conditions, to disentangle processes and dynamics that are normally present and co-occurring in railway operations. We exploit the unique chance to observe a systematic change in railway operations conditions, without a correspondent system change of infrastructure or timetable, coming from the occurrence of the large-scale disruption at Rastatt, Germany, in 2017. We define new statistical methods able to detect weak signals in the noisy dataset of recorded punctuality for passenger traffic in Switzerland, in the disrupted and undisrupted state, along a period of 1 year. We determine how delay propagation changed, and quantify the heterogeneous, large-scale cascading effects of the Rastatt disruption towards the Swiss network, hundreds of kilometers away. Operational measures of transport performance (i.e. punctuality and delays), while globally being very decreased, had a statistically relevant positive increase (though very geographically heterogeneous) on the Swiss passenger traffic during the disruption period. We identify two factors for this: (1) the reduced delay propagation at an international scale; and (2) to a minor extent, rerouted railway freight traffic; which show to combine linearly in the observed outcomes.


id: cord-305132-jspxlk1a
author: Homma, Takujiro
date: 2014-08-08
txt: ./txt/cord-305132-jspxlk1a.txt
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url: https://www.ncbi.nlm.nih.gov/pubmed/25103253/
doi: 10.1038/srep06006
summary:
  In this study, we analyzed murine IRF-3 promoter activity in detail and its relationship to prion infection, and have shown that the octamer-binding transcription factor-1 (Oct-1) positively regulates murine IRF-3, and the expression levels of Oct-1 decreased in prion-infected cells. Furthermore, in the persistently other prion strain-infected cells by the mouse-adapted Gerstmann-Sträussler-Schenker syndrome (GSS) Fukuoka-1 strain (FK-N2a58), IRF-3 mRNA and the promoter activity were also significantly decreased (Supplementary Fig. S6a and S6b). PCR analysis revealed that the Oct-1 antibody precipitated the promoter region (nt -119 to -1) from N2a58 cells (Fig. 4a) , while the negative control (anti-rabbit IgG) did not exhibit the DNA binding activity. These results demonstrate that reduced IRF-3 promoter activity in prion-infected cells is accompanied by decreased levels of Oct-1. In summary, our results demonstrated that Oct-1 binds to the murine IRF-3 promoter region and increases the transcription level and IRF-3 expression is reduced by prion infection.

title:
  Persistent prion infection disturbs the function of Oct-1, resulting in the down-regulation of murine interferon regulatory factor-3

abstract:
  As a prompt response against invasion of various viruses, interferon regulatory factor-3 (IRF-3) is initially phosphorylated to become activated and upregulates mainly Type I Interferons (IFN-I) in most cell types. We previously reported that IRF-3-dependent host innate immune responses partially interfere in infection of prions. Here, we found that stable infection of prion suppressed IRF-3 gene-expression. The decreased promoter activity of IRF-3 was significantly restored along with treatment of anti-prion drugs in the prion-infected cells, suggesting that infection of prion directly influence the regulation of IRF-3 transcription. We further investigated promoter activity of 5′- flanking region of murine IRF-3 using a luciferase reporter system and found that the nucleotides -119 to -1 were indispensable for the promoter activity. Within this region, mutations in the Oct-1 binding site significantly reduced the promoter activity and chromatin immunoprecipitation (ChIP) assay revealed that Oct-1 indeed binds to the region. In addition, overexpression of Oct-1 increased the promoter activity of IRF-3. Intriguingly, Oct-1 protein was significantly reduced in prion-infected cells and mice brains compared with uninfected groups. Taken together, we concluded that prion infection could interfere in the function of Oct-1, resulting in the down-regulation of IRF-3.


id: cord-305473-w30hsr4m
author: Jiang, Lili
date: 2017-02-20
url: https://doi.org/10.1038/srep42963
doi: 10.1038/srep42963
title:
  Detection of viral respiratory pathogens in mild and severe acute respiratory infections in Singapore

abstract:
  To investigate the performance of laboratory methods and clinical case definitions in detecting the viral pathogens for acute respiratory infections (ARIs) from a prospective community cohort and hospital inpatients, nasopharyngeal swabs from cohort members reporting ARIs (community-ARI) and inpatients admitted with ARIs (inpatient-ARI) were tested by Singleplex Real Time-Polymerase Chain Reaction (SRT-PCR), multiplex RT-PCR (MRT-PCR) and pathogen-chip system (PathChip) between April 2012 and December 2013. Community-ARI and inpatient-ARI was also combined with mild and severe cases of influenza from a historical prospective study as mild-ARI and severe-ARI respectively to evaluate the performance of clinical case definitions. We analysed 130 community-ARI and 140 inpatient-ARI episodes (5 inpatient-ARI excluded because multiple pathogens were detected), involving 138 and 207 samples respectively. Detection by PCR declined with days post-onset for influenza virus; decrease was faster for community-ARI than for inpatient-ARI. No such patterns were observed for non-influenza respiratory virus infections. PathChip added substantially to viruses detected for community-ARI only. Clinical case definitions discriminated influenza from other mild-ARI but performed poorly for severe-ARI and for older participants. Rational strategies for diagnosis and surveillance of influenza and other respiratory virus must acknowledge the differences between ARIs presenting in community and hospital settings.


id: cord-306517-tls0849i
author: Leidenberger, S.
date: 2017-09-07
url: https://www.ncbi.nlm.nih.gov/pubmed/28883628/
doi: 10.1038/s41598-017-11160-w
title:
  Virulence of current German PEDV strains in suckling pigs and investigation of protective effects of maternally derived antibodies

abstract:
  Porcine epidemic diarrhea (PED) has caused tremendous losses to the United States pig industry since 2013. From 2014, outbreaks were also reported from Central Europe. To characterize the Central European PEDV strains regarding their virulence in suckling piglets, and to assess the protective effect of maternally derived antibodies (MDA), four trial groups were randomly assigned, each consisting of two pregnant sows and their litter. To induce MDA in a subset of piglets, two sows received a cell culture-adapted PEDV strain, and another two sows were inoculated with field material from German PED outbreaks. Four sows stayed naïve. Subsequently, all piglets were inoculated with the corresponding PEDV strains at an age of 3 to 6 days, and virus shedding, clinical signs and occurrence of specific antibodies were assessed. Piglets without MDA showed a morbidity of 100% and low lethality, while almost all MDA-positive piglets stayed clinically healthy and showed considerably lower virus shedding. Taken together, the Central European PEDV strains showed rather low virulence under experimental conditions, and pre-inoculation of sows led to a solid protection of their offspring. The latter is the prerequisite for a sow vaccination concept that could help to prevent PED induced losses in the piglet sector.


id: cord-308302-5yns1hg9
title: A prediction model of outcome of SARS-CoV-2 pneumonia based on laboratory findings
author: Wu, Gang
date: 2020-08-20
txt: ./txt/cord-308302-5yns1hg9.txt
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mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32820210/
doi: 10.1038/s41598-020-71114-7
summary:
  We used machine learning for processing laboratory findings of 110 patients with SARS-CoV-2 pneumonia (including 51 non-survivors and 59 discharged patients). Thus it is feasible to establish an accurate prediction model of outcome of SARS-CoV-2 pneumonia based on laboratory findings. Laboratory tests for SARS-CoV-2 pneumonia included: blood routine test, serum biochemical (including glucose, renal and liver function, creatine kinase, lactate dehydrogenase, and electrolytes), coagulation profile, cytokine test, markers of myocardial injury, infection-related makers, and other enzymes. 68 discharged patients with SARS-CoV-2 pneumonia whose age and gender matched the non-survivors were selected (46 male, median age 66 years). A number of laboratory features were compared between non-survivors and discharged patients with SARS-CoV-2 pneumonia. With machine learning methods previously used in radiomics, a prediction model combining seven out of thirty-eight laboratory features was built for predicting the outcome of SARS-CoV-2 pneumonia.

abstract:
  The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in thousands of deaths in the world. Information about prediction model of prognosis of SARS-CoV-2 infection is scarce. We used machine learning for processing laboratory findings of 110 patients with SARS-CoV-2 pneumonia (including 51 non-survivors and 59 discharged patients). The maximum relevance minimum redundancy (mRMR) algorithm and the least absolute shrinkage and selection operator logistic regression model were used for selection of laboratory features. Seven laboratory features selected in the model were: prothrombin activity, urea, white blood cell, interleukin-2 receptor, indirect bilirubin, myoglobin, and fibrinogen degradation products. The signature constructed using the seven features had 98% [93%, 100%] sensitivity and 91% [84%, 99%] specificity in predicting outcome of SARS-CoV-2 pneumonia. Thus it is feasible to establish an accurate prediction model of outcome of SARS-CoV-2 pneumonia based on laboratory findings.


id: cord-308687-wrzzb9cy
title: Pooled samples and eDNA-based detection can facilitate the “clean trade” of aquatic animals
author: Brunner, Jesse L.
date: 2020-06-24
txt: ./txt/cord-308687-wrzzb9cy.txt
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mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32581260/
doi: 10.1038/s41598-020-66280-7
summary:
  swabs) and eDNA samples collected from finite populations and discuss key assumptions and considerations for their use with a focus on detecting Batrachochytrium salamandrivorans, an emerging pathogen that threatens global salamander diversity. www.nature.com/scientificreports www.nature.com/scientificreports/ context of screening U.S. service members for syphilis, pooling samples to reduce the number of tests required to detect rare infections is common in numerous contexts 22 , including surveys for disease freedom. In this paper I therefore develop formulae for imperfect tests of pooled samples in closed populations and eDNA, discuss the key assumptions and considerations in their application, and illustrate how eDNA may be especially useful for detecting infections in the live animal trade. Pooling and batch-processing samples collected from individual animals (e.g., swabs) can reduce several fold the number of diagnostic tests (e.g., DNA extractions and PCR reactions) required to detect rare infections.

abstract:
  The regional and international trade of live animals facilitates the movement, spillover, and emergence of zoonotic and epizootic pathogens around the world. Detecting pathogens in trade is critical for preventing their continued movement and introduction, but screening a sufficient fraction to ensure rare infections are detected is simply infeasible for many taxa and settings because of the vast numbers of animals involved—hundreds of millions of live animals are imported into the U.S.A. alone every year. Batch processing pools of individual samples or using environmental DNA (eDNA)—the genetic material shed into an organism’s environment—collected from whole consignments of animals may substantially reduce the time and cost associated with pathogen surveillance. Both approaches, however, lack a framework with which to determine sampling requirements and interpret results. Here I present formulae for pooled individual samples (e.g,. swabs) and eDNA samples collected from finite populations and discuss key assumptions and considerations for their use with a focus on detecting Batrachochytrium salamandrivorans, an emerging pathogen that threatens global salamander diversity. While empirical validation is key, these formulae illustrate the potential for eDNA-based detection in particular to reduce sample sizes and help bring clean trade into reach for a greater number of taxa, places, and contexts.


id: cord-309127-kxivgxbg
author: Haverkamp, Ann-Kathrin
date: 2018-06-27
txt: ./txt/cord-309127-kxivgxbg.txt
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mime: text/plain
url: https://doi.org/10.1038/s41598-018-28109-2
doi: 10.1038/s41598-018-28109-2
summary:
  title: Experimental infection of dromedaries with Middle East respiratory syndrome-Coronavirus is accompanied by massive ciliary loss and depletion of the cell surface receptor dipeptidyl peptidase 4 In line with these observations, high amounts of MERS-CoV antigen were detected within the respiratory epithelium of the nasal turbinates of mock-vaccinated dromedaries at 4 dpi by immunohistochemistry in areas SciEntiFic REpORTS | (2018) 8:9778 | DOI:10.1038/s41598-018-28109-2 with most severe lesions ( Fig. 2A) . To finally elucidate the histogenesis of cells staining positive for MERS-CoV nucleocapsid antigen within the lamina propria of the nasal turbinates of mock-vaccinated dromedaries, additional double immunofluorescence labeling was performed. Since DPP4 was only detectable within the apical brush border of the surface epithelium and submucosal glands, but not on the surface of inflammatory cells within lamina propria and submucosa of the nasal turbinates by immunofluorescence, dromedary and human lymphoid tissue were stained for comparison and control.

title:
  Experimental infection of dromedaries with Middle East respiratory syndrome-Coronavirus is accompanied by massive ciliary loss and depletion of the cell surface receptor dipeptidyl peptidase 4

abstract:
  Middle East respiratory syndrome (MERS) represents an important respiratory disease accompanied by lethal outcome in one-third of human patients. Recent data indicate that dromedaries represent an important source of infection, although information regarding viral cell tropism and pathogenesis is sparse. In the current study, tissues of eight dromedaries receiving inoculation of MERS-Coronavirus (MERS-CoV) after recombinant Modified-Vaccinia-Virus-Ankara (MVA-S)-vaccination (n = 4), MVA-vaccination (mock vaccination, n = 2) and PBS application (mock vaccination, n = 2), respectively, were investigated. Tissues were analyzed by histology, immunohistochemistry, immunofluorescence, and scanning electron microscopy. MERS-CoV infection in mock-vaccinated dromedaries revealed high numbers of MERS-CoV-nucleocapsid positive cells, T cells, and macrophages within nasal turbinates and trachea at day four post infection. Double immunolabeling demonstrated cytokeratin (CK) 18 expressing epithelial cells to be the prevailing target cell of MERS-CoV, while CK5/6 and CK14 expressing cells did not co-localize with virus. In addition, virus was occasionally detected in macrophages. The acute disease was further accompanied by ciliary loss along with a lack of dipeptidyl peptidase 4 (DPP4), known to mediate virus entry. DPP4 was mainly expressed by human lymphocytes and dromedary monocytes, but overall the expression level was lower in dromedaries. The present study underlines significant species-specific manifestations of MERS and highlights ciliary loss as an important finding in dromedaries. The obtained results promote a better understanding of coronavirus infections, which pose major health challenges.


id: cord-312777-5925lvue
author: Pan, Feng
date: 2020-07-09
url: https://doi.org/10.1038/s41598-020-68057-4
doi: 10.1038/s41598-020-68057-4
title:
  Different computed tomography patterns of Coronavirus Disease 2019 (COVID-19) between survivors and non-survivors

abstract:
  This study aimed to compare the chest computed tomography (CT) findings between survivors and non-survivors with Coronavirus Disease 2019 (COVID-19). Between 12 January 2020 and 20 February 2020, the records of 124 consecutive patients diagnosed with COVID-19 were retrospectively reviewed and divided into survivor (83/124) and non-survivor (41/124) groups. Chest CT findings were qualitatively compared on admission and serial chest CT scans were semi-quantitively evaluated between two groups using curve estimations. On admission, significantly more bilateral (97.6% vs. 73.5%, p = 0.001) and diffuse lesions (39.0% vs. 8.4%, p < 0.001) with higher total CT score (median 10 vs. 4, p < 0.001) were observed in non-survivor group compared with survivor group. Besides, crazy-paving pattern was more predominant in non-survivor group than survivor group (39.0% vs. 12.0%, p < 0.001). From the prediction of curve estimation, in survivor group total CT score increased in the first 20 days reaching a peak of 6 points and then gradually decreased for more than other 40 days (R(2) = 0.545, p < 0.001). In non-survivor group, total CT score rapidly increased over 10 points in the first 10 days and gradually increased afterwards until ARDS occurred with following death events (R(2) = 0.711, p < 0.001). In conclusion, persistent progression with predominant crazy-paving pattern was the major manifestation of COVID-19 in non-survivors. Understanding this CT feature could help the clinical physician to predict the prognosis of the patients.


id: cord-313126-7hrjzapj
author: Chen, Fangzhou
date: 2019-03-08
txt: ./txt/cord-313126-7hrjzapj.txt
cache: ./cache/cord-313126-7hrjzapj.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/30850666/
doi: 10.1038/s41598-019-40564-z
summary:
  Nineteen complete TGEV genomes and a single strain of porcine respiratory coronavirus (PRCV) from the US were generated and compared to historical strains to investigate the evolution of these endemic coronaviruses. The "variant" genotype shared similar unique deletions and amino acid changes with the recent PRCV strain identified in this study, suggesting a recombination event occurred between the ''''variant'''' TGEV and PRCV. Complete genomic sequences, a key residue in the spike protein and deletions in nonstructural protein 3b of US strains of the virulent and attenuated coronaviruses, transmissible gastroenteritis virus and porcine respiratory coronavirus

title:
  Decline of transmissible gastroenteritis virus and its complex evolutionary relationship with porcine respiratory coronavirus in the United States

abstract:
  The epidemiology and genetic diversity of transmissible gastroenteritis virus (TGEV) in the United States (US) was investigated by testing clinical cases for TGEV by real time RT-PCR between January 2008 and November 2016. Prevalence of TGEV ranged between 3.8–6.8% and peaked during cold months until March 2013, in which prevalence decreased to < 0.1%. Nineteen complete TGEV genomes and a single strain of porcine respiratory coronavirus (PRCV) from the US were generated and compared to historical strains to investigate the evolution of these endemic coronaviruses. Sixteen of our TGEV strains share 8 unique deletions and 119 distinct amino acid changes, which might greatly affect the biological characteristics of the variant TGEV, and resulted in a “variant” genotype of TGEV. The “variant” genotype shared similar unique deletions and amino acid changes with the recent PRCV strain identified in this study, suggesting a recombination event occurred between the ‘‘variant’’ TGEV and PRCV. Moreover, the results indicate the “variant” genotype is the dominant genotype circulating in the US. Therefore, this study provides insight into the occurrence, origin, genetic characteristics, and evolution of TGEV and PRCV circulating in the US.


id: cord-314753-xflhxb13
title: Efficient and unbiased metagenomic recovery of RNA virus genomes from human plasma samples
author: Manso, Carmen F.
date: 2017-06-23
txt: ./txt/cord-314753-xflhxb13.txt
cache: ./cache/cord-314753-xflhxb13.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/28646219/
doi: 10.1038/s41598-017-02239-5
summary:
  The percentage of reads mapping to RNA virus genomes in the rRNA-depleted BBV Panel samples was between 40 and 150-fold higher than in corresponding untreated controls. The depth plots in Fig. 3 again show unbiased and even coverages across both genomes, and the percentages of reads mapping to viral targets was again much higher in the rRNA-depleted sample than in the untreated comparator (61-fold and 85-fold for HCV and HPgV respectively). By depleting host-derived nucleic acids and making modifications to an existing library preparation protocol to account for ultra-low RNA input quantities, we have been able to reconstruct effectively full-length genomes of HCV, HEV and HIV from plasma samples with viral loads of 10 4 IU/ml (copies/ml for HIV) and substantial fractions of complete genomes at 10 3 IU/ml. Additionally, our system was able to recover viral sequences from a panel of diverse RNA viruses diluted in human plasma, with a broad correlation between the genomic coverage and depth metrics and approximate concentration.

abstract:
  RNA viruses cause significant human pathology and are responsible for the majority of emerging zoonoses. Mainstream diagnostic assays are challenged by their intrinsic diversity, leading to false negatives and incomplete characterisation. New sequencing techniques are expanding our ability to agnostically interrogate nucleic acids within diverse sample types, but in the clinical setting are limited by overwhelming host material and ultra-low target frequency. Through selective host RNA depletion and compensatory protocol adjustments for ultra-low RNA inputs, we are able to detect three major blood-borne RNA viruses – HIV, HCV and HEV. We recovered complete genomes and up to 43% of the genome from samples with viral loads of 10(4) and 10(3) IU/ml respectively. Additionally, we demonstrated the utility of this method in detecting and characterising members of diverse RNA virus families within a human plasma background, some present at very low levels. By applying this method to a patient sample series, we have simultaneously determined the full genome of both a novel subtype of HCV genotype 6, and a co-infecting human pegivirus. This method builds upon earlier RNA metagenomic techniques and can play an important role in the surveillance and diagnostics of blood-borne viruses.


id: cord-315415-3aotsb2g
title: Development of humanized tri-specific nanobodies with potent neutralization for SARS-CoV-2
author: Dong, Jianbo
date: 2020-10-20
txt: ./txt/cord-315415-3aotsb2g.txt
cache: ./cache/cord-315415-3aotsb2g.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33082473/
doi: 10.1038/s41598-020-74761-y
summary:
  In this study we used computer-aided design to construct multi-specific VHH antibodies fused to human IgG1 Fc domains based on the epitope predictions for leading VHHs. The resulting tri-specific VHH-Fc antibodies show more potent S1 binding, S1/ACE2 blocking, and SARS-CoV-2 pseudovirus neutralization than the bi-specific VHH-Fcs or combination of individual monoclonal VHH-Fcs. Furthermore, protein stability analysis of the VHH-Fcs shows favorable developability features, which enable them to be quickly and successfully developed into therapeutics against COVID-19. (c) The binding of VHH-Fcs and ACE2 to Expi293 cells expressing SARS-CoV-2 S1 wild type (WT) or mutant proteins (del1-del5) were assessed by flow cytometry following FITC-conjugated secondary antibody treatment. Based on the binding and epitope binning data, we constructed 3D docking models that predicted the interactions between SARS-CoV-2 S1 RBD, ACE2 and lead VHH-Fcs (Fig. 2e) . Next, we tested whether the combination of individual VHHs binding to different S1 RBD epitopes into bi-specific antibody molecules would yield synergistic effects in SARS-CoV-2 binding and S/ACE2 blocking.

abstract:
  SARS-CoV-2 is a newly emergent coronavirus, which has adversely impacted human health and has led to the COVID-19 pandemic. There is an unmet need to develop therapies against SARS-CoV-2 due to its severity and lack of treatment options. A promising approach to combat COVID-19 is through the neutralization of SARS-CoV-2 by therapeutic antibodies. Previously, we described a strategy to rapidly identify and generate llama nanobodies (VHH) from naïve and synthetic humanized VHH phage libraries that specifically bind the S1 SARS-CoV-2 spike protein, and block the interaction with the human ACE2 receptor. In this study we used computer-aided design to construct multi-specific VHH antibodies fused to human IgG1 Fc domains based on the epitope predictions for leading VHHs. The resulting tri-specific VHH-Fc antibodies show more potent S1 binding, S1/ACE2 blocking, and SARS-CoV-2 pseudovirus neutralization than the bi-specific VHH-Fcs or combination of individual monoclonal VHH-Fcs. Furthermore, protein stability analysis of the VHH-Fcs shows favorable developability features, which enable them to be quickly and successfully developed into therapeutics against COVID-19.


id: cord-315483-l6dm82pp
author: Santhakumar, Diwakar
date: 2018-05-01
url: https://www.ncbi.nlm.nih.gov/pubmed/29717152/
doi: 10.1038/s41598-018-24905-y
title:
  Chicken Interferon-induced Protein with Tetratricopeptide Repeats 5 Antagonizes Replication of RNA Viruses

abstract:
  The intracellular actions of interferon (IFN)-regulated proteins, including IFN-induced proteins with tetratricopeptide repeats (IFITs), attribute a major component of the protective antiviral host defense. Here we applied genomics approaches to annotate the chicken IFIT locus and currently identified a single IFIT (chIFIT5) gene. The profound transcriptional level of this effector of innate immunity was mapped within its unique cis-acting elements. This highly virus- and IFN-responsive chIFIT5 protein interacted with negative sense viral RNA structures that carried a triphosphate group on its 5′ terminus (ppp-RNA). This interaction reduced the replication of RNA viruses in lentivirus-mediated IFIT5-stable chicken fibroblasts whereas CRISPR/Cas9-edited chIFIT5 gene knockout fibroblasts supported the replication of RNA viruses. Finally, we generated mosaic transgenic chicken embryos stably expressing chIFIT5 protein or knocked-down for endogenous chIFIT5 gene. Replication kinetics of RNA viruses in these transgenic chicken embryos demonstrated the antiviral potential of chIFIT5 in ovo. Taken together, these findings propose that IFIT5 specifically antagonize RNA viruses by sequestering viral nucleic acids in chickens, which are unique in innate immune sensing and responses to viruses of both poultry and human health significance.


id: cord-315781-dejh8q22
title: Re-evaluation of the evolution of influenza H1 viruses using direct PCA
author: Konishi, Tomokazu
date: 2019-12-17
txt: ./txt/cord-315781-dejh8q22.txt
cache: ./cache/cord-315781-dejh8q22.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-019-55254-z
doi: 10.1038/s41598-019-55254-z
summary:
  It should be noted that avian viruses showed lower PC values and appeared around the centre of the PCA, while swine and human viruses exhibited extreme values (Figs. Thus, avian viruses had sequences that were similar to the average among samples at amino acids that were characteristic to the three groups of human and swine viruses: R, M, and U. Avian samples also showed characteristic motifs at other positions, which may appear in lower PCs. The relationships observed among the strains presented here are different from the classic ones 4, [8] [9] [10] [11] [12] in several elements. www.nature.com/scientificreports www.nature.com/scientificreports/ One of the major differences observed was the direct shift from avian to swine or human viruses. Drifts and spreading: the genomes of the R group of human viruses have been changing yearly (Figs.

abstract:
  The history of influenza H1 virus was re-evaluated by applying a new methodology to sequencing data; this objective method enables comparisons among viral types. The approach led to the segregation of all segments of swine and human viruses into three distinct groups: two of them included the pandemic 1977 and 2009 human viruses, and the remaining group may be new in humans. These three groups might have originated from avian viruses and drifted out independently. Genome shifts occurred occasionally among swine viruses; however, distances between avian and swine/human viruses negated the existence of direct shifts from avian viruses. In humans, only one or two viruses appeared each year, which suggests the presence of competition among viruses that migrated freely. All segments drifted continuously under certain rules and constant velocity. Viruses that had caused an outbreak did not appear again over subsequent decades, which may mean populations had become immune to such viruses. In contrast, the viruses in livestock were rather conserved and maintained unique strains in small, separate areas. Such collections of swine strains included human segments, which could become an epidemic in the future.


id: cord-316930-0s7k9guq
author: Caldas, Lucio Ayres
date: 2020-09-30
url: https://www.ncbi.nlm.nih.gov/pubmed/32999356/
doi: 10.1038/s41598-020-73162-5
title:
  Ultrastructural analysis of SARS-CoV-2 interactions with the host cell via high resolution scanning electron microscopy

abstract:
  SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. Here, we investigated the interaction of this new coronavirus with Vero cells using high resolution scanning electron microscopy. Surface morphology, the interior of infected cells and the distribution of viral particles in both environments were observed 2 and 48 h after infection. We showed areas of viral processing, details of vacuole contents, and viral interactions with the cell surface. Intercellular connections were also approached, and viral particles were adhered to these extensions suggesting direct cell-to-cell transmission of SARS-CoV-2.


id: cord-316983-h4mtpcyc
author: Mathé-Hubert, Hugo
date: 2016-10-25
url: https://doi.org/10.1038/srep35873
doi: 10.1038/srep35873
title:
  Comparative venomics of Psyttalia lounsburyi and P. concolor, two olive fruit fly parasitoids: a hypothetical role for a GH1 β-glucosidase

abstract:
  Venom composition of parasitoid wasps attracts increasing interest – notably molecules ensuring parasitism success on arthropod pests – but its variation within and among taxa is not yet understood. We have identified here the main venom proteins of two braconid wasps, Psyttalia lounsburyi (two strains from South Africa and Kenya) and P. concolor, olive fruit fly parasitoids that differ in host range. Among the shared abundant proteins, we found a GH1 β-glucosidase and a family of leucine-rich repeat (LRR) proteins. Olive is extremely rich in glycoside compounds that are hydrolyzed by β-glucosidases into defensive toxic products in response to phytophagous insect attacks. Assuming that Psyttalia host larvae sequester ingested glycosides, the injected venom GH1 β-glucosidase could induce the release of toxic compounds, thus participating in parasitism success by weakening the host. Venom LRR proteins are similar to truncated Toll-like receptors and may possibly scavenge the host immunity. The abundance of one of these LRR proteins in the venom of only one of the two P. lounsburyi strains evidences intraspecific variation in venom composition. Altogether, venom intra- and inter-specific variation in Psyttalia spp. were much lower than previously reported in the Leptopilina genus (Figitidae), suggesting it might depend upon the parasitoid taxa.


id: cord-317579-ige2h4pd
author: Nie, Lei
date: 2020-08-13
txt: ./txt/cord-317579-ige2h4pd.txt
cache: ./cache/cord-317579-ige2h4pd.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32792661/
doi: 10.1038/s41598-020-70776-7
summary:
  The results confirmed that the SeO(3)(2−) was doped at the PO(4)(3−) position and silver nanoparticles were deposited on the surface of SeB-NPs. Next, Transmission Electron Microscopy (TEM) analysis displayed that the prepared (Ag)SeB-NPs had a needle-cluster-like morphology. At the same time, biphasic calcium phosphate nanoparticles (BCP-NPs) and selenium-doped hydroxyapatite nanoparticles (SeHA-NPs) were prepared for comparison (Electronic Supplementary Material). Compared with the control group, the doping selenium into BCP-NPs had slight influence on the antibacterial activity, and it had a slight inhibitory effect against bacteria of SeB-NPs after 12 h of culture. The stated objective of this study was to synthesis new-style biphasic calcium phosphate nanoparticles (BCP-NPs) with excellent cytocompatibility and antibacterial activity for further hard-tissue engineering applications. After the deposition of silver, cells cultured with all Ag SeB-NPs samples had similar proliferation profiles compared with SeB-NPs. Not only can the addition of selenium and silver improve the growth of the cells with BCP-NPs, but the antibacterial activity was acquired, which has potential for infection-resistant replacement materials 61, 62 .

title:
  Nanostructured selenium-doped biphasic calcium phosphate with in situ incorporation of silver for antibacterial applications

abstract:
  Selenium-doped nanostructure has been considered as an attractive approach to enhance the antibacterial activity of calcium phosphate (CaP) materials in diverse medical applications. In this study, the selenium-doped biphasic calcium phosphate nanoparticles (SeB-NPs) were first synthesized. Then, silver was in situ incorporated into SeB-NPs to obtain nanostructured composite nanoparticles ((Ag)SeB-NPs). Both SeB-NPs and (Ag)SeB-NPs were characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), ultraviolet–visible spectroscopy (UV–Vis), X-ray photoelectron spectroscopy (XPS), and Raman spectra. The results confirmed that the SeO(3)(2−) was doped at the PO(4)(3−) position and silver nanoparticles were deposited on the surface of SeB-NPs. Next, Transmission Electron Microscopy (TEM) analysis displayed that the prepared (Ag)SeB-NPs had a needle-cluster-like morphology. CCK-8 analysis revealed SeB-NPs and (Ag)SeB-NPs had good cytocompatibility with osteoblasts. The antibacterial activity of the prepared (Ag)SeB-NPs was confirmed by using Gram-negative E. coli and Gram-positive S. aureus. The above results manifested the significance of the final (Ag)SeB-NPs for biomedical applications.


id: cord-317813-sisfxdso
title: Microbiome analysis reveals the abundance of bacterial pathogens in Rousettus leschenaultii guano
author: Banskar, Sunil
date: 2016-11-15
txt: ./txt/cord-317813-sisfxdso.txt
cache: ./cache/cord-317813-sisfxdso.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/27845426/
doi: 10.1038/srep36948
summary:
  Applying in-depth bacterial community analysis using high-throughput 16 S rRNA gene sequencing, a high inter-individual variation was observed among the studied guano samples. Additionally, 16 S rRNA gene sequencing was performed using Ion Torrent PGM to identify the bacterial communities and screened for the presence of putative human pathogens. Sequence analysis of the cytochrome B (cytB) gene amplified from total extracted DNA of the guano pellets revealed that the collected fecal pellets were from a single bat species i.e. Rousettus leschenaultii, a predominant bat species reported from the Robber''s cave 23 . Further, computation of core microbiome from Ion Torrent sequences of fresh guano revealed the presence of five bacterial phyla i.e. Proteobacteria, Tenericutes, Candidate division TM7, Firmicutes and Actinobacteria but in different proportions (Fig. 5, Supplementary Figure S7 ). Additionally, Ion Torrent sequencing of 16 S rRNA gene provided information about the general bacterial communities with specific emphasis on pathogens among the total communities present in bat guano.

abstract:
  Bats are crucial for proper functioning of an ecosystem. They provide various important services to ecosystem and environment. While, bats are well-known carrier of pathogenic viruses, their possible role as a potential carrier of pathogenic bacteria is under-explored. Here, using culture-based approach, employing multiple bacteriological media, over thousand bacteria were cultivated and identified from Rousettus leschenaultii (a frugivorous bat species), the majority of which were from the family Enterobacteriaceae and putative pathogens. Next, pathogenic potential of most frequently cultivated component of microbiome i.e. Escherichia coli was assessed to identify its known pathotypes which revealed the presence of virulent factors in many cultivated E. coli isolates. Applying in-depth bacterial community analysis using high-throughput 16 S rRNA gene sequencing, a high inter-individual variation was observed among the studied guano samples. Interestingly, a higher diversity of bacterial communities was observed in decaying guano representative. The search against human pathogenic bacteria database at 97% identity, a small proportion of sequences were found associated to well-known human pathogens. The present study thus indicates that this bat species may carry potential bacterial pathogens and advice to study the effect of these pathogens on bats itself and the probable mode of transmission to humans and other animals.


id: cord-318187-c59c9vi3
title: Numerical evaluation of spray position for improved nasal drug delivery
author: Basu, Saikat
date: 2020-06-29
txt: ./txt/cord-318187-c59c9vi3.txt
cache: ./cache/cord-318187-c59c9vi3.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32601278/
doi: 10.1038/s41598-020-66716-0
summary:
  The protocol involves re-orienting the spray axis to harness inertial motion of particulates and has been developed using computational fluid dynamics simulations of respiratory airflow and droplet transport in medical imaging-based digital models. Of interest are nasal spray simulation studies on in silico models, re-constructed from medical imaging, to measure drug delivery along the nasal passages 9 , in the sinuses 10, 11 , and on the effects of surgical alterations of the anatomy on nasal airflow [12] [13] [14] [15] as well as on topical transport of drugs [16] [17] [18] [19] . The computational fluid dynamics (CFD) models of droplet transport and the in silico prediction of their deposition sites along the nasal airway walls have been compared with in vitro spray experiments in 3D-printed solid replicas of the same anatomic reconstructions.

abstract:
  Topical intra-nasal sprays are amongst the most commonly prescribed therapeutic options for sinonasal diseases in humans. However, inconsistency and ambiguity in instructions show a lack of definitive knowledge on best spray use techniques. In this study, we have identified a new usage strategy for nasal sprays available over-the-counter, that registers an average 8-fold improvement in topical delivery of drugs at diseased sites, when compared to prevalent spray techniques. The protocol involves re-orienting the spray axis to harness inertial motion of particulates and has been developed using computational fluid dynamics simulations of respiratory airflow and droplet transport in medical imaging-based digital models. Simulated dose in representative models is validated through in vitro spray measurements in 3D-printed anatomic replicas using the gamma scintigraphy technique. This work breaks new ground in proposing an alternative user-friendly strategy that can significantly enhance topical delivery inside human nose. While these findings can eventually translate into personalized spray usage instructions and hence merit a change in nasal standard-of-care, this study also demonstrates how relatively simple engineering analysis tools can revolutionize everyday healthcare. Finally, with respiratory mucosa as the initial coronavirus infection site, our findings are relevant to intra-nasal vaccines that are in-development, to mitigate the COVID-19 pandemic.


id: cord-318314-oxlv847d
author: O’Boyle, Nicky
date: 2020-09-11
txt: ./txt/cord-318314-oxlv847d.txt
cache: ./cache/cord-318314-oxlv847d.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32917945/
doi: 10.1038/s41598-020-71604-8
summary:
  Comparison of single representative pathogenic and non-pathogenic ovine isolates over ten time-points by enumeration of tissue-associated bacteria, histology, immunofluorescence microscopy and scanning electron microscopy revealed temporal differences in adhesion, proliferation, bacterial cell physiology and host cell responses. Comparison of eight isolates of bovine and ovine origin at three key time-points (2 h, 48 h and 72 h), revealed that colonisation was not strictly pathogen or serotype specific, with isolates of serotype A1, A2, A6 and A12 being capable of colonising the cell layer regardless of host species or disease status of the host. haemolytica 11, 38 , coupled with a suggested role for the polysaccharide capsule (on which the serotyping classification is based) in cell adhesion 17 , indicates that isolates may be specifically adapted to colonising the airway tissues of discrete hosts. We assessed whether interactions with differentiated OTECs could reflect this species-specificity by analysing colonisation of pathogenic and non-pathogenic isolates of both bovine and ovine origin.

title:
  Differentiated ovine tracheal epithelial cells support the colonisation of pathogenic and non-pathogenic strains of Mannheimia haemolytica

abstract:
  Mannheimia haemolytica is the primary bacterial species associated with respiratory disease of ruminants. A lack of cost-effective, reproducible models for the study of M. haemolytica pathogenesis has hampered efforts to better understand the molecular interactions governing disease progression. We employed a highly optimised ovine tracheal epithelial cell model to assess the colonisation of various pathogenic and non-pathogenic M. haemolytica isolates of bovine and ovine origin. Comparison of single representative pathogenic and non-pathogenic ovine isolates over ten time-points by enumeration of tissue-associated bacteria, histology, immunofluorescence microscopy and scanning electron microscopy revealed temporal differences in adhesion, proliferation, bacterial cell physiology and host cell responses. Comparison of eight isolates of bovine and ovine origin at three key time-points (2 h, 48 h and 72 h), revealed that colonisation was not strictly pathogen or serotype specific, with isolates of serotype A1, A2, A6 and A12 being capable of colonising the cell layer regardless of host species or disease status of the host. A trend towards increased proliferative capacity by pathogenic ovine isolates was observed. These results indicate that the host-specific nature of M. haemolytica infection may result at least partially from the colonisation-related processes of adhesion, invasion and proliferation at the epithelial interface.


id: cord-318587-ewvnkdr2
author: Steeds, Kimberley
date: 2020-08-31
txt: ./txt/cord-318587-ewvnkdr2.txt
cache: ./cache/cord-318587-ewvnkdr2.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32868837/
doi: 10.1038/s41598-020-71225-1
summary:
  We evaluated the suitability of EBOV GP pseudotyped human immunodeficiency virus type 1 (HIV-1) and vesicular stomatitis virus (VSV) to measure the neutralising ability of plasma from EVD survivors, when compared to results from a live EBOV neutralisation assay. The aim of this study was to assess the suitability of EBOV GP pseudotyped HIV-1 and VSV systems to measure neutralisation by EVD survivor plasma, in comparison with results from a live EBOV neutralisation assay. To determine the optimal pseudotyped virus input to use in the HIV-and VSV-based assays, neutralisation of different amounts of the EBOV GP pseudotyped viruses by plasma from a Guinean EVD survivor donor or human anti-EBOV GP mAb KZ52 was assessed. When IC 50 values of EBOV GP pseudotyped HIV-1 neutralisation of the 30 EVD survivor and 10 negative plasma samples were compared with GMT values for the live EBOV neutralisation assay, a positive correlation (r s = 0.54) was determined using the nonparametric Spearman correlation coefficient (Fig. 5a) and this was statistically significant (p = 0.0004).

title:
  Pseudotyping of VSV with Ebola virus glycoprotein is superior to HIV-1 for the assessment of neutralising antibodies

abstract:
  Ebola virus (EBOV) is an enveloped, single-stranded RNA virus that can cause Ebola virus disease (EVD). It is thought that EVD survivors are protected against subsequent infection with EBOV and that neutralising antibodies to the viral surface glycoprotein (GP) are potential correlates of protection. Serological studies are vital to assess neutralising antibodies targeted to EBOV GP; however, handling of EBOV is limited to containment level 4 laboratories. Pseudotyped viruses can be used as alternatives to live viruses, which require high levels of bio-containment, in serological and viral entry assays. However, neutralisation capacity can differ among pseudotyped virus platforms. We evaluated the suitability of EBOV GP pseudotyped human immunodeficiency virus type 1 (HIV-1) and vesicular stomatitis virus (VSV) to measure the neutralising ability of plasma from EVD survivors, when compared to results from a live EBOV neutralisation assay. The sensitivity, specificity and correlation with live EBOV neutralisation were greater for the VSV-based pseudotyped virus system, which is particularly important when evaluating EBOV vaccine responses and immuno-therapeutics. Therefore, the EBOV GP pseudotyped VSV neutralisation assay reported here could be used to provide a better understanding of the putative correlates of protection against EBOV.


id: cord-319118-47ovbto5
title: Structural basis for the neutralization of MERS-CoV by a human monoclonal antibody MERS-27
author: Yu, Xiaojuan
date: 2015-08-18
txt: ./txt/cord-319118-47ovbto5.txt
cache: ./cache/cord-319118-47ovbto5.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/26281793/
doi: 10.1038/srep13133
summary:
  We previously reported two human monoclonal antibodies that target the receptor binding domain (RBD) of the spike and exhibit strong neutralization activity against live and pesudotyped MERS-CoV infection. We found Trp535 as an anchor residue in the RBD for MERS-27 recognition, and its interaction with N-linked carbohydrates of DPP4 is important for the binding to DPP4 and for viral entry of MERS-CoV. In sum, results of viral entry, neutralization, and binding assays consistently indicated that Trp535 and Asp539 are critical for both MERS-CoV spike glycoprotein recognition by MERS-27 and binding with receptor DPP4. The interaction between Trp535 of RBD and the DPP4 carbohydrate is also important for receptor binding and viral entry of MERS-CoV. The receptor binding domain of the new Middle East respiratory syndrome coronavirus maps to a 231-residue region in the spike protein that efficiently elicits neutralizing antibodies A conformation-dependent neutralizing monoclonal antibody specifically targeting receptor-binding domain in Middle East respiratory syndrome coronavirus spike protein

abstract:
  The recently reported Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory illness in humans with an approximately 30% mortality rate. The envelope spike glycoprotein on the surface of MERS-CoV mediates receptor binding, membrane fusion, and viral entry. We previously reported two human monoclonal antibodies that target the receptor binding domain (RBD) of the spike and exhibit strong neutralization activity against live and pesudotyped MERS-CoV infection. Here we determined the crystal structure of MERS-CoV RBD bound to the Fab fragment of MERS-27 antibody at 3.20 Å resolution. The MERS-27 epitope in the RBD overlaps with the binding site of the MERS-CoV receptor DPP4. Further biochemical, viral entry, and neutralization analyses identified two critical residues in the RBD for both MERS-27 recognition and DPP4 binding. One of the residues, Trp535, was found to function as an anchor residue at the binding interface with MERS-27. Upon receptor binding, Trp535 interacts with the N-linked carbohydrate moiety of DPP4. Thus, MERS-27 inhibits MERS-CoV infection by directly blocking both protein-protein and protein-carbohydrate interactions between MERS-CoV RBD and DPP4. These results shed light on the molecular basis of MERS-27 neutralization and will assist in the optimization of MERS-27 as a tool to combat MERS-CoV infection.


id: cord-320709-2pnqpljt
title: Replication and shedding of MERS-CoV in Jamaican fruit bats (Artibeus jamaicensis)
author: Munster, Vincent J.
date: 2016-02-22
url: https://doi.org/10.1038/srep21878
doi: 10.1038/srep21878
abstract:
  The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) highlights the zoonotic potential of Betacoronaviruses. Investigations into the origin of MERS-CoV have focused on two potential reservoirs: bats and camels. Here, we investigated the role of bats as a potential reservoir for MERS-CoV. In vitro, the MERS-CoV spike glycoprotein interacted with Jamaican fruit bat (Artibeus jamaicensis) dipeptidyl peptidase 4 (DPP4) receptor and MERS-CoV replicated efficiently in Jamaican fruit bat cells, suggesting there is no restriction at the receptor or cellular level for MERS-CoV. To shed light on the intrinsic host-virus relationship, we inoculated 10 Jamaican fruit bats with MERS-CoV. Although all bats showed evidence of infection, none of the bats showed clinical signs of disease. Virus shedding was detected in the respiratory and intestinal tract for up to 9 days. MERS-CoV replicated transiently in the respiratory and, to a lesser extent, the intestinal tracts and internal organs; with limited histopathological changes observed only in the lungs. Analysis of the innate gene expression in the lungs showed a moderate, transient induction of expression. Our results indicate that MERS-CoV maintains the ability to replicate in bats without clinical signs of disease, supporting the general hypothesis of bats as ancestral reservoirs for MERS-CoV.


id: cord-321667-jkzxjk54
author: Papineau, Amber
date: 2019-04-11
url: https://www.ncbi.nlm.nih.gov/pubmed/30976080/
doi: 10.1038/s41598-019-42355-y
title:
  Genome Organization of Canada Goose Coronavirus, A Novel Species Identified in a Mass Die-off of Canada Geese

abstract:
  The complete genome of a novel coronavirus was sequenced directly from the cloacal swab of a Canada goose that perished in a die-off of Canada and Snow geese in Cambridge Bay, Nunavut, Canada. Comparative genomics and phylogenetic analysis indicate it is a new species of Gammacoronavirus, as it falls below the threshold of 90% amino acid similarity in the protein domains used to demarcate Coronaviridae. Additional features that distinguish the genome of Canada goose coronavirus include 6 novel ORFs, a partial duplication of the 4 gene and a presumptive change in the proteolytic processing of polyproteins 1a and 1ab.


id: cord-322486-qwl7nzkr
author: Omori, Ryosuke
date: 2020-10-06
txt: ./txt/cord-322486-qwl7nzkr.txt
cache: ./cache/cord-322486-qwl7nzkr.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-020-73777-8
doi: 10.1038/s41598-020-73777-8
summary:
  We estimated the parameter which describes the age-dependency of susceptibility by fitting the model to reported data, including the effect of change in contact patterns during the epidemics of COVID-19, and the fraction of symptomatic infections. Our study revealed that if the mortality rate or the fraction of symptomatic infections among all COVID-19 cases does not depend on age, then unrealistically different age-dependencies of susceptibilities against COVID-19 infections between Italy, Japan, and Spain are required to explain the similar age distribution of mortality but different basic reproduction numbers (R(0)). Assuming that the age-dependency of mortality by COVID-19 is determined by only age-dependent susceptibility (model 1), i.e., the mortality rate does not depend on age, the exponent parameter, φ, describing the variation of susceptibility among age groups for each country, Italy, Japan, and Spain, was estimated as shown in Fig. 4 .

title:
  The age distribution of mortality from novel coronavirus disease (COVID-19) suggests no large difference of susceptibility by age

abstract:
  Among Italy, Spain, and Japan, the age distributions of COVID-19 mortality show only small variation even though the number of deaths per country shows large variation. To understand the determinant for this situation, we constructed a mathematical model describing the transmission dynamics and natural history of COVID-19 and analyzed the dataset of mortality in Italy, Spain, and Japan. We estimated the parameter which describes the age-dependency of susceptibility by fitting the model to reported data, including the effect of change in contact patterns during the epidemics of COVID-19, and the fraction of symptomatic infections. Our study revealed that if the mortality rate or the fraction of symptomatic infections among all COVID-19 cases does not depend on age, then unrealistically different age-dependencies of susceptibilities against COVID-19 infections between Italy, Japan, and Spain are required to explain the similar age distribution of mortality but different basic reproduction numbers (R(0)). Variation of susceptibility by age itself cannot explain the robust age distribution in mortality by COVID-19 infections in those three countries, however it does suggest that the age-dependencies of (i) the mortality rate and (ii) the fraction of symptomatic infections among all COVID-19 cases determine the age distribution of mortality by COVID-19.


id: cord-323087-3cxyogor
title: Tissue Distribution of the MERS-Coronavirus Receptor in Bats
author: Widagdo, W.
date: 2017-04-26
url: https://www.ncbi.nlm.nih.gov/pubmed/28446791/
doi: 10.1038/s41598-017-01290-6
abstract:
  Middle East respiratory syndrome coronavirus (MERS-CoV) has been shown to infect both humans and dromedary camels using dipeptidyl peptidase-4 (DPP4) as its receptor. The distribution of DPP4 in the respiratory tract tissues of humans and camels reflects MERS-CoV tropism. Apart from dromedary camels, insectivorous bats are suggested as another natural reservoir for MERS-like-CoVs. In order to gain insight on the tropism of these viruses in bats, we studied the DPP4 distribution in the respiratory and extra-respiratory tissues of two frugivorous bat species (Epomophorus gambianus and Rousettus aegyptiacus) and two insectivorous bat species (Pipistrellus pipistrellus and Eptesicus serotinus). In the frugivorous bats, DPP4 was present in epithelial cells of both the respiratory and the intestinal tract, similar to what has been reported for camels and humans. In the insectivorous bats, however, DPP4 expression in epithelial cells of the respiratory tract was almost absent. The preferential expression of DPP4 in the intestinal tract of insectivorous bats, suggests that transmission of MERS-like-CoVs mainly occurs via the fecal-oral route. Our results highlight differences in the distribution of DPP4 expression among MERS-CoV susceptible species, which might influence variability in virus tropism, pathogenesis and transmission route.


id: cord-324696-htx0ul4o
title: Avian and human influenza virus compatible sialic acid receptors in little brown bats
author: Chothe, Shubhada K.
date: 2017-04-06
txt: ./txt/cord-324696-htx0ul4o.txt
cache: ./cache/cord-324696-htx0ul4o.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-017-00793-6
doi: 10.1038/s41598-017-00793-6
summary:
  This first ever study of IAV receptors in a bat species suggest that LBBs, a widely-distributed bat species in North America, could potentially be co-infected with avian and human IAVs, facilitating the emergence of zoonotic strains. To resolve this enigma, we investigated for the first time the distribution of SA receptors in little brown bats (LBBs) (Myotis lucifugus), a widely-distributed bat species in North America and their compatibility to support avian and human IAV binding. H5N2 virus binding pattern was in accordance with the relative abundance of SA α2,3-Gal receptors in tissues such that greater virus binding to the tracheal ( In addition to the virus binding assay using antibody-based detection, we also visualized virus binding using scanning electron microscopy (SEM) which also confirmed abundant binding of avian H5N2 virus (Fig. 5A ) and human H1N1 virus (Fig. 5B ) to LBB trachea (Fig. 5) . time, this study demonstrated that little brown bats (LBBs), a widely-distributed bat species in North America, co-express both avian and human type influenza receptors in their respiratory and gastrointestinal systems.

abstract:
  Influenza A viruses (IAVs) continue to threaten animal and human health globally. Bats are asymptomatic reservoirs for many zoonotic viruses. Recent reports of two novel IAVs in fruit bats and serological evidence of avian influenza virus (AIV) H9 infection in frugivorous bats raise questions about the role of bats in IAV epidemiology. IAVs bind to sialic acid (SA) receptors on host cells, and it is widely believed that hosts expressing both SA α2,3-Gal and SA α2,6-Gal receptors could facilitate genetic reassortment of avian and human IAVs. We found abundant co-expression of both avian (SA α2,3-Gal) and human (SA α2,6-Gal) type SA receptors in little brown bats (LBBs) that were compatible with avian and human IAV binding. This first ever study of IAV receptors in a bat species suggest that LBBs, a widely-distributed bat species in North America, could potentially be co-infected with avian and human IAVs, facilitating the emergence of zoonotic strains.


id: cord-325405-cu4nx891
author: Luo, Lingfei
date: 2019-07-10
txt: ./txt/cord-325405-cu4nx891.txt
cache: ./cache/cord-325405-cu4nx891.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/31292502/
doi: 10.1038/s41598-019-46480-6
summary:
  Logistic regression analyses with sex stratification showed that abdominal pain, fever and ingestion of unsafe food at restaurants were independent factors more frequently associated with bacterial gastroenteritis irrespective of sex; red cell-positive fecal matter was associated with bacterial gastroenteritis with an odds ratio (OR) of 3.28 only in males; and white blood cell count was associated with bacterial gastroenteritis with an OR of 1.02 only in females. No significant differences in the age, percentage of local residents, frequency of vomiting, frequency of watery stools, frequency of diarrhea, duration of diarrhea, rate dehydration, heart rate, blood pressure, or rate of ingesting possible unsafe food variables was observed between the viral and bacterial gastroenteritis groups ( Independent factors differentially associated with pathogen by sex. Among males, univariate analyses showed that nausea, vomiting frequency, watery stools, abdominal pain, fever, ingesting unsafe food at restaurants, fecal leukocyte-positive, fecal red cell-positive and white blood cell count were potential independent factors that were differentially associated with viral and bacterial gastroenteritis.

title:
  Epidemiological and clinical differences between sexes and pathogens in a three-year surveillance of acute infectious gastroenteritis in Shanghai

abstract:
  Acute infectious gastroenteritis cases in Shanghai, reported over three years, were analyzed. Pathogens were identified in 1031 patients; of these, 725 and 306 were bacterial and viral cases, respectively. Vibrio parahemolyticus and Salmonella were the dominant bacteria, and Caliciviridae and Reoviridae were the dominant viral families in the local area. The acute gastroenteritis epidemic peaks appeared in August and January, which represented the active peak periods of bacteria and viruses, respectively. Logistic regression analyses with sex stratification showed that abdominal pain, fever and ingestion of unsafe food at restaurants were independent factors more frequently associated with bacterial gastroenteritis irrespective of sex; red cell-positive fecal matter was associated with bacterial gastroenteritis with an odds ratio (OR) of 3.28 only in males; and white blood cell count was associated with bacterial gastroenteritis with an OR of 1.02 only in females. Pathogen stratification showed that age, vomiting and red cell-positive fecal matter were associated with males with ORs of 0.99, 0.61 and 1.71, respectively, in bacterial gastroenteritis; and the migrant ratio was higher in males with an OR of 2.29 only in viral gastroenteritis. In conclusion, although bacterial and viral gastroenteritis shared many features, epidemiological and clinical factors differed between sexes and pathogens.


id: cord-325657-s2vdazq0
title: SARS-CoV-2 failure to infect or replicate in mosquitoes: an extreme challenge
author: Huang, Yan-Jang S.
date: 2020-07-17
url: https://doi.org/10.1038/s41598-020-68882-7
doi: 10.1038/s41598-020-68882-7
abstract:
  This research addresses public speculation that SARS-CoV-2 might be transmitted by mosquitoes. The World Health Organization has stated “To date there has been no information nor evidence to suggest that the new coronavirus could be transmitted by mosquitoes”. Here we provide the first experimental data to investigate the capacity of SARS-CoV-2 to infect and be transmitted by mosquitoes. Three widely distributed species of mosquito; Aedes aegypti, Ae. albopictus and Culex quinquefasciatus, representing the two most significant genera of arbovirus vectors that infect people, were tested. We demonstrate that even under extreme conditions, SARS-CoV-2 virus is unable to replicate in these mosquitoes and therefore cannot be transmitted to people even in the unlikely event that a mosquito fed upon a viremic host.


id: cord-326868-3az13h1h
title: Temporal dynamics of resting EEG networks are associated with prosociality
author: Schiller, Bastian
date: 2020-08-03
txt: ./txt/cord-326868-3az13h1h.txt
cache: ./cache/cord-326868-3az13h1h.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32747655/
doi: 10.1038/s41598-020-69999-5
summary:
  The present study takes a neural trait approach, examining whether the temporal dynamics of resting EEG networks are associated with inter-individual differences in prosociality. In two experimental sessions, we collected 55 healthy males'' resting EEG, their self-reported prosocial concern and values, and their incentivized prosocial behavior across different reward domains (money, time) and social contexts (collective, individual). On the basis of resting EEG networks'' significance for non-social behavior, personality, and psychiatric conditions 20,31 , we expected that revealing an individual''s tendency to engage these networks at rest would help explain inter-individual differences in prosociality and illuminate the potential psychological processes that underlie these differences. Correlative analyses revealed that participants with more transitions from microstate C to A were more prosocial [R(53) = 0.414, P = 0.002, Scientific RepoRtS | (2020) 10:13066 | https://doi.org/10.1038/s41598-020-69999-5 www.nature.com/scientificreports/ significant after Bonferroni-correction for multiple testing; prosocial concern: R s (53) = 0.261, P = 0.054; prosocial values: R s (53) = 0.366, P = 0.006; collective prosocial behavior: R s (53) = 0.081, P > 0.20; individual prosocial behavior: R s (53) = 0.261, P = 0.054, see Fig. 4 ].

abstract:
  As prosociality is key to facing many of our societies’ global challenges (such as fighting a global pandemic), we need to better understand why some individuals are more prosocial than others. The present study takes a neural trait approach, examining whether the temporal dynamics of resting EEG networks are associated with inter-individual differences in prosociality. In two experimental sessions, we collected 55 healthy males’ resting EEG, their self-reported prosocial concern and values, and their incentivized prosocial behavior across different reward domains (money, time) and social contexts (collective, individual). By means of EEG microstate analysis we identified the temporal coverage of four canonical resting networks (microstates A, B, C, and D) and their mutual communication in order to examine their association with an aggregated index of prosociality. Participants with a higher coverage of microstate A and more transitions from microstate C to A were more prosocial. Our study demonstrates that temporal dynamics of intrinsic brain networks can be linked to complex social behavior. On the basis of previous findings on links of microstate A with sensory processing, our findings suggest that participants with a tendency to engage in bottom-up processing during rest behave more prosocially than others.


id: cord-327405-xgtqfwyn
author: Liu, Bing
date: 2020-10-19
txt: ./txt/cord-327405-xgtqfwyn.txt
cache: ./cache/cord-327405-xgtqfwyn.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-020-73955-8
doi: 10.1038/s41598-020-73955-8
summary:
  37 non-severe patients with persistent SARS-CoV-2 presence that were transferred to Zhongnan hospital of Wuhan University were retrospectively recruited to the PP (persistently positive) group, which was further allocated to PPP group (n = 19) and PPN group (n = 18), according to their testing results after 7 days (N = negative). Finally, paired results of these lymphocyte subpopulations from 10 PPN patients demonstrated that the number of T cells and B cells significantly increased when the SARS-CoV-2 tests turned negative. These results indicated that non-severe COVID-19 patients (PA group) have already dysregulated immune system at disease onset, and those with persistent SARS-CoV-2 shedding could restore this abnormality to certain level. Together, these results indicated that the abnormalities in adaptive immune cells, but not symptoms and laboratory indicators, were associated with SARS-CoV-2 viral RNA detection in non-severe COVID-19 patients.

title:
  Reduced numbers of T cells and B cells correlates with persistent SARS-CoV-2 presence in non-severe COVID-19 patients

abstract:
  COVID-19 has been widely spreading. We aimed to examine adaptive immune cells in non-severe patients with persistent SARS-CoV-2 shedding. 37 non-severe patients with persistent SARS-CoV-2 presence that were transferred to Zhongnan hospital of Wuhan University were retrospectively recruited to the PP (persistently positive) group, which was further allocated to PPP group (n = 19) and PPN group (n = 18), according to their testing results after 7 days (N = negative). Epidemiological, demographic, clinical and laboratory data were collected and analyzed. Data from age- and sex-matched non-severe patients at disease onset (PA [positive on admission] patients, n = 37), and lymphocyte subpopulation measurements from matched 54 healthy subjects were extracted for comparison (HC). Compared with PA patients, PP patients had much improved laboratory findings. The absolute numbers of CD3(+) T cells, CD4(+) T cells, and NK cells were significantly higher in PP group than that in PA group, and were comparable to that in healthy controls. PPP subgroup had markedly reduced B cells and T cells compared to PPN group and healthy subjects. Finally, paired results of these lymphocyte subpopulations from 10 PPN patients demonstrated that the number of T cells and B cells significantly increased when the SARS-CoV-2 tests turned negative. Persistent SARS-CoV-2 presence in non-severe COVID-19 patients is associated with reduced numbers of adaptive immune cells. Monitoring lymphocyte subpopulations could be clinically meaningful in identifying fully recovered COVID-19 patients.


id: cord-329155-ddpfox68
author: Mindikoglu, Ayse L.
date: 2020-10-27
txt: ./txt/cord-329155-ddpfox68.txt
cache: ./cache/cord-329155-ddpfox68.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33110154/
doi: 10.1038/s41598-020-73767-w
summary:
  Our results showed that 30-day intermittent fasting from dawn to sunset, the human activity phase, was associated with an anticancer serum proteome response and upregulated several key regulatory proteins that play a key role in tumor suppression, DNA repair, insulin signaling, glucose, and lipid metabolism, circadian clock, cytoskeletal remodeling, immune system, and cognitive function 15 . In accord with the findings of these murine and human studies 13,25 , we found a significant fold increase in the levels of specific tumor suppressor/anticancer proteins at the end of 4th week during 4-week intermittent fasting from dawn to sunset and/or 1 week after 4-week intermittent fasting from dawn to sunset, including CALR, CALU, INTS6, KIT, CROCC, PIGR, IGFBP4, and SEMA4B that are downregulated in several cancers resulting in cancer metastasis and poor prognosis (Table 2, Fig. 2 ).

title:
  Intermittent fasting from dawn to sunset for four consecutive weeks induces anticancer serum proteome response and improves metabolic syndrome

abstract:
  Metabolic syndrome is characterized by central obesity, insulin resistance, elevated blood pressure, and dyslipidemia. Metabolic syndrome is a significant risk factor for several common cancers (e.g., liver, colorectal, breast, pancreas). Pharmacologic treatments used for the components of the metabolic syndrome appear to be insufficient to control cancer development in subjects with metabolic syndrome. Murine models showed that cancer has the slowest progression when there is no food consumption during the daily activity phase. Intermittent fasting from dawn to sunset is a form of fasting practiced during human activity hours. To test the anticancer effect of intermittent fasting from dawn to sunset in metabolic syndrome, we conducted a pilot study in 14 subjects with metabolic syndrome who fasted (no eating or drinking) from dawn to sunset for more than 14 h daily for four consecutive weeks. We collected serum samples before 4-week intermittent fasting, at the end of 4th week during 4-week intermittent fasting and 1 week after 4-week intermittent fasting. We performed serum proteomic analysis using nano ultra-high performance liquid chromatography-tandem mass spectrometry. We found a significant fold increase in the levels of several tumor suppressor and DNA repair gene protein products (GP)s at the end of 4th week during 4-week intermittent fasting (CALU, INTS6, KIT, CROCC, PIGR), and 1 week after 4-week intermittent fasting (CALU, CALR, IGFBP4, SEMA4B) compared with the levels before 4-week intermittent fasting. We also found a significant reduction in the levels of tumor promoter GPs at the end of 4th week during 4-week intermittent fasting (POLK, CD109, CAMP, NIFK, SRGN), and 1 week after 4-week intermittent fasting (CAMP, PLAC1) compared with the levels before 4-week intermittent fasting. Fasting from dawn to sunset for four weeks also induced an anti-diabetes proteome response by upregulating the key regulatory proteins of insulin signaling at the end of 4th week during 4-week intermittent fasting (VPS8, POLRMT, IGFBP-5) and 1 week after 4-week intermittent fasting (PRKCSH), and an anti-aging proteome response by upregulating H2B histone proteins 1 week after 4-week intermittent fasting. Subjects had a significant reduction in body mass index, waist circumference, and improvement in blood pressure that co-occurred with the anticancer, anti-diabetes, and anti-aging serum proteome response. These findings suggest that intermittent fasting from dawn to sunset actively modulates the respective genes and can be an adjunct treatment in metabolic syndrome. Further studies are needed to test the intermittent fasting from dawn to sunset in the prevention and treatment of metabolic syndrome-induced cancers.


id: cord-329424-hmsidrc7
author: Grunwell, Jocelyn R.
date: 2020-11-04
txt: ./txt/cord-329424-hmsidrc7.txt
cache: ./cache/cord-329424-hmsidrc7.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33149247/
doi: 10.1038/s41598-020-76122-1
summary:
  title: Differential type I interferon response and primary airway neutrophil extracellular trap release in children with acute respiratory distress syndrome Since viral lower respiratory tract infections are a primary trigger for PARDS, we questioned whether differential ISG expression was associated with neutrophil responses in intubated children at risk or with PARDS. We hypothesized that children with PARDS would have a greater type I IFN response resulting in more neutrophil extracellular trap (NET) release. Our study assessed neutrophil activation, the differential expression of ISGs and activation of the STAT1 signaling pathway, and NETosis in the airways of intubated children with acute respiratory failure due to lower respiratory tract infections. While we detected higher type I IFN signaling and NET production in the airways of children with versus without PARDS, due to the clinical nature of our study, we are not able to attribute causation of neutrophil dysfunction to high ISG expression in study participants.

title:
  Differential type I interferon response and primary airway neutrophil extracellular trap release in children with acute respiratory distress syndrome

abstract:
  Acute respiratory distress syndrome (ARDS) is a heterogeneous condition characterized by the recruitment of large numbers of neutrophils into the lungs. Neutrophils isolated from the blood of adults with ARDS have elevated expression of interferon (IFN) stimulated genes (ISGs) associated with decreased capacity of neutrophils to kill Staphylococcus aureus and worse clinical outcomes. Neutrophil extracellular traps (NETs) are elevated in adults with ARDS. Whether pediatric ARDS (PARDS) is similarly associated with altered neutrophil expression of ISGs and neutrophil extracellular trap release is not known. Tracheal aspirate fluid and cells were collected within 72 h from seventy-seven intubated children. Primary airway neutrophils were analyzed for differential ISG expression by PCR, STAT1 phosphorylation and markers of degranulation and activation by flow cytometry. Airway fluid was analyzed for the release of NETs by myeloperoxidase-DNA complexes using an ELISA. Higher STAT1 phosphorylation, markers of neutrophil degranulation, activation and NET release were found in children with versus without PARDS. Higher NETs were detected in the airways of children with ventilator-free days less than 20 days. Increased airway cell IFN signaling, neutrophil activation, and NET production is associated with PARDS. Higher levels of airway NETs are associated with fewer ventilator-free days.


id: cord-329766-9bwdb6o2
author: Liu, Xiaofan
date: 2020-06-24
url: https://www.ncbi.nlm.nih.gov/pubmed/32581324/
doi: 10.1038/s41598-020-66895-w
title:
  Temporal radiographic changes in COVID-19 patients: relationship to disease severity and viral clearance

abstract:
  COVID-19 is “public enemy number one” and has placed an enormous burden on health authorities across the world. Given the wide clinical spectrum of COVID-19, understanding the factors that can predict disease severity will be essential since this will help frontline clinical staff to stratify patients with increased confidence. To investigate the diagnostic value of the temporal radiographic changes, and the relationship to disease severity and viral clearance in COVID-19 patients. In this retrospective cohort study, we included 99 patients admitted to the Renmin Hospital of Wuhan University, with laboratory confirmed moderate or severe COVID-19. Temporal radiographic changes and viral clearance were explored using appropriate statistical methods. Radiographic features from HRCT scans included ground-glass opacity, consolidation, air bronchogram, nodular opacities and pleural effusion. The HRCT scores (peak) during disease course in COVID-19 patients with severe pneumonia (median: 24.5) were higher compared to those with pneumonia (median: 10) (p = 3.56 × 10 (−12)), with more frequency of consolidation (p = 0.025) and air bronchogram (p = 7.50 × 10(−6)). The median values of days when the peak HRCT scores were reached in pneumonia or severe pneumonia patients were 12 vs. 14, respectively (p = 0.048). Log-rank test and Spearman’s Rank-Order correlation suggested temporal radiographic changes as a valuable predictor for viral clearance. In addition, follow up CT scans from 11 pneumonia patients showed full recovery. Given the values of HRCT scores for both disease severity and viral clearance, a standardised HRCT score system for COVID-19 is highly demanded.


id: cord-330057-3vucm0s1
author: Franzo, Giovanni
date: 2020-04-29
txt: ./txt/cord-330057-3vucm0s1.txt
cache: ./cache/cord-330057-3vucm0s1.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-020-64477-4
doi: 10.1038/s41598-020-64477-4
summary:
  In the present study, 361 IBV QX (the most relevant field genotype in Italy) sequences were obtained between 2012 and 2016 from the two main Italian integrated poultry companies. Finally, the different viral population pattern observed in the two companies over the same time period supports the pivotal role of management and control strategies on IBV epidemiology. Almost identical results were obtained including a third "ghost" deme (i.e. an estimated deme for which no sequences were available, representative of other unsampled companies and farms) in the analysis or using the "traditional" coalescent approach. In the particular Italian QX scenario, the serially sampled (i.e. with known collection date) strains were used to infer the migration rate and history between the two integrated poultry companies (i.e. considered as different demes) over time.

title:
  Phylodynamic analysis and evaluation of the balance between anthropic and environmental factors affecting IBV spreading among Italian poultry farms

abstract:
  Infectious bronchitis virus (IBV) control is mainly based on wide vaccine administration. Although effective, its efficacy is not absolute, the viral circulation is not prevented and some side effects cannot be denied. Despite this, the determinants of IBV epidemiology and the factors affecting its circulation are still largely unknown and poorly investigated. In the present study, 361 IBV QX (the most relevant field genotype in Italy) sequences were obtained between 2012 and 2016 from the two main Italian integrated poultry companies. Several biostatistical and bioinformatics approaches were used to reconstruct the history of the QX genotype in Italy and to assess the effect of different environmental, climatic and social factors on its spreading patterns. Moreover, two structured coalescent models were considered in order to investigate if an actual compartmentalization occurs between the two integrated poultry companies and the role of a third “ghost” deme, representative of minor industrial poultry companies and the rural sector. The obtained results suggest that the integration of the poultry companies is an effective barrier against IBV spreading, since the strains sampled from the two companies formed two essentially-independent clades. Remarkably, the only exceptions were represented by farms located in the high densely populated poultry area of Northern Italy. The inclusion of a third deme in the model revealed the likely role of other poultry companies and rural farms (particularly concentrated in Northern Italy) as sources of strain introduction into one of the major poultry companies, whose farms are mainly located in the high densely populated poultry area of Northern Italy. Accordingly, when the effect of different environmental and urban parameters on IBV geographic spreading was investigated, no factor seems to contribute to IBV dispersal velocity, being poultry population density the only exception. Finally, the different viral population pattern observed in the two companies over the same time period supports the pivotal role of management and control strategies on IBV epidemiology. Overall, the present study results stress the crucial relevance of human action rather than environmental factors, highlighting the direct benefits that could derive from improved management and organization of the poultry sector on a larger scale.


id: cord-330562-dabjcvno
title: The 2020 coronavirus lockdown and seismic monitoring of anthropic activities in Northern Italy
author: Poli, Piero
date: 2020-06-10
url: https://doi.org/10.1038/s41598-020-66368-0
doi: 10.1038/s41598-020-66368-0
abstract:
  In March/April 2020 the Italian government drastically reduced vehicle traffic and interrupted all non-essential industrial activities over the entire national territory. Italy thus became the first country in the world, with the exception of Hubei, to enact lockdown measures as a consequence of the COVID-19 outbreak and the need to contain it. Italy is also a seismically active area, and as such is monitored by a dense permanent network of seismic stations. We analyse continuous seismic data from many stations in northern and central Italy, and quantify the impact of the lockdown on seismic ambient noise, as a function of time and location. We find that the lockdown reduces ambient noise significantly in the 1–10 Hz frequency range; because natural sources of seismic noise are not affected by the lockdown, the seismic signature of anthropic noise can be characterised with unprecedented clarity, by simply comparing the signal recorded before and after the lockdown. Our results correlate well with independent evaluations of the impact of the lockdown (e.g., cell phone displacements), and we submit that ambient-noise seismology is a useful tool to monitor containment measures such as the coronavirus lockdowns.


id: cord-331148-40gvay7i
author: Hsieh, Yu-Chia
date: 2018-10-23
txt: ./txt/cord-331148-40gvay7i.txt
cache: ./cache/cord-331148-40gvay7i.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-018-34077-4
doi: 10.1038/s41598-018-34077-4
summary:
  Independently, a retrospective cohort study (which enrolled 639 infected patients during the five seasons) was conducted at Chang Gung Memorial Hospital to explore the risk factors associated with influenza A(H1N1)pdm09-related complications. The results of the logistic regression analysis on the risk factors associated with influenza A(H1N1)pdm09-related complications and pneumonia are shown in Table 4 , and respiratory failure with mechanical ventilation and ARDS are also presented in Table 5 . In the univariate analysis, 6B/6B.1/6B.2 season, age (50-64 years), onset to presentation, underlying conditions, obesity, smoking, alcoholism, and antiviral therapy were significant risk factors of complications, pneumonia, mechanical ventilation, and ARDS (Tables 4 and 5 ). In the multivariate logistic regression analysis, 6B/6B.1/6B.2 season, age (50-64 years and ≥65 years), underlying conditions, and antiviral therapy were significant independent risk factors of complications, pneumonia, and mechanical ventilation (Tables 4 and 5).

title:
  Clinical characteristics of patients with laboratory-confirmed influenza A(H1N1)pdm09 during the 2013/2014 and 2015/2016 clade 6B/6B.1/6B.2-predominant outbreaks

abstract:
  A novel pandemic influenza A(H1N1)pdm09 virus emerged in 2009 globally, and it continues to circulate in humans. The National Influenza Surveillance Network in Taiwan identified five A(H1N1)pdm09-predominant seasons, representing the 2009/2010, 2010/2011, 2012/2013, 2013/2014, and 2015/2016 outbreaks from 2009 to 2016. Independently, a retrospective cohort study (which enrolled 639 infected patients during the five seasons) was conducted at Chang Gung Memorial Hospital to explore the risk factors associated with influenza A(H1N1)pdm09-related complications. A phylogenetic analysis of hemagglutinin (HA) sequences showed that the circulating A(H1N1)pdm09 virus belonged to clades 1, 2, and 8 in 2009/2010; clades 3, 4, 5, and 7 in 2010/2011; clades 7 and 6C in 2012/2013; clades 6B in 2013/2014; and 6B/6B.1/6B.2 in 2015/2016. Compared to individuals infected in non-6B/6B.1/6B.2 seasons (2009/2010, 2010/2011, and 2012/2013), those infected in 6B/6B.1/6B.2 seasons (2013/2014 and 2015/2016) were at higher risk for influenza-related complications (adjusted odds ratio [aOR]: 1.6, 95% confidence interval [CI]: 1.0–2.8), pneumonia (aOR: 1.78, 95% CI: 1.04–3.04), mechanical ventilation (aOR: 2.6, 95% CI: 1.2–5.6), and acute respiratory distress syndrome (aOR: 5.5, 95% CI: 1.9–15.9). For the increased severity of infection during the influenza A(H1N1)pdm09 clade 6B/6B.1/6B.2 seasons, aspects related to the antigenic change of A(H1N1)pdm09 virus, immune response of the host, and environmental factors required further investigation.


id: cord-331475-mmcu18c8
author: Sahu, Amit Ranjan
date: 2018-10-29
txt: ./txt/cord-331475-mmcu18c8.txt
cache: ./cache/cord-331475-mmcu18c8.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-018-34236-7
doi: 10.1038/s41598-018-34236-7
summary:
  title: Selection and validation of suitable reference genes for qPCR gene expression analysis in goats and sheep under Peste des petits ruminants virus (PPRV), lineage IV infection In this study, we evaluated the expression stability of ten most commonly used reference genes (GAPDH, ACTB, HSP90, HMBS, 18S rRNA, B2M, POLR2A, HPRT1, ACAC, YWHAZ) in fourteen different Peste des petits ruminants virus (PPRV) infected tissues of goats and sheep. GAPDH (Glyceraldehyde-3-phosphate dehydrogenase), 18S rRNA (18S ribosomal RNA), B2M (β 2 microglobulin), HSP 90 (heat shock protein 90), ACAC-alpha (Acetyl coenzyme carboxylase alpha), HMBS (Hydroxymethylbilane synthase), YWHAZ (Tyrosine 3-monooxygenase activation protein zeta polypeptide), POLR2A (Polymerase 32 II (DNA directed) polypeptide A), ACTB (beta actin) and HPRT1 (Hypoxanthin Phosphoribosyl transferase 1) in fourteen different tissues obtained from healthy and PPRV infected goats and sheep to identify the best possible reference gene(s) for qRT-PCR normalization.

title:
  Selection and validation of suitable reference genes for qPCR gene expression analysis in goats and sheep under Peste des petits ruminants virus (PPRV), lineage IV infection

abstract:
  Identification of suitable candidate reference genes is an important prerequisite for validating the gene expression data obtained from downstream analysis of RNA sequencing using quantitative real time PCR (qRT-PCR). Though existence of a universal reference gene is myth, commonly used reference genes can be assessed for expression stability to confer their suitability to be used as candidate reference genes in gene expression studies. In this study, we evaluated the expression stability of ten most commonly used reference genes (GAPDH, ACTB, HSP90, HMBS, 18S rRNA, B2M, POLR2A, HPRT1, ACAC, YWHAZ) in fourteen different Peste des petits ruminants virus (PPRV) infected tissues of goats and sheep. RefFinder and RankAggreg software were used to deduce comprehensive ranking of reference genes. Our results suggested HMBS and B2M in goats and HMBS and HPRT1 in sheep can be used as suitable endogenous controls in gene expression studies of PPRV infection irrespective of tissues and condition as a whole, thus eliminating the use of tissue specific/ condition specific endogenous controls. We report for the first time suitable reference genes for gene expression studies in PPRV infected tissues. The reference genes determined here can be useful for future studies on gene expression in sheep and goat infected with PPRV, thus saving extra efforts and time of repeating the reference gene determination and validation.


id: cord-331775-iaxkfszq
author: Nachman, Dean
date: 2020-10-19
url: https://doi.org/10.1038/s41598-020-74686-6
doi: 10.1038/s41598-020-74686-6
title:
  Wireless, non-invasive, wearable device for continuous remote monitoring of hemodynamic parameters in a swine model of controlled hemorrhagic shock

abstract:
  Accurate and continuous monitoring of critically ill patients is frequently achieved using invasive catheters, which is technically complex. Our purpose was to evaluate the validity and accuracy of a photoplethysmography (PPG)-based remote monitoring device compared to invasive methods of arterial line (AL) and Swan-Ganz (SG) catheters in a swine model of controlled hemorrhagic shock. Following a baseline phase, hemorrhagic shock was induced in 11 pigs by bleeding 35% of their blood volume, followed by a post-bleeding follow-up phase. Animals were monitored concomitantly by the PPG device, an AL and a SG catheter, for a median period of 447 min. Heart rate (HR), systolic and diastolic blood pressure (SBP and DBP, respectively), and cardiac output (CO) were recorded continuously. The complete data set consisted of 1312 paired observations. Correlations between the PPG-based technique and the invasive methods were significant (p < 0.001) during baseline, bleeding and follow-up phases for HR (r = 0.90–0.98), SBP (r = 0.90–0.94), DBP (r = 0.89–0.93), and CO (r = 0.76–0.90). Intraclass correlations for all phases combined were 0.96, 0.92, 0.93 and 0.87 for HR, SBP, DBP and CO, respectively. Correlations for changes in CO, SBP and DBP were significant (p < 0.001) and strong (r > 0.88), with concordance rates (determined by quadrant plots) of 86%, 66% and 68%, respectively. The novel PPG-based device was accurate and valid compared to existing invasive techniques and might be used for continuous monitoring in several clinical settings following further studies.


id: cord-333067-3zan82yf
author: Counoupas, Claudio
date: 2017-08-17
url: https://www.ncbi.nlm.nih.gov/pubmed/28819247/
doi: 10.1038/s41598-017-09119-y
title:
  Delta inulin-based adjuvants promote the generation of polyfunctional CD4(+) T cell responses and protection against Mycobacterium tuberculosis infection

abstract:
  There is an urgent need for the rational design of safe and effective vaccines to protect against chronic bacterial pathogens such as Mycobacterium tuberculosis. Advax™ is a novel adjuvant based on delta inulin microparticles that enhances immunity with a minimal inflammatory profile and has entered human trials to protect against viral pathogens. In this report we determined if Advax displays broad applicability against important human pathogens by assessing protective immunity against infection with M. tuberculosis. The fusion protein CysVac2, comprising the M. tuberculosis antigens Ag85B (Rv1886c) and CysD (Rv1285) formulated with Advax provided significant protection in the lungs of M. tuberculosis-infected mice. Protection was associated with the generation of CysVac2-specific multifunctional CD4(+) T cells (IFN-γ(+)TNF(+)IL-2(+)). Addition to Advax of the TLR9 agonist, CpG oligonucleotide (Advax(CpG)), improved both the immunogenicity and protective efficacy of CysVac2. Immunisation with CysVac2/Advax(CpG) resulted in heightened release of the chemoattractants, CXCL1, CCL3, and TNF, and rapid influx of monocytes and neutrophils to the site of vaccination, with pronounced early priming of CysVac2-specific CD4(+) T cells. As delta inulin adjuvants have shown an excellent safety and tolerability profile in humans, CysVac2/Advax(CpG) is a strong candidate for further preclinical evaluation for progression to human trials.


id: cord-334228-n69iewmx
author: Li, Chunmei
date: 2016-02-16
txt: ./txt/cord-334228-n69iewmx.txt
cache: ./cache/cord-334228-n69iewmx.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/26879383/
doi: 10.1038/srep20918
summary:
  Like other known CoV-3CLpro structures, such as TGEV, hCoV-229E, hCoV-HKU1, and IBV 2-5 , SARS-3CLpro has a highly conserved three-dimensional structure, dimer interface, catalysis dyad, and substrate binding site, but an extremely low homology with cellular proteases. Ser139 and Phe140 are two key residues that not only contribute to interactions between the two protomers in the parent dimer but also maintain the correct conformation of the S1 subsite in the substrate-binding pocket. Other residue mutations, which are neither on the dimer interface nor key to catalysis, can also influence enzyme activity and dimer association-dissociation of SARS-3CLpro via long-range interactions 15, 16 . Our molecular dynamics simulations showed that Ser139-Leu141 maintains a stable 3 10 -helix conformation in the inactive monomer structure and a well-defined loop conformation in the active protomer of the dimer structure. Although SARS-3CLpro uses the dimer structure to maintain its enzyme activity, our study shows that the monomer can also be evolved into an active enzyme via mutations.

title:
  Conformational Flexibility of a Short Loop near the Active Site of the SARS-3CLpro is Essential to Maintain Catalytic Activity

abstract:
  The SARS 3C-like proteinase (SARS-3CLpro), which is the main proteinase of the SARS coronavirus, is essential to the virus life cycle. This enzyme has been shown to be active as a dimer in which only one protomer is active. However, it remains unknown how the dimer structure maintains an active monomer conformation. It has been observed that the Ser139-Leu141 loop forms a short 3(10)-helix that disrupts the catalytic machinery in the inactive monomer structure. We have tried to disrupt this helical conformation by mutating L141 to T in the stable inactive monomer G11A/R298A/Q299A. The resulting tetra-mutant G11A/L141T/R298A/Q299A is indeed enzymatically active as a monomer. Molecular dynamics simulations revealed that the L141T mutation disrupts the 3(10)-helix and helps to stabilize the active conformation. The coil-3(10)-helix conformational transition of the Ser139-Leu141 loop serves as an enzyme activity switch. Our study therefore indicates that the dimer structure can stabilize the active conformation but is not a required structure in the evolution of the active enzyme, which can also arise through simple mutations.


id: cord-335055-gzuug3p5
author: Kwiyolecha, Elizabeth
date: 2020-10-28
txt: ./txt/cord-335055-gzuug3p5.txt
cache: ./cache/cord-335055-gzuug3p5.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-020-74555-2
doi: 10.1038/s41598-020-74555-2
summary:
  title: Patterns of viral pathogens causing upper respiratory tract infections among symptomatic children in Mwanza, Tanzania Therefore, there is a paramount need to establish information on the common etiologies of RTIs in Tanzania, the information that can stimulate further studies and possible control interventions including introduction of cheap and reliable methods to detect these pathogens in clinical settings. In addition due to increased use of antibiotic without a support of a diagnostic test in the treatment of URTI as observed in number of previous studies [11] [12] [13] , make the availability of epidemiological data on the patterns of etiology of URTI of paramount important. A cross sectional hospital based study involving 339 children aged 1-59 months presenting with RTI symptoms was conducted from October 2017 to February 2018 in the city of Mwanza, Tanzania. A previous study 33 , documented Rhinovirus to cause up to 25-85% of the upper respiratory tract infections.

title:
  Patterns of viral pathogens causing upper respiratory tract infections among symptomatic children in Mwanza, Tanzania

abstract:
  Upper-respiratory tract infections (URTI) are the leading causes of childhood morbidities. This study investigated etiologies and patterns of URTI among children in Mwanza, Tanzania. A cross-sectional study involving 339 children was conducted between October-2017 and February-2018. Children with features suggestive of URTI such as nasal congestion, dry cough, painful swallowing and nasal discharge with/without fever were enrolled. Pathogens were detected from nasopharyngeal and ear-swabs by multiplex-PCR and culture respectively. Full blood count and C-reactive protein analysis were also done. The median age was 16 (IQR: 8–34) months. Majority (82.3%) had fever and nasal-congestion (65.5%). Rhinitis (55.9%) was the commonest diagnosis followed by pharyngitis (19.5%). Viruses were isolated in 46% of children, the commonest being Rhinoviruses (23.9%). Nineteen percent of children had more than 2 viruses; Rhinovirus and Enterovirus being the commonest combination. The commonest bacteria isolated from ears were Staphylococcus aureus and Pseudomonas aeruginosa. Children with viral pathogens had significantly right shift of lymphocytes (73%—sensitivity). Majority (257/339) of children were symptoms free on eighth day. Viruses are the commonest cause of URTI with Rhinitis being the common diagnosis. Rapid diagnostic assays for URTI pathogens are urgently needed in low-income countries to reduce unnecessary antibiotic prescriptions which is associated with antibiotic resistance.


id: cord-335576-b34nc3ay
title: Impact of tocilizumab administration on mortality in severe COVID-19
author: Tsai, Andrew
date: 2020-11-05
txt: ./txt/cord-335576-b34nc3ay.txt
cache: ./cache/cord-335576-b34nc3ay.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33154452/
doi: 10.1038/s41598-020-76187-y
summary:
  Patients were stratified according to the receipt of tocilizumab for cytokine storm and matched to controls using propensity scores. The current analysis does not support the use of tocilizumab for the management of cytokine storm in patients with COVID-19. The objective of this analysis was to evaluate the clinical outcome of in-hospital mortality in patients with COVID-19 treated with tocilizumab in a single medical center. Subsequently, propensity score matching was performed to account for treatment strategy influenced by confounding by indication (the tendency of clinicians to prescribe tocilizumab in patients perceived to have cytokine storm and worsening trajectory). Currently Food and Drug Administration approved for use in the management of rheumatoid conditions and cytokine release storm-related to chimeric antigen receptor (CAR)-T cell therapy, tocilizumab has gained momentum as a potentially effective option in reducing IL-6 associated fevers and preventing clinical deterioration in COVID-19.

abstract:
  The novel coronavirus disease 2019 (COVID-19) worldwide pandemic has placed a significant burden on hospitals and healthcare providers. The immune response to this disease is thought to lead to an aberrant inflammatory response or cytokine storm, which contributes to the severity of illness. There is an urgent need to confirm whether the use of tocilizumab provides a benefit in individuals with COVID-19. A single-center propensity-score matched cohort study, including all consecutive COVID-19 patients, admitted to the medical center who were either discharged from the medical center or expired between March 1, 2020, and May 5, 2020, was performed. Patients were stratified according to the receipt of tocilizumab for cytokine storm and matched to controls using propensity scores. The primary outcome was in-hospital mortality. A total of 274 patients meeting inclusion and exclusion criteria were identified and 132 patients were included in the matched dataset (tocilizumab = 66; no tocilizumab = 66). Approximately 73% of the patients were male. Hypertension (55%), diabetes mellitus (31%), and chronic pulmonary disease (15%) were the most common comorbidities present. There were 18 deaths (27.3%) in the tocilizumab group and 18 deaths (27.3%) in the no tocilizumab group (odds ratio, 1.0; 95% confidence interval, 0.465 – 2.151; p = 1.00). Advanced age, history of myocardial infarction, dementia, chronic pulmonary disease, heart failure, and malignancy were significantly more common in patients who died. The current analysis does not support the use of tocilizumab for the management of cytokine storm in patients with COVID-19. Use of this therapeutic agent should be limited to the context of a clinical trial until more evidence is available.


id: cord-336493-ggo9wsrm
author: Huang, Stephen S. H.
date: 2013-04-23
url: https://doi.org/10.1038/srep01698
doi: 10.1038/srep01698
title:
  Immunity toward H1N1 influenza hemagglutinin of historical and contemporary strains suggests protection and vaccine failure

abstract:
  Evolution of H1N1 influenza A outbreaks of the past 100 years is interesting and significantly complex and details of H1N1 genetic drift remains unknown. Here we investigated the clinical characteristics and immune cross-reactivity of significant historical H1N1 strains. We infected ferrets with H1N1 strains from 1943, 1947, 1977, 1986, 1999, and 2009 and showed each produced a unique clinical signature. We found significant cross-reactivity between viruses with similar HA sequences. Interestingly, A/FortMonmouth/1/1947 antisera cross-reacted with A/USSR/90/1977 virus, thought to be a 1947 resurfaced virus. Importantly, our immunological data that didn't show cross-reactivity can be extrapolated to failure of past H1N1 influenza vaccines, ie. 1947, 1986 and 2009. Together, our results help to elucidate H1N1 immuno-genetic alterations that occurred in the past 100 years and immune responses caused by H1N1 evolution. This work will facilitate development of future influenza therapeutics and prophylactics such as influenza vaccines.


id: cord-336901-q6kgzuob
title: Integrated micro-optofluidic platform for real-time detection of airborne microorganisms
author: Choi, Jeongan
date: 2015-11-02
url: https://www.ncbi.nlm.nih.gov/pubmed/26522006/
doi: 10.1038/srep15983
abstract:
  We demonstrate an integrated micro-optofluidic platform for real-time, continuous detection and quantification of airborne microorganisms. Measurements of the fluorescence and light scattering from single particles in a microfluidic channel are used to determine the total particle number concentration and the microorganism number concentration in real-time. The system performance is examined by evaluating standard particle measurements with various sample flow rates and the ratios of fluorescent to non-fluorescent particles. To apply this method to real-time detection of airborne microorganisms, airborne Escherichia coli, Bacillus subtilis, and Staphylococcus epidermidis cells were introduced into the micro-optofluidic platform via bioaerosol generation, and a liquid-type particle collection setup was used. We demonstrate successful discrimination of SYTO82-dyed fluorescent bacterial cells from other residue particles in a continuous and real-time manner. In comparison with traditional microscopy cell counting and colony culture methods, this micro-optofluidic platform is not only more accurate in terms of the detection efficiency for airborne microorganisms but it also provides additional information on the total particle number concentration.


id: cord-338041-gl65i3s0
title: Inferring the hosts of coronavirus using dual statistical models based on nucleotide composition
author: Tang, Qin
date: 2015-11-26
url: https://doi.org/10.1038/srep17155
doi: 10.1038/srep17155
abstract:
  Many coronaviruses are capable of interspecies transmission. Some of them have caused worldwide panic as emerging human pathogens in recent years, e.g., severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). In order to assess their threat to humans, we explored to infer the potential hosts of coronaviruses using a dual-model approach based on nineteen parameters computed from spike genes of coronaviruses. Both the support vector machine (SVM) model and the Mahalanobis distance (MD) discriminant model achieved high accuracies in leave-one-out cross-validation of training data consisting of 730 representative coronaviruses (99.86% and 98.08% respectively). Predictions on 47 additional coronaviruses precisely conformed to conclusions or speculations by other researchers. Our approach is implemented as a web server that can be accessed at http://bioinfo.ihb.ac.cn/seq2hosts.


id: cord-338142-acqiyqwz
title: Signal amplification by reversible exchange for COVID-19 antiviral drug candidates
author: Jeong, Hye Jin
date: 2020-08-31
url: https://doi.org/10.1038/s41598-020-71282-6
doi: 10.1038/s41598-020-71282-6
abstract:
  Several drug candidates have been proposed and tested as the latest clinical treatment for coronavirus pneumonia (COVID-19). Chloroquine, hydroxychloroquine, ritonavir/lopinavir, and favipiravir are under trials for the treatment of this disease. The hyperpolarization technique has the ability to further provide a better understanding of the roles of these drugs at the molecular scale and in different applications in the field of nuclear magnetic resonance/magnetic resonance imaging. This technique may provide new opportunities in diagnosis and research of COVID-19. Signal amplification by reversible exchange-based hyperpolarization studies on large-sized drug candidates were carried out. We observed hyperpolarized proton signals from whole structures, due to the unprecedented long-distance polarization transfer by para-hydrogen. We also found that the optimal magnetic field for the maximum polarization transfer yield was dependent on the molecular structure. We can expect further research on the hyperpolarization of other important large molecules, isotope labeling, as well as polarization transfer on nuclei with a long spin relaxation time. A clinical perspective of these features on drug molecules can broaden the application of hyperpolarization techniques for therapeutic studies.


id: cord-338588-rc1h4drd
title: Seven decades of chemotherapy clinical trials: a pan-cancer social network analysis
author: Li, Xuanyi
date: 2020-10-16
url: https://www.ncbi.nlm.nih.gov/pubmed/33067482/
doi: 10.1038/s41598-020-73466-6
abstract:
  Clinical trials establish the standard of cancer care, yet the evolution and characteristics of the social dynamics between the people conducting this work remain understudied. We performed a social network analysis of authors publishing chemotherapy-based prospective trials from 1946 to 2018 to understand how social influences, including the role of gender, have influenced the growth and development of this network, which has expanded exponentially from fewer than 50 authors in 1946 to 29,197 in 2018. While 99.4% of authors were directly or indirectly connected by 2018, our results indicate a tendency to predominantly connect with others in the same or similar fields, as well as an increasing disparity in author impact and number of connections. Scale-free effects were evident, with small numbers of individuals having disproportionate impact. Women were under-represented and likelier to have lower impact, shorter productive periods (P < 0.001 for both comparisons), less centrality, and a greater proportion of co-authors in their same subspecialty. The past 30 years were characterized by a trend towards increased authorship by women, with new author parity anticipated in 2032. The network of cancer clinical trialists is best characterized as strategic or mixed-motive, with cooperative and competitive elements influencing its appearance. Network effects such as low centrality, which may limit access to high-profile individuals, likely contribute to the observed disparities.


id: cord-339973-kj56zi59
title: Bioaerosol Sampling for Respiratory Viruses in Singapore’s Mass Rapid Transit Network
author: Coleman, Kristen K.
date: 2018-11-30
txt: ./txt/cord-339973-kj56zi59.txt
cache: ./cache/cord-339973-kj56zi59.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-018-35896-1
doi: 10.1038/s41598-018-35896-1
summary:
  Although baseline metagenomic maps created from these studies are said to be useful for mitigating bioterrorism and infectious disease outbreaks, most of them focus largely on mapping surface-borne bacterial DNA 17 and neglect to address the threat of weaponized or global catastrophic biological risk-level (GCBR-level) agents, both of which would likely be aerosolized or respiratory-borne RNA viruses 19 . Bioaerosol sampling in the field provides a noninvasive way to monitor and characterize the community of aerosolized respiratory viruses that regularly infect the public, as well as potentially detect or discover novel pathogens with pandemic potential, such as the influenza A(H7N9) virus. Although the air pump flow rate and sample collection times used in our study have been demonstrated to efficiently capture aerosolized influenza virus and RSV RNA [33] [34] [35] , it is possible that these parameters are not optimal for capturing the other respiratory virus DNA/RNA targeted in our study.

abstract:
  As a leading global city with a high population density, Singapore is at risk for the introduction of novel biological threats. This risk has been recently reinforced by human epidemics in Singapore of SARS coronavirus, 2009 pandemic H1N1 influenza A virus, and enterovirus 71. Other major threats to Singapore include MERS-coronavirus and various avian and swine influenza viruses. The ability to quickly identify and robustly track such threats to initiate an early emergency response remains a significant challenge. In an effort to enhance respiratory virus surveillance in Singapore, our team conducted a pilot study employing a noninvasive bioaerosol sampling method to detect respiratory viruses in Singapore’s Mass Rapid Transit (MRT) network. Over a period of 52 weeks, 89 aerosol samples were collected during peak MRT ridership hours. Nine (10%) tested positive for adenovirus, four (4.5%) tested positive for respiratory syncytial virus type A, and one (1%) tested positive for influenza A virus using real-time RT-PCR/PCR. To our knowledge, this is the first time molecular evidence for any infectious respiratory agent has been collected from Singapore’s MRT. Our pilot study data support the possibility of employing bioaerosol samplers in crowded public spaces to noninvasively monitor for respiratory viruses circulating in communities.


id: cord-340105-471x03f9
title: Niclosamide inhibits leaf blight caused by Xanthomonas oryzae in rice
author: Kim, Sung-Il
date: 2016-02-16
txt: ./txt/cord-340105-471x03f9.txt
cache: ./cache/cord-340105-471x03f9.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/srep21209
doi: 10.1038/srep21209
summary:
  First, to determine the minimum concentration of niclosamide that would block bacterial blight, we examined the niclosamide dosage effect on disease responses to the representative Xoo strain PXO99. These results clearly indicate that niclosamide blocks the development of rice leaf blight by directly inhibiting Xoo bacterial growth (Figs 2c and 3c) and/or by inducing defense-related gene expression (Fig. 6) . In conclusion, the results presented herein indicate that niclosamide protects rice plants from bacterial leaf blight by inhibiting Xoo growth, inducing SA accumulation, and/or by inducing the expression of defense-related gene pathways. To examine the systemic effect of niclosamide on Xoo-mediated leaf blight development, the fully expanded uppermost leaves of 80-day-old rice plants were inoculated with PXO99 by the leaf-clipping as described above. Plant growth-promoting rhizobacteria mediate induced systemic resistance in rice against bacterial leaf blight caused by Xanthomonas oryzae pv

abstract:
  Rice leaf blight, which is caused by the bacterial pathogen Xanthomonas oryzae pv. oryzae (Xoo), results in huge losses in grain yield. Here, we show that Xoo-induced rice leaf blight is effectively controlled by niclosamide, an oral antihelminthic drug and molluscicide, which also functions as an anti-tumor agent. Niclosamide directly inhibited the growth of the three Xoo strains PXO99, 10208 and K3a. Niclosamide moved long distances from the site of local application to distant rice tissues. Niclosamide also increased the levels of salicylate and induced the expression of defense-related genes such as OsPR1 and OsWRKY45, which suppressed Xoo-induced leaf wilting. Niclosamide had no detrimental effects on vegetative/reproductive growth and yield. These combined results indicate that niclosamide can be used to block bacterial leaf blight in rice with no negative side effects.


id: cord-340781-z348xbn0
author: Namvar, Ali
date: 2019-10-23
txt: ./txt/cord-340781-z348xbn0.txt
cache: ./cache/cord-340781-z348xbn0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/31645650/
doi: 10.1038/s41598-019-51679-8
summary:
  Moreover, in vivo studies indicated that the combination of L1 and L2 DNA constructs without any adjuvant or delivery system induced effective immune responses, and protected mice against C3 tumor cells (the percentage of tumor-free mice: ~66.67%). The framework begins with conservancy analysis of all 13 high-risk HPV strains following with (1) B-cell epitope mapping, (2) T-cell epitope mapping (CD4 + and CD8 + ), (3) allergenicity assessment, (4) tap transport and proteasomal cleavage, (5) population coverage, (6) global and template-based docking and (7) data collection, analysis, and design of the L1 and L2 DNA constructs. In this study, for the first time, comprehensively integrated methods (using sequence-based tools in combination with flexible peptide-protein docking) were used to design highly immunogenic and protective vaccine candidates which were able to boost both humoral and cellular Table 12 .

title:
  In silico/In vivo analysis of high-risk papillomavirus L1 and L2 conserved sequences for development of cross-subtype prophylactic vaccine

abstract:
  Human papillomavirus (HPV) is the most common sexually transmitted infection in the world and the main cause of cervical cancer. Nowadays, the virus-like particles (VLPs) based on L1 proteins have been considered as the best candidate for vaccine development against HPV infections. Two commercial HPV (Gardasil and Cervarix) are available. These HPV VLP vaccines induce genotype-limited protection. The major impediments such as economic barriers especially gaps in financing obstructed the optimal delivery of vaccines in developing countries. Thus, many efforts are underway to develop the next generation of vaccines against other types of high-risk HPV. In this study, we developed DNA constructs (based on L1 and L2 genes) that were potentially immunogenic and highly conserved among the high-risk HPV types. The framework of analysis include (1) B-cell epitope mapping, (2) T-cell epitope mapping (i.e., CD4(+) and CD8(+) T cells), (3) allergenicity assessment, (4) tap transport and proteasomal cleavage, (5) population coverage, (6) global and template-based docking, and (7) data collection, analysis, and design of the L1 and L2 DNA constructs. Our data indicated the 8-epitope candidates for helper T-cell and CTL in L1 and L2 sequences. For the L1 and L2 constructs, combination of these peptides in a single universal vaccine could involve all world population by the rate of 95.55% and 96.33%, respectively. In vitro studies showed high expression rates of multiepitope L1 (~57.86%) and L2 (~68.42%) DNA constructs in HEK-293T cells. Moreover, in vivo studies indicated that the combination of L1 and L2 DNA constructs without any adjuvant or delivery system induced effective immune responses, and protected mice against C3 tumor cells (the percentage of tumor-free mice: ~66.67%). Thus, the designed L1 and L2 DNA constructs would represent promising applications for HPV vaccine development.


id: cord-342122-certy2v8
title: Pro-inflammatory properties of H-ferritin on human macrophages, ex vivo and in vitro observations
author: Ruscitti, Piero
date: 2020-07-22
txt: ./txt/cord-342122-certy2v8.txt
cache: ./cache/cord-342122-certy2v8.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-020-69031-w
doi: 10.1038/s41598-020-69031-w
summary:
  In this work, we tested (1) FeH and FeL in bone marrow (BM) and sera in patients with macrophage activation syndrome (MAS); (2) pro-inflammatory effects of ferritin, FeL, and FeH on macrophages; (3) ability of FeH-stimulated macrophages to stimulate the proliferation of peripheral blood mononuclear cells (PBMCs); (4) production of mature IL-1β and IL-12p70 in extracellular compartments of FeH-stimulated macrophages. Finally, www.nature.com/scientificreports/ FeH-treated macrophages enhanced the proliferation of co-cultured PBMCs. Taking together all these results and considering that AOSD and MAS could be included in the so-called "hyperferritinaemic syndrome" 14 , our data could reinforce the hypothesis that higher levels of ferritin may not only be considered a consequence or an epiphenomenon of the inflammation, but it may actively play a role in pathogenic mechanisms of those diseases, thus enhancing the inflammatory burden.

abstract:
  Ferritin is an iron-binding molecule, which comprises 24 subunits, heavy (FeH) and light (FeL) subunits, suggested to have a pathogenic role by the ‘hyperferritinemic syndrome’. In this work, we tested (1) FeH and FeL in bone marrow (BM) and sera in patients with macrophage activation syndrome (MAS); (2) pro-inflammatory effects of ferritin, FeL, and FeH on macrophages; (3) ability of FeH-stimulated macrophages to stimulate the proliferation of peripheral blood mononuclear cells (PBMCs); (4) production of mature IL-1β and IL-12p70 in extracellular compartments of FeH-stimulated macrophages. Immunofluorescence analysis and liquid chromatography mass spectrometry (LC–MS/MS) based proteomics were performed to identify FeL and FeH in BM and sera, respectively, in the same patients. Macrophages were stimulated with ferritin, FeH, and FeL to assess pro-inflammatory effects by RT-PCR and western blot. The proliferation of co-cultured PBMCs with FeH-stimulated macrophages was tested. Immunofluorescence showed an increased FeH expression in BMs, whereas LC–MS/MS identified that FeL was mainly represented in sera. FeH induced a significant increase of gene expressions of IL-1β, IL-6, IL-12, and TNF-α, more marked with FeH, which also stimulated NLRP3. FeH-stimulated macrophages enhanced the proliferation of PBMCs. The ELISA assays showed that mature form of IL-1β and IL-12p70 were increased, in extracellular compartments of FeH-stimulated macrophages. Our results showed FeH in BM biopsies of MAS patients, whereas, LC–MS/MS identified FeL in the sera. FeH showed pro-inflammatory effects on macrophages, stimulated NLRP3, and increased PBMCs proliferation.


id: cord-342289-zpstb7h9
author: Cui, Tingting
date: 2018-10-12
txt: ./txt/cord-342289-zpstb7h9.txt
cache: ./cache/cord-342289-zpstb7h9.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/30315177/
doi: 10.1038/s41598-018-33305-1
summary:
  As subepithelial myofibroblasts secrete extracellular matrix and growth factors contributing to the attachment, proliferation and differentiation of epithelial cells, co-cultures of primary porcine enterocytes (ileocytes and colonocytes) with myofibroblasts were developed and evaluated for their susceptibility to enteric viruses. The differentiation status of porcine intestinal epithelial cells of 3 days old piglets and the co-cultured enterocytes were analyzed by scanning electron microscopy. To determine the percentage of rotavirus infected cells in primary porcine enterocytes, cells were fixed at different time points (0, 3, 6, 9, 12, 24 h) post inoculation with a low-passage archival RVA strain. Therefore, the susceptibility of primary porcine enterocytes co-cultured with myofibroblasts to four different genotypes of rotavirus A contained in fecal suspensions was tested by RT-qPCR (Fig. 7) . Although rotavirus was reported to have an exclusive tropism for small intestinal enterocytes 41 , rotavirus RVA/Pig-tc/BEL/RV277/1977/G1P [7] strain could infect both primary ileum and colon epithelial cells with a trypsin treatment.

title:
  Establishment of porcine enterocyte/myofibroblast co-cultures for the growth of porcine rota- and coronaviruses

abstract:
  A stable culture of primary porcine enterocytes is necessary to study porcine enteric virus replication characteristics. Because the direct cultivation of primary porcine enterocytes is difficult, alternatives have to be considered. As subepithelial myofibroblasts secrete extracellular matrix and growth factors contributing to the attachment, proliferation and differentiation of epithelial cells, co-cultures of primary porcine enterocytes (ileocytes and colonocytes) with myofibroblasts were developed and evaluated for their susceptibility to enteric viruses. First, it was demonstrated that the co-cultured ileocytes and colonocytes were susceptible to an archival rotavirus strain RVA/pig-tc/BEL/RV277/1977/G1P[7] and different other rotavirus genotypes (fecal samples containing G5P[7], G5P[13], G9P[23], G4P[6]). Next, the TGEV Purdue strain infected both ileocytes and colonocytes whereas the Miller strain only infected ileocytes. Last, the PEDV CV777 Vero adapted and non-adapted (fecal suspension) strains could infect co-cultured ileocytes but not colonocytes. The infectivity of the CV777 Vero adapted strain was higher when the cells were cultured without fetal bovine serum and the CV777 fecal suspension only infected the ileocytes cultured without fetal bovine serum. In conclusion, a novel co-culture of porcine enterocytes with myofibroblasts was established, which can be used for the investigation of the replication of enteric viruses.


id: cord-342676-ykog278j
author: Stewart, H.
date: 2016-03-14
txt: ./txt/cord-342676-ykog278j.txt
cache: ./cache/cord-342676-ykog278j.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/26972799/
doi: 10.1038/srep22952
summary:
  To identify the regions of the viral genome involved in this process, we used SELEX (systematic evolution of ligands by exponential enrichment) to identify RNA aptamers which bind specifically to Core in vitro. Comparison of these aptamers to multiple HCV genomes revealed the presence of a conserved terminal loop motif within short RNA stem-loop structures. We wished to investigate the possibility that similar specific secondary structures are present within HCV RNAs destined for packaging, and whether their interactions with Core cooperatively drive the RNA encapsidation and nucleocapsid assembly processes. A mutant genome unable to form such structures displays impaired viral infectivity whilst RNA replication is unaffected, indicating these motifs may interact specifically with Core. Role of RNA structures in genome terminal sequences of the hepatitis C virus for replication and assembly

title:
  Identification of novel RNA secondary structures within the hepatitis C virus genome reveals a cooperative involvement in genome packaging

abstract:
  The specific packaging of the hepatitis C virus (HCV) genome is hypothesised to be driven by Core-RNA interactions. To identify the regions of the viral genome involved in this process, we used SELEX (systematic evolution of ligands by exponential enrichment) to identify RNA aptamers which bind specifically to Core in vitro. Comparison of these aptamers to multiple HCV genomes revealed the presence of a conserved terminal loop motif within short RNA stem-loop structures. We postulated that interactions of these motifs, as well as sub-motifs which were present in HCV genomes at statistically significant levels, with the Core protein may drive virion assembly. We mutated 8 of these predicted motifs within the HCV infectious molecular clone JFH-1, thereby producing a range of mutant viruses predicted to possess altered RNA secondary structures. RNA replication and viral titre were unaltered in viruses possessing only one mutated structure. However, infectivity titres were decreased in viruses possessing a higher number of mutated regions. This work thus identified multiple novel RNA motifs which appear to contribute to genome packaging. We suggest that these structures act as cooperative packaging signals to drive specific RNA encapsidation during HCV assembly.


id: cord-342782-xty16m8w
title: Repositioning salicylanilide anthelmintic drugs to treat adenovirus infections
author: Marrugal-Lorenzo, José A.
date: 2019-01-09
txt: ./txt/cord-342782-xty16m8w.txt
cache: ./cache/cord-342782-xty16m8w.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/30626902/
doi: 10.1038/s41598-018-37290-3
summary:
  Data suggests that the studied salicylanilide anthelmintic drugs could be suitable for further clinical evaluation for the development of new antiviral drugs to treat infections by adenovirus in immunosuppressed patients and in immunocompetent individuals with community-acquired pneumonia. The three salicylanilide anthelmintic drugs showed a dose-dependent anti-HAdV activity against both HAdV5 and HAdV16, with 100% inhibition of plaques formation at 1.25, 5 and 2.5 μM for NIC, OXY and RAF, respectively ( Fig. 2a,b) . The CC 50 values for these molecules were in all cases significantly higher than the IC 50 concentrations required for inhibition in our antiviral activity and mechanistic assays for both 293β5 cells (Table 1 ) and A549 cells (22.9 ± 9.8 µM, 76.1 ± 14.4 µM and 80.6 ± 34.7 µM for NIC, OXY and RAF, respectively). The aim of this study was to evaluate the anti-HAdV activity of NIC, a salicylanilide anthelmintic drug of human use to set the basis for its further experimental and clinical development as a potential new treatment for HAdV infections.

abstract:
  The repositioning of drugs already approved by regulatory agencies for other indications is an emerging alternative for the development of new antimicrobial therapies. The repositioning process involves lower risks and costs than the de novo development of novel antimicrobial drugs. Currently, infections by adenovirus show a steady increment with a high clinical impact in immunosuppressed and immunocompetent patients. The lack of a safe and efficacious drug to treat these infections supports the search for new antiviral drugs. Here we evaluated the anti-adenovirus activity of niclosanide, oxyclozanide, and rafoxanide, three salicylanilide anthelmintic drugs. Also, we carried out the cytotoxicity evaluation and partial characterization of the mechanism of action of these drugs. The salicylanilide anthelmintic drugs showed significant anti-adenovirus activity at low micromolar concentrations with little cytotoxicity. Moreover, our mechanistic assays suggest differences in the way the drugs exert anti-adenovirus activity. Niclosamide and rafoxanide target transport of the HAdV particle from the endosome to the nuclear envelope, whilst oxyclozanide specifically targets adenovirus immediately early gene E1A transcription. Data suggests that the studied salicylanilide anthelmintic drugs could be suitable for further clinical evaluation for the development of new antiviral drugs to treat infections by adenovirus in immunosuppressed patients and in immunocompetent individuals with community-acquired pneumonia.


id: cord-343302-g9vcchrh
author: Agrawal, Anurodh Shankar
date: 2016-08-19
url: https://doi.org/10.1038/srep31629
doi: 10.1038/srep31629
title:
  Passive Transfer of A Germline-like Neutralizing Human Monoclonal Antibody Protects Transgenic Mice Against Lethal Middle East Respiratory Syndrome Coronavirus Infection

abstract:
  Middle East Respiratory Syndrome coronavirus (MERS-CoV) has repeatedly caused outbreaks in the Arabian Peninsula. To date, no approved medical countermeasures (MCM) are available to combat MERS-CoV infections. Several neutralizing human monoclonal antibodies (mAbs), including m336, a germline-like human mAb, have been chosen as promising MCM for MERS-CoV. However, their clinical development has been hindered by the lack of a robust animal model that recapitulate the morbidity and mortality of human infections. We assessed the prophylactic and therapeutic efficacy of m336 by using well-characterized transgenic mice shown to be highly sensitive to MERS-CoV infection and disease. We found that mice treated with m336 prior to or post lethal MERS-CoV challenging were fully protected, compared to control mice which sufferered from profound weight loss and uniform death within days after infection. Taken together, these results support further development of m336 and other human monoclonal antibodies as potential therapeutics for MERS-CoV infection.


id: cord-343528-5283jsnu
title: Evolutionary Dynamics of MERS-CoV: Potential Recombination, Positive Selection and Transmission
author: Zhang, Zhao
date: 2016-05-04
url: https://doi.org/10.1038/srep25049
doi: 10.1038/srep25049
abstract:
  Middle East respiratory syndrome coronavirus (MERS-CoV) belongs to beta group of coronavirus and was first discovered in 2012. MERS-CoV can infect multiple host species and cause severe diseases in human. We conducted a series of phylogenetic and bioinformatic analyses to study the evolution dynamics of MERS-CoV among different host species with genomic data. Our analyses show: 1) 28 potential recombinant sequences were detected and they can be classified into seven potential recombinant types; 2) The spike (S) protein of MERS-CoV was under strong positive selection when MERS-CoV transmitted from their natural host to human; 3) Six out of nine positive selection sites detected in spike (S) protein are located in its receptor-binding domain which is in direct contact with host cells; 4) MERS-CoV frequently transmitted back and forth between human and camel after it had acquired the human-camel infection capability. Together, these results suggest that potential recombination events might have happened frequently during MERS-CoV’s evolutionary history and the positive selection sites in MERS-CoV’s S protein might enable it to infect human.


id: cord-344344-q32b742a
title: Alcohol abrogates human norovirus infectivity in a pH-dependent manner
author: Sato, Shintaro
date: 2020-09-28
url: https://doi.org/10.1038/s41598-020-72609-z
doi: 10.1038/s41598-020-72609-z
abstract:
  Alcohol-based disinfectants are widely used for the sanitization of microorganisms, especially those that cause infectious diseases, including viruses. However, since the germicidal mechanism of alcohol is lipolysis, alcohol-based disinfectants appear to have a minimal effect on non-enveloped viruses, such as noroviruses. Because there is no cultivation method for human norovirus (HuNoV) in vitro, murine norovirus and feline calicivirus have been used as surrogates for HuNoV to analyze the efficacy of disinfectant regents. Therefore, whether these disinfectants and their conditions are effective against HuNoVs remain unknown. In this study, we report that ethanol or isopropanol alone can sufficiently suppress GII.4 genotype HuNoV replication in human iPSC-derived intestinal epithelial cells. Additionally, pH adjustments and salting-out may contribute toward the virucidal effect of alcohol against other HuNoV genotypes and cancel the impediment of organic substance contamination, respectively. Therefore, similar to sodium hypochlorite, alcohol-based disinfectants containing electrolytes can be used for HuNoV inactivation.


id: cord-344421-rmnck42f
author: Theuns, Sebastiaan
date: 2018-06-29
url: https://doi.org/10.1038/s41598-018-28180-9
doi: 10.1038/s41598-018-28180-9
title:
  Nanopore sequencing as a revolutionary diagnostic tool for porcine viral enteric disease complexes identifies porcine kobuvirus as an important enteric virus

abstract:
  Enteric diseases in swine are often caused by different pathogens and thus metagenomics are a useful tool for diagnostics. The capacities of nanopore sequencing for viral diagnostics were investigated here. First, cell culture-grown porcine epidemic diarrhea virus and rotavirus A were pooled and sequenced on a MinION. Reads were already detected at 7 seconds after start of sequencing, resulting in high sequencing depths (19.2 to 103.5X) after 3 h. Next, diarrheic feces of a one-week-old piglet was analyzed. Almost all reads (99%) belonged to bacteriophages, which may have reshaped the piglet’s microbiome. Contigs matched Bacteroides, Escherichia and Enterococcus phages. Moreover, porcine kobuvirus was discovered in the feces for the first time in Belgium. Suckling piglets shed kobuvirus from one week of age, but an association between peak of viral shedding (10(6.42)–10(7.01) copies/swab) and diarrheic signs was not observed during a follow-up study. Retrospective analysis showed the widespread (n = 25, 56.8% positive) of genetically moderately related kobuviruses among Belgian diarrheic piglets. MinION enables rapid detection of enteric viruses. Such new methodologies will change diagnostics, but more extensive validations should be conducted. The true enteric pathogenicity of porcine kobuvirus should be questioned, while its subclinical importance cannot be excluded.


id: cord-344871-486sk4wc
author: Wu, Jianping
date: 2016-09-16
txt: ./txt/cord-344871-486sk4wc.txt
cache: ./cache/cord-344871-486sk4wc.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/srep33382
doi: 10.1038/srep33382
summary:
  We have previously shown that a non-structural protein 1 (NS1)-binding monoclonal antibody, termed as 2H6, can significantly reduce influenza A virus (IAV) replication when expressed intracellularly. As comparative ELISA in this and previous studies 29 showed that residues N48 and T49 in NS1(RBD) are important for the interaction with mAb 2H6, they were defined as active residues involved in the binding interaction to generate a series of models of the NS1(RBD) and 2H6-Fab complex. Overall, the predicted model from cluster 2 is consistent with our comparative ELISA data and suggests that residues N48 and T49 are important for the binding between NS1(RBD) and 2H6-Fab because their side-chains could make hydrogen bonds with residues in the VH-CDR2 of the Fab. In addition, R44 of NS1(RBD) was distal from the antibody-antigen interface, which is consistent with the results from comparative ELISA ( Figure S1 ) showing that substitution of R44 of NS1(RBD) with K did not affect its interaction with mAb 2H6.

title:
  Biochemical and structural characterization of the interface mediating interaction between the influenza A virus non-structural protein-1 and a monoclonal antibody

abstract:
  We have previously shown that a non-structural protein 1 (NS1)-binding monoclonal antibody, termed as 2H6, can significantly reduce influenza A virus (IAV) replication when expressed intracellularly. In this study, we further showed that 2H6 binds stronger to the NS1 of H5N1 than A/Puerto Rico/8/1934(H1N1) because of an amino acid difference at residue 48. A crystal structure of 2H6 fragment antigen-binding (Fab) has also been solved and docked onto the NS1 structure to reveal the contacts between specific residues at the interface of antibody-antigen complex. In one of the models, the predicted molecular contacts between residues in NS1 and 2H6-Fab correlate well with biochemical results. Taken together, residues N48 and T49 in H5N1 NS1 act cooperatively to maintain a strong interaction with mAb 2H6 by forming hydrogen bonds with residues found in the heavy chain of the antibody. Interestingly, the pandemic H1N1-2009 and the majority of seasonal H3N2 circulating in humans since 1968 has N48 in NS1, suggesting that mAb 2H6 could bind to most of the currently circulating seasonal influenza A virus strains. Consistent with the involvement of residue T49, which is well-conserved, in RNA binding, mAb 2H6 was also found to inhibit the interaction between NS1 and double-stranded RNA.


id: cord-344953-gtg12hiu
author: Prather, Randall S.
date: 2017-10-17
txt: ./txt/cord-344953-gtg12hiu.txt
cache: ./cache/cord-344953-gtg12hiu.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-017-13794-2
doi: 10.1038/s41598-017-13794-2
summary:
  title: Knockout of maternal CD163 protects fetuses from infection with porcine reproductive and respiratory syndrome virus (PRRSV) After infection of the porcine dam at about 90 days of gestation, porcine reproductive and respiratory syndrome virus (PRRSV) crosses the placenta and begins to infect fetuses. In this study, CD163-positive fetuses, recovered between 109 days of gestation or 20 days after maternal infection, were completely protected from PRRSV in dams possessing a complete knockout of the CD163 receptor. The hypothesis to be tested was that the presence of the CD163 KO genotype of the dam would be sufficient to protect fetuses following maternal infection with PRRSV. PRRSV nucleic acid, measured at 7 dpi, showed a viremia level for Dam No. 139 of 5.5 log 10 templates per reaction, demonstrating the presence of a productive PRRSV infection. Gene-edited pigs are protected from porcine reproductive and respiratory syndrome virus

title:
  Knockout of maternal CD163 protects fetuses from infection with porcine reproductive and respiratory syndrome virus (PRRSV)

abstract:
  After infection of the porcine dam at about 90 days of gestation, porcine reproductive and respiratory syndrome virus (PRRSV) crosses the placenta and begins to infect fetuses. Outcomes of include abortion, fetal death and respiratory disease in newborn piglets. CD163 is the receptor for the virus. In this study, CD163-positive fetuses, recovered between 109 days of gestation or 20 days after maternal infection, were completely protected from PRRSV in dams possessing a complete knockout of the CD163 receptor. The results demonstrate a practical means to eliminate PRRSV-associated reproductive disease, a major source of economic hardship to agriculture.


id: cord-345359-okmkgsbr
author: Ohno, Marumi
date: 2020-07-02
txt: ./txt/cord-345359-okmkgsbr.txt
cache: ./cache/cord-345359-okmkgsbr.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-020-67879-6
doi: 10.1038/s41598-020-67879-6
summary:
  After infecting mice with intranasal applications of 500 plaque-forming units of A/Puerto Rico/8/34 (H1N1; PR8) virus, the serum levels of most intermediates in the tricarboxylic acid (TCA) cycle and related metabolic pathways were significantly reduced. www.nature.com/scientificreports/ investigated metabolic changes by determining the serum levels of metabolites, insulin sensitivity in the liver, glucose availability, and hepatic gene expressions in the early stages of symptom onset as well as the lethal phase of influenza in a mouse model. The results of this study indicate that influenza virus infection dysregulates glucose and fatty acid metabolism and decreases tricarboxylic acid (TCA) cycle activity, leading to enhanced degradation of adenosine triphosphate (ATP) and guanosine triphosphate (GTP). Metabolites that were present at reduced levels in the sera of PR8 virus-infected mice were mainly related to the TCA cycle, urea cycle, and amino acid metabolism, as indicated by the serum levels of metabolite in these pathways at 1, 3, and 6 dpi (Fig. 2) .

title:
  Influenza virus infection affects insulin signaling, fatty acid-metabolizing enzyme expressions, and the tricarboxylic acid cycle in mice

abstract:
  Although the severity of influenza virus infections has been associated with host energy metabolism, the related mechanisms have not yet been clarified. Here we examined the effects of influenza virus infection on host energy metabolism in mice. After infecting mice with intranasal applications of 500 plaque-forming units of A/Puerto Rico/8/34 (H1N1; PR8) virus, the serum levels of most intermediates in the tricarboxylic acid (TCA) cycle and related metabolic pathways were significantly reduced. These data suggest that substrate supply to the TCA cycle is reduced under these conditions, rather than specific metabolic reactions being inhibited. Then, we focused on glucose and fatty acid metabolism that supply substrates to the TCA cycle. Akt phosphorylation following insulin injections was attenuated in the livers of PR8 virus-infected mice. Furthermore, glucose tolerance tests revealed that the PR8 virus-infected mice showed higher blood glucose levels than the vehicle-inoculated control mice. These results suggest that influenza virus infection impairs insulin signaling, which regulates glucose uptake. However, increases in the hepatic expressions of fatty acid-metabolizing enzymes suggest that fatty acids accumulate in liver cells of infected mice. Collectively, our data indicate that influenza virus infection dysregulates host energy metabolism. This line of investigation provides novel insights into the pathogenesis of influenza.


id: cord-346483-jc0xklzk
author: Chen, Jun
date: 2020-11-05
url: https://www.ncbi.nlm.nih.gov/pubmed/33154542/
doi: 10.1038/s41598-020-76282-0
title:
  Deep learning-based model for detecting 2019 novel coronavirus pneumonia on high-resolution computed tomography

abstract:
  Computed tomography (CT) is the preferred imaging method for diagnosing 2019 novel coronavirus (COVID19) pneumonia. We aimed to construct a system based on deep learning for detecting COVID-19 pneumonia on high resolution CT. For model development and validation, 46,096 anonymous images from 106 admitted patients, including 51 patients of laboratory confirmed COVID-19 pneumonia and 55 control patients of other diseases in Renmin Hospital of Wuhan University were retrospectively collected. Twenty-seven prospective consecutive patients in Renmin Hospital of Wuhan University were collected to evaluate the efficiency of radiologists against 2019-CoV pneumonia with that of the model. An external test was conducted in Qianjiang Central Hospital to estimate the system’s robustness. The model achieved a per-patient accuracy of 95.24% and a per-image accuracy of 98.85% in internal retrospective dataset. For 27 internal prospective patients, the system achieved a comparable performance to that of expert radiologist. In external dataset, it achieved an accuracy of 96%. With the assistance of the model, the reading time of radiologists was greatly decreased by 65%. The deep learning model showed a comparable performance with expert radiologist, and greatly improved the efficiency of radiologists in clinical practice.


id: cord-348515-bqqyly23
author: Zhao, Suhui
date: 2014-12-08
txt: ./txt/cord-348515-bqqyly23.txt
cache: ./cache/cord-348515-bqqyly23.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/25482188/
doi: 10.1038/srep07365
summary:
  Recombination analysis reveals this genome differs from the 1950s-era prototype and vaccine strains by a lateral gene transfer, substituting the coding region for the L1 52/55 kDa DNA packaging protein from HAdV-16. Recombination analysis reveals this genome differs from the 1950s-era prototype and vaccine strains by a lateral gene transfer, substituting the coding region for the L1 52/55 kDa DNA packaging protein from HAdV-16. Thorough characterization of these pathogens is evidenced by the availability of two genome sequences (JF800905 and JX625134), both of which are further identified as the HAdV-7d genome type in this report, and shown to be nearly identical to this report of an isolate from a 2011 ARD outbreak in Guangdong Province (strain DG01_2011) by comparative genomics and, in particular, in silico REA pattern analysis, as presented in Figure 2 .

title:
  Re-emergent Human Adenovirus Genome Type 7d Caused an Acute Respiratory Disease Outbreak in Southern China After a Twenty-one Year Absence

abstract:
  Human adenoviruses (HAdVs) are highly contagious pathogens causing acute respiratory disease (ARD), among other illnesses. Of the ARD genotypes, HAdV-7 presents with more severe morbidity and higher mortality than the others. We report the isolation and identification of a genome type HAdV-7d (DG01_2011) from a recent outbreak in Southern China. Genome sequencing, phylogenetic analysis, and restriction endonuclease analysis (REA) comparisons with past pathogens indicate HAdV-7d has re-emerged in Southern China after an absence of twenty-one years. Recombination analysis reveals this genome differs from the 1950s-era prototype and vaccine strains by a lateral gene transfer, substituting the coding region for the L1 52/55 kDa DNA packaging protein from HAdV-16. DG01_2011 descends from both a strain circulating in Southwestern China (2010) and a strain from Shaanxi causing a fatality and outbreak (Northwestern China; 2009). Due to the higher morbidity and mortality rates associated with HAdV-7, the surveillance, identification, and characterization of these strains in population-dense China by REA and/or whole genome sequencing are strongly indicated. With these accurate identifications of specific HAdV types and an epidemiological database of regional HAdV pathogens, along with the HAdV genome stability noted across time and space, the development, availability, and deployment of appropriate vaccines are needed.


id: cord-350255-tthttyl3
author: Poirier, Canelle
date: 2020-10-12
txt: ./txt/cord-350255-tthttyl3.txt
cache: ./cache/cord-350255-tthttyl3.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-020-74089-7
doi: 10.1038/s41598-020-74089-7
summary:
  To disentangle if our reproductive number estimates could be explained by importation of cases from Wuhan, Hubei, alone; and if they could be interpreted as indicators of local transmission, we formulated a linear model with the local R proxy as the response variable, and human mobility as a predictor at the province level. In all steps of filtering at the province-level, and for both time periods, τ 1 and τ 2 , absolute humidity was not associated to R proxy , with P values ranging between 0.161 and 0.922 (Tables 9, 10 , 11, 12, 13, 14, 15) . For cities, for time-period τ 1 , and after the first step of filtering, absolute humidity appeared to be associate with R proxy with a p value equal to 0.004 (Supplementary Table S5 ).

title:
  The role of environmental factors on transmission rates of the COVID-19 outbreak: an initial assessment in two spatial scales

abstract:
  First identified in Wuhan, China, in December 2019, a novel coronavirus (SARS-CoV-2) has affected over 16,800,000 people worldwide as of July 29, 2020 and was declared a pandemic by the World Health Organization on March 11, 2020. Influenza studies have shown that influenza viruses survive longer on surfaces or in droplets in cold and dry air, thus increasing the likelihood of subsequent transmission. A similar hypothesis has been postulated for the transmission of COVID-19, the disease caused by SARS-CoV-2. It is important to propose methodologies to understand the effects of environmental factors on this ongoing outbreak to support decision-making pertaining to disease control. Here, we examine the spatial variability of the basic reproductive numbers of COVID-19 across provinces and cities in China and show that environmental variables alone cannot explain this variability. Our findings suggest that changes in weather (i.e., increase of temperature and humidity as spring and summer months arrive in the Northern Hemisphere) will not necessarily lead to declines in case counts without the implementation of drastic public health interventions.


id: cord-350468-32qin4ak
title: Immune dysfunction following COVID-19, especially in severe patients
author: Song, Cong-Ying
date: 2020-09-28
txt: ./txt/cord-350468-32qin4ak.txt
cache: ./cache/cord-350468-32qin4ak.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-020-72718-9
doi: 10.1038/s41598-020-72718-9
summary:
  Multivariate logistic regression analysis showed that CD4(+) cell count, neutrophil-to-lymphocyte ratio (NLR) and D-dimer were risk factors for severe cases. Afterward, the CD4 + cell count (P = 0.015), NLR (P = 0.032) and D-dimer (P = 0.016) were considered the independent risk factors of the severe COVID-19 cases (Table 3) www.nature.com/scientificreports/ To evaluate the predictive value of CT score, CPIS, and three independent risk factors, the ROC curve analysis was performed (Fig. 7) . In our study, we compared clinical characteristics between healthy people and COVID-19 patients, and then compared these features between severe and mild cases. Parameters including CD4 + T cell count, NLR, and D-dimer, CT score, and CPIS had quite great value for predicting disease severity, which could be considered in early warning of severe patients. Several studies have shown that severe SARS-CoV-2-infected patients have a higher NLR 11, 12 , an independent risk factor for mortality in COVID-19 patients 13 .

abstract:
  The coronavirus disease 2019 (COVID-19) has been spreading worldwide. Severe cases quickly progressed with unfavorable outcomes. We aim to investigate the clinical features of COVID-19 and identify the risk factors associated with its progression. Data of confirmed SARS-CoV-2-infected patients and healthy participants were collected. Thirty-seven healthy people and 79 confirmed patients, which include 48 severe patients and 31 mild patients, were recruited. COVID-19 patients presented with dysregulated immune response (decreased T, B, and NK cells and increased inflammatory cytokines). Also, they were found to have increased levels of white blood cell, neutrophil count, and D-dimer in severe cases. Moreover, lymphocyte, CD4(+) T cell, CD8(+) T cell, NK cell, and B cell counts were lower in the severe group. Multivariate logistic regression analysis showed that CD4(+) cell count, neutrophil-to-lymphocyte ratio (NLR) and D-dimer were risk factors for severe cases. Both CT score and clinical pulmonary infection score (CPIS) were associated with disease severity. The receiver operating characteristic (ROC) curve analysis has shown that all these parameters and scores had quite a high predictive value. Immune dysfunction plays critical roles in disease progression. Early and constant surveillance of complete blood cell count, T lymphocyte subsets, coagulation function, CT scan and CPIS was recommended for early screening of severe cases.


id: cord-350957-10wcqgaq
author: Shen, Zu T.
date: 2016-06-28
txt: ./txt/cord-350957-10wcqgaq.txt
cache: ./cache/cord-350957-10wcqgaq.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/srep28672
doi: 10.1038/srep28672
summary:
  Recently, based on our model of immune signaling, the Signaling Chain HOmoOLigomerization (SCHOOL) model, we suggested specific molecular mechanisms used by different viruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) to modulate the host immune response mediated by members of the family of multichain immune recognition receptors (MIRRs). Previously, we reported that incorporation of another immunomodulatory peptide, GF9, that employs the SCHOOL mechanisms of action and targets triggering receptor expressed on myeloid cells 1 (TREM-1), into synthetic HDL-like nanoparticles of spherical shape (sHDL) significantly reduces the effective therapeutic dosage of GF9 in animal models of sepsis, lung cancer, and RA 33, 34 . As expected from the anti-arthritic activities demonstrated in animal models of autoimmune arthritis for TCR CP 20,21,23 and HIV gp41 FP 18 , the SARS-CoV FP-derived peptide sequence MG11 significantly suppresses CIA in mice: the peptide at 25 mg/kg/day inhibits inflammation in CIA as assessed by clinical evaluation and scoring of the disease (Fig. 2) .

title:
  SARS Coronavirus Fusion Peptide-Derived Sequence Suppresses Collagen-Induced Arthritis in DBA/1J Mice

abstract:
  During the co-evolution of viruses and their hosts, the viruses have evolved numerous strategies to counter and evade host antiviral immune responses in order to establish a successful infection, replicate and persist in the host. Recently, based on our model of immune signaling, the Signaling Chain HOmoOLigomerization (SCHOOL) model, we suggested specific molecular mechanisms used by different viruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) to modulate the host immune response mediated by members of the family of multichain immune recognition receptors (MIRRs). This family includes T cell receptor (TCR) that is critically involved in immune diseases such as autoimmune arthritis. In the present study, we provide compelling experimental in vivo evidence in support of our hypothesis. Using the SCHOOL approach and the SARS-CoV fusion peptide sequence, we rationally designed a novel immunomodulatory peptide that targets TCR. We showed that this peptide ameliorates collagen-induced arthritis in DBA/1J mice and protects against bone and cartilage damage. Incorporation of the peptide into self-assembling lipopeptide nanoparticles that mimic native human high density lipoproteins significantly increases peptide dosage efficacy. Together, our data further confirm that viral immune evasion strategies that target MIRRs can be transferred to therapeutic strategies that require similar functionalities.


id: cord-351295-4toxlskr
title: Identification of hepadnavirus in the sera of cats
author: Lanave, Gianvito
date: 2019-07-23
txt: ./txt/cord-351295-4toxlskr.txt
cache: ./cache/cord-351295-4toxlskr.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/31337847/
doi: 10.1038/s41598-019-47175-8
summary:
  Also, in 7/10 animals with suspected hepatic disease, virus load was >10(4) genome copies per mL, i.e. above the threshold considered at risk of active hepatitis and liver damage for HBV. DCH DNA was detected in 31 (17.8%) out of 174 sera collected with a request for diagnosis of infectious diseases (collection A) and in 11 (5.1%) out of 216 sera submitted to the laboratory for pre-surgical evaluation or for suspected metabolic or neoplastic disease (collection B) that were used to generate a baseline. In this study we observed a marked and significantly higher prevalence (17.8%, 31/174) in the cohort of cats with suspected infectious diseases (collection A) with respect to a group of animals (collection B) used as baseline. Almost half of the sera positive for DCH (14/31, 45 .2%) of this cohort were collected from cats with retroviral infection (FIV and/or feline leukemia virus, FeLV).

abstract:
  Hepadnaviruses infect several animal species. The prototype species, human hepatitis B virus (HBV), increases the risk of liver diseases and may cause cirrhosis and hepatocellular carcinoma. Recently a novel hepadnavirus, similar to HBV, has been identified through transcriptomics studies in a domestic cat with large cell lymphoma in Australia. Herewith, a collection of 390 feline serum samples was screened for hepadnavirus. Overall, the virus was identified in 10.8% of the sera with a significantly higher prevalence (17.8%) in the sera of animals with a clinical suspect of infectious disease. Upon genome sequencing, the virus was closely related (97.0% nt identity) to the prototype Australian feline virus Sydney 2016. The mean and median values of hepadnavirus in the feline sera were 1.3 × 10(6) and 2.1 × 10(4) genome copies per mL (range 3.3 × 10(0)–2.5 × 10(7) genome copies per mL). For a subset of hepadnavirus-positive samples, information on the hemato-chemical parameters was available and in 10/20 animals a profile suggestive of liver damage was present. Also, in 7/10 animals with suspected hepatic disease, virus load was >10(4) genome copies per mL, i.e. above the threshold considered at risk of active hepatitis and liver damage for HBV.


id: cord-351659-ujbxsus4
title: A retrospective analysis of the dynamic transmission routes of the COVID-19 in mainland China
author: Jiang, Xiandeng
date: 2020-08-19
txt: ./txt/cord-351659-ujbxsus4.txt
cache: ./cache/cord-351659-ujbxsus4.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-020-71023-9
doi: 10.1038/s41598-020-71023-9
summary:
  We propose a time-varying sparse vector autoregressive (VAR) model to retrospectively analyze and visualize the dynamic transmission routes of this outbreak in mainland China over January 31–February 19, 2020. Our results demonstrate that the influential inter-location routes from Hubei have become unidentifiable since February 4, 2020, whereas the self-transmission in each provincial-level administrative region (location, hereafter) was accelerating over February 4–15, 2020. Implications of our results suggest that in addition to the origin of the outbreak, virus preventions are of crucial importance in locations with the largest migrant workers percentages (e.g., Jiangxi, Henan and Anhui) to controlling the spread of COVID-19. This enables the detection and visualization of time-varying inter-location and self-transmission routes of the COVID-19 on the daily basis. On the fifth day (February 4, 2020), no influential transmission routes were found from Hubei to directly affect other locations, and there were only three influential routes identified nationally, including Zhejiang-Shaanxi, www.nature.com/scientificreports/ Zhejiang-Jiangxi and Jiangxi-Shanghai.

abstract:
  The fourth outbreak of the Coronaviruses, known as the COVID-19, has occurred in Wuhan city of Hubei province in China in December 2019. We propose a time-varying sparse vector autoregressive (VAR) model to retrospectively analyze and visualize the dynamic transmission routes of this outbreak in mainland China over January 31–February 19, 2020. Our results demonstrate that the influential inter-location routes from Hubei have become unidentifiable since February 4, 2020, whereas the self-transmission in each provincial-level administrative region (location, hereafter) was accelerating over February 4–15, 2020. From February 16, 2020, all routes became less detectable, and no influential transmissions could be identified on February 18 and 19, 2020. Such evidence supports the effectiveness of government interventions, including the travel restrictions in Hubei. Implications of our results suggest that in addition to the origin of the outbreak, virus preventions are of crucial importance in locations with the largest migrant workers percentages (e.g., Jiangxi, Henan and Anhui) to controlling the spread of COVID-19.


id: cord-352020-9wxwktck
author: Zhang, Baoshan
date: 2020-10-23
txt: ./txt/cord-352020-9wxwktck.txt
cache: ./cache/cord-352020-9wxwktck.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33097791/
doi: 10.1038/s41598-020-74949-2
summary:
  To alleviate this issue, we developed a plug-and-play platform using the spontaneous isopeptide-bond formation of the SpyTag:SpyCatcher system to display trimeric antigens on self-assembling nanoparticles, including the 60-subunit Aquifex aeolicus lumazine synthase (LuS) and the 24-subunit Helicobacter pylori ferritin. The versatile platform described here thus allows for multivalent plug-and-play presentation on self-assembling nanoparticles of trimeric viral antigens, with SARS-CoV-2 spike-LuS nanoparticles inducing particularly potent neutralizing responses. To improve protein solubility and expression, we added glycans to the surface of the nanoparticles, designing a panel of LuS and ferritin constructs with SpyTag and SpyCatcher (Table 1 and Supplementary Table S1 ). To demonstrate the versatility of our SpyTag-displaying nanoparticles in immunogen development, we conjugated them to three viral antigens of vaccine interest, the DS2-preF stabilized RSV F 33 , a DS2-stabilized version of PIV3 F 34 , and the 2P-stabilized version of SARS-CoV-2 spike 24 .

title:
  A platform incorporating trimeric antigens into self-assembling nanoparticles reveals SARS-CoV-2-spike nanoparticles to elicit substantially higher neutralizing responses than spike alone

abstract:
  Antigens displayed on self-assembling nanoparticles can stimulate strong immune responses and have been playing an increasingly prominent role in structure-based vaccines. However, the development of such immunogens is often complicated by inefficiencies in their production. To alleviate this issue, we developed a plug-and-play platform using the spontaneous isopeptide-bond formation of the SpyTag:SpyCatcher system to display trimeric antigens on self-assembling nanoparticles, including the 60-subunit Aquifex aeolicus lumazine synthase (LuS) and the 24-subunit Helicobacter pylori ferritin. LuS and ferritin coupled to SpyTag expressed well in a mammalian expression system when an N-linked glycan was added to the nanoparticle surface. The respiratory syncytial virus fusion (F) glycoprotein trimer—stabilized in the prefusion conformation and fused with SpyCatcher—could be efficiently conjugated to LuS-SpyTag or ferritin-SpyTag, enabling multivalent display of F trimers with prefusion antigenicity. Similarly, F-glycoprotein trimers from human parainfluenza virus-type 3 and spike-glycoprotein trimers from SARS-CoV-2 could be displayed on LuS nanoparticles with decent yield and antigenicity. Notably, murine vaccination with 0.08 µg of SARS-CoV-2 spike-LuS nanoparticle elicited similar neutralizing responses as 2.0 µg of spike, which was ~ 25-fold higher on a weight-per-weight basis. The versatile platform described here thus allows for multivalent plug-and-play presentation on self-assembling nanoparticles of trimeric viral antigens, with SARS-CoV-2 spike-LuS nanoparticles inducing particularly potent neutralizing responses.


id: cord-352061-x6tt9kx5
title: Smoking cessation increases levels of osteocalcin and uncarboxylated osteocalcin in human sera
author: Kiyota, Yasuhiro
date: 2020-10-08
url: https://doi.org/10.1038/s41598-020-73789-4
doi: 10.1038/s41598-020-73789-4
abstract:
  Smoking is thought to be a risk factor for osteoporosis development; however, the consequences of stopping smoking for bone homeostasis remain unknown. Here we conducted two separate human studies and show that bone mineral density was significantly lower in smokers than in non-smokers. The first was an observational study of pre- and post-menopausal healthy female smokers and non-smokers; the second included 139 current smokers determined to stop smoking. In the second study, levels of bone formation markers such as osteocalcin and uncarboxylated osteocalcin significantly increased after successful smoking cessation, as verified by significantly reduced levels of serum cotinine, a nicotine metabolite. Moreover, nicotine administration to mice reduced bone mineral density and significantly increased the number of osteoclasts in bone. Reduced bone mass phenotypes seen in nicotine-treated mice were significantly increased following nicotine withdrawal, an outcome accompanied by significantly reduced serum levels of tartrate-resistant acid phosphatase, a bone resorption marker. Taken together, our findings suggest that bone homeostasis is perturbed but can be rescued by smoking cessation.


id: cord-355179-wmfwl2bh
author: Jung, Eunhye
date: 2019-06-18
url: https://www.ncbi.nlm.nih.gov/pubmed/31213630/
doi: 10.1038/s41598-019-45095-1
title:
  Neutralization of Acidic Intracellular Vesicles by Niclosamide Inhibits Multiple Steps of the Dengue Virus Life Cycle In Vitro

abstract:
  Dengue fever is one of the most important mosquito-borne viral infections in large parts of tropical and subtropical countries and is a significant public health concern and socioeconomic burden. There is an urgent need to develop antivirals that can effectively reduce dengue virus (DENV) replication and decrease viral load. Niclosamide, an antiparasitic drug approved for human use, has been recently identified as an effective antiviral agent against a number of pH-dependent viruses, including flaviviruses. Here, we reveal that neutralization of low-pH intracellular compartments by niclosamide affects multiple steps of the DENV infectious cycle. Specifically, niclosamide-induced endosomal neutralization not only prevents viral RNA replication but also affects the maturation of DENV particles, rendering them non-infectious. We found that niclosamide-induced endosomal neutralization prevented E glycoprotein conformational changes on the virion surface of flaviviruses, resulting in the release of non-infectious immature virus particles with uncleaved pr peptide from host cells. Collectively, our findings support the potential application of niclosamide as an antiviral agent against flavivirus infection and highlight a previously uncharacterized mechanism of action of the drug.


id: cord-356027-ckdx56j1
title: Association between secondary thrombocytosis and viral respiratory tract infections in children
author: Zheng, Shou-Yan
date: 2016-03-11
txt: ./txt/cord-356027-ckdx56j1.txt
cache: ./cache/cord-356027-ckdx56j1.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/26965460/
doi: 10.1038/srep22964
summary:
  Compared with the normal group, the detection rates of respiratory syncytial virus (RSV) and human rhinovirus (HRV) were significantly higher in the thrombocytosis group (P = 0.017 and 0.042, respectively). Multiplex nested polymerase chain reaction (PCR) was used to detect the following common respiratory viruses, as described previously [11] [12] [13] [14] [15] : RSV subtypes A and B (RSVA, RSVB); influenza virus (IFV) subtypes A, B and C (IFVA, IFVB, IFVC); human coronaviruses (HCoV); metapneumovirus (MPV); parainfluenza virus type 1 to 4 (PIV1-4); adenovirus (ADV); human bocavirus type 1 (HBoV1) and human rhinovirus (HRV) subtypes A and C (HRVA, HRVC). Compared with the normal group, the total detection rates of RSV and HRV were both significantly higher (P = 0.001 and 0.033, respectively) in the thrombocytosis group, and ADV and IFV were lower (P = 0.001 and 0.007, respectively). ST was especially common in patients with lower respiratory tract infections and occurred most frequently in the mild thrombocytosis group (500-699 × 10 9 /L).

abstract:
  Secondary thrombocytosis (ST) is frequently observed in children with a variety of clinical conditions. The leading cause of ST is respiratory tract infection (RTI) in children. Nasopharyngeal aspirate samples were collected and assessed for common respiratory viruses. The relationships between virus infections and secondary thrombocytosis were analyzed retrospectively. The blood platelet count and the presence of respiratory viruses were determined for 3156 RTI patients, and 817 (25.9%) cases with platelet ≥500 × 10(9)/L were considered as the thrombocytosis group. Compared with the normal group, the detection rates of respiratory syncytial virus (RSV) and human rhinovirus (HRV) were significantly higher in the thrombocytosis group (P = 0.017 and 0.042, respectively). HRV single infection was a risk factor associated with thrombocytosis [odds ratio (OR) = 1.560, 95% confidence interval (CI) = 1.108–2.197]. Furthermore, ST was more likely to occur in younger patients who had clinical manifestations of wheezing and dyspnea and who had been diagnosed with bronchiolitis. Furthermore, the course of disease lasted longer in these patients. ST is associated with viral respiratory tract infections, especially RSV and HRV infections. HRV single infection is a risk factor associated with thrombocytosis.


