Summary of your 'study carrel' ============================== This is a summary of your Distant Reader 'study carrel'. The Distant Reader harvested & cached your content into a collection/corpus. It then applied sets of natural language processing and text mining against the collection. The results of this process was reduced to a database file -- a 'study carrel'. The study carrel can then be queried, thus bringing light specific characteristics for your collection. These characteristics can help you summarize the collection as well as enumerate things you might want to investigate more closely. This report is a terse narrative report, and when processing is complete you will be linked to a more complete narrative report. Eric Lease Morgan Number of items in the collection; 'How big is my corpus?' ---------------------------------------------------------- 33 Average length of all items measured in words; "More or less, how big is each item?" ------------------------------------------------------------------------------------ 6029 Average readability score of all items (0 = difficult; 100 = easy) ------------------------------------------------------------------ 44 Top 50 statistically significant keywords; "What is my collection about?" ------------------------------------------------------------------------- 31 RAS 11 Ang 11 ACE2 9 SARS 6 COVID-19 4 angiotensin 3 ace 2 covid-19 2 CoV-2 2 ANG 2 ACE-2 2 ACE 1 sex 1 senescence 1 renin 1 ras 1 podocyte 1 patient 1 injury 1 drug 1 cell 1 bone 1 at2 1 at1 1 VSMC 1 SASP 1 Receptor 1 Ras 1 Protein 1 PRR 1 PDR3 1 ORX 1 NEP 1 Kinase 1 Insulin 1 HXT11 1 Golgi 1 GBM 1 Angiotensin 1 Ang-(1 1 Activation 1 ARB 1 AII 1 ACEI 1 ACE1 1 61L Top 50 lemmatized nouns; "What is discussed?" --------------------------------------------- 1294 angiotensin 1251 receptor 1050 cell 807 patient 660 disease 651 protein 643 renin 633 effect 629 study 599 enzyme 588 system 576 expression 498 role 455 inhibitor 422 lung 414 gene 398 level 375 mouse 368 activity 365 hypertension 363 tissue 363 rat 336 injury 325 pathway 310 infection 310 activation 309 function 301 ace 296 factor 289 type 280 blood 278 risk 277 coronavirus 265 response 261 mechanism 258 kidney 257 virus 257 % 255 treatment 253 brain 251 membrane 246 drug 240 inflammation 230 r 226 pressure 225 group 224 model 220 heart 195 use 194 mortality Top 50 proper nouns; "What are the names of persons or places?" -------------------------------------------------------------- 1165 ACE2 1050 RAS 1030 II 889 Ang 747 SARS 452 COVID-19 413 CoV-2 361 al 293 ACE 276 et 245 . 234 Angiotensin 192 podocyte 188 ras 163 CoV 141 Fig 118 ACE-2 114 AngII 113 AT 110 ANG 105 Ang-(1 102 ARB 95 I 93 C 92 China 91 DN 83 Mas 83 ACEI 74 NEP 74 ARDS 71 angiotensinogen 70 Kinase 68 AT1 67 podocytes 66 AT1R 62 losartan 62 Wuhan 60 TGF 60 III 59 ROS 58 mRNA 58 Protein 56 TMPRSS2 52 Receptor 52 IV 51 Coronavirus 48 angiotensin 45 K 45 CVD 45 AGT Top 50 personal pronouns nouns; "To whom are things referred?" ------------------------------------------------------------- 443 it 221 we 136 i 91 they 29 them 9 us 7 you 7 itself 6 themselves 6 one 4 he 2 endothelin-1 2 atp6ap2 1 phiscada 1 ours 1 mg 1 gln37?ile Top 50 lemmatized verbs; "What do things do?" --------------------------------------------- 5017 be 1152 have 536 increase 516 induce 490 convert 358 show 316 mediate 281 associate 273 include 269 reduce 251 use 237 bind 232 activate 223 suggest 212 regulate 210 lead 193 report 193 express 188 inhibit 182 cause 163 signal 156 compare 153 relate 152 demonstrate 151 promote 150 result 143 do 142 involve 142 decrease 126 play 126 find 122 provide 114 contribute 108 target 105 identify 103 require 101 circulate 100 prevent 100 know 98 indicate 97 stimulate 97 produce 93 develop 92 attenuate 92 affect 91 enhance 90 base 86 act 85 treat 85 infect Top 50 lemmatized adjectives and adverbs; "How are things described?" --------------------------------------------------------------------- 490 also 470 - 456 not 384 high 344 human 291 renal 276 severe 271 vascular 270 clinical 264 such 258 cardiovascular 242 acute 236 other 234 more 231 inflammatory 214 respiratory 206 viral 200 cardiac 199 covid-19 194 diabetic 193 however 189 pulmonary 175 endothelial 174 well 173 anti 168 low 156 therapeutic 152 novel 151 only 147 important 145 further 139 specific 136 critical 133 hypertensive 132 thus 132 new 132 glomerular 130 potential 129 immune 124 non 120 significant 120 cellular 118 local 117 early 116 several 116 active 114 functional 112 as 111 significantly 108 many Top 50 lemmatized superlative adjectives; "How are things described to the extreme?" ------------------------------------------------------------------------- 36 most 15 least 13 high 8 Most 5 low 4 great 4 good 3 simple 3 late 2 large 2 bad 1 weighs~1.5 1 strong 1 severe 1 safe 1 old 1 mTORC2 1 hexose 1 early 1 -t Top 50 lemmatized superlative adverbs; "How do things do to the extreme?" ------------------------------------------------------------------------ 55 most 5 least 2 well 1 highest Top 50 Internet domains; "What Webbed places are alluded to in this corpus?" ---------------------------------------------------------------------------- 3 orcid.org 2 doi.org 1 www.ncbi.nlm.nih.gov 1 www.medicalillustration.com.au 1 www.cancer.org 1 www.who.int.ictrp 1 creat 1 biogps.org Top 50 URLs; "What is hyperlinked from this corpus?" ---------------------------------------------------- 1 http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=1636 1 http://www.medicalillustration.com.au/ 1 http://www.cancer.org/cancer/ 1 http://www.WHO.int.ictrp 1 http://orcid.org/0000-0003-3843-4173 1 http://orcid.org/0000-0001-5944-6718 1 http://orcid.org/0000-0001-5444-4895 1 http://doi.org/10.5256/f1000research.27922.r67707 1 http://doi.org/10.1016/B978-0-12-820472-6.00002-5 1 http://creat 1 http://biogps.org Top 50 email addresses; "Who are you gonna call?" ------------------------------------------------- 1 research@f1000.com 1 frej.fyhrquist@helsinki.fi Top 50 positive assertions; "What sentences are in the shape of noun-verb-noun?" ------------------------------------------------------------------------------- 80 angiotensin converting enzyme 7 ace2 expressing cells 6 ace2 is also 6 receptor binding domain 3 covid-19 is not 3 patients was significantly 3 ras is also 3 ras signaling pathway 3 studies did not 3 study did not 2 ace2 converts ang 2 ace2 is critical 2 ace2 is not 2 ace2 is sufficient 2 ace2 is well 2 ace2 is widely 2 cells expressing ace2 2 disease were more 2 diseases are still 2 diseases including hypertension 2 effect was not 2 effects including vasoconstriction 2 expression did not 2 expression has not 2 gene do not 2 genes were able 2 ii increases vascular 2 ii induced proteolytic 2 ii induces apoptosis 2 ii induces smooth 2 ras are present 2 ras is highly 2 ras regulates much 2 rats reduces blood 2 rats were randomly 2 receptor mediates skeletal 2 receptor signaling pathway 2 receptor signaling pathways 2 receptor was also 2 renin expressing cells 2 tissues using clinical 1 ace2 activating agents 1 ace2 are also 1 ace2 are proteolytically 1 ace2 converts aii 1 ace2 converts angiotensin 1 ace2 does not 1 ace2 expressing glomerular 1 ace2 expressing tissues 1 ace2 has also Top 50 negative assertions; "What sentences are in the shape of noun-verb-no|not-noun?" --------------------------------------------------------------------------------------- 1 cells are not able 1 covid-19 is not clear 1 covid-19 is not traditional 1 disease is not clearly 1 effects have not yet 1 expression do not always 1 expression has not yet 1 expression is not completely 1 patients increased not only 1 podocyte has no proliferative 1 ras are not yet 1 studies did not adequately 1 studies showing no detriment 1 system has not yet A rudimentary bibliography -------------------------- id = cord-322966-o65fo853 author = Arnold, Ruth H. title = COVID-19 – Does This Disease Kill Due to Imbalance of the Renin Angiotensin System (RAS) Caused by Genetic and Gender Differences in the Response to Viral ACE 2 Attacks? date = 2020-05-25 keywords = ACE-2; COVID-19; RAS summary = title: COVID-19 – Does This Disease Kill Due to Imbalance of the Renin Angiotensin System (RAS) Caused by Genetic and Gender Differences in the Response to Viral ACE 2 Attacks? ABSTRACT Debate continues in the medical literature on the role of the renin angiotensin system (RAS) in Coronavirus disease 2019 (COVID-19) pathophysiology and the implications for the use of cardiovascular drugs acting on the RAS. Debate continues in the medical literature on the role of the renin angiotensin system (RAS) in Coronavirus disease 2019 (COVID19) pathophysiology and the implications for the use of cardiovascular drugs acting on the RAS. Debate has arisen due to the finding that underlying cardiovascular disease and hypertension are associated with significantly increased risk of hospitalisation and death in COVID-19 [1, 2] , in addition to the viral receptor being angiotensin-converting enzyme-2 (ACE-2) [3 -5] . Association of renin-angiotensin system inhibitorswith severity or risk of death in patients with hypertension hospitalised for coronavirus disease 19 (COVID-19) infection in Wuhan, China doi = 10.1016/j.hlc.2020.05.004 id = cord-280662-gakayv6e author = Bian, Jingwei title = Angiotensin-converting enzyme 2 (ACE2): SARS-CoV-2 receptor and RAS modulator date = 2020-10-13 keywords = ACE2; CoV-2; RAS; SARS summary = Angiotensin-converting enzyme 2 (ACE2) was rapidly identified as the critical functional receptor for SARS-CoV-2. Given that ACE2 functions as both a SARS-CoV-2 receptor and a RAS modulator, the treatment for COVID-19 presents a dilemma of how to limit virus entry but protect ACE2 physiological functions. We propose five novel working modes for functional receptor for SARS-CoV-2 infection and the routes of ACE2-mediated virus entering host cells, as well as its regulatory mechanism. SARS-CoV-2 has been shown to share the same functional receptor, angiotensin-converting enzyme 2 (ACE2), with severe acute respiratory syndrome coronavirus (SARS-CoV) 4, 5 . SARS-CoV S-protein binding facilitates ADAM17-dependent ACE2 shedding and has been shown to induce viral entry into the cell 52 . Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2) doi = 10.1016/j.apsb.2020.10.006 id = cord-006737-7h8vvim7 author = Chen, Xiang-Fan title = Inhibition on angiotensin-converting enzyme exerts beneficial effects on trabecular bone in orchidectomized mice date = 2018-02-07 keywords = ORX; RAS; bone summary = BACKGROUND: This study aimed to study the osteo-preservative effects of captopril, an inhibitor on angiotensin-converting enzyme (ACE), on bone mass, micro-architecture and histomorphology as well as the modulation of captopril on skeletal renin-angiotensin system (RAS) and regulators for bone metabolism in mice with bilateral orchidectomy. The mRNA expressions of renin receptor, angiotensinogen, carbonic anhydrase II, matrix metalloproteinase-9, and tumor necrosis factor-alpha were significantly decreased in tibia of ORX mice following treatment with captopril. This study demonstrated that the treatment with captopril effectively attenuated the orchidectomy-induced pathological alterations of micro-structure of trabecular bone at lumbar vertebra (LV)-4, distal metaphysis of femur and proximal metaphysis of tibia as observed by histological staining, moreover, bone mineral density (BMD) at both LV-2 and LV-5 was significantly enhanced in ORX mice in response to captopril treatment for 6 weeks. This study demonstrated that captopril effectively reversed orchidectomy-induced down-regulation of B1R protein expression in mice, indicating that bradykinin receptor was involved in management of captopril on bone metabolism in ORX mice. doi = 10.1016/j.pharep.2018.02.008 id = cord-317878-bqpj0ey0 author = Czick, Maureen title = COVID’s Razor: RAS Imbalance, the Common Denominator Across Disparate, Unexpected Aspects of COVID-19 date = 2020-09-11 keywords = ACE2; AII; RAS; ace; angiotensin; at1; at2; covid-19 summary = Silent hypoxia, atypical acute respiratory distress syndrome (ARDS), stroke, olfactory loss, myocarditis, and increased mortality rates in the elderly, in men, in African-Americans, and in patients with obesity, diabetes, and cancer—all bear the fingerprints of the renin-angiotensin system (RAS) imbalance, suggesting that RAS is the common culprit. Subpopulations manifesting higher rates of COVID-19 mortality-including hypertensives, the elderly, the obese, diabetics, men, and African-Americans-correlate with preexisting RAS imbalance, with ACE overactivity and/or ACE2 underactivity priming these patients for more severe COVID-19 outcomes. 159 Males generally have higher levels of RAS than premenopausal females, 160 perhaps explaining why male hypertensive rats show a greater blood pressure decrease with ACEIs. 161 Estrogen downregulates the expression of the AT1 gene 162, 163 and suppresses both ROS production in vascular smooth muscle and the enzymatic activity of ACE. doi = 10.2147/dmso.s265518 id = cord-303555-mwu72q7w author = Dent, Paul title = Cell Signaling and Translational Developmental Therapeutics date = 2020-10-06 keywords = Activation; Insulin; Kinase; Protein; RAS; Receptor; cell; drug summary = Thus, by the mid-to late-1980s a large body of literature existed which argued that signal transduction pathways consisted of a receptor linked to a large GTP-binding protein which in turn regulated an enzyme that generated "second messengers;" the second messengers would then diffuse throughout the cytosol activating cellular processes, predominantly for metabolism. For the EGFR and other subsequently discovered membrane associated tyrosine kinases, e.g. the non-receptor SCR family and the fibroblast growth factor receptor (FGFR) family, understanding how these enzymes signaled into the cell again initially rested on studies using traditional biochemical methods. [71] [72] [73] [74] [75] [76] Contemporaneously with these studies, researchers were determining how receptor tyrosine kinases regulated RAS family small GTP binding proteins, and other groups determining how RAS proteins signaled downstream off the plasma membrane and into the cytosol. doi = 10.1016/b978-0-12-820472-6.00002-5 id = cord-257558-dgnbfzli author = Diamond, Betty title = The renin–angiotensin system: An integrated view of lung disease and coagulopathy in COVID-19 and therapeutic implications date = 2020-06-18 keywords = ACE2; RAS summary = ACE2 cleaves angiotensin II to produce a small peptide, ang1-7, which binds to a G protein-coupled receptor Mas to induce an anti-inflammatory and anti-apoptotic program and vasodilation (Simões e Silva et al., 2013) . When the viral spike protein binds ACE2, however, another protease termed TACE, or ADAM 17, is activated; this causes ACE2 to be shed from the cell membrane, leading to decreased degradation of angiotensin II and decreased production of ang1-7 (Shah and Catt, 2006) . A model of COVID-19 might be that SARS-CoV-2 infects lung alveolar epithelial cells, the source of surfactant, causing a cytopathic effect. First, COVID-19 patients will have a high level of angiotensin II, perhaps even African Americans, and a low level of ang1-7 due to the diminished activity of ACE2. Right: In a SARS-CoV-2-infected individual, there is an imbalanced RAS, with viral spike protein causing ACE2 shedding, diminished production of ang1-7, and high AT1 with low AT2. doi = 10.1084/jem.20201000 id = cord-001961-0ic7twhy author = Ding, Dan title = Vaccination against type 1 angiotensin receptor prevents streptozotocin-induced diabetic nephropathy date = 2015-09-26 keywords = Ang; RAS summary = In addition to lower blood pressure, ATRQβ-001 vaccination ameliorated biochemical parameter changes of renal dysfunction, mesangial expansion, and fibrosis through inhibiting oxidative stress, macrophage infiltration, and proinflammatory factor expression. Furthermore, ATRQβ-001 vaccination suppressed renal Ang II-AT1R activation and abrogated the downregulation of angiotensin-converting enzyme 2-Ang (1–7), similar to olmesartan treatment, while no obvious feedback activation of circulating or local renin-angiotensin system (RAS) was only observed in vaccine group. In conclusion, the ATRQβ-001 vaccine ameliorated streptozotocin-induced diabetic renal injury via modulating two RAS axes and inhibiting TGF-β1/Smad3 signal pathway, providing a novel, safe, and promising method to treat diabetic nephropathy. Recently, we developed a therapeutic hypertensive vaccine ATRQβ-001, a peptide (ATR-001) derived from human Ang II receptor type 1 (AT1R) conjugated with Qβ bacteriophage virus-like particles, which decreased the blood pressure of hypertensive animals effectively through diminishing the pressure response and inhibiting signal transduction initiated by Ang II with no obvious feedback activation of circulating or local RAS [11] . doi = 10.1007/s00109-015-1343-6 id = cord-313664-qq0h68vc author = Fyhrquist, F. title = Renin‐angiotensin system revisited date = 2008-08-08 keywords = ACE2; Ang; RAS summary = The classical RAS as it looked in the middle 1970s consisted of circulating renin, acting on angiotensinogen to produce angiotensin I, which in turn was converted into angiotensin II (Ang II) by angiotensin‐converting enzyme (ACE). The importance of RAS in cardiovascular disease has been demonstrated by the clinical benefits of ACE inhibitors and AT1 receptor blockers. It was not until the discovery of orally effective angiotensin-converting enzyme (ACE) inhibitors, the first of which was captopril [2] , that the paramount importance of RAS in cardiovascular homeostasis and disease was being appreciated. Angiotensin-converting enzyme 2 and Ang 1-7 may play an important role in cardiovascular physiology and pathophysiology, e.g. by modulating or counterbalancing excess activity of the ''classical'' RAS [45, 46] . Angiotensin-converting enzyme inhibitors and ARBs (Fig. 5) are well established corner stones in the prevention and treatment of hypertension and cardiovascular disease, as demonstrated by numerous clinical trials and world wide clinical practice. doi = 10.1111/j.1365-2796.2008.01981.x id = cord-289905-dvl2pud2 author = Gan, Rosemary title = COVID-19 as a Viral Functional ACE2 Deficiency Disorder with ACE2 Related Multi-organ Disease date = 2020-06-23 keywords = ACE2; COVID-19; RAS; SARS summary = Appreciating the clear differences between SARS and COVID-19 in presentation, poor prognostic indicators related to individuals'' co-morbid status, and biochemical and radiologic profiles, a novel disease model may assist in: 1) the early recognition of atypical (non-respiratory) presentations of disease; 2) early prophylactic treatment intervention for individuals at risk of severe and critical disease which could take place 6 in the community; 3) revised management of pulmonary complications including those related to prone posturing and ventilation protocols; 4) allowing better utilisation of data collated at a global level in the absence of an evidence-based disease model at this time; 5) identification of different markers of disease progression in at-risk individuals. An upregulation of ACE2 expressing cells related to chronic ATII elevation [18] or treatment with ACEinhibitors [19] , may increase the infective potential of SARS-CoV-2 in this group as a consequence of the duality of ACE2 functioning as both a receptor for viral entry to cells and as an enzyme. doi = 10.1016/j.mehy.2020.110024 id = cord-318327-9sh2eksm author = Garg, M. title = Review article: the pathophysiological roles of the renin–angiotensin system in the gastrointestinal tract date = 2012-01-05 keywords = ACE; Ang; RAS; angiotensin summary = Animal studies investigating the effects of RAS blockade in a range of conditions including inflammatory bowel disease, functional gut disorders, gastrointestinal malignancy and even intestinal ischaemia have been encouraging to date. Animal studies investigating the effects of RAS blockade in a range of conditions including inflammatory bowel disease, functional gut disorders, gastrointestinal malignancy and even intestinal ischaemia have been encouraging to date. The contemporary view of the RAS has evolved from that of a simple linear pathway involving the conversion of angiotensinogen to angiotensin II (Ang II) via a two-step process facilitated by renin and angiotensin converting enzyme (ACE), to a much more complex system involving homologues of ACE and multiple angiotensin peptides which play supplementary and counter-regulatory roles ( Figure 1 ). Angiotensin converting enzyme inhibition or angiotensin receptor antagonism have been shown to produce a number of beneficial anti-inflammatory effects in rodent models of intestinal inflammation. doi = 10.1111/j.1365-2036.2011.04971.x id = cord-326498-8oa5gkrp author = Gemmati, Donato title = COVID-19 and Individual Genetic Susceptibility/Receptivity: Role of ACE1/ACE2 Genes, Immunity, Inflammation and Coagulation. Might the Double X-Chromosome in Females Be Protective against SARS-CoV-2 Compared to the Single X-Chromosome in Males? date = 2020-05-14 keywords = ACE1; ACE2; COVID-19; RAS; SARS; sex summary = Firstly, SARS-CoV-2 has a strong interaction with the human ACE2 receptor, which plays an essential role in cell entry together with transmembrane serine protease 2 (TMPRSS2); it is interesting to note that the ACE2 gene lays on the X-chromosome, thus allowing females to be potentially heterozygous and differently assorted compared to men who are definitely hemizygous. Therefore, proper ACE2 functionality is essential for both virus cell entry and local pulmonary homeostasis, and although it has been previously described that polymorphisms in the ACE2 gene do not affect the outcome of SARS [43] , females might have a higher degree of heterodimer assembling than males, which in turn might show different affinity for the SARS-CoV-2 spike receptor. Therefore, proper ACE2 functionality is essential for both virus cell entry and local pulmonary homeostasis, and although it has been previously described that polymorphisms in the ACE2 gene do not affect the outcome of SARS [43] , females might have a higher degree of heterodimer assembling than males, which in turn might show different affinity for the SARS-CoV-2 spike receptor. doi = 10.3390/ijms21103474 id = cord-344012-npob20n0 author = Gheblawi, Mahmoud title = Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2 date = 2020-05-08 keywords = ACE2; Ang; COVID-19; RAS; SARS; angiotensin summary = ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system, facilitator of amino acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the renin-angiotensin system, together with implications for the coronavirus disease 2019 pandemic and associated cardiovascular diseases. 21, 22 Ongoing global efforts are focused on manipulating the ACE2/Ang 1-7 axis to curtail SARS-CoV-2 infection while affording maximal protective effects against lung and cardiovascular damage in patients with In this review, we summarize the diverse roles of ACE2, highlighting its role as the SARS-CoV-2 receptor and negative regulator of the RAS, and the implications for the COVID-19 pandemic. doi = 10.1161/circresaha.120.317015 id = cord-002632-6he8sjpf author = Goldstein, Benjamin title = Alterations in Gene Expression of Components of the Renin-Angiotensin System and Its Related Enzymes in Lung Cancer date = 2017-07-16 keywords = Ang; RAS summary = There were a number of profound differences in the expression of the genes encoding the proteins comprising and closely associated with the renin-angiotensin system (RAS), between normal lung tissue and the lung tumor tissue (Figures 1 and 2 and Table 2 ). The gene expression for both Ang II receptor subtypes was dramatically reduced, 69 and 74%, respectively, ( Figure S1 ), for AT 1 and AT 2 in the lung tumor tissue ( < 0.01, corrected for multiple comparisons, Table 2 ). ACE, the gene that encodes the enzyme that converts the inactive precursor angiotensin I (Ang I) to the active hormone, Ang II, was expressed at a lower level and its expression was reduced by about half in the lung tumor tissue ( < 0.01 corrected for multiple comparisons Table 2 ). doi = 10.1155/2017/6914976 id = cord-277766-rxmpi61o author = Guang, Cuie title = Three key proteases – angiotensin-I-converting enzyme (ACE), ACE2 and renin – within and beyond the renin-angiotensin system date = 2012-06-15 keywords = ACE2; Ang; RAS; ace; angiotensin; renin summary = In a classical RAS, the substrate angiotensinogen (AGT), which is released into the circulation from the liver, is degraded by the enzyme renin that originates in the kidney, generating the inactive angiotensin I (Ang I). The initial drug development of clinical ACE inhibitors was based on the assumption of an active site related to that of carboxypeptidase A but organized to remove a dipeptide rather than a single amino acid from the Cterminus of its substrate. The protective role of XNT against hypertension-induced cardiac fibrosis is associated with activation of ACE2, increases in Ang-(1-7) and inhibition of extracellular signal-regulated kinases [83] . The hemoregulatory peptide N-acetyl-Ser-Asp-Lys-Pro is a natural and specific substrate of the N-terminal active site of human angiotensinconverting enzyme The N-terminal active centre of human angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide Angiotensin-converting enzyme 2 activation protects against hypertension-induced cardiac fibrosis involving extracellular signal-regulated kinases doi = 10.1016/j.acvd.2012.02.010 id = cord-352854-che3iwu3 author = Hart, Kristen C title = Derivatives of activated H-ras lacking C-terminal lipid modifications retain transforming ability if targeted to the correct subcellular location date = 1997-12-18 keywords = 61L; Golgi; ras summary = However, when examined in focus formation assays, transformation of NIH3T3 cells were seen with derivatives of ras(61L) containing a mutated E1 targeting sequence that results in plasma membrane localization. These results demonstrate that: (1) activated ras targeted to Golgi membranes is unable to cause transformation; (2) lipid modifications at the C-terminus are not required for the transforming activity of plasma membrane-anchored ras(61L) derivatives, and serve primarily a targeting function; (3) a transmembrane domain can effectively substitute for C-terminal modifications that would normally target ras to the inner surface of the plasma membrane, indicating that ras(61L) does not need to reversibly dissociate from the membrane as might be allowed by the normal lipidation; and (4) in order to function properly, there exists a critical distance that the ras protein must reside from the plasma membrane. doi = 10.1038/sj.onc.1200908 id = cord-324364-9p04oeac author = Hasan, Syed Shahzad title = Mortality and Disease Severity Among COVID-19 Patients Receiving Renin-Angiotensin System Inhibitors: A Systematic Review and Meta-analysis date = 2020-09-12 keywords = ACEI; ARB; COVID-19; RAS summary = Original, observational (prospective or retrospective) studies Included patients with coronavirus disease 2019 (COVID19) Documented use of either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) Reported frequency, percentage, and/or adjusted estimate of mortality or disease severity and/or adverse clinical outcomes (septic shock, admission to intensive care units) associated with COVID-19 From any region or language The reported odds ratios (ORs) and hazard ratios (HRs) that had been adjusted for potential covariates in the respective original studies and the corresponding 95% confidence intervals (CIs) were extracted and pooled in a random-effects model to estimate the association between the use of ACEIs/ ARBs and the risk of mortality and severe/critical illness in COVID-19 patients. In fact, the other studies [52, 78, 80, 84] included in the subgroup pooled analysis reported no difference in the risk of severe/ critical illness with the use of ACEIs compared to non-use of the ACEIs. A key strength of this systematic review and meta-analysis was the pooling of adjusted estimates on the mortality and severe/critical outcomes from the use of RAS inhibitors in COVID-19 patients. doi = 10.1007/s40256-020-00439-5 id = cord-335076-mmpox655 author = Izumi, Yasukatsu title = Angiotensin II Peptides date = 2013-03-01 keywords = Ang; RAS summary = Ang II, via the Ang II type 1 receptor, directly causes cellular phenotypic changes and cell growth, regulates the gene expression of various bioactive substances, and activates multiple intracellular signaling cascades in cardiac myocytes and fibroblasts, as well as vascular endothelial and smooth muscle cells. Recently, new factors have been discovered, such as angiotensin-converting enzyme 2, angiotensin-(1-7), and its receptor Mas. This section summarizes the current knowledge about the broad RAS in the pathophysiology of cardiac hypertrophy and remodeling, heart failure, vascular thickening, and atherosclerosis. Ang II infusion stimulated aortic thrombin receptor mRNA expression in rats, which was blocked by either ARB or the heparin-binding chimera of human Cu/Zn superoxide dismutase but not by normalization of blood pressure with hydralazine treatment, suggesting that Ang II increases vascular thrombin receptor by AT 1 R-mediated superoxide production and may be implicated in the pathophysiology of atherosclerosis by thrombin cascade activation. doi = 10.1016/b978-0-12-385095-9.00186-x id = cord-010329-rcx450b6 author = Khazak, Vladimir title = Development of a Yeast Two-Hybrid Screen for Selection of Human Ras-Raf Protein Interaction Inhibitors date = 2005 keywords = HXT11; PDR3; Ras summary = The methods outlined below describe (1) the construction of expression plasmids bearing conditionally regulated yeast HXT9 and HXT11 hexose transporter genes, (2) integration of HXT9-and HXT11-containing DNA fragments in the PDR1 and PDR3 chromosomal loci of yeast two-hybrid strains, (3) analysis of the permeability of newly developed yeast strains with selected known smallmolecule inhibitors, and by screen of a large combinatorial library of compounds, and (4) selection of inhibitors of the interaction between human Ras and Raf-1 by screening the combinatorial library of compounds in the obtained hyperpermeable yeast two-hybrid strain. cerevisiae to small-molecular-weight compounds, the two yeast hexose transporters HXT9 and HXT11 were subcloned under control of the galactose-inducible GAL1 promoter and subsequently integrated by homologous recombination into the genetic loci for PDR1 and PDR3, thereby destroying the coding sequence of these genes. The plasmid pPDR3-HisInt was digested with AatII-SacI and the purified integrative cassette, hisG-URA3-PDR3-Int (see Fig. 2C ) was transformed into parental strains SKY48 and SKY191. doi = 10.1007/978-1-59259-948-6_18 id = cord-007707-c38fu1jv author = Lu, Chen-Chen title = Role of Podocyte Injury in Glomerulosclerosis date = 2019-06-19 keywords = Ang; GBM; RAS; injury; podocyte summary = Increased intracellular glucose could induce multiple cell and molecular events in podocyte: (1) generation of reactive oxygen species (ROS) and advanced glycation end products (AGEs), (2) increased flux of polyols and hexosamines, (3) activation of protein kinase C (PKC), (4) increased cytokines and growth factors, (5) aberrant Notch signaling, and (6) activate the renal RAS. High glucose induces generation of advanced glycation end products (AGEs) and reactive oxygen species (ROS), increased flux of polyols and hexosamines, increased activity of protein kinase C (PKC), upregulated expression of cytokines and growth factors including vascular endothelial growth factor (VEGF), and transforming growth factor-beta (TGF-β), induces aberrant Notch signaling, and activates the renal RAS (Anil Kumar et al. (2013) findings elaborated that Rac1/PAK1 signaling contributed to high glucose-induced podocyte EMT via promoting β-catenin and Snail transcriptional activities, which could be a potential mechanism involved in podocytes injury in response to stimuli under diabetic conditions. doi = 10.1007/978-981-13-8871-2_10 id = cord-012837-fuwp08qt author = Lu, Chen-chen title = Gut microbiota dysbiosis-induced activation of the intrarenal renin–angiotensin system is involved in kidney injuries in rat diabetic nephropathy date = 2020-03-17 keywords = RAS summary = Therefore, we speculated that in the development of diabetes, the gut microbiota was likely to produce excessive SCFAs, especially acetate, which could bind to renal-related signal receptors, thus activating intrarenal RAS and mediating the early pathophysiological processes of DN. The immunofluorescence staining results also showed significantly decreased expression of glomerular podocyte-specific protein WT-1 and nephrin in the DM group compared with that in the control group, which was relatively recovered in the DM + AB group (Fig. 5e-g) , suggesting that unbalanced gut microbiota might be a key factor resulting in injuries to the glomerular filtration membrane in early DN. The Western blot results to evaluate the degree of intrarenal RAS activation showed that compared with the control group, the protein expression of ACE, Ang II, and AT1R in the kidney of the DM group was significantly increased, and antibiotic treatment showed a suppressing effect on these three RAS-activating indicators (Fig. 6d, e) . doi = 10.1038/s41401-019-0326-5 id = cord-311099-59pnm4fn author = Lubel, John S title = Liver disease and the renin–angiotensin system: Recent discoveries and clinical implications date = 2008-06-28 keywords = ACE; Ang; Ang-(1; RAS summary = Drug therapies targeting the RAS by inhibiting Ang II formation (ACE inhibitors) or binding to its receptor (angiotensin receptor blockers) are now in widespread clinical use and have been shown to reduce tissue injury and fibrosis in cardiac and renal disease independently of their effects on blood pressure. Interestingly, ACE inhibitors and angiotensin receptor blockers increase Ang‐(1–7) production and it has been proposed that some of the beneficial effects of these drugs are mediated through upregulation of Ang‐(1–7) rather than inhibition of Ang II production or receptor binding. 42 A great deal of evidence supporting the role of the RAS in hepatic fibrosis has come from animal studies using ACE inhibitors and angiotensin receptor blockers (ARB). A pilot study examining the effects of 6 months of losartan treatment on liver fibrosis in chronic hepatitis C demonstrated a significant decrease in fibrosis stage in the treated group compared to control patients. doi = 10.1111/j.1440-1746.2008.05461.x id = cord-269289-6uog10j4 author = Mabillard, Holly title = Electrolyte Disturbances in SARS-CoV-2 Infection date = 2020-07-22 keywords = CoV-2; RAS; SARS; patient summary = These include additional respiratory complications (pulmonary fibrosis -reported in 21% of those hospitalised with SARS-CoV-2 9 months post-discharge in one study 3 ) 7 , cardiovascular complications (acute cardiac injury (7% 8 ), cardiomyopathy (1/3 patients 9 ), cardiac tamponade, heart failure, dysrhythmias (17% 8 ) and venous thromboembolic events (20% 10 )) 11 , neurological complications (myopathy, acute stroke (5.7% of those with severe infection 12 ), Guillain-Barre syndrome (0.4% hospitalised patients 11 ) and encephalopathy) 13 , acute liver and/or pancreatic injury (29% and 17% respectively in one cohort) 14 , cytokine storm syndrome, septic shock, DIC, diarrhoea, Kawasaki-like disease 14 and renal complications (acute tubular injury, rhabdomyolysis, proteinuria, secondary focal segmental glomerulosclerosis and possible renin-angiotensinaldosterone system activation) 15 . The study reported that the degree of hypokalaemia correlated with severity of SARS-CoV-2 symptoms and they suggested that hypokalaemia can be difficult to correct as seen in two patients because the renal potassium wasting persists until clinical recovery from the virus. doi = 10.12688/f1000research.24441.2 id = cord-351875-e4aw7gkd author = Messerli, Franz H. title = COVID-19 and Renin Angiotensin Blockers: Current Evidence and Recommendations date = 2020-04-13 keywords = RAS summary = B oth angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have repeatedly, but not consistently, been documented to slow progression of pulmonary complications in vulnerable patients. 1 These seemingly beneficial findings of renin angiotensin system (RAS) blockade on outcomes in pneumonia resurfaced in the recent literature in relation to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease 2019 (COVID-19), infection. Presently, there are no data regarding a favorable effect of RAS blockade on pulmonary outcome in SARS-CoV-2-infected patients. Direct renin inhibitors ACE indicate angiotensin-converting enzyme; ACEI, angiotensin-converting enzyme inhibitor; ALI, acute-lung injury; ARB, angiotensin II receptor blocker; AT1, angiotensin 1; PCR, polymerase chain reaction; RAS, renin-angiotensin system; RSV, respiratory syncytial virus; and SARS-CoV, severe acute respiratory syndromecoronavirus. There is inconsistent evidence to suggest that RAS blockers exert a favorable effect on pulmonary outcome in viral pneumonia, but no data are available specifically for SARS-CoV-2-infected patients. doi = 10.1161/circulationaha.120.047022 id = cord-349445-yh6ndtgm author = Mohammed El Tabaa, Manar title = Targeting Neprilysin (NEP) pathways: A potential new hope to defeat COVID-19 ghost date = 2020-05-27 keywords = ACE-2; Ang; Angiotensin; COVID-19; NEP; RAS; SARS summary = Therefore, researchers suggested that the use of angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs), may show a positive trend towards the severe inflammatory reactions and endothelial dysfunction caused by stimulating the function of ACE/Ang II/AT-1 axis and thereby, towards the bad pulmonary effects associated with the COVID-19 infection [29, 30] . Since IL-6 would inactivate endothelial nitric oxide synthase (eNOS), it could disrupt NO production [90] , decreasing its level and inducing a state of oxidative stress that may lead to Ang II-induced impairment in endothelial responses [91] Postulating impaired endothelium functions as a principal factor in the pathogenesis of heart failure, hypertension and diabetes, it will be expected to classify the patients of such diseases as high risk groups for COVID-19 development [92] [93] [94] . Taken into consideration the numerous harmful effects possibly induced by Ang II during COVID-19 pathogenesis, we found that most novel studies aim to use the anti-hypertensive drugs which act either by inhibiting the ACE activity or by blocking AT1 receptor, suggesting that action may mitigate the disease severity in COVID-19 patients. doi = 10.1016/j.bcp.2020.114057 id = cord-006439-q7m4srvp author = Nakagawa, Pablo title = The Renin-Angiotensin System in the Central Nervous System and Its Role in Blood Pressure Regulation date = 2020-01-10 keywords = ANG; PRR; RAS summary = Central administration of ANG-II elicits potent dipsogenic responses, induces sodium intake, triggers sympathetic outflow to the kidney and other organs, and recently, evidence has established that the brain RAS modulates metabolic function primarily through distinct nuclei within the hypothalamus [14] [15] [16] [17] . In the final section of this article, we will discuss how the development of state-of-the-art technology to study precise molecular signaling and neuronal circuits within the CNS are appropriate to elucidate the key mechanisms regulating generation and action of angiotensin peptides within different neuroanatomical regions. Intracerebroventricular infusion of ACE inhibitor prevents and reverses high blood pressure, demonstrating that production of ANG-II in the brain is required for DOCA-salt hypertension even though circulating RAS activity is suppressed [71] . Therefore, the development of novel drugs modulating the brain RAS might represent an effective solution to treat resistant hypertension coincident with elevated sympathetic activity and suppressed circulating renin activity. doi = 10.1007/s11906-019-1011-2 id = cord-276260-iccaqz8u author = Namsolleck, Pawel title = Does activation of the protective Renin-Angiotensin System have therapeutic potential in COVID-19? date = 2020-08-17 keywords = RAS summary = On the other hand, as part of the Protective Arm of RAS, Ang II also stimulates the angiotensin II type 2 receptor (AT 2 R) and this octapeptide can be further cleaved by the carboxypeptidase ACE2 to yield angiotensin-(1-7) (Ang-(1-7)), an agonist of the Mas receptor (MasR). Here we consider therapeutic perspectives of stable and specific AT 2 R and MasR agonists in The balance between the Detrimental and Protective Arm of RAS is in several aspects seriously disturbed in COVID-19, thus causing a potentially lethal disease (Fig. 1) . Abbreviations RAS: Renin angiotensin system; SARS: Severe acute respiratory syndrome; CoV-2: Coronavirus 2; COVID-19: Coronavirus disease 2019; ARDS: Acute respiratory distress syndrome; AT 2 R: Angiotensin II type 2 receptor; MasR: Mas receptor; ARB: Angiotensin II type 1 receptor blocker; ACE: Angiotensin converting enzyme; ACEi: Angiotensin converting enzyme inhibitor; Ang II: Angiotensin II; Ang-(1-7): Angiotensin-(1-7) doi = 10.1186/s10020-020-00211-0 id = cord-298490-p1msabl5 author = Obukhov, Alexander G. title = SARS-CoV-2 Infections and ACE2: Clinical Outcomes Linked With Increased Morbidity and Mortality in Individuals With Diabetes date = 2020-07-15 keywords = ACE2; Ang; RAS; SARS summary = As suggested by the recent reports regarding the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), upon entry into the host, this virus binds to the extracellular domain of ACE2 in nasal, lung, and gut epithelial cells through its spike glycoprotein subunit S1. In this Perspective, we bring attention to specific factors that may complicate COVID-19 in individuals with diabetes including 1) the presence of bone marrow changes (myeloidosis) that predispose those with diabetes to an excessive proinflammatory response (cytokine storm) and contribute to insulin resistance and reduced vascular repair, and worsening function of the heart, kidney, and systemic vasculature as a whole; 2) increased circulating furin levels that could cleave the spike protein and increase infectivity of SARS-CoV-2; 3) dysregulated autophagy that may promote replication and/or reduce viral clearance; and 4) gut dysbiosis that leads to widespread systemic inflammation, increased gut glucose and sodium absorption, and reduced tryptophan and other key amino acid absorption needed for incretin secretion and glucose homeostasis. doi = 10.2337/dbi20-0019 id = cord-328846-q52fjx99 author = Okuno, Keisuke title = Targeting Molecular Mechanism of Vascular Smooth Muscle Senescence Induced by Angiotensin II, A Potential Therapy via Senolytics and Senomorphics date = 2020-09-09 keywords = RAS; SASP; VSMC; senescence summary = Accordingly, in this review article, we discuss potential molecular mechanisms of VSMC senescence such as those induced by AngII and the therapeutic manipulations of senescence to control age-related CVD and associated conditions such as by senolytic. Accordingly, EGFR, mitochondrial fission/Drp1 and ER stress likely play upstream roles in AngII-induced vascular senescence and SASP thus contributing to RAS-mediated pathophysiology in CVDs (Figure 4) . Mitochondrial fission and ER stress likely play upstream roles in AngII-induced vascular senescence and SASP contributing to RAS-mediated pathophysiology in CVDs. In addition to the molecular mechanisms illustrated in Figure 2 , mitochondrial fission and ER stress are enhanced under chronic RAS activation contributing to VSMC senescence [6] . Mitochondrial fission and ER stress likely play upstream roles in AngII-induced vascular senescence and SASP contributing to RAS-mediated pathophysiology in CVDs. In addition to the molecular mechanisms illustrated in Figure 2 , mitochondrial fission and ER stress are enhanced under chronic RAS activation contributing to VSMC senescence [6] . doi = 10.3390/ijms21186579 id = cord-005931-iggkxbbf author = Phillips, M. Ian title = Brain renin angiotensin in disease date = 2008-04-02 keywords = ANG; RAS; ace summary = Transgenic mice and rats bearing renin and extra copies of angiotensinogen genes revealed the importance of brain RAS. Taking the concept a step further, it was reasoned that if ANG II, formed by brain renin, was involved in hypertension, then inhibiting brain RAS would lower blood pressure. Minute injections of ANG II into key brain nuclei showed that ANG II could differentially produce pressor effects, elicit drinking, release vasopressin, inhibit the baroreflex, and increase sympathetic nervous system activity [20, 21] . In the double transgenic mice developed by Sigmund and colleagues [35] , to overexpress both human renin and human AGT so that they constantly have high ANG II levels, antisense to AT1R mRNA dramatically reduced the blood pressure. ACE-2, ANG (1-7), and Mas receptors are all localized in brain areas related to the control of cardiovascular function. doi = 10.1007/s00109-008-0331-5 id = cord-337511-20yaol5r author = Ryan, Paul MacDaragh title = COVID-19 and relative angiotensin-converting enzyme 2 deficiency: role in disease severity and therapeutic response date = 2020-06-11 keywords = ACE2; RAS; SARS summary = Interestingly, comparative analysis of two successive SARS epidemics in early 2000s showed that increased affinity of the SARS virus for human ACE2 receptor strongly predicted severity of clinical disease suggesting that spike protein conformation is potentially a key determinant of virulence. 15 Interestingly, in several Wuhan cohorts cardiac injury and arrythmia were prominent in high-risk Figure 3 Homeostasis of RAS-ACE2 under normal healthy conditions 10 19 ; perturbation of RAS-ACE2 homeostasis in cardiovascular disease, hypertension and diabetes mellitus 22 27 ; COVID-19 may potentially further upregulate RAS in CVD patients and deplete ACE2 33 ; proposition that rhACE2 replacement therapy improves RAS-ACE2 balance by augmenting ACE2 and decreasing RAS activation. 35 If the same holds true for SARS-CoV-2, then soluble rhACE2 may reduce ongoing SARS-CoV-2 access to membrane-bound ACE2 receptor, alter favourably local AngII/Ang1-7 levels and inhibit deleterious RAS effects on remaining at risk tissues in COVID-19 patients. doi = 10.1136/openhrt-2020-001302 id = cord-317423-3nkzp1z2 author = Turk, Can title = In vitro analysis of the renin–angiotensin system and inflammatory gene transcripts in human bronchial epithelial cells after infection with severe acute respiratory syndrome coronavirus date = 2020-06-03 keywords = ACE2; RAS; SARS summary = RESULTS: The whole-genome expression data of the lung epithelial cells infected with SARS-CoV for 12, 24, and 48 hours were analyzed, and a total of 15 RAS family and 29 immune genes were found to be highly correlated with the exposure time to the virus in the studied groups. 13, 21 The main purpose of this present in silico genomic study was to assess how the expressions of the RAS gene family changes after cellular infection with SARS-CoV in the lung epithelial cell culture. The whole normalized gene expression data of lung epithelial cells infected with SARS-CoV for 12, 24, and 48 hours were compared between different groups in order to determine significantly and differentially expressed RAS family genes. Based on our results, in this phase, as the exposure time to SARS-CoV increases, EGFR and IGF2R, two receptors with key roles in the RAS signaling pathway, were significantly down-regulated in the infected human bronchial epithelial cells. doi = 10.1177/1470320320928872 id = cord-272546-zznm13ik author = Van den Eynde, Jef title = Cardiothoracic robotic assisted surgery in times of COVID-19 date = 2020-05-08 keywords = RAS; covid-19 summary = At a time when elective surgeries are being suspended and questions are being raised about how the remaining procedures on COVID-19 positive patients can be performed safely, it is important to consider the potential role of robotic assisted surgery within the current pandemic. To date, however, no specific recommendations are available for cardiothoracic robotic assisted surgery in COVID-19 positive patients. Here, we discuss the potential risks, benefits, and preventive measures that need to be taken into account when considering robotic assisted surgery for cardiothoracic indications in patients with confirmed COVID-19. In response to this situation, various surgical societies have already issued their recommendations on adequate patient selection and preparation, as well as measures that can be taken to minimize the spread of viral particles. Provided that the above discussed risks are taken into account and met with these preventive measures, cardiothoracic RAS might on the other hand have various benefits to offer during the current COVID-19 pandemic when compared to conventional open surgery. doi = 10.1007/s11701-020-01090-7 id = cord-259243-1lkzcslx author = Álvarez-Aragón, Luis Miguel title = Inquiring into Benefits of Independent Activation of Non-Classical Renin-Angiotensin System in the Clinical Prognosis and Reduction of COVID-19 mortality date = 2020-04-08 keywords = RAS summary = title: Inquiring into Benefits of Independent Activation of Non-Classical Renin-Angiotensin System in the Clinical Prognosis and Reduction of COVID-19 mortality We have read with great interest the elegant manuscript by Hanff et al [1] proposing a very interesting association between the classical renin-angiotensin system (RAS) and angiotensinconverting enzyme 2 (ACE2) dysregulation present in cardiovascular disease (CVD) and the high mortality index in patients with CVD and coronavirus disease 2019 (COVID-19). On the one hand, it will decrease the proinflammatory effect of Angiotensin II with its subsequent benefit on decreasing the risk of acute respiratory distress syndrome (ARDS) observed in these patients, and on the other hand, it will increase ACE2 expression and therefore the virulence of SARS-Cov2. In addition, in vitro studies in human renal cells treated with SLGT2 inhibitors have shown an increment in Angiotensin(1-7) due to the independent activation of the non-classical RES, leading to important anti-inflammatory and anti-M a n u s c r i p t fibrotic effects [6, 7] . doi = 10.1093/cid/ciaa402