key: cord-0278638-sf03jc1w authors: Thapliyal, N.; Joshi, G.; Gahtori, P. title: Implicit, Intrinsic, Extrinsic, and Host Factors Attributing the Covid-19 Pandemic. Part 1- Intrinsic Factor Nitrous Oxide Emissions: A Systematic Analysis date: 2021-09-14 journal: nan DOI: 10.1101/2021.09.07.21263196 sha: 8738611f5d09ed817f8919149d7f0de14cba419b doc_id: 278638 cord_uid: sf03jc1w Despite Nitrous oxide (N2O) being the most widely used anesthetics in dental and other medical applications, it is associated with global warming and stratospheric ozone destruction. With globalization, a larger amount of N2O emissions arearticulated especially from human activities (30%, 6.7 Tg N per year), which are primarily dominated by agriculture that is even above the emissions of all oceans (26%). The synthesis of N2O reflects the general chemistry and readily from a substrate Nitric oxide (NO) in the environment. The modeling of infectious disease dynamics covering common pathogen-transmission factors, for example intrinsic (or microbes nutrient supply) at a population level, is indeed imperative to curb the menace of any disease. Nonetheless, in areas where novel coronavirus disease (COVID-19) was at its worst, for example, Wuhan China, Mumbai India, Milan Italy, Washington USA etc., the reduction in N2O emissions was well noticed. Nonetheless, viruses exhibit greater mobility than humans and hijack nutrients including nitrogen to complete their epidemiological cycle all due to limited sequence space of viral genomes, the high probability of genetic drift, extremely large population sizes, the high mutation and recombination rates. In consequence of drastic fall in N2O emissions, lower human transport can not be an all alone contributor, but contrarily it may also be associated with coronavirus intrinsic factors. This prompted us to analyze freely accessible and large global data from two authenticated sources, the World Health Organization and World Bank. We hereby argue that intrinsic factor N2O emissions fueling the COVID-19 progression significantly. Entire predictions were found consistent with the recently observed shreds of evidence. These insights enhanced scientific ability to interrogate viral epidemiology and recommended a 7-points framework covering all-natural lifestyle and dietary supplements for COVID-19 prevention before the arrival of a front-line therapeutic(s) or preventable vaccine. Over the years, the oxides of nitrogen have become increasingly important in contemporary science and are subjected to many reviews [1, 2] . Among them three oxides, Nitrous oxide (N 2 O) popularly known as laughing gas, Nitrogen dioxide (NO 2 ) and a free radical molecule Nitric oxide (NO) are the most abundant in the air [3] . N 2 O oxidation by ozone can occur at any temperature and considered as an ozone depleting substance with a long half-life (100 to 150 years). The NO (k ~10 7 lit mol -1 sec -1 ) is very rapidly oxidized to NO 2 by ozone. The NO 2 (k ~3X10 4 lit mol -1 sec -1 ) is still rapidly but slowly than NO oxidized to NO 3 by ozone. N The NO is produced in many tissues from L-arginine and molecular oxygen by four distinct isoforms of Nitric Oxide Synthase (NOS): (i) neuronal NOS-1 (nNOS), (ii) inducible NOS-2 (iNOS), (iii) endothelial NOS-3 (eNOS) and (iv) mitochondrial NOS (mtNOS). Nitric oxide reductases (NOR) play a predominant role in the detoxification of NO and likely to increase fitness of many Gram-positive andnegative pathogens during their associations with invertebrate and vertebrate hosts. The presence of an unpaired electron with uncharged molecule turns NO as an ideal messenger in human with a very short half-life of 2 to 30 seconds [4] . These characteristics of NO also allow its free diffusion across biomembranes and spontaneous signal transmission to perform a wide variety of physiological functions including an olfactory signal procession; platelet clotting; smooth muscle relaxation and vasodilation; blood flow regulation in the brain, heart, lung, gastrointestinal tract, and kidney; blood pressure regulation; cardiac contractility; and killing or inhibition of pathogens etc. [5, 6] Despite having large physiological functions, the Global warming potential of 1 gram of N 2 O is 265-298 times of same carbon dioxide for a 100-year timescale. A recent report published in Nature by Tian and coworkers highlighted that N 2 O emissions from human activities such as agriculture, fuel combustion, wastewater management, and industrial processes have ballooned 30% over the past forty years [7] . Here agriculture constitutes the largest source of N 2 O gas emissions, 100-, 8-, and 5-folds in comparison to transport, industry, and international bunkers respectively. Needless to say, that a well-balanced ecosystem is a cornerstone of human health and well-being [8, 9] . However, research into how natural environments relates to human health remains limited in important respects. The COVID-19 disease surge caused by the novel corona (SARS-COV2) virus is posing enormous health challenges since its first detection in China during December 2019, and subsequently its declaration as a pandemic by the World Health Organization (WHO) on dated March 11, 2020 [10] . Recent MEDLINE records of COVID-19 accessed via PubMed shares 0.155931 million results during the writing of the manuscript as on July 13, 2021, which further emphasize several successful scientific accomplishments across its virology, biology, prevention, therapeutics, diagnostics, etc. [11] Despite these success stories, still the eradication of COVID-19 is limited to 3Ts plus P i.e. Tracing (immediate patient isolation), Testing (early diagnosis), Treatment (supportive respiratory care) and Prevention (vaccination). However, according to a recent estimate, there has been a total of 185.29153 million confirmed COVID-19 cases, resulting in 4.010834 million deaths and 0.458355 million new cases are still appearing worldwide on daily basis. [12] The COVID-19 patients have mild to severe symptoms, most of are seeming closely linked with the physiological functions of NO such as loss of olfactory sensation; platelet clotting; difficulty in breathing; multi-organ brain, heart, lung, gastrointestinal tract, and kidney failure etc. [13] In fact, recently the FDA approved an inhaled nitric oxide (iNO plus) for COVID-19 emergency use to a biotherapeutics company, Bellerophon Therapeutics. [14] In addition, a fall in N 2 O gas emissions was noticed in local affected areas after the surge of the SARS-CoV-2 virus. Consequently, these real evidences convince us about the physiological role of substrate NO in COVID-19 management and huge spread of SARS-CoV-2 virus may be due to atmospheric imbalance of N 2 O. Furthermore, there is considerable evidence that intrinsic, extrinsic (or environment), implicit, and host factors are key regulators of any pathogen transmission [15] and an intrinsic factor both operationally and conceptually have yet to be reached for full annihilation of COVID-19. Supressing N 2 O emissions seems the most viable pathway for attaining the great health challenges posed by COVID-19 pandemic. This prompted us to perform a wider sampling of global COVID-19 infectious cases with both nitric oxide and carbon dioxide emissions in understanding the SARS-COV2 transmission in atmosphere and human population. A large authenticated data set with both Covid-19 cases and nitrous oxide/ carbon dioxide emissions consisting 97 countries/ territories is freely accessible, and retrieved from two reliable sources, the World Health Organization (WHO) and the World Bank (n= 97). All COVID-19 infectious cases (n= 97) were collected from five WHO situation reports-dated 09-Jul-2021, 22-Dec-2020, 13-Mar-2020, 19-Mar-2020, and 28-Mar-2020 [16] . All recent value pertaining to both nitrous oxide and carbon dioxide All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Carbon dioxide emissions listed in per capita were multiplied with country's population and finaly converted into thousand metric tons. Here, 97 Countries/ Territories randomly fitted to top variable indices of correlation coefficient for unbiased cause-effect relationships ( Table 1) . All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted September 14, 2021. ; All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted September 14, 2021. ; We ascertained a large data set involving a total of ninty seven Countries/ Territories randomly who fulfilled the unbiased study criteria used in the assessment of role of nitrous oxide emissions over Covid-19 pandemic. There was a large variation among both N 2 O emissions (variation= 4.53 X 10 9 ) and cumulative COVID-19 cases (variation ranges from 2.48X10 13 to 2.88X10 8 dated from 28-March-2020 to 09-July-2021) across all Countries/ Territories (Table 1) . Here with the large variation, we observed a good and consistent correlation (r 2 = 0.6 ± 0.06) between N 2 O emissions and Cumulative covid-19 cases from last one year plus (Table 2) Other hands, in the case of CO 2 emissions, a weak and inconsistent correlation (r 2 = 0.2 ± 0.23) exist, suggesting that COVID-19 cases are independent of CO 2 utilization. These statistical findings were overall supportive of N 2 O emission's impact on enhancing SARS-COV2 spread in the human population. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted September 14, 2021. Once again, COVID-19 pathophysiology and common symptoms fever, apnoea, cough, tiredness, and highly vulnerable groups, such as hypertensive, diabetics, smoker, and obese people, all observed reduced bioactive NO after the COVID-19 viral entry. [21] NO is a gaseous secondary messenger known to be involved in numerous intra-and intercellular signaling events [22] [23] [24] , for example, regulation of non-specific immune defense, body temperature, blood sugar, inflammation, vasodilation, airway tone, etc. More specifically, reports by Dantonio et al. suggested systemic inhibition of NO synthesis attenuates bacterial endotoxin-induced fever [25] , Hori et al. highlighted NO is involved in an ovalbumin-induced increase in cough reflex sensitivity [26] , Prado et al. outlined role of nitric oxide in the various pathologic mechanisms of allergic asthma [27] . As a result of NO inhibition, common symptoms fever, cough, tiredness, and difficulty in breathing were appearing after COVID infection. The NO inducible agents, for example, hydroxychloroquine is being clinically relevant in COVID-19 treatment. A review of Nitric oxide enhancement strategies emphasizes many dietary strategies for more safe and effective NO based solutions than NO donating therapeutics [28] . The NO inactivation concept has evolved from the current approach and, endorse novel SARS- 5. Consumption of natural L-Arginine-rich sources, for example, dairy products, soybeans, peanuts, spirulina, lentils, eggs, etc. (L-Arginine is a precursor of NO production) and Citrulline supplementation using natural sources, for example, watermelon, pumpkins, cucumber, etc. (Citrulline stimulates de novo Arginine production) 6 . Moderate consumption of nitrate-rich natural sources, such as beetroot, spinach, lettuce, chervil, radish, celery, pomegranate, etc. (Nitrate-nitrite-NO is second metabolic pathway). In line with modern science multi-factorial approach, this study is endorsing nature's role in direct pathogen invasion and to limit the transmission of SARS-COV-2 pathogen. Thus, similar approach help researchers think undoubtedly about the causation of COVID-19 disease. We hope the insights presented All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted September 14, 2021. ; https://doi.org/10.1101/2021.09.07.21263196 doi: medRxiv preprint above along with disease reduction framework will be a game-changer in fighting against the COVID-19 pandemic before the launch of a front-line therapeutic(s) or preventable vaccine. Human alteration of the global nitrogen cycle: sources and consequences Review of greenhouse gas emissions from crop production systems and fertilizer management effects Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin Nitric oxide: a physiologic messenger Nitrous oxide-a study of physiological and psychomotor effects The basics about nitric oxide. 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Current opinion in clinical nutrition and metabolic care Nitric oxide and fever: immune-to-brain signaling vs. thermogenesis in chicks Involvement of nitric oxide (NO) in cough reflex sensitivity between non-sensitized and OVA-sensitized guinea pigs Nitric oxide in asthma physiopathology. ISRN allergy Nitric oxide enhancement strategies The authors are thankful to the World Health Organization and Worldbank for keeping data free to use.The authors are also thankful to GEHU India for providing necessary facilities and technical support. The authors declare no competing financial interest.Author contributions PG devised the project and the main conceptual ideas. NT drafted the manuscript. GJ critically revised the manuscript and all authors approved the final version for submission.