BackgroundCoronavirus disease-2019 (COVID-19) has caused a great global threat to public health. The World Health Organization (WHO) has declared COVID-19 disease as a pandemic, affecting the human respiratory and other body systems, which urgently demands for better understanding of COVID-19 histopathogenesis.ObjectiveData on pathological changes in different organs are still scarce, thus we aim to review and summarise the latest histopathological changes in different organs observed after autopsy of COVID-19 cases.Materials and methodsOver the period of 3 months, authors performed vast review of the articles. The search engines included were PubMed, Medline (EBSCO & Ovid), Google Scholar, Science Direct, Scopus and Bio-Medical. Search terms used were ‘Histopathology in COVID-19’, ‘COVID-19’, ‘Pathological changes in different organs in COVID-19’ or ‘SARS-CoV-2’. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 guidelines were used for review writing.ResultWe identified various articles related to the histopathology of various organs in COVID-19 positive patients. Overall, 45 articles were identified as full articles to be included in our study. Histopathological findings observed are summarised according to the systems involved.ConclusionAlthough COVID-19 mainly affects respiratory and immune systems, but other systems like cardiovascular, urinary, gastrointestinal tract, reproductive system, nervous system and integumentary system are not spared, especially in elderly cases and those with comorbidity. This review would help clinicians and researchers to understand the tissue pathology, which can help in better planning of the management and avoiding future risks.

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More than one and a half years have elapsed since the commencement of the coronavirus disease 2019 (COVID-19) pandemic, and the world is struggling to contain it. Being caused by a previously unknown virus, in the initial period, there had been an extreme paucity of knowledge about the disease mechanisms, which hampered preventive and therapeutic measures against COVID-19. In an endeavor to understand the pathogenic mechanisms, extensive experimental studies have been conducted across the globe involving cell culture-based experiments, human tissue organoids, and animal models, targeted to various aspects of the disease, viz., viral properties, tissue tropism and organ-specific pathogenesis, involvement of physiological systems, and the human immune response against the infection. The vastly accumulated scientific knowledge on all aspects of COVID-19 has currently changed the scenario from great despair to hope. Even though spectacular progress has been made in all of these aspects, multiple knowledge gaps are remaining that need to be addressed in future studies. Moreover, multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have emerged across the globe since the onset of the first COVID-19 wave, with seemingly greater transmissibility/virulence and immune escape capabilities than the wild-type strain. In this review, we narrate the progress made since the commencement of the pandemic regarding the knowledge on COVID-19 mechanisms in the human body, including virus–host interactions, pulmonary and other systemic manifestations, immunological dysregulations, complications, host-specific vulnerability, and long-term health consequences in the survivors. Additionally, we provide a brief review of the current evidence explaining molecular mechanisms imparting greater transmissibility and virulence and immune escape capabilities to the emerging SARS-CoV-2 variants.

The SARS-CoV-2 is a recently identified positive sense single stranded RNA virus and member of the coronavirus family of viruses. It is thought to be the etiological factor for the ongoing COVID-19 pandemic. This virus is thought to have originated from bats and acquired ability of human-to-human transmission. While SARS-CoV-2 is relatively benign, it has infected more than half a million people (as of March 29 th 2020) worldwide and the number of infected people continues to rise. More than 170 countries have reported COVID-19 positive cases. With a mortality rate of less than both the previous coronavirus outbreaks, COVID-19 has (conversely) caused the death of over 33,980 (as of 29 th March, 2020 at 22.00 hours EDT) people worldwide and the number is increasing. Given the enormous impact of this virus on human health and wellbeing and consequent devastating impacts on world trade, economics and quality of life, it is important to understand this virus better and get insight into its pathogenic mechanisms which will aid in devising effective measure to curb its spread and predict future pattern of its interaction with humans. Though very little is known about this SARS-CoV-2 but its mechanisms and patterns of spread can be speculated (with caution, nevertheless) from what we know about its closest relatives SARS-CoV-1 (responsible for SARS-2002 epidemic) and MERS-CoV (responsible for MERS-2012 epidemic). In the present review, we aim at bringing together the coherent and peer reviewed literature about the SARS-CoV-2 and its close relatives and try to understand its infection patterns and reconstruct its pathogenic mechanisms with anecdotes on diagnosis and future directions. We hope that this paper will serve the purpose of being a reliable source of information to scientists, clinicians and general public. 2020) named Huanan which was subsequently closed on January 1 st , 2020. It was later reported that individual greater than 60 years of age and those with other comorbid conditions are susceptible to severe disease and may even die (Cascella et al., 2020). The emergence of

IntroductionCOVID-19, is caused by a new strain of coronavirus called SARS-coronavirus-2 (SARS-CoV-2), which is a positive sense single strand RNA virus. In humans, it binds to angiotensin converting enzyme 2 (ACE2) with the help a structure on its surface called the S-spike. COVID-19 poses intriguing issues with imperative relevance to clinicians. The pathogenesis of GI symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 are of particular relevance because they cannot be sufficiently explained from the existing knowledge of the viral diseases. Tissue specific variation of ACE2 expression in healthy individuals can help in understanding the pathophysiological basis the aforementioned collection of symptoms. Materials and MethodsThe data were downloaded from the Human Protein Atlas available at (https://www.proteinatlas.org/search/ACE2) and the tissue specific expression (both mRNA and protein) of ACE2 as yielded from the studies with RNA sequencing and immunohistochemistry (IHC) was analyzed as a function of the various components of the digestive tract. A digestive system specific functional enrichment map of ACE2 gene was created using g:profiler (https://biit.cs.ut.ee/gprofiler/gost) utility and the data were visualized using Cytoscape software, version 3.7.2 (https://cytoscape.org/). ResultsThe correlated expression (genomic and proteomic) of ACE2 (to which SARS-CoV-2 binds through the S-spike) was found to be enriched in the lower gastrointestinal tract (GIT) (highest in small intestine, followed by colon and rectum), and was undetectable in the upper GIT components: mouth cavity (tongue, oral mucosa, and salivary glands), esophagus, and stomach. High expression of ACE2 was noted in the glandular cells as well as in the enterocytes in the lining epithelium (including brush border epithelium). Among other digestive system organs, gallbladder (GB) showed high expression of ACE2 in glandular cells, while any protein expression was undetectable in liver and pancreas. ConclusionsBased on the findings of this study and supportive evidence from the literature we propose that a SARS-CoV-2 binding with ACE2 mediates dysregulation of the sodium dependent nutrient transporters and hence may be a plausible basis for the digestive symptoms in COVID-19 patients. ACE2 mediated dysregulation of sodium dependent glucose transporter (SGLT1 or SLC5A1) in the intestinal epithelium also links it to the pathogenesis of diabetes mellitus which can be a possible reason for the associated mortality in COVID-19 patients with diabetes. High expression of ACE2 in mucosal cells of the intestine and GB make these organs potential sites for the virus entry and replication. Continued replication of the virus at these ACE2 enriched sites may be a basis for the disease recurrence reported in some, thought to be cured, patients. Highlights SARS-CoV-2 binding receptor ACE2 expression is enriched in human intestine  ACE2 regulates neutral amino acid (B0AT1) and glucose transporter (SGLT1) in intestinal epithelium  Muc...

Owing to the reports of microcephaly as a consistent outcome in the fetuses of pregnant women infected with ZIKV in Brazil, Zika virus (ZIKV)—microcephaly etiomechanistic relationship has recently been implicated. Researchers, however, are still struggling to establish an embryological basis for this interesting causal handcuff. The present study reveals robust evidence in favor of a plausible ZIKV-microcephaly cause-effect liaison. The rationale is based on: (1) sequence homology between ZIKV genome and the response element of an early neural tube developmental marker “retinoic acid” in human DNA and (2) comprehensive similarities between the details of brain defects in ZIKV-microcephaly and retinoic acid embryopathy. Retinoic acid is considered as the earliest factor for regulating anteroposterior axis of neural tube and positioning of structures in developing brain through retinoic acid response elements (RARE) consensus sequence (5′–AGGTCA–3′) in promoter regions of retinoic acid-dependent genes. We screened genomic sequences of already reported virulent ZIKV strains (including those linked to microcephaly) and other viruses available in National Institute of Health genetic sequence database (GenBank) for the RARE consensus repeats and obtained results strongly bolstering our hypothesis that ZIKV strains associated with microcephaly may act through precipitation of dysregulation in retinoic acid-dependent genes by introducing extra stretches of RARE consensus sequence repeats in the genome of developing brain cells. Additional support to our hypothesis comes from our findings that screening of other viruses for RARE consensus sequence repeats is positive only for those known to display neurotropism and cause fetal brain defects (for which maternal-fetal transmission during developing stage may be required). The numbers of RARE sequence repeats appeared to match with the virulence of screened positive viruses. Although, bioinformatic evidence and embryological features are in favor of our hypothesis, additional studies including animal models are warranted to validate our proposition. Such studies are likely to unfold ZIKV-microcephaly association and may help in devising methods to combat it.

AbstractNerve growth factors (NGFs), especially the prototype NGF and brain-derived neurotrophic factor (BDNF), have a diverse array of functions in the central nervous system through their peculiar set of receptors and intricate signaling. They are implicated not only in the development of the nervous system but also in regulation of neurocognitive functions like learning, memory, synaptic transmission, and plasticity. Evidence even suggests their role in continued neurogenesis and experience-dependent neural network remodeling in adult brain. They have also been associated extensively with brain disorders characterized by neurocognitive dysfunction. In the present article, we aimed to make an exhaustive review of literature to get a comprehensive view on the role of NGFs in neurocognitive functions in health and disease. Starting with historical perspective, distribution in adult brain, implied molecular mechanisms, and developmental basis, this article further provides a detailed account of NGFs’ role in specified neurocognitive functions. Furthermore, it discusses plausible NGF-based homeostatic and adaptation mechanisms operating in the pathogenesis of neurocognitive disorders and has presents a survey of such disorders. Finally, it elaborates on current evidence and future possibilities in therapeutic applications of NGFs with an emphasis on recent research updates in drug delivery mechanisms. Conclusive remarks of the article make a strong case for plausible role of NGFs in comprehensive regulation of the neurocognitive functions and pathogenesis of related disorders and advocate that future research should be directed to explore use of NGF-based mechanisms in the prevention of implicated diseases as well as to target these molecules pharmacologically.

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