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Leptospirosis is an emerging zoonotic and neglected disease across the world causing huge loss of life and economy. In this study, we did whole genome sequencing of one Leptospira isolate and a comparative genomic analysis with 69 other species of Leptospira available in RefSeq database provided insight into taxonomic and evolutionary relationship between species. AAI and whole genome based phylogenomic analysis established 3 clusters of Leptospira i.e. pathogenic, intermediate and saprophytic correlating with level of virulence of species. Leptospira has large closed core genome of 1038 genes and an open pan genome with 20,822 genes. The mobilome related genes were found mainly in pan-genome of pathogenic clade. A total of 498 genes have been identified as virulomes, with 329 virulent genes exhibiting presence/absence in various Leptospira species contributing to each species specific virulence profile. The hierarchical clustering of the congregated pathogenic genes yielded five groups, each with a distinct pattern of predominant genes that were either unique or common among clades, indicating lineage uniqueness. Most of the virulent gene pool identified were significantly enriched in COG functional categories of Nucleotide transport and metabolism, Intracellular trafficking, secretion and vesicular transport, cell motility and amino acid transport & metabolism. Pathogenic leptospires exhibit fewer clade-specific genes than non-pathogenic and intermediate leptospires, indicating gene loss and gain events in the evolution of pathogenic leptospires from non-pathogenic. The study’s clade-specific and virulent genes can be utilised as markers for defining clade and associated virulence levels in any new Leptospira isolates. Wet-lab validation of virulent genes will help in accurately targeting pathogenic pathways of Leptospira and controlling leptospirosis.

Background and objective Coronavirus disease (COVID-19) is an ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to the incessant spread of the disease with substantial morbidity and mortality rates, there is an urgent demand for effective therapeutics and vaccines to control and diminish this pandemic. A critical step in the crosstalk between the virus and the host cell is the binding of SARS-CoV-2 spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor present on the surface of the host cells. Hence, inhibition of this interaction could be a promising strategy to combat the SARS-CoV-2 infection. Methods Docking and Molecular Dynamics (MD) simulation studies revealed that designed peptide maintains their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2. Results We have designed a novel peptide that could inhibit SARS-CoV-2 spike protein interaction with ACE2, thereby blocking the cellular entry of the virus. Conclusion Our findings suggest that computationally developed inhibitory peptide may be developed as an anti-SARS-CoV-2 agent for the treatment of SARS-CoV-2 infection. We further plan to pursue the peptide in cell-based assays and eventually for clinical trials.

Hepatic stellate cells (HSCs) are known to play a key role in the progression of liver fibrosis by producing excessive extracellular matrix (ECM). Matrix metalloproteinases (MMPs) belong to a family of endopeptidases, which have a well-established role in the degradation of ECM. Our study suggests that, besides the degradation of the extracellular matrix, matrix metalloproteinase-8 (MMP-8) has a non-canonical role in activating the quiescent HSCs to myofibroblasts by regulating the expression of Col1A1 and αSMA. We have identified that MMP-8 secreted from macrophages as a response to LPS stimulation activates HSCs via ERK1/2-dependent pathway. In addition to this, we determined that MMP-8 may regulate the homodimerization of c-Jun in LX-2 cells, during the trans-differentiation process from quiescent HSC to activate myofibroblasts. Macrophage-released MMP-8 plays a master role in activating the dormant HSCs to activate myofibroblasts through the Erk-mediated pathway and Jun cellular translocation leading to liver fibrosis. Significance MMP-8 can be used as a therapeutic target against liver fibrosis.

The outbreak of the coronavirus disease 2019 caused by the severe acute respiratory syndrome coronavirus 2 triggered a global pandemic where control is needed through therapeutic and preventive interventions. This study aims to identify natural compounds that could affect the fusion between the viral membrane (receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 spike protein) and the human cell receptor angiotensin-converting enzyme 2. Accordingly, we performed the enzyme-linked immunosorbent assay-based screening of 10 phytochemicals that already showed numerous positive effects on human health in several epidemiological studies and clinical trials. Among these phytochemicals, epigallocatechin gallate, a polyphenol and a major component of green tea, could effectively inhibit the interaction between the receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 spike protein and the human cell receptor angiotensin-converting enzyme 2. Alternately, in silico molecular docking studies of epigallocatechin gallate and angiotensin-converting enzyme 2 indicated a binding score of −7.8 kcal/mol and identified a hydrogen bond between R393 and angiotensin-converting enzyme 2, which is considered as a key interacting residue involved in binding with the severe acute respiratory syndrome coronavirus 2 spike protein receptor-binding domain, suggesting the possible blocking of interaction between receptor-binding domain and angiotensin-converting enzyme 2. Furthermore, epigallocatechin gallate could attenuate severe acute respiratory syndrome coronavirus 2 infection and replication in Caco-2 cells. These results shed insight into identification and validation of severe acute respiratory syndrome coronavirus 2 entry inhibitors.

Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat–response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case–control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 ( P =1.65 × 10 −8 ); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N -methyltransferase on chromosomal band 2p21 ( P =2.86 × 10 −9 ). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.

The mammalian Transient Receptor Potential Canonical (TRPC) subfamily comprises seven transmembrane proteins (TRPC1–7) forming cation channels in the plasma membrane of mammalian cells. TRPC channels mediate Ca2+ and Na+ influx into the cells. Amongst TRPCs, TRPC6 deficiency or increased activity due to gain-of-function mutations has been associated with a multitude of diseases, such as kidney disease, pulmonary disease, and neurological disease. Indeed, the TRPC6 protein is expressed in various organs and is involved in diverse signalling pathways. The last decade saw a surge in the investigative studies concerning the physiological roles of TRPC6 and describing the development of new pharmacological tools modulating TRPC6 activity. The current review summarizes the progress achieved in those investigations.

BackgroundThis review focuses on exosomes derived from various cancer cells. The review discusses the possibility of differentiating macrophages in alternatively activated anti-inflammatory pro-tumorigenic M2 macrophage phenotypes and classically activated pro-inflammatory, anti-tumorigenic M1 macrophage phenotypes in the tumor microenvironment (TME). The review is divided into two main parts, as follows: (1) role of exosomes in alternatively activating M2-like macrophages-breast cancer-derived exosomes, hepatocellular carcinoma (HCC) cell-derived exosomes, lung cancer-derived exosomes, prostate cancer-derived exosomes, Oral squamous cell carcinoma (OSCC)—derived exosomes, epithelial ovarian cancer (EOC)—derived exosomes, Glioblastoma (GBM) cell-derived exosomes, and colorectal cancer-derived exosomes, (2) role of exosomes in classically activating M1-like macrophages, oral squamous cell carcinoma-derived exosomes, breast cancer-derived exosomes, Pancreatic-cancer derived modified exosomes, and colorectal cancer-derived exosomes, and (3) exosomes and antibody-dependent cellular cytotoxicity (ADCC). This review addresses the following subjects: (1) crosstalk between cancer-derived exosomes and recipient macrophages, (2) the role of cancer-derived exosome payload(s) in modulating macrophage fate of differentiation, and (3) intracellular signaling mechanisms in macrophages regarding the exosome’s payload(s) upon its uptake and regulation of the TME.EvidenceUnder the electron microscope, nanoscale exosomes appear as specialized membranous vesicles that emerge from the endocytic cellular compartments. Exosomes harbor proteins, growth factors, cytokines, lipids, miRNA, mRNA, and DNAs. Exosomes are released by many cell types, including reticulocytes, dendritic cells, B-lymphocytes, platelets, mast cells, and tumor cells. It is becoming clear that exosomes can impinge upon signal transduction pathways, serve as a mediator of signaling crosstalk, thereby regulating cell-to-cell wireless communications.ConclusionBased on the vesicular cargo, the molecular constituents, the exosomes have the potential to change the fate of macrophage phenotypes, either M1, classically activated macrophages, or M2, alternatively activated macrophages. In this review, we discuss and describe the ability of tumor-derived exosomes in the mechanism of macrophage activation and polarization.

The Toll-interleukin-1 Receptor (TIR) domain-containing adaptor protein (TIRAP) represents a key intracellular signalling molecule regulating diverse immune responses. Its capacity to function as an adaptor molecule has been widely investigated in relation to Toll-like Receptor (TLR)-mediated innate immune signalling. Since the discovery of TIRAP in 2001, initial studies were mainly focused on its role as an adaptor protein that couples Myeloid differentiation factor 88 (MyD88) with TLRs, to activate MyD88-dependent TLRs signalling. Subsequent studies delineated TIRAP’s role as a transducer of signalling events through its interaction with non-TLR signalling mediators. Indeed, the ability of TIRAP to interact with an array of intracellular signalling mediators suggests its central role in various immune responses. Therefore, continued studies that elucidate the molecular basis of various TIRAP-protein interactions and how they affect the signalling magnitude, should provide key information on the inflammatory disease mechanisms. This review summarizes the TIRAP recruitment to activated receptors and discusses the mechanism of interactions in relation to the signalling that precede acute and chronic inflammatory diseases. Furthermore, we highlighted the significance of TIRAP-TIR domain containing binding sites for several intracellular inflammatory signalling molecules. Collectively, we discuss the importance of the TIR domain in TIRAP as a key interface involved in protein interactions which could hence serve as a therapeutic target to dampen the extent of acute and chronic inflammatory conditions.

Cotton leaf curl disease (CLCuD), caused by begomoviruses in combination with betasatellite molecule, has adversely affected cotton industry of Indian subcontinent. To devise a CLCuD-control strategy, RNAi-mediated approach was followed in this study. Gossypium hirsutum cv. HS6 plants were transformed with intron-hairpin RNAi (ihpRNAi-C4) construct carrying silencing suppressor C4 gene of Cotton leaf curl Multan virus (CLCuMuV). Efficacy of the construct in imparting CLCuD resistance was evaluated in transgenic (T 0 , T 1 ) cotton lines. Accumulation of CLCuMuV/betasatellite and attenuation of CLCuD symptoms in the transgenic lines were monitored at different times interval after virus inoculation. Northern hybridization revealed the expression of C4-gene derived siRNA. Expression of the ihpRNAi transcript was recorded higher in transgenic lines expressing siRNA which supposedly targeted the C4 gene. A significant delay in detection of virus as well as betasatellite was observed in the transgenic lines. At 30 days post inoculation (dpi), none of the lines tested positive. At 45 dpi, however, it could be detected in few lines having much lower titre as compared to non-transformed control plants. Notably, till 60 dpi, no significant progression of the virus/betasatellite DNA was observed and the plants did not exhibit any characteristic CLCuD symptoms. A tolerance phenomenon leading to escape of CLCuD symptoms in the transformed cotton was described.