Rahul Vivek

TDP-43 is an RNA binding protein implicated in neurodegenerative disease. TDP-43 binds to GU dinucleotide repeats, which are highly abundant sequences in human RNA. Here we show TDP-43 has one of the highest affinities and specificities measured for an RNA binding protein. Binding prevents formation of the pUG fold, an intramolecular quadruplex, and conversely pUG fold formation prevents TDP-43 binding. Slow pUG folding and a rapid on-rate enable TDP-43 to capture single-stranded RNA. The protein recognizes the RNA as a 1D lattice, in which overlapping binding sites produce efficient initial binding events that interfere with subsequent interactions. This effect is overcome by RNA facilitated protein-protein interactions, which serve to increase the on-rate of a second TDP-43 molecule, and an auto-inhibitory interaction that increases the off-rate. These data reveal how TDP-43 recognizes GU repeats and identify an interplay between RNA folding and protein recognition that may be relevant to human disease.

TDP-43 is an RNA binding protein implicated in neurodegenerative disease. TDP-43 binds to GU dinucleotide repeats, which are highly abundant sequences in human RNA. Here we show TDP- 43 has one of the highest affinities and specificities measured for an RNA binding protein. Binding prevents formation of the pUG fold, an intramolecular quadruplex, and conversely pUG fold formation prevents TDP-43 binding. A rapid on-rate allows TDP-43 to capture single stranded RNA prior to folding. The protein recognizes the RNA as a 1D lattice, in which overlapping binding sites produce efficient initial binding events that interfere with subsequent interactions. This effect is partially overcome by RNA facilitated protein-protein interactions, which serve to increase the on-rate of a second TDP-43 molecule. In conjunction with all atom models, these data reveal how TDP-43 recognizes RNA repeat sequences and identify an interplay between RNA folding and protein recognition that may be relevant to human disease.

Coronaviruses infect lungs leading to death due to asphyxiation. SARS-CoV-2 is treated by targeting symptoms, repurposing drugs and plasma therapy. Several synthetic drugs are being prescribed that cause major side effects in liver, kidney and heart. Therefore new compounds with low toxicity must be investigated. We have identified antiviral compounds like Eritadenine, Gallic Acid, Ergosterol Peroxide and Pleuran from various edible mushrooms such as Lentinula edodes , Agaricus bisporus , Pleutorus ostreatus and Hericium erinaceus with evidence of literature review. The docking and simulation studies with the targets of SARS-CoV-2 such as Main Protease (M Pro) and Spike Protein were highly successful. In silico ADMET studies further proved that these compounds are druggable with low toxicity. These compounds have potential to prevent the cellular entry to prohibit assembly of new viruses inside the cell. But further studies are required to substantiate their bioactivity claim by in vitro and in vivo assay methods.

The addition of poly(UG) (‘pUG’) repeats to 3′ termini of mRNAs drives gene silencing and transgenerational epigenetic inheritance in the metazoan Caenorhabditis elegans. pUG tails promote silencing by recruiting an RNA-dependent RNA polymerase (RdRP) that synthesizes small interfering RNAs. Here we show that active pUG tails require a minimum of 11.5 repeats and adopt a quadruplex (G4) structure we term the pUG fold. The pUG fold differs from known G4s in that it has a left-handed backbone similar to Z-RNA, no consecutive guanosines in its sequence, and three G quartets and one U quartet stacked non-sequentially. The compact pUG fold binds six potassium ions and brings the RNA ends into close proximity. The biological importance of the pUG fold is emphasized by our observations that porphyrin molecules bind to the pUG fold and inhibit both gene silencing and binding of RdRP. Moreover, specific 7-deaza substitutions that disrupt the pUG fold neither bind RdRP nor induce RNA silencing. These data define the pUG fold as a previously unrecognized RNA structural motif that drives gene silencing. The pUG fold can also form internally within larger RNA molecules. Approximately 20,000 pUG-fold sequences are found in noncoding regions of human RNAs, suggesting that the fold probably has biological roles beyond gene silencing.

Coronary artery disease is an inflammatory disorder characterized by narrowing of coronary arteries due to atherosclerotic plaque formation. To date, the accumulated epidemiological evidence supports an association between oral bacterial diseases and coronary artery disease, but has failed to prove a causal link between the two. Due to the recent surge in microbial identification and analyses techniques, a number of bacteria have been independently found in atherosclerotic plaque samples from coronary artery disease patients. In this study, we present meta-analysis from published studies that have independently investigated the presence of bacteria within atherosclerotic plaque samples in coronary artery disease patients. Data were collated from 63 studies covering 1791 patients spread over a decade. Our analysis confirms the presence of 23 oral commensal bacteria, either individually or in co-existence, within atherosclerotic plaques in patients undergoing carotid endarterectomy, catheter-based atherectomy, or similar procedures. Of these 23 bacteria, 5 (Campylobacter rectus,Porphyromonas gingivalis,Porphyromonas endodontalis,Prevotella intermedia,Prevotella nigrescens) are unique to coronary plaques, while the other 18 are additionally present in non-cardiac organs, and associate with over 30 non-cardiac disorders. We have cataloged the wide spectrum of proteins secreted by above atherosclerotic plaque-associated bacteria, and discuss their possible roles during microbial migration via the bloodstream. We also highlight the prevalence of specific poly-microbial communities within atherosclerotic plaques. This work provides a resource whose immediate implication is the necessity to systematically catalog landscapes of atherosclerotic plaque-associated oral commensal bacteria in human patient populations.