A5101891031- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Pancreatic function and diabetes
- Bacterial Genetics and Biotechnology
- Microbial Community Ecology and Physiology
- Bacterial biofilms and quorum sensing
- Immune cells in cancer
- RNA Research and Splicing
- Receptor Mechanisms and Signaling
- Genomics and Phylogenetic Studies
- Microbial Fuel Cells and Bioremediation
- interferon and immune responses
- Diabetes and associated disorders
- Peptidase Inhibition and Analysis
- Protease and Inhibitor Mechanisms
- Metabolism and Genetic Disorders
- Biochemical and Structural Characterization
- Birth, Development, and Health
- Protist diversity and phylogeny
- Retinopathy of Prematurity Studies
- Protein Kinase Regulation and GTPase Signaling
- Amoebic Infections and Treatments
- Neuropeptides and Animal Physiology
- Signaling Pathways in Disease
- Retinal Development and Disorders
Yale University
2012-2024
Moderna Therapeutics (United States)
2018-2024
Al Jalila Foundation
2023
Skåne University Hospital
2021-2022
Lund University
2020-2022
Indian Institute of Science Bangalore
2014-2022
The University of Texas Southwestern Medical Center
2018-2022
Government Medical College
2019
Sri Aurobindo Institute of Technology
2015
Lady Hardinge Medical College
2010-2013
Developing an effective mRNA therapeutic often requires maximizing protein output per delivered molecule. We previously found that coding sequence (CDS) design can substantially affect output, with variants containing more optimal codons and higher secondary structure yielding the highest outputs due to their slow rates of decay. Here, we demonstrate CDS-dependent differences in translation initiation elongation lead translation- deadenylation-dependent decay rates, thus explaining effect...
The advent of therapeutic mRNAs significantly increases the possibilities protein-based biologics beyond those that can be synthesized by recombinant technologies (eg, monoclonal antibodies, extracellular enzymes, and cytokines). In addition to their application in areas vaccine development, immune-oncology, protein replacement therapies, one exciting possibility is use program undesired, diseased cells synthesize a toxic intracellular protein, causing self-destruct. For this approach work,...
Reactive oxygen species (ROS) increase in activated T cells because of metabolic activity induced to support cell proliferation and differentiation. We show that these ROS trigger an oxidative stress response leads translation repression. This is countered by Schlafen 2 (SLFN2), which directly binds transfer RNAs (tRNAs) protect them from cleavage the ribonuclease angiogenin. cell-specific SLFN2 deficiency results accumulation tRNA fragments, inhibit promote stress-granule formation....
Elderly patients often suffer from multiple age-related diseases. Here we show that the expression of DJ-1, an antioxidant protein with reduced in central nervous system Parkinson's disease, is pancreatic islets type 2 diabetes mellitus (T2DM). In contrast, under non-diabetic conditions, DJ-1 increases mouse and human during aging. islets, prevents increase reactive oxygen species levels as mice age. This function preserves mitochondrial integrity physiology, prerequisites for...
Type IVa pili (T4P) are bacterial surface structures that enable motility, adhesion, biofilm formation and virulence. T4P assembled by nanomachines span the cell envelope. Cycles of assembly retraction, powered ATPases PilB PilT, allow bacteria to attach pull themselves along surfaces, so-called "twitching motility". These opposing ATPase activities must be coordinated limited one pole for show directional movement. How this occurs is still incompletely understood. Herein, we c-di-GMP...
Pseudomonas aeruginosa is a Gram-negative, opportunistic pathogen that utilizes polar type IV pili (T4P) for twitching motility and adhesion in the environment during infection. Pilus assembly requires FimX, GGDEF/EAL domain protein binds hydrolyzes cyclic di-GMP (c-di-GMP). Bacteria lacking FimX are deficient microcolony formation. We carried out an extragenic suppressor screen PA103ΔfimX bacteria to identify additional regulators of pilus assembly. Multiple mutations were mapped PA0171,...
Significance Activation of Toll-like receptors by microbes or host-derived molecules triggers signaling that promotes inflammation and may contribute to the development autoimmunity. Here we show excessive innate immune (TLRs) TLR3, TLR7, TLR9 is causative for inflammatory disease in mice with mutations Smcr8 . The cellular mechanism their hyperactivation likely prolonged ligand–receptor contact lysosomes phagosomes, trafficking which regulated SMCR8-WDR41-C9ORF72 complex cells. We also...
The remarkable capacity of bacteria to adapt in response selective pressures drives antimicrobial resistance. Pseudomonas aeruginosa illustrates this point, establishing chronic infections during which it evolves survive antimicrobials and evade host defenses. Many adaptive changes occur on the P. cell surface but methods identify these are limited. Here we combine phage display with high-throughput DNA sequencing create a high throughput, multiplexed technology for surveying bacterial...
Hen1 is an RNA ribose 2'-O-methyltransferase that modifies the 3' terminal nucleoside of eukaryal small regulatory RNAs. Here, we report homologs are present in bacterial proteomes from eight different phyla. Bacterial encoded by proximal ORF a two-gene operon also encodes polynucleotide kinase-phosphatase (Pnkp), repair enzyme. Purified recombinant Clostridium thermocellum homodimer 465-amino acid polypeptide. CthHen1 catalyzes methyl transfer AdoMet to oligonucleotide, but unreactive with...
Clp1 proteins are essential components of the eukaryal mRNA 3′ cleavage-polyadenylation machinery. Human has an additional function as RNA-specific 5′-OH polynucleotide kinase, which is implicated in RNA end healing. Yeast no kinase activity, although it binds ATP. Here we report that Clp1-like extant archaea. Purification and characterization Pyrococcus horikoshii ( Pho Clp1) reveals to be a thermostable optimally active at 55°C 85°C. catalyzes transfer gamma phosphate from ATP K m 16 μM)...
Triphosphate tunnel metalloenzymes (TTMs) are a newly recognized superfamily of phosphotransferases defined by unique active site residing within an eight-stranded β barrel. The prototypical members the eukaryal metal-dependent RNA triphosphatases, which catalyze initial step in mRNA capping. Little is known about activities and substrate specificities scores TTM homologs present bacterial archaeal proteomes, nearly all annotated as adenylate cyclases. Here we have conducted biochemical...
tRNA anticodon damage inflicted by secreted ribotoxins such as Kluyveromyces lactis gamma-toxin and bacterial colicins underlies a rudimentary innate immune system that distinguishes self from nonself species. The intracellular expression of (a 232-amino acid polypeptide) arrests the growth Saccharomyces cerevisiae incising single RNA phosphodiester 3' modified wobble base tRNA(Glu). Fungal bears no primary structure similarity to any known nuclease has plausible homologs in protein...
The availability of technological advances like ultrasonography (USG) and magnetic resonance imaging (MRI) has made the diagnosis rudimentary horn pregnancy possible at an early gestation. However, in advanced pregnancy, such cases can sometimes pose a diagnostic dilemma are recognized only when patient presents with abdominal pain collapse is taken for laparotomy. We report one rare case nulliparous female who was carrying on well her till she developed symptoms acute abdomen 28 weeks She...
The RNA methyltransferase Hen1 and the end-healing/sealing enzyme Pnkp comprise an repair system encoded by operon-like cassette present in bacteria from eight different phyla. Clostridium thermocellum ( Cth Hen1) is a manganese-dependent ribose 2′O-methyltransferase that marks 3′ terminal nucleoside of broken RNAs protects junctions iterative damage transesterifying endonucleases. Here we used crystal structure homologous plant to guide mutational analysis Hen1, results which provide new...