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rabindra.tharu.np@gmail.com
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Flexibility and sensitivity in gene regulation out of equilibrium
Cells adapt to environments and tune gene expression by controlling the concentrations of proteins and their kinetics in regulatory networks. In both eukaryotes and prokaryotes, experiments and theory increasingly attest that these networks can and do consume biochemical energy. How does this dissipation enable cellular behaviors forbidden in equilibrium? This open question demands quantitative models…
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rabindra.tharu.np@gmail.com
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tRNA modification enzyme-dependent redox homeostasis regulates synapse formation and memory
Post-transcriptional modification of RNA regulates gene expression at multiple levels. ALKBH8 is a tRNA-modifying enzyme that methylates wobble uridines in a subset of tRNAs to modulate translation. Through methylation of tRNA-selenocysteine, ALKBH8 promotes selenoprotein synthesis and regulates redox homeostasis. Pathogenic variants in have been linked to intellectual disability disorders in the human population, but the…
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rabindra.tharu.np@gmail.com
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A meiotic driver hijacks an epigenetic reader to disrupt mitosis in noncarrier offspring
Killer meiotic drivers (KMDs) are selfish genetic elements that distort Mendelian inheritance by selectively killing meiotic products lacking the KMD element, thereby promoting their own propagation. Although KMDs have been found in diverse eukaryotes, only a limited number of them have been characterized at the molecular level, and their killing mechanisms remain largely unknown. In…
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rabindra.tharu.np@gmail.com
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Structural duality enables a single protein to act as a toxin-antidote pair for meiotic drive
In sexual reproduction, selfish genetic elements known as killer meiotic drivers (KMDs) bias inheritance by eliminating gametes that do not carry them. The selective killing behavior of most KMDs can be explained by a toxin-antidote model, where a toxin harms all gametes while an antidote provides resistance to the toxin in carriers. This study investigates…
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rabindra.tharu.np@gmail.com
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Cellular-resolution optogenetics reveals attenuation-by-suppression in visual cortical neurons
The relationship between neurons’ input and spiking output is central to brain computation. Studies in vitro and in anesthetized animals suggest that nonlinearities emerge in cells’ input-output (IO; activation) functions as network activity increases, yet how neurons transform inputs in vivo has been unclear. Here, we characterize cortical principal neurons’ activation functions in awake mice…
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rabindra.tharu.np@gmail.com
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2.6-Å resolution cryo-EM structure of a class Ia ribonucleotide reductase trapped with mechanism-based inhibitor N(3)CDP
Ribonucleotide reductases (RNRs) reduce ribonucleotides to deoxyribonucleotides using radical-based chemistry. For class Ia RNRs, the radical species is stored in a separate subunit (β2) from the subunit housing the active site (α2), requiring the formation of a short-lived α2β2 complex and long-range radical transfer (RT). RT occurs via proton-coupled electron transfer (PCET) over a long…
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rabindra.tharu.np@gmail.com
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Evaluating large language models in theory of mind tasks
Eleven large language models (LLMs) were assessed using 40 bespoke false-belief tasks, considered a gold standard in testing theory of mind (ToM) in humans. Each task included a false-belief scenario, three closely matched true-belief control scenarios, and the reversed versions of all four. An LLM had to solve all eight scenarios to solve a single…
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rabindra.tharu.np@gmail.com
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Protein language models learn evolutionary statistics of interacting sequence motifs
Protein language models (pLMs) have emerged as potent tools for predicting and designing protein structure and function, and the degree to which these models fundamentally understand the inherent biophysics of protein structure stands as an open question. Motivated by a finding that pLM-based structure predictors erroneously predict nonphysical structures for protein isoforms, we investigated the…
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rabindra.tharu.np@gmail.com
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Live-cell imaging under centrifugation characterized the cellular force for nuclear centration in the Caenorhabditis elegans embryo
Organelles in cells are appropriately positioned, despite crowding in the cytoplasm. However, our understanding of the force required to move large organelles, such as the nucleus, inside the cytoplasm is limited, in part owing to a lack of accurate methods for measurement. We devised a method to apply forces to the nucleus of living embryos…
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rabindra.tharu.np@gmail.com
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Delivery of functional Cas:DNA nucleoprotein complexes into recipient bacteria through a type IV secretion system
CRISPR-associated (Cas) endonucleases and their derivatives are widespread tools for the targeted genetic modification of both prokaryotic and eukaryotic genomes. A critical step of all CRISPR-Cas technologies is the delivery of the Cas endonuclease to the target cell. Here, we investigate the possibility of using bacterial conjugation to translocate Cas proteins into recipient bacteria. Conjugative…
