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rabindra.tharu.np@gmail.com
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Sequence modeling and design from molecular to genome scale with Evo
The genome is a sequence that encodes the DNA, RNA, and proteins that orchestrate an organism’s function. We present Evo, a long-context genomic foundation model with a frontier architecture trained on millions of prokaryotic and phage genomes, and report scaling laws on DNA to complement observations in language and vision. Evo generalizes across DNA, RNA,…
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rabindra.tharu.np@gmail.com
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Acoustic cognitive map-based navigation in echolocating bats
Bats are known for their ability to use echolocation for obstacle avoidance and orientation. However, the extent to which bats utilize their highly local and directional echolocation for kilometer-scale navigation is unknown. In this study, we translocated wild Kuhl’s pipistrelle bats and tracked their homing abilities while manipulating their visual, magnetic, and olfactory sensing and…
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rabindra.tharu.np@gmail.com
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Two codependent routes lead to high-level MRSA
Methicillin-resistant (MRSA), in which acquisition of [which encodes the cell wall peptidoglycan biosynthesis component penicillin-binding protein 2a (PBP2a)] confers resistance to β-lactam antibiotics, is of major clinical concern. We show that, in the presence of antibiotics, MRSA adopts an alternative mode of cell division and shows an altered peptidoglycan architecture at the division septum. PBP2a…
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rabindra.tharu.np@gmail.com
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Group 2 innate lymphoid cells promote inhibitory synapse development and social behavior
The innate immune system shapes brain development and is implicated in neurodevelopmental diseases. It is critical to define the relevant immune cells and signals and their impact on brain circuits. In this work, we found that group 2 innate lymphoid cells (ILC2s) and their cytokine interleukin-13 (IL-13) signaled directly to inhibitory interneurons to increase inhibitory…
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rabindra.tharu.np@gmail.com
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A solution to the anti-Bredt olefin synthesis problem
The π-bonds in unsaturated organic molecules are typically associated with having well-defined geometries that are conserved across diverse structural contexts. Nonetheless, these geometries can be distorted, leading to heightened reactivity of the π-bond. Although π-bond-containing compounds with bent geometries are well utilized in synthetic chemistry, the corresponding leveraging of π-bond-containing compounds that display twisting or…
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rabindra.tharu.np@gmail.com
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A ubiquitous mobile genetic element changes the antagonistic weaponry of a human gut symbiont
DNA transfer is ubiquitous in the human gut microbiota, especially among species of the order Bacteroidales. In silico analyses have revealed hundreds of mobile genetic elements shared between these species, yet little is known about the phenotypes they encode, their effects on fitness, or pleiotropic consequences for the recipient’s genome. In this work, we show…
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rabindra.tharu.np@gmail.com
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Helicase-assisted continuous editing for programmable mutagenesis of endogenous genomes
Deciphering the context-specific relationship between sequence and function is a major challenge in genomics. Existing tools for inducing locus-specific hypermutation and evolution in the native genome context are limited. Here we present a programmable platform for long-range, locus-specific hypermutation called helicase-assisted continuous editing (HACE). HACE leverages CRISPR-Cas9 to target a processive helicase-deaminase fusion that incurs…
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rabindra.tharu.np@gmail.com
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Direct optical measurement of intramolecular distances with angstrom precision
Optical investigations of nanometer distances between proteins, their subunits, or other biomolecules have been the exclusive prerogative of Förster resonance energy transfer (FRET) microscopy for decades. In this work, we show that MINFLUX fluorescence nanoscopy measures intramolecular distances down to 1 nanometer-and in planar projections down to 1 angstrom-directly, linearly, and with angstrom precision. Our…
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rabindra.tharu.np@gmail.com
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Creation of de novo cryptic splicing for ALS and FTD precision medicine
Loss of function of the RNA-binding protein TDP-43 (TDP-LOF) is a hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Here we describe TDP-REG, which exploits the specificity of cryptic splicing induced by TDP-LOF to drive protein expression when and where the disease process occurs. The SpliceNouveau algorithm combines deep learning with rational design…
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rabindra.tharu.np@gmail.com
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A multivalent mRNA-LNP vaccine protects against Clostridioides difficile infection
infection (CDI) is an urgent public health threat with limited preventative options. In this work, we developed a messenger RNA (mRNA)-lipid nanoparticle (LNP) vaccine targeting toxins and virulence factors. This multivalent vaccine elicited robust and long-lived systemic and mucosal antigen-specific humoral and cellular immune responses across animal models, independent of changes to the intestinal microbiota.…
