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rabindra.tharu.np@gmail.com
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Cryo-EM structure of Alzheimer’s disease tau filaments with PET ligand MK-6240
Positron Emission Tomography (PET) ligands have advanced Alzheimer’s disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identify AD brain tissue with elevated tau burden, purify filaments, and determine the structure of second-generation high avidity PET ligand MK-6240 at 2.31 Å resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament…
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rabindra.tharu.np@gmail.com
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Evolutionary origin and population diversity of a cryptic hybrid pathogen
Cryptic fungal pathogens pose disease management challenges due to their morphological resemblance to known pathogens. Here, we investigated the genomes and phenotypes of 53 globally distributed isolates of Aspergillus section Nidulantes fungi and found 30 clinical isolates-including four isolated from COVID-19 patients-were A. latus, a cryptic pathogen that originated via allodiploid hybridization. Notably, all A.…
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rabindra.tharu.np@gmail.com
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Massively parallel characterization of insulator activity across the genome
A key question in regulatory genomics is whether cis-regulatory elements (CREs) are modular elements that can function anywhere in the genome, or whether they are adapted to certain genomic locations. To distinguish between these possibilities we develop MPIRE (Massively Parallel Integrated Regulatory Elements), a technology for recurrently assaying CREs at thousands of defined locations across…
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rabindra.tharu.np@gmail.com
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Massive multiplexing of spatially resolved single neuron projections with axonal BARseq
Neurons in the cortex are heterogeneous, sending diverse axonal projections to multiple brain regions. Unraveling the logic of these projections requires single-neuron resolution. Although a growing number of techniques have enabled high-throughput reconstruction, these techniques are typically limited to dozens or at most hundreds of neurons per brain, requiring that statistical analyses combine data from…
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rabindra.tharu.np@gmail.com
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A hierarchical atlas of the human cerebellum for functional precision mapping
The human cerebellum is activated by a wide variety of cognitive and motor tasks. Previous functional atlases have relied on single task-based or resting-state fMRI datasets. Here, we present a functional atlas that integrates information from seven large-scale datasets, outperforming existing group atlases. The atlas has three further advantages. First, the atlas allows for precision…
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rabindra.tharu.np@gmail.com
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Mettl1-dependent m(7)G tRNA modification is essential for maintaining spermatogenesis and fertility in Drosophila melanogaster
Modification of guanosine to N-methylguanosine (mG) in the variable loop region of tRNA is catalyzed by the METTL1/WDR4 heterodimer and stabilizes target tRNA. Here, we reveal essential functions of Mettl1 in Drosophila fertility. Knockout of Mettl1 (Mettl1-KO) causes no major effect on the development of non-gonadal tissues, but abolishes the production of elongated spermatids and…
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rabindra.tharu.np@gmail.com
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Immune profiling-based targeting of pathogenic T cells with ustekinumab in ANCA-associated glomerulonephritis
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a life-threatening autoimmune disease that often results in kidney failure caused by crescentic glomerulonephritis (GN). To date, treatment of most patients with ANCA-GN relies on non-specific immunosuppressive agents, which may have serious adverse effects and be only partially effective. Here, using spatial and single-cell transcriptome analysis, we characterize inflammatory…
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rabindra.tharu.np@gmail.com
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Deep generative models of protein structure uncover distant relationships across a continuous fold space
Our views of fold space implicitly rest upon many assumptions that impact how we analyze, interpret and understand protein structure, function and evolution. For instance, is there an optimal granularity in viewing protein structural similarities (e.g., architecture, topology or some other level)? Similarly, the discrete/continuous dichotomy of fold space is central, but remains unresolved. Discrete…
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rabindra.tharu.np@gmail.com
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Multiplex, single-cell CRISPRa screening for cell type specific regulatory elements
CRISPR-based gene activation (CRISPRa) is a strategy for upregulating gene expression by targeting promoters or enhancers in a tissue/cell-type specific manner. Here, we describe an experimental framework that combines highly multiplexed perturbations with single-cell RNA sequencing (sc-RNA-seq) to identify cell-type-specific, CRISPRa-responsive cis-regulatory elements and the gene(s) they regulate. Random combinations of many gRNAs are introduced…
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rabindra.tharu.np@gmail.com
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A comparative analysis of planarian genomes reveals regulatory conservation in the face of rapid structural divergence
The planarian Schmidtea mediterranea is being studied as a model species for regeneration, but the assembly of planarian genomes remains challenging. Here, we report a high-quality haplotype-phased, chromosome-scale genome assembly of the sexual S2 strain of S. mediterranea and high-quality chromosome-scale assemblies of its three close relatives, S. polychroa, S. nova, and S. lugubris. Using…
