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rabindra.tharu.np@gmail.com
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p21 regulates expression of ECM components and promotes pulmonary fibrosis via CDK4 and Rb
Fibrosis and accumulation of senescent cells are common tissue changes associated with aging. Here, we show that the CDK inhibitor p21 (CDKN1A), known to regulate the cell cycle and the viability of senescent cells, also controls the expression of extracellular matrix (ECM) components in senescent and proliferating cells of the fibrotic lung, in a manner…
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rabindra.tharu.np@gmail.com
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Human genomic DNA is widely interspersed with i-motif structures
DNA i-motif structures are formed in the nuclei of human cells and are believed to provide critical genomic regulation. While the existence, abundance, and distribution of i-motif structures in human cells has been demonstrated and studied by immunofluorescent staining, and more recently NMR and CUT&Tag, the abundance and distribution of such structures in human genomic…
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rabindra.tharu.np@gmail.com
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A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma
Glioma cells hijack developmental programs to control cell state. Here, we uncover a glioma cell state-specific metabolic liability that can be therapeutically targeted. To model cell conditions at brain tumor inception, we generated genetically engineered murine gliomas, with deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling…
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rabindra.tharu.np@gmail.com
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Modular control of vertebrate axis segmentation in time and space
How the timing of development is linked to organismal size is a longstanding question. Although numerous studies have reported a correlation of temporal and spatial traits, the developmental or selective constraints underlying this link remain largely unexplored. We address this question by studying the periodic process of embryonic axis segmentation in-vivo in Oryzias fish. Interspecies…
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rabindra.tharu.np@gmail.com
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An ancient role for CYP73 monooxygenases in phenylpropanoid biosynthesis and embryophyte development
The phenylpropanoid pathway is one of the plant metabolic pathways most prominently linked to the transition to terrestrial life, but its evolution and early functions remain elusive. Here, we show that activity of the t-cinnamic acid 4-hydroxylase (C4H), the first plant-specific step in the pathway, emerged concomitantly with the CYP73 gene family in a common…
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rabindra.tharu.np@gmail.com
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CMG helicase disassembly is essential and driven by two pathways in budding yeast
The CMG helicase is the stable core of the eukaryotic replisome and is ubiquitylated and disassembled during DNA replication termination. Fungi and animals use different enzymes to ubiquitylate the Mcm7 subunit of CMG, suggesting that CMG ubiquitylation arose repeatedly during eukaryotic evolution. Until now, it was unclear whether cells also have ubiquitin-independent pathways for helicase…
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rabindra.tharu.np@gmail.com
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A common mechanism for recruiting the Rrm3 and RTEL1 accessory helicases to the eukaryotic replisome
The eukaryotic replisome is assembled around the CMG (CDC45-MCM-GINS) replicative helicase, which encircles the leading-strand DNA template at replication forks. When CMG stalls during DNA replication termination, or at barriers such as DNA-protein crosslinks on the leading strand template, a second helicase is deployed on the lagging strand template to support replisome progression. How these…
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rabindra.tharu.np@gmail.com
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T4 DNA polymerase prevents deleterious on-target DNA damage and enhances precise CRISPR editing
Unintended on-target chromosomal alterations induced by CRISPR/Cas9 in mammalian cells are common, particularly large deletions and chromosomal translocations, and present a safety challenge for genome editing. Thus, there is still an unmet need to develop safer and more efficient editing tools. We screened diverse DNA polymerases of distinct origins and identified a T4 DNA polymerase…
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rabindra.tharu.np@gmail.com
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The tyrosine phosphatases LAR and PTPRδ act as receptors of the nidogen-tetanus toxin complex
Tetanus neurotoxin (TeNT) causes spastic paralysis by inhibiting neurotransmission in spinal inhibitory interneurons. TeNT binds to the neuromuscular junction, leading to its internalisation into motor neurons and subsequent transcytosis into interneurons. While the extracellular matrix proteins nidogens are essential for TeNT binding, the molecular composition of its receptor complex remains unclear. Here, we show that…
