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rabindra.tharu.np@gmail.com
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Targeting a key protein-protein interaction surface on mitogen-activated protein kinases by a precision-guided warhead scaffold
For mitogen-activated protein kinases (MAPKs) a shallow surface-distinct from the substrate binding pocket-called the D(ocking)-groove governs partner protein binding. Screening of broad range of Michael acceptor compounds identified a double-activated, sterically crowded cyclohexenone moiety as a promising scaffold. We show that compounds bearing this structurally complex chiral warhead are able to target the conserved MAPK…
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rabindra.tharu.np@gmail.com
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Single-cell transcriptomes identify patient-tailored therapies for selective co-inhibition of cancer clones
Intratumoral cellular heterogeneity necessitates multi-targeting therapies for improved clinical benefits in advanced malignancies. However, systematic identification of patient-specific treatments that selectively co-inhibit cancerous cell populations poses a combinatorial challenge, since the number of possible drug-dose combinations vastly exceeds what could be tested in patient cells. Here, we describe a machine learning approach, scTherapy, which leverages…
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rabindra.tharu.np@gmail.com
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Whole-genome sequencing in 333,100 individuals reveals rare non-coding single variant and aggregate associations with height
The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare ( < 0.1% minor-allele-frequency) single-variant…
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rabindra.tharu.np@gmail.com
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Immune escape and attenuated severity associated with the SARS-CoV-2 BA.2.86/JN.1 lineage
The SARS-CoV-2 BA.2.86 lineage, and its sublineage JN.1 in particular, achieved widespread transmission in the US during winter 2023-24. However, this surge in infections was not accompanied by COVID-19 hospitalizations and mortality commensurate with prior waves. To understand shifts in COVID-19 epidemiology associated with JN.1 emergence, we compared characteristics and clinical outcomes of time-matched cases…
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rabindra.tharu.np@gmail.com
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Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration
In lung disease, persistence of KRT8-expressing aberrant basaloid cells in the alveolar epithelium is associated with impaired tissue regeneration and pathological tissue remodeling. We analyzed single cell RNA sequencing datasets of human interstitial lung disease and found the profibrotic Interleukin-11 (IL11) cytokine to be highly and specifically expressed in aberrant KRT8 basaloid cells. IL11 is…
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rabindra.tharu.np@gmail.com
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Minimal exposure durations reveal visual processing priorities for different stimulus attributes
Human vision can detect a single photon, but the minimal exposure required to extract meaning from stimulation remains unknown. This requirement cannot be characterised by stimulus energy, because the system is differentially sensitive to attributes defined by configuration rather than physical amplitude. Determining minimal exposure durations required for processing various stimulus attributes can thus reveal…
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rabindra.tharu.np@gmail.com
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Diminished circadian and ultradian rhythms of human brain activity in pathological tissue in vivo
Chronobiological rhythms, such as the circadian rhythm, have long been linked to neurological disorders, but it is currently unknown how pathological processes affect the expression of biological rhythms in the brain. Here, we use the unique opportunity of long-term, continuous intracranially recorded EEG from 38 patients (totalling 6338 hours) to delineate circadian (daily) and ultradian…
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rabindra.tharu.np@gmail.com
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De novo design of mini-protein binders broadly neutralizing Clostridioides difficile toxin B variants
Clostridioides difficile toxin B (TcdB) is the key virulence factor accounting for C. difficile infection-associated symptoms. Effectively neutralizing different TcdB variants with a universal solution poses a significant challenge. Here we present the de novo design and characterization of pan-specific mini-protein binders against major TcdB subtypes. Our design successfully binds to the first receptor binding…
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rabindra.tharu.np@gmail.com
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A transient high-dimensional geometry affords stable conjunctive subspaces for efficient action selection
Flexible action selection requires cognitive control mechanisms capable of mapping the same inputs to different output actions depending on the context. From a neural state-space perspective, this requires a control representation that separates similar input neural states by context. Additionally, for action selection to be robust and time-invariant, information must be stable in time, enabling…
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rabindra.tharu.np@gmail.com
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Evolutionarily conserved fMRI network dynamics in the mouse, macaque, and human brain
Evolutionarily relevant networks have been previously described in several mammalian species using time-averaged analyses of fMRI time-series. However, fMRI network activity is highly dynamic and continually evolves over timescales of seconds. Whether the dynamic organization of resting-state fMRI network activity is conserved across mammalian species remains unclear. Using frame-wise clustering of fMRI time-series, we find…
