Biology subjects

Jha, S.

Publications and source records attributed to Jha, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Moving object generates topographic responses in the majority of entorhinal neurons

Vision is crucial in generating a complex array of responses in rodents during spatial exploration and in humans during memory tasks. These tasks involve other variables too, e.g. multisensory cues in rodents and complex memories in humans. Further, there are major differences between the medial and lateral entorhinal cortical (MEC and LEC) functional cell types. To understand the contribution of purely visual information to entorhinal responses, we presented a simple, moving vertical bar of light to head-fixed mice, without any task or reward. Surprisingly, 66% (2391/3601) of the MEC broad spiking neurons were significantly modulated by the bar position on the screen. Visual tuning in MEC had a pronounced dorsoventral topography --the tuning strength dropped from 79% in the dorsal most quartile to 40% in the ventral most quartile. Unlike major differences in spatial and other codes between MEC and LEC during free foraging experiments, LEC cells showed very similar visual tuning (392/606, 65%), including the dorso-ventral gradient in LEC5. Additionally, the majority of putative interneurons, from MEC as well as LEC, showed similar, widespread visual tuning, unlike spatial tasks. Neurons also encoded the object motion direction (naso-temporal vs. temporo-nasal visual motion) with changes in mean rate, tuning strength and/or tuning location. Such directional nature of visual tuning indicates significant history-dependence or sequence encoding. Consistently, replacing the continuous motion by randomly flashing bar of light abolished bar-tuning in two-thirds of continuous bar-tuned cells and substantially altered tuning in the rest. These results reveal the contribution of purely visual inputs in generating anatomically organized responses in the majority of entorhinal neurons. The prevalence and similarity of visual tuning across all layers of MEC as well as LEC exceeds that of other known functional cell types (like grid cells in MEC or egocentric object tuning/time-cells in LEC) during spatial navigation tasks and could be foundational in understanding entorhinal complexity.

neuroscience↗

bioRxiv2026

Genetic and structural interpretation of NLRP1 FIIND domain variants in glioma in an Indian cohort: a pilot study

Gliomas, particularly glioblastoma (GBM), are aggressive primary brain tumors associated with dysregulated NLR signaling, a pathway central to innate immunity and inflammation. NLRP1 triggers proinflammatory cytokine release and pyroptotic cell death via autoproteolytic cleavage. The FIIND missense variant rs11651270 (M1184V) may modulate this cleavage process. While NLRP1 polymorphisms are associated with various diseases and cancers, their specific impact on glioma remains to be investigated. In our study, five FIIND-domain single-nucleotide polymorphisms (SNPs) of NLRP1 rs371579423, rs58604457, rs57636751, rs11651270, and rs2301583, were investigated by Sanger sequencing in a clinical cohort of glioma patients and compared against population-matched controls from the GenomeIndia dataset (Rajasthan cohort) using genetic association models. Molecular dynamics simulations were performed to evaluate the structural effects of the missense variant rs11651270 (M1184V) in NLRP1 during pre- and post-cleavage states. The linked variants rs58604457 (G>A) and rs57636751 (C>T) exhibited complete linkage disequilibrium (r2=1.00) and were significantly associated with lower odds of glioma (odds ratio ~0.5). The missense variant rs11651270 (T>C) showed no association with glioma risk. Notably, the SNP rs2301583 had a higher allelic frequency in glioma cases despite being absent in the GenomeIndia population-based control catalogue. Molecular dynamics simulations revealed that the M1184V substitution stabilizes local FIIND architecture by preserving {beta}-strand organization through persistent interactions with neighboring residues. This study provides the first combined genetic and structural analysis of NLRP1 FIIND-domain variants in an Indian glioma cohort. These findings illustrate the potential value of integrating population-based genetic association with structural modelling to generate hypotheses and uncover potential functional mechanisms of inflammasome-gene variants in neuro-oncology.

cancer biology↗

bioRxiv2026

miRNA-mRNA Interaction Network Analysis in Alzheimer's Disease for Biomarker Discovery

--Alzheimers disease (AD) is a complex neurodegenerative disorder characterized by widespread dysregulation of gene expression and regulatory pathways. MicroRNAs (miRNAs) act as key post-transcriptional regulators by modulating messenger RNAs (mRNAs), and their disruption can influence synaptic function, neuroinflammation, and neuronal survival. In this study, we present an integrative transcriptome-driven framework to identify AD-associated miRNA-mRNA regulatory signatures and potential biomarkers. Transcriptomic and clinical data were obtained from the Alzheimers Disease Neuroimaging Initiative (ADNI) and the GEO dataset GSE48552. Differential expression analysis (Welchs t-test with FDR correction) identified 148 significantly dysregulated genes (35 up-regulated, 113 down-regulated) between AD and cognitively normal controls. Experimentally validated and predicted miRNA-target interactions were integrated using miRTarBase and additional target resources, yielding 1,669,089 miRNA-gene interactions involving 3,055 unique miRNAs, with strong enrichment toward down-regulated gene targeting. Functional enrichment analysis revealed convergence of miRNA-regulated genes on synaptic signaling, neuronal communication, intracellular transport, apoptosis, oxidative stress, and PI3K-Akt/MAPK-related pathways. A bipartite miRNA-mRNA regulatory network (2,343 nodes; 14,603 edges) was constructed and analyzed using centrality metrics, highlighting key hub regulators including PBX1 and SLC7A5. Finally, supervised machine learning models trained on selected molecular features achieved strong performance, with ensemble approaches (XGBoost/LightGBM) demonstrating robust discrimination of AD from controls.

bioinformatics↗

bioRxiv2025

NLRP3 Inflammasome Exhibits Context-Dependent Roles in Glioblastoma-Astrocyte Crosstalk

Glioblastoma (GBM) is a highly aggressive brain tumor characterized by molecular and cellular heterogeneity and poor patient survival. NLRP3 inflammasome regulates inflammation and cell death with context-specific roles in cancer, but its functions in GBM tumour and astrocyte interactions remain unclear. In this study, we analyzed NLRP3 expression and function in GBM cell lines (LN-229 and LN18), astrocytes (SVG), patient-derived tissues, and organoids. Basal NLRP3 expression was higher in astrocytes than in GBM cells and increased after LPS stimulation, altering astrocyte morphology and NLRP3 subcellular localization. siRNA-mediated silencing of NLRP3 reduced GBM proliferation, migration, and viability in GBM cells, while enhancing proliferation and cytokine secretion in astrocytes, highlighting its context-dependent effects. NLRP3 deficiency exhibited reciprocal cytokine paracrine signaling, with GBM cells releasing elevated levels of IL-6 and TNF-, and astrocytes releasing elevated levels of IL-1{beta}. Glyburide treatment reduced NLRP3 expression and IL-1{beta} release in GBM cells but elevated NLRP3 and IL-1{beta} in astrocytes. Overall, these data reveal NLRP3s dual roles in GBM-astrocyte crosstalk, suggesting cell-type-selective inhibition for therapeutic exploration.

cancer biology↗

bioRxiv2025

NLRP12-mediated Glioblastoma-Astrocyte Cross-talk Promotes Tumor Growth

Nucleotide-binding domain leucine-rich repeat-containing receptors (NLR) are cytosolic pattern recognition receptors that regulate inflammation by sensing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). NLRP12 is a cytosolic protein with inflammation-promoting and inflammation-attenuating properties. NLRP12 exhibits tumor-suppressive or tumor-promoting effects that may be cancer, cell-type, context-dependent, aided by differences in the microenvironment contributing to the pathophysiology of hepatocellular carcinoma, prostate cancer, colitis-associated cancer, and glioblastoma (GBM). GBM is a grade IV malignant brain tumor with poor patient survival and high tumor recurrence due to a heterogeneous cell population and angiogenesis. Our previous research reported NLRP12 as a potential prognostic marker for GBM with high expression in GBM patient tissues. In the present study, we investigated the role of NLRP12-mediated signalling between GBM and tumor-adjacent astrocytes, using a comprehensive panel of experimental models, including LN-229 GBM and SVG astrocyte cell lines, cell line-derived spheroids, patient-derived primary glioma cells, and patient-derived glioma organoids. We report that NLRP12 deficiency reduces cell proliferation and viability in the LN-229 cells, but increases these parameters in SVG cells. Furthermore, NLRP12-deficient LN-229 cells display attenuated ability to form three-dimensional spheroids, indicating a role of NLRP12 in anchorage-independent growth, which is considered a hallmark of tumorigenicity. Analysis of patient-derived glioma tissue and patient-derived GBM organoids revealed differential expression of NLRP12. Our findings suggest that NLRP12 modulates GBM cell proliferation, viability, and anchorage-independent growth in a cell-context dependent manner. The cell-type-specific roles of NLRP12 may underlie its complex contribution to GBM pathophysiology with implications for therapy and prognosis. SummaryNLRP12, a cytosolic regulator of inflammation, exhibits context-dependent roles in cancer. Its deficiency reduces glioblastoma cell proliferation, viability, and spheroid formation, while enhancing these properties in astrocytes, indicating a cell-type-dependent role for NLRP12 in GBM progression.

cancer biology↗

bioRxiv2025

Repurposing Nelfinavir: AIM2 Inflammasome-Driven Anti-tumor Effects in Glioblastoma

Nelfinavir (NFR), originally developed as an antiretroviral agent for the human immunodeficiency virus, has demonstrated anti-cancer properties across various malignancies; however, its therapeutic potential in Glioblastoma (GBM) remains largely unexplored. In the present study, we investigated the anti-tumor effects of NFR in GBM using a comprehensive panel of experimental models, including established GBM cell lines, GBM cell line-derived spheroids, patient-derived primary glioma cells, and patient-derived glioma organoids. We further evaluated the synergistic potential of NFR in combination with standard chemotherapeutic agents, Carboplatin and Doxorubicin, across these platforms. In vitro analyses revealed that NFR significantly inhibits GBM cell proliferation and induces both apoptotic and necrotic cell death. Mechanistically, we identified activation of the AIM2 inflammasome as a potential additional pathway mediating the anti-tumor effects of NFR. Collectively, our findings highlight NFR as a promising therapeutic candidate for GBM, exerting its effects through anti-proliferative and pro-death mechanisms potentially linked to AIM2 inflammasome activation.

cancer biology↗

bioRxiv2025

Bumblebee queens differ in brain morphology but not learning performance across life stages

Animal cognition and brain morphology can vary between individuals and across a lifetime as a function of social and ecological requirements. Bumblebees have distinct ecological pressures acting upon individuals at different times: young queens (gynes) and workers share similar challenges as they both forage as part of the colony, but only queens overwinter and start a colony the following season, switching to a reproductive stage. Here we compared bumblebee (Bombus impatiens) visual learning and brain morphology across age-matched workers and gynes and older reproductive queens. We expected foraging-stage gynes to be better at visual learning than reproductive queens and visual regions to be reduced in the reproductive queens, in line with work in other social insects. However, we found that gynes and queens performed similarly, while both performed better than workers. We also found that reproductive queens had larger olfactory regions (antennal lobes) than gynes, while visual regions (medulla and lobula) did not differ, indicating a greater investment in olfactory regions in this later reproductive stage. Brain regions also scaled differently with body size for gynes and workers. Overall, our results provide behavioral and morphological evidence that social and ecological roles in a colony shape cognition and neural investment.

animal behavior and cognition↗

bioRxiv2024

Innate Immune Receptor NLRX1: Potential Modulator of Glioblastoma Pathophysiology

Gliomas are primary brain tumors that develop from glial cells within the central nervous system and are among the deadliest human cancers. Glioblastoma (GBM) is the most malignant form of glioma. NLRX1 is an innate immune pattern recognition receptor that exhibits tumor-suppressive and tumor-promoting effects that may be cancer or cell-type, context-dependent, aided by differences in the microenvironment. Here, we report that NLRX1 is differentially expressed in microglia, astrocytes, GBM cell lines, and glioma patient tissues. siRNA-mediated silencing of Nlrx1 decreases the ability of the GBM cell line, LN-229, to proliferate and migrate. Nlrx1-/- GBM cells exhibit attenuated ability to generate 3D spheroids and enhanced capability to form tunneling nanotubes. Moreover, Nlrx1-/- GBM cells show decreased expression of autophagy markers, suggesting that NLRX1 plays a role in maintaining autophagy in GBM. In summary, our findings indicate that NLRX1 may modulate GBM pathophysiology by regulating GBM cell proliferation, migration, and metabolism. We believe our understanding of NLRX1 in GBM pathophysiology paves the potential development of GBM-targeting therapeutics that may delay disease progression and/or improve survival.

cancer biology↗

bioRxiv2024

Structures of Multiple Peptide Resistance Factor from Pseudomonas aeruginosa

The aminoacylation of lipid head group in many bacteria is carried out by bi-functional enzymes called MprF, which encode for a soluble synthase domain that typically transfers lysine or alanine from a tRNA to lipid head groups, and the modified lipid is translocated across the leaflets by a transmembrane domain. This modification of the lipids probably evolved to adapt to the environment where the microbes reside. Here, we describe the cryoEM structures of MprF enzyme from Pseudomonas aeruginosa revealing a dimeric enzyme with a distinct architecture when compared with the homologous Rhizobium enzymes and validate this arrangement with biochemical analysis. The cryoEM maps and the models in detergent micelle and nanodisc reveal a conformational change of the terminal helix of the synthase domain, highlighting the dynamic elements in the enzyme that might facilitate catalysis. Several lipid-like densities are observed in the cryoEM maps, which might indicate the path taken by the lipids and the coupling function of the two functional domains. Thus, the structure of a well-characterised PaMprF lays a platform for understanding the mechanism of amino acid transfer to a lipid head group and subsequent flipping across the leaflet that changes the property of the membrane.

biochemistry↗

bioRxiv2024

Floral visitors differentially respond to local and landscape grassland features

O_LIPredicting how habitat composition alters communities of mobile ecosystem service providers remains a major challenge in community ecology. This is partially because separate taxonomic groups that provide the same service may respond uniquely to changes in habitat and associated resource availability. Further, the spatial scale at which habitat features impact each group can vary. Failure to account for these differences significantly limits the ability to quantify shared versus contrasting responses to habitat for important ecosystem service-providing groups. C_LIO_LIWe investigated the impacts of local (habitat patch level) and landscape features in the US Southern Great Plains on groups of pollinating insects with different basic biologies: Coleoptera, Diptera, Hymenoptera, and Lepidoptera. Habitat features included local flower and shelter resources as well as landscape-scale semi-natural habitat. C_LIO_LIWe found that bare ground supported more Hymenoptera and Lepidoptera but fewer Diptera, while more diverse flower communities supported more Hymenoptera but fewer Coleoptera. Interestingly, given that this study occurred in a grassland system, forest cover in the surrounding landscape more strongly affected pollinator diversity than grassland cover did. Landscapes with more woodland had higher Coleoptera and Diptera richness. C_LIO_LIOur results highlight that pollinator conservation and sustainable land management depend on understanding the habitat needs, including shelter, of diverse pollinators. Because taxa can have opposite responses to specific habitat features or scales, providing a range of grassland management practices (e.g., variety in the timing and type of biomass removal) may be the most effective approach to support the broader pollinator community. C_LI

ecology↗

bioRxiv2024

Impairment of proteasome-associated deubiquitinating enzyme Uchl5/UBH-4 affects autophagy

The autophagy-lysosomal pathway (ALP) and the ubiquitin-proteasome system (UPS) are the two major intracellular proteolytic systems that mediate protein turnover in eukaryotes. Although a crosstalk exists between these two systems, it is still unclear how UPS and ALP interact in vivo. Here, we have investigated how impaired function of the proteasome-associated deubiquitinating enzyme (DUB) Uchl5/UBH-4, a regulator of proteasome activity, affects autophagy in human cells and in various tissues in a multicellular organism. We have used the established GFP-LC3-RFP-LC3{Delta}G autophagy reporter HeLa cell line and show that downregulation of Uchl5 by siRNA reduces autophagy, which is similar to a previously reported role of the proteasome-associated DUB Usp14 on autophagy. Exposing Caenorhabditis elegans carrying the autophagy reporter mCherry::GFP::LGG-1 to ubh-4 or usp-14 RNAi, or to their pharmacological inhibitors, results in diverse effects regarding the numbers of autophagosomes and autolysosomes in the intestine, hypodermal seam cells and the pharynx. Our results reveal that the proteasome-associated DUBs Uchl5/UBH-4 and Usp14 affect autophagy in a differential tissue manner. A deeper insight into the interplay between UPS and ALP in various tissues in vivo has the potential to promote development of therapeutic approaches for disorders associated with proteostasis dysfunction. SummaryModulation of UPS via pharmacological or genetic impairment of the proteasome-associated DUB Uchl5/UBH-4 affects autophagy in human cells and in a tissue-differential manner in C. elegans.

cell biology↗

bioRxiv2023

Oryza genera-specific novel Histone H4 variant predisposes H4 Lysine5 Acetylation marks to modulate salt stress responses

Paralogous variants of canonical histones guide accessibility to DNA and function as additional layers of genome regulation. Across eukaryotes, the occurrence, mechanism of action and functional significance of several variants of core histones are well known except that of histone H4. Here we show that a novel variant of H4 (H4.V), expressing tissue-specifically among members of Oryza genera, mediates specific epigenetic changes contributing majorly to salt tolerance. H4.V was incorporated to specific chromosomal locations where it blocked deposition of active histone marks. Under salt stress, large scale re-distribution of H4.V enabled incorporation of stress dependent histone H4 Lysine5 Acetylation (H4K5Ac) marks. Mis-expression of H4.V led to defects at morphological level especially in reproductive tissues, and in mounting stress responses. H4.V mediated these alterations by condensing chromatin at specific genomic regions as seen with cryo-EM structure of reconstituted H4.V containing nucleosomes. These results not only uncovered the presence of a H4 variant in plants, but also a novel chromatin regulation of stress responses that might have contributed to success of semi-aquatic Oryza members under variable water-limiting conditions. One-line summaryHistone H4 variant predisposes chromatin for stress responses O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/551207v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@101fa0forg.highwire.dtl.DTLVardef@c7fda9org.highwire.dtl.DTLVardef@1de9a0aorg.highwire.dtl.DTLVardef@1532641_HPS_FORMAT_FIGEXP M_FIG C_FIG

plant biology↗

bioRxiv2023

Detergent induced structural perturbations in peanut agglutinin: Insights from spectroscopic and molecular dynamic simulation studies

The three dimensional structure of a protein is very important for its structure. Studies relating to protein structure have been numerous and the effect of denaturants on proteins can help understand the process of protein folding and misfolding. Detergents are important denaturants and play important roles in various fields. Here we explored the effect of sodium dodecyl sulphate (SDS) and cetyltrimethylammonium bromide (CTAB) on the structure of peanut agglutinin (PNA). The protein was purified from its natural source and impact of SDS and CTAB was studied by circular dichroism, intrinsic fluorescence, 8-anilino-1-napthalenesulfonic acid, molecular docking and molecular dynamics simulation. Pure peanut agglutinin showed a trough at 220 nm and positive ellipticity peak at 195 nm, specific for lectins. Results from the experimental and simulation studies suggest how oppositely charged detergents can interact differently and lead to varied structural perturbations in PNA. Both the surfactants induce all protein-like circular dichroism in the protein, above its critical micelle concentrations, with significant change in accessible surface area that became more hydrophobic upon the treatment. Major interactions between the surfactants and protein, resulting in PNA conformational rearrangement, are electrostatic and van der Waals interactions. However, CTAB, like a cationic surfactant, has similar effects as anionic surfactant (SDS) but at significantly very low concentration. Though the effects followed same pattern in both the surfactant treatment, i.e. above respective CMC, the surfactants were inducing -helix/coil like conformation in PNA.

biochemistry↗

bioRxiv2023

Mutations in S2 subunit of SARS-CoV-2 Omicron spike strongly influence its conformation, fusogenicity and neutralization sensitivity

SARS-CoV-2 has remarkable ability to respond to and evolve against the selection pressure by host immunity exemplified by emergence of Omicron lineage. Here, we characterized the functional significance of mutations in Omicron spike. By systematic transfer of mutations in WT spike we assessed neutralization sensitivity, fusogenicity, and TMPRSS2-dependence for entry. The data revealed that the mutations in both S1 and S2 complement to make Omicron highly resistant. Strikingly, the mutations in Omicron S2 modulated the neutralization sensitivity to NTD- and RBD-antibodies, but not to S2 specific neutralizing antibodies, suggesting that the mutations in S2 were primarily acquired to gain resistance to S1-antibodies. Although all six mutations in S2 appeared to act in concert, D796Y showed greatest impact on neutralization sensitivity and rendered WT virus >100-fold resistant to S309, COVA2-17, and 4A8. S2 mutations greatly reduced the antigenicity for NAbs due to reduced exposure of epitopes. In terms of the entry pathway, S1 or S2 mutations only partially altered the entry phenotype of WT and required both sets of mutations for complete switch to endosomal route and loss of syncytia formation. In particular, N856K and L981F in Omicron reduced fusion capacity and explain why subsequent Omicron variants lost them to regain fusogenicity.

microbiology↗

bioRxiv2023

E4F1 and ZNF148 are transcriptional activators of the A57C and wildtype TERT promoter

Point mutations within the TERT promoter are the most recurrent somatic non-coding mutations identified across different cancer types, including glioblastoma, melanoma, hepatocellular carcinoma, and bladder cancer. They are most abundant at C146T and C124T and rarer at A57C, with the latter originally described as a familial case but subsequently shown also to occur somatically. All three mutations create de novo ETS (E-twenty-six specific) binding sites and result in the reactivation of the TERT gene, allowing cancer cells to achieve replicative immortality. Here, we employed a systematic proteomics screen to identify transcription factors preferentially binding to the C146T, C124T and A57C mutations. While we confirmed binding of multiple ETS factors to the mutant C146T and C124T sequences, we identified E4F1 as an A57C-specific binder and ZNF148 as a TERT WT binder that is excluded from the TERT promoter by the C124T allele. Both proteins are activating transcription factors that bind specifically to the A57C and wildtype (at position 124) TERT promoter sequence in corresponding cell lines and upregulate TERT transcription and telomerase activity. Our work describes new regulators of TERT gene expression with possible roles in cancer.

cancer biology↗

bioRxiv2021

Scalable Adaptive Protein Ensemble Refinement Integrating Flexible Fitting

Recent advances in cryo-electron microscopy (cryo-EM) have enabled modeling macromolecular complexes that are essential components of the cellular machinery. The density maps derived from cryo-EM experiments are often integrated with manual, knowledge or artificial intelligence driven, and physics-guided computational methods to build, fit, and refine molecular structures. Going beyond a single stationary-structure determination scheme, it is becoming more common to interpret the experimental data with an ensemble of models, which contributes to an average observation. Hence, there is a need to decide on the quality of an ensemble of protein structures on-the-fly, while refining them against the density maps. We introduce such an adaptive decision making scheme during the molecular dynamics flexible fitting (MDFF) of biomolecules. Using RADICAL-Cybertools, and the new RADICAL augmented MDFF implementation (R-MDFF) is examined in high-performance computing environments for refinement of two protein systems, Adenylate Kinase and Carbon Monoxide Dehy-drogenase. For the test cases, use of multiple replicas in flexible fitting with adaptive decision making in R-MDFF improves the overall correlation to the density by 40% relative to the refinements of the brute-force MDFF. The improvements are particularly significant at high, 2 - 3 [A] map resolutions. More importantly, the ensemble model captures key features of biologically relevant molecular dynamics that is inaccessible to a single-model interpretation. Finally, the pipeline is applicable to systems of growing sizes, which is demonstrated using ensemble refinement of capsid proteins from Chimpanzee adenovirus. The overhead for decision making remaining low and robust to computing environments. The software is publicly available on GitHub and includes a short user guide to install the R-MDFF on different computing environments, from local Linux based workstations to High Performance Computing (HPC) environments.

biophysics↗

bioRxiv2021

In vitro reconstitution demonstrates the amyloid-beta mediated myelin membrane deformation

Amyloid-beta (A{beta}) aggregation mediated neuronal membrane deformation, although poorly understood, is implicated in Alzheimers Disease (AD). Particularly, whether A{beta} aggregation can induce neuronal demyelination remains unknown. Here we show that A{beta}-40 binds and induces extensive tubulation in the myelin membrane in vitro. The binding of A{beta}-40 depends predominantly on the lipid packing defect densities and electrostatic interactions and results in rigidification of the myelin membrane in the early time scales. Furthermore, elongation of A{beta}-40 into higher oligomeric and fibrillar species leads to eventual fluidization of the myelin membrane followed by extensive membrane tubulation observed in the late phase. Taken together, our results capture mechanistic insights into snapshots of temporal dynamics of A{beta}-40 - myelin membrane interaction and demonstrate how short timescale, local phenomena of binding, and fibril mediated load generation manifests into long timescale, global phenomena of myelin tubulation and demonstrates the ability of A{beta}-40 to demyelinate.

biophysics↗

bioRxiv2021

Integrative Epigenomic and High-Throughput Functional Enhancer Profiling Reveals Determinants of Enhancer Heterogeneity in Gastric Cancer

BackgroundEnhancers are distal cis-regulatory elements required for cell-specific gene expression and cell fate determination. In cancer, enhancer variation has been proposed as a major cause of inter-patient heterogeneity - however, most predicted enhancer regions remain to be functionally tested. ResultsAnalyzing 128 epigenomic histone modification profiles of primary GC samples, normal gastric tissues, and GC cell lines, we report a comprehensive catalog of 75,730 recurrent predicted enhancers, the majority of which are tumor-associated in vivo (>50,000) and associated with lower somatic mutation rates inferred by whole-genome sequencing. Applying Capture-based Self-Transcribing Active Regulatory Region sequencing (CapSTARR-seq) to the enhancer catalog, we observed significant correlations between CapSTARR-seq functional activity and H3K27ac/H3K4me1 levels. Super-enhancer regions exhibited increased CapSTARR-seq signals compared to regular enhancers even when decoupled from native chromatin contexture. We show that combining histone modification and CapSTARR-seq functional enhancer data improves the prediction of enhancer-promoter interactions and pinpointing of germline single nucleotide polymorphisms (SNPs), somatic copy number alterations (SCNAs), and trans-acting TFs involved in GC expression. Specifically, we identified cancer-relevant genes (e.g. ING1, ARL4C) whose expression between patients is influenced by enhancer differences in genomic copy number and germline SNPs, and HNF4 as a master trans-acting factor associated with GC enhancer heterogeneity. ConclusionsOur study indicates that combining histone modification and functional assay data may provide a more accurate metric to assess enhancer activity than either platform individually, and provides insights into the relative contribution of genetic (cis) and regulatory (trans) mechanisms to GC enhancer functional heterogeneity.

cancer biology↗