- BioRxiv Biochemistry
- BioRxiv Bioinformatics
- BioRxiv Biophysics
- BioRxiv Cancer Biology
- BioRxiv Pharmacology and Toxicology
- BioRxiv Systems Biology
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- by Curtis, D.UK Biobank has released whole genome sequence data for 500,000 participants, including allele counts for hundreds of millions of variants and these were considered in the context of the pentanucleotide background on which they occurred. Frequencies of singleton variants were obtained and compared with frequencies of more common variants. Results were highly correlated across chromosomes, reflecting systematic effects. C>T singleton variants were less frequent in the CG context but the opposite was true for more common variants, suggesting that they […]
- by Bergelova, B., Fornaini, N. R., Tlapkova, T., Vavra, J., Plevakova, M., Cernohorska, H., Kubickova, S., Krylov, V., Evans, B. J., Knytl, M.Genomic rearrangements are fundamental drivers of biodiversity, yet dynamics of structural evolution following polyploidization remain poorly understood. Genus Xenopus provides a valuable tool to study these phenomena. Utilizing the diploid X. tropicalis as a reference, we employed cytogenetic and genomic mapping to track the structural evolution of the allotetraploids X. borealis and X. laevis across a 50-million-year timeline. Based on chromosome morphometrics and C-banding patterns, we characterized the X. borealis pseudotetraploid karyotype (2n = 4x = 36), localizing the nucleolus […]
- by Yisraeli, J. K., Izraely, S., Tabach, Y.The Insulin-like growth factor 2 mRNA-binding protein (Igf2bp) family comprises three paralogous RNA-binding proteins – Igf2bp1, Igf2bp2, and Igf2bp3 – that are highly conserved across chordates. Originally identified through diverse experimental screens probing intracellular RNA localization, RNA stability, and translational control, Igf2bps were initially studied in isolation from one another and within narrowly defined molecular contexts. Over time, it has become clear that these proteins act as multifunctional regulators of RNA metabolism and participate in a broad range of developmental […]
- by Iradukunda, C., Salter, E. A., Uredi, D., Wang, X., Wierzbicki, A., Rameh, L. E.mTORC1 integrates growth factor and nutrient signals to regulate cellular metabolism, yet there are no metabolites known to directly regulate mTORC1 activity in cells. Cryo-EM studies revealed that inositol hexakisphosphate (IP6) associates with the FAT domain of mTOR, suggesting that inositol phosphates may directly modulate mTOR activity. We previously showed that higher-order inositol phosphates enhance mTORC1 kinase activity and stability in vitro. Here, we investigated whether inositol phosphate metabolism regulates mTORC1 signaling in pancreatic {beta}-cells. Suppression or acute inhibition of […]
- by Li, B., Hagy, K., Safi, A., Beer, M. A., Barrera, A., Geraghty, S., Rai, R., Pederson, A. N., Reisman, S. J., Love, M. I., Sullivan, P. F., Eroglu, C., Crawford, G. E., Gersbach, C. A.Heterotypic cell-cell interactions are critical to governing cellular physiology, disease progression, and responses to the environment and pharmacologic interventions. For example, neurons and astrocytes engage in intricate interactions that are essential for brain development and function. However, the transformation of these extracellular signals into epigenomic regulation that governs cell function is poorly understood. Here, we report that weeks of co-culture between human induced pluripotent stem cell (hiPSC)-derived neurons and mouse cortical astrocytes extensively reprograms gene expression and the chromatin accessibility […]
- by Gu, Y., Ruan, L., Hou, Y., Gilbert-Ross, M., Brown, T., Kalinsky, K. M., Badve, S. S., Gokmen-Polar, Y.Resistance to cyclin-dependent kinase 4/6 inhibitors remains a major clinical challenge in treating estrogen receptor-positive breast cancer, with no reliable predictive biomarkers currently available for patient selection. To investigate resistance mechanisms, we generated drug-tolerant persisters (DTPs) to abemaciclib and palbociclib in a panel of estrogen receptor-positive breast cancer cell lines. Functional analyses revealed that DTPs showed resistance to CDK4/6 inhibition, maintained G1 arrest, and exhibited increased senescence phenotype. To identify clinically relevant markers of resistance, we compared transcriptomic profiles from […]
- by Zinnah, K. M. A., Nabil, F. A., Darda, A., Islam, E., Hossain, F. M. A.Marburg virus (MARV) is a highly pathogenic filovirus that causes hemorrhagic fever with a high mortality rate, with very limited treatment options. The urgent need for targeted antiviral agents emphasizes the importance of structure-based drug discovery approaches. The present study aimed to evaluate the antiviral potential of Withaferin A (PubChem CID-265237) against three key proteins of MARV: viral protein 35 (VP35), and nucleoproteins (NP). Three-dimensional structures of these proteins were retrieved from RCSB-Protein Data Bank and docked with Withaferin A […]
- by Brigleb, P. H., Frank, M., Rowland, L., Bub, T., Guy, C., Livingston, B., Mandarano, A., Sekera, E. R., Bowling, J., Schultz-Cherry, S.Obesity is a major risk factor for severe influenza A virus (IAV) infection, however, the innate immune mechanisms underlying this increased vulnerability remain unclear. Here, we identify significant defects in natural killer (NK) cell antiviral responses in mice with diet-induced obesity. In lean mice, NK cells are critical for protection as NK cell depletion during IAV infection led to increased lung viral load, morbidity, and mortality. In contrast, in obese mice NK cell depletion had minimal impact on viral replication […]
- by Izert-Nowakowska, M. A., Szybowska, P. E., Klimecka, M. M., Gorna, M. W.Fluorescent reporters provide a useful tool for studying degron motifs. Fusing a degron of interest to a fluorescent protein allows to accurately track protein levels overtime to characterise the degradation kinetics of studied degrons. Here we describe a rapid and simple method to study degron peptides in Escherichia coli using plasmid-encoded eGFP-degron fusion constructs. The described methods provide an accessible workflow to evaluate degrons. We provide protocols for generation of pBAD plasmids encoding the studied constructs and two different methods […]
- by Lorber, D., Azuri, I., Kumar, A., Rotkopf, R., Safran, S., Volk, T.The intrinsic tendency of chromatin to self-attract competes with its association with RNA Polymerase II (RNAPII), a prerequisite for efficient transcription. Using high-resolution live imaging of chromatin and RNAPII organization in Drosophila larval muscle nuclei, we demonstrate that chromatin tethering to the nuclear envelope via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex is essential for maintaining chromatin three-dimensional organization. Disruption of chromatin-lamina interactions either in LINC mutants or following knockdown of Barrier-to-Autointegration Factor (BAF) results in enhanced chromatin clustering […]
- by Kong, K. W., Poh, S. E., Wong, F. T., Seow, Y., Koh, W.DNA methylation is a critical epigenetic modification that regulates gene expression, maintains genome stability, and influences cellular function during development and disease. Accurate analysis of DNA methylation often requires amplification to generate sufficient material, yet preserving the original epigenetic information during this process is challenging because standard amplification methods can disrupt methylation patterns. To address this, we developed a one-pot strategy that combines helicase-dependent amplification (HDA) with DNA methyltransferase 1 (DNMT1)-mediated methylation, enabling simultaneous DNA amplification and preservation of native […]
- by Razaghi, E., Tuzuner, S., Gungoosingh, T., Cil, K., Wong, W. S., Alonaizan, R., Richardson, R., Simoes, F. C.Adult zebrafish regenerate their hearts after injury, a process that requires macrophages, yet how local tissue microenvironments instruct macrophage states and function remains unclear. Here we combine single cell RNA sequencing with Visium and high-resolution MERFISH spatial transcriptomics to map the cardio-immune landscape of homeostatic and regenerating zebrafish hearts. We identify a mpeg1.1 compartment comprising macrophages, dendritic, B and NK-like cells, and show that injury establishes a macrophage-centred immune environment with transcriptional programmes spanning resident surveillance, damage sensing, inflammation, antigen […]
- by Ferrando-Marco, M., Berger, S., Barkoulas, M.Asymmetric cell division in the epidermal stem cells of Caenorhabditis elegans, known as seam cells, relies on the Wnt/-catenin asymmetry pathway to generate daughter cells with distinct fates. However, whether components of this pathway components are transcriptionally regulated during these divisions remains unclear. Here, we employ single molecule fluorescence in situ hybridisation to quantify mRNA distributions of key Wnt pathway components during L2 symmetric and asymmetric seam cell divisions. We find that transcripts encoding the negative regulators pry-1/Axin and apr-1/APC […]
- by Xu, H., Tao, Z., Zhang, T., Zhang, X., Zhou, Y., Cen, Z., Liu, J., Zhang, H., Maimaitijiang, A., Chen, D., Li, D., Yin, S., An, L., Huang, X., Zhang, Y.Background and Aims: Propionic acidemia (PA) is a rare autosomal recessive disorder caused by mutations in PCCA or PCCB, which encode the two subunits of propionyl-CoA carboxylase (PCC). PCC deficiency causes toxic metabolite accumulation and multi-organ damage. Current management, including dietary restriction, pharmacological support, and liver transplantation, does not restore enzymatic activity. We developed a dual-gene adeno-associated virus (AAV) therapy that delivers both PCC subunits to treat both PA subtypes. Methods: We generated a clinically relevant PCCA-R73W knock-in mouse model […]
- by Liu, Z., Liu, Y., Li, W., Cui, R., Liu, X.Social decision making relies on dynamic affect cognition interactions across distributed brain networks, yet how incidental positive affect modulates these mechanisms at a millisecond timescale remains unclear. This study investigated the impact of music-induced positive emotion on the neural dynamics of decision-making in the Ultimatum Game. Fifty six participants were assigned to either a happy music group or an active control (rain sound) group. Fifty six participants were assigned to either a happy music group or an active control (rain […]
- by Heller, E., dos Santos Dias, L., Lionakis, M. S.Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by impaired central immune tolerance due to deficiency of the Autoimmune Regulator (AIRE) and is characterized by severe, multiorgan autoimmunity. We recently identified interferon-{gamma} (IFN-{gamma}) as a dominant driver of immunopathology in APECED and showed that treatment with the JAK1/2 inhibitor ruxolitinib ameliorates disease in both AIRE-deficient mice and patients. However, broad JAK inhibition is associated with clinically relevant toxicities, raising the question of whether selective targeting of individual JAK pathways can retain efficacy […]
- by Bathini, P., Schilling, S., Rahfeld, J. U., Holtzman, D. M., Sado, T. C., Lemere, C. A.Anti-amyloid antibody treatment for Alzheimers disease is linked to Amyloid-Related Imaging Abnormalities (ARIA), including vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H), especially in ApoE {epsilon} 4/4 carriers. To investigate mechanisms underlying ARIA, we examined the binding and temporal vascular effects of immunization with 3D6, the precursor to the anti-amyloid antibody bapineuzumab, in two aged Alzheimers disease amyloid mouse models. Acutely, 3D6 bound to cerebral amyloid angiopathy (CAA), resulting in C1q binding and classical complement activation. Weekly short-term immunization over 7 weeks […]
- by White, W. L., Moseley, E., Tremblay, J. M., Reilly, J., Da'Darah, A. A., Skelly, P., Cowen, L. J., Shoemaker, C. B.Nanobodies have recently emerged as alternatives to classical antibodies in therapeutic and diagnostic contexts from parasites to bacteria to viruses, promising improved stability and simpler manufacturing. To improve nanobody discovery efficiency, we developed an integrated experimental and computational pipeline for detailed characterization of the target binding properties of complete alpaca immune repertoires using our custom Nanobody Meta-clustering Analysis Platform (NanoMAP). We tested our pipeline on three distinct pools of targets, immunizing two alpacas with each pool and generating cDNA and […]
- by Vanmechelen, M., Nazari, P., Beckervordersandforth, J. J. C., Caprioli, C., Leunissen, D. D. J. G., Cole, B., Bravo Gonzalez-Blas, C., Decraene, B., De Visser, Y., Shankar, G., Verduin, M., Pantano, D., Bevers, S., Moors, T., Zielinski, S., Telang, J., Messiaen, J., Van Herck, Y., Geens, E., Eekers, D., Claeys, A., Derweduwe, M., zur Hausen, A. A., Chui, J., Bosisio, F. M., Weyns, F., Daenekindt, T., Oosterbos, C., Van Eyken, P., Govers, M., Mennens, F., Hovinga, K. K. E., De Vleeschouwer, S., Clement, P., Broen, M. M. P. G., Vooijs, M., Sciot, R., Antoranz Martinez, A., Pey, J., Speel, E. J.Glioblastoma remains an invariably recurring and lethal brain tumor shaped by complex interactions between malignant and microenvironmental cells. How these interactions evolve under first-line standard-of-care (SOC) therapy remains unclear. We performed spatial single-cell profiling of 671 paired newly diagnosed and recurrent glioblastoma samples from 96 patients to map tumor-ecosystem evolution and its clinical relevance. We delineated five distinct patient subgroups, each characterized by unique ecosystem trajectories that correlated with clinical outcome. Patients whose tumors transitioned into oligodendrocyte-progenitor-like niches with enhanced […]
- by Enya, T., Zhao, W., Geetanjali, G., He, B., Ross, S. R.Aim2-like receptors (ALRs) play crucial roles in innate immune signaling pathways and demonstrate strong positive selection likely driven by pathogens. IFI207, an ALR found in all Mus species, enhances interaction with and stabilization of STING, contributing to the control of Murine Leukemia Virus (MLV) infection. We show here that IFI207 enhances the type 1 interferon response by inhibiting activation-induced K63-linked ubiquitination of STING, thereby preventing its recognition by hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), a key component of the […]