Biology subjects

Feng, Y.

Publications and source records attributed to Feng, Y..

At least 127 records · Page 7Linked to original sources

bioRxiv2024

Age-associated modulation of TREM1/2- expressing macrophages promotes melanoma progression and metastasis

Aging is a known risk factor for melanoma, yet mechanisms underlying melanoma progression and metastasis in older populations remain largely unexplored. Among the current knowledge gaps is how aging alters phenotypes of cells in the melanoma microenvironment. Here we demonstrate that age enriches the immunosuppressor tumor microenvironment, which is linked to phenotypes associated with melanoma metastasis. Among cellular populations enriched by aging were macrophages with a tolerogenic phenotype expressing TREM2 and dysfunctional CD8-positive cells with an exhausted phenotype, while macrophages with profibrotic phenotype expressing TREM1 were depleted. Notably, TREM1 inhibition decreased melanoma growth in young but not old mice, whereas TREM2 inhibition prevented lung metastasis in aged mice. These data identify novel targets associated with melanoma metastasis and may guide aged-dependent immunotherapies.

cancer biology↗

bioRxiv2024

Targeting eIF4G1-dependent translation in melanoma

Expression of components of the translation initiation complex (eIF4F) is frequently elevated in cancer, resulting in enhanced synthesis of oncogenic proteins. We thus set out to limit eIF4F pro-oncogenic activity, a notable challenge given its essential role in normal tissues. CRISPR-Cas9-based functional screen using tiling sgRNAs identified the eIF4G1 MA3 domain, a subunit of the eIF4F complex, as a target for developing small molecule inhibitors. Combination of structure-guided in silico modeling and chemical library screening led to the identification of small molecule candidates M19 and its analog M19-6 that binds to the MA3 domain of eIF4G1 and disrupts eIF4F complex. M19-6 treatment reprograms the melanoma translatome, limiting synthesis of factors that promote cell proliferation and neoplastic growth, as well as reducing translation of mRNAs encoding ferroptosis suppressors. Whole genome CRISPR screen indentified ferroptosis activators to augment M19-6 activity, which was confirmed in cultured melanoma cells. M19-6 alleviates melanoma resistance to BRAF and MEK inhibitors, while eliciting anti-tumor and anti-metastatic effects in preclinical mouse models. Among several biomarkers found in M19-6 sensitive cell lines, THBS1 and TGF{beta}I expression were elevated in patients who are non-responders to PD-1 therapy as in patients with metastasis. Our studies identify M19-6 as a therapeutic candidate, offering a novel insights into targeting the eIF4F complex to overcome melanoma resistance to therapy and metastasis. SignificanceWe identify M19-6 as a small molecule that disrupts the eIF4F, translation initiation complex, by targeting the MA3 domain of eIF4G1, resulting in elimination of melanoma cells in culture, overcoming therapy resistance while inhibiting melanoma growth and metastasis in vivo. As M19-6 causes minimal toxicity to melanocytes, it offers a therapeutic modality for melanoma.

cancer biology↗

bioRxiv2024

A systematic assessment of phylogenomic approaches for microbial species tree reconstruction

A key challenge in microbial phylogenomics is that microbial gene families are often affected by extensive horizontal gene transfer (HGT). As a result, most existing methods for microbial phylogenomics can only make use of a small subset of the gene families present in the microbial genomes under consideration, potentially biasing their results and affecting their accuracy. To address this challenge, several methods have recently been developed for inferring microbial species trees from genome-scale datasets of gene families affected by evolutionary events such as HGT, gene duplication, and gene loss. In this work, we use extensive simulated and real biological datasets to systematically assess the accuracies of four recently developed methods for microbial phylogenomics, SpeciesRax, ASTRAL-Pro 2, PhyloGTP, and AleRax, under a range of different conditions. Our analysis reveals important insights into the relative performance of these methods on datasets with different characteristics, identifies shared weaknesses when analyzing complex biological datasets, and demonstrates the importance of accounting for gene tree inference error/uncertainty for improved species tree reconstruction. Among other results, we find that (i) AleRax, the only method that explicitly accounts for gene tree inference error/uncertainty, shows the best species tree reconstruction accuracy among all tested methods, (ii) PhyloGTP (developed previously by the authors of this paper) shows the best overall accuracy among methods that do not account for gene tree error and uncertainty, (iii) ASTRAL-Pro 2 is less accurate than the other methods across nearly all tested conditions, and (iv) explicitly accounting for gene tree inference error/uncertainty can lead to substantial improvements in species tree reconstruction accuracy. Importantly, we also find that all methods, including AleRax and PhyloGTP, are susceptible to biases present in complex real biological datasets and can sometimes yield misleading phylogenies.

bioinformatics↗

bioRxiv2024

Phosphorylation of MdWRKY70L by MdMPK6/02G mediates reactive oxygen synthesis to regulate apple fruit senescence

Apple (Malus domestica) is a globally significant crop and a vital dietary component worldwide. During ripening, apples exhibit a longitudinal gradient, ripening first at the stalk cavity and extending toward the calyx pit. Over-ripening in the stalk cavity leads to early senescence, characterized by peel browning, which diminishes fruit quality. This study examines the natural senescence process in 6-year-old Ruixue apples by screening transcriptome data to uncover senescence-related genes and validate their molecular functions. Our analysis of antioxidant capacity and reactive oxygen species in different peel regions revealed that malondialdehyde, hydrogen peroxide, and superoxide anion levels increased with senescence, especially in the stalk cavity. Transcriptome clustering and enrichment analyses across developmental stages revealed MdWRKY70L, MdSAG101, and MdZAT12 as key regulators of peel senescence. Further in vitro and in vivo studies demonstrated that MdWRKY70L is phosphorylated at Ser199 by MdMPK6/02G, enhancing its stability and promoting peel senescence. These findings offer insights for developing strategies to delay fruit senescence and improve postharvest quality control.

plant biology↗

bioRxiv2024

Spatiotemporal transcriptomic analyses reveal molecular gradient patterning during development and the tonotopic organization along cochlear axis

While cochlear tonotopic organization is essential for sound frequency discrimination, the spatiotemporal molecular programs shaping this architecture remain unresolved. Here, we integrate spatiotemporal transcriptomics (E17.5-P8-adult) with single-cell RNA-seq to construct a single-cell-resolution atlas of mouse cochlear development. As marked by differential gradient expression genes, distinct spatially and molecularly defined hair cell (HC) subtypes along the apical-basal axis were identified: such as the apical Myo7a+++/Calb1+++ outer hair cell (OHC) subtype, the basal Myo7a+/Calb1{square} OHC subtype, the apical vGlut3+++/Calb2+ inner hair cell (IHC) subtype, and the basal vGlut3+/Calb2+++ IHC subtype. In addition, the spatial data also demonstrate the developmental reversal of Myo7a/Calb2Nefh gradient patterns in HCs and spiral ganglion neurons (SGNs), revealing dynamic plasticity and complexity in frequency coding during development. Spatial analyses further demonstrate regional heterogeneity in cell communication intensity between HCs and SGNs, and also reveal core signaling hubs coordinating tonotopic organization, such as Fgf10-Fgfr2 pathway in the basal region and Ptn-Sdc pathway in the apical region HC or SGNs at P8 stage. Our study provides an open-access spatial database and reveals the morphological and molecular foundations underlying cochlear tonotopic organization, linking molecular and developmental mechanisms to auditory pathophysiology.

developmental biology↗

bioRxiv2024

Phage CRISPR-like regulatory RNAs silence bacterial adaptive and innate immunity

CRISPR RNAs (crRNAs) encoded by CRISPR arrays direct Cas nucleases against viruses. Some CRISPR-Cas loci also contain mini-arrays encoding crRNA-like RNAs (crlRNAs), which modulate transcription of cas or associated toxin genes that safeguard CRISPR-Cas activity. Here, we report that phages hijack these host crlRNA regulatory circuits to suppress bacterial immunity. Viral crlRNAs compete with host crRNAs for Cas protein binding and reprogram Cas proteins to silence their own expression or suppress transcription of CRISPR-safeguarding toxins. These anti-defense crlRNAs are found across diverse phages and plasmids, frequently organized into multiplexed transcriptional units resembling CRISPR arrays, and often synergize with co-encoded anti-CRISPR proteins to disable hierarchical host immune responses. Furthermore, we demonstrate that these compact viral crlRNA architectures can be harnessed for efficient mammalian genome editing. Our findings uncover widespread viral hijacking of host Cas proteins via crlRNAs, highlighting the recurrent exaptation of CRISPR-Cas regulatory functions to counter multilayered bacterial immune defenses.

microbiology↗

bioRxiv2024

DNMT3AR882H Is Not Required for Disease Maintenance in Primary Human AML, but Is Associated With Increased Leukemia Stem Cell Frequency

Genetic mutations are being thoroughly mapped in human cancers, yet a fundamental question in cancer biology is whether such mutations are functionally required for cancer initiation, maintenance of established cancer, or both. Here, we study this question in the context of human acute myeloid leukemia (AML), where DNMT3AR882 missense mutations often arise early, in pre-leukemic clonal hematopoiesis, and corrupt the DNA methylation landscape to initiate leukemia. We developed CRISPR-based methods to directly correct DNMT3AR882 mutations in leukemic cells obtained from patients. Surprisingly, DNMT3AR882 mutations were largely dispensable for disease maintenance. Replacing DNMT3AR882 mutants with wild-type DNMT3A did not impair the ability of AML cells to engraft in vivo, and minimally altered DNA methylation. Taken together, DNMT3AR882 mutations are initially necessary for AML initiation, but are largely dispensable for disease maintenance. The notion that initiating oncogenes differ from those that maintain cancer has important implications for cancer evolution and therapy. STATEMENT OF SIGNIFICANCEUnderstanding which driver mutations are required for cancer initiation, maintenance, or both phases remains poorly understood. Here, we uncover that highly prevalent pre-leukemic DNMT3A mutations are only required during disease initiation, but become dispensable after leukemic transformation, uncovering the context-specific role of this driver mutation with important therapeutic implications.

cancer biology↗

bioRxiv2024

NLGN3 contributes to angiogenesis in myocardial infarction via activation of the Gαi1/3-Akt Pathway

BACKGROUNDAngiogenesis is an important repair mechanism for myocardial infarction. Neuroligin-3 (NLGN3) can promote angiogenesis by activating Gi1/3-Akt signaling following ischemic brain injury. This study investigated the role of NLGN3 in myocardial infarction (MI). METHODS AND RESULTSOn the 7th day after MI, the plasma level of NLGN3 in patients was significantly higher than in the control group. A mouse model of MI also showed significantly increased expression of NLGN3 in heart tissue. Single-nucleus transcriptome analysis revealed that NLGN3 was located predominantly in cardiac fibroblasts and endothelial cells (ECs). Endothelial-specific knockdown of NLGN3, or inhibition of NLGN3 using ADAM10i, significantly increased the ischemic area, reduced angiogenesis, and worsened cardiac function. Co-immunoprecipitation (Co-IP) experiments showed that NLGN3 interacted with Gi1/3. The Gi1/3 knockout (Gi1/3-KO) mouse model of MI showed an increased ischemic area, decreased angiogenesis, and impaired cardiac function. Mechanistic studies showed that the NLGN3-Gi1/3 signaling pathway exerts cardioprotective effects by promoting EC proliferation and tube formation through the PI3K-Akt-mTOR pathway. Silencing of Gi1/3 largely eliminated the ability of NLGN3-promoting cardiac ECs to proliferate and form tubes. CONCLUSIONOur findings suggest the endothelial NLGN3-Gi1/3 signaling pathway promotes angiogenesis and reduces the ischemic area following MI, which is critical for maintaining cardiac function and repairing tissues. Targeting of the NLGN3-Gi1/3 signaling pathway may have clinical therapeutic potential in protecting the heart from ischemic injury. What Is Known?O_LIMyocardial infarction (MI) leads to a significantly increased risk of recurrent events in individually vascularized regions, which then stimulates adverse systemic vascular effects. C_LIO_LIGi proteins play a key role in receptor tyrosine kinase (RTK) and other non-GPCR receptor-mediated signaling. C_LIO_LINeuroligin 3 (NLGN3) is a major member of the NLGN family of proteins that help to form synapses between neurons. It is known be cleaved and secreted in an activity-dependent manner, but its function in heart disease is still poorly understood. C_LI What New Information Does This Article Contribute?O_LINLGN3 expression was found to be markedly increased in the heart after MI, especially in cardiac ECs. C_LIO_LIKnockdown of Gi1/3 significantly reduced angiogenesis and impaired cardiac function, while knockdown of NLGN3 increased the ischemic area and reduced angiogenesis through Gi1/3. C_LIO_LINLGN3-Gi1/3 signaling promotes vascular EC proliferation and tube formation through the PI3K-Akt-mTOR pathway, thereby protecting the ischemic heart. C_LI

molecular biology↗

bioRxiv2024

The cyclin-G associated kinase (GAK) is a novel mitotic kinase and therapeutic target in diffuse large B-cell lymphoma

New drug targets are needed for diffuse large B-cell lymphoma (DLBCL), the most common lymphoma subtype, to enable enable development better treatments for patients not cured by standard care. We conducted a phenotypic screen of kinase inhibitors and identified the cyclin G-associated kinase (GAK) as a tumor-selective target. Though GAK is previously described primarily as a participant in membrane trafficking, we found its kinase activity is a key mitotic regulator in DLBCL. Inhibition caused G2/M-phase arrest, chromosome misalignment, and spindle distortion, effects absent in non-malignant controls. Transcriptomics data from clinical samples showed increased GAK expression associates with RB1 deficiency in DLBCL cases, suggesting dependency on GAK linked to retinoblastoma associated protein (RB) loss of function, a common DLBCL driver. RB-deficient DLBCL cells treated with a selective GAK tool compound showed complete arrest at G2/M, pronounced distortion of mitotic spindles, and widespread chromosomal damage. High-content live-cell imaging revealed onset of mitotic catastrophe in response to GAK inhibition, which was more rapid and severe in isogenic cells with RB1 deletion. No GAK-selective inhibitors suitable for clinical development are currently available, but several drugs approved or under development inhibit GAK activity even more potently than thier intended clinical targets. For instance, OTS167, developed against MELK for use in solid tumors, has particularly potent anti-GAK potency and has achieved single-agent tumor-burden reduction in vivo against a DLBCL patient-derived xenograft. GAK is therefore a novel mitotic kinase in DLBCL, linked to the common, undruggable RB loss of function biomarker, and suitable for rapid clinical translation through drug repurposing. SignificanceWe identify cyclin-G associated kinase (GAK) as a novel therapeutic vulnerability in diffuse large B-cell lymphoma. Clinical kinase inhibitors with GAK activity create an opportunity for rapid therapeutic translation through drug repurposing.

cancer biology↗

bioRxiv2024

Deletion of Zyxin Reduces Endothelial Inflammation and Mitigates Atherosclerosis

BACKGROUNDOscillatory shear stress (OSS)-induced endothelial inflammation plays a critical role in the pathogenesis of atherosclerosis. However, the involvement of endothelial zyxin, a mechanosensor, in OSS-associated atherosclerosis and its underlying mechanisms remains unclear. METHODSTo investigate the role of zyxin in vivo, ZyxiniECKOApoE-/- mice were utilized in atherosclerosis model induced by carotid artery ligation; in vitro, endothelial cells were subjected to disturbed flow in Ibidi systerm. RESULTSZyxin was significantly upregulated in the OSS regions of both human and mouse arteries. The specific deletion of zyxin in endothelial cells (ECs) in ApoE-/- (ZyxiniECKOApoE-/-) mice reversed the ECs activation and atherosclerosis induced by OSS. In vitro studies indicated that the absence of zyxin reduced the induction of adhesion molecules and pro-inflammatory cytokines stimulated by OSS. Mechanistic investigations demonstrated that 14-3-3{beta} facilitated yes-associated protein (YAP) phosphorylation at Serine 127, which played a critical role in retaining YAP within the cytoplasm. Under OSS stimulation, zyxin inhibited the phosphorylation of YAP at Serine 127 through its interaction with 14-3-3{beta}, rather than direct regulation of YAP. This inhibition enhanced YAPs nuclear translocation and promoted endothelial inflammation. Furthermore, it was shown that rosuvastatin inhibited zyxin expression in human umbilical vein endothelial cells and the vascular endothelium of ApoE-/- mice. This inhibition led to decreased levels of inflammatory markers and adhesion molecules associated with atherosclerotic lesions observed in the partially ligated left common carotid arteries of ApoE-/- mice. CONCLUSIONSThis study further confirms that zyxin is a mechanoreceptor in endothelial cells and elucidates the indispensable role of the zyxin-14-3-3{beta}-YAP axis in endothelial inflammation and atherogenesis. This indicates that Zyxin plays a crucial role in protecting against atherosclerosis.

cell biology↗

bioRxiv2024

BBATProt: A Framework Predicting Biological Function with Enhanced Feature Extraction via Explainable Deep Learning

Accurately predicting the functions of peptides and proteins from their amino acid sequences is essential for understanding life processes and advancing biomolecule engineering. Due to the time-consuming and resource-intensive nature of experimental procedures, computational approaches, especially those based on machine learning frameworks, have garnered significant interest. However, many existing machine learning tools are limited to specific tasks and lack adaptability across different predictions. Here we propose a versatile framework BBATProt for the prediction of various protein and peptide functions. BBATProt employs transfer learning with a pre-trained Bidirectional Encoder Representations from Transformers (BERT) model, to effectively capture high-dimensional features from amino acid sequences. The whole custom-designed network, integrating Bidirectional Long Short-Term Memory (Bi-LSTM) and Temporal Convolutional Networks (TCN), can align with the spatial characteristics of proteins. It combines local and global feature extraction through attention mechanisms for precise functional prediction. This approach ensures that key features are adaptively extracted and balanced across diverse tasks. Comprehensive evaluations show BBATProt outperforms state-of-the-art models in predicting functions like hydrolytic catalysis, activity of peptides, and post-translational modification sites. Visualizations of feature evolution and refinement via attention mechanisms validate the frameworks interpretability, providing transparency into the evolutional process and offering deeper insights into function prediction.

bioinformatics↗

bioRxiv2024

Mechanism of allosteric activation in human mitochondrial ClpP protease

Human ClpP protease contributes to mitochondrial protein quality control by degrading misfolded proteins. ClpP is overexpressed in cancers such as acute myeloid leukemia (AML), where its inhibition leads to the accumulation of damaged respiratory chain subunits and cell death. Conversely, hyperactivating ClpP with small-molecule activators, such as the recently-discovered ONC201, disrupts mitochondrial protein degradation and impairs respiration in cancer cells. Despite its critical role in human health, the mechanism underlying the structural and functional properties of human ClpP remain elusive. Notably, human ClpP is paradoxically activated by active-site inhibitors. All available structures of human ClpP published to date are in the inactive compact or compressed states, surprisingly even when ClpP is bound to an activator molecule such as ONC201. Here, we present the first structures of human mitochondrial ClpP in the active extended state, including a pair of structures where ClpP is bound to an active-site inhibitor. We demonstrate that amino acid substitutions in the handle region (A192E and E196R) recreate a conserved salt bridge found in bacterial ClpP, stabilizing the extended active state and significantly enhancing ClpP activity. We elucidate the ClpP activation mechanism, highlighting a hormetic effect where sub-stoichiometric inhibitor binding triggers an allosteric transition that drives ClpP into its active extended state. Our findings link the conformational dynamics of ClpP to its catalytic function and provide high-resolution structures for the rational design of potent and specific ClpP inhibitors, with implications for targeting AML and other disorders with ClpP involvement. Significance statementHuman ClpP protease is essential for maintaining mitochondrial protein quality by degrading damaged proteins. In cancers like acute myeloid leukemia (AML), ClpP is overexpressed, and inhibiting it causes cancer cell death by disrupting mitochondrial function. Conversely, activating ClpP with small molecules, such as ONC201, also leads to cancer cell death by impairing mitochondrial respiration. However, the structural details of ClpP activation have been elusive. Our research presents the first structures of human ClpP in its active state, revealing a novel activation mechanism where inhibitors unexpectedly trigger activity through allosteric changes. These insights provide a foundation for designing targeted therapies for AML and other diseases where ClpP plays a crucial role.

biochemistry↗

bioRxiv2024

Lysophospholipid headgroup size, and acyl chain length and saturation differentially affect vacuole acidification, Ca2+ transport, and fusion

SNARE-mediated membrane fusion is regulated by the lipid composition of the engaged bilayers. Lipids impact fusion through direct protein-lipid interactions or through modulating the physical properties of membranes to affect protein function. Lysophospholipids (LPLs) can affect membrane curvature, fluidity and energy of deformation. Their effects are due to their head group, and the length and saturation of their single acyl chains. Here we examined how the properties of LPLs affect yeast vacuole fusion and ion transport. We found that lysophosphatidylcholine (LPC) with acyl chains containing 14-18 carbons inhibited fusion with IC50 values of {cong} 40-120 {micro}M. While acyl chain length moderately affected fusion, the head group played a major role. Unlike LPCs, Lysophosphatidic acid (LPA 18:1) failed to fully inhibit fusion, while lysophosphatidylethanolamine (LPE 18:1) had no effect. Separately we found that changes in acyl chain length and saturation differentially affected Ca2+ transport and vacuole acidification. Together these data show that the effects of LPLs on membrane fusion and ion transport were due to a combination of head group type and acyl chain length.

biochemistry↗

bioRxiv2024

Rfx3 controls outer hair cell differentiation, maintenance, and hair bundle formation by regulating the expression of Insm1, Ikzf2, and Triobp genes

The RFX family of transcription factors plays crucial roles in the regulation of ciliogenesis and organ development. Mutations of RFX transcription factors lead to various genetic diseases, including ciliopathies and hearing loss, although the underlying mechanisms remain unclear. This study comprehensively analyzed the expression patterns of RFX family members during different inner ear developmental stages. Rfx3 and Rfx7 were identified as the dominantly expressed members in cochlear hair cells, exhibiting alternative splicing variants and dynamic subcellular localization at different stages. Integration of single-cell transcriptomics, ChIP-seq, and ATAC-seq data indicates that Rfx3 functions as either a transcriptional activator or repressor, binding to numerous genes related to ciliogenesis, hair bundle structures, and planar cell polarity. Rfx3 regulates the spatiotemporal expression of hair bundle gene Triobp in hair cells by binding to and modulating its intronic enhancer. Additionally, Rfx3 binds to hair cell differentiation and fate determination genes Tbx2, Insm1, and Ikzf2. The results demonstrate that Rfx3 and Rfx7 are dominantly expressed in outer hair cells, with their subcellular localization shifting to cytoplasm at later developmental stages. This suggests a previously unknown function of Rfx3 and Rfx7 beyond transcriptional regulation, highlighting their complex roles in hair cell differentiation and maintenance.

developmental biology↗

bioRxiv2024

LRRC8 complexes are adenosine nucleotide release channels regulating platelet activation and arterial thrombosis

Platelet shape and volume changes are early mechanical events contributing to platelet activation and thrombosis. Here, we identify single-nucleotide polymorphisms in Leucine-Rich Repeat Containing 8 (LRRC8) protein subunits that form the Volume-Regulated Anion Channel (VRAC) which are independently associated with altered mean platelet volume. LRRC8A is required for functional VRAC in megakaryocytes (MKs) and regulates platelet volume, adhesion, and agonist-stimulated activation, aggregation, ATP secretion and calcium mobilization. MK-specific LRRC8A cKO mice have reduced arteriolar thrombus formation and prolonged arterial thrombosis without affecting bleeding times. Mechanistically, platelet LRRC8A mediates swell-induced ATP/ADP release to amplify agonist-stimulated calcium and PI3K-AKT signaling via P2X1, P2Y1 and P2Y12 receptors. Small-molecule LRRC8 channel inhibitors recapitulate defects observed in LRRC8A-null platelets in vitro and in vivo. These studies identify the mechanoresponsive LRRC8 channel complex as an ATP/ADP release channel in platelets which regulates platelet function and thrombosis, providing a proof-of-concept for a novel anti-thrombotic drug target.

cell biology↗

bioRxiv2024

Comparison of Explainable AI Models for MRI-based Alzheimer's Disease Classification

Deep learning models based on convolutional neural networks (CNNs) have been used to classify Alzheimers disease or infer dementia severity from 3D T1-weighted brain MRI scans. Here, we examine the value of adding occlusion sensitivity analysis (OSA) and gradient-weighted class activation mapping (Grad-CAM) to these models to make the results more interpretable. Much research in this area focuses on specific datasets such as the Alzheimers Disease Neuroimaging Initiative (ADNI) or National Alzheimers Coordinating Center (NACC), which assess people of North American, predominantly European ancestry, so we examine how well models trained on these data generalize to a new population dataset from India (NIMHANS cohort). We also evaluate the benefit of using a combined dataset to train the CNN models. Our experiments show feature localization consistent with knowledge of AD from other methods. OSA and Grad-CAM resolve features at different scales to help interpret diagnostic inferences made by CNNs.

neuroscience↗

bioRxiv2024

Small mammals in biodiversity hotspot harbor viruses of epidemic potential

Metagenomic sequencing has transformed our understanding of viral diversity in wildlife and its threat to human health. Despite this progress, many studies have lacked systematic and ecologically informed sampling, which has left numerous potentially emergent viruses undiscovered, and the drivers of their ecology and evolution poorly understood. We conducted an extensive analysis of viruses in the lung, spleen, and gut of 1,688 animals from 38 mammalian species across 428 sites in Yunnan, China--a hotspot for zoonotic diseases. We identified 162 mammalian viral species, including 102 novel species and 24 posing potential risks to humans due to their relationships with known pathogens associated with serious diseases and their ability to cross major host species barriers. Our findings offer an in-depth view of virus organotropism, cross-species transmission, host sharing patterns, and the ecological factors influencing viral evolution, all of which are critical for anticipating and mitigating future zoonotic outbreaks.

microbiology↗

bioRxiv2024

Intrinsically Disordered Regions Define Unique Protein Interaction Networks in CHD Family Remodelers

Chromodomain helicase DNA-binding (CHD1-9) enzymes reposition nucleosomal DNA for transcription, recombination, and replication. They possess highly conserved ATPase domains flanked by poorly characterised N- and C-termini, which are enriched with intrinsically disordered regions (IDRs) and short aggregation-prone regions (APRs). The roles of IDRs and APRs in CHD function has remained elusive. Here, by integrating proteomics and AlphaFold Multimer analysis, we defined the protein-protein interaction (PPI) networks within the N- and C-termini of all CHDs. We generated a comprehensive map of CHD1-9-specific binding proteins, revealing dozens of novel interactions with transcription regulators. We identified APR regions that contribute to PPI formation and demonstrated that a highly conserved APR within the C-terminus of CHD4 is critical for its interaction with the nucleosome remodeling and deacetylase (NuRD), as well as the CHD, ADNP, and HP1 (ChAHP) complexes. Further analysis unravels a regulatory role for the CHD4 APR in gene transcription during erythrocyte formation. Our results emphasize that the N- and C-termini of CHD chromatin remodelers establish PPI networks that drive unique transcriptional programs.

biochemistry↗