Biology subjects

Chen, M.

Publications and source records attributed to Chen, M..

At least 253 records · Page 14Linked to original sources

bioRxiv2024

Mapping Endothelial-Macrophage Interactions in Diabetic Vasculature: Role of TREM2 in Vascular Inflammation and Ischemic Response

Diabetes mellitus (DM) significantly accelerates vascular diseases like peripheral arterial disease (PAD). Endothelial cells (ECs) and macrophages (M{Phi}s) singularly and synergistically are important contributors to DM-associated vascular dysfunction. Single-cell (sc) profiling technologies are revealing the true heterogeneity of ECs and M{Phi}s, but how this cellular diversity translates to cell-cell interactions, and consequentially vascular function, remains unknown. We leveraged scRNA sequencing and spatial transcriptome (ST) profiling to analyze human mesenteric arteries from non-diabetic (ND) and type 2 diabetic (T2D) donors. We generated a transcriptome and interactome map encompassing the major arterial cells and highlighted Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) as a top T2D-induced gene in mononuclear phagocytes (MPs), with concomitant increases of TREM2 ligands in ECs. We verified DM-associated TREM2 induction in cell and mouse models, and found that TREM2 inhibition decreases pro-inflammatory responses in MPs and ECs, as well as increases EC migration in vitro. Furthermore, TREM2 inhibition using a neutralizing antibody enhanced ischemic recovery and flow reperfusion in DM mice subjected to hindlimb ischemia, suggesting that TREM2 promotes ischemic injury in DM. Finally, in human PAD, co-existing DM was associated with greater expression of TREM2 and its interaction with ECs, with a further increase in ischemic tissue compared to patient-matched non-ischemic tissue. Collectively, our study presents the first atlas of human diabetic vessels with single cell and spatial resolution, and identifies TREM2-EC interaction as a key driver of diabetic vasculopathies, the targeting of which may offer an opportunity to ameliorate vascular dysfunction associated with DM-PAD.

cell biology↗

bioRxiv2024

Interleukin-1 prevents SARS-CoV-2-induced membrane fusion to restrict viral transmission via induction of actin bundles

Innate immune responses triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection play pivotal roles in the pathogenesis of COVID-19, while host factors including pro-inflammatory cytokines are critical for viral containment. By utilizing quantitative and qualitative models, we discovered that soluble factors secreted by human monocytes potently inhibit SARS-CoV-2-induced cell-cell fusion in viral-infected cells. Through cytokine screening, we identified that interleukin-1{beta} (IL-1{beta}), a key mediator of inflammation, inhibits syncytia formation mediated by various SARS-CoV-2 strains. Mechanistically, IL-1{beta} activates RhoA/ROCK signaling through a non-canonical IL-1 receptor-dependent pathway, which drives the enrichment of actin bundles at the cell-cell junctions, thus prevents syncytia formation. Notably, in vivo infection experiments in mice confirms that IL-1{beta} significantly restricted SARS-CoV-2 spreading in the lung epithelia. Together, by revealing the function and underlying mechanism of IL-1{beta} on SARS-CoV-2-induced cell-cell fusion, our study highlights an unprecedented antiviral function for cytokines during viral infection.

immunology↗

bioRxiv2024

Tuning single-molecule ClyA nanopore tweezers for real-time tracking ofthe conformational dynamics of West Nile viral NS2B/NS3 protease

The flaviviral NS2B/NS3 protease is a conserved enzyme required for flavivirus replication. Its highly dynamic conformation poses major challenges but also offers opportunities for antiviral inhibition. Here, we established a nanopore tweezers-based platform to monitor NS2B/NS3 conformational dynamics in real-time. Molecular simulations coupled with electrophysiology revealed that the protease could be captured in the middle of the ClyA nanopore lumen, stabilized mainly by dynamic electrostatic interactions. We designed a new Salmonella typhi ClyA nanopore with enhanced nanopore/protease interaction that can resolve the open and closed states at the single-molecule level for the first time. We demonstrated that the tailored ClyA could track the conformational transitions of the West Nile NS2B/NS3 protease and unravel the conformational energy landscape of various protease constructs through population and kinetic analysis. The new ClyA-protease platform paves a way to high-throughput screening strategies for discovering new allosteric inhibitors that target the NS2B and NS3 interface.

biophysics↗

bioRxiv2024

Parkinson's Disease-Linked Kir4.2 Mutation R28C Leads to Loss of Ion Channel Function

Parkinsons disease (PD) is a complex, progressive neurodegenerative disorder driven by multiple pathogenetic factors, including oxidative stress, mitochondria dysfunction, neuroinflammation, and ion imbalance. Recent evidence highlights the significant role of potassium channels in the pathophysiology of PD. We recently identified a PD-linked genetic mutation in the KCNJ15 gene (KCNJ15p.R28C), encoding the inwardly rectifying potassium channel Kir4.2, within a four-generation family with familial PD. However, the role of the Kir4.2 channel in neurodegenerative diseases remains largely unexplored. This study aimed to elucidate the impact of the KCNJ15p.R28C (Kir4.2R28C) mutation on the biophysical and biochemical properties of Kir4.2. Employing Kir4.2-overexpressing HEK293T cells as a model, we investigated how the mutation affects the channels functional properties, total protein expression, intracellular processing in the endoplasmic reticulum and lysosomes, and plasma membrane trafficking. Patch clamp studies revealed that the Kir4.2R28C mutation results in loss of channel function with significant dominant-negative effects. This dysfunction is partially attributed to the substantial reduction in overall mutant channel protein expression compared to the wild-type (Kir4.2WT). We observed that both Kir4.2WT and Kir4.2R28C proteins undergo glycosylation during the post-translational modification process, albeit with differing protein turnover efficiencies. Furthermore, the Kir4.2R28C mutant exhibits reduced stability and compromised plasma membrane trafficking capacity compared to Kir4.2WT. These findings suggest that the Kir4.2R28C mutant has unique biomolecular and biophysical characteristics distinct from the Kir4.2WT channel, which potentially elucidates its role in the pathogenesis of PD. Key Points[tpltrtarr] Inwardly rectifying potassium channels are increasingly recognized for their critical role in the complex pathogenesis of Parkinsons disease (PD) [tpltrtarr]We previously identified a genetic mutation, Kir4.2R28C, in the inwardly rectifying potassium channel Kir4.2, which strongly segregates with familial PD in a multi- generational pedigree. [tpltrtarr]This study confirms Kir4.2R28C as a loss-of-function mutation with significant dominant- negative effects, impairing channel activity even in heterozygous conditions. [tpltrtarr]The Kir4.2R28C mutation significantly reduces overall protein levels, impairs protein stability and disrupts plasma membrane trafficking in in vitro cell models.

cell biology↗

bioRxiv2024

Host-derived Interleukin 1α induces an immunosuppressive tumor microenvironment via regulating monocyte-to-macrophage differentiation

Tumor-associated macrophages exhibit high heterogeneity and contribute to the establishment of an immunosuppressive tumor microenvironment (TME). Although numerous studies have demonstrated that extracellular factors promote macrophage proliferation and polarization, the regulatory mechanisms governing the differentiation process to generate phenotypically, and functionally diverse macrophage subpopulations remain largely unexplored. In this study, we examined the influence of interleukin 1 (IL-1) on the development of an immunosuppressive TME using orthotopic transplantation murine models of breast cancer. Deletion of host Il1 led to the rejection of inoculated congenic tumors. Single-cell sequencing analysis revealed that CX3CR1+ macrophage cells were the primary sources of IL-1 in the TME. The absence of IL-1 reprogrammed the monocyte-to-macrophage differentiation process within the TME, characterized by a notable decrease in the subset of CX3CR+ ductal-like macrophages and an increase in iNOS-expressing inflammatory cells. Comparative analysis of gene signatures in both human and mouse macrophage subsets suggested that IL-1 deficiency shifted the macrophage polarization from M2 to M1 phenotypes, leading to enhanced cytotoxic T lymphocyte activity in the TME. Importantly, elevated levels of IL-1 in human cancers were associated with worse prognosis following immunotherapy. These findings underscore the pivotal role of IL-1 in shaping an immune-suppressive TME through the regulation of macrophage differentiation and activity, highlighting IL-1 as a potential target for breast cancer treatment. TeaserInterleukin 1 dictates macrophage behavior, influencing an immunosuppressive microenvironment in breast cancer, suggesting it as a treatment target.

cancer biology↗

bioRxiv2024

Structural Basis for Intermodular Communication in Assembly-Line Polyketide Biosynthesis

Assembly-line polyketide synthases are large multienzyme systems with considerable potential for genetic reprogramming. To investigate the mechanisms by which reactive biosynthetic intermediates are directionally channeled across a defined sequence of active sites in a naturally occurring assembly line, we employed a bifunctional reagent to crosslink transient domain-domain interfaces of the 6-deoxyerythronolide B synthase. Structural resolution of these crosslinked states by single-particle cryogenic electron microscopy (cryo-EM) together with statistical per-particle image analysis of cryo-EM data revealed ketosynthase - acyl carrier protein (KS-ACP) interactions that discriminate between intra- and inter-modular communication, while reinforcing the relevance of asymmetric conformations during the catalytic cycle. Our findings provide a new foundation for the structure-based design of hybrid polyketide synthases comprised of biosynthetic modules from different assembly lines.

biochemistry↗

bioRxiv2024

The ANTsX Ecosystem for Mapping the Mouse Brain

Precision mapping techniques coupled with high resolution image acquisition of the mouse brain permit the study of the spatial organization of gene expression and their mutual interaction for a comprehensive view of salient structural/functional relationships. Such research is facilitated by standardized anatomical coordinate systems, such as the well-known Allen Common Coordinate Framework (AllenCCFv3), and the ability to spatially map to such standardized spaces. The Advanced Normalization Tools Ecosystem is a comprehensive open-source software toolkit for generalized quantitative imaging with applicability to multiple organ systems, modalities, and animal species. Herein, we illustrate the utility of ANTsX for generating precision spatial mappings of the mouse brain and potential subsequent quantitation. We describe ANTsX-based workflows for mapping domain-specific image data to AllenCCFv3 accounting for common artefacts and other confounds. Novel contributions include ANTsX functionality for velocity flow-based mapping spanning the spatiotemporal domain of a longitudinal trajectory which we apply to the Developmental Common Coordinate Framework. Additionally, we present an automated structural morphological pipeline for determining volumetric and cortical thickness measurements analogous to the well-utilized ANTsX pipeline for human neuroanatomical structural morphology which illustrates a general open-source framework for tailored brain parcellations.

neuroscience↗

bioRxiv2024

Quantitative tests of albendazole resistance in beta-tubulin mutants

Benzimidazole (BZ) anthelmintics are among the most important treatments for parasitic nematode infections in the developing world. Widespread BZ resistance in veterinary parasites and emerging resistance in human parasites raise major concerns for the continued use of BZs. Knowledge of the mechanisms of resistance is necessary to make informed treatment decisions and circumvent resistance. Benzimidazole resistance has traditionally been associated with mutations and natural variants in the C. elegans beta-tubulin gene ben-1 and orthologs in parasitic species. However, variants in ben-1 alone do not explain the differences in BZ responses across parasite populations. Here, we examine the roles of five C. elegans beta-tubulin genes (tbb-1, mec-7, tbb-4, ben-1, and tbb-6) to identify the role each gene plays in BZ response. We generated C. elegans strains with a loss of each beta-tubulin gene, as well as strains with a loss of tbb-1, mec-7, tbb-4, or tbb-6 in a genetic background that also lacks ben-1 to test beta-tubulin redundancy in BZ response. We found that only the individual loss of ben-1 conferred a substantial level of BZ resistance, although the loss of tbb-1 was found to confer a small benefit in the presence of albendazole (ABZ). The loss of ben-1 was found to confer an almost complete rescue of animal development in the presence of 30 {micro}M ABZ, likely explaining why no additive effects caused by the loss of a second beta-tubulin were observed. We demonstrate that ben-1 is the only beta-tubulin gene in C. elegans where loss confers substantial BZ resistance. Highlights- Loss of ben-1 provides almost complete rescue of development in albendazole (ABZ) - Loss of different beta-tubulin genes does not confer ABZ resistance - Loss of ben-1 and a second beta-tubulin does not enhance the ben-1 level of ABZ resistance

molecular biology↗

bioRxiv2024

Let-7i-5p regulates osteogenic differentiation of bone marrow mesenchymal stem cells induced by psoralen by targeting CKIP-1

AbstractPrevious studies have shown that psoralen can treat osteoporosis by inducing osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). CKIP-1 is an inhibitor of bone formation and plays a negative regulatory role in the osteogenic differentiation of BMSCs. MicroRNA (miRNA) is a kind of small single-stranded non-coding RNA, which regulates the occurrence and development process of cell proliferation, apoptosis, differentiation and metabolism. Studies have shown that miRNA can affect the proliferation and differentiation of BMSCs by targeting and regulating the expression of related genes. However, whether microRNA can regulate psoralen-induced osteogenic differentiation and its specific mechanisms remain unclear. The aim of this study was to identify miRNA target genes regulating the osteogenic differentiation of BMSCs induced by psoralen and further analyze the mechanism.miRNA microarray was performed to screen the differentially expressed mirnas induced by psoralen, and bioinformatics analysis and luciferase reporter gene assay were used to determine the target sites of let-7i-5p. The mechanism of let-7i-5p in psoralen induced osteogenic differentiation of BMSCs was investigated using in vitro overexpression or inhibition approaches.The results showed that miRNA microarray analysis and reverse transcription quantitative PCR further confirmed that let-7i-5p was up-regulated during the process of psoralin-induced osteogenic differentiation of BMSCs.Bioinformatics analysis and luciferase reporter gene assay confirmed CKIP-1 as a potential target of let-7i-5p.Overexpression of CKIP-1 by transfection with CKIP-1 mimetic significantly inhibited the expression of BMP, Runx2, and Smad1, while CKIP-1 inhibitor promoted their expression.Overexpression of let-7i-5p partially relieved the inhibitory effect of CKIP-1 on osteogenic differentiation of BMSCs.Our results suggest that let-7i-5p regulates psoralen-induced osteogenic differentiation of BMSCs by targeting CKIP-1, which provides a new therapeutic target for osteoporosis.

genetics↗

bioRxiv2024

MALAT1 mediates miR-206/CDC42/PAK1/Paxillin signaling axis to alleviate erectile dysfunction in rats

Erectile dysfunction (ED) is a male sexual dysfunction with a gradually increasing prevalence, and current treatments are ineffective. This study aims to find a safer and more effective treatment for erectile dysfunction. Bone marrow-derived mesenchymal stem cells (BM-MSCs) treated with VEGFA. The expression of endothelial markers vWF, VE-cadherin and eNOS were determined by overexpressing MALAT1 and CDC42, respectively. The results showed that interference with CDC42 and MALAT1 expression inhibited the differentiation of BM-MSCs to ECs and the expression of endothelial marker-related proteins. Moreover, MALAT1 induced differentiation of BM-MCs to ECs through the CDC42/PAK1/Paxillin pathway was explored by transfecting si-MALAT1 and overexpressing CDC42 as well as PAK1 in the BM-MSCs. Next, miR-206 was overexpressed within BM-MCs to determine CDC42 expression. The binding sites of MALAT1, miR-206 and CDC42 were reported using luciferase. it was found that the MALAT1 competes with CDC42 3-UTR for binding miR-206, which in turn is involved in differentiating BM-MSCs to ECs. Finally, DMED rat modeling success was demonstrated by APO experiments. MALAT1 overexpression-modified BM-MSCs had significant therapeutic effects in DMED rats.

molecular biology↗

bioRxiv2024

Bioorthogonal labeling and enrichment of histone monoaminylation reveal its accumulation and regulatory function in cancer cell chromatin

Histone monoaminylation (i.e., serotonylation and dopaminylation) is an emerging category of epigenetic mark occurring on the fifth glutamine (Q5) residue of H3 N-terminal tail, which plays significant roles in gene transcription. Current analysis of histone monoaminylation is mainly based on site-specific antibodies and mass spectrometry, which either lacks high resolution or is time-consuming. In this study, we report the development of chemical probes for bioorthogonal labeling and enrichment of histone serotonylation and dopaminylation. These probes were successfully applied for the monoaminylation analysis of in vitro biochemical assays, cells, and tissue samples. The enrichment of monoaminylated histones by the probes further confirmed the crosstalk between H3Q5 monoaminylation and H3K4 methylation. Finally, combining the ex vivo and in vitro analyses based on the developed probes, we have shown that both histone serotonylation and dopaminylation are highly enriched in tumor tissues that overexpress transglutaminase 2 (TGM2) and regulate the three-dimensional architecture of cellular chromatin. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/586010v3_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1bee3f7org.highwire.dtl.DTLVardef@1687013org.highwire.dtl.DTLVardef@1960bd0org.highwire.dtl.DTLVardef@1e19a04_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Spatial integration of sensory input and motor output in Pseudomonas aeruginosa chemotaxis through colocalized distribution

The opportunistic pathogen Pseudomonas aeruginosa serves as a model organism for studying multiple signal transduction pathways. The chemoreceptor cluster, a core component of the chemotaxis pathway, is assembled from hundreds of proteins. The unipolar distribution of receptor clusters has long been recognized, yet the precise mechanism governing their assembly remains elusive. Here, we directly observed the relative positions of the flagellar motor and chemoreceptor cluster using flagellar filament labeling and gene editing techniques. Surprisingly, we found that both are located at the same cell pole, with the distribution pattern controlled by the polar anchor protein FlhF. Additionally, the efficient assembly of the chemoreceptor cluster is partially dependent on the integrity of the motor structure. Furthermore, we discovered that overexpression of the chemotaxis regulatory protein CheY leads to high intracellular levels of the second messenger c-di-GMP, triggering cell aggregation. Therefore, the colocalization of the chemoreceptor cluster and flagellum in P. aeruginosa serves to avoid cross-pathway signaling interference, enabling cells to conduct various physiological activities in an orderly manner.

microbiology↗

bioRxiv2024

Glioma-associated fibroblasts promote glioblastoma resistance to temozolomide through CCL2-CCR2 paracrine signaling

Complicated tumor microenvironment contributes mostly to chemoresistance in glioblastoma. Glioma-associated fibroblasts (GAFs) were recently identified as non-tumor stromal cells in the glioblastoma microenvironment, whereas their function in glioblastoma chemoresistance is unclear. Herein, we interrogated the correlation between GAFs and chemoresistance of glioblastoma by examining a series of patient-derived GAFs and glioblastoma organoids (GBOs), revealing that GAFs could promote temozolomide resistance in glioblastoma. Mechanistically, C-C motif chemokine ligand 2 (CCL2) secreted by GAFs selectively activated the ERK1/2 signaling in glioblastoma cells to potentiate temozolomide resistance. Pharmacologically disrupting the CCL2-CCR2 axis or MEK1/2-ERK1/2 pathway effectively improved the therapeutic efficacy of temozolomide in GBM cells and patient-derived GBOs, and both decreased phospho-ERK1/2 expression. Collectively, our results identified that targeting the GAF-dominated CCL2-ERK1/2 pathway may be an alternative strategy to alleviate the GAF-mediated chemoresistance of glioblastoma. SignificanceComprehensive interpretation of the mutual support between tumor microenvironment and cancer cells is demanded for glioma with poor response rates to chemotherapy. This study demonstrates that GAFs promote the temozolomide resistance of glioblastoma by secreting cytokine CCL2 to activate ERK1/2 pathway, which may serve as a potential druggable candidate. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/581575v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@167b955org.highwire.dtl.DTLVardef@b892bcorg.highwire.dtl.DTLVardef@1a9b082org.highwire.dtl.DTLVardef@18327a8_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic abstract.C_FLOATNO Schematic illustration for GAFs mediated chemoresistance of GBMs and underlying mechanisms. We demonstrate that Glioma-associated Fibroblasts (GAFs) grow in gliomas by isolating and identifying a panel of patient-derived GAFs. CCL2 secreted by GAFs stimulates CCR2 in GBM cells, which promotes activation of the ERK1/2 expression to potentiate GBM chemoresistance. C_FIG

cancer biology↗

bioRxiv2024

Molecular mechanism of α-latrotoxin action

The potent neurotoxic venom of the black widow spider contains a cocktail of seven phylum-specific latrotoxins (LTXs), but only one, -LTX, targets vertebrates. This 130 kDa toxin binds to receptors at presynaptic nerve terminals and triggers a massive release of neurotransmitters. It is widely accepted that LTXs tetramerize and insert into the presynaptic membrane, thereby forming Ca2+-conductive pores, but the underlying mechanism remains poorly understood. LTXs are homologous and consist of an N-terminal region with three distinct domains, along with a C-terminal domain containing up to 22 consecutive ankyrin repeats. Here we report the first high resolution structures of the vertebrate-specific -LTX tetramer in its prepore and pore state. Our structures, in combination with AlphaFold2-based structural modeling and molecular dynamics simulations, reveal dramatic conformational changes in the N-terminal region of the complex. Four distinct helical bundles synchronously rearrange to progressively form a highly stable 15 nm cation-impermeable coiled-coil stalk. This stalk, in turn, positions an N-terminal pair of helices within the membrane, thereby enabling the assembly of a cation-permeable channel. Taken together, these data unveil a unique mechanism for membrane insertion and channel formation, characteristic of the LTX family, and provide the necessary framework for advancing novel therapeutics and biotechnological applications.

biochemistry↗

bioRxiv2024

Degradation of indole-3-acetic acid by plant-associated microbes

Plant-associated microbiota affect pant growth and development by regulating plant hormones homeostasis. Indole-3-acetic acid (IAA), a well-known plant hormone, can be produced by various plant-associated bacteria. However, the prevalence of microbes with the capacity to degrade IAA in the rhizosphere has not been systematically studied. In this study, we analyzed the IAA degradation capabilities of bacterial isolates from the roots of Arabidopsis and rice. Using genomics analysis and in vitro assays, we found that 21 out of 189 taxonomically diverse bacterial isolates possess the ability to degrade IAA. Through comparative genomics and transcriptomic assays, we identified iac-like or iad-like operon in the genomes of these IAA degraders. Additionally, the regulator of the operon was found to be highly conserved among these strains through protein structure similarity analysis. Some of the IAA degraders could utilize IAA as their sole carbon and energy source. In planta, most of the IAA degrading strains mitigated Arabidopsis seedling root growth inhibition (RGI) triggered by exogenous IAA. Importantly, we observed increased colonization preference of IAA degraders from soil to root according to the frequency of the biomarker genes in metagenome-assembled genomes (MAGs) collected from different habitats, suggesting that there is a close association between IAA degraders and IAA-producers. In summary, our findings further the understanding of the functional diversity and roles of plant-associated microbes.

microbiology↗

bioRxiv2024

SEraster: a rasterization preprocessing framework for scalable spatial omics data analysis

MotivationSpatial omics data demand computational analysis but many analysis tools have computational resource requirements that increase with the number of cells analyzed. This presents scalability challenges as researchers use spatial omics technologies to profile millions of cells. ResultsTo enhance the scalability of spatial omics data analysis, we developed a rasterization preprocessing framework called SEraster that aggregates cellular information into spatial pixels. We apply SEraster to both real and simulated spatial omics data prior to spatial variable gene expression analysis to demonstrate that such preprocessing can reduce resource requirements while maintaining high performance. We further integrate SEraster with existing analysis tools to characterize cell-type spatial cooccurrence. Finally, we apply SEraster to enable analysis of a mouse pup spatial omics dataset with over a million cells to identify tissue-level and cell-type-specific spatially variable genes as well as cooccurring cell-types that recapitulate expected organ structures. Availability and implementationSource code is available on GitHub (https://github.com/JEFworks-Lab/SEraster) with additional tutorials at https://JEF.works/SEraster.

bioinformatics↗

bioRxiv2024

Multiple Loci for Foveolar Vision in Macaque Monkey

A common tenet of neural sensory representation is that species-specific behaviors are reflected in specialized brain organizations1. In humans and nonhuman primates, the central one degree of vision is processed by the foveola2, a retinal structure which comprises a high density of photoreceptors and is crucial for primate-specific high acuity vision, color vision, and gaze-directed visual attention3,4,5. In this study, we have developed high spatial resolution ultrahigh field 7T fMRI methods for functional mapping of foveolar visual cortex in awake monkeys. We provide evidence that, in the ventral pathway (V1-V4 and TEO), viewing of a central small spot elicits a ring of multiple (at least 8) foveolar representations per hemisphere. This ring surrounds a large area called the foveolar core. This is an area populated by millimeter-scale functional domains sensitive to fine stimuli and high spatial frequencies, consistent with foveolar visual acuity, as well as color and achromatic information, and motion. The unique position of the foveolar core suggests it may be a hub subserving higher order needs of foveolar function, such as integrating different spatial scales of representation, integrating local and global features in object perception, and bringing together the four quadrants of visual space. Thus, this elaborate re-representation of central vision signifies a cortical specialization for various foveation behaviors.

neuroscience↗

bioRxiv2024

PackDock: a Diffusion Based Side Chain Packing Model for Flexible Protein-Ligand Docking

Structure-based drug design (SBDD) relies on accurate knowledge of protein structure and ligand-binding conformations. However, most of the static conformations obtained by advanced methods such as structural biology and de novo protein folding algorithms often dont meet the needs for drug design. We introduce PackDock, a flexible docking method that combines "conformation selection" and "induced fit" mechanisms in a two-stage docking pipeline. The core module of this method is PackPocket, which uses a diffusion model to explore the side-chain conformation space in ligand binding pockets, both with or without a ligand. We evaluate our method using several tests that reflect real-world application scenarios. (1) Side-chain packing and Re-docking experiments validate the ability of PackDock to predict accurate side-chain conformations and ligand conformations. (2) Cross-docking experiments with apo and non-homologous ligand-induced holo structures align with real docking scenarios, demonstrating PackDocks practical value. (3) Docking experiments with hypothetical models show that PackPocket can potentially conduct SBDD starting from protein sequence information only. Additionally, we found that PackDock can identify key amino acid conformation changes, which may provide insights for lead compound optimization. We demonstrate PackDock can accurately predict the complex conformations in various application scenarios, by combining the conformation selection theory and the induced fit theory, and by using the ability of PackPocket to accurately predict the side chain conformations in the pocket region. We believe this method can improve the usability of existing structures, providing a new perspective for the SBDD community.

bioinformatics↗