Biology subjects

Tang, X.

Publications and source records attributed to Tang, X..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Spliformer-v2 predicts multi-tissue RNA splicing and reveals functional genomic links with neurodegenerative diseases

Precise regulation of pre-mRNA splicing underlies transcriptomic diversity and is disrupted in aging and disease, yet tissue-specific splice-altering genetic variants remain poorly resolved. Here, we present Spliformer-V2, a SegmentNT-based deep learning model for predicting and interpreting variant effects on RNA splicing across human tissues. We generated a diploid sequence resolved RNA splice map from paired whole-genome-sequencing and RNA-seq data across 12 central nervous system (CNS) and 6 peripheral tissues for model development. Spliformer-V2 outperformed SpliceTransformer, Pangolin and AlphaGenome in predicting splice-site usage, identified tissue-specific splicing regulatory motifs, and revealed tissue vulnerability to pathogenic splice-altering variants. Analyses of loci associated with 8 neurological diseases prioritized CNS-specific mis-splice-vulnerable genes. In 1,405 amyotrophic lateral sclerosis (ALS) genomes, Spliformer-V2 nominated rare splice-altering variants enriched in PTPRN2, which showed reduced expression in TDP-43-depleted neurons. PTPRN2 overexpression rescued C9ORF72-patient derived motor neuron degeneration and modulated TDP-43 mislocalization, indicating it as a potential therapeutic modifier in ALS.

bioinformatics↗

bioRxiv2025

Precision culturomics enabled by unlabeled single-cell morphology and Raman spectra

Selective enrichment of target bacteria from complex communities such as the human microbiome has remained a challenge. Here we report a solution based on morphology, Raman spectrometry and the Laser-Induced Forward Transfer technology, which works at microbial single cells, many generations before they appear as colonies. We develop a machine learning-based framework that enables species-level targeted sorting of single microbial cells from complex microbiome. We illustrate the utility of this approach in selecting for or against specific bacteria in fecal microbiome samples and the potential for quantifying the molecules expressed based on Raman spectra. Analysis of single-cell cultured genomes reveals that brief antibiotic use drives both pre-existing resistance and de novo mutations in the transpeptidase or efflux pumps of gut commensals, along with convergent evolution between different species. Our precision culturomics method should enable detailed morphological, metabolic, and genomic insights into variations in microbial phenotypes at the single-cell level for microbiome studies.

microbiology↗

bioRxiv2025

Unveiling the biochemical catalysis and regulatory mechanisms of the E3-independent E2 enzyme hUBE2O

UBE2O, an E3-independent E2 ubiquitin-conjugation enzyme, directly engages substrates to mediate Ubiquitin conjugation and ligation. Despite its critical role in ubiquitination of multiple substrates, the catalytic and regulatory mechanisms of Homo sapiens UBE2O (hUBE2O) remain incompletely understood. Here, combining domain truncation, systematic mutagenesis and well-designed biochemical approaches, we demonstrate that hUBE2O mediates both mono- and polyubiquitination through a unique catalytic architecture. While none cysteines function for hUBE2Os E3 activity, the coiled-coil (CC) and C-terminal regulatory (CTR) domains maintain catalytic competence, with the N-terminal regions impose activity constraints. Interestingly, hUBE2O activity is refractory to its self-ubiquitination and phosphorylation state. Instead, specific non-cysteine residues (H939, T995, S1042A, S1046A, S1060A and H1130) emerge as critical regulators of substrate selectivity and catalytic optimization. Surprisingly, zinc ions emerge as potent allosteric inhibitors that bind cysteines of hUBE2O, sterically occluding the access of catalytic site C1040 to Ubiquitin. Our findings reveal that hUBE2O-mediated E3-independent ubiquitination is governed by dynamic interdomain cooperation and allosteric modulation, establishing a mechanistic framework for understanding non-canonical ubiquitination and informing the development of targeted hUBE2O modulators.

biochemistry↗

bioRxiv2025

Multi-Level Regulation in RNA-Protein Hybrid Incoherent Feedforward Loop Circuits for Tunable Pulse Dynamics in Escherichia coli

Regulating gene expression with precision is essential for cellular engineering and biosensing applications, where rapid, programmable, and sensitive control is desired. Current approaches to regulatory circuit design often rely on control at a single regulatory level, primarily the transcriptional level, thereby limiting the capability of fine-tuning the regulatory dynamics in response to complex stimuli. To address this challenge, we developed four novel RNA-protein hybrid type-1 incoherent feed-forward loop (I1-FFL) circuits in Escherichia coli that integrate transcriptional and translational regulators to achieve multi-level control of gene expression. These hybrid circuits leverage the modularity and rapid dynamics of RNA-based activators alongside the versatile inhibition capabilities of the protein-based repressors, to endow tunable pulse dynamics through engineered delays that act as transient repressor decoys. By repurposing synthetic RNA regulators at multiple regulatory levels together with aptamer and RNA-binding proteins, we demonstrate previously unexplored circuits with tunable dynamics. Complementary simulation results highlighted the importance of the engineered delays in achieving tunable pulse dynamics in these circuits. Integrating modeling insights with experimental validation, we demonstrated the flexibility of designing the RNA-protein hybrid I1-FFL circuits, as well as the tunability of their dynamics, highlighting their suitability for applications in environmental monitoring, metabolic engineering, and other engineered biological systems, where precise temporal control and adaptable gene regulation are desired.

synthetic biology↗

bioRxiv2025

Global profiling of the proteome and acetylome in mice with abdominal aortic aneurysms

BackgroundAbdominal Aortic Aneurysm (AAA) is a life-threatening vascular condition characterized by a progressive dilation of the abdominal aorta and a high risk of rupture. Currently, no effective pharmacological therapies are available, and treatment relies mainly on surgical intervention. The lack of drug targets is largely due to limited understanding of the molecular mechanisms underlying AAA development. This study aims to identify potential therapeutic targets by performing comprehensive proteomic and acetylomic analyses in a mouse model of AAA. MethodsWe conducted global proteomic and acetylomic profiling on abdominal aortic tissues collected from an AAA mouse model. A total of 7,858 proteins and 1,790 acetylated proteins encompassing 4,581 acetylation sites were quantified. Bioinformatics analyses were performed to investigate the regulatory networks and biological pathways associated with these proteins and post-translational modifications. ResultsIntegrated analysis revealed that histone-related proteins were significantly enriched in pathways co-regulated by the proteome and acetylome. These pathways are influenced by histone acetyltransferases and deacetylases, implicating histone acetylation in AAA-related inflammatory and immune processes. Notably, the deacetylases Sirt2 and Sirt5 were identified as potential regulators of neutrophil extracellular trap (NET) formation through suppression of histone acetylation. ConclusionsThis study provides the first comprehensive proteomic and acetylomic dataset for abdominal aortic tissues in a mouse model of AAA, substantially expanding the mouse acetylation database. The results highlight the central role of histone modifications in immune dysregulation and inflammation, and propose Sirt2 and Sirt5 as candidate therapeutic targets that may inhibit NET formation and slow AAA progression. These findings suggest new avenues for drug development targeting the sirtuin family, although further experimental validation and cross-species studies are needed to confirm translational relevance. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/657536v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1c397a3org.highwire.dtl.DTLVardef@188180org.highwire.dtl.DTLVardef@de1a59org.highwire.dtl.DTLVardef@193e740_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2025

Targeting HMGA1-driven leukemic transformation in myeloproliferative neoplasms with pacritinib

Progression of myeloproliferative neoplasms (MPNs) to secondary acute myeloid leukemia (sAML) is a lethal transition lacking reliable early biomarkers and effective therapies. Integrating multi-omics analyses, a cohort of 240 patient biopsies, and functional studies, we identify High Mobility Group A1 (HMGA1) as a critical driver and predictor of this transformation. HMGA1 expression, readily detectable by immunohistochemistry, progressively increases from chronic MPN phases to sAML, outperforming established markers (CD34/CD117) in predicting impending leukemic transformation (AUC = 0.96). Mechanistically, HMGA1 cooperates with JAK2V617F and TP53 mutations to promote leukemogenesis. Clinically, high HMGA1 levels correlate with resistance to first-generation JAK inhibitors and portend poor overall survival. Importantly, the next generation JAK2/FLT3 inhibitor pacritinib abrogates HMGA1-driven proliferation and significantly extends survival in preclinical models, offering an immediate therapeutic strategy for this high-risk population. Our findings establish HMGA1 as an actionable biomarker for risk stratification and early intervention, and a therapeutic target to overcome therapeutic resistance in MPN-sAML. HighlightsO_LIHMGA1 IHC staining serves as a readily implementable biomarker, outperforming existing marker for early prediction of MPN progression to sAML and identifying patients at high risk. C_LIO_LIElevated HMGA1 expression correlates with resistance to first-generation JAK inhibitors and predicts poor overall survival in MPN-sAML patients, highlighting a critical unmet therapeutic need. C_LIO_LIThe next-generation JAK2 inhibitor pacritinib effectively overcomes HMGA1-driven aggressive disease and therapy resistance, offering a rational, clinically available treatment strategy for HMGA1-high MPN-sAML. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/657170v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@18b835org.highwire.dtl.DTLVardef@e5b31dorg.highwire.dtl.DTLVardef@5245caorg.highwire.dtl.DTLVardef@163f5de_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

A Transcriptomics-Based Computational Drug Repositioning Pipeline Identifies Simvastatin And Primaquine As Novel Therapeutics For Endometriosis Pain

Endometriosis has limited treatment options, prompting the search for novel therapeutics. We previously used a transcriptomics-based computational drug repositioning pipeline to analyze public bulk transcriptomic data of eutopic endometrium from cases and controls and identified several drug candidates. Fenoprofen, our top in silico candidate, was validated in a rat model of endometriosis-associated pain. Building on this, we evaluated herein two additional candidates, simvastatin (a cholesterol-lowering drug) and primaquine (an antimalarial), based on strong endometrial gene expression reversal scores and favorable safety profiles. Using the rat model, we conducted behavioral testing, bulk RNA sequencing, and differential expression analysis to assess their therapeutic potential. We also assessed endometriosis diagnosis among patients prescribed simvastatin in electronic medical records (EMR) across six University of California (UC) healthcare institutions. In vivo validation using a rat model of endometriosis demonstrated that both simvastatin and primaquine significantly reduced vaginal hyperalgesia, a surrogate marker of endometriosis-related pain. RNA-seq of uteri and lesions confirmed reversal of disease-associated gene expression signatures following treatment. Analysis of UC-wide EMR data found lower relative risk of endometriosis among those prescribed simvastatin compared to a matched control group. Overall, simvastatin and primaquine attenuated pain-associated behaviors and reversed endometriosis-related gene expression changes in an animal model. Moreover, simvastatin prescription was associated with a lower relative risk of endometriosis in our retrospective multi-center cohort study. These findings highlight their potential as repurposed therapeutics for endometriosis and support the effectiveness of computational drug repositioning in identifying new treatment strategies. One Sentence SummarySimvastatin and primaquine reduced endometriosis pain and reversed gene signatures, with simvastatin also linked to lower disease risk.

bioinformatics↗

bioRxiv2025

Endothelial AGO1 Drives Vascular Inflammation and Atherosclerosis via a Non-Canonical Nuclear Mechanism

BACKGROUNDEndothelial cell (EC) dysfunction is a cause and consequence of vascular inflammation and lipid dysregulation in atherosclerosis, yet the molecular drivers linking EC dysfunction to systemic metabolic derangements remain incompletely understood. Moreover, whether inhibiting an endogenous gene in ECs can impact liver function, lipid profile, and the vascular inflammation in the context of atherosclerosis has not been demonstrated. We previously identified Argonaute 1 (AGO1), a component of the RNA-induced silencing complex, as a regulator of EC function in angiogenesis and obesity. However, the role of endothelial AGO1 in vascular inflammation and liver function in the context of hyperlipidemia and atherosclerosis is unknown. METHODSEC-conditional AGO1 knockout (EC-AGO1-KO) and wildtype mice were subjected to pro-atherosclerotic models induced by AAV9-PCSK9 coupled with a Western diet or partial carotid ligation. Metabolic and vascular phenotype and gene expression were analyzed. In human liver sinusoidal and aortic ECs, AGO1 was knocked down using antisense oligonucleotides (ASO), followed by assessment of inflammatory responses (qPCR, RNA-seq, ELISA, and monocyte adhesion assays). To identify the molecular mechanisms linking AGO1 and EC inflammation, Cut&Tag sequencing, chromatin immunoprecipitation, immunofluorescence, proximal ligation assay, and co-immunoprecipitation were performed. The therapeutic effect of AGO1 inhibition was assessed using ASO-delivered via lipid nanoparticle (LNP) for systemic distribution and monocyte membrane-coated nanoparticles (MoNP) to target the inflamed endothelium. RESULTSEC-AGO1-KO mice exhibited improved plasma lipid profiles, reduced hepatic steatosis, inflammation, and fibrosis, and decreased aortic atherosclerotic burden. AGO1 knockdown in ECs attenuated inflammatory responses. Mechanistically, AGO1 interacted with NF-{kappa}B p65 and promoted p65 nuclear translocation and the transcriptional activation of pro-inflammatory genes, including ICAM1 and THBS1. AGO1-ASO delivered through LNP or MoNP achieved the anti-inflammatory, anti-hyperlipidemic, and anti-atherosclerotic effects, recapitulating the phenotypes observed with EC-AGO1-KO. CONCLUSIONSEndothelial AGO1 promotes vascular inflammation and liver dysfunction in the context of hyperlipidemia and atherosclerosis, in part through a non-canonical nuclear action of AGO1 as an NF-{kappa}B coactivator. Inhibition of endothelial AGO1 provides the dual benefits of ameliorating lipid dysregulation and suppressing vascular inflammation. These results highlight EC-AGO1 as a possible therapeutic target for atherosclerosis and cardiometabolic diseases.

pathology↗

bioRxiv2025

Neural trajectories reveal orchestration of cortical coding underlying natural language composition

Language is a hierarchically structured system that enables humans to communicate complex meanings. Despite recent advances, the neurocomputational mechanism underlying the composition of natural language remains unclear. Building on the neural population theory, we investigated how neural trajectories in latent spaces underpin natural language composition that integrates diverse lexical content and syntactic relations. We found that neural trajectories derived from human neocortical responses show an orchestration of distinct coding strategies during naturalistic story comprehension. Neural latent geometry is primarily associated with syntactic relations and exhibits more efficient compression relative to lexical content. We further demonstrate that these trajectories can be simulated by brain-inspired computing systems with near-critical dynamics and a preference for historical information. Overall, by positioning structure-based integration as a key computation of natural language comprehension, our findings provide a novel perspective on the mechanism underlying real-world language use and emphasize the importance of contextual information in the development of brain-inspired intelligent systems.

neuroscience↗

bioRxiv2025

Investigating the Impact of Measurement Variance on Gene Circuit Model Parameterization

Ordinary differential equation (ODE)-based modeling is a powerful tool in the design and characterization of synthetic gene circuits. Despite its popularity, identifying the model parameters based off experimental measurement is a nontrivial task. In this study, we leverage cell-free experimental measurement of two RNA-based regulators to investigate the impact and the incorporation of measurement variance in the pair-wise squared error objective function used for ODE-model parameterization. Our findings suggest that while unweighted objective function and weighting by the inverse variance can provide reasonably accurate parameter estimation, weighing the objective function with the inverse stabilized variance could further improve the parameterization, by also capturing the system variance with a mitigated prediction variance.

synthetic biology↗

bioRxiv2025

Influence of Gut Microbiota on Oral Drug Absorption and Metabolism

Gut bacteria influence host intestinal phenotype in ways that impact drug absorption and metabolism. By comparing colonic tissue from germ-free mice to that of mice colonized with human microbiota, this study evaluates microbiota-driven differences in gene expression, mucosal permeability, and P-gp efflux capacity. Transcriptomic analysis revealed upregulation of genes coding ATP-binding cassette drug transporters P-gp (Abcb1a, Abcb1b), BCRP (Abcg2), and MRP3 (Abcc3), along with increased expression of solute carriers MCT1 (Slc16a1) and OCTN2 (Slc22a5). Immunohistochemistry indicated greater P-gp expression and apical localization in humanized mice. No relevant gene expression changes were observed in human homologs of drug-metabolizing cytochrome P450 enzymes, though cytochrome P450 oxidoreductase (Por) upregulation suggests increased cytochrome activity. Other phase I drug-metabolizing enzymes, including multiple homologs of human carboxylesterase 2 (CES2) and several reductases, were upregulated with high significance. Regarding phase II metabolism, genes encoding most UDP-glucuronosyltransferases and glutathione S-transferases were upregulated, along with the enzymes responsible for synthesizing their corresponding co-substrates, UDP-glucuronic acid and glutathione. Small intestinal mucosal explants demonstrated higher permeability to 14C-labeled polyethylene glycol 4000 (14C-PEG4000) in germ-free mice than in humanized mice. The 14C-PEG4000 permeability differences are in agreement with changes in paracellular tight junctional proteins such as claudins, zonula occludens, and myosin II-related genes. These results demonstrate the broader impact of gut microbiome on oral drug absorption and metabolism and implicate the contributions of gut microbiome to individual variations in drug efficacy and toxicity.

pharmacology and toxicology↗

bioRxiv2025

MethylProphet: A Generalized Gene-Contextual Model for Inferring Whole-Genome DNA Methylation Landscape

AO_SCPLOWBSTRACTC_SCPLOWDNA methylation (DNAm) is a key epigenetic modification that regulates gene expression and is pivotal in development and disease. However, profiling DNAm at genome scale is challenging: of [~]28 million CpG sites in the human genome, only about 1-3% are typically assayed in common datasets due to technological limitations and cost. Recent deep learning approaches, including masking-based generative Transformer models, have shown promise in capturing DNAm-gene expression relationships, but they rely on partially observed DNAm values for unmeasured CpGs and cannot be applied to completely unmeasured samples. To overcome this barrier, we introduce MethylProphet, a gene-guided, context-aware Transformer model for whole-genome DNAm inference without any measured DNAm input. MethylProphet compresses comprehensive gene expression profiles ([~]25K genes) through an efficient bottleneck multilayer perceptron, and encodes local CpG sequence context with a specialized DNA tokenizer. These representations are integrated by a Transformer encoder to predict site-specific methylation levels. Trained on large-scale pan-tissue whole-genome bisulfite sequencing data from ENCODE (1.6 billion CpG-sample pairs, [~]322 billion tokens), MethylProphet demonstrates strong performance in hold-out evaluations, accurately inferring DNAm at unmeasured CpGs and generalizing to unseen samples. Furthermore, application to TCGA pan-cancer data (chromosome 1, 9,194 samples; [~]450 million training pairs, 91 billion tokens) highlights its potential for pan-cancer whole-genome methylome imputation. MethylProphet offers a powerful and scalable foundation model for epigenetics, providing high-resolution methylation landscape reconstruction and advancing both biological research and precision medicine.

bioinformatics↗

bioRxiv2025

Swimming motions evoke Ca2+ events in vascular endothelial cells of larval zebrafish via mechanical activation of Piezo1

Calcium signaling in blood vessels regulates their growth1,2, immune response3, and vascular tone4. Vascular endothelial cells are known to be mechanosensitive5-7, and it has been assumed that this mechanosensation mediates calcium responses to pulsatile blood flow8-10. Here we show that in larval zebrafish, the dominant trigger for vascular endothelial Ca2+ events comes from body motion, not heartbeat-driven blood flow. Through a series of pharmacological and mechanical perturbations, we showed that body motion is necessary and sufficient to induce endothelial Ca2+ events, while neither neural activity nor blood circulation is either necessary or sufficient. Knockout and temporally restricted knockdown of piezo1 eliminated the motion-induced Ca2+ events. Our results demonstrate that swimming-induced tissue motion is an important driver of endothelial Ca2+ dynamics in larval zebrafish. HighlightsO_LISwimming motions in larval zebrafish evoke large, rapid, and pervasive Ca2+ transients in vascular endothelial cells. C_LIO_LIThese Ca2+ transients do not require neural firing, muscular electrical activity, endocrine factors, or heart-driven blood flow. C_LIO_LIMechanical forces are necessary and sufficient for endothelial Ca2+ transients. C_LIO_LIEndothelial Ca2+ transients require the mechanosensitive ion channel Piezo1. C_LI

physiology↗

bioRxiv2025

Elucidating Molecular Mechanisms Governing TNF-Alpha-Mediated Regulation of Amyloid Beta 42 Uptake in Blood-Brain Barrier Endothelial Cells

Cerebrovascular inflammation is prevalent in a majority of Alzheimers patients. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), circulating in the plasma have been shown to cause the inflammation of blood-brain barrier (BBB) endothelium lining the cerebral microvasculature. The BBB inflammation has been implicated in the increase of toxic A{beta} accumulation within Alzheimers disease (AD) brain. TNF-alpha in the peripheral circulation can aggravate the accumulation of amyloid-beta (A{beta}) peptides in Alzheimers disease brain. In the current study, we have shown that the exposure to TNF-alpha leads to an increase in A{beta}42 accumulation in mice and BBB endothelial cells in vitro. Moreover, dynamic SPECT/CT imaging in wild-type (WT) mice infused with TNF-alpha increased the permeability and influx of A{beta}42 into the mice brain. In addition, our results show that TNF-alpha modifies the expression of cofilin, actin, and dynamin, which are critical components for A{beta} endocytosis by BBB endothelial cells. These results offer a mechanistic understanding of how TNF-alpha may promote A{beta} accumulation at the BBB and the underlying interactions between inflammation and A{beta} exposure that drives BBB dysfunction. Hence, a therapeutic intervention aimed at addressing cerebrovascular inflammation in Alzheimers disease may potentially reduce A{beta} induced cerebrovascular toxicity in Alzheimers disease brain. Significance statementIncreased levels of TNF-alpha circulating in the plasma are considered significant factors in the consequences of A{beta} pathology in Alzheimers disease, where it can promote cerebrovascular inflammation and BBB dysfunction. However, the role of TNF-alpha, in exacerbating A{beta} pathology by increasing A{beta} accumulation at the BBB endothelial cells remains only partially understood. In this study, we demonstrated that TNF-alpha enhances A{beta}42 accumulation in the BBB endothelium by altering the expression of the BBB endocytosis machinery, specifically cofilin, actin, and dynamin. These findings are anticipated to contribute to the development of therapeutic approaches aimed at addressing elevated cytokine levels in Alzheimers disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/635286v2_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@6b27a4org.highwire.dtl.DTLVardef@f7b37dorg.highwire.dtl.DTLVardef@28efbcorg.highwire.dtl.DTLVardef@193408c_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

molecular biology↗

bioRxiv2024

Comparison of imaging-based single-cell resolution spatial transcriptomics profiling platforms using formalin-fixed, paraffin-embedded tumor samples

Imaging-based spatial transcriptomics (ST) is evolving rapidly as a pivotal technology in studying the biology of tumors and their associated microenvironments. However, the strengths of the commercially available ST platforms in studying spatial biology have not been systematically evaluated using rigorously controlled experiments. In this study, we used serial 5-m sections of formalin-fixed, paraffin-embedded surgically resected lung adenocarcinoma and pleural mesothelioma tumor samples in tissue microarrays to compare the performance of the single cell ST platforms CosMx, MERFISH, and Xenium (uni/multi-modal) platforms in reference to bulk RNA sequencing, multiplex immunofluorescence, GeoMx Digital Spatial Profiler, and hematoxylin and eosin staining data for the same samples. In addition to objective assessment of automatic cell segmentation and phenotyping, we performed pixel-resolution manual evaluation of phenotyping to carry out pathologically meaningful comparison between ST platforms. Our study detailed the intricate differences between the ST platforms, revealed the importance of parameters such as tissue age and probe design in determining the data quality, and suggested reliable workflows for accurate spatial profiling and molecular discovery.

bioinformatics↗

bioRxiv2024

Data-driven discovery of cell-type-directed network-correcting combination therapy for Alzheimer's disease

Alzheimers disease (AD) is a multifactorial neurodegenerative disorder characterized by heterogeneous molecular changes across diverse cell types, posing significant challenges for treatment development. To address this, we introduced a cell-type-specific, multi-target drug discovery strategy grounded in human data and real-world evidence. This approach integrates single-cell transcriptomics, drug perturbation databases, and clinical records. Using this framework, letrozole and irinotecan were identified as a potential combination therapy, each targeting AD-related gene expression changes in neurons and glial cells, respectively. In an AD mouse model, this combination therapy significantly improved memory function and reduced AD-related pathologies compared to vehicle and single-drug treatments. Single-nuclei transcriptomic analysis confirmed that the therapy reversed disease-associated gene networks in a cell-type-specific manner. These results highlight the promise of cell-type-directed combination therapies in addressing multifactorial diseases like AD and lay the groundwork for precision medicine tailored to patient-specific transcriptomic and clinical profiles. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/627436v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1e67fd5org.highwire.dtl.DTLVardef@1d2b779org.highwire.dtl.DTLVardef@10b6efforg.highwire.dtl.DTLVardef@1a44394_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2024

Secretory leukocyte protease inhibitor influences periarticular joint inflammation in B. burgdorferi-infected mice

Lyme disease, caused by Borrelia burgdorferi, is the most common tick-borne infection in the United States. Arthritis is a major clinical manifestation of infection, and synovial tissue damage has been attributed to the excessive pro-inflammatory responses. The secretory leukocyte protease inhibitor (SLPI) promotes tissue repair and exerts anti-inflammatory effects. The role of SLPI in the development of Lyme arthritis in C57BL/6 mice, which can be infected with B. burgdorferi, but only develop mild joint inflammation, was therefore examined. SLPI-deficient C57BL/6 mice challenged with B. burgdorferi had a higher infection load in the tibiotarsal joints and marked periarticular swelling, compared to infected wild type control mice. The ankle joint tissues of B. burgdorferi-infected SLPI-deficient mice contained significantly higher percentages of infiltrating neutrophils and macrophages. B. burgdorferi-infected SLPI-deficient mice also exhibited elevated serum levels of IL-6, neutrophil elastase, and MMP-8. Moreover, using a recently developed BASEHIT (BActerial Selection to Elucidate Host-microbe Interactions in high Throughput) library, we found that SLPI directly interacts with B. burgdorferi. These data demonstrate the importance of SLPI in suppressing periarticular joint inflammation in Lyme disease.

microbiology↗

bioRxiv2024

In Situ Integration of Porous Polyethylene Nanomembrane with Wound Exudates for Scarless Healing

Achieving scarless wound repair through innovative material designs, such as hydrogels infused with growth factors and cells, has been extensively explored. In this study, we introduce a scarless healing material called pgPE, which is based on a porous and biologically inert ultra-high molecular weight polyethylene (UHMWPE) nanomembrane. This highly flexible nanomembrane conforms closely to the wound site and effectively absorbs wound-associated species into its nanopores, forming pgPE in situ. The resulting pgPE creates an ideal environment that fosters physiological metabolism while acting as a barrier against pathogens. Our findings demonstrate that pgPE facilitates complete skin reconstruction, including the regeneration of hair follicles. Additionally, we characterized the immune microenvironment and hypoxic conditions, revealing that pgPE alleviates hypoxia and modulates immune responses, thereby promoting healing towards a scar-free outcome. The integration of wound-associated species within pgPE has been evidenced through three-dimensional Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) analysis of postmortem samples. This study highlights the potential of personalized solutions that align with physiological systems for enhanced wound healing.

bioengineering↗