Biology subjects

Ren, Q.

Publications and source records attributed to Ren, Q..

At least 19 recordsLinked to original sources

bioRxiv2026

Senescent peripheral fibroblasts initiate chemotherapy-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating complication of cancer therapy. Although axonal degeneration defines CIPN, the initiating cellular events remain unknown. Here, we show that CIPN is initiated by senescent peripheral fibroblasts rather than by the neuron itself. Across the mechanistically distinct chemotherapeutic agents paclitaxel and cisplatin, chemotherapy-induced senescence is unexpectedly restricted to peripheral fibroblasts rather than neurons and acts upstream of neuronal SARM1 activation. Genetic or pharmacological ablation of senescent fibroblasts prevents neuropathy and reverses established disease, demonstrating that these cells are required for both disease initiation and maintenance. Mechanistically, senescent fibroblasts drive neuropathic injury through an MK2-dependent senescence-associated secretory phenotype (SASP), and genetic or pharmacological inhibition of MK2 suppresses the SASP, preserves peripheral innervation and restores sensory function. Together, these findings redefine the cellular origin of CIPN and identify MK2-dependent fibroblast senescence as a therapeutic target.

cancer biology↗

bioRxiv2026

Nature-inspired nanodiscs for lesion-targeted delivery reprogram macrophages and attenuate established abdominal aortic aneurysms

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease characterized by chronic inflammation and immune dysregulation, with lesional macrophages playing a pivotal role in disease progression. However, effective and safe delivery of immune modulators to macrophages at the site of AAA remains a major clinical challenge. To address this unmet need, we report a nature-inspired nanodisc platform based on high-density lipoproteins for targeted delivery to lesional macrophages, further engineered with a multi-component targeting strategy incorporating an aneurysm-homing peptide and phosphatidylserine lipids. Nanodiscs encapsulating an anti-inflammatory protein kinase R-like endoplasmic reticulum kinase (PERK) inhibitor remarkably attenuated progression of established AAA in an elastase-induced mouse model. Using a combination of in vivo biodistribution and immune profiling approaches, we demonstrate that nanodisc-assisted PERK inhibitor delivery selectively reprograms the local immune microenvironment and attenuates pathological inflammation in AAA disease models. Notably, a single administration achieves sustained therapeutic efficacy with favorable safety profiles, effectively limiting the progression of established AAA in a clinically relevant setting. This work presents a new avenue of designer nanomedicines for targeted immunomodulation and maybe broadly applicable for a wide range of vascular and immune-mediated pathologies.

bioengineering↗

bioRxiv2026

The Par complex regulates apical-basal cell polarity through modulation of FAK signaling homeostasis

Cell polarity complexes are essential for embryogenesis, but their regulatory mechanisms during early developmental transitions remain incompletely understood. Here, we individually deleted the Crumbs, Par, and Scrib polarity complexes in mouse embryonic stem cells (mESCs). While loss of any single complex did not affect pluripotency or proliferation, deletion of Par complex disrupted the naive-to-primed transition and impaired subsequent differentiation, particularly lumen formation in neural tube organoids. Mechanistically, Par complex deficiency led to hyperphosphorylation of focal adhesion kinase (FAK) at the primed stage, driving a morphological shift from flat monolayer clusters to dome-shaped colonies. FAK inhibition rescued the aberrant morphology. Upstream, Par complex loss increased AKT phosphorylation, which remodeled extracellular matrix (ECM) and regulated integrin signaling via FURIN-LEFTY, ultimately modulating FAK activity. In addition, conditioned medium from wild-type cells partially rescued differentiation defects in Par knockout cells in a LEFTY-dependent manner. These phenotypes were consistently observed in naive-to-primed transition, neural stem cell differentiation, embryoid body formation, teratoma assays, and neural tube organoid differentiation. Together, these findings establish a Par complex-AKT-FURIN-LEFTY-ECM-integrin-FAK signaling cascade that links apical-basal polarity to early lineage specification and morphogenesis, providing a mechanistic framework for how polarity cues are translated into developmental outcomes. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/722465v1_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@179e0adorg.highwire.dtl.DTLVardef@8d83bdorg.highwire.dtl.DTLVardef@c425fforg.highwire.dtl.DTLVardef@19a8ee5_HPS_FORMAT_FIGEXP M_FIG C_FIG Significance StatementThis study elucidates the molecular mechanism by which the Par complex regulates the establishment of cell polarity. The authors demonstrate that the Par complex promotes the expression of the protein convertase FURIN via AKT signaling, thereby enhancing the maturation and secretion of LEFTY protein. This process remodels the ECM and modulates integrin signaling, ultimately regulating FAK activity and controlling the establishment of cell polarity. These findings reveal how polarity cues govern early lineage specification and morphogenesis, with implications across multiple developmental contexts.

developmental biology↗

bioRxiv2026

IR-AMES uncovers structure and composition of Alzheimer' s tau oligomers

The structure and composition of biomolecular assemblies shape their biological functions and disease processes. Yet existing approaches either require homogeneous samples or lack chemical specificity and sensitivity, limiting the elucidation of transient oligomeric species under native conditions. Here we report infrared absorbance-modulated evanescent scattering (IR-AMES) that enables ultrasensitive structural and compositional profiling of individual biomolecular assemblies in aqueous environments. This capability is achieved by photothermally encoding mid-infrared vibrational absorption into scattering contrast using a total-internal-reflection geometry. Applying IR-AMES to recombinant tau assemblies, we resolve random-coil monomers and the emergence of heterogeneous oligomers beyond ensemble-averaged measurements. In Alzheimer's disease brain-derived tau, IR-AMES reveals enrichment of antiparallel {beta}-sheet structures and RNA components in oligomers. Using lipid nanodiscs as membrane mimics, we find that pathological tau oligomers exhibit enhanced interactions with anionic membranes. IR-AMES enables spectroscopic imaging of diverse biomolecular assemblies, opening opportunities to elucidate structure-function relationships in heterogeneous biomolecular systems.

biophysics↗

bioRxiv2026

Tirzepatide improves pancreatic β-cell function in mice and patients with type 2 diabetes.

The dual incretin receptor agonist tirzepatide improves {beta}-cell function in T2D patients, but the underlying mechanism remains unclear. This study aimed to elucidate the molecular pathway through which tirzepatide restores {beta}-cell functional improvement. High-fat diet (HFD)-fed C57BL/6J mice were treated with vehicle, a GIP analogue, semaglutide or tirzepatide. Tirzepatide significantly reduced body weight and improved glucose tolerance in HFD-fed mice without altering {beta}-cell mass, proliferation, or apoptosis. Instead, tirzepatide reversed {beta}-cell dedifferentiation, as indicated by reduced ALDH1A3 expression and restored levels of the identity transcription factors PDX1 and MAFA. Single-cell RNA sequencing (scRNA seq) and in vitro studies revealed that tirzepatide up-regulated FOXO1, reactivating the FOXO1-PDX1/MAFA axis. In T2D patients, tirzepatide improved glycemic control, reduced insulin demand, increased HOMA-{beta}, and decreased HOMA-IR. Improvement in HOMA-{beta} correlated positively with baseline insulin resistance. Hence, our study suggested that tirzepatide restores {beta}-cell function in T2D by reprogramming stressed {beta} cells and re-establishing {beta}-cell identity through FOXO1-dependent transcriptional reactivation. These findings provide a mechanistic basis for the superior efficacy of dual incretin receptor agonism in T2D management. ARTICLE HIGHLIGHTSO_LITirzepatide restores {beta} cell identity and function without altering {beta} cell mass in HFD induced diabetic mice. C_LIO_LITirzepatide reverses {beta}-cell dedifferentiation and restores key {beta}-cell transcription factors (PDX1, MAFA) through reactivation of the AKT-FOXO1 signaling pathway. C_LIO_LITirzepatide increases HOMA-{beta} and decreases HOMA-IR in T2D patients, and improvements in HOMA-{beta} positively correlate with baseline insulin resistance. C_LIO_LIThese results demonstrate that tirzepatides therapeutic benefits are not only metabolic but also involve direct restoration of {beta}-cell identity and function. This highlights {beta}-cell reprogramming as a novel therapeutic avenue, thus supporting the broader clinical adoption of dual incretin receptor agonists. C_LI

physiology↗

bioRxiv2026

Improving peptide vaccine manufacturability without sacrificing immunogenicity: substitution of methionine and cysteine with oxidation-resistant isosteres

AO_SCPLOWBSTRACTC_SCPLOWVaccines comprising peptide antigens for inducing T cell immunity are being developed for a broad range of therapeutic applications including prevention and treatment of cancer, autoimmunity, and infectious diseases. However, many peptide antigens contain cysteine and/or methionine, which are prone to form oxidation products that can present challenges to manufacturing and reduce biological activity. To address this challenge, we introduced oxidation resistant (OXR) antigens wherein the cysteine and methionine residues of naturally occurring, wild type (WT) peptide antigens are substituted with isosteric residues that are structurally related but omit the oxidation-prone sulfur atom. Our results showed that vaccination with OXR antigens substituting cysteine and methionine with isosteres alpha-aminobutyric acid and norleucine, respectively, induced immune responses to the WT antigen that were equivalent or higher than those induced by vaccination with WT antigens. T cell responses were not affected by the position of the amino acid substitutions indicating that the isosteres do not negatively impact major histocompatibility complex (MHC) binding or T cell recognition. The T cells induced were high quality and associated with anti-tumor efficacy in vivo. Interestingly, substitution of cysteine with serine, which replaces the sulfur for an oxygen, did not yield cross-reactive T cell responses, highlighting the high degree of molecular discernment of peptide-MHC processing and presentation. In sum, OXR antigens provide a generalizable strategy for eliminating sulfur oxidation products and improving the manufacturability and shelf-life of peptide-based vaccines without affecting desired biologic activity.

immunology↗

bioRxiv2026

Iron Deficiency Drives Sarcopenia in the Elderly: HIF-1α-Mediated Fibro-Adipogenic Progenitor Differentiation Induces Fat Infiltration and Impairs Muscle Function

Abnormal iron metabolism is closely linked to sarcopenia; however, the specific iron metabolism features of fat-infiltrating sarcopenia remain poorly understood. Proteomic sequencing revealed that in skeletal muscle with severe fat infiltration, the expression of iron utilization-related proteins was significantly downregulated, whereas that of iron uptake and storage proteins was markedly upregulated, thereby presenting an abnormal iron deficiency (ID) phenotype. Nevertheless, the mechanism by which ID drives intramuscular fat infiltration has not been fully elucidated. Using clinical samples, aged murine ID models, and in vitro cell assays, this study is the first to demonstrate that ID stabilizes hypoxia-inducible factor-1 (HIF-1), promoting aberrant adipogenic differentiation of fibro-adipogenic progenitors (FAPs), disrupting the homeostatic balance between satellite cells (SCs) and FAPs, exacerbating skeletal muscle fat infiltration, and impairing muscle repair capacity. Notably, treatment with the HIF-1 inhibitor PX478 reversed these pathological alterations and improved muscle function. Collectively, our findings identify the ID-HIF-1-FAPs axis as a key driver of intramuscular fat infiltration, offering a novel therapeutic target for the clinical management of fat-infiltrating sarcopenia.

cell biology↗

bioRxiv2025

Sampling Function-Related Metastable States of Proteins With DASH

Rational discovery of function-specific protein modulators as well as activity-enhanced engineering proteins underscore the need to identify function-related metastable states (FMSs) of proteins. However, current experimental and computational methods struggle to generate these states directly from their native state (NS), likely because the NS [->] FMS transition is non-spontaneous. To address this challenge, we introduce Deep learning guided Adaptive sampling with seed Selection and Hopping (DASH), integrating both deep learning and physical functions to guide molecular dynamics (MD) simulation towards FMS. DASH successfully sampled NS [->] FMS transitions in 18 cases across two tasks: protein activation and cryptic allosteric site opening. DASH combined with secondary-structure collective variables is further able to sample folding of disordered regions. Compared to existing methods, DASH demonstrates superior performance while requiring comparable simulation time. Crucially, we applied DASH to sample new conformations of proteins, by which revealing new folding states, previously unknown allosteric sites, and potential activators. These predictions have been further verified in wet-lab experiments and crystal structures determinations. Collectively, our framework provides a robust strategy for function-specific pharmacy research and could accelerate future drug discovery efforts.

bioinformatics↗

bioRxiv2025

Immune-Derived THBS1-CD47 Axis Induces Cellular Senescence and Suppresses Osteogenesis in Diabetic Periosteum

Type 2 diabetes mellitus (T2DM) weakens bone repair and increases fracture risk, but how the periosteal environment contributes to this problem is not fully understood. We found that diabetic mice showed thinning of the periosteum, reduced bone mass, and poor function of bone-forming cells. Using single-cell RNA sequencing, we discovered that immune cells and bone-lineage cells interact more strongly in diabetes through the THBS1-CD47 pathway. THBS1 was mainly produced by macrophages, while its receptor CD47 was abundant in osteogenic cells. Laboratory experiments showed that THBS1 blocked bone gene activity, increased inflammation and cell death, and damaged mitochondria, leading to higher oxidative stress. Knocking down CD47 reversed these effects, restoring bone cell activity and energy balance. In diabetic fracture models, blocking THBS1 improved callus formation and bone healing. These findings identify THBS1-CD47 as a key driver of periosteal dysfunction in T2DM and highlight it as a potential target to improve skeletal repair in diabetic patients.

cell biology↗

bioRxiv2025

Experimental transmission of African swine fever virus by Ornithodoros lahorensis (Acari: Argasidae)

African swine fever (ASF) is an acute, highly contagious infectious disease that affects both domestic and wild pigs, caused by the African swine fever virus (ASFV). ASFV is the only known DNA virus transmitted by arthropod vectors, with acute infection in pigs leading to morbidity and mortality rates as high as 100%.The virus can persist in a transmission cycle among wild boars, soft ticks, and domestic pigs. To date, nine Ornithodoros spp. have been confirmed to be capable of transmitting ASFV worldwide. However, the potential soft tick species capable of transmitting ASFV in China remain unclear. In this study, we compared the ability of Argasidae spp. Ornithodoros lahorensis and Argas persicus, as well as Ixodidae spp., Haemaphysalis longicornis, Rhipicephalus sanguineus and Dermacentor silvarum, to transmit ASFV via animal transmission experiments. The results revealed that O. lahorensis soft ticks, but not A. persicus or Ixodes, could act as competent vectors through transstadial and transovarial transmission of ASFV. The virus titers horizontally transmitted ASFV to ticks were 105.83, 106.59 and 104.31, HAD50/ml respectively. These viruses were detected in the nymphs developed from larvae, adults developed from nymphs, and larvae hatched from eggs by adults. Thus, O. lahorensis ticks are likely an important natural vectors of ASFV, although both mammalian and tick hosts are likely required for the maintenance of ASFV in the sylvatic cycle.

microbiology↗

bioRxiv2025

Multi-omics profiling of cross-resistance between ceftazidime-avibactam and meropenem identifies common and strain-specific mechanisms in Pseudomonas aeruginosa clinical isolates

Pseudomonas aeruginosa is a highly versatile and resilient pathogen that can infect different tissues and rapidly develop resistance to multiple drugs. Ceftazidime-avibactam (CZA) is an antibiotic often used to treat multidrug resistant infections, however, the knowledge on the CZA resistance mechanisms in P. aeruginosa is limited. Here we performed laboratory evolution of eight clinical isolates of P. aeruginosa exposed to either CZA or meropenem (MEM) in sub-inhibitory concentrations, and used multi-omics profiling to investigate emerging resistance mechanisms. The majority of strains exposed to MEM developed high resistance (83%, 20/24 strains from eight clinical isolates), with only 17% (4/24) acquiring cross-resistance to CZA. The rate of resistance evolution to CZA was substantially lower (21%, 5/24), while 38% (9/24) acquired cross-resistance to MEM. Whole-genome sequencing revealed strain heterogeneity and different evolutionary paths, with three genes mutated in three or more strains: dacB in CZA-treated strains and oprD and ftsI in MEM-treated strains. Transcriptomic and proteomic analysis underlined heterogeneous strain response to antibiotic treatment with few commonly regulated genes and proteins. To identify genes potentially associated with antibiotic resistance, we built a machine learning model that could separate CZA- and MEM-resistant from sensitive strains based on gene expression and protein abundances. To test some of the identified associations, we performed CRISPR/Cas9 genome editing that demonstrated that mutations in dacB, ampD, and to a lesser extent in mexR directly affected CZA resistance. Overall, this study provides novel insights into the strain-specific molecular mechanisms regulating CZA resistance in Pseudomonas aeruginosa. ImportancePseudomonas aeruginosa is one of the most difficult-to-treat pathogens in the hospital, which often acquires resistance to multiple antibiotics. Ceftazidime-avibactam (CZA) is an essential antibiotic used to treat multidrug resistant infections, but its resistance mechanisms are not well understood. Here we investigated the evolution of resistance to CZA and meropenem (MEM) in eight clinical bacterial isolates from patients blood, urine, and sputum. While the rate of resistance evolution to MEM was higher than to CZA, MEM-resistant strains rarely acquired cross-resistance towards CZA. To identify changes at the genome, transcriptome and proteome levels during antibiotic exposure, we performed multi-omics profiling of the evolved strains, and confirmed the effect of several genes on antibiotic resistance with genetic engineering. Altogether, our study provides insights into the molecular response of P. aeruginosa to CZA and MEM and informs therapeutic interventions, suggesting that CZA could still be effective for patients infected with MEM-resistant pathogens.

microbiology↗

bioRxiv2024

Lipid bilayers determine the allostery but not intrinsic affinity of cAMP binding to pacemaker channels

Cyclic adenosine monophosphate (cAMP), a second messenger, binds to hyperpolarization and cyclic nucleotide-gated (HCN) ion channels and regulates the automaticity of pacemaking activity. While cellular studies suggest that cAMP binding to HCN channels exhibits unusual cooperativity, recent findings using purified detergent-solubilized channels indicate independent binding to each subunit. This discrepancy raises the question of whether the lipid environment or endogenous cellular cofactors influence cAMP-dependent gating. To address this, we reconstituted purified human HCN channels in nanodiscs and resolved cAMP binding energetics at single-molecule resolution using nanophotonic waveguides. Our measurements reveal that, in contrast to detergent-solubilized channels, cAMP binds cooperatively to HCN channels reconstituted in a variety of lipid nanodiscs. Remarkably, the presence of lipid bilayer promotes ligand-binding allostery but not intrinsic binding affinity. To explore the molecular basis of bilayer-induced allostery, we determine the cryo-EM structure of HCN1 in soy polar lipid nanodiscs at a nominal resolution of 3.77 [A] resolution. Although the overall architecture is conserved, the average interfacial distance between the transmembrane domain and C-terminal domain of neighboring subunits are shorter in lipid nanodiscs. These findings indicate that the lipid bilayer regulates the function of pacemaker ion channels by enhancing inter-subunit interactions and underscore the fundamental role of membranes in amplifying the gating sensitivity of ion channels by promoting long-range cooperative interactions. Significance StatementLipid membranes are essential for the structure and function of membrane proteins, including ion channels. Lipid mimetics, such as non-ionic detergents, are widely used as surrogates for the membrane environment in structural and biophysical studies. Here, we demonstrate that while the overall structure of the pacemaker ion channel remains similar, lipid membranes--unlike detergents--promote cooperative ligand-binding transitions by modifying interactions at intersubunit interfaces. These findings provide new insights into the mechanism of ion channel regulation by lipid membranes.

biophysics↗

bioRxiv2024

DeFrND: detergent-free reconstitution into native nanodiscs with designer membrane scaffold peptides

Membrane scaffold proteins-based nanodiscs (NDs) have facilitated unprecedented structural and biophysical analysis of membrane proteins in a near-native lipid environment. However, successful reconstitution of membrane proteins in NDs requires prior solubilization and purification in detergents, which may impact their physiological structure and function. Furthermore, the detergent-mediated reconstitution of NDs is unlikely to recapitulate the precise composition or asymmetry of native membranes. To circumvent this fundamental limitation of traditional ND technology, we herein describe the development of membrane-solubilizing peptides to directly extract membrane proteins from native cell membranes into nanoscale discoids. By systematically protein engineering and screening, we created a new class of chemically modified Apolipoprotein-A1 mimetic peptides to enable the formation of detergent-free NDs (DeFrNDs) with high efficiency. NDs generated with these engineered membrane scaffold peptides are suitable for obtaining high-resolution structures using single-particle cryo-EM with native lipids. To further highlight the versatility of DeFrNDs, we directly extract a sampling of membrane signaling proteins with their surrounding native membranes for biochemical and biophysical interrogations.

biophysics↗

bioRxiv2024

The molecular mechanism of temperature-dependent phase separation of Heat shock factor 1

Heat shock factor 1 (HSF1) is the critical orchestrator for a cell responding to heat shock, and its dysfunction is linked to cancers and neurodegenerative diseases. HSF1 undergoes phase separation upon heat shock, and its activity is regulated by various post-translational modifications (PTMs). Despite its importance, the molecular details underlying HSF1 phase separation, temperature sensing, and post-translational modifications (PTMs) regulation remain poorly understood. Here, we discovered that HSF1 exhibits temperature-dependent phase separation with a lower critical solution temperature (LCST) behavior due to entropy contribution from solvent molecules, providing a new conceptual mechanism accounting for HSF1 activation. We employed a synergistic approach combining coarse-grain simulation and nuclear magnetic resonance spectroscopy to reveal the residue-level molecular details of the interactions driving the phase separation of wild-type HSF1 and its distinct PTM patterns at various temperatures. The identified interaction sites were further validated with biochemistry assays and mapped interface accounts for HSF1 functions reported. Importantly, the amino acid substitution experiment reveals the molecular grammar for temperature-dependent HSF1 phase separation is species-specific and physiologically relevant. These findings delineate chemical code that integrates protein PTM patterns with accurate phase separation for body physiological temperature control in animals.

biochemistry↗

bioRxiv2023

Bio-Mol:Pretraining Multimodality Bioactivity Profile for Enhancing Small Molecule Property Prediction

Non-optimized pharmacokinetic parameters serve as the primary cause of failure in clinical trials of drugs. Therefore, the successful prediction of pharmacokinetic parameters during the pre-clinical stage is crucial for the success of drug candidates. Conventional methods primarily rely on 2D structural information, while advanced models extend the features to other structural-related information or use advanced computational models to improve prediction accuracy. However, to gain a comprehensive understanding of small molecules, integrating bioactivity profiles with chemical structural information is essential. One significant challenge in this integration is the high proportion of missing values within experimentally validated bioactivity profiles for most small molecules. To address this challenge, we introduce Bio-Mol, an artificial intelligence model designed to effectively handle this issue. Bio-Mol utilizes a pretrain and finetune strategy, enabling the incorporation of a large proportion of missing bioactivity profiles during the small molecule representation learning process. Comprehensive evaluations of Bio-Mol demonstrate a notable improvement in predicting molecule properties. The integration of missing bioactivity profiles enhances the AUROC of average 5.2% compared to the previous state-of-the-art models predictions. Furthermore, we explore the potential of Bio-Mol in predicting synergistic drug combinations, highlighting its versatility and broader applications in the field of drug discovery. The successful implementation of Bio-Mol showcases its efficacy in over-coming the challenges posed by missing bioactivity profile data. This model paves the way for optimizing small molecule pharmacokinetics prediction, providing valuable insights for drug development and discovery processes.

bioinformatics↗

bioRxiv2023

Spatial transcriptomics and single-nucleus RNA sequencing reveal a transcriptomic atlas of adult human spinal cord

Despite the recognized importance of the spinal cord in sensory processing, motor behaviors, and neural diseases, the underlying organization of neuronal clusters and their spatial location remain elusive. Recently, several studies have attempted to define the neuronal types and functional heterogeneity in the spinal cord using single-cell or single-nucleus RNA sequencing in animal models or developing humans. However, molecular evidence of cellular heterogeneity in the adult human spinal cord is limited. Here, we classified spinal cord neurons into 21 subclusters and determined their distribution from nine human donors using single-nucleus RNA sequencing and spatial transcriptomics. Moreover, we compared the human findings with previously published single-nucleus data of the mouse adult spinal cord, which revealed an overall similarity in the neuronal composition of the spinal cord between the two species while simultaneously highlighting some degree of heterogeneity. Additionally, we examined the sex differences in the spinal neuronal subclusters. Several genes, such as SCN10A and HCN1, showed sex differences in motor neurons. Finally, we classified human dorsal root ganglia (DRG) neurons using spatial transcriptomics and explored the putative interactions between DRG and spinal cord neuronal subclusters. In summary, these results illustrate the complexity and diversity of spinal neurons in humans and provide an important resource for future research to explore the molecular mechanisms underlying spinal cord physiology and diseases.

neuroscience↗

bioRxiv2023

An explainable artificial intelligence-based typification of chronic inflammatory responses enhances glioma prognosis

Glioma is one of the most aggressive solid brain tumors with a poor prognosis. A chronic tumor inflammatory microenvironment drives glioma promotion and progression. The neutrophil-to-lymphocyte ratio and other clinicopathological variables usually serve as prognostic glioma markers. However, they are not ubiquitous prognostic markers for glioma as they fail to reveal the intricacy between the glioma-specific tumor inflammatory microenvironment and the systemic inflammatory responses, especially those chronic inflammatory responses, which vary among individuals fabricating diverse prognostic outcomes. Here, we introduced an explainable artificial intelligence model to typify chronic inflammatory responses as prognostic markers for glioma using 694-patients data from The Cancer Genome Atlas. We characterized the glioma-specific personalized inflammatory mediators using multi-layered regulators such as transcriptional networks, cellular infiltration markers, and cellular senescence markers, which identified five unique chronic inflammatory responses (p-value<0.0001). We defined its prognostic significance using overall survival analyses. The chronic inflammatory responses were positively correlated with poor overall survival in glioma. The patients with higher chronic inflammatory responses showed significantly shorter overall survival than those with lower chronic inflammatory responses. Interestingly, optimizing those chronic inflammatory responses improved the overall survival of glioma patients. We identified the effector genes within the personalized inflammatory mediators networks, indicating them as the targets for optimizing individualized chronic inflammatory response profiles through co-drug intervention. SignificanceExplainable artificial intelligence-based typification of chronic inflammatory responses accelerates glioma prognosis and supports co-drug discovery to modulate inflammatory responses alongside cancer therapy, suggested by 694-glioma patients data analysis.

systems biology↗

bioRxiv2023

Rapid and accurate taxonomic classification of cpn60 amplicon sequence variants

The "universal target" region of the gene encoding the 60 kDa chaperonin protein (cpn60, also known as groEL or hsp60) is a proven sequence barcode for bacteria and a useful target for marker gene amplicon-based studies of complex microbial communities. To date, identification of cpn60 sequence variants from microbiome studies has been accomplished by alignment of queries to a reference database. Naive Bayesian classifiers including the RDP classifier offer an alternative identification method that provides variable rank classification and shorter analysis times. We curated a set of cpn60 barcode sequences to train the RDP classifier and tested its performance on data from previous human microbiome studies. Results showed that sequences accounting for 79%, 86% and 92% of the observations (read counts) in saliva, vagina and infant stool microbiome data sets were classified to the species rank. We also established a threshold confidence value of 0.6 at phylum rank for filtering non-target amplicon sequences from study data and demonstrated that trimming the training sequences to match the lengths of the queries is not needed for accurate cpn60 sequence classification. Successful implementation of a naive Bayesian classifier for cpn60 sequences will facilitate future microbiome studies and open opportunities to integrate cpn60 amplicon sequence identification into existing analysis pipelines.

microbiology↗