Biology subjects

Wei, Z.

Publications and source records attributed to Wei, Z..

At least 109 records · Page 6Linked to original sources

bioRxiv2024

Coordinated regulation by lncRNAs results in tight lncRNA-target couplings

The determination of long non-coding RNA (lncRNA) function is a major challenge in RNA biology with applications to basic, translational, and medical research [1-7]. Our efforts to improve the accuracy of lncRNA-target inference identified lncRNAs that coordinately regulate both the transcriptional and post-transcriptional processing of their targets. Namely, these lncRNAs may regulate the transcription of their target and chaperone the resulting message until its translation, leading to tightly coupled lncRNA and target abundance. Our analysis suggested that hundreds of cancer genes are coordinately and tightly regulated by lncRNAs and that this unexplored regulatory paradigm may propagate the effects of non-coding alterations to effectively dysregulate gene expression programs. As a proof-of-principle we studied the regulation of DICER1 [8, 9]--a cancer gene that controls microRNA biogenesis--by the lncRNA ZFAS1, showing that ZFAS1 activates DICER1 transcription and blocks its post-transcriptional repression to phenomimic and regulate DICER1 and its target microRNAs.

bioinformatics↗

bioRxiv2024

Senolytic therapy preserves blood-brain barrier integrity and promotes microglia homeostasis in a tauopathy model

Cellular senescence, characterized by expressing the cell cycle inhibitory proteins, is evident in driving age-related diseases. Senescent cells play a crucial role in the initiation and progression of tau-mediated pathology, suggesting that targeting cell senescence offers a therapeutic potential for treating tauopathy associated diseases. This study focuses on identifying non-invasive biomarkers and validating their responses to a well-characterized senolytic therapy combining dasatinib and quercetin (D+Q), in a widely used tauopathy mouse model, PS19. We employed human-translatable MRI measures, including water extraction with phase-contrast arterial spin tagging (WEPCAST) MRI, T2 relaxation under spin tagging (TRUST), longitudinally assessed brain physiology and high-resolution structural MRI evaluated the brain regional volumes in PS19 mice. Our data reveal increased BBB permeability, decreased oxygen extraction fraction, and brain atrophy in 9-month-old PS19 mice compared to their littermate controls. (D+Q) treatment effectively preserves BBB integrity, rescues cerebral oxygen hypometabolism, attenuates brain atrophy, and alleviates tau hyperphosphorylation in PS19 mice. Mechanistically, D+Q treatment induces a shift of microglia from a disease-associated to a homeostatic state, reducing a senescence-like microglial phenotype marked by increased p16/INK4a. D+Q-treated PS19 mice exhibit enhanced cue-associated cognitive performance in the tracing fear conditioning test compared to the vehicle-treated littermates, implying improved cognitive function by D+Q treatment. Our results pave the way for application of senolytic treatment as well as these noninvasive MRI biomarkers in clinical trials in tauopathy associated neurological disorders.

neuroscience↗

bioRxiv2024

Variation and interaction of distinct subgenomes contribute to growth diversity in intergeneric hybrid fish

Intergeneric hybridization greatly reshapes regulatory interactions among allelic and non-allelic genes. However, their effects on growth diversity remain poorly understood in animals. In this study, we conducted whole-genome sequencing and mRNA-seq analyses in diverse hybrid varieties resulting from the intergeneric hybridization of goldfish (Carassius auratus red var.) and common carp (Cyprinus carpio). These hybrid individuals were characterized by distinct mitochondrial genomes and copy number variations. Through a weighted gene correlation network analysis, we identified 3693 genes as candidate growth-regulated genes. Among them, the expression of 3672 genes in subgenome R (originating from goldfish) displayed negative correlations with growth rate, whereas 20 genes in subgenome C (originating from common carp) exhibited positive correlations. Notably, we observed intriguing patterns in the expression of slc2a12 in subgenome C, showing opposite correlations with body weight that changed with water temperatures, suggesting differential interactions between feeding activity and weight gain in response to seasonal changes for hybrid animals. In 40.31% of alleles, we observed dominant trans-regulatory effects in the regulatory interaction between distinct alleles from subgenomes R and C. Integrating analyses of allelic-specific expression and DNA methylation data revealed that the influence of DNA methylation on both subgenomes shapes the relative contribution of allelic expression to the growth rate. These findings provide novel insights into the interaction of distinct subgenomes that underlie heterosis in growth traits and contribute to a better understanding of multiple-allele traits in animals.

genetics↗

bioRxiv2024

The segmented flavivirus Alongshan virus reduces mitochondrial mass via degrading STAT2 to suppress innate immune response

Alongshan virus (ALSV) is a newly discovered pathogen of the Flaviviridae family, characterized by a multi-segmented genome distantly related to the canonical flaviviruses. Understanding the pathogenic mechanism of the emerging segmented flavivirus is crucial for the development of intervention strategies. Here we show that ALSV can infect multiple mammalian cells and induces the expression of antiviral genes. Moreover, ALSV is sensitive to IFN-{beta} and possesses the ability to counteract type I IFN response. Mechanistically, ALSVs nonstructural protein NSP1 binds to and degrades human STAT2 through an autophagy pathway in a species-dependent manner, resulting in direct inhibition of the expression of interferon-stimulated genes (ISGs). Specifically, NSP1 methyltransferase domain binds to the key sites of F175/R176 located in coiled-coil domain of STAT2. Moreover, NSP1-mediated degradation of STAT2 results in a reduction in mitochondrial mass by disrupting mitochondrial dynamics to induce mitophagy and inhibiting mitochondrial biogenesis, thereby suppressing the innate immune response. Interestingly, inhibiting mitophagy using 3-Methyladenine and enhancing mitochondrial biogenesis using the PPAR{gamma} agonist pioglitazone can reverse NSP1-mediated inhibition of ISGs, suggesting that promoting mitochondrial mass presents an effective antiviral strategy. Our findings elucidate the intricate regulatory crosstalk between ALSV and the hosts innate immune response, providing valuable insights into the pathogenesis and intervention strategy of emerging segmented flavivirus.

microbiology↗

bioRxiv2024

Cortico-spinal Mechanisms of Periphery Neuromodulation induced Analgesia

BackgroundTranscutaneous Electrical Nerve Stimulation (TENS) is widely used for pain management, yet how different parameters--Conventional (high frequency, low intensity) versus Acupuncture-Like (low frequency, high intensity)--modulate pain remains controversial. These modes produce variable analgesic effects, but their underlying brain-spinal mechanisms are unclear. Clarifying these pathways could refine TENS protocols, optimize clinical outcomes, and reduce opioid reliance, highlighting the need for more precise, non-pharmacological approaches to advanced pain care. MethodsThis single-blind, three-arm randomized trial recruited 95 healthy adults (18-30 years) and assigned them (1:1:1) to Conventional TENS, Acupuncture-Like TENS, or sham. Participants underwent a 30-minute TENS intervention on the left forearm (C5-C6 dermatome) with simultaneous brain-spinal fMRI before and after thermal nociceptive stimuli. The primary outcomes were changes in Numeric Rating Scale (NRS) pain scores and brain-spinal BOLD signals. Secondary outcomes included psycho-physiological interaction (PPI) and mediation analyses of periaqueductal gray (PAG) activity and brain- cord connectivity. FindingsBoth TENS modes significantly reduced pain but engaged distinct cortico-spinal pathways. Conventional TENS yielded local analgesia via dlPAG-driven spinal inhibition plus partial cortical involvement (PAG-vmPFC). By contrast, Acupuncture-Like TENS produced diffuse analgesia through vlPAG-linked top-down modulation reliant on spinal gating. Correlation and mediation analyses confirmed that Conventional TENS integrates spinal and cortical synergies, whereas Acupuncture-Like TENS is dominated by robust descending control. InterpretationDifferent TENS parameters yield distinct analgesic mechanisms. Conventional TENS couples direct spinal inhibition with partial cortical regulation, while Acupuncture-Like TENS relies heavily on top-down pathways passing through the spinal cord. Recognizing these unique descending networks can guide targeted TENS protocols for diverse pain conditions, optimizing clinical outcomes and reducing reliance on pharmacological approaches. FundingsThis work was supported by the National Key R&D Program of China (2022YFC3500603), the National Natural Science Foundation of China (32071061, 82072010, 82030121 and 32100861, 82330057), the Beijing Natural Science Foundation (IS23108, JQ22018).

neuroscience↗

bioRxiv2024

PerturBase: a comprehensive database for single-cell perturbation data analysis and visualization

Single-cell perturbation sequencing techniques (scPerturbation), represented by single cell genetic perturbation sequencing (e.g., Perturb-seq) and single cell chemical perturbation sequencing (e.g., sci-Plex), result from the integration of single-cell toolkits with conventional bulk screening methods. These innovative sequencing techniques empower researchers to dissect perturbation functions and mechanisms in complex biological systems at an unprecedented resolution. Despite these advancements, a notable gap exists in the availability of a dedicated database for exploring and querying scPerturbation data. To address this gap and facilitate seamless data sharing for researchers, we present PerturBase--the first and most comprehensive database designed for the analysis and visualization of scPerturbation data (http://www.perturbase.cn/). PerturBase consolidates 122 datasets from 46 publicly accessible research studies, covering 115 single-modal and 7 multi-modal datasets that include 24254 genetic and 230 chemical perturbations from about 6 million cells. The database provides insights through various software-analyzed results, encompassing quality control, denoising, differential expression gene analysis, perturbation function analysis, and correlation characterization between perturbations. All datasets and in-depth analyses are presented in user-friendly, easy-to-browse pages and can be visualized through intuitive tables and various image formats. In summary, PerturBase stands as a pioneering high-content database, intended for searching, visualizing, and analyzing scPerturbation datasets, contributing to an enhanced understanding of perturbation functions and mechanisms. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=159 SRC="FIGDIR/small/578767v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@15bdfcborg.highwire.dtl.DTLVardef@c1be77org.highwire.dtl.DTLVardef@1bf7e32org.highwire.dtl.DTLVardef@f62e8b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

LRG1 promotes atherosclerosis by activating macrophages

BackgroundAtherosclerosis is a chronic inflammatory disease of the arterial wall characterized by the accumulation of cholesterol-rich lipoproteins in macrophages. Leucine-rich alpha-2 glycoprotein 1 (LRG1) is a circulating protein associated with inflammation, however, its role in atherosclerosis remains unclear. This study identified its role in macrophage pro-inflammatory differentiation and revealed the relationship between LRG1 and atherosclerosis. MethodWe evaluated the impact of LRG1 on atherosclerosis progression by analyzing atherosclerotic tissue and serum samples from patients with coronary artery disease (CAD) and healthy individuals and analyzed its role in such a process using two types of mice models: Apoe knock-out mice (Apoe-/-) and Apoe and Lrg1 double knock-out mice (Apoe-/-/Lrg1-/-). These mice were fed with a high-fat diet for 16 to 32 weeks to simulate conditions exacerbating atherosclerosis. To examine the effects of inhibiting LRG1 on atherogenesis, we administered intraperitoneal injections of LRG1 neutralizing antibody (50g/kg) weekly to Apoe-/- mice for 8 weeks. We conducted in vitro assays using bone marrow-derived macrophages isolated from wild-type mice and analyzed transcriptional signatures using RNA sequencing. Additionally, we utilized small molecular inhibitors to validate the signaling pathway through which LRG1 promotes macrophage-driven inflammation. ResultsLRG1 levels were found to be elevated in patients with atherosclerosis and correlated with higher levels of a plasma pro-inflammatory biomarker high-sensitive C-reactive protein (hsCRP), and several macrophage-related pro-inflammatory markers including CD68, VE-Cadherin and VCAM-1. In a high fat diet induced Apoe-/- mouse atherosclerosis model, the deletion of LRG1 gene significantly delayed atherogenesis progression and reduced levels of macrophage-related pro-inflammatory cytokines. Addition of purified LRG1 to cultured macrophages stimulated those macrophages to pro-inflammatory M1-like polarization regulated by the activation of ERK and JNK pathways. An anti-LRG1 neutralizing antibody effectively blocked LRG1-induced macrophage M1-like polarization in vitro and conferred therapeutic benefits to animals with ApoE deficiency-induced atherosclerosis. ConclusionLRG1 plays an important pro-inflammatory role in atherosclerosis by influencing macrophage polarization towards a pro-inflammatory state. The inhibition of LRG1 with neutralizing antibodies may offer a potential therapeutic strategy for patients with atherosclerosis by mitigating the pro-inflammatory response and delaying disease progression, offering a novel therapy in atherosclerosis management. Translational PerspectiveAtherosclerosis, a persistent inflammatory condition affecting the arterial wall, serves as the underlying pathophysiological basis for acute ischemic cardiovascular events. The involvement of macrophages is crucial in the advancement of atherosclerosis. In this investigation, heightened levels of plasma LRG1 were observed in individuals with coronary artery disease. Moreover, this study presents initial evidence highlighting LRG1 as a pivotal activator of macrophages, instigating a pro-inflammatory M1 polarization during atherogenesis through the activation of ERK1/2 and JNK pathways. The use of an anti-LRG1 neutralizing antibody demonstrated a delay in atherosclerosis progression in an animal model, suggesting a potential therapeutic target for atherosclerosis treatment. Suppression of LRG1 production could impede atherosclerosis advancement and enhance plaque stability. Utilizing neutralizing antibodies against LRG1 emerges as a promising therapeutic approach for treating atherosclerosis.

pathology↗

bioRxiv2024

Characterization of Cancer Stem Cells in Laryngeal Squamous Cell Carcinoma by Single-Cell RNA Sequencing

Cancer stem cells (CSCs) constitute a pivotal element within the tumor microenvironment (TME), driving the initiation and progression of cancer. However, the identification of CSCs and their underlying molecular mechanisms in laryngeal squamous cell carcinoma (LSCC) remains a formidable challenge. We employed single-cell RNA sequencing of matched primary tumor tissues, paracancerous tissues, and local lymph nodes from three LSCC patients. Two distinct clusters of stem cells originating from epithelial populations were delineated and verified as CSCs and normal stem cells (NSCs) respectively. CSCs were abundant in the paracancerous tissues compared to the tumor tissues. CSCs showed high expression of stem cell marker genes such as PROM1, ALDH1A1, and SOX4, and increased activity of tumor-related hypoxia, Wnt/{beta}-catenin, and notch signaling pathways. We then explored the intricate crosstalk between CSCs and the TME cells and identified targets within the TME that related with CSCs. We also find eight marker genes of CSCs that correlated significantly with the prognosis of LSCC patients. Furthermore, bioinformatics analyses showed that drugs such as erlotinib, OSI-027, and ibrutinib selectively targeted the CSC-specifically expressed genes. In conclusion, our results represent the first comprehensive characterization of CSCs properties in LSCC at the single-cell level.

bioinformatics↗

bioRxiv2024

Toward subtask decomposition-based learning and benchmarking for genetic perturbation outcome prediction and beyond

Deciphering cellular responses to genetic perturbations is fundamental for a wide array of biomedical applications, ranging from uncovering gene roles and interactions to unraveling effective therapeutics. Accurately predicting the transcriptional outcomes of genetic perturbations is indispensable for optimizing experimental perturbations and deciphering cellular response mechanisms; however, three scenarios present principal challenges, i.e., predicting single genetic perturbation outcomes, predicting multiple genetic perturbation outcomes and predicting genetic outcomes across cell lines. In this study, we introduce SubTAsk decomposition Modeling for genetic Perturbation prediction (STAMP), a conceptually novel computational strategy for genetic perturbation outcome prediction and downstream applications. STAMP innovatively formulates genetic perturbation prediction as a subtask decomposition (STD) problem by resolving three progressive subtasks in a divide-and-conquer manner, i.e., identifying differentially expressed gene (DEG) postperturbations, determining the regulatory directions of DEGs and finally estimating the magnitudes of gene expression changes. In addition to facilitating perturbation prediction, STAMP also serves as a robust and generalizable benchmark guide for evaluating various genetic perturbation prediction models. As a result, STAMP exhibits a substantial improvement in terms of its genetic perturbation prediction ability over the existing approaches on three subtasks and beyond, including revealing the ability to identify key regulatory genes and pathways on small samples and to reveal precise genetic interactions. Overall, STAMP serves as a fundamentally novel and effective prediction and generalizable benchmarking strategy that can facilitate genetic perturbation prediction, guide the design of perturbation experiments, and broaden the understanding of perturbation mechanisms.

bioinformatics↗

bioRxiv2024

Integrated Analyses of Multi-omic Data Derived from Paired Primary Lung Cancer and Brain Metastasis Reveals the Metabolic Vulnerability as a Novel Therapeutic Target

Lung cancer brain metastases (LC-BrMs) are frequently associated with dismal mortality rates in patients with lung cancer; however, standard of care therapies for LC-BrMs are still limited in their efficacy. A deep understanding of molecular mechanisms and tumor microenvironment of LC-BrMs will provide us with new insights into developing novel therapeutics for treating patients with LC-BrMs. Here, we performed integrated analyses of genomic, transcriptomic, proteomic and metabolomic data which were derived from a total number of 174 patients with paired and unpaired primary lung cancer and LC-BrM, spanning four published and two newly generated patient cohorts on both bulk and single cell levels. We uncovered that LC-BrMs exhibited significantly higher intra-tumor heterogeneity. We also observed that mutations in a subset of genes were almost always shared by both primary lung cancers and LC-BrM lesions, including TTN, TP53, MUC16, LRP1B, RYR2, and EGFR. In addition, the genome-wide landscape of somatic copy number alterations was similar between primary lung cancers and LC-BrM lesions. Nevertheless, several regions of focal amplification were significantly enriched in LC-BrMs, including 5p15.33 and 20q13.33. Intriguingly, integrated analyses of transcriptomic, proteomic and metabolomic data revealed mitochondrial-specific metabolism was activated but tumor immune microenvironment was suppressed in LC-BrMs. Subsequently, we validated our results by conducting real-time quantitative reverse transcription PCR experiments, immunohistochemistry and multiplexed immunofluorescence staining of patients paired tumor specimens. Patients with a higher expression of mitochondrial metabolism genes but a lower expression of immune genes in their LC-BrM lesions tended to have a worse survival outcome. Therapeutically, targeting oxidative phosphorylation with gamitrinib in patient-derived organoids specific to LC-BrMs induced apoptosis and inhibited cell proliferation. The combination of gamitrinib plus anti-PD-1 immunotherapy significantly improved survival of mice bearing LC-BrMs. In conclusion, our findings not only provide comprehensive and integrated perspectives of molecular underpinnings of LC-BrMs but also contribute to the development of a potential, rationale-based combinatorial therapeutic strategy with the goal of translating it into clinical trials for patients with LC-BrMs.

cancer biology↗

bioRxiv2023

Nuclear cytoophidia assembly represses transcriptional activity to control skeletal development and homeostasis

Compartmentation via filamentation is an evolutionarily conserved subcellular structure that fine-tunes the inherent activity of proteins. Cytoophidia represent a typical class of filamentous structures controlling enzymatic activities. Despite eukaryotic cells containing both cytoplasmic cytoophidia and nuclear cytoophidia, the physiological significance of nuclear cytoophidia is largely unknown. Here we show that nuclear filamentation inhibits the transcriptional activity of Impdh2 required for limb formation and bone resorption. Impdh2 deletion in mouse limb mesenchymal progenitors causes severe skeletal dysplasia by impairing endochondral ossification and chondrocyte differentiation. Additionally, Impdh2 deficiency in myeloid lineages leads to an increased bone mass via impeding osteoclast differentiation. Furthermore, Impdh2 regulates osteoclastic mitochondrial biogenesis and function. We propose that the nuclear compartmentalization of Impdh2 regulates the transcriptional activity during skeletal development and homeostasis.

cell biology↗

bioRxiv2023

Structural insights into specific recognition of PTENα/β-NTE by WDR5 in cancer progression

PTEN/{beta}, two variants of PTEN, play a key role in promoting tumor growth by interacting with WDR5 through their N-terminal extensions (NTEs). This interaction facilitates the recruitment of the SET1/MLL methyltransferase complex, resulting in histone H3K4 trimethylation and upregulation of oncogenes such as NOTCH3, which in turn promotes tumor growth. However, the molecular mechanism underlying this interaction has remained elusive. In this study, we determined the crystal structure of PTEN-NTE in complex with WDR5, which reveal that PTEN specifically binds to the WIN site of WDR5 through a novel binding motif specifically found in the NTE domain of PTEN/{beta}. Disruption of this interaction significantly impedes cell proliferation and tumor growth, highlighting the potential of the WIN site inhibitors of WDR5 as therapeutic agents for PTEN/{beta} associated cancers. These findings not only shed light on the important role of the PTEN/{beta}-WDR5 interaction in carcinogenesis, but also present a promising avenue for developing cancer treatments that target this pathway.

cancer biology↗

bioRxiv2023

Altered Orbitofrontal Cortex Activation and Gaze Patterns to Happy Faces in Autistic Children Predict Adaptive Difficulties but Challenge the Social Motivation Hypothesis

Individuals diagnosed with Autism Spectrum Disorder (ASD) generally have altered responses to social reward, which the "social motivation" hypothesis posits as the primary contributor to their social deficits. Aberrant perception of rewarding faces is considered to be one of the most significant markers of this hypothesis. The orbitofrontal cortex (OFC) plays an important role in modulating reward and arousal responses to happy faces but few studies have investigated whether young autistic children with limited cognitive or language ability have altered neural and behavioral responses to reward related tasks. We therefore conducted an eye-tracking task where autistic (n = 36) and typically developing (n = 36) young children (aged 2.5-6 years) viewed the faces of happy children or of simplified faces (emoticons), combined with OFC activation measurement using functional near infrared spectroscopy (fNIRS), to compare ASD and typically developing (TD) children. Results revealed no differences between the two groups for time spent viewing happy faces although TD children spent more time looking at the eyes of real faces and at the mouths of emoticons whereas children with ASD did not. Children with ASD showed a greater pupil diameter (PD) and OFC activation compared to TD children during presentation of happy faces. Indeed, greater PD and OFC responses were predictive of greater adaptive behavior difficulties and severity of symptoms. Our results therefore demonstrate different gaze patterns and greater arousal and brain reward system responses to happy faces in young children with ASD which are incongruent with social motivation hypothesis. Availability of dataOur ethics approval does not permit public archiving of individual anonymized raw data. Those who wish to access the raw data should contact the corresponding author. Access will be granted to named individuals who adhere to the ethical procedures governing the reuse of sensitive data. They must complete a formal data sharing agreement to obtain the data. The data that support the main group different finding figures related anonymized data of this study are openly available via the Open Science Framework (OSF) Repository https://osf.io/sxkhc/?view_only=6eb51e64a9b54fce909b5ff6eacdc668 Ethics approval statementThe study was conducted in accordance with the principles of the Declaration of Helsinki. It was approved by the Local Ethics Committee (number 202165). Research Highlights[bullet] The present study examined whether altered social reward processing in ASD is caused by reduced behavioral and neural responses to rewarding stimuli. [bullet]Typically developing children showed a preference for viewing specific informative facial features (such as child eyes or emoticon mouths), children with autism did not. [bullet]Children with autism enhanced arousal (pupil dilation) and brain reward (orbitofrontal cortex) responses to happy child faces. [bullet]Altered, gaze patterns, arousal and brain reward responses were highly predictive of adaptive behavior abilities and autistic symptom severity.

neuroscience↗

bioRxiv2023

From sequence to ecology: siderophore-receptor coevolution algorithm predicts bacterial interactions in complex communities

Predicting bacterial social interactions from genome sequences is notoriously difficult. Here, we developed bioinformatic tools to predict whether secreted iron-scavenging siderophores stimulate or inhibit the growth of community members. Siderophores are chemically diverse and can be stimulatory or inhibitory depending on whether bacteria possess or lack corresponding uptake receptors. We focused on 1928 representative Pseudomonas genomes and developed a co-evolution algorithm to match all encoded siderophore synthetases to corresponding receptor gene groups with >90% accuracy based on experimental validation. We derived community-level iron interaction networks to show that selection for siderophore-mediated interactions differs across habitats and lifestyles. Specifically, dense networks of siderophore sharing and competition were observed among environmental (soil/water/plant) strains and non-pathogenic species, while only fragmented networks occurred among human-derived strains and pathogenic species. Altogether, our sequence-to-ecology approach empowers the analyses of social interactions among thousands of bacterial strains and uncovers ways for targeted intervention to microbial communities. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC="FIGDIR/small/565711v3_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@60d907org.highwire.dtl.DTLVardef@48756eorg.highwire.dtl.DTLVardef@115aac1org.highwire.dtl.DTLVardef@17d76e5_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2023

From sequence to molecules: Feature sequence-based genome mining uncovers the hidden diversity of bacterial siderophore pathways

Microbial secondary metabolites are a rich source for pharmaceutical discoveries and play crucial ecological functions. While tools exist to identify secondary metabolite clusters in genomes, precise sequence-to-function mapping remains challenging because neither function nor substrate specificity of biosynthesis enzymes can accurately be predicted. Here we developed a knowledge-guided bioinformatic pipeline to solve these issues. We analyzed 1928 genomes of Pseudomonas bacteria and focused on iron-scavenging pyoverdines as model metabolites. Our pipeline predicted 188 chemically different pyoverdines with nearly 100% structural accuracy and the presence of 94 distinct receptor groups required for the uptake of iron-loaded pyoverdines. Our pipeline unveils an enormous yet overlooked diversity of siderophores (151 new structures) and receptors (91 new groups). Our approach, combining feature sequence with phylogenetic approaches, is extendable to other metabolites and microbial genera, and thus emerges as powerful tool to reconstruct bacterial secondary metabolism pathways based on sequence data. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/564663v5_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1dedad4org.highwire.dtl.DTLVardef@1f0a39eorg.highwire.dtl.DTLVardef@185e345org.highwire.dtl.DTLVardef@10beec6_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2023

Long-Term In Vivo Molecular Monitoring Using Aptamer-Graphene Microtransistors

Long-term, real-time molecular monitoring in complex biological environments is critical for our ability to understand, prevent, diagnose, and manage human diseases. Aptamer-based electrochemical biosensors possess the promise due to their generalizability and a high degree of selectivity. Nevertheless, the operation of existing aptamer-based biosensors in vivo is limited to a few hours. Here, we report a first-generation long-term in vivo molecular monitoring platform, named aptamer-graphene microtransistors (AGMs). The AGM incorporates a layer of pyrene- (polyethylene glycol)5-alcohol and DNase inhibitor-doped polyacrylamide hydrogel coating to reduce biofouling and aptamer degradation. As a demonstration of function and generalizability, the AGM achieves the detection of biomolecules such as dopamine and serotonin in undiluted whole blood at 37 {degrees}C for 11 days. Furthermore, the AGM successfully captures optically evoked dopamine release in vivo in mice for over one week and demonstrates the capability to monitor behaviorally-induced endogenous dopamine release even after eight days of implantation in freely moving mice. The results reported in this work establish the potential for chronic aptamer-based molecular monitoring platforms, and thus serve as a new benchmark for molecular monitoring using aptamer-based technology.

bioengineering↗

bioRxiv2023

scDILT: a model-based and constrained deep learning framework for single-cell Data Integration, Label Transferring, and clustering

The scRNA-seq technology enables high-resolution profiling and analysis of individual cells. The increasing availability of datasets and advancements in technology have prompted researchers to integrate existing annotated datasets with newly sequenced datasets for a more comprehensive analysis. It is important to ensure that the integration of new datasets does not alter the cell clusters defined in the old/reference datasets. Although several methods have been developed for scRNA-seq data integration, there is currently a lack of tools that can simultaneously achieve the aforementioned objectives. Therefore, in this study, we have introduced a novel tool called scDILT, which leverages a conditional autoencoder and deep embedding clustering to effectively remove batch effects among different datasets. Moreover, scDILT utilizes homogeneous constraints to preserve the cell-type/clustering patterns observed in the reference datasets, while employing heterogeneous constraints to map cells in the new datasets to the annotated cell clusters in the reference datasets. We have conducted extensive experiments to demonstrate that scDILT outperforms other methods in terms of data integration, as confirmed by evaluations on simulated and real datasets. Furthermore, we have shown that scDILT can be successfully applied to integrate multi-omics single-cell datasets. Based on these findings, we conclude that scDILT holds great promise as a tool for integrating single-cell datasets derived from different batches, experiments, times, or interventions.

bioinformatics↗

bioRxiv2023

Neural stem cells protect the integrity of blood-brain barrier via the p38, JNK and ERK1/2 pathways following intracerebral hemorrhage in rats

Neural stem cells (NSCs) have displayed great potential in ameliorating brain damage following intracerebral hemorrhage (ICH) via proliferation, differentiation, and immunomodulation. However, it remains unclear whether NSCs can improve microvascular function, e.g., blood-brain barrier (BBB) integrity, after ICH. In this study, we investigate the potential therapeutic benefit of NSCs on BBB integrity as well as the underlying mechanism. Adult male Sprague-Dawley rats were randomly divided into sham, ICH+PBS, and ICH+NSCs groups for comparisons. ICH was induced by intrastriatal injection of bacterial collagenase. An aliquot of NSCs or PBS was injected via the tail vein 2 h after ICH induction. The following multiparametric measurements were compared: brain edema, hematoma volume, behavior, BBB permeability, and mitogen-activated protein kinase (MAPK) signaling pathway activity. We found that NSCs treatment attenuates BBB permeability, reduces brain edema, and promotes brain function recovery after ICH by inhibiting ERK1/2, p38, and JNK signaling pathway activation. These findings provide novel insight for future therapies aiming to prevent BBB dysfunction and improve functional recovery in ICH patients.

neuroscience↗