Biology subjects

Hu, J.

Publications and source records attributed to Hu, J..

At least 199 records · Page 11Linked to original sources

bioRxiv2024

Identification of SMARCA1 as a key regulator for Colorectal Cancer

Emerging evidence indicates that aberrations in the writing, reading, or erasure of chromatin modification codes are pivotal events in various human cancers. In this study, we conducted a systematic investigation of histone modification recognition proteins in a pair of colorectal cancer cell lines, SW480 and SW620. Using chromatin fractionation combined with data-independent acquisition mass spectrometry (DIA-MS), we developed a robust method to identify changes in histone modification recognition proteins during cancer progression. Our analysis revealed 22 proteins that were significantly upregulated and 22 proteins that were significantly downregulated in SW620 cells compared to SW480 cells. Notably, SMARCA1, a member of the ISWI family belonging to ATP-dependent chromatin remodeling complexes, was downregulated in SW620 cells compared to SW480 cells. Its high expression was strongly correlated with poor patient prognosis, aligning with the proposed role of SMARCA1 in promoting colorectal cancer (CRC) metastasis. Furthermore, reduced SMARCA1 expression altered the levels of metastasis-related matrix metalloproteinases (MMPs) in these cells. In conclusion, by systematically profiling histone modification recognition proteins in a matched pair of primary and metastatic CRC cell lines, we identified SMARCA1 as a potential driver of CRC metastasis and a promising therapeutic target for CRC patients.

cancer biology↗

bioRxiv2024

A photorespiratory glyoxylate shunt in the cytosol supports photosynthesis and plant growth under high light conditions in Arabidopsis

Photorespiration, a central aspect of plant metabolism that is tightly connected to photosynthesis, functions in part to support photosynthetic performance, especially under stress conditions such as high light. However, our understanding of the mechanisms underlying the role and regulation of photorespiration in plant response to high light is limited. To identify modulators of photorespiration under high light, we isolated genetic suppressors of the photorespiratory mutant hpr1, which is defective in the peroxisomal hydroxypyruvate reductase 1. A suppressor that partially rescued hpr1 under high light was mapped to GLYR1, which encodes the cytosolic glyoxylate reductase 1 enzyme that converts glyoxylate to glycolate. Independent GLYR1 loss-of-function mutants also partially rescued hpr1 and another photorespiratory mutant, catalase 2. Our genetic, transcriptomic and metabolic profiling analyses together suggested a novel connection between cytosolic glyoxylate and a non-canonical photorespiratory route mediated by the cytosolic HPR2 enzyme, which we named the photorespiratory glyoxylate shunt. This shunt is especially critical under high light intensities when a high rate of photorespiratory flux is required and in the absence of a properly functional major photorespiratory pathway. Our findings support the metabolic flexibility of photorespiration and may help future efforts to improve crop performance under stress.

plant biology↗

bioRxiv2024

State-specific Peptide Design Targeting G Protein-coupled Receptors

G protein-coupled receptors (GPCRs) play critical roles in various physiological processes and serve as pivotal targets for drug discovery. Peptides are particularly compelling therapeutic agents for targeting GPCRs, as they frequently exhibit superior affinity, selectivity, and potency compared to small-molecule drugs. However, the states (active and inactive) of GPCRs profoundly influence their interactions with ligands, highlighting the need for state-specific strategies in peptide design. To address this, we developed an efficient state-specific peptide design pipeline targeting GPCRs. This framework enables the tailored design of agonists or antagonists based on the active or inactive conformational states of GPCR structures. A state-specific folding model, optimized for GPCR-peptide complexes, was used to select high-potential peptides from the pool of designed candidates. Using this approach, we successfully identified both agonist and antagonist peptides for the Apelin Receptor (APJR) and the Growth Hormone Secretagogue Receptor (GHSR), as well as a competitive inhibitor for the Glucagon-Like Peptide-1 Receptor (GLP-1R).

bioinformatics↗

bioRxiv2024

Structural Basis for Catalysis and Substrate Specificity of a LarA Racemase with a Broad Substrate Spectrum

The LarA family consists of diverse racemases/epimerases that interconvert the diastereomers of a variety of -hydroxyacids by using a nickel-pincer nucleotide (NPN) cofactor. The hidden redox reaction catalyzed by the NPN cofactor makes LarA enzymes attractive engineering targets for applications. However, how a LarA enzyme binds its natural substrate and recognizes different -hydroxyacids has not been elucidated. Here, we report three high-resolution structures of the enzyme-substrate complexes of a broad-spectrum LarA enzyme from Isosphaera pallida (LarAIp). The substrate binding mode reveals an optimal orientation and distance between the hydride donor and acceptor, strongly supporting the proposed proton-coupled hydride transfer mechanism. The experimentally solved structures, together with the structural models of other LarA enzymes, allow us to identify the residues/structural elements critically involved in the interactions with different -hydroxyacid substrates. Collectively, this work provides a critical structural basis for catalysis and substrate recognition of the diverse enzymes in the LarA family, thus building a foundation for enzyme engineering.

biochemistry↗

bioRxiv2024

VaxLLM: Leveraging Fine-tuned Large Language Model for automated annotation of Brucella Vaccines

BackgroundVaccines play a vital role in enhancing immune defense and preventing the hosts against a wide range of diseases. However, research relating to vaccine annotation remains a labor-intensive task due to the ever-increasing volume of scientific literature. This study explores the application of Large Language Models (LLMs) to automate the classification and annotation of scientific literature on vaccines as exemplified on Brucella vaccines. ResultsWe developed an automatic pipeline to automatically perform the classification and annotation of Brucella vaccine-related articles, using abstract and title. The pipeline includes VaxLLM (Vaccine Large Language Model), which is a fine-tuned Llama 3 model. VaxLLM systematically classifies articles by identifying the presence of vaccine formulations and extracts the key information about vaccines, including vaccine antigen, vaccine formulation, vaccine platform, host species used as animal models, and experiments used to investigate the vaccine. The model demonstrated high performance in classification (Precision: 0.90, Recall: 1.0, F1-Score: 0.95) and annotation accuracy (97.9%), significantly outperforming a corresponding non-fine-tuned Llama 3 model. The outputs from VaxLLM are presented in a structured format to facilitate the integration into databases such as the VIOLIN vaccine knowledgebase. To further enhance the accuracy and depth of the Brucella vaccine data annotations, the pipeline also incorporates PubTator, enabling cross comparison with VaxLLM annotations and supporting downstream analyses like gene enrichment. ConclusionVaxLLM rapidly and accurately extracted detailed itemized vaccine information from publications, significantly outperforming traditional annotation methods in both speed and precision. VaxLLM also shows great potential in automating knowledge extraction in the domain of vaccine research. AvailabilityAll data is available at https://github.com/xingxianli/VaxLLM, and the model was also uploaded to HuggingFace (https://huggingface.co/Xingxian123/VaxLLM).

bioinformatics↗

bioRxiv2024

Cardiolipin-mimic lipid nanoparticles without antibody modification delivered senolytic in-vivo CAR-T therapy for inflamm-aging

mRNA-based in vivo CAR T cell engineering offers advantages over ex vivo therapies, including streamlined manufacturing and transient expression. However, current delivery requires antibody-modified vehicles with manufacturing challenges. In this study, inspired by cardiolipin, we identified a cardiolipin-like di-phosphoramide lipid that improved T cell transfection without targeting ligands, both in vivo and in vitro. The T cell-favored tropism is likely due to the lipids packing, shape, and rigidity. Encapsulating circular RNA further prolonged mRNA expression in the spleen and T cells. Using PL40 lipid nanoparticles, we delivered mRNA encoding a CAR targeting the senolytic and inflammatory antigen urokinase-type plasminogen activator receptor (uPAR), alleviating uPAR-related liver fibrosis and rheumatoid arthritis (RA). Single cell sequencing in humans confirmed uPARs relevance to senescence and inflammation in RA. To further enhance clinical translation, we screened and humanized scFvs against uPAR, establishing PL40 mRNA encoding a circular human uPAR CAR, with potential for treating aging-inflamed disorders. One Sentence SummaryWeve developed a unique class of Cardiolipin-mimic lipids that facilitate mRNA delivery to T cells in vivo without the need for antibody modification, enhancing the treatment of liver fibrosis and rheumatoid arthritis through circular CAR uPAR RNA and propelling the clinical application of humanized CAR against human uPAR.

bioengineering↗

bioRxiv2024

Heat Acclimation in Mice Requires Preoptic BDNF Neurons and Postsynaptic Potentiation

Heat acclimation (HA) is a key adaptive response in mammals to repeated heat exposure, essential for fitness and survival1-3. HA improves cardiovascular function, thermal comfort, and exercise capacity4, 5. However, the lack of a genetically tractable model has hindered understanding of the molecular and neural mechanisms underlying HA. Here, we show that 10 days of daily 38{degrees}C exposure lowers core body temperature (Tcore) and reduces anxiety during subsequent heat exposures in mice. HA increases brain-derived neurotrophic factor (BDNF) expression in the medial preoptic area (MPO). BDNF-expressing MPO neurons (MPOBDNF) show increased intrinsic heat sensitivity after HA. These neurons orchestrate downstream targets in the dorsomedial hypothalamus (DMH) and rostral raphe pallidus (rRPa) to mediate HA effects. BDNF, acting through its receptor tropomyosin-related kinase B (TrkB) in the DMH, facilitates the anxiolytic effect of HA by enhancing excitatory synaptic connections between MPOBDNF and DMH neurons. This study provides new insights into HA mechanisms, setting the stage for future research on heat stress reduction and exercise optimization.

neuroscience↗

bioRxiv2024

Pan-Cancer Drug Sensitivity Prediction from Gene Expression using Deep Learning

Cancer is a group of complex diseases, with tumor heterogeneity, durable drug efficacy, emerging resistance, and host toxicity presenting major challenges to the development of effective cancer therapeutics. While traditionally used methods have remained limited in their capacity to overcome these challenges in cancer drug development, efforts have been made in recent years toward applying "big data" to cancer research and precision oncology. By curating, standardizing, and integrating data from various databases, we developed deep learning architectures that use perturbation and baseline transcriptional signatures to predict efficacious small molecule compounds and genetic dependencies in cancer. A series of internal validations followed by prospective validation in prostate cancer cell lines were performed to ensure consistent performance and model applicability. We report SensitivitySeq, a novel bioinformatics tool for prioritizing small molecule compounds and gene dependencies in silico to drive the development of targeted therapies for cancer. To the best of our knowledge, this is the first supervised deep learning approach, validated in vitro, to predict drug sensitivity using baseline cancer cell line gene expression alongside cell line-independent perturbation-response consensus signatures. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/623715v1_ufig1.gif" ALT="Figure 1"> View larger version (73K): org.highwire.dtl.DTLVardef@9f48bcorg.highwire.dtl.DTLVardef@16056f7org.highwire.dtl.DTLVardef@1ed9095org.highwire.dtl.DTLVardef@1af3fce_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

Regulating of Koisio technology-produced fluid on Vascular Adventitial Interstitial Fluid flow and its Effect on heart rate by delivering Esmolol

Acupoint-originated interstitial fluid (ISF) circulatory network along the vasculature has been demonstrated to play a role as an extravascular drug delivery pathway. We aim to reveal the regulation of Koisio technology-produced fluid (KF), which is rich in Ultra-small Particle Size Nanobubbles (UsNBs), on vascular adventitial ISF flow and its Effect on heart rate by delivering Esmolol. In animal experiments, using real-time fluorescent imaging technology, it was found that: when normal saline-fluorescent liquid was given at Kunlun acupoint, the velocity of the adventitial ISF along the femoral vein was measured to be about 600 m/sec, and the width of the tunica ISF channel on the adventitia surface of the femoral vein was about 210m; when KF-fluorescent liquid was injected into the subcutaneous tissue of Kunlun acupoint, the velocity of the adventitia ISF slowed down by about 24% compared with before; the width of the tunica ISF channel on the adventitia surface of the femoral vein increased by about 35% compared with before; When 150L of KF with high-concentration UsNBs was injected into Kunlun acupoint, it was observed that the adventitial ISF flow velocity was decreased by 43%, and recovered after 30 minutes. Administration of normal saline-esmolol solution at Kunlun acupoint caused the heart rate to drop from 410 bpm to 380 bpm, a decrease of 7.3%, which continued for 5 minutes before recovery. Administration of KF-esmolol solution at Kunlun acupoint caused the heart rate to drop from 410 bpm to 371 bpm, a decrease of 9.5%, which continued for 15 minutes before recovery. Thus, acupoint injection of KF can regulate the velocity of the adventitia ISF flow along the femoral vein and increase the width of the tunica ISF channel. These results may reveal a new mechanism of the physiological effect of Koisio drinking water rich in ultra-small particle size nanobubbles. KF may not only regulate the acupoint-originated ISF circulatory system, but also play a role in adventitial drug delivery, nutrient supply, and waste removal.

physiology↗

bioRxiv2024

Synergistic effects of tRNA modification defects in Escherichia coli K12.

Transfer RNAs (tRNAs) are essential components of the translation machinery and carry numerous post-transcriptional modifications that contribute to decoding accuracy, efficiency and cellular fitness. In Escherichia coli K-12, all tRNA modification pathways have been identified, yet the functional interactions between these pathways remain largely unexplored. Here, we systematically analyze genetic interactions between 29 non-essential tRNA modification genes using a pairwise synthetic lethal screen based on P1 transduction. Most combinations of tRNA modification gene deletions are tolerated during growth in rich medium; however, we identify five synthetically lethal pairs and fifteen additional combinations that display negative genetic interactions. Deletions of truA, which encodes the pseudouridine synthase responsible for modifications at positions 38-40 of multiple tRNAs, show the highest frequency of negative epistasis. Synthetic lethality associated with truA can be complemented by expression of truA in trans and, in specific cases, partially suppressed by overexpression of its tRNA substrates, indicating substrate-specific functional dependencies. Analysis of tRNA abundance by northern blotting and AQRNA-seq demonstrates that loss of individual tRNA modification enzymes does not generally lead to widespread tRNA destabilization. Instead, further phenotypic characterization of viable double mutants reveals condition-dependent growth defects influenced by carbon source, temperature and metabolic stress, as well as toxicity associated with overexpression of specific tRNAs. Together, these results reveal a limited but distinct set of genetic interactions among bacterial tRNA modification pathways and highlight the importance of physiological context in uncovering their cellular roles.

microbiology↗

bioRxiv2024

Influenza Virus Enhances Bacterial Growth in the Lungs through Weakening Capsule Receptor-Mediated Bacterial Capture by Neutrophils

Certain serotypes of encapsulated bacteria are more associated with severe pneumonia than others, but the biological reason behind this association has remained largely unknown. This study has uncovered a causal relationship between capsule serotype and virulence phenotype of Streptococcus pneumoniae, a leading cause of community-acquired pneumonia, in mice using isogenic bacteria. Certain high-virulence (HV) serotypes persist in the lungs and lead to severe pneumonia, whereas the low-virulence (LV) serotypes are effectively cleared. The capsule type-dependent difference in virulence is determined by the capsule-binding receptors, which recognize the capsular polysaccharides of the LV serotypes (but not the HV serotypes) and enable pathogen capture by neutrophils through complement activation. The capsule receptor-driven immunity of lung neutrophils is significantly compromised by pre-infection of influenza virus, which enhances the survival and virulence of the LV S. pneumoniae serotypes, and recurs in the heightened pathogenicity of Haemophilus influenzae. This study not only unravels the long-sought mechanistic mystery of serotype-dependent virulence in bacterial lung infections, but also provides an explanation for the well-known pathogenesis synergism between influenza virus and respiratory bacteria. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/622589v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1464164org.highwire.dtl.DTLVardef@16f34e5org.highwire.dtl.DTLVardef@1f9ad46org.highwire.dtl.DTLVardef@df104d_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2024

Reduced Liver Mitochondrial Energy Metabolism Impairs Food Intake Regulation Following Gastric Preloads and Fasting

ObjectiveThe capacity of the liver to serve as a peripheral sensor in the regulation of food intake has been debated for over half a century. The anatomical position and physiological roles of the liver suggest it is a prime candidate to serve as an interoceptive sensor of peripheral tissue and systemic energy state. Importantly, maintenance of liver ATP levels and within-meal food intake inhibition is impaired in human subjects with obesity and obese pre-clinical models. Previously, we have shown decreased hepatic mitochondrial energy metabolism (i.e., oxidative metabolism & ADP-dependent respiration) in male liver-specific, heterozygous PGC1a mice results in increased short-term diet-induced weight gain with increased within meal food intake. Herein, we tested the hypothesis that decreased liver mitochondrial energy metabolism impairs meal termination following nutrient oral pre-loads. MethodsLiver mitochondrial respiratory response to changes in {Delta}GATP and adenine nucleotide concentration following fasting were examined in male liver-specific, heterozygous PGC1a mice. Further, food intake and feeding behavior during basal conditions, following nutrient oral pre-loads, and following fasting were investigated. ResultsWe observed male liver-specific, heterozygous PGC1a mice have reduced mitochondrial response to changes in {Delta}GATP and tissue ATP following fasting. These impairments in liver energy state are associated with larger and longer meals during chow feeding, impaired dose-dependent food intake inhibition in response to mixed and individual nutrient oral pre-loads, and greater acute fasting-induced food intake. ConclusionThese data support previous work proposing liver-mediated food intake regulation through modulation of peripheral satiation signals.

physiology↗

bioRxiv2024

A multi-subunit autophagic capture complex facilitates degradation of ER stalled MHC-I in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) evades immune detection partly via autophagic capture and lysosomal degradation of major histocompatibility complex class I (MHC-I). Why MHC-I is susceptible to capture via autophagy remains unclear. By synchronizing exit of proteins from the endoplasmic reticulum (ER), we show that PDAC cells display prolonged retention of MHC-I in the ER and fail to efficiently route it to the plasma membrane. A capture-complex composed of NBR1 and the ER-phagy receptor TEX264 facilitates targeting of MHC-I for autophagic degradation, and suppression of either receptor is sufficient to increase total levels and re-route MHC-I to the plasma membrane. Binding of MHC-I to the capture complex is linked to antigen presentation efficiency, as inhibiting antigen loading via knockdown of TAP1 or beta 2-Microglobulin led to increased binding between MHC-I and the TEX264-NBR1 capture complex. Conversely, expression of ER directed high affinity antigenic peptides led to increased MHC-I at the cell surface and reduced lysosomal degradation. A genome-wide CRISPRi screen identified NFXL1, as an ER-resident E3 ligase that binds to MHC-I and mediates its autophagic capture. High levels of NFXL1 are negatively correlated with MHC-I protein expression and predicts poor patient prognosis. These data highlight an ER resident capture complex tasked with sequestration and degradation of non-conformational MHC-I in PDAC cells, and targeting this complex has the potential to increase PDAC immunogenicity.

cancer biology↗

bioRxiv2024

Iridescent structural coloration in a crested Cretaceous enantiornithine bird from Jehol Biota

A combination of sectioning and microscopy techniques, along with the application of finite-difference-time-domain modeling on a fossil feather, results in the novel estimation of the range of iridescent colors from the fossilized melanosome type and organization preserved in the elongate head crest feathers of a new Cretaceous enantiornithine bird. The densely packed rod-like melanosomes are estimated to have yielded from red to deep blue iridescent coloration of the head feathers. The shape and density of these melanosomes also may have further increased the feathers structural strength. This occurrence on a likely male individual is highly suggestive of both a signaling function of the iridescent crest, and a potential behavioral role in adjusting the angle of light incidence to control the display of this iridescent structural coloration.

evolutionary biology↗

bioRxiv2024

Emodin-Enhanced hUC-MSC Extracellular Vesicles Alleviate Acute Pancreatitis by Targeting Inflammation and Pyroptosis

Acute pancreatitis (AP) is a complex condition requiring immediate treatment. Both extracellular vesicles derived from human umbilical cord mesenchymal stem cells (hUC-MSC-EVs) and emodin, a naturally occurring anthraquinone used in traditional Chinese medicine, have shown therapeutic potential in treating AP. However, the mechanisms by which hUC-MSC-EVs and emodin alleviate AP, and whether they exert a synergistic effect on inflamed pancreatic tissues, remain unclear. In this study, we developed AP cell, organoid, and animal models to compare the effects of emodin, hUC-MSC-EVs, and emodin-loaded hUC-MSC-EVs on cell viability, inflammation, and pyroptosis. Our data revealed that all three treatments improved cell viability, reduced pro-inflammatory cytokine expression, and inhibited pyroptosis in the AP models. Notably, the encapsulation of emodin significantly enhanced the protective effects of hUC-MSC-EVs. These findings suggest that emodins protective effects on inflamed pancreatic tissues may be attributed, at least in part, to its anti-inflammatory and anti-pyroptotic properties. Additionally, our study proposes a novel strategy for engineering hUC-MSC-EVs for potential therapeutic applications in AP treatment.

cell biology↗

bioRxiv2024

C-Reactive Protein Drives Potent Clearance of Blood Bacteria in the Liver by Activating the Complement System

Plasma C-reactive protein (CRP) is widely used as a biomarker for bacterial infections due to its massive induction during infections, however, the precise function of CRP in bacterial infections remains undefined. Here we show that CRP enables Kupffer cells (liver macrophages) to capture and eliminate a wide range of encapsulated bacteria from the bloodstream of mice and thereby provides rapid and effective immunity. Mechanistically, CRP binds to the structurally diverse capsular polysaccharides of major Gram-positive and -negative pathogens, and thereby activates complement C3 at the bacterial surface. The C3-opsonized microbes are in turn captured by C3 receptors on the surface of Kupffer cells, and eliminated in the liver sinusoids. Since CRP principally shares the functional features of antibodies in pathogen recognition/execution, CRP-based defense combines the broad spectrum of the innate immunity with the swiftness, potency and specificity of the adaptive immunity, which helps explain massive rise of CRP during systemic bacterial infections.

immunology↗

bioRxiv2024

Diversification mitigates pesticide but not microplastic effects on bees without compromising rapeseed yield in China

Humanity depends on agriculture for food, fiber and energy provisioning, but input-intensive agricultural production is impacting ecosystem services such as pollination. Pollution effects from neonicotinoid insecticides on pollinators receive much attention, but nothing is known on the synergistic effects with emerging plastic contaminants and the mitigation potential of agricultural diversification. Here, we conduct the first large-scale and full-factorial mesocosm study to understand two-generation effects of diversified floral resources (diversification treatment), neonicotinoid and microplastic pollution (pollution treatments) on Osmia cornifrons bees in 72 mesocosms. In our three-year experiment, we found that diversification can mitigate individual neonicotinoid effects. We did not find any individual or synergistic effects of microplastic on reproductive performance of solitary bees. None of our treatments affected rapeseed yield. Our results confirm the benefits of diversified flower resources to mitigate pesticide effects on bees in China and suggest that microplastics have no acute individual or interaction toxicity in semi-natural environment at realistic exposure levels. Diversified flower resources in Chinese agricultural landscapes to mitigate pesticide pollution effects on pollinators is an important policy argument for pollinator protection with downstream implications for food security.

ecology↗

bioRxiv2024

Tumor-induced endothelial RhoA activation mediates tumor cell transendothelial migration and metastasis

Abstract/SummaryThe endothelial barrier plays an active role in transendothelial tumor cell migration during metastasis, however, the endothelial regulatory elements of this step remain obscure. Here we show that endothelial RhoA activation is a determining factor during this process. Breast tumor cell-induced endothelial RhoA activation is the combined outcome of paracrine IL-8-dependent and cell-to-cell contact {beta}1 integrin-mediated mechanisms, with elements of this pathway correlating with clinical data. Endothelial-specific RhoA blockade or in vivo deficiency inhibited the transendothelial migration and metastatic potential of human breast tumor and three murine syngeneic tumor cell lines, similar to the pharmacological blockade of the downstream RhoA pathway. These findings highlight endothelial RhoA as a potent, universal target in the tumor microenvironment for anti-metastatic treatment of solid tumors.

physiology↗