Biology subjects

Zhang, W.

Publications and source records attributed to Zhang, W..

At least 451 records · Page 25Linked to original sources

bioRxiv2024

An effector XopL enhances ethylene biosynthesis to promote Xanthomonas fragariae infection in strawberry

Xanthomonas fragariae (Xaf) is the cause for strawberry crown dry cavity rot and strawberry leaf angular spots. Despite having a long evolutionary history with strawberries, the plant-pathogen connection is poorly understood. Pathogenicity for the majority of plant pathogens is mostly dependent on the type-III secretion system, which introduces virulence type III effectors (T3Es) into eukaryotic hosts cells. For most of these T3Es, the subcellular targets are yet unclear. Here, We used the yeast-two-hybrid (Y2H) technique to construct an interaction network of strawberry-Xaf T3Es. Multiple T3Es were discovered to converge onto the strawberry 1-aminocyclopropane-1-carboxylic acid oxidases (ACOs), which are the last rate-limited step in the production of ethylene. We then concentrated on the connection between XopL and FveACO9. Strawberry plants that overexpressed XopL accumulated higher levels of ethylene and exhibited more severe Xaf infection. XopL boosted ethylene production by stabilizing the accumulation of FveACO9 protein and enhancing ACO enzyme activity. Additionally, strawberries treated with ACC or overexpressing FveACO9 were particularly vulnerable to Xaf infection. On the other hand, pre-treatment with -aminoinoisobutyric acid (AIB), an ACO inhibitor, effectively reduced Xaf infection. Our research indicates that Xaf utilizes a distinct approach to regulate the ethylene production of host plants in order to promote infection.

pathology↗

bioRxiv2024

FLASH Irradiation Regulates IFN-β induction by mtDNA via Cytochrome c Leakage

Ultrahigh dose rate radiotherapy (FLASH-RT) is under intensive investigation for its biological benefits. The mechanisms underlying its ability to spare normal tissues while suppress tumor growth still remain controversial. Here we reveal that compared to the low dose rate electron irradiation (0.36 Gy/s), FLASH electron irradiation at 61 or 610 Gy/s enhances the cytochrome c leakage from mitochondria in human breast cells MCF-10A, which elicits substantial caspase activation, suppresses both the cytosolic mitochondrial DNA (mtDNA) accumulation and IFN-{beta} secretion. Besides, the deletion of mtDNA severely decreases the radiation-induced cGAS-STING activation. Conversely, the cytochrome c leakage in carcinoma cells MDA-MB-231 post electron irradiation is limited, especially for the case of FLASH irradiation, resulting in less cytosolic cytochrome c but stronger cGAS-STING activation than those in MCF-10A cells. The enhanced difference of cytochrome c leakage between cancer cells and normal cells post FLASH irradiation indicates a potential mechanism of FLASH effect by regulating the apoptotic and inflammatory pathway.

biophysics↗

bioRxiv2024

Identify compound-protein interaction with knowledge graph embedding of perturbation transcriptomics

The emergence of perturbation transcriptomics provides a new perspective and opportunity for drug discovery, but existing analysis methods suffer from inadequate performance and limited applicability. In this work, we present PertKGE, a method designed to improve compound-protein interaction with knowledge graph embedding of perturbation transcriptomics. PertKGE incorporates diverse regulatory elements and accounts for multi-level regulatory events within biological systems, leading to significant improvements compared to existing baselines in two critical "cold-start" settings: inferring binding targets for new compounds and conducting virtual ligand screening for new targets. We further demonstrate the pivotal role of incorporating multi- level regulatory events in alleviating dataset bias. Notably, it enables the identification of ectonucleotide pyrophosphatase/phosphodiesterase-1 as the target responsible for the unique anti- tumor immunotherapy effect of tankyrase inhibitor K-756, and the discovery of five novel hits targeting the emerging cancer therapeutic target, aldehyde dehydrogenase 1B1, with a remarkable hit rate of 10.2%. These findings highlight the potential of PertKGE to accelerate drug discovery by elucidating mechanisms of action and identifying novel therapeutic compounds.

bioinformatics↗

bioRxiv2024

CTCF mutation at R567 causes developmental disorders via 3D genome rearrangement and abnormal neurodevelopment

The three-dimensional genome structure organized by CTCF is required for development. Clinically identified mutations in CTCF have been linked to adverse developmental outcomes. Nevertheless, the underlying mechanism remains elusive. In this investigation, we explored the regulatory roles of a clinically relevant R567W point mutation, located within the 11th zinc finger of CTCF, by introducing this mutation into both murine models and human embryonic stem cell-derived cortical organoid models. Mice with homozygous CTCFR567W mutation exhibited growth impediments, resulting in postnatal mortality, and deviations in brain, heart, and lung development at the pathological and single- cell transcriptome levels. This mutation induced premature stem-like cell exhaustion, accelerated the maturation of GABAergic neurons, and disrupted neurodevelopmental and synaptic pathways. Additionally, it specifically hindered CTCF binding to peripheral motifs upstream to the core consensus site, causing alterations in local chromatin structure and gene expression, particularly at the clustered protocadherin locus. Comparative analysis using human cortical organoids mirrored the consequences induced by this mutation. In summary, this study elucidates the influence of the CTCFR567W mutation on human neurodevelopmental disorders, paving the way for potential therapeutic interventions.

molecular biology↗

bioRxiv2024

Determinants in the HTLV-1 capsid major homology region that are critical for virus particle assembly

The Gag protein of retroviruses is the primary driver of virus particle assembly. Particle morphologies among retroviral genera are distinct, with intriguing differences observed relative to HIV-1, particularly that of human T-cell leukemia virus type 1 (HTLV-1). In contrast to HIV-1 and other retroviruses where the capsid (CA) carboxy-terminal domain (CTD) possesses the key amino acid determinants involved in driving Gag-Gag interactions, we have previously demonstrated that the amino-terminal domain (NTD) encodes the key residues crucial for Gag multimerization and immature particle production. Here in this study, we sought to thoroughly interrogate the conserved HTLV-1 major homology region (MHR) of the CACTD to determine whether this region harbors residues important for particle assembly. In particular, site-directed mutagenesis of the HTLV-1 MHR was conducted, and mutants were analyzed for their ability to impact Gag subcellular distribution, particle production and morphology, as well as the CA-CA assembly kinetics. Several key residues (i.e., Q138, E142, Y144, F147 and R150), were found to significantly impact Gag multimerization and particle assembly. Taken together, these observations imply that while the HTLV-1 CANTD acts as the major region involved in CA-CA interactions, residues in the MHR can impact Gag multimerization, particle assembly and morphology, and likely play an important role in the conformation the CACTD that is required for CA-CA interactions.

molecular biology↗

bioRxiv2024

Determining the Youngs Modulus of the Bacterial Cell Envelope

Bacteria experience substantial physical forces in their natural environment including forces caused by osmotic pressure, growth in constrained spaces, and fluid shear. The cell envelope is the primary load-carrying structure of bacteria, but the mechanical properties of the cell envelope are poorly understood; reports of Youngs modulus of the cell envelope of E. coli are widely range from 2 MPa to 18 MPa. We have developed a microfluidic system to apply mechanical loads to hundreds of bacteria at once and demonstrated the utility of the approach for evaluating whole-cell stiffness. Here we extend this technique to determine Youngs modulus of the cell envelope of E. coli and of the pathogens V. cholerae and S. aureus. An optimization-based inverse finite element analysis was used to determine the cell envelope Youngs modulus from observed deformations. The Youngs modulus of the cell envelope was 2.06 {+/-} 0.04 MPa for E. coli, 0.84 {+/-} 0.02 MPa for E. coli treated with a chemical known to reduce cell stiffness, 0.12 {+/-} 0.03 MPa for V. cholerae, and 1.52 {+/-} 0.06 MPa for S. aureus (mean {+/-} SD). The microfluidic approach allows examining hundreds of cells at once and is readily applied to Gram-negative and Gram-positive organisms as well as rod-shaped and cocci cells, allowing further examination of the structural causes of differences in cell envelope Youngs modulus among bacteria species and strains.

bioengineering↗

bioRxiv2024

Pro-renin Receptor Inhibited ABCA1/G1 Expression Associated with Low HDL-c and Promoted Atherosclerosis

Background(Pro)renin receptors [(P)RR] binding both renin and its inactive proenzyme for prorenin induce increasing the efficiency of angiotensin I conversion and the production of angiotensin II (Ang II). Recently, (P)RR was reported to played a pathological role in diabetic renal disease independent of Ang II. Ang II is involved in lipid metabolism and atherosclerosis, but the (P)RR participation in atherosclerosis remains unclear. Thus, the objective of this study was to examine the relative importance of Ang II-independent actions of (P)RR and its mechanism in the development of atherosclerosis. MethodsClinical demographic characteristics and laboratory profile data of 1189 essential hypertensive were collected. Patients were divided into four groups based on the quartiles of plasma renin activity (PRA). The plasma lipoprotein levels of four groups were compared. Furthermore, we examined serum and liver lipoprotein levels, as well as ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) expression in ApoE-/- mice treated with prorenin. ABCA1 and ABCG1 expression and their function in mediating cholesterol efflux were evaluated in THP-1 cells by prorenin treatment. Agonists of the peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) and liver X receptor (LXR) were used to investigate the mechanism involved in vitro. ResultsPlasma TC, TG, LDL-c, and apoB were significantly increased, and HDL-c and apoA were dramatically decreased with a trend of higher plasma renin activity (PRA) ( all P < 0.05) in hypertensive patients. Prorenin accelerated atherosclerosis by inhibiting mRNA and protein expression of ABCA1/ABCG1 in the liver of ApoE-/- mice. Prorenin binding to (P)RR inhibited the functions of ABCA1- and ABCG1-mediated cholesterol efflux. Furthermore, Prorenin reduced ABCA1/G1 expression of THP-1 cells through PPAR{gamma}/LXR pathway. Conclusions(P)RR activated by prorenin inhibited the expression of ABCA1/ABCG1 through the PPAR{gamma}/LXR pathway and the functions of ABCA1- and ABCG1-mediated cholesterol efflux, resulting in dyslipidemia and eventually atherosclerosis. HighlightsWith RPA increases in hypertension, plasma TC, TG, LDL-c, and apoB were higher, while HDL-c and apoA were lower. Prorenin binding to (P)RR accelerated atherosclerosis by inhibiting ABCA1/G1 expression and function. Prorenin reduced ABCA1/G1 expression of THP-1 cells through PPAR{gamma}/LXR pathway.

pathology↗

bioRxiv2024

msCNVS: medium throughput single cell copy number variation sequencing with barcoded library construction free of preamplification toward clinical implementation

Single cell copy number variation sequencing (scCNV-seq) is valuable for genomic analysis of a variety of health and disease systems, yet the available methods either depend on either preamplification of the whole genome of each cell, special devices or untracable, which hinder scCNV-seq practice in clinics. Here we provide scalable multiplex scCNV-seq (msCNVS) that allows direct medium-throughput library construction for single cells, which are barcoded individually with Tn5 transposome in a microplate and immediately pooled for downstream processes, elevating the efficiency by orders of magnitude. An algorithm is developed on the distribution of segmented normalized read count density to identify the major peaks associating with integer copy numbers, further improving the accuracy for objective CNV calling. Here msCNVS faithfully distinguishes the unique CNV patterns of 5 cell lines. The individual msCNVS profiles of 70 individual K562 cells highly correlate with the profile of K562 bulk cells (R=0.90-0.98), and the triplicates of HeLa3 bulk cells correlated nearly perfect (R=0.99). The msCNVS CNV profiles of primary cell cultures of amniotic fluid are confirmed by G-banding karyotype analysis and chromosomal microarray analysis. Additionally, the coverage uniformity of msCNVS is superior to that of MDA and MALBAC and approaches what eMDA and DOP-PCR achieves. Furthermore, msCNVS detects CNV deletions in 2 stunted, abnormal blastocysts, one with CNV mosaicism, and uncovered variants of CNVs in circulated tumor cells, cancerous pleural effusion cells, and patient-derived xenograft nuclei. Thus, msCNVS promises a robust, reliable and highly efficient approach to genomic testing of precious and rare cells like those typically obtained in reproductive and cancer clinics. One-Sentence SummaryBy early pooling of multiple single cells individually barcoded with Tn5 transposome, msCNVS enables efficient CNV profiling of rare clinic samples

genomics↗

bioRxiv2024

The Genomes of Nematode-Trapping Fungi Provide Insights into the Origin and Diversification of Fungal Carnivorism

Nematode-trapping fungi (NTF), most of which belong to a monophyletic lineage in Ascomycota, cannibalize nematodes and other microscopic animals, raising questions regarding the types and mechanisms of genomic changes that enabled carnivorism and adaptation to the carbon-rich and nitrogen-poor environment created by the Permian-Triassic extinction event. Here, we conducted comparative genomic analyses of 21 NTF and 21 non-NTF to address these questions. Carnivorism-associated changes include expanded genes for nematode capture, infection, and consumption (e.g., adhesive proteins, CAP superfamily, eukaryotic aspartyl proteases, and serine-type peptidases). Although the link between secondary metabolite (SM) production and carnivorism remains unclear, we found that the numbers of SM gene clusters among NTF are significantly lower than those among non-NTF. Significantly expanded cellulose degradation gene families (GH5, GH7, AA9, and CBM1) and contracted genes for carbon-nitrogen hydrolases (enzymes that degrade organic nitrogen to ammonia) are likely associated with adaptation to the carbon-rich and nitrogen-poor environment. Through horizontal gene transfer events from bacteria, NTF acquired the Mur gene cluster (participating in synthesizing peptidoglycan of the bacterial cell wall) and Hyl (a virulence factor in animals). Disruption of MurE reduced NTFs ability to attract nematodes, supporting its role in carnivorism. This study provides new insights into how NTF evolved and diversified after the Permian-Triassic mass extinction event.

evolutionary biology↗

bioRxiv2024

Higher amplitudes of visual networks are associated with trait but not state- depression.

Despite depression being a leading cause of global disability, neuroimaging studies have struggled to identify replicable neural correlates of depression or explain limited variance. This challenge may, in part, stem from the intertwined state (current symptoms; variable) and trait (general propensity; stable) experiences of depression. Here, we sought to disentangle state from trait experiences of depression by leveraging a longitudinal cohort and stratifying individuals into four groups: those in remission ( trait depression group), those with large longitudinal severity changes in depression symptomatology ( state depression group), and their respective matched control groups (total analytic n=1,030). We hypothesized that spatial network organization would be linked to trait depression due to its temporal stability, whereas functional connectivity between networks would be more sensitive to state-dependent depression symptoms due to its capacity to fluctuate. We identified 15 large-scale probabilistic functional networks from resting-state fMRI data and performed group comparisons on the amplitude, connectivity, and spatial overlap between these networks, using matched control participants as reference. Our findings revealed higher amplitude in visual networks for the trait depression group at the time of remission, in contrast to controls. This observation may suggest altered visual processing in individuals predisposed to developing depression over time. No significant group differences were observed in any other network measures for the trait-control comparison, nor in any measures for the state-control comparison. These results underscore the overlooked contribution of visual networks to the psychopathology of depression and provide evidence for distinct neural correlates between state and trait experiences of depression.

neuroscience↗

bioRxiv2024

Characterization of Genome-wide Phylogenetic Conflict Uncovers Evolutionary Modes of Carnivorous Fungi

Mass extinction has often paved the way for rapid evolutionary radiation, resulting in the emergence of diverse taxa within specific lineages. While the emergence and diversification of carnivorous nematode-trapping fungi (NTF) in Ascomycota has been linked to the Permian-Triassic (PT) extinction, the processes underlying NTF radiation remain unclear. Here, we conducted phylogenomic analyses using 23 genomes spanning three NTF lineages, each employing distinct nematode traps -- mechanical traps (Drechslerella spp.), three-dimensional (3-D) adhesive traps (Arthrobotrys spp.), and two-dimensional (2-D) adhesive traps (Dactylellina spp.), and one non-NTF species as the outgroup. This analysis revealed how diverse mechanisms contributed to the tempo of NTF evolution and rapid radiation. The genome-scale species tree of NTFs suggested that Drechslerella emerged earlier than Arthrobotrys and Dactylellina. Extensive genome-wide phylogenetic discordance was observed, mainly due to incomplete lineage sorting (ILS) between lineages ([~]81.3%). Modes of non-vertical evolution (i.e., introgression and horizontal gene transfer) also contributed to phylogenetic discordance. The ILS genes that are associated with hyphal growth and trap morphogenesis (e.g., those associated with the cell membrane system and cellular polarity division) exhibited signs of positive selection.

evolutionary biology↗

bioRxiv2024

Identification and characterization of the de novo methyltransferases for eukaryotic N6-methyladenine (6mA)

DNA N6-adenine methylation (6mA) is rediscovered as an important epigenetic mark in eukaryotes. We previously identified the MT-A70 family member AMT1 as the maintenance methyltransferase (MTase), but the identity of the de novo MTase(s) for 6mA establishment remains unidentified. The unicellular model eukaryote Tetrahymena thermophila offers a unique opportunity for studying de novo methylation: during sexual reproduction, the 6mA-free zygotic nucleus develops into 6mA-positive new macronucleus (MAC) marked by genome-wide de novo methylation. Here we identified that TET1 and TET2 are essential for de novo 6mA in the new MAC, but not for maintenance 6mA in the somatic MAC. Knockout of TET1 and/or TET2 not only abolished methylation on most methylatable ApT positions, but also attenuated methylation on the rest. The substantial 6mA decrease in turn altered gene expression pattern and reduced the survival rate of sexual progenies, highlighting the importance of dedicated de novo MTase activity.

molecular biology↗

bioRxiv2024

LncRNA-Snhg3 Aggravates Hepatic Steatosis by Regulating PPARγ via SND1/H3K27me3

LncRNAs are involved in modulating the individual risk and the severity of progression in metabolic dysfunction-associated fatty liver disease (MASLD), but their precise roles remain largely unknown. This study aimed to investigate the role of lncRNA Snhg3 in the development and progression of MASLD, along with the underlying mechanisms. The result showed that Snhg3 was significantly downregulated in the liver of high-fat diet-induced obesity (DIO) mice. Notably, palmitic acid promoted the expression of Snhg3 and overexpression of Snhg3 increased lipid accumulation in primary hepatocytes. Furthermore, hepatocyte-specific Snhg3 deficiency decreased body and liver weight, alleviated hepatic steatosis and promoted hepatic fatty acid metabolism in DIO mice, whereas overexpression induced the opposite effect. Mechanistically, Snhg3 promoted the expression, stability and nuclear localization of SND1 protein via interacting with SND1, thereby inducing K63-linked ubiquitination modification of SND1. Moreover, Snhg3 decreased the H3K27me3 level and induced SND1-mediated chromatin loose remodeling, thus reducing H3K27me3 enrichment at the Ppar{gamma} promoter and enhancing Ppar{gamma} expression. The administration of PPAR{gamma} antagonist T0070907 improved Snhg3-aggravated hepatic steatosis. Our study revealed a new signaling pathway, Snhg3/SND1/H3K27me3/PPAR{gamma}, responsible for MASLD and indicates that lncRNA-mediated epigenetic modification has a crucial role in the pathology of MASLD.

molecular biology↗

bioRxiv2024

Feather degradation in Stenotrophomonas maltophilia relies on conversion and internalization of keratin monomer

Feather keratin is the most abundant nitrogen source waste in nature. This insoluble material cannot be directly utilized as nutrition by most organisms, especially animals and plants. While feathers are naturally decomposed by some microorganisms through keratinase-based degradation which remains mechanistically not fully understood. In this study, we find that when feathers serve as the only nutrient source for Stenotrophomonas maltophilia culture, keratin monomer of about 10 kDa is present in the medium as a predominant hydrolyzed product. We further show that keratin monomers bind to cells and in turn enter cells via an undetermined pathway. The cell entry of keratin monomer elicits keratinase activity to promote the forward reaction in keratin hydrolysis. This study highlights the importance of keratin monomer production as the first step in feather biodegradation, in which the insoluble feather is converted into soluble intermediate to facilitate its internalization and complete hydrolysis. ImportanceA large amount of feathers have been produced in poultry breeding, which could cause environmental pollution if not processed in time. On the other hand, amino acids degraded from feathers can be used in many fields, such as feed, fertilizer, daily chemicals and other fields. Biodegradable feathers have the advantages of low energy consumption, mild conditions and no destruction of the amino acids obtained from degradation. We previously isolated and identified a highly efficient feather-degrading bacterium, Stenotrophomonas maltophilia DHHJ, which can grow well on the medium with feathers as the only nutrient and completely degrade feathers. We know, feather particles are much larger than bacterial cells. In what form and how they are absorbed into cells by bacteria are interesting and critical questions for feather degradation. In our research, feathers had been first degraded extracellularly by basically expressed keratinase into keratin monomers. The keratin monomers bound to cells and enter across the membrane and can induce further expression of keratinase. The understanding of keratin monomers provides new clues for the study of feather degradation mechanisms.

microbiology↗

bioRxiv2024

Mapping single-cell developmental potential in health and disease with interpretable deep learning

Single-cell RNA sequencing (scRNA-seq) has transformed our understanding of cell fate in developmental systems. However, identifying the molecular hallmarks of potency - the capacity of a cell to differentiate into other cell types - has remained challenging. Here, we introduce CytoTRACE 2, an interpretable deep learning framework for characterizing potency and differentiation states on an absolute scale from scRNA-seq data. Across 31 human and mouse scRNA-seq datasets encompassing 28 tissue types, CytoTRACE 2 outperformed existing methods for recovering experimentally determined potency levels and differentiation states covering the entire range of cellular ontogeny. Moreover, it reconstructed the temporal hierarchy of mouse embryogenesis across 62 timepoints; identified pan-tissue expression programs that discriminate major potency levels; and facilitated discovery of cellular phenotypes in cancer linked to survival and immunotherapy resistance. Our results illuminate a fundamental feature of cell biology and provide a broadly applicable platform for delineating single-cell differentiation landscapes in health and disease.

genomics↗

bioRxiv2024

CADTAD: CAncer Driver Topologically Associated Domains identify oncogenic and tumor suppressive lncRNAs

Cancer long noncoding RNAs (lncRNAs) have been identified by experimental and in silico methods. However, current approaches for identifying cancer lncRNAs are not sufficient and effective. To uncover them, we focused on the core cancer driver lncRNAs, which directly interact with cancer driver protein-coding genes (PCGs). We investigated various aspects of cancer lncRNAs, including their expression patterns, genomic locations, and direct interactions with cancer driver PCGs, and developed a pipeline to unearth candidate cancer driver lncRNAs. Finally, we validated the reliability of potential cancer driver lncRNAs through functional analysis of bioinformatics data and CRISPR-Cas9 knockout experiments. We found that cancer lncRNAs were more concentrated in cancer driver topologically associated domains (CDTs), and CDT is an important feature in identifying cancer lncRNAs. Moreover, cancer lncRNAs showed a high tendency to co-express with and bind to cancer driver PCGs. Utilizing these distinctive characteristics, we developed a pipeline CADTAD to unearth candidate cancer driver lncRNAs in pan-cancer, including 256 oncogenic lncRNAs, 177 tumor suppressive lncRNAs, and 75 dual-function lncRNAs, as well as in three individual cancer types, and validated their cancer-related function. More importantly, the function of 10 putative cancer driver lncRNAs in prostate cancer was subsequently validated to influence cancer phenotype through cell studies. In light of these findings, our study offers a new perspective from the 3D genome to study the roles of lncRNAs in cancer. Furthermore, we provide a valuable set of potential lncRNAs that could deepen our understanding of the oncogenic mechanism of cancer driver lncRNAs.

genomics↗

bioRxiv2024

Blocking Src-PSD-95 interaction rescues glutamatergic signaling dysregulation in schizophrenia.

The complex and heterogeneous genetic architecture of schizophrenia inspires us to look beyond individual risk genes for therapeutic strategies and target their interactive dynamics and convergence. Postsynaptic NMDA receptor (NMDAR) complexes are a site of such convergence. Src kinase is a molecular hub of NMDAR function, and its protein interaction subnetwork is enriched for risk-genes and altered protein associations in schizophrenia. Previously, Src activity was found to be decreased in post-mortem studies of schizophrenia, contributing to NMDAR hypofunction. PSD-95 suppresses Src via interacting with its SH2 domain. Here, we devised a strategy to suppress the inhibition of Src by PSD-95 via employing a cell penetrating and Src activating PSD-95 inhibitory peptide (TAT-SAPIP). TAT-SAPIP selectively increased post-synaptic Src activity in humans and mice, and enhanced synaptic NMDAR currents in mice. Chronic ICV injection of TAT-SAPIP rescued deficits in trace fear conditioning in Src hypomorphic mice. We propose blockade of the Src-PSD-95 interaction as a proof of concept for the use of interfering peptides as a therapeutic strategy to reverse NMDAR hypofunction in schizophrenia and other illnesses.

neuroscience↗

bioRxiv2024

Role of Hepatocyte RIPK1 in Maintaining Liver Homeostasis during Metabolic Challenges

As a central hub for metabolism, the liver exhibits strong adaptability to maintain homeostasis in response to food fluctuations throughout evolution. However, the mechanisms governing this resilience remain incompletely understood. In this study, we identified Receptor interacting protein kinase 1 (RIPK1) in hepatocytes as a critical regulator in preserving hepatic homeostasis during metabolic challenges, such as short-term fasting or high-fat dieting. Our results demonstrated that hepatocyte-specific deficiency of RIPK1 sensitized the liver to short-term fasting-induced liver injury and hepatocyte apoptosis in both male and female mice. Despite being a common physiological stressor that typically does not induce liver inflammation, short-term fasting triggered hepatic inflammation and compensatory proliferation in hepatocyte-specific RIPK1-deficient (Ripk1{Delta}hep) mice. Transcriptomic analysis revealed that short-term fasting oriented the hepatic microenvironment into an inflammatory state in Ripk1{Delta}hep mice, with upregulated expression of inflammation and immune cell recruitment-associated genes. Single-cell RNA sequencing further confirmed the altered cellular composition in the liver of Ripk1{Delta}hep mice during fasting, highlighting the increased recruitment of macrophages to the liver. Mechanically, our results indicated that ER stress was involved in fasting-induced liver injury in Ripk1{Delta}hep mice. Overall, our findings revealed the role of RIPK1 in maintaining liver homeostasis during metabolic fluctuations and shed light on the intricate interplay between cell death, inflammation, and metabolism.

immunology↗