Biology subjects

zhang, l.

Publications and source records attributed to zhang, l..

11 recordsLinked to original sources

bioRxiv2026

Chronic kidney disease promotes anxiety susceptibility through an angiotensin II central amygdala axis

Background: Neuropsychiatric comorbidities are highly prevalent in chronic kidney disease (CKD), yet the underlying neural mechanisms remain poorly defined. Methods: We established multiple mouse models of CKD and identified an adenine-induced model as the most suitable platform to study neurobehavioral alterations. Anxiety susceptibility was operationalized as the emergence of anxiety-like behavior after subthreshold unpredictable stress (SUS) and was assessed using the SUS paradigm combined with behavioral assays. Region-focused c-Fos mapping, fiber photometry, and chemogenetic manipulation were used to interrogate neural circuit activity. Pharmacological and genetic approaches were applied to investigate the role of angiotensin II (Ang II) signaling. Finally, hypothalamic paraventricular nucleus (PVN) activation was used to explore brain-to-kidney feedback by using in vivo multiphoton microscopy imaging techniques. Results: CKD mice showed no consistent baseline anxiety-like phenotype across standard assays but developed robust anxiety-like behavior after subthreshold unpredictable stress. Region-focused c-Fos profiling and fiber photometry identified the central amygdala (CeA) as a stress-sensitized limbic node in CKD. Chemogenetic inhibition of CeA GABAergic neurons attenuated anxiety-like behavior, supporting a functional role for CeA activity. Mechanistically, CKD elevated circulating Ang II and enhanced CeA accumulation of peripherally administered FAM-Ang II-associated signal. CeA-specific Agtr1a knockdown attenuated anxiety-like behavior and exaggerated stress evoked CeA calcium responses. Exploratory experiments further showed that sustained PVN glutamatergic activation aggravated early renal injury markers in a mild renal injury model. These findings support a kidney-to-brain model in which CKD primes CeA stress circuits, while local Ang II AT1R signaling contributes to the behavioral expression of stress-induced anxiety-like behavior, with a potential brain to kidney feedback component. Conclusions: CKD promotes stress-induced anxiety susceptibility through a CeA-centered mechanism involving local Ang II AT1R signaling. These findings identify CeA Ang II AT1R signaling as a potential contributor to CKD-associated stress-related affective vulnerability.

animal behavior and cognition↗

bioRxiv2026

Ancient admixture catalyzes homoploid hybrid speciation and intense genomic erosion in Asian langurs

Ancient admixture catalyzes evolutionary innovation, yet its long-term genomic consequences for newly formed lineages remain poorly understood. Here, based on 53 genomes covering 19 species of the Asian langur genus Trachypithecus, we explore admixtures role in shaping a reticulated radiation. Genome-wide analyses of phylogenomic triplet topologies demonstrate that phylogenetic discordance across this radiation is primarily driven by widespread introgression rather than incomplete lineage sorting. To mitigate historical noise and resolve the ancestral species tree, we anchored our phylogenetic analysis on the X-linked recombination desert (XLRD), which exhibits an 84.5% introgression reduction compared to autosomes. We identify Delacours langur as a clear case of homoploid hybrid speciation, arising from ancient admixture with [~]70:30 genomic contributions from ancestral northern and southern limestone langur lineages. This hybrid species fixed key reproductive isolation loci; notably, alternate inheritance of pigmentation genes (SLC45A4, HPS5, ADCY10) systematically coupled with a fixed RNF175 chimeric allele to drive its diagnostic pelage phenotype. This illustrates how introgressed multi-gene networks rapidly establish prezygotic visual barriers and profound phenotypic divergence. However, subsequent spatial isolation within fragmented karst landscapes forced a major conversion of genetic burden into realized load. Genome-wide, over 82% of loss-of-function variants occur in a homozygous state, reflecting the expression of lethal recessive mutations within long runs of homozygosity. Together, our findings demonstrate that ancient admixture can trigger homoploid hybrid speciation, yet subsequent ecological restriction locks derived lineages into severe, long-term genomic erosion, revealing a fundamental trade-off in reticulate evolutionary radiations.

evolutionary biology↗

bioRxiv2025

HPV16 E2 protein possesses intrinsic helicase activity and sterically hinders E1 function through direct interaction

HPV16 E2 protein is a key regulatory protein essential for viral replication, yet no enzymatic activity had been attributed to it until now. In this study, we report for the first time that E2 possesses intrinsic ATP-dependent DNA unwinding activity. Mutational analysis identified residues K299, Y303, and K306 as critical for this helicase function. We further demonstrate that podophyllotoxin directly binds to E2 and inhibits its unwinding activity with an IC50 of 0.1074 {micro}M, mediated primarily by residues Q320 and H342. Comparative analysis revealed that the ATPase and helicase activities of E2 are considerably weaker than those of E1. Notably, we discovered that E2 potently inhibits the helicase activity of E1. This suppression is facilitated by the N-terminal domain of E2 (amino acids 1-245) through direct interaction with E1, with residue E39 playing a critical role. Our findings not only unveil a previously unrecognized enzymatic function of E2 but also suggest its role as a potential antiviral target. Moreover, the observed inhibitory effect of E2 on E1 highlights a novel regulatory mechanism for HPV DNA replication. Synopsis O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/676238v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@12fd0aforg.highwire.dtl.DTLVardef@2dc50forg.highwire.dtl.DTLVardef@e46f5eorg.highwire.dtl.DTLVardef@14b87da_HPS_FORMAT_FIGEXP M_FIG C_FIG E2 protein has traditionally been recognized primarily for its DNA-binding and transcriptional regulatory functions. This study provides the first evidence that E2 protein possesses intrinsic enzymatic activity, identifies a small-molecule inhibitor targeting this activity, and reveals a novel mechanism of E1-E2 interaction. O_LIHPV16 E2 Protein Exhibits ATPase and Helicase Activities C_LIO_LIIdentification of Key Amino Acid Residues for HPV16 E2 Protein Enzymatic Activity C_LIO_LIPPT Effectively Inhibits E2 Protein Helicase Activity In Vitro C_LIO_LIE2 Protein Exhibits Weaker Enzymatic Activity Than E1 and Inhibits E1 Helicase Activity C_LIO_LIE2 Inhibits E1 Helicase Activity Through Protein-Protein Interaction C_LI

molecular biology↗

bioRxiv2025

SUMO proteases SPF1/2 inhibit seed filling and fatty acid biosynthesis by deSUMOylating WRI1

Seed filling and fatty acid biosynthesis are critical processes for seed development and oil accumulation in plants, regulated by intricate post-translational mechanisms. Here, we elucidate the molecular mechanism by which SUMO proteases SPF1 and SPF2 regulate seed filling and fatty acid biosynthesis by modulating the stability of the WRI1 protein through deSUMOylation in Arabidopsis. SPF1 and SPF2 were found to negatively regulate seed filling and oil accumulation by promoting WRI1 degradation via deSUMOylation, which enhances its interaction with BPM proteins and subsequent ubiquitination. Our findings establish a dynamic interplay between deSUMOylation and ubiquitination in controlling WRI1 stability, unveiling a novel mechanism for seed filling. These findings establish SPF1/2 as crucial factor in maintaining WRI1 stability and seed filling, providing valuable genetic resources and a theoretical foundation for improving seed quality and oil content in agricultural production.

plant biology↗

bioRxiv2025

FGF8 promotes lipid droplet accumulation via the FGFR1/p-p38 axis in chondrocytes

Chondrocytes store lipids in the form of lipid droplets (LDs) and maintain cartilage lipid metabolic homeostasis by consuming or regenerating LDs. This modulation is largely mediated by a series of biochemical factors. Fibroblast growth factor 8 (FGF8) is one of the most important factors involved in the proliferation, differentiation, and migration of chondrocytes, and has attracted increasing attention in the physiology and pathology of cartilage. However, the effect of FGF8 on LD accumulation in chondrocytes remains unclear. This study aimed to elucidate the role of FGF8 in LDs and explore the underlying biomechanism involved. The results showed that FGF8 promoted LD accumulation in chondrocytes by upregulating perilipin1 (Plin1) expression. FGF8 activates the cytoplasmic p-p38 signaling pathway via fibroblast growth factor receptor 1 (FGFR1) to increase LD accumulation in chondrocytes. Subsequent experiments with siRNAs and specific inhibitors further confirmed the importance of the FGFR1/p38 axis for LD accumulation in chondrocytes exposed to FGF8. These results increase our understanding of the role of FGF8 in the lipid metabolic homeostasis of chondrocytes and provide insights into the physiology and pathology of cartilage.

cell biology↗

bioRxiv2024

Cadmium Disrupts Blood-Testis Barrier (BTB) via An Oxidative Stress-Dependent Autophagy in Prepubertal Rats

Blood testis barrier (BTB) is an important target of cadmium (Cd) toxicology, but the mechanism underlying the Cd-induced impairment of BTB function remains fully elucidated. The mammalian target of rapamycin (mTOR) complex 2 (mTOR2) regulates BTB function via its effects on cellular junctions and the cytoskeleton of Sertoli cells. In this study, we investigated whether mTOR2 was involved in the effects of Cd exposure on BTB integrity. A Cd exposure model in vivo was established in prepubertal male rats using a single intraperitoneal injection of Cadmium Chloride (CdCl2). A Cd exposure model of Sertoli cell was established using a CdCl2-treated TM4 cell line. The Acute cadmium exposure decreased the activity of mTOR2 signaling and adhesin proteins which is linked to the induction of oxidative stress-induced autophagy. In the presence of CdCl2, mTOR, the catalytic subunit of the mTOR2 complex, exhibits a reduction in levels of phosphorylation, accompanied by decreased adhesin proteins and Rictor, the key component of the mTOR2 complex. CdCl2 treatment also drives a process of oxidative stress-induced autophagy, evidenced by alterations in cellular markers for oxidative stress and autophagy. Pharmaceutical inhibition of oxidative stress and/or autophagy alleviates the alternations in mTOR2 signaling and adhesin proteins upon CdCl2 treatment in TM4, a Sertoli cell line. This work is the first to examine the effects of cadmium exposure on rictor/mTOR2 signaling pathways. Our results suggest that Cadmium might exert testicular toxicology via the perturbation in mTOR2 signaling, which can be associated with the cellular stress-related protolysis in Sertoli cells.

pharmacology and toxicology↗

bioRxiv2023

BL-Hi-C reveals the 3D genome structure of Brassica crops with high efficiency and sensitivity

High-throughput chromatin conformation capture (Hi-C) technologies can be used to investigate the three-dimensional genomic structure of plants. However, complex protocol and high background noise in Hi-C hinder its practical application in plant 3D genomics. Here, we took the approach of modified Bridge Linker Hi-C technology (BL-Hi-C) to explore plant 3D landscape. We modified the BL-Hi-C method by simplifing nuclei extraction step. By using Brassica rapa and Brassica oleracea, BL-Hi-C showed higher signal value and lower background noise than Hi-C. The high sensitivity of BL-Hi-C was further demonstrated by its capacity to identify gene loops involving BrFLC1, BrFLC2 and BrFLC3 which were undetectable in Hi-C. BL-Hi-C also showed promising performance with input as low as 100 mg leaf tissue. By analyzing of the generated data from BL-Hi-C, we found that the simulated 3D genome structure of B. rapa leaf cells was Bouquet configuration. Our results showed that the modified BL-Hi-C is a powerful tool for the investigation of plants genomic organization, gene regulation, and genome assembly. IN A NUTSHELL Background3D genome structure play a critical role in regulating spatiotemporal gene expression. However, there is a lack of simple, efficient and sensitive Hi-C technique in plants. QuestionHow to study plant 3D genomics more simple and efficientHow to detect plant chromatin loops more sensitive? FindingsWe showed that BL-Hi-C is more simple, efficient and sensitive than coventional Hi-C by using Brassica rapa and Brassica oleracea. Furthermore, BL-Hi-C demonstrated its high sensitivity by detecting gene loops involving BrFLC1, BrFLC2, and BrFLC3 which could not be detected by Hi-C. In addition, BL-Hi-C demonstrated promising performance with inputs as low as 100 mg leaf tissue. By analyzing BL-Hi-C data, we found that the simulated 3D genome structure of B. rapa leaf cells was Bouquet configuration. Next stepsHow chromatin loops are formed and regulated gene expression are key questions to be answered in plants. Our dataset of BL-Hi-C will enable future investigations to improve our understanding of chromatin loops.

genomics↗

bioRxiv2021

TaEXPB5 is responsible for male fertility in thermo-sensitive male-sterility wheat with Aegilops kotschyi cytoplasm

Thermo-sensitive male sterility is of vital importance to heterosis, or hybrid vigor in crop production and hybrid breeding. Therefore, it is meaningful to study the function of the genes related to pollen development and male sterility, which is still not fully understand currently. Here, we conducted comparative analyses to screen fertility related genes using RNA-seq, iTRAQ, and PRM-based assay. A gene encoding expansin protein in wheat, TaEXPB5, was isolated in KTM3315A, which was in the cell wall and preferentially upregulated expression in the fertility anthers. The silencing of TaEXPB5 displayed pollen abortion, the declination or sterility of fertility. Further, cytological investigation indicated that the silencing of TaEXPB5 induced the early degradation of tapetum and abnormal development of pollen wall. These results revealed that the silencing of TaEXPB5 could eliminate the effects of temperature on male fertility, and resulting in functional loss of fertility conversion, which implied that TaEXPB5 may be essential for anther or pollen development and male fertility of KTM3315A. These findings provide a novel insight into molecular mechanism of fertility conversion for thermo-sensitive cytoplasmic male-sterility wheat, and contribute to the molecular breeding of hybrid wheat in the future. HighlightTaEXPB5 coffers to anther or pollen development and male fertility in KTM3315A, its silencing could eliminate the effects of temperature on male fertility, and resulting in functional loss of fertility conversion.

molecular biology↗

bioRxiv2020

Overcoming resistance to immune checkpoint therapy in PTEN-null prostate cancer by sequential intermittent anti-PI3Ka/b/δ and anti-PD-1 treatment

Prostate cancers generally lack T cell infiltration and display resistance to immune checkpoint therapies (ICT). We found that intermittent but not daily dosing of PI3K/{beta}/{delta} inhibitor BAY1082439 on a Pten-null spontaneous prostate cancer model could overcome ICT resistance and unleash CD8+ T cell-dependent anti-tumor immunity in vivo. Mechanistically, BAY1082439 converts Pten-null cancer cell-intrinsic immune-suppression to immune-stimulation by promoting IFN/{gamma} pathway activation, {beta}2-microglubin expression and CXCL10/CCL5 secretion. Together with its preferential Treg inhibition activity, BAY1082439 promotes clonal expansion of tumor-associated CD8+ T cells. Once primed, tumors remain as T cell-inflamed and become responsive to anti-PD-1 therapy. Our data suggest that intermittent PI3K inhibition can alleviate Pten-null cancer cell-intrinsic immunosuppressive activity and turn "cold" tumors into T cell-inflamed ones, paving the way for successful ICT. SignificanceThe combination of ICT and targeted therapies holds great promises for broad and long-lasting therapeutic effects for cancers. However, combining ICT with anti-PI3K inhibitors have been difficult because the multifaceted effects of PI3K on both cancer cells and immune cells within the tumor microenvironment. Here we show a carefully designed anti-PI3K treatment, both in its specificity and dosing schedule, to inhibit cancer cell growth while promoting anti-tumor immunity, is critically important for successful ICT. Since the PI3K pathway is one of the most frequently altered signaling pathways in human cancers, our work may shed light on treating those cancers with PI3K activation and overcome resistance to ICT. HighlightsO_LIIntermittent PI3K/{beta}/{delta} inhibitor BAY1082439 treatment overcomes ICT resistance C_LIO_LIBAY1082439 turns Pten-null prostate cancer from "cold" to T cell-inflamed C_LIO_LIBAY1082439 inhibits cancer cell-intrinsic immunosuppressive activity and Treg C_LIO_LIBAY1082439 promotes clonal expansion and immunity of tumor-associated CD8+ T cells C_LI

cancer biology↗

bioRxiv2019

The Structural Basis for Glycerol Permeation by human AQP7

Human glycerol channel AQP7 conducts glycerol release from adipocyte and entry into the cells in pancreatic islets, muscles and kidney tubule, and thus regulate glycerol metabolism in those tissues. Compared with other human aquaglyceroporins, AQP7 shows a less conserved "NPA" motif in the center cavity, and a pair of aromatic residues at Ar/R selectivity filter. To understand the structural basis for the glycerol conductance, we crystallized the human AQP7 and determined the structure at 3.7 [A]. A substrate binding pocket was found near to the Ar/R filter and the bound glycerol molecule stabilized by R229. In vivo functional assay on human AQP7 as well as AQP3 and AQP10 demonstrated strong glycerol transportation activities at physiological condition. The human AQP7 structure reveals a fully closed conformation with its permeation pathway strictly confined by Ar/R filter at the exoplasmic side and the gate at the cytoplasmic side, and the dislocation of the residues at narrowest parts of glycerol pathway in AQP7 play a critical role in controlling the glycerol flux.

molecular biology↗

bioRxiv2019

Long noncoding RNA AVAN promotes antiviral innate immunity by interacting with TRIM25 and enhancing the transcription of FOXO3a

Accumulating evidence has shown that long noncoding RNAs (lncRNAs) are involved in several biological processes, including immune responses. However, the role of lncRNAs in antiviral innate immune responses remains largely unexplored. Here, we identify an uncharacterized human lncRNA from influenza A virus (IAV) patients, antivirus and activate neutrophil (AVAN), that is significantly up-regulated upon virus infection. Mechanistically, nuclear lncRNA-AVAN positively regulates the transcription of forkhead box O3A (FOXO3a) by associating with its promoter and inducing chromatin remodeling to promote neutrophil chemotaxis. Furthermore, we also found that cytoplasmic lncRNA-AVAN directly binds tripartite motif containing 25 (TRIM25) and enhances the association of TRIM25 and Retinoic acid inducible gene-1 proteins (RIG-I) and the ubiquitylation of RIG-I, thereby promoting TRIM25- and RIG-I-mediated antiviral innate immune signaling. More importantly, we enforced the expression of AVAN in transgenic mice and found that it significantly alleviated IAV virulence and virus production. Collectively, these findings highlight the potential clinical implications of lncRNA-AVAN as a key positive regulator of the antiviral innate immune response and a promising target for developing broad antiviral therapeutics.

immunology↗