Biology subjects

liu, y.

Publications and source records attributed to liu, y..

17 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

From local motifs to global dynamical stability in the mouse brain connectome

Brain connectomics provides insights into the architectural organization of neural circuits across the brain. But it remains unclear how neurons and their connections give rise to brain-wide activity. Here, using a sparse detailed mouse brain connection map called "bouton-net," we studied how specific neuron patterns (motifs) and groups (modules) affect information processing. We discovered that complex, "two-way" connections are much more common than expected. These patterns appear across all brain regions, suggesting they are a universal rule for brain wiring. We also found that different brain modules do not communicate randomly; instead, they talk through a small group of highly connected neurons. By testing these organization patterns with computer models, we found that the brain may not be wired for the best memory capacity or nonlinear processing capability, but to ensure that capability remains stable. This structure provides the foundation for a reliable, "crash-proof" biological network.

neuroscience↗

bioRxiv2025

Association between KCNC1 gene polymorphism and blood lipid levels in determining the efficacy of high-intensity interval training

ObjectiveThe potassium voltage-gated channel subfamily C member 1 (KCNC1) gene plays a crucial role in both neural excitability and lipid metabolism. However, the impact of its genetic polymorphisms on individual blood lipid levels and the efficacy of exercise interventions remains unclear. This study aimed to investigate the association between KCNC1 single nucleotide polymorphisms (SNPs) and baseline blood lipid levels in young Han Chinese individuals, as well as the relationship between lipid profiles and sensitivity to high-intensity interval training (HIIT). This research provides theoretical support for developing personalised exercise prescriptions based on genetic background to improve lipid health. MethodsThis study recruited 245 healthy Han Chinese university students (114 males, 131 females) without regular exercise habits. Participants underwent a standardised 12-week HIIT intervention programme, conducted three times weekly. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels were measured before and after the intervention. Genotyping of the KCNC1 gene SNP was performed using the Infinium CGA chip. PLINK software was employed to construct linear regression models (with age, sex, BMI, and baseline lipid levels as covariates) to analyse the association between genetic polymorphisms and changes ({Delta}) in lipid parameters. ResultsFollowing 12 weeks of HIIT, all participants demonstrated significant improvements in TC, HDL-C, LDL-C, and TG levels (P<0.01). Association analysis revealed: 1) At baseline, the rs757511 locus was significantly correlated with HDL-C levels in males ({beta} = -0.112, P = 0.0445), with individuals carrying the A allele exhibiting higher baseline HDL-C; 2) Regarding HIIT responsiveness, three loci exhibited significant sex-specific associations: the C allele at rs6083540 was significantly associated with improved TG levels in females ({beta} = 0.1564, P = 0.025); the A allele at rs61882396 was significantly associated with improved TG levels in females ({beta} = -0.129, P = 0.032); the C allele at rs12574348 was significantly associated with improved LDL-C levels in males ({beta} = 0.1608, P = 0.048). ConclusionThis study first demonstrates an association between KCNC1 gene polymorphisms (rs6083540, rs12574348, rs61882396) and lipid sensitivity to HIIT in young Han Chinese populations, with this association exhibiting significant sex specificity. The findings suggest that the KCNC1 gene may serve as a key genetic mediator in exercise-regulated lipid metabolism. Future development of tailored HIIT programmes should account for individual genotypic and gender variations.

physiology↗

bioRxiv2025

BLTP2 orchestrates lysobisphosphatidic acid synthesis and exosome biogenesis via SCAMP3-dependent ER contacts in tumorigenesis

Multivesicular bodies (MVBs) contain intraluminal vesicles (ILVs) designated for degradation in lysosomes or release as exosomes for cell-to-cell communication. The mechanisms governing ILV/exosome formation are not fully understood. Here, we show that the integral endoplasmic reticulum (ER) membrane protein bridge-like lipid transfer protein 2 (BLTP2; KIAA0100) is indispensable in ILV/exosome formation and that secretory carrier membrane protein 3 (SCAMP3) recruits BLTP2 to ER-MVB membrane contact sites (MCSs) in a Rab5-dependent manner. Our results indicate that this recruitment is hindered by NEDD4-mediated ubiquitination of SCAMP3. Depletion of BLTP2 was found to impede ILV/exosome formation and selectively diminish the levels of cone-shaped phospholipids, including bis(monoacylglycero)phosphate (BMP) and the BMP precursor phosphatidylglycerol (PG) within endosomes. BLTP2 knockout also hampered cell proliferation and tumorigenicity, which could be restored to a significant extent by supplementation with exosomes from wild-type cells. Since BLTP2 is associated with acute monocytic leukemia and is highly expressed in breast cancer, our findings suggest that BLTP2 transfers the BMP/LBPA precursor PG to MVBs for BMP/LBPA synthesis and promotes ILV/exosome formation at SCAMP3-dependent ER-MVB MCSs, a process crucial for cell proliferation and tumorigenesis.

cell 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↗

bioRxiv2024

scRCA: a Siamese network-based pipeline for the annotation of cell types using imperfect single-cell RNA-seq reference data

A critical step in the analysis of single-cell transcriptomic (scRNA-seq) data is the accurate identification and annotation of cell types. Such annotation is usually conducted by comparative analysis with known (reference) data sets - which assumes an accurate representation of cell types within the reference sample. However, this assumption is often incorrect, because factors, such as human errors in the laboratory or in silico, and methodological limitations, can ultimately lead to annotation errors in a reference dataset. As current pipelines for single-cell transcriptomic analysis do not adequately consider this challenge, there is a major demand for a computational pipeline that achieves high-quality cell type annotation using imperfect reference datasets that contain inherent errors (often referred to as "noise"). Here, we built a Siamese network-based pipeline, termed scRCA, that achieves an accurate annotation of cell types employing imperfect reference data. For researchers to decide whether to trust the scRCA annotations, an interpreter was developed to explore the factors on which the scRCA model makes its predictions. We also implemented 3 noise-robust losses-based cell type methods to improve the accuracy using imperfect dataset. Benchmarking experiments showed that scRCA outperforms the proposed noise-robust loss-based methods and methods commonly in use for cell type annotation using imperfect reference data. Importantly, we demonstrate that scRCA can overcome batch effects induced by distinctive single cell RNA-seq techniques. We anticipate that scRCA (https://github.com/LMC0705/scRCA) will serve as a practical tool for the annotation of cell types, employing a reference dataset-based approach.

bioinformatics↗

bioRxiv2023

A glutamatergic DRN-VTA pathway for neuropathic pain and comorbid depression-like behavior modulation

Chronic pain causes both physical suffering and comorbid mental disorders such as depression. However, the neural circuits and molecular mechanisms underlying these maladaptive behaviors remain elusive. Here, we report a pathway from vesicular glutamate transporter3 neurons in the dorsal raphe nucleus to dopamine neurons in the ventral tegmental area (VGluT3DRN[->]DAVTA), of which population activity in response to innocuous mechanical stimuli and sucrose consumption, is respectively inhibited and attenuated by chronic neuropathic pain. Mechanistically, neuropathic pain dampens VGluT3DRN[->]DAVTA glutamatergic transmission and DAVTA neural excitability. VGluT3DRN[->]DAVTA activation alleviates neuropathic pain and comorbid depression-like behavior (CDB) by releasing glutamate, which subsequently promotes DA release in the nucleus accumbens medial shell (NAcMed) and produces analgesia and antidepressant effects via D2 and D1 receptors, respectively. In addition, VGluT3DRN[->]DAVTA inhibition produces pain-like hypersensitivity and depression-like behavior in healthy mice. These findings reveal a novel VGluT3DRN[->]DAVTA[->]D2/D1NAcMed pathway in establishing and modulating chronic pain and comorbid depressive-like behavior.

neuroscience↗

bioRxiv2023

Microglial IL-1β plays a protective role in epilepsy

Epilepsy is a neurological disorder characterized by recurrent seizures that affect about 50 million people worldwide. Although the exact mechanisms underlying epilepsy remain elusive, it is known that neuroinflammation contributes to the pathogenesis of the disease. Microglia, the resident immune cells of the central nervous system, play a key role in neuroinflammation and are activated in response to seizures. Interleukin-1{beta} (IL-1{beta}) is a pro-inflammatory cytokine produced by microglia and other immune cells. While IL-1{beta} has been implicated in the pathogenesis of various neurological disorders, recent studies have revealed a protective role for microglial IL-1{beta} in epilepsy. This paper aims to review the current knowledge about microglial IL-1{beta} and its potential therapeutic implications for epilepsy.

molecular biology↗

bioRxiv2022

Rational design of Cas9 ribonucleoprotein with a "gRNA-shRNA" for multidimensional genome manipulation and enhanced homology-directed repair

Gene perturbation approaches have evolved as powerful tools for understanding the function of genes and curing inherited diseases. Here, we develop a method that combines the merits of RNAi and CRISPR technology by rational design of Cas9 ribonucleoprotein (RNP) with a "gRNA-shRNA" component. The RNP, termed Cas9-RNAi, has a gRNA containing a 3 extension that can be processed to a functional siRNA via dorsha/dicer enzyme mediated cleavage within cells. We prepared the Cas9-RNAi RNPs by streamline co-expression of Cas9 enzymes and the "gRNA-shRNA" ribonucleotides in Escherichia coli strain HT115(DE)3. Transferring the Cas9-RNAi RNPs into mammalian cells achieves multidimensional genome manipulation, e.g., simultaneously knock out and knock down the target genes. Moreover, by introduction of a shRNA against the gene of human DNA ligase 4 (LIG4), significantly improved homology-directed repair was attained. Together, we develop a simple-to-use CRISPR RNP tool that has great potentials in precise genome editing, gene function analysis and gene therapy.

bioengineering↗

bioRxiv2021

OaAEP1-mediated PNA-protein conjugation enables erasable imaging of membrane protein

Methods to efficiently and site-specifically conjugate proteins to nucleic acids could enable exciting application in bioanalytics and biotechnology. Here, we report the use of the strict protein ligase to covalently ligate a protein to a peptide nucleic acid (PNA). The rapid ligation requires only a short N-terminal GL dipeptide in target protein and a C-terminal NGL tripeptide in PNA. We demonstrate the versatility of this approach by conjugating three different types of proteins with a PNA strand. The biostable PNA strand then serves as a generic landing platform for nucleic acid hybridization. Lastly, we show the erasable imaging of EGFR on HEK293 cell membrane through toehold-mediated strand displacement. This work provides a controlled tool for precise conjugation of proteins with nucleic acids through an extremely small peptide linker and facilitates further study of membrane proteins. TOC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=56 SRC="FIGDIR/small/467647v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@a8e3adorg.highwire.dtl.DTLVardef@1fba15borg.highwire.dtl.DTLVardef@11e606eorg.highwire.dtl.DTLVardef@14cfc49_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2021

RFRSN: Improving protein fold recognition by siamese network

Protein fold recognition is the key to study protein structure and function. As a representative pattern recognition task, there are two main categories of approaches to improve the protein fold recognition performance: 1) extracting more discriminative descriptors, and 2) designing more effective distance metrics. The existing protein fold recognition approaches focus on the first category to finding a robust and discriminative descriptor to represent each protein sequence as a compact feature vector, where different protein sequence is expected to be separated as much as possible in the fold space. These methods have brought huge improvements to the task of protein fold recognition. However, so far, little attention has been paid to the second category. In this paper, we focus not only on the first category, but also on the second point that how to measure the similarity between two proteins more effectively. First, we employ deep convolutional neural network techniques to extract the discriminative fold-specific features from the potential protein residue-residue relationship, we name it SSAfold. On the other hand, due to different feature representation usually subject to varying distributions, the measurement of similarity needs to vary according to different feature distributions. Before, almost all protein fold recognition methods perform the same metrics strategy on all the protein feature ignoring the differences in feature distribution. This paper presents a new protein fold recognition by employing siamese network, we named it PFRSN. The objective of PFRSN is to learns a set of hierarchical nonlinear transformations to project protein pairs into the same fold feature subspace to ensure the distance between positive protein pairs is reduced and that of negative protein pairs is enlarged as much as possible. The experimental results show that the results of SSAfold and PFRSN are highly competitive.

bioinformatics↗

bioRxiv2021

Vibrio cholerae may be transmitted to humans from bullfrog through food or water

Bullfrog is one of the most important economic aquatic animals in China. It is widely cultured in southern China, and is a key breed recommended as an industry of poverty alleviation in China. During recent years, a fatal bacterial disease has often been found in cultured bullfrogs. The clinical manifestations of the diseased bullfrogs were severe intestinal inflammation and even anal prolapse. A bacterial pathogen was isolated from the diseased bullfrog intestines. The bacterium was identified as Vibrio cholerae using morphological, biochemical and 16S rRNA phylogenetic analysis. In this study, V. cholerae was isolated and identified from diseased bullfrogs for the first time, providing a basis for the diagnosis and control of the disease. At the same time, it was also found that V. cholerae may be transmitted to humans from bullfrogs through bullfrog food and aquaculture water, creating a serious threat for human health. Therefore, society should pay attention to the modes of transmission of Vibrio cholerae from bullfrog and formulate reasonable safety measures to avoid disasters.

pathology↗

bioRxiv2020

CPEB2 m6A Methylation Regulates BTB Permeability via Affecting Splicing Factor SRSF5 Stability

The existence of the blood tumor barrier (BTB) severely hinders the delivery of anti-tumor drugs to gliomas, affecting the targeted therapeutic effects of drugs. Therefore, BTB selective opening has become a hot spot for glioma treatment. This study found that the up-regulated METTL3 and IGF2BP3 in GECs increase the stability of CPEB2 mRNA through m6A methylation of CPEB2 mRNA; CPEB2 binds and increases the stability of splicing factor SRSF5 mRNA; SRSF5 promotes the ETS1 exon inclusion; P51-ETS1 promotes the transcriptional expression of tight junction related proteins ZO-1, occludin and claudin-5, regulating BTB permeability. CPEB2, SRSF5 and P51-ETS1 alone or in combination can effectively enhance the role of Dox in promoting glioma cell apoptosis through BTB. The results of this study provide a new theoretical and experimental basis for the molecular regulation of BTB from the perspective of epigenetics, as well as new ideas for the comprehensive treatment of glioma.

cancer biology↗

bioRxiv2019

Sensitivity in the antioxidant system of discus fish (Symphysodon spp.) to cold temperature: evidence for species-specific cold resistance

The discus fish (Symphysodon spp.) is an endemic species of the Amazon that is among the most popular ornamental fish around the world, and is usually used as the model animal for studying the diversification of Amazon fish. Here, a comparative analysis of two species of discus fish, i.e., S. haraldi and S. aequifasciatus, based on several antioxidant indexes was conducted, to test the hypothesis that cold resistance might correlate with the diversification of discus fish. We set up a continuous sequence of three temperature programs, namely cooling (28 {degrees}C to 14 {degrees}C; -1 {degrees}C/h), cold maintenance (14 {degrees}C for 12 h) and recovery (14 {degrees}C to 28 {degrees}C; +1 {degrees}C/h). Subordinate function (SF) combined with principal component analysis (PCA) showed that the cold hardiness of S. haraldi during cold treatment was in the order of cooling > cold maintenance {approx} recovery, but the cold hardiness of S. aequifasciatus during cold treatment was in the order of cold maintenance > cooling > recovery. Specifically, the lowest cold hardiness was observed in S. aequifasciatus during recovery, indicating that cold stress resulted in more seriously oxidative stress in S. aequifasciatus than in S. haraldi. Overall, these results show a significant interspecific variation, indicating the correlation between environmental adaptation and the diversification of discus fish.

ecology↗

bioRxiv2018

Direct purification of CRISPR/Cas ribonucleoprotein from E. coli in a single step

CRISPR/Cas ribonucleoprotein (RNP) complexes have been recently used as promising biological tools with plenty of applications, however, there are by far no efficient methods to prepare them at large scale and low cost. Here, we present a simple method to directly produce and purify Cas RNP, including the widely used Cas9 and Cas12a nuclease, from E.coli in a single step using an ultra-high-affinity CL7/Im7 purification system. The prepared Cas RNP shows high stability, solid nuclease activity in vitro, and profound genome editing efficiency in vivo. Our method is convenient, cost-effective, and applicable to prepare other CRISPR associated nucleases.

synthetic biology↗

bioRxiv2018

Direct preparation of Cas9 ribonucleoprotein from E. coli for PCR-free seamless DNA assembly

CRISPR-Cas9 is a versatile and powerful genome engineering tool. Recently, Cas9 ribonucleoprotein (RNP) complexes have been used as promising biological tools with plenty of in vivo and in vitro applications, but there are by far no efficient methods to produce Cas9 RNP at large scale and low cost. Here, we describe a simple and effective approach for direct preparation of Cas9 RNP from E. coli by co-expressing Cas9 and target specific single guided RNAs. The purified RNP showed in vivo genome editing ability, as well as in vitro endonuclease activity that combines with an unexpected superior stability to enable routine uses in molecular cloning instead of restriction enzymes. We further develop a RNP-based PCR-free method termed Cas-Brick in a one-step or cyclic way for seamless assembly of multiple DNA fragments with high fidelity up to 99%. Altogether, our findings provide a general strategy to prepare Cas9 RNP and supply a convenient and cost-effective DNA assembly method as an invaluable addition to synthetic biological toolboxes.

synthetic biology↗