Search bioRxiv⌕ Search

Biology subjects

Xu, Q.

Publications and source records attributed to Xu, Q..

At least 145 records · Page 8Linked to original sources

Cortical somatostatin interneuron subtypes form cell-type specific circuits

The cardinal interneuron classes are a useful simplification of cortical interneuron diversity, but such broad subgroupings glosses over the molecular, morphological, and circuit specificity of interneuron subtypes, most notably among the somatostatin interneuron class. The organizing principles by which the connectivity of these subtypes is specified are unknown. To address this knowledge gap, we designed a series of genetic strategies to target the breadth of somatostatin interneuron subtypes. Using these strategies to target three subtypes that span the entire cortical column, we examined their afferent and efferent connectivity. Our data demonstrated that each of these possesses remarkable reciprocal connectivity with the intracortical or corticofugal pyramidal classes, as well as parvalbumin interneurons. Even when two interneuron subtypes shared the same efferent target, their synaptic targeting proved selective for particular dendritic compartments. We thus provide evidence that subtypes of somatostatin cortical interneurons form cell-type specific cortical circuits.

neuroscience↗

A pan-variant mRNA-LNP T cell vaccine protects HLA transgenic mice from mortality after infection with SARS-CoV-2 Beta

Clinically licensed COVID-19 vaccines ameliorate viral infection by inducing vaccinee production of neutralizing antibodies that bind to the SARS-CoV-2 Spike protein to inhibit viral cellular entry (Walsh et al., 2020; Baden et al., 2021), however the clinical effectiveness of these vaccines is transitory as viral variants arise that escape antibody neutralization (Tregoning et al., 2021; Willett et al., 2022). Vaccines that solely rely upon a T cell response to combat viral infection could be transformational because they can be based on highly conserved short peptide epitopes that hold the potential for pan-variant immunity, but a mRNA-LNP T cell vaccine has not been shown to be sufficient for effective antiviral prophylaxis. Here we show that a mRNA-LNP vaccine based on highly conserved short peptide epitopes activates a CD8+ and CD4+ T cell response that prevents mortality in HLA-A*02:01 transgenic mice infected with the SARS-CoV-2 Beta variant of concern (B.1.351). In mice vaccinated with the T cell vaccine, 24% of the nucleated cells in lung were CD8+ T cells on day 7 post infection. This was 5.5 times more CD8+ T cell infiltration of the lungs in response to infection compared to the Pfizer-BioNTech Comirnaty(R) vaccine. Between days 2 and 7 post infection, the number of CD8+ T cells in the lung increased in mice vaccinated with the T cell vaccine and decreased in mice vaccinated with Comirnaty(R). The T cell vaccine did not produce neutralizing antibodies, and thus our results demonstrate that SARS-CoV-2 viral infection can be controlled by a T cell response alone. Our results suggest that further study is merited for pan-variant T cell vaccines, and that T cell vaccines may be relevant for individuals that cannot produce neutralizing antibodies or to help mitigate Long COVID.

immunology↗

Effect and mechanism of black soybean peptides alleviating oxidative damage in the celiac disease cell model

Alpha gliadin peptide induces damage and apoptosis of intestinal cells and aggravates pathology of celiac disease (CD) by inducing oxidative stress. Therefore, inhibition or alleviation of oxidative stress in CD may be an effective approach to the adjunctive treatment of CD. Black soybean peptides (BSPs) have been shown to inhibit oxidative stress and inflammation. The effect of BSPs on CD remains unknown. In this paper, the effect and mechanism of BSPs on the -gliadin peptide (p31-43)-induced Caco-2 cytotoxicity were studied. We identified BSPs that alleviated the cytotoxicity of p31-43 in the CD cell model: Caco-2 cells were pre-treated with bioactive peptides for 3 hours before the addition of p31-43 for treatment for 24 hours, and then cells were collected for subsequent experiments. Our results show that p31-43 can significantly increase the ROS and MDA levels of Caco-2 cells, disrupt the glutathione redox cycle, reduce the activity of the antioxidant enzyme, and inhibit the activation of antioxidant signaling pathways. BSPs pretreatment can inhibit the increase of Keap1 protein induced by p31-43, activate antioxidant genes through Nrf2 protein, improve the activity of the antioxidant enzyme, alleviates glutathione redox cycle imbalance, promote the expression of GCLC or GCLM, and reduce oxidative damage. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/508472v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@b0b8c3org.highwire.dtl.DTLVardef@322434org.highwire.dtl.DTLVardef@1e70b77org.highwire.dtl.DTLVardef@1a1e8f9_HPS_FORMAT_FIGEXP M_FIG Pattern of BSPs against oxidative damage in CD cell mode. C_FIG

cell biology↗

openNAU: An open-source platform for normalizing, analyzing, and visualizing untargeted metabolomics data

MotivationAs an important part of metabolomics analysis, untargeted metabolomics has become a powerful tool in the study of tumor mechanisms and the discovery of metabolic markers with high-throughput spectrometric data which also brings great challenges to data analysis from the extraction of raw data to the identification of differential metabolites. To date, a large number of analytical tools and processes have been developed and constructed to serve untargeted metabolomics research. The different selection of analytical tools and parameter settings lead to varied results of untargeted metabolomics data. Our goal is to establish an easily operated platform and obtain a repeatable analysis result. ResultsWe used the R language basic environment to construct the preprocessing system of the original data and the LAMP (Linux + Apache + MySQL + PHP) architecture to build a cloud mass spectrum data analysis system. An open-source analysis software for untargeted metabolomics data (openNAU) was constructed. It includes the extraction of raw mass data and quality control for the identification of differential metabolic ion peaks. A reference metabolomics database based on public databases was also constructed. Finally, a complete analysis system platform for untargeted metabolomics was established. This platform provides a complete template interface for the addition and updating of the analysis process, so we can finish complex analyses of untargeted metabolomics with simple human-computer interactions. Availability and ImplementationThe source code can be downloaded from https://github.com/zjuRong/openNAU. Contactsunqingrong@zju.edu.cn

bioinformatics↗

Senescent cells develop PDK4-dependent hypercatabolism and form an acidic microenvironment to drive cancer resistance

Cellular senescence is a state of stable growth arrest, usually accompanied by development of the senescence-associated secretory phenotype (SASP). Although senescent cells remain metabolically active, little is known about their metabolic landscape and in vivo pathophysiological implications. Here we show that expression of the pyruvate dehydrogenase (PDH) inhibitory enzyme, pyruvate dehydrogenase kinase 4 (PDK4), is significantly upregulated in human senescent stromal cells. Preferentially expressed upon genotoxicity-induced senescence (GIS), PDK4 is negatively correlated with posttreatment survival of cancer patients. Upon cellular senescence, PDK4 shifts glucose metabolic flux from oxidative phosphorylation to aerobic glycolysis, causing enhanced lactate production and forming an acidic microenvironment. However, distinct from the cancer cell-featured Warburg effect, senescent cells maintain an intensive use of pyruvate through the tricarboxylic acid cycle (TCA), displaying increased respiration and redox activity, indicative of a special form of metabolic reprogramming. Conditioned media from PDK4+ stromal cells change global expression and promote malignancy of recipient cancer cells in vitro and accelerate tumor progression in vivo. Pharmacologically targeting PDK4 restrains the adverse effects of PDK4 in cell-based assays, while promoting tumor regression and extending posttreatment survival in preclinical trials. Together, our study substantiates the hypercatabolic nature of senescent cells, and reveals a metabolic link between senescence-associated acidic microenvironment and age-related pathologies including but not limited to cancer.

cell biology↗

The Protein Common Assembly Database (ProtCAD): A comprehensive structural resource of protein complexes

Proteins often act through oligomeric interactions with other proteins. X-ray crystallography and cryo-electron microscopy provide detailed information on the structures of biological assemblies, defined as the most likely biologically relevant structures derived from experimental data. In crystal structures, the most relevant assembly may be ambiguously determined, since multiple assemblies observed in the crystal lattice may be plausible. It is estimated that 10-15% of PDB entries may have incorrect or ambiguous assembly annotations. Accurate assemblies are required for understanding functional data and training of deep learning methods for predicting assembly structures. As with any other kind of biological data, replication via multiple independent experiments provides important validation for the determination of biological assembly structures. Here we present the Protein Common Assembly Database (ProtCAD), which presents clusters of protein assembly structures observed in independent structure determinations of homologous proteins in the Protein Data Bank (PDB). ProtCAD is searchable by PDB entry, UniProt identifiers, or Pfam domain designations and provides downloads of coordinate files, PyMol scripts, and publicly available assembly annotations for each cluster of assemblies. About 60% of PDB entries contain assemblies in clusters of at least 2 independent experiments. All clusters and coordinates are available on ProtCAD web site (http://dunbrack2.fccc.edu/protcad).

bioinformatics↗

Eye movement based information system indicates human behavior in virtual driving

Humans modulate the behavior flexibly after timely receiving and processing information from the environment. To better understand and measure human behavior in the driving process, we integrate humans and the environment as a system. The eye-movement methodologies are used to provide a bridge between humans and environment. Thus, we conduct a goal-directed task in virtual driving to investigate the law of eye-movement that could characterize the humans (internal) and environmental (external) state measured by fixation distribution and optical flows distribution. The analysis of eye-movement data combined with the information-theoretic tool, transfer entropy, active information storage, quantify the humans cognitive effort and receiving information, and in fact, there is a balance (optimal) range between two, because of the mutual synergy and inhibition, whose quantified value is named balance of information processing. Subsequently, we update a system-level model, finding that those information measurements, transfer entropy, active information storage, and balance of information processing, all are included. This information set is information flow, which is quantified by the square root of Jensen-Shannon divergence (SRJSD), named information flow gain. Whats more, results also demonstrate that the influence of system-level information flow correlated with behavioral performance stronger than the separate measurements. In conclusion, we research humans eye-movement based on information theory to analyze behavioral performance. Besides driving, these measurements may be a predictor for other behaviors such as walking, running, etc. Still, the limitation is that the information flow may be a proxy of determinants of behavior.

neuroscience↗

The 5-hydroxytryptaminergic Neurons Locating in the Dorsal Raphe Nucleus and Different Receptors of 5-HT Were Implicated in Mediating the Arousal from Sevoflurane Anesthesia

In order to explore the mechanism of general anesthesia emergence, based on the common clinical phenomenon-delayed emergence, we explore the role of 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nucleus in promoting awakening from sevoflurane anesthesia in mice model. In this study, C57BL/6J male mice were selected to specifically activate or inhibit 5-HT neurons in the dorsal raphe nucleus (DRN) and different 5-HT receptors by intraperitoneal, lateral ventricle, intranuclear or DRN injection of agonists/antagonists and optogenetics during the sevoflurane anesthesia to record and observe the anesthesia induction and emergence time of mice. Through intraventricular infusion and intranuclear microinjection of 5-HT and the agonists or antagonists of different 5-HT receptors, our data showed that 5-HT and 5-HT1A and 2A/C receptors, especially 5-HT1A receptor, are involved in the regulation of delayed awakening mediated by DRN 5-HT neurons. This can provide a reliable theoretical basis as well as potential targets for clinical intervention to prevent delayed emergence and some postoperative risks. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/492958v2_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@ff4f7forg.highwire.dtl.DTLVardef@1bc56dborg.highwire.dtl.DTLVardef@1ea5737org.highwire.dtl.DTLVardef@41548_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

The role of dynamic DNA methylation in liver transplant rejection in children

BackgroundTranscriptional regulation of liver transplant (LT) rejection may reveal novel predictive and therapeutic targets. PurposeTo test the role of differential DNA methylation in children with biopsy-proven acute cellular rejection (rejectors, R) after LT. MethodsPaired peripheral blood DNA samples were obtained before and after LT from 17 children, including 4R and 13 non-rejector (NR), and assayed with MethylC capture sequencing (MCC-Seq) approach covering 5 million CpGs in immune-cell specific regulatory elements. Differentially methylated CpGs (DMCs) were identified using generalized linear regression models adjusting for sex and age and merged into differentially methylated regions (DMR) comprising 3 or more DMCs. ResultsContrasting R vs NR, we identified 2238 DMCs in post-LT and 2620 DMCs in pre-LT samples, which clustered in 216 and 282 DMRs respectively. DMCs associated with R were enriched in enhancers and depleted in promoters. The proportion of hypomethylated versus hypermethylated DMRs increased from 22% to 48% (p<0.0001) in pre-LT vs. post-LT DMCs, respectively. The highest-ranked biological processes enriched in post-LT DMCs were antigen processing and presentation via MHC class I, MHC class I complex, and peptide binding (p<7.92E-17), respectively. Top-ranked DMRs mapped to genes which mediate B-cell receptor signaling (ADAP1) or regulate several immune cells (ARRB2) (p<3.75E-08). DMRs in MHC class I genes were enriched for SNPs which bind TFs, affect gene expression and splicing, or alter peptide-binding amino acid sequences. ConclusionsDynamic methylation in distal regulatory regions reveals known transplant-relevant MHC-dependent rejection pathways, and identifies novel loci for future mechanistic evaluations in pediatric transplant subcohorts.

genomics↗

Accelerated aging induced by stress in experimental murine ocular hypertension.

Aging, a universal process that affects all cells in an organism, is a major risk factor for a group of neuropathies called glaucoma, where elevated intraocular pressure is one of the known stresses affecting the tissue. Our understanding of molecular impact of aging on response to stress in retina is very limited, therefore we developed a new mouse model to approach this question experimentally. Here we show that susceptibility to response to stress increases with age and is primed on epigenetic level. We demonstrate that program activated by hypertension is similar to natural aging, and that one of the earliest pathways activated upon stress is senescence. Finally, we show that multiple instances of pressure elevation cause accelerated aging of young retina as measured on transcriptional and epigenetic level. Our work emphasizes the importance of early diagnosis and prevention as well as age-specific management of age-related eye-diseases, including glaucoma.

molecular biology↗

OncoPubMiner: A platform for oncology publication mining

Knowledge bases that are up-to-date and of expert quality are fundamental in biomedical research fields. A knowledge base established with human participation and subjected to multiple inspections is crucial for supporting clinical decision-making, especially in the exponentially growing field of precision oncology. The number of original publications in the field has skyrocketed with the advancement of technology and in-depth research evolved. It has become an increasingly pressing issue that researchers need to consider how to gather and mine these articles accurately and efficiently. In this paper, we present OncoPubMiner (https://oncopubminer.chosenmedinfo.com), a free and powerful system that combines text mining, data structure customization, publication search with online reading, project-centered and team-based data collection to realize a one-stop "keyword in, knowledge out" oncology publication mining platform. It was built by integrating all the open-access abstracts from PubMed and full-text articles from PubMed Central, and is updated on a daily basis. The system makes it straightforward to obtain precision oncology knowledge from scientific articles. OncoPubMiner will assist researchers in developing professional structured knowledge base systems efficiently, and bringing the oncology community closer to achieving precision oncology goals. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/483968v1_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@68235aorg.highwire.dtl.DTLVardef@e9256aorg.highwire.dtl.DTLVardef@9783daorg.highwire.dtl.DTLVardef@15193e2_HPS_FORMAT_FIGEXP M_FIG OncoPubMiners one-stop "keyword in, knowledge out" workflow (A) is built on key features such as text mining (B), publication search (C), form customization (D), and team-based curation (E). C_FIG

bioinformatics↗

Assessing base-resolution DNA mechanics on the genome scale

Intrinsic DNA properties such as bending play a crucial role in diverse biological systems. A recent advantage in the high-throughput method called loop-seq makes it possible to determine bendability of hundred thousand 50-bp DNA duplexes in one experiment. However, its still infeasible to assess whole sequence bendability in large genomes such as human, which needs thousands of loop-seq experiments. Here we introduce BendNet - a neural network to accurately predict the intrinsic DNA bending at base-resolution by only given DNA sequences. BendNet can increase the resolution of experimental results, and can predict DNA bendability for any new given sequences in high accuracy. We applied BendNet to the human genome and observed high-stiffness regions located at both transcriptional start sites and transcriptional end sites. Such stiffness patterns are different for coding and non-coding genes, which matches distinct nucleosome occupancy patterns. As expected, most transcription factors (TFs) bind in DNA of low bendability. In contrast, we observed an unusually high bendability within binding elements of specific TFs such as EBF1 and regulators of genome folding such as CTCF. These factors either co-bind or compete with nucleosomes to carry out their functions. More interestingly, CTCF binding regions exhibit the highest bendability than other DNA elements, implying their potential role in trapping and holding the CTCF in the exact locations to make sure CTCF as stable anchor in loop extrusion process. Our work provides a tool to assess DNA bendability for large-scale DNA sequences and expands our understanding on DNA mechanics in chromatin regulation and genome folding.

genomics↗

Clonal behaviour of myogenic precursor cells throughout the vertebrate lifespan.

To address questions of stem cell diversity during skeletal myogenesis, a Brainbow-like genetic cell lineage tracing method, dubbed Musclebow, was derived by enhancer trapping in zebrafish. It is shown that at least 15 muscle precursor cells (mpcs) seed each somite, where they proliferate but contribute little to muscle growth prior to hatching. Thereafter, dermomyotome-derived mpc clones rapidly expand while some progeny undergo terminal differentiation, leading to stochastic clonal drift. No evidence of cell lineage-based clonal fate diversity was obtained. Neither fibre nor mpc death was observed in uninjured animals. Individual marked muscle fibres persist across much of the lifespan indicating low rates of nuclear turnover. In adulthood, early-marked mpc clones label stable blocks of tissue comprising a significant fraction of either epaxial or hypaxial somite. Fusion of cells from separate early-marked clones occurs in regions of clone overlap. Wounds are regenerated from many/most local mpcs; no evidence for specialised stem mpcs was obtained. In conclusion, our data indicate that most mpcs in muscle tissue contribute to local growth and repair and suggest that cellular turnover is low in the absence of trauma. Summary StatementMusclebow clonal cell lineage analysis is introduced to reveal the cellular dynamics of skeletal muscle formation, repair and maintenance throughout the life of zebrafish.

developmental biology↗

Hinokitiol alters Gene Expression in Aspergillus fumigatus, protects against fungal keratitis by Reducing Fungal Load, LOX-1, Proinflammatory cytokines and Neutrophil Infiltration

Hinokitiol (HK), a tropolone-related compound found in cupressaceous plants, has antifungal and anti-inflammatory properties. But its roles in Aspergillus fumigatus ( A.F. ) keratitis remains unknown. This study examined the antifungal activity of HK against A.F. and investigated its possible mechanisms at the ultrastructural and transcriptional levels. We tested the minimum inhibitory concentration (MIC) of HK against A.F.. Our data showed that the MIC50 was 2 g/ml and MIC90 was 8 g/ml, and HK could significantly inhibit the spore germination and mycelial growth of A.F.. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) observations showed that HK induced significant changes in hyphal morphology and microstructure, including cell membrane rupture and intracellular structural disorder. Adhesion assay and biofilm assay experiments showed that HK reduced the adhesion of spores to human corneal epithelial cells (HCECs) and inhibited the formation of biofilms. The genetic changes of A.F. after HK treatment were analyzed by RNA sequencing, and a total of 2487 differentially expressed genes (DEGs) were identified, including the down-regulated DEGs related to carbohydrate and various amino acid metabolism, ribosome biogenesis, asexual reproduction, and up-regulated DEGs related to steroid biosynthesis through GO and KEGG enrichment analysis. RNA-seq results suggested that HK may play an antifungal effect by destroying the structural integrity of its wall and membrane, inhibiting protein biosynthesis and the growth and reproduction of A.F..10 g/ml HK, which had no effect on proliferation and migration of HCECs, was used in the treatment of murine fungal keratitis (FK). We found that HK eyedrop treatment could reduce the severity of FK by reducing corneal fungal burden, neutrophil infiltration, and the expression of LOX-1 and pro-inflammatory factors. HK is expected to be a safe and effective new drug for FK treatment. Author summaryFK is a serious common blind-causing eye disease. The current clinical antifungal drugs have the disadvantages of low bioavailability and high corneal toxicity, which greatly limit the clinical effectiveness. Therefore, there is an urgent need for a new, safe and effective treatment for FK. HK had shown great antifungal capacity against A.F., amazingly well anti-inflammatory effect and real improvement in murine FK in our research. These findings provide a theoretical basis for the application of HK as an antifungal drug and reveal the potential of HK to be applied in the clinical treatment of FK.

microbiology↗

A reference single-cell regulomic and transcriptomic map of cynomolgus monkeys

Non-human primates (NHP) are attractive laboratory animal models that accurately reflect both developmental and pathological features of humans. Here we present a compendium of cell types from the cynomolgus monkey Macaca fascicularis (denoted as Monkey Atlas) using both single-cell chromatin accessibility (scATAC-seq) and RNA sequencing (scRNA-seq) data at the organism-wide level. The integrated cell map enables in-depth dissection and comparison of molecular dynamics, cell-type composition and cellular heterogeneity across multiple tissues and organs. Using single-cell transcriptomic data, we inferred pseudotime cell trajectories and cell-cell communications to uncover key molecular signatures underlying their cellular processes. Furthermore, we identified various cell-specific cis-regulatory elements and constructed organ-specific gene regulatory networks at the single-cell level. Finally, we performed a comparative analysis of single-cell landscapes among mouse, cynomolgus monkey and human, and we showed that cynomolgus monkey has significantly higher degree of cell-type similarity to human than mouse. Taken together, our study provides a valuable resource for NHP cell biology.

bioinformatics↗

Enhancement of central norepinephrinergic neurotransmission contributes to inhibition of seizure-induced respiratory arrest by targeting the beta-1 adrenergic receptor (β1-AR) locating in the cardiomyocytes in the DBA/1 mouse SUDEP model

Sudden unexpected death of epilepsy (SUDEP) is the leading cause of of death in patients with epilepsy. Due to the complicated pathogenesis of SUDEP, however, the exact mechanism of SUDEP remains elusive. Currently, although it is recognized that the seizure-induced respiratory arrest (S-IRA) may be a main cause for SUDEP, other factors resulting in SUDEP can not be excluded e.g arrhythmias. Our previous findings indicated that the incidence of S-IRA and SUDEP evoked by acoustic stimulation or pentetrazol (PTZ) injection was significantly reduced by atomoxetine, a norepinephrine reuptake inhibitor (NRI), suggesting that noradrenergic neurotransmission modulates S-IRA and SUDEP. Given that norepinephrine acts on the target to modulate respiratory and circulation function by targeting adrenergic receptor and beta (a-AR and {beta}-AR) and the arrhythmias can be contributed to SUDEP. Meanwhile, to further test whether cardiac factors are implicated in S-IRA and SUDEP, we choose esmolol hydrochloride, a selective antagonist of {beta}1-AR to test it in our models. Our findings demonstrated that the lower incidence of S-IRA and SUDEP evoked by acoustic stimulation or PTZ injection in DBA/1 mice by administration with atomoxetine was significantly reversed by intraperitoneal (IP) of esmolol hydrochloride. Importantly, the data of electrocardiogram (ECG) showed that the cardiac arrhythmia including the ventricular tachycardia, ventricular premature beat and atrioventricular block can be evoked by acoustic stimulation or PTZ injection in our model. Administration of atomoxetine significantly reduced these arrhythmias and the incidence of S-IRA and SUDEP in our models. However, administration of esmolol hydrochloride with the dose without affecting ECG and mortality changing of DBA/1 significantly blocking the protective effects of atomoxetine on S-IRA and SUDEP in our models. Thus, the dysfunction of respiratory and circulation may be implicated in the pathogenesis of S-IRA and SUDEP. Enhancing the central norepinephrinergic neurotransmission in the brain contributes to inhibition of seizure-induced respiratory arrest by targeting {beta}1-AR locating in the cardiomyocytes. Furthermore, the suppression effects of S-IRA by atomoxetine was significantly reversed by the norepinephrine neuronal degradation in the LC in our models. Furthermore, PTZ-induced Tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of norepinephrine, activity but not TH content from the serum of left ventricle and the whole heart tissue was reduced following the S-IRA. Our findings will show a new light on decoding the pathogenesis of SUDEP concerning the pathway between the LC and heart.

neuroscience↗

TACAN is a novel regulator of PKD2

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in membrane receptor PKD1 or cation channel PKD2. TACAN (also named TMEM120A), recently reported as an ion channel in neuron cells for mechano and pain sensing, is also distributed in diverse non-neuronal tissues such as kidney, heart and intestine, suggesting its involvement in other functions. In this study, we found that TACAN is in complex with PKD2 in native renal cell lines. Using the two-electrode voltage clamp in Xenopus oocytes we found that TACAN inhibited the channel activity of PKD2 gain-of-function mutant F604P. The first and last transmembrane domains of TACAN were found to interact with the PKD2 C-and N-terminal portions, respectively. We showed that the TACAN N-terminus acted as a blocking peptide and that TACAN inhibits the PKD2 function through the PKD2/TACAN binding. By patch clamping in mammalian cells, we found that TACAN inhibits both the single channel conductance and open probability of PKD2 and mutant F604P. PKD2 co-expressed with TACAN, but not PKD2 alone, exhibited pressure sensitivity. Furthermore, we also found that TACAN aggravates PKD2-dependent tail curvature and pronephric cysts in larval zebrafish, in support of the in vitro inhibitory effects of TACAN. In summary, this study revealed that TACAN acts as a PKD2 inhibitor and mediates mechano sensitivity of the PKD2/TACAN channel complex.

physiology↗

MAL suppresses OSCC tumorigenesis by maintaining epithelial cell differentiation

Oral squamous cell carcinoma (OSCC) is widely recognized as an optimal model for precise medicine guided molecular biomarkers of cancer, however, few clinical practices were applied till now. Based on the data from our own studies and published papers, it was found that the expression of MAL was significantly decreased in epithelial cancer as compared with normal tissues, and exhibited a opposite association with pathological grade. To study the molecular events related to deficiency of MAL during carcinogenesis, occurrence and development, a Mal knockout mouse model was constructed and consistently reproduced and bred. The Mal knockout mice are highly vulnerable to tumor induction by carcinogen of 4NQO, evidenced by their extremely earlier carcinogenesis, higher incidence, and more aggressive growth. Analysis of scRNA-seq data indicated that Mal knockout mice lost the ability in maintaining epithelial cell differentiation and get more prone to carcinogen with a remarkably higher incidence of epithelial malignancy. Further analyses identified putative co-functional genes of MAL, including DSG1, AQP3 and S100A8, which are key factors in maintaining epithelial cell differentiation. To conclude, the current study exhibits the clinical significance and explains the tumor suppressing function of MAL. The results also suggest the potential of MAL and its co-functional genes being biomarkers for designing the prevention and/or differentiation therapy strategies in OSCC. SignificanceMAL is found to be strongly opposite with tumor pathological grade from clinical and in vivo studies in OSCC. We propose MAL and its co-functional genes, including DSG1, AQP3 and S100A8, as key factors in maintaining epithelial cell differentiation and are valuable targets for designing prevention and differentiation therapy strategies in OSCC.

cell biology↗