Biology subjects

Zhao, J.

Publications and source records attributed to Zhao, J..

At least 397 records · Page 22Linked to original sources

bioRxiv2022

Temporal gradient characteristics of automatic neural representation for orthographic consistency in Chinese characters

Visual word processing involves the automatic decoding of orthographic, phonological and semantic information. The mappings of these information in a writing system comprise an important feature of visual words: orthographic regularity and consistency. Recent electroencephalography (EEG) studies have investigated the automatic processing mechanism of orthographic regularity (i.e., words vs. pseudowords) among visual words. However, the automated mechanism and temporal dynamics of different types of orthographic consistency effects (e.g., orthographic positional consistency, orthography-to-phonology consistency vs. orthography-to-semantics consistency) have never been studied. This study explored automatic neural representation for orthographic consistency effects in visual words and its temporal dynamics through an oddball paradigm. Three types of oddball sequences were designed with Chinese characters as stimuli, including consistent Chinese characters as standard stimuli and three types of inconsistent characters (orthographic positional inconsistent, orthography-to-phonology inconsistent vs. orthography-to-semantics inconsistent) as deviant stimuli, respectively. Significant visual mismatch negativity (vMMN) activities were observed in all three types of inconsistent characters, which suggests automatic processing caused by orthographic consistency violations. Time-resolved representational similarity analysis (RSA) further revealed that there are different temporal dynamics of automatic neural representations for the three types of consistency features. The representation of positional consistency emerged earlier within an independent time window, while the representation of phonetic and semantic consistency emerged later, and partially overlapped. These findings provide novel insights for the temporal gradient characteristics of automated representation structure of orthography consistency information.

neuroscience↗

bioRxiv2022

Transcriptomic and proteomic profiling of NaV1.8-expressing mouse nociceptors

Nociceptors play an essential role in both acute pain and chronic pain conditions. and have recently been classified into distinct subsets using single-cell transcriptional profiling. In this study, we examined protein levels in dorsal root ganglia using DIA Mass-spectrometry technologies with NaV1.8Cre+/-; ROSA26-flox-stop-flox-DTA (Diphtheria toxin fragment A) mutant mice (NaV1.8Cre-DTA), in which NaV1.8-expressing neurons (mainly nociceptors) in dorsal root ganglia (DRG) were ablated. The results show that 353 transcripts and 78 proteins, including nociceptor-specific sodium channels NaV1.8 (Scn10a) and NaV1.9 (Scn11a), were specifically expressed in nociceptors of DRG. A comparative analysis revealed that about 40% of nociceptor-specific proteins are shared within the nociceptor-specific transcript dataset. Scatter plots show that the proteome and transcriptome datasets in nociceptors have a moderate correlation (r = 0.4825), indicating the existence of post-transcriptional and post-translational gene regulation in nociceptors. This combined profiling study provides a unique resource for sensory studies, especially for pain research.

neuroscience↗

bioRxiv2022

White matter connectivity in uncinate fasciculus accounts for visual attention span in developmental dyslexia

The present study aimed to investigate the role of connectivity disruptions in two fiber pathways, the uncinate fasciculus (UF) and the frontal aslant tract (FAT), in developmental dyslexia and determine the relationship between the connectivity of these pathways and behavioral performance in children with dyslexia. A total of 26 French children with dyslexia and 31 age-matched control children were included. Spherical deconvolution tractography was used to reconstruct the two fiber pathways. Hindrance-modulated oriented anisotropy (HMOA) was used to measure the connectivity of each fiber pathway in both hemispheres. The boys with dyslexia showed reduced HMOA in the UF compared to control boys, but this difference was not observed in girls. Furthermore, HMOA of the UF correlated with individual differences in the visual attention span in participants with dyslexia. All significant results found in HMOA of the UF were verified in fractional anisotropy (FA) of the UF using standard diffusion imaging model. This study suggests a differential sex effect on the connectivity disruption in the UF in developmental dyslexia. It also indicates that the UF may play an essential role in the visual attention span deficit in developmental dyslexia. Significance StatementThis study presents the first account of connectivity disruption in the uncinate fasciculus in developmental dyslexia. In particular, this connectivity disruption only appears in boys with dyslexia but not in girls with dyslexia. We also show that the connectivity of the uncinate fasciculus accounts for individual differences in the visual attention span in children with dyslexia, expanding the current understanding of the function of the uncinate fasciculus.

neuroscience↗

bioRxiv2022

Context and Domain Matter: The Error-Related Negativity in Peer Presence Predicts Fear of Negative Evaluation, not Global Social Anxiety, in Adolescents

BackgroundSocial anxiety symptoms are most likely to emerge during adolescence, a developmental window marked by heightened concern over peer evaluation. However, the neurocognitive mechanism(s) underlying adolescent social anxiety remain unclear. Emerging work points to the error-related negativity (ERN) as a potential neural marker of exaggerated self/error-monitoring in social anxiety, particularly for errors committed in front of peers.However, social anxiety symptoms are marked by heterogeneity and it remains unclear exactly what domain(s) of social anxiety symptoms are associated with ERN variation in peer presence, particularly within the adolescent period. MethodsTo advance and deepen the mechanistic understanding of the ERNs putative role as a neural marker for social anxiety in adolescence, we leveraged a social manipulation procedure and assessed a developmentally-salient domain of social anxiety during adolescence--Fear of Negative Evaluation (FNE). Adolescents residing in Hanzhong, a small city in the southwestern region of mainland China, had EEG recorded while performing a flanker task, twice (peer presence/absence); FNE, as well as global social anxiety symptoms were assessed. ResultsOverall ERN increases in peer presence. FNE specifically, but not global levels of social anxiety symptoms, predicted ERN in peer presence. ConclusionsThese data are the first demonstration that the ERN relates to a specific domain of social anxiety in adolescents, as well as the first evidence of such relations within a non-WEIRD (Western, Educated, Industrialized, Rich and Democratic) sample. Results have important implications for theory and research into adolescent social anxiety.

neuroscience↗

bioRxiv2022

Nonlinear effect of light intensity on normal axial development of rhesus monkeys

PurposeTo investigate the effects of different indoor lighting intensity (500 lx, 750 lx and 1,000 lx) on normal ocular axial length growth by using juvenal rhesus monkeys. MethodsTwenty-four juvenile monkeys were exposed continuously to normal intensity light (NIL, 500 lx, n=16), medium intensity light (MIL, 750 lx, n=8) and high intensity light (HIL, 1 000 lx, n=8), with a same CCT value (about 3000 K) for 246 days. Axial length, anterior chamber depth, corneal curvature radius were measured at about a monthly interval. ResultsAfter 246 days of light exposure, the growth of axial length of the MIL group (750 lx) were 0.151 {+/-} 0.081 mm and 0.139 {+/-} 0.070 mm in the right and left eyes, respectively, and significantly larger in comparison with the NIL group (500lx, OD: 0.068 {+/-} 0.055 mm, OS: 0.074 {+/-} 0.057 mm) and the HIL group (1000lx,OD:0.063 {+/-} 0.093 mm, OS: 0.084 {+/-} 0.052 mm) monkeys. This effect was stable and robust during the whole experimental period. ConclusionThe effects of different intensity lighting on normal ocular axial development was not linear as most people currently think. We must be cautious when it comes to elevate light intensity in classrooms. Whether this conclusion is correct under lights of other CCT value needs further study.

developmental biology↗

bioRxiv2022

The LncRNA Carmn is a Critical Regulator for Gastrointestinal Smooth Muscle Contractile Function and Motility

Background & aimsVisceral smooth muscle cells (SMCs) are an integral component of the gastrointestinal (GI) tract and are critical for regulating motility. SMC contraction is regulated by changes in post-translational signaling and the state of differentiation. Impaired SMC contraction is associated with significant morbidity and mortality but the mechanisms regulating the expression levels of SMC-specific contractile proteins, including the role of long non-coding RNAs (lncRNAs), remains largely unexplored. Herein, we have uncovered an important role of Carmn (Cardiac mesoderm enhancer-associated noncoding RNA), a SMC-specific lncRNA, in regulating the phenotype of visceral SMCs of the GI tract. MethodsAnalysis of GTEx and publicly available single-cell RNA sequencing (scRNA-seq) datasets from embryonic, adult human and mouse GI tissues were used to identify SMC-specific lncRNAs. The functional role of Carmn was investigated using a novel GFP knock-in (KI) reporter/knockout (KO) mouse model. Bulk RNA sequencing (RNA-seq) and single nuclei RNA sequencing (snRNA-seq) of colonic muscularis were used to investigate underlying mechanisms. ResultsUnbiased in silico analyses and GFP expression patterns in Carmn GFP KI mice revealed that Carmn is specifically expressed in SMCs in human and mouse GI tract. Premature lethality was observed in global Carmn KO (gKO) and inducible SMC-specific KO (iKO) mice due to colonic pseudo-obstruction, severe distension of the GI tract with blockages in cecum and colon segments. Histology, whole-gut GI transit time and muscle myography analysis revealed severe dilation, significantly delayed GI transit and impaired GI contractility in Carmn KO mice versus control mice. Bulk RNA-seq of colonic muscularis revealed that Carmn deficiency promotes SMC de-differentiation as evidenced by up-regulation of extracellular matrix genes and down-regulation of SMC contractile genes including Mylk, a key regulator of SMC contraction. SnRNA-seq further revealed SMC Carmn deficiency not only compromised myogenic motility by reducing expression of contractile genes but also impaired neurogenic motility by disrupting cell-cell connectivity in the colonic muscularis. These findings may have translational significance as silencing CARMN in human colonic SMCs significantly attenuated contractile gene expression including MYLK and decreased SMC contractility. Luciferase reporter assays showed that CARMN enhances the transactivation activity of the master regulator of SMC contractile phenotype, myocardin, thereby maintaining the GI SMC myogenic program. ConclusionOur data suggest that Carmn is indispensable for maintaining GI SMC contractile function in mice, and that loss of function of CARMN may contribute to human visceral myopathy. To our knowledge this is the first study showing an essential role of lncRNA in the regulation of visceral SMC phenotype.

cell biology↗

bioRxiv2022

APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimers disease (AD); however, how it modulates brain homeostasis is not clear. The apoE protein is a major lipid carrier in the brain transporting lipids such as cholesterol among different brain cell types. Here, we show that APOE deficiency in human iPSC-derived cerebral organoids impacts brain lipid homeostasis by modulating multiple cellular and molecular pathways. Molecular profiling through single cell RNA-sequencing revealed that APOE deficiency leads to changes in cellular composition of isogenic cerebral organoids likely by modulating the EIF2 signaling pathway as these events were alleviated by the treatment of a pathway inhibitor ISRIB. APOE deletion also leads to activation of the Wnt/{beta}-catenin signaling pathway with concomitant decrease of SFRP1 expression in glia cells. Importantly, the critical role of apoE in cell type-specific lipid homeostasis was observed upon APOE deletion in cerebral organoids with a specific upregulation of cholesterol biosynthesis in excitatory neurons and excessive lipid accumulation in astrocytes. Relevant to human AD, APOE4 cerebral organoids show altered neurogenesis and cholesterol metabolism compared to those with APOE3. Our work demonstrates critical roles of apoE in brain homeostasis and offers critical insights into the APOE4-related pathogenic mechanisms.

cell biology↗

bioRxiv2022

Aspartate reduces liver inflammation and fibrosis by suppressing the NLRP3 inflammasome pathway via upregulating NS3TP1 expression

Aspartate (Asp) can act on liver Kupffer cells, inhibit NOD-like receptor-P 3 (NLRP3) inflammatory bodies, and improve liver inflammation in acute hepatitis. However, the effect of Asp on the role of hepatic stellate cells (HSCs) in the pathogenesis of liver fibrosis in chronic liver injury remains unexplored. This study aimed to investigate the effects of Asp on CCl4-induced liver fibrosis in mice and HSCs via the NF-{kappa}B/ NLRP3 signaling pathway. Liver fibrosis was induced in C57BL/6J mice by intraperitoneally (IP) injecting 0.5 mL/kg 2% CCl4 three times weekly for 8 weeks. Asp was administered to mice by gavage once every morning for 4 weeks. Massons trichrome staining, Sirius red staining and hematoxylin and eosin staining were used to detect and analyze the pathological changes in liver tissues. Western blot analysis and immunohistochemistry were applied to determine the protein expression levels of -smooth muscle actin (-SMA), collagen III (COL III), NLRP3, and IL-1{beta}. Also, reverse transcription-quantitative PCR was performed to detect the mRNA expression levels. In the liver fibrosis model, the pathological changes in liver tissues improved following treatment with Asp. A marked decrease was observed in protein and mRNA expression levels of -SMA, COL III, NLRP3, and IL-1{beta}. In addition, HSCs were treated with Asp. The expression levels of -SMA, COL III, NLRP3, and IL-1{beta} reduced in dose- and time-dependent manners. Furthermore, Asp upregulated the expression of NS3TP1 in vivo and in vitro, and NS3TP1 had a significant inhibitory effect on liver fibrosis. Asp attenuated liver fibrosis and reduced collagen production by suppressing the NF-{kappa}B/ NLRP3 signaling pathway via upregulating the expression of NS3TP1.

molecular biology↗

bioRxiv2022

Defining the Ligand-dependent Interactome of the Sigma 1 Receptor

Sigma 1 Receptor (S1R) is a therapeutic target for a wide spectrum of pathological conditions ranging from neurodegenerative diseases to cancer and COVID-19. S1R is ubiquitously expressed throughout the visceral organs, nervous, immune and cardiovascular systems. It is proposed to function as a ligand-dependent molecular chaperone that modulates multiple intracellular signaling pathways. The purpose of this study was to define the S1R interactome under native conditions and upon binding to well-characterized ligands. This was accomplished by fusing the biotin ligase, Apex2, to the C terminus of S1R. Cells stably expressing S1R-Apex or a GFP-Apex control were used to map specific protein interactions. Biotinylated proteins were labeled under native conditions and in a ligand dependent manner, then purified and identified using quantitative mass spectrometry. Under native conditions, S1R biotinylates over 200 novel proteins, many of which localize within the endomembrane system (ER, Golgi, secretory vesicles) and function within the secretory pathway. Under conditions of cellular exposure to either S1R agonist or antagonist, results show enrichment of proteins integral to secretion, extracellular matrix formation, and cholesterol biosynthesis. Notably, Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) displays increased binding to S1R under conditions of treatment with Haloperidol, a well-known S1R antagonist; whereas Low density lipoprotein receptor (LDLR) binds more efficiently to S1R upon treatment with (+)-Pentazocine ((+)-PTZ), a classical S1R agonist. Our results are consistent with the postulated role of S1R as an intracellular chaperone and further suggest important and novel functionalities related to cholesterol metabolism and biosynthesis.

cell biology↗

bioRxiv2022

HDL-C as a potential medium between depletion of Lachnospiraceae genera and hypertension under high-calorie diet

Gut microbial dysbiosis has been associated with hypertension. An extremely high incidence of essential hypertension was found in the Han and the Yugur who resided in Sunan county in East Asias nomadic steppes with little population movement. In attempt to investigate the gut microbial role in hypertension, we recruited a total of 1, 242 Yugur and Han people, who had resided in Sunan County for more than 15 years and accounted for 3% of the local population. The epidemiological survey of 1,089 individuals indicated their nearly 1.8 times higher prevalence of hypertension (38.2-43.3%) than the average in China (23.2%), under a special high-calorie diet based on wheat, cattle, mutton, and animal offal. The 16S rRNA gene sequencing on the fecal samples of 153 individuals revealed that certain Lachnospiraceae genera were negatively correlated with high-density lipoprotein cholesterol (HDL-C, P = 5.46 x 10-6), systolic blood pressure (SBP, P = 7.22 x 10-3), diastolic blood pressure (DBP, P = 1.8 x 10-3). HDL-C was positively correlated with SBP (P = 0.023). We further observed that serum butyrate content was lower in both Han (P = 1.99 x 10-3) and Yugur people (P = 0.031) with hypertension than those without hypertension. This study gives a novel insight into the role of gut microbial dysbiosis in hypertension modulation under a high-calorie diet, where the notable depletion of Lachnospiraceae genera might lead to less production of butyrate, contributing to the lower level of HDL-C, and elevating blood pressure in hypertension. IMPORTANCEDietary nutrients can be converted by gut microbiota into metabolites such as short-chain fatty acids, which may serve as disease-preventing agents in hypertension. Due to limited population mobility and a unique high-calorie dietary habit, the recruited cohort in this study could be a representative for elucidating the associations between gut microbiota and hypertension under high-calorie diet. Moreover, low levels of HDL-C have previously been associated with an increased risk of various cardiovascular diseases (CVDs). Our findings provide a new insight that low levels of HDL-C may be a potential medium between depletion of Lachnospiraceae genera and hypertension under high-calorie diet, which might also be a potential candidate for other CVDs.

microbiology↗

bioRxiv2022

The highly expressed ERV1 forms virus-like particles for regulating early embryonic development

In mammals, the transcription of transposable elements (TEs) is important for maintaining early embryonic development. Here, we systematically analyzed the expression characteristics of TE-derived transcripts in early embryos by constructing a database of TEs and transcriptome data from goats and using it to study the function of endogenous retroviruses (ERVs) in regulating early embryo development. We found that ERV1 made up the highest proportion of TE sequences and exhibited a stage-specific expression pattern during early embryonic development. Among ERV elements, ERV1 had the potential to encode the Gag protein domain to form virus-like particles (VLPs) in early goat embryos. Knockdown of ERV1_1_574 significantly reduced the embryo development rate and the number of trophoblast cells (P< 0.05). Transcriptome sequencing analysis of morula embryos showed that ERV1_1_574 mainly regulated the expression of genes related to embryo compaction and trophoblast cell differentiation, such as CX43 and CDX2. In summary, we found that ERV1 expression was essential for early embryonic development in goats through regulation of trophoblast cell differentiation.

developmental biology↗

bioRxiv2022

A pangenome analysis pipeline (PSVCP) provides insights into rice functional gene identification

BackgroundA pangenome aims to capture the complete genetic diversity within a species and reduce bias in genetic analysis inherent in using a single reference genome. However, the current linear format of most plant pangenomes limits the presentation of position information for novel sequences. Graph pangenomes have been developed to overcome this limitation. However, there is a lack of bioinformatics analysis tools for graph format genomes. ResultsTo overcome this problem, we have developed a novel pangenome construction strategy and a downstream pangenome analysis pipeline that captures position information while maintaining a linearized layout. We applied this strategy to construct a high-quality rice pangenome using 12 representative rice genomes and analyze an international rice panel with 413 diverse accessions using the pangenome reference. Our results provide insights into rice population structure and genomic diversity. Applying the pangenome for PAV-based GWAS analysis can identify causal structural variations for rice grain weight and plant height, while SNP-based GWAS can only identify approximate genomic locations. Additionally, a new locus (qPH8-1) was found to be associated with plant height on chromosome 8 that could not be detected using the SNP-based GWAS. ConclusionsOur results demonstrate that the pangenome constructed by our pipeline combined with PAV-based GWAS can provide additional power for genomic and genetic analysis. The pangenome constructed in this study and associated genome sequence data provide valuable genomic resources for future rice crop improvement.

genetics↗

bioRxiv2022

Triangulation fails when neither linguistic, genetic, nor archaeological data support the Transeurasian narrative

Robbeets et al.1 argue that the dispersal of the so-called "Transeurasian" languages, a highly disputed language superfamily comprising the Turkic, Mongolian, Tungusic, Koreanic, and Japonic language families, was driven by Neolithic farmers in the West Liao River region of China. They adduce evidence from linguistics, archaeology, and genetics to support their claim. An admirable feature of the Robbeets et al.s paper is that all their datasets can be accessed. However, a closer investigation of all three types of evidence reveals fundamental problems with each of them. Robbeets et al.s analysis of the linguistic data does not conform to the minimal standards required by traditional scholarship in historical linguistics and contradicts their own stated sound correspondence principles. A reanalysis of the genetic data finds that they do not conclusively support the farming-driven dispersal of Turkic, Mongolian, and Tungusic, nor the two-wave spread of farming to Korea. Their archaeological data contain little phylogenetic signal, and we failed to reproduce the results supporting their core hypotheses about migrations. Given the severe problems we identify in all three parts of the "triangulation" process, we conclude that there is neither conclusive evidence for a Transeurasian language family nor for associating the five different language families with the spread of Neolithic farmers from the West Liao River region.

genetics↗

bioRxiv2022

Human hematopoietic stem cell vulnerability to ferroptosis

Hematopoietic stem cells (HSCs) have a number of unique physiologic adaptations that enable lifelong maintenance of blood cell production, including a highly regulated rate of protein synthesis. Yet the precise vulnerabilities that arise from such adaptations have not been fully characterized. Here, inspired by a bone marrow failure disorder due to loss of the histone deubiquitinase MYSM1, characterized by selectively disadvantaged HSCs, we show how reduced protein synthesis in HSCs results in increased ferroptosis. HSC maintenance can be fully rescued by blocking ferroptosis, despite no alteration in protein synthesis rates. Importantly, this selective vulnerability to ferroptosis not only underlies HSC loss in MYSM1 deficiency, but also characterizes a broader liability of human HSCs. Increasing protein synthesis rates via MYSM1 overexpression makes HSCs less susceptible to ferroptosis, more broadly illuminating the selective vulnerabilities that arise in somatic stem cell populations as a result of physiologic adaptations.

genetics↗

bioRxiv2022

Genome-wide identification of microsatellite markers and their application in genetic studies of wolfberry (Lycium barbarum)

The wolfberry (Lycium barbarum) has been an important traditional Chinese food and medicine for hundreds of years. However, few microsatellite markers have been developed for assessing the genetic diversity and genetic linkage maps among Lycium species in genetic research. In the present study, a total of 397,558 microsatellite loci were identified from whole wolfberry genome sequences with an overall density of 212.1 Mb/SSRs. Dinucleotide microsatellites were the most abundant type, representing 58.26% of the total microsatellite loci, followed by tri-, penta-, hexa-, and tetranucleotide. The AT motifs were the most abundant of all nucleotide repeat motifs, accounting for 44.52%. A set of 600 primer pairs were synthesized and preliminarily screened among four wolfberry accessions. Of these, 277 primer pairs were selected as polymorphic markers. In total, 22 highly polymorphic SSR markers were selected for the characterization of genetic diversity among 37 wolfberry accessions. A total of 323 alleles were detected with an average of 14.7 alleles per marker. The polymorphic information content (PIC) values ranged from 0.612 to 0.911. The dendrogram revealed that the phylogenetic relationships among these wolfberry accessions were consistent with their genetic background. Thus, the large number of genome-wide microsatellite markers developed from the wolfberry genome provides a valuable resource for genetic diversity, genetic map construction, quantitative trait locus (QTL) mapping, and marker-assisted selection breeding in Lycium species.

molecular biology↗

bioRxiv2022

USP11 promotes endothelial apoptosis-resistance in pulmonary hypertension by deubiquitinating HINT3

IntroductionPulmonary arterial hypertension (PAH) is a progressive, lethal, and incurable disease of the pulmonary vasculature. Evolving evidence indicates that the ubiquitin-specific proteases (USPs), play an important role in the pathogenesis of PAH by deubiquitinating key proteins involved in cell proliferation, migration, and apoptosis. Our genome-wide association study (GWAS) analysis-paired with transcriptomic profiling indicated that deubiquitinase USP11 and histidine triad nucleotide binding protein 3 (HINT3) are positively correlated and that their expression increased in lungs of PAH patients compared to control (fail donor) group, and inversely correlated with survival. However, mechanisms and function of the USP11/HNT3 axis have not been explored in PAH. Therefore, we aimed to investigate that HINT3 stabilized by USP11 activation links to endothelial apoptosis-resistance in PAH. Methods and ResultsExpression of USP11 and HINT3 was increased in the lungs of idiopathic PAH (IPAH) patients and Hypoxia/Sugen-treated mice using qRT-PCR and Western blot analyses. USP11 and HINT3 interacted physically as shown by co-immunoprecipitation (co-IP) assay in human pulmonary artery endothelial cells (HPAECs). HINT3 levels were decreased upon transfection of HA-tagged Ubi plasmid into HPAECs. Pretreatment with the potent proteasome inhibitor MG132 prolonged the half-life of HINT3 protein, indicating that HINT3 is degraded by polyubiquitination. HINT3 was stabilized and destabilized by forced overexpression or siRNA knockdown of USP11 respectively. Similarly, treatment with mitoxantrone, a USP11 antagonist, reduced HPAEC HINT3 expression. HINT3 interacted with the antiapoptotic mediator, BCL2. Overexpression of USP11 increased BCL2 content, congruent to elevated lung tissue levels seen in IPAH patients and Hypoxia/Sugen-treated mice. Conversely, knockdown of HINT3 function led to depletion of BCL2. ConclusionsThe HINT3-USP11 axis contributes to apoptosis-resistance in pulmonary artery endothelial cells, as is potentially a novel and attractive therapeutic target for ubiquitination modulators.

physiology↗

bioRxiv2022

Genomic insights into the adaptive and convergent evolution of Leuciscus waleckii inhabiting extremely alkaline environments

Leuciscus waleckii is widely distributed in Northeast Asia and has high economic value. Different from its freshwater counterparts, the population in Lake Dali Nur has a strong alkalinity tolerance and can adapt to extremely alkaline-saline water with bicarbonate over 50 mmol/L (pH 9.6), thus providing an exceptional model with which to explore the mechanisms of adaptive evolution under extreme alkaline environments. Here, we assembled a high quilty chromosome-level reference genome for L. waleckii from Lake Dali Nur, which provides an important genomic resource for the exploitation of alkaline water fishery resources and adaptive evolution research across teleost fish. Notably, we identified significantly expanded long terminal repeats (LTRs) and long interspersed nuclear elements (LINEs) in L. waleckii compared to other Cypriniformes fish, suggesting their more recent insertion into the L. waleckii genome. We also identified expansions in genes encoding gamma-glutamyltransferase, which possibly underlie the adaptation to extreme environmental stress. Based on the resequencing of 85 L.waleckii individuals from divergent populations, the historical population size of L.waleckii in Lake Dali Nur dramatically expanded in a thousand years approximately 13,000 years ago, and experienced a cliff recession in the process of adapting to the alkaline environment of Lake Dali Nur approximately 6,000 years ago. Genome scans further revealed the significant selective sweep regions from Lake Dali Nur, which harbour a set of candidate genes involved in hypoxia tolerance, ion transport, acid-base regulation and nitrogen metabolism. In particular, 5 alkali population specific nonsynonymous mutations were identified in CA15 gene copies. In addition, two sites with convergent amino acid mutation were detected in the RHCG-a gene among several alkali environment adapted Cypriniformes fish, this mutation may increase the NH3 excretion rate of the RHCG channel. Our findings provide comprehensive insight into the genomic mechanisms of L. waleckii and reveal their adaptative evolution under extreme alkaline environments.

evolutionary biology↗

bioRxiv2022

Intermittent fasting mitigates cognitive deficits in Alzheimer's disease via the gut-brain axis

Intermittent fasting (IF) is suggested to mitigate cognitive impairment in Alzheimers disease (AD). We detailed the effects of IF in AD development and assessed the contribution of the gut microbiota-metabolite-brain axis in promoting the effects of fasting. A 16-week IF regimen significantly improved spatial memory and cognitive function in AD transgenic mice; this improvement was accompanied by decreased A{beta} accumulation and suppression of neuroinflammation. IF reshaped the microbiota and beneficially altered the microbial metabolites related to cognitive function. Multi-OMICs integration demonstrated a strong connection between IF induced changes in hippocampus gene expression, the composition of the gut microbes, and the serum metabolites beneficial for cognitive function. Removal of gut microbes with antibiotics abolished the neuroprotective effects of IF. These findings suggest new avenues for therapy and nutritional intervention to prevent the development of AD and other neurodegenerative diseases.

animal behavior and cognition↗