Biology subjects

Xia, Z.

Publications and source records attributed to Xia, Z..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

The Evidence of Cough Contagion in Human Beings

There is the evidence for cough contagion in human beings caused by empathy rather than physiology.Due to limited study on cough contagion,researchers have doubted whether cough was contagious from emtional contagion like yawn contagion.To deal with the doubts,we observed coughs from 34 adults in Ocean University of China in real time and recorded individual s gender and local time.Then we developed a mathematical model to divide the cough process into several bouts and set a threshold for contagion to construct a response graph.With the graph,we first saw a strong effect of contagion for around 30 seconds no matter how long the bin(< 30s) was.Afterwards with mutiple measures,we extracted seven features(e.g.,duration) to describe the transmission chain and then found that there s no time difference in cough contagion.Moreover,we also discovered tthe gender difference that males were more likely to be induced by triggers.Thus,cough contagion seems to be a normal phenomenon in human beings providing support to the experimental studies of empathy theory.

animal behavior and cognition↗

bioRxiv2023

Muscle-specific MEF2D alpha 2 isoform regulates mice exercise capacity, muscle ketolysis, and systemic ketone body availability in mice

Ketone bodies are an alternate fuel source generated by the liver in response to low carbohydrate availability in neonates and after starvation and exhausting exercise in adulthood. The postnatal alternative splicing generates a highly conserved muscle-specific MEF2D2 protein isoform of the transcription factor MEF2D. Here, we discovered that compared to WT mice, MEF2D2 exon knockout (Eko) mice displayed reduced running capacity and muscle expression of all three ketolytic genes, BDH1, OXCT1, and ACAT1. Consistent with reduced muscle utilization of ketone bodies, MEF2D2 Eko mice also showed increased ketone body levels in a tolerance test, after exercise, and upon feeding a ketogenic diet. Lastly, using mitochondria isolated from skeletal muscle, we showed reduced ketone body utilization and respiration in Eko compared to WT mice. Thus, we identified a new role of MEF2D2 protein isoform in regulating skeletal muscle ketone body oxidation, exercise capacity, and its effect on systemic ketone body levels.

molecular biology↗

bioRxiv2023

Supervised learning of high-confidence phenotypic subpopulations from single-cell data

Accurately identifying phenotype-relevant cell subsets from heterogeneous cell populations is crucial for delineating the underlying mechanisms driving biological or clinical phenotypes. Here, by deploying a learning with rejection strategy, we developed a novel supervised learning framework called PENCIL to identify subpopulations associated with categorical or continuous phenotypes from single-cell data. By embedding a feature selection function into this flexible framework, for the first time, we were able to select informative features and identify cell subpopulations simultaneously, which enables the accurate identification of phenotypic subpopulations otherwise missed by methods incapable of concurrent gene selection. Furthermore, the regression mode of PENCIL presents a novel ability for supervised phenotypic trajectory learning of subpopulations from single-cell data. We conducted comprehensive simulations to evaluate PENCILs versatility in simultaneous gene selection, subpopulation identification and phenotypic trajectory prediction. PENCIL is fast and scalable to analyze 1 million cells within 1 hour. Using the classification mode, PENCIL detected T-cell subpopulations associated with melanoma immunotherapy outcomes. Moreover, when applied to scRNA-seq of a mantle cell lymphoma patient with drug treatment across multiple time points, the regression mode of PENCIL revealed a transcriptional treatment response trajectory. Collectively, our work introduces a scalable and flexible infrastructure to accurately identify phenotype-associated subpopulations from single-cell data.

bioinformatics↗

bioRxiv2023

Augmentation of Histone Deacetylase 6 Activity Impairs Mitochondrial Respiratory Complex I in Ischemic/Reperfused Diabetic Hearts

BACKGROUNDDiabetes augments activity of histone deacetylase 6 (HDAC6) and generation of tumor necrosis factor (TNF) and impairs the physiological function of mitochondrial complex I (mCI) which oxidizes reduced nicotinamide adenine dinucleotide (NADH) to nicotinamide adenine dinucleotide to sustain the tricarboxylic acid cycle and {beta}-oxidation. Here we examined how HDAC6 regulates TNF production, mCI activity, mitochondrial morphology and NADH levels, and cardiac function in ischemic/reperfused diabetic hearts. METHODSHDAC6 knockout, streptozotocin-induced type 1 diabetic, and obese type 2 diabetic db/db mice underwent myocardial ischemia/reperfusion injury in vivo or ex vivo in a Langendorff-perfused system. H9c2 cardiomyocytes with and without HDAC6 knockdown were subjected to hypoxia/reoxygenation injury in the presence of high glucose. We compared the activities of HDAC6 and mCI, TNF and mitochondrial NADH levels, mitochondrial morphology, myocardial infarct size, and cardiac function between groups. RESULTSMyocardial ischemia/reperfusion injury and diabetes synergistically augmented myocardial HDCA6 activity, myocardial TNF levels, and mitochondrial fission and inhibited mCI activity. Interestingly, neutralization of TNF with an anti-TNF monoclonal antibody augmented myocardial mCI activity. Importantly, genetic disruption or inhibition of HDAC6 with tubastatin A decreased TNF levels, mitochondrial fission, and myocardial mitochondrial NADH levels in ischemic/reperfused diabetic mice, concomitant with augmented mCI activity, decreased infarct size, and ameliorated cardiac dysfunction. In H9c2 cardiomyocytes cultured in high glucose, hypoxia/reoxygenation augmented HDAC6 activity and TNF levels and decreased mCI activity. These negative effects were blocked by HDAC6 knockdown. CONCLUSIONSAugmenting HDAC6 activity inhibits mCI activity by increasing TNF levels in ischemic/reperfused diabetic hearts. The HDAC6 inhibitor, tubastatin A, has high therapeutic potential for acute myocardial infarction in diabetes. Novelty and SignificanceO_ST_ABSWhat Is Known?C_ST_ABSO_LIIschemic heart disease (IHS) is a leading cause of death globally, and its presence in diabetic patients is a grievous combination, leading to high mortality and heart failure. C_LIO_LIDiabetes impairs assembly of mitochondrial complex I (mCI), complex III dimer, and complex IV monomer into the respiratory chain supercomplexes, resulting in electron leak and the formation of reactive oxygen species (ROS). C_LIO_LIBy oxidizing reduced nicotinamide adenine dinucleotide (NADH) and reducing ubiquinone, mCI physiologically regenerates NAD+ to sustain the tricarboxylic acid cycle and {beta}-oxidation. C_LI What New Information Does This Article Contribute?O_LIMyocardial ischemia/reperfusion injury (MIRI) and diabetes as comorbidities augment myocardial HDCA6 activity and generation of tumor necrosis factor (TNF), which inhibit myocardial mCI activity. C_LIO_LIGenetic disruption of histone deacetylase 6 (HDAC6) decreases mitochondrial NADH levels and augments mCI activity in type 1 diabetic mice undergoing MIRI via decreasing TNF production, leading to decreases in MIRI. C_LIO_LIPretreatment of type 2 diabetic db/db mice with a HDAC6 inhibitor, tubastatin A (TSA), decreases mitochondrial NADH levels and augments mCI activity by decreasing TNF levels, leading to improvements in cardiac function. C_LI Patients with diabetes are more susceptible to MIRI than non-diabetics with greater mortality and resultant heart failure. There is an unmet medical need in diabetic patients for the treatment of IHS. Our biochemical studies find that MIRI and diabetes synergistically augment myocardial HDAC6 activity and generation of TNF, along with cardiac mitochondrial fission and low bioactivity of mCI. Intriguingly, genetic disruption of HDAC6 decreases the MIRI-induced increases in TNF levels, concomitant with augmented mCI activity, decreased myocardial infarct size, and ameliorated cardiac dysfunction in T1D mice. Importantly, treatment of obese T2D db/db mice with TSA reduces the generation of TNF and mitochondrial fission and enhances mCI activity during reperfusion after ischemia. Our isolated heart studies revealed that genetic disruption or pharmacological inhibition of HDAC6 reduces mitochondrial NADH release during ischemia and ameliorates dysfunction of diabetic hearts undergoing MIRI. Furthermore, HDAC6 knockdown in cardiomyocytes blocks high glucose- and exogenous TNF-induced suppression of mCI activity in vitro, implying that HDAC6 knockdown can preserve mCI activity in high glucose and hypoxia/reoxygenation. These results demonstrate that HDAC6 is an important mediator in MIRI and cardiac function in diabetes. Selective inhibition of HDAC6 has high therapeutic potential for acute IHS in diabetes.

pharmacology and toxicology↗

bioRxiv2023

Natural Killer cell contractility and cytotoxicity is driven by TLR3 agonist-mediated TAZ cytoplasmic sequestration

The evolutionarily conserved YAP/TAZ mechano-responsive transcription cofactors regulate development and tumorigenesis. Here, we show for the first time that human natural killer (NK) cells specifically express TAZ but not YAP, and TAZ serves to limit NK cytotoxicity. The TLR3 agonist, hiltonol, was able to trigger cytoplasmic sequestration of TAZ, which increased NK cytotoxicity. Mechanistically, a low dose of hiltonol enhanced the intracellular contractility of NK cells accompanied by an increase in active RhoA and myosin light chain phosphorylation, conceivably through an increase in ERK1/2 activation-dependent ROS production. Importantly, we showed that the dissociation of LATS1 from actin upon activation of contractility, is required to sequester TAZ in the cytoplasm. Functionally, hiltonol also reduced the NK cell surface inhibitory receptors, KIR3DL1 through c-Myc inhibition and PD-1 through enhanced contractility. Direct inhibition of c-Myc promoted NK cytotoxicity against K562 lymphoblast. We corroborated our findings by coculturing hiltonol-pretreated NK cells with breast and lung cancer cells, and demonstrated increased NK-mediated cancer killing, which conceivably occurred via sequestration of TAZ to the cytoplasm which facilitated NK cytotoxicity. Our findings pave the way for ex vivo rejuvenation of NK cells for in vivo immunotherapies, which could involve a cocktail of hiltonol and c-Myc inhibitor.

cell biology↗

bioRxiv2022

PathExpSurv: Pathway Expansion for Explainable Survival Analysis and Disease Gene Discovery

MotivationIn the field of biology and medicine, the interpretability and accuracy are both important when designing predictive models. The interpretability of many machine learning models such as neural networks is still a challenge. Recently, many researchers utilized prior information such as biological pathways to develop bioinformatics methods based on neural networks, so that the prior information can provide some insights and interpretability for the models. However, the prior biological knowledge may be incomplete and there still exists some unknown information to be explored. ResultsWe proposed a novel method, named PathExpSurv, to gain an insight into the black-box model of neural network for cancer survival analysis. We demonstrated that PathExpSurv could not only incorporate the known prior information into the model, but also explore the unknown possible expansion to the existing pathways. We performed downstream analyses based on the expanded pathways and successfully identified some key genes associated with the diseases and original pathways. AvailabilityPython source code of PathExpSurv is freely available at https://github.com/Wu-Lab/PathExpSurv. Contactlywu@amss.ac.cn Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2022

Integrated transcriptome and lineage analyses reveal novel catecholaminergic cardiomyocytes contributing to the cardiac conduction system in murine heart

Cardiac conduction system (CCS) morphogenesis is essential for correct heart function yet is incompletely understood. Here we established the transcriptional landscape of cell types populating the developing heart by integrating single-cell RNA sequencing and spatial enhanced resolution omics-sequencing (Stereo-seq). Stereo-seq provided a spatiotemporal transcriptomic cell fate map of the murine heart with a panoramic field of view and in situ cellular resolution of the CCS. This led to the identification of a previously unrecognized cardiomyocyte population expressing dopamine beta-hydroxylase (Dbh+-CMs), which is closely associated with the CCS in transcriptomic analyses. To confirm this finding, genetic fate mapping by using DbhCre/Rosa26-tdTomato reporter mouse line was performed with Stereo-seq, RNAscope, and immunohistology. We revealed that Dbh+-derived CMs first emerged in the sinus venosus at E12.5, then populated the atrial and ventricular CCS components at E14.5, with increasing abundance towards perinatal stages. Further tracing by using DbhCFP reporter and DbhCreERT/Rosa26-tdTomato inducible reporter, we confirmed that Dbh+-CMs are mostly abundant in the AVN and ventricular CCS and this persists in the adult heart. By using DbhCre/Rosa26-tdTomato/Cx40-eGFP compound reporter line, we validated a clear co-localization of tdTomato and eGFP signals in both left and right ventricular Purkinje fibre networks. Finally, electrophysiological optogenetic study using cell-type specific Channelrhodopsin2 (ChR2) expression further elucidated that Dbh+-derived CMs form a functional part of the ventricular CCS and display similar photostimulation-induced electrophysiological characteristics to Cx40CreERT/ChR2-tdTomato CCS components. Thus, by utilizing advanced transcriptomic, mouse genetic, and optogenetic functional analyses, our study provides new insights into mammalian CCS development and heterogeneity by revealing novel Dbh+-CMs. HighlightsO_LIStereo-seq provided a spatiotemporal transcriptomic cell fate map of the murine heart with a panoramic field of view and in situ cellular resolution of the CCS. C_LIO_LIEstablished the transcriptional landscape of cell types populating the developing murine heart. C_LIO_LIRevealed previously unreported catecholaminergic cardiomyocyte populations contributing to the developing and mature murine cardiac conduction system. C_LI

cell biology↗

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

Zinc Finger MYND-Type Containing 8 (ZMYND8) is epigenetically regulated in mutant Isocitrate Dehydrogenase 1 (IDH1) glioma to promote radioresistance

Mutant isocitrate dehydrogenase 1 (mIDH1) alters the epigenetic regulation of chromatin, leading to a hypermethylation phenotype in adult glioma. Establishment of glioma-specific methylation patterns by mIDH1 reprogramming drives oncogenic features of cancer metabolism, stemness and therapeutic resistance. This work focuses on identifying gene targets epigenetically dysregulated by mIDH1. Treatment of glioma cells with mIDH1 specific inhibitor AGI-5198, upregulated gene networks involved in replication stress. Specifically, we found that the expression of ZMYND8, a regulator of DNA damage response was decreased in three patient-derived glioma cell cultures (GCC) after treatment with AGI-5198. ZMYND8 functions as a chromatin reader to modulate enhancer activity and recruit DNA repair machinery. Knockdown of ZMYND8 expression sensitized mIDH1 GCCs to radiotherapy marked by decreased cellular viability. Following IR, mIDH1 glioma cells with ZMYND8 knockout (KO) exhibit significant phosphorylation of ATM and sustained {gamma}H2AX activation. ZMYND8 KO mIDH1 GCCs were further responsive to IR when treated with either BRD4 or HDAC inhibitors. The accumulation of DNA damage in ZMYND8 KO mIDH1 GCCs promoted the phosphorylation of cell cycle checkpoint proteins Chk1 and Chk2. In addition, the recruitment of ZMYND8 to sites of DNA damage has been shown to be PARP- dependent. PARP inhibition further enhanced the efficacy of radiotherapy in ZMYND8 KO mIDH1 glioma cells. These findings indicate the impact of ZMYND8 in the maintenance of genomic integrity and repair of IR-induced DNA damage in mIDH1 glioma. Translational RelevanceOur understanding of radioresistance mechanisms in patient-derived glioma cell cultures (GCC) that endogenously express mIDH1-R132H are limited. We have uncovered a novel gene target Zinc Finger MYND-Type Containing 8 (ZMYND8) that is downregulated following treatment of human mIDH1 GCCs with mIDH1 specific inhibitors. We demonstrate that suppression of ZMYND8 expression by shRNA knockdown or genetic knockout reduces the cellular viability of mIDH1 GCCs to ionizing radiation (IR). Our findings reveal an epigenetic vulnerability of mIDH1 GCCs to ZMYND8 knockout (KO) which results in impaired resolution of IR-induced DNA damage and induction of cell cycle arrest. Additionally, ZMYND8 KO mIDH1 GCCs display increased radiosensitivity to inhibition of epigenetic regulators BRD4, HDAC, and PARP which could be mediated by enhanced replicative stress.

cancer biology↗

bioRxiv2022

Chromosome-level Genomes Reveal the Genetic Basis of Descending Dysploidy and Sex Determination in Morus Plants

Multiple plant lineages have independently evolved sex chromosomes and variable karyotypes to maintain their sessile lifestyles through constant biological innovation. Morus notabilis, a dioecious mulberry species, has the fewest chromosomes among Morus spp., but the genetic basis of sex determination and karyotype evolution in this species have not been identified. Three high-quality genome assemblies generated of Morus spp. (including those of dioecious M. notabilis and Morus yunnanensis) were within the range 301-329 Mb in size which were grouped into six pseudochromosomes. Using a combination of genomic approaches, we showed that the putative ancestral karyotype of Morus was close to 14 protochromosomes, and that several chromosome fusion events resulted in descending dysploidy (2n = 2x = 12). We also characterized a [~]6.2-Mb sex-determining region on chromosome 3. The four potential male-specific genes, including a partially duplicated DNA helicase gene orthologue (named MSDH) and three Ty3_Gypsy long terminal repeat retrotransposons (named MSTG), were solely identified in the Y-linked area and considered to be strong candidate genes for sex determination or differentiation. Population genomic analysis showed that Guangdong accessions in China were genetically similar to Japanese accessions of mulberry. In addition, genomic areas containing selective sweeps that distinguish domesticated mulberry trees from wild populations in terms of flowering and disease resistance were identified. Our findings provide an important genetic resource for sex identification and molecular breeding in mulberry.

genomics↗

bioRxiv2022

Staphylococcus aureus nt5 gene contributes to bacterial infection ability to form kidney abscess

Staphylococcus aureus (S. aureus) is a commonly conditional infection pathogen, in which several key virulence genes are responsible for bacterial infection ability. The S. aureus nt5 gene, encoding 5-nucleotidase, mediates bacterial nucleic acid pathway, yet it is nearly unknown of nt5 function for staphylococcal infection ability. Herein we have constructed S. aureus mutant with the gene nt5C166T silence (S. aureus {Delta}nt5) by a CRISPR RNA-guided base editing system to investigate bacterial infection ability in vitro and in vivo. As expected, several nt5-related genes are disturbed in S. aureus {Delta}nt5, in which gene transcription level of py is decreased compared with the wild-type S. aureus. Bacterial gene nt5 is downregulated and py/adk are upregulated when S. aureus is exposed to antibiotics daptomycin, which indicates nt5-mediated nucleic acid pathway is interfered upon with daptomycin treatment. Furthermore, the mutant {Delta}nt5 displays about a 40-fold reduction of bacterial loading in mouse kidney on a mouse sepsis model, and the infection ability of {Delta}nt5 is reduced than the wild-type bacteria. The gene nt5 contributes to S. aureus-infected abscess formation in mouse kidney, and the silence of nt5 gene promotes phagocytosis of S. aureus by mouse and human immunocytes. In general, our findings reveal nt5 silence impedes bacterial loading in kidney to form abscess but enhances S. aureus to be phagocytosed by host cell immune system in vitro and in vivo, which indicates that nt5 gene plays an important role in bacterial infection and immune evasion.

immunology↗

bioRxiv2021

Genetic diversity patterns of human ethnic groups as inferred from the 1000 genomes

Human genetic diversity remains to be better understood. We here analyzed data from the 1000 Genomes Project and defined group specific fixed alleles (GSFAs) as those that are likely fixed in one ethnic group but non-fixed in at least one other group. The fraction of derived alleles in GSFAs indicates relative distance to apes because such alleles are absent in apes. Our results show that different groups differed in GSFA numbers consistent with known genetic diversity patterns, but also differed in the fraction of derived alleles in GSFAs throughout the entire genome, with East Asians having the largest fraction, followed by South Asians, Europeans, Native Americans, and Africans. Fast evolving sites such as intergenic regions were enriched with derived alleles and showed greater differences in GSFA numbers between East Asians and Africans. Furthermore, GSFAs in East Asians are mostly not fixed in other groups especially Africans, which was particularly more pronounced for fast evolving noncoding variants, while GSFAs in Africans are mostly also fixed in East Asians. Finally, variants that are likely non-neutral such as those leading to stop codon gain/loss and splice donor/acceptor gain/loss showed patterns similar to those of fast-evolving noncoding variants. These results can be accounted for by the maximum genetic diversity theory but not by the neutral theory or its inference that Eurasians suffered bottlenecks, and have implications for better management of group specific genetic diseases.

genomics↗

bioRxiv2021

Atypical relationships between neurofunctional features of print-sound integration and reading abilities in Chinese children with dyslexia

Conquering print-sound mappings (e.g., grapheme-phoneme correspondence rules) is vital for developing fluent reading skills. In neuroimaging research, this ability can be indexed by activation differences between audiovisual congruent against incongruent conditions in brain areas such as the left superior temporal cortex. In line with it, individuals with dyslexia have difficulty in tasks requiring print-sound processing, accompanied by a reduced neural integration. However, existing evidence is almost restricted to alphabetic languages. Whether and how multisensory processing of print and sound is impaired in Chinese dyslexia remains underexplored. In this study, we applied a passive audiovisual integration paradigm with functional magnetic resonance imaging to investigate the possible dysfunctions in processing character-sound (opaque; semantics can be automatically accessed) and pinyin-sound associations (transparent; no particular meaning can be confirmed) in Chinese dyslexic children. Unexpectedly, the dyslexic group did not show reduced neural integration compared with typically developing readers in either character or pinyin experiment. However, the results revealed atypical correlations between neural integration and different reading abilities in dyslexia. Specifically, while the neural integration in the left inferior frontal cortex in processing character-sound pairs correlated with silent reading comprehension in both children with and without dyslexia, it was associated with morphological awareness (semantic-related) in controls but with rapid naming (phonological-related) in dyslexics. This result indicates Chinese dyslexic children may not use the same grapho-semantic processing strategy as their typical peers do. As for pinyin-sound processing, while a stronger neural integration in the direction of "congruent > incongruent" in the left occipito-temporal cortex and bilateral superior temporal cortices was associated with better oral reading fluency in the control group, an opposite pattern was found in dyslexia. This finding may reflect dyslexias dysfunctional recruitment of the regions in grapho-phonological processing, which further impedes character learning. HighlightsO_LINeurofunctional correlates of print-sound integration in Chinese children with and without dyslexia are investigated. C_LIO_LIDyslexic children show atypical relationships between neural audiovisual integration and reading abilities. C_LIO_LIChinese children with dyslexia are likely to use inefficient strategies to process characters and pinyin. C_LI

neuroscience↗

bioRxiv2021

AN ECONOMIC, SQUARE-SHAPED FLAT-FIELD ILLUMINATION MODULE FOR TIRF-BASED SUPER-RESOLUTION MICROSCOPY

Super-resolution (SR) microscopy allows complex biological assemblies to be observed with remarkable resolution. However, the presence of uneven Gaussian-shaped illumination hinders its use in quantitative imaging or high-throughput assays. Methods developed to circumvent this problem are often expensive, hard-to-implement, or not applicable to total internal reflection fluorescence (TIRF) imaging. We herein demonstrate a cost-effective method to overcome these challenges using a small square-core multimodal optical fibre as the coupler. We characterise our method with synthetic, recombinant and cellular systems imaged under TIRF and highly inclined and laminated optical sheet (HILO) illuminations to demonstrate its ability to produce highly uniform images under all conditions.

biophysics↗

bioRxiv2021

An atlas of human viruses provides new insights into diversity and tissue tropism of human viruses

Viruses continue to threaten human health. Yet, the complete viral species carried by humans and their infection characteristics have not been fully revealed. This study curated an atlas of human viruses from public databases and literatures, and built the Human Virus Database (HVD) available at http://computationalbiology.cn/humanVirusBase/#/. The HVD contains 1,131 virus species of 54 viral families which were more than twice the number of the human-infecting virus species reported in previous studies. These viruses were identified in human samples including 68 human tissues, the excreta and body fluid. The viral diversity in humans was age-dependent with a peak in the infant and a valley in the teenager. The tissue range of viruses was found to be associated with several factors including the viral group (DNA, RNA or reverse-transcribing viruses), enveloped or not, viral genome length and GC content, viral receptors and the virus-interacting proteins. Finally, the tissue range of DNA viruses was predicted using a random-forest algorithm with a medium performance. Overall, the study not only provides a valuable resource for further studies of human viruses, but also deepens our understanding towards the diversity and tissue tropism of human viruses.

microbiology↗

bioRxiv2021

Genomic insights into the differentiated population admixture structure and demographic history of North East Asians

North China and South Siberia, mainly populated by Altaic-speaking populations, possess extensive ethnolinguistic diversity and serve as the crossroad for the initial peopling of America and western-eastern trans-continental communication. Yet, the complex scenarios of genetic origin, population structure, and admixture history of North-East Asia remain to be fully characterized, especially for Mongolic people in China with a genome-wide perspective. Thus, we genotyped genome-wide SNPs for 510 individuals from 38 Chinese Mongolic, Tungusic, and Sinitic populations to explore the sharing alleles and haplotypes within the studied groups and following merged it with 3508 modern and ancient Eurasian individuals to reconstruct the deep evolutionary and natural selection history of northern East Asians. We identified significant substructures within Altaic-speaking populations with the primary common ancestry linked to the Neolithic northern East Asians: Western Turkic people harbored more western Eurasian ancestry; Northern Mongolic people in Siberia and eastern Tungusic people in Amur River Basin (ARB) possessed dominant Neolithic Mongolian Plateau (MP) or ARB ancestry; Southern Mongolic people in China owned obvious genetic impact from Neolithic Yellow River Basin (YRB) farmers. Additionally, we found the differentiated admixture history between western and eastern Mongolians and geographically close Northeast Hans: the former received a genetic impact from western Eurasians and the latter retained the dominant YRB and ARB Neolithic ancestry. Moreover, we demonstrated that Kalmyk people from the northern Caucasus Mountain possessed a strong genetic affinity with Neolithic MP people, supporting the hypothesis of their eastern Eurasian origin and long-distance migration history. We also illuminated that historic pastoral empires in the MP contributed considerably to the gene pool of northern Mongolic people but rarely to southern ones. We finally found natural signatures in Mongolians associated with alcohol metabolism. Generally, our results not only illuminated that complex population migration and admixture of Neolithic ancestral sources from the MP or ARB played an important role in the spread of Altaic-speaking populations and Proto-Altaic language, which partly supported the Northeast Asia-origin hypothesis, but also demonstrated that the observed multi-sources of genetic diversity contributed significantly to the modern existing extensive ethnolinguistic diversity in North-East Asia.

genomics↗

bioRxiv2021

Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer's disease

Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimers Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-{beta} (A{beta}) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with A{beta} in the early stages of aggregation and then fall away as fibrillation happens. ApoE-A{beta} co-aggregates account for [~]50% of the mass of soluble A{beta} aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of A{beta}. Selectively removing non-lipidated apoE4-A{beta} co-aggregates enhances clearance of toxic A{beta} by glial cells, and reduces inflammation and membrane damage, demonstrating a clear path to AD therapeutics.

neuroscience↗

bioRxiv2021

Mesenchymal Lineage Heterogeneity Underlies Non-Redundant Functions of Pancreatic Cancer-Associated Fibroblasts

Cancer-associated fibroblast (CAF) heterogeneity is increasingly appreciated, but the origins and functions of distinct CAF subtypes remain poorly understood. The abundant and transcriptionally diverse CAF population in pancreatic ductal adenocarcinoma (PDAC) is thought to arise from a common cell of origin, pancreatic stellate cells (PSCs), with diversification resulting from cytokine and growth factor gradients within the tumor microenvironment. Here we analyzed the differentiation and function of PSCs during tumor progression in vivo. Contrary to expectations, we found that PSCs give rise to a numerically minor subset of PDAC CAFs. Targeted ablation of PSC-derived CAFs within their host tissue revealed non-redundant functions for this defined CAF population in shaping the PDAC microenvironment, including production of specific components of the extracellular matrix. Together, these findings link stromal evolution from distinct cells of origin to transcriptional heterogeneity among PDAC CAFs, and demonstrate unique functions for CAFs of a defined cellular origin. Statement of significanceBy tracking and ablating a specific CAF population, we find that a numerically minor CAF subtype from a defined cell of origin plays unique roles in establishing the pancreatic tumor microenvironment. Together with prior studies, this work suggests that mesenchymal lineage heterogeneity as well as signaling gradients diversify PDAC CAFs.

cancer biology↗