Biology subjects

Shen, X.

Publications and source records attributed to Shen, X..

At least 235 records · Page 13Linked to original sources

bioRxiv2019

SHIV.CH505-infected infant and adult rhesus macaques exhibit similar HIV Env-specific antibody kinetics, despite distinct T-follicular helper (Tfh) and germinal center B cell landscapes

Pediatric HIV infection remains a large global health concern despite the widespread use of antiretroviral therapy (ART). Thus, global elimination of pediatric HIV infections will require the development of novel immune-based approaches, and understanding infant immunity to HIV is critical to guide the rational design of these intervention strategies. Despite their immunological immaturity, HIV-infected children develop broadly neutralizing antibodies (bnAbs) more frequently and earlier than adults do. Furthermore, T-follicular helper (Tfh) cells have been associated with bnAb development in HIV-infected children and adults. To further our understanding of age-related differences in the development of HIV-specific immunity, we evaluated the generation of virus-specific humoral immune responses in infant (n=6) and adult (n=12) rhesus macaques (RMs) infected with a transmitted/founder (T/F) simian-human immunodeficiency virus (SHIV.C.CH505). The plasma HIV envelope-specific IgG antibody kinetics were similar in SHIV-infected infant and adult RMs, with no significant differences in the magnitude or breadth of these responses. Interestingly, autologous tier 2 virus neutralization responses also developed with similar frequency and kinetics in infant and adult RMs, despite infants exhibiting significantly higher Tfh and germinal center B cell frequencies compared to adults. Our results indicate that the humoral immune response to SHIV infection develops with similar kinetics among infant and adult RMs, suggesting that the early life immune system is equipped to respond to HIV-1 and promote the production of neutralizing HIV antibodies. ImportanceThere is a lack of understanding on how the maturation of the infant immune system influences immunity to HIV infection, or how these responses differ from those of adults. Improving our knowledge of infant HIV immunity will help guide antiviral intervention strategies that take advantage of the unique infant immune environment to successfully elicit protective immune responses. We utilized a rhesus macaque model of SHIV infection as a tool to distinguish the differences in HIV humoral immunity in infants versus adults. Here, we demonstrate that the kinetics and quality of the infant humoral immune response to HIV are highly comparable to that of adults during the early phase of infection, despite distinct differences in their Tfh responses, indicating that slightly different mechanisms may drive infant and adult humoral immunity.

immunology↗

bioRxiv2019

Trajectory of brain maturation in adolescent individuals at familial risk of mood disorder

BackgroundAccelerated biological ageing has been proposed as a mechanism underlying mood disorder, but has been predominantly studied cross-sectionally in adult populations. It remains unclear whether differential ageing/maturation trajectories emerge earlier in life, in particular during the neurodevelopmental period of adolescence, and whether they are associated with onset of mood disorder and/or presence of familial risk. MethodsParticipants were young individuals (16-25 years) from the prospective longitudinal Scottish Bipolar Family Study (SBFS) with and without family history of mood disorder. All were well at time of recruitment. Implementing a structural MRI-based brain age prediction model, individual maturational trajectories were captured by the difference between predicted brain age and chronological age (brain-PAD) at baseline and two-year follow-up. Based on clinical assessment at follow-up, individuals were categorised into three groups: (i) controls who remained well (C-well, n=94), (ii) high familial risk who remained well (HR-well, n=73) and (iii) high familial risk who developed a mood disorder (HR-MD, n=38). ResultsResults showed no differences in brain-PAD between groups at baseline or follow-up. However, we found negative trajectories of brain-PAD for HR-MD versus C-well ({beta}= -0.68 years, p<.001) and versus HR-well ({beta}= -0.38 years, p=.01), and for HR-well versus C-well ({beta}= -0.30 years, p=.03). ConclusionsThese findings suggest that within young individuals, onset of mood disorder and familial risk may be associated with a deceleration in brain maturation trajectory. However, without significantly differential status of brain maturation at follow-up, extended longitudinal research will need to show whether this marks the emergence of maturational lag.

neuroscience↗

bioRxiv2019

Evolution in small steps - A nearly-universal rule of negative selection on codons

The widely accepted view that evolution proceeds in small steps is based on two premises: i) negative selection acts strongly against large differences (Kimura 1983); and ii) positive selection favors small-step changes (Fisher 1930). The two premises are not biologically connected and should be evaluated separately. We now extend the approach of Tang et al. (2004) to codon evolution for the entire genome. Codon substitution rate is a function of the physico-chemical distance between amino acids (AAs), equated with the step size of evolution. This step size depends on a large number of physico-chemical properties as 46 of the 48 properties examined affect the rate. Between 9 pairs of closely-related species of plants, invertebrates and vertebrates, the evolutionary rate is indeed strongly and negatively correlated with the AA distance ({Delta}U, scaled to [0, 1]). While the analyses corroborate the published results that relied on partial genomes, there is an important difference: {Delta}U is strongly correlated with the evolutionary rate (R2 > 0.8) only when the genes are under predominant negative selection. Nevertheless, since most genes in most taxa are strongly constrained by negative selection, {Delta}U would appear to be a nearly-universal measure of codon evolution. In conclusion, the driving force of the small-step evolution at the codon level is negative selection. The unanswered question of whether positive selection may, or may not, follow the small-step rule will be addressed in a companion study (Chen, et al. 2019).

evolutionary biology↗

bioRxiv2019

Professional Swimmers and Normal Populations have Different Patterns of Epidermal Green Autofluorescence

Our recent studies have suggested that green autofluorescence of the fingernails and certain regions of skin may be novel biomarkers for disease diagnosis and evaluation of the injury state of cardiovascular system. Our study has also suggested that oxidative stress may produce the increased epidermal green AF by altering keratin 1. Since athletes body may have increased oxidative stress and inflammation, we proposed our hypothesis that athletes may have increased green AF in their fingernails and certain regions of their skin. In current study we tested this hypothesis by determining the green AF of professional swimmers. We found that compared with age-matched controls, both the green AF intensity and AF asymmetry in both right and left antebrachium and Ventriantebrachium of the professional swimmers is significantly higher. In left Dorsal Centremetacarpus, the green AF intensity of the professional swimmers is significantly higher than that of the age-matched controls. In contrast, the green AF intensity or AF asymmetry of the professional swimmers is not significantly different from that of the age-matched controls in Centremetacarpus, Ventroforefinger, Dorsal Index Finger and Index Fingernails. Collectively, our study has provided first evidence suggesting that athletes have increased green AF intensity and asymmetry in certain regions of their skin. Based on this finding, we may evaluate non-invasively the levels of oxidative damage and inflammation in athletes body.

biophysics↗

bioRxiv2019

Associations between vascular risk factors and brain MRI indices in UK Biobank

AimsSeveral factors are known to increase risk for cerebrovascular disease and dementia, but there is limited evidence on associations between multiple vascular risk factors (VRFs) and detailed aspects of brain macro- and microstructure in large community-dwelling populations across middle- and older age.\n\nMethods and ResultsAssociations between VRFs (smoking, hypertension, pulse pressure, diabetes, hypercholersterolaemia, BMI, and waist-hip ratio) and both global and regional brain structural and diffusion MRI markers were examined in UK Biobank (N = 9722, age range 44-77 years). A larger number of VRFs was associated with greater brain atrophy, lower grey matter volume, and poorer white matter health. Effect sizes were small (brain structural R2 [≤] 1.8%). Higher aggregate vascular risk was related to multiple regional MRI hallmarks associated with dementia risk: lower frontal and temporal cortical volumes, lower subcortical volumes, higher white matter hyperintensity volumes, and poorer white matter microstructure in association and thalamic pathways. Smoking pack years, hypertension and diabetes showed the most consistent associations across all brain measures. Hypercholesterolaemia was not uniquely associated with any MRI marker.\n\nConclusionHigher levels of VRFs were associated with poorer brain health across grey and white matter macro- and microstructure. Effects are mainly additive, converging upon frontal and temporal cortex, subcortical structures, and specific classes of white matter fibres. Though effect sizes were small, these results emphasise the vulnerability of brain health to vascular factors even in relatively healthy middle and older age, and the potential to partly ameliorate cognitive decline by addressing these malleable risk factors.

neuroscience↗

bioRxiv2018

The long noncoding RNA Hand2as orchestrates heart development through regulation of precise expression of HAND2

Rigorous exploration and dissection of potential actions and effects of long noncoding RNA (lncRNA) in animals remain challenging. Here using multiple knockout mouse models and single-cell RNA sequencing, we demonstrate that the divergent lncRNA Hand2as has a key, complex modulatory effect on the expression of its neighboring gene HAND2 and subsequently on heart development and function, largely independent of Hand2as transcription and transcripts. Full-length deletion of Hand2as in mouse causes moderate yet prevalent upregulation of HAND2 in hundreds of cardiac cells, resulting in profound biological consequences, including dysregulated cardiac gene programs, congenital heart defects and perinatal lethality. We propose a cis-functional role for the Hand2as locus in dampening HAND2 expression to restrain cardiomyocyte proliferation, thereby orchestrating a balanced development of cardiac cell lineages. This study highlights the need for complementary genetic and single-cell approaches to delineate the function and primary molecular effects of an lncRNA in animals.\n\nImpact statementThe long noncoding RNA Hand2as critically controls the precise expression of its neighboring gene HAND2, thereby balancing cardiac lineages and expression programs that are essential for heart development and function.

developmental biology↗

bioRxiv2018

The landscapes of DNA methylation associated with the transcriptomic network in laying hens and broilers get insight to embryonic muscle development in chicken

As DNA methylation is one of the key epigenetic mechanisms involved in embryonic development, elucidating its relationship with non-coding RNA and genes is essential for understanding early development. In this study, we performed single-base-resolution bisulfite sequencing together with RNA-seq to explore the genetic basis of embryonic muscle development in chicken. Comparison of methylome profiles between broilers and laying hens revealed that lower methylation in broilers might contribute to muscle development. Differential methylated region (DMR) analysis between two chicken lines showed that the majority of DMRs were hypo-DMRs for broilers. Differential methylated genes were significantly enriched in muscle development-related terms at E13 and E19. Furthermore, by constructing the network of the lncRNAs, we identified a lncRNA, which we named MYH1-AS, that potentially regulated muscle development. These findings reveal an integrative landscape of late period of embryonic myogenesis in chicken and give rise to a comprehensive understanding of epigenetic and transcriptional regulation, in skeletal muscle development. Our study provides a reliable data resource for further muscle studies.

bioinformatics↗

bioRxiv2018

Simultaneous mesoscopic and two-photon imaging of neuronal activity in cortical circuits

Spontaneous and sensory-evoked activity propagates across spatial scales in the mammalian cortex but technical challenges have generally precluded establishing conceptual links between the function of local circuits of neurons and brain-wide network dynamics. To solve this problem, we developed a method for simultaneous cellular-resolution two-photon calcium imaging of a local microcircuit and mesoscopic widefield calcium imaging of the entire cortical mantle in awake, behaving mice. Our method employs an orthogonal axis design whereby the mesoscopic objective is oriented downward directly above the brain and the two-photon objective is oriented horizontally, with imaging performed through a glass right angle microprism implanted in the skull. In support of this method, we introduce a suite of analysis tools for relating the activity of individual cells to distal cortical areas, as well as a viral method for robust and widespread gene delivery in the juvenile mouse brain. We use these methods to characterize the diversity of associations of individual, genetically-defined neurons with cortex-wide network motifs.

neuroscience↗

bioRxiv2018

Spanning spatiotemporal scales with simultaneous mesoscopic Ca2+ imaging and functional MRI

Neuroscience encompasses the investigation of brain function across multiple spatiotemporal scales. Yet, most research is confined to Ca2+ one spatiotemporal milieu limiting the integration of knowledge across scales. Here we describe an imaging and analytic approach that spans spatiotemporal scales by combining simultaneous wide field mesoscopic 1-photon Ca2+ imaging and functional magnetic resonance imaging (fMRI) at 11.7T. Given the confined space within the magnet, that metal is prohibited, and the unique/conflicting needs of each methodology, these techniques have never before been combined. In addition to describing the new hardware and software, we present evoked and spontaneous activity measurements made in lightly anesthetized animals. We have three findings: (1) for both evoked and spontaneous activity the magnitude of the Ca2+ and fMRI signals show correspondence, (2) connectivity matrices derived from Ca2+ and fMRI measurements are stable throughout an imaging session, and (3) there is correspondence between Ca2+ and fMRI spontaneous activity patterns.

neuroscience↗

bioRxiv2018

The LIM-Only Protein FHL2 is Involved in Autophagy to Regulate the Development of Skeletal Muscle

Four and a half LIM domain protein 2 (FHL2) is a LIM domain protein expressed in muscle tissue whose deletion is causative of myopathies. Although FHL2 has a confirmed important role in muscle development, its autophagy-related function in muscle differentiation has not been fully determined. To explore the role of FHL2 in autophagy-related muscle regulation, FHL2-silenced and -overexpressing C2C12 mouse cells were examined. Immunofluorescence and co-immunoprecipitation assay findings showed that FHL2 silencing reduced LC3- protein expression and the amount of LC3 that co-immunoprecipitated with FHL2, indicating that FHL2 interacts with LC3- in the formation of autophagosomes. Moreover, the expression of muscle development marker genes such as MyoD1 and MyoG was lower in FHL2-silenced C2C12 cells but not in FHL2-overexpressing C2C12 cells. Electron microscopy analysis revealed large empty autophagosomes in FHL2-silenced myoblasts, while flow cytometry suggested that FHL2 silencing made cells more vulnerable to staurosporine-induced cell death. In conclusion, we propose that FHL2 interacts with LC3- in autophagosome formation to regulate the development of muscle cells.

molecular biology↗

bioRxiv2018

The effect of heavy metal contamination on human and animal health in the vicinity of a zinc smelter

A diagnosis of heavy metal poisoning in sheep living on pasture in the vicinity of a zinc smelter was made based on laboratory tests and clinical signs in livestock in the Wumeng mountain area of China. Heavy metal contamination has generated serious harm to the health of local farmers after passing through the food chain. The levels of copper, zinc, cadmium, and lead in irrigation water, soil, forages, and animal tissues were measured in samples taken from within the vicinity of a zinc smelter and control samples. Heavy metal concentrations in foods (corn, rice, and wheat) and human tissues (blood and hair) from local farmers living in affected areas and controls were also determined. Hematological values were determined in human and animal samples. The copper, zinc, cadmium, and lead concentrations in irrigation water, soils, and forages were markedly higher than the levels in healthy pastures. Cadmium and lead concentrations were 177.82 and 16.61 times greater in forages than controls, respectively, and 68.71 and 15.66 times greater in soils than controls, respectively. Heavy metal concentrations in food (corn, rice, and wheat) in affected areas were markedly higher than in the control samples. Cadmium and lead concentrations in the tissues of affected sheep were markedly higher than in control animals (P< 0.01). Cadmium and lead concentrations in blood and hair samples from affected farmers were markedly higher than the control samples (P < 0.01). The occurrence of anemia in affected persons and animals followed a hypochromic and microcytic pattern. The intake of cadmium and lead was estimated according to herbage ingestion rates. It was found that the levels of cadmium and lead accumulated in sheep through the ingestion of vegetation growing in the sites closest to the zinc smelter were approximately 3.36 mg Cd/kg body wt./day and 38.47 mg Pb/kg body wt./day. This surpassed the fatal dosages for sheep of 1.13 mg Cd/kg body wt/day and 4.42 mg Pb/kg body wt./day. Serum total antioxidant capacity in affected humans and animals was significantly lower than in the controls (P < 0.01). The serum protein parameters in affected humans and animals were significantly reduced (P < 0.01). It was therefore concluded that heavy metal contamination has caused serious harm to sheep in this area. The heavy metal concentrations in food and grain also pose a significant risk to human health in the Chinese Wumeng mountain area.

ecology↗

bioRxiv2018

Genome-wide meta-analysis of depression in 807,553 individuals identifies 102 independent variants with replication in a further 1,507,153 individuals

Major depression is a debilitating psychiatric illness that is typically associated with low mood, anhedonia and a range of comorbidities. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximise sample size, we meta-analysed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 gene-sets associated with depression, including both genes and gene-pathways associated with synaptic structure and neurotransmission. Further evidence of the importance of prefrontal brain regions in depression was provided by an enrichment analysis. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant following multiple testing correction. Based on the putative genes associated with depression this work also highlights several potential drug repositioning opportunities. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding aetiology and developing new treatment approaches.

genetics↗

bioRxiv2018

There is no single functional atlas even for a single individual: Parcellation of the human brain is state dependent

The goal of human brain mapping has long been to delineate the functional subunits in the brain and elucidate the functional role of each of these brain regions. Recent work has focused on whole-brain parcellation of functional Magnetic Resonance Imaging (fMRI) data to identify these subunits and create a functional atlas. Functional connectivity approaches to understand the brain at the network level, require such an atlas to assess connections between nodes and extract network properties. While no single functional atlas has emerged as the dominant atlas to date, there remains an underlying assumption that such an atlas exists. Using fMRI data from a highly sampled subject as well as two independent replication data sets, we demonstrate that functional atlases reconfigure substantially and in a meaningful manner, according to brain state.

neuroscience↗

bioRxiv2018

The Evolutionary Landscape of Pan-Cancer Drives Clinical Aggression

Although cancer mechanisms differ from occurrence and development, some of them have similar oncogenesis, which leads to similar clinical phenotypes. Most existing genotyping studies look at \"omics\" data, but intentionally or unintentionally avoided that cancer is a time-dependent evolutionary process, biologically represented by the time evolution of tumor clones. We used the Bayesian mutation landscape approach to reconstruct the evolutionary process of cancer by acquiring somatic mutation data consisting of 21 cancer types. Four representative evolution patterns of pan-cancer have been discovered: trees, chaos, biconvex, and Cambrian, and a strong correlation between these four evolutionary patterns and clinical aggressivity. We further explained the characteristics of the corresponding biological systems in the evolution of pan cancer by analyzing the function of differentially expressed protein-protein interaction networks. Our results explained the difference in clinical aggressivity between cancer evolution patterns from the evolution of tumor clones and exposed the functional mechanism behind.

cancer biology↗

bioRxiv2018

Genomic underpinnings of lifespan allow prediction and reveal basis in modern risks

We use a multi-stage genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near CDKN2B-AS1, ATXN2/BRAP, FURIN/FES, ZW10, PSORS1C3, and 13q21.31, and identify and replicate novel findings near GADD45G, KCNK3, LDLR, POM121C, ZC3HC1, and ABO. We also validate previous findings near 5q33.3/EBF1 and FOXO3, whilst finding contradictory evidence at other loci. Gene set and tissue-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer -but not other cancers-explain the most variance, possibly reflecting modern susceptibilities, whilst cancer may act through many rare variants, or the environment. Resultant polygenic scores predict a mean lifespan difference of around five years of life across the deciles.

genomics↗

bioRxiv2018

U1 snRNP regulates chromatin retention of noncoding RNAs

Thousands of noncoding transcripts exist in mammalian genomes, and they preferentially localize to chromatin. Here, to identify cis-regulatory elements that control RNA-chromatin association, we developed a high-throughput method named RNA element for subcellular localization by sequencing (REL-seq). Coupling REL-seq with random mutagenesis (mutREL-seq), we discovered a key 7-nt U1 recognition motif in chromatin-enriched RNA elements. Reporter assays indicated a direct role for U1 snRNP recognition in regulating RNA-chromatin localization. Globally, U1 motifs and U1 binding are strongly enriched in long noncoding RNA (lncRNA) transcripts. Inhibition of U1 snRNA, and of U2 to a lesser degree, led to global reduction in chromatin association of hundreds of lncRNAs. For promoter- and enhancer-associated noncoding RNAs, U1 binds to their genomic neighborhoods, and their chromatin association depends on both U1 and U2 snRNAs. These findings reveal that U1 snRNP, perhaps together with the splicing machinery, acts widely to promote the chromatin association of noncoding transcripts.

molecular biology↗

bioRxiv2018

Metabolic Reaction Network-based Recursive Metabolite Identification for Untargeted Metabolomics

Metabolite identification is a long-standing challenge in untargeted metabolomics and a major hurdle for functional metabolomics studies. Here, we developed a metabolic reaction network-based recursive algorithm and webserver called MetDNA for the large-scale and unambiguous identification of metabolites (available at http://metdna.zhulab.cn). We showcased the versatility of our workflow using different instrument platforms, data acquisition methods, and biological sample types and demonstrated that over 2,000 metabolites could be identified from one experiment.

bioinformatics↗

bioRxiv2018

Destabilization of Ran C-terminus promotes GTP loading and occurs in multiple Ran cancer mutations

Ran (Ras-related nuclear protein) plays several important roles in nucleo-cytoplasmic transport, mitotic spindle formation, nuclear envelope/nuclear pore complex assembly, and other diverse functions in the cytoplasm, as well as in cellular transformation when activated. Unlike other Ras superfamily proteins, Ran contains an auto-inhibitory C-terminal tail, which packs against its G domain and bias Ran towards binding GDP over GTP. The biological importance of this C-terminal tail is not well understood. By disrupting the interaction between the C-terminus and the G domain, we were able to generate Ran mutants that are innately active and potently bind to RanBP1 (Ran Binding Protein 1), nuclear export factor CRM1 and nuclear import factor KPNB1. In contrast to previously reported activated Ran mutants, the C-terminus destabilized mutants are hydrolysis competent in cells, support nuclear transport, and do not form nuclear rim staining. Crystal structures show that one of these C-terminal mutations slightly changes its mode of binding to RanBP1. Finally, a high percentage of Ran C-terminus mutations from cancer patients were found to be destabilizing and hyperactivating, suggesting that Ran C-destabilization might be an unprecedented cellular transformation mechanism in affected cancers. This study also highlights a new drug design strategy towards treating patients with hyperactivated Ras proteins including K-Ras.

biochemistry↗