Biology subjects

Zhao, M.

Publications and source records attributed to Zhao, M..

12 recordsLinked to original sources

bioRxiv2026

Neural signatures of spontaneous transitions between internal and external thought

The human mind constantly shifts between internal representations and the external environment, yet the neural mechanisms underlying such spontaneous transitions remain underexplored. Here, we analyzed a think-aloud functional magnetic resonance imaging dataset, in which participants continuously verbalized their thoughts, to identify neural activity predicting transitions between internally and externally oriented thought. Internal-to-external transitions were preceded by increased activation in the salience/ventral attention network, with the strongest effect observed in the right temporoparietal junction. The spatial pattern of this pre-transition activation was positively associated with acetylcholine receptor density, suggesting a role for cholinergic signaling in cognitive reorientation. Pre-transition activation was itself preceded by a large-scale brain state proposed to serve as a flexible hub between functionally specialized states, indicating that spontaneous transitions are more likely when the brain occupies this intermediate configuration. Together, these findings suggest that multilevel neural mechanisms support flexible reorientation along the internal-external dimension of spontaneous cognition.

neuroscience↗

bioRxiv2018

Cell-type-specific methylome-wide association studies implicate neurodegenerative processes and neuroimmune communication in major depressive disorder

We studied the methylome in three collections of human postmortem brain (N=206) and blood samples (N=1,132) of subjects with major depressive disorder (MDD) and controls. Using an epigenomic deconvolution approach we performed cell-type-specific methylome-wide association studies (MWAS) within sub-populations of neurons/glia and granulocytes/T-cells/B-cells/monocytes for bulk brain and blood data, respectively. Multiple MWAS findings in neurons/glia replicated across brain collections (ORs=509-538, P-values<1x10-5) and were reproducible in an array-based MWAS of sorted neurons/glia from a fourth brain collection (N=58). Pathway analyses implicated p75NTR/VEGF signaling, neurodegeneration, and blood-brain barrier perturbation. Cell-type-specific analysis in blood identified associations in CD14+ monocytes -- a cell type strongly linked to neuroimmune processes and stress. Top results in neurons/glia/bulk and monocytes were enriched for genes supported by GWAS for MDD (ORs=2.02-2.87, P-values=0.003 to <1x10-5), neurodegeneration and other psychiatric disorders. In summary, we identified novel MDD-methylation associations by using epigenomic deconvolution that provided important mechanistic insights for the disease.

genomics↗

bioRxiv2018

Infection-generated electric field in gut epithelium drives bidirectional migration of macrophages

Many bacterial pathogens hijack macrophages to egress from the port of entry to the lymphatic/blood-stream, causing dissemination of life-threatening infections. However, the underlying mechanisms are not well understood. Here, we report that Salmonella infection generates directional electric fields (EF) in the follicle-associated epithelium of mouse cecum. In vitro application of an EF, mimicking the infection-generated electric field (IGEF), induces directional migration of primary mouse macrophages to the anode, which is reversed to the cathode upon Salmonella infection. This infection-dependent directional switch is independent of the Salmonella pathogenicity island 1 (SPI-1) type III secretion system. The switch is accompanied by a reduction of sialic acids on glycosylated surface components during phagocytosis of bacteria, which is absent in macrophages challenged by microspheres. Moreover, enzymatic cleavage of terminally exposed sialic acids reduces macrophage surface negativity and severely impairs directional migration of macrophages in response to EF. Based on these findings, we propose that macrophages are attracted to the site of infection by a combination of chemotaxis and galvanotaxis; after phagocytosis of bacteria, surface electrical properties of the macrophage change, and galvanotaxis directs the cells away from the site of infection.\n\nAbbreviationsCFU, colony-forming unit; Con A, Concanavalin A; EF, electric field; FAE, follicle-associated epithelium; GNL, Galanthus Nivalis lectin; IGEF, infection-generated electric field; Ji, electric current density; MAL-2, Maackia Amurensis lectin II; MLN, mesenteric lymph node; MOI, multiplicity of infection; nMFI, normalized mean fluorescence intensity; RCA-1, Ricinus Communis Agglutinin I; SNA, Sambucus Nigra lectin; S. Typhimurium, Salmonella enterica serotype Typhimurium; SPI-1, Salmonella pathogenicity island 1; PDMS, polydimethylsiloxane; TEP, trans-epithelial potential difference; TLR, Toll-like receptors; WGEF, wound-generated electric field

cell biology↗

bioRxiv2018

Quantitative Real-Time Imaging of Glutathione with Sub-Cellular Resolution

Quantitative imaging of glutathione with high spatial and temporal resolution is essential for studying the roles of glutathione in redox biology. We developed a fluorescent glutathione probe--HaloRT--that targets organelles of interest through expressing organelle-specific HaloTag proteins. Using HaloRT, we quantitatively measure the glutathione concentrations in the nucleus and the cytosol and find no appreciable concentration gradient between these two organelles, challenging the view of nuclear compartmentalization of glutathione.

cell biology↗

bioRxiv2018

Integrated RNA-seq and sRNA-seq revealed differences in transcriptome between susceptible and resistant tomato responding to Fusarium oxysporum

Tomato wilt disease caused by Fusarium oxysporum f. sp. lycopersici (FOL) is a worldwide destructive disease of tomato. As exploring gene expression and function approaches constitute an initial point for investigating pathogen-host interaction, we performed RNA-seq and sRNA-seq analysis to unravel regulated genes and miRNAs in tomato infected by FOL. Differentially expressed (DE) protein coding gene and miRNA gene profiles upon inoculation with FOL were presented at twenty-four hours post-inoculation including four treatments. Total of more than 182.6 million and 132.2 million high quality clean reads were obtained by RNA-seq and sRNA-seq, respectively. A large overlap was found in DE mRNAs between susceptible cultivar Moneymaker and resistant cultivar Motelle. All Gene Ontology terms were mainly classified into catalytic activity, metabolic process and binding. Combining with qRT-PCR, five disease resistance genes, Solyc01g095630, Solyc03g059080, Solyc00g174340, Solyc11g071750 and Solyc05g050350, were verified to involved in the disease resistance in the resistant cultivar Motelle treated with FOL. Northern blot analysis further confirmed the results from sRNA-Seq and demonstrated that several miRNAs including Sly-miR477-5p, sly-miR167a, novel_mir_675, novel_mir_504 and novel_mir_762 conferred FOL infection. Our data resulted that pathogen resistant genes/miRNAs may play a critical role with the benefit of a coordinated machinery in prompting the response in prompting FOL response in tomato, which offered us with a future direction and surely help in generating models of mediated resistance responses with assessment of genomic gene expression patterns.

molecular biology↗

bioRxiv2018

Whole-exome sequencing identified rare variants associated with body length and girth in cattle

Body measurements can be used in determining body size to monitor the cattle growth and examine the response to selection. Despite efforts putting into the identification of common genetic variants, the mechanism understanding of the rare variation in complex traits about body size and growth remains limited. Here, we firstly performed GWAS study for body measurement traits in Simmental cattle, however there were no SNPs exceeding significant level associated with body measurements. To further investigate the mechanism of growth traits in beef cattle, we conducted whole exome analysis of 20 cattle with phenotypic differences on body girth and length, representing the first systematic exploration of rare variants on body measurements in cattle. By carrying out a three-phase process of the variant calling and filtering, a sum of 1158, 1151, 1267, and 1303 rare variants were identified in four phenotypic groups of two growth traits, higher/ lower body girth (BG_H and BG_L) and higher/lower body length (BL_H and BL_L) respectively. The subsequent functional enrichment analysis revealed that these rare variants distributed in 886 genes associated with collagen formation and organelle organization, indicating the importance of collagen formation and organelle organization for body size growth in cattle. The integrative network construction distinguished 62 and 66 genes with different co-expression patterns associated with higher and lower phenotypic groups of body measurements respectively, and the two sub-networks were distinct. Gene ontology and pathway annotation further showed that all shared genes in phenotypic differences participate in many biological processes related to the growth and development of the organism. Together, these findings provide a deep insight into rare genetic variants of growth traits in cattle and this will have a promising application in animal breeding.

genetics↗

bioRxiv2017

Advances in computer-assisted syndrome recognition and differentiation in a set of metabolic disorders

Significant improvements in automated image analysis have been achieved over the recent years and tools are now increasingly being used in computer-assisted syndromology. However, the recognizability of the facial gestalt might depend on the syndrome and may also be confounded by severity of phenotype, size of available training sets, ethnicity, age, and sex. Therefore, benchmarking and comparing the performance of deep-learned classification processes is inherently difficult.\n\nFor a systematic analysis of these influencing factors we chose the lysosomal storage diseases Mucolipidosis as well as Mucopolysaccharidosis type I and II, that are known for their wide and overlapping phenotypic spectra. For a dysmorphic comparison we used Smith-Lemli-Opitz syndrome as a metabolic disease and Nicolaides-Baraitser syndrome as another disorder that is also characterized by coarse facies. A classifier that was trained on these five cohorts, comprising 288 patients in total, achieved a mean accuracy of 62%.\n\nThe performance of automated image analysis is not only significantly higher than randomly expected but also better than in previous approaches. In part this might be explained by our large training sets. We therefore set up a simulation pipeline that is suited to analyze the effect of different potential confounders, such as cohort size, age, sex, or ethnic background on the recognizability of phenotypes. We found that the true positive rate increases for all analyzed disorders for growing cohorts (n=[10...40]) while ethnicity and sex have no significant influence.\n\nThe dynamics of the accuracies strongly suggest that the maximum recognizability is a phenotype-specific value, that hasnt been reached yet for any of the studied disorders. This should also be a motivation to further intensify data sharing efforts, as computer-assisted syndrome classification can still be improved by enlarging the available training sets.\n\nAvailability: software for classification: https://app.face2gene.com/research,

genetics↗

bioRxiv2017

Characterization of Glycosylphosphatidylinositol Biosynthesis Defects by Clinical Features, Flow Cytometry, and Automated Image Analysis

BackgroundGlycosylphosphatidylinositol Biosynthesis Defects (GPIBDs) cause a group of phenotypically overlapping recessive syndromes with intellectual disability, for which pathogenic mutations have been described in 16 genes of the corresponding molecular pathway. An elevated serum activity of alkaline phosphatase (AP), a GPI-linked enzyme, has been used to assign GPIBDs to the phenotypic series of Hyperphosphatasia with Mental Retardation Syndrome (HPMRS) and to distinguish them from another subset of GPIBDs, termed Multiple Congenital Anomalies Hypotonia Seizures syndrome (MCAHS). However, the increasing number of individuals with a GPIBD shows that hyperphosphatasia is a variable feature that is not ideal for a clinical classification.\n\nMethodsWe studied the discriminatory power of multiple GPI-linked substrates that were assessed by flow cytometry in blood cells and fibroblasts of 39 and 14 individuals with a GPIBD, respectively. On the phenotypic level, we evaluated the frequency of occurrence of clinical symptoms and analyzed the performance of computer-assisted image analysis of the facial gestalt in 91 individuals.\n\nResultsWe found that certain malformations such as Morbus Hirschsprung and Diaphragmatic defects are more likely to be associated with particular gene defects (PIGV, PGAP3, PIGN). However, especially at the severe end of the clinical spectrum of HPMRS, there is a high phenotypic overlap with MCAHS. Elevation of AP has also been documented in some of the individuals with MCAHS, namely those with PIGA mutations. Although the impairment of GPI-linked substrates is supposed to play the key role in the pathophysiology of GPIBDs, we could not observe gene-specific profiles for flow cytometric markers or a correlation between their cell surface levels and the severity of the phenotype. In contrast, it was facial recognition software that achieved the highest accuracy in predicting the disease-causing gene in a GPIBD.\n\nConclusionsDue to the overlapping clinical spectrum of both, HPMRS and MCAHS, in the majority of affected individuals, the elevation of AP and the reduced surface levels of GPI-linked markers in both groups, a common classification as GPIBDs is recommended. The effectiveness of computer-assisted gestalt analysis for the correct gene inference in a GPIBD and probably beyond is remarkable and illustrates how the information contained in human faces is pivotal in the delineation of genetic entities.

genetics↗

bioRxiv2017

Early urinary candidate biomarkers in a rat model of experimental autoimmune encephalomyelitis

Multiple sclerosis is a chronic autoimmune demyelinating disease of the central nervous system and is difficult to diagnose in early stages. Without homeostatic control, urine was reported to have the ability to accumulate early changes in the body. We expect that urinary proteome can reflect early changes in the nervous system. In this study, the early urinary proteome changes in a most employed multiple sclerosis rat model (experimental autoimmune encephalomyelitis (EAE)) were analyzed to explore early urinary candidate biomarkers, and early treatment of methylprednisolone were used to evaluate the therapeutic effect. Compare with controls, twenty-five urinary proteins were altered at day 7 when there were no clinical symptoms and no obvious histological changes. Among them, twenty-three have human homologs and fourteen were reported to be differently expressed in the serum/cerebrospinal fluid/brain tissues of multiple sclerosis patients or animal models. Functional analysis showed that the dysregulated proteins were associated with asparagine degradation, neuroinflammation and lipid metabolism. After the early treatment of methylprednisolone, the incidence of encephalomyelitis in the intervention group was only 1/13. This study demonstrates that urine may be a good source of biomarkers for the early detection of multiple sclerosis and early treatment can significantly delay disease progression. These findings may provide important information for early diagnosis and intervention of multiple sclerosis in the future.

biochemistry↗

bioRxiv2017

Urinary candidate biomarkers in an experimental autoimmune myocarditis rat model

Urine is a better source than plasma for biomarker studies, as it can accumulate all changes in the body. Various candidate urinary biomarkers of physiological conditions, kidney disease and even brain dysfunction, have been detected in urine; however, urine has rarely been used to reflect cardiac diseases. As the clinical presentations of myocarditis are heterogeneous, reliable and sensitive diagnostic biomarkers of myocarditis are very important. In this study, candidate urinary biomarkers in the myosin-induced autoimmune myocarditis rat models were characterized using the isobaric tandem mass tag labeling approach coupled with high-resolution mass spectrometry. Compared with controls, forty-six urinary proteins were significantly changed in the myocarditis rats; among them, ten had previously been associated with myocarditis, twelve corresponding gene products have been annotated as mainly cardiovascular network genes by the Ingenuity Pathway Analysis, and four urinary proteins were validated by western blot.

molecular biology↗

bioRxiv2017

Role of inhibitory control in modulating spread of focal ictal activity

Focal seizure propagation is classically thought to be spatially contiguous. However, distribution of seizures through a large-scale epileptic network has been theorized. Here, we used a multielectrode array, wide field calcium imaging, and two-photon calcium imaging to study focal seizure propagation pathways in an acute rodent neocortical 4-aminopyridine model. Although ictal neuronal bursts did not propagate beyond a 2-3 mm region, they were associated with hemisphere-wide field potential fluctuations and parvalbumin-positive interneuron activity outside the seizure focus. While bicuculline surface application enhanced contiguous seizure propagation, focal bicuculline microinjection at sites distant to the 4-aminopyridine focus resulted in epileptic network formation with maximal activity at the two foci. Our study suggests that both classical and epileptic network propagation can arise from localized inhibition defects, and that the network appearance can arise in the context of normal brain structure without requirement for pathological connectivity changes between sites.

neuroscience↗

bioRxiv2017

Comparative Transcriptome Profiling Conferring Of Resistance To Fusarium Oxysporum Infection Between Resistant And Susceptible Tomato

ABASTRCATTomato Fusarium wilt caused by Fusarium oxysporum f. sp. lycopersici (FOL) is a destructive disease of tomato worldwide which causes severe yield loss of the crops. As exploring gene expression and function approaches constitute an initial point for investigating pathogen-host interaction, we performed a transcriptional analysis to unravel regulated genes in tomato infected by FOL. Differentially expressed genes (DEG) upon inoculation with FOL were presented at twenty-four hours post-inoculation including four treatments: Moneymaker_H2O, Moneymaker_FOL, Motelle_H2O and Motelle_FOL. A total of more than 182.6 million high quality clean reads from the four libraries were obtained. A large overlap was found in DEGs between susceptible tomato cultivar Moneymaker and resistant tomato cultivar Motelle. All Gene Ontology terms were mainly classified into catalytic activity, metabolic process and binding. However, Gene Ontology enrichment analysis evidenced specific categories in infected Motelle. Statistics of pathway enrichment of DEGs resulted that the taurine and hypotaurine metabolism, the stibenoid, diarylheptanoid and gingerol biosynthesis, the starch and sucrose metabolism were the top three pathway affected in both groups. Interestingly, plant-pathogen pathway was greatly regulated in Motelle treated with FOL. Combining with qRT-PCR facilitated the identification of regulated pathogenicity associated genes upon infected resistant or susceptible tomato. Our data showed that a coordinated machinery played a critical role in prompting the response, which could help in generating models of mediated resistance responses with assessment of genomic gene expression patterns.

pathology↗