Biology subjects

Ye, Z.

Publications and source records attributed to Ye, Z..

At least 145 records · Page 8Linked to original sources

bioRxiv2020

A targetable epigenetic vulnerability in PI3K/AKT inhibitor resistant cancers

Acquisition of resistance to PI3K/AKT-targeted monotherapy implies the existence of common resistance mechanisms independent of cancer type. Here we demonstrate that PI3K/AKT inhibitors cause glycolytic crisis, acetyl-CoA shortage and a global decrease in histone acetylation. Also, PI3K/AKT inhibitors induce drug resistance by selectively augmenting H3K27 acetylation and binding of CBP/p300 and BRD4 proteins at a subset of growth factor and receptor (GF/R) gene loci. BRD4 occupation at these loci and drug resistant cell growth are vulnerable to both bromodomain and HDAC inhibitors. Little or none occupation of HDAC proteins at the GF/R gene loci underscores the paradox that cells respond equivalently to the two classes of inhibitors with opposite modes of action. Targeting this unique epigenetic vulnerability offers two viable strategies to overcome PI3K/AKT inhibitor resistance in different cancers.

cancer biology↗

bioRxiv2020

Dynamic control over feedback regulatory mechanisms improves NADPH fluxes and xylitol biosynthesis in engineered E. coli

We report improved NADPH flux and xylitol biosynthesis in engineered E. coli. Xylitol is produced from xylose via an NADPH dependent reductase. We utilize two-stage dynamic metabolic control to compare two approaches to optimize xylitol biosynthesis, a stoichiometric approach, wherein competitive fluxes are decreased, and a regulatory approach wherein the levels of key regulatory metabolites are reduced. The stoichiometric and regulatory approaches lead to a 16 fold and 100 fold improvement in xylitol production, respectively. Strains with reduced levels of enoyl-ACP reductase and glucose-6-phosphate dehydrogenase, led to altered metabolite pools resulting in the activation of the membrane bound transhydrogenase and a new NADPH generation pathway, namely pyruvate ferredoxin oxidoreductase coupled with NADPH dependent ferredoxin reductase, leading to increased NADPH fluxes, despite a reduction in NADPH pools. These strains produced titers of 200 g/L of xylitol from xylose at 86% of theoretical yield in instrumented bioreactors. We expect dynamic control over enoyl-ACP reductase and glucose-6-phosphate dehydrogenase to broadly enable improved NADPH dependent bioconversions. HighlightsO_LIDecreases in NADPH pools lead to increased NADPH fluxes C_LIO_LIPyruvate ferredoxin oxidoreductase coupled with NADPH-ferredoxin reductase improves NADPH production in vivo. C_LIO_LIDynamic reduction in acyl-ACP/CoA pools alleviate inhibition of membrane bound transhydrogenase and improve NADPH flux C_LIO_LIXylitol titers > 200g/L in fed batch fermentations with xylose as a sole feedstock. C_LI

bioengineering↗

bioRxiv2020

The E. coli Cas1/2 endonuclease complex reduces CRISPR/Cascade guide array stability

CRISPR based interference has become common in various applications from genetic circuits to dynamic metabolic control. In E. coli the native CRISPR Cascade system can be utilized for silencing by deletion of the cas3 nuclease along with expression of guide RNA arrays, where multiple genes can be silenced from a single transcript. We notice the loss of protospacer sequences from guide arrays utilized for dynamic silencing. We report that unstable guide arrays are due to expression of the Cas1/2 endonuclease complex. A cas1 deletion improves guide array stability. We propose a model wherein basal Cas1/2 endonuclease activity results in the loss of protospacers from guide arrays. Subsequently, mutant guide arrays can be amplified through selection. Replacing a constitutive promoter driving Cascade complex expression with a tightly controlled inducible promoter improves guide array stability, while minimizing leaky gene silencing. HighlightsO_LICas1/2 endonuclease complex mediates CRISPR/Cascade protospacer loss in E. coli C_LIO_LITightly controlled Cascade operon expression increases guide array stability. C_LI

synthetic biology↗

bioRxiv2020

Dynamic control over feedback regulation improves stationary phase fluxes in engineered E. coli.

We demonstrate the use of two-stage dynamic metabolic control to manipulate feedback regulation in central metabolism and improve stationary phase biosynthesis in engineered E. coli. Specifically, we report the impact of dynamic control over two enzymes: citrate synthase, and glucose-6-phosphate dehydrogenase, on stationary phase fluxes. Firstly, reduced citrate synthase levels lead to a reduction in -ketoglutarate, which is an inhibitor of sugar transport, resulting in increased stationary phase glucose uptake and glycolytic fluxes. Reduced glucose-6-phosphate dehydrogenase activity activates the SoxRS regulon and expression of pyruvate-ferredoxin oxidoreductase, which is in turn responsible for large increases in acetyl-CoA production. The combined reduction in citrate synthase and glucose-6-phosphate dehydrogenase, leads to greatly enhanced stationary phase metabolism and the improved production of citramalic acid enabling titers of 126{+/-}7g/L. These results identify pyruvate oxidation via the pyruvate-ferredoxin oxidoreductase as a "central" metabolic pathway in stationary phase E. coli, which coupled with ferredoxin reductase comprise a pathway whose physiologic role is maintaining NADPH levels. HighlightsO_LIDynamic reduction in -keto-glutarate pools alleviate inhibition of PTS dependent transport improving stationary phase sugar uptake. C_LIO_LIDynamic reduction in glucose-6-phosphate dehydrogenase activates pyruvate flavodoxin/ferredoxin oxidoreductase and improves stationary acetyl-CoA flux. C_LIO_LIPyruvate flavodoxin/ferredoxin oxidoreductase is responsible for large stationary phase acetyl-CoA fluxes under aerobic conditions. C_LIO_LIProduction of citramalate to titers 126 {+/-} 7g/L at > 90 % of theoretical yield. C_LI

bioengineering↗

bioRxiv2020

ZNF416 is a pivotal transcriptional regulator of fibroblast mechano-activation

Matrix stiffness is a central regulator of fibroblast function. However, the transcriptional mechanisms linking matrix stiffness to changes in fibroblast phenotype are incompletely understood. Here, we evaluated the effect of matrix stiffness on genome-wide chromatin accessibility in freshly-isolated lung fibroblasts using assay for transposase-accessible chromatin followed by sequencing (ATAC-seq). We found higher matrix stiffness profoundly increased global chromatin accessibility relative to lower matrix stiffness, and these alterations were in close genomic proximity to known pro-fibrotic gene programs. Motif analysis of these regulated genomic loci identified ZNF416 as a putative mediator of fibroblast stiffness responses. Similarly, motif analysis of the promoters of differentially expressed genes observed in freshly sorted fibroblasts from an experimental bleomycin lung fibrosis model also identified ZNF416 as a putative mediator of in vivo fibroblast activation. Genome occupancy analysis using chromatin-immunoprecipitation followed by sequencing (ChIP-seq) confirmed that ZNF416 occupies a broad range of genes implicated in fibroblast activation and tissue-fibrosis, with relatively little overlap in genomic occupancy with other mechanoresponsive and pro-fibrotic transcriptional regulators. Using loss and gain of function studies we demonstrated that ZNF416 plays a critical role in fibroblast proliferation, extracellular matrix synthesis and contractile function. Together these observations identify ZNF416 as novel mechano-activated transcriptional regulator of fibroblast biology.

cell biology↗

bioRxiv2020

Gene Editing Reveals Obligate and Modulatory Components of the CO2 Receptor Complex in the Malaria Vector Mosquito, Anopheles coluzzii

The sensitivity to volatile carbon dioxide (CO2) produced by humans and other animals is a critical component in the host preference behaviors of the malaria vector mosquito Anopheles coluzzii. The molecular receptors responsible for the ability to sense CO2 are encoded by three putative gustatory receptor (Gr) genes (Gr22,23,24) which are expressed in a distinctive array of sensory neurons housed in maxillary palp capitate peg sensilla of An. coluzzii. Despite the identification of these components and subsequent studies, there is a paucity of understanding regarding the respective roles of these three GRs in the mosquitos CO2 transduction process. To address this, we have used CRISPR/Cas9-based gene editing techniques combined with in vivo electrophysiological recordings to directly examine the role of Gr22,23,24 in detecting CO2 in An. coluzzii. These studies reveal that both Gr23 and Gr24 are absolutely required to maintain in vivo CO2 sensitivity while, in contrast, Gr22 knock out mutants are still able to respond to CO2 stimuli albeit with significantly weaker sensitivity. Our data supports a model in which Gr22 plays a modulatory role to enhance the functionality of Gr23/24 complexes that are responsible for CO2 sensitivity of mosquitoes.

neuroscience↗

bioRxiv2020

Stearoyl-CoA desaturase mediated monounsaturated fatty acid availability supports humoral immunity

ABSTRACTImmune cells can metabolize glucose, amino acids, and fatty acids (FAs) to generate energy. The role of different FA species, and their impacts on humoral immunity remains poorly understood. Here we report that proliferating B cells require monounsaturated FAs (MUFA) to maintain mitochondrial metabolism and mTOR activity, and to prevent excessive autophagy and endoplasmic reticulum (ER) stress. Furthermore, B cell extrinsic Stearoyl-CoA desaturase (SCD) activity generates MUFA to support early B cell development and germinal center (GC) formation in vivo during immunization and influenza infection. Thus, SCD-mediated MUFA production is critical for humoral immunity.Competing Interest StatementThe authors have declared no competing interest.View Full Text

immunology↗

bioRxiv2020

Diffusion Basis Spectrum Imaging with Deep Neural Network Differentiates Distinct Histology in Pediatric Brain Tumors

High-grade pediatric brain tumors constitute the highest mortality of cancer-death in children. While conventional MRI has been widely adopted for examining pediatric high-grade brain tumor clinically, accurate neuroimaging detection and differentiation of tumor histopathology for improved diagnosis, surgical planning, and treatment evaluation, remains an unmet need in the clinical management of pediatric brain tumor. We employed a novel Diffusion Histology Imaging (DHI) approach that incorporates diffusion basis spectrum imaging (DBSI) and deep neural network. DHI aims to detect, differentiate, and quantify heterogenous areas in pediatric high-grade brain tumors, which include normal white matter (WM), densely cellular tumor (DC tumor), less densely cellular tumor (LDC tumor), infiltrating edge, necrosis, and hemorrhage. Distinct diffusion metric combination would thus indicate the unique distributions of each distinct tumor histology features. DHI, by incorporating DBSI metrics and the deep neural network algorithm, classified pediatric tumor histology with an overall accuracy of 83.3%. Receiver operating analysis (ROC) analysis suggested DHIs great capability in distinguishing individual tumor histology with AUC values (95%CI) of 0.983 (0.985-0.989), 0.961 (0.957-0.964), 0.993 (0.992-0.994), 0.953 (0.947-0.958), 0.974 (0.970-0.978) and 0.980 (0.977-0.983) for normal WM, DC tumor, LDC tumor, infiltrating edge, necrosis and hemorrhage, respectively. Our results suggest that DBSI-DNN, or DHI, accurately characterized and classified multiple tumor histologic features in pediatric high-grade brain tumors. If further validated in patients, the novel DHI might emerge as a favorable alternative to the current neuroimaging techniques to better guide biopsy and resection as well as monitor therapeutic response in patients with high-grade brain tumors.

neuroscience↗

bioRxiv2020

HCFC1R1 Deficiency Blocks Herpes Simplex Virus-1 Infection by Inhibiting Nuclear Translocation of HCFC1 and VP16

Upon HSV-1 infection, viral protein 16 (VP16), supported by Host Cell Factor C1 (HCFC1), is rapidly transported into the nucleus, and help to express a series of HSV-1 immediate-early proteins to begin its lytic replication. However, no direct evidence has shown if the HCFC1 deficiency can affect the proliferation of HSV-1 so far. Here, we showed that the HCFC1 deficiency led to a strong resistance to HSV-1 infection. Moreover, we identified Host Cell Factor C1 Regulator 1 (HCFC1R1) as a new host factor acting early in HSV infection for the transport of the HSV-1 capsid to the nucleus. The HCFC1R1 deficiency also led to a strong resistance to HSV-1 infection. The HCFC1R1 deficiency did not affect the attachment of HSV-1 to host cells but act early in HSV-1 infection by perturbing the formation of HCFC1/VP16 complex. Remarkably, in addition to wild-type HSV-1 infection, the host cells in the absence of either HCFC1 or HCFC1R1 showed strong resistant to the infection of TK-deficient HSV-1, which strain can course severe symptoms and tolerate to the current anti-HSV drug Acyclovir. Our data suggest that HCFC1 or HCFC1R1 may be used as the novel target for developing anti-HSV-1 therapies. IMPORTANCEHerpes simplex virus-1 (HSV-1) is widely spread in the human population and can cause a variety of herpetic diseases. Acyclovir, a guanosine analogue that targets the TK protein of HSV-1, is the first specific and selective anti-HSV-1 drug. However, the rapid emergence of resistant HSV-1 strains is occurring worldwide, endangering the efficacy of Acyclovir. Alternatively, targeting host factors is another strategy to stop HSV-1 infection. Unfortunately, although the HSV-1s receptor, Nectin-1, was discovered in 1998, no effective antiviral drug to date has been developed by targeting Nectin-1. Targeting multiple pathways is the ultimate choice to prevent HSV-1 infection. Here we demonstrated that the deletion of HCFC1 or HCFC1R1 exhibits a strong inhibitory effect on both wild-type and TK-deficient HSV-1. Overall, we present evidence that HCFC1 or HCFC1R1 may be used as the novel target for developing anti-HSV-1 therapies with a defined mechanism of action.

microbiology↗

bioRxiv2020

The recombinational landscape in Daphnia pulex

Through the analysis of linkage disequilibrium from genome-wide sequencing data for multiple individuals from eight populations, the general features of the recombinational landscape are revealed in the microcrustacean Daphnia pulex. The data suggest an exceptionally uniform pattern of recombination across the genome, while also confirming general patterns that are inconsistent with existing population-genetic models for the relationship between linkage dis-equilibrium and physical distances between genomic sites. Patterns of linkage disequilibrium are highly consistent among populations, and average rates of recombination are quite similar for all chromosomes. There is no evidence of recombination hotspots, and although there does appear to be suppressed recombination in the vicinity of gene bodies, this effect is quite small. Although this species reproduces asexually in [~] 80% of generations, the mean per-generation recombination rate per nucleotide site is [~] 37x the per-nucleotide mutation rate. Contrary to expectations for models in which crossing-over is the primary mechanism of recombination, and consistent with data for other species, the gradient of linkage disequilibrium with increasing physical distance between sites is far too high at short distances and far too low at long distances, suggesting an important role for factors such as the nonindependent appearance of pairs of mutations on haplotypes and long-range gene-conversion-like processes. Combined with other observations on patterns of nucleotide variation, these results provide a strong case for the utility of D. pulex as a model system for the study of mechanisms of evolution in natural populations.

evolutionary biology↗

bioRxiv2020

Proteomics, lipidomics, metabolomics and 16S rDNA sequencing of dental plaque from patients with diabetes and periodontal disease

Oral microbiome influences human health, specifically pre- and type 2 diabetes (Pre-DM/DM) and periodontal diseases (PD), through complex microbial interactions. To explore these relations, we performed 16S rDNA sequencing, metabolomics, lipidomics, and proteomics analyses on supragingival dental plaque collected from individuals with Pre-DM/DM (n=39), Pre-DM/DM and PD (n=37), PD alone (n=11), or neither (n=10). We identified on average 2,790 operational taxonomic units and 2,025 microbial and host proteins per sample and quantified 110 metabolites and 415 lipids. Plaque samples from Pre-DM/DM patients contained higher abundance of Fusobacterium and Tannerella vs. plaques from metabolically healthy. Phosphatidylcholines, plasmenyl-phosphatidylcholines, ceramides containing non-OH fatty acids, and host proteins related to actin filament rearrangement were elevated in plaques from PD vs. non-PD. Cross-omic correlation analysis enabled the detection of a strong association between Lautropia and mono-methyl phophospotidlyethanolamine (PE-NMe), striking because synthesis of PE-NMe is uncommon in oral bacteria. Lipidomics analysis of in vitro cultures of Lautropia mirabilis confirmed the bacterias synthesis of PE-NMe. This comprehensive analysis revealed a novel microbial metabolic pathway and significant associations of host-derived proteins with PD.

systems biology↗

bioRxiv2020

Robustness testing and scalability of phosphate regulated promoters useful for two-stage autoinduction in E. coli

A key challenge in synthetic biology is the successful utilization of characterized parts, such as promoters, in different biological contexts. We report the robustness testing of a small library of E. coli PhoB regulated promoters that enable heterologous protein production in two-stage cultures. Expression levels were measured both in a rich Autoinduction Broth as well as a minimal mineral salts media. Media dependent differences were promoter dependent. 4 out of 16 promoters tested were identified to have tightly controlled expression which was also robust to media formulation. Improved promoter robustness led to more predictable scale up and consistent expression in instrumented bioreactors. This subset of PhoB activated promoters, useful for two-stage autoinduction, highlight the impact of the environment on the performance of biological parts, and the importance of robustness testing in synthetic biology. HighlightsO_LICharacterization of the impact of media on promoter activity C_LIO_LIIdentification of promoters robust to environmental variables C_LIO_LIIdentification of promoters whose expression scale from microtiter plates to bioreactors C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=62 SRC="FIGDIR/small/920280v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@94f035org.highwire.dtl.DTLVardef@264edaorg.highwire.dtl.DTLVardef@102ee30org.highwire.dtl.DTLVardef@163d16e_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

synthetic biology↗

bioRxiv2019

Diffusion Histology Imaging Detects and Classifies Glioblastoma Pathology Missed by Conventional Magnetic Resonance Imaging

PurposeGlioblastoma (GBM) is one of the deadliest cancers with no cure. While conventional MRI has been widely adopted for examining GBM clinically, accurate neuroimaging assessment of tumor histopathology for improved diagnosis, surgical planning, and treatment evaluation, remains an unmet need in the clinical management of GBMs. Experimental DesignWe employ a novel Diffusion Histology Imaging (DHI) approach, combining diffusion basis spectrum imaging (DBSI) and machine learning, to detect, differentiate, and quantify areas of high cellularity, tumor necrosis, and tumor infiltration in GBM. ResultsGd-enhanced T1W or hyper-intense FLAIR failed to reflect the morphological complexity underlying tumor in GBM patients. Contrary to the conventional wisdom that apparent diffusion coefficient (ADC) negatively correlates with increased tumor cellularity, we demonstrate disagreement between ADC and histologically confirmed tumor cellularity in glioblastoma specimens, whereas DBSI-derived restricted isotropic diffusion fraction positively correlated with tumor cellularity in the same specimens. By incorporating DBSI metrics as classifiers for a supervised machine learning algorithm, we accurately predicted high tumor cellularity, tumor necrosis, and tumor infiltration with 87.5%, 89.0% and 93.4% accuracy, respectively. ConclusionOur results suggest that DHI could serve as a favorable alternative to current neuroimaging techniques for guiding biopsy or surgery as well as monitoring therapeutic response in the treatment of glioblastoma. Translational RelevanceCurrent clinical diagnosis, surgical planning, and assessment of treatment response for GBM patients relies heavily on gadolinium-enhanced T1-weighted MRI, which is non-specific for tumor growth and merely reflects a disrupted blood-brain barrier. The complex tumor microenvironment and spatial heterogeneity make GBM difficult to characterize using current clinical imaging modalities. In this study, we developed a novel imaging technique to characterize and accurately predict key histological features of GBM - high tumor cellularity, tumor necrosis, and tumor infiltration. While further validation in a larger cohort of patients is needed, the current proof-of-concept approach could provide a solution to resolve important clinical questions such as the identification of true tumor progression vs. pseudoprogression or radiation necrosis.

neuroscience↗

bioRxiv2019

The Impact of Edema and Fiber Crossing on Diffusion MRI Metrics: DBSI vs. Diffusion ODF

PurposeDiffusion tensor imaging (DTI) has been employed for over two decades to noninvasively quantify central nervous system (CNS) diseases/injuries. However, DTI is an inadequate simplification of diffusion modeling in the presence of co-existing inflammation, edema, and crossing nerve fibers.\n\nMethodsWe employed a tissue phantom using fixed mouse trigeminal nerves coated with various amounts of agarose gel to mimic crossing fibers in the presence of vasogenic edema. Diffusivity measures derived by DTI and diffusion basis spectrum imaging (DBSI) were compared at increasing levels of simulated edema and degrees of fiber crossing. Further, we assessed the ability of DBSI, diffusion kurtosis imaging (DKI), generalized q-sampling imaging (GQI), q-ball imaging (QBI), and neurite orientation dispersion and density imaging (NODDI) to resolve fiber crossing, in reference to the gold standard angles measured from structural images.\n\nResultsDTI-computed diffusivities and fractional anisotropy (FA) were significantly confounded by gelmimicked edema and crossing fibers. Conversely, DBSI calculated accurate diffusivities of individual fibers regardless of the extent of simulated edema and degrees of fiber crossing angles. Additionaly, DBSI accurately and consistently estimated crossing angles in various conditions of gel-mimicked edema when comparing with gold standard (r2=0.92, p=1.9x10-9, bias=3.9{degrees}). Small crossing angles and edema sinficantly impact dODF, making DKI, GQI and QBI less accurate in detecting and estimating fibers corrsing angles. Lastly, we demonstrate DBSIs superiority over DTI for recovering and delineating white matter tracts in peritumoral edema for preoperative planning of surgical resection.\n\nConclusionsDBSI is able to separate two crossing fibers and accurately recover their diffusivities in a complex environment characterized by increasing crossing angles and amounts of gel-mimicked edema. DBSI also indicated better angular resolution capability compared with DKI, QBI and GQI.

neuroscience↗

bioRxiv2019

Improved, scalable, two-stage, autoinduction of recombinant protein expression in E. coli utilizing phosphate depletion.

We report the improved production of recombinant proteins in E. coli, reliant on tightly controlled autoinduction, triggered by phosphate depletion in stationary phase. The method, reliant on engineered strains and plasmids, enables improved protein expression across scales. Expression levels using this approach have reached as high as 55% of total cellular protein. Initial use of the method in instrumented fed batch fermentations enables cell densities of [~]30 grams dry cell weight (gCDW) per liter and protein titers up to 8.1+/-0.7 g/L ([~]270 mg/gCDW). The process has also been adapted to an optimized autoinduction media, enabling routine batch production at culture volumes of 20 L (384 well plates), 100 L (96 well plates), 20 mL and 100 mL. In batch cultures, cells densities routinely reach [~] 5-7 gCDW per liter, offering protein titers above 2 g/L. The methodology has been validated with a set of diverse heterologous proteins and is of general use for the facile optimization of routine protein expression from high throughput screens to fed-batch fermentation. HighlightsO_LIStationary phase protein expression results in high titers. C_LIO_LIAutoinduction by phosphate depletion enables protein titers from 2-8 g/L. C_LIO_LIAutoinduction has been validated from 384 well plates to instrumented bioreactors. C_LI

synthetic biology↗

bioRxiv2019

Genomic analyses of population structure reveal metabolism as a primary driver of local adaptation in Daphnia pulex.

Elucidating population structure is important for understanding evolutionary features of an organism. In the freshwater microcrustacean Daphnia pulex, an emerging model system in evolutionary genomics, previous studies using a small number of molecular markers indicated that genetic differentiation among populations is high. However, the dispersal ability of D. pulex is potentially high, and evolutionary forces shaping genetic differentiation among populations are not understood well. In this study, we carried out genomic analyses using high-throughput sequencing to investigate the population structure of D. pulex. We analyzed 10 temporary-pond populations widely distributed across the midwestern United States, with each sample consisting of 71 to 93 sexually reproducing individuals. The populations are generally in Hardy-Weinberg equilibrium and have relatively large effective sizes. The genetic differentiation among the populations is moderate and positively correlated with geographic distance. To find outlier regions showing significantly high or low genetic differentiation, we carried out a sliding-window analysis of the differentiation estimates using the bootstrap. Genes with significantly high genetic differentiation show striking enrichment of gene ontology terms involved in food digestion, suggesting that differences in food quality and/or quantity among populations play a primary role in driving local adaptation of D. pulex.

evolutionary biology↗

bioRxiv2019

Satellite Imaging of Global Urbanicity relate to Adolescent Brain Development and Behavior

Urbanicity, the impact of living in urban areas, is among the greatest environmental challenges for mental health. While urbanicity might be distinct in different sociocultural conditions and geographic locations, there are likely to exist common features shared in different areas of the globe. Understanding these common and specific relations of urbanicity with human brain and behavior will enable to assess the impact of urbanicity on mental disorders, especially in childhood and adolescence, where prevention and early interventions are likely to be most effective.\n\nWe constructed from satellite-based remote sensing data a factor for urbanicity that was highly correlated with population density ground data. This factor, UrbanSat was utilized in the Chinese CHIMGEN sample (N=831) and the longitudinal European IMAGEN cohort (N=810) to investigate if exposure to urbanicity during childhood and adolescence is associated with differences in brain structure and function in young adults, and if these changes are linked to behavior.\n\nUrbanicity was found negatively correlated with medial prefrontal cortex volume and positively correlated with cerebellar vermis volume in young adults from both China and Europe. We found an increased correlation of urbanicity with functional network connectivity within- and between- brain networks in Chinese compared to European participants. Urbanicity was highly correlated with a measure of perceiving a situation from the perspective of others, as well as symptoms of depression in both datasets. These correlations were mediated by the structural and functional brain changes observed. Susceptibility to urbanicity was greatest in two developmental windows during mid-childhood and adolescence.\n\nUsing innovative technology, we were able to probe the relationship between urban upbringing with brain change and behavior in different sociocultural conditions and geographic locations. Our findings help to identify shared and distinct determinants of adolescent brain development and mental health in different regions of the world, thus contributing to targeted prevention and early-intervention programs for young people in their unique environment. Our approach may be relevant for public health, policy and urban planning globally.

neuroscience↗

bioRxiv2019

γ-Secretase controls the specification of astrocytes from oligodendrocyte precursor cells via Stat3

Oligodendrocytes (OLs) and astrocytes play critical roles in a variety of brain functions. OL precursor cells (OPCs) are known to give rise to OLs as well as astrocytes. However, little is known about the mechanism by which OPCs determine their specification choice for OLs versus astrocytes in the central nervous system (CNS). Here we show that genetic inhibition of {gamma}-secretase in OPCs reduces OL differentiation but enhances astrocyte specification. Mechanistic analysis reveals that inhibition of {gamma}-secretase results in decreased levels of Hes1, and that Hes1 down-regulates the expression of signal transducer and activator of transcription3 (Stat3) via binding to specific regions of its promoter. We demonstrate that conditional inactivation of Stat3 in OL lineages restores the number of astrocytes in {gamma}-secretase mutant mice. In summary, this study identifies a key mechanism which controls OPCs specification choice for OL versus astrocyte during postnatal development. This {gamma}-secretase-dependent machinery may be essential for the CNS to maintain the population balance between OLs and astrocytes.

neuroscience↗