PRRC2B modulates oligodendrocyte progenitor cell development and myelination by stabilizing Sox2 mRNA.

Oligodendrocyte progenitor cells (OPCs) differentiate into myelin-producing cells and modulate neuronal activity. Defects in OPC development are associated with neurological diseases. N6-methyladenosine (m6A) contributes to neural development; however, the mechanism by which m6A regulates OPC development remains unclear. Here, we demonstrate that PRRC2B is an m6A reader that regulates OPC development and myelination. Nestin-Cre-mediated Prrc2b deletion affects neural stem cell self-renewal and glial differentiation. Moreover, the oligodendroglia lineage-specific deletion of Prrc2b reduces the numbers of OPCs and oligodendrocytes, causing hypomyelination and impaired motor coordination. Integrative methylated RNA immunoprecipitation sequencing, RNA sequencing, and RNA immunoprecipitation sequencing analyses identify Sox2 as the target of PRRC2B. Notably, PRRC2B, displaying separate and cooperative functions with PRRC2A, stabilizes mRNA by binding to m6A motifs in the coding sequence and 3' UTR of Sox2. In summary, we identify the posttranscriptional regulation of PRRC2B in OPC development, extending the understanding of PRRC2 family proteins and providing a therapeutic target for myelin-related disorders.

Spatial continuous modeling of early Cenozoic carbon cycle and climate.

A real spatial continuous modeling of climate and carbon cycle is developed, and tested for early Cenozoic from 60 Ma to 40 Ma.

Spatial transcriptomic analysis of the mouse brain following chronic social defeat stress.

Depression is a highly prevalent and disabling mental disorder, involving numerous genetic changes that are associated with abnormal functions in multiple regions of the brain. However, there is little transcriptomic-wide characterization of chronic social defeat stress (CSDS) to comprehensively compare the transcriptional changes in multiple brain regions. Spatial transcriptomics (ST) was used to reveal the spatial difference of gene expression in the control, resilient (RES) and susceptible (SUS) mouse brains, and annotated eight anatomical brain regions and six cell types. The gene expression profiles uncovered that CSDS leads to gene synchrony changes in different brain regions. Then it was identified that inhibitory neurons and synaptic functions in multiple regions were primarily affected by CSDS. The brain regions Hippocampus (HIP), Isocortex, and Amygdala (AMY) present more pronounced transcriptional changes in genes associated with depressive psychiatric disorders than other regions. Signalling communication between these three brain regions may play a critical role in susceptibility to CSDS. Taken together, this study provides important new insights into CSDS susceptibility at the ST level, which offers a new approach for understanding and treating depression.

Identification and Characterization of Elevated Expression of Transferrin and Its Receptor TfR1 in Mouse Models of Depression.

Depression has become one of the severe mental disorders threatening global human health. In this study, we first used the proteomics approach to obtain the differentially expressed proteins in the liver between naive control and chronic social defeat stress (CSDS) induced depressed mice. We have identified the upregulation of iron binding protein transferrin (TF) in the liver, the peripheral blood, and the brain in CSDS-exposed mice. Furthermore, bioinformatics analysis of the Gene Expression Omnibus (GEO) database from various mouse models of depression revealed the significantly upregulated transcripts of TF and its receptor TfR1 in multiple brain regions in depressed mice. We also used the recombinant TF administration via the tail vein to detect its permeability through the blood-brain barrier (BBB). We demonstrated the permeability of peripheral TF into the brain through the BBB. Together, these results identified the elevated expression of TF and its receptor TfR1 in both peripheral liver and the central brain in CSDS-induced depressed mice, and peripheral administration of TF can be transported into the brain through the BBB. Therefore, our data provide a compelling information for understanding the potential role and mechanisms of the cross-talk between the liver and the brain in stress-induced depression.

Is There a Missing Link? Exploring the Effects of Institutional Pressures on Environmental Performance in the Chinese Construction Industry.

Although institutional pressures have huge strategic implications for organizational activities, this certainly does not mean that organizations under institutional pressures can improve environmental performance automatically. Institutional pressures are critical but not sufficient to affect environmental performance directly. Therefore, additional research is needed to explore the missing link between institutional pressures and environmental performance. Based on the "pressure-response-performance" framework, this study integrates perspectives of institutional theory and organizational learning to argue the mediating role of organizational learning in the relationship between institutional pressures and environmental performance. Data were collected via 268 valid questionnaires from construction firms located in Shanxi Province in central China. Hypotheses in the conceptual model were tested with structural equation modeling. Empirical results reveal that both coercive and mimetic pressures have significantly positive effects on organizational learning, whereas normative pressures have a non-significant effect on organizational learning. Besides that, organizational learning has a significantly positive effect on environmental performance. In addition, organizational learning partially mediates the relationship between coercive pressures and environmental performance and completely mediates the relationship between mimetic pressures and environmental performance. By exploring the mediating role of organizational learning, the article uncovers the missing link in the relationship between institutional pressures and environmental performance.

dsCellNet: A new computational tool to infer cell-cell communication networks in the developing and aging brain.

Cell-cell interactions mediated by ligand-receptor complexes are critical to coordinating organismal development and functions. Majority of studies focus on the key time point, the mediator cell types or the critical genes during organismal development or diseases. However, most existing methods are specifically designed for stationary paired samples, there hasn't been a repository to deal with inferring cell-cell communications in developmental series RNA-seq data, which usually contains multiple developmental stages. Here we present a cell-cell interaction networks inference method and its application for developmental series RNA-seq data (termed dsCellNet) from the developing and aging brain. dsCellNet is implemented as an open-access R package on GitHub. It identifies interactions according to protein localizations and reinforces them via dynamic time warping within each time point and between adjacent time points, respectively. Then, fuzzy clustering of those interactions helps us refine key time points and connections. Compared to other published methods, our methods display high accuracy and high tolerance based on both simulated data and real data. Moreover, our methods can help identify the most active cell type and genes, which may provide a powerful tool to uncover the mechanisms underlying the organismal development and disease.

O-GlcNAcylation promotes cerebellum development and medulloblastoma oncogenesis via SHH signaling.

Sonic hedgehog (Shh) signaling plays a critical role in regulating cerebellum development by maintaining the physiological proliferation of granule neuron precursors (GNPs), and its dysregulation leads to the oncogenesis of medulloblastoma. O-GlcNAcylation (O-GlcNAc) of proteins is an emerging regulator of brain function that maintains normal development and neuronal circuitry. Here, we demonstrate that O-GlcNAc transferase (OGT) in GNPs mediate the cerebellum development, and the progression of the Shh subgroup of medulloblastoma. Specifically, OGT regulates the neurogenesis of GNPs by activating the Shh signaling pathway via O-GlcNAcylation at S355 of GLI family zinc finger 2 (Gli2), which in turn promotes its deacetylation and transcriptional activity via dissociation from p300, a histone acetyltransferases. Inhibition of OGT via genetic ablation or chemical inhibition improves survival in a medulloblastoma mouse model. These data uncover a critical role for O-GlcNAc signaling in cerebellar development, and pinpoint a potential therapeutic target for Shh-associated medulloblastoma.

EspF of Enterohemorrhagic Escherichia coli Enhances Apoptosis via Endoplasmic Reticulum Stress in Intestinal Epithelial Cells: An Isobaric Tags for Relative and Absolute Quantitation-Based Comparative Proteomic Analysis.

There have been large foodborne outbreaks related to Enterohemorrhagic Escherichia coli (EHEC) around the world. Among its virulence proteins, the EspF encoded by locus of enterocyte effacement is one of the most known functional effector proteins. In this research, we infected the HT-29 cells with the EHEC wild type strain and EspF-deficient EHEC strain. Via the emerging technique isobaric tags for relative and absolute quantitation (iTRAQ), we explored the pathogenic characteristics of EspF within host cells. Our data showed that the differences regarding cellular responses mainly contained immune regulation, protein synthesis, signal transduction, cellular assembly and organization, endoplasmic reticulum (ER) stress, and apoptosis. Notably, compared with the EspF-deficient strain, the protein processing in the ER and ribosome were upregulated during wild type (WT) infection. Our findings proved that the EspF of Enterohemorrhagic Escherichia coli induced ER stress in intestinal epithelial cells; the ER stress-dependent apoptosis pathway was also activated within the host cells. This study provides insight into the virulence mechanism of protein EspF, which will deepen our general understanding of A/E pathogens and their interaction with host proteins.

Cryo-EM structures reveal distinct apo conformations of sortilin-related receptor SORLA.

Sorting-related receptor with A-type repeats (SORLA) is an important receptor for regulating normal cellular functions via protein sorting. Here, we determined the structures of the full-length SORLA and identified two distinct conformations of apo-SORLA using single-particle cryogenic electron microscopy. In contrast to homologous proteins, both monomer and dimer forms of SORLA existed in a neutral solution. Only three hydrogen bonds in the vicinity of the dimer interface implied the involvement in dimerization. The orientation of residue R490 was a key point for ligand binding. These results suggest a unique mechanism of SORLA dimerization for protein trafficking.

Aberrant NAD+ metabolism underlies Zika virus-induced microcephaly.

Zika virus (ZIKV) infection during pregnancy can cause microcephaly in newborns, yet the underlying mechanisms remain largely unexplored. Here, we reveal extensive and large-scale metabolic reprogramming events in ZIKV-infected mouse brains by performing a multi-omics study comprising transcriptomics, proteomics, phosphoproteomics and metabolomics approaches. Our proteomics and metabolomics analyses uncover dramatic alteration of nicotinamide adenine dinucleotide (NAD+)-related metabolic pathways, including oxidative phosphorylation, TCA cycle and tryptophan metabolism. Phosphoproteomics analysis indicates that MAPK and cyclic GMP-protein kinase G signaling may be associated with ZIKV-induced microcephaly. Notably, we demonstrate the utility of our rich multi-omics datasets with follow-up in vivo experiments, which confirm that boosting NAD+ by NAD+ or nicotinamide riboside supplementation alleviates cell death and increases cortex thickness in ZIKV-infected mouse brains. Nicotinamide riboside supplementation increases the brain and body weight as well as improves the survival in ZIKV-infected mice. Our study provides a comprehensive resource of biological data to support future investigations of ZIKV-induced microcephaly and demonstrates that metabolic alterations can be potentially exploited for developing therapeutic strategies.

Effects of topical oxygen therapy on chronic traumatic wounds and its impact on granulation tissue.

OBJECTIVE: To evaluate the effects of topical oxygen therapy and its impacts on granulation tissue in patients with chronic traumatic wounds. METHOD: A total of 112 patients with chronic traumatic wounds were randomly divided into the control group (n=56, receiving negative-pressure wound therapy) and the intervention group (n=56, receiving negative-pressure wound therapy plus topical oxygen therapy) using a random number table and they were treated continuously for 2 weeks. Then, the scores from the Pressure Ulcer Scale for Healing (PUSH), the coverage rate of granulation tissue, the severity of pain and Transcutaneous Oxygen Partial Pressure (TcPO2) before and after treatment were compared between the two groups. Also, the bacterial culture-positive rate, the healing rate and the healing time were compared between the two groups. RESULTS: The PUSH scores were significantly decreased after treatment compated to those before treatment in the two groups, and those in the intervention group were lower than those in the control group (all P<0.05). The coverage rate of granulation tissue gradually increased in the two groups from day 3 to day 14 after treatment, with that in the intervention group being higher than in the control group during the same period (all P<0.05). The bacterial culture-positive rate that was detected was significantly lower after treatment than that before treatment in the intervention group, and lower in the intervention group than in the control group after treatment (all P<0.05). The VAS scores significantly decreased and TcPO2 increased after treatment compared to those before treatment in the two groups, with changes in the intervention group being more significant than those in the control group (all P<0.05). During the 3-month follow-up, the wound healing rate was higher and the healing time shorter in the intervention group than those in the control group (all P<0.05). CONCLUSION: Negative-pressure wound therapy plus topical oxygen therapy can substantially increase the coverage rate of granulation tissue and TcPO2 at the traumatic site, thus facilitating the healing process and shortening the time for healing. So, the efficacy of negative-pressure wound therapy in combination with topical oxygen therapy is more effective in treating patients with chronic traumatic wounds than negative-pressure wound therapy alone.

High spatial resolution imaging of the dynamics of cuticular lipid deposition during Arabidopsis flower development.

The extensive collection of glossy (gl) and eceriferum (cer) mutants of maize and Arabidopsis have proven invaluable in dissecting the branched metabolic pathways that support cuticular lipid deposition. This bifurcated pathway integrates a fatty acid elongation-decarbonylative branch and a fatty acid elongation-reductive branch, which collectively has the capacity to generate hundreds of cuticular lipid metabolites. In this study, a combined transgenic and biochemical strategy was implemented to explore and compare the physiological function of three homologous genes, Gl2, Gl2-like, and CER2, in the context of this branched pathway. These biochemical characterizations integrated new extraction chromatographic procedures with high spatial resolution mass spectrometric imaging methods to profile the cuticular lipids on developing floral tissues transgenically expressing these transgenes in wild-type or cer2 mutant lines of Arabidopsis. Collectively, these datasets establish that both the maize Gl2 and Gl2-like genes are functional homologs of the Arabidopsis CER2 gene. In addition, the dynamic distribution of cuticular lipid deposition follows distinct floral organ localization patterns indicating that the fatty acid elongation-decarbonylative branch of the pathway is differentially localized from the fatty acid elongation-reductive branch of the pathway.

3D car-detection based on a Mobile Deep Sensor Fusion Model and real-scene applications.

Unmanned vehicles need to make a comprehensive perception of the surrounding environmental information during driving. Perception of automotive information is of significance. In the field of automotive perception, the sterevision of car-detection plays a vital role and sterevision can calculate the length, width, and height of a car, making the car more specific. However, under the existing technology, it is impossible to obtain accurate detection in a complex environment by relying on a single sensor. Therefore, it is particularly important to study the complex sensing technology based on multi-sensor fusion. Recently, with the development of deep learning in the field of vision, a mobile sensor-fusion method based on deep learning is proposed and applied in this paper--Mobile Deep Sensor Fusion Model (MDSFM). The content of this article is as follows. It does a data processing that projects 3D data to 2D data, which can form a dataset suitable for the model, thereby training data more efficiently. In the modules of LiDAR, it uses a revised squeezeNet structure to lighten the model and reduce parameters. In the modules of cameras, it uses the improved design of detecting module in R-CNN with a Mobile Spatial Attention Module (MSAM). In the fused part, it uses a dual-view deep fusing structure. And then it selects images from the KITTI's datasets for validation to test this model. Compared with other recognized methods, it shows that our model has a fairly good performance. Finally, it implements a ROS program on the experimental car and our model is in good condition. The result shows that it can improve performance of detecting easy cars significantly through MDSFM. It increases the quality of the detected data and improves the generalized ability of car-detection model. It improves contextual relevance and preserves background information. It remains stable in driverless environments. It is applied in the realistic scenario and proves that the model has a good practical value.

H3K18ac Primes Mesendodermal Differentiation upon Nodal Signaling.

Cellular responses to transforming growth factor ß (TGF-ß) depend on cell context. Here, we explored how TGF-ß/nodal signaling crosstalks with the epigenome to promote mesendodermal differentiation. We find that expression of a group of mesendodermal genes depends on both TRIM33 and nodal signaling in embryoid bodies (EBs) but not in embryonic stem cells (ESCs). Only in EBs, TRIM33 binds these genes in the presence of expanded H3K18ac marks. Furthermore, the H3K18ac landscape at mesendodermal genes promotes TRIM33 recruitment. We reveal that HDAC1 binds to active gene promoters and interferes with TRIM33 recruitment to mesendodermal gene promoters. However, the TRIM33-interacting protein p300 deposits H3K18ac and further enhances TRIM33 recruitment. ATAC-seq data demonstrate that TRIM33 primes mesendodermal genes for activation by maintaining chromatin accessibility at their regulatory regions. Altogether, our study suggests that HDAC1 and p300 are key factors linking the epigenome through TRIM33 to the cell context-dependent nodal response during mesendodermal differentiation.

Piezoelectric arsenite aptasensor based on the use of a self-assembled mercaptoethylamine monolayer and gold nanoparticles.

The authors describe a piezoelectric aptasensor for arsenite. A self assembeled monolayer (SAM) of mercaptoethylamine was prepared to immobilize arsenite on the surface of a quartz crystal microbalance. Gold nanoparticles were modified with arsenite aptamer to amplify the response frequency of the biosensor. Arsenite first binds to the SAM on the gold surface of the QCM. On addition of gold nanoparticles with aptamer (DNA-AuNp), the SAM-As(III)-aptamer sandwich is formed. This increases the resonance frequency of the sensor and allows trace concentration of arsenite to be determined. The aptasensor can detect arsenite in the 8 to 1000 nmol·L-1 concentration range with a 4.4 nmol·L-1 lower detection limit (at S/N = 3). The sandwich structure improves the specificity of the aptasensor without considering the conformational transition of the aptamer. The strategy described here conceivably has a large potential as it shows that small molecules can be sensed by using aptamers with unknown working mechanism. Graphical abstract Schematic presentation of a piezoelectric biosensor for arsenite detection by using a mercaptoethylamine monolayer and gold nanoparticles with respect to Arsenite first binds to the SAM on the gold surface of the QCM. Next, gold nanoparticles with aptamer (DNA-AuNp) are added to form a SAM-As(III)-aptamer sandwich which affects the resonance frequency.

PCBP1 depletion promotes tumorigenesis through attenuation of p27Kip1 mRNA stability and translation.

BACKGROUND: Poly C Binding Protein 1 (PCBP1) is an RNA-binding protein that binds and regulates translational activity of subsets of cellular mRNAs. Depletion of PCBP1 is implicated in various carcinomas, but the underlying mechanism in tumorigenesis remains elusive. METHODS: We performed a transcriptome-wide screen to identify novel bounding mRNA of PCBP1. The bind regions between PCBP1 with target mRNA were investigated by using point mutation and luciferase assay. Cell proliferation, cell cycle, tumorigenesis and cell apoptosis were also evaluated in ovary and colon cancer cell lines. The mechanism that PCBP1 affects p27 was analyzed by mRNA stability and ribosome profiling assays. We analyzed PCBP1 and p27 expression in ovary, colon and renal tumor samples and adjacent non-tumor tissues using RT-PCR, Western Blotting and immunohistochemistry. The prognostic significance of PCBP1 and p27 also analyzed using online databases. RESULTS: We identified cell cycle inhibitor p27Kip1 (p27) as a novel PCBP1-bound transcript. We then demonstrated that binding of PCBP1 to p27 3'UTR via its KH1 domain mainly stabilizes p27 mRNA, while enhances its translation to fuel p27 expression, prior to p27 protein degradation. The upregulated p27 consequently inhibits cell proliferation, cell cycle progression and tumorigenesis, whereas promotes cell apoptosis under paclitaxel treatment. Conversely, knockdown of PCBP1 in turn compromises p27 mRNA stability, leading to lower p27 level and tumorigenesis in vivo. Moreover, forced depletion of p27 counteracts the tumor suppressive ability of PCBP1 in the same PCBP1 over-expressing cells. Physiologically, we showed that decreases of both p27 mRNA and its protein expressions are well correlated to PCBP1 depletion in ovary, colon and renal tumor samples, independent of the p27 ubiquitin ligase Skp2 level. Correlation of PCBP1 with p27 is also found in the tamoxifen, doxorubincin and lapatinib resistant breast cancer cells of GEO database. CONCLUSION: Our results thereby indicate that loss of PCBP1 expression firstly attenuates p27 expression at post-transcriptional level, and subsequently promotes carcinogenesis. PCBP1 could be used as a diagnostic marker to cancer patients.

Coexpression network revealing the plasticity and robustness of population transcriptome during the initial stage of domesticating energy crop Miscanthus lutarioriparius.

KEY MESSAGE: Coexpression network revealing genes with Co-variation Expression pattern (CE) and those with Top rank of Expression fold change (TE) played different roles in responding to new environment of Miscanthus lutarioriparius. Variation in gene expression level, the product of genetic and/or environmental perturbation, determines the robustness-to-plasticity spectrum of a phenotype in plants. Understanding how expression variation of plant population response to a new field is crucial to domesticate energy crops. Weighted Gene Coexpression Network Analysis (WGCNA) was used to explore the patterns of expression variation based on 72 Miscanthus lutarioriparius transcriptomes from two contrasting environments, one near the native habitat and the other in one harsh domesticating region. The 932 genes with Co-variation Expression pattern (CE) and other 932 genes with Top rank of Expression fold change (TE) were identified and the former were strongly associated with the water use efficiency (r ≥ 0.55, P ≤ 10-7). Functional enrichment of CE genes were related to three organelles, which well matched the annotation of twelve motifs identified from their conserved noncoding sequence; while TE genes were mostly related to biotic and/or abiotic stress. The expression robustness of CE genes with high genetic diversity kept relatively stable between environments while the harsh environment reduced the expression robustness of TE genes with low genetic diversity. The expression plasticity of CE genes was increased less than that of TE genes. These results suggested that expression variation of CE genes and TE genes could account for the robustness and plasticity of acclimation ability of Miscanthus, respectively. The patterns of expression variation revealed by transcriptomic network would shed new light on breeding and domestication of energy crops.

Coagulation factor V gene 1691G>A polymorphism as an indicator for risk and prognosis of lower extremity deep venous thrombosis in Chinese Han population.

The purpose of this study was to explore the negative influence coagulation factor V (FV) 1691G>A polymorphism had on the risk and prognosis of lower extremity deep venous thrombosis (LDVT) in Chinese Han population.A total of 348 patients with LDVT (LDVT group) and 398 healthy individuals (control group) were selected to further this study. A polymerase chain reaction-restriction fragment length polymorphism method was used to analyze the FV gene 1691G>A polymorphism; coagulation and anticoagulation indexes of patients with LDVT were detected as a result. A 3-year follow-up and logistic regression analysis were conducted to determine the corresponding correlations between FV gene and LDVT.In comparison with the control group, the frequencies of GA and AA genotypes and A allele of 1691G>A polymorphism significantly increased in the LDVT group. Also, in comparison with patients with LDVT carrying GG genotype of FV gene 1691G>A polymorphism, the following activities reduced significantly: prothrombin time, activated partial thromboplastin time, fibrinogen, protein C, and protein S, while activated protein C resistance and lupus anticoagulant positive rate increased in patients carrying A allele (GA + AA). Logistic regression analysis indicated that FV gene 1691G>A polymorphism, total cholesterol, low-density lipoprotein cholesterol, and LDVT family histories were all closely related with LDVT and were subsequent independent risk factors for LDVT. Moreover, patients with LDVT carrying A allele (GA + AA) had both higher patency and recurrence rates than those carrying GG genotype.FV gene 1691G>A polymorphism may be associated with both the risk and prognosis of LDVT, potentially being a useful index for monitoring LDVT prognosis and risk.

High expression of Parkin predicts easier recurrence of patients with adjuvant transarterial chemoembolization.

AIM: To investigate the clinical significance of E3 ubiquitin ligase Parkin in patients with adjuvant transarterial chemoembolization after curative resection of hepatocellular carcinoma. METHODS: Parkin expression of hepatocellular carcinomas was detected and its correlation with clinicopathological factors was analyzed with χ2 test. The significance of Parkin in prognosis and recurrence was analyzed with log-rank test and the Cox-regression model. RESULTS: High expression of Parkin could result in lower recurrence-free survival rate instead of overall survival rate. Larger tumor size, positive tumor recurrence, advanced T, N, M and TNM stage were significantly associated with poorer prognosis. Larger tumor size, advanced T and TNM stage could lead to higher recurrence. CONCLUSION: High Parkin expression could predict easier recurrence to patients with adjuvant transarterial chemoembolization.