Commercial Activities and Their Historical Impact in the Three Gorges Area From Seventh to Ninth Century

From Seventh to Ninth century, business in the Three Gorges region along Yangtze River in China had presented unprecedented prosperity which featured the growing business groups, flourishing salt trades, many commodity markets and active shipping trading. The prosperity of the commercial economy in the Three Gorges region during this period of time was attributed to many factors including the natural conditions, the population growth, the development of shipping and local specialties and others. During this period of time, the business prosperity in the Three Gorges region had promoted the local economic and social development and also established its important position of the trade and commerce in the upper Yangtze River region

Systematic reconstruction of autism biology from massive genetic mutation profiles

Autism spectrum disorder (ASD) affects 1% of world population and has become a pressing medical and social problem worldwide. As a paradigmatic complex genetic disease, ASD has been intensively studied and thousands of gene mutations have been reported. Because these mutations rarely recur, it is difficult to (i) pinpoint the fewer disease-causing versus majority random events and (ii) replicate or verify independent studies. A coherent and systematic understanding of autism biology has not been achieved. We analyzed 3392 and 4792 autism-related mutations from two large-scale whole-exome studies across multiple resolution levels, that is, variants (single-nucleotide), genes (protein-coding unit), and pathways (molecular module). These mutations do not recur or replicate at the variant level, but significantly and increasingly do so at gene and pathway levels. Genetic association reveals a novel gene + pathway dual-hit model, where the mutation burden becomes less relevant. In multiple independent analyses, hundreds of variants or genes repeatedly converge to several canonical pathways, either novel or literature-supported. These pathways define recurrent and systematic ASD biology, distinct from previously reported gene groups or networks. They also present a catalog of novel ASD risk factors including 118 variants and 72 genes. At a subpathway level, most variants disrupt the pathway-related gene functions, and in the same gene, they tend to hit residues extremely close to each other and in the same domain. Multiple interacting variants spotlight key modules, including the cAMP (adenosine 3′,5′-monophosphate) second-messenger system and mGluR (metabotropic glutamate receptor) signaling regulation by GRKs (G protein–coupled receptor kinases). At a superpathway level, distinct pathways further interconnect and converge to three biology themes: synaptic function, morphology, and plasticity

A clustering property of highly-degenerate transcription factor binding sites in the mammalian genome

Transcription factor binding sites (TFBSs) are short DNA sequences interacting with transcription factors (TFs), which regulate gene expression. Due to the relatively short length of such binding sites, it is largely unclear how the specificity of protein–DNA interaction is achieved. Here, we have performed a genome-wide analysis of TFBS-like sequences for the transcriptional repressor, RE1 Silencing Transcription Factor (REST), as well as for several other representative mammalian TFs (c-myc, p53, HNF-1 and CREB). We find a nonrandom distribution of inexact sites for these TFs, referred to as highly-degenerate TFBSs, that are enriched around the cognate binding sites. Comparisons among human, mouse and rat orthologous promoters reveal that these highly-degenerate sites are conserved significantly more than expected by random chance, suggesting their positive selection during evolution. We propose that this arrangement provides a favorable genomic landscape for functional target site selection

Profiling alternatively spliced mRNA isoforms for prostate cancer classification

BACKGROUND: Prostate cancer is one of the leading causes of cancer illness and death among men in the United States and world wide. There is an urgent need to discover good biomarkers for early clinical diagnosis and treatment. Previously, we developed an exon-junction microarray-based assay and profiled 1532 mRNA splice isoforms from 364 potential prostate cancer related genes in 38 prostate tissues. Here, we investigate the advantage of using splice isoforms, which couple transcriptional and splicing regulation, for cancer classification. RESULTS: As many as 464 splice isoforms from more than 200 genes are differentially regulated in tumors at a false discovery rate (FDR) of 0.05. Remarkably, about 30% of genes have isoforms that are called significant but do not exhibit differential expression at the overall mRNA level. A support vector machine (SVM) classifier trained on 128 signature isoforms can correctly predict 92% of the cases, which outperforms the classifier using overall mRNA abundance by about 5%. It is also observed that the classification performance can be improved using multivariate variable selection methods, which take correlation among variables into account. CONCLUSION: These results demonstrate that profiling of splice isoforms is able to provide unique and important information which cannot be detected by conventional microarrays

Research progress on the two-phase flow migration law of coal and gas outburst

Coal and gas outburst is an extremely complex dynamic phenomenon in coal mines. It is mainly manifested as gas suffocation, pulverized coal impact and burial, which seriously threatens the safety production of coal mines. Revealing the migration law and its main controlling factors of two-phase flow in coal and gas outburst is of great significance for clarifying the disaster-causing mechanism of outburst and guiding disaster prevention and avoidance on site. In recent years, relevant scholars had carried out a large number of coal and gas outburst two-phase flow test and theoretical research, and had achieved fruitful research results. This paper summarized and analyzed the two-phase flow simulation test device and the research results obtained by domestic and foreign scholars in the two-phase flow field. Firstly, the existing two-phase flow physical simulation test devices for coal and gas outburst were systematically reviewed, and the key parameters and functional advantages of different test devices were compared and analyzed. On this basis, the migration velocity, migration pattern and accumulation distribution characteristics of outburst pulverized coal flow, as well as the formation reason, propagation velocity and attenuation law of outburst shock wave were summarized. Finally, the influence and control effect of roadway structure, gas pressure, coal particle size, ground stress and gas composition on outburst two-phase flow were analyzed. According to the analysis, the research on the two-phase flow of coal and gas outburst at the present stage shown the characteristics of visualization of outburst process, complexity of roadway structure, diversification of data collection, comprehensiveness of influencing factors and diversification of research methods, and basically grasped the occurrence mechanism, propagation and disaster-causing law of outburst two-phase flow. However, the establishment and improvement of similarity system (similarity criteria and materials), the coexistence and mutual interference principle of two-phase flow and ventilation system, the multi-factor coupling disaster-causing mechanism of two-phase flow, and the integration of disaster-causing and prevention and control of two-phase flow still need further in-depth study

Trans-cellular control of synapse properties by a cell type-specific splicing regulator

The recognition of synaptic partners and specification of synaptic properties are fundamental for the function of neuronal circuits. ‘Terminal selector’ transcription factors coordinate the expression of terminal gene batteries that specify cell type-specific properties. Moreover, pan-neuronal alternative splicing regulators have been implicated in directing neuronal differentiation. However, the cellular logic of how splicing regulators instruct specific synaptic properties remains poorly understood. Here, we combine genome-wide mapping of mRNA targets and cell type-specific loss-of-function studies to uncover the contribution of the nuclear RNA binding protein SLM2 to hippocampal synapse specification. Focusing on hippocampal pyramidal cells and SST-positive GABAergic interneurons, we find that SLM2 preferentially binds and regulates alternative splicing of transcripts encoding synaptic proteins, thereby generating cell type-specific isoforms. In the absence of SLM2, cell type-specification, differentiation, and viability are unaltered and neuronal populations exhibit normal intrinsic properties. By contrast, cell type-specific loss of SLM2 results in highly selective, non-cell autonomous synaptic phenotypes, altered synaptic transmission, and associated defects in a hippocampus-dependent memory task. Thus, alternative splicing provides a critical layer of gene regulation that instructs specification of neuronal connectivity in a trans-synaptic manner

A cell-type-specific alternative splicing regulator shapes synapse properties in a trans-synaptic manner

The specification of synaptic properties is fundamental for the function of neuronal circuits. "Terminal selector" transcription factors coordinate terminal gene batteries that specify cell-type-specific properties. Moreover, pan-neuronal splicing regulators have been implicated in directing neuronal differentiation. However, the cellular logic of how splicing regulators instruct specific synaptic properties remains poorly understood. Here, we combine genome-wide mapping of mRNA targets and cell-type-specific loss-of-function studies to uncover the contribution of the RNA-binding protein SLM2 to hippocampal synapse specification. Focusing on pyramidal cells and somatostatin (SST)-positive GABAergic interneurons, we find that SLM2 preferentially binds and regulates alternative splicing of transcripts encoding synaptic proteins. In the absence of SLM2, neuronal populations exhibit normal intrinsic properties, but there are non-cell-autonomous synaptic phenotypes and associated defects in a hippocampus-dependent memory task. Thus, alternative splicing provides a critical layer of gene regulation that instructs specification of neuronal connectivity in a trans-synaptic manner

Selective laser melting of high-performance pure tungsten: parameter design, densification behavior and mechanical properties

Selective laser melting (SLM) additive manufacturing of pure tungsten encounters nearly all intractable difficulties of SLM metals fields due to its intrinsic properties. The key factors, including powder characteristics, layer thickness, and laser parameters of SLM high density tungsten are elucidated and discussed in detail. The main parameters were designed from theoretical calculations prior to the SLM process and experimentally optimized. Pure tungsten products with a density of 19.01 g/cm3 (98.50% theoretical density) were produced using SLM with the optimized processing parameters. A high density microstructure is formed without significant balling or macrocracks. The formation mechanisms for pores and the densification behaviors are systematically elucidated. Electron backscattered diffraction analysis confirms that the columnar grains stretch across several layers and parallel to the maximum temperature gradient, which can ensure good bonding between the layers. The mechanical properties of the SLM-produced tungsten are comparable to that produced by the conventional fabrication methods, with hardness values exceeding 460 HV0.05 and an ultimate compressive strength of about 1 GPa. This finding offers new potential applications of refractory metals in additive manufacturing

Precise temporal regulation of alternative splicing during neural development

Alternative splicing (AS) is one crucial step of gene expression that must be tightly regulated during neurodevelopment. However, the precise timing of developmental splicing switches and the underlying regulatory mechanisms are poorly understood. Here we systematically analyze the temporal regulation of AS in a large number of transcriptome profiles of developing mouse cortices, in vivo purified neuronal subtypes, and neurons differentiated in vitro. Our analysis reveals early-switch and late-switch exons in genes with distinct functions, and these switches accurately define neuronal maturation stages. Integrative modeling suggests that these switches are under direct and combinatorial regulation by distinct sets of neuronal RNA-binding proteins including Nova, Rbfox, Mbnl, and Ptbp. Surprisingly, various neuronal subtypes in the sensory systems lack Nova and/or Rbfox expression. These neurons retain the “immature” splicing program in early-switch exons, affecting numerous synaptic genes. These results provide new insights into the organization and regulation of the neurodevelopmental transcriptome