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SummaryGenetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional role of many loci has remained unexplored. In this study, we engineered isogenic knockout human embryonic stem cell (hESC) lines for 20 genes associated with T2D risk. We systematically examined β-cell differentiation, insulin production and secretion, and survival. We performed RNA-seq and ATAC-seq on hESC-β cells from each knockout line. Analyses of T2D GWAS signals overlapping with HNF4A-dependent ATAC peaks identified a specific SNP as a likely causal variant. In addition, we performed integrative association analyses and identified four genes (CP, RNASE1, PCSK1NandGSTA2) associated with insulin production, and two genes (TAGLN3andDHRS2) associated with sensitivity to lipotoxicity. Finally, we leveraged deep ATAC-seq read coverage to assess allele-specific imbalance at variants heterozygous in the parental hESC line, to identify a single likely functional variant at each of 23 T2D GWAS signals.

It takes a huge amount of works to take pictures of transmission line towers and check electrical fittings manually. In spite of the introduction of deep learning technology to transmission line inspection, it is not well utilized that fine-grained contexts on components in state-of-the-art research. On the basis of region-based fully convolutional network (R-FCN), a novel object detection method is proposed considering fine-grained contexts among electrical fittings. Deformable convolution layers and squeeze-and-excitation (SE) blocks are adopted in the detection method. A comparison experiment is conducted on a transmission line aerial inspection dataset. The proposed method shows better accuracy than R-FCN.

Traditional visual servo control based on location needs to convert two-dimensional information into three-dimensional space information, and the conversion process is subject to many interference factors, leading to large control errors. Aiming at the above problems, the visual servo positioning control of distribution line insulated wrapping robot and manipulator is studied. The position and pose of the manipulator are described and homogeneous transformed so as to calibrate the camera vision system of the manipulator. The image Jacobian matrix is established to realize the visual servo positioning control of the manipulator. Compared with the traditional control method, the experimental verification shows that the control method can reduce the pose error by at least 39.7%, and the control effect is more stable and the reliability is better.

The paper proposes a new location method of faulty segment for hybrid transmission lines combined with overhead line and cable. Conventional location method of faulty segment identify faulty segment through position calculation of fault point. However, affected by error, the fault at cable-overhead line joint is hard to be identified. In this approach, faulty segment is identified through characteristics comparison of transient travelling wave under different condition. Compared with situation that fault occurs on overhead line, if fault occurs in cable, there is an additional impedance discontinuity in cable. Thus, the amplitude and wave of various reflected wave will change significantly. The proposed method extracts various reflected waves based on time windows and polarity. It makes use of the relative amplitude and time difference between first travelling wave and secondary reflected wave of cable-overhead line joint as criterion of faulty segment location. To verify its effectiveness, fault simulations based on EMTDC are performed; the simulation results reveal that the proposed method can correctly identify the faulty segment for hybrid transmission lines.

Hypoxia plays important roles in embryonic vasculogenesis, hematopoiesis and has been applied in embryonic stem (ES) cell differentiation towards endothelial and hematopoietic cells. However, the precise role of hypoxia and its underlying mechanisms on the hematopoietic differentiation remains unclear. In this study, we found that hypoxia enhanced the generation of CD31 + TIE 2+ hemato-vascular progenitor cells from human ES-derived mesoderm cells, and followed by the gene expression of definitive hematopoietic genes after two days. Importantly, we found that hypoxia functioned on the hemato-vascular progenitor differentiation by stimulating the enhanced secretion of Wnt5a, while Wnt5a disrupted with shRNA inhibited the generation of hemato-vascular progenitor cells. Wnt5a added in normoxia promoted the generation of hemato-vascular progenitor cells and this effect is similar to that generated by hypoxia to enhance the generation of hemato-vascular progenitor cells. In conclusion, our study is the first to identify that hypoxia enhanced the generation of hemato-vascular progenitor cells from human ES cell-derived mesoderm through up-regulating Wnt5a signal. This finding provides new clues for studying the mechanism of committed differentiation of hemogenic endothelium and HPC/HSCs from human ES cells.

Genome wide association studies (GWAS) have identified over 100 signals associated with type 1 diabetes (T1D). However, translating any given T1D GWAS signal into mechanistic insights, including putative causal variants and the context (cell type and cell state) in which they function, has been limited. Here, we present a comprehensive multi-omic integrative analysis of single-cell/nucleus resolution profiles of gene expression and chromatin accessibility in healthy and autoantibody + (AAB+) human islets, as well as islets under multiple T1D stimulatory conditions. We broadly nominate effector cell types for all T1D GWAS signals. We further nominated higher-resolution contexts, including effector cell types, regulatory elements, and genes for three independent T1D risk variants acting through islet cells within the pancreas at the DLK1/MEG3, RASGRP1, and TOX loci. Subsequently, we created isogenic gene knockouts DLK1 -/- , RASGRP1 -/- , and TOX -/- , and the corresponding regulatory region knockout, RASGRP1 Δ , and DLK1 Δ hESCs. Loss of RASGRP1 or DLK1 , as well as knockout of the regulatory region of RASGRP1 or DLK1, increased β cell apoptosis. Additionally, pancreatic β cells derived from isogenic hESCs carrying the risk allele of rs3783355 A/A exhibited increased β cell death. Finally, RNA-seq and ATAC-seq identified five genes upregulated in both RASGRP1 -/- and DLK1 -/- β-like cells, four of which are associated with T1D. Together, this work reports an integrative approach for combining single cell multi-omics, GWAS, and isogenic hESC-derived β-like cells to prioritize the T1D associated signals and their underlying context-specific cell types, genes, SNPs, and regulatory elements, to illuminate biological functions and molecular mechanisms., Competing Interests: Conflict of Interest. S.C. is the co-founders of OncoBeat, LLC. and a consultant of Vesalius Therapeutics. The other authors declare no competing interest.

Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional role of many loci has remained unexplored. In this study, we engineered isogenic knockout human embryonic stem cell (hESC) lines for 20 genes associated with T2D risk. We systematically examined β-cell differentiation, insulin production and secretion, and survival. We performed RNA-seq and ATAC-seq on hESC-β cells from each knockout line. Analyses of T2D GWAS signals overlapping with HNF4A-dependent ATAC peaks identified a specific SNP as a likely causal variant. In addition, we performed integrative association analyses and identified four genes ( CP, RNASE1, PCSK1N and GSTA2 ) associated with insulin production, and two genes ( TAGLN3 and DHRS2 ) associated with sensitivity to lipotoxicity. Finally, we leveraged deep ATAC-seq read coverage to assess allele-specific imbalance at variants heterozygous in the parental hESC line, to identify a single likely functional variant at each of 23 T2D GWAS signals.