Neighbor Contrastive Learning on Learnable Graph Augmentation

Recent years, graph contrastive learning (GCL), which aims to learn representations from unlabeled graphs, has made great progress. However, the existing GCL methods mostly adopt human-designed graph augmentations, which are sensitive to various graph datasets. In addition, the contrastive losses originally developed in computer vision have been directly applied to graph data, where the neighboring nodes are regarded as negatives and consequently pushed far apart from the anchor. However, this is contradictory with the homophily assumption of networks that connected nodes often belong to the same class and should be close to each other. In this work, we propose an end-to-end automatic GCL method, named NCLA to apply neighbor contrastive learning on learnable graph augmentation. Several graph augmented views with adaptive topology are automatically learned by the multi-head graph attention mechanism, which can be compatible with various graph datasets without prior domain knowledge. In addition, a neighbor contrastive loss is devised to allow multiple positives per anchor by taking network topology as the supervised signals. Both augmentations and embeddings are learned end-to-end in the proposed NCLA. Extensive experiments on the benchmark datasets demonstrate that NCLA yields the state-of-the-art node classification performance on self-supervised GCL and even exceeds the supervised ones, when the labels are extremely limited. Our code is released at https://github.com/shenxiaocam/NCLA

Massive nutrients offshore transport off the Changjiang Estuary in flooding summer of 2020

Flood events significantly increase water discharges and terrigenous material inputs to coastal waters. Riverine nutrients in the Changjiang Estuary are transported by the dispersion of Changjiang Diluted Water (CDW) plumes and detached low-salinity water patches. However, the effects of flooding on nutrient offshore transports have not been well explored. Here, we present the nutrient conditions in the Changjiang Estuary and adjacent East China Sea in the historical flooding year 2020. Comparisons of nutrient distributions between flooding years, drought year and non-flooding years were also made. Our results showed that nitrate flux from the Changjiang River in August 2020 was 1.5 times that of the multi-year averaged flux in non-flooding years. Enormous riverine nutrient input resulted in much higher nutrient concentrations in the outer estuary than those in non-flooding years. In addition, a detached low-salinity water patch was observed, which made the salinity of the northern estuary even lower than that in the historical flooding year 1998. Surface dissolved inorganic nitrate (DIN) level in the low-salinity water patch was even ~16 times of that at nearby station in the drought year 2006. While phosphate (PO43−) concentrations were less than 0.1 μmol L−1 east of 123°E, which was probably caused by intensive biological uptake, as indicated by a high Chlorophyll a (Chl a) concentration (29.08 μg L−1). The depleted PO43− and high N/P of the low-salinity water patch suggested PO43− limitation even under flood conditions. A three end-member mixing model was adopted to identify the contributions of the CDW end-member (CDWend-member) and biological process to nutrient distributions. Our model results showed that the nutrient contribution of the CDWend-member to the estuary (122–124°E, 31–32.5°N) in flooding year 2020 was over double that in drought year 2006. Model-derived biological DIN uptake was as high as 24.65 μmol L−1 at the low-salinity water patch. Accordingly, the estimated net community production was 566–1131 mg C m−2 d−1 within the euphotic zone. The offshore transport of a low-salinity, high-DIN water patch during flooding could probably have a significant influence on biogeochemical cycles in the broad shelf, and even the adjacent Japan Sea

Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing

RBM15, an RNA binding protein, determines cell-fate specification of many tissues including blood. We demonstrate that RBM15 is methylated by protein arginine methyltransferase 1 (PRMT1) at residue R578 leading to its degradation via ubiquitylation by an E3 ligase (CNOT4). Overexpression of PRMT1 in acute megakaryocytic leukemia cell lines blocks megakaryocyte terminal differentiation by downregulation of RBM15 protein level. Restoring RBM15 protein level rescues megakaryocyte terminal differentiation blocked by PRMT1 overexpression. At the molecular level, RBM15 binds to pre-mRNA intronic regions of genes important for megakaryopoiesis such as GATA1, RUNX1, TAL1 and c-MPL. Furthermore, preferential binding of RBM15 to specific intronic regions recruits the splicing factor SF3B1 to the same sites for alternative splicing. Therefore, PRMT1 regulates alternative RNA splicing via reducing RBM15 protein concentration. Targeting PRMT1 may be a curative therapy to restore megakaryocyte differentiation for acute megakaryocytic leukemia

Neighbor Contrastive Learning on Learnable Graph Augmentation

Recent years, graph contrastive learning (GCL), which aims to learn representations from unlabeled graphs, has made great progress. However, the existing GCL methods mostly adopt human-designed graph augmentations, which are sensitive to various graph datasets. In addition, the contrastive losses originally developed in computer vision have been directly applied to graph data, where the neighboring nodes are regarded as negatives and consequently pushed far apart from the anchor. However, this is contradictory with the homophily assumption of net-works that connected nodes often belong to the same class and should be close to each other. In this work, we propose an end-to-end automatic GCL method, named NCLA to apply neighbor contrastive learning on learnable graph augmentation. Several graph augmented views with adaptive topology are automatically learned by the multi-head graph attention mechanism, which can be compatible with various graph datasets without prior domain knowledge. In addition, a neighbor contrastive loss is devised to allow multiple positives per anchor by taking network topology as the supervised signals. Both augmentations and embeddings are learned end-to-end in the proposed NCLA. Extensive experiments on the benchmark datasets demonstrate that NCLA yields the state-of-the-art node classification performance on self-supervised GCL and even exceeds the supervised ones, when the labels are extremely limited. Our code is released at https://github.com/shenxiaocam/NCLA

Insight into Fructose-to-Sucrose Ratio as the Potential Target of Urinalysis in Bladder Cancer

Bladder cancer usually has been diagnosed in elderly patients as it stays asymptomatic until it presents. Current detection methods for bladder cancer cannot be considered as an adequate screening strategy due to their high invasiveness and low sensitivity. However, there remains uncertainty about targets with high sensitivity and specificity for non-invasive bladder cancer examination. Our study aims to investigate the actionable non-invasive screening biomarkers in bladder cancer. Here, we employed scRNA-seq to explore the crucial biological processes for bladder cancer development. We then utilized bidirectional Mendelian randomization (MR) analysis to explore the bidirectional causal relationship between ATP-associated metabolites in urine and bladder cancer. Lastly, we used a BBN-induced mouse model of bladder cancer to validate the crucial gene identified by scRNA-seq and MR analysis. We found that (1) the ATP metabolism process plays a critical role in bladder cancer development; (2) there is a bidirectional and negative causal relationship between fructose-to-sucrose ratio in urine and the risk of bladder cancer; and (3) the higher expression of TPI1, a critical gene in the fructose metabolism pathway, was validated in BBN-induced bladder tumors. Our results reveal that fructose-to-sucrose ratio can serve as a potential target of urinalysis in bladder cancer

Train timetabling with dynamic and random passenger demand: A stochastic optimization method

Considering the dynamics and randomness of passenger demand, this paper investigates a train timetabling problem in the stochastic environment for an urban rail transit system. With the scenario-based representation of passenger distribution, an integer nonlinear programming (INLP) model is first formulated to simultaneously optimize the total number of train services, headway settings and speed profile selection decision during the planning time horizon, in which the expected total service cost is treated as the objective function. Through an analysis of the features of the nonlinear constraints, a reformulation method is proposed to develop an equivalent integer linear programming (ILP) model that can be easily solved by commercial software. Moreover, a variable neighborhood search algorithm is developed to find the approximate optimal solutions for large-scale problems within the tolerable computing time. Finally, two sets of numerical experiments, with the operation environments of a simple urban rail transit line and Fuzhou Metro Line 1, are implemented to verify the solution quality and effectiveness of the proposed methods

Rapid tagging of endogenous mouse genes by recombineering and ES cell complementation of tetraploid blastocysts

The construction of knockin vectors designed to modify endogenous genes in embryonic stem (ES) cells and the generation of mice from these modified cells is time consuming. The timeline of an experiment from the conception of an idea to the availability of mature mice is at least 9 months. We describe a method in which this timeline is typically reduced to 3 months. Knockin vectors are rapidly constructed from bacterial artificial chromosome clones by recombineering followed by gap-repair (GR) rescue, and mice are rapidly derived by injecting genetically modified ES cells into tetraploid blastocysts. We also describe a tandem affinity purification (TAP)/floxed marker gene plasmid and a GR rescue plasmid that can be used to TAP tag any murine gene. The combination of recombineering and tetraploid blastocyst complementation provides a means for large-scale TAP tagging of mammalian genes

Structural and Functional Insights into the Unwinding Mechanism of Bacteroides sp Pif1

Pif1 is a conserved SF1B DNA helicase involved in maintaining genome stability through unwinding double-stranded DNAs (dsDNAs), DNA/RNA hybrids, and G quadruplex (G4) structures. Here, we report the structures of the helicase domain of human Pif1 and Bacteroides sp Pif1 (BaPif1) in complex with ADP-AlF4– and two different single-stranded DNAs (ssDNAs). The wedge region equivalent to the β hairpin in other SF1B DNA helicases folds into an extended loop followed by an α helix. The Pif1 signature motif of BaPif1 interacts with the wedge region and a short helix in order to stabilize these ssDNA binding elements, therefore indirectly exerting its functional role. Domain 2B of BaPif1 undergoes a large conformational change upon concomitant binding of ATP and ssDNA, which is critical for Pif1’s activities. BaPif1 cocrystallized with a tailed dsDNA and ADP-AlF4–, resulting in a bound ssDNA bent nearly 90° at the ssDNA/dsDNA junction. The conformational snapshots of BaPif1 provide insights into the mechanism governing the helicase activity of Pif1