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The limited success of immunotherapies targeting immune checkpoint inhibitors is largely ascribed to the lack of infiltrating CD8+ T lymphocytes. Circular RNAs (circRNAs) are a novel type of prevalent noncoding RNA that have been implicated in tumorigenesis and progression, while their roles in modulating CD8+ T cells infiltration and immunotherapy in bladder cancer have not yet been investigated. Herein, we uncover circMGA as a tumor-suppressing circRNA triggering CD8+ T cells chemoattraction and boosting the immunotherapy efficacy. Mechanistically, circMGA functions to stabilize CCL5 mRNA by interacting with HNRNPL. In turn, HNRNPL increases the stability of circMGA, forming a feedback loop that enhances the function of circMGA/HNRNPL complex. Intriguingly, therapeutic synergy between circMGA and anti-PD-1 could significantly suppress xenograft bladder cancer growth. Taken together, the results demonstrate that circMGA/HNRNPL complex may be targetable for cancer immunotherapy and the study advances our understanding of the physiological roles of circRNAs in antitumor immunity.

Maize is a globally valuable commodity and one of the most extensively studied genetic model organisms. However, we know surprisingly little about the extent and potential utility of the genetic variation found in wild relatives of maize. Here, we characterize a high-density genomic variation map from 744 genomes encompassing maize and all wild taxa of the genus Zea, identifying over 70 million single-nucleotide polymorphisms. The variation map reveals evidence of selection within taxa displaying novel adaptations. We focus on adaptive alleles in highland teosinte and temperate maize, highlighting the key role of flowering-time-related pathways in their adaptation. To show the utility of variants in these data, we generate mutant alleles for two flowering-time candidate genes. This work provides an extensive sampling of the genetic diversity of Zea, resolving questions on evolution and identifying adaptive variants for direct use in modern breeding.

BackgroundMaize (Zea maysL.) is at the vanguard facing the upcoming breeding challenges. However, both a super pan-genome for theZeagenus and a comprehensive genetic variation map for maize breeding are still lacking.ResultsHere, we construct an approximately 6.71-Gb pan-Zeagenome that contains around 4.57-Gb non-B73 reference sequences from fragmented de novo assemblies of 721 pan-Zeaindividuals. We annotate a total of 58,944 pan-Zeagenes and find around 44.34% of them are dispensable in the pan-Zeapopulation. Moreover, 255,821 common structural variations are identified and genotyped in a maize association mapping panel. Further analyses reveal gene presence/absence variants and their potential roles during domestication of maize. Combining genetic analyses with multi-omics data, we demonstrate how structural variants are associated with complex agronomic traits.ConclusionsOur results highlight the underexplored role of the pan-Zeagenome and structural variations to further understand domestication of maize and explore their potential utilization in crop improvement.

As a new type of gear transmission developed in recent years, curve-face gear transmission has not appeared before. In order to solve the problem of root bending strength of the eccentric straight and helical curve face gear, a calculating method of the tooth root bending strength was proposed. According to the principle of space meshing, differential geometry and design of machinery, the parametric equations of pitch curve was obtained, the pressure angle and the contact ratio in the meshing process were derived. The plane equivalent pitch curve was obtained, and the formula for calculating the equivalent tooth form factor and the equivalent stress correction factor was acquired. The calculation method of the bending strength of the gear pair was established, and the influence of the basic structural parameters on the bending stress was also analyzed in detail. The position of the stress hazard of the eccentric curve-face gear was determined. Through the finite element analysis and transmission experiment, the accuracy of the calculation method of strength of the gear pair was verified.

Background Cisplatin (CDDP) has become a standard-of-care treatment for muscle-invasive bladder cancer (MIBC), while chemoresistance remains a major challenge. Accumulating evidence indicates that circular RNAs (circRNAs) are discrete functional entities. However, the regulatory functions as well as complexities of circRNAs in modulating CDDP-based chemotherapy in bladder cancer are yet to be well revealed. Methods Through analyzing the expression profile of circRNAs in bladder cancer tissues, RNA FISH, circRNA pull-down assay, mass spectrometry analysis and RIP, circLIFR was identified and its interaction with MSH2 was confirmed. The effects of circLIFR and MSH2 on CDDP-based chemotherapy were explored by flow cytometry and rescue experiments. Co-IP and Western blot were used to investigate the molecular mechanisms underlying the functions of circLIFR and MSH2. Biological implications of circLIFR and MSH2 in bladder cancer were implemented in tumor xenograft models and PDX models. Results CircLIFR was downregulated in bladder cancer and expression was positively correlated with favorable prognosis. Moreover, circLIFR synergizing with MSH2, which was a mediator of CDDP sensitivity in bladder cancer cells, positively modulated sensitivity to CDDP in vitro and in vivo. Mechanistically, circLIFR augmented the interaction between MutSα and ATM, ultimately contributing to stabilize p73, which triggered to apoptosis. Importantly, MIBC with high expression of circLIFR and MSH2 was more sensitive to CDDP-based chemotherapy in tumor xenograft models and PDX models. Conclusions CircLIFR could interact with MSH2 to positively modulate CDDP-sensitivity through MutSα/ATM-p73 axis in bladder cancer. CircLIFR and MSH2 might be act as promising therapeutic targets for CDDP-resistant bladder cancer.

Growing evidence has revealed that brain pericytes are multifunctional and contribute to the pathogenesis of a number of neurological disorders. However, the role of pericytes in cerebral ischemia, and especially the pathophysiological alterations in pericytes, remains unclear. In the present study, our aim was to determine whether the proliferation of pericytes is affected by cerebral ischemia and, if so, to identify the underlying mechanism(s). Cultured brain pericytes subjected to oxygen-glucose deprivation (OGD) were used as our model of cerebral ischemia; the protein expression levels of cyclin D1, cyclin E, cdk4, and cyclin B1 were determined by Western blot analysis, and cell cycle analysis was assessed by flow cytometry. The OGD treatment reduced the brain pericyte proliferation by causing G2/M phase arrest and downregulating the protein levels of cyclin D1, cyclin E, cdk4, and cyclin B1. Further studies demonstrated a simultaneous decrease in the activity of extracellular regulated protein kinases (ERK), suggesting a critical role of the ERK signaling cascade in the inhibition of OGD-induced pericyte proliferation. We suggest that OGD inhibition of the proliferation of brain pericytes is associated with the inactivation of the ERK signaling pathway, which arrests them in the G2/M phase.

RhoA, a small GTPase, is involved in a wide array of cellular functions in the central nervous system, such as cell motility, cytoskeleton rearrangement, transcriptional regulation, phagocytosis and cell growth. It is not known how spinal cord injury (SCI) affects the expression of RhoA in different nerve cells. In the present study, we investigated the changes of RhoA expression in remote areas of the injury at the 3rd, 7th and 30th day after SCI, which was established by T10 contusion method. Moreover, we examine its expression profile in neurons, astrocytes and microglia. RhoA was found to be weakly expressed in these nerve cells in normal spinal cord. Western blotting showed that, after SCI, the total RhoA expression was up-regulated, and the RhoA expression was increased and peaked at the 7th day. Double immunostaining revealed specific and temporal expression patterns of RhoA in different nerve cells. The expression of RhoA in neurons started to increase at day 3, peaked at day 7 and then decreased slightly at day 30. Expression of RhoA in astrocytes increased moderately after SCI and peaked at day 7. There was no obvious change in RhoA expression in microglia after SCI in remote areas. This study demonstrated that, after SCI, RhoA expression exhibited different patterns with different nerve cells of spinal cord. RhoA expression patterns also changed with time after SCI, and among different nerve cells in the injured spinal cord. These findings can help us better understand the roles of RhoA in SCI.

Numerical schemes for solving fractional differential equations are computationally heavy, due to the floating-point operations needed and, more importantly, the data flow within the entire memory system of a computer. We choose the fractional Adams-Bashforth-Moulton method as a representative numerical scheme, and review various code optimizations that can be applied to its serial and parallel implementations. As the most important contribution of this paper, we propose a simple methodology to analyze the achievable serial and parallel performance, based on quantifying the amount of data flow through various stages of the entire memory system, together with a small set of easily obtainable hardware parameters. This quantitative approach to performance modeling can in most cases pinpoint the real performance bottleneck, while also verifying the actual performance improvements due to various code optimizations. Moreover, the optimization techniques and performance modeling approach can both be applied to other convolution-intensive numerical methods for solving fractional differential equations.

The key to achieving high performance on a GPU-enhanced cluster is efficient exploitation of each GPU's powerful computing capability. Moreover, rationally balancing the workload between CPUs and GPUs can release additional computing power, which arises from the CPUs. In this paper, we extend our earlier work on using a hybrid CPU-GPU cluster for real-world sedimentary basin simulation, by further improving the involved CUDA implementations. A thorough analysis of the achieved new performance is also carried out. By using 1024 GPUs and 12288 CPU cores together, our best CPU-GPU hybrid implementation is able to achieve a double-precision performance of 72.8 TFlops, in connection with simulations on a huge 131072×131072 mesh.

To explore the reference value of intraoperative ultrasonography in the operative procedure and postoperative treatment with relation to hepatopancreatobiliary surgery. 103 cases of hepatopancreatobiliary operations were collected in our hospital from January 1996 to October 2005, in which 68 cases were males and the others were females, age ranged from 45 to 76 years. Hepatocellular carcinoma were 26 cases, gallbladder carcinoma were 5 cases, cholangiocarcinoma were 6 cases, pancreatic carcinoma were 10 cases and other 56 cases were gall stone and/or choledocholithiasis. Intraoperative ultrasonography with high frequency probe was used in all cases. Some minimal occult focuses was found by intraoperative ultrasonography. We found vascular tumor thrombosis in 70% cases of hepatocellular carcinomas. One case was diagnosed as pancreatic carcinoma before operation and found choledochal tract dilatation concurrently with cholangitis by intraoperative ultrasonography. Eight cases of gallstones with no choledochal stones before operation were found by intraoperative ultrasonography that stone lain in low segment of common bile duct. The image data of high quality obtained by intraoperative ultrasonography could not only direct our more proper operative practice but also favor us to make more reasonable postoperative treatment plan.