Model-based assessment of longitudinal dynamic performance and energy consumption of heavy haul train on long-steep downgrades

Longitudinal dynamics performance and energy consumption of heavy haul train should be considered in the design of heavy haul railway profile of long-steep downgrades. A quantitative analytical tool is developed to assess the longitudinal dynamic performance and energy consumption of heavy haul trains with large axle loads on grades with different longitudinal profiles, including a longitudinal dynamic model of the train and a method of calculating the energy consumption during the operation of heavy haul train. The model is then preliminarily validated by the data of coupler force collected in two comprehensive tests. Finally, the proposed analytical tool is used to assess the designed longitudinal track profile of a long-deep downgrade segment of the central south heavy haul railway of Shanxi (China)

PARP inhibitor-related haemorrhages: What does the real-world study say?

BackgroundPARP inhibitors (PARPis) are novel molecular targeted therapeutics for inhibition of DNA repair in tumor cells, which are commonly used in ovarian cancer. Recent case reports have indicated that haemorrhages-related adverse events may be associated with PARPis. However, little is known about the characteristics and signal strength factors of this kind of adverse event.MethodsA pharmacovigilance study from January 2004 to March 2022 based on the FDA adverse event reporting system (FAERS) database was conducted by adopting the proportional imbalance method based on the four algorithms, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural networks (BCPNN) and multi-item gamma Poisson shrinker (MGPS).Results725 cases of PARPi-haemorrhages-related adverse events were identified with a fatality rate of 4.72% (30/725) and a median age of 67 years. About 88% of the adverse events occurred within 6 months, and the median duration (IQR) was 68 days. Most adverse events (n=477, 75.11%) were related to the treatment of niraparib. Importantly, niraparib exposure was associated with a significant increase in haemorrhages-related adverse events (ROR (95% CI), 1.13(1.03,1.23), PRR (χ2), 1.12(7.32), IC (IC 025), 0.17(0.15). In addition, petechiae, gingival bleeding, bloody urine, as well as rectal haemorrhage should be monitored when using niraparib.ConclusionRecognition and management of PARPi-haemorrhages-related adverse events is of significance to clinical practice. In this study, we provided a safety signal that haemorrhage-related adverse events should be monitored for when using niraparib. However, larger and more robust post-market safety studies are needed to improve the quality of this evidence

A systematic analysis of the role of GGDEF-EAL domain proteins in virulence and motility in Xanthomonas oryzae pv. oryzicola

The second messenger c-di-GMP is implicated in regulation of various aspects of the lifestyles and virulence of Gram-negative bacteria. Cyclic di-GMP is formed by diguanylate cyclases with a GGDEF domain and degraded by phosphodiesterases with either an EAL or HD-GYP domain. Proteins with tandem GGDEF-EAL domains occur in many bacteria, where they may be involved in c-di-GMP turnover or act as enzymatically-inactive c-di-GMP effectors. Here, we report a systematic study of the regulatory action of the eleven GGDEF-EAL proteins in Xanthomonas oryzae pv. oryzicola, an important rice pathogen causing bacterial leaf streak. Mutational analysis revealed that XOC_2335 and XOC_2393 positively regulate bacterial swimming motility, while XOC_2102, XOC_2393 and XOC_4190 negatively control sliding motility. The ΔXOC_2335/XOC_2393 mutant that had a higher intracellular c-di-GMP level than the wild type and the ΔXOC_4190 mutant exhibited reduced virulence to rice after pressure inoculation. In vitro purified XOC_4190 and XOC_2102 have little or no diguanylate cyclase or phosphodiesterase activity, which is consistent with unaltered c-di-GMP concentration in ΔXOC_4190. Nevertheless, both proteins can bind to c-di-GMP with high affinity, indicating a potential role as c-di-GMP effectors. Overall our findings advance understanding of c-di-GMP signaling and its links to virulence in an important rice pathogen

miR-33a Mediates the Anti-Tumor Effect of Lovastatin in Osteosarcoma by Targeting CYR61

Background/Aims: Preventing cell metastasis is an effective therapeutic strategy to treat osteosarcoma and improve prognosis. Statins have been found to have anticancer effects in addition to their cholesterol-lowering action. As a new target of statins, cysteine-rich 61 (CYR61) was recently identified to promote cell migration and metastasis in osteosarcoma. However, the underlying mechanisms mediating the regulation of CYR61 expression by statins remain unknown. Methods: Human osteosarcoma cell lines MG63 and SaOS2 were used to clarify the effect of lovastatin on CYR61 expression. Real-time PCR was performed to detect mRNA or microRNA (miRNA) levels and western blot was performed to detect protein levels. Cell invasive ability was determined using Transwell assays. Lentivirus encoding CYR61 cDNA or sterol regulatory element-binding protein 2 (SREBP-2) shRNA was used to upregulate CYR61 expression or downregulate SREBP-2 expression. Binding of the CYR61 3’ untranslated region (UTR) and miR-33a was analyzed by luciferase reporter assay. Results: We found that lovastatin treatment decreased CYR61 expression, inhibited cell invasion and altered epithelial-to-mesenchymal-transition (EMT)-related protein expression, while CYR61 overexpression abolished the effect of lovastatin. Moreover, lovastatin increased the expression of SREBP-2 and miR-33a, which were then downregulated by SREBP-2 silencing. Bioinformatics analysis indicated that the CYR61 3′UTR harbored a potential miR-33a binding site and luciferase reporter assay demonstrated that CYR61 was a target of miR-33a in osteosarcoma cells. Furthermore, miR-33a could inhibit cell invasion and alter EMT-related protein expression. SREBP-2 silencing or miR-33a inhibitor upregulated CYR61 expression and reversed the effects of lovastatin on cell invasion and EMT-related proteins. Conclusion: Our findings suggest lovastatin suppresses osteosarcoma cell invasion through the SREBP-2/miR-33a/CYR61 pathway

Three-Dimensional Manipulation of Micromodules Using Twin Optothermally Actuated Bubble Robots

A 3D manipulation technique based on two optothermally generated and actuated surface-bubble robots is proposed. A single laser beam can be divided into two parallel beams and used for the generation and motion control of twin bubbles. The movement and spacing control of the lasers and bubbles can be varied directly and rapidly. Both 2D and 3D operations of micromodules were carried out successfully using twin bubble robots. The cooperative manipulation of twin bubble robots is superior to that of a single robot in terms of stability, speed, and efficiency. The operational technique proposed in this study is expected to play an important role in tissue engineering, drug screening, and other fields

Cerebellar repetitive transcranial magnetic stimulation versus propranolol for essential tremor

Abstract Background Propranolol, a nonselective beta‐adrenergic blocker, has long been used as one of the standard treatments for essential tremor (ET). Repetitive transcranial magnetic stimulation (rTMS) has also been used for a long time as a substitution therapy for ET patients. Objective The main aim of this study was to evaluate the antitremor effect of 1‐Hz (low‐frequency) cerebellar rTMS and compare it to the use of propranolol in ET patients. Methods In this single‐blinded, randomized, controlled pilot study, a total of 38 patients with ET were randomized into two groups. One group (n = 20) received 1200 pulses of 1‐Hz rTMS at an intensity of 90% of the resting motor threshold to the bilateral cerebellar region for 10 days. Another group (n = 18) received oral propranolol for 30 days. The initial dose was 30 mg/day, which was increased to 60 mg/day after 5 days, then to 90 mg/day on the 11th day, and continued thereafter for 20 days. The Fahn–Tolosa–Marin (FTM) clinical scale was assessed at baseline and at days 5, 10, and 30 to evaluate tremor severity, specific motor tasks, and functional disability. Results Low‐frequency rTMS of the cerebellum significantly improved tremor severity, specific motor tasks (writing, spiral drawing, and pouring), and FTM total scores on days 10 and 30. Nevertheless, we found no significant difference in functional disability at any point in time (p > .05). There were no statistically significant differences in FTM Part A, Part B, Part C scores and total scores of patients in propranolol group on days 5 and 10 compared with before treatment (p > .05). However, FTM total scores and FTM Part A, Part B, and Part C scores were significantly improved for patients when the dose of propranolol was 90 mg/day on day 30. Our study showed that there was no statistically significant difference in the total FTM scores and FTM Part A, Part B, and Part C scores between rTMS and propranolol on days 5, 10, and 30 (p > .05). Conclusion We conclude that both cerebellar low‐frequency rTMS and propranolol could be effective treatment options for patients with ET, but it is not clear which method is more effective