Unveiling the potential of Butylphthalide: inhibiting osteoclastogenesis and preventing bone loss

Osteoporosis, resulting from overactive osteoclasts and leading to elevated fracture risk, has emerged as a global public health concern due to the aging population. Therefore, inhibiting osteoclastogenesis and bone resorption function represents a crucial approach for preventing and treating osteoporosis. The purpose of this study was to examine the effects and molecular mechanisms of Butylphthalide (NBP) on the differentiation and function of osteoclasts induced by RANKL. Osteoclastogenesis was assessed through TRAP staining and bone slice assay. An animal model that underwent ovariectomy, simulating postmenopausal women’s physiological characteristics, was established to investigate the impact of Butylphthalide on ovariectomy-induced bone loss. To delve deeper into the specific mechanisms, we employed Western blot, PCR, immunofluorescence, and immunohistochemical staining to detect the expression of proteins that are associated with the osteoclast signaling pathway. In this study, we found that Butylphthalide not only suppressed osteoclastogenesis and bone resorption in vitro but also significantly decreased TRAcP-positive osteoclasts and prevented bone loss in vivo. Further mechanistic experiments revealed that Butylphthalide reduces intracellular ROS in osteoclasts, inhibits the MAPK and NFATc1 signaling pathways, and downregulates the key genes and proteins of osteoclasts. This inhibits osteoclast formation and function. The reduction in ROS in osteoclasts is intricately linked to the activity of Butylphthalide-modulated antioxidant enzymes. Overall, NBP may offer a alternative treatment option with fewer side effects for skeletal diseases such as osteoporosis

Joint Machine Selection and Buffer Allocation in Large Split and Merge Manufacturing Systems

This study focuses on the simultaneous optimization of machines and buffers in split and merge production systems. The objective was to minimize the total investment cost under a minimum throughput rate and maximum cycle time constraints. It is challenging to solve this type of stochastic resource allocation problem due to the phenomenon of the combinatorial explosion search space and the inability to obtain closed-form expressions for the optimization model. In this paper, a decomposition-coordination method (DCM) is proposed to optimize the machine types used, the number of machines, and the capacities of buffers of general feed-forward topology systems efficiently and accurately. Instead of directly targeting large-scale systems, the DCM decomposes the original system into several small decoupled systems with added coordination variables and then separately optimizes each decomposed system. An optimal or near-optimal solution is obtained after several iterations of the decoupled system optimization and coordination variable updating. Moreover, we develop a simulated annealing algorithm and non-dominated sorting genetic algorithm-II as benchmark algorithms and provide a parameter calibration analysis of the two metaheuristics. Finally, comprehensive numerical experiments are performed to demonstrate the performances of the DCM, and a multifactorial experimental analysis is conducted to determine the influence of the split and merge system parameters on the performances of the DCM. The results confirmed that the scale of the system, complexity of topology, cycle time constraint, traffic intensity, price ratio, and their interactions significantly influenced the total cost obtained from the DCM, whereas the scale of the system, traffic intensity, and price ratio significantly affected the computation time

Species composition and environmental adaptation of indigenous Chinese cattle

Abstract Indigenous Chinese cattle combine taurine and indicine origins and occupy a broad range of different environments. By 50 K SNP genotyping we found a discontinuous distribution of taurine and indicine cattle ancestries with extremes of less than 10% indicine cattle in the north and more than 90% in the far south and southwest China. Model-based clustering and f4-statistics indicate introgression of both banteng and gayal into southern Chinese cattle while the sporadic yak influence in cattle in or near Tibetan area validate earlier findings of mitochondrial DNA analysis. Geographic patterns of taurine and indicine mitochondrial and Y-chromosomal DNA diversity largely agree with the autosomal cline. The geographic distribution of the genomic admixture of different bovine species is proposed to be the combined effect of prehistoric immigrations, gene flow, major rivers acting as genetic barriers, local breeding objectives and environmental adaptation. Whole-genome scan for genetic differentiation and association analyses with both environmental and morphological covariables are remarkably consistent with previous studies and identify a number of genes implicated in adaptation, which include TNFRSF19, RFX4, SP4 and several coat color genes. We propose indigenous Chinese cattle as a unique and informative resource for gene-level studies of climate adaptation in mammals

Life Beyond Kinases: Structure-Based Discovery of Sorafenib as Nanomolar Antagonist of 5-HT Receptors

Of great interest in recent years has been computationally predicting the novel polypharmacology of drug molecules. Here, we applied an “induced-fit” protocol to improve the homology models of 5-HT_2A receptor, and we assessed the quality of these models in retrospective virtual screening. Subsequently, we computationally screened the FDA approved drug molecules against the best induced-fit 5-HT_2A models and chose six top scoring hits for experimental assays. Surprisingly, one well-known kinase inhibitor, sorafenib, has shown unexpected promiscuous 5-HTRs binding affinities, <i>K</i>_i = 1959, 56, and 417 nM against 5-HT_2A, 5-HT_2B, and 5-HT_2C, respectively. Our preliminary SAR exploration supports the predicted binding mode and further suggests sorafenib to be a novel lead compound for 5HTR ligand discovery. Although it has been well-known that sorafenib produces anticancer effects through targeting multiple kinases, carefully designed experimental studies are desirable to fully understand whether its “off-target” 5-HTR binding activities contribute to its therapeutic efficacy or otherwise undesirable side effects

The 2022 report of synergetic roadmap on carbon neutrality and clean air for China: Accelerating transition in key sectors

China is now confronting the intertwined challenges of air pollution and climate change. Given the high synergies between air pollution abatement and climate change mitigation, the Chinese government is actively promoting synergetic control of these two issues. The Synergetic Roadmap project was launched in 2021 to track and analyze the progress of synergetic control in China by developing and monitoring key indicators. The Synergetic Roadmap 2022 report is the first annual update, featuring 20 indicators across five aspects: synergetic governance system and practices, progress in structural transition, air pollution and associated weather-climate interactions, sources, sinks, and mitigation pathway of atmospheric composition, and health impacts and benefits of coordinated control. Compared to the comprehensive review presented in the 2021 report, the Synergetic Roadmap 2022 report places particular emphasis on progress in 2021 with highlights on actions in key sectors and the relevant milestones. These milestones include the proportion of non-fossil power generation capacity surpassing coal-fired capacity for the first time, a decline in the production of crude steel and cement after years of growth, and the surging penetration of electric vehicles. Additionally, in 2022, China issued the first national policy that synergizes abatements of pollution and carbon emissions, marking a new era for China's pollution-carbon co-control. These changes highlight China's efforts to reshape its energy, economic, and transportation structures to meet the demand for synergetic control and sustainable development. Consequently, the country has witnessed a slowdown in carbon emission growth, improved air quality, and increased health benefits in recent years