Infiltration by monocytes of the central nervous system and its role in multiple sclerosis: reflections on therapeutic strategies.

Mononuclear macrophage infiltration in the central nervous system is a prominent feature of neuroinflammation. Recent studies on the pathogenesis and progression of multiple sclerosis have highlighted the multiple roles of mononuclear macrophages in the neuroinflammatory process. Monocytes play a significant role in neuroinflammation, and managing neuroinflammation by manipulating peripheral monocytes stands out as an effective strategy for the treatment of multiple sclerosis, leading to improved patient outcomes. This review outlines the steps involved in the entry of myeloid monocytes into the central nervous system that are targets for effective intervention: the activation of bone marrow hematopoiesis, migration of monocytes in the blood, and penetration of the blood-brain barrier by monocytes. Finally, we summarize the different monocyte subpopulations and their effects on the central nervous system based on phenotypic differences. As activated microglia resemble monocyte-derived macrophages, it is important to accurately identify the role of monocyte-derived macrophages in disease. Depending on the roles played by monocyte-derived macrophages at different stages of the disease, several of these processes can be interrupted to limit neuroinflammation and improve patient prognosis. Here, we discuss possible strategies to target monocytes in neurological diseases, focusing on three key aspects of monocyte infiltration into the central nervous system, to provide new ideas for the treatment of neurodegenerative diseases.

Diosmetin-7-O-ß-D-glucopyranoside from Pogostemonis Herba alleviated SARS-CoV-2-induced pneumonia by reshaping macrophage polarization and limiting viral replication.

ETHNOPHARMACOLOGICAL RELEVANCE: Viral pneumonia is the leading cause of death after SARS-CoV-2 infection. Despite effective at early stage, long-term treatment with glucocorticoids can lead to a variety of adverse effects and limited benefits. The Chinese traditional herb Pogostemonis Herba is the aerial part of Pogostemon Cablin (Blanco) Benth., which has potent antiviral, antibacterial, anti-inflammatory, and anticancer effects. It was used widely for treating various throat and respiratory diseases, including COVID-19, viral infection, cough, allergic asthma, acute lung injury and lung cancer. AIM OF THE STUDY: To investigate the antiviral and anti-inflammatory effects of chemical compounds from Pogostemonis Herba in SARS-CoV-2-infected hACE2-overexpressing mouse macrophage RAW264.7 cells and hACE2 transgenic mice. MATERIALS AND METHODS: The hACE2-overexpressing RAW264.7 cells were exposed with SARS-CoV-2. The cell viability was detected by CCK8 assay and cell apoptotic rate was by flow cytometric assay. The expressions of macrophage M1 phenotype markers (TNF-α and IL-6) and M2 markers (IL-10 and Arg-1) as well as the viral loads were detected by qPCR. The mice were inoculated intranasally with SARS-CoV-2 omicron variant to induce viral pneumonia. The levels of macrophages, neutrophils, and T cells in the lung tissues of infected mice were analyzed by full spectrum flow cytometry. The expressions of key proteins were detected by Western blot assay. RESULTS: Diosmetin-7-O-ß-D-glucopyranoside (DG) presented the strongest anti-SARS-CoV-2 activity. Intervention with DG at the concentrations of 0.625-2.5 µM not only reduced the viral replication, cell apoptosis, and the productions of inflammatory cytokines (IL-6 and TNF-α) in SARS-CoV-2-infected RAW264.7 cells, but also reversed macrophage polarity from M1 to M2 phenotype. Furthermore, treatment with DG (25-100 mg/kg) alleviated acute lung injury, and reduced macrophage infiltration in SARS-COV-2-infected mice. Mechanistically, DG inhibited SARS-COV-2 gene expression and HK3 translation via targeting YTHDF1, resulting in the inactivation of glycolysis-mediated NF-κB pathway. CONCLUSIONS: DG exerted the potent antiviral and anti-inflammatory activities. It reduced pneumonia in SARS-COV-2-infected mice via inhibiting the viral replication and accelerating M2 macrophage polarization via targeting YTHDF1, indicating its potential for COVID-19 treatment.

Asymptomatic enteric pathogen carriage and its association with proton pump inhibitors use in men who have sex with men in Taiwan, 2019-2022.

OBJECTIVES: Currently recognized risk factors for sexually transmitted enteric infections (STEIs) among men who have sex with men (MSM) include oroanal sex, multiple sexual partners, and chemsex. This study aimed to investigate the prevalence of the asymptomatic carriage of enteric pathogens in men who have sex with men (MSM) and to identify the associated risk factors. METHODS: Questionnaires were completed by 375 MSM in Taiwan from December 2019 to November 2022. Fecal samples were analyzed by multiplex PCR to determine whether seven enteric pathogens, including Entamoeba histolytica, Giardia duodenalis, Shiga toxin-producing Escherichia coli, Cryptosporidium, Campylobacter, Salmonella, and Shigella species, were present. RESULTS: Among 375 fecal samples from asymptomatic MSM, 27 (7.2%) fecal samples tested positive for at least one enteric pathogen. The recent use of proton pump inhibitors (PPIs) was significantly associated with asymptomatic fecal carriage (22.2% vs. 2.0%, P < 0.001). G. duodenalis (2.1%, 8 cases), E. histolytica (1.6%, 6 cases), and Shigella species (1.3%, 5 cases) were commonly detected. Oroanal sex and PPI use were associated with the asymptomatic carriage of enteric pathogens. Specifically, Shigella, Salmonella, or Campylobacter carriage was significantly correlated with PPI use. In contrast, rectal gonorrhea was associated with multiple sexual partners and prior syphilis. CONCLUSIONS: Recent use of PPIs was associated with the asymptomatic carriage of enteric pathogens. Therefore, targeted education about the appropriate use of PPIs is necessary to mitigate the risk of STEIs among MSM.

Fish oil supplementation, genetic susceptibility and risk of new-onset hypertension.

OBJECTIVES: The risk of new-onset hypertension is influenced by habitual fish oil supplementation, but whether the association is modified by genetic predisposition is unknown. METHODS: A total of 213,604 participants without hypertension were identified at baseline from the UK Biobank between 2006 and 2010. The weighted polygenetic risk score (PRS) comprising 118 identified single-nucleotide polymorphisms (SNPs) was used to quantify genetic susceptibility. Cox regression models were applied to determine the association between fish oil supplementation, PRS, and hypertension and evaluate the effect modification of genetic susceptibility. RESULTS: During a median follow-up of 13.8 years, 18,498 new-onset hypertension cases were identified. Approximately 30.6 % (65,452) of participants were habitual fish oil users. The hazard ratio (HR) of habitual fish oil users for hypertension was 0.94 (95 % confidence interval [CI], 0.91-0.98). Fish oil nonusers with a high genetic risk had an increased risk of hypertension (HR, 1.52; 95 % CI, 1.41-1.64) compared to fish oil users with a low genetic risk. In addition, an interaction on the additive scale between the fish oil use and intermediate or high levels of genetic susceptibility was observed. The interactive effects accounted for approximately 7 % and 22 % of the risk of developing hypertension, respectively. CONCLUSIONS: This cohort study indicates regular fish oil supplementation could be beneficial in preventing hypertension, particularly among individuals with intermediate or high genetic susceptibility on an additive scale.

Bio-guided isolation of anti-inflammatory compounds from Tilia tuan Szyszyl. flowers via in vitro and in silico study.

ETHNOPHARMACOLOGICAL RELEVANCE: Tilia tuan Szyszyl. is a perennial arboreal plant renowned for its medicinal and economic significance. All the roots, stems, leaves, flowers, and fruits have been used medicinally by the folk Bai and Yi people in Yunnan province, China, to treat inflammation, rheumatism and pain for a long time. The detailed chemical constituents and their anti-inflammatory mechanisms remain unexplored. AIM OF THE STUDY: The objective of this study was to investigate the main anti-inflammatory constituents of T. tuan flowers through bio-guided isolation and to evaluate their anti-inflammatory effects relevant to its traditional medicinal use. MATERIAL AND METHODS: Bio-guided isolation was conducted on the extract of T. tuan flowers using a combination of column chromatography and preparative HPLC. The structures were established by a combination of extensive spectroscopic analyses and single-crystal X-ray diffraction analysis. The anti-inflammatory activity in vitro was evaluated by measuring the inhibition of nitric oxide (NO) production in LPS-stimulated RAW 264.7 cells. TNF-α and IL-6 levels were evaluated by ELISA. The expression of COX-2 and NF-κB was assayed via western blotting, and in-silico molecular docking was conducted to explore the potential mechanism. RESULTS: Twenty-two compounds, including ten flavonoids (1-10), seven phenylpropanoids (11-17), three triterpenoids (19-21), one sterol glucoside 18, and one glyceride 22, were identified from T. tuan flowers for the first time. Among them, 1 is a new compound. It is noted that 1, 5, 7, 8, 10, 17, and 22 exhibited remarkable anti-inflammatory activity against NO production with a range of 5.2-34.5 µM, superior to the positive control L-NMMA. Moreover, the new compound 1 inhibited significantly inflammatory factors IL-6 and TNF-α. CONCLUSION: The results show that flavonoids including the new one and the phenyl-propanoid are the primary active constituents of T. tuan flowers, responsible for its ethno-pharmacological uses on osteoarthritis and rheumatism. T. tuan flowers could be a promising therapeutic agent to modulate inflammatory diseases.

Mitochondrial modulation treating postoperative cognitive dysfunction neuroprotection via DRP1 inhibition by Mdivi1.

This study investigated the role of mitochondrial dynamics in postoperative cognitive dysfunction (POCD) and assessed the therapeutic potential of mitochondrial modulation, particularly through the inhibition of dynamin-related protein 1 (DRP1) with Mdivi-1. Our findings indicated that DRP1 inhibition substantially mitigated neuroinflammation mediated by microglial cells, contributing to improved cognitive function in POCD models. The administration of Mdivi-1 led to a notable decrease in mitochondrial fission, reduced reactive oxygen species (ROS) production, and stabilization of mitochondrial membrane potential, all of which correlate with diminished neuroinflammation, as evidenced by lower NOD-like receptor family pyrin domain containing 3 (NLRP3)/ interleukin-1ß (IL-1ß) expression in microglial cells. Importantly, Mdivi-1 treatment was also found to enhance synaptic plasticity, increasing synaptic spine density in the hippocampal region of POCD mice. This improvement in mitochondrial health and synaptic integrity was paralleled by enhanced cognitive performance, as demonstrated in Y-maze tests. These results underscored the critical role of mitochondrial dynamics in the pathophysiology of POCD and suggested that targeting mitochondrial dysfunction, specifically through DRP1 inhibition, could be an effective approach for POCD treatment.

S100A8 knockdown activates the PI3K/AKT signaling pathway to inhibit microglial autophagy and improve cognitive impairment mediated by chronic sleep deprivation.

OBJECTIVE: Cognitive dysfunction is one of the major symptoms of chronic sleep deprivation (CSD). Abnormal autophagy and apoptosis are thought to be important mechanisms. S100 Calcium Binding Protein A8 (S100A8) plays a key role in autophagy and apoptosis of microglia. This study investigated whether S100A8 knockdown can effectively inhibit aberrant autophagy in microglia and improve cognitive function by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway under CSD conditions. METHODS: CSD mouse models and BV2 cell autophagy models were established in vivo and in vitro. Transcriptome sequencing was used to determine the key regulator related to autophagy. The Morris water maze test was used to evaluate the cognitive behavior of the mice. RT-qPCR and western blot were conducted to examine S100A8 expression and autophagy signalling. HE, TUNEL, transmission electron microscopy, immunofluorescence, and histochemistry were performed to detect pathological changes, neuronal autophagy, apoptosis, or positive cells in hippocampal tissues, respectively. RESULTS: Transcriptome sequencing showed that S100A8 was significantly elevated in CSD mice, and fluorescence colocalization results further suggested that S100A8 mainly colocalizes with microglia. In vivo studies revealed that knockdown of S100A8 alleviated CSD-induced cognitive impairment in mice. Through further mechanistic investigations employing both in vivo and in vitro models, we demonstrated that silencing S100A8 can activate the PI3K/AKT pathway, thereby reducing CSD-induced abnormal autophagy and apoptosis in microglia. Aberrant autophagy and apoptosis in microglia were reversed with the PI3K/AKT pathway inhibitor LY294002. CONCLUSION: The S100A8/PI3K/AKT axis plays a crucial role in chronic sleep deprivation-mediated autophagy and apoptosis in microglia.

Preliminary human health risk assessment of antibiotic exposures in human waste handling occupations.

Exposure to biosolids in human waste handling occupations is associated with a risk for illness due to microbial infections. Although several years of exposure to biosolids might be hypothesized to be a prophylaxis against infection, the risks associated with infections from antibiotic-resistant organisms can also be a potential concern. Therefore, this study aimed to conduct a screening level risk assessment by deriving occupational exposure limits (OELs) characterizing the risks of adverse health effects among workers in human waste handling occupations with a focus on exposure to two pharmaceuticals commonly found in biosolids: ciprofloxacin (CIP) and azithromycin (AZ). Epidemiological and exposure studies of workers exposed to biosolids were identified through searches of major scientific databases. Screening OELs (sOELs) for these antibiotics were derived using a standardized methodology. The airborne concentrations of CIP and AZ antibiotics were determined using an exposure factors approach. The health-based exposure limits (i.e., sOELs) and the acceptable daily exposure (ADE) values for both of these antibiotics were derived as 80 µg/m3 and 12 µg/kg-day, respectively. An exposure factor approach suggested that inhalation route exposures to CIP and AZ are well below the sOELs and ADE daily doses, and likely too low to cause direct adverse health effects through antibiotic inhalation. A critical review of epidemiological studies on different occupations handling biosolids showed that the workers in industries with potential biosolids exposure have experienced an increased incidence of microbial-exposure-related illness. The health effects seen in the workers have been attributed to bacterial, viral, and protozoan infections. To the extent that bacteria are the pathogen of concern, it is not clear whether these bacteria are resistant to antibiotics commonly found in biosolids. It is also unclear whether the presence of antibiotics or antibiotic-resistant bacteria increases the susceptibility of these workers. Additional studies will provide more definitive estimates of inhalation and dermal exposures to CIP and AZ and could verify the exposure estimates in this study based on the literature and common exposure factors.

Deciphering the regulatory mechanisms and biological implications of ARID1A missense mutations in cancer.

ARID1A is a key component of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex and functions as a critical tumor suppressor in various cancers. In this study, we find that tumor cells with hotspot missense mutations in ARID1A (AT-rich interactive domain-containing protein 1A) exhibit a malignant phenotype. Mechanistically, these mutations facilitate the translocation of ARID1A mutant proteins to the cytoplasm by the nucleocytoplasmic shuttler XPO1 (exportin 1). Subsequently, the E3 ubiquitin ligase STUB1 ubiquitinates the ARID1A mutant protein, marking it for degradation. Knocking down STUB1 or inhibiting XPO1 stabilizes the ARID1A mutant protein, retaining it in the nucleus, which restores the assembly of the cBAF complex, the chromatin remodeling function, and the normal expression of genes related to the MAPK and anti-apoptotic pathways, thereby decreasing the tumor burden. Our research shows that nuclear-localized mutated ARID1A proteins retain tumor-suppressive function. We identify promising strategies to treat cancers harboring missense mutations in the BAF complex.

Withaferin a modulation of microglia autophagy mitigates neuroinflammation and enhances cognitive function in POCD.

With the aging process of the global population and the development of medical technology, the cases of postoperative cognitive dysfunction (POCD) are also increasing. Due to the complexity of the pathogenesis, urgent treatment has been sought. Neuroinflammation induced by the accumulation of lipid droplets (LDs) in microglia has been closely watched in recent years and is also considered to be an important cause of nerve damage. Our study found that derived from Withania somnifera, Withaferin A (WA) could reduce the accumulation of LDs in the hippocampus of POCD mice, inhibit the expression of inflammatory factor interleukin-1ß (IL-1ß), and improve the cognitive ability of mice. Further in vitro experimental studies showed that WA increased the autophagy level of microglia, promoted the degradation of LDs, and reduced the production of inflammatory factors. In this regard, our comprehensive research endeavor holds the potential to furnish novel insights into therapeutic strategies aimed at addressing POCD and its associated neural impairments.

Development and evaluation of a panel of newly screened Y chromosome InDels for inferring paternal ancestry information in Southwest China.

Y-InDels (insertions/deletions) are genetic markers which are extremely understudied. It is unknown whether this type of markers can be utilized for genetic ancestry inference. We have developed an innovative Y chromosome ancestry inference system tailored for forensic applications. This panel amplifies 21 Y chromosome loci, encompassing Y-InDels and Y-SNPs (Single Nucleotide Polymorphism), utilizing the capillary electrophoresis (CE) platform. The system performed well at DNA concentrations greater than 0.125 ng/ul and produced accurate results at a 1:100 mixing ratio of male and female DNA. The Cumulative probability of matching (CPM) was between 0.95 and 0.97 in the experimental population. The system's efficacy in inferring ancestral origins was demonstrated through intercontinental population discrimination, revealing high discrimination power between African and East Asian populations. Population genetic analyses conducted on Han, Qiang and Hui populations in Southwest China, where the smallest FST value was 0.0002 between Han Chinese in Beijing (from 1000 Genomes Project) and Qiang Chinese from Sichuan (CQSC). Phylogenetic tree construction further illuminated distinct haplotypes among populations, with ethnically unique haplotypes observed in 34.6% of Hui and 7.1% of Qiang populations. K-fold cross-validation show the system's inference abilities at the intercontinental level. In addition, our investigations identified potential associations between the Y-InDel locus Y: 15,385,547 (GRCh37) and haplogroup R1a1a1b2a2- Z2124, as well as locus Y: 13,990,180 (GRCh37) and haplogroup F-M89. In conclusion, we have established a Y-chromosome inference system tailored for grassroots-level application, underscoring the value of incorporating Y-InDel markers in forensic analyses.

Effects of Streptomyces melanosporofaciens X216 on microbial diversity in oilseed rape soil.

Introduction: Clubroot disease is a devastating soil borne disease caused by infection with Plasmodiophora brassicae, which primarily affects cruciferous plants. The microbial diversity of the soil is an essential indicator of its quality. Methods: This study measured the physicochemical properties of the soil to study the effect of its microbial diversity on the infection of oilseed rape with P. brassicae. High-throughput sequences of the soil bacteria and fungi in the inter-root soils of P. brassicae were analyzed under different treatment conditions. Results: In the study, it was found that the efficiency of strain X216 in preventing and controlling the root disease of rapeseed was positively correlated with the amount of solution used to irrigate the root system. The results of the greenhouse and field trials showed that the efficiency of strain X216 against the root disease of rapeseed was 43.16% in the field and 62.14% in the greenhouse. Proteobacteria, Chloroflexi, Rozellomycota, and Basidiomycota are critical phylum in the development of clubroot disease. The application of biocontrol increased the relative abundance of Actinobacteria, Bacillus, Mesorhizobium, Mycobacterium, Streptomyces and Filobasidium, which affected the structure and abundance of microbial communities. A principal coordinate analysis showed that the microbial structure in the soil varied substantially in the bacterial community, and there was no significant difference in soil structure in the fungal community. Discussion: The occurrence of clubroot disease affected the structure of inter-root microbial community composition in the soil, which resulted in a decrease in its community diversity. The application of the biocontrol bacterium X216 increased the soil microbial diversity. It effectively reduced the occurrence of P. brassicae, and this study provides a basis to study the microbial diversity in cruciferous crops.

Beyond conventional treatment: ASGR1 Leading the new era of hypercholesterolemia management.

Cardiovascular disease (CVD) remains a leading cause of mortality worldwide, with hypercholesterolemia being a major risk factor. Although various lipid-lowering therapies exist, many patients fail to achieve optimal cholesterol control, highlighting the need for novel therapeutic approaches. ASGR1 (asialoglycoprotein receptor 1), predominantly expressed on hepatocytes, has emerged as a key regulator of cholesterol metabolism and low-density lipoprotein (LDL) clearance. This receptor's ability to regulate lipid homeostasis positions it as a promising target for therapeutic intervention in hypercholesterolemia and related cardiovascular diseases. This review critically examines the biological functions and regulatory mechanisms of ASGR1 in cholesterol metabolism, with a focus on its potential as a therapeutic target for hypercholesterolemia and related cardiovascular diseases. By analyzing recent advances in ASGR1 research, this article explores its role in liver-specific pathways, the implications of ASGR1 variants in CVD risk, and the prospects for developing ASGR1-targeted therapies. This review aims to provide a foundation for future research and clinical applications in hypercholesterolemia management.

Syntheses and performance study of three POM-viologen compounds with photo- and electric-stimulation response.

In recent years, stimulus responsive materials have received widespread attention. Under solvothermal conditions, three polyoxometalates-viologen organic-inorganic hybrid compounds were successfully constructed by combining a viologen ligand 1-(3-Nitro-benzyl)-[4,4']bipyridinyl-1-ium bromide (1,3-nibipy·Br) with octamolybdate, namely [Cu2(1,3-nibipy)4(H2O)2(ß-Mo8O26)2]·2H2O (1), [Cu2(1,3-nibipy)4(H2O)4(ß-Mo8O26)]·(ß-Mo8O26) (2) and (1,3-Hnibipy)2·(ß-Mo8O26) (3). These three compounds can exhibit color changing properties under both light and electrical stimulation. Through characterizations of PXRD, FT-IR, UV-vis spectra, XPS, EPR, CV, and other tests, the photochromic and electrochromic properties of these three compounds are caused by the generation of viologen radicals. Compounds 1-3 have a rapid photoresponse efficiency and can be made into mixed matrix films for use as ultraviolet detectors. In addition, coated filter paper synthesized from acetonitrile and compounds can serve as an innovative erasable ink-free printing material medium, which is suitable for various erasable ink-free printing and anti-counterfeiting fields. We further investigated the electrochromic devices prepared from compounds 1-3, which achieved color change at a voltage of around -0.2 V and exhibited good stability after 500 cycles.

EphrinB2-mediated chondrocyte autophagy induces post-traumatic arthritis via rupture of cartilage homeostasis.

EphrinB2, a member of the Ephrin family, has been linked to several orthopaedic conditions. Nevertheless, the correlation between ephrinB2 and post-traumatic arthritis (PTOA) remains unclear. Human PTOA cartilage from human and mouse knee joints was systematically analysed to investigate the relationship between EphrinB2 and PTOA using SO-FG and toluidine blue staining, micro-CT, histomorphometry, immunohistochemistry, immunofluorescence, lentiviral articular injection and in situ end labeling (TUNEL) assays. EphrinB2 expression was significantly downregulated in PTOA chondrocytes. Blocking EphrinB2 increased the breakdown of cartilage matrix in mice with PTOA via reducing the process of chondrocyte autophagy. The presence of severe cartilage damage was evident, as indicated by a considerable decrease in both cartilage thickness and area, accompanied by an increase in chondrocyte death. Altogether, EphrinB2 is required for the maintenance of cartilage homeostasis in post-traumatic arthritis, and EphrinB2 ablation is associated with accelerated chondrocyte matrix degeneration, finally causing damage to the articular cartilage.

Causal associations between intermediate very-low-density lipoprotein cholesterol-to-total lipids ratio and peptic ulcer: A bidirectional Mendelian randomization study.

BACKGROUND: Previous epidemiologic investigations have consistently demonstrated a strong association between the ratio of cholesterol to total lipids in medium very-low-density lipoprotein (VLDL) and the occurrence of peptic ulcers (PU). However, the precise causal relationship between these factors remains ambiguous. Consequently, this study aims to elucidate the potential correlation between the ratio of cholesterol to total lipids in medium VLDL and the incidence of peptic ulcer. AIM: To investigate the ratio of cholesterol to total lipids in medium very-low-density lipoprotein (VLDL) association with PU via genetic methods, guiding future clinical research. METHODS: Genome-wide association study (GWAS) datasets for the ratio of cholesterol to total lipids in intermediate VLDL and peptic ulcer were retrieved from the IEU OpenGWAS project (https://gwas.mrcieu.ac.uk). For the forward Mendelian randomization (MR) analysis, 72 single nucleotide polymorphisms (SNPs) were identified as instrumental variables. These SNPs were selected based on their association with the ratio of cholesterol to total lipids in intermediate VLDL, with peptic ulcer as the outcome variable. Conversely, for the inverse MR analysis, no SNPs were identified with peptic ulcer as the exposure variable and the ratio of cholesterol to total lipids in intermediate VLDL as the outcome. All MR analyses utilized inverse variance weighted (IVW) as the primary analytical method. Additionally, weighted median and MR-Egger methods were employed as supplementary analytical approaches to assess causal effects. Egger regression was used as a supplementary method to evaluate potential directional pleiotropy. Heterogeneity and multiplicity tests were conducted using the leave-one-out method to evaluate result stability and mitigate biases associated with multiple testing. RESULTS: The genetically predicted ratio of cholesterol to total lipids in medium VLDL was significantly associated with an elevated risk of peptic ulcer (IVW: OR = 2.557, 95%CI = 1.274-5.132, P = 0.008). However, no causal association of peptic ulcer with the ratio of cholesterol to total lipids in medium VLDL was observed in the inverse Mendelian randomization analysis. CONCLUSION: In conclusion, our study reveals a significant association between the ratio of cholesterol to total lipids in medium VLDL and an elevated risk of peptic ulcers. However, further validation through laboratory investigations and larger-scale studies is warranted to strengthen the evidence and confirm the causal relationship between these factors.

Consensus on the monitoring, treatment, and prevention of leukaemia relapse after allogeneic haematopoietic stem cell transplantation in China: 2024 update.

The consensus in 2018 from The Chinese Society of Haematology (CSH) on the monitoring, treatment, and prevention of leukaemia relapse after allogeneic haematopoietic stem cell transplantation (HSCT) facilitated the standardization of clinical practices in China and progressive integration with the world. To integrate recent developments and further improve the consensus, a panel of experts from the CSH recently updated the following consensus: (1) integrate risk-adapted, measurable residual disease (MRD)-guided strategy on modified donor lymphocyte infusion (DLI) and interferon-α into total therapy, which was pioneered and refined by Chinese researchers; (2) provide additional evidence of the superiority of haploidentical HSCT (the dominant donor source in China) to matched HSCT for high-risk populations, especially for pre-HSCT MRD-positive patients; (3) support the rapid progress of techniques for MRD detection, such as next-generation sequencing (NGS) and leukaemia stem cell-based MRD detection; and (4) address the role of new targeted options in transplant settings. In conclusion, the establishment of a "total therapy" strategy represents a great step forward. We hope that the consensus updated by Chinese scholars will include the latest cutting-edge developments and inspire progress in post-HSCT relapse management.

Effect of irisin on ovarian phosphatidylinositol-3-kinase/protein kinase B signaling pathway and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways of rats with polycystic ovary syndrome.

OBJECTIVE: To investigate the independent effects of irisin on insulin resistance (IR) in ovary of polycystic ovary syndrome (PCOS) and explore possible pathways. METHODS: We established PCOS medel using Poretsky L's method, then PCOS rats were randomly divided into model group (M) and irisin group (I), and normal rats (N) were used as the control. Then rats in the group I were injected with recombinant irisin. Then the levels of circulating fasting blood glucose (FBG), fasting insulin (FINS), homeostasis model assessment of IR (HOMA-IR) and PI3K/AKT and MAPK/ERK pathways in each group were observed, as well as the effects of irisin on the levels of circulating HOMA-IR and PI3K/AKT and MAPK/ERK pathways in ovary of PCOS rats were evaluated. RESULTS: Compared with normal group, levels of FBG, FINS, and HOMA-IR of model group were significantly increased (p < 0.001, p < 0.001, and p < 0.001, respectively), levels of average optical density by IHC of p-PI3K, PI3K, p-AKT, and AKT (p = 0.015, p = 0.010, p = 0.005, and p = 0.009, respectively) and levels of mRNA concentration of PI3K and AKT (p = 0.001, and p = 0.005, respectively) were decreased, while the levels of average optical density of p-ERK, ERK (p = 0.011, and p = 0.013, respectively) and level of mRNA concentration of ERK (p < 0.001) were increased in ovary. After irisin intervention, compared with model group, levels of FBG, FINS, and HOMA-IR of rats in irisin group were significantly decreased (p = 0.001, p < 0.001, and p < 0.001, respectively), levels of average optical density by IHC of p-PI3K, PI3K, p-AKT, and AKT (p = 0.030, p = 0.024, p = 0.012, and p = 0.025, respectively) and levels of mRNA concentration of PI3K and AKT (p = 0.002, and p = 0.003, respectively) were significantly increased, while the levels of average optical density of p-ERK, ERK (p = 0.004, and p = 0.026, respectively) and level of mRNA concentration of ERK (p = 0.001) were significantly decreased. CONCLUSION: Our study demonstrated that irisin could not only improve circulating insulin resistance, but may also improve ovarian IR through an increase in the activity of PI3K/AKT signaling and a decrease of MAPK/ERK signaling.

Two functionally interchangeable Vps9 isoforms mediate pollen tube penetration of style.

Style penetration by pollen tubes is essential for reproductive success, a process requiring canonical Rab5s in Arabidopsis. However, functional loss of Arabidopsis Vps9a, the gene encoding for guanine nucleotide exchange factor (GEF) of Rab5s, did not affect male transmission, implying the presence of a compensation program or redundancy. By combining genetic, cytological, and molecular approaches, we report that Arabidopsis Vps9b is a pollen-preferential gene, redundantly mediating pollen tube penetration of style with Vps9a. Vps9b is functionally interchangeable with Vps9a, whose functional distinction results from distinct expression profiles. Functional loss of Vps9a and Vps9b results in the mis-targeting of Rab5-dependent tonoplast proteins, defective vacuolar biogenesis, disturbed distribution of post-Golgi vesicles, increased cellular turgor, cytosolic acidification, and disrupted organization of actin microfilaments (MF) in pollen tubes, which collectively lead to the failure of pollen tubes to grow through style.

Cu/Pd-Catalyzed Tandem Carbonylative Synthesis of Ester-Containing 3,4-Dihydroquinolin-2(1H)-one Derivatives from Alkyne-Tethered α-Bromocarbonyls.

A Cu/Pd-catalyzed tandem radical cyclization and carbonylation of alkyne-tethered α-bromocarbonyls with phenols has been developed for the expedited construction of ester-containing 3,4-dihydroquinolin-2(1H)-one scaffolds. By employing benzene-1,3,5-triyl triformate (TFBen) as the CO source, the reaction proceeded smoothly to afford a series of ester-containing 3,4-dihydroquinolin-2(1H)-one derivatives in high yields. Moreover, this method could be utilized in the late-stage modifications of bioactive molecules.