Functions of Basic Helix-Loop-Helix (bHLH) Proteins in the Regulation of Plant Responses to Cold, Drought, Salt, and Iron Deficiency: A Comprehensive Review.

Abiotic stresses including cold, drought, salt, and iron deficiency severely impair plant development, crop productivity, and geographic distribution. Several bodies of research have shed light on the pleiotropic functions of BASIC HELIX-LOOP-HELIX (bHLH) proteins in plant responses to these abiotic stresses. In this review, we mention the regulatory roles of bHLH TFs in response to stresses such as cold, drought, salt resistance, and iron deficiency, as well as in enhancing grain yield in plants, especially crops. The bHLH proteins bind to E/G-box motifs in the target promoter and interact with various other factors to form a complex regulatory network. Through this network, they cooperatively activate or repress the transcription of downstream genes, thereby regulating various stress responses. Finally, we present some perspectives for future research focusing on the molecular mechanisms that integrate and coordinate these abiotic stresses. Understanding these molecular mechanisms is crucial for the development of stress-tolerant crops.

Association of genetic variants related to combined lipid-lowering and antihypertensive therapies with risk of cardiovascular disease: 2 × 2 factorial Mendelian randomization analyses.

BACKGROUND: Lipid-lowering drugs and antihypertensive drugs are commonly combined for cardiovascular disease (CVD). However, the relationship of combined medications with CVD remains controversial. We aimed to explore the associations of genetically proxied medications of lipid-lowering and antihypertensive drugs, either alone or both, with risk of CVD, other clinical and safety outcomes. METHODS: We divided 423,821 individuals in the UK Biobank into 4 groups via median genetic scores for targets of lipid-lowering drugs and antihypertensive drugs: lower low-density lipoprotein cholesterol (LDL-C) mediated by targets of statins or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lower systolic blood pressure (SBP) mediated by targets of ß-blockers (BBs) or calcium channel blockers (CCBs), combined genetically lower LDL-C and SBP, and reference (genetically both higher LDL-C and SBP). Associations with risk of CVD and other clinical outcomes were explored among each group in factorial Mendelian randomization. RESULTS: Independent and additive effects were observed between genetically proxied medications of lipid-lowering and antihypertensive drugs with CVD (including coronary artery disease, stroke, and peripheral artery diseases) and other clinical outcomes (ischemic stroke, hemorrhagic stroke, heart failure, diabetes mellitus, chronic kidney disease, and dementia) (P > 0.05 for interaction in all outcomes). Take the effect of PCSK9 inhibitors and BBs on CVD for instance: compared with the reference, PCSK9 group had a 4% lower risk of CVD (odds ratio [OR], 0.96; 95%CI, 0.94-0.99), and a 3% lower risk was observed in BBs group (OR, 0.97; 95%CI, 0.94-0.99), while combined both were associated with a 6% additively lower risk (OR, 0.94; 95%CI, 0.92-0.97; P = 0.87 for interaction). CONCLUSIONS: Genetically proxied medications of combined lipid-lowering and antihypertensive drugs have an independent and additive effects on CVD, other clinical and safety outcomes, with implications for CVD clinical practice, subsequent trials as well as drug development of polypills.

Arginase 2 is a Diagnostic and Prognostic Marker for Prostate Cancer and Is Associated with Metabolism.

Objective: Metabolism, a basic need and biochemical process for cell survival and proliferation, is closely connected with the pathogenesis and progression of prostate cancer. Methods: A four-gene signature construct that includes CKM (CKM), CD38, Enoyl Coenzyme A(EHHADH), and Arginase 2(ARG2) was created by bioinformatics. Finally, hub genes were validated by IHC and in vitro experiments. Results: The results showed the AUCs of the logistic regression and neural networks diagnostic model for the diagnosis of two subtypes were 0.920 and 0.936, respectively. The risk score demonstrated by univariable and multivariable Cox analysis is an independent predictive component of the prognostic signature for DFS. According to immunohistochemical analyses, ARG2 and CD38 expression levels were considerably under-expressed, but CKM and EHHADH expression levels were significantly overexpressed. Furthermore, The expression of ARG2 was significantly down-regulated in the late Gleason score. Finally, we found that ARG2 is lowly expressed in prostate cancer cells. Furthermore, based on the effect of ARG2 on the malignant phenotype of PCa in vitro, we also found that ARG2 may be a tumor suppressor that plays an important role in inhibiting proliferation, migration, and invasion. Conclusions: These findings suggest that ARG2 has been tentatively identified as a new target for research into how PCa develops in metabolism and for the development of innovative targeted treatments.

ß-Nicotinamide mononucleotide supplementation prolongs the lifespan of prematurely aged mice and protects colon function in ageing mice.

Ageing is defined as the degeneration of physiological functions in numerous tissues and organs of an organism, which occurs with age. As we age, the gut undergoes a series of changes and weaknesses that may contribute to overall ageing. Emerging evidence suggests that ß-nicotinamide mononucleotide (NMN) plays a role in regulating intestinal function, but there is still a lack of literature on its role in maintaining the colon health of ageing mice. In our research, Zmpste24-/- mice proved that NMN prolonged their life span and delayed senescence. This study was designed to investigate the effects of long-term intervention on regulating colon function in ageing mice. Our results indicated that NMN improved the pathology of intestinal epithelial cells and intestinal permeability by upregulating the expression of intestinal tight junction proteins and the number of goblet cells, increasing the release of anti-inflammatory factors, and increasing beneficial intestinal bacteria. NMN increased the expression of the proteins SIRT1, NMNAT2, and NMNAT3 and decreased the expression of the protein P53. It also regulated the activity of ISCs by increasing Wnt/ß-catenin and Lgr5. Our findings also revealed that NMN caused a significant increase in the relative abundance of Akkermansia muciniphila and Bifidobacterium pseudolongum and notable differences in metabolic pathways related to choline metabolism in cancer. In summary, NMN supplementation can delay frailty in old age, aid healthy ageing, and delay gut ageing.

Identification of Novel QTL for Mercury Accumulation in Maize Using an Enlarged SNP Panel.

Mercury (Hg) pollution not only poses a threat to the environment but also adversely affects the growth and development of plants, with potential repercussions for animals and humans through bioaccumulation in the food chain. Maize, a crucial source of food, industrial materials, and livestock feed, requires special attention in understanding the genetic factors influencing mercury accumulation. Developing maize varieties with low mercury accumulation is vital for both maize production and human health. In this study, a comprehensive genome-wide association study (GWAS) was conducted using an enlarged SNP panel comprising 1.25 million single nucleotide polymorphisms (SNPs) in 230 maize inbred lines across three environments. The analysis identified 111 significant SNPs within 78 quantitative trait loci (QTL), involving 169 candidate genes under the Q model. Compared to the previous study, the increased marker density and optimized statistical model led to the discovery of 74 additional QTL, demonstrating improved statistical power. Gene ontology (GO) enrichment analysis revealed that most genes participate in arsenate reduction and stress responses. Notably, GRMZM2G440968, which has been reported in previous studies, is associated with the significant SNP chr6.S_155668107 in axis tissue. It encodes a cysteine proteinase inhibitor, implying its potential role in mitigating mercury toxicity by inhibiting cysteine. Haplotype analyses provided further insights, indicating that lines carrying hap3 exhibited the lowest mercury content compared to other haplotypes. In summary, our study significantly enhances the statistical power of GWAS, identifying additional genes related to mercury accumulation and metabolism. These findings offer valuable insights into unraveling the genetic basis of mercury content in maize and contribute to the development of maize varieties with low mercury accumulation.

PSA-GNN: An augmented GNN framework with priori subgraph knowledge.

Graph neural networks have become the primary graph representation learning paradigm, in which nodes update their embeddings by aggregating messages from their neighbors iteratively. However, current message passing based GNNs exploit the higher-order subgraph information other than 1st-order neighbors insufficiently. In contrast, the long-standing graph research has investigated various subgraphs such as motif, clique, core, and truss that contain important structural information to downstream tasks like node classification, which deserve to be preserved by GNNs. In this work, we propose to use the pre-mined subgraphs as priori knowledge to extend the receptive field of GNNs and enhance their expressive power to go beyond the 1st-order Weisfeiler-Lehman isomorphism test. For that, we introduce a general framework called PSA-GNN (Priori Subgraph Augmented Graph Neural Network), which augments each GNN layer by a pair of parallel convolution layers based on a bipartite graph between nodes and priori subgraphs. PSA-GNN intrinsically builds a hybrid receptive field by incorporating priori subgraphs as neighbors, while the embeddings and weights of subgraphs are trainable. Moreover, PSA-GNN can purify the noisy subgraphs both heuristically before training and deterministically during training based on a novel metric called homogeneity. Experimental results show that PSA-GNN achieves an improved performance compared with state-of-the-art message passing based GNN models.

Development of a CD8+ T cell associated signature for predicting the prognosis and immunological characteristics of gastric cancer by integrating single-cell and bulk RNA-sequencing.

The universally poor clinical outcome makes gastric cancer (GC) still a significant public health threat, the main goal of our research is to develop a prognostic signature that can forecast the outcomes and immunological characteristics of GC via integrating single-cell and bulk RNA-sequencing. The CD8+ T cell feature genes were screened out by exploring single-cell RNA-sequencing (scRNA-seq) profiles retrieved from the TISCH2 database. Then, Cox and LASSO regressions were exploited for constructing a prognostic model in TCGA cohort based on these CD8+ T cell feature genes. Survival analysis was conducted to investigate the predictive capability of the signature for the clinical outcome of GC patients in TCGA and GEO cohorts. Additionally, we further examined the correlations between the risk signature and tumor immunotherapeutic response from the perspectives of immune infiltration, tumor mutation burden (TMB), immune checkpoint biomarker (ICB) expression, tumor microenvironment (TME), microsatellite instability (MSI), TIDE, and TCIA scores. In total, 703 CD8+ T cell feature genes were identified, eight of which were selected for constructing a prognostic signature. GC patients who possess high-risk score had significantly poorer survival outcomes than those who possess low-risk score in TCGA and GEO cohorts. Immune infiltration analysis proved that the risk score was negatively connected with the infiltration abundance of CD8+ T cells. Then, our findings demonstrated that GC patients in the high-risk subgroup possess a higher proportion of MSI-L/MSS, lower immune checkpoint biomarker expression, lower TMB, higher TIDE scores and lower TCIA scores compared to those in the low-risk subgroup. What's more, immunotherapy cohort analysis confirmed that patients who possess high-risk score are not sensitive to anti-cancer immunotherapy. Our study developed a reliable prognostic signature for GC that was significantly correlated with the immune landscape and immunotherapeutic responsiveness. The risk signature may guide clinicians to adopt more accurate and personalized treatment strategies for GC patients.

Somatic and Germline Variants and Coronary Heart Disease in a Chinese Population.

Importance: The genetic basis of coronary heart disease (CHD) has expanded from a germline to somatic genome, including clonal hematopoiesis of indeterminate potential (CHIP). How CHIP confers CHD risk in East Asian individuals, especially those with small clones (variant allele fraction [VAF] 0.5%-2%) and different genetic backgrounds, was completely unknown. Objective: To investigate the CHIP profile in a general Chinese cohort by deep sequencing and further explore the association between CHIP and incident CHD considering germline predisposition. Design, Setting, and Participants: This cohort study used data from 3 prospective cohorts in the project Prediction for Atherosclerotic Cardiovascular Disease Risk in China. Participants without cardiovascular disease or cancer at baseline were enrolled in 2001 and 2008 and had a median follow-up of 12.17 years extending into 2021. Exposures: CHIP mutations were detected by targeted sequencing (mean depth, 916×). A predefined CHD polygenic risk score (PRS) comprising 531 variants was used to evaluate germline predisposition. Main Outcomes and Measures: The main outcome was first incident CHD. Results: Among 6181 participants, the median (IQR) age was 53.83 years (45.35-62.39 years); 3082 participants (49.9%) were female, and 3099 (50.1%) were male. A total of 1100 individuals (17.80%) harbored 1372 CHIP mutations at baseline. CHIP was independently associated with incident CHD (hazard ratio [HR], 1.42; 95% CI, 1.18-1.72; P = 2.82 × 10-4) and presented a risk gradient with increasing VAF (P = 3.98 × 10-3 for trend). Notably, individuals with small clones, nearly half of CHIP carriers, also demonstrated a higher CHD risk compared with non-CHIP carriers (HR, 1.33; 95% CI, 1.02-1.74; P = .03) and were 4 years younger than those with VAF of 2% or greater (median age, 58.52 vs 62.70 years). Heightened CHD risk was not observed among CHIP carriers with low PRS (HR, 1.02; 95% CI, 0.64-1.64; P = .92), while high PRS and CHIP jointly contributed a 2.23-fold increase in risk (95% CI, 1.51-3.29; P = 6.29 × 10-5) compared with non-CHIP carriers with low PRS. Interestingly, the diversity in CHIP-related CHD risk within each PRS group was substantially diminished when removing variants in the inflammatory pathway from the PRS. Conclusions: This study revealed that elevated CHD risk attributed to CHIP was nonnegligible even for small clones. Inflammation genes involved in CHD could aggravate or abrogate CHIP-related CHD risk.

Preserving the left colonic artery in radical sigmoid and rectal cancer surgery is feasible: A meta-analysis.

BACKGROUND: This study aims to investigate the safety and feasibility of preserving left colonic artery (LCA) in radical sigmoid and rectal cancer surgery. METHODS: Relevant articles were systematically searched on the PubMed, Embase, and Cochrane Library. The quality of included studies was evaluated using the Cochrane Handbook. A meta-analysis was conducted to assess the surgical outcomes and oncological outcomes by RevMan 5.4 software. RESULTS: Fifteen studies with a total of 5054 patients, including 2432 patients with LCA preservation and 2622 patients without LCA preservation, were included and analyzed in this study. The meta-analysis revealed that preserving LCA in radical surgery of sigmoid and rectal cancer has lower anastomotic leakage incidence (OR = 1.03, 95% confidence interval = 0.83-1.27, P < .0001). There were no significant differences in the operative time, intraoperative blood loss, number of dissected lymph nodes, postoperative complications as well as the oncological outcomes including systemic recurrence, local recurrence, 5-year overall survival rate, and 5-year disease-free survival rate. CONCLUSION SUBSECTIONS: This pooled analysis showed that preserving the LCA is safe and feasible in radical sigmoid and rectal cancer surgery.

Lifestyle improvement and the reduced risk of cardiovascular disease: the China-PAR project.

BACKGROUND: The benefits of healthy lifestyles are well recognized. However, the extent to which improving unhealthy lifestyles reduces cardiovascular disease (CVD) risk needs to be discussed. We evaluated the impact of lifestyle improvement on CVD incidence using data from the China-PAR project (Prediction for Atherosclerotic Cardiovascular Disease Risk in China). METHODS: A total of 12,588 participants free of CVD were followed up for three visits after the baseline examination. Changes in four lifestyle factors (LFs) (smoking, diet, physical activity, and alcohol consumption) were assessed through questionnaires from the baseline to the first follow-up visit. Cox proportional hazard models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). The risk advancement periods (RAPs: the age difference between exposed and unexposed participants reaching the same incident CVD risk) and population-attributable risk percentage (PAR%) were also calculated. RESULTS: A total of 909 incident CVD cases occurred over a median follow-up of 11.14 years. Compared with maintaining 0-1 healthy LFs, maintaining 3-4 healthy LFs was associated with a 40% risk reduction of incident CVD (HR = 0.60, 95% CI: 0.45-0.79) and delayed CVD risk by 6.31 years (RAP: -6.31 [-9.92, -2.70] years). The PAR% of maintaining 3-4 unhealthy LFs was 22.0% compared to maintaining 0-1 unhealthy LFs. Besides, compared with maintaining two healthy LFs, improving healthy LFs from 2 to 3-4 was associated with a 23% lower risk of CVD (HR = 0.77, 95% CI: 0.60-0.98). CONCLUSIONS: Long-term sustenance of healthy lifestyles or improving unhealthy lifestyles can reduce and delay CVD risk.

Evaluation of the serum tRNA-derived fragment tRF-5022B as a potential biomarker for the diagnosis of osteoarthritis.

Osteoarthritis (OA) is a degenerative disease. It is common in middle-aged and elderly people and is one of the main causes of disability. Currently, the etiology of OA is unclear, and no specific biomarkers for the diagnosis of OA have been identified. Therefore, finding a highly sensitive biomarker is essential for a proper diagnosis.TRNA-derived fragments (tRFs) and tRNA-derived stress-induced RNAs (tiRNAs) are newly discovered classes of noncoding RNAs. tRF has been proven in several studies to have significant associations with tumor diagnosis, making it a promising biomarker in cancer research. However, the diagnostic utility of tRF in OA patients and the correlation between OA progression and trf differential expression have yet to be elaborated. The purpose of this research was to identify tRFs with differential expression in OA to assess their potential as OA biomarkers. To determine the tRF-5022B expression level in this research, real-time fluorescence quantitative PCR has been employed. Agarose gel electrophoresis, Sanger sequencing, and other investigations have been employed for evaluating tRF-5022B's molecular properties. Receiver operating characteristic curve analysis has been utilized for assessing the diagnostic effectiveness of the tRF-5022B. The findings demonstrated that tRF-5022B expression was considerably lower in OA serum. The Kellgren-Lawrence grading scale was shown to correspond with serum expression levels. The ROC curve confirmed that tRF-5022B serum expression levels might differentiate OA cases from healthy individuals and RA patients. According to the aforementioned findings, tRF-5022B may be employed as a novel biomarker for OA diagnosis due to its excellent diagnostic value.

Identification and validation of a novel prognostic model for gastric cancer based on m7G-related genes.

Background: The role of N7-methyladenosine (m7G)-related genes in the progression and prognosis of gastric cancer (GC) remains unclear. This study aimed to explore prognostic biomarkers for GC based on m7G methylation regulators and to construct a prognostic risk model. Methods: RNA sequencing profiles with corresponding clinicopathological information associated with GC of which the histological type was stomach adenocarcinoma (STAD) were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), respectively. A total of 29 m7G regulators were extracted from previous studies. According to the expression similarity of m7G regulators, the GC samples obtained from TCGA were further classified into 2 clusters demonstrating different overall survival (OS) rates and genetic heterogeneity, and the differentially expressed genes (DEGs) between these 2 clusters were defined as m7G-related genes. Univariate regression analysis and regression analysis were then used to obtain the prognostic m7G-related genes. The samples in TCGA and Genotype-Tissue Expression (GTEx) were used to verify the differential expression and prognostic value of these m7G-related genes contained in the prognostic model. Subsequently, the risk score was combined with other prognostic factors to develop a nomogram. The predictive ability of the nomogram was evaluated by the standard receiver operating characteristic (ROC) curve. Gene set enrichment analysis (GSEA) was used to identify activation pathways in both groups. Finally, the association between the prognostic model and the immune characteristics of GC were appraised. Results: A prognostic model consisting of 11 m7G-related genes was constructed. GC patients in the high-risk group were shown to have a poor prognosis and this result was further demonstrated in each group. The risk model can be applied for patients with different clinical features. The results of GSEA showed that cell adhesion, cell junction, and focal adhesion were highly enriched in the high-risk group. In addition, we found that the expression of programmed cell death ligand 1 (PD-L1) was significantly elevated in the low-risk group, whereas programmed cell death ligand 2 (PD-L2) and tumor necrosis factor receptor superfamily member 4 (TNFRSF4) were overexpressed in the high-risk group. Conclusions: We successfully built and verified a m7G relevant prognostic model for predicting prognosis and providing a new train of thought for improving the treatment of GC.

An immune-related multi-omics analysis of dolichyl-diphosphooligosaccharide protein glycosyltransferase in glioma: Prognostic value exploration and competitive endogenous RNA network identification.

Dolichyl-diphosphooligosaccharide protein glycosyltransferase (DDOST) plays a pivotal role in the glycosylation of asparagine residues on nascent polypeptides. However, the biological role of DDOST in glioma remains unclear. The mRNA expression of DDOST in glioma was identified using TCGA, CGGA, GEO and Rembrandt datasets. Immunohistochemistry assay was conducted to examine the protein level of DDOST. Cox regression analysis, nomograms and calibration plots were used to evaluate the prognostic value of DDOST. The association between DDOST and immune cell infiltration was evaluated using CIBERSORT algorithm. Additionally, DNA methylation and ceRNA regulatory network of DDOST expression were investigated using the LinkedOmics and ENCORI databases. The authors found that DDOST was substantially expressed at the mRNA and protein levels. Functional enrichment analysis revealed close associations between DDOST and immune-related pathways, as well as immune cell infiltration. In addition, DDOST exhibited synergistic effects with tumour mutational burden (TMB) and other immune checkpoints. For expression regulation mechanisms, DDOST had low DNA methylation levels in high-grade gliomas and may be involved in multiple ceRNA networks in glioma. Thus, DDOST may serve as an unfavourable biomarker for gliomas. DNA methylation and ceRNA regulatory networks of DDOST expression were identified for the first time in this multi-omics study.

Cuproptosis-Related 4-Gene Risk Model for Predicting Immunotherapy Drug Response and Prognosis of Kidney Renal Clear Cell Carcinoma.

Background Kidney renal clear cell carcinoma (KIRC) is one of the most common renal malignancies with a high mortality rate. Cuproptosis, a novel form of cell death, is strongly linked to mitochondrial metabolism and is mediated by protein lipoylation, leading to a proteotoxic stress response and cell death. To date, few studies have ellucidated the holistic role of cuproptosis-related genes (CRGs) in the pathogenesis of KIRC.Methods We comprehensively and completely analyzed the RNA sequencing data and corresponding clinical information from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We screened for differentially expressed CRGs and constructed a prognostic risk model using univariate and multivariate Cox proportional regression analyses. Kaplan-Meier analysis was performed and receiver operating characteristic (ROC) curves were plotted to predict the prognosis of KIRC patients. Functional enrichment analysis was utilized to explore the internal mechanisms. Immune-related functions were analyzed using single-sample gene set enrichment analysis (ssGSEA), tumour immune dysfunction and exclusion (TIDE) scores, and drug sensitivity analysis.Results We established a concise prognostic risk model consisting of four CRGs (DBT, DLAT, LIAS and PDHB) to predict the overall survival (OS) in KIRC patients. The results of the survival analysis indicated a significantly lower OS in the high-risk group as compared to the patients in the low-risk group. The area under the time-dependent ROC curve (AUC) at 1, 3, and 5 year was 0.691, 0.618, and 0.614 in KIRC. Functional enrichment analysis demonstrated that CRGs were significantly enriched in tricarboxylic acid (TCA) cycle-related processes and metabolism-related pathways. Sorafenib, doxorubicin, embelin, and vinorelbine were more sensitive in the high-risk group.Conclusions We constructed a concise CRGs risk model to evaluate the prognosis of KIRC patients and this may be a new direction for the diagnosis and treatment of KIRC.

Comprehensive analysis of the oncogenic roles of vascular endothelial growth factors and their receptors in stomach adenocarcinoma.

Background: Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) play complicated oncogenic roles in multiple tumors by initiating and promoting tumor angiogenesis and lymphangiogenesis. The main goal of our study was to comprehensively investigate the oncogenic roles of VEGFs and VEGFRs in stomach adenocarcinoma (STAD). Methods: The present study applied multiple bioinformatic tools to comprehensively explore the expression levels, prognostic values, genetic alterations and immune infiltrations of VEGFs and VEGFRs in STAD patients. Results: We found that VEGFA, VEGFC, placenta growth factor, FLT1, KDR, FLT4, and Neuropilin 1 were overexpressed in STAD, while the expression of VEGFB and VEGFD were decreased. Survival analysis revealed that higher transcription levels of VEGF/VEGFRs were obviously correlated with worse clinical outcome in STAD patients. Additionally, high alteration frequencies of VEGFs and VEGFRs (27%) were observed in STAD patients, and alterations of VEGFs and VEGFRs improved their prognosis. The expression of VEGFs and VEGFRs was remarkably associated with immune cell infiltration and immune checkpoint expression in STAD patients. Conclusion: Our study systematically explored the transcriptome profiles and distinct prognostic values of VEGFs and their receptors in STAD and contributed to a better understanding of the oncogenic roles of VEGF/VEGFR members in STAD.

Efficacy and safety of low levels of low-density lipoprotein cholesterol: trans-ancestry linear and non-linear Mendelian randomization analyses.

AIMS: LDL cholesterol (LDL-C) is a well-established risk factor for coronary artery disease (CAD). However, the optimal LDL-C level with regard to efficacy and safety remains unclear. We aimed to investigate the causal relationships between LDL-C and efficacy and safety outcomes. METHODS AND RESULTS: We analyzed 353 232 British from the UK Biobank and 41 271 Chinese from the China-PAR project. Linear and non-linear Mendelian randomization (MR) analyses were performed to evaluate the causal relation between genetically proxied LDL-C and CAD, all-cause mortality, and safety outcomes (including haemorrhagic stroke, diabetes mellitus, overall cancer, non-cardiovascular death, and dementia). No significant non-linear associations were observed for CAD, all-cause mortality, and safety outcomes (Cochran Q P > 0.25 in British and Chinese) with LDL-C levels above the minimum values of 50 and 20 mg/dL in British and Chinese, respectively. Linear MR analyses demonstrated a positive association of LDL-C with CAD [British: odds ratio (OR) per unit mmol/L increase, 1.75, P = 7.57 × 10-52; Chinese: OR, 2.06, P = 9.10 × 10-3]. Furthermore, stratified analyses restricted to individuals with LDL-C levels less than the guideline-recommended 70 mg/dL demonstrated lower LDL-C levels were associated with a higher risk of adverse events, including haemorrhagic stroke (British: OR, 0.72, P = 0.03) and dementia (British: OR, 0.75, P = 0.03). CONCLUSION: In British and Chinese populations, we confirmed a linear dose-response relationship of LDL-C with CAD and found potential safety concerns at low LDL-C levels, providing recommendations for monitoring adverse events in people with low LDL-C in the prevention of cardiovascular disease.

We used the Mendelian randomization method to estimate the causal relationships between LDL-C and efficacy and safety outcomes in the UK Biobank and the China-PAR project.We found a linear rather than a non-linear relationship between genetically proxied LDL cholesterol and coronary artery disease.There are potential safety concerns (including haemorrhagic stroke and dementia) for people who have low LDL-C levels.

Saponin extract from Achyranthes bidentata Blume alleviates disuse-induced muscle atrophy through PI3K/Akt signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The roots of Achyranthes bidentata Blume are one of the regularly used herbal drugs in Chinese medicine, and has been applied for strengthening the muscle and bone for a long time. However, its effect on muscle remains unclear. AIM OF THE STUDY: This paper aims to explore the anti-muscle atrophy effect of A. bidentata, and to clarify the possible signaling pathways involved. MATERIALS AND METHODS: The saponin extract of the roots of A. bidentata (ABSE) was prepared and analyzed, and its activity on myoblast differentiation was assayed with C2C12 cell culture. ABSE was then orally administered at dosage of 35, 70 and 140 mg/kg/day to disuse-induced muscle atrophy mice. The studies on mice body weight and muscle quality were conducted, and Western blot was used for exploring the possible signaling pathways involved in the muscle protective action aided with transcriptome analysis. RESULTS: The total saponin content of ABSE was 59.1%. ABSE promoted the C2C12 cells differentiation to myotube in C2C12 differentiation assay. Further study with disuse-induced muscle atrophy mice model demonstrated that ABSE significantly increased muscle fiber diameter as well as the proportion of slow muscle fibers. Possible mechanism study aided with transcriptome analysis revealed that ABSE alleviated muscle atrophy at least through activation of PI3K/Akt pathway in vivo & vitro. CONCLUSIONS: The saponin extract of the root of A. bidentata (ABSE) has a protective effect on muscle atrophy, and showed a considerable potential in prevention and treatment of muscle atrophy.

Clinical characteristics of pediatric allogeneic hematopoietic stem cell transplantation-associated thrombotic microangiopathy (TA-TMA): a retrospective single-center analysis.

OBJECTIVES: To investigate the clinical features of thrombotic microangiopathy associated with allogeneic hematopoietic stem cell transplantation in children. METHODS: A retrospective analysis of continuous clinical data from HSCT received in the Department of Hematology and Oncology of Wuhan Children's Hospital from August 1, 2016 to December 31, 2021. RESULTS: During this period, 209 patients received allo-HSCT in our department, 20 (9.6%) of whom developed TA-TMA. TA-TMA was diagnosed at a median of 94 (7-289) days post-HSCT. Eleven (55%) patients had early TA-TMA within 100 days post-HSCT, while the other 9 (45%) patients had TA-TMA thereafter. The most common symptom of TA-TMA was ecchymosis (55%), while the main signs were refractory hypertension (90%) and multi-cavity effusion (35%). Five (25%) patients had central nervous system symptoms (convulsions and lethargy). All 20 patients had progressive thrombocytopenia, with 16 patients receiving transfusion of platelets that was ineffective. Ruptured red blood cells were visible in only two patients with peripheral blood smears. Cyclosporine A or Tacrolimus (CNI) dose was reduced once TA-TMA was diagnosed. Nineteen cases were treated with low-molecular-weight heparin, 17 patients received plasma exchange, and 12 patients were treated with rituximab. TA-TMA-related mortality percentage in this study was 45% (9/20). CONCLUSION: Platelet decline and/or ineffective transfusion post-HSCT should be considered an early indicator of TA-TMA in pediatric patients. TA-TMA in pediatric patients may occur without evidence of peripheral blood schistocytes. Aggressive treatment is required once diagnosis is confirmed, but the long-term prognosis is poor.

Demulsifier-Inspired Superhydrophilic/Underwater Superoleophobic Membrane Modified with Polyoxypropylene Polyoxyethylene Block Polymer for Enhanced Oil/Water Separation Properties.

Demulsifiers are considered the key materials for oil/water separation. Various works in recent years have shown that demulsifiers with polyoxypropylen epolyoxyethylene branched structures possess better demulsification effects. In this work, inspired by the chemical structure of demulsifiers, a novel superhydrophilic/underwater superoleophobic membrane modified with a polyoxypropylene polyoxyethylene block polymer was fabricated for enhanced separation of O/W emulsion. First, a typical polyoxypropylene polyoxyethylene triblock polymer (Pluronic F127) was grafted onto the poly styrene-maleic anhydride (SMA). Then, the Pluronic F127-grafted SMA (abbreviated as F127@SMA) was blended with polyvinylidene fluoride (PVDF) for the preparation of the F127@SMA/PVDF ultrafiltration membrane. The obtained F127@SMA/PVDF ultrafiltration membrane displayed superhydrophilic/underwater superoleophobic properties, with a water contact angle of 0° and an underwater oil contact angle (UOCA) higher than 150° for various oils. Moreover, it had excellent separation efficiency for SDS-stabilized emulsions, even when the oil being emulsified was crude oil. The oil removal efficiency was greater than 99.1%, and the flux was up to 272.4 L·m-2·h-1. Most importantly, the proposed F127@SMA/PVDF membrane also exhibited outstanding reusability and long-term stability. Its UOCA remained higher than 150° in harsh acidic, alkaline, and high-salt circumstances. Overall, the present work proposed an environmentally friendly and convenient approach for the development of practical oil/water separation membranes.

Colorectal cancer lymph node metastasis prediction with weakly supervised transformer-based multi-instance learning.

Lymph node metastasis examined by the resected lymph nodes is considered one of the most important prognostic factors for colorectal cancer (CRC). However, it requires careful and comprehensive inspection by expert pathologists. To relieve the pathologists' burden and speed up the diagnostic process, in this paper, we develop a deep learning system with the binary positive/negative labels of the lymph nodes to solve the CRC lymph node classification task. The multi-instance learning (MIL) framework is adopted in our method to handle the whole slide images (WSIs) of gigapixels in size at once and get rid of the labor-intensive and time-consuming detailed annotations. First, a transformer-based MIL model, DT-DSMIL, is proposed in this paper based on the deformable transformer backbone and the dual-stream MIL (DSMIL) framework. The local-level image features are extracted and aggregated with the deformable transformer, and the global-level image features are obtained with the DSMIL aggregator. The final classification decision is made based on both the local and the global-level features. After the effectiveness of our proposed DT-DSMIL model is demonstrated by comparing its performance with its predecessors, a diagnostic system is developed to detect, crop, and finally identify the single lymph nodes within the slides based on the DT-DSMIL and the Faster R-CNN model. The developed diagnostic model is trained and tested on a clinically collected CRC lymph node metastasis dataset composed of 843 slides (864 metastasis lymph nodes and 1415 non-metastatic lymph nodes), achieving the accuracy of 95.3% and the area under the receiver operating characteristic curve (AUC) of 0.9762 (95% confidence interval [CI]: 0.9607-0.9891) for the single lymph node classification. As for the lymph nodes with micro-metastasis and macro-metastasis, our diagnostic system achieves the AUC of 0.9816 (95% CI: 0.9659-0.9935) and 0.9902 (95% CI: 0.9787-0.9983), respectively. Moreover, the system shows reliable diagnostic region localizing performance: the model can always identify the most likely metastases, no matter the model's predictions or manual labels, showing great potential in avoiding false negatives and discovering incorrectly labeled slides in actual clinical use.