Evaluation of 5'-tRF-His-GTG As a Molecular Biomarker in Breast Cancer Diagnoses and Prognosis.

Background: Breast cancer (BC) is the most prevalent cancer among women worldwide. Although advances have been made in the identification of predictive biomarkers, current options for early diagnosis and prognostic analysis are still suboptimal. Recently, transfer-RNA-derived RNA fragments (tRFs) have emerged as a class of small noncoding RNAs that play a role in the cancer progression. The authors aimed to identify a specific class of tRFs as a molecular marker for BC diagnosis and prognosis in clinical management. Methods: The levels of 5'-tRF-His-GTG were quantified in BC tissue (n = 101) and inflammatory normal breast tissue (n = 22) using in situ hybridization. Clinicopathological parameters were obtained, including age, tumor node metastasis stage, hormone receptor status, histopathological grade, lymphovascular invasion, and recurrence. The correlation between the expression of 5'-tRF-His-GTG and these parameters in different BC subtypes was analyzed. Patient death and cancer progression were regarded as clinical endpoints in the survival analysis. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were also performed to predict the involvement in pivotal biological process. Results: The expression of 5'-tRF-His-GTG was significantly downregulated in BC tissues and was in connection with T stage in human epidermal growth factor 2-positive and basal-like BC, as well as N stage and histopathological grade in luminal BC. Patients with low expression of 5'-tRF-His-GTG had a poor overall survival rate. Statistics of GO and KEGG pathway revealed that cation channel activity, protein catabolic process, response to temperature stimulus, cell cycle, focal adhesion, and glycerophospholipid metabolism were significantly enriched. Conclusions: This study suggests that the assessment of 5'-tRF-His-GTG expression could serve as a novel biomarker for individual diagnosis and prognosis in BC.

Efficient, narrow-band, and stable electroluminescence from organoboron-nitrogen-carbonyl emitter.

Organic light-emitting diodes (OLEDs) exploiting simple binary emissive layers (EMLs) blending only emitters and hosts have natural advantages in low-cost commercialization. However, previously reported OLEDs based on binary EMLs hardly simultaneously achieved desired comprehensive performances, e.g., high efficiency, low efficiency roll-off, narrow emission bands, and high operation stability. Here, we report a molecular-design strategy. Such a strategy leads to a fast reverse intersystem crossing rate in our designed emitter h-BNCO-1 of 1.79×105 s-1. An OLED exploiting a binary EML with h-BNCO-1 achieves ultrapure emission, a maximum external quantum efficiency of over 40% and a mild roll-off of 14% at 1000 cd·m-2. Moreover, h-BNCO-1 also exhibits promising operational stability in an alternative OLED exploiting a compact binary EML (the lifetime reaching 95% of the initial luminance at 1000 cd m-2 is ~ 137 h). Here, our work has thus provided a molecular-design strategy for OLEDs with promising comprehensive performance.

Improving cardiovascular risk prediction through machine learning modelling of irregularly repeated electronic health records.

Aims: Existing electronic health records (EHRs) often consist of abundant but irregular longitudinal measurements of risk factors. In this study, we aim to leverage such data to improve the risk prediction of atherosclerotic cardiovascular disease (ASCVD) by applying machine learning (ML) algorithms, which can allow automatic screening of the population. Methods and results: A total of 215 744 Chinese adults aged between 40 and 79 without a history of cardiovascular disease were included (6081 cases) from an EHR-based longitudinal cohort study. To allow interpretability of the model, the predictors of demographic characteristics, medication treatment, and repeatedly measured records of lipids, glycaemia, obesity, blood pressure, and renal function were used. The primary outcome was ASCVD, defined as non-fatal acute myocardial infarction, coronary heart disease death, or fatal and non-fatal stroke. The eXtreme Gradient boosting (XGBoost) algorithm and Least Absolute Shrinkage and Selection Operator (LASSO) regression models were derived to predict the 5-year ASCVD risk. In the validation set, compared with the refitted Chinese guideline-recommended Cox model (i.e. the China-PAR), the XGBoost model had a significantly higher C-statistic of 0.792, (the differences in the C-statistics: 0.011, 0.006-0.017, P < 0.001), with similar results reported for LASSO regression (the differences in the C-statistics: 0.008, 0.005-0.011, P < 0.001). The XGBoost model demonstrated the best calibration performance (men: Dx = 0.598, P = 0.75; women: Dx = 1.867, P = 0.08). Moreover, the risk distribution of the ML algorithms differed from that of the conventional model. The net reclassification improvement rates of XGBoost and LASSO over the Cox model were 3.9% (1.4-6.4%) and 2.8% (0.7-4.9%), respectively. Conclusion: Machine learning algorithms with irregular, repeated real-world data could improve cardiovascular risk prediction. They demonstrated significantly better performance for reclassification to identify the high-risk population correctly.

A Rigid Multiple Resonance Thermally Activated Delayed Fluorescence Core Toward Stable Electroluminescence and Lasing.

The investigation of organic light-emitting diodes (OLEDs) and organic laser devices with thermally activated delayed fluorescence (TADF) molecules is emerging due to the potential of harnessing triplets. In this work, a boron/nitrogen multiple-resonance TADF polycyclic framework fusing carbazole units (CzBNPh) was proposed. CzBNPh exhibited a narrowband emission (<30 nm), a unity photoluminescence quantum yield, and a fast radiative rate. Consequently, CzBNPh demonstrated a low distributed feedback (DFB) lasing threshold of 0.68 µJ cm-2 . Furthermore, the stimulated emission zone of CzBNPh was effectively separated from its singlet and triplet absorption, thereby minimizing the singlet-triplet annihilation under long-pulsed excitation ranging from 20 µs to 2.5 ms. Significantly, the enhanced rigid molecular conformation, thermal stability, and photo-stability resulted in improved lasing and electroluminescence stability compared to that of 5,9-diphenyl-5,9-diaza-13b-boranaphtho[3,2,1-de]anthracene (DABNA)-core. These findings indicate the potential of CzBN-core as a promising framework for achieving long-pulsed wave and electrically-pumped lasing in the future.

Milk fat globule membrane promotes brain development in piglets by enhancing the connection of white matter fiber trace.

Introduction: Brain development during infancy is crucial for later health and development. Although Milk Fat Globule Membrane (MFGM) has been demonstrated to enhance brain development, further investigation is needed to determine the optimal dose. Methods: In this study, 80 piglets aged 2 days were randomly assigned to four groups: Control group, MFGM-L (1.74 g MFGM per 100 g diet), MFGM-M (4.64 g MFGM per 100 g diet), and MFGM-H (6.09 g MFGM per 100 g diet). Daily body weight and milk intake of the piglets were recorded until 31 days postnatal. Learning and memory abilities were evaluated using the spatial T-maze test on day 15. MRI analysis was conducted to assess functional and structural changes in brain tissues. Additionally, mRNA and protein expression of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NTF-3) in the hippocampus and prefrontal cortex were evaluated. Results: The results indicated that the MFGM supplemented diet significantly improved the accuracy of the piglets in the T-maze test, with the MFGM-L group exhibiting the best performance. MRI showed no volumetric differences in the gray and white matter between the groups. However, the fractional anisotropy in the left and right hippocampus of piglets in the MFGM-L group was significantly higher than in the other three groups. Furthermore, there was a strong correlation between the accuracy of the T-maze test and hippocampal fractional anisotropy. Discussion: The MFGM supplemented diet also increased the expression of BDNF in the cerebral cortex. However, the changes in BDNF were not consistent with the results of the T-maze test. In conclusion, adding 1.74 g MFGM per 100 g diet can significantly improve neonatal piglets' learning and memory abilities, potentially by enhancing the connection of white matter fiber bundles in the brain.

RNA-seq provides insights into potato deubiquitinase responses to drought stress in seedling stage.

Ubiquitination is a specific protein degradation and reversible post-translational modification process that can be reversed by deubiquitinase (DUBs). DUBs can hydrolyze and release ubiquitin in the substrate protein so that the substrate can avoid degradation or change its activity, and it has an impact on plant growth and development, cell cycle, abiotic stress response, and other biological processes. Transcript sequences of potato varieties "DM1-3", "Atlantic" and "Cooperation-88" downloaded from Potato Genome Resources were used for genome-wide identification of the DUB gene family using Hidden Markov Models and verified in the NCBI CD-Search tool. The characteristics of DUB genes from different potato varieties were analyzed including subcellular localization, gene structural motifs, phylogenetic tree, and sequence homology. Polyethylene glycol 6000 (PEG6000) induced drought stress transcriptome analysis was performed on the "Atlantic", and differentially expressed genes were screened, with emphasis on the characterization of deubiquitinase. DUB genes have a complex gene structure, often with a large number of exons and alternative splicing. Their promoters contain abundant abiotic stress-responsive elements, such as 425 MYC, 325 ABRE, and 320 MYB. There are also a large number of orthologous genes in the DUBs of the three potato varieties, and these genes are often clustered in similar regions on the genome. We performed transcriptome sequencing of the potato under PEG-induced drought stress and analyzed it for the first time using the Atlantic as a reference genome. We identified a total of 6067 down-regulated differentially expressed genes (DEGs) and 4950 up-regulated DEGs under PEG-induced drought stress. We screened the expression of DUBs and observed that 120 DUBs were up-regulated where most of them functioned in the nucleus, and the interacting proteins of DUBs were also localized in the nucleus. We have comprehensively identified and analyzed potato DUBs, and the accurately aligned transcriptome data which will further deepen the understanding of DUBs involved in the regulation of osmotic stress.

CTRP3 attenuates inflammation, oxidative and cell death in cisplatin induced HK-2 cells.

Cisplatin has been widely studied and found to be a highly effective anti-tumor drug. It has several side effects, including acute kidney injury (AKI). Cisplatin-induced AKI can be primarily attributed to oxidative stress, inflammation, and apoptosis. The CTRP3 adipokine is a new adipokine that exhibits antioxidant, anti-inflammatory, and antiapoptotic properties. Despite this, the role of CTRP3 in AKI remain unclear. In cisplatin-induced AKI models, our findings demonstrated that CTRP3 expression was decreased in human proximal tubule epithelial cells (HK-2). In the in vitro experiments, HK-2 cells were first transfected with an overexpression plasmid of CTRP3 (pcDNA-CTRP3) or a small interfering RNA for CTRP3 (si-CTRP3) and induced by cisplatin; and cell oxidative stress, inflammation, proliferation, and apoptosis were found to be present. Overexpressing CTRP3 inhibited oxidative stress through decreasing malondialdehyde (MDA) levels and increasing the activity of SOD and CAT. The mRNA levels of SOD1 and SOD2 were increased in response to CTRP3 overexpression. Additionally, CTRP3 decreased TNF-α and MCP-1 levels. Moreover, CTRP3 overexpression increased cisplatin-induced cell activity and decreased cell apoptosis, as indicated by the elevated numbers of EdU positive cells and decreased numbers of apoptotic cells. Consistent with these results, the overexpression of CTRP3 effectively elevated the mRNA levels of Bcl-2 and reduced the mRNA levels of Bax. In contrast, inhibition of CTRP3 expression by si-CTRP3 reversed the cisplatin-induced indices. Mechanistically, we found that the overexpression of CTRP3 can increase expression of Nrf2 and inhibit the activation of MAPK phosphorylation (ERK, JNK, and p38). Furthermore, inhibition of ERK, JNK and p38 activity eliminated aggravation of cisplatin-induced inflammation and apoptosis caused by CTRP3 knockdown. Additionally, the cisplatin-induced oxidative stress and activation of MAPK phosphorylation (ERK, JNK, and p38) in HK-2 cells were reversed by Nrf2 suppression by siRNA. Collectively, these results indicated that CTRP3 may identify as a novel target for AKI treatment and protect against cisplatin-induced AKI through the Nrf2/MAPK pathway.

Clinical significance of hemoglobin level and blood transfusion therapy in elderly sepsis patients: A retrospective analysis.

INTRODUCTION: The clinical significance of hemoglobin level and blood transfusion therapy in elderly sepsis patients remains controversial. The study investigated the relationship between mortality, hemoglobin levels, and blood transfusion in elderly sepsis patients. METHODS: Elderly sepsis patients were included in the Marketplace for Medical Information in Intensive Care (MIMIC-IV) database. A multivariate regression model analyzed the relationship between the Hb level and the 28-day mortality risk. Logistic Multivariate analysis, Propensity Matching (PSM) analysis, an Inverse Probabilities Weighting (IPW) model and doubly robust estimation were applied to analyze the 28-day mortality risk between transfused and non-transfused patients in Hb at 7-8 g/dL, 8-9 g/dL, 9-10 g/dL, and 10-11 g/dL groups. RESULTS: 7473 elderly sepsis patients were enrolled in the study. The Hb level in the ICU and the 28-day mortality risk of patients with sepsis shared a non-linear relationship. The patients with Hb levels of <10 g/dL(p < 0.05) and > 15 g/dL(p < 0.05) within 24 h had a high mortality risk in multivariate analysis. In the Hb level 7-8 g/dL and 8-9 g/dL subgroup, the Multivariate analysis (p < 0.05), PSM (p < 0.05), IPW (p < 0.05) and doubly robust estimation (p < 0.05) suggested that blood transfusion could reduce the mortality risk. In the subgroup with a Hb level of 10-11 g/dL, IPW (p < 0.05) and doubly robust estimation (p < 0.05) suggested that blood transfusion could increase the mortality risk of elderly sepsis patients. CONCLUSION: A non-linear relationship between the Hb level and the 28-day mortality risk and Hb levels of <10 g/dL and > 15 g/dL may increase the mortality risk, and blood transfusion with a Hb level of <9 g/dL may minimize mortality risk in elderly sepsis patients.

Validation and comparison of cardiovascular risk prediction equations in Chinese patients with Type 2 diabetes.

AIMS: For patients with diabetes, the European guidelines updated the cardiovascular disease (CVD) risk prediction recommendations using diabetes-specific models with age-specific cut-offs, whereas American guidelines still advise models derived from the general population. We aimed to compare the performance of four cardiovascular risk models in diabetes populations. METHODS AND RESULTS: Patients with diabetes from the CHERRY study, an electronic health records-based cohort study in China, were identified. Five-year CVD risk was calculated using original and recalibrated diabetes-specific models [Action in Diabetes and Vascular disease: PreterAx and diamicroN-MR Controlled Evaluation (ADVANCE) and the Hong Kong cardiovascular risk model (HK)] and general population-based models [Pooled Cohort Equations (PCE) and Prediction for Atherosclerotic cardiovascular disease Risk in China (China-PAR)]. During a median 5.8-year follow-up, 46 558 patients had 2605 CVD events. C-statistics were 0.711 [95% confidence interval: 0.693-0.729] for ADVANCE and 0.701 (0.683-0.719) for HK in men, and 0.742 (0.725-0.759) and 0.732 (0.718-0.747) in women. C-statistics were worse in two general population-based models. Recalibrated ADVANCE underestimated risk by 1.2% and 16.8% in men and women, whereas PCE underestimated risk by 41.9% and 24.2% in men and women. With the age-specific cut-offs, the overlap of the high-risk patients selected by every model pair ranged from only 22.6% to 51.2%. When utilizing the fixed cut-off at 5%, the recalibrated ADVANCE selected similar high-risk patients in men (7400) as compared to the age-specific cut-offs (7102), whereas age-specific cut-offs exhibited a reduction in the selection of high-risk patients in women (2646 under age-specific cut-offs vs. 3647 under fixed cut-off). CONCLUSION: Diabetes-specific CVD risk prediction models showed better discrimination for patients with diabetes. High-risk patients selected by different models varied significantly. Age-specific cut-offs selected fewer patients at high CVD risk especially in women.

This large electronic health records-based real-world study indicated that the diabetes-specific cardiovascular risk models had better discriminative abilities than the models derived from the general population in Chinese patients with Type 2 diabetes.Current guidelines-recommended models, i.e. ADVANCE, PCE, and China-PAR, selected significantly different high-risk groups with various observed cardiovascular risks, indicating the potential considerable misclassification of risk stratification in clinical decision-making for preventive interventions.Compared with the fixed cut-off, the influence of the age-specific cut-offs for high risk of cardiovascular disease was different in men and women: age-specific cut-offs selected ∼27% fewer high-risk patients in women but similar in men.

Convolutional neural network-based colloidal self-assembly state classification.

Colloidal self-assembly is a viable solution to making advanced metamaterials. While the physicochemical properties of the particles affect the properties of the assembled structures, particle configuration is also a critical determinant factor. Colloidal self-assembly state classification is typically achieved with order parameters, which are aggregate variables normally defined with nontrivial exploration and validation. Here, we present an image-based framework to classify the state of a 2-D colloidal self-assembly system. The framework leverages deep learning algorithms with unsupervised learning for state classification and a supervised learning-based convolutional neural network for state prediction. The neural network models are developed using data from an experimentally validated Brownian dynamics simulation. Our results demonstrate that the proposed approach gives a satisfying performance, comparable and even outperforming the commonly used order parameters in distinguishing void defective states from ordered states. Given the data-based nature of the approach, we anticipate its general applicability and potential automatability to different and complex systems where image or particle coordination acquisition is feasible.

Role of bZIP Transcription Factors in Plant Salt Stress.

Soil salinity has become an increasingly serious problem worldwide, greatly limiting crop development and yield, and posing a major challenge to plant breeding. Basic leucine zipper (bZIP) transcription factors are the most widely distributed and conserved transcription factors and are the main regulators controlling various plant response processes against external stimuli. The bZIP protein contains two domains: a highly conserved, DNA-binding alkaline region, and a diverse leucine zipper, which is one of the largest transcription factor families in plants. Plant bZIP is involved in many biological processes, such as flower development, seed maturation, dormancy, and senescence, and plays an important role in abiotic stresses such as salt damage, drought, cold damage, osmotic stress, mechanical damage, and ABA signal response. In addition, bZIP is involved in the regulation of plant response to biological stresses such as insect pests and pathogen infection through salicylic acid, jasmonic acid, and ABA signal transduction pathways. This review summarizes and discusses the structural characteristics and functional characterization of the bZIP transcription factor group, the bZIP transcription factor complex and its molecular regulation mechanisms related to salt stress resistance, and the regulation of transcription factors in plant salt stress resistance. This review provides a theoretical basis and research ideas for further exploration of the salt stress-related functions of bZIP transcription factors. It also provides a theoretical basis for crop genetic improvement and green production in agriculture.

Progress and Perspective toward Continuous-Wave Organic Solid-State Lasers.

A continuous-wave (CW) organic solid-state laser is highly desirable for spectroscopy, sensing, and communications, but is a significant challenge in optoelectronics. The accumulation of long-lived triplet excitons and relevant excited-state absorptions, as well as singlet-triplet annihilation, are the main obstacles to CW lasing. Here, progress in singlet- and triplet-state utilizations in organic gain media is reviewed to reveal the issues in working with triplets. Then, exciton behaviors that inhibit light oscillations during long excitation pulses are discussed. Further, recent advances in increasing organic lasing pulse widths from microseconds toward the indication of CW operation are summarized with respect to molecular designs, advanced resonator architectures, triplet scavenging, and potential triplet contribution strategies. Finally, future directions and perspectives are proposed for achieving stable CW organic lasers with significant triplet contribution.

HSP90AB1 as the Druggable Target of Maggot Extract Reverses Cisplatin Resistance in Ovarian Cancer.

Cisplatin resistance is a crucial factor affecting ovarian cancer patient's survival rate, but the primary mechanism underlying cisplatin resistance in ovarian cancer remains unclear, and this prevents the optimal use of cisplatin therapy. Maggot extract (ME) is used in traditional Chinese medicine for patients with comas and patients with gastric cancer when combined with other drug treatments. In this study, we investigated whether ME enhances the sensitivity of ovarian cancer cells to cisplatin. Two ovarian cancer cells-A2780/CDDP and SKOV3/CDDP-were treated with cisplatin and ME in vitro. SKOV3/CDDP cells that stably expressed luciferase were subcutaneously or intraperitoneally injected into BALB/c nude mice to establish a xenograft model, and this was followed by ME/cisplatin treatment. In the presence of cisplatin, ME treatment effectively suppressed the growth and metastasis of cisplatin-resistant ovarian cancer in vivo and in vitro. RNA-sequencing data showed that HSP90AB1 and IGF1R were markedly increased in A2780/CDDP cells. ME treatment markedly decreased the expression of HSP90AB1 and IGF1R, thereby increasing the expression of the proapoptotic proteins p-p53, BAX, and p-H2AX, while the opposite effects were observed for the antiapoptotic protein BCL2. Inhibition of HSP90 ATPase was more beneficial against ovarian cancer in the presence of ME treatment. In turn, HSP90AB1 overexpression effectively inhibited the effect of ME in promoting the increased expression of apoptotic proteins and DNA damage response proteins in SKOV3/CDDP cells. Inhibition of cisplatin-induced apoptosis and DNA damage by HSP90AB1 overexpression confers chemoresistance in ovarian cancer. ME can enhance the sensitivity of ovarian cancer cells to cisplatin toxicity by inhibiting HSP90AB1/IGF1R interactions, and this might represent a novel target for overcoming cisplatin resistance in ovarian cancer chemotherapy.

Maggot extracts chemo-prevent inflammation and tumorigenesis accompanied by changes in the intestinal microbiome and metabolome in AOM/DSS-induced mice.

Inflammatory responses and intestinal microbiome play a crucial role in the progression of colitis-associated carcinoma (CAC). The traditional Chinese medicine maggot has been widely known owing to its clinical application and anti-inflammatory function. In this study, we investigated the preventive effects of maggot extract (ME) by intragastric administration prior to azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced CAC in mice. The results showed that ME had superior advantages in ameliorating disease activity index score and inflammatory phenotype, in comparison with the AOM/DSS group. The number and size of polypoid colonic tumors were decreased after pre-administration of ME. In addition, ME was found to reverse the downregulation of tight junction proteins (zonula occluden-1 and occluding) while suppressing the levels of inflammatory factors (IL-1ß and IL-6) in models. Moreover, Toll-like receptor 4 (TLR4) mediated intracellular nuclear factor-κB (NF-κB)-containing signaling cascades, including inducible nitric oxide synthase and cyclooxygenase-2, and exhibited decreasing expression in the mice model after ME pre-administration. 16s rRNA analysis and untargeted-metabolomics profiling of fecal samples inferred that ME revealed ideal prevention of intestinal dysbiosis in CAC mice, accompanied by and correlated with alterations in the composition of metabolites. Overall, ME pre-administration might be a chemo-preventive candidate in the initiation and development of CAC.

Functional characterization and transcriptional activity analysis of Dryopteris fragrans farnesyl diphosphate synthase genes.

Farnesyl diphosphate synthase (FPS), a key enzyme of the terpene metabolic pathway, catalyzes the precursor of sesquiterpene compounds farnesyl diphosphate (FPP) synthesis, and plays an important role in regulating plant growth and development. Dryopteris fragrans is a medicinal plant rich terpenoids. In this study, the function of the gene was verified in vitro and in vivo, the promoter of the gene was amplified and its transcriptional activity was analyzed. In the present study, we report the molecular cloning and functional characterization of DfFPS1 and DfFPS2, two FPS genes from D. fragrans. We found that the two genes were evolutionarily conserved. Both DfFPS genes were highly expressed in the gametophyte and mature sporophyte leaves, and their expression levels increased in response to methyl jasmonate (MeJA) and high temperature. Both DfFPS proteins were localized in the cytoplasm and could catalyze FPP synthesis in vitro. We also found that the overexpression of DfFPS genes in tobacco plants promoted secondary metabolite accumulation but exhibited negligible effect on plant growth and development. However, the transgenic plants exhibited tolerance to high temperature and drought. The promoters of the two genes were amplified using fusion primer and nested integrated polymerase chain reaction (FPNI-PCR). The promoter sequences were truncated and their activity was examined using the ß-glucuronidase (GUS) gene reporter system in tobacco leaves, and we found that both genes were expressed in the stomata. The transcriptional activity of the promoters was found to be similar to the expression pattern of the genes, and the transcriptional core regions of the two genes were mainly between -943 bp and -740 bp of proDfFPS1. Therefore, we present a preliminary study on the function and transcriptional activity of the FPS genes of D. fragrans and provide a basis for the regulation of terpene metabolism in D. fragrans. The results also provide a novel basis for the elucidation of terpene metabolic pathways in ferns.

Mendelian Randomization Analysis Provides Insights into the Pathogenesis of Serum Levels of Branched-Chain Amino Acids in Cardiovascular Disease.

Several observational studies have indicated an association between high serum levels of branched-chain amino acids (BCAAs) and an increased risk of cardiovascular disease (CVD). To assess whether theses associations reflect causality, we carried out two-sample Mendelian randomization (MR). Single-nucleotide polymorphisms (SNPs) associated with BCAA were evaluated in 10 studies, including 24,925 participants. The association between SNPs and coronary artery disease (CAD) were assessed using summary estimates from the CARDIoGRAMplusC4D consortium. Further MR analysis of BCAAs and seven CVD outcomes was performed. The BCAA-raising gene functions were also analyzed. MR analyses revealed a risk-increasing causal relationship between serum BCAA concentrations and CAD (odds ratio 1.08; 95% confidence interval (CI) 1.02-1.14), which was partly mediated by blood pressure and type 2 diabetes. BCAA also demonstrated a causal relationship with ischemic CVD events induced by plaque rupture and thrombosis (false discovery rate <0.05). Two BCAA-raising genes (MRL33 and CBLN1) were preferentially associated with myocardial infarction risk in the presence of atherosclerosis (p < 0.003). Functional analysis of the BCAA-raising genes suggested the causal involvement of two pathophysiological pathways, including glucose metabolism (PPM1K and TRMT61A) related to plaque progression, and the newly discovered neuroendocrine disorders regulating blood pressure (MRPL33, CBLN1, and C2orf16) related to plaque rupture and thrombosis. This comprehensive MR analysis provided insights into the potential causal mechanisms linking BCAA with CVD risk and suggested targeting neuroendocrine disorders as a potential strategy for the prevention of CVD. These results warrant further studies to elucidate the mechanisms underlying these reported causal associations.

Strategies to inTerrupt RAbies Transmission for the Elimination Goal by 2030 In China (STRATEGIC): a modelling study.

BACKGROUND: A global plan has been set to end human deaths from dog-mediated rabies by 2030 ("Zero-by-30"), but whether it could be achieved in some countries, such as China, remains unclear. Although elimination strategies through post-exposure prophylaxis (PEP) use, dog vaccination, and patient risk assessments with integrated bite case management (IBCM) were proposed to be cost-effective, evidence is still lacking in China. We aim to evaluate the future burdens of dog-mediated human rabies deaths in the next decade and provide quantitative evidence on the cost-effectiveness of different rabies-control strategies in China. METHODS: Based on data from China's national human rabies surveillance system, we used decision-analytic modelling to estimate dog-mediated human rabies death trends in China till 2035. We simulated and compared the expected consequences and costs of different combination strategies of the status quo, improved access to PEP, mass dog vaccination, and use of IBCM. RESULTS: The predicted human rabies deaths in 2030 in China will be 308 (95%UI: 214-411) and remain stable in the next decade under the status quo. The strategy of improved PEP access alone could only decrease deaths to 212 (95%UI: 147-284) in 2028, remaining unchanged till 2035. In contrast, scaling up dog vaccination to coverage of 70% could eliminate rabies deaths by 2033 and prevent approximately 3,265 (95%UI: 2,477-3,687) extra deaths compared to the status quo during 2024-2035. Moreover, with the addition of IBCM, the "One Health" approach through mass dog vaccination could avoid unnecessary PEP use and substantially reduce total cost from 12.53 (95%UI: 11.71-13.34) to 8.73 (95%UI: 8.09-9.85) billion US dollars. Even if increasing the total costs of IBCM from 100 thousand to 652.10 million US dollars during 2024-2035, the combined strategy of mass dog vaccination and use of IBCM will still dominate, suggesting the robustness of our results. CONCLUSIONS: The combined strategy of mass dog vaccination and IBCM requires collaboration between health and livestock/veterinary sectors, and it could eliminate Chinese rabies deaths as early as 2033, with more deaths averted and less cost, indicating that adding IBCM could reduce unnecessary use of PEP and make the "One Health" rabies-control strategy most cost-effective.

Stock volatility and hospital admissions for cardiovascular disease: results from the National Insurance Claims for Epidemiological Research (NICER) study.

Background: The association between stock volatility and cardiovascular diseases (CVD) was described during the 2008 Global Stock Market Crash; however, whether the finding in an occasional stock market crash is spurious remains unclear. Methods: A time-series design was used to evaluate the association between short-term exposure to daily returns of two major indices and daily hospital admissions for CVD and its subtypes based on claims data from the National Insurance Claims for Epidemiological Research (NICER) study covering 174 major cities in China. The average percentage change in daily hospital admissions for cause-specific CVD per 1% change in daily index returns was calculated because the Chinese stock market policy limits its change by 10% of the previous day's closing price. A Poisson regression in a generalised additive model was used to assess the city-specific association; then, overall national estimations were pooled by random-effects meta-analysis. Findings: Totally 8,234,164 hospital admissions for CVD were recorded during 2014-2017. Points of the Shanghai closing indices ranged from 1991·3 to 5166·4. A U-shaped association was observed between daily index returns and CVD admissions. Changes of 1% in daily returns of the Shanghai index corresponded to 1·28%(95%CI: 1·04%-1·53%), 1·25%(0·99%-1·51%), 1·42%(1·13%-1·72%), and 1·14%(0·39%-1·89%) increases in hospital admissions for total CVD, ischaemic heart disease, stroke, or heart failure on the same day, respectively. Similar results were observed for the Shenzhen index. Interpretation: Stock market volatility is associated with an increased CVD admission. Funding: Chinese Ministry of Science and Technology (2020YFC2003503) and National Natural Science Foundation of China (81973132, 81961128006).

Functional Characterization of Potato UBC13-UEV1s Genes Required for Ubiquitin Lys63 Chain to Polyubiquitination.

Ubiquitin-conjugating enzymes (E2s/UBC) are components of the ubiquitin proteasome system (UPS), and the ubiquitin-conjugating enzyme variant (UEV) is one of E2s (ubiquitin-conjugating enzymes, UBC) subfamily. The UEVs and UBC13 play an auxiliary role in mediating Lys63-linked polyUb chain assembly, which is correlated with target protein non-proteolytic functions, such as DNA repair or response to stress. However, the collaborative mechanism of StUBC13 (homologue of AtUBC13) and StUEVs (the UEVs in potato) involved in potato are not fully understood understood. Here, we identified two StUBC13 and seven StUEVs from potato genome. We analyzed protein motif and conserved domain, gene structure, phylogenetic features, cis-acting elements of StUBC13 and StUEVs. Subsequently, we screened StUBC13 partners protein and verified interaction between StUBC13 and StUEVs using yeast two-hybrid, split luciferase complementation (SLC) and bimolecular fluorescence complementation (BiFC) approach. The expression profile and qRT-PCR analysis suggested that StUBC13 and StUEVs gene exhibited a tissue-specific expression and were induced by different stress. Overall, this investigative study provides a comprehensive reference and view for further functional research on StUBC13 and StUEV1s in potato.

Stu-miR827-Targeted StWRKY48 Transcription Factor Negatively Regulates Drought Tolerance of Potato by Increasing Leaf Stomatal Density.

Stomata are specialized portals in plant leaves to modulate water loss from plants to the atmosphere by control of the transpiration, thereby determining the water-use efficiency and drought resistance of plants. Despite that the stomata developmental progression is well-understood at the molecular level, the experimental evidence that miRNA regulates stomata development is still lacking, and the underlying mechanism remains elusive. This study demonstrates the involvement of stu-miR827 in regulating the drought tolerance of potato due to its control over the leaf stomatal density. The expression analysis showed that stu-miR827 was obviously repressed by drought stresses and then rapidly increased after rewatering. Suppressing the expression of stu-miR827 transgenic potato lines showed an increase in stomatal density, correlating with a weaker drought resistance compared with wildtype potato lines. In addition, StWRKY48 was identified as the target gene of stu-miR827, and the expression of StWRKY48 was obviously induced by drought stresses and was greatly upregulated in stu-miR827 knockdown transgenic potato lines, suggesting its involvement in the drought stress response. Importantly, the expression of genes associated with stomata development, such as SDD (stomatal density and distribution) and TMM (too many mouths), was seriously suppressed in transgenic lines. Altogether, these observations demonstrated that suppression of stu-miR827 might lead to overexpression of StWRKY48, which may contribute to negatively regulating the drought adaptation of potato by increasing the stomatal density. The results may facilitate functional studies of miRNAs in the process of drought tolerance in plants.