Upgrade of crystallography beamline BL19U1 at the Shanghai Synchrotron Radiation Facility.

BL19U1, an energy-tunable protein complex crystallography beamline at the Shanghai Synchrotron Radiation Facility, has emerged as one of the most productive MX beamlines since opening to the public in July 2015. As of October 2023, it has contributed to over 2000 protein structures deposited in the Protein Data Bank (PDB), resulting in the publication of more than 1000 scientific papers. In response to increasing interest in structure-based drug design utilizing X-ray crystallography for fragment library screening, enhancements have been implemented in both hardware and data collection systems on the beamline to optimize efficiency. Hardware upgrades include the transition from MD2 to MD2S for the diffractometer, alongside the installation of a humidity controller featuring a rapid nozzle exchanger. This allows users to opt for either low-temperature or room-temperature data collection modes. The control system has been upgraded from Blu-Ice to MXCuBE3, which supports website-mode data collection, providing enhanced compatibility and easy expansion with new features. An automated data processing pipeline has also been developed to offer users real-time feedback on data quality.

Herb induced liver injury by Xianling Gubao Tablets: A case assessed for causality using updated RUCAM and integrated evidence chain.

Objective: A typical case of Xianling Gubao (XLGB) Tablets-induced liver injury was systematically studied in the clinic and the laboratory. Methods: A patient with herb-induced liver injury (HILI) and a history of taking XLGB Tablets before disease onset was engaged as the study subject, and the case was diagnosed according to the updated Roussel Uclaf Causality Assessment Method (RUCAM) and the integrated evidence chain (iEC) method recommended by the Guidelines for Diagnosis and Treatment of Herb-induced Liver Injury (HILI Guidelines). Results: Clinical history, biochemical indexes and imaging tests were used to exclude the influence of fundamental diseases and confusing liver diseases such as viral, alcoholic and autoimmune liver diseases on the diagnosis. Based on an investigation of the patient's medication history, she was suspected to have HILI caused by XLGB Tablets, as the patient was only taking an oral preparation of XLGB Tablets, and the influence of other drugs on the diagnosis was excluded. This patient with alanine aminotransferase (ALT) ≥ 3 × upper limit of normal (ULN) and a calculated R of 6 was diagnosed with possible acute drug-induced hepatocellular injury. The relationship was considered "highly probable" (score of 9) using the updated RUCAM of 2016. Moreover, the fingerprint similarity between the preparation taken by the patient and a commercially available preparation was 0.99, suggesting that the patient was consuming XLGB Tablets rather than another drug. LC-MS technology and the Agilent Fake TCM-Drugs database were used to investigate the drug, and no chemical additions were found. Examination of the drug for pesticide residues, heavy metals, aflatoxins and other exogenous substances indicated compliance with the content limits of the Chinese Pharmacopoeia. Conclusion: In summary, the final diagnosis of XLGB-induced liver injury reached the clinical diagnosis of HILI and was acute severe hepatocellular injury type by the updated RUCAM and iEC. Therefore, this study provides scientific evidence regarding the causality evaluation of compound preparations of traditional Chinese medicines-induced liver injury.

The impact of maternal smoking during pregnancy and the age of smoking initiation on incident dementia: A prospective cohort study.

INTRODUCTION: The impact of early-life tobacco exposure on dementia has remained unknown. METHODS: Using the UK Biobank, the associations of maternal smoking during pregnancy (MSDP) and age of smoking initiation (ASI) with the onset time of all-cause dementia were estimated with accelerated failure time models. The effects of MSDP and ASI on brain structure and their genetic correlation to Alzheimer's disease (AD) were analyzed. A Mendelian randomization (MR) analysis was conducted. RESULTS: The time ratios for smokers starting in childhood, adolescence, and adulthood (vs never smokers) were 0.87 (0.76 to 0.99), 0.92 (0.88 to 0.96), and 0.95 (0.89 to 1.01). MSDP and smoking in adolescence altered many brain regions, including the hippocampus. In genetic analysis, MSDP was genetically and causally linked to AD, and a younger ASI was genetically correlated to a higher AD risk. DISCUSSION: Early-life smoking accelerated dementia onset and was genetically correlated to AD. MSDP demonstrated genetic and causal linkage to AD risks. HIGHLIGHTS: Unlike the commonly used Cox proportional hazards model, this article uses a parametric survival analysis method - the accelerated failure model - to explore the relationship between exposure to onset time. It can be used as an alternative method when the proportional hazards assumption is not met. Genetic analyses including genetic correlation study and MR analysis and brain structure analyses were conducted to support our findings and explore the potential mechanisms. The study reveals the relationship between different smoking initiation periods and the onset time of dementia and shows that earlier smoking exposure has a more significant impact on dementia. It emphasizes the importance of preventing early smoking. In the future, more research focusing on the relationship between early exposure and dementia is called for to provide more detailed prevention measures for dementia that cover all age groups.

Calcium channel blockers and Parkinson's disease: a systematic review and meta-analysis.

Background: The calcium channel has been considered to have great potential as a drug target for neuroprotective therapy in Parkinson's disease (PD), but previous studies yielded inconsistent results. Objectives: This study aimed to conduct a systematic review and meta-analysis to assess the relationship between using calcium channel blockers (CCBs) and the risk and progression of PD. Data sources and methods: The terms such as 'Parkinson's disease', 'PD', 'calcium channel blockers', and 'CCB' were used to search the literature published before 1 May 2023 in English databases, including PubMed, Embase, and Cochrane Library, for studies on CCB and PD. Data analysis was performed using Review Manager 5.3 software. Results: A total of 190 works of literature were preliminarily retrieved, and 177 works of literature were excluded by eliminating duplicates, reading abstracts, and reading full texts. A total of nine studies were finally included in the meta-analysis of the CCB and the risk of PD, and five studies were included in the systematic review of the CCB and the progression of PD. A total of 2,961,695 participants were included in the meta-analysis. The random-effects model was used for analysis due to significant heterogeneity. The main results of the meta-analysis showed that the use of CCB could reduce the risk of PD (relative risk 0.78, 95% confidence interval 0.62-0.99). Conclusion: CCB use was associated with a significantly reduced risk of PD. Whether CCB use has a disease-modifying effect on PD needs further study. Registration: PROSPERO: CRD42024508242.

Alzheimer's disease and oral manifestations: a bi-directional Mendelian randomization study.

Background: Epidemiological studies have provided evidence suggesting an association between Alzheimer's disease (AD) and various oral manifestations. However, conflicting conclusions have been drawn, and whether a causal association truly exists remains unclear. Methods: In order to investigate the potential causal association between AD and prevalent oral diseases, we conducted a bi-directional two-sample Mendelian randomization analysis based on summary statistics from genome-wide association studies of AD (N = 63,926), as well as mouth ulcer (N = 461,103), oral cavity cancer (N = 4,151), and periodontal disease (N = 527,652). Results: We identified that one standard increase in the risk of AD was causally associated with a reduced risk of oral cavity cancer (OR = 0.76, 95% CI: 0.63-0.92, p = 3.73 × 10-3). In the opposite direction, oral conditions were not causally associated with risk of AD. Conclusion: The present findings contributed to a better understanding of the correlation between AD and oral conditions, specifically oral cavity cancer. These results also identified new avenues for exploring the underlying mechanisms of oral cavity cancer.

Follicular fluid exosome-derived miR-339-5p enhances in vitro maturation of porcine oocytes via targeting SFPQ, a regulator of the ERK1/2 pathway.

In this study, we aimed to investigate cytoplasmic maturation and miRNA expression of mature oocytes cultured in porcine follicular fluid exosomes. We also examined the effect of miR-339-5p on oocyte maturation. Twenty eight differentially expressed miRNAs were detected using miRNA-seq. We then transfected cumulus oocyte complexes with miR-339-5p mimics and inhibitor during culture. The results showed that exosomes increased endoplasmic reticulum levels and the amount of lipid droplets, and decreased ROS levels, lipid droplet size, and percentage of oocytes with abnormal cortical granule distribution. Overexpressing miR-339-5p significantly decreased cumulus expansion genes, oocyte maturation-related genes, target gene proline/glutamine-rich splicing factor (SFPQ), ERK1/2 phosphorylation levels, oocyte maturation rate, blastocyst rate, and lipid droplet number, but increased lipid droplet size and the ratio of oocytes with abnormal cortical granule distribution. Inhibiting miR-339-5p reversed the decrease observed during overexpression. Mitochondrial membrane potential and ROS levels did not differ significantly between groups. In summary, exosomes promote oocyte cytoplasmic maturation and miR-339-5p regulating ERK1/2 activity through SFPQ expression, thereby elevating oocyte maturation and blastocyst formation rate in vitro.

Research on regenerative braking control of electric vehicles based on game theory optimization.

The energy-efficient, clean, and quiet attributes of electric vehicles offer solutions to conventional challenges related to resource scarcity and environmental pollution. Consequently, thorough research into harmonizing energy recuperation during braking, enhancing vehicle stability, and ensuring occupant comfort in electric vehicles is imperative for their effective advancement. The study introduces a regenerative braking control strategy for electric vehicles founded on game theory optimization to enhance braking performance and optimize braking energy utilization. Develop a regenerative braking control approach based on the dynamic model of an electric vehicle equipped with hub motors. Employing game theory, we establish participants, control variables, strategy sets, benefit functions, and constraints to optimize the coefficient K for regenerative braking. The efficacy and superiority of the control strategy model are validated through joint simulations using Matlab/Simulink and AVL Cruise. Research findings indicate: (1) Speed tracking error remains below 3% in both NEDC and CLTC-P simulations, underscoring the effectiveness of the dynamic model and control strategy devised in this study. (2) The energy recovery rate achieved by the game theory-based optimization strategy surpasses that of the Cruise self-contained strategy and fuzzy control strategy by 18.06% and 4.5% in the NEDC simulation, and by 13.48% and 3.85% in the CLTC-P simulation, respectively. The adhesion coefficient curves implemented on the front and rear axles, derived from the game theory optimization control strategy, closely approximate the ideal adhesion coefficient curve, leading to a substantial enhancement in the car's braking stability. The degree of jerk magnitude regulated by the game theory optimization strategy consistently falls within the ±3 m/s³ threshold, resulting in a considerable enhancement in the comfort of vehicle occupants. These outcomes underscore the efficacy of the game theory-based optimized control strategy in enhancing energy recovery, braking stability, and comfort throughout the braking process of the vehicle.

The MdMYB44-MdTPR1 repressive complex inhibits MdCCD4 and MdCYP97A3 expression through histone deacetylation to regulate carotenoid biosynthesis in apple.

Carotenoids are photosynthetic pigments and antioxidants that contribute to different plant colors. However, the involvement of TOPLESS (TPL/TPR)-mediated histone deacetylation in the modulation of carotenoid biosynthesis through ethylene-responsive element-binding factor-associated amphiphilic repression (EAR)-containing transcription factors (TFs) in apple (Malus domestica Borkh.) is poorly understood. MdMYB44 is a transcriptional repressor that contains an EAR repression motif. In the present study, we used functional analyses and molecular assays to elucidate the molecular mechanisms through which MdMYB44-MdTPR1-mediated histone deacetylation influences carotenoid biosynthesis in apples. We identified two carotenoid biosynthetic genes, MdCCD4 and MdCYP97A3, that were confirmed to be involved in MdMYB44-mediated carotenoid biosynthesis. MdMYB44 enhanced ß-branch carotenoid biosynthesis by repressing MdCCD4 expression, whereas MdMYB44 suppressed lutein level by repressing MdCYP97A3 expression. Moreover, MdMYB44 partially influences carotenoid biosynthesis by interacting with the co-repressor TPR1 through the EAR motif to inhibit MdCCD4 and MdCYP97A3 expression via histone deacetylation. Our findings indicate that the MdTPR1-MdMYB44 repressive cascade regulates carotenoid biosynthesis, providing profound insights into the molecular basis of histone deacetylation-mediated carotenoid biosynthesis in plants. These results also provide evidence that the EAR-harboring TF/TPL repressive complex plays a universal role in histone deacetylation-mediated inhibition of gene expression in various plants.

Comprehensive analysis of immunogenic cell death-related gene and construction of prediction model based on WGCNA and multiple machine learning in severe COVID-19.

The death of coronavirus disease 2019 (COVID-19) is primarily due to from critically ill patients, especially from ARDS complications caused by SARS-CoV-2. Therefore, it is essential to contribute an in-depth understanding of the pathogenesis of the disease and to identify biomarkers for predicting critically ill patients at the molecular level. Immunogenic cell death (ICD), as a specific variant of regulatory cell death driven by stress, can induce adaptive immune responses against cell death antigens in the host. Studies have confirmed that both innate and adaptive immune pathways are involved in the pathogenesis of SARS-CoV-2 infection. However, the role of ICD in the pathogenesis of severe COVID-19 has rarely been explored. In this study, we systematically evaluated the role of ICD-related genes in COVID-19. We conducted consensus clustering, immune infiltration analysis, and functional enrichment analysis based on ICD differentially expressed genes. The results showed that immune infiltration characteristics were altered in severe and non-severe COVID-19. In addition, we used multiple machine learning methods to screen for five risk genes (KLF5, NSUN7, APH1B, GRB10 and CD4), which are used to predict COVID-19 severity. Finally, we constructed a nomogram to predict the risk of severe COVID-19 based on the classification and recognition model, and validated the model with external data sets. This study provides a valuable direction for the exploration of the pathogenesis and progress of COVID-19, and helps in the early identification of severe cases of COVID-19 to reduce mortality.

Aminocyclopropenium as a novel hydrogen bonding organocatalyst for cycloaddition of carbon disulfide and epoxide to prepare cyclic dithiocarbonate.

The smallest Hückel aromatic ring cyclopropenium substituted by electron-donating C-amino groups produced a aminocyclopropenium electron-rich cation. A bifunctional aminocyclopropenium halide catalyst installed with bis-(hydroxyethyl) functions on the amino group was then designed. A typical (diethanolamino)cyclopropenium halide catalyst C5·I was screened optimally for the cycloaddition of carbon disulfide into an epoxide to produce cyclic dithiocarbonate with an excellent conversion (95%) and high selectivity (92%). The electrostatic enhancement of alkyl C-H HBD capability was implemented via vicinal positive charges on the cyclopropenium core, and the acidity of the terminal O-H hydrogen proton increased by intramolecular H-bonding between the two hydroxy groups on the diethanolamino group (O-H⋯O-H). Then, a hybrid H-bond donor comprising enhanced alkyl C-H and hydroxy O-H was formed. The hybrid HBD offered by aminocyclopropenium was vital in activating the epoxide and stabilizing the intermediate, resulting in reduced O/S scrambling. Moreover, weakly coordinated iodide anion served as a nucleophilic reagent to open the ring of the epoxide. The cooperative catalytic mechanism of the HBD cation and halide anion was supported by NMR titrations and control experiments. Eleven epoxides with various substituents were converted into the corresponding cyclic thiocarbonate with high conversion and selectivity under mild conditions (25 °C, 6 h) without a solvent. The cycloaddition of carbon disulfide with epoxides catalyzed by aminocyclopropenium developed a new working model for hydrogen bonding organocatalysis.

Predictors for survival in patients with Alzheimer's disease: a large comprehensive meta-analysis.

The prevalence of Alzheimer's disease (AD) is increasing as the population ages, and patients with AD have a poor prognosis. However, knowledge on factors for predicting the survival of AD remains sparse. Here, we aimed to systematically explore predictors of AD survival. We searched the PubMed, Embase and Cochrane databases for relevant literature from inception to December 2022. Cohort and case-control studies were selected, and multivariable adjusted relative risks (RRs) were pooled by random-effects models. A total of 40,784 reports were identified, among which 64 studies involving 297,279 AD patients were included in the meta-analysis after filtering based on predetermined criteria. Four aspects, including demographic features (n = 7), clinical features or comorbidities (n = 13), rating scales (n = 3) and biomarkers (n = 3), were explored and 26 probable prognostic factors were finally investigated for AD survival. We observed that AD patients who had hyperlipidaemia (RR: 0.69) were at a lower risk of death. In contrast, male sex (RR: 1.53), movement disorders (including extrapyramidal signs) (RR: 1.60) and cancer (RR: 2.07) were detrimental to AD patient survival. However, our results did not support the involvement of education, hypertension, APOE genotype, Aß42 and t-tau in AD survival. Our study comprehensively summarized risk factors affecting survival in patients with AD, provided a better understanding on the role of different factors in the survival of AD from four dimensions, and paved the way for further research.

Sleep characteristics and risk of Alzheimer's disease: a systematic review and meta-analysis of longitudinal studies.

BACKGROUND: Alzheimer's disease (AD) is on the rise in our aging society, making it crucial to identify additional risk factors to mitigate its increasing incidence. This systematic review and meta-analysis aimed to provide updated evidence regarding the association between sleep and AD. METHODS: We conducted a comprehensive search of MEDLINE, EMBASE, and Web of Science databases from inception to July 2023 to identify longitudinal studies. Adjusted relative risks were pooled for each sleep characteristic, and a dose-response analysis was performed specifically for sleep duration. RESULTS: A total of 15,278 records were initially retrieved, and after screening, 35 records were ultimately included in the final analysis. The results showed that insomnia (RR, 1.43; 95%CI, 1.17-1.74), sleep-disordered breathing (RR, 1.22; 95%CI, 1.07-1.39), as well as other sleep problems, including sleep fragmentation and sleep-related movement disorders, were associated with a higher risk of developing AD, while daytime napping or excessive daytime sleepiness (RR, 1.18; 95%CI, 1.00-1.40) only exhibited a trend toward a higher risk of AD development. Furthermore, our analysis revealed a significant association between self-reported sleep problems (RR, 1.34; 95%CI, 1.26-1.42) and the incidence of AD, whereas this association was not observed with sleep problems detected by objective measurements (RR, 1.14; 95%CI, 0.99-1.31). Moreover, both quite short sleep duration (< 4 h) and long duration (> 8 h) were identified as potential risk factors for AD. CONCLUSIONS: Our study found the association between various types of sleep problems and an increased risk of AD development. However, these findings should be further validated through additional objective device-based assessments. Additional investigation is required to establish a definitive causal connection between sleep problems and AD.

New advances in the study of PD-1/PD-L1 inhibitors-induced liver injury.

The application of immune checkpoint inhibitors (ICIs) has made extraordinary achievements in tumor treatment. Among them, programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors can improve the prognosis of advanced tumors, and have been widely used in clinical practice to treat many types of cancers. However, excessive immune response can also induce immune-related adverse events (irAEs) involving many organs. Of these, immune-related liver injury is the relatively common and carries the highest morbidity, which has attracted the attention of hepatologists all over the world. The incidence of this type of liver injury depends specifically on factors such as the type of drug being combined, viral infection, type of cancer and liver transplantation. Although there is no unanimity on the mechanism of PD-1/PD-L1 inhibitor-induced liver injury, in this review, we also summarize the current evidence that provides insights into the pathogenesis of PD-1/PD-L1 inhibitor-induced liver injury, including the fact that PD-1/PD-L1 inhibitors cause reactivation of CTLs, aberrant presentation of autoantigens, hepatic immune tolerance environment is disrupted, and cytokine secretion, among other effects. Patients usually develop liver injury after the use of PD-1/PD-L1 inhibitors, and clinical symptoms mainly include weakness, muscle pain, nausea and vomiting, and jaundice. Histologically, the main manifestation is lobular hepatitis with lobular inflammatory infiltration. Since the specific biomarkers for PD-1/PD-L1 inhibitor-associated liver injury have not been identified yet, alpha-fetoprotein, IL-6, and IL-33 have the potential to be biomarkers for predicting this type of liver injury in the future, but this requires further research. We also describe the examination and treatment of this type of liver injury, which usually includes eliminating related influencing factors, regularly monitoring liver function, temporarily retaining or permanently stopping ICIs treatment according to the severity of toxicity, and using corticosteroids. This review may provide useful information for the future clinical practice of PD-1/PD-L1 inhibitors.

MaSMG7-Mediated Degradation of MaERF12 Facilitates Fusarium oxysporum f. sp. cubense Tropical Race 4 Infection in Musa acuminata.

Modern plant breeding relies heavily on the deployment of susceptibility and resistance genes to defend crops against diseases. The expression of these genes is usually regulated by transcription factors including members of the AP2/ERF family. While these factors are a vital component of the plant immune response, little is known of their specific roles in defense against Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4) in banana plants. In this study, we discovered that MaERF12, a pathogen-induced ERF in bananas, acts as a resistance gene against Foc TR4. The yeast two-hybrid assays and protein-protein docking analyses verified the interaction between this gene and MaSMG7, which plays a role in nonsense-mediated RNA decay. The transient expression of MaERF12 in Nicotiana benthamiana was found to induce strong cell death, which could be inhibited by MaSMG7 during co-expression. Furthermore, the immunoblot analyses have revealed the potential degradation of MaERF12 by MaSMG7 through the 26S proteasome pathway. These findings demonstrate that MaSMG7 acts as a susceptibility factor and interferes with MaERF12 to facilitate Foc TR4 infection in banana plants. Our study provides novel insights into the biological functions of the MaERF12 as a resistance gene and MaSMG7 as a susceptibility gene in banana plants. Furthermore, the first discovery of interactions between MaERF12 and MaSMG7 could facilitate future research on disease resistance or susceptibility genes for the genetic improvement of bananas.

Longitudinal evolution and plasma biomarkers for excessive daytime sleepiness in Parkinson's disease.

BACKGROUND: Excessive daytime sleepiness (EDS) is one of the most frequent non-motor symptoms in Parkinson's disease (PD); however, the pathogenesis of EDS is unclear, and there is a lack of information on plasma biomarkers for EDS in PD. We aimed to investigate the plasma biomarkers of EDS in a large PD cohort. METHODS: A total of 159 PD patients were included in the prospective cohort study and followed up annually for three years. Plasma biomarkers including glial fibrillary acidic protein, amyloid-beta, p-tau181, and neurofilament light chain (NfL), were measured using an ultrasensitive single-molecule array (SimoaTM) technology at each visit. EDS was evaluated using the Epworth Sleepiness Scale (ESS). RESULTS: The frequency of EDS in PD increased from 15.1% at baseline to 25.0% after three years. The mean ESS scores increased from 5.1 [Standard Deviation (SD): 4.8] at baseline to 6.1 [SD: 5.5] at the third year of follow-up. At baseline, compared with patients with PD without EDS, those with EDS were more likely to be male, had poorer cognitive performance, and more severe motor and non-motor symptoms. The adjusted generalized estimating equations models showed that higher plasma NfL levels (OR 1.047 [1.002-1.094], p = 0.042) were associated with EDS during follow-ups. The adjusted linear mixed-effects model showed that higher plasma NfL levels (ß 0.097 [0.012-0.183], p = 0.026) were associated with ESS scores during follow-ups. CONCLUSIONS: Higher plasma NfL levels were associated with EDS in PD, indicating an association between neuro-axonal degeneration and EDS in PD.

Abscisic acid activates transcription factor module MdABI5-MdMYBS1 during carotenoid-derived apple fruit coloration.

Carotenoids are major pigments contributing to fruit coloration. We previously reported that the apple (Malus domestica Borkh.) mutant fruits of 'Beni Shogun' and 'Yanfu 3' show a marked difference in fruit coloration. However, the regulatory mechanism underlying this phenomenon remains unclear. In this study, we determined that carotenoid is the main factor influencing fruit flesh color. We identified an R1-type MYB transcription factor, MdMYBS1, which was found to be highly associated with carotenoids and abscisic acid (ABA) contents of apple fruits. Overexpression of MdMYBS1 promoted, and silencing of MdMYBS1 repressed, ß-branch carotenoids synthesis and ABA accumulation. MdMYBS1 regulates carotenoid biosynthesis by directly activating the major carotenoid biosynthetic genes encoding phytoene synthase (MdPSY2-1) and lycopene ß-cyclase (MdLCYb). 9-cis-epoxycarotenoid dioxygenase 1 (MdNCED1) contributes to ABA biosynthesis, and MdMYBS1 enhances endogenous ABA accumulation by activating the MdNCED1 promoter. In addition, the basic leucine zipper domain transcription factor ABSCISIC ACID-INSENSITIVE5 (MdABI5) was identified as an upstream activator of MdMYBS1, which promotes carotenoid and ABA accumulation. Furthermore, ABA promotes carotenoid biosynthesis and enhances MdMYBS1 and MdABI5 promoter activities. Our findings demonstrate that the MdABI5-MdMYBS1 cascade activated by ABA regulates carotenoid-derived fruit coloration and ABA accumulation in apple, providing avenues in breeding and planting for improvement of fruit coloration and quality.

MiR-522-3p Attenuates Cardiac Recovery by Targeting FOXP1 to Suppress Angiogenesis.

Angiogenesis is crucial for blood supply reconstitution after myocardial infarction in patients with acute coronary syndrome (ACS). MicroRNAs are recognized as important epigenetic regulators of endothelial angiogenesis. The purpose of this study is to determine the roles of miR-522-3p in angiogenesis after myocardial infarction. The expression levels of miR-522-3p in rats' plasma and in the upper part of the ligation of the heart tissues at 28 days after myocardial infarction were significantly higher than those of the sham group. miR-522-3p mimics inhibited cell proliferations, migrations, and tube formations under hypoxic conditions in HUVECs (human umbilical vein endothelial cells), whereas miR-522-3p inhibitors did the opposite. Furthermore, studies have indicated that the inhibition of miR-522-3p by antagomir infusion promoted angiogenesis and accelerated the recovery of cardiac functions in rats with myocardial infarction.Data analysis and experimental results revealed that FOXP1 (Forkhead-box protein P1) was the target gene of miR-522-3p. Our study explored the mechanism of cardiac angiogenesis after myocardial infarction and provided a potential therapeutic approach for the treatment of ischemic heart disease in the future.

Combination Nano-Delivery Systems Remodel the Immunosuppressive Tumor Microenvironment for Metastatic Triple-Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer for which effective therapies are lacking. Targeted remodeling of the immunosuppressive tumor microenvironment (TME) and activation of the body's immune system to fight tumors with well-designed nanoparticles have emerged as pivotal breakthroughs in tumor treatment. To simultaneously remodel the immunosuppressive TME and trigger immune responses, we designed two potential therapeutic nanodelivery systems to inhibit TNBC. First, the bromodomain-containing protein 4 (BRD4) inhibitor JQ1 and the cyclooxygenase-2 (COX-2) inhibitor celecoxib (CXB) were coloaded into chondroitin sulfate (CS) to obtain CS@JQ1/CXB nanoparticles (NPs). Then, the biomimetic nanosystem MM@P3 was prepared by coating branched polymer poly(ß-amino ester) self-assembled NPs with melittin embedded macrophage membranes (MM). Both in vitro and in vivo, the CS@JQ1/CXB and MM@P3 NPs showed excellent immune activation efficiencies. Combination treatment exhibited synergistic cytotoxicity, antimigration ability, and apoptosis-inducing and immune activation effects on TNBC cells and effectively suppressed tumor growth and metastasis in TNBC tumor-bearing mice by activating the tumor immune response and inhibiting angiogenesis. In summary, this study offers a novel combinatorial immunotherapeutic strategy for the clinical TNBC treatment.

Plasma GFAP as a prognostic biomarker of motor subtype in early Parkinson's disease.

Parkinson's disease (PD) is a heterogeneous movement disorder with different motor subtypes including tremor dominant (TD), indeterminate and postural instability, and gait disturbance (PIGD) motor subtypes. Plasma glial fibrillary acidic protein (GFAP) was elevated in PD patients and may be regarded as a biomarker for motor and cognitive progression. Here we explore if there was an association between plasma GFAP and different motor subtypes and whether baseline plasma GFAP level can predict motor subtype conversion. Patients with PD classified as TD, PIGD or indeterminate subtypes underwent neurological evaluation at baseline and 2 years follow-up. Plasma GFAP in PD patients and controls were measured using an ultrasensitive single molecule array. The study enrolled 184 PD patients and 95 control subjects. Plasma GFAP levels were significantly higher in the PIGD group compared to the TD group at 2-year follow-up. Finally, 45% of TD patients at baseline had a subtype shift and 85% of PIGD patients at baseline remained as PIGD subtypes at 2 years follow-up. Baseline plasma GFAP levels were significantly higher in TD patients converted to PIGD than non-converters in the baseline TD group. Higher baseline plasma GFAP levels were significantly associated with the TD motor subtype conversion (OR = 1.283, P = 0.033) and lower baseline plasma GFAP levels in PIGD patients were likely to shift to TD and indeterminate subtype (OR = 0.551, P = 0.021) after adjusting for confounders. Plasma GFAP may serve as a clinical utility biomarker in differentiating motor subtypes and predicting baseline motor subtypes conversion in PD patients.

Genome-wide DNA methylation analysis related to ALS patient progression and survival.

BACKGROUND: Epigenetics contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS). We aimed to characterize the DNA methylation profiles associated with clinical heterogeneity in disease progression and survival among patients. METHODS: We included a cohort of 41 patients with sporadic ALS, with a median follow-up of 86.9 months, and 27 rigorously matched healthy controls. Blood-based genome-wide DNA methylation analysis was conducted. RESULTS: A total of 948 progression rate-associated differentially methylated positions, 298 progression rate-associated differentially methylated regions (R-DMRs), 590 survival time-associated DMPs, and 197 survival time-associated DMRs (S-DMRs) were identified, using complementary grouping strategies. Enrichment analysis of differentially methylated genes highlighted the involvement of synapses and axons in ALS progression and survival. Clinical analysis revealed a positive correlation between the average methylation levels of the R-DMR in PRDM8 and disease progression rate (r = 0.479, p = 0.002). Conversely, there was an inverse correlation between the average methylation levels of the R-DMR in ANKRD33 and disease progression rate (r = - 0.476, p = 0.002). In addition, patients with higher methylation levels within the S-DMR of ZNF696 experienced longer survival (p = 0.016), while those with elevated methylation levels in the S-DMR of RAI1 had shorter survival (p = 0.006). CONCLUSION: DNA methylation holds promise as a potential biomarker for tracking disease progression and predicting survival outcome and also offers targets for precision medicine.