ß-Hydroxybutyrate Prevents Vascular Senescence through hnRNP A1-Mediated Upregulation of Oct4.

ß-hydroxybutyrate (ß-HB) elevation during fasting or caloric restriction is believed to induce anti-aging effects and alleviate aging-related neurodegeneration. However, whether ß-HB alters the senescence pathway in vascular cells remains unknown. Here we report that ß-HB promotes vascular cell quiescence, which significantly inhibits both stress-induced premature senescence and replicative senescence through p53-independent mechanisms. Further, we identify heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) as a direct binding target of ß-HB. ß-HB binding to hnRNP A1 markedly enhances hnRNP A1 binding with Octamer-binding transcriptional factor (Oct) 4 mRNA, which stabilizes Oct4 mRNA and Oct4 expression. Oct4 increases Lamin B1, a key factor against DNA damage-induced senescence. Finally, fasting and intraperitoneal injection of ß-HB upregulate Oct4 and Lamin B1 in both vascular smooth muscle and endothelial cells in mice in vivo. We conclude that ß-HB exerts anti-aging effects in vascular cells by upregulating an hnRNP A1-induced Oct4-mediated Lamin B1 pathway.

Ultra-low-field magnetization transfer imaging at 0.055T with low specific absorption rate.

PURPOSE: To demonstrate magnetization transfer (MT) effects with low specific absorption rate (SAR) on ultra-low-field (ULF) MRI. METHODS: MT imaging was implemented by using sinc-modulated RF pulse train (SPT) modules to provide bilateral off-resonance irradiation. They were incorporated into 3D gradient echo (GRE) and fast spin echo (FSE) protocols on a shielding-free 0.055T head scanner. MT effects were first verified using phantoms. Brain MT imaging was conducted in both healthy subjects and patients. RESULTS: MT effects were clearly observed in phantoms using six SPT modules with total flip angle 3600° at central primary saturation bands of approximate offset ±786 Hz, even in the presence of large relative B0 inhomogeneity. For brain, strong MT effects were observed in gray matter, white matter, and muscle in 3D GRE and FSE imaging using six and sixteen SPT modules with total flip angle 3600° and 9600°, respectively. Fat, cerebrospinal fluid, and blood exhibited relatively weak MT effects. MT preparation enhanced tissue contrasts in T2-weighted and FLAIR-like images, and improved brain lesion delineation. The estimated MT SAR was 0.0024 and 0.0008 W/kg for two protocols, respectively, which is far below the US Food and Drug Administration (FDA) limit of 3.0 W/kg. CONCLUSION: Robust MT effects can be readily obtained at ULF with extremely low SAR, despite poor relative B0 homogeneity in ppm. This unique advantage enables flexible MT pulse design and implementation on low-cost ULF MRI platforms to achieve strong MT effects in brain and beyond, potentially augmenting their clinical utility in the future.

Ultra-low-field magnetic resonance angiography at 0.05 T: A preliminary study.

We aim to explore the feasibility of head and neck time-of-flight (TOF) magnetic resonance angiography (MRA) at ultra-low-field (ULF). TOF MRA was conducted on a highly simplified 0.05 T MRI scanner with no radiofrequency (RF) and magnetic shielding. A flow-compensated three-dimensional (3D) gradient echo (GRE) sequence with a tilt-optimized nonsaturated excitation RF pulse, and a flow-compensated multislice two-dimensional (2D) GRE sequence, were implemented for cerebral artery and vein imaging, respectively. For carotid artery and jugular vein imaging, flow-compensated 2D GRE sequences were utilized with venous and arterial blood presaturation, respectively. MRA was performed on young healthy subjects. Vessel-to-background contrast was experimentally observed with strong blood inflow effect and background tissue suppression. The large primary cerebral arteries and veins, carotid arteries, jugular veins, and artery bifurcations could be identified in both raw GRE images and maximum intensity projections. The primary brain and neck arteries were found to be reproducible among multiple examination sessions. These preliminary experimental results demonstrated the possibility of artery TOF MRA on low-cost 0.05 T scanners for the first time, despite the extremely low MR signal. We expect to improve the quality of ULF TOF MRA in the near future through sequence development and optimization, ongoing advances in ULF hardware and image formation, and the use of vascular T1 contrast agents.

Effects of catechin on the malignant biological behavior of gastric cancer cells through the PI3K/Akt signaling pathway.

Catechin is a kind of flavonoids, mainly derived from the plant Camellia sinensis. It has a strong antioxidant effect, and it also has significant therapeutic effects on anti-cancer, anti-diabetes, and anti-infection. This study was intended to look at how catechin affected the malignant biological activity of gastric cancer cells. We used databases to predict the targets of catechin and the pathogenic targets of gastric cancer. Venn diagram was used to find the intersection genes, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were performed on intersection genes. Using the STRING database, the Protein-Protein Interaction (PPI) network was built. The top 8 genes were screened by Cytoscape 3.9.1, then their binding was verified by molecular docking. The proliferation ability, cell cycle, apoptosis and migration of gastric cancer cells were detected, as well as the protein expression levels of PI3K, p-AKT, and AKT and the mRNA expression levels of AKT1, VEGFA, EGFR, HRAS, and HSP90AA1 in gastric cancer cells. Our research revealed that different concentrations of catechin could effectively inhibit the proliferation and migration of gastric cancer cells, regulate the cell cycle, and promote the death of these cells, and it's possible that the PI3K/Akt pathway was crucial in mediating this impact. Moreover, adding the PI3K/Akt pathway agonist significantly reduced the promoting effect of catechin on the apoptosis of gastric cancer cells. This study suggested that catechin was a potential drug for the treatment of gastric cancer.

Maternal Dietary Cholesterol and Egg Intake during Pregnancy and Large-for-Gestational-Age Infants: A Prospective Cohort Study.

BACKGROUND: Cholesterol plays a vital role in fetal growth and development during pregnancy. There remains controversy over whether pregnant females should limit their cholesterol intake. OBJECTIVES: The objective of this study was to investigate the association between maternal dietary cholesterol intake during pregnancy and infant birth weight in a Chinese prospective cohort study. METHODS: A total of 4146 mother-child pairs were included based on the Jiangsu Birth Cohort study. Maternal dietary information was assessed with a semiquantitative food-frequency questionnaire. Birth weight z-scores and large-for-gestational-age (LGA) infants were converted by the INTERGROWTH-21st neonatal weight-for-gestational-age standard. Poisson regression and generalized estimating equations were employed to examine the relationships between LGA and maternal dietary cholesterol across the entire pregnancy and trimester-specific cholesterol intake, respectively. RESULTS: The median intake of maternal total dietary cholesterol during the entire pregnancy was 671.06 mg/d, with eggs being the main source. Maternal total dietary cholesterol and egg-sourced cholesterol were associated with an increase in birth weight z-score, with per standard deviation increase in maternal total and egg-sourced dietary cholesterol being associated with an increase of 0.16 [95% confidence interval (CI): 0.07, 0.25] and 0.06 (95% CI: 0.03, 0.09) in birth weight z-score, respectively. Egg-derived cholesterol intake in the first and third trimesters was positively linked to LGA, with an adjusted relative risk of 1.11 (95% CI: 1.04, 1.18) and 1.09 (95% CI: 1.00, 1.18). Compared with mothers consuming ≤7 eggs/wk in the third trimester, the adjusted relative risk for having an LGA newborn was 1.37 (95% CI: 1.09, 1.72) for consuming 8-10 eggs/wk and 1.45 (95% CI: 1.12, 1.86) for consuming >10 eggs/wk (P-trend = 0.015). CONCLUSIONS: Maternal total dietary cholesterol intake, as well as consuming over 7 eggs/wk during pregnancy, displayed significant positive relationships with the incidence of LGA, suggesting that mothers should avoid excessive cholesterol intake during pregnancy to prevent adverse birth outcomes.

Pre-electroacupuncture Ameliorates Cerebral Ischemia-reperfusion Injury by Inhibiting Microglial RhoA/pyrin/GSDMD Signaling Pathway.

Cerebral ischemia reperfusion injury is a severe neurological impairment that occurs after blood flow reconstruction in stroke, and microglia cell pyroptosis is one of its important mechanisms. Electroacupuncture has been shown to be effective in mitigating and alleviating cerebral ischemia reperfusion injury by inhibiting neuroinflammation, reducing cellular pyroptosis, and improving neurological function. In this experiment, we divided the rats into three groups, including the sham operation (Sham) group, the middle cerebral artery occlusion/reperfusion (MCAO/R) group, and the pre-electroacupuncture (EAC) group. Pre-electroacupuncture group was stimulated with electroacupuncture of a certain intensity on the Baihui (GV 20) and Dazhui (GV 14) of the rat once a day from the 7th day to the 1st day before the MCAO/R operation. The extent of cerebral infarction was detected by TTC staining. A modified Zea-Longa five-point scale scoring system was used to determine neurologic function in MCAO rats. The number of neurons and morphological changes were accessed by Nissl staining and HE staining. The cellular damage was detected by TUNEL staining. In addition, the expression levels of RhoA, pyrin, GSDMD, Caspase1, cleaved-Caspase1, Iba-1, CD206, and ROCK2 were examined by western blotting and immunofluorescence. The results found that pre-electroacupuncture significantly attenuated neurological impairment and cerebral infarction compared to the post-MCAO/R rats. In addition, pre-electroacupuncture therapy promoted polarization of microglia to the neuroprotective (M2) phenotype. In addition, pre-electroacupuncture inhibited microglia pyroptosis by inhibiting RhoA/pyrin/GSDMD signaling pathway, thereby reducing neuronal injury and increasing neuronal survival in the MCAO/R rats. Taken together, these results demonstrated that pre-acupuncture could attenuate cerebral ischemia-reperfusion injury by inhibiting microglial pyroptosis. Therefore, pre-electroacupuncture might be a potential preventive strategy for ischemic stroke patients.

Single-cell RNA-seq analysis hearts in patients with fetal tetralogy of Fallot.

INTRODUCTION: To explore the cytological characteristics of tetralogy of Fallot (TOF), we collected samples and studied the differences in cytological classification between normal fetal hearts and fetuses with TOF, and then we searched for possible differential genes of disease markers through single-cell sequencing analysis. METHODS: In this study, we analyzed the right ventricle of a TOF and a healthy human fetal heart sample by single-cell sequencing. Utilizing Cellranger to perform data quality control filtering, comparison, quantification, and identification of recovered cells on the raw data, ultimately obtaining gene expression matrices for each cell. Subsequently, Seurat was used for further cell filtration, standardization, cell subgroup classification, differential expression gene analysis of each subgroup, and Marker gene screening. RESULTS: Bioinformatic analysis identified 9979 and 15224 cells derived from the healthy and disease samples, respectively, with an average read depth of 25000/cell. The cardiomyocyte cell populations derived from the abnormal samples identified by the first-level graph-based analysis were separated into six distinct cell clusters. CONCLUSIONS: Our study reveals some information on TOF in a fetus, which can provide a new reference for early detection and treatment of TOF by comparing it with normal heart cells.

Clinical impact of sarcopenia for overweight or obese patients with colorectal cancer.

BACKGROUND: Sarcopenia, overweight and obesity are all dynamic changes in body composition, which may have a negative effect on the prognosis for patients with colorectal cancer. The aim of this study was to investigate the predictive role of sarcopenia on overweight or obese patients with colorectal cancer. METHODS: We conducted an observative study on the population of overweight or obese patients with colorectal cancer who underwent curative surgeries in two centers between 2015 and 2021. They were grouped by the presence of sarcopenia. Propensity score match analysis was used to balance the baseline of clinicopathologic characteristics of the two groups. Then, the postoperative outcomes between the two groups were compared. Independent risk factors were evaluated for complications using univariate and multivariate analysis. RESULTS: Of 827 patients enrolled, 126 patients were matched for analysis. Patients with sarcopenia had a higher incidence of total complication and medical complications, a higher rate of laparoscopic surgery performed and higher hospitalization costs. Old age (≥65 years, P = 0.012), ASA grade (III, P = 0.008) and sarcopenia (P = 0.036) were independent risk factors for total complications. ASA grade (III, P = 0.002) and sarcopenia (P = 0.017) were independent risk factors for medical complications. CONCLUSIONS: Sarcopenia was prevalent among overweight or obese patients with colorectal cancer and was associated with negative postoperative outcomes. Early recognition of changes in body composition could help surgeons be well prepared for surgical treatment for overweight or obese patients.

Interaction between antiretroviral therapy regimens and body mass index on triglyceride levels in people living with HIV: a cross-sectional and longitudinal study.

OBJECTIVE: To investigate how antiretroviral therapy (ART) regimens and body mass index (BMI) interact to affect triglyceride (TG) levels in people living with HIV (PLWH). METHODS: This research involved 451 men living with HIV for cross-sectional analysis, and 132 underwent follow-up assessments in 2021 and 2023. Multivariate logistic regression identified key factors, while covariance regression models assessed interactions between ART regimens and BMI on TG levels. RESULTS: The result of this cross-sectional study indicated that advanced AIDS (acquired immune deficiency syndrome) stage (OR = 2.756, P = 0.003), higher BMI (OR = 1.131, P = 0.003), and waist-hip ratio (WHR, OR = 44.684, P = 0.019) are closely associated with high triglyceride levels. Additionally, regimens containing zidovudine (AZT) (OR = 3.927, P < 0.001) or protease inhibitors/integrase strand transfer inhibitors (PI/INSTI) (OR = 5.167, P < 0.001) were significantly linked to hypertriglyceridemia. Cross-sectional and longitudinal analyses from 2021 to 2023 emphasized that changes in BMI interact with antiretroviral treatment regimens to affect TG levels in PLWH (Pinteraction < 0.05). Especially in the AZT-based drug regimen, the correlation between BMI and TG is more prominent. CONCLUSION: The interaction between ART regimens and BMI influences TG levels in PLWH, indicating that weight management is crucial for reducing the risk of hypertriglyceridemia in this population.

Protective effect of melatonin on imidacloprid-induced pyroptosis and ferroptosis by mediating peptidoglycan in the gut of the common carp (Cyprinus carpio).

Imidacloprid (IMI) is a contaminant widespread in surface water, causing serious intestinal damage in the common carp. Melatonin (MT), an endogenous indoleamine hormone, plays a crucial role in mitigating pesticide-induced toxicity. Our previous research has demonstrated that MT effectively reduces the production of intestinal microbial-derived signal peptidoglycan (PGN) induced by IMI, thereby alleviating intestinal tight junction injuries in the common carp. In this study, we performed a transcriptomic analysis to explore the effect of MT on the IMI exposure-induced gut damage of the common carp. The results elucidated that the ferroptosis, mitogen-activated protein kinases (MAPKs), and nucleotide oligomerization domain (NOD)-like signaling pathways were significantly associated with IMI exposure and MT treatment. Meanwhile, the exposure to IMI resulted in the formation of pyroptotic bodies and distinct morphological features of ferroptosis, both mitigated with the addition of MT. Immunofluorescence double staining demonstrated that MT abolished the elevated expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and Gasdermin D (GSDMD) induced by IMI, as well as reduced expression of ferritin heavy chains (FTH) and glutathione peroxidase 4 (GPX4) in gut tissues. Subsequently, we found that the exposure to IMI or PGN enhanced the expression of toll-like receptors (TLR) 2 (a direct recognition receptor of PGN) triggering the P38MAPK signaling pathway, thereby aggravating the process of pyroptosis and ferroptosis of cell models. The addition of MT or SB203580 (a P38MAPK inhibitor) significantly reduced pyroptotic cells, and also decreased iron accumulation. Consequently, these results indicate that MT alleviates IMI-induced pyroptosis and ferroptosis in the gut of the common carp through the PGN/TLR2/P38MAPK pathway.

Implementation and Validation of an OpenMM Plugin for the Deep Potential Representation of Potential Energy.

Machine learning potentials, particularly the deep potential (DP) model, have revolutionized molecular dynamics (MD) simulations, striking a balance between accuracy and computational efficiency. To facilitate the DP model's integration with the popular MD engine OpenMM, we have developed a versatile OpenMM plugin. This plugin supports a range of applications, from conventional MD simulations to alchemical free energy calculations and hybrid DP/MM simulations. Our extensive validation tests encompassed energy conservation in microcanonical ensemble simulations, fidelity in canonical ensemble generation, and the evaluation of the structural, transport, and thermodynamic properties of bulk water. The introduction of this plugin is expected to significantly expand the application scope of DP models within the MD simulation community, representing a major advancement in the field.

Indoleamine 2,3-Dioxygenase 1 Deletion-Mediated Kynurenine Insufficiency in Vascular Smooth Muscle Cells Exacerbates Arterial Calcification.

BACKGROUND: IDO1 (indoleamine 2,3-dioxygenase 1) is the rate-limiting enzyme for tryptophan metabolism. IDO1 malfunction is involved in the pathogenesis of atherosclerosis. Vascular smooth muscle cells (VSMCs) with an osteogenic phenotype promote calcification and features of plaque instability. However, it remains unclear whether aberrant IDO1-regulated tryptophan metabolism causes VSMCs osteogenic reprogramming and calcification. METHODS: We generated global Apoe (apolipoprotein E) and Ido1 double knockout mice, and Apoe knockout mice with specific deletion of IDO1 in VSMCs or macrophages. Arterial intimal calcification was evaluated by a Western diet-induced atherosclerotic calcification model. RESULTS: Global deficiency of IDO1 boosted calcific lesion formation without sex bias in vivo. Conditional IDO1 loss of function in VSMCs rather than macrophages promoted calcific lesion development and the abundance of RUNX2 (runt-related transcription factor 2). In contrast, administration of kynurenine via intraperitoneal injection markedly delayed the progression of intimal calcification in parallel with decreased RUNX2 expression in both Apoe-/- and Apoe-/-Ido1-/- mice. We found that IDO1 deletion restrained RUNX2 from proteasomal degradation, which resulted in enhanced osteogenic reprogramming of VSMCs. Kynurenine administration downregulated RUNX2 in an aryl hydrocarbon receptor-dependent manner. Kynurenine acted as the endogenous ligand of aryl hydrocarbon receptor, controlled resultant interactions between cullin 4B and aryl hydrocarbon receptor to form an E3 ubiquitin ligase that bound with RUNX2, and subsequently promoted ubiquitin-mediated instability of RUNX2 in VSMCs. Serum samples from patients with coronary artery calcification had impaired IDO1 activity and decreased kynurenine catabolites compared with those without calcification. CONCLUSIONS: Kynurenine, an IDO1-mediated tryptophan metabolism main product, promotes RUNX2 ubiquitination and subsequently leads to its proteasomal degradation via an aryl hydrocarbon receptor-dependent nongenomic pathway. Insufficient kynurenine exerts the deleterious role of IDO1 ablation in promoting RUNX2-mediated VSMCs osteogenic reprogramming and calcification in vivo.

Constant advance replicas method for locating minimum energy paths and transition states.

The chain-of-states (CoS) constant advance replicas (CAR) method and its climbing image variant (CI-CAR) for locating minimum energy paths (MEPs) and transition states are reported. The CAR algorithm applies the Lagrange multiplier method for imposing holonomic constraints on a chain-of-replicas, aiming to maintain equal mass-weighted/scaled root-mean-square (RMS) distances between the adjacent replicas by removing the sliding-down displacements contributed by the potential gradients during path optimization. Two contextual regularization schemes with clear geometrical interpretations are implemented to jointly promote high convergence and numerical robustness of the CAR algorithm. We show that the constrained reaction path can be solved normally within 5 steps of Lagrange multiplier updates with remarkably high numerical precision via the CAR approach. The efficacy of the CAR methods is demonstrated by testing on multiple analytical, classical, and quantum mechanical transition paths: the Müller potential, the alanine dipeptide isomerization, the helix unwinding of the VIVITLVMLKKK 12-mer peptide, and the Baker set of reactions. We also explore the potential of applying adaptive momentum (AdaM) optimizers for locating optimal transition paths under complex conformational changes. Most importantly, we discuss extensively the differences and connections between our newly proposed CAR methods and several related methods, with focuses on the reaction path with holonomic constraints (RPCons) approach of Brokaw et al. [J. Chem. Theory Comput. 2009, 5 (8), 2050-2061] and the state-of-the-art string method (SM) of E et al. [J. Chem. Phys. 2007, 126 (16), 164103]. The CAR approach represents a latest update to the general theoretical framework of reaction path finding algorithms in the two-ended CoS regime.

Femtosecond Laser-Driven Phase Engineering of WS2 for Nano-Periodic Phase Patterning and Sub-ppm Ammonia Gas Sensing.

Laser-driven phase transition of 2D transition metal dichalcogenides has attracted much attention due to its high flexibility and rapidity. However, there are some limitations during the laser irradiation process, especially the unsatisfied surface ablation, the inability of nanoscale phase patterning, and the unexploited physical properties of new phase. In this work, the well-controlled femtosecond (fs) laser-driven transformation from the metallic 2M-WS2 to the semiconducting 2H-WS2 is reported, which is confirmed to be a single-crystal to single-crystal transition without layer thinning or obvious ablation. Moreover, a highly ordered 2H/2M nano-periodic phase transition with a resolution of ≈435 nm is achieved, breaking through the existing size bottleneck of laser-driven phase transition, which is attributed to the selective deposition of plasmon energy induced by fs laser. It is also demonstrated that the achieved 2H-WS2 after laser irradiation contains rich sulfur vacancies, which exhibits highly competitive ammonia gas sensing performance, with a detection limit below 0.1 ppm and a fast response/recovery time of 43/67 s at room temperature. This study provides a new strategy for the preparation of the phase-selective transition homojunction and high-performance applications in electronics.

Pushing the limits of low-cost ultra-low-field MRI by dual-acquisition deep learning 3D superresolution.

PURPOSE: Recent development of ultra-low-field (ULF) MRI presents opportunities for low-power, shielding-free, and portable clinical applications at a fraction of the cost. However, its performance remains limited by poor image quality. Here, a computational approach is formulated to advance ULF MR brain imaging through deep learning of large-scale publicly available 3T brain data. METHODS: A dual-acquisition 3D superresolution model is developed for ULF brain MRI at 0.055 T. It consists of deep cross-scale feature extraction, attentional fusion of two acquisitions, and reconstruction. Models for T1 -weighted and T2 -weighted imaging were trained with 3D ULF image data sets synthesized from the high-resolution 3T brain data from the Human Connectome Project. They were applied to 0.055T brain MRI with two repetitions and isotropic 3-mm acquisition resolution in healthy volunteers, young and old, as well as patients. RESULTS: The proposed approach significantly enhanced image spatial resolution and suppressed noise/artifacts. It yielded high 3D image quality at 0.055 T for the two most common neuroimaging protocols with isotropic 1.5-mm synthetic resolution and total scan time under 20 min. Fine anatomical details were restored with intrasubject reproducibility, intercontrast consistency, and confirmed by 3T MRI. CONCLUSION: The proposed dual-acquisition 3D superresolution approach advances ULF MRI for quality brain imaging through deep learning of high-field brain data. Such strategy can empower ULF MRI for low-cost brain imaging, especially in point-of-care scenarios or/and in low-income and mid-income countries.

CYD0281, a Bcl-2 BH4 domain antagonist, inhibits tumor angiogenesis and breast cancer tumor growth.

BACKGROUND: B-cell lymphoma 2 (Bcl-2) family proteins are key regulators of apoptosis, which possess four conserved Bcl-2 homologies (BH) domains. Among the BH domains, the BH3 domain is considered as a potent 'death domain' while the BH4 domain is required for anti-apoptotic activity. Bcl-2 can be converted to a pro-apoptotic molecule through the removal or mutation of the BH4 domain. Bcl-2 is considered as an inducer of angiogenesis, which can promote tumor vascular network formation and further afford nutrients and oxygen to promote tumor progression. However, whether disrupting the function of the BH4 domain to convert Bcl-2 into a pro-apoptotic molecule could make Bcl-2 possess the potential for anti-angiogenic therapy remains to be defined. METHODS: CYD0281 was designed and synthesized according to the lead structure of BDA-366, and its function on inducing a conformational change of Bcl-2 was further evaluated via immunoprecipitation (IP) and immunofluorescence (IF) assays. Moreover, the function of CYD0281 on apoptosis of endothelial cells was analyzed via cell viability, flow cytometry, and western blotting assays. Additionally, the role of CYD0281 on angiogenesis in vitro was determined via endothelial cell migration and tube formation assays and rat aortic ring assay. Chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models, breast cancer cell xenograft tumor on CAM and in mouse models as well as the Matrigel plug angiogenesis assay were used to explore the effects of CYD0281 on angiogenesis in vivo. RESULTS: We identified a novel potent small-molecule Bcl-2-BH4 domain antagonist, CYD0281, which exhibited significant anti-angiogenic effects both in vitro and in vivo, and further inhibited breast cancer tumor growth. CYD0281 was found to induce conformational changes in Bcl-2 through the exposure of the BH3 domain and convert Bcl-2 from an anti-apoptotic molecule into a cell death inducer, thereby resulting in the apoptosis of vascular endothelial cells. CONCLUSIONS: This study has revealed CYD0281 as a novel Bcl-2-BH4 antagonist that induces conformational changes of Bcl-2 to convert to a pro-apoptotic molecule. Our findings indicate that CYD0281 plays a crucial role in anti-angiogenesis and may be further developed as a potential anti-tumor drug candidate for breast cancer. This work also provides a potential anti-angiogenic strategy for breast cancer treatment.

Comorbidities in congenital heart disease: different patterns in childhood and adulthood.

BACKGROUND: Existing studies were no exploration of the association between congenital heart disease (CHD) in children and comorbidities. This study was to assess the prevalence and number of comorbidities in CHD among children and adults, and to compare the comorbidity patterns by children and adults using association rule analysis. METHODS: Patients identified by the International Classification of Diseases, Ninth Revision (ICD-9) code in the Medical Information Mart for Intensive Care III (MIMIC-III) 2001-2012 and MIMIC-IV 2008-2018 were included in this cross-sectional study. Association rule analysis was used to explore associations between CHD and comorbidities in children and adults using values of support (%), confidence (%), and lift. RESULTS: Among 60,400 eligible patients, 1.54% of adults had CHD and 0.83% of adults had CHD with at least one comorbidity, 13.79% had CHD and 12.37% had CHD with at least one comorbidity in children. The most common comorbidities were circulatory system diseases (53.78%), endocrine diseases (35.76%), and respiratory system diseases (23.46%) in adults with CHD, and the most common comorbidities were perinatal diseases (87.50%) in children with CHD. The comorbidity rate was 90.19% and 56.68% in children and adults, respectively. In children, perinatal diseases, circulatory system diseases, and endocrine diseases had the highest prevalence. The incidence of circulatory system diseases, perinatal diseases and endocrine diseases in CHD adults was confidence = 31.56%, 36.11%, and 23.23%, respectively. Perinatal diseases were common comorbidities among all CHD severity groups in children and adults. CONCLUSION: The prevalence of comorbidities in children with CHD was higher than that in adults with CHD. The most common comorbidities were perinatal diseases and endocrine diseases among children and adults with CHD, respectively. Our study provided insights into comorbidity patterns in children and adults with CHD.

Development and validation of a novel food exchange system for Chinese pregnant women.

BACKGROUND: The dietary nutritional status of pregnant women is critical for maintaining the health of both mothers and infants. Food exchange systems have been employed in the nutritional guidance of patients in China, although their application in the dietary guidance of healthy pregnant women is quite limited. This study aimed to develop a novel food exchange system for Chinese pregnant women (NFES-CPW) and evaluate the relative validation of its application. METHODS: NFES-CPW covers approximately 500 types of food from ten categories and has more elaborate food portion sizes. It established a recommendation index for guiding food selection and used energy, water content, and protein as the exchange basis to balance the supply of energy and important nutrients throughout pregnancy. Furthermore, dietitians used the NFES-CPW and traditional food exchange system to generate new recipes based on the sample recipe. There were 40 derived recipes for each of the two food exchange methods. The food consumption, energy, and key nutrients of each recipe were calculated, and the differences between the two food exchange systems were compared using the Wilcoxon rank sum test or the Chi-square test. RESULTS: The results revealed that compared to those derived from traditional food exchange system, the NFES-CPW derived recipes had a better dietary structure, as evidenced by the intakes of whole-grain cereals, beans excluding soybeans, potatoes, fruits, fish, shrimp and shellfish, as well as eggs (P < 0.05), which were more conducive to reaching the recommended range of balanced dietary pagoda. After calculating energy and nutrients, although these two food exchange systems have similar effects on the dietary energy and macronutrient intake of pregnant women, the intake of micronutrients in NFES-CPW derived recipes was significantly higher than that from the traditional food exchange system, which was more conducive to meeting the dietary requirements of pregnant women. The outstanding improvement are primarily vitamin A, vitamin B2, folic acid, vitamin B12, vitamin C, calcium, iron, and iodine (P < 0.05). Moreover, when compared to recipes obtained from the traditional food exchange system, the error ranges of energy and most nutrients were significantly reduced after employing the NFES-CPW. CONCLUSIONS: Therefore, NFES-CPW is an appropriate tool that adheres to Chinese dietary characteristics and can provide suitable dietary guidance to pregnant women.

DeePMD-kit v2: A software package for deep potential models.

DeePMD-kit is a powerful open-source software package that facilitates molecular dynamics simulations using machine learning potentials known as Deep Potential (DP) models. This package, which was released in 2017, has been widely used in the fields of physics, chemistry, biology, and material science for studying atomistic systems. The current version of DeePMD-kit offers numerous advanced features, such as DeepPot-SE, attention-based and hybrid descriptors, the ability to fit tensile properties, type embedding, model deviation, DP-range correction, DP long range, graphics processing unit support for customized operators, model compression, non-von Neumann molecular dynamics, and improved usability, including documentation, compiled binary packages, graphical user interfaces, and application programming interfaces. This article presents an overview of the current major version of the DeePMD-kit package, highlighting its features and technical details. Additionally, this article presents a comprehensive procedure for conducting molecular dynamics as a representative application, benchmarks the accuracy and efficiency of different models, and discusses ongoing developments.

RP5-1148A21.3 (lncRP5) exerts oncogenic function in human ovarian carcinoma.

Ovarian cancer (OC) is a fatal gynecological malignancy that is difficult to diagnose at early stages. Various long non-coding RNAs (lncRNAs) are aberrantly expressed in OC and exert regulatory effects on OC; however, the underlying mechanism requires in-depth investigation. This work is designed to explore the molecular regulatory axis of a newly identified lncRNA in OC, that is, lncRNA RP5-1148A21.3 (lncRP5). RT-qPCR shows lncRP5 is significantly upregulated in OC patients and cell lines, and it is mainly located in the cytoplasm of OC cells. The results of CCK-8, colony formation, and transwell assays demonstrate that overexpression of lncRP5 greatly contributes to malignant behaviors of OC cells, while inhibition of lncRP5 shows the opposite effects. Moreover, the binding relationship between lncRP5 and miR-545-5p is predicted by bioinformatics and is further verified by luciferase assay. Functionally, the regulatory effects of lncRP5 and miR-545-3p are negatively related; miR-545-5p serves as a tumor suppressor in OC. Further studies demonstrate that PTP4A1 is the target gene of miR-545-5p. Overexpression of PTP4A1 abrogates the inhibitory function of miR-545-5p on OC cell growth and metastasis. The lncRP5/miR-545-5p/PTP4A1 axis is subsequently demonstrated in vivo, and knockdown of lncRP5 notably inhibits tumor growth. This study provides a novel regulatory mechanism of OC, which may contribute to the diagnosis and therapy of OC.