Using machine learning algorithms based on patient admission laboratory parameters to predict adverse outcomes in COVID-19 patients.

Amidst the global COVID-19 pandemic, the urgent need for timely and precise patient prognosis assessment underscores the significance of leveraging machine learning techniques. In this study, we present a novel predictive model centered on routine clinical laboratory test data to swiftly forecast patient survival outcomes upon admission. Our model integrates feature selection algorithms and binary classification algorithms, optimizing algorithmic selection through meticulous parameter control. Notably, we developed an algorithm coupling Lasso and SVM methodologies, achieving a remarkable area under the ROC curve of 0.9277 with the use of merely 8 clinical laboratory parameters collected upon admission. Our primary contribution lies in the utilization of straightforward laboratory parameters for prognostication, circumventing data processing intricacies, and furnishing clinicians with an expeditious and precise prognostic assessment tool.

TIN2-mediated reduction of mitophagy induces RPE senescence under high glucose.

The telomere-associated protein TIN2 localizes to both telomeres and mitochondria. Nevertheless, the impact of TIN2 on retinal pigment epithelial (RPE) cells in diabetic retinopathy (DR) remains unclear. This research aims to examine the role of TIN2 in the senescence of RPE and its potential as a therapeutic target. Western blotting and immunofluorescence staining were utilized to identify TIN2 expression and mitophagy. RT-qPCR was employed to identify senescent associated secretory phenotype (SASP) in ARPE-19 cells infected with TIN2 overexpression. To examine mitochondria and the cellular senescence of RPE, TEM, SA-ß-gal staining, and cell cycle analysis were used. The impact of TIN2 was examined using OCT and immunohistochemistry in mice. DHE staining and ZO-1 immunofluorescence were applied to detect RPE oxidative stress and tight junctions. Our research revealed that increased mitochondria-localized TIN2 aggravated the cellular senescence of RPE cells both in vivo and in vitro under hyperglycemia. TIN2 overexpression stimulated the mTOR signaling pathway in ARPE-19 cells and exacerbated the inhibition of mitophagy levels under high glucose, which can be remedied through the mTOR inhibitor, rapamycin. Knockdown of TIN2 significantly reduced senescence and mitochondrial oxidative stress in ARPE-19 cells under high glucose and restored retinal thickness and RPE cell tight junctions in DR mice. Our study indicates that increased mitochondria-localized TIN2 induced cellular senescence in RPE via compromised mitophagy and activated mTOR signaling. These results propose that targeting TIN2 could potentially serve as a therapeutic strategy in the treatment of DR.

Spread of antibiotic resistance genes in drinking water reservoirs: Insights from a deep metagenomic study using a curated database.

The exploration of antibiotic resistance genes (ARGs) in drinking water reservoirs is an emerging field. Using a curated database, we enhanced the ARG detection and conducted a comprehensive analysis using 2.2 Tb of deep metagenomic sequencing data to determine the distribution of ARGs across 16 drinking water reservoirs and associated environments. Our findings reveal a greater diversity of ARGs in sediments than in water, underscoring the importance of extensive background surveys. Crucial ARG carriers-specifically Acinetobacter, Pseudomonas, and Mycobacterium were identified in drinking water reservoirs. Extensive analysis of the data uncovered a considerable concern for drinking water safety, particularly in regions reliant on river sources. Mobile genetic elements have been found to contribute markedly to the propagation of ARGs. The results of this research suggest that the establishment of drinking water reservoirs for supplying raw water may be an effective strategy for alleviating the spread of water-mediated ARGs.

Potential probiotic characteristics and genomic analysis of a new folate-producing lactic acid bacteria Lactiplantibacillus plantarum ZFM55.

BACKGROUND: Folate is crucial for maintaining health, but humans are unable to synthesize folate and need to obtain it from food. Lactiplantibacillus plantarum can produce the necessary vitamin B for the human body, including folate. Whole genome sequencing technology can clarify the physiological characteristics of folate production in Lactiplantibacillus plantarum. In order to explore new Lactiplantibacillus plantarum that produce folate, the folate production and probiotic characteristics of Lactiplantibacillus plantarum ZFM55 isolated from infant feces were investigated, and whole genome sequencing was performed. RESULTS: The folate synthesis ability of Lactiplantibacillus plantarum ZFM55 were measured, and its total folate production was 299.72 ± 28.81 ng mL-1. Subsequently, its probiotic properties were explored. The antibacterial test showed that its inhibition zone diameter against Staphylococcus aureus and Salmonella typhimurium was 15.5 ± 0.82 mm and 13.88 ± 0.98 mm, respectively. The tolerance test results indicated that it maintained good activity in simulated gastrointestinal tract and bile salt environments. In vitro intestinal simulation experiments had confirmed that Lactiplantibacillus plantarum ZFM55 can increase the abundance of beneficial bacteria such as Bifidobacteria in the intestine and inhibit the growth of harmful bacteria such as Escherichia_Shigella. Genomic sequencing indicated that the genetic material of Lactiplantibacillus plantarum ZFM55 contains one chromosome and three plasmids, and it has 20 genes related to folate synthesis, which explains its ability to produce folate. CONCLUSION: This study reports a new potential probiotic that produces folate, and provides ideas for exploring probiotics with specific probiotic characteristics. © 2024 Society of Chemical Industry.

Increased glycemic variability results in abnormal differentiation of T cell subpopulation in type 2 diabetes patients.

AIMS: We aimed to investigate the association between glycemic variability (GV) and the abnormal differentiation of T-cell subpopulations in patients with type 2 diabetes mellitus (T2DM). METHODS: In total, 108 hospitalized patients with T2DM were enrolled and divided into two subgroups (normal glycemic excursion (NGE) and high glycemic excursion (HGE)) according to their mean amplitude of glycemic excursion (MAGE) level. The MAGE was evaluated via continuous glucose monitoring for 72 h consecutively. Flow cytometry was used to determine the proportions of T cell subpopulations. RESULTS: The T helper (Th) 1 cell/Th2 cell ratio was significantly higher, and the proportion of regulatory T cells (Tregs) was significantly lower in the NGE group than in the HGE group (all P < 0.05). After fully adjusting for confounders, the MAGE was positively associated with the Th1 cell/Th2 cell ratio (ß = 0.370; P = 0.009) and negatively associated with the proportion of Tregs (ß = -0.554; P = 0.001). CONCLUSION: The MAGE was an independent risk factor for abnormally high Th1 cell/Th2 cell ratio and proportion of Tregs. Abnormal differentiation of T cell subpopulations induced by GV may impair ß-cell function, aggravate insulin resistance, and contribute to the development of diabetic complications.

A novel bacteriocin against methicillin-resistant Staphylococcus aureus, purified from Lactiplantibacillus plantarum ZFM9.

A novel bacteriocin, plantaricin ZFM9, was purified from Lactiplantibacillus plantarum ZFM9 using a combination of ammonium sulfate precipitation, XAD-2 macroporous resin, Sephadex G-50, Sephadex LH-20, and reversed-phase high performance liquid chromatography. The molecular mass of plantaricin ZFM9 was 1151.606 Da, and the purity was 98.3%. Plantaricin ZFM9 has thermal stability (95.6% retention at 120 °C for 30 min), pH stability (pH ≤ 5), and sensitivity to the pepsin, trypsin, papain, and proteinase K. Plantaricin ZFM9 exhibited broad-spectrum antimicrobial activity and notably inhibit methicillin-resistant Staphylococcus aureus D48 (MRSA). According to the results of electron microscopy and fluorescence leakage assay, it was found that plantaricin ZFM9 caused damage to the cells membrane and leakage of the contents of S. aureus D48. In addition, Lipid II was not the anti-MRSA target of plantaricin ZFM9. This study underscores the potential of plantaricin ZFM9 for applications in the food field and biopharmaceuticals against MRSA infection.

Temporal trend in mortality due to congenital heart disease in China from 2008 to 2021.

BACKGROUND: Congenital heart disease (CHD) is a leading cause of birth defect-related mortality. However, more recent CHD mortality data for China are lacking. Additionally, limited studies have evaluated sex, rural-urban, and region-specific disparities of CHD mortality in China. METHODS: We designed a population-based study using data from the Dataset of National Mortality Surveillance in China between 2008 and 2021. We calculated age-adjusted CHD mortality using the sixth census data of China in 2010 as the standard population. We assessed the temporal trends in CHD mortality by age, sex, area, and region from 2008 to 2021 using the joinpoint regression model. RESULTS: From 2008 to 2021, 33,534 deaths were attributed to CHD. The period witnessed a two-fold decrease in the age-adjusted CHD mortality from 1.61 to 0.76 per 100,000 persons (average annual percent change [AAPC] = -5.90%). Females tended to have lower age-adjusted CHD mortality than males, but with a similar decline rate from 2008 to 2021 (females: AAPC = -6.15%; males: AAPC = -5.84%). Similar AAPC values were observed among people living in urban (AAPC = -6.64%) and rural (AAPC = -6.12%) areas. Eastern regions experienced a more pronounced decrease in the age-adjusted CHD mortality (AAPC = -7.86%) than central (AAPC = -5.83%) and western regions (AAPC = -3.71%) between 2008 and 2021. Approximately half of the deaths (46.19%) due to CHD occurred during infancy. The CHD mortality rates in 2021 were lower than those in 2008 for people aged 0-39 years, with the largest decrease observed among children aged 1-4 years (AAPC = -8.26%), followed by infants (AAPC = -7.01%). CONCLUSIONS: CHD mortality in China has dramatically decreased from 2008 to 2021. The slower decrease in CHD mortality in the central and western regions than in the eastern regions suggested that public health policymakers should pay more attention to health resources and health education for central and western regions.

Green Light from Red-Emitting Nanocrystals: Broadband, Low-Threshold Lasing from Colloidal Quantum Shells in Optical Nanocavities.

Spherical semiconductor nanoplatelets, known as quantum shells (QSs), have captured significant interest for their strong suppression of Auger recombination, which leads to long multiexciton lifetimes and wide optical gain bandwidth. Yet, the realization of benefits associated with the multiexciton lasing regime using a suitably designed photonic cavity remains elusive. Here, we demonstrate broadly tunable lasing from close-packed films of CdS/CdSe/CdS QSs deposited over nanopillar arrays on Si substrates. Wide spectral tuning of the stimulated emission in QSs with a fixed bandgap value was achieved by engaging single exciton (λX ∼ 634 nm), biexciton (λBX ∼ 627 nm), and multiple exciton (λMX ∼ 615-565 nm) transitions. The ensemble-averaged gain threshold of ∼ 2.6 electron-hole pairs per QS particle and the low photonic cavity fluence threshold of ∼4 µJ/cm2 were attributed to Auger suppression. The tuning of the lasing emission closely aligns with our model predictions achieved by varying the array period while preserving mode confinement and quality (Q) factors. These results mark a notable step toward the development of colloidal nanocrystal lasers.

Lactobacillus paracasei ZFM54 alters the metabolomic profiles of yogurt and the co-fermented yogurt improves the gut microecology of human adults.

Gut microbiota imbalance could lead to various diseases, making it important to optimize the structure of flora in adults. Lactobacillus paracasei ZFM54 is a bacteriocin and folic acid producing Lactobacillus strain. Herein ZFM54 was used as the potentialy probiotic bacterium to ferment milk together with a yogurt starter. We optimized the fermentation conditions and the obtained yogurts were then subjected to volatile and non-volatile metabolome analysis, showing that ZFM54 cannot only improve the acidity, water holding capacity and live lactic acid bacteria counts, but also improve many volatile acid contents and increase some beneficial non-volatile metabolites such as N-ethyl glycine and L-Lysine, endowing the yogurt with more flavor and better function. The regulatory effects of the co-fermented yogurt on intestinal microecology of volunteers were investigated by 16S rRNA sequencing and short-chain fatty acids (SCFAs) analysis after a continuous consuming the yogurt of 2-week, showing better effect to increase the relative abundance of beneficial bacteria such as Ruminococcus and Alistipes, decrease harmful bacteria (Escherichia-Shigella and Enterobacter), and enhance the production of SCFAs (acetate, propionate and butyric acid) than the control yogurt. In conclusion, L. paracasei ZFM54 can significantly improve the health benefits of yogurt, laying the foundation for its commercial application in improving gut microbiota.

Effect of off-label targeted drugs on long-term survival in chronic thromboembolic pulmonary hypertension: Insights from a national multicentre prospective registry.

BACKGROUND AND OBJECTIVE: Off-label pulmonary arterial hypertension (PAH)-targeted drugs are commonly prescribed for non-operated chronic thromboembolic pulmonary hypertension (CTEPH), but their effect on the long-term prognosis of CTEPH remains unknown. This study investigated the effect of off-label PAH-targeted drugs on the long-term survival of CTEPH patients. METHODS: CTEPH patients were enrolled from a prospective multicentre national registry. Except for licensed riociguat and treprostinil, other PAH-targeted drugs were off-label. In the original and propensity score-matched (PSM) samples, five-year survival was compared in two groups: (a) patients not receiving off-label PAH-targeted drugs (control) versus (b) patients receiving off-label PAH-targeted drugs (treatment). The latter group was investigated for the effect of started off-label PAH-targeted drugs at baselines (initial) or during follow-up (subsequent). RESULTS: Of 347 enrolled patients, 212 were treated with off-label PAH-targeted drugs initially (n = 173) or subsequently (n = 39), and 135 were untreated. The 1-, 2-, 3- and 5-year survival of the treatment group was significantly higher than that of the control group (97.1% vs. 89.4%, 92.3% vs. 82.1%, 83.2% vs. 75.1% and 71.1% vs. 55.3%, respectively, log-rank test, p = 0.005). Initial treatment was correlated with better 5-year survival after excluding patients with subsequent treatment to reduce the immortal-time bias (hazard ratio: 0.611; 95% CI: 0.397-0.940; p = 0.025). In PSM samples, patients given initial treatment showed significantly better 5-year survival than untreated patients (68.9% vs. 49.3%, log-rank test, p = 0.008). CONCLUSION: Off-label targeted drugs contributed to improved long-term survival in CTEPH patients receiving pharmacotherapies.

Soybean-derived antihypertensive hydrolysates attenuate Ang II-induced renal damage by modulating MAPK and NF-κB signaling pathways.

Hypertension-induced kidney injury is considered a vital consequence of long-term and uncontrolled hypertension, which is commonly associated with an excessive accumulation of angiotensin II (Ang II) from hyperactivated RAS. Antihypertensive peptides have a significant effect on blood pressure regulation, but few studies have focused on the ameliorative function of antihypertensive peptides on renal injury. This study explored the effects of soybean protein-derived hydrolysate (SPH) on SHR and Ang II-induced HK-2 cells. SPH significantly attenuated blood pressure and alleviated renal pathological injury in SHRs after oral gavage administration. According to the pathological results, the kidneys of SHRs showed inflammation and SPH attenuated inflammatory cell infiltration in the kidneys of SHRs. Immunohistochemical analysis further revealed that SPH inhibited MCP-1 expression and increased Nrf2 expression in the kidneys. An in vitro HK-2 cell model demonstrated that SPH exhibited optimal activity for reducing Ang II-induced inflammatory cytokines and ROS overproduction. Mechanistically, SPH was observed to regulate MAPK/JNK and NF-κB signaling pathways. These findings indicate that potent antihypertensive SPH significantly ameliorates hypertension-induced kidney damage.

Effects of an explain-simulate-practice-communicate-support intervention on quality of life for patients with chronic heart failure: A randomized control trial.

Background: Patients with New York Heart Association (NYHA) grade III chronic heart failure (CHF) present with low capacity for daily activities, severe self-perceived burden, and poor quality of life. Effective nursing interventions may reduce patients' self-perceived burden and improve their quality of life. Objectives: To explore the effects of an explain-simulate-practice-communicate-support intervention on the self-perceived burden, cardiac function, and activities of daily living (ADL) ability in patients with New York Heart Association grade III chronic heart failure. Methods: Of the 100 patients with New York Heart Association grade III chronic heart failure who were electronically randomized and equally divided into control and intervention groups, data from 88 patients who completed our study were analyzed. The primary outcome was quality of life; secondary outcomes were self-perceived burden, 6-min walking test distances, serum N-terminal pro-brain natriuretic peptide levels, New York Heart Association cardiac function classification, and ability to perform activities of daily living. Results: After 12 weeks' intervention, the intervention group had significantly lower self-perceived burden, Minnesota Living with Heart Failure Questionnaire scores, N-terminal pro-brain natriuretic peptide levels, and New York Heart Association grades compared with the control group, while 6-min walking test distances, left ventricular ejection fraction, and modified Barthel Index scale scores were significantly higher than those in the control group (P > 0.05). Conclusions: The explain-simulate-practice-communicate-support intervention improved patients' quality of life through reducing the level of self-perceived burden, and improving cardiac function and activities of daily living ability. This intervention was found to be effective for patients with New York Heart Association grade III chronic heart failure.

SCpRh(III)-Catalyzed Asymmetric C-H Trifluoromethylalkylation of N-Methoxybenzamides with ß-Trifluoromethyl-α,ß-Unsaturated Ketones.

Asymmetric C-H trifluoromethylalkylation represents a novel and straightforward synthetic method for the construction of chiral CF3-containing compounds. However, the reported examples remain limited, given the challenges of reactivity and enantioselective control. Herein, we report a SCpRh(III)-catalyzed asymmetric aryl and alkenyl C-H trifluoromethylalkylation reaction with ß-trifluoromethyl-α,ß-unsaturated ketones. The chiral CF3-bearing adducts were obtained in moderate to good yields with high enantioselectivity (up to 81% yield and 96% ee). The reaction features mild conditions and broad substrate scope. The chiral CF3-bearing products could undergo diverse functional group transformations.

SLC6A14 promotes ulcerative colitis progression by facilitating NLRP3 inflammasome-mediated pyroptosis.

BACKGROUND: Ulcerative colitis (UC) is an inflammatory condition with frequent relapse and recurrence. Evidence suggests the involvement of SLC6A14 in UC pathogenesis, but the central regulator remains unknown. AIM: To explore the role of SLC6A14 in UC-associated pyroptosis. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR), immunoblotting, and immunohistochemical were used to assess SLC6A14 in human UC tissues. Lipopolysaccharide (LPS) was used to induce inflammation in FHC and NCM460 cells and model enteritis, and SLC6A14 levels were assessed. Pyroptosis markers were quantified using enzyme-linked immunosorbent assay, Western blotting, and qRT-PCR, and EdU incubation, CCK-8 assays and flow cytometry were used to examine proliferation and apoptosis. Mouse models of UC were used for verification. RESULTS: SLC6A14 was increased and correlated with NLRP3 in UC tissues. LPS-induced FHC and NCM460 cells showed increased SLC6A14 levels. Reducing SLC6A14 increased cell proliferation and suppressed apoptosis. Reducing SLC6A14 decreased pyroptosis-associated proteins (ASC, IL-1ß, IL-18, NLRP3). NLRP3 overexpression counteracted the effects of sh-SLC6A14 on LPS-induced FHC and NCM460 cell pyroptosis. SLC6A14 improved the mucosa in mice with dextran sulfate sodium-induced colitis. CONCLUSION: SLC6A14 promotes UC pyroptosis by regulating NLRP3, suggesting the therapeutic potential of modulating the SLC6A14/NLRP3 axis.

Selecting autochthonous lactic acid bacteria for co-inoculation in Chinese bayberry wine production: Stress response, starter cultures application and volatilomic study.

This study focused on isolating and characterising autochthonous lactic acid bacteria (LAB) from spontaneously fermented Chinese bayberry (CB) and their potential application in CB wine fermentation in co-inoculation with yeast starter cultures. Numerous LAB, including Lactiplantibacillus (Lp.) plantarum (9), Limosilactobacillus (Lb.) fermentum (6), Lactococcus (Lc.) lactis (3), Enterococcus (Ec.) hirae (1), Leuconostoc (Le.) mesenteroides (1), and Weissella (Ws.) cibaria (1), were isolated and identified. The isolated strains Lp. plantarum ZFM710 and ZFM715, together with Lb. fermentum ZFM720 and ZFM722, adapted well to unfavourable fermentation environment, including ethanol, osmolality, and acidity stresses, were selected for producing CB wine by co-inoculation with Saccharomyces cerevisiae. During fermentation, the presence of LAB promoted the development of S. cerevisiae, while the population dynamics of LAB in different groups at different stages showed strain-specific differences. Fermentation trials involving LAB yielded a lower ethanol concentration except for Lp. plantarum ZFM715. Compared to the pure S. cerevisiae fermented sample, the addition of LAB led to a clear modulation in organic acid composition. Lb. fermentum strains in co-fermentation led to significant decreases in each classified group of aroma compounds, while Lp. plantarum ZFM715 significantly increased the complexity and intensity of aroma compounds, as well as the intensities of fruity and floral notes. The study selects interesting strains for the design of starter cultures for use in CB wine production, underlining the interest in the selection of autochthonous LAB in fruit wines, with the aim of improving the adaptation of bacteria to specific environmental conditions and shaping the unique traits of the finished products.

Mechanism of the Effect of Scopolamine on Breast Cancer: Determination by Network Pharmacology and Bioinformatics.

BACKGROUND: To a certain extent, traditional Chinese medicine (TCM)-based anesthesia has replaced opiate administration in recent years. Preliminary drug screening has revealed that scopolamine may affect breast cancer (BC) metastasis by an unknown mechanism. METHODS: Network pharmacology, bioinformatics, and protein-protein interaction (PPI) topological analysis were implemented to identify the core genes linking scopolamine and BC. The core genes were then subjected to gene expression profiling interactive analysis (GEPIA). The top ten pathways were detected by gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The impact of immune infiltration on the core gene difference and survival analyses was then determined. Molecular docking was then performed on the core genes and the main active components. RESULTS: Protein kinase 1 (AKT1), epidermal growth factor receptor (EGFR), heat shock protein 90 alpha class A (HSP90AA1), caspase 3 (CASP3), and estrogen receptor 1 (ESR1) were the key genes in the interaction between scopolamine and BC cells. The KEGG enrichment analysis disclosed that the top ten pathways significantly associated with the scopolamine response in BC included "protein glycosylation," "phosphoinositide 3-kinase (PI3K)-Akt signaling," "mitogen- activated protein kinase (MAPK) signaling" and others. The AKT1, EGFR, and especially the HSP90AA1 expression levels were correlated with survival in patients with BC. Immune infiltration also influenced the survival outcome. Molecular docking demonstrated that scopolamine bound and formed stable complexes with the protein products of all five aforementioned genes. CONCLUSION: Scopolamine has multiple targets regulating BC cell function and may increase the risk of metastasis during treatment. Therefore, it should be preoperatively administered with caution to patients with BC.

Bacteriocins: Curial guardians of gastrointestinal tract.

The human gastrointestinal (GI) tract microbiome secretes various metabolites that play pivotal roles in maintaining host physiological balance and influencing disease progression. Among these metabolites, bacteriocins-small, heat-stable peptides synthesized by ribosomes-are notably prevalent in the GI region. Their multifaceted benefits have garnered significant interest in the scientific community. This review comprehensively explores the methods for mining bacteriocins (traditional separation and purification, bioinformatics, and artificial intelligence), their effects on the stomach and intestines, and their complex bioactive mechanisms. These mechanisms include flora regulation, biological barrier restoration, and intervention in epithelial cell pathways. By detailing each well-documented bacteriocin, we reveal the diverse ways in which bacteriocins interact with the GI environment. Moreover, the future research direction is prospected. By further studying the function and interaction of intestinal bacteriocins, we can discover new pharmacological targets and develop drugs targeting intestinal bacteriocins to regulate and improve human health. It provides innovative ideas and infinite possibilities for further exploration, development, and utilization of bacteriocins. The inevitable fact is that the continuously exploration of bacteriocins is sure to bring the promising future for demic GI health understanding and interference strategy.

UCP2-SIRT3 Signaling Relieved Hyperglycemia-Induced Oxidative Stress and Senescence in Diabetic Retinopathy.

Purpose: Diabetic retinopathy (DR) is one of the most common reasons for blindness. uncoupling protein 2 (UCP2), an uncoupling protein located in mitochondria, has been reported to be related to metabolic and vascular diseases. This research aimed to illustrate the function and mechanism of UCP2 in the pathogenesis of DR. Methods: Human epiretinal membranes were collected to investigate the expression of UCP2 by quantitative real-time polymerase chain reaction (qRT-PCR) and immunofluorescence. Primary human retinal microvascular endothelial cells (HRECs) were cultured in high glucose (HG) to establish an in vitro cell model for DR. Flow cytometry analysis was used to measure intracellular reactive oxygen species (ROS). Senescence levels were evaluated by the senescence-associated beta-galactosidase (SA-ß-gal) assay, the expression of senescence marker P21, and cell-cycle analysis. Adenovirus-mediated UCP2 overexpression or knockdown and specific inhibitors were administered to investigate the underlying regulatory mechanism. Results: Proliferative fibrovascular membranes from patients with DR illustrated the downregulation of UCP2 and sirtuin 3 (SIRT3) by qRT-PCR and immunofluorescence. Persistent hyperglycemia-induced UCP2 downregulation in the progress of DR and adenovirus-mediated UCP2 overexpression protected endothelial cells from hyperglycemia-induced oxidative stress and senescence. Under hyperglycemic conditions, UCP2 overexpression attenuated NAD+ downregulation; hence, it promoted the expression and activity of SIRT3, an NAD+-dependent deacetylase regulating mitochondrial function. 3-TYP, a selective SIRT3 inhibitor, abolished the UCP2-mediated protective effect against oxidative stress and senescence. Conclusions: UCP2 overexpression relieved oxidative stress and senescence based on a novel mechanism whereby UCP2 can regulate the NAD+-SIRT3 axis. Targeting oxidative stress and senescence amelioration, UCP2-SIRT3 signaling may serve as a method for the prevention and treatment of DR and other diabetic vascular diseases.

Biventricular intraventricular mechanical and electrical dyssynchrony in pulmonary arterial hypertension.

Background: Pulmonary arterial hypertension (PAH) leads to myocardial remodeling, manifesting as mechanical dyssynchrony (M-dys) and electrical dyssynchrony (E-dys), in both right (RV) and left ventricles (LV). However, the impacts of layer-specific intraventricular M-dys on biventricular functions and its association with E-dys in PAH remain unclear. Methods: Seventy-nine newly diagnosed patients with PAH undergoing cardiac magnetic resonance scanning were consecutively recruited between January 2011 and December 2017. The biventricular volumetric and layer-specific intraventricular M-dys were analyzed. The QRS duration z-scores were calculated after adjusting for age and sex. Results: 77.22 % of patients were female (mean age 30.30 ± 9.79 years; median follow-up 5.53 years). Further, 29 (36.71 %) patients succumbed to all-cause mortality by the end of the study. At the baseline, LV layer-specific intraventricular M-dys had apparent transmural gradients compared with RV in the radial and circumferential directions. However, deceased patients lost the transmural gradients. The LV longitudinal strain rate time to late diastolic peak in the myocardial region (LVmyoLSRTTLDPintra) predicted long-term survival. The Kaplan-Meier curve revealed that patients with PAH with LVmyoLSRTTLDPintra <20.01 milliseconds had a worse prognosis. Larger right ventricle (RV) intraventricular M-dys resulted in worse RV ejection fraction. However, larger LV intraventricular M-dys in the late diastolic phase indicated remarkable exercise capacity and higher LV stroke volume index. E-dys and intraventricular M-dys had no direct correlations. Conclusions: The layer-specific intraventricular M-dys had varying impacts on biventricular functions in PAH. PAH patients with LVmyoLSRTTLDPintra <20.01 milliseconds had a worse prognosis. LV intraventricular M-dys in the late diastolic phase needs more attention to precisely evaluate LV function.

Role of folic acid in regulating gut microbiota and short-chain fatty acids based on an in vitro fermentation model.

Folic acid deficiency is common worldwide and is linked to an imbalance in gut microbiota. However, based on model animals used to study the utilization of folic acid by gut microbes, there are challenges of reproducibility and individual differences. In this study, an in vitro fecal slurry culture model of folic acid deficiency was established to investigate the effects of supplementation with 5-methyltetrahydrofolate (MTHF) and non-reduced folic acid (FA) on the modulation of gut microbiota. 16S rRNA sequencing results revealed that both FA (29.7%) and MTHF (27.9%) supplementation significantly reduced the relative abundance of Bacteroidetes compared with control case (34.3%). MTHF supplementation significantly improved the relative abundance of Firmicutes by 4.49%. Notably, compared with the control case, FA and MTHF supplementation promoted an increase in fecal levels of Lactobacillus, Bifidobacterium, and Pediococcus. Short-chain fatty acid (SCFA) analysis showed that folic acid supplementation decreased acetate levels and increased fermentative production of isobutyric acid. The in vitro fecal slurry culture model developed in this study can be utilized as a model of folic acid deficiency in humans to study the gut microbiota and demonstrate that exogenous folic acid affects the composition of the gut microbiota and the level of SCFAs. KEY POINTS: • Establishment of folic acid deficiency in an in vitro culture model. • Folic acid supplementation regulates intestinal microbes and SCFAs. • Connections between microbes and SCFAs after adding folic acid are built.