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Emerging evidence shows that psychological stress promotes the progression of Parkinson's disease (PD) and the onset of dyskinesia in non-PD individuals, highlighting a potential avenue for therapeutic intervention. We previously reported that chronic restraint-induced psychological stress precipitated the onset of parkinsonism in 10-month-old transgenic mice expressing mutant human α-synuclein (αSyn) (hαSyn A53T). We refer to these as chronic stress-genetic susceptibility (CSGS) PD model mice. In this study we investigated whether ginsenoside Rg1, a principal compound in ginseng notable for soothing the mind, could alleviate PD deterioration induced by psychological stress. Ten-month-old transgenic hαSyn A53T mice were subjected to 4 weeks' restraint stress to simulate chronic stress conditions that worsen PD, meanwhile the mice were treated with Rg1 (40 mg· kg-1 ·d-1, i.g.), and followed by functional magnetic resonance imaging (fMRI) and a variety of neurobehavioral tests. We showed that treatment with Rg1 significantly alleviated both motor and non-motor symptoms associated with PD. Functional MRI revealed that Rg1 treatment enhanced connectivity between brain regions implicated in PD, and in vivo multi-channel electrophysiological assay showed improvements in dyskinesia-related electrical activity. In addition, Rg1 treatment significantly attenuated the degeneration of dopaminergic neurons and reduced the pathological aggregation of αSyn in the striatum and SNc. We revealed that Rg1 treatment selectively reduced the level of the stress-sensitive protein RTP801 in SNc under chronic stress conditions, without impacting the acute stress response. HPLC-MS/MS analysis coupled with site-directed mutation showed that Rg1 promoted the ubiquitination and subsequent degradation of RTP801 at residues K188 and K218, a process mediated by the Parkin RING2 domain. Utilizing αSyn A53T+; RTP801-/- mice, we confirmed the critical role of RTP801 in stress-aggravated PD and its necessity for Rg1's protective effects. Moreover, Rg1 alleviated obstacles in αSyn autophagic degradation by ameliorating the RTP801-TXNIP-mediated deficiency of ATP13A2. Collectively, our results suggest that ginsenoside Rg1 holds promise as a therapeutic choice for treating PD-sensitive individuals who especially experience high levels of stress and self-imposed expectations.

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Manipulating the atomic structure of the catalyst and tailoring the dissociative water-hydrogen bonding network at the catalyst-electrolyte interface is essential for propelling alkaline hydrogen evolution reactions (HER) and hydrazine oxidation reaction (HzOR), but remains a great challenge. Herein, we constructed an advanced a-RuMo/NiMoO4/NF heterogeneous electrocatalysts with amorphous RuMo alloy nanoclusters anchored to amorphous NiMoO4 skeletons on Ni foam by a heteroatom implantation strategy. Theoretical calculations and in-situ Raman tests show that the amorphous and alloying structure of a-RuMo/NiMoO4/NF not only induces the directional evolution of interfacial H2O, but also lowers the d-band center (from -0.43 to -2.22 eV) of a-RuMo/NiMoO4/NF, the Gibbs free energy of hydrogen adsorption (ΔGH*, from -1.29 to -0.06 eV), and the energy barrier of HzOR (ΔGN2(g) = 1.50 eV to ΔGN2* = 0.47 eV). Profiting from these favorable factors, the a-RuMo/NiMoO4/NF exhibits excellent electrocatalytic performances, especially at large current densities, with an overpotential of 13 and 129 mV to reach 10 and 1000 mA cm-2 for HER. While for HzOR, it needs only -91 and 276 mV to deliver 10 and 500 mA cm-2, respectively. Further, the constructed a-RuMo/NiMoO4/NF||a-RuMo/NiMoO4/NF electrolyzer demands only 7 and 420 mV to afford 10 and 500 mA cm-2.

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Importance: The effect of high-intensity noninvasive positive pressure ventilation (NPPV) on the need for endotracheal intubation in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD) is unknown. Objective: To determine whether the use of high-intensity NPPV vs low-intensity NPPV reduces the need for endotracheal intubation in patients with an acute exacerbation of COPD and hypercapnia. Design, Setting, and Participants: Randomized clinical trial conducted at 30 general respiratory non-intensive care unit wards of Chinese hospitals from January 3, 2019, to January 31, 2022; the last 90-day follow-up was on April 22, 2022. The included patients had an acute exacerbation of COPD and a Paco2 level greater than 45 mm Hg after receiving 6 hours of low-intensity NPPV. Interventions: Patients were randomized 1:1 to receive high-intensity NPPV with inspiratory positive airway pressure that was adjusted to obtain a tidal volume 10 mL/kg to 15 mL/kg of predicted body weight (n = 147) or to continue receiving low-intensity NPPV with inspiratory positive airway pressure that was adjusted to obtain a tidal volume of 6 mL/kg to 10 mL/kg of predicted body weight (n = 153). Patients in the low-intensity NPPV group who met the prespecified criteria for the need for endotracheal intubation were allowed to crossover to high-intensity NPPV. Main Outcomes and Measures: The primary outcome was the need for endotracheal intubation during hospitalization, which was defined by prespecified criteria. There were 15 prespecified secondary outcomes, including endotracheal intubation. Results: The trial was terminated by the data and safety monitoring board and the trial steering committee after an interim analysis of the first 300 patients. Among the 300 patients who completed the trial (mean age, 73 years [SD, 10 years]; 68% were men), all were included in the analysis. The primary outcome of meeting prespecified criteria for the need for endotracheal intubation occurred in 7 of 147 patients (4.8%) in the high-intensity NPPV group vs 21 of 153 (13.7%) in the low-intensity NPPV group (absolute difference, -9.0% [95% CI, -15.4% to -2.5%], 1-sided P = .004). However, rates of endotracheal intubation did not significantly differ between groups (3.4% [5/147] in the high-intensity NPPV group vs 3.9% [6/153] in the low-intensity NPPV group; absolute difference, -0.5% [95% CI, -4.8% to 3.7%], P = .81). Abdominal distension occurred more frequently in the high-intensity NPPV group (37.4% [55/147]) compared with the low-intensity NPPV group (25.5% [39/153]). Conclusions and Relevance: Patients with COPD and persistent hypercapnia in the high-intensity NPPV group (vs patients in the low-intensity NPPV group) were significantly less likely to meet criteria for the need for endotracheal intubation; however, patients in the low-intensity NPPV group were allowed to crossover to high-intensity NPPV, and the between-group rate of endotracheal intubation was not significantly different. Trial Registration: ClinicalTrials.gov Identifier: NCT02985918.

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In sweet potato, rational nitrogen (N) assimilation and distribution are conducive to inhibiting vine overgrowth. Nitrate (NO3-) is the main N form absorbed by roots, and cultivar is an important factor affecting N utilization. Herein, a hydroponic experiment was conducted that included four NO3- concentrations of 0 (N0), 4 (N1), 8 (N2) and 16 (N3) mmol L-1 with two cultivars of Jishu26 (J26, N-sensitive) and Xushu32 (X32, N-tolerant). For J26, with increasing NO3- concentrations, the root length and root surface area significantly decreased. However, no significant differences were observed in these parameters for X32. Higher NO3- concentrations upregulated the expression levels of the genes that encode nitrate reductase (NR2), nitrite reductase (NiR2) and nitrate transporter (NRT1.1) in roots for both cultivars. The trends in the activities of NR and NiR were subject to regulation of NR2 and NiR2 transcription, respectively. For both cultivars, N2 increased the N accumulated in leaves, growth points and roots. For J26, N3 further increased the N accumulation in these organs. Under higher NO3- nutrition, compared with X32, J26 exhibited higher expression levels of the NiR2, NR2 and NRT1.1 genes, a higher influx NO3- rate in roots, and higher activities of NR and NiR in leaves and roots. Conclusively, the regulated effects of NO3- supplies on root growth and NO3- utilization were more significant for J26. Under high NO3- conditions, J26 exhibited higher capacities of NO3- absorption and distributed more N in leaves and in growth points, which may contribute to higher growth potential in shoots and more easily cause vine overgrowth.

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Esculetin (ESC) is a coumarin-derived phytochemical prevalent in traditional Chinese medicine that exhibits anti-acute ischemic stroke activities. Our previous studies demonstrate that CKLF1 is a potential anti-stroke target for coumarin-derived compound. In this study we investigated whether CKLF1 was involved in the neuroprotective effects of ESC against photothrombotic stroke in mice. The mice were treated with ESC (20, 40 or 80 mg·kg-1·d-1, i.g.) for two weeks. The therapeutic effect of ESC was assessed using MRI, neurological function evaluation, and a range of behavioral tests on D1, 3, 7 and 14 of ESC administration. We showed that oral administration of ESC dose-dependently reduced the cerebral infarction volume within one week after stroke, improved behavioral performance, and alleviated neuropathological damage within two weeks. Functional MRI revealed that ESC significantly enhanced the abnormal low-frequency fluctuation (ALFF) value of the motor cortex and promoted functional connectivity between the supplementary motor area (SMA) and multiple brain regions. We demonstrated that ESC significantly reduced the protein levels of CKLF1 and CCR5, as well as the CKLF1/CCR5 protein complex in the peri-infarcted area. We showed that ESC (0.1-10 µM) dose-dependently blocked CKLF1-induced chemotactic movement of neutrophils in the Transwell assay, reducing the interaction of CKLF1/CCR5 on the surface of neutrophils, thereby reducing neutrophil infiltration, and decreasing the expression of ICAM-1, VCAM-1 and MMP-9 in the peri-infarct tissue. Knockout of CKLF1 reduced brain infarction volume and motor dysfunction after stroke but also negated the anti-stroke efficacy and neutrophil infiltration of ESC. These results suggest that the efficacy of ESC in promoting post-stroke neural repair depends on its inhibition on CKLF1-mediated neutrophil infiltration, which offering novel perspectives for elucidating the therapeutic properties of coumarins.

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Background: HIGD1B (HIG1 Hypoxia Inducible Domain Family Member 1B) is a protein-coding gene linked to the occurrence and progression of various illnesses. However, its precise function in gastric cancer (GC) remains unclear. Methods: The expression of HIGD1B is determined through the TCGA and GEO databases and verified using experiments. The association between HIGD1B and GC patients' prognosis was analyzed via the Kaplan-Meier (K-M) curve. Subsequently, the researchers utilized ROC curves to assess the diagnostic capacity of HIGD1B and employed COX analysis to investigate risk factors for GC. The differentially expressed genes (DEGs) were then subjected to functional enrichment analysis, and a nomogram was generated to forecast the survival outcome and probability of GC patients. Additionally, we evaluated the interaction between HIGD1B and the immune cell infiltration and predicted the susceptibility of GC patients to therapy. Results: HIGD1B is markedly elevated in GC tissue and cell lines, and patients with high HIGD1B expression have a poorer outcome. In addition, HIGD1B is related to distinct grades, stages, and T stages. The survival ROC curves of HIGD1B and nomogram for five years were 0.741 and 0.735, suggesting appropriate levels of diagnostic efficacy. According to Cox regression analysis, HIGD1B represents a separate risk factor for the prognosis of gastric cancer (p<0.01). GSEA analysis demonstrated that the HIGD1B is closely related to cancer formation and advanced pathways. Moreover, patients with high HIGD1B expression exhibited a higher level of Tumor-infiltration immune cells (TIICs) and were more likely to experience immune escape and drug resistance after chemotherapy and immunotherapy. Conclusion: This study explored the potential mechanisms and diagnostic and prognostic utility of HIGD1B in GC, as well as identified HIGD1B as a valuable biomarker and possible therapeutic target for GC.

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PURPOSE: To explore the application possibility of macrocephalic sperm from a patient with 100% macrocephalic sperm and AURKC gene variations. METHODS: We diagnosed a case of macrozoospermia with 100% macrocephalic sperm and 39.5% multi-tailed spermatozoa by morphological analysis. Whole-exome sequencing (WES) was used for the patient and his wife. Sanger sequencing technique was used to verify the AURKC mutations in the patient's parents and his offspring. Sperm's ploidy was tested by flow cytometry. The couple asked for intra-couple ART therapy. RESULTS: The patient presented novel compound heterozygous AURKC mutations (c.434C > T, c.497A > T) by WES. Sanger sequencing validation showed that variant of c.434C > T was observed in his father and c.497A > T was observed in his mother. Flow cytometry revealed that there existed a certain proportion of haploid sperm. Macrocephalic spermatozoa whose heads were smaller than the diameter of injection needle were selected for microinjection. A singleton pregnancy was achieved after embryo transfer. Prenatal diagnosis revealed that the fetus had normal chromosomal karyotype. Sanger sequencing technique showed that the fetus carried a c.434C > T mutation in one AURKC allele. A 3730 g healthy male fetus was delivered at term. CONCLUSION: Our study reported a successful live birth from a patient with definite AURKC gene variants and may provide insights for such patients to choose donor sperm or their own sperm.

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To guarantee the safety and sustainability of coal mining by effectively mitigating the substantial risk associated with coal spontaneous combustion, this study proposes a multifaceted prevention strategy aligned with green environmental principles. A compound flame retardant with a physicochemical control mechanism was prepared using indigenous microorganisms to mineralize residual coal after mining, utilizing Bacillus pasteurelli as a substitute material for inorganic salts. Under laboratory conditions simulating coal self-combustion, biobased flame retardants were employed to investigate the physical and chemical transformations of heat and mass evolution from ambient temperature to combustion in two representative low-rank coals. By quantitatively comparing alterations in microbiome-based groups among raw lignite, bioretarded lignite, and two control samples, the inhibitory mechanism of biobased materials on the oxygen reaction pathway was elucidated. The findings substantiated that biobased modification can consolidate the methyl and methylene groups present in aliphatic hydrocarbon side chains, which are prone to instigating low-temperature oxidation reactions. Additionally, the preventive performance of biobased flame retardants was assessed through temperature-programmed experiments, which involved estimating the critical self-heating temperature, oxygen consumption, and gas production rates of compared coal samples. The results demonstrated significant enhancements in the resistance to spontaneous combustion following bioretarded modification. Notably, the identification grade of long flame coal shifted from easy to moderate susceptibility to spontaneous combustion. Furthermore, biobased flame retardants exhibited remarkable flame retardancy rates of approximately 80% for lignite, thereby validating their efficacy as more environmentally friendly and technologically advanced substitute materials for inhibiting spontaneous combustion in low-rank coals.

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Liver cancer, which most commonly manifests as hepatocellular carcinoma (HCC), is the sixth most common cancer in the world. In HCC, the immune system plays a crucial role in the growth and proliferation of tumor cells. HCC achieve immune escape through the tumor microenvironment, which significantly promotes the development of this cancer. Here, this article introduces and summarizes the functions and effects of regulatory T cells (Tregs) in the tumor microenvironment, highlighting how Tregs inhibit and regulate the functions of immune and tumor cells, cytokines, ligands and receptors, etc, thereby promoting tumor immune escape. In addition, it discusses the mechanism of CAR-T therapy for HCC and elaborate on the relationship between CAR-T and Tregs.

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Objectives. Anti-fungal agents are increasingly becoming less effective due to the development of resistance. In addition, it is difficult to treat Candida organisms that form biofilms due to a lack of ability of drugs to penetrate the biofilms. We are attempting to assess the effect of a new therapeutic agent, N-acetylcysteine (NAC), on adhesion and biofilm formation in Candida parapsilosis clinical strains. Meanwhile, to detect the transcription level changes of adhesion and biofilm formation-associated genes (CpALS6, CpALS7, CpEFG1 and CpBCR1) when administrated with NAC in C. parapsilosis strains, furthermore, to explore the mechanism of drug interference on biofilms.Hypothesis/Gap statement. N-acetylcysteine (NAC) exhibits certain inhibitory effects on adhesion and biofilm formation in C. parapsilosis clinical strains from CRBSIs through: (1) down-regulating the expression of the CpEFG1 gene, making it a highly potential candidate for the treatment of C. parapsilosis catheter-related bloodstream infections (CRBSIs), (2) regulating the metabolism and biofilm -forming factors of cell structure.Methods. To determine whether non-antifungal agents can exhibit inhibitory effects on adhesion, amounts of total biofilm formation and metabolic activities of C. parapsilosis isolates from candidemia patients, NAC was added to the yeast suspensions at different concentrations, respectively. Reverse transcription was used to detect the transcriptional levels of adhesion-related genes (CpALS6 and CpALS7) and biofilm formation-related factors (CpEFG1 and CpBCR1) in the BCR1 knockout strain, CP7 and CP5 clinical strains in the presence of NAC. To further explore the mechanism of NAC on the biofilms of C. parapsilosis, RNA sequencing was used to calculate gene expression, comparing the differences among samples. Gene Ontology (GO) enrichment analysis helps to illustrate the difference between two particular samples on functional levels.Results. A high concentration of NAC reduces the total amount of biofilm formation in C. parapsilosis. Following co-incubation with NAC, the expression of CpEFG1 in both CP7 and CP5 clinical strains decreased, while there were no significant changes in the transcriptional levels of CpBCR1 compared with the untreated strain. GO enrichment analysis showed that the metabolism and biofilm-forming factors of cell structure were all regulated after NAC intervention.Conclusions. The non-antifungal agent NAC exhibits certain inhibitory effects on clinical isolate biofilm formation by down-regulating the expression of the CpEFG1 gene, making it a highly potential candidate for the treatment of C. parapsilosis catheter-related bloodstream infections.

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Background: Stress hyperglycemia ratio (SHR) is a newly suggested measure of stress-induced hyperglycemia that combines both short-term and long-term glycemic conditions. The study aimed to explore the association between SHR and the incidence of adverse clinical events with heart failure (HF) through a meta-analysis. Methods: Cohort studies relevant to the aim of the meta-analysis were retrieved by search of electronic databases including PubMed, Web of Science, Embase, Wanfang, and CNKI. A random-effects model was used to combine the data by incorporating the influence of between-study heterogeneity. Results: Ten studies involving 15250 patients with HF were included. Pooled results showed that compared to patients with lower SHR at baseline, those with a higher SHR were associated with an increased risk of all-cause mortality during follow-up (risk ratio [RR]: 1.61, 95% confidence interval [CI]: 1.17 to 2.21, p = 0.003; I2 = 82%). Further meta-regression analysis suggests that different in the cutoff of SHR significantly modify the results (coefficient = 1.22, p = 0.02), and the subgroup analysis suggested a more remarkable association between SHR and all-cause mortality in studies with cutoff of SHR ≥ 1.05 than those with cutoff of SHR < 1.05 (RR: 2.29 versus 1.08, p for subgroup difference < 0.001). Subsequent meta-analyses also showed that a high SHR at baseline was related to the incidence of cardiovascular death (RR: 2.19, 95% CI: 1.55 to 3.09, p < 0.001; I2 = 0%), HF-rehospitalization (RR: 1.83, 95% CI: 1.44 to 2.33, p < 0.001; I2 = 0%), and major adverse cardiovascular events (RR: 1.54, 95% CI: 1.15 to 2.06, p = 0.004; I2 = 74%) during follow-up. Conclusion: A high SHR at baseline is associated with a poor clinical prognosis of patients with HF. Systematic review registration: https://inplasy.com, identifier INPLASY202430080.

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This study aimed to evaluate the efficacy and safety of intravitreal dexamethasone implants in the treatment of ocular toxocariasis (OT). A retrospective analysis was performed on 6 cases in which laboratory tests diagnosed OT. All patients were administered with intravitreal dexamethasone implants with or without vitrectomy. The average follow-up time was 19.7 months. All operated eyes achieved anatomic success, and all patients' visual acuity was improved. Five of these six had a visual acuity of 20/100, and three had final acuity of 20/40 or even better. Intravitreal dexamethasone implants can be used to treat different types of OT, which not only effectively control inflammation and improve the patient's vision but also reduce the use of systemic glucocorticoids.

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A high-efficiency tandem process has been developed for the formation of two C-N bonds through a cross-dehydrogenative coupling (CDC) amination of spiro[acridine-9,9'-fluorene]s (SAFs) with amines. This method offers a strategically innovative and atom-economical approach to obtaining diamine-substituted SAFs. Notably, the approach eliminates the need for metal catalysts and other additives, relying solely on O2 as the oxidant. A self-activation mechanism has been proposed to elucidate the effective double amination in the CDC process.

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BACKGROUND: The combination of preoperative chemotherapy and surgical treatment has been shown to significantly enhance the prognosis of colorectal cancer with liver metastases (CRLM) patients. Nevertheless, as a result of variations in clinicopathological parameters, the prognosis of this particular group of patients differs considerably. This study aimed to develop and evaluate Cox proportional risk regression model and competing risk regression model using two patient cohorts. The goal was to provide a more precise and personalized prognostic evaluation system. METHODS: We collected information on individuals who had a pathological diagnosis of colorectal cancer between 2000 and 2019 from the Surveillance, Epidemiology, and End Results (SEER) Database. We obtained data from patients who underwent pathological diagnosis of colorectal cancer and got comprehensive therapy at the hospital between January 1, 2010, and June 1, 2022. The SEER data collected after screening according to the inclusion and exclusion criteria were separated into two cohorts: a training cohort (training cohort) and an internal validation cohort (internal validation cohort), using a random 1:1 split. Subgroup Kaplan-Meier (K-M) survival analyses were conducted on each of the three groups. The data that received following screening from the hospital were designated as the external validation cohort. The subsequent variables were chosen for additional examination: age, gender, marital status, race, tumor site, pretreatment carcinoembryonic antigen level, tumor size, T stage, N stage, pathological grade, number of tumor deposits, perineural invasion, number of regional lymph nodes examined, and number of positive regional lymph nodes. The primary endpoint was median overall survival (mOS). In the training cohort, we conducted univariate Cox regression analysis and utilized a stepwise regression approach, employing the Akaike information criterion (AIC) to select variables and create Cox proportional risk regression models. We evaluated the accuracy of the model using calibration curve, receiver operating characteristic curve (ROC), and area under curve (AUC). The effectiveness of the models was assessed using decision curve analysis (DCA). To evaluate the non-cancer-related outcomes, we analyzed variables that had significant impacts using subgroup cumulative incidence function (CIF) and Gray's test. These analyses were used to create competing risk regression models. Nomograms of the two models were constructed separately and prognostic predictions were made for the same patients in SEER database. RESULTS: This study comprised a total of 735 individuals. The mOS of the training cohort, internal validation cohort, and QDU cohort was 55.00 months (95%CI 46.97-63.03), 48.00 months (95%CI 40.65-55.35), and 68.00 months (95%CI 54.91-81.08), respectively. The multivariate Cox regression analysis revealed that age, N stage, presence of perineural infiltration, number of tumor deposits and number of positive regional lymph nodes were identified as independent prognostic risk variables (p < 0.05). In comparison to the conventional TNM staging model, the Cox proportional risk regression model exhibited a higher C-index. After controlling for competing risk events, age, N stage, presence of perineural infiltration, number of tumor deposits, number of regional lymph nodes examined, and number of positive regional lymph nodes were independent predictors of the risk of cancer-specific mortality (p < 0.05). CONCLUSION: We have developed a prognostic model to predict the survival of patients with synchronous CRLM who undergo preoperative chemotherapy and surgery. This model has been tested internally and externally, confirming its accuracy and reliability.

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We report the first room-temperature synthesis of ternary CdTeSe magic-size clusters (MSCs) that have mainly the surface ligand oleate (OA). The MSCs display sharp optical absorption peaking at ∼399 nm and are thus referred to as MSC-399. They are made from prenucleation-stage samples of binary CdTe and CdSe, which are prepared by two reactions in 1-octadecene (ODE) of cadmium oleate (Cd(OA)2) and tri-n-octylphosphine chalcogenide (ETOP, E = Te and Se) at 25 °C for 120 min and 80 °C for 15 min, respectively. When the two binary samples are mixed at room temperature and dispersed in a mixture of toluene (Tol) and octylamine (OTA), the CdTeSe MSC-399 develops. Also, when the CdSe sample is added to CdTe MSC-371 in a dispersion, the transformation from CdTe MSC-371 to CdTeSe MSC-399 is seen. We propose that the MSCs develop from their precursor compounds (PCs) that are relatively transparent in optical absorption, such as CdTeSe MSC-399 from CdTeSe PC-399 and CdTe MSC-371 from CdTe PC-371. The formation of CdTeSe PC-399 undergoes monomer substitution and not anion exchange, which is the reaction of CdTe PC-371 and the CdSe monomer to produce CdTeSe PC-399 and the CdTe monomer. Our study provides evidence of monomer substitution for the transformation from binary CdTe to ternary CdTeSe PCs.

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BACKGROUND: Chronic heart failure (CHF) has always posed a significant threat to human survival and health. The efficacy of thiamine supplementation in CHF patients remains uncertain. HYPOTHESIS: Receiving supplementary thiamine may not confer benefits to patients with CHF. METHODS: A comprehensive search was conducted across the Cochrane Library, PubMed, EMBASE, ClinicalTrials.gov, and Web of Science databases up until May 2023 to identify articles investigating the effects of thiamine supplementation in CHF patients. Predefined criteria were utilized for selecting data on study characteristics and results. RESULTS: Seven randomized, double-blind, controlled trials (five parallel trials and two crossover trials) involving a total of 274 patients were enrolled. The results of the meta-analysis pooling these studies did not reveal any significant effect of thiamine treatment compared with placebo on left ventricular ejection fraction (WMD = 1.653%, 95% CI:  -1.098 to 4.405, p = 0.239, I2 = 61.8%), left ventricular end-diastolic volume (WMD = -6.831 mL, 95% CI:  -26.367 to 12.704, p = 0.493, I2 = 0.0%), 6-min walking test (WMD = 16.526 m, 95% CI:  -36.582 to 69.634, p = 0.542, I2 = 66.3%), N-terminal pro-B type natriuretic peptide (WMD = 258.150 pg/mL, 95% CI:  -236.406 to 752.707, p = 0.306, I2 = 21.6%), or New York Heart Association class (WMD = -0.223, 95% CI:  -0.781 to 0.335, p = 0.434, I2 = 87.1%). However, it effectively improved the status of thiamine deficiency (TD). CONCLUSIONS: Our meta-analysis indicates that thiamine supplementation does not have a direct therapeutic effect on CHF, except for correcting TD.

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BACKGROUND: Sporadic parathyroid adenoma (PA) is the most common cause of hyperparathyroidism, yet the mechanisms involved in its pathogenesis remain incompletely understood. METHODS: Surgically removed PA samples, along with normal parathyroid gland (PG) tissues that were incidentally dissected during total thyroidectomy, were analysed using single-cell RNA-sequencing with the 10× Genomics Chromium Droplet platform and Cell Ranger software. Gene set variation analysis was conducted to characterise hallmark pathway gene signatures, and single-cell regulatory network inference and clustering were utilised to analyse transcription factor regulons. Immunohistochemistry and immunofluorescence were performed to validate cellular components of PA tissues. siRNA knockdown and gene overexpression, alongside quantitative polymerase chain reaction, Western blotting and cell proliferation assays, were conducted for functional investigations. RESULTS: There was a pervasive increase in gene transcription in PA cells (PACs) compared with PG cells. This is associated with high expression of histone-lysine N-methyltransferase 2A (KMT2A). High KMT2A levels potentially contribute to promoting PAC proliferation through upregulation of the proto-oncogene CCND2, which is mediated by the transcription factors signal transducer and activator of transcription 3 (STAT3) and GATA binding protein 3 (GATA3). PA tissues are heavily infiltrated with myeloid cells, while fibroblasts, endothelial cells and macrophages in PA tissues are commonly enriched with proinflammatory gene signatures relative to their counterparts in PG tissues. CONCLUSIONS: We revealed the previously underappreciated involvement of the KMT2A‒STAT3/GATA3‒CCND2 axis and chronic inflammation in the pathogenesis of PA. These findings underscore the therapeutic promise of KMT2A inhibition and anti-inflammatory strategies, highlighting the need for future investigations to translate these molecular insights into practical applications. HIGHLIGHTS: Single-cell RNA-sequencing reveals a transcriptome catalogue comparing sporadic parathyroid adenomas (PAs) with normal parathyroid glands. PA cells show a pervasive increase in gene expression linked to KMT2A upregulation. KMT2A-mediated STAT3 and GATA3 upregulation is key to promoting PA cell proliferation via cyclin D2. PAs exhibit a proinflammatory microenvironment, suggesting a potential role of chronic inflammation in PA pathogenesis.

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Small extracellular vesicles (sEVs) hold considerable promise for drug delivery due to their natural origin and inherent qualities. However, their clinical application is impeded by two main challenges: low yield and potential side effects. Therefore, it is crucial to obtain substantial quantities of sEVs that adhere to rigorous biosafety standards to ensure successful translation into clinical practice. To address this need, we propose exploring optimized methods for sourcing and separating sEVs, taking inspiration from clinical blood transfusion. In particular, we have identified blood sEVs as a viable alternative and developed a novel separation technique for their isolation. Our approach involves incubating dopamine solution with serum, resulting in the formation of polydopamine (PDA) nanoparticles on the surface of blood sEVs. These nanoparticles have minimal impact on blood sEVs, facilitating their easy separation under standard centrifugal conditions with high purity. This innovative technique enables the development of nanocarriers using blood sEVs with efficient drug-loading capabilities and enhanced pharmacokinetics. Additionally, the incorporation of PDA nanoparticles imparts a photothermal effect to the nanomedicines, enabling the integration of chemotherapy and photothermal therapy. Moreover, the photothermal effect holds the potential to facilitate the membrane fusion of sEVs and cells. In summary, our straightforward surface functionalization technique utilizing PDA effectively isolates blood sEVs and enables chemo-thermal tumor therapy. This approach significantly enhances the feasibility of translating sEV-based nanomedicines into clinical applications.

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Diazotrophic microorganisms regulate marine productivity by alleviating nitrogen limitation. So far chemolithoautotrophic bacteria are widely recognized as the principal diazotrophs in oligotrophic marine and terrestrial ecosystems. However, the contribution of chemolithoautotrophs to nitrogen fixation in organic-rich habitats remains unclear. Here, we utilized metagenomic and metatranscriptomic approaches integrated with cultivation assays to investigate the diversity, distribution, and activity of diazotrophs residing in Zhangzhou mangrove sediments. Physicochemical assays show that the studied mangrove sediments are typical carbon-rich, sulfur-rich, nitrogen-limited, and low-redox marine ecosystems. These sediments host a wide phylogenetic variety of nitrogenase genes, including groups I-III and VII-VIII. Unexpectedly diverse chemolithoautotrophic taxa including Campylobacteria, Gammaproteobacteria, Zetaproteobacteria, and Thermodesulfovibrionia are the predominant and active nitrogen fixers in the 0-18 cm sediment layer. In contrast, the 18-20 cm layer is dominated by active diazotrophs from the chemolithoautotrophic taxa Desulfobacterota and Halobacteriota. Further analysis of MAGs show that the main chemolithoautotrophs can fix nitrogen by coupling the oxidation of hydrogen, reduced sulfur, and iron, with the reduction of oxygen, nitrate, and sulfur. Culture experiments further demonstrate that members of chemolithoautotrophic Campylobacteria have the nitrogen-fixing capacity driven by hydrogen and sulfur oxidation. Activity measurements confirm that the diazotrophs inhabiting mangrove sediments preferentially drain energy from diverse reduced inorganic compounds other than from organics. Overall, our results suggest that chemolithoautotrophs rather than heterotrophs are dominant nitrogen fixers in mangrove sediments. This study underscores the significance of chemolithoautotrophs in carbon-dominant ecosystems.

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Gridization is an emerging molecular integration technology that enables the creation of multifunctional organic semiconductors through precise linkages. While Friedel-Crafts gridization of fluorenols is potent, direct linkage among fluorene molecules poses a challenge. Herein, we report an achiral Pd-PPh3-cataylized diastereoselective (>99:1 d.r.) gridization based on the C-H-activation of fluorene to give dimeric and trimeric windmill-type nanogrids (DWGs and TWGs). These non-conjugated stereo-nanogrids showcase intramolecular multiple H…H interactions with a low field shift to 8.51 ppm and circularly polarized luminescence with high luminescent dissymmetry factors (|gPL | = 0.012). Significantly, the nondoped organic light-emitting diodes (OLEDs) utilizing cis-trans-TWG1 emitter present an ultraviolet electroluminescent peak at ~386 nm (CIE: 0.17, 0.04) with a maximum external quantum efficiency of 4.17%, marking the highest record among nondoped ultraviolet OLEDs based on hydrocarbon compounds and the pioneering ultraviolet OLEDs based on macrocycles. These nanohydrocarbon offer potential nanoscafflolds for ultraviolet light-emitting optoelectronic applications.