Value of cardiac enzyme spectrum for the risk assessment of mortality in critically ill children: a single-centre retrospective study.

OBJECTIVES: Identifying high-risk paediatric patients with a poor prognosis and providing timely and adequate treatment are critical. This study aimed to evaluate the effects of different types of cardiac enzyme spectrum within 24 hours of admission on the short-term prognosis of patients in paediatric intensive care units. DESIGN: A retrospective study. SETTING: A single-centre, tertiary care hospital in China, with patient data from 2010 to 2018. PARTICIPANTS: A total of 4343 critically ill children were enrolled. INTERVENTION: None. PRIMARY AND SECONDARY OUTCOME MEASURES: The main outcome measure was in-hospital mortality, which was defined as death from any cause during hospitalisation. The secondary outcome was 30-day mortality, intensive care unit (ICU) length of stay (LOS) and total LOS. RESULTS: Using the local polynomial regression fitting method, an approximately linear increase in in-hospital mortality was detected for creatine kinase (CK), creatine kinase MB (CK-MB), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH). Among the different types of cardiac enzyme spectrum, LDH had the highest area under the curve value (0.729), followed by AST (0.701), CK-MB (0.613) and CK (0.557). The Kaplan‒Meier analysis showed that the patients in the high LDH group had higher 30-day mortality. The multivariate logistic regression revealed that high LDH was independently associated with in-hospital mortality (OR 2.45, 95% CI 1.84 to 3.24). After propensity score matching (PSM) and sensitivity analysis, the results remained consistent. CONCLUSIONS: LDH is a reliable outcome predictor in critically ill children, including those with various comorbidities.

Pancreatic agenesis and altered m6A methylation in the pancreas of PDX1-mutant cynomolgus macaques.

As an essential transcriptional activator, PDX1 plays a crucial role in pancreatic development and ß-cell function. Mutations in the PDX1 gene may lead to type 4 maturity-onset diabetes of the young (MODY4) and neonatal diabetes mellitus. However, the precise mechanisms underlying MODY4 remain elusive due to the paucity of clinical samples and pronounced differences in pancreatic architecture and genomic composition between humans and existing animal models. In this study, three PDX1-mutant cynomolgus macaques were generated using CRISPR/Cas9 technology, all of which succumbed shortly postpartum, exhibiting pancreatic agenesis. Notably, one tri-allelic PDX1-mutant cynomolgus macaque (designated as M4) developed a pancreas, whereas the two mono-allelic PDX1-mutant cynomolgus macaques displayed no anatomical evidence of pancreatic formation. RNA sequencing of the M4 pancreas revealed substantial molecular changes in both endocrine and exocrine functions, indicating developmental delay and PDX1 haploinsufficiency. A marked change in m6A methylation was identified in the M4 pancreas, confirmed through cultured PDX1-mutant islet organoids. Notably, overexpression of the m6A modulator METTL3 restored function in heterozygous PDX1-mutant islet organoids. This study highlights a novel role of m6A methylation modification in the progression of MODY4 and provides valuable molecular insights for preclinical research.

The relationship between resistance evolution and carbon metabolism in Staphylococcus xylosus under ceftiofur sodium stress.

Staphylococcus xylosus has emerged as a bovine mastitis pathogen with increasing drug resistance, resulting in substantial economic impacts. This study utilized iTRAQ analysis to investigate the mechanisms driving resistance evolution in S. xylosus under ceftiofur sodium stress. Findings revealed notable variations in the expression of 143 proteins, particularly glycolysis-related proteins (TpiA, Eno, GlpD, Ldh) and peptidoglycan (PG) hydrolase Atl. Following the induction of ceftiofur sodium resistance in S. xylosus, the emergence of resistant strains displaying characteristics of small colony variants (SCVs) was observed. The transcript levels of TpiA, Eno, GlpD and Ldh were up-regulated, TCA cycle proteins (ICDH, MDH) and Atl were down-regulated, lactate content was increased, and NADH concentration was decreased in SCV compared to the wild strain. That indicates a potential role of carbon metabolism, specifically PG hydrolysis, glycolysis, and the TCA cycle, in the development of resistance to ceftiofur sodium in S. xylosus.

Find alternative for bovine and porcine gelatin: Study on physicochemical, rheological properties and water-holding capacity of chicken lungs gelatin by ultrasound treatment.

In this study, the study on physicochemical, rheological properties and water-holding capacity of gelatin of chicken lungs was investigated to replace bovine and porcine gelatin. The extraction rates of chicken, bovine and porcine lung gelatin by ultrasound assisted alkaline protease were 52.12 %, 69.06 % and 70 %, respectively. Three lung gelatins had similar molecular weight distribution in SDS-PAGE with low content of high molecular weight subunits. The amino acid content of bovine lung gelatin (18.03 %) was higher than in chicken (16.62 %) and porcine lung (15.30 %). The highest intensity of 2θ = 7.5° diffraction peak in bovine lung gelatin was observed, which indicated that the triple helix content of bovine lung gelatin was higher than that of chicken and porcine lung gelatin. The lowest apparent viscosity of chicken lung gelatin was 0.253 mPa·s, but the highest water holding capacity of chicken lung gelatin was 331.72 %. Therefore, chicken lung gelatin can be used as a substitute for bovine and porcine gelatin in some functional properties.

Responses of Intraspecific and Interspecific Trait Variations to Nitrogen Addition in a Tibetan Alpine Meadow.

A community functional structure may respond to environmental changes such as nitrogen (N) enrichment by altering intraspecific and interspecific trait variations. However, the relative contributions of both components in determining the community response to N enrichment are unclear. In this study, we measured the plant height (H), leaf area (LA), leaf dry matter content (LDMC), and specific leaf area (SLA) based on a nine-year N addition gradient experiment in an alpine meadow on the Tibetan Plateau. We examined the intraspecific and interspecific variations within and among the communities, the responses of traits in terms of community weighted mean (CWM) and non-weighted mean (CM) to N addition, and the effects of these trait variations on aboveground net primary productivity (ANPP). Our results show that N addition increased the interspecific variation in H while decreasing that of LA within the community, whereas it had no significant effects on the intraspecific variations in the four traits within the community. In contrast, N addition significantly increased the intraspecific variation in H and decreased that of LA among the communities. Moreover, the contribution of intraspecific variation was greater than that of the interspecific variation in terms of CWM for all traits, while the opposite contribution was observed in terms of CM, suggesting that the dominant species would have greater resilience while subdominant species would become less resistant to N addition. Further, intraspecific variations of LA and LDMC within the community played an important role in explaining community productivity. Our results highlight the importance of both intraspecific and interspecific variations in mediating functional trait responses to N enrichment, and intraspecific variation within the communities has important implications for community functioning that should be considered to better understand and predict the responses of the alpine grasslands to N enrichment.

Single-stage Auricular Reconstruction in Hemifacial Microsomia With Low Hairline by Using Temporoparietal Fascia Flap.

BACKGROUND: Auricular reconstruction is one of the most complicated operations in plastic surgery and is more difficult for patients with a low hairline due to limited skin availability. In traditional operations, the skin of the mastoid area was used to cover the front of the ear scaffold, and the retroauricular fascia, combined with a free skin graft, was used to cover the back of the ear framework. This may cause problems such as inadequate skin coverage and affecting the shape of the reconstructed ear when the hairline is low. METHODS: Hemifacial microsomia patients with low hairline have little skin flap to perform the ear reconstruction, and we refined a single-stage ear reconstruction surgery to solve the problem. The temporoparietal fascia is used to cover the entire costal cartilage scaffold, and its surface is covered with a free split-thickness skin taken from the chest wall, thigh, and other parts. RESULTS: From December 2019 to December 2020, 12 patients with hemifacial microsomia underwent single-stage reconstruction with temporoparietal fascia. The duration of patient follow-up was 6 to 24 months. The application of this technique can solve the problem of insufficient available skin flap, complete the ear reconstruction through 1 operation, reduce the treatment cycle, achieve a good shape of the reconstructed ear, and the postoperative effect is satisfactory. CONCLUSION: According to the characteristics of the HFM patients with low hairline, we recommend this new, improved single-stage auricular reconstruction using the temporoparietal fascia for these patients. This method is a suitable choice for HFM patients with low hairline.Level of Evidence: Level-IV, Cases Study.

The Impact of Prone Position Ventilation on the Prognosis of Patients with Pulmonary Infections in Intensive Care Units.

Objective: This retrospective study aimed to analyze the impact of prone position ventilation compared to supine position ventilation on the prognosis of patients with pulmonary infections in the intensive care unit (ICU). Prone position ventilation has been suggested to enhance oxygenation, reduce ventilation-perfusion mismatch, and alleviate lung compression, which may contribute to improved respiratory mechanics and better outcomes in patients with pulmonary infections. By comparing these two ventilation positions, we sought to evaluate their respective effects on patient prognosis and shed light on the potential advantages of prone position ventilation in the ICU setting. Methods: A total of 160 critically ill patients with pulmonary infections were included in the study and divided into two groups: the prone position ventilation group (n=80) and the supine position ventilation group (n=80). Inclusion criteria for patient selection in this study included individuals between the ages of 18 and 75 who were critically ill with pulmonary infections and receiving treatment in the Intensive Care Unit (ICU). Basic vital sign monitoring, airway pathogen examinations, multidrug-resistant bacterial detection rates analysis, and prognosis assessments were conducted. Results: The prone position ventilation group demonstrated several advantages compared to the supine position ventilation group. The positive rate of airway pathogen examinations in the prone position ventilation group was 55%, significantly lower than the 75% in the supine position ventilation group (P = .005). The detection rate of multidrug-resistant bacteria was 20%, significantly lower than the 43.75% in the supine position group (P = .002). Furthermore, the prone position ventilation group showed shorter mechanical ventilation duration, intubation time, and ICU length of stay. Specifically, the duration of mechanical ventilation in the prone position ventilation group was 12.34±3.45 days, compared to 13.89±4.12 days in the supine position ventilation group. The intubation time was 10.56±2.78 days in the prone position group and 11.67±3.01 days in the supine position group. The ICU length of stay was 16.45±4.56 days in the prone position group and 18.67±5.34 days in the supine position group (P < .05). The two groups had no significant differences in total hospital stay and survival rate. Conclusion: Compared to supine position ventilation, prone position ventilation significantly improved airway pathogen examination results and reduced the detection rate of multidrug-resistant bacteria in patients with pulmonary infections in the ICU. Additionally, it decreased the duration of mechanical ventilation and ICU stay, although it did not significantly impact the survival rate. Further validation through larger-scale, multicenter studies is warranted. ICU practices may consider incorporating prone position ventilation as a standard intervention for patients with severe pulmonary infections. This could involve developing guidelines and protocols for the appropriate selection and implementation of prone position ventilation, as well as providing training to healthcare providers on its safe and effective use.

Factors associated with risk analysis for asymptomatic left ventricular diastolic dysfunction in nondialysis patients with chronic kidney disease.

Heart failure (HF) constitutes a major determinant of outcome in chronic kidney disease (CKD) patients. The main pattern of HF in CKD patients is preserved ejection fraction (HFpEF), and left ventricular diastolic dysfunction (LVDD) is a frequent pathophysiological mechanism and specific preclinical manifestation of HFpEF. Therefore, exploring and intervention of the factors associated with risk for LVDD is of great importance in reducing the morbidity and mortality of cardiovascular disease (CVD) complications in CKD patients. We designed this retrospective cross-sectional study to collect clinical and echocardiographic data from 339 nondialysis CKD patients without obvious symptoms of HF to analyze the proportion of asymptomatic left ventricular diastolic dysfunction (ALVDD) and its related factors associated with risk by multivariate logistic regression analysis. Among the 339 nondialysis CKD patients, 92.04% had ALVDD. With the progression of CKD stage, the proportion of ALVDD gradually increased. The multivariate logistic regression analysis revealed that increased age (OR 1.237; 95% confidence interval (CI) 1.108-1.381, per year), diabetic nephropathy (DN) and hypertensive nephropathy (HTN) (OR 25.000; 95% CI 1.355-48.645, DN and HTN vs chronic interstitial nephritis), progression of CKD stage (OR 2.785; 95% CI 1.228-6.315, per stage), increased mean arterial pressure (OR 1.154; 95% CI 1.051-1.268, per mmHg), increased urinary protein (OR 2.825; 95% CI 1.484-5.405, per g/24 h), and low blood calcium (OR 0.072; 95% CI 0.006-0.859, per mmol/L) were factors associated with risk for ALVDD in nondialysis CKD patients after adjusting for other confounding factors. Therefore, dynamic monitoring of these factors associated with risk, timely diagnosis and treatment of ALVDD can delay the progression to symptomatic HF, which is of great importance for reducing CVD mortality, and improving the prognosis and quality of life in CKD patients.

Dissipation and potential risk of tristyrylphenol ethoxylate homologs in peanuts by spraying and root irrigation: A comparative assessment.

Peanuts, known for their nutritional value, health benefits, and delicious taste, are susceptible to agricultural chemical contamination, posing a challenge to the peanut industry in China. While tristyrylphenol ethoxylates (TSPEOs) have garnered attention for their widespread use in pesticide formulations, their dissipation and potential risks in peanuts remain a gap in knowledge. This study, unique in its focus on TSPEOs, investigates their dissipation and potential risks under two common application modes: spraying and root irrigation. The concentration of total TSPEOs in peanut plants was significantly higher when sprayed (435-37,693 µg/kg) than in root irrigation (24-1602 µg/kg). The dissipation of TSPEOs was faster in peanuts and soil when sprayed, with half-lives of 3.67-5.59 d (mean: 4.37 d) and 5.41-7.07 d (mean: 5.95 d), respectively. The residue of TSPEOs in peanut shells and soil were higher with root irrigation (8.9-65.2 and 25.4-305.1 µg/kg, respectively) than with spraying (5.4-30.6 and 8.8-146.5 µg/kg, respectively). These results indicated that the dissipation behavior of TSPEOs in peanuts was influenced by application modes. While the healthy and ecological risk assessments of TSPEOs in soil and peanut shells showed no risks, root irrigation might pose a higher potential risk than spraying. This research provides valuable data for the judicious application of pesticides during peanut cultivation to enhance pesticide utilization and reduce potential risks.

The Role and Potential Mechanisms of Rehabilitation Exercise Improving Cardiac Remodeling.

Rehabilitation exercise is a crucial non-pharmacological intervention for the secondary prevention and treatment of cardiovascular diseases, effectively ameliorating cardiac remodeling in patients. Exercise training can mitigate cardiomyocyte apoptosis, reduce extracellular matrix deposition and fibrosis, promote angiogenesis, and regulate inflammatory response to improve cardiac remodeling. This article presents a comprehensive review of recent research progress, summarizing the pivotal role and underlying mechanism of rehabilitation exercise in improving cardiac remodeling and providing valuable insights for devising effective rehabilitation treatment programs. Graphical Abstract.

Functional Groups Dominate Aboveground Net Primary Production under Long-Term Nutrient Additions in a Tibetan Alpine Meadow.

Anthropogenic nutrient additions are influencing the structure and function of alpine grassland ecosystems. However, the underlying mechanisms of the direct and indirect effects of nutrient additions on aboveground net primary productivity (ANPP) are not well understood. In this study, we conducted an eight-year field experiment to explore the ecological consequences of nitrogen (N) and/or phosphorous (P) additions on the northern Tibetan Plateau. ANPP, species diversity, functional diversity, and functional groups were used to assess species' responses to increasing nutrients. Our results showed that nutrient additions significantly increased ANPP due to the release in nutrient limitations. Although N addition had a significant effect on species richness and functional richness, and P and N + P additions altered functional diversity, it was functional groups rather than biodiversity that drove changes in ANPP in the indirect pathways. We identified the important roles of N and P additions in begetting the dominance of grasses and forbs, respectively. The study highlights that the shift of functional groups should be taken into consideration to better predict the structure, function, and biodiversity-ANPP relationship in grasslands, particularly under future multifaceted global change.

Imidacloprid triggered changes in strawberry fruits on edible quality and phenolic profiles by applied at two growth stages.

Increasing evidence showed that imidacloprid affects plants' abiotic or biotic stress tolerance. However, the effects of imidacloprid on the quality of fruits remain elusive. This work aimed to study the effects of imidacloprid applied at different growth stages on the edible quality and phenolic profile of strawberry fruit in the field experiment. For the first time, lower fruit quality was observed in the mature strawberry fruits after imidacloprid treatment at the fruit-bearing completion stage (five days after pollination). Compared to the control group, the mature strawberry fruit wights and the SCC/TA ratio declined about 18.2-30.0 % and 10.3-16.8 %, respectively. However, those attributes did not occur in the mature strawberry fruits by imidacloprid treatment at the fruit maturation stage (30 days after pollination). Among the 30 phenolic compounds, nine presented significant up-regulation or down-regulation after imidacloprid application at two different growth stages, suggesting that the application period played an essential role in evaluating the effects of imidacloprid on the quality of fruits. A significant effect on fruit quality was presented at the strawberry early growth stage treated by imidacloprid. This study provided a new insight into how and when imidacloprid affects the quality of strawberry fruits, contributing to the future's more scientific application of imidacloprid on strawberries.

STAR-121: A Phase III Randomized Study of Domvanalimab and Zimberelimab in Combination With Chemotherapy Versus Pembrolizumab With Chemotherapy in Untreated Metastatic Non-Small Cell Lung Cancer With No Actionable Gene Alterations.

INTRODUCTION: Dual inhibition with a T-cell immunoreceptor with immunoglobulin and ITIM domains plus programmed death (ligand)-1 (PD[L]-1) inhibitors, with or without chemotherapy, is an emerging therapeutic strategy in metastatic non-small cell lung cancer (mNSCLC). The STAR-121 (NCT05502237) phase III, global, randomized, open-label study will investigate first-line domvanalimab (anti-TIGIT) and zimberelimab (anti-PD-1) plus chemotherapy versus pembrolizumab plus chemotherapy in mNSCLC with no actionable gene alterations. PARTICIPANTS AND METHODS: Approximately 720 participants (≥18 years old) with untreated mNSCLC and no EGFR and ALK mutations will be randomized into 3 groups (A, B, or C) in a 4:4:1 ratio and stratified by baseline PD-L1 expression (tumor cells <50% vs. ≥50%), histology (squamous vs. nonsquamous), and geographic region (East Asia vs. non-East Asia). Group A will receive domvanalimab 1200 mg plus zimberelimab 360 mg plus platinum-doublet chemotherapy (PT), group B will receive pembrolizumab 200 mg plus PT, and group C will receive zimberelimab 360 mg plus PT, every 3 weeks. Treatment will be administered until disease progression or intolerable toxicity. Dual primary endpoints are progression-free survival (by blinded independent central review [BICR]) and overall survival for group A versus B. Key secondary endpoints comprise overall response rate (by BICR), safety, and quality of life. Exploratory endpoints include efficacy and safety between groups A and C, pharmacokinetics, patient-reported outcomes, and biomarkers. CONCLUSION: Enrollment in the STAR-121 study commenced on October 12, 2022, and is currently ongoing with completion planned by September 2024. The study completion is expected by December 2027.

Exogenous methionine contributes to reversing the resistance of Streptococcus suis to macrolides.

Streptococcus suis (S. suis) has been increasingly recognized as a porcine zoonotic pathogen that threatens the health of both pigs and humans. Multidrug-resistant Streptococcus suis is becoming increasingly prevalent, and novel strategies to treat bacterial infections caused by these organisms are desperately needed. In the present study, an untargeted metabolomics analysis showed that the significant decrease in methionine content and the methionine biosynthetic pathway were significantly affected by the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis in drug-resistant S. suis. The addition of L-methionine restored the bactericidal activity of macrolides, doxycycline, and ciprofloxacin on S. suis in vivo and in vitro. Further studies showed that the exogenous addition of methionine affects methionine metabolism by reducing S-adenosylmethionine synthetase activity and the contents of S-adenosylmethionine, S-adenosyl homocysteine, and S-ribose homocysteine. Methionine can decrease the total methylation level and methylesterase activity in multidrug resistant S. suis. The drug transport proteins and efflux pump genes were significantly downregulated in S. suis by exogenous L-methionine. Moreover, the exogenous addition of methionine can reduce the survival of S. suis by affecting oxidative stress and metal starvation in bacteria. Thus, L-methionine may influence the development of resistance in S. suis through methyl metabolism and metal starvation. This study provides a new perspective on the mitigation of drug resistance in S. suis.IMPORTANCEBacterial antibiotic resistance has become a severe threat to human and animal health. Increasing the efficacy of existing antibiotics is a promising strategy against antibiotic resistance. Here, we report that L-methionine enhances the efficacy of macrolides, doxycycline, and ciprofloxacin antibiotics in killing Streptococcus suis, including multidrug-resistant pathogens. We investigated the mechanism of action of exogenous methionine supplementation in restoring macrolides in Streptococcus suis and the role of the methionine cycle pathway on methylation levels, efflux pump genes, oxidative stress, and metal starvation in Streptococcus suis. It provides a theoretical basis for the rational use of macrolides in clinical practice and also identifies a possible target for restoring drug resistance in Streptococcus suis.

BAF45D-binding to HOX genes was differentially targeted in H9-derived spinal cord neural stem cells.

Chromatin accessibility has been used to define how cells adopt region-specific neural fates. BAF45D is one of the subunits of a specialised chromatin remodelling BAF complex. It has been reported that BAF45D is expressed in spinal cord neural stem cells (NSCs) and regulates their fate specification. Within the developing vertebrate spinal cord, HOX genes exhibit spatially restricted expression patterns. However, the chromatin accessibility of BAF45D binding HOX genes in spinal cord NSCs is unclear. In the present study, we found that in H9-derived spinal cord NSCs, BAF45D targets TBX6, a gene that regulates spinal cord neural mesodermal progenitors. Furthermore, BAF45D binding to the NES gene is much more enriched in H9-derived spinal cord NSCs chromatin compared to ESCs chromatin. In addition, BAF45D binding to anterior and trunk/central HOX genes, but not to lumbosacral HOX genes, was much more enriched in NSCs chromatin compared to ESCs chromatin. These results may shed new light on the role of BAF45D in regulating region-specific spinal cord NSCs by targeting HOX genes.

The association of SPARC with hypertension and its function in endothelial-dependent relaxation.

BACKGROUND AND AIMS: Secreted protein acidic and rich in cysteine (SPARC) is involved in the pathological processes of many metabolic diseases. However, studies on the relevance of SPARC to hypertension and its involvement in endothelial function are scarce. In this study, we aim to explore the relevance of SPARC to hypertension and investigate its role in endothelium-dependent relaxation (EDR). METHODS: 110 patients who met the criteria were recruited as participants. Serum SPARC concentrations were determined by Luminex assay. The correlation between SPARC levels and hypertension was analyzed. After treatment with SPARC ex vivo or in vivo, endothelial-dependent relaxation (EDR) was measured by wire myography. Western blotting was performed to detect the expression of proteins relevant to endothelial function. RESULTS: Our results showed that serum SPARC levels were significantly higher in the hypertensive group and were positively associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP). Functional results demonstrated that SPARC dramatically impaired EDR and induced the excess production of reactive oxygen species (ROS) in endothelial cells. Further experimental results confirmed that SPARC reduced angiotensin-converting enzyme 2 (ACE2) expression and ACE2 overexpression or activation completely abolished the impairing effect of SPARC on endothelial function. CONCLUSIONS: The present study reveals the correlation between elevated SPARC and hypertension and confirms its adverse effect on endothelial function, helping establish a comprehensive understanding of hypertension-related endothelial dysfunction in a new scope.

Immunophilin FKB20-2 participates in oligomerization of Photosystem I in Chlamydomonas.

PSI is a sophisticated photosynthesis protein complex that fuels the light reaction of photosynthesis in algae and vascular plants. While the structure and function of PSI have been studied extensively, the dynamic regulation on PSI oligomerization and high light response is less understood. In this work, we characterized a high light-responsive immunophilin gene FKB20-2 (FK506-binding protein 20-2) required for PSI oligomerization and high light tolerance in Chlamydomonas (Chlamydomonas reinhardtii). Biochemical assays and 77-K fluorescence measurement showed that loss of FKB20-2 led to the reduced accumulation of PSI core subunits and abnormal oligomerization of PSI complexes and, particularly, reduced PSI intermediate complexes in fkb20-2. It is noteworthy that the abnormal PSI oligomerization was observed in fkb20-2 even under dark and dim light growth conditions. Coimmunoprecipitation, MS, and yeast 2-hybrid assay revealed that FKB20-2 directly interacted with the low molecular weight PSI subunit PsaG, which might be involved in the dynamic regulation of PSI-light-harvesting complex I supercomplexes. Moreover, abnormal PSI oligomerization caused accelerated photodamage to PSII in fkb20-2 under high light stress. Together, we demonstrated that immunophilin FKB20-2 affects PSI oligomerization probably by interacting with PsaG and plays pivotal roles during Chlamydomonas tolerance to high light.

Outcomes of Upgrading to LBBP in CRT Nonresponders: A Prospective, Multicenter, Nonrandomized, Case-Control Study.

BACKGROUND: Cardiac resynchronization therapy (CRT) nonresponders account for nearly 30% of CRT candidates. Left-bundle branch pacing (LBBP) is an alternative to CRT. OBJECTIVES: This study aimed to evaluate the feasibility, clinical efficacy, and outcomes of upgrading to LBBP in CRT nonresponders, using propensity-score matching (PSM) analysis. METHODS: CRT nonresponders were defined as those with an implantable CRT-pacemaker or CRT-defibrillator for more than 12 months who remained nonresponsive (a decrease in left ventricular end-systolic volume of <15% or a left ventricular ejection fraction [LVEF] absolute increase of <5%) after optimal medical therapy and device optimization compared with baseline. In total, 145 CRT nonresponders were prospectively enrolled and randomly divided into 2 groups: upgraded to LBBP (n = 48), and continuing biventricular pacing (BVP) (control; n = 97). PSM was performed at a 1:1 ratio, and clinical evaluation and echocardiographic assessments were compared at baseline and follow-up in paired cohorts. The primary composite endpoint for clinical outcomes (heart failure-related rehospitalization events, all-cause death, or heart transplantation) was analyzed. RESULTS: Successful upgrading to LBBP was achieved in 48/49 patients (97.96%), with a significant decrease in QRS duration (P < 0.001). In the paired LBBP group, LVEF significantly increased (baseline: 29.75% ± 7.79%; 6 months: 37.78% ± 9.25% [P < 0.001]; 12 months: 38.84% ± 12.13% [P < 0.001]) with 21/44 patients (47.73%) classified as echocardiographically responsive, whereas in the BVP control group, no significant improvement was observed (29.55% ± 6.74% vs 29.22% ± 8.10%; P = 0.840). In a multivariate logistic regression model, LV end-diastolic volume and baseline LBBB QRS morphology were independent predictors of echocardiographic response after upgrading to LBBP. At a median 24 months, the primary composite endpoint was significantly lower in the LBBP group (HR: 0.31; 95% CI: 0.14-0.72; log-rank P = 0.007). CONCLUSIONS: Upgrading to LBBP is feasible and effective in achieving significant heart function improvement and better clinical outcomes in CRT nonresponders, making it a reasonable and promising pacing strategy. (LBBP in CRT Non-Response patients; ChiCTR1900028131).

Network pharmacology integrated with molecular docking technology to reveal the potential mechanism of Shuganfang against drug-induced liver injury.

This study aimed to investigate the active composition and mechanism of the Shuganfang (SGF) in treating drug-induced liver injury (DILI) using network pharmacology and molecular docking. The potential active ingredients and targets of SGF were obtained from the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) database. DILI-related targets were queried from various databases including GEO, GeneCards, OMIM, NCBI, and DisGeNET. The STRING database was used to establish a protein-protein interaction (PPI) network. DAVID was utilized for conducting gene ontology (GO) function enrichment and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses. The data visualization and analysis of herb-ingredient-target and disease-pathway-target-ingredient networks were conducted using Cytoscape software (version 3.7.2). PyMoL and AutoDock software was used to select the best binding target for molecular docking. A total of 177 active ingredients,126 targets and 10112 disease targets were obtained, including 122 intersection targets. The identified potential active ingredients consisted of quercetin, kaempferol, luteolin, tanshinone IIa, nobiletin, isorhamnetin, beta-sitosterol and naringenin. The core targets implicated in the study were IL6, estrogen receptor 1 (ESR1), hypoxia-inducible factor alpha subunit 1 (HIF1A), MYC and vascular endothelial growth factor A (VEGFA). KEGG analysis revealed that the treatment of DILI with SGF mainly acted through apoptosis, the PI3K-Akt signaling pathway, and the tumor necrosis factor (TNF) signaling pathway. Furthermore, the binding affinities between the potential ingredients and the core targets were subsequently confirmed through molecular docking experiments. The findings indicated that the docking outcomes remained consistent and demonstrated a favorable capacity for binding. SGF exerts a therapeutic effect on DILI through multiple active ingredients, multiple targets and multiple pathways. Our findings contribute to a positive investigation and establish a theoretical basis for further extensive exploration of SGF as a potential treatment for DILI in future research.