Exploring the mechanism of Si-Miao-Yong-An decoction on heart failure based on molecular docking and network pharmacology.

The SwissTargetPrediction was employed to predict the potential drug targets of the active component of Si-Miao-Yong-An decoction (SMYAD). The therapeutic targets for HF were searched in the Genecard database, and Cytoscape3.9.1 software was used to construct the "drug-component-target-disease network" diagram. In addition, the String platform was used to construct Protein-Protein Interaction (PPI) network, and the DAVID database was used for GO and KEGG analysis. AutoDockTools-1.5.6 software was used for molecular docking verification. Network pharmacology studies have shown that AKT 1, ALB, and CASP 3 are the key targets of action of SMYAD against heart failure. The active compounds are quercetin and kaempferol.

Artemisinins ameliorate polycystic ovarian syndrome by mediating LONP1-CYP11A1 interaction.

Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic ovaries. Despite its high prevalence, specific pharmacologic intervention for PCOS is challenging. In this study, we identified artemisinins as anti-PCOS agents. Our finding demonstrated the efficacy of artemisinin derivatives in alleviating PCOS symptoms in both rodent models and human patients, curbing hyperandrogenemia through suppression of ovarian androgen synthesis. Artemisinins promoted cytochrome P450 family 11 subfamily A member 1 (CYP11A1) protein degradation to block androgen overproduction. Mechanistically, artemisinins directly targeted lon peptidase 1 (LONP1), enhanced LONP1-CYP11A1 interaction, and facilitated LONP1-catalyzed CYP11A1 degradation. Overexpression of LONP1 replicated the androgen-lowering effect of artemisinins. Our data suggest that artemisinin application is a promising approach for treating PCOS and highlight the crucial role of the LONP1-CYP11A1 interaction in controlling hyperandrogenism and PCOS occurrence.

Neferine inhibits BMECs pyroptosis and maintains blood-brain barrier integrity in ischemic stroke by triggering a cascade reaction of PGC-1α.

Blood-brain barrier disruption is a critical pathological event in the progression of ischemic stroke (IS). Most studies regarding the therapeutic potential of neferine (Nef) on IS have focused on neuroprotective effect. However, whether Nef attenuates BBB disruption during IS is unclear. We here used mice underwent transient middle cerebral artery occlusion (tMCAO) in vivo and bEnd.3 cells exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) injury in vitro to simulate cerebral ischemia. We showed that Nef reduced neurobehavioral dysfunction and protected brain microvascular endothelial cells and BBB integrity. Molecular docking, short interfering (Si) RNA and plasmid transfection results showed us that PGC-1α was the most binding affinity of biological activity protein for Nef. And verification experiments were showed that Nef upregulated PGC-1α expression to reduce mitochondrial oxidative stress and promote TJ proteins expression, further improves the integrity of BBB in mice. Intriguingly, our study showed that neferine is a natural PGC-1α activator and illustrated the mechanism of specific binding site. Furthermore, we have demonstrated Nef reduced mitochondria oxidative damage and ameliorates endothelial inflammation by inhibiting pyroptosis to improve BBB permeability through triggering a cascade reaction of PGC-1α via regulation of PGC-1α/NLRP3/GSDMD signaling pathway to maintain the integrity of BBB in ischemia/reperfusion injury.

The Autophagy-Related Protein ATG8 Orchestrates Asexual Development and AFB1 Biosynthesis in Aspergillus flavus.

Autophagy, a conserved cellular recycling process, plays a crucial role in maintaining homeostasis under stress conditions. It also regulates the development and virulence of numerous filamentous fungi. In this study, we investigated the specific function of ATG8, a reliable autophagic marker, in the opportunistic pathogen Aspergillus flavus. To investigate the role of atg8 in A. flavus, the deletion and complemented mutants of atg8 were generated according to the homologous recombination principle. Deletion of atg8 showed a significant decrease in conidiation, spore germination, and sclerotia formation compared to the WT and atg8C strains. Additionally, aflatoxin production was found severely impaired in the ∆atg8 mutant. The stress assays demonstrated that ATG8 was important for A. flavus response to oxidative stress. The fluorescence microscopy showed increased levels of reactive oxygen species in the ∆atg8 mutant cells, and the transcriptional result also indicated that genes related to the antioxidant system were significantly reduced in the ∆atg8 mutant. We further found that ATG8 participated in regulating the pathogenicity of A. flavus on crop seeds. These results revealed the biological role of ATG8 in A. flavus, which might provide a potential target for the control of A. flavus and AFB1 biosynthesis.

Nitric oxide-mediated regulation of Aspergillus flavus asexual development by targeting TCA cycle and mitochondrial function.

Nitric oxide (NO) is a signaling molecule with diverse roles in various organisms. However, its role in the opportunistic pathogen Aspergillus flavus remains unclear. This study investigates the potential of NO, mediated by metabolites from A. oryzae (AO), as an antifungal strategy against A. flavus. We demonstrated that AO metabolites effectively suppressed A. flavus asexual development, a critical stage in its lifecycle. Transcriptomic analysis revealed that AO metabolites induced NO synthesis genes, leading to increased intracellular NO levels. Reducing intracellular NO content rescued A. flavus spores from germination inhibition caused by AO metabolites. Furthermore, exogenous NO treatment and dysfunction of flavohemoglobin Fhb1, a key NO detoxification enzyme, significantly impaired A. flavus asexual development. RNA-sequencing and metabolomic analyses revealed significant metabolic disruptions within tricarboxylic acid (TCA) cycle upon AO treatment. NO treatment significantly reduced mitochondrial membrane potential (Δψm) and ATP generation. Additionally, aberrant metabolic flux within the TCA cycle was observed upon NO treatment. Further analysis revealed that NO induced S-nitrosylation of five key TCA cycle enzymes. Genetic analysis demonstrated that the S-nitrosylated Aconitase Acon and one subunit of succinate dehydrogenase Sdh2 played crucial roles in A. flavus development by regulating ATP production. This study highlights the potential of NO as a novel antifungal strategy to control A. flavus by compromising its mitochondrial function and energy metabolism.

Widely targeted metabolomics-based analysis of the impact of L. plantarum and L. paracasei fermentation on rosa roxburghii Tratt juice.

Rosa roxburghii Tratt fruits (RRT) exhibit extremely high nutritional and medicinal properties due to its unique phytochemical composition. Probiotic fermentation is a common method of processing fruits. Variations in the non-volatile metabolites and bioactivities of RRT juice caused by different lactobacilli are not well understood. Therefore, we aimed to profile the non-volatile components and investigate the impact of L. plantarum fermentation (LP) and L. paracasei fermentation (LC) on RRT juice (the control, CG). There were both similarities and differences in the effects of LP and LC on RRT juice. Both of the two strains significantly increased the content of total phenolic, total flavonoid, and some bioactive compounds such as 2-hydroxyisocaproic acid, hydroxytyrosol and indole-3-lactic acid in RRT juice. Interestingly, compared with L. paracasei, L. plantarum showed better ability to increase the content of total phenolic and these valuable compounds, as well as certain bioactivities. The antioxidant capacity and α-glucosidase inhibitory activity of RRT juice were notably enhanced after the fermentations, whereas its cholesterol esterase inhibitory activity was reduced significantly. Moreover, a total of 1466 metabolites were identified in the unfermented and fermented RRT juices. There were 278, 251 and 134 differential metabolites in LP vs CG, LC vs CG, LC vs LP, respectively, most of which were upregulated. The key differential metabolites were classified into amino acids and their derivatives, organic acids, nucleotides and their analogues, phenolic acids and alkaloids, which can serve as potential markers for authentication and discrimination between the unfermented and lactobacilli fermented RRT juice samples. The KEGG enrichment analysis uncovered that metabolic pathways, purine metabolism, nucleotide metabolism and ABC transporters contributed mainly to the formation of unique composition of fermented RRT juice. These results provide good coverage of the metabolome of RRT juice in both unfermented and fermented forms and also provide a reference for future research on the processing of RRT or other fruits.

Triterpenoids from Juglans mandshurica with anti-hyaluronidase activities.

Phytochemical study on 90% ethanol extract from the green walnut husks of Juglans mandshurica Maxim. resulted into the isolation of three undescribed triterpenoids, juglansmanoids A-C (1-3). Structural elucidation of all the compounds were performed by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. The isolated components were evaluated in vitro for anti-hyaluronidase activities. As a result, triterpenoid 1 exhibited potent anti-hyaluronidase activity (IC50 = 9.78 µg/ml) three times more than the positive control drug oleanolic acid (IC50 = 40.12 µg/ml).

Endometrial preparation protocols did not impact pregnancy outcomes of patients with cured chronic endometritis.

RESEARCH QUESTION: Do endometrial preparation protocols have an effect on pregnancy outcomes in patients with cured chronic endometritis? DESIGN: A retrospective study was conducted on 3721 infertile patients from December 2018 to August 2020. Endometrial tissues obtained during the proliferative phase were immunostained for CD138. The presence of CD138-positive cells within the stromal cells indicated chronic endometritis. All patients diagnosed with chronic endometritis received oral antibiotics. Patients underwent endometrial preparation and frozen embryo transfer once chronic endometritis was cured. This study compared various endometrial preparation protocols to assess their effects on pregnancy outcomes. Additionally, it aimed to investigate differences in pregnancy outcomes between patients without chronic endometritis and patients with cured chronic endometritis while following the same endometrial preparation protocol. RESULTS: Almost no differences in pregnancy outcomes were observed between natural cycle, hormone replacement therapy (HRT) and gonadotrophin-releasing hormone agonist-HRT (GnRH agonist-HRT) protocols in patients without chronic endometritis and patients with cured chronic endometritis. The only notable difference was that, among women without chronic endometritis, the early miscarriage rate was higher for the GnRH agonist-HRT protocol (25.8%) compared with the natural cycle (17.4%) and HRT (17.7%) protocols (P = 0.025). However, this difference was not significant after adjusting for confounders (adjusted OR 1.383, 95% CI 0.931-2.055). The live birth rate, clinical pregnancy rate, early miscarriage rate, ectopic pregnancy rate and ongoing pregnancy rate did not differ significantly (P > 0.05) between patients without chronic endometritis and patients with cured chronic endometritis who underwent natural cycle, HRT and GnRH agonist-HRT protocols. CONCLUSION: Endometrial preparation protocols had no impact on pregnancy outcomes in patients with cured chronic endometritis.

Prediction of Aureococcus anophageffens using machine learning and deep learning.

The recurrent brown tide phenomenon, attributed to Aureococcus anophagefferens (A. anophagefferens), constitutes a significant threat to the Qinhuangdao sea area in China, leading to pronounced ecological degradation and substantial economic losses. This study utilized machine learning and deep learning techniques to predict A. anophagefferens population density, aiming to elucidate the occurrence mechanism and influencing factors of brown tide. Specifically, Random Forest (RF) algorithm was utilized to impute missing water quality data, facilitating its direct application in subsequent algal population prediction models. The results revealed that all four models-RF, Support Vector Regression (SVR), Multilayer Perceptron (MLP), and Convolutional Neural Network (CNN)-exhibited high accuracy in predicting A. anophagefferens population densities, with R2 values exceeding 0.75. RF, in particular, showed exceptional accuracy and reliability, with an R2 value surpassing 0.8. Additionally, the study ascertained five critical factors influencing A. anophagefferens population density: ammonia nitrogen, pH, total nitrogen, temperature, and silicate.

Irritable bowel syndrome in children: the placebo response rate and influencing factors a meta-analysis.

BACKGROUND: Irritable bowel syndrome is common in children and exhibits a high placebo response. This study was to explore the placebo response rate and its influencing factors in children with irritable bowel syndrome. METHODS: A systematic search was performed on Pubmed, Embase, MEDLINE, Cochrane Library, CNKI, Wanfang, and CBM from database inception to March 2022. Randomized controlled trials of irritable bowel syndrome in children were included in the study. The primary outcome was the placebo response rate of improvement. RESULTS: Thirteen studies were included, with 445 patients in the placebo group. The rate of improvement and abdominal pain disappearance were 28.2% (95% CI, 16.6-39.9%) and 5% (95% CI, 0-18.4%). The placebo response based on the abdominal pain score was 0.675 (95% CI, 0.203-1.147). The mode of administration (P < 0.01), dosing schedule (P < 0.01), and clinical outcome assessor (P = 0.04) have a significant impact on the magnitude of placebo effect. CONCLUSIONS: The placebo response rate for pediatric irritable bowel syndrome was 28.2%. In clinical trials, reducing dosing frequency, selecting appropriate dosage forms, and using patient-reported outcomes can help mitigate the placebo effect. IMPACT: This is the first meta-analysis to assess the placebo response rates for improvement and disappearance in children with IBS. The finding suggested that the mode of administration, dosing schedule, and clinical outcome assessor could potentially influence the magnitude of the placebo effect in children with IBS. This study would provide a basis for estimating sample size in clinical trial design with a placebo control.

Ultrasonically functionalized chitosan-gallic acid films inactivate Staphylococcus aureus through envelope-disruption under UVA light exposure.

The significant threat of foodborne pathogens contamination has continuously promoted the development of efficient antimicrobial food packaging materials. Here, an antimicrobial film was prepared with gallic acid-grafted-chitosan (CS/GA) that obtained by a two-step ultrasound method. The resultant films exhibited good transparency, improved UV barrier performance, and enhanced mechanical strength. Specifically, with the grafting of 1.2 % GA, the UV blocking ability of CS/GA film at 400 nm was significantly increased by 19.7 % and the tensile strength was nearly two times higher than that of CS film. Moreover, the CS/GA films exhibited an inspiring photoactivated bactericidal ability under 400 nm UVA light irradiation that eradicated almost 99.9 % of Staphylococcus aureus (S. aureus) cells within 60 min. To gain more insights into the antibacterial mechanism, the treated S. aureus cells were further investigated by visualizing bacterial ultrastructure and analyzing membrane properties. The results pointed to the peptidoglycan layer as the primary action target when bacteria come into contact with CS/GA films. Afterward, the intracellular oxidative lesions, disrupted bacterial integrity, and disordered membrane functional properties collectively resulted in eventual cell death. The findings revealed the unique peptidoglycan targeting and membrane disruptive mechanisms of CS/GA films, confirming the application values in controlling foodborne pathogens.

Mechanism of Rhodiola rosea-Euonymus alatus drug pair against rheumatoid arthritis: Network pharmacology and experimental validation.

PURPOSE: The present study aimed to explore the potential components and mechanisms of Rhodiola rosea-Euonymus alatus drug pair (TY) that ameliorate rheumatoid arthritis (RA). METHODS: The main active components, core targets, and important pathways of TY against RA were predicted by network pharmacology analysis. The binding activity between the main active components and the core targets was verified by the molecular docking technique. Collagen-induced arthritis (CIA) rat model and tumor necrosis factor (TNF)-α-induced fibroblast-like synovial cells in human RA (HFLS-RA) model were established, respectively. The core targets were verified by cell counting kit-8 assay, hematoxylin eosin, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and Western blot analysis, and the therapeutic effect of TY was evaluated. RESULTS: A total of 18 possible components and 34 core targets were obtained by network pharmacology, among which inflammatory response, phosphatidylinositide 3-kinases (PI3K)-AKT and MAPK pathways were involved in the therapeutic effect of TY on RA. The results of molecular docking showed that kaempferol and quercetin had high binding affinity to interleukin (IL)-1ß, IL-6, matrix metalloproteinase (MMP)9, and TNF-α. In vivo and in vitro experiments showed that TY dose-dependently inhibited the proliferation of HFLS-RA cells induced by TNF-α, and significantly reduced the paw swelling and arthritis scores in CIA rats. At the same time, TY inhibited the production of inflammatory factors in CIA rat serum and TNF-α-induced HFLS-RA cells. It also decreased the expression of PI3K, phospho-protein kinase B, MMP1, MMP3, MMP9, and increased the protein and mRNA levels of tissue inhibitors of MMPs (TIMP)1 in synovial tissue. CONCLUSION: TY can inhibit the PI3K/AKT signaling pathway and regulate the balance between MMPs and TIMP, thus playing a therapeutic role in RA.

Prognosis and Prediction of Asymptomatic Intracranial Hemorrhage After Endovascular Thrombectomy: A Multi-Center Study.

PURPOSE: The impact of asymptomatic intracranial hemorrhage (aICH) on functional outcomes after endovascular thrombectomy (EVT) remains unclear, and tools for forecasting this complication are lacking. We aim to evaluate the clinical relevance of aICH and establish a prediction model. METHODS: Data of patients who received EVT for acute anterior-circulation large vessel occlusion in 3 comprehensive hospitals were retrospectively analyzed. Asymptomatic intracranial hemorrhage was defined as any hemorrhage detected after EVT that did not fulfill the definition of symptomatic intracranial hemorrhage in the European Cooperative Acute Stroke Study. Logistic regression models were performed to assess the impact of aICH on 90-day functional outcomes and identify the predictors of aICH, which were then used to establish a prediction model. The discrimination, calibration, and clinical utility of the model were evaluated. RESULTS: This study included 460 patients, among whom 152 (33.0%) developed aICH after EVT. Asymptomatic intracranial hemorrhage was negatively associated with 90-day excellent outcomes (adjusted odds ratio [OR]: 0.414, 95% confidence interval [CI]: 0.230-0.745, p=0.003) and good outcome (adjusted OR: 0.603, 95% CI: 0.374-0.971, p=0.037), but not with mortality (adjusted OR: 1.110, 95% CI: 0.611-2.017, p=0.732) after adjusted for other predictors of functional outcome. Pre-stroke anticoagulant therapy (OR: 2.233, 95% CI: 1.073-4.647, p=0.032), Alberta stroke program early CT score (OR: 0.842, 95% CI: 0.754-0.939, p=0.002), site of occlusion (internal carotid artery occlusion as the reference; M1 segment of middle cerebral artery occlusion, OR: 2.827, 95% CI: 1.409-5.674, p=0.003; tandem occlusion, OR: 3.928, 95% CI: 1.752-8.806, p=0.001), intravenous thrombolysis (OR: 2.091, 95% CI: 1.362-3.209, p=0.001), and successful recanalization (OR: 0.383, 95% CI: 0.213-0.689, p=0.001) were identified as the predictors of aICH, which were incorporated into a nomogram model. The area under the receiver operating characteristic curve of the model was 0.707 (95% CI: 0.657-0.757), and the calibration plot demonstrated good consistency between actual observed and predicted probability of aICH. Decision curve analysis showed that patients might benefit from the model. CONCLUSION: Asymptomatic intracranial hemorrhage was negatively associated with favorable functional outcome after EVT. We established a nomogram model for predicting aICH, which requires external clinical validation. CLINICAL IMPACT: The impact of asymptomatic intracranial hemorrhage after endovascular thrombectomy on mid-term functional outcome has been controversial. We found that asymptomatic intracranial hemorrhage may also decreased the likelihood of 90-day favourable functional outcome after endovascular thrombectomy, supporting the notion that asymptomatic intracranial hemorrhage at the acute stage may not be benign. Moreover, we established a prediction model for this complication, which may improve clinical evaluation and management of patients who would receive endovascular thrombectomy for large vessel occlusion.

A Hydrolase Produced by Rhodococcus erythropolis HQ Is Responsible for the Detoxification of Zearalenone.

Zearalenone (ZEN), an estrogenic mycotoxin, is one of the prevalent contaminants found in food and feed, posing risks to human and animal health. In this study, we isolated a ZEN-degrading strain from soil and identified it as Rhodococcus erythropolis HQ. Analysis of degradation products clarified the mechanism by which R. erythropolis HQ degrades ZEN. The gene zenR responsible for degrading ZEN was identified from strain HQ, in which zenR is the key gene for R. erythropolis HQ to degrade ZEN, and its expression product is a hydrolase named ZenR. ZenR shared 58% sequence identity with the hydrolase ZenH from Aeromicrobium sp. HA, but their enzymatic properties were significantly different. ZenR exhibited maximal enzymatic activity at pH 8.0-9.0 and 55 °C, with a Michaelis constant of 21.14 µM, and its enzymatic activity is 2.8 times that of ZenH. The catalytic triad was identified as S132-D157-H307 via molecular docking and site-directed mutagenesis. Furthermore, the fermentation broth of recombinant Bacillus containing ZenR can be effectively applied to liquefied corn samples, with the residual amount of ZEN decreased to 0.21 µg/g, resulting in a remarkable ZEN removal rate of 93%. Thus, ZenR may serve as a new template for the modification of ZEN hydrolases and a new resource for the industrial application of biological detoxification. Consequently, ZenR could potentially be regarded as a novel blueprint for modifying ZEN hydrolases and as a fresh resource for the industrial implementation of biological detoxification.

Congenital leukemia: A case report and review of literature.

BACKGROUND: Acute leukemia in newborns is also known as neonatal or congenital leukemia (CL) and is a rare disease with an incidence rate of 1-5 per 1000000 live births. After birth, infants with CL exhibit infiltrative cutaneous nodules, hepatosplenomegaly, thrombocytopenia, and immature leukocytes in the peripheral blood. These symptoms are frequently accompanied by congenital abnormalities including trisomy 21, trisomy 9, trisomy 13, or Turner syndrome. Despite significant advances in disease management, the survival rate is approximately 25% at 2 years. CASE SUMMARY: Here, we document a case of trisomy 21-related acute myeloid leukemia (AML) in a female neonate. The baby was sent to the neonatal intensive care unit because of anorexia, poor responsiveness, and respiratory distress. She was diagnosed with AML based on bone marrow aspiration and immunophenotyping. Genetic sequencing identified a mutation in the GATA1 gene. After receiving the diagnosis, the parents decided against medical care for their child, and the baby died at home on day 9 after birth. CONCLUSIONS: The newborn infant was diagnosed with trisomy 21-related AML. Genetic sequencing identified a mutation in the GATA1 gene. The parents abandoned medical treatment for their infant after receiving the diagnosis, and the infant died at home on the 9th day after birth.

Case report: Retrograde endovascular recanalization of vertebral artery occlusion with non-tapered stump via the deep cervical collateral.

Introduction: Vertebral artery (VA) occlusive disease is the major cause of posterior circulation ischemic stroke. Endovascular recanalization has been reported as a feasible treatment for patients with symptomatic VA occlusion refractory to optimal medical therapy. However, VA occlusion with non-tapered stump exhibits a low technique success rate when treated by antegrade endovascular therapy because of increased difficulty in passing the guidewire into the occluded segment. Herein, we presented a novel endovascular approach to recanalize chronically occluded VA with a non-tapered stump using a retrograde method via the deep cervical collateral, which has not been reported before. Case presentation: The present case was a patient with VA ostial occlusion with non-tapered stump and distal severe stenosis of the left VA who had recurrent posterior circulation transit ischemic attacks under optimal medical therapy. CT angiography demonstrated proximal non-tapered occlusion and distal severe stenosis of the left VA, and that the right VA did not converge with the left VA into basilar artery. Endovascular treatment was recommended and performed on this patient. However, antegrade endovascular recanalization of the left VA origin occlusion failed because the micro guidewire was unable to traverse the occluded segment. Fortunately, robust collateral from the deep cervical artery to the V3 segment of the left VA developed, in which we advanced the micro guidewire to the V3 segment of the left VA and reversely passed the micro guidewire through the occluded segment. Then, the occlusion and stenosis of the left VA were successfully resolved with angioplasty and stenting. After the procedure, the patient reported no neurological symptoms under medical therapy during 3-month follow-up. Conclusion: Antegrade endovascular recanalization of VA occlusion with a non-tapered stump is a challenge. The retrograde endovascular method via the cervical collateral may be an alternative for this type of VA occlusion, which requires further exploration.

Efficient exon skipping by base-editor-mediated abrogation of exonic splicing enhancers.

Duchenne muscular dystrophy (DMD) is a severe genetic disease caused by the loss of the dystrophin protein. Exon skipping is a promising strategy to treat DMD by restoring truncated dystrophin. Here, we demonstrate that base editors (e.g., targeted AID-mediated mutagenesis [TAM]) are able to efficiently induce exon skipping by disrupting functional redundant exonic splicing enhancers (ESEs). By developing an unbiased and high-throughput screening to interrogate exonic sequences, we successfully identify novel ESEs in DMD exons 51 and 53. TAM-CBE (cytidine base editor) induces near-complete skipping of the respective exons by targeting these ESEs in patients' induced pluripotent stem cell (iPSC)-derived cardiomyocytes. Combined with strategies to disrupt splice sites, we identify suitable single guide RNAs (sgRNAs) with TAM-CBE to efficiently skip most DMD hotspot exons without substantial double-stranded breaks. Our study thus expands the repertoire of potential targets for CBE-mediated exon skipping in treating DMD and other RNA mis-splicing diseases.

Estimating the individual singleton preterm birth risk: nomogram establishment and independent validation.

Background: To establish and independently validate nomograms for predicting singleton preterm birth (PTB) risk based on a large sample size comprising data from two independent datasets. Methods: This cohort study used data from 50 states and the District of Columbia in the National Vital Statistics System (NVSS) database between January 2016 and December 2020. Multivariate logistic regression analysis was used to confirm the independent risk factors for PTB. Statistically significant variables were incorporated into the logistic regression models to establish PTB prediction nomograms. The models were developed using the United States (US)-derived data and were independently validated using data from US Territories. Results: A total of 16,294,529 mother-newborn pairs from the US were included in the training set, and 54,708 mother-newborn pairs from the US Territories were included in the validation set. In all, 4 nomograms were built: 1 to predict PTB probability, and another 3 to predict moderately and late PTB probability, very PTB probability, and extremely PTB probability, respectively. Hypertensive eclampsia and infertility treatment were found to be the top 2 contributors to PTB. Conclusions: We developed and validated nomograms to predict the individualized probability of PTB, which could be useful to physicians for improved early identification of PTB and in making individualized clinical decisions.

Cytokine and chemokine map of peripheral specific immune cell subsets in Parkinson's disease.

Peripheral immune cells play a vital role in the development of Parkinson's disease (PD). However, their cytokine and chemokine secretion functions remain unclear. Therefore, we aimed to explore the cytokine and chemokine secretion functions of specific immune cell subtypes in drug-naïve patients with PD at different ages of onset. We included 10 early-onset and 10 late-onset patients with PD and age-matched healthy controls (HCs). We used mass cytometry to select specific immune cell subsets and evaluate intracellular cytokine and chemokine expression. Statistical tests included t-tests, analysis of variance, bivariate correlation analysis, and linear regression analysis. Compared with HCs, patients with PD exhibited significantly decreased intracellular pro-inflammatory cytokines and chemokines in selected clusters (e.g., tumor necrosis factor (TNF)-α, interleukin (IL)-8, IL-1ß, and CC-chemokine ligand (CCL)17). Specific cytokines and cell clusters were associated with clinical symptoms. TNF-α played an important role in cognitive impairment. Intracellular TNF-α levels in the naïve CD8+ T-cell cluster C16 (CD57- naïve CD8+ T) and natural killer (NK) cell cluster C32 (CD57- CD28- NK) were negatively correlated with Montreal Cognitive Assessment scores. The C16 cluster affected cognitive function and motor symptoms. Increased TNF-α and decreased interferon-γ expression in C16 correlated with increased Unified Parkinson's Disease Rating Scale III scores in patients with PD. In summary, we developed a more detailed cytokine and chemokine map of peripheral specific CD8+ T cell and NK cell subsets, which revealed disrupted secretory function in patients with PD and provided unique clues for further mechanistic exploration.

Obesity-induced inflammatory miR-133a mediates apoptosis of granulosa cells and causes abnormal folliculogenesis.

Obesity has been reported to promote disordered folliculogenesis, but the exact molecular mechanisms are still not fully understood. In this study, we find that miR-133a is involved in obesity-induced follicular development disorder. After feeding with a high-fat diet (HFD) and fructose water for nine weeks, the mouse body weight is significantly increased, accompanied by an inflammatory state and increased expression of miR-133a in the adipose tissues and ovaries as well as accelerated follicle depletion. Although miR-133a is increased in the fat and ovaries of HFD mice, the increased miR-133a in the HFD ovaries is not derived from exosome transferred from obese adipose tissues but is synthesized by ovarian follicular cells in response to HFD-induced inflammation. In vivo experiments show that intrabursal injection of miR-133a agomir induces a decrease in primordial follicles and an increase in antral follicles and atretic follicles, which is similar to HFD-induced abnormal folliculogenesis. Overexpression of miR-133a modestly promotes granulosa cell apoptosis by balancing the expression of anti-apoptotic proteins such as C1QL1 and XIAP and pro-apoptotic proteins such as PTEN. Overall, this study reveals the function of miR-133a in obesity-induced ovarian folliculogenesis dysfunction and sheds light on the etiology of female reproductive disorders.