Preparation and Reactivity of Core-Shell Al@CL-20 Composites Embedded with Graphene-Based Complexes as Catalysts.

Incomplete combustion of Al in solid propellants can be effectively resolved by coating of an oxidizer at the microscale. In this paper, Al@CL-20 composites with polydopamine as the interfacial layer were prepared using this strategy. The structure, heat of reaction, thermal decomposition properties, and combustion performances of these composites under the effects of graphene oxide (GO) and graphene-based carbohydrazide complexes (GO-CHZ-M, M = Co2+, Ni2+) have been comprehensively investigated. The experimental results show that the heat of reaction of Al@CL-20 is 6482 J g-1, which is 561 J g-1 higher than that of the corresponding mechanical mixture. The presence of GO-CHZ-Co can further increase the heat of reaction of Al@CL-20 to 6729 J g-1 with a decreased activation energy by about 54.8%. Under the synergistic effect of interfacial control and GO-CHZ-M, the ignition delay time of Al@CL-20-Co decreases from 5.1 to 4.2 ms. Besides, the D50 of the combustion condensed products (CCPs) decreased from 5.62 to 4.33 µm, indicating the combustion efficiency of Al is greatly improved.

Gas6/AXL Alleviates Hepatic Ischemia/Reperfusion Injury by Inhibiting Ferroptosis via the PI3K/AKT Pathway.

BACKGROUND: Hepatic ischemia/reperfusion (I/R) injury is a major cause of complications in clinical liver surgery. AXL receptor tyrosine kinase (AXL) is a member of the TAM receptor tyrosine kinase family (TYRO3, AXL, and MERTK). Our previous study has shown that AXL expression was markedly upregulated in liver transplantation patients. However, the underlying mechanism of AXL in hepatic I/R injury remains unclear. METHODS: A mouse liver warm I/R model and a primary hepatocyte hypoxia/reoxygenation model were established to investigate the role of AXL activation and ferroptosis in hepatic I/R injury by pretreating with recombinant mouse growth arrest-specific protein 6 (AXL activator) or R428 (AXL inhibitor). Moreover, we used LY294002 (phosphatidylinositol 3-kinase [PI3K] inhibitor) to evaluate the relationship between the PI3K/AKT (the Ser and Thr kinase AKT) pathway and ferroptosis in hepatic I/R injury. RESULTS: Hepatic I/R injury decreased phosphorylation AXL expression and enhanced ferroptosis in liver transplantation patients and hepatic I/R-subjected mice. AXL activation attenuated lipid peroxidation and ferroptosis in hepatic I/R injury in vivo and in vitro. Inhibition of AXL activation exacerbated liver pathological damage and liver dysfunction, as well as iron accumulation and lipid peroxidation in hepatic I/R injury. Mechanistically, activated growth arrest-specific protein 6/AXL and its downstream PI3K/AKT signaling pathway inhibited ferroptosis during hepatic I/R injury. CONCLUSIONS: AXL activation protects against hepatic I/R injury by preventing ferroptosis through the PI3K/AKT pathway. This study is the first investigation on the AXL receptor and ferroptosis, and activating AXL to mitigate ferroptosis may be an innovative therapeutic strategy to combat hepatic I/R injury.

Identification and validation of oxidative stress-related genes in sepsis-induced myopathy.

BACKGROUND: Sepsis-induced myopathy (SIM) a complication of sepsis that results in prolonged mechanical ventilation, long-term functional disability, and increased patient mortality. This study was performed to identify potential key oxidative stress-related genes (OS-genes) as biomarkers for the diagnosis of SIM using bioinformatics. METHODS: The GSE13205 was obtained from the Gene Expression Omnibus (GEO) database, including 13 SIM samples and 8 healthy samples, and the differentially expressed genes (DEGs) were identified by limma package in R language. Simultaneously, we searched for the genes related to oxidative stress in the Gene Ontology (GO) database. The intersection of the genes selected from the GO database and the genes from the GSE13205 was considered as OS-genes of SIM, where the differential genes were regarded as OS-DEGs. OS-DEGs were analyzed using GO enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and protein-protein interaction (PPI) networks. Hub genes in OS-DEGs were selected based on degree, and diagnostic genes were further screened by gene expression and receiver operating characteristic (ROC) curve. Finally, a miRNA-gene network of diagnostic genes was constructed. RESULTS: A total of 1089 DEGs were screened from the GSE13205, and 453 OS-genes were identified from the GO database. The overlapping DEGs and OS-genes constituted 25 OS-DEGs, including 15 significantly upregulated and 10 significantly downregulated genes. The top 10 hub genes, including CD36, GPX3, NQO1, GSR, TP53, IDH1, BCL2, HMOX1, JAK2, and FOXO1, were screened. Furthermore, 5 diagnostic genes were identified: CD36, GPX3, NQO1, GSR, and TP53. The ROC analysis showed that the respective area under the curves (AUCs) of CD36, GPX3, NQO1, GSR, and TP53 were 0.990, 0.981, 0.971, 0.971, and 0.971, which meant these genes had very high diagnostic values of SIM. Finally, based on these 5 diagnostic genes, we found that miR-124-3p and miR-16-5p may be potential targets for the treatment of SIM. CONCLUSIONS: The results of this study suggest that OS-genes might play an important role in SIM. CD36, GPX3, NQO1, GSR, and TP53 have potential as specific biomarkers for the diagnosis of SIM.

Topological disruption of low- and high-order functional networks in presbycusis.

Prior efforts have manifested that functional connectivity (FC) network disruptions are concerned with cognitive disorder in presbycusis. The present research was designed to investigate the topological reorganization and classification performance of low-order functional connectivity (LOFC) and high-order functional connectivity (HOFC) networks in patients with presbycusis. Resting-state functional magnetic resonance imaging (Rs-fMRI) data were obtained in 60 patients with presbycusis and 50 matched healthy control subjects (HCs). LOFC and HOFC networks were then constructed, and the topological metrics obtained from the constructed networks were compared to evaluate topological differences in global, nodal network metrics, modularity and rich-club organization between patients with presbycusis and HCs. The use of HOFC profiles boosted presbycusis classification accuracy, sensitivity and specificity compared to that using LOFC profiles. The brain networks in both patients with presbycusis and HCs exhibited small-world properties within the given threshold range, and striking differences between groups in topological metrics were discovered in the constructed networks (LOFC and HOFC). NBS analysis identified a subnetwork involving 26 nodes and 23 signally altered internodal connections in patients with presbycusis in comparison to HCs in HOFC networks. This study highlighted the topological differences between LOFC and HOFC networks in patients with presbycusis, suggesting that HOFC profiles may help to further identify brain network abnormalities in presbycusis.

NUP85 alleviates lipid metabolism and inflammation by regulating PI3K/AKT signaling pathway in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the common causes of chronic liver disease in the world. The problem of NAFLD had become increasingly prominent. However, its pathogenesis is still indistinct. As we all know, NAFLD begins with the accumulation of triglyceride (TG), leading to fatty degeneration, inflammation and other liver tissues damage. Notably, structure of nucleoporin 85 (NUP85) is related to lipid metabolism and inflammation of liver diseases. In this study, the results of researches indicated that NUP85 played a critical role in NAFLD. Firstly, the expression level of NUP85 in methionine-choline-deficient (MCD)-induced mice increased distinctly, as well as the levels of fat disorder and inflammation. On the contrary, knockdown of NUP85 had the opposite effects. In vitro, AML-12 cells were stimulated with 2 mm free fatty acids (FFA) for 24 h. Results also proved that NUP85 significantly increased in model group, and increased lipid accumulation and inflammation level. Besides, NUP85 protein could interact with C-C motif chemokine receptor 2 (CCR2). Furthermore, when NUP85 protein expressed at an extremely low level, the expression level of CCR2 protein also decreased, accompanied with an inhibition of phosphorylation of phosphoinositol-3 kinase (PI3K)-protein kinase B (AKT) signaling pathway. What is more, trans isomer (ISRIB), a targeted inhibitor of NUP85, could alleviate NAFLD. In summary, our findings suggested that NUP85 functions as an important regulator in NAFLD through modulation of CCR2.

A preliminary exploration of the regression equation for performance in amateur half-marathon runners: a perspective based on respiratory muscle function.

This document presents a study on the relationship between physical characteristics, respiratory muscle capacity, and performance in amateur half-marathon runners. The aim of this study was to establish a preliminary predictive model to provide insights into training and health management for runners. Participants were recruited from the 2023 Beijing Olympic Forest Park Half-Marathon, comprising 233 individuals. Personal information including age, gender, height, weight, and other relevant factors were collected, and standardized testing methods were used to measure various parameters. Correlation analysis revealed significant associations between gender, height, weight, maximum expiratory pressure, maximal inspiratory pressure, and half-marathon performance. Several regression equations were developed to estimate the performance of amateur marathon runners, with a focus on gender, weight, maximum expiratory pressure, and height as predictive factors. The study found that respiratory muscle training can delay muscle fatigue and improve athletic performance. Evaluating the level of respiratory muscle capacity in marathon athletes is crucial for defining the potential speed limitations and achieving optimal performance. The information from this study can assist amateur runners in optimizing their training methods and maintaining their physical wellbeing.

Long-term prognosis of patients with gallbladder carcinoma after curative-intent resection based on changes in the ratio of carbohydrate antigen 19-9 to total bilirubin (CA19-9/TB): a multicenter retrospective cohort study.

BACKGROUND: The prognostic value of carbohydrate antigen 19-9 (CA19-9) is known to be affected by elevated bilirubin levels in patients with gallbladder carcinoma (GBC). The clinical significance of changes in the ratio of CA19-9 levels to total bilirubin (TB) levels in patients with GBC after curative-intent resection remains unknown. The aim of this study was to determine the prognostic value of changes in preoperative and postoperative CA19-9/TB ratio in these patients. METHODS: Prospectively colleced data on consecutive patients who underwent curative-intent resection for GBC between January 2015 and December 2020 stored in a multicenter database from 10 hospitals were analysed in this retrospective cohort study. Based on the adjusted CA19-9 defined as the ratio of CA19-9 to TB, and using 2×103 U/µmol as the upper normal value, patients were divided into a normal group (with normal preoperative and postoperative adjusted CA19-9), a normalization group (with abnormal preoperative but normal postoperative adjusted CA19-9), and a non-normalization group (with abnormal postoperative adjusted CA19-9). The primary outcomes were overall survival (OS) and recurrence-free survival (RFS). The log-rank test was used to compare OS and RFS among the groups. The Cox regression model was used to determine factors independently associated with OS and RFS. RESULTS: The normal group (n=179 patients) and the normalization group (n=73 patients) had better OS and RFS than the non-normalization group (n=65 patients) (the 3-year OS rates 72.0%, 58.4% and 24.2%, respectively; the RFS rates 54.5%, 25.5% and 11.8%, respectively; both P<0.001). There were no significant differences between the normal and the normalization groups in OS and RFS (OS, P=0.255; RFS, P=0.130). Cox regression analysis confirmed that the non-normalization group was independently associated with worse OS and RFS. Subgroup analysis revealed that the non-normalization group of patients who received adjuvant therapy had significantly improved OS and RFS as compared to those who did not receive adjuvant therapy (OS, P=0.025; RFS, P=0.003). CONCLUSIONS: Patients with GBC who underwent curative-intent surgical resection with postoperative abnormal levels of adjusted CA19-9 (the CA19-9/TB ratio) were associated with poorer long-term survival outcomes. Adjuvant therapy after surgery improved the long-term outcomes of these patients.

Endoplasmic reticulum stress and death receptor-mediated apoptosis in the neuronal differentiation of adult adipose-derived stromal cells.

Apoptosis is the primary cause of cell death in the differentiation of Adipose-derived stromal cells (ADSCs) into neurons. However, the relationship between endoplasmic reticulum stress (ERS) and death receptor-mediated apoptosis in ADSC-induced neuronal differentiation is not clear. ADSCs were isolated and induced to differentiate into neurons using ß-mercaptoethanol. The expression of neuron-specific enolase (NSE), GRP94, CHOP, Fas/FasL, TNFR1/TNF-α, DR5/TRAIL, Caspase8, and Caspase3 in ADSCs was examined using immunocytochemistry and Western blotting before induction, during pre-induction, and after induction. Transmission electron microscopy (TEM) was used to observe changes in the morphology of the endoplasmic reticulum (ER), and the MTT assay was employed to measure cell viability in the uninduced and induced groups. Additionally, the number of apoptotic cells during the induction process was measured using flow cytometry with Annexin V/PI. With increasing induction time, the positive expression rates of CHOP, Fas/FasL, Caspase8, Caspase-3, and NSE gradually increased, while the positive expression rate of GRP94 decreased. TNFR1/TNF-α and DR5/TRAIL peaked at 5 h post-induction and then decreased at 8 h. TEM revealed swelling and expansion of the ER, vacuolar changes, and degranulation in cells. The MTT assay showed a gradual decrease in the absorbance of surviving cells in all groups. Flow cytometry indicated an increasing rate of apoptosis in cells. Therefore, ERS in the normal culture and growth of ADSCs, manifesting as enhanced unfolded protein response (UPR), maintains the normal survival of ADSCs. However, in the process of ADSC-induced differentiation into neurons, ERS and death receptor-mediated apoptosis are significant causes of cell death.

Danggui Sini decoction alleviates oxaliplatin-induced peripheral neuropathy by regulating gut microbiota and potentially relieving neuroinflammation related metabolic disorder.

BACKGROUND: Danggui Sini decoction (DSD), a traditional Chinese medicine formula, has the function of nourishing blood, warming meridians, and unblocking collaterals. Our clinical and animal studies had shown that DSD can effectively protect against oxaliplatin (OXA)-induced peripheral neuropathy (OIPN), but the detailed mechanisms remain uncertain. Multiple studies have confirmed that gut microbiota plays a crucial role in the development of OIPN. In this study, the potential mechanism of protective effect of DSD against OIPN by regulating gut microbiota was investigated. METHODS: The neuroprotective effects of DSD against OIPN were examined on a rat model of OIPN by determining mechanical allodynia, biological features of dorsal root ganglia (DRG) as well as proinflammatory indicators. Gut microbiota dysbiosis was characterized using 16S rDNA gene sequencing and metabolism disorders were evaluated using untargeted and targeted metabolomics. Moreover the gut microbiota mediated mechanisms were validated by antibiotic intervention and fecal microbiota transplantation. RESULTS: DSD treatment significantly alleviated OIPN symptoms by relieving mechanical allodynia, preserving DRG integrity and reducing proinflammatory indicators lipopolysaccharide (LPS), IL-6 and TNF-α. Besides, DSD restored OXA induced intestinal barrier disruption, gut microbiota dysbiosis as well as systemic metabolic disorders. Correlation analysis revealed that DSD increased bacterial genera such as Faecalibaculum, Allobaculum, Dubosiella and Rhodospirillales_unclassified were closely associated with neuroinflammation related metabolites, including positively with short-chain fatty acids (SCFAs) and sphingomyelin (d18:1/16:0), and negatively with pi-methylimidazoleacetic acid, L-glutamine and homovanillic acid. Meanwhile, antibiotic intervention apparently relieved OIPN symptoms. Furthermore, fecal microbiota transplantation further confirmed the mediated effects of gut microbiota. CONCLUSION: DSD alleviates OIPN by regulating gut microbiota and potentially relieving neuroinflammation related metabolic disorder.

Functional modification of recombinant brain-derived neurotrophic factor and its protective effect against neurotoxicity.

Brain-derived neurotrophic factor (BDNF) is a neurotrophic protein that promotes neuronal survival, increases neurotransmitter synthesis, and has potential therapeutic effects in neurodegenerative and psychiatric diseases, but its drug development has been limited by the fact that recombinant proteins of BDNF are unstable and do not penetrate the blood-brain barrier (BBB). In this study, we fused a TAT membrane-penetrating peptide with BDNF to express a recombinant protein (TBDNF), which was then PEG-modified to P-TBDNF. Protein characterization showed that P-TBDNF significantly improved the stability of the recombinant protein and possessed the ability to penetrate the BBB, and in cellular experiments, P-TBDNF prevented MPTP-induced nerve cell oxidative stress damage, apoptosis and inflammatory response, and its mechanism of action was closely related to the activation of tyrosine kinase B (TrkB) receptor and inhibition of microglia activation. In animal experiments, P-TBDNF improved motor and cognitive deficits in MPTP mice and inhibited pathological changes in Parkinson's disease (PD). In conclusion, this paper is expected to reveal the mechanism of action of P-TBDNF in inhibiting neurotoxicity, provide a new way for treating PD, and lay the foundation for the future development of recombinant P-TBDNF.

Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial.

BACKGROUND: DESTINY-Lung01 is a multicentre, open-label, phase 2 study evaluating the antitumour activity and safety of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpressing or HER2 (ERBB2)-mutant unresectable or metastatic non-small-cell lung cancer (NSCLC). The results of the HER2-mutant cohort (cohort 2) have been reported elsewhere. Herein, we report the primary analysis of cohorts 1 and 1A, which aimed to evaluate the activity and safety of trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg in patients with HER2-overexpressing NSCLC. METHODS: Patients aged 18 years or older with unresectable or metastatic (or both unresectable and metastatic) non-squamous NSCLC who had relapsed following or were refractory to standard treatment or for whom no standard treatment was available, with an HER2 immunohistochemistry score of 3+ or 2+ (without known HER2 mutations) and an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled at 20 specialist hospitals in France, Japan, the Netherlands, Spain, and the USA. Patients were assigned to cohorts sequentially, first to cohort 1, to receive trastuzumab deruxtecan 6·4 mg/kg (cohort 1), then to cohort 1A, to receive trastuzumab deruxtecan 5·4 mg/kg, both administered intravenously once every 3 weeks. The primary endpoint was confirmed objective response rate by independent central review and was assessed in the full analysis set, which included all patients who signed an informed consent form and were enrolled in the study. Safety was assessed in all enrolled patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT03505710, and is ongoing (closed to recruitment). FINDINGS: Between Aug 27, 2018, and Jan 28, 2020, 49 patients were enrolled in cohort 1 (median age 63·0 years [IQR 58·0-68·0], 30 [61%] male, 19 [39%] female, and 31 [63%] White), and from June 16 to Dec 9, 2020, 41 patients were enrolled in cohort 1A (median age 62·0 years [IQR 56·0-66·0], 22 [54%] male, 19 [46%] female, and 31 [76%] White). As of data cutoff (Dec 3, 2021), the median treatment duration was 4·1 months (IQR 1·4-7·1) in cohort 1 and 5·5 months (1·4-8·7) in cohort 1A, and median follow-up was 12·0 months (5·4-22·4) in cohort 1 and 10·6 months (4·5-13·5) in cohort 1A. Confirmed objective response rate by independent central review was 26·5% (95% CI 15·0-41·1; 13 of 49, all partial responses) in cohort 1 and 34·1% (20·1-50·6; 14 of 41; two complete responses and 12 partial responses) in cohort 1A. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (12 [24%] of 49 in cohort 1, none in cohort 1A), pneumonia (six [12%] and two [5%], respectively), fatigue (six [12%] and three [7%], respectively), and disease progression (six [12%] and four [10%], respectively). Drug-related treatment-emergent adverse events of grade 3 or worse occurred in 26 (53%) of 41 patients in cohort 1 and nine (22%) of 49 patients in cohort 1A. Drug-related serious adverse events were reported in ten (20%) patients and three (7%) patients, respectively. Deaths due to treatment-emergent adverse events occurred in ten (20%) patients in cohort 1 (disease progression in six (12%) patients and bronchospasm, hydrocephalus, respiratory failure, and pneumonitis in one [2%] patient each), and in seven (17%) patients in cohort 1A (due to disease progression in four (10%) patients and dyspnoea, malignant neoplasm, and sepsis in one (2%) patient each). One death due to a treatment-emergent adverse event was determined to be due to study treatment by the investigator, which was in cohort 1 (pneumonitis). Independent adjudication of interstitial lung disease or pneumonitis found that drug-related interstitial lung disease or pneumonitis occurred in ten (20%) patients in cohort 1 (two [4%] grade 1, five [10%] grade 2, and three [6%] grade 5) and two (5%) patients in cohort 1A (one [2%] grade 2 and one [2%] grade 5). An additional patient in cohort 1A had grade 4 pneumonitis after the data cutoff, which was subsequently adjudicated as drug-related grade 5 interstitial lung disease or pneumonitis. INTERPRETATION: Given the low antitumour activity of existing treatment options in this patient population, trastuzumab deruxtecan might have the potential to fill a large unmet need in HER2-overexpressing NSCLC. Our findings support further investigation of trastuzumab deruxtecan in patients with HER2-overexpressing NSCLC. FUNDING: Daiichi Sankyo and AstraZeneca.

Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies.

Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via ß2-adrenergic receptor (ß2-AR) activation leads to improved MDSC function through metabolic reprograming, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of Nrf2 and the oxidative stress response, enhancing MDSC survival. Using ß2-AR blockade, we target the STAT3 pathway and ATP and itaconate metabolism, disrupting ATP generation by the electron transport chain and decreasing itaconate generation causing diminished MDSC mitochondrial fitness. This disruption increases the response to doxorubicin and could be tested clinically.

Relationship between serum apelin, visfatin levels, and body composition in Polycystic Ovary Syndrome patients.

OBJECTIVE: To investigate the relationship between body composition and serum visfatin and apelin levels in patients with polycystic ovary syndrome (PCOS). METHODS: In this prospective observational study, the differences in body composition, levels of gonadal hormone concentrations, glucose metabolism, apelin, and visfatin were compared between PCOS patients and the control group. PCOS patients were further divided into different subgroups according to different obesity criteria and the differences between serum visfatin and apelin levels in different subgroups were compared. Finally, the correlation of serum visfatin levels and apelin levels with body composition, and metabolism-related indicators in PCOS patients was explored. RESULTS: A total collected 178 cases of PCOS patients and 172 cases of healthy women (control group) between 2020 July and 2021 November. In PCOS patients, their weight, Body Mass Index (BMI), Waist Hip Rate (WHR), Fat-Free Mass Index (FFMI), Percent Body Fat (PBF), Fat mass index (FMI), PBF of Arm, PBF of Leg, PBF of the Trunk, Visceral Fat Level (VFL), fasting insulin (FINS), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and Luteinizing hormone (LH) were significantly higher than in the control group (all P < 0.001), Percent Skeletal Muscle (PSM), PSM of Leg, and PSM of the Trunk were significantly decreased than in the control group (all P < 0.001). The PCOS patients had significantly higher serum visfatin levels and apelin levels compared with the control group (all P < 0.001). In PBF > 35 % PCOS patients, the apelin and visfatin levels were significantly higher than the PBF ≤ 35 % PCOS patients. In WHR ≥ 0.85 and BMI ≥ 24 kg/m2 PCOS patients, the visfatin levels were significantly higher than the WHR < 0.85 and BMI < 24 kg/m2 PCOS patients. Serum apelin and visfatin positively correlated with BMI level, WHR, FFMI, PBF, FMI, PBF of arms, PBF of legs, PBF of the trunk, VFL, FBG, HOMA-IR index and negatively correlated with PSM, PSM of legs, and PSM of the trunk (all P < 0.001). CONCLUSIONS: Compared with healthy women, Patients with PCOS have an increased fat content in various parts of the body, reduced skeletal muscle content, and are often complicated by metabolic abnormalities. Serum visfatin and apelin correlated not only with obesity, fat mass, and fat distribution but also with muscle mass and distribution. It may be possible to reduce the long-term risk of metabolic disease in PCOS through the monitoring and management of the body composition in PCOS patients or to reflect the therapeutic effect of PCOS.

Role of HCN channels in the functions of basal ganglia and Parkinson's disease.

Parkinson's disease (PD) is a motor disorder resulting from dopaminergic neuron degeneration in the substantia nigra caused by age, genetics, and environment. The disease severely impacts a patient's quality of life and can even be life-threatening. The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel is a member of the HCN1-4 gene family and is widely expressed in basal ganglia nuclei. The hyperpolarization-activated current mediated by the HCN channel has a distinct impact on neuronal excitability and rhythmic activity associated with PD pathogenesis, as it affects the firing activity, including both firing rate and firing pattern, of neurons in the basal ganglia nuclei. This review aims to comprehensively understand the characteristics of HCN channels by summarizing their regulatory role in neuronal firing activity of the basal ganglia nuclei. Furthermore, the distribution and characteristics of HCN channels in each nucleus of the basal ganglia group and their effect on PD symptoms through modulating neuronal electrical activity are discussed. Since the roles of the substantia nigra pars compacta and reticulata, as well as globus pallidus externus and internus, are distinct in the basal ganglia circuit, they are individually described. Lastly, this investigation briefly highlights that the HCN channel expressed on microglia plays a role in the pathological process of PD by affecting the neuroinflammatory response.

Efficacy and safety of Wuhu oral liquid in treating acute soft tissue injuries: a multicenter, randomized, double-blind, double-dummy, parallel-controlled trial.

Background: Wuhu Oral Liquid (WHOL) is a modified preparation derived from the famous Wuhu Powder, which has a long history of use in treating traumatic injuries. This preparation has anti-inflammatory and analgesic properties and accelerates recovery following acute soft tissue injuries. Aims: To evaluate the efficacy and safety of WHOL in treating acute soft tissue injury associated with qi stagnation and blood stasis syndrome and to provide a basis for applying for the protection of varieties of Chinese medicine for WHOL. Methods: This study was a randomized, controlled, double-blind, multicenter clinical trial in which Fufang Shang Tong Capsule (FFSTC) was selected as the control drug. A total of 480 subjects with acute soft tissue injury associated with qi stagnation and blood stasis syndrome were randomly divided into a test and control group in a 3:1 ratio. The duration of drug treatment was 10 days. The primary outcome was Visual Analogue Scale (VAS) score for pain (including pain at rest and pain on activity). Secondary outcomes included the disappearance time of the pain at rest and on activity; the curative effect of TCM syndrome and improvement in the individual symptoms of TCM (swelling, ecchymosis, and dysfunction); and changes in C-reactive protein (CRP) and interleukin-6 (IL-6) levels. Safety was assessed using vital signs, laboratory examinations, electrocardiograms, and physical examinations. Results: Patient compliance was satisfactory in both groups (all between 80% and 120%). After 4 days of treatment, the WHOL group was superior to the FFSTC group in decreasing the VAS scores for pain at rest (-1.88 ± 1.13 vs. -1.60 ± 0.93, p < 0.05) and on activity (-2.16 ± 1.18 vs. -1.80 ± 1.07, p < 0.05). After 7 days of treatment, the WHOL group was superior to the FFSTC group in decreasing the VAS scores for pain on activity (-3.87 ± 1.60 vs. -3.35 ± 1.30, p < 0.01) and improving swelling (cure rate: 60.4% vs. 46.2%, p < 0.05; obvious effective rate: 60.7% vs. 47.0%, p < 0.05). After 10 days of treatment, the WHOL group was superior to the FFSTC group in decreasing the levels of CRP (-0.13 ± 2.85 vs. 0.25 ± 2.09, p < 0.05) and improving the TCM syndrome (cure rate: 44.1% vs. 30.8%, p < 0.05) and swelling (cure rate: 75.6% vs. 67.5%, p < 0.01; obvious effective rate: 75.6% vs. 68.4%, p < 0.05; effective rate: 77.0% vs. 71.8%, p < 0.05). The disappearance time of pain at rest was 8 days in both groups and 9 days on activity in both groups. In addition, there was no statistical difference between the incidence of adverse events (4.5% vs. 2.6%, p > 0.05) and adverse reactions (0.3% vs. 0%, p > 0.05) between the WHOL group and the FFSTC group. No serious adverse events occurred in either group, and no subjects were withdrawn because of adverse events. Conclusion: WHOL relieves the symptoms caused by acute soft tissue injury associated with qi stagnation and blood stasis syndrome more rapidly than FFSTC, and it is effective and safe in the treatment of acute soft tissue injury. Future studies still need a larger sample size to verify its efficacy and safety. Clinical Trial Registration: https:// www.chictr.org.cn/showproj.html?proj=149531, Identifier ChiCTR2200056411.

Malate, a natural inhibitor of 6PGD, improves the efficacy of chemotherapy in lung cancer.

OBJECTIVE: Metabolic reprogramming is an important coordinator of tumor development and resistance to therapy, such as the tendency of tumor cells to utilize glycolytic energy rather than oxidative phosphorylation, even under conditions of sufficient oxygen. Therefore, targeting metabolic enzymes is an effective strategy to overcome therapeutic resistance. MATERIALS AND METHODS: We explored the differential expression and growth-promoting function of MDH2 by immunohistochemistry and immunoblotting experiments in lung cancer patients and lung cancer cells. Pentose phosphate pathway-related phenotypes (including ROS levels, NADPH levels, and DNA synthesis) were detected intracellularly, and the interaction of malate and proteinase 6PGD was detected in vitro. In vivo experiments using implanted xenograft mouse models to explore the growth inhibitory effect and pro-chemotherapeutic function of dimethyl malate (DMM) on lung cancer. RESULTS: We found that the expression of malate dehydrogenase (MDH2) in the tricarboxylic acid cycle (TCA cycle) was increased in lung cancer. Biological function enrichment analysis revealed that MDH2 not only promoted oxidative phosphorylation, but also promoted the pentose phosphate pathway (PPP pathway). Mechanistically, it was found that malate, the substrate of MDH2, can bind to the PPP pathway metabolic enzyme 6PGD, inhibit its activity, reduce the generation of NADPH, and block DNA synthesis. More importantly, DMM can improve the sensitivity of lung cancer to the clinical drug cisplatin. CONCLUSION: We have identified malate as a natural inhibitor of 6PGD, which will provide new leads for the development of 6PGD inhibitors. In addition, the metabolic enzyme MDH2 and the metabolite malate may provide a backup option for cells to inhibit their own carcinogenesis, as the accumulated malate targets 6PGD to block the PPP pathway and inhibit cell cycle progression.

Diving into CDC pregnancy data in the United States: longitudinal study and interactive application.

Objective: Preterm birth (PTB) is a major determinant of neonatal mortality, morbidity, and childhood disability. In this article, we present a longitudinal analysis of the risk factors associated with PTB and how they have varied over the years: starting from 1968 when the CDC first started, reporting the natality data, up until 2021. Along with this article, we are also releasing an RShiny web application that will allow for easy consumption of this voluminous dataset by the research community. Further, we hope this tool can aid clinicians in the understanding and prevention of PTB. Materials and Methods: This study used the CDC Natality data from 1968 to 2021 to analyze trends in PTB outcomes across the lens of various features, including race, maternal age, education, and interval length between pregnancies. Our interactive RShiny web application, CDC NatView, allows users to explore interactions between maternal risk factors and maternal morbidity conditions and the aforementioned features. Results: Our study demonstrates how CDC data can be leveraged to conduct a longitudinal analysis of natality trends in the United States. Our key findings reveal an upward trend in late PTBs, which is concerning. Moreover, a significant disparity exists between African American and White populations in terms of PTB. These disparities persist in other areas, such as education, body-mass index, and access to prenatal care later in pregnancy. Discussion: Another notable finding is the increase in maternal age over time. Additionally, we confirm that short interpregnancy intervals (IPIs) are a risk factor for PTBs. To facilitate the exploration of pregnancy risk factors, infections, and maternal morbidity, we developed an open-source RShiny tool called CDC NatView. This software offers a user-friendly interface to interact with and visualize the CDC natality data, which constitutes an invaluable resource. Conclusion: In conclusion, our study has shed light on the rise of late PTBs and the persistent disparities in PTB rates between African American and White populations in the US. The increase in maternal age and the confirmation of a short IPI as a risk factor for PTB are noteworthy findings. Our open-source tool, CDC NatView, can be a valuable resource for further exploration of the CDC natality data to enhance our understanding of pregnancy risk factors and the interaction of PTB outcomes and maternal morbidities.

Cell membrane tension gradients, membrane flows and cellular processes.

Cell membrane tension affects and is affected by many fundamental cellular processes, yet it is poorly understood. Recent experiments show that membrane tension can propagate at vastly different speeds in different cell types, reflecting physiological adaptations. Here we briefly review the current knowledge about membrane tension gradients, membrane flows, and their physiological context.

Ferroptosis in age-related vascular diseases: Molecular mechanisms and innovative therapeutic strategies.

Aging, an inevitable aspect of human existence, serves as one of the predominant risk factors for vascular diseases. Delving into the mystery of vascular disease's pathophysiology, the profound involvement of programmed cell death (PCD) has been extensively demonstrated. PCD is a fundamental biological process that plays a crucial role in both normal physiology and pathology, including a recently discovered form, ferroptosis. Ferroptosis is characterized by its reliance on iron and lipid peroxidation, and its significant involvement in vascular disease pathophysiology has been increasingly acknowledged. This phenomenon not only offers a promising therapeutic target but also deepens our understanding of the complex relationship between ferroptosis and age-related vascular diseases. Consequently, this article aims to thoroughly review the mechanisms that enable the effective control and inhibition of ferroptosis. It focuses on genetic and pharmacological interventions, with the goal of developing innovative therapeutic strategies to combat age-related vascular diseases.

Frequency-potency analysis of IgG+ memory B cells delineates neutralizing antibody responses at single-cell resolution.

Identifying individual functional B cell receptors (BCRs) is common, but two-dimensional analysis of B cell frequency versus BCR potency would delineate both quantity and quality of antigen-specific memory B cells. We efficiently determine quantitative BCR neutralizing activities using a single-cell-derived antibody supernatant analysis (SCAN) workflow and develop a frequency-potency algorithm to estimate B cell frequencies at various neutralizing activity or binding affinity cutoffs. In an HIV-1 fusion peptide (FP) immunization study, frequency-potency curves elucidate the quantity and quality of FP-specific immunoglobulin G (IgG)+ memory B cells for different animals, time points, and antibody lineages at single-cell resolution. The BCR neutralizing activities are mainly determined by their affinities to soluble envelope trimer. Frequency analysis definitively demonstrates dominant neutralizing antibody lineages. These findings establish SCAN and frequency-potency analyses as promising approaches for general B cell analysis and monoclonal antibody (mAb) discovery. They also provide specific rationales for HIV-1 FP-directed vaccine optimization.