Search

Abstract Breastfeeding is the most complete nutritional method of feeding infants, but several impediments affect the decision to breastfeed, including questions of drug safety for medications needed during lactation. Despite recent FDA guidance, few labels provide clear dosing advice during lactation. Physiologically based pharmacokinetic modeling (PBPK) is well suited to mechanistically explore pharmacokinetics and dosing paradigms to fill gaps in the absence of extensive clinical studies and complement existing real‐world data. For lactation‐focused PBPK (Lact‐PBPK) models, information on system parameters (e.g., expression of drug transporters in mammary epithelial cells) is sparse. The breast cancer resistance protein (BCRP) is expressed on the apical side of mammary epithelial cells where it actively transports drugs/substrates into milk (reported milk: plasma ratios range from 2 to 20). A critical review of BCRP and its role in lactation was conducted. Longitudinal changes in BCRP mRNA expression have been identified in women with a maximum reached around 5 months postpartum. Limited data are available on the ontogeny of BCRP in infant intestine; however, data indicate lower BCRP abundance in infants compared to adults. Current status of incorporation of drug transporter information in Lact‐PBPK models to predict active secretion of drugs into breast milk and consequential exposure of breast‐fed infants is discussed. In addition, this review highlights novel clinical tools for evaluation of BCRP activity, namely a potential non‐invasive BCRP biomarker (riboflavin) and liquid biopsy that could be used to quantitatively elucidate the role of this transporter without the need for administration of drugs and to inform Lact‐PBPK models.

Abstract Power electronic switches (PES) play a crucial role in transferring and clearing fault currents in hybrid DC circuit breakers. The PES encounters switching transients that require a dependable external power source. Usually, a power supply system utilizes an isolation transformer and many magnetic rings. However, the existence of inconsistent parameters might easily cause an imbalance in load power, which could potentially result in power supply failure for the loads. Therefore, to enhance the reliability of power supply, this study proposes a load constant voltage self‐balancing design approach that utilizes feedback circuits to achieve stability and balance in load voltage. At first, two feedback circuits are shown, and the analytical formulas for load active power and load voltage are derived. Moreover, a parameter design methodology is shown for the equivalent circuit of the magnetic rings in the power supply. Additionally, a power supply system is built with 24 V outputs. In conclusion, this study utilizes simulations and tests to assess the effectiveness of the proposed power supply system by analysing its performance during start‐up, load power‐off, and steady‐state operations.

Abstract The lack of an MMC reliability evaluation approach that incorporates data on essential components' health monitoring in the already related research prevents reliability from being further improved. Therefore, this article proposes a real‐time reliability evaluation method of the multi‐state IGBT module in MMC through iterative calculation of the Markov chain model. The degradation process of the IGBT module is divided into multiple states based on the monitored bond wire failure, and the failure rate of the IGBT module is updated in real time using the accumulated monitoring data of junction temperature. The proposed method can more accurately reflect the real state of MMC compared with the binary state evaluation method. Besides, a multi‐channel high‐speed data acquisition board is designed to measuring the gate voltage and collector voltage of the IGBT for the health evaluation of IGBT modules in MMC; the typically measured results validate the effectiveness of the data acquisition board.

Abstract This study aimed to explore the impact of Brassica rapa L. polysaccharides (BRP) on the growth, immune response, antioxidant capacity, and cecal microbiota in yellow-feathered quails. A total of 250 one-day-old yellow-feathered quails, evenly divided by sex, were randomly assigned to five groups, with each group comprising ten replicates of five quails each. The control group (CON) received a basic diet, while the antibiotic control group (CTC) was fed a basic diet supplemented with chlortetracycline (0.05 g/kg). BRP was administered at concentrations of 0.25 g/kg (Low dose BRP, LBRP), 0.5 g/kg (Medium dose BRP, MBRP), and 1 g/kg (High dose BRP, HBRP). The duration of the experiment was 42 days. The results indicated that, compared to the CON group, the final body weight of quails in the MBRP group significantly increased (P 0.05); at 42 days of age, the average weight of the thymus in the MBRP group was significantly greater than that in the CON group (P 0.05). At 21 days of age, the levels of IgA and IgG in the MBRP group were significantly elevated compared to the CON group (P 0.05). Additionally, the MBRP group showed significant increases in CAT, T-SOD, and GSH-Px levels (P

Background: Over the past two decades, modern spine surgery has become increasingly intellectualized and minimally invasive. However, whether using robots in spine surgery results in more accurate pedicle screw placement remains a topic of debate. This study aimed to evaluate the certainty and quality of the available evidence on the efficacy of robot-assisted pedicle screw placement. Methods: We performed an overview of reviews including systematic reviews (SRs) and meta-analyses (MAs) regarding the accuracy of robot-assisted pedicle screw placement. Regarding the SRs/MAs, five electronic databases were searched from inception to 28 April 2023. There were no restrictions on the language or population. The quality and certainty of the evidence were evaluated with PRISMA, AMSTAR-2, ROBIS, Veritas plot, and GRADE tools. Results: Fifteen SRs/MAs were analyzed. The findings indicated that the accuracy of pedicle screw placement in the robot-assisted group was not superior to that in the freehand group. All the SRs/MAs were of low or critically low quality. The main reasons for this include missing data, lack of transparency, lack of sensitivity analysis, and measurement of heterogeneity in the included studies, registration of reporting protocols, and deficiencies in the study inclusion methods and selection criteria. Conclusions: While there is potential for robot-assisted pedicle screw placement to offer superior accuracy compared to conventional surgery, the current evidence is limited by methodological shortcomings. The quality of the studies analyzed was insufficient to provide a robust basis for developing clinical guidelines. Further high-quality research is necessary to confirm the benefits and establish clearer recommendations.

Abstract Advances in symmetry-breaking engineering of heterointerfaces for optoelectronic devices have garnered significant attention due to their immense potential in tunable moiré quantum geometry and enabling polarization light detection. Despite several proposed approaches to breaking the symmetry of low-dimensional materials, there remains a lack of universal methods to create materials with prominent polarization detection capabilities. Here, we introduce a reliable strategy for manipulating the symmetry of low-dimensional materials through a programmable ferroelectric-doping patterns technique. This method introduces a spontaneous photocurrent and enables the detection of linearly polarization light in isotropic 2H-MoTe2. The 2H-MoTe2 photodetector exhibits a significant short-circuit photocurrent intensity (J sc = 29.9 A/cm2) and open-circuit voltage V oc of 0.12 V ( ~ 3 × 105 V/cm). Under a specific bias, the polarization ratio transitions from 1 to ∞/−∞, shifting from a positive state (unipolar regime) to a negative state (bipolar regime). These findings underscore the potential of ferroelectric-doping patterns as a promising approach to creating composite materials with artificial bulk photovoltaic effect and achieving high-performance polarization light detection.

Malignant tumors remain a serious threat to human health and life and are a major public health problem globally. Herein, we designed and synthesized a novel nucleic acid nanomedicine AS1411-siRNA-LNPs (As@LNPs). Bmi-1 siRNA was coated with cationic liposomes, and a nucleic acid aptamer AS1411 with tumor cell-targeting ability was attached to the outermost layer of the liposomes. The average particle size of As@LNPs was 183 nm, and the polydispersion coefficient was 0.187. The encapsulation rate and drug loading of As@LNPs were 85% and 4.6%, respectively. The average electron mobility of the drug was 2.64 (μ/s)/(V/cm), and the zeta potential of As@LNPs was 33.79 ± 0.78 mV. The microstructure of the nanomedicine was evaluated via transmission electron microscopy. In vitro and in vivo experiments showed that As@LNPs significantly inhibited tumor growth and promoted tumor cell apoptosis. As@LNPs showed favorable biosafety with major tissues and organs, except glomerulus and renal epithelial cells.

Abstract Background Qin-Yu-Qing-Chang decoction (QYQC), an herbal formula from China, is extensively employed to manage ulcerative colitis (UC) and exhibits potential benefits for colonic function. Nevertheless, the fundamental molecular mechanisms of QYQC remain largely uncharted. Methods The primary constituents of QYQC were determined utilizing UHPLC-MS/MS analysis and the effectiveness of QYQC was assessed in a mouse model of colitis induced by dextran sulfate sodium. Evaluations of colon inflammatory responses and mucosal barrier function were thoroughly assessed. RNA sequencing, molecular docking, colonic energy metabolism, and 16S rRNA sequencing analysis were applied to uncover the complex mechanisms of QYQC in treating UC. Detect the signal transduction of the peroxisome proliferator-activated receptor-γ (PPAR-γ) both in the nucleus and cytoplasm. Furthermore, a PPAR-γ antagonist was strategically utilized to confirm the functional targets that QYQC exerts. Results Utilizing UHPLC-MS/MS, the principal constituents of the nine traditional Chinese medicinal herbs comprising QYQC were systematically identified. QYQC treatment substantially ameliorated colitis in mice, as evidenced by the improvement in symptoms and the reduction in colonic pathological injuries. Besides, QYQC treatment mitigated the inflammatory response and improved mucosal barrier function. Furthermore, QYQC enhanced the mitochondria citrate cycle (TCA cycle) by triggering PPAR-γ signaling and increasing the proportion of PPAR-γ entering the nucleus. This prevented the unconstrained expansion of facultative anaerobes, particularly pathogenic Escherichia coli (E. coli, family Enterobacteriaceae) and thus improved colitis. Results of molecular docking indicated that the representative chemical components of QYQC including Baicalin, Paeoniflorin, Mollugin, and Imperatorin bound well with PPAR-γ. The impact of QYQC on colitis was diminished in the presence of a PPAR-γ antagonist. Conclusions In summary, QYQC ameliorates UC by activating PPAR-γ signaling and increasing the proportion of PPAR-γ entering the nucleus, which enhances the energy metabolism of intestinal epithelial cells and thereby preventing the uncontrolled proliferation of facultative anaerobes.

Abstract Background The long-term impacts of COVID-19 on human health are a major concern, yet comprehensive evaluations of its effects on various health conditions are lacking. Methods This study aims to evaluate the role of various diseases in relation to COVID-19 by analyzing genetic data from a large-scale population over 2,000,000 individuals. A bidirectional two-sample Mendelian randomization approach was used, with exposures including COVID-19 susceptibility, hospitalization, and severity, and outcomes encompassing 86 different diseases or traits. A reverse Mendelian randomization analysis was performed to assess the impact of these diseases on COVID-19. Results Our analysis identified causal relationships between COVID-19 susceptibility and several conditions, including breast cancer (OR = 1.0073, 95% CI = 1.0032–1.0114, p = 5 × 10 − 4), ER + breast cancer (OR = 0.5252, 95% CI = 0.3589–0.7685, p = 9 × 10 − 4), and heart failure (OR = 1.0026, 95% CI = 1.001–1.0042, p = 0.002). COVID-19 hospitalization was causally linked to heart failure (OR = 1.0017, 95% CI = 1.0006–1.0028, p = 0.002) and Alzheimer’s disease (OR = 1.5092, 95% CI = 1.1942–1.9072, p = 0.0006). COVID-19 severity had causal effects on primary biliary cirrhosis (OR = 2.6333, 95% CI = 1.8274–3.7948, p = 2.059 × 10 − 7), celiac disease (OR = 0.0708, 95% CI = 0.0538–0.0932, p = 9.438 × 10–80), and Alzheimer’s disease (OR = 1.5092, 95% CI = 1.1942–1.9072, p = 0.0006). Reverse MR analysis indicated that rheumatoid arthritis, diabetic nephropathy, multiple sclerosis, and total testosterone (female) influence COVID-19 outcomes. We assessed heterogeneity and horizontal pleiotropy to ensure result reliability and employed the Steiger directionality test to confirm the direction of causality. Conclusions This study provides a comprehensive analysis of the causal relationships between COVID-19 and diverse health conditions. Our findings highlight the long-term impacts of COVID-19 on human health, emphasizing the need for continuous monitoring and targeted interventions for affected individuals. Future research should explore these relationships to develop comprehensive healthcare strategies.

Abstract Pathological cardiac hypertrophy is the primary cause of heart failure, yet its underlying mechanisms remain incompletely understood. Transmembrane protein 100 (TMEM100) plays a role in various disorders, such as nervous system disease, pain and tumorigenesis, but its function in pathological cardiac hypertrophy is still unknown. In this study, we observed that TMEM100 is upregulated in cardiac hypertrophy. Functional investigations have shown that adeno-associated virus 9 (AAV9) mediated-TMEM100 overexpression mice attenuates transverse aortic constriction (TAC)-induced cardiac hypertrophy, including cardiomyocyte enlargement, cardiac fibrosis, and impaired heart structure and function. We subsequently demonstrated that adenoviral TMEM100 (AdTMEM100) mitigates phenylephrine (PE)-induced cardiomyocyte hypertrophy and downregulates the expression of cardiac hypertrophic markers in vitro, whereas TMEM100 knockdown exacerbates cardiomyocyte hypertrophy. The RNA sequences of the AdTMEM100 group and control group revealed that TMEM100 was involved in oxidative stress and the MAPK signaling pathway after PE stimulation. Mechanistically, we revealed that the transmembrane domain of TMEM100 (amino acids 53–75 and 85–107) directly interacts with the C-terminal region of TAK1 (amino acids 1–300) and inhibits the phosphorylation of TAK1 and its downstream molecules JNK and p38. TAK1-binding-defective TMEM100 failed to inhibit the activation of the TAK1-JNK/p38 pathway. Finally, the application of a TAK1 inhibitor (iTAK1) revealed that TAK1 is necessary for TMEM100-mediated cardiac hypertrophy. In summary, TMEM100 protects against pathological cardiac hypertrophy through the TAK1-JNK/p38 pathway and may serve as a promising target for the treatment of cardiac hypertrophy.

Abstract Acquiring multi-dimensional optical information, such as intensity, spectrum, polarization, and phase, can significantly enhance the performance of photodetectors. Incorporating these dimensions allows for improved image contrast, enhanced recognition capabilities, reduced interference, and better adaptation to complex environments. However, the challenge lies in obtaining these dimensions on a single photodetector. Here we propose a misaligned unipolar barrier photodetector based on van der Waals heterojunction to address this issue. This structure enables spectral detection by switching between two absorbing layers with different cut-off wavelengths for dual-band detection. For polarization detection, anisotropic semiconductors like black phosphorus and black arsenic phosphorus inherently possess polarization-detection capabilities without additional complex elements. By manipulating the crystal direction of these materials during heterojunction fabrication, the device becomes sensitive to incident light at different polarization angles. This research showcases the potential of the misaligned unipolar barrier photodetector in capturing multi-dimensional optical information, paving the way for next-generation photodetectors.

IntroductionThis study aimed to investigate the effects of Isalo scorpion cytotoxic peptide (IsCT) on the growth performance, immune function, and gut microbiota of yellow-feathered broilers.MethodsThe experiment involved supplementing a corn-soybean meal-based diet with various dietary levels of IsCT. The experiment adopted a completely randomized design. A total of 240 one-day-old yellow-feathered broilers were randomly divided into six groups: a control group (CON), a chlortetracycline group (CTC), and four groups receiving a basal diet with 50, 100, 150, or 200 mg/ kg IsCT (IsCT50, IsCT100, IsCT150, and IsCT200). The trial period lasted 60 days.ResultsThe results showed that the average final body weight and average daily weight gain of the IsCT150 and IsCT200 groups were significantly higher than those of the CON group (p

Background Despite the high risk of eating disorder (ED)-related attitudes and behaviors among female dancers, targeted scientific dietary regimens are currently inadequate. Time-restricted eating (TRE), a popular intermittent fasting protocol, has been shown to be effective in enhancing body composition and exercise performance in athletes. In this study, TRE was employed as a dietary regimen to improve body composition and exercise performance and address ED attitudes and behaviors in DanceSport dancers.Methods Twenty female DanceSport dancers were recruited and divided into two groups: TRE (n = 10) and normal diet (ND) (n = 10). The TRE group consumed their self-selected necessary energy intake exclusively between 11 a.m. and 7 p.m. (utilizing a 16-hour fasting and 8-hour eating window) for 6 weeks, while the ND group maintained their regular dieting patterns. The consumption of water, black tea, or coffee without added sugar or milk was not restricted. Physical activity and calorie intake were systematically recorded during the TRE intervention. Body composition, aerobic and anaerobic performance, and ED attitudes and behaviors were assessed before and after the TRE intervention. The trial was registered in the Chinese Clinical Trial Registry under the identifier ChiCTR2200063780.Results The fixed effects tests (p 0.05). TRE resulted in a reduction in hip circumference (p = 0.039), fat mass (kg) (p = 0.0004), and body fat percentage (p = 0.0005), with no significant decrease in fat-free mass (p > 0.05). No significant improvement was observed in aerobic performance (p > 0.05). The average power (AP) (p = 0.01) and AP/Body weight ratio (p = 0.003) significantly increased. Additionally, the power drop decreased significantly (p = 0.019). Group-by-time interactions were observed for fat mass (kg) (p = 0.01), body fat percentage (p = 0.035), and AP/Body weight (p = 0.020).Conclusion TRE can be considered a feasible nutritional strategy for DanceSport dancers, facilitating improvements in body composition without compromising aerobic and anaerobic exercise performance or exacerbating ED attitudes and behaviors. Moreover, TRE may facilitate more favorable physiological adaptations, potentially contributing to improved exercise performance.

PurposeEpidemiological studies have demonstrated the clinical link between Hunner interstitial cystitis (HIC) and autoimmune diseases (ADs), suggesting potential shared genetic bases for their comorbidity. We aimed to investigate the shared genetic architecture and causal relationships between HIC and ADs.MethodsWe conducted a genome-wide cross-trait study with ~170000 individuals of East Asian ancestry to investigate the shared architecture between HIC and ADs. Bidirectional Mendelian randomization (MR) was used to assess potential causal relationships and a multi-trait analysis of GWAS (MTAG) was conducted to identify their associated pleiotropic loci. Fine-mapping analysis narrowed candidate gene susceptibility loci and colocalization analysis was performed to identify shared variants at specific locus. Lastly, transcriptome-wide association (TWAS) and functional analysis were utilized to explore potential shared gene-tissue associations.ResultsThrough bidirectional MR analysis, we observed a positive causal effect of AIH(ORIVW=1.09, PIVW=1.00×10-3) and RA (ORIVW=1.47, PIVW

Abstract Aortic valve replacement (AVR) is a critical procedure for patients with aortic valve diseases. This study compares the effectiveness of three minimally-invasive surgical approaches for AVR: totally thoracoscopic (TT), right anterior mini-thoracotomy, and upper mini-sternotomy. We analyzed retrospective data from 130 patients who underwent one of these surgeries, focusing on various factors such as duration of hospital stay, operation time, times for cardiopulmonary bypass and aortic cross-clamping, postoperative complications, levels of cardiac biomarkers, pain intensity using the Visual Analog Scale, and mid-term survival rates. Results show that while the TT method had the longest operation times, it also had the shortest hospital stays and faster pain reduction post-surgery. Although the TT group initially showed higher cardiac biomarker levels after surgery, these levels normalized by the third day, similar to the other groups. There were no significant differences in mid-term survival and major adverse cardiac and cerebrovascular event (MACCE) rates among the groups. These findings suggest that the TT method, despite longer surgical times, offers a quicker initial recovery, making it a viable option for AVR.

Abstract Background Platelet dysfunction plays a critical role in the pathogenesis of inflammatory bowel disease (IBD). Despite clinical observations indicating abnormalities in platelet parameters among IBD patients, inconsistencies persist, and these parameters lack standardization for diagnosis or clinical assessment. Methods A comprehensive search was conducted in the PubMed, Embase, Web of Science, and Cochrane Library databases for relevant articles published up to December 16th, 2023. A random-effects model was employed to pool the weighted mean difference (WMD) and 95% confidence interval (95% CI) of platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT) between IBD patients and healthy controls, and subgroup analyses were performed. Results The meta-analysis included 79 articles with 8,350 IBD patients and 13,181 healthy individuals. The results revealed significantly increased PLT and PCT levels (WMD: 69.910, 95% CI: 62.177, 77.643 109/L; WMD: 0.046%, 95% CI: 0.031%, 0.061%), and decreased MPV levels (WMD: -0.912, 95% CI: -1.086, -0.739 fL) in IBD patients compared to healthy individuals. No significant difference was found in PDW between the IBD and control groups (WMD: -0.207%, 95% CI: -0.655%, 0.241%). Subgroup analysis by disease type and disease activity showed no change in the differences for PLT, PCT, and MPV in the ulcerative colitis and Crohn’s disease groups, as well as the active and inactive groups. Notably, the active group exhibited significantly lower PDW levels than the control group (WMD: -1.138%, 95% CI: -1.535%, -0.741%). Conclusions Compared with healthy individuals, IBD patients display significantly higher PLT and PCT and significantly lower MPV. Monitoring the clinical manifestations of platelet abnormalities serves as a valuable means to obtain diagnostic and prognostic information. Conversely, proactive measures should be taken to prevent the consequences of platelet abnormalities in individuals with IBD. Systematic review registration PROSPERO CRD42023493848.

Abstract Significant developments in cancer treatment have been made since the advent of immune therapies. However, there are still some patients with malignant tumors who do not benefit from immunotherapy. Tumors without immunogenicity are called “cold” tumors which are unresponsive to immunotherapy, and the opposite are “hot” tumors. Immune suppressive cells (ISCs) refer to cells which can inhibit the immune response such as tumor‐associated macrophages (TAMs), myeloid‐derived suppressor cells (MDSCs), regulatory T (Treg) cells and so on. The more ISCs infiltrated, the weaker the immunogenicity of the tumor, showing the characteristics of “cold” tumor. The dysfunction of ISCs in the tumor microenvironment (TME) may play essential roles in insensitive therapeutic reaction. Previous studies have found that epigenetic mechanisms play an important role in the regulation of ISCs. Regulating ISCs may be a new approach to transforming “cold” tumors into “hot” tumors. Here, we focused on the function of ISCs in the TME and discussed how epigenetics is involved in regulating ISCs. In addition, we summarized the mechanisms by which the epigenetic drugs convert immunotherapy‐insensitive tumors into immunotherapy‐sensitive tumors which would be an innovative tendency for future immunotherapy in “cold” tumor.

Abstract Background Tunlametinib (HL-085) is a novel, highly selective MEK inhibitor with substantial clinical activities in patients with NRAS-mutant melanoma. This phase I study evaluated the safety and preliminary efficacy of tunlametinib plus vemurafenib in patients with advanced BRAF V600-mutant solid tumors. Methods Patients with confirmed advanced BRAF V600-mutant solid tumors who had progressed on or shown intolerance or no available standard therapies were enrolled and received tunlametinib plus vemurafenib. This study consisted of a dose-escalation phase and a dose-expansion phase. Primary end points of this study were safety, the recommended phase II dose (RP2D), and preliminary efficacy. Results From August 17, 2018 to April 19, 2022, 72 patients were enrolled. No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. The RP2D for BRAF V600-mutant non-small cell lung cancer (NSCLC) patients was tunlametinib 9 mg plus vemurafenib 720 mg, twice daily (BID, bis in die). Until the data cut-off date of December 15, 2023, of 33 NSCLC patients with evaluable disease, the objective response rate (ORR) was 60.6% (20/33; 95% confidence interval [CI], 42.1–77.1), the median progression free survival (PFS) was 10.5 months (95%CI, 5.6–14.5) and median duration of response (DoR) was 11.3 months (95%CI, 6.8-NE). At the RP2D, ORR was 60.0% (9/15; 95% CI, 32.3–83.7), the median PFS was 10.5 months (95%CI, 5.6 -NE) and median DoR was 11.3 months (95%CI, 3.9-NE). Of 24 colorectal cancer patients with evaluable disease, the ORR was 25.0% (6/24; 95% CI, 5.6-NE). All 72 patients had treatment-related adverse events (TRAEs), and the most common grade 3–4 TRAEs were anemia (n = 13, 18.1%) and blood creatine phosphokinase increased (n = 10, 13.9%). Tunlametinib was absorbed rapidly with Tmax of 0.5–1 h. Vemurafeinib did not influence the system exposure of tunlametinib and vice versa, indicating no drug-drug interaction for this combination. Conclusions Tunlametinib (HL-085) plus vemurafenib had a favorable safety profile and showed promising antitumor activity in patients with BRAF V600-mutant solid tumors. The RP2D for NSCLC was tunlametinib 9 mg BID plus vemurafeinib 720 mg BID. Trial Registration ClinicalTrials.gov, NCT03781219.

Malignant pleural mesothelioma (MPM) is a rare cancer with high malignancy and aggressiveness on the pleural, caused by the following risk factors including asbestos inhalation, genetic factors, and genetic mutation. The present chemotherapy, antiangiogenic therapy, and immunotherapy methods are ineffective and the survival time of patients is very short. There is an urgent need to find potential therapeutic targets for MPM. At present, it has been found the following types of targets: gene mutation targets such as BRCA associated protein 1 (BAP1) and cyclin-dependent kinase 2A (CDKN2A); epigenetic targets such as lysine (K)-specific demethylase 4A (KDM4A) and lysine-specific demethylase 1 (LSD1), and signal protein targets such as glucose-regulated protein 78 (GRP78) and signal transducer and activator of transcription 3 (STAT3). So far, available clinical trials include phase II clinical trials of histone methyltransferase inhibitor Tazemetostat, poly (ADP-ribose) polymerase (PARP) inhibitor Rucaparib and cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor Abemaciclib, as well as phase I clinical trials of mesothelin-targeting chimeric antigen receptor T-cell immunotherapy (CAR-T) cell injection in the thoracic cavity and TEA domain family member (TEAD) inhibitor VT3989 and IK-930, and the results of these trials have showed certain clinical efficacy.

Abstract Fluid dynamics computations for tube-like geometries are crucial in biomedical evaluations of vascular and airways fluid dynamics. Physics-Informed Neural Networks (PINNs) have emerged as a promising alternative to traditional computational fluid dynamics (CFD) methods. However, vanilla PINNs often demand longer training times than conventional CFD methods for each specific flow scenario, limiting their widespread use. To address this, multi-case PINN approach has been proposed, where varied geometry cases are parameterized and pre-trained on the PINN. This allows for quick generation of flow results in unseen geometries. In this study, we compare three network architectures to optimize the multi-case PINN through experiments on a series of idealized 2D stenotic tube flows. The evaluated architectures include the ‘Mixed Network’, treating case parameters as additional dimensions in the vanilla PINN architecture; the “Hypernetwork”, incorporating case parameters into a side network that computes weights in the main PINN network; and the “Modes” network, where case parameters input into a side network contribute to the final output via an inner product, similar to DeepONet. Results confirm the viability of the multi-case parametric PINN approach, with the Modes network exhibiting superior performance in terms of accuracy, convergence efficiency, and computational speed. To further enhance the multi-case PINN, we explored two strategies. First, incorporating coordinate parameters relevant to tube geometry, such as distance to wall and centerline distance, as inputs to PINN, significantly enhanced accuracy and reduced computational burden. Second, the addition of extra loss terms, enforcing zero derivatives of existing physics constraints in the PINN (similar to gPINN), improved the performance of the Mixed Network and Hypernetwork, but not that of the Modes network. In conclusion, our work identified strategies crucial for future scaling up to 3D, wider geometry ranges, and additional flow conditions, ultimately aiming towards clinical utility.

Highlights The low FODMAP diet is the most recommended dietary intervention for the clinical management of IBS symptoms. Bibliometrics analysis provides a comprehensive perspective and direction on global research trend and hotspot in the low FODMAP diet research. The restriction stage of the low FODMAP diet is superior to other dietary therapies for IBS in terms of symptom response, but it has a negative impact on the abundance of gut Bifidobacteria and diet quality. Identification of biomarkers to predict response to the low FODMAP diet has become the current research hotspot. Large, well-designed clinical research studies are needed in the future to investigate the long-term efficacy and safety of the low FODMAP diet, including FODMAP reintroduction and personalization stages.

Abstract Only ~20% of heavy drinkers develop alcohol cirrhosis (AC). While differences in metabolism, inflammation, signaling, microbiome signatures and genetic variations have been tied to the pathogenesis of AC, the key underlying mechanisms for this interindividual variability, remain to be fully elucidated. Induced pluripotent stem cell-derived hepatocytes (iHLCs) from patients with AC and healthy controls differ transcriptomically, bioenergetically and histologically. They include a greater number of lipid droplets (LDs) and LD-associated mitochondria compared to control cells. These pre-pathologic indicators are effectively reversed by Aramchol, an inhibitor of stearoyl-CoA desaturase. Bioenergetically, AC iHLCs have lower spare capacity, slower ATP production and their mitochondrial fuel flexibility towards fatty acids and glutamate is weakened. MARC1 and PNPLA3, genes implicated by GWAS in alcohol cirrhosis, show to correlate with lipid droplet-associated and mitochondria-mediated oxidative damage in AC iHLCs. Knockdown of PNPLA3 expression exacerbates mitochondrial deficits and leads to lipid droplets alterations. These findings suggest that differences in mitochondrial bioenergetics and lipid droplet formation are intrinsic to AC hepatocytes and can play a role in its pathogenesis.

BackgroundAsparaginase-associated pancreatitis (AAP) is a major challenge for continuing asparaginase therapy. We aimed to investigate the acute and long-term complications and survival rates related to first and second AAP episodes in Chinese children with haematological malignancies.MethodsWe retrospectively analysed clinical data of children with pancreatitis who received asparaginase chemotherapy for acute lymphoblastic leukaemia (ALL), acute mixed cell leukaemia, and non-Hodgkin’s lymphoma at Shanghai Children’s Medical Center from November 2013 to November 2023.ResultsOf the 76 children included in the study, 12 had local complications (15.79%), with no deaths recorded. Systemic complications manifested in 28 patients (36.84%), resulting in 3 deaths (3.95%). Four patients (5.26%) developed long-term complications (chronic pancreatitis or insulin-dependent diabetes mellitus). No significant differences in local or long-term complications were recorded between children in the asparaginase re-exposed (n=39) and non-re-exposed (n=45) groups. Among the re-exposed patients, eight (25.81%) experienced a second attack without fatalities or complications. Survival analysis of intermediate- to high-risk patients revealed a significantly higher event-free survival (EFS) rate for the re-exposed group than for the non-re-exposed group. The second AAP episode’s occurrence and severity had no relation to the first AAP episode’s severity, and the second AAP episode was significantly less severe than the first (p

A novel acrylic monomer containing a nitrofuran motif, referred to as long-chain nitrofuran methacrylate (LNFMA), is reported. In comparison to the previously reported nitrofuran methacrylate (NFMA), LNFMA has a longer side chain, and when incorporated into bone cement, the resulting LNFMA bone cement exhibits improved mechanical strength. At the same concentration, NFMA-5% cement has only 21.6 ± 1.3 MPa, while LNFMA-5% cement has a compressive strength of 42.64 ± 0.94 MPa. LNFMA bone cements exhibit antimicrobial activity against Staphylococcus aureus, with LNFMA-30% cement reaching 57.38% ± 5.53%. Moreover, LNFMA cement demonstrates excellent biocompatibility both in vitro and in vivo. The results showed that LNFMA monomer had optimized mechanical strength compared with previously reported NFMA monomers, and LNFMA bone cement had good antibacterial activity and biocompatibility.

In this study, Ginkgo biloba leave polyprenols (GBP) and polypyridine metal complex were individually utilized as functional ligand and main ligand, four kinds of novel GBP-based polypyridine metal complexes were successfully synthesized and their cell absorption capacity, light-dark stability, photodissociation efficiency, ROS production capacity, light-controlled antibacterial and anti-tumor activities as well as mechanisms were systematically investigated by ultraviolet visible spectrophotometer (UV–vis), confocal laser scanning microscope (CLSM), gel electrophoresis (GE), scanning electron microscope (SEM), oxford cup method, MTT method etc. The lipid water distribution coefficients of complex 1, 2 and 4 were all within the range of 0∼3, demonstrating their better cell absorption capacity and more competitive bioavailability potentiality compared with GBP. All of the synthesized complexes possessed excellent stability in a dark environment, and could conduct ligand dissociation under the condition of visible light irradiation except complex 1. In which, complex 2 and complex 4 were able to achieve degradation rates of 37.9 % and 54.4 % within 5 min, separately. In addition, complex 2 and complex 4 exhibited superior inhibitory activities on the HN-3 tumor cells on account of their stronger ROS production capacity. Moreover, the constricted expression of BCL-2 and NF-kB p-p65, especially the promoted expression of BAX may be one of the root cause. The four synthesized complexes had preferable inhibition effects against S. aureus under the condition of visible light irradiation in contrast to darkness, in which complex 4 was the best and its MIC and MBC values were 6.25 and 12.5 μg/mL, respectively. The antibacterial mechanism of the complex 4 may be in relation to the synergistic effect of multiple factors, including leakage of bacterial inclusion, change of cell membrane permeability and disruption of cell wall etc. All of the above generalized researches will pave a way for the high-value development and application of GBP-based functional products.

Abstract Objective This study aimed to confirm the safety and feasibility of totally endoscopic repair for mitral regurgitation (MR) in Barlow’s disease. Methods From June 2018 to December 2022, 21 consecutive Barlow’s disease patients (aged 33 ± 12 years; 57.1% male) underwent totally endoscopic mitral valve (MV) repair with leaflets folding, multiple artificial chordae implantation and ring annuloplasty. The safety and feasibility of this technique was evaluated by its mid-term clinical outcomes. Results There was no operative death or complications. The mean cardiopulmonary bypass (CPB) time was 190 ± 41 (128–267) min, and the aortic cross-clamp time was 145 ± 32 (66–200) min. The average number of artificial chordae implantation was 2.9 ± 0.7 (1–4) pairs. The mean MV coaptation length was 1.4 ± 0.3 (0.8–1.8) cm, and the median transvalvular gradient was 1 [interquartile range (IQR), 1–2] mmHg. During a median follow-up time of 24 (IQR, 10–38) months, all patients showed persistent effective valve function with no significant MR or systolic anterior motion. Conclusions Totally endoscopic repair was a safe, effective, and reproducible procedure with satisfied mid-term clinical outcomes for MR in Barlow’s disease. However, further randomized and long-term follow-up studies were warranted to determine its clinical effects.

Abstract Background Premature ovarian insufficiency (POI) is a major cause of infertility. In this study, we aimed to investigate the effects of the combination of bone marrow mesenchymal stem cells (BMSCs) and moxibustion (BMSCs-MOX) on POI and evaluate the underlying mechanisms. Methods A POI rat model was established by injecting different doses of cyclophosphamide (Cy). The modeling of POI and the effects of the treatments were assessed by evaluating estrous cycle, serum hormone levels, ovarian weight, ovarian index, and ovarian histopathological analysis. The effects of moxibustion on BMSCs migration were evaluated by tracking DiR-labeled BMSCs and analyzing the expression of chemokines stromal cell-derived factor 1 (Sdf1) and chemokine receptor type 4 (Cxcr4). Mitochondrial function and mitophagy were assessed by measuring the levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), ATP, and the mitophagy markers (Drp1, Pink1, and Parkin). Furthermore, the mitophagy inhibitor Mdivi-1 and the mitophagy activator CCCP were used to confirm the role of mitophagy in Cy-induced ovarian injury and the underlying mechanism of combination therapy. Results A suitable rat model of POI was established using Cy injection. Compared to moxibustion or BMSCs transplantation alone, BMSCs-MOX showed improved outcomes, such as reduced estrous cycle disorders, improved ovarian weight and index, normalized serum hormone levels, increased ovarian reserve, and reduced follicle atresia. Moxibustion enhanced Sdf1 and Cxcr4 expression, promoting BMSCs migration. BMSCs-MOX reduced ROS levels; upregulated MMP and ATP levels in ovarian granulosa cells (GCs); and downregulated Drp1, Pink1, and Parkin expression in ovarian tissues. Mdivi-1 significantly mitigated mitochondrial dysfunction in ovarian GCs and improved ovarian function. CCCP inhibited the ability of BMSCs-MOX treatment to regulate mitophagy and ameliorate Cy-induced ovarian injury. Conclusions Moxibustion enhanced the migration and homing of BMSCs following transplantation and improves their ability to repair ovarian damage. The combination of BMSCs and moxibustion effectively reduced the excessive activation of mitophagy, which helped prevent mitochondrial damage, ultimately improving ovarian function. These findings provide a novel approach for the treatment of pathological ovarian aging and offer new insights into enhancing the efficacy of stem cell therapy for POI patients. Graphical abstract

Two new termite-pathogenic species, Ophiocordyceps globiperitheciata and O. longistipes, are described from Yunnan Province, China. Six-locus (ITS, nrSSU, nrLSU, tef-1α, rpb1 and rpb2) phylogenetic analyses in combination with morphological observations were employed to characterize these two species. Phylogenetically, O. globiperitheciata is most closely related to Hirsutella cryptosclerotium and O. communis, whereas O. longistipes shares a sister relationship with O. fusiformis. However, O. globiperitheciata differs from H. cryptosclerotium by parasitizing Blattodea and producing clavate, unbifurcated stromata. Ophiocordyceps globiperitheciata is distinguished from O. communis by multiple stromata, shorter asci and ascospores. Ophiocordyceps longistipes differs from O. fusiformis in producing larger stromata, perithecia, asci and ascospores, as well as smaller citriform or oval conidia. Morphological descriptions of the two new species and a dichotomous key to the 19 termite-pathogenic Ophiocordyceps species are presented.

Background Since 2009, community health management for type 2 diabetes mellitus (T2DM) has been significantly promoted and implemented as a national public health service program. However, the impact of clinical inertia, defined as failure to take timely interventions when therapeutic goals are unmet, hinders the achievement of long-term optimal glycemic control in T2DM patients. Therefore, addressing clinical inertia to improve glycemic control rates is an important and urgent task for optimizing diabetes health management. Objective To identify the key failure modes of clinical inertia in community health management for T2DM, systematically analyze the underlying causes of these failure modes, and propose corresponding intervention measures. Methods Based on community realities and guided by the Healthcare Failure Mode and Effect Analysis (HFMEA) framework, a foundational comprehension of community health management processes for T2DM, the root causes of clinical inertia, and prospective intervention measures were obtained through field research, interviews, and literature review from 2020-01-01 to 2023-06-30. The Delphi method was employed based on this basis to engage 16 experts in two rounds of expert consultation during 2022-01-10—02-25, to delineate the key failure modes, their root causes, and intervention measures concerning clinical inertia in community health management for T2DM. Results The expert authority coefficients for the first and second rounds were 0.791 and 0.729, respectively, ten key failure modes of clinical inertia in community health management for T2DM were quantitatively identified by calculating the risk priority number (RPN) metric and ranked in descending RPN value as follows: untimely insulin treatment, untimely alcohol cessation, untimely routine referral, untimely smoking cessation, untimely emergency referral, untimely triple therapy, untimely weight control, untimely dietary modification, untimely dichotomous therapy, and untimely detection of hypoglycemia. The root causes of these key failure modes were explored from the perspectives of patients, physicians, and the healthcare system, enabling the formulation of targeted intervention measures. Conclusion The devised intervention measures to address clinical inertia exhibit substantial scientific validity and authority, providing a robust foundation for enhancing the community health management model for T2DM.

Humans and microbes (e.g., bacteria, fungi, and microalgae) have coexisted and coevolved toward reciprocal adaptation. As omics technologies have rapidly advanced, the relevance of microbes to human health and disease as well as other fields has been progressively unraveled. This review focuses on the human gut microbiota, which is an emerging focus of microbiological research. This review synthesizes recent advances in exploring the fundamentals and multiple functions of the human gut microbiota and its associations with human health and diseases as well as microbiota-targeted therapies.

Effective detection of the contours of cloud masks and estimation of their distribution can be of practical help in studying weather changes and natural disasters. Existing deep learning methods are unable to extract the edges of clouds and backgrounds in a refined manner when detecting cloud masks (shadows) due to their unpredictable patterns, and they are also unable to accurately identify small targets such as thin and broken clouds. For these problems, we propose MDU-Net, a multiscale dual up-sampling segmentation network based on an encoder–decoder–decoder. The model uses an improved residual module to capture the multi-scale features of clouds more effectively. MDU-Net first extracts the feature maps using four residual modules at different scales, and then sends them to the context information full flow module for the first up-sampling. This operation refines the edges of clouds and shadows, enhancing the detection performance. Subsequently, the second up-sampling module concatenates feature map channels to fuse contextual spatial information, which effectively reduces the false detection rate of unpredictable targets hidden in cloud shadows. On a self-made cloud and cloud shadow dataset based on the Landsat8 satellite, MDU-Net achieves scores of 95.61% in PA and 84.97% in MIOU, outperforming other models in both metrics and result images. Additionally, we conduct experiments to test the model’s generalization capability on the landcover.ai dataset to show that it also achieves excellent performance in the visualization results.