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Abstract Background Dry powder inhalers (DPIs) rely on both internal resistance and patients’ inspiratory capacity for effective operation. Optimal inspiratory technique is crucial for DPI users. This study assessed the accuracy and repeatability of two available devices, PF810® and In-Check DIAL®, and analyzed their measurement errors and consistency in detecting inspiratory capacity. Methods The accuracy and repeatability of peak inspiratory flow (PIF) and forced inspiratory vital capacity (FIVC) against various internal resistances of the two devices were assessed using standard waveforms generated by a breathing simulator. The agreement of PIF measurements between the two devices in healthy volunteers and chronic obstructive pulmonary disease (COPD) patients was analyzed with the intraclass correlation coefficient and Bland–Altman graphical analysis. Results PF810® showed great accuracy and repeatability in measuring PIF, except for square waveforms at the lowest flow rate (20 L/min). In-Check DIAL® exhibited poor accuracy against high resistance levels. In scenarios with no resistance, In-Check DIAL® had significantly smaller measurement errors than PF810®, but larger errors against high resistance levels. The two devices showed excellent agreement (ICC > 0.80, P

Abstract Background Comparisons between endurance training (ET) and resistance training (RT) have produced equivocal findings in chronic obstructive pulmonary disease (COPD) patients. The purpose of our study is to investigate the effectiveness and long-term outcomes of adding ET and RT to conventional medical treatment in patients with COPD. A secondary objective is to investigate the clinical improvements resulting from exercise training in patients with different disease severities. Methods The study was a multicenter, prospective trial in people with stable COPD. The cohort was randomized to three groups: individualized medical treatment group (MT), MT + endurance training group (MT + ET) and MT + resistance training group (MT + RT). Exercise was performed 3 times weekly over a 12-week period. The endpoints of exercise capacity, health-related quality of life, COPD symptoms, lung function, and anxiety and depression questionnaires were re-evaluated at baseline, at the completion of the intervention and at 6 and 12-month follow-up. According to the COPD assessment tool offered by GOLD guidelines, patients were stratified into GOLD A and B groups and GOLD C and D groups for further subgroup analysis. Results The intention-to-treat (ITT) population included 366 patients, 328 of them completed the study protocol over 12 months (the PP-population). There were no significant differences in the primary outcome, quality of life, between patients who underwent medical treatment (MT) alone, MT + endurance training (MT + ET), or MT + resistance training (MT + RT) at the completion of the intervention, 6-, or 12-month follow-up. Additionally, no significant differences were observed between MT, MT + RT, or MT + ET groups concerning the primary outcome, exercise capacity (3MWD), after initial 3 months of intervention. However, a small statistically significant difference was noted in favor of MT + ET compared to MT + RT at 12 months (ITT: Δ3MWD in ET vs RT = 5.53 m, 95% confidence interval: 0.87 to 13.84 m, P = 0.03) (PP: Δ3MWD in ET vs RT = 7.67 m, 95% confidence interval: 0.93 to 16.27 m, P = 0.04). For patients in the GOLD C and D groups, improvement in quality of life following ET or RT was significantly superior to medical intervention alone. Furthermore, upon completion of the exercise regimen, RT exhibited a greater improvement in anxiety compared to ET in these patients (ITT: ΔHAD-A at 3-month: RT = -1.63 ± 0.31 vs ET = -0.61 ± 0.33, p

Abstract Cyclin-dependent kinase 7 (CDK7) serves as a pivotal regulator in orchestrating cellular cycle dynamics and gene transcriptional activity. Elevated expression levels of CDK7 have been ubiquitously documented across a spectrum of malignancies and have been concomitantly correlated with adverse clinical outcomes. This review delineates the biological roles of CDK7 and explicates the molecular pathways through which CDK7 exacerbates the oncogenic progression of breast cancer. Furthermore, we synthesize the extant literature to provide a comprehensive overview of the advancement of CDK7-specific small-molecule inhibitors, encapsulating both preclinical and clinical findings in breast cancer contexts. The accumulated evidence substantiates the conceptualization of CDK7 as a propitious therapeutic target in breast cancer management.

Abstract Background Little attention has been paid to the pathophysiological changes in the natural history of chronic obstructive pulmonary disease (COPD). The destructions of the small airways were visualized on thoracic micro-computed tomography scan. We investigated whether small airway inflammation (SAI) was the risk for the development of COPD. Methods A total of 1062 patients were enrolled and analyzed in the study. The partitioned airway inflammation was determined by exhaled nitric oxide (NO) of FnNO, FeNO50, FeNO200, and calculated CaNOdual. Both FeNO200 and CaNOdual were compared to detect the promising predictor for peripheral airway/alveolar inflammation in COPD. The correlation between exhaled NO and white cell classification was evaluated to determine the inflammation type during the development of COPD. Results Exhaled NO levels (FnNO, FeNO50, FeNO200, and CaNOdual) were the highest in the COPD group compared with all other groups. Furthermore, compared with controls, exhaled NO levels (FeNO50, FeNO200, and CaNOdual) were also significantly higher in the emphysema, chronic bronchitis, and smoking groups. FeNO200 was found to be a promising predictor for peripheral airway/alveolar inflammation (area under the curve [AUC] of the receiver operating characteristic [ROC] curve, area under the curve [AUC] = 0.841) compared with CaNOdual (AUC ROC = 0.707) in COPD. FeNO200 was the main risk factor (adjusted odds ratio, 2.191; 95% CI, 1.797–2.671; p = 0.002) for the development of COPD. The blood eosinophil and basophil levels were correlated with FeNO50 and FeNO200. Conclusion The complete airway inflammations were shown in COPD, whereas SAI was the main risk factor for the development of COPD, which might relate to eosinophil and basophil levels.

Oral squamous cell carcinoma (OSCC), a major subtype of head and neck cancers, presents significant challenges due to its aggressive feature and limited therapeutic efficacy of conventional treatments. In response to these challenges, Natural Killer (NK) cells, a vital component of the innate immune system, are being explored for their therapeutic potential in OSCC due to their inherent ability to target and eliminate cancer cells without prior sensitization. This review uniquely focuses on the evolving role of NK cells specifically in OSCC, incorporating recent advancements in CAR-NK cell engineering and personalized therapy approaches that have not been comprehensively covered in previous reviews. The mechanisms through which NK cells exert cytotoxic effects on tumor cells include direct killing through the engagement of natural cytotoxic receptors and antibody-dependent cellular cytotoxicity (ADCC), making them promising agents in cancer immunotherapy. Additionally, the article explores recent advancements in engineering NK cells to enhance their antitumor activity, such as the modification with chimeric antigen receptors (CARs) to target specific tumor antigens. Clinical implications of NK cell-based therapies, including the challenges of integrating these treatments with existing protocols and the potential for personalized therapy, are examined. The review highlights the promise of NK cell therapies in improving outcomes for OSCC patients and outlines future directions for research in this dynamic field of oncological immunotherapy.

Background: Less attention has been paid to the pathophysiological changes in atypical asthma such as cough variant asthma (CVA) and chest tightness variant asthma (CTVA). The obstruction of large and small airways is the important component in the development of asthma. We investigated whether small airway inflammation (SAI) induced small airway dysfunction (SAD) in these atypical asthmatics. Methods: Six hundred and eighty-six patients were enrolled and analyzed in the study. The partitioned airway inflammation was assessed by fractional exhaled nitric oxide (FeNO), such as FnNO, FeNO50, FeNO200, and calculated alveolar fraction of exhaled NO (CaNOdual). Correlations between exhaled NOs and SAD-related variables were assessed, whereas cell classification was evaluated by Spearman's rank tests. Classic asthma, CVA, and CTVA about potential risk were conducted using binary logistic regression models. Results: The whole airway inflammation increased in classic and atypical asthma than controls, whereas the central and peripheral airway inflammation in the CVA and CTVA groups increased compared with the classic asthma group. Smoking exposure was found to increase the central and peripheral airway inflammation in patients with asthma. The exhaled NO of FeNO50 and FeNO200 was associated with SAD in classic asthma, but not in CVA and CTVA. FeNO200 was the main risk (adjusted odds ratio [OR], 1.591; 95 % CI, 1.121–2.259; P = .009) in classic asthma and (adjusted OR, 1.456; 95 % CI, 1.247–1.700; P = .000) in CVA. The blood eosinophil levels were correlated with FeNO50 and FeNO200 in classic asthma and atypical asthma. Conclusion: More severe inflammatory process was present in central and peripheral airways in CVA and CTVA, which might reflect a pre-asthmatic state. SAI was the predominant risk factor in the development of asthma before SAD.

IntroductionExploring monocytes’ roles within the tumor microenvironment is crucial for crafting targeted cancer treatments.MethodsThis study unveils a novel methodology utilizing four 20-color flow cytometry panels for comprehensive peripheral immune system phenotyping, specifically targeting classical, intermediate, and non-classical monocyte subsets. ResultsBy applying advanced dimensionality reduction techniques like t-distributed stochastic neighbor embedding (tSNE) and FlowSom analysis, we performed an extensive profiling of monocytes, assessing 50 unique cell surface markers related to a wide range of immunological functions, including activation, differentiation, and immune checkpoint regulation. DiscussionThis in-depth approach significantly refines the identification of monocyte subsets, directly supporting the development of personalized immunotherapies and enhancing diagnostic precision. Our pioneering panel for monocyte phenotyping marks a substantial leap in understanding monocyte biology, with profound implications for the accuracy of disease diagnostics and the success of checkpoint-inhibitor therapies. Key findings include revealing distinct marker expression patterns linked to tumor progression and providing new avenues for targeted therapeutic interventions.

Leaf color is one of the most important phenotypic features in horticultural crops and directly related to the contents of photosynthetic pigments. Most leaf color mutants are determined by the altered chlorophyll or carotenoid, which can be affected by light quality and intensity. Our previous study obtained a Chinese cabbage yellow cotyledon mutant that exhibited obvious yellow phenotypes in the cotyledons and the new leaves. However, the underlying mechanisms in the formation of yellow cotyledons and leaves remain unclear. In this study, the Chinese cabbage yellow cotyledon mutant 19YC-2 exhibited obvious difference in leaf color and abnormal chloroplast ultrastructure compared to the normal green cotyledon line 19GC-2. Remarkably, low-intensity light treatment caused turn-green leaves and a significant decrease in carotenoid content in 19YC-2. RNA-seq analysis revealed that the pathways of photosynthesis antenna proteins and carotenoid biosynthesis were significantly enriched during the process of leaf color changes, and many differentially expressed genes related to the two pathways were identified to respond to different light intensities. Remarkably, BrPDS and BrLCYE genes related to carotenoid biosynthesis showed significantly higher expression in 19YC-2 than that in 19GC-2, which was positively related to the higher carotenoid content in 19YC-2. In addition, several differentially expressed transcription factors were also identified and highly correlated to the changes in carotenoid content, suggesting that they may participate in the regulatory pathway of carotenoid biosynthesis. These findings provide insights into the molecular mechanisms of leaf color changes in yellow cotyledon mutant 19YC-2 of Chinese cabbage.

Phosphorus (P) deficiency is one of the most critical factors for plant growth and productivity, including its inhibition of lateral root initiation. Auxin response factors (ARFs) play crucial roles in root development via auxin signaling mediated by genetic pathways. In this study, we found that the transcription factor ZmARF1 was associated with low inorganic phosphate (Pi) stress-related traits in maize. This superior root morphology and greater phosphate stress tolerance could be ascribed to the overexpression of ZmARF1. The knock out mutant zmarf1 had shorter primary roots, fewer root tip number, and lower root volume and surface area. Transcriptomic data indicate that ZmLBD1, a direct downstream target gene, is involved in lateral root development, which enhances phosphate starvation tolerance. A transcriptional activation assay revealed that ZmARF1 specifically binds to the GC-box motif in the promoter of ZmLBD1 and activates its expression. Moreover, ZmARF1 positively regulates the expression of ZmPHR1, ZmPHT1;2, and ZmPHO2, which are key transporters of Pi in maize. We propose that ZmARF1 promotes the transcription of ZmLBD1 to modulate lateral root development and Pi-starvation induced (PSI) genes to regulate phosphate mobilization and homeostasis under phosphorus starvation. In addition, ZmERF2 specifically binds to the ABRE motif of the promoter of ZmARF1 and represses its expression. Collectively, the findings of this study revealed that ZmARF1 is a pivotal factor that modulates root development and confers low-Pi stress tolerance through the transcriptional regulation of the biological function of ZmLBD1 and the expression of key Pi transport proteins.

AbstractObjectives Recent evidence suggested that long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) play critical roles in the pathogenesis of vascular calcification (VC). In this study, we tried to explore the expression and role of a lncRNA, i.e., metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and a miRNA, i.e., miR-30c, in VC.Methods In vitro VC model was induced in human vascular smooth muscle cells (VSMCs) after 10 days culture in calcifying medium containing 2 mM Na2HPO4. Alizarin red S staining, calcium assay and western blot analysis of runt-related transcription factor 2 (Runx2) and alpha smooth muscle actin (α-SMA) were performed to evaluate VC. Knockdown of MALAT1 and up-regulation of MALAT1, miR-30c and Runx2 was performed to determine the impact of these molecules on VSMCs calcification. Dual-luciferase report assay was performed to confirm the relationship between MALAT1 and miR-30c or miR-30c and Runx2. In addition, quantitative reverse transcription PCR and western blot were used to determine gene and protein expression.Results MALAT1 was increased, while miR-30c was decreased in calcified VSMCs. Knockdown of MALAT1 suppressed VSMCs calcification; on the contrary, up-regulation of MALAT1 promoted VSMCs calcification. The effect of MALAT1 over-expression on VSMCs calcification was reversed by upregulation of miR-30c, which was reversed again by upregulation of Runx2. Dual-luciferase report assay confirmed that there is a direct interaction between MALAT1 and miR-30c, and Runx2 is a direct target of miR-30c.Conclusion MALAT1 over-expression promoted VSMCs calcification, which was at least partially through regulating the miR-30c/Runx2 axis.

Abstract Reprogrammed cellular metabolism is essential for maintaining cancer stem cells (CSCs) state. Here, we report that mitochondrial D-lactate catabolism is a necessary initiating oncogenic event during tumorigenesis of esophageal squamous cell carcinoma (ESCC). We discover that cyclin-dependent kinase 7 (CDK7) phosphorylates nuclear Yes-associated protein 1 (YAP) at S127 and S397 sites and enhances its transcription function, which promotes D-lactate dehydrogenase (LDHD) protein expression. Moreover, LDHD is enriched significantly in ESCC-CSCs rather than differentiated tumor cells and high LDHD status is connected with poor prognosis in ESCC patients. Mechanistically, the CDK7-YAP-LDHD axis helps ESCC-CSCs escape from ferroptosis induced by D-lactate and generates pyruvate to satisfy energetic demands for their elevated self-renewal potential. Hence, we conclude that esophageal CSCs adopt a D-lactate elimination and pyruvate accumulation mode dependent on CDK7-YAP-LDHD axis, which drives stemness-associated hallmarks of ESCC-CSCs. Reasonably, targeting metabolic checkpoints may serve as an effective strategy for ESCC therapy.

Abstract Oral administration is preferred over other drug delivery methods due to its safety, high patient compliance, ease of ingestion without discomfort, and tolerance of a wide range of medications. However, oral drug delivery is limited by the poor oral bioavailability of many drugs, caused by extreme conditions and absorption challenges in the gastrointestinal tract. This review thoroughly discusses the targeted drug vehicles to the intestinal lymphatic system (ILS). It explores the structure and physiological barriers of the ILS, highlighting its significance in dietary lipid and medication absorption and transport. The review presents various approaches to targeting the ILS using spatially precise vehicles, aiming to enhance bioavailability, achieve targeted delivery, and reduce first-pass metabolism with serve in clinic. Furthermore, the review outlines several methods for leveraging these vehicles to open the ILS window, paving the way for potential clinical applications in cancer treatment and oral vaccine delivery. By focusing on targeted drug vehicles to the ILS, this article emphasizes the critical role of these strategies in improving therapeutic efficacy and patient outcomes. Overall, this article emphasizes the critical role of targeted drug vehicles to the ILS and the potential impact of these strategies on improving therapeutic efficacy and patient outcomes.

Abstract As large-scale genomic studies have progressed, it has been revealed that a single reference genome pattern cannot represent genetic diversity at the species level. While domestic animals tend to have complex routes of origin and migration, suggesting a possible omission of some population-specific sequences in the current reference genome. Conversely, the pangenome is a collection of all DNA sequences of a species that contains sequences shared by all individuals (core genome) and is also able to display sequence information unique to each individual (variable genome). The progress of pangenome research in humans, plants and domestic animals has proved that the missing genetic components and the identification of large structural variants (SVs) can be explored through pangenomic studies. Many individual specific sequences have been shown to be related to biological adaptability, phenotype and important economic traits. The maturity of technologies and methods such as third-generation sequencing, Telomere-to-telomere genomes, graphic genomes, and reference-free assembly will further promote the development of pangenome. In the future, pangenome combined with long-read data and multi-omics will help to resolve large SVs and their relationship with the main economic traits of interest in domesticated animals, providing better insights into animal domestication, evolution and breeding. In this review, we mainly discuss how pangenome analysis reveals genetic variations in domestic animals (sheep, cattle, pigs, chickens) and their impacts on phenotypes and how this can contribute to the understanding of species diversity. Additionally, we also go through potential issues and the future perspectives of pangenome research in livestock and poultry.

DGUOK deficiency has primarily been associated with lethal hepatic failure with or without hypotonia, nystagmus, and psychomotor retardation, features typical of mitochondrial disease. A study in 3 Turkish children identified homozygosity for a variant in DGUOK as associated with idiopathic non-cirrhotic portal hypertension (INCPH). However, no further instances of INCPH associated with DGUOK variants have been reported. We here describe a fourth patient with DGUOK variants and childhood-onset INCPH, a 12-year-old Han Chinese boy, reporting clinical manifestations, histopathologic findings, and results of genetic studies. The child presented with hepatosplenomegaly; portal hypertension and hypersplenism were found. Vascular changes with hepatic fibrosis (Scheuer score 3) were observed on liver biopsy. Whole-exome sequencing and family analyses revealed compound heterozygosity for the DGUOK (NM_080916.3) variants c.778_781dup, (p.Thr261Serfs*28) and c.831_832del, (p.*278Thrfs*9) in the proband. These observations support ascription of instances of INCPH in children to variation in DGUOK.

Abstract Although some tumor has become a curable disease for many patients, involvement of the central nervous system (CNS) is still a major concern. The blood–brain barrier (BBB), a special structure in the CNS, protects the brain from bloodborne pathogens via its excellent barrier properties and hinders new drug development for brain tumor. Recent breakthroughs in nanotechnology have resulted in various nanovehicless (NPs) as drug carriers to cross the BBB by different strategys. Here, the complex compositions and special characteristics of causes of brain tumor formation and BBB are elucidated exhaustively. Additionally, versatile drug nanovehicles with their recent applications and their pathways on different drug delivery strategies to overcome the BBB obstacle for anti-brain tumor are briefly discussed. Customizing nanoparticles for brain tumor treatments is proposed to improve the efficacy of brain tumor treatments via drug delivery from the gut to the brain. This review provides a broad perspective on customizing delivery nano-vehicles characteristics facilitate drug distribution across the brain and pave the way for the creation of innovative nanotechnology-based nanomaterials for brain tumor treatments.

● Agricultural intensification reduced the complexity and connectance of soil food webs. ● Agricultural intensification impaired the robustness of pollination networks. ● High connectance in co-occurrence networks indicates efficient nutrient utilization. Complex network theory has been increasingly used in various research areas, including agroecosystems. This paper summarizes the basic concepts and approaches commonly used in complex network theory, and then reviews recent studies on the applications in agroecosystems of three types of common ecological networks, i.e., food webs, pollination networks and microbial co-occurrence networks. In general, agricultural intensification is considered to be a key driver of the change of agroecosystems. It causes the simplification of landscape, leads to the loss of biocontrol through cascading effect in food webs, and also reduces the complexity and connectance of soil food webs. For pollination networks, agricultural intensification impaired the robustness by reducing specialization and enhancing generality. The microbial co-occurrence networks with high connectance and low modularity generally corresponded to high efficiency in utilization of nutrients, and high resistance to crop pathogens. This review aims to show the readers the advances of ecological networks in agroecosystems and inspire the researchers to conduct their studies in a new network perspective.

Positive relationships between biodiversity and temporal stability through species asynchrony are well-documented, but the underlying mechanisms remain debated. Here, the authors show that statistical averaging is the main mechanism of plant diversity effects on community stability.

BackgroundGlucagon-like peptide-1 receptor agonists (GLP-1RAs) have been widely used in treating type 2 diabetes mellitus (T2DM) and obesity in adults, but scientific research about the indication in children and adolescents is scarce. The current study aims to explore the prescriptions of GLP-1RAs in children and adolescents in China and to evaluate its rationality.MethodsGLP-1RA prescriptions of children and adolescents were retrospectively obtained from the Hospital Prescription Analysis Cooperative Project. The study extracted information on patient’s demographic characteristics, monotherapy and combination therapy of GLP-1RAs, and trends in GLP-1RA usage from 2016 to 2021. The rationality of GLP-1RA prescriptions was comprehensively assessed based on the indications approved by China National Medical Products Administration (NMPA), the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), Pharmaceuticals and Medical Devices Agency (PMDA), and published randomized controlled trials (RCTs).ResultsA total of 234 prescriptions from 46 hospitals were included, with a median age of 17 years old. The majority of patients were diagnosed with overweight/obesity or prediabetes/diabetes, accounting for 43.59% and 46.15%, respectively. There were 88 patients on GLP-1RA monotherapy. GLP-1RAs plus metformin was the most common combination therapy (38.89%). 12.39% of patients were found a co-administration with orlistat. The share of overweight/obesity prescriptions increased from 27% in 2016 to 54% in 2021, whereas prediabetes/diabetes prescriptions declined from 55% to 42%. The prescriptions were divided into appropriate and questionable groups according to the diagnosis, and the potentially questionable prescription was related to age (p = 0.017), department visited (p = 0.002), and any hospitalization (p < 0.001).ConclusionsThis study described the prescribing of GLP-1RAs in children and adolescents. Our findings indicated that the utilization of GLP-1RAs has increased from 2016 to 2021. There was a strong basis for administering GLP-1RAs in overweight/obesity and prediabetes/diabetes, whereas the evidence was insufficient in other conditions. It is crucial to demand robust and sustained efforts to enhance the awareness of the safety of utilization of GLP-1RAs in children and adolescents.

Energy harvesters based on a piecewise linear system make it possible to extract more energy from environment vibrations. The amplitude truncation effect is a phenomenon of an energy harvester with a piecewise linear system. It shows a wider energy harvesting bandwidth and a lower voltage response than the purely linear counterpart. This work investigates the influence of spring length on the amplitude truncation effect and power density of electromagnetic energy harvesters. We first establish an analytical model of the piecewise linear system. Then, we apply the averaging method to explore the voltage responses in the frequency domain and compare the influence of various parameters. Later, we conduct a finite element simulation to analyze the voltage response at a constant frequency. The results obtained by the finite element simulation and averaging method match well with the experimental measurements. The experimental results demonstrate that the amplitude truncation effect is more visible at the shorter spring. Spring length plays a key role in the power density of an electromagnetic energy harvester. The case of 40 mm yields a maximum average power of 45.13 mW. The case of 30 mm displays a maximum power density of 2.35 mW/cm 3.

Genetic diversity, population structure, and population expansion of goats worldwide (4 165 individuals from 196 breeds) were analyzed using published mitochondrial DNA (mtDNA) D_loop hypervariable region sequences. Results showed that 2 409 haplotypes and 301 polymorphic sites were present within the 401-bp length D_loop region, the nucleotide diversity (Pi) was 0.03471, and the haplotype diversity (Hd) was 0.9983. Phylogenetic analysis revealed that 98.92% of haplotypes were divided into six obvious clusters, consistent with the classification of the known mitochondrial haplogroups of goats. Haplogroup A accounted for the largest proportion (86%). Interestingly, two unknown divisions (Unknown I and Unknown II) were discovered from goats in Southwest China, suggesting that Southwest China has unique maternal haplogroups. Analysis of molecular variance (AMOVA) and the average number of pairwise differences between populations (PiXY) indicated that geographical variation was small but significant. Neutrality tests (Tajima's D and Fu's FS tests) and mismatch distribution showed that haplogroups B, C, and G had expansion histories. In addition, the phylogenetic relationship between domestic and wild goats suggested that Capra aegagrus is the most likely wild ancestor and may have participated in the domestication of ancestral populations of A, B, C, and F haplogroups. A meta-analysis on the mtDNA sequences of goats from international databases was conducted to analyze goats’ genetic diversity, population structure, and matrilineal system evolution worldwide. The results may help further understand the domestication history and gene flow of goats worldwide.

Abstract Different medical treatment choices may affect the health of patients with chronic diseases. This study aims to assess the relationship between treatment choices, including the use of traditional Chinese medicine (TCM), and the health levels of middle-aged and elderly patients with six chronic diseases. The sample data comes from China Health and Retirement Longitudinal Study (CHARLS 2018). Basic conditions, medical choices and health status of patients are incorporated. The ordered Logit and Logit regression models are used to analyze and compare the effects of six chronic disease patients’ medical options on their self-rated health (SRH) and depression. The overall average score of SRH is the highest in patients with heart disease (the worst in SRH), which is 3.433. Arthritis patients have the highest overall depression average score (depression) at 0.444. Under the premise of controlling a variety of socio-demographic factors, compared with the non-treatment group, taking TCM has a significant positive effect on SRH of patients with five diseases except hypertension. Both taking western medicine (WM) and taking integrated Chinese and Western medicine (IM) have a significant positive effect on SRH scores of patients with six chronic diseases in middle and old age. Taking TCM has effect on depression of patients with heart or stomach diseases, and taking WM and IM affects depression of middle-aged and elderly chronic patients except diabetes. Taking IM has a greater effect on SRH and depression of chronically ill patients, followed by taking WM, and the effect of taking TCM is relatively small, which is related to the development stage of the disease. Therefore, in the future, the control and treatment of chronic diseases in the middle and late stages can be discussed from the perspective of integrated traditional Chinese and western medicine, but attention should be paid to drug interactions. In order to improve the treatment rate and health level of patients with chronic diseases, their economic burden should be reduced, and they should be guided to choose more reasonable treatment methods.

Abstract Objective Falling is one of the main causes of death and morbidity in the elderly. This study aims to explore the association between elderly patients with chronic diseases and their health-related behaviors and falls in the elderly, and to provide clues for the prevention and intervention of injuries caused by falls in the elderly. Methods Based on the basic demographic characteristics data, number of chronic diseases, health-related behaviors, and physical and mental health data of 5867 elderly people aged 60 and above in the 2018 CHARLS data, this paper used ordered logit regression to analyze the correlation between chronic diseases and their health-related behaviors and falls of Chinese elderly. On this basis, it also distinguishes whether there is care or not, explores whether the related factors of falls of elderly people will be different, and tests the intermediary effect of health status to further explore its mechanism. Results The number of chronic diseases and health-related behaviors in the four dimensions of sleeptime, drinking, smoking, and activity are significantly correlated with falls in the elderly. Among them, health status plays a significant mediating role in the relationship of the number of chronic diseases and sleeptime and activity on the falls of the elderly. In addition, compared with the elderly without care, the risk of falls in the elderly in care is only related to the number of chronic diseases and sleeptime, while the elderly without care is related to the number of chronic diseases and multiple factors such as smoking, drinking and activity. Conclusion Falls are significantly associated with chronic disease and health-related behaviors, while risk or protective factors for falls vary according to whether older adults are cared for. Therefore, targeted interventions can be made for the factors that affect the fall of the elderly according to different situations.

ObjectiveScientifically organizing emergency rescue activities to reduce mortality in the early stage of earthquakes.MethodsA robust casualty scheduling problem to reduce the total expected death probability of the casualties is studied by considering scenarios of disrupted medical points and routes. The problem is described as a 0-1 mixed integer nonlinear programming model. An improved particle swarm optimization (PSO) algorithm is introduced to solve the model. A case study of the Lushan earthquake in China is conducted to verify the feasibility and effectiveness of the model and algorithm.ResultsThe results show that the proposed PSO algorithm is superior to the compared genetic algorithm, immune optimization algorithm, and differential evolution algorithm. The optimization results are still robust and reliable even if some medical points fail and routes are disrupted in affected areas when considering point-edge mixed failure scenarios.ConclusionDecision makers can balance casualty treatment and system reliability based on the degree of risk preference considering the uncertainty of casualties, to achieve the optimal casualty scheduling effect.

The influence of metal ions, the state of metal salt, and ligands on the sterilization ability of (Metalorganic frameworks) MOFs to effectively achieve sterilization has been investigated in this study. Initially, the MOFs were synthesized by elements of Zn, Ag, and Cd for the same periodic and main group of Cu. This illustrated that the atomic structure of Cu was more beneficial for coordinating with ligands. To further induce the maximum amount of Cu2+ ions in the Cu-MOFs to achieve the highest sterilization, various Cu-MOFs synthesized by the different valences of Cu, various states of copper salts, and organic ligands were performed, respectively. The results demonstrated that Cu-MOFs synthesized by 3, 5-dimethyl-1, 2, 4-triazole and tetrakis (acetonitrile) copper(I) tetrafluoroborate presented the largest inhibition-zone diameter of 40.17 mm towards Staphylococcus Aureus (S. aureus) under dark conditions. The proposed mechanism of Cu (Ⅱ) in MOFs could significantly cause multiple toxic effects, such as the generation of reactive oxygen species, and lipid peroxidation in S. aureus cells, when the bacteria was anchored by the Cu-MOFs via electrostatic interaction. Finally, the broad antimicrobial properties of Cu-MOFs against Escherichia coli (E. coli), Acinetobacter baumannii (A. baumannii), and S. aureus were demonstrated. In conclusion, the Cu-3, 5-dimethyl-1, 2, 4-triazole MOFs appeared to be potential antibacterial catalysts in the antimicrobial field.

BackgroundPoststroke depression (PSD) is a common complication that can seriously affect patients' functional recovery and quality of life after a stroke. Various side effects have been found to be associated with the pharmacological therapies used for PSD. Studies have shown that Chinese herbal medicine (CHM) can effectively improve PSD-like behavior and neurological function in clinical and animal studies. The efficacy of CHM on PSD in animal models has not been systematically analyzed.MethodsThe following electronic databases were searched for articles published up to September 2022: PubMed, Web of Science, the Cochrane Library, and Embase. Studies that reported the efficacy of CHM in animals with PSD and were written in English were included. Depression-like behavior and the neurological deficit score were assessed as measures of efficacy. The included studies assessed depression-like behavior using sucrose preference, open-field, forced swimming, and tail suspension tests, as well as body weight. The Review Manager version 5.4 and STATA version 13.1 software packages were used for the meta-analysis. The standardized mean difference (SMD) with 95% confidence intervals was used to assess all the outcomes. Subgroup analyses were performed to explore the sources of heterogeneity. The Egger's test and funnel plots were used to assess the potential publication bias. Sensitivity analyses were used to identify the stability of the results.ResultsA total of 14 studies, including 12 CHMs involving 442 rats, fulfilled the inclusion criteria for meta-analysis. The pooled results showed that CHM significantly alleviated neurological deficits (−1.72 SMD, −2.47– −0.97) and was efficacious in improving the depression-like behavior of rats in the sucrose preference (2.08 SMD, 1.33–2.84), open-field (2.85 SMD, 1.88–3.83), forced swimming (−1.83 SMD, −2.23−1.44), and tail suspension tests (−1.35 SMD, −1.94−0.76).ConclusionOur results suggest that CHM could significantly improve depression-like behavior and neurological function in animals with PSD. The current results should be interpreted with caution because only animal studies were included.

Summary: The electric signals of cantilever energy harvesting devices with/without a crack were mainly obtained by external sensors, so detecting device damage on a large scale is difficult. To tackle the issue, a cantilever-structure freestanding triboelectric nanogenerator (CSF-TENG) device was proposed, which can scavenge ambient energy and act as a self-powered sensor. Firstly, the relation between the peak-to-peak voltage and amplitude of the CSF-TENG was established. Next, the output performance of the CSF-TENG was measured. Then, depending on electric signals output by the CSF-TENG, a cantilever defect identification model was built by using the wavelet packet and long short-term memory (LSTM) algorithms. The experimental results manifest that the accuracy of the model is about 98.6%. Thus, the CSF-TENG with a crack can be detected timely due to its self-monitoring ability, which is of great significance for the development of self-powered sensor networks.

Abstract Background There may be differences in gender and marital status in the impact of grandchild care on the depression of the Chinese older adults. This research explores the effect of grandchild care on the depression of Chinese older adults of different genders and marital status, and explores the mediating role of intergenerational support from children between grandchild care and depression. Methods This research uses the data of 3540 Chinese older adults from the China Health and Retirement Longitudinal Study (CHARLS) in 2018. The OLS model is used to analyze the effect of grandchild care on the depression of the older adults. and the older adults are classified according to gender and marital status, and the differences in the effect of grandchild care on the depression of the elderly of different genders and marital status is explored. Finally, the bootstrap method is used to test the mediating effect of intergenerational support from children. Results The research finds that grandchild care has a significant impact on the depression of the older adults in China, and providing grandchild care can significantly reduce the depression of the older adults. The effect of grandchild care on the depression of the older adults is different between different genders and marital status. After categorizing the older adults by gender, the grandchild care only has a significant impact on the depression of female older adults; after classified by marital status, grandchild care only has a significant impact on the depression of the older adults who don’t have a spouse. The mediating effect analysis shows that both children’s emotional support and children’s economic support have a mediating effect between grandchild care and depression of the older adults. Conclusion The depression of the Chinese older adults is affected by grandchild care, and this effect is more prominent in female older adults and the older adults who don’t have a spouse. The society should support and encourage capable older adults to participate in grandchild care, and children should also provide more intergenerational support to the older adults who provide grandchild care, so as to further play the role of grandchild care in relieving depression of the older adults.

Abstract Background Biallelic variants in HSD3B7 cause 3β-hydroxy-Δ5-C27-steroid oxidoreductase (HSD3B7) deficiency, a life-threatening but treatable liver disease. The goal of this study was to obtain detailed information on the correlation between the genotype and phenotype of HSD3B7 deficiency and to report on responses to primary bile acid therapy. Methods The medical records of a cohort of 39 unrelated patients with genetically and biochemically confirmed HSD3B7 deficiency were examined to determine whether there exist genotype-phenotype relationships in this bile acid synthesis disorder. Results In all, 34 of the 44 variants identified in HSD3B7 were novel. A total of 32 patients presented early with neonatal cholestasis, and 7 presented after 1-year of age with liver failure (n = 1), liver cirrhosis (n = 3), cholestasis (n = 1), renal cysts and abnormal liver biochemistries (n = 1), and coagulopathy from vitamin K1 deficiency and abnormal liver biochemistries (n = 1). Renal lesions, including renal cysts, renal stones, calcium deposition and renal enlargement were observed in 10 of 35 patients. Thirty-three patients were treated with oral chenodeoxycholic acid (CDCA) resulting in normalization of liver biochemistries in 24, while 2 showed a significant clinical improvement, and 7 underwent liver transplantation or died. Remarkably, renal lesions in 6 patients resolved after CDCA treatment, or liver transplantation. There were no significant correlations between genotype and clinical outcomes. Conclusions In what is the largest cohort of patients with HSD3B7 deficiency thus far studied, renal lesions were a notable clinical feature of HSD3B7 deficiency and these were resolved with suppression of atypical bile acids by oral CDCA administration.

Background: Whether deep saturation diving causes injury to lung function remains controversial and the mechanism is unclear. The present study aimed to evaluate the effects of a 500 m simulated single saturation dive on lung function.Methods: A retrospective study was performed in nine professional divers who spent 176 h in a high-pressure environment simulating a depth of 500-m saturation dive (51 atm, 5.02 Mpa). Pulmonary function parameters were investigated and compared before and on 3 days after the dive.Results: Nine professional divers aged (36 ± 7) years were enrolled. Three days after the dive, the parameters related to expiratory flow (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC)) were decreased; the parameters related to small airway function (forced expiratory flow at 50%, 75% of FVC exhaled and forced mid-expiratory flow) were decreased compared with those before the dive (both p < 0.05). Additionally, after the dive, the parameters related to pulmonary diffusion function were decreased compared with those before the dive (both p < 0.05). The parameters related to lung volume (residual volume, vital capacity and total lung volume) and those related to respiratory exertion (peak expiratory flow and forced expiratory flow at 75% of FVC exhaled) were not significantly different between after and before the dive. Two divers with small airway dysfunction before the dive had obstructive ventilatory dysfunction after the dive. Additionally, mild obstructive ventilatory dysfunction in three divers before the dive became severe after the dive. After a bronchial dilation test, five divers showed improvement of FEV1, which ranged from 0.10 to 0.55 L. Chest radiographs and echocardiography of all divers were normal after diving.Conclusion: 500 m simulated saturation diving induces a decrease in small airway function and diffusion function. This injury may be associated with small airway and diffusion membrane lesions.

Abstract Due to their efficient recognition and lysis of malignant cells, natural killer (NK) cells are considered as specialized immune cells that can be genetically modified to obtain capable effector cells for adoptive cellular treatment of cancer patients. However, biological and technical hurdles related to gene delivery into NK cells have dramatically restrained progress. Recent technological advancements, including improved cell expansion techniques, chimeric antigen receptors (CAR), CRISPR/Cas9 gene editing and enhanced viral transduction and electroporation, have endowed comprehensive generation and characterization of genetically modified NK cells. These promising developments assist scientists and physicians to design better applications of NK cells in clinical therapy. Notably, redirecting NK cells using CARs holds important promise for cancer immunotherapy. Various preclinical and a limited number of clinical studies using CAR-NK cells show promising results: efficient elimination of target cells without side effects, such as cytokine release syndrome and neurotoxicity which are seen in CAR-T therapies. In this review, we focus on the details of CAR-NK technology, including the design of efficient and safe CAR constructs and associated NK cell engineering techniques: the vehicles to deliver the CAR-containing transgene, detection methods for CARs, as well as NK cell sources and NK cell expansion. We summarize the current CAR-NK cell literature and include valuable lessons learned from the CAR-T cell field. This review also provides an outlook on how these approaches may transform current clinical products and protocols for cancer treatment.

Abstract Background To meet the needs of foetal growth and development, marked changes in lipid profiles occur during pregnancy. Abnormal lipid metabolism is often accompanied by adverse pregnancy outcomes, which seriously affect maternal and infant health. Further understanding of the mechanism of lipid metabolism during pregnancy would be helpful to reduce the incidence of adverse pregnancy outcomes. Methods Pregnant mice were euthanized in the virgin (V) state, on day 5 of pregnancy (P5), on day 12 of pregnancy (P12), on day 19 of pregnancy (P19) and on lactation day 2 (L2). Body weight and energy expenditure were assessed to evaluate the general condition of the mice. Triglyceride (TG) levels, the cholesterol content in the liver, liver histopathology, serum lipid profiles, serum β-hydroxybutyrate levels, fibroblast growth factor-21 (FGF21) levels and the levels of relevant target genes were analysed. Results During early pregnancy, anabolism was found to play a major role in liver lipid deposition. In contrast, advanced pregnancy is an overall catabolic condition associated with both increased energy expenditure and reduced lipogenesis. Moreover, the accumulation of hepatic TG did not appear until P12, after the onset of endoplasmic reticulum (ER) stress on P5. Then, catabolism was enhanced, and FGF21 secretion was increased in the livers of female mice in late pregnancy. We further found that the expression of sec23a, which as the coat protein complex II (COPII) vesicle coat proteins regulates the secretion of FGF21, in the liver was decreased on P19. Conclusion With the activation of ER stress and increased FGF21 secretion during pregnancy, the hepatic TG content changes, suggesting that ER stress and FGF21 may play an important role in balancing lipid homeostasis and meeting maternal and infant energy requirements in late pregnancy.

Abstract The Wnt/β-catenin signaling pathway appears to be particularly important for bone homeostasis, whereas nuclear accumulation of β-catenin requires the activation of Rac1, a member of the Rho small GTPase family. The aim of the present study was to investigate the role of RhoA/Rho kinase (Rock)-mediated Wnt/β-catenin signaling in the regulation of aging-associated bone loss. We find that Lrp5/6-dependent and Lrp5/6-independent RhoA/Rock activation by Wnt3a activates Jak1/2 to directly phosphorylate Gsk3β at Tyr216, resulting in Gsk3β activation and subsequent β-catenin destabilization. In line with these molecular events, RhoA loss- or gain-of-function in mouse embryonic limb bud ectoderms interacts genetically with Dkk1 gain-of-function to rescue the severe limb truncation phenotypes or to phenocopy the deletion of β-catenin, respectively. Likewise, RhoA loss-of-function in pre-osteoblasts robustly increases bone formation while gain-of-function decreases it. Importantly, high RhoA/Rock activity closely correlates with Jak and Gsk3β activities but inversely correlates with β-catenin signaling activity in bone marrow mesenchymal stromal cells from elderly male humans and mice, whereas systemic inhibition of Rock therefore activates the β-catenin signaling to antagonize aging-associated bone loss. Taken together, these results identify RhoA/Rock-dependent Gsk3β activation and subsequent β-catenin destabilization as a hitherto uncharacterized mechanism controlling limb outgrowth and bone homeostasis.

ObjectivesThe elderly face multiple vulnerabilities such as health, economy and society, and are prone to catastrophic health expenditures. This study aims to analyze the impact of children's intergenerational economic support, emotional support, and illness on the catastrophic health expenditures of middle-aged and elderly families.MethodsUsing China Health and Retirement Longitudinal Study (CHARLS 2018) data to calculate the catastrophic health expenditure of Chinese households as the dependent variable. Taking children's intergenerational economic support, emotional support and multimorbidity as core independent variables, gender, age, marital status, medical insurance and other variables as control variables, and perform logistic regression analysis. According to the heterogeneity analysis of age and gender, the impact of intergenerational economic support, emotional support and multimorbidity on the catastrophic health expenditure of middle-aged and elderly families is explored.ResultsWhen catastrophic health expenditures occur in middle-aged and elderly families, the children's intergenerational economic support will increase significantly, especially in families with members aged 60–74. Children's emotional support can effectively reduce the risk of catastrophic health expenditures for middle-aged and elderly families. Compared with children's intergenerational economic support and emotional support, the impact of multimorbidity on the catastrophic health expenditures of middle-aged and elderly families is the most significant. Suffering from multimorbidity can increase the risk of catastrophic health expenditures for middle-aged and elderly families, especially families with male members suffering from multiple diseases.ConclusionsIt is recommended that we should do a good job in popularizing the knowledge of chronic diseases to minimize the occurrence of multimorbidity. The government should establish group medical insurance related to chronic disease diagnosis. According to the severity of the disease or the special circumstances of the patient, the level of medical insurance reimbursement is divided in detail, especially for chronic disease clinics and drug reimbursement. Children should be encouraged to strengthen the emotional connection and effective care of the elderly, focusing on the elderly 60–74 years old, in order to reduce their care pressure and maintain the physical and mental health of the elderly.

Abstract Gastric cancer is one of the most common cancers globally and has a poor prognosis. MiR‐936 has been reported to regulate cell activity and tumor progression in non‐small cell lung cancer, glioma, and epithelial ovarian cancer. However, the specific role and mechanism of miR‐936 in gastric cancer have not been explored. In present study, gastric cancer cells were transfected with miR‐936 mimic, and cell proliferation, cell cycle distribution, cell apoptosis, migration and invasion were assessed via cell‐counting kit‐8, flow cytometry, wound healing, and transwell assay, respectively. Dual luciferase reporter assay was used to check miR‐936 binding to its downstream target. It was shown that miR‐936 was downregulated in gastric cancer tissues and cells. Erb‐B2 Receptor Tyrosine Kinase 4 (ERBB4) was confirmed as a direct target of miR‐936 and negatively regulated its expression by miR‐936. Overexpression of miR‐936 suppressed cell proliferation, cell cycle progression, cell migration and invasion, and enhanced cell apoptosis in gastric cancer cells, which could be reversed by further ERBB4 overexpression. Western blot results showed that miR‐936/ERBB4 axis regulated Akt‐related pathways to control gastric cancer cell activities. Therefore, our data suggest that miR‐936 overexpression inhibits cell proliferation and invasion and promotes cell apoptosis through Akt‐related pathways by targeting ERBB4, which provides novel insight to target miR‐936 or miR‐936/ERBB4 axis for the treatment of gastric cancer.

A structural strain reconstruction based on the grey wolf optimizer (GWO) algorithm using fiber Bragg grating (FBG) sensors is described in this paper. The fiber strain data obtained by the GWO algorithm and a modified transfer-matrix method (TMM) are verified by experimental data obtained using the digital image correlation (DIC) method. In the GWO algorithm, the optimization goal is set as the minimum error between the target experimental deformation spectrum and a random simulation strain spectrum, and the strain reconstruction is obtained by means of continuous iterative optimization. The validity of this method is confirmed by experimental strain data obtained by DIC, and the verification results show that the method proposed in this paper can be used as an accurate and efficient method of strain reconstruction.

The prediction of newly-fallen snow depth is a key and difficult task for winter meteorological service in Northern China. The es-timation of newly-fallen snow density is its essential technology. In this paper we review the important influencing factors on newly-fallen snow density, and introduce and compare several most widely applied estimating methods. Then we discuss their characteristics, limitations and the relations among them. Finally, we envision the developing direction of newly-fallen snow density estimation in the future. The main conclusions are as follows. (1) Temperature, wind speed, humidity, solar radiation and precipitation are important meteorological factors af-fecting newly-fallen snow density. (2) At present, the most widely used newly-fallen snow density estimation methods include those assum-ing a constant, building formulae, performing post diagnosis and invoking microphysical processes. They all have their own characteristics and limitations, and have fore-and-aft connections. (3) The relatively scientific post diagnosing and microphysical processes methods have their own relative superiorities and deficiencies that are difficult to overcome. The developing of newly-fallen snow density estimation needs the mutual promoting and common progress of those two methods.

Adoptive natural killer (NK) cell therapy is attaining promising clinical outcomes in recent years, but improvements are needed. Genetic modification of NK cells with a tumor antigen-specific receptor on their surface coupled to intracellular signaling domains may lead to enhanced cytotoxicity against malignant cells. One of the most common approaches is by lentivirus-mediated transduction. However, NK cells are difficult to transduce and various methods have been attempted with different success rates. Because the low-density lipoprotein-receptor (LDLR) is the receptor of vesicular stomatitis virus (VSV) and is expressed only at low levels on NK cells, we tested the potential of 5 statins and 5 non-statin compounds to increase the LDLR expression, thereby facilitating viral transduction. We found that the transduction efficiency of VSV-G pseudotyped lentivirus is augmented by statins that induced higher LDLR expression. In both NK-92 cells and primary NK cells, the transduction efficiency increased after treatment with statins. Furthermore, statins have been reported to suppress NK cell cytotoxicity; however, we showed that this can be completely reversed by adding geranylgeranyl-pyrophosphate (GGPP). Among the statins tested, we found that the combination of rosuvastatin with GGPP most potently improved viral transduction without affecting the cytotoxic properties of the NK cells.

Abstract Background Interleukin-10 (IL10) signalling pathway deficiency results in severe very early onset inflammatory bowel disease (VEOIBD), and enterostomy is often inevitable. However, studies in these surgical populations are lacking. This study aims to determine the enterostomy characteristics, postoperative complications and related risk factors in enterostomy patients. Methods From March 1, 2015, to December 31, 2018, patients with IL10R-mutation who underwent enterostomy were recruited for analysis. We collected data on the patients’ clinical characteristics, enterostomy characteristics, postoperative complications and related risk factors. Results Twelve patients required emergency enterostomy, and 10 patients underwent elective enterostomy. Twelve patients experienced postoperative complications, including wound infection (27.3%), wound dehiscence (18.2%), reoperation (18.2%), etc. Compared with the pre-enterostomy values, there was a decrease in C-reactive protein (CRP) (P = 0.001), an increase in albumin (P = 0.001) and an improvement in the weight-for-age (P = 0.029) and body mass index (BMI) Z-scores (P = 0.004) after enterostomy. There was a significant difference between the pre-operation and postoperation medicine expenses (P = 0.002). Univariate binary logistic regression analysis revealed a statistically significant influence of CRP (OR: 1.43, 95% CI: 1.07–1.91, P = 0.016) and a tendency towards a significant influence of intestinal perforation, albumin level, BMI Z-score and weighted paediatric Crohn’s disease activity index (wPCDAI). Multivariate logistic regression analysis showed that CRP (OR: 1.40), wPCDAI (OR: 2.88) and perforation (OR: 1.72) showed a tendency to behave as independent risk factors for postoperative complications, but the results were not significant (all P > 0.05). Conclusions Surgery and enterostomy showed benefits for VEOIBD with IL-10 signalling deficiency. The timing of intervention, potential postoperative complications, economic burden and other related problems should be considered.

Purpose: The dependence of patients with chronic diseases on drugs may affect their health-related quality of life (HRQoL). This study aims to assess the relationship between the direct economic burden caused by out-of-pocket (OOP) payments, drug accessibility, sociodemographic characteristics, and health-related quality of life.Methods: 1,055 patients with chronic diseases from Gansu, Hebei, Sichuan, Zhejiang, and Tianjin were investigated. Data collection included basic conditions and economic and health insurance conditions of patients with chronic diseases. The CLAD and Tobit regression models were used to analyze and compare the health-related quality of life and influencing factors of patients with chronic diseases in five districts. Differentiated analysis was conducted through sub-sample regression to explore the variable health effects of patients with single and multiple diseases.Results: A total of 1,055 patients with chronic diseases participated in the study, 54.4% of whom were women. The overall average utility score was 0.727, of which Sichuan Province was the highest with 0.751. Participants reported the highest proportion of pain/discomfort problems, while patients reported the least problems with self-care. The improvement of drug accessibility and the reduction of the burden of out-of-pocket expenses have significant positive effects on HRQoL. Various sociodemographic factors such as age and gender also have significant impact on HRQoL of patients with chronic diseases. HRQoL of patients with multiple chronic diseases is more affected by various influencing factors than that of patients with single disease.Conclusion: In order to improve the quality of life of patients with chronic diseases, it is of great importance to ensure the accessibility of drugs and reduce patients' medication burden. Future focus should shift from preventing and controlling chronic diseases as individual diseases to meeting the comprehensive health needs of people suffering from multiple diseases.

Purpose: This study investigated the role of natriuretic peptide receptor 2 (NPR2) on cell proliferation and testosterone secre-tion in mouse Leydig cells.Materials and Methods: Mouse testis of different postnatal stages was isolated to detect the expression C-type natriuretic peptide (CNP) and its receptor NPR2 by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Leydig cells isolated from mouse testis were cultured and treated with shNPR2 lentiviruses or CNP. And then the cyclic guanosine mono-phosphate production, testosterone secretion, cell proliferation, cell cycle and cell apoptosis in mouse Leydig cells were ana-lyzed by ELISA, RT-qPCR, Cell Counting Kit-8, and flow cytometry. Moreover, the expression of NPR2, cell cycle, apoptosis proliferation and cell cycle related gene were detected by RT-qPCR and Western blot. Results: Knockdown of NPR2 by RNAi resulted in S phase cell cycle arrest, cell apoptosis, and decreased testosterone secre-tion in mouse Leydig cells.Conclusions: Our study provides more evidences to better understand the function of CNP/NPR2 pathway in male reproduc-tion, which may help us to treat male infertility.

Background: Targeting PLK1 has recently been proven as a viable therapeutic strategy against oesophageal squamous cell carcinom (ESCC). Therefore, this study aimed to explore whether the PLK1 inhibitor BI2536 is able to sensitize ESCC cells to cisplatin (DDP) and determine the underlying mechanisms. Methods: Viability, clonogenicity, cell cycle distribution and apoptosis were assessed in ESCC cells treated with BI2536 or DDP alone or in combination. Checkpoint activation was examined by immunoblotting and immunohistochemistry. Xenograft model was used to assess the efficacy of the co-treatment. The expression level of GSDME in tissue samples were examined by immunohistochemistry. Findings: We found that the combination of BI2536 and DDP was synergistic in ESCC cells, which induced pyroptosis in ESCC cells at low doses. Mechanistic studies revealed that BI2536 significantly induced DNA damage and impaired the DNA damage repair pathway in DDP-treated cells both in vitro and in vivo. Interestingly, we found that co-treatment with BI2536 and DDP induced pyroptosis in ESCC cells depending on the caspase-3/GSDME pathway. Importantly, our study found that GSDME was more highly expressed in tumour tissue than that in normal adjacent tissues, and could serve as a prognostic factor. Interpretation: BI2536 sensitizes ESCC cells to DDP by inhibiting the DNA damage repair pathway and inducing pyroptosis, which provides new information for understanding pyroptosis. Our study also reveals that the PLK1 inhibitor BI2536 may be an attractive candidate for ESCC targeted therapy, especially when combined with DDP for treating the GSDME overexpression subtype. Fund: National 973 Program and National Natural Science Fundation of China. Keywords: ESCC, PLK1 inhibitor, Pyroptosis, GSDME, Combination

Objectives: This study aimed to measure the induction level of drug welfare in Chinese patients with chronic diseases using a bivariate Theil index.Design: The bivariate Theil-T index was used to hierarchically decompose the relevant survey data, and the contribution rate of the intragroup gap and the intergroup gap to the total gap was investigated to better understand the current drug welfare induction level of Chinese patients with chronic diseases.Setting: The study was based in Gansu, Sichuan, Hebei, and Zhejiang provinces in China.Participants: Survey data was from patients with chronic diseases in 20 hospitals in four provinces.Primary and secondary outcome measures: Data was collected through a questionnaire designed by the research team after expert consultation. Using the variables represented by the index system to decompose the Theil index from the two dimensions of the region and urban and rural areas. SPSS 22.0 was used for reliability and validity analysis and Theil index calculation.Results: The overall level of drug welfare induction in Chinese patients with chronic diseases had a high degree of equalization. The overall Theil index was 0.0003, but there were still some differences among groups.Conclusions: To improve the drug welfare equalization induction level of patients with chronic diseases in China, the government should start from western rural areas, and policy should target the provinces that were in a disadvantaged position within the region to promote the equalization of drug welfare induction level for patients with chronic diseases in China.

Thyroxine metabolism is an important topic of pathogenesis research and treatment schedule of subclinical hypothyroidism (SCH). L-Thyroxine replacement therapy (LRT) is usually recommended for severe SCH patients only. Our previous studies reported that disordered serum lipid of mild SCH people could also benefit from LRT. However, the benefits were different among individuals, as shown by the variations in drug dosage that required to maintain thyroid-stimulating hormone (TSH) stability. Alternative pathways, such as sulfation and glucuronidation of iodothyronine, may play a role in thyroid hormones metabolism in peripheral tissues aside from thyroid. Conjugated thyroxine can be hydrolyzed and reused in tissues including gastrointestinal tract, in which gut microbiota are one of the most attractive physiological components. On this site, the roles of gut microbiota in thyroidal metabolism should be valued. In this study, a cross-sectional study was performed by analyzing 16S rDNA of gut microbiota in mild SCH patients treated with L-thyroxine or not. Subjects were divided by serum lipid level, L-thyroxine treatment, or L-thyroxine dosage, respectively. Relationship between gut microbiome and serum profile, L-thyroxine treatment, and dose were discussed. Other metabolic disorders such as type 2 diabetes and hypertension were also taken into consideration. It turned out that microbiome varied among individuals divided by dose and the increment of L-thyroxine but not by serum lipid profile. Relative abundance of certain species that were associated with thyroxine metabolism were found varied among different L-thyroxine doses although in relatively low abundance. Moreover, serum cholesterol may perform relevance effects with L-thyroxine in shaping microbiome. Our findings suggested that the differences in L-thyroxine dosage required to maintain TSH level stability, as well as the SCH development, which was displayed by the increased L-thyroxine doses in subsequent follow-up, had relationship with gut microbial composition. The reason may due to the differences in thyroxine metabolic capacity in gut. In addition, the metabolic similarity of iodothyronines and bile acid in gut also provides possibilities for the correlation between host's thyroxine and cholesterol levels.This study was registered with ClinicalTrials.gov as number NCT01848171.

Plant growth and development are closely related to phosphate (Pi) and auxin. However, data regarding auxin response factors (ARFs) and their response to phosphate in maize are limited. Here, we isolated ZmARF4 in maize and dissected its biological function response to Pi stress. Overexpression of ZmARF4 in Arabidopsis confers tolerance of Pi deficiency with better root morphology than wild-type. Overexpressed ZmARF4 can partially restore the absence of lateral roots in mutant arf7 arf19. The ZmARF4 overexpression promoted Pi remobilization and up-regulated AtRNS1, under Pi limitation while it down-regulated the expression of the anthocyanin biosynthesis genes AtDFR and AtANS. A continuous detection revealed higher activity of promoter in the Pi-tolerant maize P178 line than in the sensitive 9782 line under low-Pi conditions. Meanwhile, GUS activity was specifically detected in new leaves and the stele of roots in transgenic offspring. ZmARF4 was localized to the nucleus and cytoplasm of the mesophyll protoplast and interacted with ZmILL4 and ZmChc5, which mediate lateral root initiation and defense response, respectively. ZmARF4 overexpression also conferred salinity and osmotic stress tolerance in Arabidopsis. Overall, our findings suggest that ZmARF4, a pleiotropic gene, modulates multiple stress signaling pathways, and thus, could be a candidate gene for engineering plants with multiple stress adaptation.

OBJECTIVES:The present study aims to elucidate the underlying mechanism how PFKP is regulated by BRCA1 and the clinical significance of PFKP in breast cancer. METHODS:MEF-BRCA1△/△ and the wild type counterpart MEF-BRCA1+/+ cell lines were used to test the sensitivity of glucose depletion in culture medium. Glucose Assay Kit was used to quantify glucose levels in cultural supernatant and cell lysate. Real time PCR was used to measure the mRNA expression levels of genes. Western blot was used to detect protein levels. Chromatin immunoprecipitation was used to verify the bindings between transcription factors and DNA elements. Luciferase reporter assay was performed to determine the transcriptional activity. Histochemistry assay was performed on tissue microarray. RESULTS:We found that MEF-BRCA1△/△ cells consumed more glucose and were more vulnerable to glucose-deprived culture medium. The mRNA profiles and qPCR assay of MEF-BRCA1△/△ and MEF-BRCA1+/+ cells revealed that PFKP, the rate-limiting enzyme of glycolysis, was significantly upregulated in MEF-BRCA1△/△ cells. Consistently, the repressive effects of BRCA1 on PFKP were confirmed by overexpression or knockdown of BRCA1. Moreover, we also demonstrated that PFKP was suppressed by ZBRK1 as well, which was the co-repression partner of BRCA1. Mechanistically, we figured out that BRCA1 formed a transcriptional repression complex with ZBRK1 on the promoter of PFKP and consequently restrained its expression. Importantly, the expression levels of PFKP were demonstrated to associate with poor survival of patients with breast cancer. CONCLUSION:Our study provided a new insight into the dysregulation of glycolysis in breast cancer, which might be partially due to the deficiency of BRCA1/ZBRK1 axis and subsequently reversed the transcriptional repressive effect on PFKP. We also found that PFKP overexpressed in a subset of breast cancer patients and could serve as a prognostic factor, which represented a potential target for BC therapy.

Over the last few decades, candidiasis has exhibited an increasing incidence worldwide, causing high mortality in immunocompromised patients. Candida albicans is one of the leading opportunistic fungal pathogens. However, due to the increased use of antifungal agents, resistance of C. albicans to conventional agents, especially fluconazole, has frequently emerged. Therefore, research on the use of combinations of current drugs to sensitize antifungal agents and overcome fungal resistance has attracted considerable attention. This study demonstrated for the first time that D-penicillamine (PCA) combined with fluconazole showed a synergistic effect against C. albicans. PCA combined with fluconazole not only showed synergistic effects against planktonic cells of C. albicans, but also showed synergistic effects against C. albicans biofilms formed within 12 h in vitro. In addition, a Galleria mellonella infection model was used to evaluate the in vivo effects of this drug combination. The results showed that the combination of the two drugs could improve the survival rate, decrease the fungal burden, and reduce the tissue invasion of G. mellonella larvae. Finally, we explored the potential synergistic mechanisms of the drug combination, mainly including inhibition of the morphological transformation, reduction of the intracellular calcium concentration, and the activation of metacaspase, which is closely related to cell apoptosis. These findings might provide novel insights into antifungal drug discovery and the treatment of candidiasis caused by C. albicans.