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Abstract Hepatocellular Carcinoma (HCC) remains a leading cause of cancer deaths. Despite the rise of immunotherapies, many HCC patients don't benefit. There's a clear need for biomarkers to guide treatment decisions. This research aims to identify such biomarkers by combining radiological data and machine learning. We analyzed clinical and CT imaging data of 54 HCC patients undergoing immunotherapy. Radiologic features were examined to develop a model predicting short-term immunotherapy effects. We utilized 9 machine learning and 2 ensemble learning techniques using RapidMiner for model construction. We conducted the validation of the above feature combination using 29 HCC patients who received immunotherapy from another hospital, and tested and validated it using XGBoost combined with a genetic algorithm. In 54 HCC patients, radiomics features varied significantly between those with partial response (PR) and stable disease (SD). Key features in Gray Level Run Length Matrix (GLRLM) and in adjacent tissues' Intensity Direct, Neighborhood Gray Tone Difference Matrix (NGTDM), and Shape correlated with short-term immunotherapy efficacy. Selected feature combinations of 15, 19, and 8/15 features yielded better outcomes. Deep learning, random forest, and naive bayes outperformed other methods, with Bagging being more reliable than Adaboost. In the validation set of 29 HCC patients, the mentioned feature combination also demonstrated favorable performance. Furthermore, we achieved improved results when employing XGBoost in conjunction with a genetic algorithm for testing and validation. The machine learning model built with CT image features derived from GLCM, GLRLM, IntensityDirect, NGTDM, and Shape can accurately forecast the short-term efficacy of immunotherapy for HCC.

4-1BB agonists for cancer immunotherapy have shown good preliminary efficacy in clinical trials, but several of the first-generation 4-1BB agonistic antibodies entering the clinic have failed due to safety issues. Selenium nanoparticles (SeNPs) exhibit anti-inflammatory, anti-tumor, antioxidant, and immune-modulating properties. In addition, they have been shown to have detoxifying effects and prevent oxidative liver damage. In this study, we used an anti-4-1BB antibody in combination with SeNPs to evaluate the anti-lung cancer effects in in vitro and in vivo experiments and explore the underlying mechanisms by pathological analyses, quantitative PCR, and enzyme-linked immunoassay. We found that 5 μmol·L–1 anti-4-1BB antibody combined with 1 μmol·L–1 SeNPs increased the expression of IFN-γ and promoted the killing effects of peripheral blood mononuclear cells on Lewis lung carcinoma cells, with a lethality rate up to 56.88 %. Experiments in tumor-bearing mice showed that the tumor inhibition rate was 58.61 % after treatment with 3.5 mg/kg anti-4-1BB antibody combined with 0.25 mg/kg SeNPs, and the liver function index returned to normal. When the combined treatment was compared with the antibody treatment alone, detection of immune relevant factors demonstrated that the expression of FOXP3, IL-2, IL-12, and TNF-α in the spleen was downregulated, whereas the expression of IFN-γ in the spleen, serum, and tumor was upregulated, accompanied by increased Fas ligand expression in the tumor tissues. Based on these findings, we get the conclusion that anti-4-1BB antibody combined with SeNPs may alleviate the immunosuppression of regulatory T cells, promote the immune cell proliferation and metastasis to synergistically kill tumor cells. This combination also reduces the inflammatory damage to normal tissues and slows overstimulation of the splenic immune response.

Objectives This study aimed to assess the factors influencing pregnant women’s participation in perinatal education and their demand for educational courses.Design A cross-sectional study.Setting Tertiary hospital in Suzhou, China, July–September 2022.Participants Pregnant women from a general grade A tertiary hospital in Suzhou were recruited via online survey invitations during the specified period.Measures A self-designed scale was used to evaluate pregnant women’s demand for perinatal education. Multiple response sets were employed for the assessment of multiple-choice items and analyses included frequency and cross-tabulation. Logistic regression analysis was conducted to assess the factors influencing pregnant women’s participation in perinatal education.Outcome The primary outcome measured was the demand for perinatal education among pregnant women.Results A majority (53.8%) of pregnant women expressed a preference for a mixed teaching mode combining online and offline formats. Logistic regression analysis showed that education level significantly influenced pregnant women’s participation in online learning. Specifically, women with higher education levels were more likely to participate actively in online courses. Additionally, compared with those with first-born children, pregnant women with second-born children participated less actively in online learning. Pregnant women in their second and third trimesters showed greater engagement in online learning compared with those in their first trimester.Conclusions These findings indicate that Chinese pregnant women’s preferences for perinatal education are influenced by their educational background, pregnancy history and the mode of teaching employed. The variability in educational needs underscores the importance of regularly updating course content based on participant feedback.

Abstract Foxtail millet is a highly nutritious crop, which is widely cultivated in arid and semi-arid areas worldwide. Humic acid (HA), as a common plant growth regulator, is used as an organic fertilizer and feed additive in agricultural production. However, the impact of potassium humate KH on the photosynthetic rate and yield of foxtail millet has not yet been studied. We explored the effects of KH application on the morphology, photosynthetic ability, carbon and nitrogen metabolism, and yield of foxtail millet. A field experiment was performed using six concentrations of KH (0, 20, 40, 80, 160, and 320 kg ha−1) supplied foliarly at the booting stage in Zhangza 10 cultivar (a widely grown high-yield variety). The results showed that KH treatment increased growth, chlorophyll content (SPAD), photosynthetic rate (Pn), transpiration rate (Tr), and stomatal conductance (Gs). In addition, soluble protein content, sugar content, and nitrate reductase activity increased in KH-treated plants. With increased KH concentration, the effects became more evident and the peak values of each factor were achieved at 80 kg ha−1. Photosynthetic rate showed significant correlation with SPAD, Tr, Gs, and soluble protein content, but was negatively correlated with intercellular CO2 concentration. Compared to that of the control, the yield of foxtail millet under the T2, T3, T4, and T5 (40, 80, 160, and 320 kg ha−1 of KH) treatments significantly increased by 6.0%, 12.7%, 10.5%, and 8.6%, respectively. Yield exhibited a significant positive correlation with Tr, Pn, and Gs. Overall, KH enhances photosynthetic rate and yield of foxtail millet, therefore it may be conducive to stable millet production. These findings may provide a theoretical basis for the green and efficient production of millet fields.

Abstract Background Digital health technologies show promise for improving the measurement of Parkinson’s disease in clinical research and trials. However, it is not clear whether digital measures demonstrate enhanced sensitivity to disease progression compared to traditional measurement approaches. Methods To this end, we develop a wearable sensor-based digital algorithm for deriving features of upper and lower-body bradykinesia and evaluate the sensitivity of digital measures to 1-year longitudinal progression using data from the WATCH-PD study, a multicenter, observational digital assessment study in participants with early, untreated Parkinson’s disease. In total, 82 early, untreated Parkinson’s disease participants and 50 age-matched controls were recruited and took part in a variety of motor tasks over the course of a 12-month period while wearing body-worn inertial sensors. We establish clinical validity of sensor-based digital measures by investigating convergent validity with appropriate clinical constructs, known groups validity by distinguishing patients from healthy volunteers, and test-retest reliability by comparing measurements between visits. Results We demonstrate clinical validity of the digital measures, and importantly, superior sensitivity of digital measures for distinguishing 1-year longitudinal change in early-stage PD relative to corresponding clinical constructs. Conclusions Our results demonstrate the potential of digital health technologies to enhance sensitivity to disease progression relative to existing measurement standards and may constitute the basis for use as drug development tools in clinical research.

Objective The association of appendicular skeletal muscle mass (ASM), grip strength and fat-to-muscle ratio (FMR) and the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) are not well known.Materials and methods This study included participants older than 40 years who underwent bioelectrical impedance assessment in Prevalence of Metabolic Diseases and Risk Factors in Shunde (SPEED-Shunde). We measured grip strength with an electronic grip strength metre. ASM and grip strength were adjusted by dividing body mass index (BMI). FMR was calculated as total fat mass to total muscle mass. Liver steatosis and liver fibrosis were evaluated by vibration-controlled transient elastography. Multifactorial logistic regression was used to analyse the relationship between ASM, grip strength, FMR, and MASLD or MASLD-associated liver fibrosis. We performed subgroup analyses according to sex, age and BMI. Interaction tests and linear trend tests were also conducted.Results This study included a total of 3277 participants. FMR was positively associated with MASLD (OR: 1.89, 95% CI: 1.66–2.15) and MASLD-associated liver fibrosis (OR: 1.70, 95% CI: 1.22–2.37). While ASM/BMI (OR: 0.59, 95% CI: 0.52–0.67) or grip strength/BMI (OR: 0.72, 95% CI: 0.66–0.78) were negatively associated with MASLD. Interactions were observed between ASM/BMI and age, grip strength and sex in MASLD, as well as FMR and MASLD-associated liver fibrosis.Conclusion In a middle-to-elderly aged population, FMR was positively associated with the risk of MASLD and MASLD-associated liver fibrosis, and muscle mass and grip strength were negatively associated with MASLD, rather than MASLD-associated liver fibrosis.

AbstractBackground We aimed to investigate the associations between thyroid hormone sensitivity indices and diabetes in euthyroid adults in the United States and China.Methods 2296 euthyroid adults from the NHANES in the United States and 8319 euthyroid adults from the SPEED-Shunde in China were involved. The thyroid sensitivity indices, namely TFQIFT4 and TFQIFT3, were calculated. Multivariable logistic regression, restricted cubic spline analysis, and general ordinal logit regression were utilized.Results In the NHANES, compared with participants in quartile 1st (Q1), those in Q4 of TFQIFT3 (OR 2.12, 95% CI (1.18, 3.81)) and those in Q3 of TFQIFT4 (OR 2.31, 95% CI (1.18, 4.53)) (both P for trend < 0.05) were associated with a greater prevalence of diabetes. In the SPEED-Shunde, compared with participants in Q1, those in Q4 of TFQIFT3 had a greater prevalence of diabetes (OR 1.36, 95% CI (1.11, 1.66) (P for trend < 0.05), while no significant associations between TFQIFT4 and diabetes were found.Conclusions TFQIFT3 was associated with a higher prevalence of diabetes both in the United States and China. However, TFQIFT4 was only associated with a higher prevalence of diabetes in the United States, not in China. Further prospective cohort studies are necessary to validate these findings.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson’s disease (PD). However, whether LRRK2 mutations cause PD and degeneration of dopaminergic (DA) neurons via a toxic gain-of-function or a loss-of-function mechanism is unresolved and has pivotal implications for LRRK2-based PD therapies. In this study, we investigate whether Lrrk2 and its functional homolog Lrrk1 play a cell-intrinsic role in DA neuron survival through the development of DA neuron-specific Lrrk conditional double knockout (cDKO) mice. Unlike Lrrk germline DKO mice, DA neuron-restricted Lrrk cDKO mice exhibit normal mortality but develop age-dependent loss of DA neurons, as shown by the progressive reduction of DA neurons in the substantia nigra pars compacta (SNpc) at the ages of 20 and 24 months. Moreover, DA neurodegeneration is accompanied with increases in apoptosis and elevated microgliosis in the SNpc as well as decreases in DA terminals in the striatum, and is preceded by impaired motor coordination. Taken together, these findings provide the unequivocal evidence for the cell-intrinsic requirement of LRRK in DA neurons and raise the possibility that LRRK2 mutations may impair its protection of DA neurons, leading to DA neurodegeneration in PD.

Abstract Ferroptosis is an iron-dependent form of regulated cell death with distinct characteristics, including altered iron homeostasis, reduced defense against oxidative stress, and abnormal lipid peroxidation. Recent studies have provided compelling evidence supporting the notion that ferroptosis plays a key pathogenic role in many diseases such as various cancer types, neurodegenerative disease, diseases involving tissue and/or organ injury, and inflammatory and infectious diseases. Although the precise regulatory networks that underlie ferroptosis are largely unknown, particularly with respect to the initiation and progression of various diseases, ferroptosis is recognized as a bona fide target for the further development of treatment and prevention strategies. Over the past decade, considerable progress has been made in developing pharmacological agonists and antagonists for the treatment of these ferroptosis-related conditions. Here, we provide a detailed overview of our current knowledge regarding ferroptosis, its pathological roles, and its regulation during disease progression. Focusing on the use of chemical tools that target ferroptosis in preclinical studies, we also summarize recent advances in targeting ferroptosis across the growing spectrum of ferroptosis-associated pathogenic conditions. Finally, we discuss new challenges and opportunities for targeting ferroptosis as a potential strategy for treating ferroptosis-related diseases.

Abstract This study was designed to evaluate the impact of methicillin resistance on the outcomes among patients with S. aureus osteomyelitis. We reviewed all extremity osteomyelitis patients treated in our clinic center between 2013 and 2020. All adult patients with S. aureus pathogen infection were included. Clinical outcome in terms of infection control, length of hospital stay, and complications were observed at the end of a 24‐month follow‐up and retrospectively analyzed between populations with/without methicillin resistance. In total, 482 osteomyelitis patients due to S. aureus were enrolled. The proportion of methicillin-resistant S. aureus (MRSA) was 17% (82) and 83% (400) of patients had Methicillin-sensitive S. aureus (MSSA). Of 482 patients, 13.7% (66) presented with infection persistence after initial debridement and antibiotic treatment (6 weeks), needed repeated debridement, 8.5% (41) had recurrence after all treatment end and a period infection cure, complications were observed in 17 (3.5%) patients (pathologic fracture; 4, nonunion; 5, amputation; 8) at final follow-up. Following multivariate analysis, we found patients with S. aureus osteomyelitis due to MRSA are more likely to develop a persistent infection (OR: 2.26; 95% CI 1.24–4.13) compared to patients with MSSA. Patients infected with MRSA also suffered more complications (8.5% vs. 2.5%, p = 0.015) and longer hospital stays (median: 32 vs. 23 days, p

ObjectivesSurveys can assist in screening oral diseases in populations to enhance the early detection of disease and intervention strategies for children in need. This paper aims to develop short forms of child-report and proxy-report survey screening instruments for active dental caries and urgent treatment needs in school-age children.MethodsThis cross-sectional study recruited 497 distinct dyads of children aged 8-17 and their parents between 2015 to 2019 from 14 dental clinics and private practices in Los Angeles County. We evaluated responses to 88 child-reported and 64 proxy-reported oral health questions to select and calibrate short forms using Item Response Theory. Seven classical Machine Learning algorithms were employed to predict children's active caries and urgent treatment needs using the short forms together with family demographic variables. The candidate algorithms include CatBoost, Logistic Regression, K-Nearest Neighbors (KNN), Naïve Bayes, Neural Network, Random Forest, and Support Vector Machine. Predictive performance was assessed using repeated 5-fold nested cross-validations.ResultsWe developed and calibrated four ten-item short forms. Naïve Bayes outperformed other algorithms with the highest median of cross-validated area under the ROC curve. The means of best testing sensitivities and specificities using both child-reported and proxy-reported responses were 0.84 and 0.30 for active caries, and 0.81 and 0.31 for urgent treatment needs respectively. Models incorporating both response types showed a slightly higher predictive accuracy than those relying on either child-reported or proxy-reported responses.ConclusionsThe combination of Item Response Theory and Machine Learning algorithms yielded potentially useful screening instruments for both active caries and urgent treatment needs of children. The survey screening approach is relatively cost-effective and convenient when dealing with oral health assessment in large populations. Future studies are needed to further leverage the customize and refine the instruments based on the estimated item characteristics for specific subgroups of the populations to enhance predictive accuracy.

Abstract In this study, we treated infected ankle bone defects with the induced membrane two-stage technique. The ankle was fused with a retrograde intramedullary nail in the second stage, and the aim of this study was to observe the clinical effect. We retrospectively enrolled patients with infected bone defects of the ankle admitted to our hospital between July 2016 and July 2018. In the first stage, the ankle was temporarily stabilized with a locking plate, and antibiotic bone cement was used to fill the defects after debridement. In the second stage, the plate and cement were removed, the ankle was stabilized with a retrograde nail, and tibiotalar-calcaneal fusion was performed. Then, autologous bone was used to rebuild the defects. The infection control rate, fusion success rate and complications were observed. Fifteen patients were enrolled in the study with an average follow-up of 30 months. Among them, there were 11 males and 4 females. The average bone defect length after debridement was 5.3 cm (2.1–8.7 cm). Finally, 13 patients (86.6%) achieved bone union without recurrence of infection, and 2 patients experienced recurrence after bone grafting. The average ankle-hindfoot function score (AOFAS) increased from 29.75 ± 4.37 to 81.06 ± 4.72 at the last follow-up. The induced membrane technique combined with a retrograde intramedullary nail for the treatment of infected bone defects of the ankle after thorough debridement is an effective treatment method.

Abstract Background Cytokine-induced memory-like natural killer (CIML NK) cells have been found to possess potent antitumor responses and induce complete remissions in patients with leukemia. However, the poor infiltration of transferred NK cells is a major obstacle in developing adoptive cell immunotherapy for solid tumors. In our study, we explored the potential of using the tumor-penetrating peptide iRGD to deliver activated CIML NK cells deep into tumor tissues. Methods After being briefly stimulated with interleukin-12 (IL-12), IL-15, and IL-18, CIML NK cells were assessed for their phenotype and function with flow cytometry. The penetrating and killing capability of iRGD-modified CIML NK cells in tumor spheroids was revealed by confocal microscopy. The anti-tumor efficacy of these modified CIML NK cells was tested in hepatocellular carcinoma (HCC) xenograft mouse models. Results Treating NK cells with cytokines led to a substantial activation, which was evidenced by the upregulation of CD25 and CD137. After a resting period of six days, CIML NK cells were still able to display strong activation when targeting HepG2 and SK-Hep-1 HCC cell lines. Additionally, CIML NK cells produced increased amounts of cytokines (interferon-gamma and tumor necrosis factor alpha) and exhibited heightened cytotoxicity towards HCC cell lines. The iRGD modification enabled CIML NK cells to infiltrate multicellular spheroids (MCSs) and, consequently, to induce cytotoxicity against the target cancer cells. Moreover, the CIML NK cells modified with iRGD significantly decreased tumor growth in a HCC xenograft mouse model. Conclusion Our findings demonstrate that CIML NK cells possess augmented potency and durability against HCC cell lines in vitro. Additionally, we have seen that the incorporation of iRGD to CIML NK cells facilitates enhanced infiltration and targeted destruction of MCSs. Moreover, the application of iRGD-modified CIML NK cells reveal remarkable anti-tumor efficacy against HCC in vivo.

Objective To explore the application effect of traditional teaching combined with problem based learning (PBL) in the teaching of transfusion medicine taking the chapter of Human Leukocyte Antigen System and Testing in Clinical Blood Transfusion Testing Technique as an example. Methods Firstly, practical problems in chapter Human Leukocyte Antigen System and Testing were analyzed. Then, in response to the key and difficult points in the teaching of this chapter, examples were given to illustrate the practical application of traditional teaching combined with PBL in the teaching of Clinical Blood Transfusion Testing Technique from the aspects of teaching objectives, teaching processes, course implementation and implementation effects. The teaching effectiveness was evaluated through a questionnaire. Results Traditional teaching combined with PBL helped students grasp important knowledge and techniques, break down thinking barriers, grasp internal connections and characteristics, simplify the learning process, stimulate interest in learning and enhance team collaboration. Meanwhile, students' exploration and innovation abilities could be further cultivated through extracurricular expansion by teachers, thus achieving ideal teaching effect. The questionnaire showed that over 90% of the students consider that combining traditional teaching with PBL was beneficial for improving teaching effect. Conclusion In the teaching of transfusion medicine, adopting traditional teaching combined with PBL according to the textbook content can improve the teaching effect, which is beneficial for the cultivation of comprehensive talents.

Abstract Nucleic acid drugs have the advantages of rich target selection, simple in design, good and enduring effect. They have been demonstrated to have irreplaceable superiority in brain disease treatment, while vectors are a decisive factor in therapeutic efficacy. Strict physiological barriers, such as degradation and clearance in circulation, blood-brain barrier, cellular uptake, endosome/lysosome barriers, release, obstruct the delivery of nucleic acid drugs to the brain by the vectors. Nucleic acid drugs against a single target are inefficient in treating brain diseases of complex pathogenesis. Differences between individual patients lead to severe uncertainties in brain disease treatment with nucleic acid drugs. In this Review, we briefly summarize the classification of nucleic acid drugs. Next, we discuss physiological barriers during drug delivery and universal coping strategies and introduce the application methods of these universal strategies to nucleic acid drug vectors. Subsequently, we explore nucleic acid drug-based multidrug regimens for the combination treatment of brain diseases and the construction of the corresponding vectors. In the following, we address the feasibility of patient stratification and personalized therapy through diagnostic information from medical imaging and the manner of introducing contrast agents into vectors. Finally, we take a perspective on the future feasibility and remaining challenges of vector-based integrated diagnosis and gene therapy for brain diseases.

Introduction: Cannabinoids including cannabidiol (CBD) have attracted enormous interest as bioactive ingredients for various dermatological and/or cosmeceutical uses. However, topical applications of cannabinoids might be limited without a fundamental understanding of their skin permeability. Herein, we aimed to evaluate the skin permeability of CBD and its topical formulations using artificial skin membrane assays. The solubility and stability of CBD in various surfactants that are commonly used in topical applications were also evaluated. Methods: CBD and two CBD-incorporated topical formulations (cream and gel) were prepared for this study. Computational predictions (SwissADME and DERMWIN™) and the parallel artificial membrane permeability assay (PAMPA) were used to evaluate the skin permeability of CBD isolate. The Franz cell diffusion (in vitro release testing) assay was used to evaluate the skin permeability of CBD formulations. The solubility and stability of CBD in surfactants were assessed by high-performance liquid chromatography and mass spectrometry analysis. Results: CBD isolate showed favorable skin permeability in the SwissADME and DERMWIN™ predictions (−Log Kp of 3.6 and 5.7 cm/s, respectively) and PAMPA (−LogPe value of 5.0 at pH of 6.5 and 7.4). In addition, CBD had higher solubility (378.4 μg/mL) in surfactant Tween 20 as compared to its solubility in polyisobutene. In an acidic environment (pH 5 and 6), Tween 20 maintained the CBD content at 81% and 70% over 30 days, respectively. CBD in the formulations of cream and gel also had moderate skin permeability in the Franz cell diffusion assay. Conclusion: Data from artificial membrane-based assays support that CBD is a skin permeable cannabinoid and the permeability and stability of its formulations may be influenced by several factors such as surfactant and pH environment. Findings from our study suggest that CBD may have suitable skin permeability for the development of dermatological and/or cosmeceutical applications but further studies using in vivo models are warranted to confirm this.

Abstract Background The cause of systemic lupus erythematosus is not completely clear so far, but the prevalence of systemic lupus erythematosus is significantly increased in people with additional X chromosomes. Case presentation We report a 17-year-old Chinese female patient with systemic lupus erythematosus complicated with trisomy X, accompanied by lupus nephritis, pancytopenia, hemolytic anemia, and multiserous effusion. The patient recovered well after treatment and returned regularly. We review the previously reported cases to summarize the clinical characteristics of these patients. Conclusion The additional X chromosome is related to the development of systemic lupus erythematosus. Whether it is a subtype of systemic lupus erythematosus remains to be further confirmed.

Abstract To evaluate the value of texture analysis based on dynamic contrast enhanced MRI (DCE-MRI) in the differential diagnosis of thymic carcinoma and thymic lymphoma. Sixty-nine patients with pathologically confirmed (thymic carcinoma, n = 32; thymic lymphoma, n = 37) were enrolled in this retrospective study. Ktrans, Kep and Ve maps were automatically generated, and texture features were extracted, including mean, median, 5th/95th percentile, skewness, kurtosis, diff-variance, diff-entropy, contrast and entropy. The differences in parameters between the two groups were compared and the diagnostic efficacy was calculated. The Ktrans-related significant features yielded an area under the curve (AUC) of 0.769 (sensitivity 90.6%, specificity 51.4%) for the differentiation between thymic carcinoma and thymic lymphoma. The Kep-related significant features yielded an AUC of 0.780 (sensitivity 87.5%, specificity 62.2%). The Ve-related significant features yielded an AUC of 0.807 (sensitivity 75.0%, specificity 78.4%). The combination of DCE-MRI textural features yielded an AUC of 0.962 (sensitivity 93.8%, specificity 89.2%). Five parameters were screened out, including age, Ktrans-entropy, Kep-entropy, Ve-entropy, and Ve-P95. The combination of these five parameters yielded the best discrimination efficiency (AUC of 0.943, 93.7% sensitivity, 81.1% specificity). Texture analysis of DCE-MRI may be helpful to distinguish thymic carcinoma from thymic lymphoma.

Abstract Living in a disadvantaged neighborhood is associated with adverse clinical outcomes among breast cancer patients, but the underlying pathway is still unclear. Limited evidence has suggested that accelerated biological aging may play an important role. In this study, using a sub-sample of 906 women with newly diagnosed breast cancer at M.D. Anderson, we examined whether levels of selected markers of biological aging (e.g., allostatic load, telomere length, and global DNA methylation) were affected by neighborhood disadvantage. The Area Deprivation Index was used to determine the neighborhood disadvantage. Based on the median ADI at the national level, the study population was divided into low and high ADI groups. Overall, breast cancer patients from the high ADI group were more likely to be younger and non-Hispanic Black than those from the low ADI group (P

Objectives The purpose of this study is to determine the associations between horizontal jump and sprint acceleration, as well as maximal speed performance. Methods A systematic literature search was performed using PubMed, MEDLINE (EBSCOhost), and Web of Science. The studies that were included in this review must meet the following criteria: (1) well-trained individuals over the age of 18 years old; (2) Pearson’s correlation coefficients between sprint time and horizontal jump distance were provided; (3) the sprint distance was limited to 0–100 m. The quality of the studies was assessed using a modified version of the Downs and Black Quality Index test. A random-effects model was used to determine the effect sizes, and heterogeneity between studies was examined using the Q statistic and I2. Results From the identified 2,815 studies, 27 studies were included in this study (two from reference lists). The sprint time of the sprint acceleration phase was moderately and negatively correlated with the standing long jump (r = − 0.45, z = 7.48, p

Abstract Amyloid precursor protein (APP) is associated with both familial and sporadic forms of Alzheimer’s disease. APP has two homologs, amyloid precursor-like protein 1 and 2 (APLP1 and APLP2), and they have functional redundancy. APP intracellular c-terminal domain (AICD), produced by sequential α- or β- and γ-secretase cleavages, is thought to control gene expression, similarly as the ICD of Notch. To investigate the role of APP family in transcriptional regulation, we examined gene expression changes in the cerebral cortex of APP/APLP1/APLP2 conditional triple knockout (cTKO) mice, in which APP family members are selectively inactivated in excitatory neurons of the postnatal forebrain. Of the 12 previously reported AICD target genes, only Nep and Npas4 mRNA levels were significantly reduced in the cerebral cortex of cTKO mice, compared to littermate controls. We further examined global transcriptional changes by RNA-seq and identified 189 and 274 differentially expressed genes in the neocortex and hippocampus, respectively, of cTKO mice relative to controls. Gene Ontology analysis indicated that these genes are involved in a variety of cellular functions, including extracellular organization, learning and memory, and ion channels. Thus, inactivation of APP family alters transcriptional profiles of the cerebral cortex and affects wide-ranging molecular pathways.

Abstract It has been well-known that built environment features influence the risk of chronic diseases. However, the existing data of its relationship with telomere length, a biomarker of biological aging, is still limited, with no study available for Mexican Americans. This study investigates the relationship between several factors of the built environment with leukocyte telomere length among 5508 Mexican American adults enrolled in Mano-A-Mano, the Mexican American Cohort Study (MACS). Based on the quartile levels of telomere length, the study population was categorized into four groups, from the lowest (1st quartile) to the highest telomere length group (4th quartile). For individual built environment factors, their levels did not differ significantly across four groups. However, in the multinominal logistic regression analysis, increased Rundle’s land use mixture (LUM) and Frank’s LUM were found statistically significantly associated with increased odds of having high levels of telomere length (Rundle’s LUM: 2nd quartile: Odds ratio (OR) 1.26, 95% Confidence interval (CI) 1.07, 1.48; 3rd quartile: OR 1.25, 95% CI 1.06, 1.46; 4th quartile: OR 1.19, 95% CI 1.01, 1.41; Frank’s LUM: 2nd quartile: OR 1.34, 95% CI 1.02, 2.63; 3rd quartile: OR 1.55, 95% CI 1.04, 2.91; 4th quartile: OR 1.36, 95% CI 1.05, 2.72, respectively). The associations for Rundle’s LUM remained significant after further adjusting other non-redundant built environment factors. Finally, in stratified analysis, we found the association between Rundle’s LUM and telomere length was more evident among younger individuals (

Abstract An internal fixation composite structure of antibiotic cement plates was created. The aim of this study was to analyse the infection control effect of this structure when applied to treat a bone infection. We retrospectively analysed patients with bone infection admitted to our hospital between January 2013 and June 2019. After debridement, an antibiotic cement plate composite structure was used to fill and stabilize the defects. The treatment effect was evaluated at six months after surgery, and the infection control rate, factors associated with the recurrence of infection, and complications were analysed. If the patients had bone defects, the defect was repaired after infection control, and the infection control rate of all of the patients was re-evaluated at 12 months after surgery. A total of 548 patients were treated with this technique, including 418 men and 130 women. The infection sites included 309 tibias, 207 femurs, 16 radii and ulnae, 13 humeri, and 3 clavicles. After at least 6 months of follow-up, 92 patients (16.79%) had an infection recurrence and needed further treatment. The recurrence rate of the tibia was higher than that of the femur (P = 0.025). Eighty-nine out of 92 patients who relapsed underwent a second debridement with the same method, and the infection control rate after the second debridement was 94.71%. Complications included 8 cases of epidermal necrosis around the incision, 6 cases of internal fixation failure, and 30 cases of lower limb swelling. By the follow-up time of 12 months, another 6 patients had experienced recurrence of infection, and 4 cases were controlled after debridement. Finally, among all 548 cases, 7 patients remained persistently infected, and 6 underwent amputation. The infection control rate was 97.6% at the 1-year follow-up. The clinical efficacy of this new antibiotic cement plate composite structure for internal fixation after debridement of bone infection is stable and reliable.

Broomcorn millet, a C4 cereal, has better tolerance to environmental stresses. Although elevated atmospheric CO2 concentration has led to grain nutrition reduction in most staple crops, studies evaluating its effects on broomcorn millet are still scarce. The yield, nutritional quality and metabolites of broomcorn millet were investigated under ambient CO2 (aCO2, 400 µmol mol–1) and elevated CO2 (eCO2, aCO2+ 200 µmol mol–1) for three years using open-top chambers (OTC). The results showed that the yield of broomcorn millet was markedly increased under eCO2 compared with aCO2. On average, eCO2 significantly increased the concentration of Mg (27.3%), Mn (14.6%), and B (21.2%) over three years, whereas it did not affect the concentration of P, K, Fe, Ca, Cu or Zn. Protein content was significantly decreased, whereas starch and oil concentrations were not changed by eCO2. With the greater increase in grain yield, eCO2 induced increase in the grain accumulations of P (23.87%), K (29.5%), Mn (40.08%), Ca (22.58%), Mg (51.31%), Zn (40.95%), B (48.54%), starch (16.96%) and oil (28.37%) on average for three years. Flavonoids such as kaempferol, apigenin, eriodictyol, luteolin, and chrysoeriol were accumulated under eCO2. The reduction in L-glutamine and L-lysine metabolites, which were the most representative amino acid in grain proteins, led to a reduction of protein concentration under eCO2. Broomcorn millet has more desirable nutritional traits for combating hidden hunger. This may potentially be useful for breeding more nutritious plants in the era of climate change.

Over the past decades, peptides and proteins have been increasingly important in the treatment of various human diseases and conditions owing to their specificity, potency, and minimized off-target toxicity. However, the existence of the practically impermeable blood brain barrier (BBB) limits the entry of macromolecular therapeutics into the central nervous systems (CNS). Consequently, clinical translation of peptide/protein therapeutics for the treatment of CNS diseases has been limited. Over the past decades, developing effective delivery strategies for peptides and proteins has gained extensive attention, in particular with localized delivery strategies, due to the fact that they are capable of circumventing the physiological barrier to directly introduce macromolecular therapeutics into the CNS to improve therapeutic effects and reduce systemic side effects. Here, we discuss various local administration and formulation strategies that have shown successes in the treatment of CNS diseases using peptide/protein therapeutics. Lastly, we discuss challenges and future perspectives of these approaches.

Though the formation of neutralizing antibodies (NAbs) during treatment with botulinum neurotoxin is rare, their presence may nonetheless affect the biological activity of botulinum toxin and negatively impact clinical response. The goal of this updated meta-analysis was to evaluate and characterize the rate of NAb formation using an expanded dataset composed of 33 prospective placebo-controlled and open-label clinical trials with nearly 30,000 longitudinal subject records prior to and following onabotulinumtoxinA treatment in 10 therapeutic and aesthetic indications. Total onabotulinumtoxinA doses per treatment ranged from 10 U to 600 U administered in ≤15 treatment cycles. The NAb formation at baseline and post-treatment was tested and examined for impact on clinical safety and efficacy. Overall, 27 of the 5876 evaluable subjects (0.5%) developed NAbs after onabotulinumtoxinA treatment. At study exit, 16 of the 5876 subjects (0.3%) remained NAb positive. Due to the low incidence of NAb formation, no clear relationship was discernable between positive NAb results and gender, indication, dose level, dosing interval, treatment cycles, or the site of injection. Only five subjects who developed NAbs post-treatment were considered secondary nonresponders. Subjects who developed NAbs revealed no other evidence of immunological reactions or clinical disorders. This comprehensive meta-analysis confirms the low NAb formation rate following onabotulinumtoxinA treatment across multiple indications, and its limited clinical impact on treatment safety and efficacy.

Objectives The primary purpose of this review was to clarify the effects of school-based integrated neuromuscular training (INT) on fundamental movement skills and physical fitness in children. The secondary purpose was to examine whether school-based INT intervention is superior to physical education (PE) intervention in enhancing motor skills and fitness. Methods A systematic literature search was performed in four electronic databases: PubMed, Web of Science, MEDLINE (EBSCOhost), and Cochrane Central Register of Controlled Trials. The last search was performed on December 21, 2021, and was limited to the English language, human species, and peer reviewed journals. Randomized controlled trials and cluster randomized controlled trials that examine the effects of school-based INT on motor skills and/or fitness in healthy children who were aged up to 14 years old were included. Moreover, studies included in this study should compare school-based INT-induced adaptions with those generated by PE interventions. Studies that involve athletic children and additional exercise training were excluded. The Physiotherapy Evidence Database (PEDro) scale was used to assess the quality of the study. Results Of 1,026 studies identified, seven original trials that meet the inclusion criteria were included in this review. Based on the PEDro scale, the PEDro score of seven studies was between six and eight points with a mean score of 5.29. Among the seven studies included in this study, four studies assessed physical fitness including muscular fitness (n = 4), speed (n = 3), endurance (n = 2), and flexibility (n = 2). Three studies examined the effects of INT on postural control and three studies explored its effects on motor skills. Concerning movement competence, significant and greater improvements in postural control and fundamental motor skills were observed following school-based INT interventions compared to PE intervention in two and three studies, respectively. Regarding physical fitness, neuromuscular training significantly increased muscular fitness, speed, endurance, flexibility in three, two, one, and one studies, respectively. However, only greater improvements in muscle fitness were observed in school-based INT group compared to PE group. The main limitations of this review were the lack of descriptions of training intensity and volume and the low methodological quality of the included studies. Conclusion This review provides evidence that school-based neuromuscular training programs are superior to PE lessons in improving postural control, fundamental motor skills and muscular strength. Therefore, INT could be incorporated into traditional physical education classes in school. Trial registration number: CRD42022297349.

Abstract To compare the clinical results of patients with low rectal cancer who underwent skin bridge loop ileostomy and traditional loop ileostomy, and provide clinical evidence for choosing a better ostomy method. We retrospectively collected data of 118 patients with rectal cancer who underwent low anterior resection and loop ileostomy. To investigate the patients characteristics, postoperative stoma-related complications and the frequency of exchanged ostomy bags. The differences of these indicators between the two groups of patients who underwent skin bridge loop ileostomy and traditional loop ileostomy were compared. The Visual Analog Scale (VAS) score of the skin bridge loop ileostomy group was lower than that of the traditional ileostomy loop group (P

Amino-terminal fragments from proteolytically cleaved gasdermins (GSDMs) form plasma membrane pores that enable the secretion of interleukin-1β (IL-1β) and IL-18. Excessive GSDM-mediated pore formation can compromise the integrity of the plasma membrane thereby causing the lytic inflammatory cell death, pyroptosis. We found that GSDMD and GSDME were the only GSDMs that were readily expressed in bone microenvironment. Therefore, we tested the hypothesis that GSDMD and GSDME are implicated in fracture healing owing to their role in the obligatory inflammatory response following injury. We found that bone callus volume and biomechanical properties of injured bones were significantly reduced in mice lacking either GSDM compared with wild-type (WT) mice, indicating that fracture healing was compromised in mutant mice. However, compound loss of GSDMD and GSDME did not exacerbate the outcomes, suggesting shared actions of both GSDMs in fracture healing. Mechanistically, bone injury induced IL-1β and IL-18 secretion in vivo, a response that was mimicked in vitro by bone debris and ATP, which function as inflammatory danger signals. Importantly, the secretion of these cytokines was attenuated in conditions of GSDMD deficiency. Finally, deletion of IL-1 receptor reproduced the phenotype of Gsdmd or Gsdme deficient mice, implying that inflammatory responses induced by the GSDM-IL-1 axis promote bone healing after fracture.

(1) Background: CC chemokine ligand 23 (CCL23) is a chemokine implicated in the inflammatory response following brain damage. The aim of this study is to identify the change in serum CCL23 levels within 24 h after aSAH and whether serum CCL23 levels are associated with initial clinical severity, delayed cerebral ischemia (DCI), and functional outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). (2) Methods: 102 patients with aSAH and 61 controls were included in this prospective observational study. All clinical data were collected prospectively, and their serum CCL23 levels were measured. Initial clinical severity was reflected by the Hunt–Hess score and mFisher score. Functional outcome was evaluated in terms of the Glasgow Outcome Scale (GOS) score at 6-month follow-up. (3) Results: Patients with aSAH had higher serum CCL23 levels than controls. The temporal profile of serum CCL23 levels and neutrophils count exhibited a sustained increase within 24 h after aSAH. Serum CCL23 levels were related to blood neutrophils count, blood CRP levels, and initial clinical severity. Serum CCL23 level was an independent predictor of DCI and 6-month poor outcome in aSAH patients. (4) Conclusions: Serum CCL23 levels emerged as an independent predictor for DCI and poor outcome in patients with aSAH.

Abstract Background Brainstem raphe (BR) hypoechogenicity in transcranial sonography (TCS) has been depicted in patients with major depression (MD) and in depressed patients with different neurodegenerative diseases. But, up to date, the association of BR alterations in TCS with depression in migraineurs has never been reported. This study was to investigate the possible role of BR examination via TCS in migraineurs with depression. Methods Forty two migraine without aura (MwoA) patients and 40 healthy controls were recruited. Echogenicity of lentiform nuclei (LN), caudate nuclei (CN), substantia nigra (SN) and brainstem raphe (BR) and width of the frontal horns of the lateral ventricles and the third ventricle were assessed with TCS. The diagnosis of depression was based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders IV (DSM –IV), and the severity of depression was measured by Hamilton Rating Scale for Depression (HAM-D) and Hospital Anxiety and Depression Scale depression subscale (HADS-D). Results There were no significant differences between migraineurs and controls in the width of frontal horn of the lateral ventricle (p = 0.955), width of third ventricle (p = 0.129) as well as in the echogenicity of SN (p = 0.942), CN (p = 0.053), LN (p = 0.052) and BR (p = 0.677). Here, it seems that more migraineurs were detected with increased echogenecity of CN and LN compared with controls (33.3% versus 15.0% for CN, 19.0% versus 5.0% for LN) though they had no statistical significance. Patients with hypoechogenic BR had significantly higher HAM-D and HADS-D scores than those with normal BR signal (p = 0.000 for both HAM-D and HADS-D), and most (83.33%) migraineurs with depression exhibited hypoechogenic raphe but none (0.00%) of the migraineurs without depression exhibited hypoechogenic raphe (p = 0.000). Conlusions TCS signal alteration of BR can be a biomarker for depression in migraine but it is not associated with migraine headache itself. LN and CN alterations in TCS may reflect a potential role of them in the pathogenesis of migraine, which needs to be further elucidated.

Background: Perimembranous ventricular septal defect combined with right coronary cusp bulge generally should be treated with surgical thoracotomy, owing to the potential aortic regurgitation. However, the minimally invasive method of transcatheter closure has always attracted the attention of cardiologists and patients. The present study aimed to apply transcatheter occlusion in treating ventricular septal defect with right coronary cusp bulge and further evaluate the clinical effect through follow-up.Materials and methods: A total of 40 children diagnosed as having a ventricular septal defect with right coronary cusp bulge, examined using transthoracic echocardiography and cardiovascular angiography, were enrolled in this study. The ventricular septal defects were closed by placing occluders through transcatheter occlusion treatment. During the operation process, the children underwent angiography and transthoracic echocardiography examinations to check the position of the occlude and the extent of aortic regurgitation. The influence of occlusion on the conduction system was evaluated using a surface electrocardiogram. The children were followed up after their procedures.Results: All 40 patients were immediately and successfully occluded. Three patients with filament residual shunts were observed during the operations. No major surgical complications occurred during the perioperative period. During the follow-up period, the positions of all the occluders were good, the residual shunts in the three patients disappeared, and no new or aggravated aortic regurgitation occurred. Electrocardiogram did not reveal any atrioventricular blocks. Only one patient suffered from an incomplete right bundle branch block.Conclusions: Children diagnosed with ventricular septal defect combined with right coronary cusp bulge could be considered for transcatheter occlusion. With appropriate indications and methods, the effect may be favorable. Keywords: aortic regurgitation, right coronary cusp bulge, transcatheter occlusion, ventricular septal defect

This study was designed to clarify whether Shikonin causes proliferation, apoptosis, and invasion in cholangiocarcinoma cells and to investigate the mechanism of action. QBC939 cells were cultured with different doses of Shikonin, and then 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium assay was used to detect cell viability. Apoptosis of cells was detected using flow cytometry with Annexin V/propidium iodide (PI) assay after being stained with Hoechst 33242. The role of Shikonin on the invasive and metastasis ability was detected using Transwell invasion assay. Real-time polymerase chain reaction and Western blotting were used to detect the expression of caspase-3, caspase-8, epidermal growth factor receptor (EGFR), and matrix metalloproteinase (MMP)-9. Shikonin inhibited proliferation and invasive ability of QBC939 cells in a dose-dependent manner; at the same time, apoptosis of cells was also observed in a concentration-dependent fashion. Moreover, Annexin V/PI assay and Transwell invasion assay results indicated that Shikonin induced apoptosis and invasion inhibitory probably due to upregulation of caspase-3 and caspase-8 expression and downregulation of MMP-9 and EGFR expression in a concentration-dependent fashion. Shikonin could enhance apoptosis and inhibit proliferation and invasion of QBC939 cells; such biological behaviors mainly occurred via upregulating the expression of caspase-3 and caspase-8 and downregulating the expression of MMP-9 and EGFR.

Background Kawasaki disease (KD) is an acute febrile illness of early childhood. The exact etiology of the disease remains unknown. At present, research on KD is mostly limited to susceptibility genes, infections, and immunity. However, research on the correlation between gut microbiota and KD is rare. Methods Children with a diagnosis of acute KD and children undergoing physical examination during the same period were included. At the time of admission, the subjects’ peripheral venous blood and feces were collected. Faecal samples were analyzed for bacterial taxonomic content via high-throughput sequencing. The abundance, diversity, composition, and characteristic differences of the gut microbiota in KD and healthy children were compared by alpha diversity, beta diversity, linear discriminant analysis and LDA effect size analysis. Blood samples were used for routine blood examination, biochemical analysis, and immunoglobulin quantitative detection. Results Compared with the control group, the community richness and structure of gut microbiota in the KD group was significantly reduced (Chao1 richness estimator, mean 215.85 in KD vs. mean 725.76 in control, p < 0.01; Shannon diversity index, mean 3.32 in KD vs. mean 5.69 in control, p < 0.05). LEfSe analysis identified two strains of bacteria significantly associated with KD: Bacteroidetes and Dorea. Bacteroidetes were enriched in healthy children (mean 0.16 in KD vs. mean 0.34 in control, p < 0.05). Dorea was also enriched in healthy children but rarely existed in children with KD (mean 0.002 in KD vs. mean 0.016 in control, p < 0.05). Compared with the control, IgA and IgG in the KD group decreased (IgA, median 0.68 g/L in KD vs. median 1.06 g/L in control, p < 0.001; IgG, median 6.67 g/L in KD vs. median 9.71 g/L in control, p < 0.001), and IgE and IgM levels were not significantly changed. Conclusions Dysbiosis of gut microbiota occurs in children with acute KD and may be related to the etiology or pathogenesis of KD. It is worth noting that for the first time, we found that Dorea, a hydrogen-producing bacterium, was significantly reduced in children with acute KD. Overall, our results provide a theoretical basis for the prevention or diagnosis of KD based on intestinal microecology.

Inflammatory osteolysis is governed by exacerbated osteoclastogenesis. Ample evidence points to central role of NF-κB in such pathologic responses, yet the precise mechanisms underpinning specificity of these responses remain unclear. We propose that motifs of the scaffold protein IKKγ/NEMO partly facilitate such functions. As proof-of-principle, we used site-specific mutagenesis to examine the role of NEMO in mediating RANKL-induced signaling in mouse bone marrow macrophages, known as osteoclast precursors. We identified lysine (K)270 as a target regulating RANKL signaling as K270A substitution results in exuberant osteoclastogenesis in vitro and murine inflammatory osteolysis in vivo. Mechanistically, we discovered that K270A mutation disrupts autophagy, stabilizes NEMO, and elevates inflammatory burden. Specifically, K270A directly or indirectly hinders binding of NEMO to ISG15, a ubiquitin-like protein, which we show targets the modified proteins to autophagy-mediated lysosomal degradation. Taken together, our findings suggest that NEMO serves as a toolkit to fine-tune specific signals in physiologic and pathologic conditions.

The aim of this study was to determine the effects and underlying molecular mechanisms of humic acid (HA) on foxtail millet (Setaria italica Beauv.) under drought conditions. The rainless climate of the Shanxi Province (37°42'N, 112°58'E) in China provides a natural simulation of drought conditions. Two foxtail millet cultivars, Jingu21 and Zhangza10, were cultivated in Shanxi for two consecutive years (2017-2018) based on a split-plot design. Plant growth, grain quality, and mineral elements were analyzed in foxtail millet treated with HA (50, 100, 200, 300, and 400 mg L-1) and those treated with clear water. Transcriptome sequencing followed by bioinformatics analysis was performed on plants in the normal control (CK), drought treatment (D), and drought + HA treatment (DHA) groups. Results were verified using real-time quantitative PCR (RT-qPCR). HA at a concentration of 100-200 mg L-1 caused a significant increase in the yield of foxtail millet and had a positive effect on dry weight and root-shoot ratio. HA also significantly increased P, Fe, Cu, Zn, and Mg content in grains. Moreover, a total of 1098 and 409 differentially expressed genes (DEGs) were identified in group D vs. CK and D vs. DHA, respectively. A protein-protein interaction network and two modules were constructed based on DEGs (such as SETIT_016654mg) between groups D and DHA. These DEGs were mainly enriched in the metabolic pathway. In conclusion, HA (100 mg L-1) was found to promote the growth of foxtail millet under drought conditions. Furthermore, SETIT_016654mg may play a role in the effect of HA on foxtail millet via control of the metabolic pathway. This study lays the foundation for research into the molecular mechanisms that underlie the alleviating effects of HA on foxtail millet under drought conditions.

Bowel health is an important factor for duck rearing that has been linked to feed uptake and growth and death rates. Because the regulatory networks associated with acute stress-mediated injury in the duck gastrointestinal tract have not clearly elucidated, we aimed to explore potential miRNA-mRNA pairs and their regulatory roles in oxidative stress injury caused by transport stress. Here, 1-day-old mallard ducklings from the same breeder flock were collected and transported for 8 h, whereas the control group was not being transported. Various parameters reflecting oxidative stress and the tissue appearance of the intestine were assessed. The data showed that the plasma T-AOC and SOD concentrations were decreased in the transported ducklings. The intestine of the transported ducklings also displayed significant damage. High-throughput sequencing of the intestine revealed 44 differentially expressed miRNAs and 75 differentially expressed genes, which constituted 344 miRNA-mRNA pairs. KEGG pathway analysis revealed that the metabolic, FoxO signaling, influenza A and TGF-β signaling pathways were mainly involved in the mechanism underlying the induction of intestinal damage induced by simulated transport stress in ducks. A miRNA-mRNA pair, miR-217-5p/CHRDL1, was selected to validate the miRNA-mRNA negative relationship, and the results showed that miR-217-5p could influence CHRDL1 expression. This study provides new useful information for future research on the regulatory network associated with mucosal damage in the duck intestine.

Presynaptic mitochondrial Ca2+ plays a critical role in the regulation of synaptic transmission and plasticity. The presynaptic bouton of the hippocampal mossy fiber (MF) is much larger in size than that of the Schaffer collateral (SC) synapse. Here we compare the structural and physiological characteristics of MF and SC presynaptic boutons to reveal functional and mechanistic differences between these two synapses. Our quantitative ultrastructural analysis using electron microscopy show many more mitochondria in MF presynaptic bouton cross-section profiles compared to SC boutons. Consistent with these results, post-tetanic potentiation (PTP), a form of presynaptic short-term plasticity dependent on mitochondrial Ca2+, is reduced by inhibition of mitochondrial Ca2+ release at MF synapses but not at SC synapses. However, blockade of mitochondrial Ca2+ release results in reduction of PTP at SC synapses by disynaptic MF stimulation. Furthermore, inhibition of mitochondrial Ca2+ release selectively decreases frequency facilitation evoked by short trains of presynaptic stimulation at MF synapses, while having no effect at SC synapses. Moreover, depletion of ER Ca2+ stores leads to reduction of PTP at MF synapses, but PTP is unaffected by ER Ca2+ depletion at SC synapses. These findings show that MF and SC synapses differ in presynaptic mitochondrial content as well as mitochondrial Ca2+ dependent synaptic plasticity, highlighting differential regulatory mechanisms of presynaptic plasticity at MF and SC synapses.

Abstract Non-thermal atmospheric plasma (NTP) has shown its selective anticancer effects in many types of tumors in vitro and one of the main mechanisms is that the different increase of intracellular ROS in cancer and homologous normal cells. In this study, we report that NTP treatment reduces the proliferation in triple negative breast cancer (TNBC) and normal cell lines. Simultaneously, STAT3 pathway is inhibited by NTP effects. However, it is observed that normal cells MCF10A are more sensitive to ROS toxicity induced by NTP than cancer cells MDA-MB-231. When 5 mM of ROS inhibitor N-acetyl cysteine (NAC) is employed in NTP treatments, the proliferation of normal breast cells MCF10A recovers. Meanwhile, NTP effects remain significant inhibition of MDA-MB-231 cells. Our results further reveal that NTP can induce apoptosis in MDA-MB-231 cells through inhibiting interleukin-6 receptor (IL-6R) pathway. Moreover, the mechanism of NTP anti-cancer selectivity relates to constantly HER2/Akt activation induced by NTP especially in MCF10A cells but not in MDA-MB-231 cells. Therefore, these two different cell signaling pathways induced by NTP treatments in TNBC and homologous normal cells make NTP becoming a potential tool in future therapy.

Foxtail millet (Setaria italic L.) is an important food and fodder crop that is cultivated worldwide. Quantifying the effects of herbicides on foxtail millet is critical for safe herbicide application. In this study, we analyzed the effects of different fluroxypyr dosages on the growth parameters and physiological parametric of foxtail millet, that is, peroxidation characteristics, photosynthetic characteristics, and endogenous hormone production, by using multivariate statistical analysis. Indicators were screened via Fisher discriminant analysis, and the growth parameters, peroxidation characteristics, photosynthesis characteristics and endogenous hormones of foxtail millet at different fluroxypyr dosages were comprehensively evaluated by principal component analysis. On the basis of the results of principal component analysis, the cumulative contribution rate of the first two principal component factors was 93.72%. The first principal component, which explained 59.23% of total variance, was selected to represent the photosynthetic characteristics and endogenous hormones of foxtail millet. The second principal component, which explained 34.49% of total variance, represented the growth parameters of foxtail millet. According to the principal component analysis, the indexes were simplified into comprehensive index Z, and the mathematical model of comprehensive index Z was set as F = 0.592Z1 + 0.345Z2. The results showed that the comprehensive evaluation score of fluroxypyr at moderate concentrations was higher than at high concentrations. Consequently, one L (active ingredient, ai) ha−1 fluroxypyr exerted minimal effects on growth parameters, oxidase activity, photosynthetic activity, and endogenous hormones, and had highest value of comprehensive evaluation, which had efficient and safe benefits in foxtail millet field.

Type 2 diabetes [T2D] and thyroid dysfunction [TD] often co-occur, have overlapping pathologies, and their risk increases with age. Since 1995, universal salt iodization has been implemented in China to prevent disorders caused by iodine deficiency. However, after two decades of implementation of universal salt iodization, the prevalence of TD in elderly Chinese patients with T2D is not well described and may have been underestimated. We conducted a questionnaire-based survey across 24 endocrinology centers in China between December 2015 and July 2016. Demographic and clinical data from 1677 patients with T2D were obtained and analyzed to examine the prevalence of TD along with T2D in these patients. We assessed TD prevalence according to the four TD subtypes [subclinical hypothyroidism, clinical hypothyroidism, subclinical hyperthyroidism, and clinical hyperthyroidism], TD history, gender, and age. The diagnosis rates were calculated for TD and also for the TD subtype. The number of patients reaching treatment goals for T2D [hemoglobin A1c

Abstract Non-thermal plasma (NTP) has been proposed as a novel therapeutic method for anticancer treatment. However, the mechanism underlying its biological effects remains unclear. In this study, we investigated the inhibitory effect of NTP on the invasion of HeLa cells and explored the possible mechanism. Our results showed that NTP exposure for 20 or 40 s significantly suppressed the migration and invasion of HeLa cells on the basis of matrigel invasion assay and wound healing assay, respectively. Moreover, NTP reduced the activity and protein expression of the matrix metalloproteinase (MMP)-9 enzyme. Western blot analysis indicated that NTP exposure effectively decreased phosphorylation level of both ERK1/2 and JNK, but not p38 MAPK. Furthermore, treatment with MAPK signal pathway inhibitors or NTP all exhibited significant depression of HeLa cells migration and MMP-9 expression. The result showed that NTP synergistically suppressed migration and MMP-9 expression in the presence of ERK1/2 inhibitor and JNK inhibitor, but not p38 MAPK inhibitor. Taken together, these findings suggested that NTP exposure inhibited the migration and invasion of HeLa cells via down-regulating MMP-9 expression in ERK1/2 and JNK signaling pathways dependent manner. These findings provide hints to the potential clinical research and therapy of NTP on cervical cancer metastasis.

The rapid development of China’s textile industry (TI) has led to severe water environmental stress. Water environmental stress of China’s TI mainly comes from large quantities of discharged wastewater and chemical oxygen demand (COD). The sustainable development of the TI is realized to achieve the decoupling between economic growth and water environmental stress. This study analyzes the decoupling elasticity results from wastewater discharge and COD discharge, respectively. Decoupling results show that TI’s wastewater has strong decoupling from economic growth for three years (2002, 2013–2014) while COD has strong decoupling for six years (2002–2003, 2008, 2010, 2013–2014). The paper further calculates the decoupling elasticity results of the TI’s three sub-sectors (manufacture of textile sector, manufacture of textile wearing and apparel sector, and manufacture of chemical fibers (MCF) sector), and calculates the factors that affect wastewater discharge. The decrement and rebound effects of wastewater discharge are analyzed based on calculated results. Decomposition results show that the scale factor is the most significant contributor to wastewater discharge, the intensity factor inhibits wastewater discharge, and the effect of the structure factor is not evident. The decrement effect of TI increases yearly, but the rebound effect shows that the absolute amount of wastewater discharge also increases. The rebound effect has declined since 2012. In the three sub-sectors, MCF’s decrement effect is the strongest, and its rebound effect is the weakest, which indicate that MCF is the biggest contributor to the discharge reduction of China’s TI.

Insects such as locusts and grasshoppers can reduce the effectiveness of pathogens and parasites by adopting different defense strategies. We investigated the behavioral thermopreference of Locusta migratoria manilensis (Meyen) (Orthoptera: Acrididae) induced by the fungus Beauveria bassiana, and the impact this behavior had on the fungal mycosis under laboratory conditions. By basking in higher temperature locations, infected nymphs elevated their thoracic temperature to 30-32.6 °C, which is higher than the optimum temperature (25°C) for B. bassiana conidial germination and hyphal development. A minimum thermoregulation period of 3 h/day increased survival of infected locusts by 43.34%. The therapeutic effect decreased when thermoregulation was delayed after initial infection. The fungus grew and overcame the locusts as soon as the thermoregulation was interrupted, indicating that thermoregulation helped the insects to cope with infection but did not completely rid them of the fungus. A significant enhancement in the number of haemocytes was observed in infected thermoregulating locusts, reaching levels that were even higher than those observed in the controls. In contrast, haemocyte concentration was severely reduced in infected insects that did not thermoregulate. In infected non-thermoregulating locusts, the reduction in haemocyte number was accompanied by an increase in fungal blastospore concentration that was obvious in the haemolymph by day four. In contrast, no circulating blastospores were found in the haemolymph of infected thermoregulating locusts three days post-inoculation. We also examined the phagocytic activity of infected insects in vivo by using fluorescein isothiocyanate (FITC)-labelled silica beads. The proportion of beads that was engulfed by haemocytes in infected, thermoregulating insects was similar to that in the controls throughout the experiment, whereas the rate of phagocytosis in infected, non-thermoregulating insects progressively decreased after infection. These findings demonstrated that behavioural thermoregulation can adversely affect B. bassiana mycosis in infected L. migratoria manilensis, thereby limiting the development of lethal entomopathogenic fungi in locusts. This is apparently accomplished through an increase in the levels of haemocytes, leading to greater phagocytic activity under certain environmental conditions.

Previous studies have demonstrated the genetic correlations between type 2 diabetes, obesity and dyslipidemia, and indicated that many genes have pleiotropic effects on them. However, these pleiotropic genes have not been well-defined. It is essential to identify pleiotropic genes using systematic approaches because systematically analyzing correlated traits is an effective way to enhance their statistical power. To identify potential pleiotropic genes for these three disorders, we performed a systematic analysis by incorporating GWAS (genome-wide associated study) datasets of six correlated traits related to type 2 diabetes, obesity and dyslipidemia using Meta-CCA (meta-analysis using canonical correlation analysis). Meta-CCA is an emerging method to systematically identify potential pleiotropic genes using GWAS summary statistics of multiple correlated traits. 2,720 genes were identified as significant genes after multiple testing (Bonferroni corrected p value < 0.05). Further, to refine the identified genes, we tested their relationship to the six correlated traits using VEGAS-2 (versatile gene-based association study-2). Only the genes significantly associated (Bonferroni corrected p value < 0.05) with more than one trait were kept. Finally, 25 genes (including two confirmed pleiotropic genes and eleven novel pleiotropic genes) were identified as potential pleiotropic genes. They were enriched in 5 pathways including the statin pathway and the PPAR (peroxisome proliferator-activated receptor) Alpha pathway. In summary, our study identified potential pleiotropic genes and pathways of type 2 diabetes, obesity and dyslipidemia, which may shed light on the common biological etiology and pathogenesis of these three disorders and provide promising insights for new therapies.

There are co-morbidity between osteoporosis (OP) and rheumatoid arthritis (RA). Some genetic risk factors have been identified for these two phenotypes respectively in previous research; however, they accounted for only a small portion of the underlying total genetic variances. Here, we sought to identify additional common genetic loci associated with OP and/or RA. The conditional false discovery rate (cFDR) approach allows detection of additional genetic factors (those respective ones as well as common pleiotropic ones) for the two associated phenotypes. We collected and analyzed summary statistics provided by large, multi-center GWAS studies of FNK (femoral neck) BMD (a major risk factor for osteoporosis) (n = 53,236) and RA (n = 80,799). The conditional quantile-quantile (Q-Q) plots can assess the enrichment of SNPs related to FNK BMD and RA, respectively. Furthermore, we identified shared loci between FNK BMD and RA using conjunction cFDR (ccFDR). We found strong enrichment of p-values in FNK BMD when conditional Q-Q was done on RA and vice versa. We identified 30 novel OP-RA associated pleiotropic loci that have not been reported in previous OP or RA GWAS, 18 of which located in the MHC (major histocompatibility complex) region previously reported to play an important role in immune system and bone health. We identified some specific novel polygenic factors for OP and RA respectively, and identified 30 novel OP-RA associated pleiotropic loci. These discovery findings may offer novel pathobiological insights, and suggest new targets and pathways for drug development in OP and RA patients.