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Abstract Background The recent Maternal Immune Activation (MIA) theory suggests maternal systemic inflammation may serve as a mediator in associations between prenatal maternal adversities and neurodevelopmental diseases in offspring. Given the co-exposure to multiple adversities may be experienced by pregnant person, it is unclear whether a quantitative index can be developed to characterize the inflammation related exposure level, and whether this index is associated with neurodevelopmental delays in offspring. Methods Based on Jiangsu Birth Cohort (JBC), a total of 3051 infants were included in the analysis. Inflammation related Prenatal Adversity Index (IPAI) was constructed using maternal data. Neurodevelopmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development, third edition, screening test in one year. Multivariate linear regression and Poisson regression model were performed to analyze the associations between IPAI and neurodevelopment in offspring. Results Compared with “low IPAI” group, offspring with “high IPAI” have lower scores of cognition, receptive communication, expressive communication, and fine motor. The adjusted β were − 0.23 (95%CI: -0.42, -0.04), -0.47 (95%CI: -0.66, -0.28), -0.30 (95%CI: -0.49, -0.11), and − 0.20 (95%CI: -0.33, -0.06). Additionally, the elevated risk for noncompetent development of cognition and receptive communication among “high IPAI” group was observed. The relative risk [RR] and 95% confidence interval [CI] were 1.35 (1.01, 1.69) and 1.37 (1.09, 1.72). Conclusions Our results revealed a significant association between higher IPAI and lower scores across cognition, receptive communication, expressive communication, and fine motor domains, and an increased risk of noncompetent development in the cognition and receptive communication domains.

BackgroundMost smokers attempting to quit will quickly relapse to tobacco use even when treated with the most efficacious smoking cessation agents currently available. This highlights the need to develop effective new smoking cessation medications. Evidence suggests that positive allosteric modulators (PAM) and other enhancers of nicotinic acetylcholine receptor (nAChR) signaling could have therapeutic utility as smoking cessation agents.Methods3-[3-(3-pyridyl)-1,2,4-oxadiazol-5-yl]benzonitrile (NS9283) was used as a starting point for medical chemistry efforts to develop novel small molecule enhancers of α4β2* nAChR stoichiometries containing a low-affinity agonist binding site at the interface of α4/α4 and α4/α5 subunits.ResultsThe NS9283 derivative SR9883 enhanced the effect of nicotine on α4β2* nAChR stoichiometries containing low-affinity agonist binding sites, with EC50 values from 0.2–0.4 μM. SR9883 had no effect on α3β2* or α3β4* nAChRs. SR9883 was bioavailable after intravenous (1 mg kg−1) and oral (10–20 mg kg−1) administration and penetrated into the brain. When administered alone, SR9883 (5–10 mg kg−1) had no effect on locomotor activity or intracranial self-stimulation (ICSS) thresholds in mice. When co-administered with nicotine, SR9883 enhanced locomotor suppression and elevations of ICSS thresholds induced by nicotine. SR9883 (5 and 10 mg kg−1) decreased responding for intravenous nicotine infusions (0.03 mg kg−1 per infusion) but had no effect on responding for food rewards in rats.ConclusionsThese data suggest that SR9883 is useful for investigating behavioral processes regulated by certain α4β2* nAChR stoichiometries. SR9883 and related compounds with favorable drug-like physiochemical and pharmacological properties hold promise as novel treatments of tobacco use disorder.

Obesity is associated with numerous metabolic disorders, and dietary polyphenols have been confirmed to have beneficial effects on the metabolism in obesity. However, the effect of 3-(3′,4′-dihydroxyphenyl)propanoic acid (DHPA) and 3′,4′-dihydroxyphenylacetic acid (DHAA), two main metabolites of dietary polyphenols, on obesity remains poorly understood. In this study, DHPA and DHAA were found to alleviate obesity, as well as regulate insulin resistance, lipid metabolism, and oxidative stress response in high-fat diet (HFD) mice. Surprisingly, the 16S rRNA sequencing and UHPLC-Q-TOF/MS demonstrated that DHPA and DHAA only slightly disturbed the intestinal microbiome, but significantly altered the urine metabolome of HFD mice mainly by regulating pentose and glucuronate interconversion, tyrosine metabolism, pentose phosphate and tricarboxylic acid (TCA) cycle as indicated by metabolic pathway analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Correlation analysis revealed that the differential metabolites are strongly associated with body weight, blood glucose, insulin level, and superoxide dismutase (SOD) enzyme activity. Our results revealed that DHPA and DHAA exert their anti-obesity effect by regulating important metabolites in the glucose, lipid and tyrosine metabolism pathways.

Background: Concerns have been raised regarding the effects of perfluoroalkyl substance (PFAS) exposure on cardiovascular diseases (CVD), but clear evidence linking PFAS exposure to CVD is lacking, and the mechanism remains unclear. Objectives: To study the association between PFASs and CVD in U.S. population, and to reveal the mechanism of PFASs’ effects on CVD. Methods: To assess the relationships between individual blood serum PFAS levels and the risk of total CVD or its subtypes, multivariable logistic regression analysis and partial least squares discriminant analysis (PLS-DA) were conducted on all participants or subgroups among 3391 adults from the National Health and Nutrition Examination Survey (NHANES). The SuperPred and GeneCards databases were utilized to identify potential targets related to PFAS and CVD, respectively. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of intersection genes were performed using Metascape. Protein interaction networks were generated, and core targets were identified with STRING. Molecular docking was achieved using Autodock Vina 1.1.2. Results: There was a positive association between Me-PFOSA-AcOH and CVD (OR = 1.28, p = 0.022), especially coronary heart disease (CHD) (OR = 1.47, p = 0.007) and heart attack (OR = 1.58, p < 0.001) after adjusting for all potential covariates. Me-PFOSA-AcOH contributed the most to distinguishing between individuals in terms of CVD and non-CVD. Significant moderating effects for Me-PFOSA-AcOH were observed in the subgroup analysis stratified by sex, ethnicity, education level, PIR, BMI, smoking status, physical activity, and hypertension (p < 0.05). The potential intersection targets were mainly enriched in CVD-related pathways, including the inflammatory response, neuroactive ligand–receptor interaction, MAPK signaling pathway, and arachidonic acid metabolism. TLR4 was identified as the core target for the effects of Me-PFOSA-AcOH on CVD. Molecular docking results revealed that the binding energy of Me-PFOSA-AcOH to the TLR4-MD-2 complex was −7.2 kcal/mol, suggesting that Me-PFOSA-AcOH binds well to the TLR4-MD-2 complex. Conclusions: Me-PFOSA-AcOH exposure was significantly associated with CVD. Network toxicology and molecular docking uncovered novel molecular targets, such as TLR4, and identified the inflammatory and metabolic mechanisms underlying Me-PFOSA-AcOH-induced CVD.

Steel fiber-reinforced geopolymer concrete (SFRGPC) is an inorganic cementitious material with environmentally friendly features. As compared to conventional concrete, SFRGPC has greater strength and durability, but it is brittle, making it similar to ordinary concrete. To date, the triaxial mechanical properties that regulate SFRGPC’s structural performance at serviceable and ultimate-limit conditions remain poorly understood. In this study, we conducted experimental and theoretical analyses of these properties. Conventional triaxial testing is used to investigate the effects of varying steel fiber contents and ratio of length to diameter under different confinement pressures on SFRGPC’s mechanical properties. The failure mode, maximal strength, stress–strain curve, maximum strain, and compressive toughness were analyzed and discussed. Under uniaxial compression, the failure mode of the SFRGPC specimens was a longitudinal split failure. The brittleness of the SFRGPC can be eliminated, and its resistance to breaking can be greatly improved by increasing the volume of steel fibers and the confining pressure in the mixture. The steel fiber content and ratio of length to diameter have obvious influence on the compressive strength of SFRGPC. As the steel fiber content increased, the compressive strength increased by 1.15–1.44 times; as the ratio of length to diameter increased, the compressive strength increased by 1.21–1.70 times. The increase in confining pressure can improve the compressive strength of concrete. With the increase in confining pressure, the increase trend of compressive strength becomes smooth. The confining pressure, steel fiber content, and steel fiber length have substantial influences on the compressive toughness index ηc3. Under increasing confining pressure, ηc3 increases linearly; however, after confining pressure is higher than 5 MPa, ηc3 tends toward a steady state when the confining pressure increases. Using numerical simulation, we also investigated the size effect of SFRGPC under triaxial load. The concrete cylinder’s strength does not significantly decrease as its size increases.

Increasing evidences have revealed a close relationship between various environmental exposures and reproductive health. The real-world complex exposure scenario along with intricate interactions effects of these exposures has high demands of exposome-wide association studies for human risk assessment. With the development of exposomic studies, applying hair exposome to link environmental factors and reproductive health outcomes has obvious potential advantages. However, the reliability of utilizing hair to characterize exposome is always of high concern for researchers. In this review, we briefly summarized studies about the effects of environmental exposures on several typical reproductive health outcomes, described state-of-the-art situation of applying hair exposome for reproductive health risk assessment, elucidated the advantages (e.g., containing abundant exposure factors, low expenses for sampling, and tracing exposure history), and proposed the unsolved issues in this area. We also conducted a comprehensive discussion about the reliability of various hair biomarkers and primarily established the biomarker databases. Finally, a standardized framework on using hair exposome for reproductive health study was proposed to provide fundamental approach for future studies. We concluded that it is promising to apply hair exposome to evaluate the effects of the environmental factors on human reproductive health.

Bee products are gaining increasing popularity among consumers for their high nutritional value and various biological activities. However, adulteration is becoming a prominent problem in the production and sale of bee products, and the mechanisms underlying their biological activities have not been fully elucidated. Proteomics and metabolomics can provide complete and comprehensive descriptions on the overall characteristics of proteins and small-molecular metabolites. In recent years, these two omics approaches have been widely used in the field of bee products, and become a powerful means to solve the problem of adulteration in bee products and elucidate the mechanisms underlying their biological activities. This paper reviews the research progress in the application of proteomics and metabolomics in bee products. Based on an overview of the advantages of proteomics and metabolomics in simultaneous identification of whole components and screening of characteristic markers, the paper also summarizes their applications in the identification of components, discrimination and authentication, and elucidation of mechanisms for biological activities of bee products in detail. In addition, the existing problems are analyzed and the future research directions are proposed. The paper is expected to provide a reference for extensive and in-depth application of omics technologies in the research of bee products.

ABSTRACTCritical-size defects (CSDs) are challenging oral clinical issues that need to be solved. Adipose-derived mesenchymal stem cells (ADSCs) and gene therapy offer a new target to solve these issues. Consequently, ADSCs attract more and more attention because of advantages such as easy obtainability and no ethical concerns. TNF receptor-associated factor 6 (TRAF6) is a significant binding protein both of tumour necrosis factor superfamily and of the toll/interleukin-1 receptor superfamily. Evidence is accumulating that TRAF6 inhibited osteoclast formation and promoted the proliferation of multiple myeloma cell lines and bone resorption. Here, we reported that overexpression of TRAF6 enhanced the proliferation, migration and osteogenesis of ADSCs through Raf-Erk-Merk-Hif1a pathway. Cell sheet of ADSCs combined with TRAF6 accelerated the healing of CSDs. In a word, TRAF6 enhanced osteogenesis, migration and proliferation through Raf-Erk-Merk-Hif1a pathway.

Nano-adjuvant vaccines could induce immune responses and enhance immunogenicity. However, the application and manufacturing of nano-adjuvant is hampered by its challenging scale-up, poor reproducibility, and low security. Therefore, the present study aimed to optimize the preparation nanoparticles (NPs) using FDA-approved biopolymer materials poly(lactic acid) (PLA) and cationic lipid didodecyl-dimethyl-ammonium bromide (DDAB), develop the scale-up process, and evaluate the stability and biosafety of it. The optimum preparation conditions of DDAB/PLA NPs on a small scale were as follows: DDAB amount of 30 mg, aqueous phase volume of 90 mL, stirring rate at 550 rpm, and solidifying time of 12 h. Under the optimum conditions, the size of the NPs was about 170 nm. In scale-up preparation experiments, the vacuum rotary evaporation of 6 h and the Tangential flow ultrafiltration (TFU) method were the optimum conditions. The results suggested that DDAB/PLA NPs exhibited a uniform particle size distribution, with an average size of 150.3 ± 10.4 nm and a narrow polydispersity index (PDI) of 0.090 ± 0.13, coupled with a high antigen loading capacity of 85.4 ± 4.0%. In addition, the DDAB/PLA NPs can be stored stably for 30 days and do not have side effects caused by residual solvents. For biosafety, the acute toxicity experiments showed good tolerance of the vaccine formulation even at a high adjuvant dose. The local irritation experiment demonstrated the reversibility of muscular irritation, and the repeated toxicity experiment revealed no significant necrosis or severe lesions in mice injected with the high-dose vaccine formulation. Overall, the DDAB/PLA NPs exhibit potential for clinical translation as a safe candidate vaccine adjuvant.

The large deviations between the partial pressure of oxygen and hydrogen can lead to severe membrane damage, which reduces the life of the polymer electrolyte membrane fuel cell (PEMFC). The deviation of pressure can be restrained by effective control of partial pressure. Considering the actual operating environment of PEMFC, its control system is not only affected by load changes, but also affected by some unknown disturbances, such as system parameter variations, failures, etc. Considering the above factors, this paper has proposed a robust nonlinear adaptive pressure control (RNAPC) employing the perturbation estimation technique to suppress the deviations. The proposed controller does not need to identify or estimate the system parameters in real time like the conventional controller based on parameter estimation technology, nor does it need to rely on the fault diagnosis and isolation technology to detect and estimate the failures in real time. It only uses the variations of system state variables caused by failures to provide the required failure information for the controller. In the design of RNAPC, an observer is designed to estimate a perturbation term containing system uncertainties, nonlinearities, and disturbances. The estimation of perturbation is used for the compensation of actual perturbation. Then, an adaptive FLC of PEMFC system can be realized. Therefore, the RNAPC requires only a few state measurements and is independent of an accurate system model. Simulation results show that the RNAPC method has smaller deviations of partial pressure of oxygen and hydrogen and better dynamic performance than traditional PI control under load disturbance, and obtains higher robustness against uncertainties and sensor failures than traditional PI control and FLC. The maximum error of partial pressure can be limited within 0.5% under four different simulation scenarios under the RNAPC.

Abstract Left ventricular non-compaction cardiomyopathy (LVNC) is one of the most common inherited cardiovascular diseases. The genetic backgrounds of most LVNC patients are not fully understood. We collected clinical data, family histories, and blood samples and performed genetic analysis using next-generation sequencing (NGS) from a Chinese family of 15 subjects. Clinically LVNC affected subjects showed marked cardiac phenotype heterogeneity. We found that these subjects with LVNC carried a missense heterozygous genetic mutation c.905G>A (p.R302Q) in γ2 subunit of AMP-activated protein kinase (PRKAG2) gene through NGS. Individuals without this mutation showed no symptoms or cardiac structural abnormalities related to LVNC. One subject was the victim of sudden cardiac death. To sum up, PRKAG2 mutation c.905G>A (p.R302Q) caused familial LVNC. Our results described a potentially pathogenic mutation associated with LVNC, which may further extend the spectrum of LVNC phenotypes related to PRKAG2 gene mutations.

Abstract Background Docetaxel (DTX) is the most widely prescribed first-line chemotherapy for advanced prostate cancer (PCa). Unfortunately, DTX resistance invariably emerges, leading to worse prognosis of PCa. Growing evidence has shown that circRNAs had complex spatiotemporal specificity during the tumor development and oncogenesis. This study was designed to investigate the biological functions and possible molecular mechanisms of circRNAs in DTX resistance of PCa. Methods circRNAs in established DTX-resistant DU145 cell line were identified by RNA sequencing. Biological function of circCYP24A1 was verified in vitro and in vivo. The potential role of circCYP24A1 in the development of DTX-resistant PCa was investigated via dual-luciferase reporter assays, RIP assays and RNA pull-down assays. Univariate and multivariate logistic regression analyses was used to predict DTX-chemotherapy response based on patients’ clinical and biological information. Results CircCYP24A1 was identified to be upregulated in DTX-resistant DU145 cells. Upregulated circCYP24A1 was found to suppress the DTX chemosensitivity in vitro and in vivo. Furthermore, we found that circCYP24A1 promoted DTX resistance in PCa via regulating ALDH1A3 expression by sponging miR-1301-3p and activating PI3K/AKT/mTOR signaling pathway. Statistical analyses elucidated that circCYP24A1 was an independent risk factor to predict DTX response (OR = 0.165; 95% CI: 0.038–0.723; P = 0.017). Conclusions This study demonstrated that circCYP24A played an essential role in DTX resistance in PCa, suggesting that circCYP24A1 could be a promising biomarker to predict DTX response and a potential therapeutic target in PCa patients resistant to DTX chemotherapy.

Parboiling is gaining increasing attention as it can enhance the head rice yield (HRY) and nutritional quality of non-pigmented rice. The traditional parboiling process with high-temperature immersion requires a long immersion period and results in hard texture of cooked parboiled black rice (PBR), which may be addressed by ultrasound-assisted immersion. In this study, we evaluated the effect of power, time and temperature of ultrasonic immersion on the HRY, texture profile and nutritional quality of PBR. Proper ultrasound-assisted immersion could increase the HRY by about 20% and the GABA content by up to 133%, as well as reduce the arsenic and cadmium content by up to 61% and 79% relative to untreated black rice (UBR), respectively. Moreover, it could increase the content of essential minerals such as calcium, iron and zinc to some extent, and free and bound polyphenols, despite of a certain loss of anthocyanins. It could also improve the palatability of cooked rice. Furthermore, response surface experiments based on the Box-Behnken design were performed to obtain and validate the optimal conditions of ultrasound-assisted immersion (540 W, 45 min, 57 °C). On this basis, morphological changes might be one reason for the improved HRY, nutrition and texture of PBR compared with those of UBR, namely the disappearance of cracks near the aleurone layer and formation of new cracks in the interior of rice.

Abstract Lymph node (LN) metastasis is associated with unfavorable prognosis of bladder cancer (BCa). Although lymphangiogenesis is functionally important in LN metastasis of tumors, the potential mechanism in BCa remains unclear. Here, we clarified a regulatory mechanism of circRNA-mediated lymphangiogenesis and LN metastasis in BCa based on next-generation sequencing data. We revealed that circDHTKD1 was positively associated with LN metastasis and significantly upregulated in BCa. By analyzing the co-expression patterns of circDHTKD1 and differentially expressed mRNAs, we identified that circDHTKD1 facilitated lymphangiogenesis by upregulating CXCL5. Mechanistically, circDHTKD1 directly interacted with miR-149-5p, and antagonized the repression of miR-149-5p on CXCL5. Furthermore, circDHTKD1-induced CXCL5 expression recruited and activated neutrophils, which participated in lymphangiogenesis by secreting VEGF-C. Our study supports circDHTKD1 as a promising diagnostic and therapeutic target for LN metastasis in BCa.

Abstract Background The burden of healthcare-associated infections (HAIs) and the spread of antimicrobial resistance can be potentially preventable through comprehensive infection prevention and control (IPC) programs. However, information on the current state of IPC implementation is rare in China. Methods A cross-sectional study was conducted in Zhejiang province, China, from April to June 2021. The Zhejiang nosocomial infection control and quality improvement center (NICQI) cooperated with 11 municipal NICQI centers to introduce the purpose of this study and invite all licensed secondary and tertiary hospitals in Zhejiang province through WeChat group. The questionnaire had three sections, including information about participating hospitals, demographic information about IPs, and the Chinese version of the Infection Prevention and Control Assessment Framework that covered eight core components (CC). Results Of the 382 hospitals invited, 222 (58.1% response rate) accepted and completed the online questionnaire. The overall median score of the participating hospitals was 682 (630–723), which corresponded to an advanced level of IPC. There was a significant difference in scores between hospitals types (P

Otoliths grow throughout a fish’s life and are important for identifying fish stocks and fish age. This study aims to differentiate different stocks of Schizothorax grahami (Regan, 1904) in the Chishui River, an upper reach of the Yangtze River, by otolith morphology. The otolith morphology of S. grahami from three different river sections was analyzed using the Shape Index, Fourier coefficients, and wavelet coefficients. The composite discrimination success rate of the Shape Index was 59.7%, and it was difficult to distinguish in the scatter plots. In contrast, canonical principal coordinate scatter plots clearly showed three distinguished stocks. The above results indicate that otolith morphology can discriminate between stocks in plateau endemic fish, and several S. grahami stocks may be separately managed in the Chishui River.

BackgroundHeart Failure (HF) is the end-stage cardiovascular syndrome with poor prognosis. Proteomics holds great promise in the discovery of novel biomarkers and therapeutic targets for HF. The aim of this study is to investigate the causal effects of genetically predicted plasma proteome on HF using the Mendelian randomization (MR) approach.MethodsSummary-level data for the plasma proteome (3,301 healthy individuals) and HF (47,309 cases; 930,014 controls) were extracted from genome-wide association studies (GWASs) of European descent. MR associations were obtained using the inverse variance-weighted (IVW) method, sensitivity analyses, and multivariable MR analyses.ResultsUsing single-nucleotide polymorphisms as instrumental variables, 1-SD increase in MET level was associated with an approximately 10% decreased risk of HF (odds ratio [OR]: 0.92; 95% confidence interval [CI]: 0.89 to 0.95; p = 1.42 × 10−6), whereas increases in the levels of CD209 (OR: 1.04; 95% CI: 1.02–1.06; p = 6.67 × 10−6) and USP25 (OR: 1.06; 95% CI: 1.03–1.08; p = 7.83 × 10−6) were associated with an increased risk of HF. The causal associations were robust in sensitivity analyses, and no evidence of pleiotropy was observed.ConclusionThe study findings suggest that the hepatocyte growth factor/c-MET signaling pathway, dendritic cells-mediated immune processes, and ubiquitin-proteasome system pathway are involved in the pathogenesis of HF. Moreover, the identified proteins have potential to uncover novel therapies for cardiovascular diseases.

Context. Excessive proliferation of vascular smooth muscle cells (VSMCs) plays a critical role in the development of cardiovascular diseases. β-Sitosterol exerts protective effects against the cardiovascular disease. However, whether β-sitosterol protects against the excessive proliferation of VSMCs remain unclear. Objective. To explore the effects of β-sitosterol on VSMC proliferation. Materials and Methods. A7r5 cells were pretreated with 2 µM angiotensin II (Ang II) for 24 hr to establish an excessive VSMC proliferation model, followed by treatment with β-sitosterol for 24 hr. Cells were divided into five groups: control, Ang II, and Ang II + β-sitosterol (2, 4, 8 µM). CCK-8 assay, flow cytometry, and Ad-mCherry-GFP-LC3B assay analyzed cell proliferation, cell cycle, cell apoptosis, and autophagic flux. Additionally, the expression of proteins was detected by the western blotting. Results. β-Sitosterol effectively inhibited Ang II-induced A7r5 cell proliferation (IC50 : 6.841 µM at 24 hr). It achieved this by arresting cell cycle progression, promoting apoptosis, inhibiting autophagy, and suppressing the contractile–synthetic phenotypic switch. Mechanistically, β-sitosterol downregulated PCNA, Cyclin D1, and Bcl-2, while upregulating pro-caspase 3, cleaved-caspase 3, and Bax to induce cell cycle arrest and apoptosis. Additionally, it suppressed the contractile–synthetic phenotypic transformation by downregulating OPN and upregulating α-SMA. The Ad-mCherry-GFP-LC3B Assay and western blotting revealed β-sitosterol’s autophagy inhibitory effects by downregulating LC3, ULK1, and Beclin-1 while upregulating P62 expression. Discussion and Conclusion. This study found for the first time that β-sitosterol could inhibit the proliferation of A7r5 cells induced by Ang II. β-Sitosterol treatment may be recommended as a therapeutic strategy to prevent the cardiovascular diseases.

Neurodegeneration is associated with defects in cytoskeletal dynamics and dysfunctions of the vesicular trafficking and sorting systems. In the last few decades, studies have demonstrated that the key regulators of cytoskeletal dynamics are proteins from the Rho family GTPases, meanwhile, the central hub for vesicle sorting and transport between target membranes is the Rab family of GTPases. In this regard, the role of Rho and Rab GTPases in the induction and maintenance of distinct functional and morphological neuronal domains (such as dendrites and axons) has been extensively studied. Several members belonging to these two families of proteins have been associated with many neurodegenerative disorders ranging from dementia to motor neuron degeneration. In this analysis, we attempt to present a brief review of the potential crosstalk between the Rab and Rho family members in neurodegenerative pathologies such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington disease, and amyotrophic lateral sclerosis (ALS).

This study investigates the stability problem of load frequency control (LFC) for power systems with interval time-varying delays. The two categories of time delays, the lower bound being zero and non-zero, are considered. The systems can be described as time delay systems of load disturbances. First, an augmented Lyapunov–Krasovskii functional (LKF) is constructed. Some delay-dependent nonintegral terms and single integral terms are additionally introduced to make full use of the information on the system state variables and the time-varying delays. Second, to overcome the problem of nonlinear inequalities caused by the augmented LKF, the nonlinear inequalities are converted into linear matrix inequalities (LMIs) by applying the new negative definite inequality equivalence transformation lemma, which can be solved easily by the MATLAB LMI toolbox. A new stability criterion is presented by applying the Lyapunov stability theory. The stability criterion is less conservative than some existing literature studies, which further improves the stability margin for the power systems based on LFC. Finally, some numerical examples are given to show the effectiveness of the proposed method and the superiority of the results.

Objective: The objective of the study was to compare the effects of assisted reproductive technology (ART) and spontaneous pregnancy on pregnancy outcomes in women with endometrial carcinoma (EC) and atypical endometrial hyperplasia (AEH) following fertility-sparing treatments. Methods: Relevant studies published through July 2020 were identified from PubMed and Web of Science literature searches. The pregnancy outcomes of ART and spontaneous pregnancy were summarized and compared for women with complete remission of EC/AEH after fertility-sparing treatments. A subgroup analysis was performed based on whether patients had received in vitro fertilization and embryo transfer (IVF-ET) treatment. The complete remission and recurrence rates of EC/AEH following fertility-sparing treatments were estimated. The effect of pregnancy on recurrence rates of EC/AEH was also calculated. Results: Sixteen observational studies reporting pregnancy outcomes or recurrence with ART or spontaneous pregnancy for women with EC/AEH after fertility-sparing treatments were included. The complete remission rate of EC/AEH was 81.5% (95%CI, 78%–85%). Compared with spontaneous pregnancy, the pregnancy rate of ART was significantly higher (66.8% vs. 43.7%, OR ​= ​2.64, 95%CI 1.71–4.05, P

Mercury ion (Hg2+) is a toxic heavy metal ion and Hg2+ is convertible to methylmercury (MeHg) by many aquatic microorganisms, leading to bioaccumulation and biomagnification in aquatic organisms, which can interfere with brain development and function in humans. This study employs a newly developed AIEgen (Aggregation-induced emission fluorogen) to quantify and visualise the process of MeHg bioaccumulation in vivo on the species of water flea Daphnia carinata. Two approaches to MeHg absorption were taken, either by direct incubation in a MeHg solution or by indirect consumption of algae contaminated with MeHg. We analysed the relationship between the ratio of photoluminescence (PL) intensities (I585/I480) and MeHg concentration (CMeHg) and generated a master curve for determining MeHg concentration based on the measurement of PL intensities. Fluorescent image analysis showed the occurrence of MeHg in D. carinata to be mainly in the compound eyes, optic nerve and carapace. This study indicates that MeHg absorption can be quantified and visualised in the body of zooplankton, and the MeHg transfer to zooplankton is more likely through direct exposure than via indirect food intake. The accumulation of MeHg in the eye and the nervous system could be the cause of the high mortality of D. carinata exposed to MeHg in water.

Abstract Background Periodontitis is the most extensive chronic inflammatory bone resorption disease. MiRNAs offer a potential way for potential therapy. Indeed, miR-30a-5p had an increasing expression in periodontitis gingivae, but whether it promotes osteogenesis and inhibits inflammation remains unknown. Methods Periodontitis model was exhibited by wire ligation and verified by micro-CT and HE staining; qPCR was used to detect the expression of miR-30a-5p; miR-30a-5p inhibitors and mimics were transfected into MC3T3-E1 cell line by lipofectamine 3000; The dual luciferase reporter gene experiment and RIP experiment were used to detect the relationship between miR-30a-5p and Runx2; Rescue experiment was used to verify the relationship between miR-30a-5p and Runx2. Results Periodontitis model was exhibited successfully and miR-30a-5p was overexpressed at the bone and gingival tissues of this model. miR-30a-5p inhibitors not only promoted the osteogenesis but also relieved inflammation. Runx2 is a target of miR-30a-5p by dual luciferase reporter gene experiment and RIP experiment. Rescue experiments revealed that miR-30a-5p inhibitors would promote osteogenesis and relieve inflammation by targeting Runx2 in inflammation of MC3T3-E1 cell line. Conclusions That all suggested that miR-30a-5p-mediated-Runx2 provided a novel understanding of mechanism of periodontitis.

Abstract Background Psychological distress may exert a negative influence on reproductive function of couples at reproductive age. Couples seeking assisted reproductive technology (ART) treatment may have a higher prevalence of psychological distress than fertile couples. However, whether psychological distress is associated with the outcome of ART treatment remains unknown. We aimed to investigate the association of pre-treatment psychological distress and clinical pregnancy rate among infertility couples undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment. Methods This nested case-control study was conducted based on women who underwent their first fresh IVF or ICSI cycle in the Jiangsu Birth Cohort Study (JBC) between November 2015 and January 2019. A total of 150 women who did not obtain clinical pregnancy after first IVF or ICSI fresh embryo transfer were identified as cases, and a total of 300 age matched women who obtained clinical pregnancy were identified as controls. Conditional logistic regression analyses were used to investigate the association between psychological distress and the outcome of first IVF or ICSI treatment, adjusting for multiple potential confounders. Results No statistically significant association was observed between score of maternal symptoms of psychological distress and clinical pregnancy. Adjusted ORs of logistic regression were 1.00 (95% CI 0.97-1.03) for anxiety, 0.98 (95% CI 0.95-1.02) for depression, and 0.98 (95% CI 0.95-1.01) for perceived stress, respectively. When treat depression and anxiety as categorical variables, 62 (13.8%) were classified as clinical depression, 11 (2.4%) were classified as clinical anxiety, among 450 women in the present study. Psychological distress symptoms were also not associated with clinical pregnancy rate. Adjusted ORs of logistic regression were 0.27 (95% CI 0.03-2.33) for anxiety, 0.88 (95% CI 0.46-1.68) for depression, respectively. Conclusions Our findings firstly indicated that psychological distress experienced prior to IVF/ICSI treatment was not associated with clinical pregnancy.

Sinomenine is a natural compound extracted from the medicinal plant Sinomenium acutum. Its supplementation has been shown to present benefits in a variety of animal models of central nervous system (CNS) disorders, such as cerebral ischemia, intracerebral hemorrhage, traumatic brain injury (TBI), Alzheimer’s disease (AD), Parkinson’s disease (PD), epilepsy, depression, multiple sclerosis, morphine tolerance, and glioma. Therefore, sinomenine is now considered a potential agent for the prevention and/or treatment of CNS disorders. Mechanistic studies have shown that inhibition of oxidative stress, microglia- or astrocyte-mediated neuroinflammation, and neuronal apoptosis are common mechanisms for the neuroprotective effects of sinomenine. Other mechanisms, including activation of nuclear factor E2-related factor 2 (Nrf2), induction of autophagy in response to inhibition of protein kinase B (Akt)-mammalian target of rapamycin (mTOR), and activation of cyclic adenosine monophosphate-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), may also mediate the anti-glioma and neuroprotective effects of sinomenine. Sinomenine treatment has also been shown to enhance dopamine receptor D2 (DRD2)-mediated nuclear translocation of αB-crystallin (CRYAB) in astrocytes, thereby suppressing neuroinflammation via inhibition of Signal Transducer and Activator of Transcription 3 (STAT3). In addition, sinomenine supplementation can suppress N-methyl-D-aspartate (NMDA) receptor-mediated Ca2+ influx and induce γ-aminobutyric acid type A (GABAA) receptor-mediated Cl− influx, each of which contributes to the improvement of morphine dependence and sleep disturbance. In this review, we outline the pharmacological effects and possible mechanisms of sinomenine in CNS disorders to advance the development of sinomenine as a new drug for the treatment of CNS disorders.

Dietary pattern is excellent in reflecting an individual's eating conditions. Longitudinal data on fetal growth can reflect the process of intrauterine growth. We aimed to evaluate the associations between maternal dietary patterns and intrauterine parameters in middle and late pregnancy. The present study was conducted within Jiangsu Birth Cohort (JBC) study. Dietary information was assessed with a food frequency questionnaire (FFQ) in the second and third trimester of gestation. B-ultrasound scans were performed to obtain fetal intrauterine parameters, including head circumference (HC), femur length (FL), abdominal circumference (AC), and estimated fetal weight (EFW). Exploratory factor analysis was used to extract dietary patterns. Multiple linear regression and linear mixed-effects model (LMM) were used to investigate the association between maternal dietary patterns and fetal growth. A total of 1,936 pregnant women were eligible for the study. We observed inverse associations of maternal “Vegetables and fish” and “Snack and less eggs” patterns during mid-pregnancy with fetal HC Z-score, respectively (“Vegetables and fish”: β = −0.09, 95% CI −0.12, −0.06; “Snack and less eggs”: β = −0.05, 95% CI −0.08, −0.02). On the contrary, “Animal internal organs, thallophyte and shellfish” pattern in the second trimester was associated with increased HC Z-scores (β = 0.04, 95% CI 0.02, 0.06). Consistently, score increase in “Vegetables and fish” pattern in the third trimester was inversely associated with the Z-scores of HC (β = −0.05, 95% CI −0.09, −0.02), while “Meat and less nuts” pattern was positively correlated with the Z-scores of HC (β = 0.04, 95% CI 0.02, 0.07). As compared to the fetus whose mothers at the lowest tertile of “Snack and less eggs” pattern in both trimesters, those whose mothers at the highest tertile demonstrated 1.08 fold (RR = 2.10, 95% CI 1.34–3.28) increased risk of small HC for gestational age (GA). No correlation was observed between maternal dietary patterns and other intrauterine parameters. Our results suggested the effects of maternal dietary patterns on fetal growth, particularly HC. These findings highlighted the adverse impact of unhealthy dietary pattern on fetal growth, might provide evidence for strategies to prevent intrauterine dysplasia and dietary guidelines during pregnancy.

Recently, innate immune system stimulants, such as lipopolysaccharide (LPS) and macrophage-colony stimulating factor (M-CSF), were reported to prevent and reverse chronic stress-induced behavioral abnormalities, suggesting that innate immune stimulation could be a potential strategy for the treatment and prevention of mental disorders. Amphotericin B liposome is a clinically available antifungal medication that can stimulate macrophages and microglia. We hypothesize that amphotericin B liposome may be used to prevent and reverse behavioral abnormalities triggered by chronic stress. As expected, our results showed that a single injection of amphotericin B liposome (1 mg/kg) immediately after stress cessation reversed the decrease in time spent in the interaction zone in the social interaction test (SIT) and the increase in immobility time in the tail suspension test (TST) and forced swimming test (FST) in mice caused by chronic social defeat stress (CSDS). In addition, a single injection of amphotericin B liposomes (1 mg/kg) 1 day before stress exposure was found to prevent the CSDS-induced decrease in time spent in the interaction zone in the SIT and the increase in immobility time in the TST and FST in mice. Pretreatment with minocycline to inhibit the innate immune response was able to abolish the reversal effect of post-stress injection of amphotericin B liposomes on CSDS-induced behavioral abnormalities and the prophylactic effect of pre-stress injection of amphotericin B liposomes on CSDS-induced behavioral abnormalities. These results demonstrate that amphotericin B liposomes have both therapeutic and prophylactic effects on chronic stress-induced behavioral abnormalities in mice by mobilizing the innate immune response.

BackgroundCardiac rupture (CR) and left ventricular thrombus (LVT) remain important complications of acute myocardial infarction (MI), and they are currently regarded as independent events. We explored the pathogenetic link between CR and LVT by investigating a murine model of MI with a high frequency of CR and in patients with acute MI.MethodsMI was induced in mice, the onset of CR was monitored, and the hearts of mice with or without fatal CR were histologically examined. Between 2015 and 2022, from patients admitted due to acute MI, the data of patients with CR or LVT were retrospectively collected and compared to uncomplicated patients (control).ResultsA total of 75% of mice (n = 65) with MI developed CR 2–4 days after MI. A histological examination of CR hearts revealed the existence of platelet-rich intramural thrombi in the rupture tunnel, which was connected at the endocardial site to platelet-fibrin thrombi within an LVT. In CR or non-CR mouse hearts, LV blood clots often contained a portion of platelet-fibrin thrombi that adhered to the infarct wall. In non-CR hearts, sites of incomplete CR or erosion of the infarct wall were typically coated with platelet thrombi and dense inflammatory cells. Of 8,936 patients with acute MI, CR and LVT occurred in 102 (1.14%) and 130 (1.45%) patients, respectively, with three cases having both complications. CR accounted for 32.8% of in-hospital deaths. The majority of CR (95%) or LVT (63%, early LVT) occurred within 7 days. In comparison to the control or LVT-late groups, patients with CR or early LVT reported increased levels of cellular and biochemical markers for inflammation or cardiac injury.ConclusionCR and LVT after MI are potentially linked in their pathogenesis. LVT occurring early after MI may be triggered by a thrombo-inflammatory response following wall rupture or endocardial erosion.

ObjectivesAdequate maternal thyroid hormone availability is crucial for fetal neurodevelopment, but the role of maternal mild hypothyroidism is not clear. We aim to investigate the association of maternal mild hypothyroidism with neurodevelopment in infants at 1 year of age among TPOAb-negative women.MethodsThe present study was conducted within the Jiangsu Birth Cohort. A total of 793 mother–infant pairs were eligible for the present study. Maternal thyroid function was assessed by measuring serum thyroid-stimulating hormone, free thyroxine, and thyroid peroxidase antibodies. Neurodevelopment of infants was assessed by using the Bayley Scales of Infant and Toddler Development third edition screening test (Bayley-III screening test).ResultsIn the multivariate adjusted linear regression analyses, infants of women with subclinical hypothyroidism and isolated hypothyroxinemia were associated with decreased receptive communication scores (β = −0.68, p = 0.034) and decreased gross motor scores (β = −0.83, p = 0.008), respectively. Moreover, infants of women with high-normal TSH concentrations (3.0–4.0 mIU/L) and low FT4 concentrations were significantly associated with lower gross motor scores (β = −1.19, p = 0.032), while no differences were observed in infants when the mothers had a high-normal TSH concentration and normal FT4 levels.ConclusionsMaternal subclinical hypothyroidism is associated with decreased receptive communication scores in infants at 1 year of age. In addition, maternal TSH concentration greater than 4.0 mIU/L and maternal isolated hypothyroxinemia are associated with impaired gross motor ability of infants, especially in infants of women with high-normal TSH concentrations (3.0–4.0 mIU/L).

For young women with early stage well differentiated endometrial cancer who have fertility desire, it is import to give comprehensive assessment before initiation of conservative treatment. Progestin based therapy with regular assessment of treatment efficacy can achieve a promising outcome. After complete remission patients are suggested with assisted reproductive technology or maintenance therapy depending on their immediate pregnancy plan. Hysterectomy is recommended for patients who have finished reproduction while re-treatment for recurrent cases should be carefully informed.

Abstract Background To compare robot-assisted simple enucleation with renal arterial cold perfusion (RACP-RASE) and RASE alone in complex renal tumors with regard to perioperative, functional and oncologic outcomes by propensity score-matched analysis. Methods Data from 351 patients who underwent RACP-RASE or RASE for complex renal tumors were recorded between September 2014 and December 2017. Propensity score-matched analysis was performed on age, sex, BMI, ECOG score, tumor side and size, preoperative estimated glomerular filtration rate (eGFR), RENAL score and PADUA score. Results The study included 31 RACP-RASE and 320 RASE procedures. RENAL score and PADUA score were higher and tumor diameter was greater under RACP-RASE than RASE. After matching, the two groups were similar in estimated blood loss (208.3 vs 230.7 ml; p = 0.696) and ischemic time (34.8 vs 32.8 min; p = 0.342). The RACP-RASE group had significantly longer operative time than the RASE group (264.1 ± 55.7 vs 206.9 ± 64.0 min, p = 0.001). There was no difference in the incidence of postoperative complications between the two groups (13.8% vs 24.1%; p = 0.315), as was the overall incidence of positive surgical margins (3.4 vs 0%; p = 1.000). The changes in eGFR significantly differed between the two groups at 3 months (p = 0.018) and 12 months (p = 0.038). More patients in the RASE group were CKD upstaged (p = 0.043). At multivariable analysis, preoperative eGFR and the type of procedure were significant predictive factors for a change of more than 10% in eGFR at 3 months postoperatively. There was no local recurrence or distant metastasis during follow-up. Conclusions RACP-RASE is an effective and safe technique for complex renal tumors that can provide appropriate temporary arterial occlusion and renal hypothermic perfusion. Renal arterial cold perfusion may be helpful in protecting renal function in RASE as compared with warm ischemia.

The effect of glucocorticoid therapy on women with unexplained positive autoantibodies is under debate. This systemic review and meta-analysis were performed to evaluate whether glucocorticoid administration can improve the pregnancy outcome of this population. Relevant publications were searched from databases, and a total of seven prospective and retrospective cohort studies that investigated the effects of glucocorticoid administration on women with unexplained positive autoantibodies, were included. The outcomes of our systematic review and meta-analysis were measured in terms of risk ratios (RR) with 95% confidence intervals (CI) using fixed or random effect models. We found that glucocorticoid treatment improved the clinical pregnancy rate (RR 2.19, 95% CI 1.64–2.92) and live birth rate (RR 1.92, 95% CI 1.17–3.16), especially when glucocorticoid administration was started before pregnancy (clinical pregnancy rate: RR 2.30, 95% CI 1.58–3.34; live birth rate: RR 2.30, 95% CI 1.58–3.34). However, no effect of glucocorticoids on the miscarriage rate was found (RR 0.75, 95% CI 0.55–1.02) regardless of the time of drug administration. Our systematic review and meta-analysis support the rational use of glucocorticoids in women with unexplained positive autoantibodies.Systematic Review Registration[www.ClinicalTrials.gov], identifier [CRD42019124442].

Microglia are key components of the central innate immune system. The over-activation of microglia, which occurs in nervous system disorders, is usually accompanied with retractions of their ramified processes. Reversing of microglial process retraction is a potential strategy for the prevention of neuroinflammation. Our previous studies have reported some endogenous molecules and drugs that can promote microglial process elongation at conditions in vitro and in vivo, such as butyrate and β-hydroxybutyrate, sulforaphane, and diallyl disulfide. Here, reported another compound that can promote microglial process elongation. We found that KRIBB11, a compound which has been reported to suppress nitric oxide production in microglia, induced significant elongations of the processes in microglia in cultured and in vivo conditions in a reversible manner. KRIBB11 pretreatment also prevented lipopolysaccharide (LPS)-induced shortenings of microglial process in cultured conditions and in vivo conditions, inflammatory responses in primary cultured microglia and the prefrontal cortex, and depression-like behaviors in mice. Mechanistic studies revealed that KRIBB11 incubation up-regulated phospho-Akt in cultured microglia and Akt inhibition blocked the pro-elongation effect of KRIBB11 on microglial process in cultured conditions and in vivo conditions, suggesting that the regulatory effect of KRIBB11 is Akt-dependent. Akt inhibition was also found to abrogate the preventive effect of KRIBB11 on LPS-induced inflammatory responses in primary cultured microglia and prefrontal cortexes as well as LPS-induced depression-like behaviors in mice. Collectively, our findings demonstrated that KRIBB11 is a novel compound that can prevent microglial activation and neuroinflammation-associated behavioral deficits possibly through inducing the Akt-mediated elongation of microglial process.

Abstract Background Cardiac rupture (CR) is a fatal complication of ST-elevation myocardial infarction (STEMI) with its incidence markedly declined in the recent decades. However, clinical features of CR patients now and the effect of reperfusion therapy to CR remain unclear. We investigated the clinical features of CR in STEMI patients and the effect of reperfusion therapy to CR in mice. Methods Two studies were conducted. In clinical study, data of 1456 STEMI patients admitted to the First Hospital, Xi’an Jiaotong University during 2015.12. ~ 2018.12. were analyzed. In experimental study, 83 male C57BL/6 mice were operated to induce MI. Of them, 39 mice were permanent MI (group-1), and remaining mice received reperfusion after 1 h ischemia (21 mice, group-2) or 4 h ischemia (23 mice, group-3). All operated mice were monitored up to day-10. Animals were inspected three times daily for the incidence of death and autopsy was done for all mice found died to determine the cause of death. Results CR was diagnosed in 40 patients: free-wall rupture in 17, ventricular septal rupture in 20, and combined locations in 3 cases. CR presented in 19 patients at admission and diagnosed in another 21 patients during 1 ~ 14 days post-STEMI, giving an in-hospital incidence of 1.4%. The mortality of CR patients was high during hospitalization accounting for 39% of total in-hospital death. By multivariate logistic regression analysis, older age, peak CK-MB and peak hs-CRP were independent predictors of CR post-STEMI. In mice with non-reperfused MI, 17 animals (43.6%) died of CR that occurred during 3–6 days post-MI. In MI mice received early or delayed reperfusion, all mice survived to the end of experiment except one mouse died of acute heart failure. Conclusion CR remains as a major cause of in-hospital death in STEMI patients. CR patients are characterized of being elderly, having larger infarct and more server inflammation. Experimentally, reperfusion post-MI prevented CR.

Abstract Background Successful implantation and delivery require both the functional embryo and receptive endometrium in assisted reproductive technology (ART) cycles. However, little is known about embryo-endometrial interaction on live-birth. We aimed to investigate the independent effect and interaction of endometrial thickness (EMT) and embryo quality on live-birth in fresh embryo transfer (ET) cycles. Methods We conducted a retrospective cohort study including 15,012 ART cycles between 2013 and 2016 in three centers in China. Poisson regression with generalized estimating equations was employed to calculate relative risks (RRs) and 95% confidence intervals (CIs). We estimated the interaction of embryo quality and EMT on live-birth rate (LBR). Results The LBR per cycle was 42.8% overall. LBR increased with increasing EMT and reached a plateau (50.6 to 54.2%) when EMT was 11 mm or thicker. Embryo quality represented by cumulative score was associated with LBR independently of number of embryos transferred and EMT. LBR was not increased with thicker EMT when only Q1 cleavage-stage embryo transferred (aRR 0.95, 95%CI 0.61–1.46). LBR was not increased significantly with thicker EMT with transfer of two good-quality cleavage-stage embryos and any blastocyst combination except Q1 group. There was significant interaction between EMT and embryo quality on LBR for cleavage-stage ETs (P=0.023). Conclusions This study demonstrated the nonlinear EMT-LBR association and the EMT cut-off value of 11 mm which may be of more clinical significance for predicting live-birth. Embryo quality is an independent prognostic tool for LBR. Our finding of significant embryo-endometrial interaction indicates combination of EMT and embryos quality might improve the prognostic value in clinical practice for live-birth in patients undergoing transfer of 1–2 fresh cleavage-stage embryos.

Abstract Background To compare the perioperative outcomes of transperitoneal laparoscopic (TLA), retroperitoneal laparoscopic (RLA), and robot-assisted transperitoneal laparoscopic (RATLA) adrenalectomy for adrenal tumors in our center. Methods Between April 2012 and February 2018, 241 minimally invasive adrenalectomies were performed. Cases were categorized based on the minimally invasive adrenalectomy technique. Demographic characteristics, perioperative information and pathological data were retrospectively collected and analyzed. Results This study included 37 TLA, 117 RLA, and 87 RATLA procedures. Any two groups had comparable age, ASA score, Charlson Comorbidity Index, and preoperative hemoglobin. The tumor size for RLA patients was 2.7 ± 1.1 cm, which was significantly smaller compared to patients who underwent TLA/RATLA (p = 0.000/0.000). Operative time was similar in any two groups, while estimated blood loss was lower for RATLA group (75.6 ± 95.6 ml) compared with the TLA group (131.1 ± 204.5 ml) (p = 0.041). Conversion to an open procedure occurred in only one (2.7%) patient in the TLA group for significant adhesion and hemorrhage. There were no significant differences between groups in terms of transfusion rate and complication rate. Length of stay was shorter for the RATLA group versus the TLA/RLA group (p = 0.000/0.029). In all groups, adrenocortical adenoma and pheochromocytoma were the most frequent histotypes. Conclusions Minimally invasive adrenalectomy is associated with expected excellent outcomes. In our study, the RATLA approach appears to provide the benefits of decreased estimated blood loss and length of stay. Robotic adrenalectomy appears to be a safe and effective alternative to conventional laparoscopic adrenalectomy.

ABSTRACTThe nucleoprotein (NP) is a highly conserved internal protein of the influenza virus, a major target for universal influenza vaccine. Our previous studies have proven NP-based subunit vaccine can provide partial protection in mice. It is reported that the protein transduction domain (PTD) TAT protein from human immunodeficiency virus-1 (HIV-1) is able to penetrate cells when added exogenous protein and could effectively enhance the immune response induced by the exogenous protein. In present study, the recombinant protein TAT-NP, a fusion of TAT and NP was effectively expressed in Escherichia coli and purified as a candidate component for an influenza vaccine. We evaluated the immunogenicity and protective efficacy of recombinant influenza TAT-NP vaccine by intranasal immunization. In vitro experiments showed that TAT-NP could efficiently penetrate into cells. Animal results showed that mice vaccinated with TAT-NP could not only induce higher levels of IgG and mucosal IgA, but also elicit a robust cellular immune response. Moreover, the TAT-NP fusion protein could significantly increase the protection of mice against lethal doses of homologous influenza virus PR8 and could also provide mice protection against a lethal dose challenge against heterosubtypic H9N2 and H3N2 influenza virus. In conclusion, the recombinant TAT-NP might be a universal vaccine candidate against influenza virus.

Abstract Background Gastrointestinal cancer is one of the most common malignancies and imposes heavy burdens on both individual health and social economy. We sought to survey the effect of a self-care education program on quality of life and fatigue in gastrointestinal cancer patients who received chemotherapy. Methods Ninety-one eligible gastrointestinal cancer patients were enrolled in this study and 86 valid samples were analyzed. Data were acquired with a demographics questionnaire, endpoint multidimensional questionnaire and the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire QLQ-C30. The collected data were analyzed using SPSS software. Results The self-care education intervention significantly improved the quality of life with respect to emotional function (p = 0.018), role function (p = 0.041), cognitive function (p = 0.038) and alleviated side effects such as nausea/vomiting (p = 0.028) and fatigue (p = 0.029). Further analysis demonstrated that the self-care education benefited total fatigue, affective fatigue and cognitive fatigue in gastrointestinal cancer patients regardless of baseline depression. Conclusion Our results suggested the beneficial effects of the self-care education in both quality of life and anti-fatigue in gastrointestinal cancer patients under chemotherapy. The self-care education could be considered as a complementary approach during combination chemotherapy in gastrointestinal cancer patients.

Background & Aims: Claudin-7 (Cldn7) is a tight junction (TJ) membrane protein located at the apical TJ and basolateral side of intestinal epithelial cells. Deletion of Cldn7 by gene targeting leads to the inflammatory bowel disease–like phenotype in mice, which includes weight loss, diarrhea, mucosa ulceration, and severe intestinal epithelial damage. In this study, we test our hypothesis that Cldn7 plays a critical role in regulating intestinal crypt stem cell functions. Methods: Gene expression microarray, quantitative reverse-transcription polymerase chain reaction, in situ hybridization, histologic examinations, immunoblotting, 3-dimensional organoid culture, and various treatments to rescue Cldn7-deficient organoid defects were conducted using global Cldn7 knockout mice and inducible, conditional Cldn7 knockout mice. Results: Gene deletion of Cldn7 in intestines showed significant alteration of expression profiles with striking down-regulation of intestinal crypt stem cell markers such as Olfm4, dislocated proliferative cells, and disrupted epithelial cell differentiation. In addition, the isolated Cldn7-deficient crypts where the stem cells reside were either unable to survive at all or formed defective spheroids, highlighting the functional impairment of crypt stem cells in the absence of Cldn7. Remarkably, the Cldn7-expressing organoids with buddings underwent rapid cell degeneration within days after turning off Cldn7 expression in the culture. We identified that activation of Wnt/β-catenin signaling rescued the organoid defects caused by Cldn7 deletion. Conclusions: In this study, we show that Cldn7 is indispensable in controlling Wnt/β-catenin signaling–dependent intestinal epithelial stem cell survival, self-renewal, and cell differentiation. This study could open a door to study roles of TJ proteins in stem cell regulations in other tissues and organs.

Chronic kidney disease (CKD) is an ongoing deterioration of renal function that often progresses to end-stage renal disease. In this study, we aimed to screen and identify potential key genes for CKD using the weighted gene coexpression network (WGCNA) analysis tool. Gene expression data related to CKD were screened from GEO database, and expression datasets of GSE66494 and GSE62792 were obtained. After discrete analysis of samples, WGCNA analysis was performed to construct gene coexpression module, and the correlation between the module and disease was calculated. The modules with a significant correlation with the disease were selected for Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Then, the interaction network of related molecules was constructed, and the high score subnetwork was selected, and the candidate key molecules were identified. A total of 882 DEGs were identified in the screening datasets. A subnetwork containing 6 nodes was found with a high score of 12.08, including CEBPZ, IFI16, LYAR, BRIX1, BMS1, and DDX18. DEGs could significantly differentiate CKD and healthy individuals in principal component analysis. In addition, the MEturquiose, MEred, and MEblue in group were significantly correlated with disease in WGCNA. These 6 hub genes were found to significantly discriminate between CKD and healthy controls in the validation dataset, suggesting that they could use these molecules as candidate markers to distinguish CKD from healthy people. Overall, our study indicated that 6 hub genes may play key roles in the occurrence and development of CKD.

Per- and poly-fluorinated substances (PFASs) with endocrine disrupting effect can efficiently transfer across the blood-follicle barrier. However, it is still controversial and attracting extensive public concern that whether PFASs can affect the human fertility potential. Therefore, we aimed to analyze the associations of women’s exposure to PFASs with pregnancy loss, the relevant processes of fertilization, zygote implantation, and embryo development by using a prospective cohort study. The women undergoing in vitro fertilization-embryo transfer (IVF-ET) treatment were recruited in Beijing City (Beijing Center) and Yantai City (Yantai Center) in China during 2015–2017. A total of 305 women were recruited before the IVF-ET treatment. Twelve PFASs were measured in their serum samples collected in the day before the IVF-ET treatment, as well as in the human chorionic gonadotropin (hCG) day. The three IVF-ET outcomes were included, i.e. hCG test negative, clinical pregnancy failure (CPF), and preclinical spontaneous abortion. Nine serum PFASs had detection rate of >70% in Beijing and Yantai centers. The exposure patterns to PFASs between these two centers were overall different. For Beijing Center, we only found a positive association of perflurodecanoic acid (PFDA) with the risk of CPF [RR = 2.28 (95 %CI: 1.02–5.11)], but there is a reverse trend in Yantai Center with [RR = 0.45 (95 %CI: 0.23–0.85)]. However, the serum concentration of PFDA in Beijing Center was relatively lower than that of Yantai Center. Other significant associations of the detected PFASs with the IVF-ET outcomes, or with the relevant clinical processes, were not found. The multi-pollutant regression model of the Bayesian kernel machine regression suggested that there were no joint effects between various PFASs on the concerned outcomes. Overall, we suggest that most PFAS were not associated with early pregnancy loss at the current exposure levels. As for the PFDA, there may exist susceptibility of different populations.

ObjectiveTo evaluate the effect of maintenance therapy for patients with atypical endometrial hyperplasia (AEH) and early endometrial cancer (EC) after successful fertility-preserving management on prognosis and pregnancy outcome.MethodsWe performed a retrospectively analysis of 109 young women with atypical endometrial hyperplasia and early endometrioid endometrial cancer who had received complete response after fertility-preserving treatment at 5centers between May 2005 and March 2021. Maintenance therapy regimes included low-dose oral progesterone, levonorgestrel intrauterine device(LNG-IUD) and combination oral contraceptive (COC). The patients were divided into two groups, maintenance therapy group and non-maintenance therapy group. Clinical characteristics, treatment regimens, prognosis, and pregnancy outcome were compared between the two groups.ResultsThe overall disease recurrence rate of the maintenance therapy group was significantly lower than that of the non-maintenance therapy group (P < 0.001). The recurrence rate of atypical endometrial hyperplasia and endometrial cancer in the maintenance therapy group were significantly lower than those in the non-maintenance group (P < 0.001). Maintenance therapy can reduce pregnancy rates and live birth rates. Maintenance therapy can protect the endometrium in patients treated with assisted reproductive technology (ART), greatly reducing the recurrence rate after ART (P

Aim: The aim of present study is to evaluate the diagnostic and prognostic value of plasma galectin 3 (Gal-3) for HF originating from different causes.Methods: We investigated the plasma levels and expression of Gal-3 in cardiac tissues in two transgenic (TG) strains of mice with cardiomyocyte-restricted overexpression of either β2- adrenergic receptor (β2- AR TG) or Mammalian sterile 20-like kinase 1 (Mst1-TG) in the present study. Additionally, 166 patients suffering from heart failure with reduced ejection fraction (HFrEF) in two hospitals within the Shaanxi province were examined in this study. All these patients were treated according to the Chinese HF guidelines of 2014; subsequently, they were followed up for 50 months, and we analyzed the prediction value of baseline Gal-3 to endpoints in these patients.Results: Gal-3 was localized in the cytoplasm and nucleus of cardiomyocytes, often formed aggregates in Mst1-TG mice. Extracellular Gal-3 staining was uncommon in Mst1-TG hearts. However, in β2-AR TG mice, although Gal-3 was also expressed in myocardial cells, it was more highly expressed in interstitial cells (e.g., fibroblasts and macrophages). Plasma Gal-3 was comparable between nTG and Mst1-TG mice. However, plasma Gal-3 was higher in β2-AR TG mice than in nTG mice. In the cohort of HFrEF patients, the median plasma Gal-3 concentration was 158.42 pg/mL. All participants were divided into two groups according to Gal-3 levels. Patients with Gal-3 concentrations above the median were older, and had lower plasma hemoglobin, but higher plasma creatinine, tissue inhibitor of metalloproteinases 1 (TIMP-1), left ventricular end systolic diameter (LVESD), left ventricular end-systolic volumes (LVESV) and end-diastolic, as well as left ventricular end-diastolic volumes (LVEDV). Spearman correlation analysis revealed that Gal-3 was positively correlated with TIMP-1 (r = 0.396, P < 0.001), LVESV (r = 0.181, P = 0.020) and LVEDV (r = 0.190, P = 0.015). The 50-month clinical follow-up revealed 43 deaths, 97 unplanned re-hospitalizations, and 111 composite endpoint events. Cox analysis demonstrated that although Gal-3 did not provide any prognostic value in either total-HF subjects or coronary-heart-disease (CHD) patients, it did provide prognostic value in non-CHD patients.Conclusion: Although plasma Gal-3 is associated with TIMP-1 and echocardiographic parameters, the diagnostic and prognostic value of Gal-3 in HFrEF is determined by the etiology of HF.

Dry weight (DW) is an important dialysis index for patients with end-stage renal disease. It can guide clinical hemodialysis. Brain natriuretic peptide, chest computed tomography image, ultrasound, and bioelectrical impedance analysis are key indicators (multisource information) for assessing DW. By these approaches, a trial-and-error method (traditional measurement method) is employed to assess DW. The assessment of clinician is time-consuming. In this study, we developed a method based on artificial intelligence technology to estimate patient DW. Based on the conventional radial basis function neural (RBFN) network, we propose a multiple Laplacian-regularized RBFN (MLapRBFN) model to predict DW of patient. Compared with other model and body composition monitor, our method achieves the lowest value (1.3226) of root mean square error. In Bland-Altman analysis of MLapRBFN, the number of out agreement interval is least (17 samples). MLapRBFN integrates multiple Laplace regularization terms, and employs an efficient iterative algorithm to solve the model. The ratio of out agreement interval is 3.57%, which is lower than 5%. Therefore, our method can be tentatively applied for clinical evaluation of DW in hemodialysis patients.

Although intestinal microbiota plays an important role in the metabolism of procyanidins, the microbial metabolic pathway of A-type procyanidins remains elusive. In this study, A-type dimer procyanidin A1 [EC-(2β-O-7,4β-8)-C] and trimer PPD [EC-(4β-6)-EC-(2β-O-7,4β-8)-C] were incubated with rat faecal microbiota in vitro, and their metabolomic profiles were analyzed by UPLC-QTOF/MS. Multivariate statistical analysis identified 24 and 30 discriminant metabolites for A1 and PPD, respectively. The C-ring opened catabolites of procyanidin A1 and PPD and the typical phenolic acid metabolites were identified, including phenylacetic acid, (4′-hydroxyphenyl)acetic acid, 3-phenylpropanoic acid, 3-(4′-hydroxyphenyl)propanoic acid, 3-(3′,4′-dihydroxyphenyl)propanoic acid, and 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone. Notably, procyanidin A1 and (epi)catechin were identified from the metabolites of PPD; however, no (epi)catechin was found in the metabolites of procyanidin A1, indicating that the faecal microbiota can destroy B-type linkage (C4-C6 interflavan bond) but not A-type linkage (C4-C8 and additional C2-O-C7 interflavan bond) in the metabolism of A-type procyanidins.

The hydraulic excitation characteristics of axial flow pump unit are studied through theoretical analysis, numerical simulation and field test in this paper. The correlation between impeller hydraulic and radial vibration displacement of impeller centroid is obtained through theoretical analysis. Through the 1-way fluid-solid-interaction (FSI) numerical simulation, the distributions of water pressure and displacement on the impeller surface are obtained, and the time-domain and frequency-domain characteristics of transient hydraulic and radial displacement are revealed. Through the field test, the external characteristics of axial flow pump unit and the time-frequency characteristics of the pressure pulsation at the measuring points beside the inlet of the impeller are obtained. The comparisons between simulation results and experimental results show that the former is accurate and reliable.

A nonlinear control without using anemometer is proposed to achieve the maximum power of the wind turbine (WT) based on two-mass model in this paper. To track the maximum power points, the optimal tip speed ratio control strategy requiring to know the optimal rotor speed of the WT (ORS) is employed. To achieve the ORS, a torque observer is designed to estimate the aerodynamic torque, then the ORS can be obtained by the corresponding calculations based on the estimated torque. Due to the high nonlinearities of the WT and time-varying wind speed, a nonlinear control based on feedback linearization control (FLC) is adopted to track the ORS. In the FLC, the WT is linearized firstly, then the rotor speed controller is designed via linear control technique. The effectiveness of the proposed control strategy is verified by simulation studies. The simulation results show that, compared with the traditional PI control based on torque estimation and FLC based on wind speed estimation, the proposed control strategy provides better dynamic performances and higher power conversion efficiency.

Abstract Background Circular RNAs (circRNAs) are a novel class of endogenous noncoding RNAs formed by a covalently closed loop, and increasing evidence has revealed that circRNAs play crucial functions in regulating gene expression. CircSLC8A1 is a circRNA generated from the SLC8A1 gene. Currently, the role and underlying molecular mechanisms of circSLC8A1 in bladder cancer remain unknown. Methods The differentially expressed circRNAs were identified from RNA-sequencing data, and circSLC8A1 was determined as a new candidate circRNA. qRT-PCR was used to detect the expression of circRNAs, miRNAs and mRNAs in human tissues and cells. RNA pull-down assay and luciferase reporter assay were used to investigate the interactions between the specific circRNA, miRNA and mRNA. The effects of circSLC8A1 on bladder cancer cells were explored by transfecting with plasmids in vitro and in vivo. The expression of PTEN was detected by Western blot. The biological roles were measured by wound healing assay, transwell assay, and CCK-8 assay. Results In the present study, we found that circSLC8A1 was down-regulated in bladder cancer tissues and cell lines, and circSLC8A1 expression was associated with the pathological stage and histological grade of bladder cancer. Over-expression of circSLC8A1 inhibited cell migration, invasion and proliferation both in vitro and in vivo. Mechanistically, circSLC8A1 could directly interact with miR-130b/miR-494, and subsequently act as a miRNA sponge to regulate the expression of the miR-130b/miR-494 target gene PTEN and downstream signaling pathway, which suppressed the progression of bladder cancer. Conclusions CircSLC8A1 acts as a tumor suppressor by a novel circSLC8A1/miR-130b, miR-494/PTEN axis, which may provide a potential biomarker and therapeutic target for the management of bladder cancer.

Classical Rho GTPases, including RhoA, Rac1, and Cdc42, are members of the Ras small GTPase superfamily and play essential roles in a variety of cellular functions. Rho GTPase signaling can be turned on and off by specific GEFs and GAPs, respectively. These features empower Rho GTPases and their upstream and downstream modulators as targets for scientific research and therapeutic intervention. Specifically, significant therapeutic potential exists for targeting Rho GTPases in neurodegenerative diseases due to their widespread cellular activity and alterations in neural tissues. This study will explore the roles of Rho GTPases in neurodegenerative diseases with focus on the applications of pharmacological modulators in recent discoveries. There have been exciting developments of small molecules, nonsteroidal anti-inflammatory drugs (NSAIDs), and natural products and toxins for each classical Rho GTPase category. A brief overview of each category followed by examples in their applications will be provided. The literature on their roles in various diseases [e.g., Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS), Frontotemporal dementia (FTD), and Multiple sclerosis (MS)] highlights the unique and broad implications targeting Rho GTPases for potential therapeutic intervention. Clearly, there is increasing knowledge of therapeutic promise from the discovery of pharmacological modulators of Rho GTPases for managing and treating these conditions. The progress is also accompanied by the recognition of complex Rho GTPase modulation where targeting its signaling can improve some aspects of pathogenesis while exacerbating others in the same disease model. Future directions should emphasize the importance of elucidating how different Rho GTPases work in concert and how they produce such widespread yet different cellular responses during neurodegenerative disease progression.