Blockage of TRPV4 Downregulates the Nuclear Factor-Kappa B Signaling Pathway to Inhibit Inflammatory Responses and Neuronal Death in Mice with Pilocarpine-Induced Status Epilepticus.

The blockage of transient receptor potential vanilloid 4 (TRPV4) inhibits inflammation and reduces hippocampal neuronal injury in a pilocarpine-induced mouse model of temporal lobe epilepsy. However, the underlying mechanisms remain largely unclear. NF-κB signaling pathway is responsible for the inflammation and neuronal injury during epilepsy. Here, we explored whether TRPV4 blockage could affect the NF-κB pathway in mice with pilocarpine-induced status epilepticus (PISE). Application of a TRPV4 antagonist markedly attenuated the PISE-induced increase in hippocampal HMGB1, TLR4, phospho (p)-IκK (p-IκK), and p-IκBα protein levels, as well as those of cytoplasmic p-NF-κB p65 (p-p65) and nuclear NF-κB p65 and p50; in contrast, the application of GSK1016790A, a TRPV4 agonist, showed similar changes to PISE mice. Administration of the TLR4 antagonist TAK-242 or the NF-κB pathway inhibitor BAY 11-7082 led to a noticeable reduction in the hippocampal protein levels of cleaved IL-1ß, IL-6 and TNF, as well as those of cytoplasmic p-p65 and nuclear p65 and p50 in GSK1016790A-injected mice. Finally, administration of either TAK-242 or BAY 11-7082 greatly increased neuronal survival in hippocampal CA1 and CA2/3 regions in GSK1016790A-injected mice. Therefore, TRPV4 activation increases HMGB1 and TLR4 expression, leading to IκK and IκBα phosphorylation and, consequently, NF-κB activation and nuclear translocation. The resulting increase in pro-inflammatory cytokine production is responsible for TRPV4 activation-induced neuronal injury. We conclude that blocking TRPV4 can downregulate HMGB1/TLR4/IκK/κBα/NF-κB signaling following PISE onset, an effect that may underlie the anti-inflammatory response and neuroprotective ability of TRPV4 blockage in mice with PISE.

Vitamin D Supplementation for the Outcomes of Patients with Gestational Diabetes Mellitus and Neonates: A Meta-Analysis and Systematic Review.

Background: Prevention and timely treatment of gestational diabetes mellitus (GDM) are important to the prognosis of pregnant women and neonates. We aimed to conduct a meta-analysis to evaluate the effects and safety of vitamin D supplementation on GDM patients and neonates, to provide insights into clinical GDM treatment. Methods: Two authors searched the Medline, PubMed, Cochrane Library, Web of Science, Embase, CNKI, and Wanfang databases for randomized controlled trials (RCTs) on the effects and safety of vitamin D supplementation in GDM patients. The quality of the included RCTs was evaluated according to Cochrane handbook. RevMan 5.3 software was used for statistical analysis. Results: A total of 20 RCTs involving 1682 GDM patients were finally included, of whom 837 received vitamin D supplementation. Vitamin D supplementation in GDM patients increased the serum 25(OH)D level (SMD = 4.07, 95% CI: (2.73, 5.41)) and HDL level (SMD = 0.41, 95% CI: (0.23, 0.58)) and reduced serum LDL (SMD = -0.49, 95% CI: (-0.68, -0.29)), TG (SMD = -0.59, 95% CI: (-1.01, -0.17)), and TC (SMD = -0.67, 95% CI: (-1.19, -0.14)) levels in GDM patients (all P < 0.05). Besides, vitamin D supplementation reduced the risk of premature birth (OR = 0.37, 95% CI: (0.22, 0.62)), hyperbilirubinemia (OR = 0.38, 95% CI: (0.25, 0.58)), and neonatal hospitalization (OR = 0.38, 95% CI: (0.25, 0.58)) of neonates (all P < 0.05). No significant publication bias in synthesized results was found (all P > 0.05). Conclusions: Vitamin D supplementation improves the blood lipid level in GDM patients and reduces adverse neonatal outcomes. The dose and duration of vitamin D supplementation for safety need to be further investigated in future high-quality studies.

Involvement of TRPV4 in changes in rapidly inactivating potassium channels in the early stage of pilocarpine-induced status epilepticus in mice.

The rapidly inactivating potassium current (IA ) is important in controlling neuronal action potentials. Altered IA function and K+ channel expression have been found in epilepsy, and activation of the transient receptor potential vanilloid 4 (TRPV4) channel is involved in epilepsy pathogenesis. This study examined whether TRPV4 affects Kv4.2 and K+ channel interacting protein (KCHIP) expression and IA changes following pilocarpine-induced status epilepticus (PISE) in mice. Herein, hippocampal protein levels of Kv4.2 and KCHIP2 increased 3 h-3 d and decreased 7-30 d; that of KCHIP1 increased 3-24 h and decreased 3-30 d post-PISE. The TRPV4 antagonist HC-067047 attenuated the increased protein levels of Kv4.2 and KCHIP2 but not that of KCHIP1 post-PISE. The TRPV4 agonist GSK1016790A increased hippocampal protein levels of Kv4.2 and KCHIP2 but had no effect on KCHIP1 expression. HC-067047 attenuated the increased IA in hippocampal pyramidal neurons 24 h and 3 d post-PISE. GSK1016790A increased IA in hippocampal pyramidal neurons, shifting the voltage-dependent inactivation curve toward depolarization. The GSK1016790A-induced increase of IA was blocked by protein kinase A and calcium/calmodulin-dependent kinase II antagonists but was unaffected by protein kinase C antagonists. We conclude that TRPV4 activation may be responsible for the increases of Kv4.2 and KCHIP2 expression in hippocampi and IA in hippocampal pyramidal neurons in PISE mice, which are likely compensatory measures for hyperexcitability at the early stage of epilepsy.

Rationale and Design of the ADIDAS Study: Association Between Dapagliflozin-Induced Improvement and Anemia in Heart Failure Patients.

BACKGROUND: Heart failure (HF) is one of the most serious health concerns worldwide. Anemia is a highly prevalent comorbidity and outcome predictor in HF patients. Sodium glucose co-transport 2 (SGLT2) inhibitors have been demonstrated to reduce the risk of cardiovascular death and HF hospitalization in HF patients. PURPOSE: This investigator-initiated, interventional, prospective, double-blind, multicenter study is designed to investigate whether anemia correction is one of the prerequisites and determinants related to the beneficial effects of dapagliflozin in HF patients. METHODS AND RESULTS: Up to 2030 HF participants receiving standard care will be randomly assigned to either oral dapagliflozin 10 mg once daily or placebo 10 mg once daily for 12 months. The primary outcome is the composite incidence of hospital admission for HF and all-cause death. Secondary outcomes include change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score and change in 6-min walk distance and hemoglobin level. Patients will be followed for 12 months after randomization. CONCLUSIONS: The ADIDAS trial offers an opportunity to assess the hemoglobin change and association between hemoglobin change and readmissions due to heart failure and all-cause death in patients with heart failure treated with dapagliflozin or placebo. This study could highlight if dynamic hemoglobin change is related to the outcome for HF patients. TRIAL REGISTRATION: ClinicalTrials.gov ; NCT04707261. Registration date, 2020/12/01, "retrospectively registered".

Iodine nutrition status and thyroid autoimmunity during pregnancy: a cross-sectional study of 4635 pregnant women.

BACKGROUND: Pregnant women in Shanghai have long been at risk for mild iodine deficiency. Because thyroid autoimmunity in pregnant women can lead to premature birth and miscarriage as well as neurodevelopmental deficits in the fetus, the aim of this study was to explore the association of iodine nutrition status with thyroid antibodies during pregnancy. METHODS: A pregnancy-birth cohort was conducted including 4635 pregnant women in Shanghai, China. The eligible participants underwent a face-to-face interview and completed questionnaire surveys to collect baseline information and diet intake. Spot urine samples were collected to test urine iodine. Thyroid antibodies including thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb) and thyrotrophic antibodies (TRAb) were tested. Single-factor analysis and logistic regression were used to evaluate the association between iodine status and thyroid autoimmunity during pregnancy. RESULTS: The median urinary iodine excretion level in the sample was 138.14 µg/L (interquartile range [IQR] 80.90-219.00 µg/L). Among all the subjects, 25.9% consumed non-iodized salt, 54.5% had iodine deficiency, and 31.0% had thyroid autoimmunity. The proportion of patients with iodine deficiency was significantly higher among those who consumed non-iodized salt (36.9% vs. 33.1%; p = 0.04). After adjusting for age, educational status, former smoker status, former drinker status, first pregnancy, and previous thyroid disease, non-iodized salt (odds ratio [OR] = 1.394 [confidence interval, CI, 1.165-1.562]; p = 0.003), iodine-rich food (OR = 0.681 [CI 0.585-0.793]; p = 0.003), iodized nutritional supplements (OR = 0.427 [CI 0.347-0.526]; p = 0.003), were found to be individually associated with thyroid autoimmunity in all participants. The results of the multivariable restricted cubic spline regression analysis showed a non-linear relationship between the continuous change in iodine intake and thyroid autoimmunity (p = 0.019). Participants with iodine deficiency (urinary iodine concentration, UIC,< 100 µg/L) had an increased risk of testing positive for thyroid antibodies (TPOAb/TgAb/TRAb[+]; OR = 1.324 [CI 1.125-1.559]; p < 0.001). Moreover, this associated existed even after removing participants with previous thyroid disease. CONCLUSION: Inadequate iodine nutrition in pregnant women is an independent risk factor for thyroid autoimmunity in Shanghai. It's important to maintain the adequate iodine status in pregnant women.

Relationship of household cooking salt and eating out on iodine status of pregnant women in environmental iodine-deficient coastal areas of China.

As city residents eat out more frequently, it is unknown that if iodised salt is still required in home cooking. We analysed the relationship of household salt and eating out on urinary iodine concentration (UIC) in pregnant women. A household condiment weighing method was implemented to collect salt data for a week. A household salt sample was collected. A urine sample was taken at the end of the week. Totally, 4640 participants were investigated. The median UIC was 139·1 µg/l in pregnant women and 148·7, 140·0 and 122·9 µg/l in the first, second and third trimesters. Median UIC in the third trimester was lower than in the other trimesters (P < 0·001). The usage rates of iodised (an iodine content ≥ 5·0 mg/kg) and qualified-iodised (an iodine content ≥ 21·0 mg/kg) salt were 73·9 and 59·3 %. The median UIC in the qualified-iodised salt group was higher than in the non-iodised group (P = 0·037). The median UIC in the non-iodised group who did not eat out was lower than in qualified-salt groups who both did and did not eat out (P = 0·007, <0·001). The proportion of qualified-iodised salt used in home cooking is low, but foods eaten out have universal salt iodisation according to the national compulsory policy. Household iodised salt did not play a decisive role in the iodine status of pregnant women. Pregnant women in their third trimester who are not eating out and using non-iodised salt at home require extra iodine.

S1P transporter SPNS2 regulates proper postnatal retinal morphogenesis.

Spinster homolog 2 (SPNS2) is the membrane transporter of sphingosine-1-phosphate (S1P), and it participates in several physiologic processes by activating different S1P receptors (S1PRs). However, its functions in the nervous system remain largely unclear. We explored the important role of SPNS2 in the process of retinal morphogenesis using a spns2-deficient rat model. In the absence of the functional SPNS2 transporter, we observed progressively aggravating laminar disorganization of the epithelium at the postnatal stage of retinal development. Disrupted cell polarity, delayed cell-cycle exit of retinal progenitor cells, and insufficient migration of newborn neurons were proposed in this study as potential mechanisms accounting for this structural disorder. In addition, we analyzed the expression profiles of spns2 and s1prs, and proposed that SPNS2 regulated retinal morphogenesis by establishing the S1P level in the eye and activating S1PR3 signaling. These data indicate that SPNS2 is indispensable for normal retinal morphogenesis and provide new insights on the role of S1P in the developing retina using an established in vivo model.-Fang, C., Bian, G., Ren, P., Xiang, J., Song, J., Yu, C., Zhang, Q., Liu, L., Chen, K., Liu, F., Zhang, K., Wu, C., Sun, R., Hu, D., Ju, G., Wang, J. S1P transporter SPNS2 regulates proper postnatal retinal morphogenesis.

Development of a Multiplexed Liquid Chromatography Multiple-Reaction-Monitoring Mass Spectrometry (LC-MRM/MS) Method for Evaluation of Salivary Proteins as Oral Cancer Biomarkers.

Multiple (selected) reaction monitoring (MRM/SRM) of peptides is a growing technology for target protein quantification because it is more robust, precise, accurate, high-throughput, and multiplex-capable than antibody-based techniques. The technique has been applied clinically to the large-scale quantification of multiple target proteins in different types of fluids. However, previous MRM-based studies have placed less focus on sample-preparation workflow and analytical performance in the precise quantification of proteins in saliva, a noninvasively sampled body fluid. In this study, we evaluated the analytical performance of a simple and robust multiple reaction monitoring (MRM)-based targeted proteomics approach incorporating liquid chromatography with mass spectrometry detection (LC-MRM/MS). This platform was used to quantitatively assess the biomarker potential of a group of 56 salivary proteins that have previously been associated with human cancers. To further enhance the development of this technology for assay of salivary samples, we optimized the workflow for salivary protein digestion and evaluated quantification performance, robustness and technical limitations in analyzing clinical samples. Using a clinically well-characterized cohort of two independent clinical sample sets (total n = 119), we quantitatively characterized these protein biomarker candidates in saliva specimens from controls and oral squamous cell carcinoma (OSCC) patients. The results clearly showed a significant elevation of most targeted proteins in saliva samples from OSCC patients compared with controls. Overall, this platform was capable of assaying the most highly multiplexed panel of salivary protein biomarkers, highlighting the clinical utility of MRM in oral cancer biomarker research.

Transient Receptor Potential Vanilloid 4 Activation-Induced Increase in Glycine-Activated Current in Mouse Hippocampal Pyramidal Neurons.

BACKGROUND/AIMS: Glycine plays an important role in regulating hippocampal inhibitory/ excitatory neurotransmission through activating glycine receptors (GlyRs) and acting as a co-agonist of N-methyl-d-aspartate-type glutamate receptors. Activation of transient receptor potential vanilloid 4 (TRPV4) is reported to inhibit hippocampal A-type γ-aminobutyric acid receptor, a ligand-gated chloride ion channel. GlyRs are also ligand-gated chloride ion channels and this paper aimed to explore whether activation of TRPV4 could modulate GlyRs. METHODS: Whole-cell patch clamp recording was employed to record glycine-activated current (IGly) and Western blot was conducted to assess GlyRs subunits protein expression. RESULTS: Application of TRPV4 agonist (GSK1016790A or 5,6-EET) increased IGly in mouse hippocampal CA1 pyramidal neurons. This action was blocked by specific antagonists of TRPV4 (RN-1734 or HC-067047) and GlyR (strychnine), indicating that activation of TRPV4 increases strychnine-sensitive GlyR function in mouse hippocampal pyramidal neurons. GSK1016790A-induced increase in IGly was significantly attenuated by protein kinase C (PKC) (BIM II or D-sphingosine) or calcium/calmodulin-dependent protein kinase II (CaMKII) (KN-62 or KN-93) antagonists but was unaffected by protein kinase A or protein tyrosine kinase antagonists. Finally, hippocampal protein levels of GlyR α1 α2, α3 and ß subunits were not changed by treatment with GSK1016790A for 30 min or 1 h, but GlyR α2, α3 and ß subunits protein levels increased in mice that were intracerebroventricularly (icv.) injected with GSK1016790A for 5 d. CONCLUSION: Activation of TRPV4 increases GlyR function and expression, and PKC and CaMKII signaling pathways are involved in TRPV4 activation-induced increase in IGly. This study indicates that GlyRs may be effective targets for TRPV4-induced modulation of hippocampal inhibitory neurotransmission.

The survival impact of delayed surgery and adjuvant chemotherapy on stage II/III rectal cancer with pathological complete response after neoadjuvant chemoradiation.

Neoadjuvant concurrent chemoradiation (CCRT) is standard treatment for clinical stage II/III rectal cancers. However, whether patients with pathological complete response (pT0N0, pCR) should receive adjuvant chemotherapy and whether delayed surgery will influence the pCR rate remains controversial. A nationwide population study was conducted using the Taiwan Cancer Registry Database from January 2007 to December 2013. Kaplan-Meier survival analysis was performed. Cox proportional hazards models were used to estimate multivariate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI). Of the 1,914 patients who received neoadjuvant CCRT, 259 (13.6%) achieved pCR and had better survival (adjusted HR: 0.37, 95% CI: 0.24-0.58; p < 0.001). The cumulative rate of pCR rose up to 83.4% in the 9th week and slowly reached a plateau after the 11th week. Among the patients with pCR, those who received adjuvant chemotherapy had no survival benefits compared to those without adjuvant chemotherapy (adjusted HR: 0.72, 95 CI: 0.27-1.93; p = 0.52). By subgroup analysis, those younger than 70-year old and received adjuvant chemotherapy had better survival benefit than those without adjuvant chemotherapy (adjusted HR: 0.19, 95% CI: 0.04-0.97; p = 0.046). Delayed surgery by 9-12 weeks after the end of neoadjuvant CCRT can maximize the pCR rate, which is correlated with better survival. Adjuvant chemotherapy may be considered in patients with pCR and aged <70-year old, but further prospectively randomized controlled trials are warranted to validate these findings.

Asthma control and severe exacerbations in patients with moderate or severe asthma in Jilin Province, China: a multicenter cross-sectional survey.

BACKGROUND: No systemic evaluation of asthma control in Jilin Province has been reported. Asthma control might provide the basis for asthma management in this region. A multicenter hospital-based cross-sectional study was performed to investigate the asthma control and related factors for severe asthma exacerbations in patients with moderate or severe asthma in Jilin Province, China. METHODS: The study enrolled 1546 patients in five grade one general hospitals from January to December 2013. Asthma medication, patient self-management, asthma control test (ACT) scores and frequency of severe asthma exacerbations during the follow-up (12 months) were collected via a follow-up questionnaire. RESULTS: In the study, 889 patients provided a complete follow-up questionnaire. Severe asthma exacerbations occurred in 54.89 % of patients. ACT score ≤15, asthma medication ≤ 3 months, severe asthma, income level lower than average Per Capita Disposable Income (PCDI) and a lower educational level were risk factors of a severe exacerbation. CONCLUSIONS: Poor adherence to asthma medication, poor asthma symptom control, lower income, a low educational level might be possible reasons for the high incidence of severe asthma exacerbations and poor asthma control in Jilin Province of China.

Tanshinone II-A is protective against human umbilical vein endothelial cell injury after exposure to serum from preeclampsia patients.

BACKGROUND/AIMS: Preeclampsia (PE) is one of the most common and dangerous complications during pregnancy and is characterized by high blood pressure and significant amounts of protein in the urine. Vascular endothelial cell dysfunction is the major pathology in PE. This study was designed to assay the effects of tanshinone II-A (TII-A) on human umbilical vein endothelial cell (HUVEC) injury after incubation with serum from PE patients and to determine the underlying mechanism. METHODS: After treating HUVECs with different TII-A concentrations, cell viability, apoptosis and CD40/CD40 ligand (CD40L) mRNA and protein expression levels were measured. RESULTS: Incubation of HUVECs with serum from PE patients induced morphological alterations, caused decreased cell viability and increased the rate of apoptosis. However, TII-A (5-40 µg/ml) significantly reversed these injuries. Importantly, preapplication of TII-A attenuated PE sera-induced expression of CD40 and CD40L mRNA and protein. CONCLUSION: TII-A has a protective effect against PE sera, likely through regulation of the CD40/CD40L signal transduction pathway.

Isolation, sequence characterization, and tissue transcription profiles of two novel buffalo genes: INSIG1 and INSIG2.

Insulin-induced genes (INSIGs) are recently discovered genes that are involved in the metabolism of cholesterol and lipogenesis in animal tissues. In this study, two INSIG genes (INSIG1 and INSIG2) were isolated and characterized in 11 buffalo. The full-length coding sequence (CDS) of the buffalo INSIG1 consists of 831 bp which encodes a 276 amino acid protein with molecular mass 29.55 kD. And the INSIG2 CDS is 678 bp in length which encodes a 225 amino acid protein with molecular mass 24.87 kD. No polymorphisms were found in the CDSs of the buffalo INSIGs, but seven and two nucleotide differences were found in the CDSs between buffalo and other bovine species. Phylogenetic analyses based on the INSIG amino acid sequences showed that buffalo was grouped with other members in the Bovidae family. Four types of putative modification sites were detected in buffalo INSIG proteins. And two predicted microRNA target sites were found respectively in the CDSs of buffalo INSIG1 and INSIG2. The tissue expression analyses by quantitative PCR (qPCR) revealed that the buffalo INSIG1 was expressed in ten tissues tested. Among these tissues, the liver and mammary gland showed high expression levels. And the INSIG2 was only expressed in the brain, mammary glands, pituitary, abomasum, heart, and liver. Among these tissues, the mammary gland, brain, and pituitary demonstrated a high expression levels. These data provide the primary foundation for further insights into the buffalo INSIG genes.

Efficacy and safety of a smartphone application-based treatment of ketogenic diet in pediatric refractory epilepsy.

OBJECTIVE: We aimed to find predictors for smartphone application-based ketogenic diet (KD) treatment effectiveness and safety. METHODS: The efficacy was evaluated according to the reduction in seizure frequency after the intervention of KD; safety was evaluated based on adverse effects. The ordinal logistic regression analysis was used to explore the influencing factors of efficacy. RESULTS: The study sample included 116 males and 65 females with a median age of 2.27 years. The baseline frequency of seizure was more than five times/day in 123 children, 50.83% of them received three or more antiepileptic drugs (AEDs). Seventy-two patients' KD initiation mode was outpatient, and 73 completed the 12-month follow-up. A total of 88 (48.62%) patients had reported a reduction in seizure ≥50%. Compared with 12 months, those who had received KD therapy for only 3 (P = 0.009) and 6 months (P = 0.005) were more likely to show negative outcomes. Outpatient initiation had better outcomes (P = 0.029) than inpatient initiation. For the number of AEDs applied, patients on two AEDs were more likely to achieve better outcomes (P = 0.001). Adverse events had been noted among 77 patients; BMI Z-score at KD initiation was associated with adverse effects (P = 0.003). SIGNIFICANCE: Our study suggested that outpatient initiation and long-term treatment of KD should be encouraged. PLAIN LANGUAGE SUMMARY: Our research shows that the KD is a helpful treatment for children with refractory epilepsy, reducing seizures by more than 50% in nearly half of the cases, with some experiencing complete seizure freedom. We used a smartphone app to improve communication between patients and their healthcare teams, resulting in a high retention, and app usage was linked to reduced adverse effects. We recommend early consideration of KD treatment for patients failing two AED, encourage outpatient initiation, and advocate for longer-term KD use.

Bayesian analysis of physiologically based toxicokinetic (PBTK) modeling for pentachlorophenol exposure in pregnant women.

Pentachlorophenol (PCP) is a persistent organic compound that is widely present in the environment. The estimation of internal exposure levels for a given external exposure using toxicokinetic models is key to the human health risk assessment of PCP. The present study developed a physiologically based multicompartmental pharmacokinetic (PBTK) model to describe and predict the behavior of pentachlorophenol (PCP) in an organism. The model consists of stomach, intestines, adipose tissue, kidneys and fast- and poorly perfused tissues that are interconnected via blood circulation. We constructed a PBTK model of PCP in rats and extrapolated it to human dietary PCP exposure. The toxicokinetic data of PCP in human tissues and excreta were obtained from the published literature. Based on the collected PCP dietary survey and internal exposure data of pregnant women in Shanghai, Bayesian statistical analysis was performed for the model using Markov chain Monte Carlo (MCMC) simulation. The posterior distributions of the sensitive parameters were estimated, and the model was parameter optimized and validated using the pregnant women's test dataset. The results showed that the root mean square error (RMSE) improved 37.3% compared to the original model, and a systematic literature search revealed that the optimized model achieved acceptable prediction results for other datasets in China. A PCP metabolism model based on the exposure characteristics of pregnant women in China was constructed in the present study. The model provides a theoretical basis for the study of PCP toxicity and risk assessment.

Synthesis, biological evaluation and molecular modeling of substituted 2-aminobenzimidazoles as novel inhibitors of acetylcholinesterase and butyrylcholinesterase.

A series of novel 2-aminobenzimidazole derivatives were synthesized under microwave irradiation. Their biological activities were evaluated on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). A number of the 2-aminobenzimidazole derivatives showed good inhibitory activities to AChE and BuChE. Among them, compounds 9, 12 and 13 were found to be >25-fold more selective for BuChE than AChE. No evidence of cytotoxicity was observed by MTT assay in PC12 cells or HepG2 cells exposed to 100µM of the compounds. Molecular modeling studies indicate that the benzimidazole moiety of compounds 9, 12 and 13 forms a face-to-face π-π stacking interaction in a 'sandwich' form with the indole ring of Trp82 (4.09Å) in the active gorge, and compounds 12 and 13 form a hydrogen bond with His438 at the catalytic site of BuChE. In addition, compounds 12 and 13 fit well into the hydrophobic pocket formed by Ala328, Trp430 and Tyr332 of BuChE. Our data suggest the 2-aminobenzimidazole drugs as promising new selective inhibitors for AChE and BuChE, potentially useful to treat neurodegenerative diseases.

The Spodoptera frugiperda effector caspase Sf-caspase-1 becomes unstable following its activation.

Sf-caspase-1 is the principal effector caspase in Spodoptera frugiperda cells. Like the caspases in other organisms, Sf-caspase-1 is processed by upstream caspases to form an active heterotetramer composed of the p19 and p12 subunits. The regulation of active caspases is crucial for cellular viability. In mammal cells, the subunits and the active form of caspase-3 were rapidly degraded relative to its proenzyme form. In the present study, the S. frugiperda Sf9 cells were transiently transfected with plasmids encoding different fragments of Sf-caspase-1: the pro-Sf-caspase-1 (p37), a prodomain deleted fragment (p31), a fragment containing the large subunit and the prodomain (p25), the large subunit (p19), and the small subunit (p12). Flow cytometry and Western blot analysis revealed that p12, p19, and p25 were unstable in the transfected cells, in contrast to p37 and p31. Lactacystin, a proteasome inhibitor, increased the accumulation of the p19 and p12 subunits, suggesting that the degradation is performed by the ubiquitin-proteasome system. During the activation, the Sf-caspase-1 produces an intermediate form and then undergoes proteolytic processing to form active Sf-caspase-1. We found that both the active and the intermediate form were unstable, indicating that once activated or during its activation, the Sf-caspase-1 was unstable.

[Study on mode of delivery and singleton newborns term birth weight in 3 hospitals].

OBJECTIVE: To study newborns weight in singleton term births and the association between newborns birth weight and mode of delivery in 3 hospitals. METHODS: From Jan. 2005 to Dec. 2009, 13 963 singleton term live neonates born in the Department of Obstetrics and Gynecology of Peking University First Hospital (PU group), 6519 neonates in Affiliated Hospital of Binzhou Medical College (BMC group,) and 8725 neonates in Miyun Hospital Affiliated to Capital Medical University, Yanjing Medical College (MYC group) were enrolled in this retrospective study. The newborns weight and the rate of macrosomia was calculated and compared. Those newborns from PU group and MYC group were divided into 2288 neonates at macrosomia group and 20 400 neonates at non-macrosomia group, their mode of deliveries were analyzed. RESULTS: (1) The mean neonatal birth weight were (3386 ± 414) g at PU group, (3389 ± 446) g at BMC group and (3445 ± 449) g at MYC group. Neonates born weight in MYC was significantly higher than those from in PU group and BMC group (P = 0.000). Neonates born weight in BMC showed higher than those in PU group, which did not reached statistical difference (P = 0.638). (2) The incidence of macrosomia were 7.935% (1108/13 963) in PU group, 9.802% (639/6519) in BMU group and 13.524% (1180/8725) in MYU group. The incidence of macrosomia in MYC group was higher than those in PU and BMC group, the incidence of macrosomia in BMC group was higher than that in PU group, which reached statistically difference (P = 0.000). (3)The proportion of cesarean delivery were 75.306% (1723/2288) at macrosomia group, 50.765% (10 356/20 400) at non-macrosomia group, which showed statistical difference (P = 0.000). CONCLUSIONS: (1) The difference of newborns birth weight existed in different administrative level hospital. (2) The risk of cesarean delivery due to macrosomia is higher than that of non-macrosomia. (3) Obstetricians should pay more attention to nutrition in gestation period to lessen the incidence of macrosomia and cesarean section.

Quantum battery based on dipole-dipole interaction and external driving field.

The Dicke model is a fundamental model in quantum optics, which describes the interaction between quantum cavity field and a large ensemble of two-level atoms. In this work, we propose an efficient charging quantum battery achieved by considering an extension Dicke model with dipole-dipole interaction and an external driving field. We focus on the influence of the atomic interaction and the driving field on the performance of the quantum battery during the charging process and find that the maximum stored energy exhibits a critical phenomenon. The maximum stored energy and maximum charging power are investigated by varying the number of atoms. When the coupling between atoms and cavity is not very strong, compared to the Dicke quantum battery, such quantum battery can achieve more stable and faster charging. In addition, the maximum charging power approximately satisfies a superlinear scaling relation P_{max}∝ßN^{α}, where the quantum advantage α=1.6 can be reached via optimizing the parameters.

Tumor-derived miRNAs as tumor microenvironment regulators for synergistic therapeutic options.

MicroRNAs (miRNAs) are a class of non-coding RNAs that perform post-transcriptional gene regulation. This review focuses on the role of tumor cell-derived miRNAs in the regulation of the tumor microenvironment (TME) via receptor cell recoding, including angiogenesis, expression of immunosuppressive molecules, formation of radiation resistance, and chemoresistance. Furthermore, we discuss the potential of these molecules as adjuvant therapies in combination with chemotherapy, radiotherapy, or immunotherapy, as well as their advantages as efficacy predictors for personalized therapy. MiRNA-based therapeutic agents for tumors are currently in clinical trials, and while challenges remain, additional research on tumor-derived miRNAs is warranted, which may provide significant clinical benefits to cancer patients.