DDX5 inhibits inflammation by modulating m6A levels of TLR2/4 transcripts during bacterial infection.

DExD/H-box helicases are crucial regulators of RNA metabolism and antiviral innate immune responses; however, their role in bacteria-induced inflammation remains unclear. Here, we report that DDX5 interacts with METTL3 and METTL14 to form an m6A writing complex, which adds N6-methyladenosine to transcripts of toll-like receptor (TLR) 2 and TLR4, promoting their decay via YTHDF2-mediated RNA degradation, resulting in reduced expression of TLR2/4. Upon bacterial infection, DDX5 is recruited to Hrd1 at the endoplasmic reticulum in an MyD88-dependent manner and is degraded by the ubiquitin-proteasome pathway. This process disrupts the DDX5 m6A writing complex and halts m6A modification as well as degradation of TLR2/4 mRNAs, thereby promoting the expression of TLR2 and TLR4 and downstream NF-κB activation. The role of DDX5 in regulating inflammation is also validated in vivo, as DDX5- and METTL3-KO mice exhibit enhanced expression of inflammatory cytokines. Our findings show that DDX5 acts as a molecular switch to regulate inflammation during bacterial infection and shed light on mechanisms of quiescent inflammation during homeostasis.

Genomic analyses of wild argali, domestic sheep, and their hybrids provide insights into chromosome evolution, phenotypic variation, and germplasm innovation.

Understanding the genetic mechanisms of phenotypic variation in hybrids between domestic animals and their wild relatives may aid germplasm innovation. Here, we report the high-quality genome assemblies of a male Pamir argali (O ammon polii, 2n = 56), a female Tibetan sheep (O aries, 2n = 54), and a male hybrid of Pamir argali and domestic sheep, and the high-throughput sequencing of 425 ovine animals, including the hybrids of argali and domestic sheep. We detected genomic synteny between Chromosome 2 of sheep and two acrocentric chromosomes of argali. We revealed consistent satellite repeats around the chromosome breakpoints, which could have resulted in chromosome fusion. We observed many more hybrids with karyotype 2n = 54 than with 2n = 55, which could be explained by the selfish centromeres, the possible decreased rate of normal/balanced sperm, and the increased incidence of early pregnancy loss in the aneuploid ewes or rams. We identified genes and variants associated with important morphological and production traits (e.g., body weight, cannon circumference, hip height, and tail length) that show significant variations. We revealed a strong selective signature at the mutation (c.334C > A, p.G112W) in TBXT and confirmed its association with tail length among sheep populations of wide geographic and genetic origins. We produced an intercross population of 110 F2 offspring with varied number of vertebrae and validated the causal mutation by whole-genome association analysis. We verified its function using CRISPR-Cas9 genome editing. Our results provide insights into chromosomal speciation and phenotypic evolution and a foundation of genetic variants for the breeding of sheep and other animals.

Canagliflozin alleviates pulmonary hypertension by activating PPARγ and inhibiting its S225 phosphorylation.

Pulmonary hypertension (PH) is a progressive fatal disease with no cure. Canagliflozin (CANA), a novel medication for diabetes, has been found to have remarkable cardiovascular benefits. However, few studies have addressed the effect and pharmacological mechanism of CANA in the treatment of PH. Therefore, our study aimed to investigate the effect and pharmacological mechanism of CANA in treating PH. First, CANA suppressed increased pulmonary artery pressure, right ventricular hypertrophy, and vascular remodeling in both mouse and rat PH models. Network pharmacology, transcriptomics, and biological results suggested that CANA could ameliorate PH by suppressing excessive oxidative stress and pulmonary artery smooth muscle cell proliferation partially through the activation of PPARγ. Further studies demonstrated that CANA inhibited phosphorylation of PPARγ at Ser225 (a novel serine phosphorylation site in PPARγ), thereby promoting the nuclear translocation of PPARγ and increasing its ability to resist oxidative stress and proliferation. Taken together, our study not only highlighted the potential pharmacological effect of CANA on PH but also revealed that CANA-induced inhibition of PPARγ Ser225 phosphorylation increases its capacity to counteract oxidative stress and inhibits proliferation. These findings may stimulate further research and encourage future clinical trials exploring the therapeutic potential of CANA in PH treatment.

Clinical significance and potential pathogenesis of VCAN in adult non-cystic fibrosis bronchiectasis: a retrospective study.

BACKGROUND: The pathogenesis of adult non-cystic fibrosis (CF) bronchiectasis is complex, and the relevant molecular mechanism remains ambiguous. Versican (VCAN) is a key factor in inflammation through interactions with adhesion molecules. This study constructs a stable panoramic map of mRNA, reveals the possible pathogenesis of bronchiectasis, and provides new ideas and methods for bronchiectasis. METHODS: Peripheral blood and tissue gene expression data from patients with bronchiectasis and normal control were selected by bioinformatics analysis. The expression of VCAN in peripheral blood and bronchial tissues of bronchiectasis were obtained by transcriptome sequencing. The protein expression levels of VCAN in serums were verified by the enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of VCAN in co-culture of Pseudomonas aeruginosa and bronchial epithelial cells were verified by real-time quantitative polymerase chain reaction (RT-qPCR). In addition, the biological function of VCAN was detected by the transwell assay. RESULTS: The expression of VCAN was upregulated in the bronchiectasis group by sequencing analysis (P < 0.001). The expression of VCAN in the bronchial epithelial cell line BEAS-2B was increased in P. aeruginosa (P.a), which was co-cultured with BEAS-2B cells (P < 0.05). The concentration of VCAN protein in the serum of patients with bronchiectasis was higher than that in the normal control group (P < 0.05). Transwell experiments showed that exogenous VCAN protein induced the migration of neutrophils (P < 0.0001). CONCLUSIONS: Our findings indicate that VCAN may be involved in the development of bronchiectasis by increasing the migration of neutrophils and play an important role in bronchial pathogenesis.

Estimating seroprevalence of SARS-CoV-2 in Ohio: A Bayesian multilevel poststratification approach with multiple diagnostic tests.

Globally, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 59 million people and killed more than 1.39 million. Designing and monitoring interventions to slow and stop the spread of the virus require knowledge of how many people have been and are currently infected, where they live, and how they interact. The first step is an accurate assessment of the population prevalence of past infections. There are very few population-representative prevalence studies of SARS-CoV-2 infections, and only two states in the United States-Indiana and Connecticut-have reported probability-based sample surveys that characterize statewide prevalence of SARS-CoV-2. One of the difficulties is the fact that tests to detect and characterize SARS-CoV-2 coronavirus antibodies are new, are not well characterized, and generally function poorly. During July 2020, a survey representing all adults in the state of Ohio in the United States collected serum samples and information on protective behavior related to SARS-CoV-2 and coronavirus disease 2019 (COVID-19). Several features of the survey make it difficult to estimate past prevalence: 1) a low response rate; 2) a very low number of positive cases; and 3) the fact that multiple poor-quality serological tests were used to detect SARS-CoV-2 antibodies. We describe a Bayesian approach for analyzing the biomarker data that simultaneously addresses these challenges and characterizes the potential effect of selective response. The model does not require survey sample weights; accounts for multiple imperfect antibody test results; and characterizes uncertainty related to the sample survey and the multiple imperfect, potentially correlated tests.

Mechanisms of adsorption and functionalization of biochar for pesticides: A review.

Agricultural production relies heavily on pesticides. However, factors like inefficient application, pesticide resistance, and environmental conditions reduce their effective utilization in agriculture. Subsequently, pesticides transfer into the soil, adversely affecting its physicochemical properties, microbial populations, and enzyme activities. Different pesticides interacting can lead to combined toxicity, posing risks to non-target organisms, biodiversity, and organism-environment interactions. Pesticide exposure may cause both acute and chronic effects on human health. Biochar, with its high specific surface area and porosity, offers numerous adsorption sites. Its stability, eco-friendliness, and superior adsorption capabilities render it an excellent choice. As a versatile material, biochar finds use in agriculture, environmental management, industry, energy, and medicine. Added to soil, biochar helps absorb or degrade pesticides in contaminated areas, enhancing soil microbial activity. Current research primarily focuses on biochar produced via direct pyrolysis for pesticide adsorption. Studies on functionalized biochar for this purpose are relatively scarce. This review examines biochar's pesticide absorption properties, its characteristics, formation mechanisms, environmental impact, and delves into adsorption mechanisms, functionalization methods, and their prospects and limitations.

Use of ABC/2 method for rapidly estimating the target mismatch on computed tomography perfusion imaging in patients with acute ischemic stroke.

BACKGROUND: Target mismatch (ischemic core, mismatch volume and mismatch ratio) in patients with acute ischemic stroke (AIS) highly relies on the automated perfusion analysis software. PURPOSE: To evaluate the feasibility and accuracy of using the ABC/2 method to rapidly estimate the target mismatch on computed tomography perfusion (CTP) imaging in patients with AIS, using RAPID results as a reference. MATERIAL AND METHODS: In total, 243 patients with anterior circulation AIS who underwent CTP imaging were retrospectively reviewed. Target mismatch associated perfusion parameters were derived from RAPID results and calculated using the ABC/2 method. Paired t-test was used to assess the difference of volumetric parameters between the two methods. The ability of using the ABC/2 method to predict the important cutoff volumetric metrics was also evaluated. RESULT: There was no significant difference in the volumes of ischemic core (P = 0.068), ischemic area (P = 0.209), and mismatch volume (P = 0.518) between ABC/2 and RAPID. Using RAPID results as reference, the ABC/2 method showed high accuracy for predicting perfusion parameters (70 mL and 90 mL: sensitivity=98.5% and 98.5%, specificity=100% and 100%, positive predictive value [PPV]=100% and 100%, negative predictive value [NPV]=93.8% and 92.9%; 10 mL and 15mL: sensitivity=99.6% and 99.5%, specificity=55.6% and 50.0%, PPV=96.6% and 94.8%, NPV=90.9% and 92.3%; 1.2 and 1.8: sensitivity=99.6% and 94.8%, specificity=75.0% and 96.9%, PPV=98.7% and 99.5%, NPV=90.0% and 73.8%). CONCLUSION: The ABC/2 method may be a feasible alternative to RAPID for estimation of target mismatch parameters on CTP in patients with AIS.

Residual Behavior and Dietary Risk Assessment of Chlorfenapyr and Its Metabolites in Radish.

Chlorfenapyr, as a highly effective and low-toxicity insect growth regulation inhibitor, has been used to control cross-cruciferous vegetable pests. However, the pesticide residue caused by its application threatens human health. In this paper, the residue digestion and final residue of chlorfenapyr in radish were studied in a field experiment. The results of the dynamic digestion test showed that the half-life of chlorfenapyr in radish leaves ranged from 6.0 to 6.4 days, and the digestion rate was fast. The median residual values of chlorfenapyr in radish and radish leaves at 14 days after treatment were 0.12 and 3.92 mg/kg, respectively. The results of the dietary intake risk assessment showed that the national estimated daily intake (NEDI) of chlorfenapyr in various populations in China were 0.373 and 5.66 µg/(kg bw·d), respectively. The risk entropy (RQ) was 0.012 and 0.147, respectively, indicating that the chronic dietary intake risk of chlorfenapyr in radish was low. The results of this study provided data support and a theoretical basis for guiding the scientific use of chlorfenapyr in radish production and evaluating the dietary risk of chlorfenapyr in vegetables.

Prognostic value of ASPECTS on post-treatment diffusion-weighted imaging for acute ischemic stroke patients after endovascular thrombectomy: comparison with infarction volume.

OBJECTIVES: To assess the prognostic value of Alberta Stroke Program Early Computed Tomography Score (ASPECTS) on post-treatment diffusion-weighted imaging (DWI) for acute ischemic stroke (AIS) patients after endovascular thrombectomy (EVT) and compare it with that of infarction volume. METHODS: Ninety-eight consecutive AIS patients who underwent EVT and post-treatment DWI were retrospectively enrolled. ASPECTS and infarction volume were evaluated based on post-treatment DWI, respectively. Good clinical outcome was defined as modified Rankin Scale score of 0-2 at 90 days. Predictors of good clinical outcome were evaluated using univariate and multivariate logistic regression analysis. Prognostic value of post-treatment DWI ASPECTS and infarction volume were assessed and compared using receiver-operating-characteristic curves and the DeLong method. RESULTS: Favorable outcome was achieved in 62 (63.3%) patients. A strong correlation was found between post-treatment DWI ASPECTS and infarction volume (ρ = -0.847). Due to strong correlation and potential collinearity, two multivariate logistic regression models were respectively developed which included post-treatment DWI ASPECTS or infarction volume. As a result, post-treatment DWI ASPECTS (OR, 2.401; 95%CI, 1.567-3.678; p < 0.001) and infarction volume (OR, 0.982; 95%CI, 0.846-0.998; p = 0.002) were both independent predictors of good clinical outcome. Setting post-treatment DWI ASPECTS ≥ 6 as a cut-off value, optimal performance (AUC = 0.836; sensitivity, 87.1%; specificity, 66.7%) could be obtained in predicting good clinical outcome, which was comparable with that of infarction volume (cut-off volume, ≤ 94.87 ml; AUC = 0.821; sensitivity, 90.3%; specificity, 55.6%). CONCLUSIONS: Post-treatment DWI ASPECTS might be a potential surrogate of infarction volume and be effective in predicting the clinical outcome of AIS patients after EVT. KEY POINTS: • Post-treatment DWI ASPECTS correlated significantly with infarction volume. • A post-treatment DWI ASPECTS ≥ 6 best predicts good outcomes for AIS patients after EVT. • Post-treatment DWI ASPECTS has the potential in substituting infarction volume in predicting the clinical outcome of AIS patients.

Prognostic value of post-treatment fluid-attenuated inversion recovery vascular hyperintensity in ischemic stroke after endovascular thrombectomy.

OBJECTIVES: To explore the value of post-treatment fluid-attenuated inversion recovery vascular hyperintensity (FVH) in predicting clinical outcome in patients with acute ischemic stroke (AIS) after endovascular thrombectomy (EVT). METHODS: This retrospective study reviewed data from consecutive patients with large vessel occlusion of anterior circulation between July 2017 and February 2021. Together with other variables, status of post-treatment FVH was assessed for each patient. Good outcome was defined as a 3-month modified Rankin Scale score of 0-2. Chi-square test, Fisher's exact test, independent-samples t test, multivariate logistic regression analysis, and receiver operating characteristic analysis were used as appropriate. RESULTS: Among 84 included patients, 48 (57.1%) patients showed post-treatment FVH. Post-treatment FVH significantly correlated with incomplete recanalization (p < 0.05) and low Alberta Stroke Project Early CT Changes Score on post-treatment diffusion-weighted imaging (p < 0.05). Higher incidence of hemorrhage transformation was observed in patients with post-treatment FVH than those without (27.1% vs. 16.7%); however, the difference did not reach significance (p = 0.259). Successful recanalization (odds ratio [OR], 0.024; 95% confidence interval [CI] 0.003-0.194; p < 0.05), lower National Institutes of Health Stroke Scale scores at admission (NIHSSpre) (OR, 1.196; 95% CI, 1.017-1.406; p < 0.05), and no post-treatment FVH (OR, 74.690; 95% CI, 4.624-1206.421; p < 0.05) were found to be independent predictors of good outcomes. Combined models integrating all three independent predictors (recanalization+NIHSSpre+post-treatment FVH) significantly outperformed the combined model without post-treatment FVH (recanalization+NIHSSpre) in predicting clinical outcome (p = 0.004). CONCLUSIONS: Post-treatment FVH may be an effective prognostic marker associated with clinical outcome in patients with AIS after EVT. KEY POINTS: • Post-treatment FVH correlates with incomplete recanalization and higher infarct volume. • Post-treatment FVH is independently associated with an unfavorable outcome. • Post-treatment FVH may provide prognostic information in patients with AIS after EVT.

Adapting and validating the log quadratic model to derive under-five age- and cause-specific mortality (U5ACSM): a preliminary analysis.

BACKGROUND: The mortality pattern from birth to age five is known to vary by underlying cause of mortality, which has been documented in multiple instances. Many countries without high functioning vital registration systems could benefit from estimates of age- and cause-specific mortality to inform health programming, however, to date the causes of under-five death have only been described for broad age categories such as for neonates (0-27 days), infants (0-11 months), and children age 12-59 months. METHODS: We adapt the log quadratic model to mortality patterns for children under five to all-cause child mortality and then to age- and cause-specific mortality (U5ACSM). We apply these methods to empirical sample registration system mortality data in China from 1996 to 2015. Based on these empirical data, we simulate probabilities of mortality in the case when the true relationships between age and mortality by cause are known. RESULTS: We estimate U5ACSM within 0.1-0.7 deaths per 1000 livebirths in hold out strata for life tables constructed from the China sample registration system, representing considerable improvement compared to an error of 1.2 per 1000 livebirths using a standard approach. This improved prediction error for U5ACSM is consistently demonstrated for all-cause as well as pneumonia- and injury-specific mortality. We also consistently identified cause-specific mortality patterns in simulated mortality scenarios. CONCLUSION: The log quadratic model is a significant improvement over the standard approach for deriving U5ACSM based on both simulation and empirical results.

Diagnostic accuracy of using Alberta Stroke Program Early Computed Tomography Score on CT perfusion map to predict a target mismatch in patients with acute ischemic stroke.

PURPOSE: To assess the diagnostic accuracy of using Alberta Stroke Program Early Computed Tomography Score (ASPECTS) on CT perfusion (CTP) map to predict a volumetric target mismatch in patients with acute ischemic stroke (AIS). METHODS: Three-hundred and seven AIS patients with an onset time within 24h or unclear onset time who underwent CTP evaluation for large vessel occlusion of anterior circulation were enrolled. CTP ASPECTS was evaluated on cerebral blood flow (CBF) and time-to-maximum (Tmax) colored maps, respectively. Automated perfusion analysis software was used to calculate the volumes of ischemic core (volumeCBF<30%) and tissue at risk (volumeTmax>6s). Target mismatch was defined as volumeCBF< 30%<70ml, volumemismatch≥15ml, and volumeTmax >6s/volume CBF< 30%≥1.8. Spearman correlation and receiver operating characteristic curves were used for statistical analyses. RESULTS: Strong correlations were found between CBF ASPECTS and volumeCBF<30%, and between Tmax ASPECTS and volumeTmax>6s for overall population (ρ=-0.872, -0.757) and late-arriving patients (ρ=-0.900, -0.789). Mismatch ASPECTS moderately correlated with mismatch volume for overall population (ρ=0.498) and late-arriving patients (ρ=0.407). A CBF ASPECTS≥5 optimally predicted an ischemic core volume<70ml in overall population (sensitivity, 94.4%; specificity, 80.4%) and late-arriving patients (sensitivity, 89.5%; specificity, 90.5%). A CBF ASPECTS≥6 combined with a Mismatch ASPECTS≥1 optimally identified a target mismatch in overall population (sensitivity, 84.5%; specificity, 77.0%) and late-arriving patients (sensitivity, 83.7%; specificity, 90.0%). CONCLUSION: CTP ASPECTS might be useful in predicting target mismatch derived from automated perfusion analysis software, and assisting in patient selection for endovascular therapy.

Comparison of time consumption and success rate between CT angiography- and CT perfusion- based imaging assessment strategy for the patients with acute ischemic stroke.

BACKGROUND: Our study aimed to compare the time consumption and success rate between CTA- and CTP- based assessment strategy, and to clarify the risk factors associated with the CTP scan failure. METHODS: Clinical and radiological data of 437 consecutive AIS patients who underwent multiphase CTA or CTP for pre-treatment evaluation were retrospectively enrolled (CTA group, n = 302; CTP group, n = 135). Time consumption and success rate of CTA- and CTP- based assessment strategy were compared using Mann-Whitney U test and Chi-Squared Test. Univariate analysis and receiver operating curve analysis were used to clarify the risk factors, and their performance in predicting the CTP scan failure. RESULTS: Time consumption of CTP scan and reconstruction was significantly longer than that of CTA [775 s vs 263.5 s, P < 0.001]. CTP scan showed significantly higher failure rate than CTA (11% vs 1%, P < 0.001). Severe motion was the most common cause of CTP failure (n = 12, 80%). Baseline National Institute of Health Stroke Scale (NIHSS) score in CTP failure group was significantly higher than that in CTP success group [17 vs 13, P = 0.007]. Baseline NIHSS score of 11 was the optimal threshold value to predict CTP failure with an area under the curve of 0.715, a sensitivity of 86.7%, and a specificity of 45.0%. CONCLUSIONS: CTP- based strategy showed longer time consumption and higher failure rate than CTA- based strategy. High baseline NIHSS score was significantly associated with CTP scan failure in AIS patients.

Total and regional ASPECT score for non-contrast CT, CT angiography, and CT perfusion: inter-rater agreement and its association with the final infarction in acute ischemic stroke patients.

BACKGROUND: Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is a grading system to assess the extent and distribution of early ischemic changes. PURPOSE: To assess inter-rater agreement for total and regional ASPECTS on non-contrast computed tomography (NCCT) images, CT angiography source images (CTA-SI), and CT-perfusion cerebral blood volume (CTP-CBV) maps, and their association with final infarction in patients with acute ischemic stroke (AIS). MATERIAL AND METHODS: A total of 96 consecutive patients with AIS who underwent pre-treatment NCCT and CTP were retrospectively enrolled. CTA-SI was reconstructed using the raw data of CTP. Total and regional ASPECTS were assessed on baseline NCCT, CTA-SI, and CTP-CBV, and on follow-up NCCT or diffusion-weighted imaging. Follow-up ASPECTS served as the reference standard for final infarction. RESULTS: CTP-CBV demonstrated higher concordance for total ASPECTS (interclass correlation coefficient, 0.895 vs. 0.771 vs. 0.777) and regional ASPECTS in internal capsule, lentiform, caudate nuclei, M5 and M6, compared with NCCT and CTA-SI. CTP-CBV showed a trend of stronger correlation with final ASPECTS than NCCT and CTA-SI (0.717 vs. 0.711 vs. 0.565; P > 0.05). ASPECTS in the internal capsule (ρ, 0.756 vs. 0.556; P = 0.016) and caudate nucleus (ρ, 0.717 vs. 0.476; P = 0.010) on CTP-CBV were more strongly correlated with follow-up ASPECTS than NCCT. CTP-CBV showed higher accuracy for predicting final infarction in the internal capsule (92.5% vs. 90.3% and 87.1%; P > 1.000, P = 0.125, respectively) and caudate nucleus (87.1% vs. 79.6% and 77.4%; P = 0.453, P = 0.039, respectively) than CTA-SI and NCCT. CONCLUSION: CTP-CBV ASPECTS might be more reliable for delineating early ischemic changes and predicting final infarction.

Stereoselective bioactivity, toxicity and degradation of novel fungicide sedaxane with four enantiomers under rice-wheat rotation mode.

Sedaxane was a novel chiral fungicide that contains four enantiomers. Unfortunately, the stereoselective bioactivity, toxicity and degradation of sedaxane have not been clarified. In this study, we identified the absolute configuration of the four sedaxane enantiomers at first time. The stereoselective bioactivity toward three wheat and rice pathogens, stereoselective acute toxicity to aquatic organisms (Selenastrum capricornutum and Daphnia magna), and stereoselective degradation of sedaxane were studied. The 1 S,2S-(+)-sedaxane possessed 5.4-7.3 times greater bioactivity than 1 R,2R-(-)-sedaxane to Rhizoctonia solani and Rhizoctonia cerealis. Contrarily, the 1 R,2S-(+)-sedaxane had 4.2 times greater activity than 1 S,2S-(+)-sedaxane against Fusarium graminearum. The 1 R,2R-(-)-sedaxane had 2.8 times greater toxicity than 1 S,2S-(+)-sedaxane to S. capricornutum. The chiral determination method used ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The recovery of sedaxane stereoisomers ranged from 83.1 % to 98.2 %, with RSDs (Relative standard deviations) of 1.2 %- 8.4 %. The trans-sedaxane existed stereoselective degradation phenomenon in the rice-wheat rotation mode, and 1 S,2S-(+)-sedaxane was preferentially degraded. Our results would provide scientific importance and practical guidance to the safety evaluation of chiral pesticides.

Drastic induction of MMP-7 by cortisol in the human amnion: implications for membrane rupture at parturition.

Preterm premature rupture of fetal membranes precedes 30-40% of preterm births. Activation of matrix metalloproteases (MMPs) is the one of the major causes of extracellular matrix (ECM) degradation in membrane rupture. Increased cortisol, regenerated by 11ß-hydroxysteroid dehydrogenase 1 in the amnion at parturition, is known to participate in a number of parturition-pertinent events. However, whether cortisol has a role in the regulation of MMPs in the membranes is not known. Here, we addressed this issue using human amnion tissue, the most tensile layer of the membranes. RNA-sequencing revealed that cortisol induced MMP7 expression dramatically in amnion fibroblasts, which was confirmed by real-time quantitative RT-PCR and Western blotting analysis in cortisol-treated amnion explants and fibroblasts. Measurement of collagen IV α5 chain (COL4A5), a substrate for MMP-7, showed that cortisol reduced its extracellular abundance, which was blocked by an antibody against MMP-7. Moreover, increased MMP-7 but decreased COL4A5 abundance was observed in the amnion tissue following labor-initiated spontaneous rupture of membranes. Mechanistic studies showed that cortisol increased the phosphorylation of c-Jun and the expression of c-Fos, the 2 major components of activated protein 1 (AP-1), respectively. The knocking down of c-Fos or c-Jun significantly attenuated the induction of MMP7 expression by cortisol. Chromatin immunoprecipitation assays showed that cortisol stimulated the enrichment of c-Fos and c-Jun at the AP-1 binding site in the MMP7 promoter. The data suggest that induction of MMP7 by cortisol via AP-1 may be a contributing factor to ECM degradation in membrane rupture at parturition.-Wang, L.-Y., Wang, W.-S., Wang, Y.-W., Lu, J.-W., Lu, Y., Zhang, C.-Y., Li, W.-J., Sun, K., Ying, H. Drastic induction of MMP-7 by cortisol in the human amnion: implications for membrane rupture at parturition.

WZ66, a novel acetyl-CoA carboxylase inhibitor, alleviates nonalcoholic steatohepatitis (NASH) in mice.

The global prevalence of nonalcoholic steatohepatitis (NASH) increases incredibly. NASH ends up to advanced liver disease, which is highly threatening to human health. Currently, treatment of NASH is very limited. Acetyl-CoA carboxylases (ACC1/ACC2) are proved as effective drug targets for NASH. We aimed to develop novel ACC inhibitors and evaluate their therapeutic value for NASH prevention. ACC inhibitors were obtained through structure-based drug design, synthesized, screened from ACC enzymatic measurement platform and elucidated in cell culture-based assays and animal models. The lipidome and microbiome analysis were integrated to assess the effects of WZ66 on lipids profiles in liver and plasma as well as gut microbiota in the intestine. WZ66 was identified as a novel ACC1/2 inhibitor. It entered systemic circulation rapidly and could accumulate in liver. WZ66 alleviated NASH-related liver features including steatosis, Kupffer cells and hepatic stellate cells activation in diet-induced obese mice. The triglycerides (TGs) and other lipids including diglycerides (DGs), phosphatidylcholine (PC) and sphingomyelin (SM) were decreased in WZ66-treated mice as evidenced by lipidome analysis in livers. The lipids profiles in plasma were also altered with WZ66 treatment. Plasma TG were moderately increased, while the activation of SREBP1c was not detected. WZ66 also downregulated the abundance of Allobaculum, Mucispirillum and Prevotella genera as well as Mucispirillum schaedleri species in gut microbiota. WZ66 is an ideal lead compound and a potential drug candidate deserving further investigation in the therapeutics of NASH.

Biases in Survey Estimates of Neonatal Mortality: Results From a Validation Study in Urban Areas of Guinea-Bissau.

Neonatal deaths (occurring within 28 days of birth) account for close to one-half of all deaths among children under age 5 worldwide. In most low- and middle-income countries, data on neonatal deaths come primarily from household surveys. We conducted a validation study of survey data on neonatal mortality in Guinea-Bissau (West Africa). We used records from an urban health and demographic surveillance system (HDSS) that monitors child survival prospectively as our reference data set. We selected a stratified sample of 599 women aged 15-49 among residents of the HDSS and collected the birth histories of 422 participants. We cross-tabulated survey and HDSS data. We used a mathematical model to investigate biases in survey estimates of neonatal mortality. Reporting errors in survey data might lead to estimates of the neonatal mortality rate that are too high, which may limit our ability to track progress toward global health objectives.

Involvement of serum amyloid A1 in the rupture of fetal membranes through induction of collagen I degradation.

The de novo synthesis of serum amyloid A1 (SAA1) is augmented in human fetal membranes at parturition. However, its role in parturition remains largely unknown. Here, we investigated whether SAA1 was involved in the rupture of fetal membranes, a crucial event in parturition accompanied with extensive degradation of collagens. Results showed that SAA1 decreased both intracellular and extracellular COL1A1 and COL1A2 abundance, the two subunits of collagen I, without affecting their mRNA levels in human amnion fibroblasts. These reductions were completely blocked only with inhibition of both matrix metalloproteases (MMPs) and autophagy. Consistently, SAA1 increased MMP-2/9 abundance and the markers for autophagic activation including autophagy related (ATG) 7 (ATG7) and the microtubule-associated protein light chain 3 ß (LC3B) II/I ratio with the formation of LC3 punctas and autophagic vacuoles in the fibroblasts. Moreover, the autophagic degradation of COL1A1/COL1A2 and activation of MMP-2/9 by SAA1 were blocked by inhibitors for the toll-like receptors 2/4 (TLR2/4) or NF-κB. Finally, reciprocal corresponding changes of SAA1 and collagen I were observed in the amnion following spontaneous rupture of membranes (ROM) at parturition. Conclusively, SAA1 may participate in membrane rupture at parturition by degradating collagen I via both autophagic and MMP pathways. These effects of SAA1 appear to be mediated by the TLR2/4 receptors and the NF-κB pathway.

Method of damage location determination based on a neural network using a single fiber Bragg grating sensor.

In this paper, a structural damage identification algorithm based on a single fiber Bragg grating (FBG) sensor is proposed. The signal detected by the FBG can be analyzed by the wavelet packet decomposition and back propagation neural network to obtain the damage location information. A high-speed FBG demodulation system based on a tunable Fabry-Perot filter and unbalanced Mach-Zehnder (M-Z) interferometer is designed to respond to a signal with a frequency range from 0 to 4 kHz, which will increase the sensing accuracy. This algorithm is verified by the aluminum plate model, which can simulate the generation of damage in reality. The experimental results show that a single FBG sensor is enough to realize accurate damage location identification according to this algorithm, and identification accuracy can reach 90.0%.