Minocycline attenuates the bilirubin-induced developmental neurotoxicity through the regulation of innate immunity and oxidative stress in zebrafish embryos.

When liver or intestinal function is impaired, bilirubin accumulates in the body and leads to neonatal jaundice. However, the potential negative effects caused by excessive accumulation of bilirubin such as developmental immunotoxicity and neurotoxicity remain unclear. We used a zebrafish model to establish bilirubin-induced jaundice symptoms and evaluated the toxic effects of bilirubin in aquatic organisms. Firstly, our results suggested that bilirubin exposure markedly decreased the survival rate, induced the developmental toxicity and increased the yellow pigment deposited in the zebrafish tail. Meanwhile, the number of macrophages and neutrophils was substantially reduced in a concentration-dependent manner. Besides, the antioxidant enzyme activities were greatly elevated while the inflammatory genes were significantly decreased after bilirubin exposure. Secondly, transcriptome analysis identified 708 genes were differentially expressed after bilirubin exposure, which animal organ morphogenesis, chemical synaptic transmission, and MAPK / mTOR signaling pathways were significantly enriched. Thirdly, bilirubin exposure leads to a significant decrease in the motility of zebrafish, including a dose-dependent decrease in the travelled distance, movement time, and average velocity. Moreover, the innate immune genes and apoptosis-related genes such as TLR4, NF-κB p65, STAT3 and p53 were elevated at a concentration of 10 µg/mL of bilirubin. Finally, our results further revealed that the anti-inflammatory and neuroprotective minocycline could partially rescue the bilirubin-induced neurobehavioral disorders in zebrafish embryos. In conclusion, our study explored the bilirubin-induced immunotoxicity and neurotoxicity in aquatic organisms, which will provide a theoretical basis for the treatment of neonatal jaundice in clinical practice.

Enhanced hepatotoxicity in zebrafish due to co-exposure of microplastics and sulfamethoxazole: Insights into ROS-mediated MAPK signaling pathway regulation.

The combined pollution of microplastics (MPs) and sulfamethoxazole (SMZ) often occurs in aquatic ecosystems, posing a serious threat to animal and human health. However, little is known about the liver damage caused by the single or co-exposure of MPs and SMZ, and its specific mechanisms are still poorly understood. In this study, we investigated the effects of co-exposure to 20 µm or 80 nm MPs and SMZ in both larval and adult zebrafish models. Firstly, we observed a significant decrease in the number of hepatocytes and the liver damage in larval zebrafish worsened following co-exposure to SMZ and MPs. Additionally, the number of macrophages and neutrophils decreased, while the expression of inflammatory cytokines and antioxidant enzyme activities increased after co-exposure in larval zebrafish. Transcriptome analysis revealed significant changes in gene expression in the co-exposed groups, particularly in processes related to oxidation-reduction, inflammatory response, and the MAPK signaling pathway in the liver of adult zebrafish. Co-exposure of SMZ and MPs also promoted hepatocyte apoptosis and inhibited proliferation levels, which was associated with the translocation of Nrf2 from the cytoplasm to the nucleus and an increase in protein levels of Nrf2 and NF-kB p65 in the adult zebrafish. Furthermore, our pharmacological experiments demonstrated that inhibiting ROS and blocking the MAPK signaling pathway partially rescued the liver injury induced by co-exposure both in larval and adult zebrafish. In conclusion, our findings suggest that co-exposure to SMZ and MPs induces hepatic dysfunction through the ROS-mediated MAPK signaling pathway in zebrafish. This information provides novel insights into the potential environmental risk of MPs and hazardous pollutants co-existence in aquatic ecosystems.

Proportional cross-ratio model.

Cross-ratio is an important local measure of the strength of dependence among correlated failure times. If a covariate is available, it may be of scientific interest to understand how the cross-ratio varies with the covariate as well as time components. Motivated by the Tremin study, where the dependence between age at a marker event reflecting early lengthening of menstrual cycles and age at menopause may be affected by age at menarche, we propose a proportional cross-ratio model through a baseline cross-ratio function and a multiplicative covariate effect. Assuming a parametric model for the baseline cross-ratio, we generalize the pseudo-partial likelihood approach of Hu et al. (Biometrika 98:341-354, 2011) to the joint estimation of the baseline cross-ratio and the covariate effect. We show that the proposed parameter estimator is consistent and asymptotically normal. The performance of the proposed technique in finite samples is examined using simulation studies. In addition, the proposed method is applied to the Tremin study for the dependence between age at a marker event and age at menopause adjusting for age at menarche. The method is also applied to the Australian twin data for the estimation of zygosity effect on cross-ratio for age at appendicitis between twin pairs.

Cross-ratio estimation for bivariate failure times with left truncation.

The cross-ratio is an important local measure that characterizes the dependence between bivariate failure times. To estimate the cross-ratio in follow-up studies where delayed entry is present, estimation procedures need to account for left truncation. Ignoring left truncation yields biased estimates of the cross-ratio. We extend the method of Hu et al., Biometrika 98:341-354 (2011) by modifying the risk sets and relevant indicators to handle left-truncated bivariate failure times, which yields the cross-ratio estimate with desirable asymptotic properties that can be shown by the same techniques used in Hu et al., Biometrika 98:341-354 (2011). Numerical studies are conducted.

Subchronic co-exposure of polystyrene nanoplastics and 3-BHA significantly aggravated the reproductive toxicity of ovaries and uterus in female mice.

Both nanoplastics (NPs) and 3-tert-butyl-4-hydroxyanisole (3-BHA) are environmental contaminants that can bio-accumulate through the food chain. However, the combined effects of which on mammalian female reproductive system remain unclear. Here, the female ICR-CD1 mice were used to evaluate the damage effects of ovaries and uterus after NPs and 3-BHA co-treatment for 35 days. Firstly, co-exposure significantly reduced the body weight and organ index of ovaries and uterus in mice. Secondly, combined effects of NPs and 3-BHA exacerbated the histopathological abnormalities to the ovaries and uterus and decreased female sex hormones such as FSH and LH while increased antioxidant activities including CAT and GSH-Px. Moreover, the apoptotic genes, inflammatory cytokines and the key reproductive development genes such as FSTL1 were significantly up-regulated under co-exposure conditions. Thirdly, through transcriptional and bioinformatics analysis, immunofluorescence and western blotting assays, together with molecular docking simulation, we determined that co-exposure up-regulated the FSTL1, TGF-ß and p-Smad1/5/9 but down-regulated the expression of BMP4. Finally, the pharmacological rescue experiments further demonstrated that co-exposure of NPs and 3-BHA mainly exacerbated the female reproductive toxicity through FSTL1-mediated BMP4/TGF-ß/SMAD signaling pathway. Taken together, our studies provided the theoretical basis of new environmental pollutants on the reproductive health in female mammals.

Constructing 3D Skeleton on Commercial Copper Foil via Electrophoretic Deposition of Lithiophilic Building Blocks for Stable Lithium Metal Anodes.

Lithium (Li) metal has been regarded as the "Holy Grail" of Li battery anodes thanks to its high theoretic specific capacity and low reduction potential, but uneven formation of Li dendrites and uncontrollable Li volume changes hinder the practical applications of Li metal anodes. A three-dimensional (3D) current collector is one of the promising strategies to address the above issues if it can be compatible with current industrialized process. Here, Au-decorated carbon nanotubes (Au@CNTs) are electrophoretically deposited on commercial Cu foil as a 3D lithiophilic skeleton to regulate Li deposition. The thickness of the as-prepared 3D skeleton can be accurately controlled by adjusting the deposition time. Benefitting from the reduced localized current density and improved Li affinity, the Au@CNTs-deposited Cu foil (Au@CNTs@Cu foil) achieves uniform Li nucleation and dendrite-free Li deposition. Compared with bare Cu foil and CNTs deposited Cu foil (CNTs@Cu foil), the Au@CNTs@Cu foil exhibits enhanced Coulombic efficiency and better cycling stability. In the full-cell configuration, the Au@CNTs@Cu foil with predeposited Li shows superior stability and rate performance. This work provides a facial strategy to directly construct a 3D skeleton on commercial Cu foils with lithiophilic building blocks for stable and practical Li metal anodes.

The Dependence of Acoustic Emission Performance on the Crystal Structures, Dielectric, Ferroelectric, and Piezoelectric Properties of the P(VDF-TrFE) Sensors.

To clarify the influence of various molar concentrations of vinylidene fluoride (VDF) on the piezoelectric and acoustic emission (AE) reception performances of poly(vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE)] sensors, we systematically investigated the crystal structures and the dielectric and ferroelectric properties of P(VDF-TrFE) films with different compositions of VDF and TrFE monomers and found that low proportion (<30 mol%) TrFE as a wedge inserted into molecular chains of P(VDF-TrFE) will not only improve the fraction of regular ß -phase crystal grains but also decrease the dielectric constant ( εr ) of these copolymers, which favors the piezoelectric voltage coefficient ( g33 ) of this P(VDF-TrFE) film. As such, a considerable remanent electric polarization ( [Formula: see text]/cm2) under 200 MV/m and a large piezoelectric coefficient ( d 33  âˆ¼ -25 pC/N) are obtained in P(VDF-TrFE) 80/20-mol% films. It is worth noting that a sensor made from P(VDF-TrFE) 80/20 mol% shows an attractive AE reception property of approximately 84 dB, a high signal voltage of above 10 mV from time-domain analysis, and a large signal voltage of above 4 mV from frequency-domain analysis, which are close to standard lead zirconate titanate (PZT) sensors. Considering its unique characters of flexibility, no required stretching, easily shaped, having high thermal Faille temperatures ( [Formula: see text]), etc., P(VDF-TrFE) piezoelectric film is considered a promising material for sensors, actuators, and energy transfer units.

A First-in-Human Phase I Study of a Bivalent MET Antibody, Emibetuzumab (LY2875358), as Monotherapy and in Combination with Erlotinib in Advanced Cancer.

Purpose: The MET/HGF pathway regulates cell proliferation and survival and is dysregulated in multiple tumors. Emibetuzumab (LY2875358) is a bivalent antibody that inhibits HGF-dependent and HGF-independent MET signaling. Here, we report dose escalation results from the first-in-human phase I trial of emibetuzumab.Experimental Design: The study comprised a 3+3 dose escalation for emibetuzumab monotherapy (Part A) and in combination with erlotinib (Part A2). Emibetuzumab was administered i.v. every 2 weeks (Q2W) using a flat dosing scheme. The primary objective was to determine a recommended phase II dose (RPTD) range; secondary endpoints included tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.Results: Twenty-three patients with solid tumors received emibetuzumab monotherapy at 20, 70, 210, 700, 1,400, and 2,000 mg and 14 non-small cell lung cancer (NSCLC) patients at 700, 1,400, and 2,000 mg in combination with erlotinib 150 mg daily. No dose-limiting toxicities and related serious or ≥ grade 3 adverse events were observed. The most common emibetuzumab-related adverse events included mild diarrhea, nausea, and vomiting, and mild to moderate fatigue, anorexia, and hypocalcemia in combination with erlotinib. Emibetuzumab showed linear PK at doses >210 mg. Three durable partial responses were observed, one for emibetuzumab (700 mg) and two for emibetuzumab + erlotinib (700 mg and 2,000 mg). Both of the responders to emibetuzumab + erlotinib had progressed to prior erlotinib and were positive for MET protein tumor expression.Conclusions: Based on tolerability, PK/PD analysis, and preliminary clinical activity, the RPTD range for emibetuzumab single agent and in combination with erlotinib is 700 to 2,000 mg i.v. Q2W. Clin Cancer Res; 23(8); 1910-9. ©2016 AACR.

Time-dependent cross ratio estimation for bivariate failure times.

In the analysis of bivariate correlated failure time data, it is important to measure the strength of association among the correlated failure times. One commonly used measure is the cross ratio. Motivated by Cox's partial likelihood idea, we propose a novel parametric cross ratio estimator that is a flexible continuous function of both components of the bivariate survival times. We show that the proposed estimator is consistent and asymptotically normal. Its finite sample performance is examined using simulation studies, and it is applied to the Australian twin data.

Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.

A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.

Identifying the genetic variants that increase the risk of type 2 diabetes (T2D) in humans has been a formidable challenge. Adopting a genome-wide association strategy, we genotyped 1161 Finnish T2D cases and 1174 Finnish normal glucose-tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. We carried out association analysis with these SNPs to identify genetic variants that predispose to T2D, compared our T2D association results with the results of two similar studies, and genotyped 80 SNPs in an additional 1215 Finnish T2D cases and 1258 Finnish NGT controls. We identify T2D-associated variants in an intergenic region of chromosome 11p12, contribute to the identification of T2D-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings the number of T2D loci now confidently identified to at least 10.