Single hormone or synthetic agonist induces Gs/Gi coupling selectivity of EP receptors via distinct binding modes and propagating paths.

To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) different cellular effectors couple to the same hormone-receptor pair [R.P. Xiao, Sci STKE 2001, re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka, Nature 402, 181-184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz, Nature 390, 88-91 (1997)]. Not only these questions lie in the heart of hormone actions and receptor signaling but also dissecting mechanisms underlying these questions could offer therapeutic routes for refractory diseases, such as kidney injury (KI) or X-linked nephrogenic diabetes insipidus (NDI). Here, we identified that Gs-biased signaling, but not Gi activation downstream of EP4, showed beneficial effects for both KI and NDI treatments. Notably, by solving Cryo-electron microscope (cryo-EM) structures of EP3-Gi, EP4-Gs, and EP4-Gi in complex with endogenous prostaglandin E2 (PGE2)or two synthetic agonists and comparing with PGE2-EP2-Gs structures, we found that unique primary sequences of prostaglandin E2 receptor (EP) receptors and distinct conformational states of the EP4 ligand pocket govern the Gs/Gi transducer coupling selectivity through different structural propagation paths, especially via TM6 and TM7, to generate selective cytoplasmic structural features. In particular, the orientation of the PGE2 ω-chain and two distinct pockets encompassing agonist L902688 of EP4 were differentiated by their Gs/Gi coupling ability. Further, we identified common and distinct features of cytoplasmic side of EP receptors for Gs/Gi coupling and provide a structural basis for selective and biased agonist design of EP4 with therapeutic potential.

SIRT5 exacerbates eosinophilic chronic rhinosinusitis by promoting polarization of M2 macrophage.

BACKGROUND: Previous studies implied that local M2 polarization of macrophage promoted mucosal edema and exacerbated TH2 type inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP). However, the specific pathogenic role of M2 macrophages and the intrinsic regulators in the development of CRS remains elusive. OBJECTIVE: We sought to investigate the regulatory role of SIRT5 in the polarization of M2 macrophages and its potential contribution to the development of CRSwNP. METHODS: Real-time reverse transcription-quantitative PCR and Western blot analyses were performed to examine the expression levels of SIRT5 and markers of M2 macrophages in sinonasal mucosa samples obtained from both CRS and control groups. Wild-type and Sirt5-knockout mice were used to establish a nasal polyp model with TH2 inflammation and to investigate the effects of SIRT5 in macrophage on disease development. Furthermore, in vitro experiments were conducted to elucidate the regulatory role of SIRT5 in polarization of M2 macrophages. RESULTS: Clinical investigations showed that SIRT5 was highly expressed and positively correlated with M2 macrophage markers in eosinophilic polyps. The expression of SIRT5 in M2 macrophages was found to contribute to the development of the disease, which was impaired in Sirt5-deficient mice. Mechanistically, SIRT5 was shown to enhance the alternative polarization of macrophages by promoting glutaminolysis. CONCLUSIONS: SIRT5 plays a crucial role in promoting the development of CRSwNP by supporting alternative polarization of macrophages, thus providing a potential target for CRSwNP interventions.

Ultraconserved elements from transcriptome and genome data provide insight into the phylogenomics of Sternorrhyncha (Insecta: Hemiptera).

Sternorrhyncha, one of the four major suborders of Hemiptera, is a phytophagous taxon inclusive of nearly 18 000 described species. The phylogenetic relationships within the taxon and the earliest-branching lineage of its infraorders remain incompletely understood. This study attempted to illuminate the phylogenetic relationships within Sternorrhyncha through the use of maximum likelihood, Bayesian inference and maximum parsimony analyses, employing ultraconserved element (UCE) data from 39 genomic and 62 transcriptomic datasets and thereby representing most families within the taxon. The probe set Hemiptera 2.7Kv1 was used to recover a total of 2731 UCE loci: from 547 to 1699 (with an average of 1084) across all genomic datasets and from 108 to 849 (with an average of 329) across all transcriptomic datasets. All three types of phylogenetic analyses employed in this study produced robust statistical support for Sternorrhyncha being a monophyletic group. The different methods of phylogenetic analysis produced inconsistent descriptions of topological structure at the infraorder level: while maximum likelihood and Bayesian inference analyses produced strong statistical evidence (100%) indicating the clade Psylloidea + Aleyrodoidea to be a sister of the clade Aphidoidea (Aphidomorpha) + Coccoidea (Coccomorpha), the maximum parsimony analysis failed to recover a similar result. Our results also provide detail on the phylogenetic relationships within each infraorder. This study presents the first use of UCE data to investigate the phylogeny of Sternorrhyncha. It also shows the viability of amalgamating genomic and transcriptomic data in studies of phylogenetic relationships, potentially highlighting a resource-efficient approach for future inquiries into diverse taxa through the integration of varied data sources.

I-III-VI Quantum Dots and Derivatives: Design, Synthesis, and Properties for Light-Emitting Diodes.

Quantum dots (QDs) are important frontier luminescent materials for future technology in flexible ultrahigh-definition display, optical information internet, and bioimaging due to their outstanding luminescence efficiency and high color purity. I-III-VI QDs and derivatives demonstrate characteristics of composition-dependent band gap, full visible light coverage, high efficiency, excellent stability, and nontoxicity, and hence are expected to be ideal candidates for environmentally friendly materials replacing traditional Cd and Pb-based QDs. In particular, their compositional flexibility is highly conducive to precise control energy band structure and microstructure. Furthermore, the quantum dot light-emitting diodes (QLEDs) exhibits superior prospects in monochrome display and white illumination. This review summarizes the recent progress of I-III-VI QDs and their application in LEDs. First, the luminescence mechanism is illustrated based on their electronic-band structural characteristics. Second, focusing on the latest progress of I-III-VI QDs, the preparation mechanism, and the regulation of photophysical properties, the corresponding application progress particularly in light-emitting diodes is summarized as well. Finally, we provide perspectives on the overall current status and challenges propose performance improvement strategies in promoting the evolution of QDs and QLEDs, indicating the future directions in this field.

Body mass index and pressure injuries risk in hospitalized adult patients: A dose-response analysis.

BACKGROUND: The association between underweight and pressure injuries (PIs) has been established in several studies. However, there is a lack of well-designed research investigating the connection between overweight and obesity with these injuries. OBJECTIVE: This meta-analysis aims to investigate the dose-response relationship between body mass index (BMI) and the risk of PIs in adult hospitalized patients. METHODS: PubMed, Web of Science, and MEDLINE Databases were searched from inception to May 2024. Observational articles with at least three BMI categories were included in the study. BMI was defined as underweight, normal weight, overweight, and morbid obesity for the meta-analysis. The non-linear relationship between BMI and the risk of PIs in hospitalized adults was investigated using restricted cubic spline models. Fractional polynomial modeling was used. RESULTS: Eleven articles reporting at least 3 categories of BMI met the inclusion criteria, including 31,389 participants. Compared to patients with normal weight, those with underweight, obesity, and morbid obesity exhibited an increased risk of PIs, with odds ratios of 1.70 (95%CI:1.50-1.91), 1.12 (95%CI:1.02-1.24), 1.70 (95%CI:1.13-2.55), respectively. A J-shaped dose-response model was established for the relationship between PI risk and BMI (Pnon-linearity < 0.001, Plinearity = 0.745). CONCLUSION: The J-shaped dose-response pattern revealed that underweight, obesity and morbid obesity heightened the risk of PIs in hospitalized adults. Lower and higher BMI values may signify an increased risk for PIs, particularly among the elderly with lower BMI, providing valuable guidance for medical staff.

A Bayesian proportional hazards mixture cure model for interval-censored data.

The proportional hazards mixture cure model is a popular analysis method for survival data where a subgroup of patients are cured. When the data are interval-censored, the estimation of this model is challenging due to its complex data structure. In this article, we propose a computationally efficient semiparametric Bayesian approach, facilitated by spline approximation and Poisson data augmentation, for model estimation and inference with interval-censored data and a cure rate. The spline approximation and Poisson data augmentation greatly simplify the MCMC algorithm and enhance the convergence of the MCMC chains. The empirical properties of the proposed method are examined through extensive simulation studies and also compared with the R package "GORCure". The use of the proposed method is illustrated through analyzing a data set from the Aerobics Center Longitudinal Study.

Mutational investigation of 17 causative genes in a cohort of 113 families with nonsyndromic early-onset high myopia in northwestern China.

High myopia (HM) is a leading cause of visual impairment in the world. To expand the genotypic and phenotypic spectra of HM in the Chinese population, we investigated genetic variations in a cohort of 113 families with nonsyndromic early-onset high myopia from northwestern China by whole-exome sequencing, with focus on 17 known genes. Sixteen potentially pathogenic variants predicted to affect protein function in eight of seventeen causative genes for HM in fifteen (13.3%) families were revealed, including seven novel variants, c.767 + 1G > A in ARR3, c.3214C > A/p.H1072N, and c.2195C > T/p.A732V in ZNF644, c.1270G > T/p.V424L in CPSF1, c.1918G > C/p.G640R and c.2786T > G/p.V929G in XYLT1, c.601G > C/p.E201Q in P4HA2; six rare variants, c.799G > A/p.E267K in NDUFAF7, c.1144C > T/p.R382W in TNFRSF21, c.1100C > T/p.P367L in ZNF644, c.3980C > T/p.S1327L in CPSF1, c.145G > A/p.E49K and c.325G > T/p.G109W in SLC39A5; and three known variants, c.2014A > G/p.S672G and c.3261A > C/p.E1087D in ZNF644, c.605C > T/p.P202L in TNFRSF21. Ten of them were co-segregated with HM. The mean (± SD) examination age of these 15 probands was 14.7 (± 11.61) years. The median spherical equivalent was - 9.50 D (IQ - 8.75 ~ - 12.00) for the right eye and - 11.25 D (IQ - 9.25 ~ - 14.13) for the left eye. The median axial length was 26.67 mm (IQ 25.83 ~ 27.13) for the right eye and 26.25 mm (IQ 25.97 ~ 27.32) for the left eye. These newly identified genetic variations not only broaden the genetic and clinical spectra, but also offer convincing evidence that the genes ARR3, NDUFAF7, TNFRSF21, and ZNF644 contribute to hereditable HM. This work improves further understanding of molecular mechanism of HM.

Racial and Ethnic Differences in Timing of Diagnosis and Clinical Services Received in Duchenne Muscular Dystrophy.

INTRODUCTION: Racial/ethnic differences in diagnostic and treatment services have been identified for a range of health conditions and outcomes. The current study aimed to analyze whether there are racial/ethnic differences in the timing of diagnostic testing and treatments for males with Duchenne muscular dystrophy (DMD). METHODS: Diagnostic and clinical data for male individuals with DMD born during 1990-2010 were analyzed from eight sites (Arizona, Colorado, Georgia, Iowa, Piedmont Region of North Carolina, Western New York, South Carolina, and Utah) of the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). Seven milestones related to diagnosis/treatment experiences were selected as outcomes. Times to each milestone were estimated and compared by four racial/ethnic groups using Kaplan-Meier estimation and Cox proportional-hazards models. Times between initial evaluation or diagnostic testing and later milestones were also compared by race/ethnicity. RESULTS: We identified 682 males with definite or probable DMD of whom 61.7% were non-Hispanic white, 20.5% Hispanic, 10.6% other, and 7.2% non-Hispanic black. Seven milestone events were studied (initial evaluation, first neurology/neuromuscular visit, diagnosis, corticosteroid treatment first offered, corticosteroid treatment started, first electrocardiogram or echocardiogram, and first pulmonary function test). The first five milestone events occurred at an older age for non-Hispanic black individuals compared to non-Hispanic white individuals. Time to first offering of corticosteroids and initiation of corticosteroid therapy was later for Hispanic individuals compared to non-Hispanic white individuals. When accounting for timing of initial evaluation/diagnosis, offering of corticosteroids continued to occur later, but first pulmonary testing occurred earlier, among Hispanic individuals compared to non-Hispanic whites. No significant delays remained for non-Hispanic black individuals after accounting for later initial evaluation/diagnosis. CONCLUSION: We described racial/ethnic differences in ages at selected diagnostic and treatment milestones. The most notable differences were significant delays for five of seven milestones in non-Hispanic black individuals, which appeared to be attributable to later initial evaluation/diagnosis. Findings for Hispanic individuals were less consistent. Efforts to address barriers to early evaluation and diagnosis for non-Hispanic black children with DMD may promote more timely initiation of recommended disease monitoring and interventions.

Harnessing technology and gamification to increase adult physical activity: a cluster randomized controlled trial of the Columbia Moves pilot.

BACKGROUND: The use of health technologies and gamification to promote physical activity has increasingly been examined, representing an opportunistic method for harnessing social support inherent within existing social ties. However, these prior studies have yielded mixed findings and lacked long-term follow-up periods. Thus, a pilot cluster randomized controlled trial was conducted to gauge the feasibility and preliminary efficacy of a digital gamification-based physical activity promotion approach among teams of insufficiently active adults with existing social ties. METHODS: Teams (N = 24; 116 total participants) were randomized to either a 12-week intervention (Fitbit, step goals, app, feedback; TECH) or the same program plus gamification (TECH + Gamification). Mixed effects models were used to compare group differences in treatment adherence, and changes in social support, steps, and moderate-to-vigorous physical activity at 12 weeks and 52 weeks from baseline, adjusted for sociodemographic characteristics and team size. RESULTS: TECH had a lower mean number of days of Fitbit self-monitoring versus TECH + Gamification during the intervention (adjusted difference: -.30; 95% CI, -.54 to -.07; P = .01). Post-intervention, TECH had 47% lower odds of self-monitoring 7 days per week versus TECH + Gamification (.53; 95% CI, .31 to .89; P = .02). No differences were observed between TECH + Gamification and TECH in increases in social support (0.04; 95% CI, -.21 to .29; P = .76), ActiGraph-measured daily steps (-425; 95% CI, -1065 to 215; P = .19), or moderate-to-vigorous physical activity minutes (-3.36; 95% CI, -8.62 to 1.91; P = .21) from baseline to 12 weeks or in the regression of these improvements by 1 year (Ps > .05). Although not significant in the adjusted models (Ps > .05), clinically meaningful differences in Fitbit-measured daily steps (TECH, 7041 ± 2520; TECH + Gamification, 7988 ± 2707) and active minutes (TECH, 29.90 ± 29.76; TECH + Gamification, 36.38 ± 29.83) were found during the intervention. CONCLUSIONS: A gamified physical activity intervention targeting teams of adults with existing social ties was feasible and facilitated favorable, clinically meaningful additive physical activity effects while in place but did not drive enhanced, long-term physical activity participation. Future investigations should explore optimal team dynamics and more direct ways of leveraging social support (training teams; gamifying social support). TRIAL REGISTRATION: Clinicaltrials.gov ( NCT03509129 , April 26, 2018).

Machine learning and density functional theory simulation of the electronic structural properties for novel quaternary semiconductors.

In order to accelerate the application of quaternary optoelectronic materials in the field of luminescence, it is crucial to develop new quaternary semiconductor materials with excellent properties. However, faced with vast alternative quaternary semiconductors, traditional trial-and-error methods tend to be laborious and inefficient. Here, we combined machine learning (ML) with density functional theory (DFT) calculation to predict the bandgaps of 2180 quaternary semiconductors, most of which were undeveloped but environmentally friendly. The evaluation coefficient (R2) of the model using a random forest algorithm was up to 0.93 in ML. Four novel quaternary semiconductors with direct bandgaps: Ag2InGaS4, AgZn2InS4, Ag2ZnSnS4, and AgZn2GaS4, were selected from the ML model. Then their electronic structures and optical properties were further verified and studied by DFT calculations, which demonstrated that the four quaternary semiconductors had direct bandgaps, a small effective mass, and a large exciton binding energy and Stokes shift. Our calculation could significantly speed up the discovery of novel optoelectronic semiconductors and has a certain reference value for the study of luminescent materials and devices.

Genetic detection of two novel LRP5 pathogenic variants in patients with familial exudative vitreoretinopathy.

BACKGROUND: Familial exudative vitreoretinopathy (FEVR) is a genetic eye disorder that leads to abnormal development of retinal blood vessels, resulting in vision impairment. This study aims to identify pathogenic variants by targeted exome sequencing in 9 independent pedigrees with FEVR and characterize the novel pathogenic variants by molecular dynamics simulation. METHODS: Clinical data were collected from 9 families with FEVR. The causative genes were screened by targeted next-generation sequencing (TGS) and verified by Sanger sequencing. In silico analyses (SIFT, Polyphen2, Revel, MutationTaster, and GERP + +) were carried out to evaluate the pathogenicity of the variants. Molecular dynamics was simulated to predict protein conformation and flexibility transformation alterations on pathogenesis. Furthermore, molecular docking techniques were employed to explore the interactions and binding properties between LRP5 and DKK1 proteins relevant to the disease. RESULTS: A 44% overall detection rate was achieved with four variants including c.4289delC: p.Pro1431Argfs*8, c.2073G > T: p.Trp691Cys, c.1801G > A: p.Gly601Arg in LRP5 and c.633 T > A: p.Tyr211* in TSPAN12 in 4 unrelated probands. Based on in silico analysis and ACMG standard, two of them, c.4289delC: p.Pro1431Argfs*8 and c.2073G > T: p.Trp691Cys of LRP5 were identified as novel pathogenic variants. Based on computational predictions using molecular dynamics simulations and molecular docking, there are indications that these two variants might lead to alterations in the secondary structure and spatial conformation of the protein, potentially impacting its rigidity and flexibility. Furthermore, these pathogenic variants are speculated to potentially influence hydrogen bonding interactions and could result in an increased binding affinity with the DKK1 protein. CONCLUSIONS: Two novel genetic variants of the LRP5 gene were identified, expanding the range of mutations associated with FEVR. Through molecular dynamics simulations and molecular docking, the potential impact of these variants on protein structure and their interactions with the DKK1 protein has been explored. These findings provide further support for the involvement of these variants in the pathogenesis of the disease.

Structure and Sequence Aligned Code Summarization with Prefix and Suffix Balanced Strategy.

Source code summarization focuses on generating qualified natural language descriptions of a code snippet (e.g., functionality, usage and version). In an actual development environment, descriptions of the code are missing or not consistent with the code due to human factors, which makes it difficult for developers to comprehend and conduct subsequent maintenance. Some existing methods generate summaries from the sequence information of code without considering the structural information. Recently, researchers have adopted the Graph Neural Networks (GNNs) to capture the structural information with modified Abstract Syntax Trees (ASTs) to comprehensively represent a source code, but the alignment method of the two information encoder is hard to decide. In this paper, we propose a source code summarization model named SSCS, a unified transformer-based encoder-decoder architecture, for capturing structural and sequence information. SSCS is designed upon a structure-induced transformer with three main novel improvements. SSCS captures the structural information in a multi-scale aspect with an adapted fusion strategy and adopts a hierarchical encoding strategy to capture the textual information from the perspective of the document. Moreover, SSCS utilizes a bidirectional decoder which generates a summary from opposite direction to balance the generation performance between prefix and suffix. We conduct experiments on two public Java and Python datasets to evaluate our method and the result show that SSCS outperforms the state-of-art code summarization methods.

FBANet: Transfer Learning for Depression Recognition Using a Feature-Enhanced Bi-Level Attention Network.

The House-Tree-Person (HTP) sketch test is a psychological analysis technique designed to assess the mental health status of test subjects. Nowadays, there are mature methods for the recognition of depression using the HTP sketch test. However, existing works primarily rely on manual analysis of drawing features, which has the drawbacks of strong subjectivity and low automation. Only a small number of works automatically recognize depression using machine learning and deep learning methods, but their complex data preprocessing pipelines and multi-stage computational processes indicate a relatively low level of automation. To overcome the above issues, we present a novel deep learning-based one-stage approach for depression recognition in HTP sketches, which has a simple data preprocessing pipeline and calculation process with a high accuracy rate. In terms of data, we use a hand-drawn HTP sketch dataset, which contains drawings of normal people and patients with depression. In the model aspect, we design a novel network called Feature-Enhanced Bi-Level Attention Network (FBANet), which contains feature enhancement and bi-level attention modules. Due to the limited size of the collected data, transfer learning is employed, where the model is pre-trained on a large-scale sketch dataset and fine-tuned on the HTP sketch dataset. On the HTP sketch dataset, utilizing cross-validation, FBANet achieves a maximum accuracy of 99.07% on the validation dataset, with an average accuracy of 97.71%, outperforming traditional classification models and previous works. In summary, the proposed FBANet, after pre-training, demonstrates superior performance on the HTP sketch dataset and is expected to be a method for the auxiliary diagnosis of depression.

Evaluation of effects of continued corticosteroid treatment on cardiac and pulmonary function in non-ambulatory males with Duchenne muscular dystrophy from MD STARnet.

INTRODUCTION/AIMS: Corticosteroids have been shown to improve muscle strength and delay loss of ambulation (LOA) in Duchenne muscular dystrophy (DMD) and are considered standard of care despite significant side-effects. The objective of this study is to evaluate whether corticosteroid treatment after LOA is beneficial for cardiac or pulmonary functions among boys with DMD. METHODS: We used the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) to characterize associations between corticosteroid use and onset of abnormal left ventricular (LV) function or abnormal percent predicted forced vital capacity (ppFVC) among 398 non-ambulatory boys with DMD. Kaplan-Meier curve estimation was used to compare time to onset by corticosteroid use groups; Cox proportional hazards modeling was used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals. RESULTS: We found no differences in time to onset of abnormal LV function by corticosteroid use groups. We observed a longer time from LOA to first abnormal ppFVC in boys that were treated with corticosteroid ≥1 y beyond LOA compared with those with no corticosteroid use or those who stopped corticosteroid use within 1 y of LOA. DISCUSSION: Our findings show no association of corticosteroid use beyond LOA with the onset of abnormal LV function, but a significant association with a delay in onset of abnormal ppFVC. Prospective studies of corticosteroid use in boys with DMD who have lost ambulation may identify benefits and can better elucidate risks, allowing for more effective counseling of patients on continuing treatment after LOA.

LncRNA PVT1 facilitates DLBCL development via miR-34b-5p/Foxp1 pathway.

Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin lymphoma and is a very aggressive malignancy with tumor growing rapidly in organs like lymph nodes. The pathogenesis of DLBCL is not clear and the prognosis of DLBCL requires improvement. Here, we investigated the mechanisms of DLBCL, with the focus on lncRNA PVT1/miR-34b-5p/Foxp1 axis. Human DLBCL tissues from diagnosed DLBCL patients and four human DLBCL cell lines, one normal human B lymphoblastoid cell line were used. qRT-PCR and western blotting were employed to measure expression levels of lncRNA PVT1, Foxp1, miR-34b-5p, ß-catenin, and proliferation-related proteins. MTT assay and colony formation assay were performed to determine cell proliferation. Flow cytometry was used to examine cell apoptosis. ChIP and Dual-luciferase assay were utilized to validate interactions of Foxp1/promoters, PVT1/miR-34b-5p and miR-34b-5p/Foxp1. Mouse tumor xenograft model was used to determine the effect of sh-PVT1 on tumor growth in vivo. In this study, we found PVT1 and Foxp1 were elevated in DLBCL tissues and cells while miR-34b-5p was decreased. Knockdown of PVT1, overexpression of miR-34b-5p, or Foxp1 knockdown repressed DLBCL cell proliferation but enhanced cell apoptosis. PVT1 directly bound miR-34b-5p to disinhibit Foxp1/ß-catenin signaling. Foxp1 regulated CDK4, CyclinD1, and p53 expression via binding with their promoters. Knockdown of Foxp1 partially reversed the effects of miR-34b-5p inhibitor on DLBCL cell proliferation and apoptosis. Inhibition of PVT1 through shRNA suppressed DLBCL tumor growth in vivo. All in all, lncRNA PVT1 promotes DLBCL progression via acting as a miR-34b-5p sponge to disinhibit Foxp1/ß-catenin signaling.

Interfacial electronic properties of metal/CsSnBr3heterojunctions.

All-inorganic lead-free perovskite CsSnBr3, has been proved good stability and optoelectronic properties in theory and experiment. However, the interfacial electronic properties of metal/CsSnBr3are still unclear in electronic devices. Herein, we systematically investigate the interfacial properties of metal electrodes (Al, Ag and Au) and CsSnBr3with different atomic terminals (SnBr2-T and CsBr-T) through the first-principles calculation. SnBr2-T and CsBr-T have various contact types and Schottky barriers due to their different interaction strengths with metals. In particular, the moderate interlayer coupling strength with Al leads to the ultra-low Schottky barrier and tunneling barrier, which makes Al possess the best contact performance among the studied metals. Furthermore, the external electric field can be effective in regulating the Schottky barrier and realizing the Ohmic contact. These findings provide useful guidance for the design of perovskite-based nanoelectronic devices with high performance.

N-n-Butyl haloperidol iodide ameliorates liver fibrosis and hepatic stellate cell activation in mice.

N-n-Butyl haloperidol iodide (F2) is a novel compound that has antiproliferative and antifibrogenic activities. In this study we investigated the therapeutic potential of F2 against liver fibrosis in mice and the underlying mechanisms. Two widely used mouse models of fibrosis was established in mice by injection of either carbon tetrachloride (CCl4) or thioacetamide (TAA). The mice received F2 (0.75, 1.5 or 3 mg·kg-1·d-1, ip) for 4 weeks of fibrosis induction. We showed that F2 administration dose-dependently ameliorated CCl4- or TAA-induced liver fibrosis, evidenced by significant decreases in collagen deposition and c-Jun, TGF-ß receptor II (TGFBR2), α-smooth muscle actin (α-SMA), and collagen I expression in the liver. In transforming growth factor beta 1 (TGF-ß1)-stimulated LX-2 cells (a human hepatic stellate cell line) and primary mouse hepatic stellate cells, treatment with F2 (0.1, 1, 10 µM) concentration-dependently inhibited the expression of α-SMA, and collagen I. In LX-2 cells, F2 inhibited TGF-ß/Smad signaling through reducing the levels of TGFBR2; pretreatment with LY2109761 (TGF-ß signaling inhibitor) or SP600125 (c-Jun signaling inhibitor) markedly inhibited TGF-ß1-induced induction of α-SMA and collagen I. Knockdown of c-Jun decreased TGF-ß signaling genes, including TGFBR2 levels. We revealed that c-Jun was bound to the TGFBR2 promoter, whereas F2 suppressed the binding of c-Jun to the TGFBR2 promoter to restrain TGF-ß signaling and inhibit α-SMA and collagen I upregulation. In conclusion, the therapeutic benefit of F2 against liver fibrosis results from inhibition of c-Jun expression to reduce TGFBR2 and concomitant reduction of the responsiveness of hepatic stellate cells to TGF-ß1. F2 may thus be a potentially new effective pharmacotherapy for human liver fibrosis.

Characterization of fetal exposure to multiple metals among an urban population: A case study of New York City.

INTRODUCTION: Metals and metalloids are ubiquitous and persistent in urban areas and are generally released into the environment as mixtures. OBJECTIVES: The purpose of this study was to establish baseline concentrations of selected elements in meconium samples among a large urban population in the US and understand the spatial variability in concentrations. The association of metal mixtures on birth weight was also assessed. METHODS: This cross-sectional study was conducted across five public hospitals located in New York City, NY (NYC) in four boroughs. We collected meconium sample from 116 infants during the first 24 h after delivery and quantified 11 metals using ICP-MS. Principal component analysis was used to determine metal mixtures and their association with birth weight. Spatial hot spots of each metal were calculated using the Getis-Ord (GI*). RESULTS: Essential elements were detected in all samples with Zn in the greatest abundance (median = 274.5 µg/g) and Mo in the least (median = 0.1845 µg/g). Pb was detected in all but two samples (median = 0.0222 µg/g), while Cd levels were detected in approximately half of the samples (median = 0.0019 µg/g). Co-located hot spots were detected for Cu, Zn, and Fe in southeast Brooklyn; Cd, Cr, and Ni in eastern Queens; and Al and Mo in south Queens. There was a significant inverse relationship between Pb concentrations (beta = -1935.7; p = 0.006) and the mixture of Cr, Cu, Mo, Zn (beta = -157.7; p = 0.045) and birth weight. CONCLUSIONS: Our findings indicate that meconium is an effective biomarker for measuring metal exposures among an urban population. We were able to quantify detectable levels of ten of the eleven metals measured in the study and characterize nutritionally necessary trace elements and metals derived from anthropogenic sources without biologic need in a cohort of NYC newborns. Further research needs to establish the change point from necessary to toxic, for the essential elements.

Impact of adrenocorticotropin hormone administration on the endocrinology, estrus onset, and ovarian function of weaned sows.

Chronic stress affects the reproductive health of mammals; however, the impact of adrenocorticotropin hormone (ACTH) level elevation during chronic stress on the reproduction of weaned sows remains unclear. In this study, nine weaned sows with the same parturition date were randomly divided into control group (n = 4) and ACTH group (n = 5). Each group received intravenous administration of ACTH three times daily for 7 days. Blood samples were collected every 3 h after injection. A radioimmunoassay was used to measure the concentrations of cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone (P4) and estradiol-17ß (E2) in the blood. Estrus was determined according to changes in the vulva and the boar contact test. The mRNA expressions of glucocorticoid receptor, FSH receptor, LH receptor (LHR) in the corpus luteum (CL) were detected by qRT-PCR. The results showed that ACTH administration substantially delayed the initiation of estrus and the pre-ovulatory LH peak. The sows of control group ovulated within 10 days and the ovulation rate was 100%, while it was 60% in the ACTH group. Two sows of ACTH group showed pseudo-estrus. The E2 concentrations significantly decreased in the ACTH group at 36 h, 42 h and 66 h of the experimental period. The P4 concentrations in the ACTH group significantly decreased at 132, 138, and 147 h of the experimental period. ACTH significantly reduced the LHR mRNA expression in CLs. In conclusion, long-term repeated ACTH administration affects the endocrinology, estrus onset, and ovarian function of weaned sows.