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Chlorinated pollutants may follow distinct degradation pathways in anaerobic environments compared to aerobic settings. However, the understanding of the behaviors and fate of dichlorodiphenyltrichloroethanes (DDTs) under anaerobic conditions remains limited. To address this knowledge gap, we conducted a study on flooded soil samples collected from three typical paddy fields in China using an integrated approach of enantiomer-specific analysis and compound-specific stable carbon isotope analysis. It is unexpected that the dichlorodiphenyldichloroethane /dichlorodiphenyldichloroethylene ratios (DDD/DDE=(o,p'-DDD+p,p'-DDD)/(o,p'-DDE+p,p'-DDE)) were below 1 in over 90 % of the samples. This might be attributed to the higher recalcitrance of p,p'-DDE, which concentrations were found to be 36 times higher than p,p'-DDD on average. There were 71.7 % of the samples showing enantiomeric fractions (EFs) of o,p'-DDT below 0.5, indicating a preferential accumulation of the (-)-enantiomer. The δ 13 C values of the anaerobic metabolite o,p'-DDD (-24.76 ± 1.35 ‰ to -34.39 ± 0.20 ‰) all deviated negatively from the initial product, while those of the aerobic metabolite o,p'-DDE (-23.61 ± 0.48 ‰ to -38.95 ± 0.81 ‰) displayed either negative or positive deviations. This demonstrates that o,p'-DDD is the primary metabolite of o,p'-DDT under anaerobic conditions. However, no clear correlations were observed between the δ 13 C and EF of o,p'-DDT. This study underscores the importance of such an integrated methodology in unraveling the fate and behaviors of DDTs in complex environmental systems., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Glaucoma is a progressive neurodegenerative disease characterized by the gradual degeneration of retinal ganglion cells, leading to irreversible blindness worldwide. Therefore, timely and accurate diagnosis of glaucoma is crucial, enabling early intervention and facilitating effective disease management to mitigate further vision deterioration. The advent of optical coherence tomography (OCT) has marked a transformative era in ophthalmology, offering detailed visualization of the macula and optic nerve head (ONH) regions. In recent years, both 2D and 3D convolutional neural network (CNN) algorithms have been applied to OCT image analysis. While 2D CNNs rely on post-prediction aggregation of all B-scans within OCT volumes, 3D CNNs allow for direct glaucoma prediction from the OCT data. However, in the absence of extensively pre-trained 3D models, the comparative efficacy of 2D and 3D-CNN algorithms in detecting glaucoma from volumetric OCT images remains unclear. Therefore, this study explores the efficacy of glaucoma detection through volumetric OCT images using select state-of-the-art (SOTA) 2D-CNN models, 3D adaptations of these 2D-CNN models with specific weight transfer techniques, and a custom 5-layer 3D-CNN-Encoder algorithm. The performance across two distinct datasets is evaluated, each focusing on the macula and the ONH, to provide a comprehensive understanding of the models' capabilities in identifying glaucoma. Our findings demonstrate that the 2D-CNN algorithm consistently provided robust results compared to their 3D counterparts tested in this study for glaucoma detection, achieving AUC values of 0.960 and 0.943 for the macular and ONH OCT test images, respectively. Given the scarcity of pre-trained 3D models trained on extensive datasets, this comparative analysis underscores the overall utility of 2D and 3D-CNN algorithms in advancing glaucoma diagnostic systems in ophthalmology and highlights the potential of 2D algorithms for volumetric OCT image-based glaucoma detection., (© 2024. The Author(s).)

The interaction between influenza A virus (IAV) and host proteins is an important process that greatly influences viral replication and pathogenicity. PB2 protein is a subunit of viral ribonucleoprotein (vRNP) complex playing distinct roles in viral transcription and replication. BAG6 (BCL2-associated athanogene 6) as a multifunctional host protein participates in physiological and pathological processes. Here, we identify BAG6 as a new restriction factor for IAV replication through targeting PB2. For both avian and human influenza viruses, overexpression of BAG6 reduced viral protein expression and virus titers, whereas deletion of BAG6 significantly enhanced virus replication. Moreover, BAG6-knockdown mice developed more severe clinical symptoms and higher viral loads upon IAV infection. Mechanistically, BAG6 restricted IAV transcription and replication by inhibiting the activity of viral RNA-dependent RNA polymerase (RdRp). The co-immunoprecipitation assays showed BAG6 specifically interacted with the N-terminus of PB2 and competed with PB1 for RdRp complex assembly. The ubiquitination assay indicated that BAG6 promoted PB2 ubiquitination at K189 residue and targeted PB2 for K48-linked ubiquitination degradation. The antiviral effect of BAG6 necessitated its N-terminal region containing a ubiquitin-like (UBL) domain (17-92aa) and a PB2-binding domain (124-186aa), which are synergistically responsible for viral polymerase subunit PB2 degradation and perturbing RdRp complex assembly. These findings unravel a novel antiviral mechanism via the interaction of viral PB2 and host protein BAG6 during avian or human influenza virus infection and highlight a potential application of BAG6 for antiviral drug development., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The study investigated the denitrification effect of the iron autotrophic denitrification process for removing nitrite under anaerobic conditions, utilizing sponge iron as the electron donor. When the C/N ratio equaled 1, defined as the ratio of chemical oxygen demand to total nitrogen (TN), and the influent nitrite nitrogen (NO 2 - -N) was at 80 mg/L, the average steady-state TN effluent concentration of this system was 41.94 mg/L during the 79-day experiment. The TN value exhibited a significant decrease compared to both the sponge iron system (68.69 mg/L) and the carbon source system (56.50 mg/L). Sponge iron is beneficial for providing an electron donor and ensuring an anaerobic system, fostering an environment that promotes microorganism growth while effectively inhibiting the conversion of nitrite to nitrate. In addition, carbon sources play a vital role in ensuring microorganism growth and reproduction, thereby aiding in TN removal. The optimal parameters based on the effectiveness of TN removal in the iron autotrophic denitrification system were determined to be s-Fe 0 dosage of 30 g/L and C/N = 1.5. These results suggest that the iron autotrophic denitrification process, driven by sponge iron, can effectively remove nitrite under anaerobic conditions.

Glaucoma is the leading cause of irreversible blindness worldwide. Often asymptomatic for years, this disease can progress significantly before patients become aware of the loss of visual function. Critical examination of the optic nerve through ophthalmoscopy or using fundus images is a crucial component of glaucoma detection before the onset of vision loss. The vertical cup-to-disc ratio (VCDR) is a key structural indicator for glaucoma, as thinning of the superior and inferior neuroretinal rim is a hallmark of the disease. However, manual assessment of fundus images is both time-consuming and subject to variability based on clinician expertise and interpretation. In this study, we develop a robust and accurate automated system employing deep learning (DL) techniques, specifically the YOLOv7 architecture, for the detection of optic disc and optic cup in fundus images and the subsequent calculation of VCDR. We also address the often-overlooked issue of adapting a DL model, initially trained on a specific population (e.g., European), for VCDR estimation in a different population. Our model was initially trained on ten publicly available datasets and subsequently fine-tuned on the REFUGE dataset, which comprises images collected from Chinese patients. The DL-derived VCDR displayed exceptional accuracy, achieving a Pearson correlation coefficient of 0.91 (P = 4.12 × 10 -412 ) and a mean absolute error (MAE) of 0.0347 when compared to assessments by human experts. Our models also surpassed existing approaches on the REFUGE dataset, demonstrating higher Dice similarity coefficients and lower MAEs. Moreover, we developed an optimization approach capable of calibrating DL results for new populations. Our novel approaches for detecting optic discs and optic cups and calculating VCDR, offers clinicians a promising tool that significantly reduces manual workload in image assessment while improving both speed and accuracy. Most importantly, this automated method effectively differentiates between glaucoma and non-glaucoma cases, making it a valuable asset for glaucoma detection., (© 2024. The Author(s).)

Background: The primary health care (PHC) system plays an important role in China's health care system, but there are challenges such as irrational allocation of health resources and inefficient operation, which need to be improved. The purpose of this study was to explore the impact of resource allocation on the efficiency of the PHC system in China., Methods: The data in 31 provinces were collected from the China Statistical Yearbook 2017-2021 and the China Health Statistical Yearbook 2017-2021. The comprehensive health resource density index (CHRDI) was constructed based on the entropy method and the health resource density index (HRDI), which was used to analyze the allocation of primary health resources in each province. The adjusted efficiency of the PHC system in each province was calculated by the bootstrap data envelopment analysis (DEA). Finally, the spatial Dubin model was used to explore the effect of the CHRDI on efficiency., Results: From 2016 to 2020, the allocation of primary health resources in 31 provinces showed an increasing trend, and the average efficiency after correction showed a decreasing state year by year. The spatial direct effect and spatial spillover effect coefficients of CHRDI were 0.820 and 1.471, which positively affect the efficiency. Per capita Gross Domestic Product (GDP), urbanization rate, and the proportion of the elderly were the factors affecting the efficiency of the PHC system., Conclusions: The allocation of primary health resources in all provinces in China has improved each year, but there are still great differences, and efficiency must be further improved. Pay attention to the spatial spillover effect of the level of resource allocation and formulate differentiated measures for different regions. Attention should also be paid to the impact of population aging and economic development on the utilization of primary health resources by increasing health needs and choices., (© 2024. The Author(s).)

Targeted removal of three key refractory toxic organic compounds (TOMs) in 2-butenal manufacturing wastewater (2-BMW) is critical for enhancing pre-treatment by hydrolysis acidification (HA). We investigated the pre-treatment of 2-BMW with HA, coupled with ozonation in this study. Our results indicated that the removal rate of these key TOMs and the detoxification rate reached almost 100% and 46.3%, respectively, by ozonation under only 0.099 mg O 3 /mg chemical oxygen demand (COD). The organic load rate (OLR) reached 10.25 ± 0.43 kg COD/m 3 ·d, and the acidification degree (AD) and detoxification efficiency reached 56.0% and 98.3%, respectively, with enhancements of 35.1% and 55.2%, respectively, compared with HA alone. The removal rate of the three key TOMs was improved by > 75%. The degradation pathways of these key TOMs were ring cleavage and ester formation by ozonation, followed by fermentation and acid production by HA. Ultimately, the synergistic role of ozonation and HA was revealed. The preferential cleavage of these key TOMs by ozonation was achieved because of their high electron cloud density and multiple reaction sites, which generated more fermentation-friendly products. The fermentation and acid production reactions may be directly involved in these products. Functional bacteria and key metabolic pathways were also enhanced by ozonation., Competing Interests: Declaration of Competing Interest This work has not been published before in whole or in part or in any language, and it is not under consideration for publication anywhere else. Its publication has been approved by all co-authors as well as by the corresponding author. And the authors declare that they have no conflict of interest.., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Directional sound radiation focuses sound in a specific direction and reduces sound radiation in other directions. This study uses a flat panel driven by an actuator array to realize two-dimensional directional sound radiation by the acoustic contrast control algorithm. The aliasing effect at higher frequencies is analyzed based on the modal vibration of the panel, and a method for estimating the high frequency limit is proposed. Actuator arrays with different parameters are simulated to verify the efficacy of the proposed method and compare the acoustic contrast response with the conventional loudspeaker arrays., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).)

Background: Stroke during pregnancy is rare, occurring in 30 of 100,000 pregnancies and accounting for 7% of maternal deaths in the United States from 2016 to 2018. Metabolic and bariatric surgery (MBS) has been shown to reduce symptoms of chronic conditions that are risk factors for stroke, including hypertension, hypercholesterolemia, and diabetes in women. However, little is known about the impact of MBS on stroke risk during pregnancy., Objectives: To examine stroke and stroke risk factors including preeclampsia, eclampsia, gestational hypertension, and embolism/thrombosis in women of reproductive age who have had MBS., Setting: We used the National Inpatient Sample, a publicly available data set from the Healthcare Cost and Utilization Project that samples 20% of hospital discharges in the United States., Methods: This cross-sectional study included women between the ages of 20 and 44 years who had a maternal admission code. Weighted logistic regression was conducted to assess the odds of stroke and stroke risk factors in women with a history of MBS compared with other women of reproductive age., Results: Women with a history of MBS have 12% lower adjusted odds of developing preeclampsia/eclampsia and 10% lower adjusted odds of gestational hypertension than women who did not undergo MBS. When stratified by race, the difference was significant in White women (preeclampsia/eclampsia: adjusted odds ratio [aOR] = .89; 95% confidence interval [CI], .81-.98; gestational hypertension: aOR = .91; 95% CI, .83-1.00). Latinas with MBS had significantly lower odds of preeclampsia/eclampsia (aOR = .75; 95% CI, .64-.90)., Conclusions: MBS helps women lose weight and decrease the incidence of some pregnancy-related risk factors for stroke. However, there is a notable racial health disparity., (Copyright © 2023 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Introduction: Although there are several FDA-approved treatments for Alzheimer's disease (AD), only recently have disease-modifying therapies received approval for use in patients. In this narrative review, we examine the history of aquaporin-4 (AQP4) as a therapeutic target for NMOSD (neuromyelitis optica spectrum disorder) and as a potential therapeutic target for AD., Areas Covered: We review the basic science and discovery of AQP4, a transmembrane water-channel essential to regulating water balance in the central nervous system (CNS). We also review the pathogenesis of NMOSD, an autoimmune disease characterized by the destruction of cells that express AQP4. Then, we review how AQP4 is likely involved in the pathogenesis of Alzheimer's disease (AD). Finally, we discuss future challenges with drug design that would modulate AQP4 to potentially slow AD development. The literature search for this article consisted of searching Google Scholar and PubMed for permutations of the keywords 'Alzheimer's disease,' 'aquaporin-4,' 'neuromyelitis optica,' and their abbreviations., Expert Opinion: We place research into AQP4 into context with other recent developments in AD research. A major difficulty with drug development for Alzheimer's is the lack of strategies to cleanly target the early pathogenesis of the disease. Targeting AQP4 may provide such a strategy.

Introduction: Our understanding of the genetic predisposition for age-at-onset (AAO) of Alzheimer's disease (AD) is limited. Here, we sought to identify genes modifying AAO and examined whether any have sex-specific effects., Methods: Genome-wide association analysis were performed on imputed genetic data of 9219 AD cases and 10,345 controls from 20 cohorts of the Alzheimer's Disease Genetics Consortium. AAO was modeled from cases directly and as a survival outcome., Results: We identified 11 genome-wide significant loci (P < 5 × 10 -8 ), including six known AD-risk genes and five novel loci, UMAD1, LUZP2, ARFGEF2, DSCAM, and 4q25, affecting AAO of AD. Additionally, 39 suggestive loci showed strong association. Twelve loci showed sex-specific effects on AAO including CD300LG and MLX/TUBG2 for females and MIR4445 for males., Discussion: Genes that influence AAO of AD are excellent therapeutic targets for delaying onset of AD. Several loci identified include genes with promising functional implications for AD., (© 2023 the Alzheimer's Association.)

Intraocular pressure (IOP) is the only modifiable risk factor for glaucoma, the leading cause of irreversible blindness worldwide. In this review, we summarize the findings of genome-wide association studies (GWASs) of IOP published in the past 10 years and prior to December 2022. Over 190 genetic loci and candidate genes associated with IOP have been uncovered through GWASs, although most of these studies were conducted in subjects of European and Asian ancestries. We also discuss how these common variants have been used to derive polygenic risk scores for predicting IOP and glaucoma, and to infer causal relationship with other traits and conditions through Mendelian randomization. Additionally, we summarize the findings from a recent large-scale exome-wide association study (ExWAS) that identified rare variants associated with IOP in 40 novel genes, six of which are drug targets for clinical treatment or are being evaluated in clinical trials. Finally, we discuss the need for future genetic studies of IOP to include individuals from understudied populations, including Latinos and Africans, in order to fully characterize the genetic architecture of IOP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gao, Chiariglione, Choquet and Arch.)

Electronic sports game (esports) gaming has seen a surge in popularity, especially during the coronavirus disease 2019 (COVID-19) pandemic, with more young people turning to it as an alternative to physical activities. However, the impact of esports gaming on mental health is a matter of concern. Previous studies have produced inconsistent findings on the relationship between gaming hours and mental health, and the moderating factors involved remain unexplored. This study aimed to investigate the moderating effect of participants' subjective attitudes toward esports gaming on the relationship between daily gaming hours and psychological well-being (PWB) among Chinese young adults during the COVID-19 lockdown. A nationwide online survey was conducted on 550 Chinese young adults using the Credamo platform. Ryff's Psychological Well-Being Scales (42-Item version) were used to assess PWB levels. The analysis included 453 participants. Gaming hours were negatively correlated with PWB scores. However, when considering the moderating effect of subjective attitudes, the association between gaming hours and PWB scores was largely positive. Our study suggests that subjective attitudes toward esports gaming outweigh gaming hours in promoting personal psychological well-being. We propose practical recommendations for healthy esports participation patterns that prioritize positive attitudes, especially in similar future scenarios like COVID-19. Our findings may inform future psychological intervention and research in the esports domain., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Shan et al.)

Alzheimer's disease (AD) is the most common late-onset neurodegenerative disorder. Identifying individuals at increased risk of developing AD is important for early intervention. Using data from the Alzheimer Disease Genetics Consortium, we constructed polygenic risk scores (PRSs) for AD and age-at-onset (AAO) of AD for the UK Biobank participants. We then built machine learning (ML) models for predicting development of AD, and explored feature importance among PRSs, conventional risk factors, and ICD-10 codes from electronic health records, a total of > 11,000 features using the UK Biobank dataset. We used eXtreme Gradient Boosting (XGBoost) and SHapley Additive exPlanations (SHAP), which provided superior ML performance as well as aided ML model explanation. For participants age 40 and older, the area under the curve for AD was 0.88. For subjects of age 65 and older (late-onset AD), PRSs were the most important predictors. This is the first observation that PRSs constructed from the AD risk and AAO play more important roles than age in predicting AD. The ML model also identified important predictors from EHR, including urinary tract infection, syncope and collapse, chest pain, disorientation and hypercholesterolemia, for developing AD. Our ML model improved the accuracy of AD risk prediction by efficiently exploring numerous predictors and identified novel feature patterns., (© 2023. The Author(s).)

Background: Gene-based association tests provide a useful alternative and complement to the usual single marker association tests, especially in genome-wide association studies (GWAS). The way of weighting for variants in a gene plays an important role in boosting the power of a gene-based association test. Appropriate weights can boost statistical power, especially when detecting genetic variants with weak effects on a trait. One major limitation of existing gene-based association tests lies in using weights that are predetermined biologically or empirically. This limitation often attenuates the power of a test. On another hand, effect sizes or directions of causal genetic variants in real data are usually unknown, driving a need for a flexible yet robust methodology of gene based association tests. Furthermore, access to individual-level data is often limited, while thousands of GWAS summary data are publicly and freely available., Results: To resolve these limitations, we propose a combination test named as OWC which is based on summary statistics from GWAS data. Several traditional methods including burden test, weighted sum of squared score test [SSU], weighted sum statistic [WSS], SNP-set Kernel Association Test [SKAT], and the score test are special cases of OWC. To evaluate the performance of OWC, we perform extensive simulation studies. Results of simulation studies demonstrate that OWC outperforms several existing popular methods. We further show that OWC outperforms comparison methods in real-world data analyses using schizophrenia GWAS summary data and a fasting glucose GWAS meta-analysis data. The proposed method is implemented in an R package available at https://github.com/Xuexia-Wang/OWC-R-package CONCLUSIONS: We propose a novel gene-based association test that incorporates four different weighting schemes (two constant weights and two weights proportional to normal statistic Z) and includes several popular methods as its special cases. Results of the simulation studies and real data analyses illustrate that the proposed test, OWC, outperforms comparable methods in most scenarios. These results demonstrate that OWC is a useful tool that adapts to the underlying biological model for a disease by weighting appropriately genetic variants and combination of well-known gene-based tests., (© 2022. The Author(s).)

Many people with coronavirus disease 2019 (COVID-19) report varying degrees of memory impairment. Neuroimaging techniques such as MRI and PET have been utilized to shed light on how COVID-19 affects brain function in humans, including memory dysfunction. In this PRISMA-based systematic review, we compared and summarized the current literature looking at the relationship between COVID-19-induced neuropathological changes by neuroimaging scans and memory symptoms experienced by patients who recovered from COVID-19. Overall, this review suggests a correlational trend between structural abnormalities (e.g., cortical atrophy and white matter hyperintensities) or functional abnormalities (e.g., hypometabolism) in a wide range of brain regions (particularly in the frontal, parietal and temporal regions) and memory impairments in COVID-19 survivors, although a causal relationship between them remains elusive in the absence of sufficient caution. Further longitudinal investigations, particularly controlled studies combined with correlational analyses, are needed to provide additional evidence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shan, Li, Xu, Nie, Xie, Han, Gao, Zheng, Xu and Dai.)

Elevated intraocular pressure (IOP) is a major risk factor for glaucoma, the leading cause of irreversible blindness worldwide. IOP is also the only modifiable risk factor for glaucoma. Previous genome-wide association studies have established the contribution of common genetic variants to IOP. The role of rare variants for IOP was unknown. Using whole exome sequencing data from 110,260 participants in the UK Biobank (UKB), we conducted the largest exome-wide association study of IOP to date. In addition to confirming known IOP genes, we identified 40 novel rare-variant genes for IOP, such as BOD1L1, ACAD10 and HLA-B, demonstrating the power of including and aggregating rare variants in gene discovery. About half of these IOP genes are also associated with glaucoma phenotypes in UKB and the FinnGen cohort. Six of these genes, i.e. ADRB1, PTPRB, RPL26, RPL10A, EGLN2, and MTOR, are drug targets that are either established for clinical treatment or in clinical trials. Furthermore, we constructed a rare-variant polygenic risk score and showed its significant association with glaucoma in independent participants (n = 312,825). We demonstrated the value of rare variants to enhance our understanding of the biological mechanisms regulating IOP and uncovered potential therapeutic targets for glaucoma., (© 2022. The Author(s).)

Avian influenza virus (AIV) can evolve multiple strategies to combat host antiviral defenses and establish efficient infectivity in mammals, including humans. H9N2 AIV and its reassortants (such as H5N6 and H7N9 viruses) pose an increasing threat to human health; however, the mechanisms involved in their increased virulence remain poorly understood. We previously reported that the M1 mutation T37A has become predominant among chicken H9N2 isolates in China. Here, we report that, since 2010, this mutation has also been found in the majority of human isolates of H9N2 AIV and its emerging reassortants. The T37A mutation of M1 protein enhances the replication of H9N2 AIVs in mice and in human cells. Interestingly, having A37 instead of T37 increases the M1 protein stability and resistance to proteasomal degradation. Moreover, T37 of the H9N2 M1 protein is phosphorylated by protein kinase G (PKG), and this phosphorylation induces the rapid degradation of M1 and reduces viral replication. Similar effects are also observed in the novel H5N6 virus. Additionally, ubiquitination at K187 contributes to M1-37T degradation and decreased replication of the virus harboring T37 in the M1 protein. The prevailing AIVs thereby evolve a phospho-resistant mutation in the M1 protein to avoid viral protein degradation by host factors, which is advantageous in terms of replication in mammalian hosts., Competing Interests: The authors have declared that no competing interests exist.

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA stage 1 and existing consortia of European and African ancestries. In our HISLA stage 1 + 2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified 3 secondary signals for BMI, 28 for height, and 2 for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification., Competing Interests: S.M.G. and A.M.S. receive funding from Seven Bridges Genomics to develop tools for the NHLBI BioData Catalyst consortium. All others authors declare no competing interests., (© 2022 The Author(s).)

Low-cost, stable, and highly active electrocatalysts for oxygen reduction reaction (ORR), especially for pH-universal ORR, are vital for developing numerous renewable energy devices. Herein, a hierarchical N, S-codoped porous carbon-based catalyst (ZFP-800) coupled with abundant FeS/ZnS heterojunctions was facilely prepared via direct pyrolysis of a Ferrocene-crosslinked pyrrole hydrogel composited with zeolitic imidazolate framework-8 (ZIF-8) templates. Compared with the heterojunction-free catalytic activity, the ZFP-800 catalytic activity was significantly higher in pH-universal ranges. Moreover, the ZFP-800 exhibited competitive ORR performance to commercial Pt/C (20%) in various electrolytes, in terms of onset (E onset ), half-wave potentials (E 1/2 ), limiting current density (J L ), durability, and methanol immunity. For instance, it exhibited super ORR catalytic activity on E onset and E 1/2 , and exceeded that of the benchmark Pt/C in both the alkaline and neutral media. Furthermore, the application of ZFP-800 as a cathode catalyst in a home-made Zn-air battery demonstrated its operation capability in ambient conditions with a competitive performance on the specific energy density (828 mA·h·g Zn -1 ), maximum discharge power density (205.6 mW·cm -2 ), rate performance, and the long-term stability (188 h at 5 mA·cm -2 ). This study can facilitate the development of advanced heterojunction-based materials for renewable energy applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Environmentally friendly lead-free piezoelectric materials have been attracting significant attention in recent years. Na 1/2 Bi 1/2 TiO 3 -based relaxor ferroelectrics have found acceptance for application in promising lead-free transducers in high-power ultrasonic devices. However, their low thermal stability, i.e., their relatively low ferroelectric-relaxor transition temperature ( T F-R ), hinders their practical application. Herein, a thermal-quenching approach is applied on a Na 1/2 Bi 1/2 TiO 3 (NBT)-based single crystal, which yields a large increase in T F-R and dramatic enhancement of its ferroelectric ordering, leading to excellent thermal stability of its dielectric, ferroelectric, and piezoelectric properties. This behavior is mainly attributed to quenching-induced domain evolution as well as its octahedral tilt, which is linked to the increased oxygen vacancies. The substitution of long-range ordered ferroelectric domains for short-range polar nanodomains contributes to its increased coherence length and, consequently, enhancement of T F-R . This work provides an approach to the optimization of the ferroelectric ordering and thermal stability of NBT as well as an in-depth understanding of the quenching effect on the local structure, which could be applied to other relaxor-based ferroelectrics for optimization of their macroscopic properties.

Chitosan is a natural polysaccharide, mainly derived from the shell of marine organisms. At present, chitosan has been widely used in the field of biomedicine due to its special characteristics of low toxicity, biocompatibility, biodegradation and low immunogenicity. Chitosan nanoparticles can be easily prepared. Chitosan nanoparticles with positive charge can enhance the adhesion of antigens in nasal mucosa and promote its absorption, which is expected to be used for intranasal vaccine delivery. In this study, we prepared chitosan nanoparticles by a gelation method, and modified the chitosan nanoparticles with mannose by hybridization. Bovine serum albumin (BSA) was used as the model antigen for development of an intranasal vaccine. The preparation technology of the chitosan nanoparticle-based intranasal vaccine delivery system was optimized by design of experiment (DoE). The DoE results showed that mannose-modified chitosan nanoparticles (Man-BSA-CS-NPs) had high modification tolerance and the mean particle size and the surface charge with optimized Man-BSA-CS-NPs were 156 nm and +33.5 mV. FTIR and DSC results confirmed the presence of Man in Man-BSA-CS-NPs. The BSA released from Man-BSA-CS-NPs had no irreversible aggregation or degradation. In addition, the analysis of fluorescence spectroscopy of BSA confirmed an appropriate binding constant between CS and BSA in this study, which could improve the stability of BSA. The cell study in vitro demonstrated the low toxicity and biocompatibility of Man-BSA-CS-NPs. Confocal results showed that the Man-modified BSA-FITC-CS-NPs promote the endocytosis and internalization of BSA-FITC in DC2.4 cells. In vivo studies of mice, Man-BSA-CS-NPs intranasally immunized showed a significantly improvement of BSA-specific serum IgG response and the highest level of BSA-specific IgA expression in nasal lavage fluid. Overall, our study provides a promising method to modify BSA-loaded CS-NPs with mannose, which is worthy of further study.

H9N2 subtype avian influenza A virus (AIV) is a causative agent that poses serious threats to both the poultry industry and global public health. In this study, we performed active surveillance to identify H9N2 AIVs from poultry (chicken, duck, and goose) and the environment of different regions in China, and we phylogenetically characterized the sequences. AIV subtype-specific reverse transcription polymerase chain reaction (RT-PCR) showed that 5.43% (83/1529) samples were AIV positive, and 87.02% (67/77) of which were H9N2 AIVs. Phylogenetic analysis revealed that all H9N2 field viruses belonged to the Y280-like lineage, exhibiting 93.9-100% and 94.6-100% of homology in the hemagglutinin (HA) gene and 94.4-100% and 96.3-100% in the neuraminidase (NA) gene, at the nucleotide (nt) and amino acid (aa) levels, respectively. All field viruses shared relatively lower identities with vaccine strains, ranging from 89.4% to 97.7%. The aa sequence at the cleavage site (aa 333-340) in HA of all the isolated H9N2 AIVs was PSRSSRG/L, which is a characteristic of low pathogenic avian influenza virus (LPAIV). Notably, all the H9N2 field viruses harbored eight glycosylation sites, whereas a glycosylation site 218 NRT was missing and a new site 313 NCS was inserted. All field viruses had NGLMR as their receptor binding sites (RBS) at aa position 224-229, showing high conservation with many recently-isolated H9N2 strains. All H9N2 field isolates at position 226 had the aa Leucine (L), indicating their ability to bind to sialic acid (SA) α, a 2-6 receptor of mammals that poses the potential risk of transmission to humans. Our results suggest that H9N2 AIVs circulating in poultry populations that have genetic variation and the potential of infecting mammalian species are of great significance when monitoring H9N2 AIVs in China., Competing Interests: The authors declare there are no competing interests., (©2021 Gao et al.)

The mechanisms that underlie the extensive phenotypic diversity in genetic disorders are poorly understood. Here, we develop a large-scale assay to characterize the functional valence (gain or loss-of-function) of missense variants identified in UBE3A, the gene whose loss-of-function causes the neurodevelopmental disorder Angelman syndrome. We identify numerous gain-of-function variants including a hyperactivating Q588E mutation that strikingly increases UBE3A activity above wild-type UBE3A levels. Mice carrying the Q588E mutation exhibit aberrant early-life motor and communication deficits, and individuals possessing hyperactivating UBE3A variants exhibit affected phenotypes that are distinguishable from Angelman syndrome. Additional structure-function analysis reveals that Q588 forms a regulatory site in UBE3A that is conserved among HECT domain ubiquitin ligases and perturbed in various neurodevelopmental disorders. Together, our study indicates that excessive UBE3A activity increases the risk for neurodevelopmental pathology and suggests that functional variant analysis can help delineate mechanistic subtypes in monogenic disorders., (© 2021. The Author(s).)

Exosomes that carry multiple proteins from the originating cells are known as emerging biomarkers for tumor diagnostics. However, it is still technically challenging to accurately evaluate subtle differences of exosomal membrane proteins. Here, we developed a rolling circle amplification (RCA)-assisted flow cytometry approach (FCA) to simultaneously profile surface proteins and quantify exosomes. In this work, specific anti-CD63 antibody-conjugated magnetic beads were first utilized to capture exosomes. Then, the captured exosomes were bound with DNA primers, which comprise exosomal surface protein-specific recognition aptamers. The RCA reaction generates repeat DNA sequences for fluorescent probe hybridization. Finally, a conventional flow cytometer was introduced to phenotype exosomal protein markers. Such a sensitive RCA-assisted FCA displays an excellent detection limit of 1.3 × 10 5 exosome/mL. The variable composition of four protein markers on different cell-derived exosomes was sensitively detected through changing the protein-recognition sequence of the DNA primer, which reveals a heterogeneous pattern. Exosomes from different cell sources could be distinguished by the abundance difference of multiple surface proteins. Furthermore, the developed RCA-assisted FCA enabled quantitative analysis of blood samples from lung cancer patients, indicating its potential for early clinical diagnosis and prognosis of cancer.

Risk genes influence the chance of an individual developing disease over their lifetime, although the age at onset (AAO) genes influence disease timing. These two categories are not disjoint; a gene that influences AAO might also appear to influence the risk. When an allele influences both AAO and risk, a reasonable question is whether we would have more power to detect association using a statistical test based on risk or AAO. To address this question, we compared power analytically for the Cochran-Armitage trend case-control test for risk and a linear regression case-only test for AAO. We also used simulations to compare the power of these tests with a 2-degree of freedom joint test (which combines the risk and AAO statistics) and the Cox proportional hazards survival model testing AAO (with censored data in controls). We found that when there is little heterogeneity, the case-control risk test has more power than the case-only AAO test (with equivalent sample sizes), but when the model is complex (e.g., with heterogeneity or reduced penetrance), the relationship reverses. The joint test generally outperforms the risk or AAO test alone and ultimately is our recommendation as a powerful alternative in many scenarios., (© 2020 Wiley Periodicals LLC.)

(K,Na)NbO 3 based ceramics are considered to be one of the most promising lead-free ferroelectrics replacing Pb(Zr,Ti)O 3 . Despite extensive studies over the last two decades, the mechanism for the enhanced piezoelectricity in multi-elements doped (K,Na)NbO 3 ceramics has not been fully understood. Here, we combine temperature-dependent synchrotron x-ray diffraction and property measurements, atomic-scale scanning transmission electron microscopy, and first-principle and phase-field calculations to establish the dopant-structure-property relationship for multi-elements doped (K,Na)NbO 3 ceramics. Our results indicate that the dopants induced tetragonal phase and the accompanying high-density nanoscale heterostructures with low-angle polar vectors are responsible for the high dielectric and piezoelectric properties. This work explains the mechanism of the high piezoelectricity recently achieved in (K,Na)NbO 3 ceramics and provides guidance for the design of high-performance ferroelectric ceramics, which is expected to benefit numerous functional materials.

As the performance of hairpin DNA (hpDNA)-based biosensors is highly dependent on the yield of stem-loop (hairpin) conformations, we report herein a versatile fluorometric in situ hybridization protocol for examining hpDNA self-assembled monolayers (SAMs) on popularly used biochip substrates. Specifically, the ratio of fluorescence (FL) intensities of hpDNA SAMs (in an array format) before and after hybridization was adopted as the key parameter for performing such a determination. Upon confirming the existence of mixed and tunable DNA conformations in binary deposition solutions and efficient hybridization of the hairpin strands with the target DNA via gel electrophoresis assays, we tested the fluorometric protocol for determining the coverages of hpDNA in hpDNA/ssDNA SAMs prepared on gold; its accuracy was validated by Exonuclease I (Exo I)-assisted electrochemical quantitation. To further confirm its versatility, this FL protocol was adopted for quantifying hairpin conformations formed on glass and polycarbonate (PC) substrates. The molar ratios of surface-tethered hairpin conformations on the three different substrates were all found to be proportional to but less than those in the binary deposition solutions, and were dependent on the substrate morphology. The findings reported herein are beneficial for the construction of highly efficient DNA hairpin-based sensing surfaces, which essentially facilitates the creation of hpDNA-based biosensors with optimal detection performance.

In terms of how the signal varies in response to increased concentration of an analyte, sensors can be classified as either "signal-on" or "signal-off" format. While both types hold potentials to be sensitive, selective, and reusable, in many situations "signal-on" sensors are preferred for their low background signal and better selectivity. In this study, with the detection of lysozyme using its DNA aptamer as a trial system, for the first time we demonstrated that such an aptamer-based electrochemical biosensor can be converted from intrinsically "signal-off" to "signal-on" with the aid of a DNA exonuclease. The fact that the stepwise cleavage of antilysozyme aptamer catalyzed by Exonuclease I (Exo I) is entirely inhibited upon binding lysozyme leads to the selective removal of unbound DNA probes (thiolate anti-lysozyme DNA aptamer strands immobilized on gold electrode) upon the introduction of Exo I to the sensor. With the aid of electrostatically bound redox cations ([Ru(NH 3 ) 6 ] 3+ ), we were able to quantitate the number of aptamer strands that are bound with lysozymes via conventional cyclic voltammetry (CV) measurements. We demonstrated that Exo I-assisted signal-on conversion protocol not only improves the sensing performance (10 times better limit of detection) but also promises a versatile strategy for DNA-based biosensor design, i.e., it can be readily adapted to other aptamer-protein binding systems (thrombin, as another example).

High-performance piezoelectric materials are pivotal to many electromechanical applications including piezoelectric actuators, sensors, and transducers. However, the general approach to achieve high piezoelectric properties by establishing morphotropic phase boundary (MPB) has limitation due to the weak anisotropy of the Gibbs free energy profile at the MPB region. Here, aliovalent Sm 3+ -doped 0.4Pb(Mg 1/3 Nb 2/3 )O 3 -(0.6- x )PbZrO 3 - x PbTiO 3 piezoelectric ceramics were fabricated by a solid-state method, where the optimized piezoelectric coefficient d 33 = 910 pC/N, dielectric constant ε r = 4090, and Curie temperature T C = 184 °C were obtained at x = 0.352, being attributed to the synergistic contributions from the MPB and enhanced local structural heterogeneity. Rayleigh analysis was adopted to study the intrinsic and extrinsic contributions in Sm-doped PMN-PZ-PT ceramics, where the extrinsic contribution was found to be on the order of 25-67% at 4 kV/cm. Of particular significance is that a large signal d 33 * = 820 pm/V (at 20 kV/cm) with a minimal strain variation of 5% was achieved for a composition of x = 0.372 over the temperature range of 20-160 °C, being superior to those previously reported piezoelectric ceramic materials. This work offers a good paradigm to simultaneously achieve high piezoelectric properties with good temperature stability in ferroelectric ceramics, which have great potential for piezoelectric application at elevated temperatures.

Graphene oxide (GO)-based aptasensors are currently one of the most popular sensing platforms for the simple and rapid detection of various targets. Unfortunately, the GO-based aptasensors with long aptamer strands typically show unsatisfactory performance resulting from insignificant structural transformations upon target binding. We report herein the utilization of an aptamer-truncating strategy to combat such a challenge. Taking a pre-selected anti-aflatoxin B1 (AFB1) aptamer (P-AFB1-50) as a trial system, we sequentially remove the extraneous nucleotides within the aptamer by means of circular dichroism (CD) spectroscopy and binding affinity analysis. Particularly, the ratio of the quenching constants between the GO sheets and the truncated aptamers (labelled with fluorophores) in the absence and presence of the target was determined for each of the truncated aptamers to evaluate the optimal sequence. As a result, the truncated aptamer comprising 40 nucleotides was confirmed to show the highest FL output and the best detection limit upon conjugation with GO sheets. More importantly, we demonstrated that this truncating strategy is versatile, i.e., it can be easily extended to other aptamer systems (anti-ochratoxin A (OTA) aptamer, P-OTA-61, as an example) for extraneous nucleotide identification. Impressively, the two optimal truncated aptamers can work together on GO sheets to achieve a simultaneous detection of two different mycotoxins (i.e., AFB1 and OTA) in one single test. Essentially, this research opens a new avenue for the design and testing of aptamer-/GO-based-sensing platforms for rapid, low-cost and multiplex quantification of analytical targets of interest.

Motivation: The risk of many complex diseases is determined by an interplay of genetic and environmental factors. The examination of gene-environment interactions (G×Es) for multiple traits can yield valuable insights about the etiology of the disease and increase power in detecting disease-associated genes. However, the methods for testing G×Es for multiple traits are very limited., Method: We developed novel approaches to test G×Es for multiple traits in sequencing association studies. We first perform a transformation of multiple traits by using either principal component analysis or standardization analysis. Then, we detect the effects of G×Es using novel proposed tests: testing the effect of an optimally weighted combination of G×Es (TOW-GE) and/or variable weight TOW-GE (VW-TOW-GE). Finally, we employ Fisher's combination test to combine the p values., Results: Extensive simulation studies show that the type I error rates of the proposed methods are well controlled. Compared to the interaction sequence kernel association test (ISKAT), TOW-GE is more powerful when there are only rare risk and protective variants; VW-TOW-GE is more powerful when there are both rare and common variants. Both TOW-GE and VW-TOW-GE are robust to directions of effects of causal G×Es. Application to the COPDGene Study demonstrates that our proposed methods are very effective., Conclusions: Our proposed methods are useful tools in the identification of G×Es for multiple traits. The proposed methods can be used not only to identify G×Es for common variants, but also for rare variants. Therefore, they can be employed in identifying G×Es in both genome-wide association studies and next-generation sequencing data analyses., (© 2020 S. Karger AG, Basel.)

This study examined the effect of short-term language-switching training on the cognitive control mechanism in bilingual word production. In two experiments, two groups of relatively proficient but unbalanced Chinese-English bilinguals performed a cued picture-naming task, in which they switched between their two languages. On two consecutive days, the participants took part in four sessions. The same procedure was employed on 2 days in Experiment 1, whereas the cue-language mapping was reversed on Day 2 in Experiment 2. In both experiments, picture naming in the dominant language (L1, Chinese) was slower than that in the weaker second language (L2, English) in all sessions. In addition, the reversed language dominance effect was enhanced with training, suggesting that training proactively increases the amount of inhibition of the dominant L1 at the global level. Furthermore, switching costs in the L1 were reduced with training in Experiment 1, but not in Experiment 2. These results indicate that language-switching training improves the efficiency of reactively exerting inhibitory control over the dominant L1 at the local level. However, when a cue matches with different target languages, the effect of training is absent at the local level. These findings reveal the plasticity and complexity of the cognitive control mechanism as a function of bilingual experience, particularly in language switching.

The complete formation of stem-loop (i.e., hairpin) configuration on chip surface is of particular importance for the application of hairpin DNA (hpDNA) in building biosensors for various analytes with optimized performance. We report herein a convenient electrochemical protocol for evaluating the yield of hairpin DNA conformations upon self-assembly on electrode surface. As of the different hydrolysis capability of Exonuclease I (Exo I) toward single-stranded DNA (ssDNA) and hpDNA, we can selectively remove ssDNA from electrode but retain hpDNA strands; based on the changes in the cyclic voltammetric (CV) responses using [Ru(NH 3 ) 6 ] 3+ as redox indicators, we can then determine the fraction of hairpin configurations in mixed DNA self-assembled monolayers (SAMs). It was discovered that the molar fraction of hairpin configuration formed on the surface is considerably lower than that in the binary deposition solution (containing both ssDNA and hpDNA). The accuracy of the Exo I-assisted electrochemical quantitative protocol has been validated by standard DNA hybridization experiments; the relationship between the overall DNA packing density and the yield of hairpin configurations was also evaluated. More importantly, taking HIV-1 gene detection as a trial system, the hpDNA-based biosensor shows significantly improved detection limit and broadened response range upon the background reduction by Exo I-catalyzed hydrolysis.

Purpose: Genome-wide association studies have identified multiple genetic variants associated with vertical cup-to-disc ratio (VCDR). Genetic risk scores (GRS) examine the aggregate genetic effect of individual variants on a trait by combining these separate genetic variants into a single measure. The purpose of this study was to construct GRS for VCDR and to determine whether the GRS are associated with VCDR and whether the GRS increase the discriminatory ability for primary open-angle glaucoma (POAG) in a Latino population., Design: Population-based genetic association study., Participants: A total of 4018 Latino participants recruited from Los Angeles., Methods: Weighted and unweighted GRS were constructed using 68 previously reported VCDR single nucleotide polymorphisms (SNPs), as well as SNPs from our own genome-wide association data. Linear and logistic regression analyses examined the associations of GRS with VCDR and POAG, respectively. To evaluate the discriminatory ability of the GRS for POAG, we conducted receiver operating characteristic (ROC) analyses., Main Outcome Measures: The relationship between GRS and VCDR in Latinos., Results: The GRS were associated significantly with VCDR (P < 0.0001), after adjusting for age, gender, central corneal thickness, intraocular pressure, and education. The weighted GRS explained an additional 2.74% of the variation in VCDR. Adding the weighted GRS derived from previously reported SNPs resulted in a moderate improvement in the discriminatory ability for POAG during ROC analyses, yielding an area under the ROC curve (AUC) of 0.735 (95% CI, 0.701-0.768). When our own SNPs were used, the AUC increased significantly to 0.809 (95% CI, 0.781-0.837; P < 0.0001). We obtained similar results for the unweighted GRS., Conclusions: To our knowledge, we identified a novel association between GRS and VCDR and its improvement in the discriminatory ability of POAG in a Latino population., (Published by Elsevier Inc.)

Population stratification (PS) is a primary consideration in studies of genetic determinants of human traits. Failure to control for PS may lead to confounding, causing a study to fail for lack of significant results, or resources to be wasted following false-positive signals. Here, historical and current approaches for addressing PS when performing genetic association studies in human populations are reviewed. Methods for detecting the presence of PS, including global and local ancestry methods, are described. Also described are approaches for accounting for PS when calculating association statistics, such that measures of association are not confounded. Many traits are being examined for the first time in minority populations, which may inherently feature PS. © 2017 by John Wiley & Sons, Inc., (Copyright © 2017 John Wiley and Sons, Inc.)

Children with attention-deficit/hyperactivity disorder (ADHD) are reported to have a significantly higher risk of showing reading difficulties or disorders. Here, we aimed to identify the relationship between electroencephalographic (EEG) marker of spatial attention and reading ability in Chinese children with ADHD. First, we demonstrated that rapid automatized naming (RAN) is a strong predictor of reading ability in Chinese-speaking children. Then, EEG data of 9-to 15-year-old children with ADHD (n = 38) and typically developing (TD) controls (n = 36) were collected while the children performed a classical visual search task. Children with ADHD showed slower RAN speed than TD children. For event-related potentials (ERPs), children with ADHD showed a reduced target-evoked N2pc component, which predicted their poorer RAN performance. However, in TD children the early occipital P1 amplitude was negatively correlated with their RAN performance. The correlation between decreased N2pc and poor RAN performance in children with ADHD suggests that their reading problems may in part be due to impaired attentional selection. In contrast, in TD children, development in early visual processing co-occurs with improvements in reading ability.

Viral infection activates a host's cellular phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, which is involved in cell differentiation, growth, survival, and apoptosis. To elucidate molecular mechanisms in the pathogenesis of Newcastle disease virus (NDV), we demonstrated that NDV transiently activates the PI3K/Akt pathway in chicken cells at an early phase of infection. Its activation was observed as early as 15 min post-infection and gradually weakened after 24 h. Incubating cells with a PI3K inhibitor, LY294002 or wortmannin, prior to NDV infection decreased NDV progeny yields and suppressed Akt phosphorylation at early times post-infection. Akt activation is triggered by NDV-GM or NDV-F48E9 and is abolished by methyl β-cyclodextrin and chlorpromazine. Treatment following NDV-La Sota infection had no obvious effect. However, inhibiting PI3K activation promoted apoptotic responses during an early stage of NDV infection. The pan caspase inhibitor ZVAD-FMK mitigated the reduction in Akt phosphorylation by inhibiting PI3K activation, which indicates the signaling pathway promotes cell survival and, in turn, facilitates viral replication. By suppressing premature apoptosis upon NDV infection, the PI3K/Akt pathway enhances the anti-apoptotic response.

Herein, we report a combined electrochemical and ESI-MS study of the enzymatic hydrolysis efficiency of DNA self-assembled monolayers (SAMs) on gold, platform systems for understanding nucleic acid surface chemistry, and for constructing DNA-based biosensors. Our electrochemical approach is based on the comparison of the amounts of surface-tethered DNA nucleotides before and after exonuclease I (Exo I) incubation using electrostatically bound [Ru(NH 3 ) 6 ] 3+ as redox indicators. It is surprising to reveal that the hydrolysis efficiency of ssDNA SAMs does not depend on the packing density and base sequence, and that the cleavage ends with surface-bound shorter strands (9-13 mers). The ex-situ ESI-MS observations confirmed that the hydrolysis products for ssDNA SAMs (from 24 to 56 mers) are dominated with 10-15 mer fragments, in contrast to the complete digestion in solution. Such surface-restrained hydrolysis behavior is due to the steric hindrance of the underneath electrode to the Exo I/DNA binding, which is essential for the occurrence of Exo I-catalyzed processive cleavage. More importantly, we have shown that the hydrolysis efficiency of ssDNA SAMs can be remarkably improved by adopting long alkyl linkers (locating DNA strands further away from the substrates).

Purpose: Vertical cup-disc ratio (VCDR) is used as a clinical assessment measure to identify and monitor glaucomatous damage to the optic nerve. Previous genetic studies conducted in European and Asian populations have identified many loci associated with VCDR. The genetic factors in other ethnic populations, such as Latino, influencing VCDR remain to be determined. Here, we describe the first genome-wide association study (GWAS) on VCDR in Latino individuals., Methods: We conducted this GWAS on VCDR using 4537 Latino individuals who were genotyped by using either the Illumina OmniExpress BeadChip (∼730K markers) or the Illumina Hispanic/SOL BeadChip (∼2.5 million markers). Study subjects were 40 years of age and older. Linear regression, adjusting for age, sex, and principal components of genetic ancestry, was conducted to assess the associations between single nucleotide polymorphisms (SNPs) and VCDR. We imputed SNPs from the 1000 Genomes Project to integrate additional SNPs not directly genotyped., Results: We replicated two previously reported SNPs that reached GWAS significance, rs1900005 and rs7916697, in the ATOH7-PBLD region, as well as identified two suggestive associations in the CDC7-TGFBR3 region on chromosome 1p22.1 and in the ZNF770-DPH6 region on chromosome 15q14. We discovered a novel SNP, rs56238729 (P = 1.22 × 10-13), in the ATOH7-PBLD region that is significantly associated with VCDR in Latino individuals. We replicated eight previously reported regions, including COL8A1, CDKN2B-CDKN2BAS, BMP2, and CHEK2 (P < 2.17 × 10-3)., Conclusions: Our results discovered a novel SNP that is significantly associated with VCDR in Latino individuals and confirmed previously reported loci, providing further insight into the genetic architecture of VCDR.

Elevation of intraocular pressure (IOP) due to therapeutic use of glucocorticoids is called steroid-induced ocular hypertension (SIOH); this can lead to steroid-induced glaucoma (SIG). Glucocorticoids initiate signaling cascades ultimately affecting expression of hundreds of genes; this provides the potential for a highly personalized pharmacological response. Studies attempting to define genetic risk factors were undertaken early in the history of glucocorticoid use, however scientific tools available at that time were limited and progress stalled. In contrast, significant advances were made over the ensuing years in defining disease pathophysiology. As the genomics age emerged, it appeared the time was right to renew investigation into genetics. Pharmacogenomics is an unbiased discovery approach, not requiring an underlying hypothesis, and provides a way to pinpoint clinically significant genes and pathways that could not have been discovered any other way. Results of the first genome-wide association study to identify polymorphisms associated with SIOH, and follow-up on two novel genes linked to the disorder, GPR158 and HCG22, is discussed in the second half of the article. However, knowledge of genetic variants determining response to steroids in the eye also has value in its own right as a predictive and diagnostic tool. This article concludes with a discussion of how the Precision Medicine Initiative ® , announced by U.S. President Obama in his 2015 State of the Union address, is beginning to touch the practice of ophthalmology. It is argued that SIOH/SIG may provide one of the next opportunities for effective application of precision medicine., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The cornea is the outermost layer of the eye and is a vital component of focusing incoming light on the retina. Central corneal thickness (CCT) is now recognized to have a significant role in ocular health and is a risk factor for various ocular diseases, such as keratoconus and primary open angle glaucoma. Most previous genetic studies utilized European and Asian subjects to identify genetic loci associated with CCT. Minority populations, such as Latinos, may aid in identifying additional loci and improve our understanding of the genetic architecture of CCT. In this study, we conducted a genome-wide association study (GWAS) in Latinos, a traditionally understudied population in genetic research, to further identify loci contributing to CCT. Study participants were genotyped using either the Illumina OmniExpress BeadChip (∼730K markers) or the Illumina Hispanic/SOL BeadChip (∼2.5 million markers). All study participants were 40 years of age and older. We assessed the association between individual single nucleotide polymorphisms (SNPs) and CCT using linear regression, adjusting for age, gender and principal components of genetic ancestry. To expand genomic coverage and to interrogate additional SNPs, we imputed SNPs from the 1000 Genomes Project reference panels. We identified a novel SNP, rs10453441 (P = 6.01E-09), in an intron of WNT7B that is associated with CCT. Furthermore, WNT7B is expressed in the human cornea. We also replicated 11 previously reported loci, including IBTK, RXRA-COL5A1, COL5A1, FOXO1, LRRK1 and ZNF469 (P < 1.25E-3). These findings provide further insight into the genetic architecture of CCT and illustrate that the use of minority groups in GWAS will help identify additional loci.

Background: Propofol is a sedative agent that at clinical concentrations acts by allosterically activating or potentiating the γ-aminobutyric acid type A (GABAA) receptor. Mutational, modeling, and photolabeling studies with propofol and its analogues have identified potential interaction sites in the transmembrane domain of the receptor. At the &quot;+&quot; of the β subunit, in the β-α interface, meta-azipropofol labels the M286 residue in the third transmembrane domain. Substitution of this residue with tryptophan results in loss of potentiation by propofol. At the &quot;-&quot; side of the β subunit, in the α-β interface (or β-β interface, in the case of homomeric β receptors), ortho-propofol diazirine labels the H267 residue in the second transmembrane domain. Structural modeling indicates that the β(H267) residue lines a cavity that docks propofol with favorable interaction energy., Method: We used two-electrode voltage clamp to determine the functional effects of mutations to the &quot;+&quot; and &quot;-&quot; sides of the β subunit on activation of the α1β3 GABAA receptor by propofol., Results: We found that while the individual mutations had a small effect, the combination of the M286W mutation with tryptophan mutations of selected residues at the α-β interface leads to strong reduction in gating efficacy for propofol., Conclusion: We conclude that α1β3 GABAA receptors can be activated by propofol interactions with the β-β, α-β, and β-α interfaces, where distinct, non-equivalent regions control channel gating. Any interface can mediate activation, hence substitutions at all interfaces are required for loss of activation by propofol.

Purpose: Intraocular pressure (IOP) is a major risk factor, as well as the only modifiable risk factor, for glaucoma. Racial differences have been observed in IOP measurements with individuals of African descent experiencing the highest IOP when compared with other ethnic groups. The purpose of this study was to examine the relationship between genetic ancestry and IOP in Latinos., Design: Population-based genetic association study., Participants: A total of 3541 participants recruited from the Los Angeles Latino Eye Study., Methods: Study participants were genotyped using the Illumina OmniExpress BeadChip (∼730K markers). We used STRUCTURE to estimate individual genetic ancestry. Simple and multiple linear regression, as well as quantile regression, analyses were performed to investigate the relationship between genetic ancestry and IOP., Main Outcome Measures: The relationship between genetic ancestry and IOP in Latinos., Results: African ancestry was significantly associated with higher IOP in Latinos in our simple linear regression analysis (P = 0.002). After adjusting for age, gender, body mass index, systolic blood pressure, central corneal thickness, and type 2 diabetes, this association remained significant (P = 0.0005). The main association was modified by a significant interaction between African ancestry and hypertension (P = 0.037), with hypertensive individuals experiencing a greater increase in IOP with increasing African ancestry., Conclusions: To our knowledge, we demonstrate for the first time that African ancestry and its interaction with hypertension are associated with higher IOP in Latinos., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To identify single nucleotide polymorphisms (SNPs) in the brain-derived neurotrophic factor (BDNF), vitamin D receptor (VDR), and DNASE1 genes that may be associated with dry eye disease (DED), and determine whether this association varies by the presence of depression., Methods: A case-control study was performed with 64 DED cases and 51 controls. We collected 2 mL of saliva following a routine eye exam. Genotyping was performed using both custom and predesigned TaqMan SNP genotyping assays for 12 hypothesized SNPs. Genotype and allele frequencies of cases and controls were evaluated. Odds ratios were calculated for allele frequencies. Stratified analysis was performed to determine if the association between SNPs and DED varied by depression status., Results: A total of 18% of cases had the minor allele A of Val66Met (rs6265) SNP in the BDNF gene compared with 9% of the controls (P = 0.05). Odds ratio was 2.22. Two SNPs (Fokl-rs2228570 and Apal-rs7975232) in the VDR genes also varied between DED cases and controls. Cases were 1.72 and 1.66 times more likely to have the minor allele A in rs2228570 and rs7975232, respectively, than controls (P = 0.06 for both). While not statistically significant, among patients with depression, DED cases were 3.93 times more likely to have the minor allele A of the Val66Met SNP compared to controls., Conclusions: This pilot study showed that Val66Met in the BDNF gene and two SNPs, Fokl and Apal, in the VDR gene may potentially be associated with DED. Additionally, the association between DED and Val66Met may vary by depression status.

Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong genetic components, although few studies have examined their genetic architecture or influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these quantitative traits influence T2D. We completed a multicohort genome-wide association study to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans. Quantitative traits were measured by the frequently sampled intravenous glucose tolerance test (four cohorts) or euglycemic clamp (three cohorts), and random-effects models were used to test the association between loci and quantitative traits, adjusting for age, sex, and admixture proportions (Discovery). Analysis revealed a significant (P < 5.00 × 10(-8)) association at 11q14.3 (MTNR1B) with acute insulin response. Loci with P < 0.0001 among the quantitative traits were examined for translation to T2D risk in 6,463 T2D case and 9,232 control subjects of Mexican ancestry (Translation). Nonparametric meta-analysis of the Discovery and Translation cohorts identified significant associations at 6p24 (SLC35B3/TFAP2A) with glucose effectiveness/T2D, 11p15 (KCNQ1) with disposition index/T2D, and 6p22 (CDKAL1) and 11q14 (MTNR1B) with acute insulin response/T2D. These results suggest that T2D and insulin secretion and sensitivity have both shared and distinct genetic factors, potentially delineating genomic components of these quantitative traits that drive the risk for T2D., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)