Changing genetic architecture of body mass index from infancy to early adulthood : an individual based pooled analysis of 25 twin cohorts

Publisher Copyright: © 2022, The Author(s).Background: Body mass index (BMI) shows strong continuity over childhood and adolescence and high childhood BMI is the strongest predictor of adult obesity. Genetic factors strongly contribute to this continuity, but it is still poorly known how their contribution changes over childhood and adolescence. Thus, we used the genetic twin design to estimate the genetic correlations of BMI from infancy to adulthood and compared them to the genetic correlations of height. Methods: We pooled individual level data from 25 longitudinal twin cohorts including 38,530 complete twin pairs and having 283,766 longitudinal height and weight measures. The data were analyzed using Cholesky decomposition offering genetic and environmental correlations of BMI and height between all age combinations from 1 to 19 years of age. Results: The genetic correlations of BMI and height were stronger than the trait correlations. For BMI, we found that genetic correlations decreased as the age between the assessments increased, a trend that was especially visible from early to middle childhood. In contrast, for height, the genetic correlations were strong between all ages. Age-to-age correlations between environmental factors shared by co-twins were found for BMI in early childhood but disappeared altogether by middle childhood. For height, shared environmental correlations persisted from infancy to adulthood. Conclusions: Our results suggest that the genes affecting BMI change over childhood and adolescence leading to decreasing age-to-age genetic correlations. This change is especially visible from early to middle childhood indicating that new genetic factors start to affect BMI in middle childhood. Identifying mediating pathways of these genetic factors can open possibilities for interventions, especially for those children with high genetic predisposition to adult obesity.Peer reviewe

Changing genetic architecture of body mass index from infancy to early adulthood: an individual based pooled analysis of 25 twin cohorts

BACKGROUND: Body mass index (BMI) shows strong continuity over childhood and adolescence and high childhood BMI is the strongest predictor of adult obesity. Genetic factors strongly contribute to this continuity, but it is still poorly known how their contribution changes over childhood and adolescence. Thus, we used the genetic twin design to estimate the genetic correlations of BMI from infancy to adulthood and compared them to the genetic correlations of height. METHODS: We pooled individual level data from 25 longitudinal twin cohorts including 38,530 complete twin pairs and having 283,766 longitudinal height and weight measures. The data were analyzed using Cholesky decomposition offering genetic and environmental correlations of BMI and height between all age combinations from 1 to 19 years of age. RESULTS: The genetic correlations of BMI and height were stronger than the trait correlations. For BMI, we found that genetic correlations decreased as the age between the assessments increased, a trend that was especially visible from early to middle childhood. In contrast, for height, the genetic correlations were strong between all ages. Age-to-age correlations between environmental factors shared by co-twins were found for BMI in early childhood but disappeared altogether by middle childhood. For height, shared environmental correlations persisted from infancy to adulthood. CONCLUSIONS: Our results suggest that the genes affecting BMI change over childhood and adolescence leading to decreasing age-to-age genetic correlations. This change is especially visible from early to middle childhood indicating that new genetic factors start to affect BMI in middle childhood. Identifying mediating pathways of these genetic factors can open possibilities for interventions, especially for those children with high genetic predisposition to adult obesity

Refining Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder Genetic Loci by Integrating Summary Data From Genome-wide Association, Gene Expression, and DNA Methylation Studies

Background: Recent genome-wide association studies (GWASs) identified the first genetic loci associated with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). The next step is to use these results to increase our understanding of the biological mechanisms involved. Most of the identified variants likely influence gene regulation. The aim of the current study is to shed light on the mechanisms underlying the genetic signals and prioritize genes by integrating GWAS results with gene expression and DNA methylation (DNAm) levels. Methods: We applied summary-data–based Mendelian randomization to integrate ADHD and ASD GWAS data with fetal brain expression and methylation quantitative trait loci, given the early onset of these disorders. We also analyzed expression and methylation quantitative trait loci datasets of adult brain and blood, as these provide increased statistical power. We subsequently used summary-data–based Mendelian randomization to investigate if the same variant influences both DNAm and gene expression levels. Results: We identified multiple gene expression and DNAm levels in fetal brain at chromosomes 1 and 17 that were associated with ADHD and ASD, respectively, through pleiotropy at shared genetic variants. The analyses in brain and blood showed additional associated gene expression and DNAm levels at the same and additional loci, likely because of increased statistical power. Several of the associated genes have not been identified in ADHD and ASD GWASs before. Conclusions: Our findings identified the genetic variants associated with ADHD and ASD that likely act through gene regulation. This facilitates prioritization of candidate genes for functional follow-up studies

Outcome measures used in pulmonary rehabilitation in patients with acute exacerbation of chronic obstructive pulmonary disease: a systematic review

Conflicting results about the effects of community-based pulmonary rehabilitation in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) exist, possibly because the variety of outcome measures used and the lack of appropriate measurement properties hinder the development of pulmonary rehabilitation guidelines. PURPOSE: The purpose of this study was to identify and review the measurement properties of patient-reported outcome measures (PROMs) and clinical outcome measures of AECOPD that are used in pulmonary rehabilitation and that can be easily applied in a community setting. DATA SOURCES: PubMed, Web of Science, Scopus, and CINAHL were searched up to July 1, 2016. STUDY SELECTION: Phase 1 identified outcome measures used in pulmonary rehabilitation for AECOPD. Phase 2 reviewed the measurement properties of the identified outcome measures. DATA EXTRACTION: One reviewer extracted the data and 2 reviewers independently assessed the methodological quality of the studies and the measurement properties of the outcome measures by using the Consensus-Based Standards for the Selection of Health Status Measurement Instruments (COSMIN) recommendations. DATA SYNTHESIS: Twenty-three PROMs and 18 clinical outcome measures were found. The outcome measures most used were the St George Respiratory Questionnaire (n = 15/37 studies) and the 6-minute walk test (n = 21/37 studies). Thirty-two studies described the measurement properties of 22 PROMs and 7 clinical outcome measures. The methodological quality of the studies was mostly poor, and the measurement properties were mostly indeterminate. The outcome measure exhibiting more robust properties was the COPD Assessment Test. LIMITATIONS: A number of studies were published without the validated search strategy used and were included a posteriori ; the fact that 3 studies presented combined results for patients who were stable and patients with exacerbation, affected the conclusions that can be drawn. CONCLUSIONS: A large variety of outcome measures have been used; however, studies on their measurement properties are needed to enhance the understanding of community pulmonary rehabilitation for AECOPD

Research and Design of a Routing Protocol in Large-Scale Wireless Sensor Networks

无线传感器网络，作为全球未来十大技术之一，集成了传感器技术、嵌入式计算技术、分布式信息处理和自组织网技术，可实时感知、采集、处理、传输网络分布区域内的各种信息数据，在军事国防、生物医疗、环境监测、抢险救灾、防恐反恐、危险区域远程控制等领域具有十分广阔的应用前景。 本文研究分析了无线传感器网络的已有路由协议，并针对大规模的无线传感器网络设计了一种树状路由协议，它根据节点地址信息来形成路由，从而简化了复杂繁冗的路由表查找和维护，节省了不必要的开销，提高了路由效率，实现了快速有效的数据传输。 为支持此路由协议本文提出了一种自适应动态地址分配算——ADAR（AdaptiveDynamicAddre...As one of the ten high technologies in the future, wireless sensor network, which is the integration of micro-sensors, embedded computing, modern network and Ad Hoc technologies, can apperceive, collect, process and transmit various information data within the region. It can be used in military defense, biomedical, environmental monitoring, disaster relief, counter-terrorism, remote control of haz...学位：工学硕士院系专业：信息科学与技术学院通信工程系_通信与信息系统学号：2332007115216

Targeting the tumour vasculature: exploitation of low oxygenation and sensitivity to NOS inhibition by treatment with a hypoxic cytotoxin.

Many cancer research efforts focus on exploiting genetic-level features that may be targeted for therapy. Tissue-level features of the tumour microenvironment also represent useful therapeutic targets. Here we investigate the presence of low oxygen tension and sensitivity to NOS inhibition of tumour vasculature as potential tumour-specific features that may be targeted by hypoxic cytotoxins, a class of therapeutics currently under investigation. We have previously demonstrated that tirapazamine (TPZ) mediates central vascular dysfunction in tumours. TPZ is a hypoxic cytotoxin that is also a competitive inhibitor of NOS. Here we further investigated the vascular-targeting activity of TPZ by combining it with NOS inhibitor L-NNA, or with low oxygen content gas breathing. Tumours were analyzed via multiplex immunohistochemical staining that revealed irreversible loss of perfusion and enhanced tumour cell death when TPZ was combined with either low oxygen or a NOS inhibitor. Tumour growth rate was reduced by TPZ + NOS inhibition, and tumours previously resistant to TPZ-mediated vascular dysfunction were sensitized by low oxygen breathing. Additional mapping analysis suggests that tumours with reduced vascular-associated stroma may have greater sensitivity to these effects. These results indicate that poorly oxygenated tumour vessels, also being abnormally organized and with inadequate smooth muscle, may be successfully targeted for significant anti-cancer effects by inhibition of NOS and hypoxia-activated prodrug toxicity. This strategy illustrates a novel use of hypoxia-activated cytotoxic prodrugs as vascular targeting agents, and also represents a novel mechanism for targeting tumour vessels

Quantified measurements of Vascular Dysfunction in tumours treated with TPZ in reduced Oxygen conditions.

<p>Please see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0076832#pone-0076832-g006" target="_blank">Figure 6</a> for statistical analyses. PF  =  perfused fraction; SD  =  standard deviation; VF  =  viable fraction; VDS  =  vascular dysfunction score; VDS_min  =  (mean control VDS) + (2× SD); 60TPZ  =  tirapazamine at 60 mg/kg.</p

NOS inhibition enhances anti-vascular effects of TPZ in HCT116 xenografts.

<p>HCT116 colorectal xenografts were treated with TPZ at 40/kg or 60 mg/kg alone or in combination with 180 mg/kg NOS inhibitor L-NNA. (A) VDS is reported for individual tumours (bars); horizontal lines represent group means. (B) graph shows staining intensity of pimonidazole as a function of distance from vasculature, showing micro regional differences in hypoxia for control and L-NNA treated tumours, with no significant differences. (C) Tumour growth rate data for control and single or combination treated groups; each point represents mean ± SE. (D) Tumour maps show staining for unperfused vasculature (CD31, red), perfused vasculature (DiOC7 (3)+ve CD31, blue), S-phase cells (BrdUrd, black) and hypoxia (pimonidazole, green). Tumours representative of central vascular dysfunction effects observed within indicated treatment groups are shown for each group; (*p<0.05) (**p<0.01); scale bars 150 µm.</p

Hypoxia enhances anti-vascular effects of TPZ in HCT116 and HT29 xenografts.

<p>HCT116 and HT29 colorectal xenografts were treated with 60/kg TPZ in room air or low oxygen conditions. (A) VDS is reported for individual (i) HCT116 and (ii) HT29 colorectal xenografts (bars) from control and treatment groups in indicated oxygen conditions; horizontal lines represent group means. (B) Staining data shows an increase in hypoxia, via pimonidazole labeling, in low oxygen conditions. (C) Tumour maps of HT29 colorectal xenografts show staining for unperfused vasculature (CD31, red), perfused vasculature (DiOC7 (3) +ve CD31, blue), S-phase cells (BrdUrd, black) and hypoxia (pimonidazole, green). Tumours representative of central vascular dysfunction effects observed within indicated treatment groups are shown for each group; scale bars 150 µm; (*p<0.05) (**p<0.01) (***p<0.001).</p