The collaborative study on the genetics of alcoholism: Genetics

This review describes the genetic approaches and results from the family-based Collaborative Study on the Genetics of Alcoholism (COGA). COGA was designed during the linkage era to identify genes affecting the risk for alcohol use disorder (AUD) and related problems, and was among the first AUD-focused studies to subsequently adopt a genome-wide association (GWAS) approach. COGA's family-based structure, multimodal assessment with gold-standard clinical and neurophysiological data, and the availability of prospective longitudinal phenotyping continues to provide insights into the etiology of AUD and related disorders. These include investigations of genetic risk and trajectories of substance use and use disorders, phenome-wide association studies of loci of interest, and investigations of pleiotropy, social genomics, genetic nurture, and within-family comparisons. COGA is one of the few AUD genetics projects that includes a substantial number of participants of African ancestry. The sharing of data and biospecimens has been a cornerstone of the COGA project, and COGA is a key contributor to large-scale GWAS consortia. COGA's wealth of publicly available genetic and extensive phenotyping data continues to provide a unique and adaptable resource for our understanding of the genetic etiology of AUD and related traits.     

The collaborative study on the genetics of alcoholism: Sample and clinical data

The collaborative study on the genetics of alcoholism (COGA) is a multi-site, multidisciplinary project with the goal of identifying how genes are involved in alcohol use disorder and related outcomes, and characterizing how genetic risk unfolds across development and in conjunction with the environment and brain function. COGA is a multi-generational family-based study in which probands were recruited through alcohol treatment centers, along with a set of community comparison families. Nearly 18,000 individuals from >2200 families have been assessed over a period of over 30 years with a rich phenotypic battery that includes semi-structured psychiatric interviews and questionnaire measures, along with DNA collection and electrophysiological data on a large subset. Participants range in age from 7 to 97, with many having longitudinal assessments, providing a valuable opportunity to study alcohol use and problems across the lifespan. Here we provide an overview of data collection methods for the COGA sample, and details about sample characteristics and comorbidity. We also review key research findings that have emerged from analyses of the COGA data. COGA data are available broadly to researchers, and we hope this overview will encourage further collaboration and use of these data to advance the field.     

Collaborative study on the genetics of alcoholism: The strength of collaboration,team science,and longitudinal data

This issue contains a series of articles describing the various resources, studies, results, and future directions for the collaborative study on the genetics of alcoholism (COGA). The collaborative and integrative approach initiated by this group ~30 years ago serves as an excellent example of the strength of team science. Individually, various aspects of COGA would be limited in their impact toward improved understanding of alcohol use disorder. Collectively, their wholistic approach which spans deep longitudinal phenotypic assessments in families to include the application of large-scale omics technologies and cell-culture based molecular studies has demonstrated the power of working together.     

磁休克治疗对重度抑郁症患者脑功能网络的影响

目的 磁休克治疗(MST)是一种新兴的神经调节干预技术,在重度抑郁症(MDD)治疗中得到广泛应用,然而其抗抑郁机制尚不清楚。探索MST对不同疗效MDD患者脑功能网络的调控作用,对MST治疗的抗抑郁作用机制研究具有重要意义。方法 本文对18例MDD患者MST作用前后的静息态脑电进行记录,基于皮尔逊相关方法构建脑功能网络;应用复杂网络理论对比分析脑功能网络拓扑结构的改变;根据HDRS-17评分变化率进一步区分治疗有效组和无效组,对网络特征进行二次比较。结果 MST后,MDD患者的脑功能网络平均节点度、平均聚类系数和平均全局效率值均比治疗前显著升高,平均路径长度值显著降低,小世界属性显著增大;相比于治疗无效组,治疗有效组的脑功能网络特征参数变化量更大。结论 MST显著改变了MDD患者脑功能网络拓扑结构,对患者的脑功能网络具有一定的调制作用,这些结果为MST治疗的抗抑郁机制研究提供了实验支持和理论依据。     

The influence of genetics on future crop production strategies: from traits to genes, and genes to traits

This paper discusses how a genetical approach to plant physiology can contribute to research underpinning the production of new crop varieties. It highlights the interactions between genetics and plant breeding and how the current advances in genetics and the new science of genomics can contribute to our understanding of the genetical control of key agronomic traits ‐ the process of ‘translating’ traits to identified and mapped genes. Advances in genomics, such as the sequencing of whole genomes and expressed sequence tags, are producing information on genes and gene structures, but without knowing their function. A great deal more biology will be necessary to translate gene structure to function ‐ the process of translating genes to traits. Combining these ‘forward’ and ‘reverse’ genetic approaches will allow us to get comprehensive knowledge of the biology of agronomic traits at the physiological, biochemical and molecular levels, so that the ‘circuitry’ of our crop plants can be elucidated. This will enable plant breeders to manipulate crop phenotype using marker‐assisted breeding or genetic engineering approaches with a precision not previously possible.     

Uncovering the genetic basis of adaptive change: on the intersection of landscape genomics and theoretical population genetics

A workshop recently held at the École Polytechnique Fédérale de Lausanne (EPFL, Switzerland) was dedicated to understanding the genetic basis of adaptive change, taking stock of the different approaches developed in theoretical population genetics and landscape genomics and bringing together knowledge accumulated in both research fields. Indeed, an important challenge in theoretical population genetics is to incorporate effects of demographic history and population structure. But important design problems (e.g. focus on populations as units, focus on hard selective sweeps, no hypothesis‐based framework in the design of the statistical tests) reduce their capability of detecting adaptive genetic variation. In parallel, landscape genomics offers a solution to several of these problems and provides a number of advantages (e.g. fast computation, landscape heterogeneity integration). But the approach makes several implicit assumptions that should be carefully considered (e.g. selection has had enough time to create a functional relationship between the allele distribution and the environmental variable, or this functional relationship is assumed to be constant). To address the respective strengths and weaknesses mentioned above, the workshop brought together a panel of experts from both disciplines to present their work and discuss the relevance of combining these approaches, possibly resulting in a joint software solution in the future.     

不同来源植物乳杆菌基因组结构和功能差异的比较研究

[目的] 本试验研究不同来源植物乳杆菌（Lactobacillus plantarum）基因特点以及在不同环境下其基因多样性,探究2株L.plantarum A8和P9在肠道生境及植物表面适应性的异同,为优良菌株的开发提供理论基础。[方法] 本研究对从动物肠道和植物表面分离获得的L.plantarum A8和L.plantarum P9的基因组进行分析,利用第二代测序技术（NextGeneration Sequencing,NGS）,基于Illumina NovaSeq测序平台,同时利用第三代单分子测序技术,基于PacBio Sequel测序平台,对L.plantarum A8和L.plantarum P9进行测序。采用Carbohydrate-active enzymes（CAZy）、Koyto encyclopedia of genes and genomes（KEGG）和Clusters of orthologous genes（COG）数据库对基因组进行功能注释;采用CGView软件绘制菌株的基因组环形图谱。应用比较基因组学与已经公开发表的其他L.plantarum基因组进行比较分析。[结果] 由研究可知L.plantarum A8和L.plantarum P9基因组大小存在差异,通过构建系统发育树发现2株菌与其他来源的L.plantarum分在同一分支,并且L.plantarum P9与母乳来源的L.plantarum WLPL04菌株距离最近,而L.plantarum A8与L.paraplantarum DSM10667距离最近。通过基因家族分析可知,2株菌共有基因为2643个,其中包括一些抗应激蛋白如热休克蛋白、冷休克蛋白。L.plantarum A8和P9独特基因分别为321和336个,L.plantarum A8中独特基因主要参与DNA复制、ABC转运系统（ABC transfer system）、PTS系统（phosphotransferase system）、磺酸盐转运系统、氨基酸生物合成等代谢通路;L.plantarum P9的独特基因以参与碳水化合物的运输和代谢基因居多,例如rpiA基因、lacZ基因、FruA基因等。[结论] 通过比较基因组学方法解析L.plantarum的基因组信息,发现动物肠道来源的L.plantarum具有较好的氨基酸转运能力,植物表面附着的L.plantarum菌株具有较好碳水化合物利用能力,从而为益生菌的开发与利用提供理论依据。     

Sweetened ethanol drinking during social isolation: enhanced intake,resistance to genetic heterogeneity and the emergence of a distinctive drinking pattern in adolescent mice

With its ease of availability during adolescence, sweetened ethanol (‘alcopops’) is consumed within many contexts. We asked here whether genetically based differences in social motivation are associated with how the adolescent social environment impacts voluntary ethanol intake. Mice with previously described differences in sociability (BALB/cJ, C57BL/6J, FVB/NJ and MSM/MsJ strains) were weaned into isolation or same‐sex pairs (postnatal day, PD, 21), and then given continuous access to two fluids on PDs 34–45: one containing water and the other containing an ascending series of saccharin‐sweetened ethanol (3–6–10%). Prior to the introduction of ethanol (PDs 30–33), increased water and food intake was detected in some of the isolation‐reared groups, and controls indicated that isolated mice also consumed more ‘saccharin‐only’ solution. Voluntary drinking of ‘ethanol‐only’ was also higher in a subset of the isolated groups on PDs 46–49. However, sweetened ethanol intake was increased in all isolated strain × sex combinations irrespective of genotype. Surprisingly, blood ethanol concentration (BEC) was not different between these isolate and socially housed groups 4 h into the dark phase. Using lickometer‐based measures of intake in FVB mice, we identified that a predominance of increased drinking during isolation transpired outside of the typical circadian consumption peak, occurring ≈8.5 h into the dark phase, with an associated difference in BEC. These findings collectively indicate that isolate housing leads to increased consumption of rewarding substances in adolescent mice independent of their genotype, and that for ethanol this may be because of when individuals drink during the circadian cycle.     

Genomewide screen and identification of gene-gene interactions for asthma-susceptibility loci in three U.S. populations: collaborative study on the genetics of asthma

The genomewide screen to search for asthma-susceptibility loci, in the Collaborative Study on the Genetics of Asthma (CSGA), has been conducted in two stages and includes 266 families (199 nuclear and 67 extended pedigrees) from three U.S. populations: African American, European American, and Hispanic. Evidence for linkage with the asthma phenotype was observed for multiple chromosomal regions, through use of several analytical approaches that facilitated the identification of multiple disease loci. Ethnicity-specific analyses, which allowed for different frequencies of asthma-susceptibility genes in each ethnic population, provided the strongest evidence for linkage at 6p21 in the European American population, at 11q21 in the African American population, and at 1p32 in the Hispanic population. Both the conditional analysis and the affected-sib-pair two-locus analysis provided further evidence for linkage, at 5q31, 8p23, 12q22, and 15q13. Several of these regions have been observed in other genomewide screens and linkage or association studies, for asthma and related phenotypes. These results were used to develop a conceptual model to delineate asthma-susceptibility loci and their genetic interactions, which provides a promising basis for initiation of fine-mapping studies and, ultimately, for gene identification.     

Single Cell Genomics of the Brain: Focus on Neuronal Diversity and Neuropsychiatric Diseases

Single cell genomics has made increasingly significant contributions to our understanding of the role that somatic genome variations play in human neuronal diversity and brain diseases. Studying intercellular genome and epigenome variations has provided new clues to the delineation of molecular mechanisms that regulate development, function and plasticity of the human central nervous system (CNS). It has been shown that changes of genomic content and epigenetic profiling at single cell level are involved in the pathogenesis of neuropsychiatric diseases (schizophrenia, mental retardation (intellectual/leaning disability), autism, Alzheimer’s disease etc.). Additionally, several brain diseases were found to be associated with genome and chromosome instability (copy number variations, aneuploidy) variably affecting cell populations of the human CNS. The present review focuses on the latest advances of single cell genomics, which have led to a better understanding of molecular mechanisms of neuronal diversity and neuropsychiatric diseases, in the light of dynamically developing fields of systems biology and “omics”.     

36 h完全睡眠剥夺对客体工作记忆相关电位的影响

目的:采用事件相关电位(ERP)技术探讨36 h完全睡眠剥夺对客体工作记忆的影响。方法:本研究采用自身前后对照设计,16名睡眠质量良好的健康大学生(平均年龄为23岁,年龄范围21～28岁)分别在清醒状态下及36 h完全睡眠剥夺后接受2-back客体工作记忆任务,同时采集脑电数据。选用重复测量方差分析的方法比较睡眠剥夺前后与客体工作记忆有关的P2、N2、P3成分的波幅和潜伏期的差异。结果:在36 h完全睡眠剥夺后,与客体工作记忆加工相关的N2波的潜伏期显著延长(P<0.05),波幅减少但未见统计学差异(P>0.05); P2波潜伏期显著延长(P<0.05),波幅未见明显变化(P>0.05)。P3波波幅、潜伏期未见统计学差异(P>0.05)。结论:36h的完全睡眠剥夺影响了客体工作记忆相关电位,损害了个体的客体工作记忆加工能力。     

The Hidden Spatial Dimension of Alpha: 10-Hz Perceptual Echoes Propagate as Periodic Traveling Waves in the Human Brain

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Focus: The Aging Brain: The Significance of the Default Mode Network (DMN) in Neurological and Neuropsychiatric Disorders: A Review

The relationship of cortical structure and specific neuronal circuitry to global brain function, particularly its perturbations related to the development and progression of neuropathology, is an area of great interest in neurobehavioral science. Disruption of these neural networks can be associated with a wide range of neurological and neuropsychiatric disorders. Herein we review activity of the Default Mode Network (DMN) in neurological and neuropsychiatric disorders, including Alzheimer’s disease, Parkinson’s disease, Epilepsy (Temporal Lobe Epilepsy - TLE), attention deficit hyperactivity disorder (ADHD), and mood disorders. We discuss the implications of DMN disruptions and their relationship to the neurocognitive model of each disease entity, the utility of DMN assessment in clinical evaluation, and the changes of the DMN following treatment.     

The quest for a message: budding yeast, a model organism to study the control of pre-mRNA splicing

Removal of introns during pre-mRNA splicing is a critical processin gene expression, and understanding its control at both single-geneand genomic levels is one of the great challenges in Biology.Splicing takes place in a dynamic, large ribonucleoprotein complexknown as the spliceosome. Combining Genetics and Biochemistry,Saccharomyces cerevisiae provides insights into its mechanisms,including its regulation by RNA–protein interactions.Recent genome-wide analyses indicate that regulated splicingis broad and biologically relevant even in organisms with arelatively simple intronic structure, such as yeast. Furthermore,the possibility of coordination in splicing regulation at genomiclevel is becoming clear in this model organism. This shouldprovide a valuable system to approach the complex problem ofthe role of regulated splicing in genomic expression.      

Effect of the alcohol consumption on osteocyte cell processes: a molecular imaging study

We have previously shown microarchitectural tissue changes with cellular modifications in osteocytes following high chronic alcohol dose. The aim of this study was to assess the dose effect of alcohol consumption on the cytoskeleton activity, the cellular lipid content and modulation of differentiation and apoptosis in osteocyte. Male Wistar rats were divided into three groups: Control (C), Alcohol 25% v/v (A25) or Alcohol 35% v/v (A35) for 17 weeks. Bone mineral density (BMD) was assessed by DXA, osteocyte empty lacunae, lacunae surface, bone marrow fat with bright field microscopy. Osteocyte lipid content was analysed with transmission electron microscopy (TEM) and epifluorescence microscopy. Osteocyte apoptosis was analysed with immunolabelling and TEM. Osteocyte differentiation and cytoskeleton activity were analysed with immunolabelling and real time quantitative PCR. At the end of the protocol, BMD was lower in A25 and A35 compared with C, while the bone marrow lipid content was increased in these groups. More empty osteocyte lacunae and osteocyte containing lipid droplets in A35 were found compared with C and A25. Cleaved caspase‐3 staining and chromatin condensation were increased in A25 and A35 versus C. Cleaved caspase‐3 was increased in A35 versus A25. CD44 and phosphopaxillin stainings were higher in A35 compared with C and A25. Paxillin mRNA expression was higher in A35 versus A25 and C and sclerostin mRNA expression was higher in A35 versus C. We only observed a dose effect of alcohol consumption on cleaved caspase‐3 osteocyte immunostaining levels and on the number of lipid droplets in the bone marrow.