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Although alcohol dependence (AD) is approximately 50% heritable, little is known about how specific genetic loci affect AD risk. In a genome-wide association study (GWAS), we identified highly significant associations between two population-specific functional variants in the alcohol dehydrogenase 1B gene (ADH1B) and AD in African-Americans (AAs; rs2066702) and European-Americans (EAs; rs1229984). In the current study, we determined which specific diagnostic criteria contributed to the observed associations of ADH1B SNPs with AD. Our analysis included both the DSM-IV and DSM-5 diagnostic systems. We also investigated the relationship of ADH1B variants to the maximum number of drinks consumed in a 24-hour period (MaxDrinks), a presumed intermediate phenotype of AD. We found that, although all criteria made strong individual contributions to the associations, the largest contributions came from those reflecting neuroadaptation: tolerance (rs2066702) and withdrawal (rs1229984). Overall, evidence for association with DSM-5 criteria was slightly stronger than for DSM-IV criteria. For rs2066702, results were similar for DSM-IV and DSM-5 criteria. However, the most significant DSM-5 criterion associated with rs1229984 was alcohol-related social/interpersonal problems. Both ADH1B variants were associated with MaxDrinks, a measure of innate tolerance, and MaxDrinks mediated the associations between ADH1B and alcohol outcomes. We replicated the findings for rs2066702 and tolerance in an independent sample of AAs. Taken together, these results suggest that variation in ADH1B affects the adaptation to heavy drinking, highlighting population-specific differences in genetic risk for AUD. They also suggest that the revisions reflected in DSM-5 AUD may enhance the utility of that diagnosis for gene finding. [ABSTRACT FROM AUTHOR]

Background Alcohol dependence ( AD) is a complex psychiatric disorder and a significant public health problem. Twin and family-based studies have consistently estimated its heritability to be approximately 50%, and many studies have sought to identify specific genetic variants associated with susceptibility to AD. These studies have been primarily linkage or candidate gene based and have been mostly unsuccessful in identifying replicable risk loci. Genome-wide association studies ( GWAS) have improved the detection of specific loci associated with complex traits, including AD. However, findings from GWAS explain only a small proportion of phenotypic variance, and alternative methods have been proposed to investigate the associations that do not meet strict genome-wide significance criteria. Methods This review summarizes all published AD GWAS and post- GWAS analyses that have sought to exploit GWAS data to identify AD-associated loci. Results Findings from AD GWAS have been largely inconsistent, with the exception of variants encoding the alcohol-metabolizing enzymes. Analyses of GWAS data that go beyond standard association testing have demonstrated the polygenic nature of AD and the large contribution of common variants to risk, nominating novel genes and pathways for AD susceptibility. Conclusions Findings from AD GWAS and post- GWAS analyses have greatly increased our understanding of the genetic etiology of AD. However, it is clear that larger samples will be necessary to detect loci in addition to those that encode alcohol-metabolizing enzymes, which may only be possible through consortium-based efforts. Post- GWAS approaches to studying the genetic influences on AD are increasingly common and could greatly increase our knowledge of both the genetic architecture of AD and the specific genes and pathways that influence risk. [ABSTRACT FROM AUTHOR]

Here, we extended our findings from a genome-wide association study of the euphoric response to d-amphetamine in healthy human volunteers by identifying enrichment between SNPs associated with response to d-amphetamine and SNPs associated with psychiatric disorders. We found that SNPs nominally associated (P ⩽ 0.05 and P ⩽ 0.01) with schizophrenia and attention deficit hyperactivity disorder were also nominally associated with d-amphetamine response. Furthermore, we found that the source of this enrichment was an excess of alleles that increased sensitivity to the euphoric effects of d-amphetamine and decreased susceptibility to schizophrenia and attention deficit hyperactivity disorder. In contrast, three negative control phenotypes (height, inflammatory bowel disease, and Parkinson disease) did not show this enrichment. Taken together, our results suggest that alleles identified using an acute challenge with a dopaminergic drug in healthy individuals can be used to identify alleles that confer risk for psychiatric disorders commonly treated with dopaminergic agonists and antagonists. More importantly, our results show the use of the enrichment approach as an alternative to stringent standards for genome-wide significance and suggest a relatively novel approach to the analysis of small cohorts in which intermediate phenotypes have been measured. [ABSTRACT FROM AUTHOR]

Many candidate gene studies use 'intermediate phenotypes' instead of disease diagnoses. It has been proposed that intermediate phenotypes have simpler genetic architectures such that individual alleles account for a larger percentage of trait variance. This implies that smaller samples can be used to identify genetic associations. Pharmacogenomic drug challenge studies may be an especially promising class of intermediate phenotype. We previously conducted a series of 12 candidate gene analyses of acute subjective and physiological responses to amphetamine in 99-162 healthy human volunteers (ADORA2A, SLC6A3, BDNF, SLC6A4, CSNK1E, SLC6A2, DRD2, FAAH, COMT, OPRM1). Here, we report our attempt to replicate these findings in over 200 additional participants ascertained using identical methodology. We were unable to replicate any of our previous findings. These results raise critical issues related to non-replication of candidate gene studies, such as power, sample size, multiple testing within and between studies, publication bias and the expectation that true allelic effect sizes are similar to those reported in genome-wide association studies. Many of these factors may have contributed to our failure to replicate our previous findings. Our results should instill caution in those considering similarly designed studies. [ABSTRACT FROM AUTHOR]

The canonical flow of visual signals proceeds from outer to inner retina (photoreceptors→bipolar cells →ganglion cells). However, melanopsin- expressing ganglion cells are photosensitive and functional sustained light signaling to retinal dopaminergic interneurons persists in the absence of rods and cones. Here we show that the sustained-type light response of retinal dopamine neurons requires melanopsin and that the response is mediated by AMPA- type glutamate receptors, defining a retrograde retinal visual signaling pathway that fully reverses the usual flow of light signals in retinal circuits. [ABSTRACT FROM AUTHOR]

Abstract: The uncatalyzed reaction of diazomethane with chiral benzoylformate esters results in the formation of α-oxiranyl esters without significant facial discrimination in almost every case. [Copyright &y& Elsevier]

To further increase our understanding of responses in potato to abiotic stress and the potato transcriptome in general, we generated 20 756 expressed sequence tags (ESTs) from a cDNA library constructed by pooling mRNA from heat-, cold-, salt-, and drought-stressed potato leaves and roots. These ESTs were clustered and assembled into a collection of 5240 unique sequences with 3344 contigs and 1896 singleton ESTs. Assignment of gene ontology terms (GOSlim/Plant) to the sequences revealed that 8101 assignments could be made with a total of 3863 molecular function assignments. Alignment to a set of 78 825 ESTs from other potato cDNA libraries derived from root, leaf, stolon, tuber, germinating eye, and callus tissues revealed 1476 sequences unique to abiotic stressed potato leaf and root tissue. Sequences present within the 5240 sequence set had similarity to genes known to be involved in abiotic stress responses in other plant species such as transcription factors, stress response genes, and signal transduction processes. In addition, we identified a number of genes unique to the abiotic stress library with unknown function, providing new candidate genes for investigation of abiotic stress responses in potato. [ABSTRACT FROM AUTHOR]

Presents three cases of resuscitative artifact that could be potentially confused with homicidal or accidental injury. Importance of the evaluation and correct identification of resuscitative artifacts for diagnosis and determination of causes of death; Resemblance of resuscitative artifacts with homocidal or accidental injury; Identification of cardiopulmonary resuscitation as a basic life support method intended to maintain perfusion of the internal organs in cases of apparent sudden cardiac arrest until advanced life support can be instituted.

A synthesis of the C(37)–C(54) segment of the antimitotic polyether macrolide halichondrin B is described. β-Ketophosphonate 1, comprising rings L, M, and N of the natural product, contains the C(44) spiroketal, about which local C2 symmetry plays a key strategic role. Based upon recognition of this local C2 symmetry, a Claisen self-condensation of 4 led to the dienone 3b. Asymmetric bis(dihydroxylation) set the C(40), C(41), C(47), and C(48) stereocenters, and the resulting bicyclic spiroketal 8a was oxidized to tetracyclic bis(lactone) 2a. Alcohol 13 was isolated from the mono-functionalization of bis(lactone) 2a via a carbonyl methylenation/hydroboration protocol. Chelation-controlled allylation of the derived aldehyde, followed by diastereoselective iodocarbonate formation and hydrolysis established the C(51)–C(54) sidechain in 17a. Protection of the side-chain hydroxyl groups, and conversion of the remaining lactone to the corresponding β-ketophosphonate provided 1, a suitable coupling subunit (with a total of 10 asymmetric centers) for the total synthesis of halichondrin B. Overall, a 22 step synthetic route from known epoxide 5 produced 1 (4% overall yield), in its natural configuration. [Copyright &y& Elsevier]

This article provides an introduction to the scholarship on religious communal experiments in nineteenth‐century United States for scholars and students of history. The author approaches this scholarship from the perspective of a historian, thus primarily exploring historians' scholarship on these communities. In a similar vein, this article highlights historical communities, as opposed to those utopias that remained exclusively within the literary genre. This article first explains the history of communal studies scholarship and its traditional focus on the "big three" communities: Oneida, the Shakers, and the Church of Jesus Christ of Latter‐Day Saints, previously referred to as the Mormons. The article then explores the evolution of the scholarship since the mid‐twentieth century, including the implementation of new historical methodologies and emphases on race and gender in the study of these communities. Finally, this article looks toward the future of communal studies scholarship, anticipating the next direction this scholarship will take. [ABSTRACT FROM AUTHOR]

Abstract: A synthesis of the bicyclo[3.3.0]octene core of the macrolactam tetramic acid geodin A is described. The key steps are a tandem metathesis and a Wharton rearrangement. [Copyright &y& Elsevier]

The article presents information on the synthesis of cylindramide A, a macrocyclic tetramic acid isolated from the sponge Halichondria cylindrata. The acid is structurally related to a number of other tetramic acid-containing macrolactams. During the synthesis of cylindramide A, two large domains were coupled. These domains are a subunit containing the bicyclo-octene and a 3-hydroxyornithine-derived subunit. The synthesis was completed by Lacey-Dieckmann cyclization to form the tetramic acid.

Aims Although studies have examined the impact of changes made in DSM-5 on the estimated prevalence of substance use disorder (SUD) diagnoses, there is limited evidence concerning the reliability of DSM-5 SUDs. We evaluated the inter-observer reliability of four DSM-5 SUDs in a sample in which we had previously evaluated the reliability of DSM-IV diagnoses, allowing us to compare the two systems. Methods: Two different interviewers each assessed 173 subjects over a 2-week period using the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). Using the percent agreement and kappa ( κ ) coefficient, we examined the reliability of DSM-5 lifetime alcohol, opioid, cocaine, and cannabis use disorders, which we compared to that of SSADDA-derived DSM-IV SUD diagnoses. We also assessed the effect of additional lifetime SUD and lifetime mood or anxiety disorder diagnoses on the reliability of the DSM-5 SUD diagnoses. Results: Reliability was good to excellent for the four disorders, with κ values ranging from 0.65 to 0.94. Agreement was consistently lower for SUDs of mild severity than for moderate or severe disorders. DSM-5 SUD diagnoses showed greater reliability than DSM-IV diagnoses of abuse or dependence or dependence only. Co-occurring SUD and lifetime mood or anxiety disorders exerted a modest effect on the reliability of the DSM-5 SUD diagnoses. Conclusions: For alcohol, opioid, cocaine and cannabis use disorders, DSM-5 criteria and diagnoses are at least as reliable as those of DSM-IV. [ABSTRACT FROM AUTHOR]

Background: Theobromine, a methylxanthine related to caffeine and present in high levels in cocoa, may contribute to the appeal of chocolate. However, current evidence for this is limited. Objectives: We conducted a within-subjects placebo-controlled study of a wide range of oral theobromine doses (250, 500, and 1,000 mg) using an active control dose of caffeine (200 mg) in 80 healthy participants. Results: Caffeine had the expected effects on mood including feelings of alertness and cardiovascular parameters. Theobromine responses differed according to dose; it showed limited subjective effects at 250 mg and negative mood effects at higher doses. It also dose-dependently increased heart rate. In secondary analyses, we also examined individual differences in the drug's effects in relation to genes related to their target receptors, but few associations were detected. Conclusions: This study represents the highest dose of theobromine studied in humans. We conclude that theobromine at normal intake ranges may contribute to the positive effects of chocolate, but at higher intakes, effects become negative. [ABSTRACT FROM AUTHOR]

Purpose: Recent preclinical and clinical studies show that dyes that excite and fluoresce in the near-infrared range may be used for tracking and detecting disease targets in vivo. A method for quantifying free dye molecules in antibody conjugate preparations is required for agent batch release and for translation into the clinic.Procedures: Herein, we developed and validated a SDS-PAGE method to determine the percentage of free IRDye 800 CW in (DTPA)(n)-trastuzumab-(IRDye 800)(m) conjugate sample preparations in which high-performance liquid chromatography (HPLC) assessment of free dye was not possible.Results: The SDS-PAGE assay was accurate and valid for free IRDye 800 CW amounts between 38 and 4 mol% of total dye. Gel sample preparation reagent affected the specificity of the assay, and lower and upper limits of quantitation and detection were determined.Conclusion: This method may be applicable to other near-infrared dye-conjugated antibody-based imaging agents in which HPLC assessment of purity is not feasible. This validated method for quality assurance will facilitate the translation of dual-labeled antibody conjugates for nuclear and optical imaging. [ABSTRACT FROM AUTHOR]

Several different approaches to the A-ring functionalization of an advanced, highly functionalized diosphenol precursor to Taxol are described. The first phase of the undertaking consists of an assessment of those reagents conducive to reaction at the enolic oxygen (silylation, methylation, allylation, and acylation). Transformations involving an alternative attack at the enol carbon center (bromination, selenation) have also been defined. Sodium borohydride reduction operates from the β-face of C-14 as long as the C-1 hydroxyl is not protected so as to offer steric exclusion. Complications associated with various aspects of these methodological undertakings are addressed. The most advanced oxygenation achievements were realized by way of a noteworthy sequence involving epoxidation of the O-methyl ether, methanolysis under mildly acidic conditions, and regioselective oxidation of diol 38 to give 39. [ABSTRACT FROM AUTHOR]

In order to identify genes involved in abiotic stress responses in potato, seedlings were grown under controlled conditions and subjected to cold (4°C), heat (35°C), or salt (100 mM NaCl) stress for up to 27 h. Using an ∼12,000 clone potato cDNA microarray, expression profiles were captured at three time points following initiation of the stress (3, 9, and 27 h) from two different tissues, roots and leaves. A total of 3,314 clones could be identified as significantly up- or down-regulated in response to at least one stress condition. The genes represented by these clones encode transcription factors, signal transduction factors, and heat-shock proteins which have been associated with abiotic stress responses in Arabidopsis and rice, suggesting similar response pathways function in potato. These stress-regulated clones could be separated into either stress-specific or shared-response clones, suggesting the existence of general response pathways as well as more stress-specific pathways. In addition, we identified expression profiles which are indicative for the type of stress applied to the plants. [ABSTRACT FROM AUTHOR]

To further explore genetic links between complex traits, we developed a comprehensive framework to harmonize and integrate extensive genotype and phenotype data from the four well-characterized cohorts with the focus on cardiometabolic diseases deposited to the database of Genotypes and Phenotypes (dbGaP). We generated a series of polygenic risk scores (PRS) to investigate pleiotropic effects of loci that confer genetic risk for 19 common diseases and traits on body height, type 2 diabetes (T2D), and myocardial infarction (MI). In a meta-analysis of 20,021 subjects, we identified shared genetic determinants of Crohn's Disease (CD), a type of inflammatory bowel disease, and body height (p = 5.5 × 10–5). The association of PRS-CD with height was replicated in UK Biobank (p = 1.1 × 10–5) and an independent cohort of 510 CD cases and controls (1.57 cm shorter height per PRS-CD interquartile increase, p = 5.0 × 10−3 and a 28% reduction in CD risk per interquartile increase in PRS-height, p = 1.1 × 10–3, with the effect independent of CD diagnosis). A pathway analysis of the variants overlapping between PRS-height and PRS-CD detected significant enrichment of genes from the inflammatory, immune-mediated and growth factor regulation pathways. This finding supports the clinical observation of growth failure in patients with childhood-onset CD and demonstrates the value of using individual-level data from dbGaP in searching for shared genetic determinants. This information can help provide a refined insight into disease pathogenesis and may have major implications for novel therapies and drug repurposing. [ABSTRACT FROM AUTHOR]

Objective: In systemic sclerosis (SSc), a persistent tissue repair process leads to progressive fibrosis of the skin and internal organs. The role of mesenchymal stem cells (MSCs), which characteristically initiate and regulate tissue repair, has not been fully evaluated. We undertook this study to investigate whether dividing metakaryotic MSCs are present in SSc skin and to examine whether exposure to the disease microenvironment activates MSCs and leads to transdifferentiation. Methods: Skin biopsy material from patients with recent‐onset diffuse SSc was examined by collagenase spread of 1‐mm–thick surface‐parallel sections, in order to identify dividing metakaryotic stem cells in each tissue plane. Adipose‐derived MSCs from healthy controls were treated with dermal blister fluid (BF) from patients with diffuse SSc and profiled by next‐generation sequencing, or they were evaluated for phenotypic changes relevant to SSc. Differential responses of dermal fibroblasts were studied in parallel. Results: MSC‐like cells undergoing active metakaryotic division were identified in SSc sections (but not control sections) most prominently in the deep dermis and adjacent to damaged microvessels, in both clinically involved and uninvolved skin. Furthermore, exposure to SSc BF caused selective MSC activation, inducing a myofibroblast signature, while reducing signatures of vascular repair and adipogenesis and enhancing migration and contractility. Microenvironmental factors implicated in inducing transdifferentiation included the profibrotic transforming growth factor β, the presence of lactate, and mechanosensing, while the microenvironment Th2 cytokine, interleukin‐31, enhanced osteogenic commitment (calcinosis). Conclusion: Dividing MSC‐like cells are present in the SSc disease microenvironment where multiple factors, likely acting in concert, promote transdifferentiation and lead to a complex and resistant disease state. [ABSTRACT FROM AUTHOR]

The South African green building industry is growing towards maturity. Stakeholders need to observe, document, and be informed about trends and development of the industry. This article evaluates whether application trends have emerged of often achieved and seldom achieved Green Star SA credits by all new office buildings that received a Green Star SA rating between 2009 and 2015 in South Africa. Any observed trends are further described by aspects such as the categories of the Green Star SA tool and the Green Star SA rating achieved. The article considers the data of 95 office buildings, made available by the Green Building Council of South Africa (GBCSA). A quantatitive research approach is used to investigate the use frequency of every credit in the Green Star SA tool and to identify trends in credit use. The study finds that 21 of the 67 credits are achieved on average by >80% of the certified projects. Another 14 credits have an average achievement rate of <20%. The nine categories of the Green Star SA tool also varies from average achievements of 84% for Water to only 19% for Innovation. The Green Star SA rating level is also found to be positively correlated to often used credits and negatively correlated to seldom used credits. This article observes industry-wide trends with the potential to negatively affect the ability of green buildings to deliver the required sustainability outcomes expected of them. This finding and the potential outcome thereof need to be monitored and managed by stakeholders such as the GBCSA. [ABSTRACT FROM AUTHOR]