High-Affinity Inhibitors of Human NAD+-Dependent 15-Hydroxyprostaglandin Dehydrogenase: Mechanisms of Inhibition and Structure-Activity Relationships

BACKGROUND: 15-Hydroxyprostaglandin dehydrogenase (15-PGDH, EC 1.1.1.141) is the key enzyme for the inactivation of prostaglandins, regulating processes such as inflammation or proliferation. The anabolic pathways of prostaglandins, especially with respect to regulation of the cyclooxygenase (COX) enzymes have been studied in detail; however, little is known about downstream events including functional interaction of prostaglandin-processing and -metabolizing enzymes. High-affinity probes for 15-PGDH will, therefore, represent important tools for further studies. PRINCIPAL FINDINGS: To identify novel high-affinity inhibitors of 15-PGDH we performed a quantitative high-throughput screen (qHTS) by testing >160 thousand compounds in a concentration-response format and identified compounds that act as noncompetitive inhibitors as well as a competitive inhibitor, with nanomolar affinity. Both types of inhibitors caused strong thermal stabilization of the enzyme, with cofactor dependencies correlating with their mechanism of action. We solved the structure of human 15-PGDH and explored the binding modes of the inhibitors to the enzyme in silico. We found binding modes that are consistent with the observed mechanisms of action. CONCLUSIONS: Low cross-reactivity in screens of over 320 targets, including three other human dehydrogenases/reductases, suggest selectivity of the present inhibitors for 15-PGDH. The high potencies and different mechanisms of action of these chemotypes make them a useful set of complementary chemical probes for functional studies of prostaglandin-signaling pathways. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S2

The effect of growth on the correlation between the spinal and rib cage deformity: implications on idiopathic scoliosis pathogenesis

<p>Abstract</p> <p>Background</p> <p>Numerous studies have attempted to quantify the correlation between the surface deformity and the Cobb angle without considering growth as an important factor that may influence this correlation. In our series, we noticed that in some younger referred children from the school-screening program there is a discrepancy between the thoracic scoliometer readings and the morphology of their spine. Namely there is a rib hump but no spinal curve and consequently no Cobb angle reading in radiographs, discrepancy which fades away in older children. Based on this observation, we hypothesized that in scoliotics the correlation between the rib cage deformity and this of the spine is weak in younger children and vice versa.</p> <p>Methods</p> <p>Eighty three girls referred on the basis of their hump reading on the scoliometer, with a mean age of 13.4 years old (range 7–18), were included in the study. The spinal deformity was assessed by measuring the thoracic Cobb angle from the postero-anterior spinal radiographs. The rib cage deformity was quantified by measuring the rib-index at the apex of the thoracic curve from the lateral spinal radiographs. The rib-index is defined as the ratio between the distance of the posterior margin of the vertebral body and the most extended point of the most projecting rib contour, divided by the distance between the posterior margin of the same vertebral body and the most protruding point of the least projecting rib contour. Statistical analysis included linear regression models with and without the effect of the variable age. We divided our sample in two subgroups, namely the younger (7–13 years old) and the older (14–18 years old) than the mean age participants. A univariate linear regression analysis was performed for each age group in order to assess the effect of age on Cobb angle and rib index correlation.</p> <p>Results</p> <p>Twenty five per cent of patients with an ATI more than or equal 7 degrees had a spinal curve under 10 degrees or had a straight spine. Linear regressions between the dependent variable "Thoracic Cobb angle" with the independent variable "rib-index" without the effect of the variable "age" is not statistical significant. After sample split, the linear relationship is statistically significant in the age group 14–18 years old (p < 0.03).</p> <p>Conclusion</p> <p>Growth has a significant effect in the correlation between the thoracic and the spinal deformity in girls with idiopathic scoliosis. Therefore it should be taken into consideration when trying to assess the spinal deformity from surface measurements. The findings of the present study implicate the role of the thorax, as it shows that the rib cage deformity precedes the spinal deformity in the pathogenesis of idiopathic scoliosis.</p

The emerging modern face of mood disorders: a didactic editorial with a detailed presentation of data and definitions

The present work represents a detailed description of our current understanding and knowledge of the epidemiology, etiopathogenesis and clinical manifestations of mood disorders, their comorbidity and overlap, and the effect of variables such as gender and age. This review article is largely based on the 'Mood disorders' chapter of the Wikibooks Textbook of Psychiatry http://en.wikibooks.org/wiki/Textbook_of_Psychiatry/Mood_Disorders

Longitudinal twin study of early literacy development: Preschool through Grade 1

Grade 1 literacy skills of twin children in Australia (New South Wales) and the United States (Colorado) were explored in a genetically sensitive design (N = 319 pairs). Analyses indicated strong genetic influence on word and nonword identification,reading comprehension, and spelling. Rapid naming showed more modest, though reliable, genetic influence. Phonological awareness was subject to high nonshared environment and no reliable genetic effects, and individual measures of memory and learning were also less affected by genes than nonshared environment. Multivariateanalyses showed that the same genes affected word identification, reading comprehension, and spelling. Country comparisons indicated that the patterns of genetic influence on reading and spelling in Grade 1 were similar, though for the U.S. but not the Australian children new genes came on stream in the move from kindergarten to Grade 1. We suggest that this is because the more intensive kindergarten literacy curriculum in New South Wales compared with Colorado, consistent with the mean differences between the two countries, means that more of the genes are "online" sooner inAustralia because of accelerated overall reading development

Preschool twin study of the relation between attention-deficit/hyperactivity disorder and prereading skills

Numerous studies have examined the etiology of the association between reading difficulties and attention-deficit hyperactivity disorder (ADHD) in school-age children, but little is known about the relation between prereading skills and ADHD behaviors prior to the beginning of formal reading instruction. A population-based sample of 809 pairs of preschool twins completed an extensive battery of prereading measures, and the parent of each twin completed an ADHD rating scale. Phenotypic analyses revealed small but significant correlations between DSM-IV inattention ratings and six prereading composite measures, whereas hyperactivity–impulsivity symptoms were not independently associated with any of the prereading scores. Multivariate twin analyses indicated that virtually all of the phenotypic correlation between inattention and prereading performance is attributable to common genetic influences, consistent with results obtained in studies of older twins. Although additional research is needed to test alternative causal models in children younger than five years old, these results are most consistent with the hypothesis that reading difficulties and inattention symptoms are attributable to common genetic influences

A behaviour-genetic analysis of orthographic learning, spelling and decoding

As part of a longitudinal twin study of literacy and language, we conducted a behaviour-genetic analysis of orthographic learning, spelling and decoding in Grade 2 children (225 identical and 214 fraternal twin pairs) in the United States and Australia. Each variable showed significant genetic and unique environment influences. Multivariate analyses revealed very high genetic correlations among the variables, indicating that the same genes are involved in their aetiology. These genes are partly independent of those contributing to intelligence. A further analysis indicated that the covariation between decoding and orthographic learning is mediated by shared genes rather than by a direct causal path. The authors argue that a learning parameter, most directly assessed by orthographic learning in this study, underlies all three literacy variables. The results are also discussed in relation to Share's self-teaching hypothesis, which may require modification

A Cross-Lagged Model of the Development of ADHD Inattention Symptoms and Rapid Naming Speed

Although previous research has identified contemporaneous associations between cognitive deficits and symptom phenotypes in Attention Deficit/ Hyperactivity Disorder, no studies have as yet attempted to identify direction of effect. The present study used cross-lagged path modeling to examine competing hypotheses about longitudinal associations between rapid naming speed and symptoms of inattention in children. 1,506 school-age twins from Australia and the U.S. were tested for inattention, hyperactivity/impulsivity, and rapid naming speed at three and four time points, respectively. Symptom severity of inattention from Kindergarten to fourth grade is consistently predicted by previous rapid naming, over and above auto-regressive and correlational associations in the model. Likewise, inattention symptoms have a small but significant predictive effect on subsequent rapid naming. The findings support a reciprocal relationship between naming speed and ADHD inattentive symptoms

A stroke gene panel for whole-exome sequencing

Extensive analyses of known monogenic causes of stroke by whole-exome/genome sequencing are technically possible today. We here aimed to compile a comprehensive panel of genes associated with monogenic causes of stroke for use in clinical and research situations. We systematically searched the publically available database Online Mendelian Inheritance in Man, and validated the entries against original peer-reviewed publications in PubMed. First, we selected known pathogenic or putatively pathogenic stroke genes reported in at least one person with stroke, and classified the stroke phenotype for each gene into eight subgroups: (1) large artery atherosclerotic, (2) large artery non-atherosclerotic (tortuosity, dolichoectasia, aneurysm, non-atherosclerotic dissection, occlusion), (3) cerebral small-vessel diseases, (4) cardioembolic (arrhythmia, heart defect, cardiomyopathy), (5) coagulation dysfunctions (venous thrombosis, arterial thrombosis, bleeding tendency), (6) intracerebral hemorrhage, (7) vascular malformations (cavernoma, arteriovenous malformations), and (8) metabolism disorders. Second, we selected other genes that may plausibly cause stroke through diseases related to stroke, but without any documented stroke patient description. A third section comprised SNPs associated with stroke in genome-wide association studies (GWAS). We identified in total 214 genes: 120 associated with stroke, 62 associated with diseases that may cause stroke, and 32 stroke-related genes from recent GWAS. We describe these 214 genes and the clinical stroke subtype(s) associated with each of them. The resulting gene panel can be used to interpret exome sequencing results regarding monogenic stroke. Based on the panel’s clinical phenotype description, the pathogenicity of novel variants in these genes may be evaluated in specific situations