Temperature dependent kinetics of biotin carboxylase

Acetyl-CoA carboxylase catalyzes the first committed step in long chain fatty acid biosynthesis. In Escherichia coli, the enzyme is composed of three distinct protein components: biotin carboxylase, biotin carboxyl carrier protein, and carboxytransferase. The biotin carboxylase component has served for many years as a model for mechanistic studies devoted toward understanding biotin-dependent carboxylases. Studies of the temperature dependence, temperature dependence of the kinetic solvent isotope effect and thermodynamics of biotin carboxylase are reported. Analysis of the van’t Hoff plot in H2O was biphasic showing an apparent transition temperature of 20°C, with corresponding DH° values of –4.55 ± 1.84 kcal/mol below the transition temperature and –1.59 ± 0.16 kcal/mol above the transition temperature, respectively, suggesting a conformational change is occurring at this temperature. Biphasic Arrhenius and Eyring plots in D2O showed an apparent transition temperature at 25°C with corresponding Ea and DH‡ values of 16.35 ± 0.90 kcal/mol and 15.86 ± 0.85 kcal/mol below the transition temperature, respectively, and Ea and DH‡ values of 4.01 ± 1.15 kcal/mol and 3.37 ± 1.06 kcal/mol above the transition temperature, respectively. This break in the plots is suggestive of either a conformational change or a change in the rate-determining step occurring at 25°C. Kinetic solvent isotope effects were used to distinguish between these two possibilities. The results of the kinetic solvent isotope effect suggest a change in the rate-determining step as a function of temperature is occurring and is not due to a conformational change. Analysis of Arrhenius preexponential factors (AH/AD) determined from the temperature dependence of the kinetic solvent isotope suggests both hydrogen and deuterium tunneling in biotin carboxylase

Arc Marine as a spatial data infrastructure : a marine data model case study in whale tracking by satellite telemetry

The Arc Marine data model is a generalized template to guide the implementation of geographic information systems (GIS) projects in the marine environment. Arc Marine developed out of a collaborative process involving research and industry shareholders in coastal and marine research. This template models and attempts to standardize common marine data types to facilitate data sharing and analytical tool development. The next step in the development of Arc Marine is adaptation to the problems of specific research communities, and specific programs, under the broad umbrella of coastal and marine research by community specific customization of Arc Marine. In this study, Arc Marine was customized from its core model to fit the research goals of the whale satellite telemetry tagging program of the Oregon State University Marine Mammal Institute (MMI). This customization serves as a case study of the ability of Arc Marine to achieve its six primary objectives in the context of the marine animal tracking community. These objectives are: 1) to create a common model for assembling, managing, and publishing tracking data sets; 2) to produce, share, and exchange these tracking data in a similar format and standard structure; 3) to provide a unified approach for community software developers extending the capabilities of ArcGIS; 4) to extend the power of marine geospatial analysis through a framework for incorporating object-oriented behaviors and for dealing with scale dependencies; 5) to provide a mechanism for the implementation of data content standards; and 6) to aid researchers in a fuller understanding of object-oriented GISs and the power of advanced spatial data structures. The primary question examined in this thesis is: How can the Arc Marine data model be customized to best meet the research objectives of the OSU MMI and the marine mammal tracking community, in order to explore the relationship of the distribution and movement of endangered marine mammal species to underlying physical and biological oceanographic processes? The MMI customization of Arc Marine is focused on the use of Argos satellite telemetry tagging. The customized database schema was described in Universal Markup Language by modification of the core Arc Marine data model in Microsoft Visio 2003 and implemented as an ArcGIS 9.2 geodatabase (personal, file, and ArcSDE). Tool development and scripting were carried out predominantly in Python 2.4. The two major schema modifications of the MMI customization were the implementation of the Animal and AnimalEvent object classes. The Animal class is a subclass of Vehicle and models the tagged animal as a tracked instrument platform carrying an array of sensors to measure its environment. The AnimalEvent class represents interactions in time between the Animal and an open-ended range of event types including field observations, tagging, sensor measurements, and satellite geolocating. A programming interface is described for AnimalEvent (AnimalEventUI) and the InstantaneousPoint feature class (InstantaneousPointUI) that represents observed animal locations. Further customization came through the development of a comprehensive development framework for animal tracking in Arc Marine. This framework implements front-end analysis tools through Python scripting, ArcGIS extensions, or standalone applications developed in VB.NET. Back-end database loading is implemented in Python through the ArcGIS geoprocessing object and the DB-API 2.0 database abstraction layer. Through a description of the multidimensional data cube model of Arc Marine, Arc Marine and the MMI customization are demonstrated to be foundation schemas for a relational database management system (RDBMS), object relational database management system (ORDBMS), or enterprise spatial data warehouse. This modeling method shows that Arc Marine is built upon atomic measures (scalar quantities, vector quantities, points, lines, and polygons) that are described by related dimensional tables (such as time, data parameters, tagged animal, or species) and concept hierarchies of different levels generalization (for example, tag < animal < social group < population < species). This data cube structure further shows that Arc Marine is an appropriate target schema for the application of on-line analytical processing (OLAP) tools, data mining, and spatial data mining to satellite telemetry tracking datasets. In this customization case study, Arc Marine partially meets each of its six major goals. In particular, the development of the MMI application development platform demonstrates full implementation of a unified approach for community software developers. Meanwhile, the data cube model of Arc Marine for OLAP demonstrates a successful extension of marine geospatial analysis to deal more effectively with scale dependencies and a mechanism for the expansion of researchers’ understanding of high power analytical methods.Keywords: geographic information systems, data model, cetacean, satellite telemetry, Argos, GIS, Arc Marine, on-line analytical processin

A longitudinal twin study of the association between childhood autistic traits and psychotic experiences in adolescence

- Background: This twin study investigated whether autistic traits during childhood were associated with adolescent psychotic experiences. - Methods: Data were collected from a community sample of approximately 5000 twin pairs, which included 32 individuals with diagnosed autism spectrum conditions (ASC). Parents rated autistic traits in the twins at four points between ages 8–16 years. Positive, negative, and cognitive psychotic experiences were assessed at age 16 years using self- and parent-report scales. Longitudinal twin analyses tested the associations between these measures. - Results: Autistic traits correlated weakly or nonsignificantly with positive psychotic experiences (paranoia, hallucinations, and grandiosity), and modestly with cognitive psychotic experiences (cognitive disorganisation). Higher correlations were observed for parent-rated negative symptoms and self-reported anhedonia, although the proportion of variance in both accounted for by autistic traits was low (10 and 31 %, respectively). The majority of the genetic influences on negative symptoms and anhedonia were independent of autistic traits. Additionally, individuals with ASC displayed significantly more negative symptoms, anhedonia, and cognitive disorganisation than controls. - Conclusions: Autistic traits do not appear to be strongly associated with psychotic experiences in adolescence; associations were also largely restricted to negative symptoms. Of note, the degree to which the genetic and environmental causes of autistic traits influenced psychotic experiences was limited. These findings thus support a phenotypic and etiological distinction between autistic traits and psychotic experiences

Improving Efficiency and Quality of the Children’s ASD Diagnostic Pathway: Lessons Learned from Practice

The ‘autism diagnosis crisis’ and long waiting times for assessment are as yet unresolved, leading to undue stress and limiting\ud access to effective support. There is therefore a significant need for evidence to support practitioners in the development of\ud efficient services, delivering acceptable waiting times and effectively meeting guideline standards. This study reports statistically\ud significant reductions in waiting times for autism diagnostic assessment following a children’s health service improvement\ud programme. The average wait between referral and first appointment reduced from 14.2 to 10.4 weeks (t(21) = 4.3,\ud p < 0.05) and between referral and diagnosis shared, reduced from 270 to 122.5 days, (t(20) = 5.5, p < 0.05). The proportion\ud of girls identified increased from 5.6 to 2.7:1. Methods reported include: local improvement action planning; evidence based\ud pathways; systematic clinical data gathering and a training plan. This is a highly significant finding for many health services\ud wrestling with the challenges of demand and capacity for autism diagnosis and assessment

Update to the effectiveness and cost-effectiveness of a mindfulness training programme in schools compared with normal school provision (MYRIAD): study protocol for a randomised controlled trial

This is the final version. Available on open access from BMC via the DOI in this recordAvailability of data and materials: Data and materials (codebook, statistical analysis plan, protocols, etc.) are available from Prof. Kuyken ([email protected]) upon request (release of data will be subject to an approved proposal and a signed data access agreement).Background: MYRIAD (My Resilience in Adolescence) is a superiority, parallel group, cluster randomised controlled trial designed to examine the effectiveness and cost-effectiveness of a mindfulness training (MT) programme, compared with normal social and emotional learning (SEL) school provision to enhance mental health, social-emotional-behavioural functioning and well-being in adolescence. The original trial protocol was published in Trials (accessible at https://doi.org/10.1186/s13063-017-1917-4). This included recruitment in two cohorts, enabling the learning from the smaller first cohort to be incorporated in the second cohort. Here we describe final amendments to the study protocol and discuss their underlying rationale. Methods: Four major changes were introduced into the study protocol: (1) there were changes in eligibility criteria, including a clearer operational definition to assess the degree of SEL implementation in schools, and also new criteria to avoid experimental contamination; (2) the number of schools and pupils that had to be recruited was increased based on what we learned in the first cohort; (3) some changes were made to the secondary outcome measures to improve their validity and ability to measure constructs of interest and to reduce the burden on school staff; and (4) the current Coronavirus Disease 2019 (SARS-CoV-2 or COVID-19) pandemic both influences and makes it difficult to interpret the 2-year follow-up primary endpoint results, so we changed our primary endpoint to 1-year follow-up. Discussion: These changes to the study protocol were approved by the Trial Management Group, Trial Steering Committee and Data and Ethics Monitoring Committees and improved the enrolment of participants and quality of measures. Furthermore, the change in the primary endpoint will give a more reliable answer to our primary question because it was collected prior to the COVID-19 pandemic in both cohort 1 and cohort 2. Nevertheless, the longer 2-year follow-up data will still be acquired, although this time-point will be now framed as a second major investigation to answer some new important questions presented by the combination of the pandemic and our study design. Trial registration: International Standard Randomised Controlled Trials ISRCTN86619085. Registered on 3 June 2016.Wellcome TrustNational Institute for Health Research (NIHR

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead