Arboretum: Reconstruction and analysis of the evolutionary history of condition-specific transcriptional modules

Comparative functional genomics studies the evolution of biological processes by analyzing functional data, such as gene expression profiles, across species. A major challenge is to compare profiles collected in a complex phylogeny. Here, we present Arboretum, a novel scalable computational algorithm that integrates expression data from multiple species with species and gene phylogenies to infer modules of coexpressed genes in extant species and their evolutionary histories. We also develop new, generally applicable measures of conservation and divergence in gene regulatory modules to assess the impact of changes in gene content and expression on module evolution. We used Arboretum to study the evolution of the transcriptional response to heat shock in eight species of Ascomycota fungi and to reconstruct modules of the ancestral environmental stress response (ESR). We found substantial conservation in the stress response across species and in the reconstructed components of the ancestral ESR modules. The greatest divergence was in the most induced stress, primarily through module expansion. The divergence of the heat stress response exceeds that observed in the response to glucose depletion in the same species. Arboretum and its associated analyses provide a comprehensive framework to systematically study regulatory evolution of condition-specific responses.Howard Hughes Medical InstituteBroad Institute of MIT and HarvardNational Institutes of Health (U.S.) (Pioneer Award)National Institutes of Health (U.S.) (R01 2R01CA119176-01)Burroughs Wellcome Fund (Career Award at the Scientific Interface)Alfred P. Sloan Foundatio

Design, Protocol and Baseline Data of Nurturing Healthy Teachers, a Cluster Non-Randomized Controlled Trial to Improve the Health, Well-Being, and Food Security of Preschool and Elementary School Teachers in Houston, Texas

BACKGROUND: We present the conceptual framework, design, and study measures of Nurturing Healthy Teachers, a quasi-experimental study to examine the short- and long-term effectiveness of the Nurturing Healthy Teachers (NHT) nutrition intervention on food insecurity, dietary behaviors, mental health and cardiometabolic health among preschool and elementary school teachers. METHODS: A convenience sample of 28 elementary schools with pre-kindergarten and elementary classrooms were recruited in Houston, Texas. Nurturing Healthy Teacher intervention includes Brighter Bites, an evidence-based coordinated school health program that combines access to fresh produce and nutrition education, and Create Healthy Futures, a web-based nutrition education program that targets nutrition knowledge, self-efficacy, mindfulness, and social support to create healthy habits among teachers. The primary outcome is food insecurity. Secondary outcomes include diet quality, mental health, and cardiometabolic health. Metabolic markers and skin carotenoid levels were assessed using in-person assessments, while all other measures were obtained via questionnaire. RESULTS: At baseline, most of the participants were female, 63 % identified as Hispanic, were highly educated, and had a mean age of 42.6 years. Overall, 50 % of teachers were classified as being obese and 20 % had high cholesterol. At baseline teachers had a mean HbA1c (%) of 5.6 %. Moderate to severe depression was experienced by 18 % of teachers and 23 % of teachers experienced moderate to severe anxiety. CONCLUSIONS: The results of this study will inform next steps towards future implementation and evaluation of teacher-focused interventions

Rare Genetic Variation in 135 Families With Family History Suggestive of X-Linked Intellectual Disability.

Families with multiple male children with intellectual disability (ID) are usually suspected of having disease due to a X-linked mode of inheritance and genetic studies focus on analysis of segregating variants in X-linked genes. However, the genetic cause of ID remains elusive in approximately 50% of affected individuals. Here, we report the analysis of next-generation sequencing data in 274 affected individuals from 135 families with a family history suggestive of X-linked ID. Genetic diagnoses were obtained for 19% (25/135) of the families, and 24% (33/135) had a variant of uncertain significance. In 12% of cases (16/135), the variants were not shared within the family, suggesting genetic heterogeneity and phenocopies are frequent. Of all the families with reportable variants (43%, 58/135), we observed that 55% (32/58) were in X-linked genes, but 38% (22/58) were in autosomal genes, while the remaining 7% (4/58) had multiple variants in genes with different modes on inheritance. This study highlights that in families with multiple affected males, X linkage should not be assumed, and both individuals should be considered, as different genetic etiologies are common in apparent familial cases

Improving mortality rate estimates for management of the Queensland saucer scallop fishery

This research was undertaken on the Queensland saucer scallop (Ylistrum balloti) fishery in southeast Queensland, which is an important component of the Queensland East Coast Otter Trawl Fishery (QECOTF). The research was undertaken by a collaborative team from the Queensland Department of Agriculture and Fisheries, James Cook University (JCU) and the Centre for Applications in Natural Resource Mathematics (CARM), University of Queensland and focused on 1) an annual fishery-independent trawl survey of scallop abundance, 2) relationships between scallop abundance and physical properties of the seafloor, and 3) deriving an updated estimate of the scallop’s natural mortality rate. The scallop fishery used to be one of the state’s most valuable commercially fished stocks with the annual catch peak at just under 2000 t (adductor muscle meat-weight) in 1993 valued at about $30 million, but in recent years the stock has declined and is currently considered to be overfished. Results from the study are used to improve monitoring, stock assessment and management advice for the fishery

Risk Factors Associated with a Second Primary Lung Cancer in Patients with an Initial Primary Lung Cancer

Objectives: Increased patient survivorship following initial primary lung cancer (IPLC) due to advancing clinical practice has uncovered new clinical challenges. With growing patient longevity, individuals post-IPLC continue to be at higher subsequent risk of developing secondary primary lung cancer (SPLC). Proper SPLC surveillance guidelines aimed at monitoring IPLC survivors is crucial to enhancing life expectancy in this population. This study aims to categorize risk factors associated with SPLC emergence in IPLC survivors for clinical use following IPLC treatment. Materials and Methods: Using the Karmanos Cancer Institute Tumor Registry, patients diagnosed with IPLC from 2000 to 2017 were identified. Patients diagnosed with SPLC were matched for histology, age and stage to individuals who did not develop SPLC. Logistic and Cox regression analyses were performed to identify potential risk factors for SPLC emergence and overall survival. Results: 121 patients diagnosed with IPLC who later developed SPLC were identified and compared to 120 patients with IPLC who did not develop SPLC. Patients who did not undergo surgical resection had a significantly lower probability of developing SPLC (OR 0.235, 95% confidence interval [CI]: 0.118 to 0.450; p\u3c0.001). Compared to surgical resection patients, individuals who did not have surgery as their primary treatment for IPLC had a significantly higher hazard of death (HR 3.088, 95% CI: 2.114 to 4.512; p\u3c0.001). Conclusion: This study uncovered notable associations and lack thereof between several competing risk factors and SPLC development as well as mortality. Further characterization of SPLC risk factors is essential for implementing effective surveillance recommendations

Abundancy of polymorphic CGG repeats in the human genome suggest a broad involvement in neurological disease.

Funder: Marguerite-Marie Delacroix foundationFunder: Fonds Wetenschappelijk Onderzoek - Vlaanderen (FWO)Funder: NIHR BioResourceFunder: Rosetrees Trust, Newton Trust, National Institute for Health Research (NIHR) for the Cambridge Biomedical Research CentreFunder: Methusalem-OEC grant – “GENOMED”Expanded CGG-repeats have been linked to neurodevelopmental and neurodegenerative disorders, including the fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS). We hypothesized that as of yet uncharacterised CGG-repeat expansions within the genome contribute to human disease. To catalogue the CGG-repeats, 544 human whole genomes were analyzed. In total, 6101 unique CGG-repeats were detected of which more than 93% were highly variable in repeat length. Repeats with a median size of 12 repeat units or more were always polymorphic but shorter repeats were often polymorphic, suggesting a potential intergenerational instability of the CGG region even for repeats units with a median length of four or less. 410 of the CGG repeats were associated with known neurodevelopmental disease genes or with strong candidate genes. Based on their frequency and genomic location, CGG repeats may thus be a currently overlooked cause of human disease

Multicenter Consensus Approach to Evaluation of Neonatal Hypotonia in the Genomic Era: A Review

IMPORTANCE: Infants with hypotonia can present with a variety of potentially severe clinical signs and symptoms and often require invasive testing and multiple procedures. The wide range of clinical presentations and potential etiologies leaves diagnosis and prognosis uncertain, underscoring the need for rapid elucidation of the underlying genetic cause of disease. OBSERVATIONS: The clinical application of exome sequencing or genome sequencing has dramatically improved the timely yield of diagnostic testing for neonatal hypotonia, with diagnostic rates of greater than 50% in academic neonatal intensive care units (NICUs) across Australia, Canada, the UK, and the US, which compose the International Precision Child Health Partnership (IPCHiP). A total of 74% (17 of 23) of patients had a change in clinical care in response to genetic diagnosis, including 2 patients who received targeted therapy. This narrative review discusses the common causes of neonatal hypotonia, the relative benefits and limitations of available testing modalities used in NICUs, and hypotonia management recommendations. CONCLUSIONS AND RELEVANCE: This narrative review summarizes the causes of neonatal hypotonia and the benefits of prompt genetic diagnosis, including improved prognostication and identification of targeted treatments which can improve the short-term and long-term outcomes. Institutional resources can vary among different NICUs; as a result, consideration should be given to rule out a small number of relatively unique conditions for which rapid targeted genetic testing is available. Nevertheless, the consensus recommendation is to use rapid genome or exome sequencing as a first-line testing option for NICU patients with unexplained hypotonia. As part of the IPCHiP, this diagnostic experience will be collected in a central database with the goal of advancing knowledge of neonatal hypotonia and improving evidence-based practice

Obesity: should there be a law against it? Introduction to a symposium

The rapid rise in rates of overweight and obesity among adults and children in Australia and New Zealand has intensified debate about the most effective policies for obesity prevention. Law has much to contribute to this policy discussion, although its role is often misunderstood. The articles in this symposium follow on from a conference hosted in September 2006 by the Centre for Health Governance, Law & Ethics in the Faculty of Law, University of Sydney, titled: Obesity: should there be a law against it? In different ways, these articles provide a variety of perspectives on regulatory responses to obesity, including theoretical justifications for a legal approach, conceptual models that assist in making sense of law's role, as well as specific legal strategies for obesity prevention in various settings

De Novo VPS4A Mutations Cause Multisystem Disease with Abnormal Neurodevelopment.

The endosomal sorting complexes required for transport (ESCRTs) are essential for multiple membrane modeling and membrane-independent cellular processes. Here we describe six unrelated individuals with de novo missense variants affecting the ATPase domain of VPS4A, a critical enzyme regulating ESCRT function. Probands had structural brain abnormalities, severe neurodevelopmental delay, cataracts, growth impairment, and anemia. In cultured cells, overexpression of VPS4A mutants caused enlarged endosomal vacuoles resembling those induced by expression of known dominant-negative ATPase-defective forms of VPS4A. Proband-derived fibroblasts had enlarged endosomal structures with abnormal accumulation of the ESCRT protein IST1 on the limiting membrane. VPS4A function was also required for normal endosomal morphology and IST1 localization in iPSC-derived human neurons. Mutations affected other ESCRT-dependent cellular processes, including regulation of centrosome number, primary cilium morphology, nuclear membrane morphology, chromosome segregation, mitotic spindle formation, and cell cycle progression. We thus characterize a distinct multisystem disorder caused by mutations affecting VPS4A and demonstrate that its normal function is required for multiple human developmental and cellular processes.This work was supported by: UK Medical Research Council Project Grants [MR/M00046X/1], [MR/R026440/1] and Project grant from National Institute of Health Research Biomedical Research Centre at Addenbrooke's Hospital (to E.R.), Fondazione Bambino Gesù (Vite Coraggiose) and Italian Ministry of Health (CCR-2017-23669081) (to M.T.), National Institute for Health Research (NIHR) for the Cambridge Biomedical Research Centre and NIHR BioResource (Grant Number RG65966) (to F.L.R.), and a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 216370/Z/19/Z) (to J.E.). CIMR was supported by a Wellcome Trust Strategic Award [100140] and Equipment Grant [093026]. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support