Prediction of gene–phenotype associations in humans, mice, and plants using phenologs

All authors are with the Center for Systems and Synthetic Biology, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712, USA. -- Ulf Martin Singh-Blom is with the Program in Computational and Applied Mathematics, The University of Texas at Austin, Austin, TX 78712, USA, and th Unit of Computational Medicine, Department of Medicine, Karolinska Institutet, Stockholm 171 76, Sweden. -- Kriston L. McGary is with the Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA.Background: Phenotypes and diseases may be related to seemingly dissimilar phenotypes in other species by means of the orthology of underlying genes. Such “orthologous phenotypes,” or “phenologs,” are examples of deep homology, and may be used to predict additional candidate disease genes. Results: In this work, we develop an unsupervised algorithm for ranking phenolog-based candidate disease genes through the integration of predictions from the k nearest neighbor phenologs, comparing classifiers and weighting functions by cross-validation. We also improve upon the original method by extending the theory to paralogous phenotypes. Our algorithm makes use of additional phenotype data — from chicken, zebrafish, and E. coli, as well as new datasets for C. elegans — establishing that several types of annotations may be treated as phenotypes. We demonstrate the use of our algorithm to predict novel candidate genes for human atrial fibrillation (such as HRH2, ATP4A, ATP4B, and HOPX) and epilepsy (e.g., PAX6 and NKX2-1). We suggest gene candidates for pharmacologically-induced seizures in mouse, solely based on orthologous phenotypes from E. coli. We also explore the prediction of plant gene–phenotype associations, as for the Arabidopsis response to vernalization phenotype. Conclusions: We are able to rank gene predictions for a significant portion of the diseases in the Online Mendelian Inheritance in Man database. Additionally, our method suggests candidate genes for mammalian seizures based only on bacterial phenotypes and gene orthology. We demonstrate that phenotype information may come from diverse sources, including drug sensitivities, gene ontology biological processes, and in situ hybridization annotations. Finally, we offer testable candidates for a variety of human diseases, plant traits, and other classes of phenotypes across a wide array of species.Center for Systems and Synthetic BiologyInstitute for Cellular and Molecular [email protected]

Broad network-based predictability of Saccharomyces cerevisiae gene loss-of-function phenotypes

Loss-of-function phenotypes of yeast genes can be predicted from the loss-of-function phenotypes of their neighbours in functional gene networks. This could potentially be applied to the prediction of human disease genes

Professional practices, training, and funding mechanisms: A survey of pediatric primary care psychologists

The integration of mental health services in primary care settings has expanded rapidly in recent years with psychologists being at the forefront of efforts to promote healthy behaviors, reduce disease, and care for behavioral, emotional, and developmental needs to promote overall health and well-being for children and families (Asarnow, Kolko, Miranda,&Kazak, 2017; Stancin& Perrin, 2014). While there are many psychologists working in pediatric primary care (PPC), little is known about the specific activities that these psychologists engage in, the training they receive, or funding mechanisms that support their work. This study sought to address this gap in the literature through a survey of psychologists working in PPC. An anonymous online survey was disseminated to members of professional organizations and listservs who were identified as having interest in PPC. Psychologists (N-65) currently practicing in PPC completed the survey by reporting on clinical roles and practices, professional training, practice settings, and funding supports in PPC settings. Results indicate that psychologists assume a number of roles in PPC including providing individual and family therapy, conducting screenings for child mental health concerns, and providing consultation to medical colleagues. Many psychologists also provide supervision and offer educational opportunities for those in related fields, such as medicine and social work. Engagement in research activities was identified as a secondary activity. It was reported that a number of clinical activities were not billed for on a regular basis. Additional areas of research will be discussed along with implications for clinical services in PPC.. © 2017 American Psychological Association

BLOC-2 subunit HPS6 deficiency affects the tubulation and secretion of von Willebrand factor from mouse endothelial cells

Hermansky-Pudlak syndrome (HPS) is a recessive disorder with bleeding diathesis, which has been linked to platelet granule defects. Both platelet granules and endothelial Weibel-Palade bodies (WPBs) are members of lysosome-related organelles (LROs) whose formation is regulated by HPS protein associated complexes such as BLOC (biogenesis of lysosome organelles complex) -1, -2, -3, AP-3 (adaptor protein complex-3) and HOPS (homotypic fusion and protein sorting complex). Von Willebrand factor (VWF) is critical to hemostasis, which is stored in a highly-multimerized form as tubules in the WPBs. In this study, we found the defective, but varying, release of VWF into plasma after desmopressin (DDAVP) stimulation in HPS1 (BLOC-3 subunit), HPS6 (BLOC-2 subunit), and HPS9 (BLOC-1 subunit) deficient mice. In particular, VWF tubulation, a critical step in VWF maturation, was impaired in HPS6 deficient WPBs. This likely reflects a defective endothelium, contributing to the bleeding tendency in HPS mice or patients. The differentially defective regulated release of VWF in these HPS mouse models suggests the need for precise HPS genotyping before DDAVP administration to HPS patients

A regenerative approach to canine osteoarthritis using allogeneic, adipose-derived mesenchymal stem cells. Safety results of a long-term follow-up

Mesenchymal stem cells (MSC) are emerging as an effective therapeutic tool in treating canine osteoarthritis (OA). In this report, we focused on the questions of whether MSC transplantation has long-term beneficial effects for the improvement in motion and also evaluated the safety of MSC injection. Visceral adipose tissue, a surgical waste obtained during routine ovariectomy served as a source of allogeneic MSCs and used to treat OA. Altogether, fifty-eight dogs were transplanted in the study suffering from OA in the elbow (42 animals), hip (5), knee (8), ankle (2), and hock (1). The effect of MSC transplantation was evaluated by the degree of lameness at a 4-5-years follow-up period based on the owners' subjective observations. The results showed that 83% of the OA patients improved or retained improvement in lameness. Clinical safety of the treatment was assessed by evaluating the coincidence of tumors or other diseases and other adverse reactions (such as local inflammation) after MSC cell therapy. Two incidences of local inflammation for <1 week at the site of injection were reported. No other adverse reactions were detected post-treatment. Sixteen dogs died during the study, 4 due to cancer and 12 due to other diseases, diagnosed by veterinarians. Overall, our survey suggests that MSC transplantation has long-term beneficial effects in reducing lameness. Moreover, no enrichment in a specific cause of death was observed in the transplanted animals, compared to reported literature. Our data suggest that MSC treatment could be an effective and safe long-term therapy for canine OA

Systematic Definition of Protein Constituents along the Major Polarization Axis Reveals an Adaptive Reuse of the Polarization Machinery in Pheromone-Treated Budding Yeast

Polarizing cells extensively restructure cellular components in a spatially and temporally coupledmanner along the major axis of cellular extension. Budding yeast are a useful model of polarized growth, helping to define many molecular components of this conserved process. Besides budding, yeast cells also differentiate upon treatment with pheromone from the opposite mating type, forming a mating projection (the ‘shmoo’) by directional restructuring of the cytoskeleton, localized vesicular transport and overall reorganization of the cytosol. To characterize the proteomic localization changes ac-companying polarized growth, we developed and implemented a novel cell microarray-based imaging assay for measuring the spatial redistribution of a large fraction of the yeast proteome, and applied this assay to identify proteins localized along the mating projection following pheromone treatment. We further trained a machine learning algorithm to refine the cell imaging screen, identifying additional shmoo-localized proteins. In all, we identified 74 proteins that specifically localize to the mating projection, including previously uncharacterized proteins (Ycr043c, Ydr348c, Yer071c, Ymr295c, and Yor304c-a) and known polarization complexes such as the exocyst. Functional analysis of these proteins, coupled with quantitative analysis of individual organelle movements during shmoo formation, suggests a model in which the basic machinery for cell polarization is generally conserved between processe

A mobile phone app to support young people in making shared decisions in therapy (Power Up): study protocol

Background: Evidence suggests that young people want to be active participants in their care and involved in decisions about their treatment. However, there is a lack of digital shared decision-making tools available to support young people in child and adolescent mental health services (CAMHS). Objective: The primary aim of this paper is to present the protocol of a feasibility trial for Power Up, a mobile phone app to empower young people in CAMHS to make their voices heard and participate in decisions around their care. Methods: In the development phase, 30 young people, parents, and clinicians will take part in interviews and focus groups to elicit opinions on an early version of the app. In the feasibility testing phase, 60 young people from across 7 to 10 London CAMHS sites will take part in a trial looking at the feasibility and acceptability of measuring the impact of Power Up on shared decision making. Results: Data collection for the development phase ended in December 2016. Data collection for the feasibility testing phase will end in December 2017. Conclusions: Findings will inform the planning of a cluster controlled trial and contribute to the development and implementation of a shared decision-making app to be integrated into CAMHS

Active growth signaling promotes senescence and cancer cell sensitivity to CDK7 inhibition

Tumor growth is driven by continued cellular growth and proliferation. Cyclin-dependent kinase 7’s (CDK7) role in activating mitotic CDKs and global gene expression makes it therefore an attractive target for cancer therapies. However, what makes cancer cells particularly sensitive to CDK7 inhibition (CDK7i) remains unclear. Here, we address this question. We show that CDK7i, by samuraciclib, induces a permanent cell-cycle exit, known as senescence, without promoting DNA damage signaling or cell death. A chemogenetic genome-wide CRISPR knockout screen identified that active mTOR (mammalian target of rapamycin) signaling promotes samuraciclib-induced senescence. mTOR inhibition decreases samuraciclib sensitivity, and increased mTOR-dependent growth signaling correlates with sensitivity in cancer cell lines. Reverting a growth-promoting mutation in PIK3CA to wild type decreases sensitivity to CDK7i. Our work establishes that enhanced growth alone promotes CDK7i sensitivity, providing an explanation for why some cancers are more sensitive to CDK inhibition than normally growing cells