Greater Engagement in Gender-Sexuality Alliances (GSAs) and GSA Characteristics Predict Youth Empowerment and Reduced Mental Health Concerns

Extracurricular groups can promote healthy development, yet the literature has given limited attention to indirect associations between extracurricular involvement and mental health or to sexual and gender minority youth. Among 580 youth (Mage = 15.59, range = 10–20 years) and adult advisors in 38 Gender-Sexuality Alliances (GSAs), multilevel structural equation models showed that greater engagement in GSAs over the school year predicted increased perceived peer validation, self-efficacy to promote social justice, and hope (baseline adjusted). Through increased hope, greater engagement indirectly predicted reduced depressive and anxiety symptoms at the year’s end (baseline adjusted). GSAs whose members had more mental health discussions and more meetings reported reduced mental health concerns. Findings suggest how groups addressing issues of equity and justice improve members’ health

A Tribute to Joseph Edward Ulrich

This tribute honors Joseph Edward Ulrich, who in thirty-one years on the W&L Law faculty and in recent years as one-called-out-of-retirement, attained legendary status amidst fellow giants Roger Groot, Uncas McThenia, and Lash LaRue

Evaluating Four Inosine-Uridine Preferring Nucleoside Hydrolases in Bacillus Anthracis for Decontamination Strategies

Andrew Roser­ is a doctoral student in the School of Biological Sciences at Louisiana Tech University. Abigail Bass, Sophie Bott, Madison Brewton, Adam Broussard, Taylor Clement, Makenzie Cude, Hunter Currie, Claire Herke, Mary Hickman, Lauren James, Hailey Johnson, Madeline Lechtenberg, Sarah Murchison, Alex Plaisance, Wil Plants, Alex Sullivan, Sara Vandenberg, and Kaitlynn Willis are undergraduate students in the School of Biological Sciences at Louisiana Tech University. Rebecca Giorno is an Associate Professor in the School of Biological Sciences at Louisiana Tech University

VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis

Clinical sequencing efforts are rapidly identifying sarcoma gene fusions that lack functional validation. An example is the fusion of transcriptional coactivators, VGLL2-NCOA2, found in infantile rhabdomyosarcoma. To delineate VGLL2-NCOA2 tumorigenic mechanisms and identify therapeutic vulnerabilities, we implement a cross-species comparative oncology approach with zebrafish, mouse allograft, and patient samples. We find that VGLL2-NCOA2 is sufficient to generate mesenchymal tumors that display features of immature skeletal muscle and recapitulate the human disease. A subset of VGLL2-NCOA2 zebrafish tumors transcriptionally cluster with embryonic somitogenesis and identify VGLL2-NCOA2 developmental programs, including a RAS family GTPase, ARF6. In VGLL2-NCOA2 zebrafish, mouse, and patient tumors, ARF6 is highly expressed. ARF6 knockout suppresses VGLL2-NCOA2 oncogenic activity in cell culture, and, more broadly, ARF6 is overexpressed in adult and pediatric sarcomas. Our data indicate that VGLL2-NCOA2 is an oncogene that leverages developmental programs for tumorigenesis and that reactivation or persistence of ARF6 could represent a therapeutic opportunity

Evolution and lineage dynamics of a transmissible cancer in Tasmanian devils.

Devil facial tumour 1 (DFT1) is a transmissible cancer clone endangering the Tasmanian devil. The expansion of DFT1 across Tasmania has been documented, but little is known of its evolutionary history. We analysed genomes of 648 DFT1 tumours collected throughout the disease range between 2003 and 2018. DFT1 diverged early into five clades, three spreading widely and two failing to persist. One clade has replaced others at several sites, and rates of DFT1 co-infection are high. DFT1 gradually accumulates copy number variants (CNVs) and its telomere lengths are short but constant. Recurrent CNVs reveal genes under positive selection, sites of genome instability and repeated loss of a small derived chromosome. Cultured DFT1 cell lines have increased CNV frequency and undergo highly reproducible convergent evolution. Overall, DFT1 is a remarkably stable lineage whose genome illustrates how cancer cells adapt to diverse environments and persist in a parasitic niche.This work was supported by grants from Wellcome (102942/Z/13/A), the National Science Foundation (DEB-1316549), the University of Tasmania Foundation (Eric Guiler Tasmanian Devil Research Grants), the Australian Research Council (DE 170101116) and a Philip Leverhulme Prize from the Leverhulme Trust. YMK was supported by a Herchel Smith Postgraduate Fellowship

Enhancer evolution across 20 mammalian species.

The mammalian radiation has corresponded with rapid changes in noncoding regions of the genome, but we lack a comprehensive understanding of regulatory evolution in mammals. Here, we track the evolution of promoters and enhancers active in liver across 20 mammalian species from six diverse orders by profiling genomic enrichment of H3K27 acetylation and H3K4 trimethylation. We report that rapid evolution of enhancers is a universal feature of mammalian genomes. Most of the recently evolved enhancers arise from ancestral DNA exaptation, rather than lineage-specific expansions of repeat elements. In contrast, almost all liver promoters are partially or fully conserved across these species. Our data further reveal that recently evolved enhancers can be associated with genes under positive selection, demonstrating the power of this approach for annotating regulatory adaptations in genomic sequences. These results provide important insight into the functional genetics underpinning mammalian regulatory evolution.We thank Stephen Watt, Frances Connor, the CRUK-CI Genomics and Bioinformatics cores, Biological Resources Unit (Matthew Clayton), Margaret Brown (West Yorkshire bat hospital), Julie E. Horvath (North Carolina Central University), and Chris Dillingham (University of Cardiff) for technical assistance; Matthieu Muffato for assistance with whole-genome alignments; Claudia Kutter, Gordon Brown, Christine Feig, and Christina Ernst for useful comments and discussions, and the EBI systems team for management of computational resources. This research was supported by Cancer Research UK (D.V., D.T.O.), the European Molecular Biology Laboratory (C.B., P.F.), the Wellcome Trust (WT095908) (P.F.) and (WT098051) (P.F., D.T.O.), the European Research Council, EMBO Young Investigator Programme (D.T.O.), the National Science Foundation (0744979) (T.J.P.), NIH (P40 OD010965, R01 OD010980, R37 MH060233) (A.J.J.) and MRC (U117588498) (J.M.A.T.). Cetacean samples were collected by the UK Cetacean Strandings Investigation Programme, funded by Defra and the Governments of Scotland and Wales.This is the final version. It originally appeared at http://www.sciencedirect.com/science/article/pii/S0092867415000070

Gene expression markers of tendon fibroblasts in normal and diseased tissue compared to monolayer and three dimensional culture systems

<p>Abstract</p> <p>Background</p> <p>There is a paucity of data regarding molecular markers that identify the phenotype of the tendon cell. This study aims to quantify gene expression markers that distinguish between tendon fibroblasts and other mesenchymal cells which may be used to investigate tenogenesis.</p> <p>Methods</p> <p>Expression levels for 12 genes representative of musculoskeletal tissues, including the proposed tendon progenitor marker scleraxis, relative to validated reference genes, were evaluated in matched samples of equine tendon (harvested from the superficial digital flexor tendon), cartilage and bone using quantitative PCR (qPCR). Expression levels of genes associated with tendon phenotype were then evaluated in healthy, including developmental, and diseased equine tendon tissue and in tendon fibroblasts maintained in both monolayer culture and in three dimensional (3D) collagen gels.</p> <p>Results</p> <p>Significantly increased expression of scleraxis was found in tendon compared with bone (P = 0.002) but not compared to cartilage. High levels of COL1A2 and scleraxis and low levels of tenascin-C were found to be most representative of adult tensional tendon phenotype. While, relative expression of scleraxis in developing mid-gestational tendon or in acute or chronically diseased tendon did not differ significantly from normal adult tendon, tenascin-C message was significantly upregulated in acutely injured equine tendon (P = 0.001). Relative scleraxis gene expression levels in tendon cell monolayer and 3D cultures were significantly lower than in normal adult tendon (P = 0.002, P = 0.02 respectively).</p> <p>Conclusion</p> <p>The findings of this study indicate that high expression of both COL1A2 and scleraxis, and low expression of tenascin-C is representative of a tensional tendon phenotype. The <it>in vitro </it>culture methods used in these experiments however, may not recapitulate the phenotype of normal tensional tendon fibroblasts in tissues as evidenced by gene expression.</p

Evolution and lineage dynamics of a transmissible cancer in Tasmanian devils

Devil facial tumour 1 (DFT1) is a transmissible cancer clone endangering the Tasmanian devil. The expansion of DFT1 across Tasmania has been documented, but little is known of its evolutionary history. We analysed genomes of 648 DFT1 tumours collected throughout the disease range between 2003 and 2018. DFT1 diverged early into five clades, three spreading widely and two failing to persist. One clade has replaced others at several sites, and rates of DFT1 coinfection are high. DFT1 gradually accumulates copy number variants (CNVs), and its telomere lengths are short but constant. Recurrent CNVs reveal genes under positive selection, sites of genome instability, and repeated loss of a small derived chromosome. Cultured DFT1 cell lines have increased CNV frequency and undergo highly reproducible convergent evolution. Overall, DFT1 is a remarkably stable lineage whose genome illustrates how cancer cells adapt to diverse environments and persist in a parasitic niche

PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of rhabdomyosarcoma tumorigenesis

International audienceAlveolar rhabdomyosarcoma is a pediatric soft-tissue sarcoma caused by PAX3/7-FOXO1 fusion oncogenes and is characterized by impaired skeletal muscle development. We developed human PAX3-FOXO1-driven zebrafish models of tumorigenesis and found that PAX3-FOXO1 exhibits discrete cell lineage susceptibility and transformation. Tumors developed by 1.6-19 months and were primitive neuroectodermal tumors or rhabdomyosarcoma. We applied this PAX3-FOXO1 transgenic zebrafish model to study how PAX3-FOXO1 leverages early developmental pathways for oncogenesis and found that her3 is a unique target. Ectopic expression of the her3 human ortholog, HES3, inhibits myogenesis in zebrafish and mammalian cells, recapitulating the arrested muscle development characteristic of rhabdomyosarcoma. In patients, HES3 is overexpressed in fusion-positive versus fusion-negative tumors. Finally, HES3 overexpression is associated with reduced survival in patients in the context of the fusion. Our novel zebrafish rhabdomyosarcoma model identifies a new PAX3-FOXO1 target, her3/HES3, that contributes to impaired myogenic differentiation and has prognostic significance in human disease