An electrophoretic analysis of the genetic relationship between Etheostoma nigrum and Etheostoma Olmstedi (percidae: etheostomatini) in the James River drainage of Virginia

Etheostoma nigrum Rafinesque 1820, the Johnny darter ranges from Alabama to the Hudson Bay and from Colorado east to the Atlantic slope in the James, Roanoke, Tar and Neuse Rivers. Etheostoma olmstedi Storer 1842, the tesselated darter, is restricted to the east coast in the Atlantic and Lake Ontario drainage. In the James and Roanoke River systems in Virginia E. nigrum occupies the piedmont and montane regions whereas E. olmstedi primarily inhabits the coastal plain. The relationship between the morphologically similar species of darters (subgenus Boleosoma) is controversial and has been investigated by several authors. Stone (1947), using multiple character analysis of the two forms in the zone of overlap in the Lake Ontario drainage, concluded that they were separate species. Hubbs and Lagler (1958) treated E. olmstedi as a subspecies of E. nigrum. Based on meristic data in a study of the two forms, Cole (1958, 1965 and 1967) supported Stone\u27s conclusions that separate species status is justified in drainages in New York, Virginia, and North Carolina. Scott and Crossman (1973) referred all Canadian Johnny darters to E. nigrum until it could be determined whether variation in the widespread form was somatic or genetic

An evaluation of Independent Child Trafficking Guardians – early adopter sites

This publication is licensed under the terms of the Open Government Licence v3.0 except where otherwise stated. To view this licence, visit nationalarchives.gov.uk/doc/open-government-licence/version/3This evaluation, conducted by the Home Office and the University of Bedfordshire has assessed the ICTG service in the three original early adopter sites (Greater Manchester, Hampshire, and Wales). The evaluation, conducted across a two-year period from February 2017 – January 2019, considers the original model for the ICTG service which provided one-to-one ICTG support for all children. The overall aim of the evaluation is to answer the question: What is the ‘added value’ of the ICTG service, and is this different for different groups of children and in different early adopter sites

Heat shock proteins are essential components in transformation and tumor progression: Cancer cell intrinsic pathways and beyond

Heat shock protein (HSP) synthesis is switched on in a remarkably wide range of tumor cells, in both experimental animal systems and in human cancer, in which these proteins accumulate in high levels. In each case, elevated HSP concentrations bode ill for the patient, and are associated with a poor outlook in terms of survival in most cancer types. The significance of elevated HSPs is underpinned by their essential roles in mediating tumor cell intrinsic traits such as unscheduled cell division, escape from programmed cell death and senescence, de novo angiogenesis, and increased invasion and metastasis. An increased HSP expression thus seems essential for tumorigenesis. Perhaps of equal significance is the pronounced interplay between cancer cells and the tumor milieu, with essential roles for intracellular HSPs in the properties of the stromal cells, and their roles in programming malignant cells and in the release of HSPs from cancer cells to influence the behavior of the adjacent tumor and infiltrating the normal cells. These findings of a triple role for elevated HSP expression in tumorigenesis strongly support the targeting of HSPs in cancer, especially given the role of such stress proteins in resistance to conventional therapies.Fil: Lang, Benjamin J.. Harvard Medical School; Estados UnidosFil: Guerrero Gimenez, Martin Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Prince, Thomas L.. Geisinger Medical Center; Estados UnidosFil: Ackerman, Andrew. Geisinger Medical Center; Estados UnidosFil: Bonorino, Cristina. Universidade Federal de Ciências da Saúde de Porto Alegre; Brasil. University of California; Estados UnidosFil: Calderwood, Stuart K.. Harvard Medical School; Estados Unido

HSF1: Primary Factor in Molecular Chaperone Expression and a Major Contributor to Cancer Morbidity

Heat shock factor 1 (HSF1) is the primary component for initiation of the powerful heat shock response (HSR) in eukaryotes. The HSR is an evolutionarily conserved mechanism for responding to proteotoxic stress and involves the rapid expression of heat shock protein (HSP) molecular chaperones that promote cell viability by facilitating proteostasis. HSF1 activity is amplified in many tumor contexts in a manner that resembles a chronic state of stress, characterized by high levels of HSP gene expression as well as HSF1-mediated non-HSP gene regulation. HSF1 and its gene targets are essential for tumorigenesis across several experimental tumor models, and facilitate metastatic and resistant properties within cancer cells. Recent studies have suggested the significant potential of HSF1 as a therapeutic target and have motivated research efforts to understand the mechanisms of HSF1 regulation and develop methods for pharmacological intervention. We review what is currently known regarding the contribution of HSF1 activity to cancer pathology, its regulation and expression across human cancers, and strategies to target HSF1 for cancer therapy.Fil: Prince, Thomas L.. Geisinger Clinic. Department of Molecular Functional Genomics; Estados UnidosFil: Lang, Benjamin J.. Harvard Medical School; Estados UnidosFil: Guerrero Gimenez, Martin Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Fernandez Muñoz, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Ackerman, Andrew. Geisinger Clinic. Department of Molecular Functional Genomics; Estados UnidosFil: Calderwood, Stuart K.. Harvard Medical School; Estados Unido

Structure and function of the human Gly1619Arg polymorphism of M6P/IGF2R domain 11 implicated in IGF2 dependent growth

The mannose 6-phosphate/IGF 2 receptor (IGF2R) is comprised of 15 extra-cellular domains that bind IGF2 and mannose 6-phosphate ligands. IGF2R transports ligands from the Golgi to the pre-lysosomal compartment and thereafter to and from the cell surface. IGF2R regulates growth, placental development, tumour suppression and signalling. The ligand IGF2 is implicated in the growth phenotype, where IGF2R normally limits bioavailability, such that loss and gain of IGF2R results in increased and reduced growth respectively. The IGF2R exon 34 (5002A>G) polymorphism (rs629849) of the IGF2 specific binding domain has been correlated with impaired childhood growth (A/A homozygotes). We evaluated the function of the Gly1619Arg non-synonymous amino acid modification of domain 11. NMR and X-ray crystallography structures located 1619 remote from the ligand binding region of domain 11. Arg1619 was located close to the fibronectin type II (FnII) domain of domain 13, previously implicated as a modifier of IGF2 ligand binding through indirect interaction with the AB loop of the binding cleft. However, comparison of binding kinetics of IGF2R, Gly1619 and Arg1619 to either IGF2 or mannose 6-phosphate revealed no differences in ‘on’ and ‘off’ rates. Quantitative PCR, 35S pulse chase and flow cytometry failed to demonstrate altered gene expression, protein half-life and cell membrane distribution, suggesting the polymorphism had no direct effect on receptor function. Intronic polymorphisms were identified which may be in linkage disequilibrium with rs629849 in certain populations. Other potential IGF2R polymorphisms may account for the correlation with childhood growth, warranting further functional evaluation

Adapting the Scar-in-a-Jar to Skin Fibrosis and Screening Traditional and Contemporary Anti-Fibrotic Therapies

Skin fibrosis still constitutes an unmet clinical need. Although pharmacological strategies are at the forefront of scientific and technological research and innovation, their clinical translation is hindered by the poor predictive capacity of the currently available in vitro fibrosis models. Indeed, customarily utilised in vitro scarring models are conducted in a low extracellular matrix milieu, which constitutes an oxymoron for the in-hand pathophysiology. Herein, we coupled macromolecular crowding (enhances and accelerates extracellular matrix deposition) with transforming growth factor beta 1 (TGF beta 1; induces trans-differentiation of fibroblasts to myofibroblasts) in human dermal fibroblast cultures to develop a skin fibrosis in vitro model and to screen a range of anti-fibrotic families (corticosteroids, inhibitors of histone deacetylases, inhibitors of collagen crosslinking, inhibitors of TGF beta 1 and pleiotropic inhibitors of fibrotic activation). Data obtained demonstrated that macromolecular crowding combined with TGF beta 1 significantly enhanced collagen deposition and myofibroblast transformation. Among the anti-fibrotic compounds assessed, trichostatin A (inhibitors of histone deacetylases); serelaxin and pirfenidone (pleiotropic inhibitors of fibrotic activation); and soluble TGF beta receptor trap (inhibitor of TGF beta signalling) resulted in the highest decrease of collagen type I deposition (even higher than triamcinolone acetonide, the gold standard in clinical practice). This study further advocates the potential of macromolecular crowding in the development of in vitro pathophysiology models.Peer reviewe