A novel familial mutation in the PCSK1 gene that alters the oxyanion hole residue of proprotein convertase 1/3 and impairs its enzymatic activity.

Four siblings presented with congenital diarrhea and various endocrinopathies. Exome sequencing and homozygosity mapping identified five regions, comprising 337 protein-coding genes that were shared by three affected siblings. Exome sequencing identified a novel homozygous N309K mutation in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, encoding the neuroendocrine convertase 1 precursor (PC1/3) which was recently reported as a cause of Congenital Diarrhea Disorder (CDD). The PCSK1 mutation affected the oxyanion hole transition state-stabilizing amino acid within the active site, which is critical for appropriate proprotein maturation and enzyme activity. Unexpectedly, the N309K mutant protein exhibited normal, though slowed, prodomain removal and was secreted from both HEK293 and Neuro2A cells. However, the secreted enzyme showed no catalytic activity, and was not processed into the 66 kDa form. We conclude that the N309K enzyme is able to cleave its own propeptide but is catalytically inert against in trans substrates, and that this variant accounts for the enteric and systemic endocrinopathies seen in this large consanguineous kindred

Transplanting the leafy liverwort Herbertus hutchinsiae : A suitable conservation tool to maintain oceanic-montane liverwort-rich heath?

Thanks to the relevant landowners and managers for permission to carry out the experiments, Chris Preston for helping to obtain the liverwort distribution records and the distribution map, Gordon Rothero and Dave Horsfield for advice on choosing experimental sites and Alex Douglas for statistical advice. Juliane Geyer’s help with fieldwork was greatly appreciated. This study was made possible by a NERC PhD studentship and financial support from the Royal Botanic Garden Edinburgh and Scottish Natural Heritage.Peer reviewedPostprin

Excavations and the afterlife of a professional football stadium, Peel Park, Accrington, Lancashire: towards an archaeology of football

Association football is now a multi-billion dollar global industry whose emergence spans the post-medieval to the modern world. With its professional roots in late 19th-century industrial Lancashire, stadiums built for the professionalization of football first appear in frequency in the North of England. While many historians of sport focus on consumerism and ‘topophilia’ (attachment to place) regarding these local football grounds, archaeological research that has been conducted on the spectator experience suggests status differentiation within them. Our excavations at Peel Park confirm this impression while also showing a significant afterlife to this stadium, particularly through children’s play

Co-occurrence of ecologically similar species of Hawaiian spiders reveals critical early phase of adaptive radiation

Background: The processes through which populations originate and diversify ecologically in the initial stages of adaptive radiation are little understood because we lack information on critical steps of early divergence. A key question is, at what point do closely related species interact, setting the stage for competition and ecological specialization? The Hawaiian Islands provide an ideal system to explore the early stages of adaptive radiation because the islands span ages from 0.5–5 Mya. Hawaiian spiders in the genus Tetragnatha have undergone adaptive radiation, with one lineage (“spiny legs�) showing four different ecomorphs (green, maroon, large brown, small brown); one representative of each ecomorph is generally found at any site on the older islands. Given that the early stages of adaptive radiation are characterized by allopatric divergence between populations of the same ecomorph, the question is, what are the steps towards subsequent co-occurrence of different ecomorphs? Using a transcriptome-based exon capture approach, we focus on early divergence among close relatives of the green ecomorph to understand processes associated with co-occurrence within the same ecomorph at the early stages of adaptive radiation. Results: The major outcomes from the current study are first that closely related species within the same green ecomorph of spiny leg Tetragnatha co-occur on the same single volcano on East Maui, and second that there is no evidence of genetic admixture between these ecologically equivalent species. Further, that multiple genetic lineages exist on a single volcano on Maui suggests that there are no inherent dispersal barriers and that the observed limited distribution of taxa reflects competitive exclusion. Conclusions: The observation of co-occurrence of ecologically equivalent species on the young volcano of Maui provides a missing link in the process of adaptive radiation between the point when recently divergent species of the same ecomorph occur in allopatry, to the point where different ecomorphs co-occur at a site, as found throughout the older islands. More importantly, the ability of close relatives of the same ecomorph to interact, without admixture, may provide the conditions necessary for ecological divergence and independent evolution of ecomorphs associated with adaptive radiation

Short Children with CHARGE Syndrome: Do They Benefit from Growth Hormone Therapy?

AIM: The aim of this study was to evaluate the response to recombinant growth hormone (GH) treatment in short children with CHARGE syndrome. PATIENTS: We identified 51 children (28 boys and 23 girls) in KIGS (Pfizer International Growth Database). The median chronological age was 7.6 years at the start of GH therapy and 13.2 years at the latest visit. Evaluation for GH deficiency (n = 33) was based on the following: peak GH level 7.3 μg/l and IGF-I level -2.01 standard deviation score (SDS). Sixteen subjects (9 boys) were followed longitudinally for 2 years. RESULTS: Birth length (median SDS, -0.47) and weight (-0.97) were slightly reduced. At the start of GH therapy, height was -3.6 SDS, BMI -0.7 SDS, and the GH dose was 0.26 mg/kg/week. At the latest visit after 2.7 years of GH therapy, height had increased to -2.2 SDS and BMI to -0.5 SDS. In the longitudinal group, height increased from -3.72 SDS at the start of GH therapy to -2.92 SDS after 1 year to -2.37 SDS after 2 years of therapy (start - 2 years: p < 0.05), height velocity increased from -1.69 to 2.98 to 0.95 SDS, and BMI and GH dose (mg/kg/week) remained almost unchanged. CONCLUSIONS: Our data show a positive effect of conventional doses of GH on short-term growth velocity for the longitudinal as well as for the total group, without any safety issues.This study was sponsored by Pfizer Inc.This is the author accepted manuscript. The final version is available from Karger via http://dx.doi.org/10.1159/00038201

The Role of the Iron Transporter ABCB7 in Refractory Anemia with Ring Sideroblasts

Refractory Anemia with Ring Sideroblasts (RARS) is an acquired myelodysplastic syndrome (MDS) characterized by an excess iron accumulation in the mitochondria of erythroblasts. The pathogenesis of RARS and the cause of this unusual pattern of iron deposition remain unknown. We considered that the inherited X-linked sideroblastic anemia with ataxia (XLSA/A) might be informative for the acquired disorder, RARS. XLSA/A is caused by partial inactivating mutations of the ABCB7 ATP-binding cassette transporter gene, which functions to enable transport of iron from the mitochondria to the cytoplasm. Furthermore, ABCB7 gene silencing in HeLa cells causes an accumulation of iron in the mitochondria. We have studied the role of ABCB7 in RARS by DNA sequencing, methylation studies, and gene expression studies in primary CD34+ cells and in cultured erythroblasts. The DNA sequence of the ABCB7 gene is normal in patients with RARS. We have investigated ABCB7 gene expression levels in the CD34+ cells of 122 MDS cases, comprising 35 patients with refractory anemia (RA), 33 patients with RARS and 54 patients with RA with excess blasts (RAEB), and in the CD34+ cells of 16 healthy controls. We found that the expression levels of ABCB7 are significantly lower in the RARS group. RARS is thus characterized by lower levels of ABCB7 gene expression in comparison to other MDS subtypes. Moreover, we find a strong relationship between increasing percentage of bone marrow ring sideroblasts and decreasing ABCB7 gene expression levels. Erythroblast cell cultures confirm the low levels of ABCB7 gene expression levels in RARS. These data provide an important link between inherited and acquired forms of sideroblastic anemia and indicate that ABCB7 is a strong candidate gene for RARS

New research directions on disparities in obesity and type 2 diabetes

Obesity and type 2 diabetes disproportionately impact U.S. racial and ethnic minority communities and lowâ income populations. Improvements in implementing efficacious interventions to reduce the incidence of type 2 diabetes are underway (i.e., the National Diabetes Prevention Program), but challenges in effectively scalingâ up successful interventions and reaching atâ risk populations remain. In October 2017, the National Institutes of Health convened a workshop to understand how to (1) address socioeconomic and other environmental conditions that perpetuate disparities in the burden of obesity and type 2 diabetes; (2) design effective prevention and treatment strategies that are accessible, feasible, culturally relevant, and acceptable to diverse population groups; and (3) achieve sustainable health improvement approaches in communities with the greatest burden of these diseases. Common features of guiding frameworks to understand and address disparities and promote health equity were described. Promising research directions were identified in numerous areas, including study design, methodology, and core metrics; program implementation and scalability; the integration of medical care and social services; strategies to enhance patient empowerment; and understanding and addressing the impact of psychosocial stress on disease onset and progression in addition to factors that support resiliency and health.This report discusses a workshop convened by the National Institutes of Health to understand how to (1) address socioeconomic and other environmental conditions that perpetuate disparities in the burden of obesity and type 2 diabetes; (2) design effective prevention and treatment strategies that are accessible, feasible, culturally relevant, and acceptable to diverse population groups; and (3) achieve sustainable health improvement approaches in communities with the greatest burden of these diseases.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154507/1/nyas14270_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154507/2/nyas14270.pd