BRG1 interacts with SOX10 to establish the melanocyte lineage and to promote differentiation

Mutations in SOX10 cause neurocristopathies which display varying degrees of hypopigmentation. Using a sensitized mutagenesis screen, we identified Smarca4 as a modifier gene that exacerbates the phenotypic severity of Sox10 haplo-insufficient mice. Conditional deletion of Smarca4 in SOX10 expressing cells resulted in reduced numbers of cranial and ventral trunk melanoblasts. To define the requirement for the Smarca4 -encoded BRG1 subunit of the SWI/SNF chromatin remodeling complex, we employed in vitro models of melanocyte differentiation in which induction of melanocyte-specific gene expression is closely linked to chromatin alterations. We found that BRG1 was required for expression of Dct, Tyrp1 and Tyr, genes that are regulated by SOX10 and MITF and for chromatin remodeling at distal and proximal regulatory sites. SOX10 was found to physically interact with BRG1 in differentiating melanocytes and binding of SOX10 to the Tyrp1 distal enhancer temporally coincided with recruitment of BRG1. Our data show that SOX10 cooperates with MITF to facilitate BRG1 binding to distal enhancers of melanocyte-specific genes. Thus, BRG1 is a SOX10 co-activator, required to establish the melanocyte lineage and promote expression of genes important for melanocyte function

Does Sex Trade with Violence among Genotypes in Drosophila melanogaster?

The evolutionary forces shaping the ability to win competitive interactions, such as aggressive encounters, are still poorly understood. Given a fitness advantage for competitive success, variance in aggressive and sexual display traits should be depleted, but a great deal of variation in these traits is consistently found. While life history tradeoffs have been commonly cited as a mechanism for the maintenance of variation, the variability of competing strategies of conspecifics may mean there is no single optimum strategy. We measured the genetically determined outcomes of aggressive interactions, and the resulting effects on mating success, in a panel of diverse inbred lines representing both natural variation and artificially selected genotypes. Males of one genotype which consistently lost territorial encounters with other genotypes were nonetheless successful against males that were artificially selected for supernormal aggression and dominated all other lines. Intransitive patterns of territorial success could maintain variation in aggressive strategies if there is a preference for territorial males. Territorial success was not always associated with male mating success however and females preferred ‘winners’ among some male genotypes, and ‘losers’ among other male genotypes. This suggests that studying behaviour from the perspective of population means may provide limited evolutionary and genetic insight. Overall patterns of competitive success among males and mating transactions between the sexes are consistent with mechanisms proposed for the maintenance of genetic variation due to nonlinear outcomes of competitive interactions

Assessing the cost of global biodiversity and conservation knowledge

Knowledge products comprise assessments of authoritative information supported by stan-dards, governance, quality control, data, tools, and capacity building mechanisms. Considerable resources are dedicated to developing and maintaining knowledge productsfor biodiversity conservation, and they are widely used to inform policy and advise decisionmakers and practitioners. However, the financial cost of delivering this information is largelyundocumented. We evaluated the costs and funding sources for developing and maintain-ing four global biodiversity and conservation knowledge products: The IUCN Red List ofThreatened Species, the IUCN Red List of Ecosystems, Protected Planet, and the WorldDatabase of Key Biodiversity Areas. These are secondary data sets, built on primary datacollected by extensive networks of expert contributors worldwide. We estimate that US$160million (range: US$116–204 million), plus 293 person-years of volunteer time (range: 278–308 person-years) valued at US$14 million (range US$12–16 million), were invested inthese four knowledge products between 1979 and 2013. More than half of this financingwas provided through philanthropy, and nearly three-quarters was spent on personnelcosts. The estimated annual cost of maintaining data and platforms for three of these knowl-edge products (excluding the IUCN Red List of Ecosystems for which annual costs were notpossible to estimate for 2013) is US$6.5 million in total (range: US$6.2–6.7 million). We esti-mated that an additional US$114 million will be needed to reach pre-defined baselines ofdata coverage for all the four knowledge products, and that once achieved, annual mainte-nance costs will be approximately US$12 million. These costs are much lower than those tomaintain many other, similarly important, global knowledge products. Ensuring that biodi-versity and conservation knowledge products are sufficiently up to date, comprehensiveand accurate is fundamental to inform decision-making for biodiversity conservation andsustainable development. Thus, the development and implementation of plans for sustain-able long-term financing for them is critical

A primary care, multi-disciplinary disease management program for opioid-treated patients with chronic non-cancer pain and a high burden of psychiatric comorbidity

BACKGROUND: Chronic non-cancer pain is a common problem that is often accompanied by psychiatric comorbidity and disability. The effectiveness of a multi-disciplinary pain management program was tested in a 3 month before and after trial. METHODS: Providers in an academic general medicine clinic referred patients with chronic non-cancer pain for participation in a program that combined the skills of internists, clinical pharmacists, and a psychiatrist. Patients were either receiving opioids or being considered for opioid therapy. The intervention consisted of structured clinical assessments, monthly follow-up, pain contracts, medication titration, and psychiatric consultation. Pain, mood, and function were assessed at baseline and 3 months using the Brief Pain Inventory (BPI), the Center for Epidemiological Studies-Depression Scale scale (CESD) and the Pain Disability Index (PDI). Patients were monitored for substance misuse. RESULTS: Eighty-five patients were enrolled. Mean age was 51 years, 60% were male, 78% were Caucasian, and 93% were receiving opioids. Baseline average pain was 6.5 on an 11 point scale. The average CESD score was 24.0, and the mean PDI score was 47.0. Sixty-three patients (73%) completed 3 month follow-up. Fifteen withdrew from the program after identification of substance misuse. Among those completing 3 month follow-up, the average pain score improved to 5.5 (p = 0.003). The mean PDI score improved to 39.3 (p < 0.001). Mean CESD score was reduced to 18.0 (p < 0.001), and the proportion of depressed patients fell from 79% to 54% (p = 0.003). Substance misuse was identified in 27 patients (32%). CONCLUSIONS: A primary care disease management program improved pain, depression, and disability scores over three months in a cohort of opioid-treated patients with chronic non-cancer pain. Substance misuse and depression were common, and many patients who had substance misuse identified left the program when they were no longer prescribed opioids. Effective care of patients with chronic pain should include rigorous assessment and treatment of these comorbid disorders and intensive efforts to insure follow up

Effects of Grassland Management Practices on Ant Functional Groups in Central North America

Tallgrass prairies of central North America have experienced disturbances including fire and grazing for millennia. Little is known about the effects of these disturbances on prairie ants, even though ants are thought to play major roles in ecosystem maintenance. We implemented three management treatments on remnant and restored grassland tracts in the central U.S., and compared the effects of treatment on abundance of ant functional groups. Management treatments were: (1) patch-burn graze—rotational burning of three spatially distinct patches within a fenced tract, and growing-season cattle grazing; (2) graze-and-burn—burning entire tract every 3 years, and growing-season cattle grazing, and (3) burn-only—burning entire tract every 3 years, but no cattle grazing. Ant species were classified into one of four functional groups. Opportunist ants and the dominant ant species, Formica montana, were more abundant in burn-only tracts than tracts managed with either of the grazing treatments. Generalists were more abundant in graze-and-burn tracts than in burn-only tracts. Abundance of F. montana was negatively associated with pre-treatment time since fire, whereas generalist ant abundance was positively associated. F. montanawere more abundant in restored tracts than remnants, whereas the opposite was true for subdominants and opportunists. In summary, abundance of the dominant F. montana increased in response to intense disturbances that were followed by quick recovery of plant biomass. Generalist ant abundance decreased in response to those disturbances, which we attribute to the effects of competitive dominance of F. montana upon the generalists

Dynamics of the Leaf-Litter Arthropod Fauna Following Fire in a Neotropical Woodland Savanna

Fire is an important agent of disturbance in tropical savannas, but relatively few studies have analyzed how soil-and-litter dwelling arthropods respond to fire disturbance despite the critical role these organisms play in nutrient cycling and other biogeochemical processes. Following the incursion of a fire into a woodland savanna ecological reserve in Central Brazil, we monitored the dynamics of litter-arthropod populations for nearly two years in one burned and one unburned area of the reserve. We also performed a reciprocal transplant experiment to determine the effects of fire and litter type on the dynamics of litter colonization by arthropods. Overall arthropod abundance, the abundance of individual taxa, the richness of taxonomic groups, and the species richness of individual taxa (Formiciade) were lower in the burned site. However, both the ordinal-level composition of the litter arthropod fauna and the species-level composition of the litter ant fauna were not dramatically different in the burned and unburned sites. There is evidence that seasonality of rainfall interacts with fire, as differences in arthropod abundance and diversity were more pronounced in the dry than in the wet season. For many taxa the differences in abundance between burned and unburned sites were maintained even when controlling for litter availability and quality. In contrast, differences in abundance for Collembola, Formicidae, and Thysanoptera were only detected in the unmanipulated samples, which had a lower amount of litter in the burned than in the unburned site throughout most of our study period. Together these results suggest that arthropod density declines in fire-disturbed areas as a result of direct mortality, diminished resources (i.e., reduced litter cover) and less favorable microclimate (i.e., increased litter desiccation due to reduction in tree cover). Although these effects were transitory, there is evidence that the increasingly prevalent fire return interval of only 1–2 years may jeopardize the long-term conservation of litter arthropod communities

Blooming Artifact Reduction in Coronary Artery Calcification by A New De-blooming Algorithm: Initial Study

The aim of this study was to investigate the use of de-blooming algorithm in coronary CT angiography (CCTA) for optimal evaluation of calcified plaques. Calcified plaques were simulated on a coronary vessel phantom and a cardiac motion phantom. Two convolution kernels, standard (STND) and high-definition standard (HD STND), were used for imaging reconstruction. A dedicated de-blooming algorithm was used for imaging processing. We found a smaller bias towards measurement of stenosis using the deblooming algorithm (STND: bias 24.6% vs 15.0%, range 10.2% to 39.0% vs 4.0% to 25.9%; HD STND: bias 17.9% vs 11.0%, range 8.9% to 30.6% vs 0.5% to 21.5%). With use of de-blooming algorithm, specificity for diagnosing significant stenosis increased from 45.8% to 75.0% (STND), from 62.5% to 83.3% (HD STND); while positive predictive value (PPV) increased from 69.8% to 83.3% (STND), from 76.9% to 88.2% (HD STND). In the patient group, reduction in calcification volume was 48.1 ± 10.3%, reduction in coronary diameter stenosis over calcified plaque was 52.4 ± 24.2%. Our results suggest that the novel de-blooming algorithm could effectively decrease the blooming artifacts caused by coronary calcified plaques, and consequently improve diagnostic accuracy of CCTA in assessing coronary stenosis

Identification of a novel zinc metalloprotease through a global analysis of clostridium difficile extracellular proteins

Clostridium difficile is a major cause of infectious diarrhea worldwide. Although the cell surface proteins are recognized to be important in clostridial pathogenesis, biological functions of only a few are known. Also, apart from the toxins, proteins exported by C. difficile into the extracellular milieu have been poorly studied. In order to identify novel extracellular factors of C. difficile, we analyzed bacterial culture supernatants prepared from clinical isolates, 630 and R20291, using liquid chromatography-tandem mass spectrometry. The majority of the proteins identified were non-canonical extracellular proteins. These could be largely classified into proteins associated to the cell wall (including CWPs and extracellular hydrolases), transporters and flagellar proteins. Seven unknown hypothetical proteins were also identified. One of these proteins, CD630_28300, shared sequence similarity with the anthrax lethal factor, a known zinc metallopeptidase. We demonstrated that CD630_28300 (named Zmp1) binds zinc and is able to cleave fibronectin and fibrinogen in vitro in a zinc-dependent manner. Using site-directed mutagenesis, we identified residues important in zinc binding and enzymatic activity. Furthermore, we demonstrated that Zmp1 destabilizes the fibronectin network produced by human fibroblasts. Thus, by analyzing the exoproteome of C. difficile, we identified a novel extracellular metalloprotease that may be important in key steps of clostridial pathogenesis

A novel mutation of the calcium sensing receptor gene is associated with chronic pancreatitis in a family with heterozygous SPINK1 mutations

BACKGROUND: The role of mutations in the serine protease inhibitor Kazal type 1 (SPINK1) gene in chronic pancreatitis is still a matter of debate. Active SPINK1 is thought to antagonize activated trypsin. Cases of SPINK1 mutations, especially N34S, have been reported in a subset of patients with idiopathic chronic pancreatitis. However, the inheritance pattern is still unknown. Some cases with N34S heterozygosity have been reported with and without evidence for CP indicating neither an autosomal recessive nor dominant trait. Therefore SPINK1 mutations have been postulated to act as a disease modifier requiring additional mutations in a more complex genetic model. Familial hypocalciuric hypercalcemia (FHH) caused by heterozygous inactivating mutations in the calcium sensing receptor (CASR) gene is considered a benign disorder with elevated plasma calcium levels. Although hypercalcemia represents a risk factor for pancreatitis, increased rates of pancreatitis in patients with FHH have not been reported thus far. METHODS: We studied a family with a FHH-related hypercalcemia and chronic pancreatitis. DNA samples were analysed for mutations within the cationic trypsinogen (N29I, R122H) and SPINK1 (N34S) gene using melting curve analysis. Mutations within CASR gene were identified by DNA sequencing. RESULTS: A N34S SPINK1 mutation was found in all screened family members. However, only two family members developed chronic pancreatitis. These patients also had FHH caused by a novel, sporadic mutation in the CASR gene (518T>C) leading to an amino acid exchange (leucine->proline) in the extracellular domain of the CASR protein. CONCLUSION: Mutations in the calcium sensing receptor gene might represent a novel as yet unidentified predisposing factor which may lead to an increased susceptibility for chronic pancreatitis. Moreover, this family analysis supports the hypothesis that SPINK1 mutations act as disease modifier and suggests an even more complex genetic model in SPINK1 related chronic pancreatitis