SOST Inhibits Prostate Cancer Invasion.

Inhibitors of Wnt signaling have been shown to be involved in prostate cancer (PC) metastasis; however the role of Sclerostin (Sost) has not yet been explored. Here we show that elevated Wnt signaling derived from Sost deficient osteoblasts promotes PC invasion, while rhSOST has an inhibitory effect. In contrast, rhDKK1 promotes PC elongation and filopodia formation, morphological changes characteristic of an invasive phenotype. Furthermore, rhDKK1 was found to activate canonical Wnt signaling in PC3 cells, suggesting that SOST and DKK1 have opposing roles on Wnt signaling in this context. Gene expression analysis of PC3 cells co-cultured with OBs exhibiting varying amounts of Wnt signaling identified CRIM1 as one of the transcripts upregulated under highly invasive conditions. We found CRIM1 overexpression to also promote cell-invasion. These findings suggest that bone-derived Wnt signaling may enhance PC tropism by promoting CRIM1 expression and facilitating cancer cell invasion and adhesion to bone. We concluded that SOST and DKK1 have opposing effects on PC3 cell invasion and that bone-derived Wnt signaling positively contributes to the invasive phenotypes of PC3 cells by activating CRIM1 expression and facilitating PC-OB physical interaction. As such, we investigated the effects of high concentrations of SOST in vivo. We found that PC3-cells overexpressing SOST injected via the tail vein in NSG mice did not readily metastasize, and those injected intrafemorally had significantly reduced osteolysis, suggesting that targeting the molecular bone environment may influence bone metastatic prognosis in clinical settings

Candida albicans Induces Arginine Biosynthetic Genes in Response to Host-Derived Reactive Oxygen Species

The interaction of Candida albicans with phagocytes of the host\u27s innate immune system is highly dynamic, and its outcome directly impacts the progression of infection. While the switch to hyphal growth within the macrophage is the most obvious physiological response, much of the genetic response reflects nutrient starvation: translational repression and induction of alternative carbon metabolism. Changes in amino acid metabolism are not seen, with the striking exception of arginine biosynthesis, which is upregulated in its entirety during coculture with macrophages. Using single-cell reporters, we showed here that arginine biosynthetic genes are induced specifically in phagocytosed cells. This induction is lower in magnitude than during arginine starvation in vitro and is driven not by an arginine deficiency within the phagocyte but instead by exposure to reactive oxygen species (ROS). Curiously, these genes are induced in a narrow window of sublethal ROS concentrations. C. albicans cells phagocytosed by primary macrophages deficient in the gp91phox subunit of the phagocyte oxidase do not express the ARG pathway, indicating that the induction is dependent on the phagocyte oxidative burst. C. albicans arg pathway mutants are retarded in germ tube and hypha formation within macrophages but are not notably more sensitive to ROS. We also find that the ARG pathway is regulated not by the general amino acid control response but by transcriptional regulators similar to the Saccharomyces cerevisiae ArgR complex. In summary, phagocytosis induces this single amino acid biosynthetic pathway in an ROS-dependent manner

Breath Stable Isotope Analysis Serves as a Non-invasive Analytical Tool to Demonstrate Dietary Changes in Adolescent Students Over Time

Concern about adolescent diets, obesity, and the associated health risks have been growing in the United States. This inspired former First Lady Michelle Obama to spearhead the Healthy Hunger-Free Kids Act (HHFKA), which made changes to the national school lunch program by increasing servings of whole grains, fruits, and vegetables. Our study examined the variability of student carbohydrate sources throughout the day and before and after the implementation of HHFKA using a stable isotope dietary biomarker. This method uses carbon stable isotope values of exhaled CO2 breath (δ13Cbreath) and provides a quantitative, non-invasive measure. δ13Cbreath samples were collected throughout the day from students (n = 31) that attended a public high school in Salt Lake City, UT. δ13Cbreath measurements reflected the short-term carbohydrate inputs from the previous meal. Carbohydrate sources were not consistent throughout the day; most students had their lowest inputs of corn/sugar-based carbohydrates after lunch. We compared our results with an earlier study that had been conducted pre-HHFKA. After-lunch δ13Cbreath values decreased significantly between the two time points, suggesting an increase in whole grain, fruit, and vegetable carbohydrates in the lunch program. Our results demonstrated that δ13Cbreath measurements provide a valuable tool to examine carbohydrate sources in an individual's diet throughout the day. We believe that this tool could be beneficial to studies examining the relationship between sugar sweetened beverages, added sugars, and refined carbohydrates and health outcomes like diabetes and obesity in both adolescent and adult populations.Fil: Mancuso, Christy J.. University of New Mexico. Department of Biology; Estados UnidosFil: Cornwall, Collette M.. Highland High School; Estados UnidosFil: Robinson, Swede. Highland High School; Estados UnidosFil: Valenzuela, Luciano Oscar. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Sociales. Departamento de Arqueología. Laboratorio de Ecología Evolutiva Humana (Sede Quequén); Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; ArgentinaFil: Ehleringer, James R.. University Of Utah. Department Of Biology; Estados Unido

A bi‐objective procedure to deliver actionable knowledge in sport services

The increase in retention of customer in gyms and health clubs is nowadays a challenge that requires concrete and personalized actions. Traditional data mining studies focused essentially on predictive analytics, neglecting the business domain. This work presents an actionable knowledge discovery system which uses the following pipeline (data collection, predictive model, retention interventions). In the first step, it extracts and transforms existing real data from databases of the sports facilities. In a second step, predictive models are applied to identify user profiles more susceptible to dropout, where actionable withdrawal rules are based on actionable attributes. Finally, in the third step, based on the previous actionable knowledge some of the values of the actionable attributes should be changed in order to increase retention. Simulation of scenarios is carried out, with test and control groups, where business utility and associate cost are measured. This document presents a bi-objective study in order to choose the more efficient scenarios.info:eu-repo/semantics/publishedVersio

Sostdc1 deficiency accelerates fracture healing by promoting the expansion of periosteal mesenchymal stem cells

Loss of Sostdc1, a growth factor paralogous to Sost, causes the formation of ectopic incisors, fused molars, abnormal hair follicles, and resistance to kidney disease. Sostdc1 is expressed in the periosteum, a source of osteoblasts, fibroblasts and mesenchymal progenitor cells, which are critically important for fracture repair. Here, we investigated the role of Sostdc1 in bone metabolism and fracture repair. Mice lacking Sostdc1 (Sostdc1−/−) had a low bone mass phenotype associated with loss of trabecular bone in both lumbar vertebrae and in the appendicular skeleton. In contrast, Sostdc1−/− cortical bone measurements revealed larger bones with higher BMD, suggesting that Sostdc1 exerts differential effects on cortical and trabecular bone. Mid-diaphyseal femoral fractures induced in Sostdc1−/− mice showed that the periosteal population normally positive for Sostdc1 rapidly expands during periosteal thickening and these cells migrate into the fracture callus at 3 days post fracture. Quantitative analysis of mesenchymal stem cell (MSC) and osteoblast populations determined that MSCs express Sostdc1, and that Sostdc1−/− 5 day calluses harbor > 2-fold more MSCs than fractured wildtype controls. Histologically a fraction of Sostdc1-positive cells also expressed nestin and α-smooth muscle actin, suggesting that Sostdc1 marks a population of osteochondral progenitor cells that actively participate in callus formation and bone repair. Elevated numbers of MSCs in D5 calluses resulted in a larger, more vascularized cartilage callus at day 7, and a more rapid turnover of cartilage with significantly more remodeled bone and a thicker cortical shell at 21 days post fracture. These data support accelerated or enhanced bone formation/remodeling of the callus in Sostdc1−/− mice, suggesting that Sostdc1 may promote and maintain mesenchymal stem cell quiescence in the periosteum

Symphonie massively parallel computer, modelling and design

The goal of this paper is to present an embedded calculator for image processing SYMPHONIE and the methodology used for its realization. In this calculator we could have up to 1024 processors . Its first application will take place in the french Rafale Aircraft as core of the infra-red system . For this application, low size and low consumption will be very important and an ASIC of a million gates has been developped . To succeed in this realization we used a VHDL model allowing simulations on the full system . Then we used VHDL synthesis methods for the conception of the ASIC . We will conclude this paper by a presentation of some perfomances of the system in some applications fields .L'objectif de cet article est de présenter le calculateur embarqué de traitement d'image SYMPHONIE, ainsi que la méthodologie mise en oeuvre pour sa réalisation. Ce calculateur dont une des applications se situe au coeur du système de veille infrarouge de l'avion Rafale pourra comporter jusqu'à 1024 processeurs. Afin de tenir compte des contraintes de volume et de consommation, un ASIC d'un million de portes a été développé. Pour réussir cette réalisation un modèle VHDL a été écrit permettant des simulations de l'ensemble du système. Par ailleurs, ce modèle a permis d'aborder la réalisation du circuit ASIC en faisant appel aux outils de synthèse VHDL. Nous terminerons cette présentation par quelques performances dans différents domaines d'applications

Nectin-4: a new prognostic biomarker for efficient therapeutic targeting of primary and metastatic triple-negative breast cancer

International audienceBackground: Triple-negative breast cancers (TNBCs) are associated with a poor prognosis. In contrast to other molecular sub-types, they have no identified specific target and chemotherapy remains the only available systemic treatment. The adhesion molecule nectin-4 represents a new potential therapeutic target in different cancer models. Here, we have tested the prognos-tic value of nectin-4 expression and assessed the therapeutic efficiency of an anti-nectin 4 antibody drug conjugate (ADC) on localised and metastatic TNBC in vitro and in vivo. Materials and methods: We analysed nectin-4/PVRL4 mRNA expression in 5673 invasive breast cancers and searched for correlations with clinicopathological features including metastasis-free survival (MFS). Immunohistochemistry was carried out in 61 TNBCs and in samples of primary TNBC Patient-Derived Xenografts (PDXs). An anti-nectin-4 antibody eligible for ADC was produced and tested in vitro and in vivo in localised and metastatic TNBC PDXs. Results: High nectin-4/PVRL4 mRNA expression was associated with poor-prognosis features including the TN and basal sub-types. High PVRL4 mRNA expression showed independent negative prognostic value for MFS in multivariate analysis in TNBCs. Nectin-4 protein expression was not detected in adult healthy tissues including mammary tissue. Membranous protein expression was found in 62% of TNBCs, with strong correlation with mRNA expression. We developed an ADC (N41mab-vcMMAE) comprising a human anti-nectin-4 monoclonal antibody conjugated to monomethyl auristatin-E (MMAE). In vitro, this ADC bound to nectin-4 with high affinity and specificity and induced its internalisation as well as dose-dependent cytotoxicity on nectin-4-expressing breast cancer cell lines. In vivo, this ADC induced rapid, complete and durable responses on nectin-4-positive xenograft TNBC samples including primary tumours, metastatic lesions, and local relapses; efficiency was dependent on both the dose and the nectin-4 tumour expression level. Conclusion: Nectin-4 is both a new promising prognostic biomarker and specific therapeutic target for ADC in the very limited armamentarium against TNBC

Young children’s impressionable use of teleology: the influence of question wording and questioned topic on teleological explanations for natural phenomena

There is a significant body of research on children's preconceptions concerning scientific concepts and the impact this has upon their science education. One active issue concerns the extent to which young children's explanations for the existence of natural kinds rely on a teleological rationale: for example, rain is for watering the grass, or tigers’ stripes are for camouflage. It has been argued that this teleological tendency hampers children's ability to learn about causality in the natural world. This paper investigates two factors (question wording and topic) which it is argued have led to a misestimation of children's teleological tendencies within the area natural phenomena: i.e., those that are time-constrained, natural events or process such as snow, clouds or night. Sixty-six (5- to 8-years-old) children took part in a repeated-measures experiment, answering both open- and leading-questions across 10 topics of natural phenomena. The findings indicate that children's teleological reasoning may have been overestimated as open question forms significantly reduced their tendency to answer teleologically. Moreover, the concept of teleology is more nuanced than often suggested. Consequently, young children may be more able to learn about causal explanations for the existence of natural phenomena than the literature implies

Indications of strong adaptive population genetic structure in albacore tuna (Thunnus alalunga) in the southwest and central Pacific Ocean

Albacore tuna (Thunnus alalunga) has a distinctly complex life history in which juveniles and adults separate geographically but at times inhabit the same spaces sequentially. The species also migrates long distances and presumably experiences varied regimes of physical stress over a lifetime. There are, therefore, many opportunities for population structure to arise based on stochastic differences or environmental factors that promote local adaptation. However, with the extent of mobility consistently demonstrated by tagged individuals, there is also a strong argument for panmixia within an ocean basin. It is important to confirm such assumptions from a population genetics standpoint for this species in particular because albacore is one of the principal market tuna species that sustains massive global fisheries and yet is also a slow‐growing temperate tuna. Consequently, we used 1,837 neutral SNP loci and 89 loci under potential selection to analyze population genetic structure among five sample groups collected from the western and central South Pacific. We found no evidence to challenge panmixia at neutral loci, but strong indications of structuring at adaptive loci. One population sample, from French Polynesia in 2004, was particularly differentiated. Unfortunately, the current study cannot infer whether the divergence is geographic or temporal, or possibly caused by sample distribution. We encourage future studies to include potentially adaptive loci and to continue fine scale observations within an ocean basin, and not to assume genome‐wide panmixia