LYVE1 Marks the Divergence of Yolk Sac Definitive Hemogenic Endothelium from the Primitive Erythroid Lineage.

The contribution of the different waves and sites of developmental hematopoiesis to fetal and adult blood production remains unclear. Here, we identify lymphatic vessel endothelial hyaluronan receptor-1 (LYVE1) as a marker of yolk sac (YS) endothelium and definitive hematopoietic stem and progenitor cells (HSPCs). Endothelium in mid-gestation YS and vitelline vessels, but not the dorsal aorta and placenta, were labeled by Lyve1-Cre. Most YS HSPCs and erythro-myeloid progenitors were Lyve1-Cre lineage traced, but primitive erythroid cells were not, suggesting that they represent distinct lineages. Fetal liver (FL) and adult HSPCs showed 35%-40% Lyve1-Cre marking. Analysis of circulation-deficient Ncx1-/- concepti identified the YS as a major source of Lyve1-Cre labeled HSPCs. FL proerythroblast marking was extensive at embryonic day (E) 11.5-13.5, but decreased to hematopoietic stem cell (HSC) levels by E16.5, suggesting that HSCs from multiple sources became responsible for erythropoiesis. Lyve1-Cre thus marks the divergence between YS primitive and definitive hematopoiesis and provides a tool for targeting YS definitive hematopoiesis and FL colonization

Affect Variability and Physical Health: The Moderating Role of Mean Affect

Research has only begun to explore how affect variability relates to physical health and has typically not assessed long-term associations nor considered the moderating role of mean affect. Therefore, we used data from the Midlife in the United States Study waves 2 (N = 1512) and 3 (N = 1499) to test how affect variability predicted concurrent and long-term physical health while also testing the moderating role of mean affect. Results indicated that greater negative affect variability was associated concurrently with a greater number of chronic conditions (p = .03) and longitudinally with worse self-rated physical health (p \u3c .01). Greater positive affect variability was associated concurrently with more chronic conditions (p \u3c .01) and medications (p \u3c .01) and longitudinally with worse self-rated physical health (p = .04). Further, mean negative affect played a moderating role such that at lower levels of mean negative affect, as affect variability increased, so did the number of concurrent chronic conditions (p \u3c .01) and medications (p = .03) and the likelihood of reporting worse long-term self-rated physical health (p \u3c .01). Thus, the role of mean affect should be considered when testing short- and long-term associations between affect variability and physical health

Resistance Training and Milk-Substitution Enhance Body Composition and Bone Health in Adolescent Girls

Background: Increased soft-drink consumption has contributed to poor calcium intake with 90% of adolescent girls consuming less than the RDA for calcium. Purpose/objectives: The purpose of this investigation was to determine the independent and additive effects of two interventions (milk and resistance training) on nutrient adequacy, body composition, and bone health in adolescent girls. Methods: The experimental design consisted of four experimental groups of adolescent girls 14–17 years of age: (1) Milk + resistance training [MRT]; n = 15; (2) Resistance training only [RT]; n = 15; (3) Milk only [M] n = 20; (4) Control [C] n = 16. A few significant differences were observed at baseline between the groups for subject characteristics. Testing was performed pre and post-12 week training period for all groups. Milk was provided (3, 8 oz servings) for both the MRT and the M groups. The MRT group and the RT groups performed a supervised periodized resistance training program consisting of supervised one-hour exercise sessions 3 d/wk (M, W, F) for 12 wk. Baseline dietary data was collected utilizing the NUT-P-FFQ and/or a 120 item FFQ developed by the Fred Hutchinson Cancer Research Center (Seattle, Washington). Body composition was measured in the morning after an overnight fast using dual-energy X-ray absorptiometry (DXA) with a total body scanner (ProdigyTM, Lunar Corporation, Madison, WI). A whole body scan for bone density and lumbar spine scans were performed on all subjects. Maximal strength of the upper and lower body was assessed via a one-repetition maximum (1-RM) squat and bench press exercise protocols. Significance was set at P ≤ 0.05. Results: Significant differences in nutrient intakes between groups generally reflected the nutrient composition of milk with greater intakes of protein and improved nutrient adequacy for several B vitamins, vitamin A, vitamin D, calcium, magnesium, phosphorus, potassium, and zinc. Mean calcium intake was 758 and 1581 mg/d, in the non-milk and milk groups, respectively, with 100% of girls in the milk groups consuming \u3e RDA of 1300 mg/d. There were no effects of milk on body composition or muscle performance, but resistance training had a main effect and significantly increased body mass, lean body mass, muscle strength, and muscle endurance. There was a main effect of milk and resistance training on several measures of bone mineral density (BMD). Changes in whole body BMD in the M, RT, MRT, and CON were 0.45, 0.52, 1.32, and −0.19%, respectively (P \u3c 0.01). Conclusions: Over the course of 12 weeks the effects of 1300 mg/d of calcium in the form of fluid milk combined with a heavy resistance training program resulted in the additive effects of greater nutrient adequacy and BMD in adolescent girls. While further studies are needed, combining increased milk consumption with resistance training appears to optimize bone health in adolescent girls

c-Met-Dependent Multipotent Labyrinth Trophoblast Progenitors Establish Placental Exchange Interface

SummaryThe placenta provides the interface for gas and nutrient exchange between the mother and the fetus. Despite its critical function in sustaining pregnancy, the stem/progenitor cell hierarchy and molecular mechanisms responsible for the development of the placental exchange interface are poorly understood. We identified an Epcamhi labyrinth trophoblast progenitor (LaTP) in mouse placenta that at a clonal level generates all labyrinth trophoblast subtypes, syncytiotrophoblasts I and II, and sinusoidal trophoblast giant cells. Moreover, we discovered that hepatocyte growth factor/c-Met signaling is required for sustaining proliferation of LaTP during midgestation. Loss of trophoblast c-Met also disrupted terminal differentiation and polarization of syncytiotrophoblasts, leading to intrauterine fetal growth restriction, fetal liver hypocellularity, and demise. Identification of this c-Met-dependent multipotent LaTP provides a landmark in the poorly defined placental stem/progenitor cell hierarchy and may help us understand pregnancy complications caused by a defective placental exchange

Somatic Mutations of PIK3R1 Promote Gliomagenesis

The phosphoinositide 3-kinase (PI3K) pathway is targeted for frequent alteration in glioblastoma (GBM) and is one of the core GBM pathways defined by The Cancer Genome Atlas. Somatic mutations of PIK3R1 are observed in multiple tumor types, but the tumorigenic activity of these mutations has not been demonstrated in GBM. We show here that somatic mutations in the iSH2 domain of PIK3R1 act as oncogenic driver events. Specifically, introduction of a subset of the mutations identified in human GBM, in the nSH2 and iSH2 domains, increases signaling through the PI3K pathway and promotes tumorigenesis of primary normal human astrocytes in an orthotopic xenograft model. Furthermore, we show that cells that are dependent on mutant P85α-mediated PI3K signaling exhibit increased sensitivity to a small molecule inhibitor of AKT. Together, these results suggest that GBM patients whose tumors carry mutant PIK3R1 alleles may benefit from treatment with inhibitors of AKT

Inhibiting the stringent response blocks Mycobacterium tuberculosis entry into quiescence and reduces persistence

The stringent response enables Mycobacterium tuberculosis (Mtb) to shut down its replication and metabolism under various stresses. Here we show that Mtb lacking the stringent response enzyme RelMtb was unable to slow its replication rate during nutrient starvation. Metabolomics analysis revealed that the nutrient-starved relMtb-deficient strain had increased metabolism similar to that of exponentially growing wild-type bacteria in nutrient-rich broth, consistent with an inability to enter quiescence. Deficiency of relMtb increased the susceptibility of mutant bacteria to killing by isoniazid during nutrient starvation and in the lungs of chronically infected mice. We screened a pharmaceutical library of over 2 million compounds for inhibitors of RelMtb and showed that the lead compound X9 was able to directly kill nutrient-starved M. tuberculosis and enhanced the killing activity of isoniazid. Inhibition of RelMtb is a promising approach to target M. tuberculosis persisters, with the potential to shorten the duration of TB treatment.This work was supported by R01AI083125, R21AI122922, and R21AI114507A to P.C.

Incorporating connectivity into conservation planning for the optimal representation of multiple species and ecosystem services

Funding was provided by the Rainforest Trust foundation. Support was also provided by the Sabah Forest Department, Forest Research Centre, the South East Asia Rainforest Research Partnership, the U.N. Development Programme, the Universiti Malaysia Sabah (FRGS0414-STWN-1/2015), PACOS Trust, BC Initiative, the Natural Environment Research Council UK (grant NE/R009597/1), and the Universities of Aberdeen, Montana, and York. We are grateful to the numerous researchers that collected the data used in our analyses, as well as the local communities and government staff who manage forested areas across Sabah.Peer reviewedPostprin

Thinking outside the channel : modeling nitrogen cycling in networked river ecosystems

Author Posting. © Ecological Society of America, 2011. This article is posted here by permission of Ecological Society of America for personal use, not for redistribution. The definitive version was published in Frontiers in Ecology and the Environment 9 (2011): 229–238, doi:10.1890/080211.Agricultural and urban development alters nitrogen and other biogeochemical cycles in rivers worldwide. Because such biogeochemical processes cannot be measured empirically across whole river networks, simulation models are critical tools for understanding river-network biogeochemistry. However, limitations inherent in current models restrict our ability to simulate biogeochemical dynamics among diverse river networks. We illustrate these limitations using a river-network model to scale up in situ measures of nitrogen cycling in eight catchments spanning various geophysical and land-use conditions. Our model results provide evidence that catchment characteristics typically excluded from models may control river-network biogeochemistry. Based on our findings, we identify important components of a revised strategy for simulating biogeochemical dynamics in river networks, including approaches to modeling terrestrial–aquatic linkages, hydrologic exchanges between the channel, floodplain/riparian complex, and subsurface waters, and interactions between coupled biogeochemical cycles.This research was supported by NSF (DEB-0111410). Additional support was provided by NSF for BJP and SMT (DEB-0614301), for WMW (OCE-9726921 and DEB-0614282), for WHM and JDP (DEB-0620919), for SKH (DEB-0423627), and by the Gordon and Betty Moore Foundation for AMH, GCP, ESB, and JAS, and by an EPA Star Fellowship for AMH

Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system philadelphia chromosome positive leukemia

Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph+) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasatinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a pre-clinical mouse model of intracranial Ph+ leukemia. Clinical dasatinib treatment in patients with CNS Ph+ leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasatinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph+ leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials. gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097)

Detection and follow-up of chronic obstructive pulmonary disease (COPD) and risk factors in the Southern Cone of Latin America. the pulmonary risk in South America (PRISA) study

<p>Abstract</p> <p>Background</p> <p>The World Health Organization has estimated that by 2030, chronic obstructive pulmonary disease will be the third leading cause of death worldwide. Most knowledge of chronic obstructive pulmonary disease is based on studies performed in Europe or North America and little is known about the prevalence, patient characteristics and change in lung function over time in patients in developing countries, such as those of Latin America. This lack of knowledge is in sharp contrast to the high levels of tobacco consumption and exposure to biomass fuels exhibited in Latin America, both major risk factors for the development of chronic obstructive pulmonary disease. Studies have also demonstrated that most Latin American physicians frequently do not follow international chronic obstructive pulmonary disease diagnostic and treatment guidelines. The PRISA Study will expand the current knowledge regarding chronic obstructive pulmonary disease and risk factors in Argentina, Chile and Uruguay to inform policy makers and health professionals on the best policies and practices to address this condition.</p> <p>Methods/Design</p> <p>PRISA is an observational, prospective cohort study with at least four years of follow-up. In the first year, PRISA has employed a randomized three-staged stratified cluster sampling strategy to identify 6,000 subjects from Marcos Paz and Bariloche, Argentina, Temuco, Chile, and Canelones, Uruguay. Information, such as comorbidities, socioeconomic status and tobacco and biomass exposure, will be collected and spirometry, anthropometric measurements, blood sampling and electrocardiogram will be performed. In year four, subjects will have repeat measurements taken.</p> <p>Discussion</p> <p>There is no longitudinal data on chronic obstructive pulmonary disease incidence and risk factors in the southern cone of Latin America, therefore this population-based prospective cohort study will fill knowledge gaps in the prevalence and incidence of chronic obstructive pulmonary disease, patient characteristics and changes in lung function over time as well as quality of life and health care resource utilization. Information gathered during the PRISA Study will inform public health interventions and prevention practices to reduce risk of COPD in the region.</p