ABSTRACT We report the Fermi Large Area Telescope (LAT) detections of high-energy (>100 MeV) γ-ray emission from two recent optically bright classical novae, V1369 Centauri 2013 and V5668 Sagittarii ...2015. At early times, Fermi target-of-opportunity observations prompted by their optical discoveries provided enhanced LAT exposure that enabled the detections of γ-ray onsets beginning ∼2 days after their first optical peaks. Significant γ-ray emission was found extending to 39-55 days after their initial LAT detections, with systematically fainter and longer-duration emission compared to previous γ-ray-detected classical novae. These novae were distinguished by multiple bright optical peaks that encompassed the time spans of the observed γ-rays. The γ-ray light curves and spectra of the two novae are presented along with representative hadronic and leptonic models, and comparisons with other novae detected by the LAT are discussed.
The Southwestern Atlantic harbors unique and relatively understudied reef systems, including the only atoll in South Atlantic: Rocas atoll. Located 230 km off the NE Brazilian coast, Rocas is formed ...by coralline red algae and vermetid mollusks, and is potentially one of the most "pristine" areas in Southwestern Atlantic. We provide the first comprehensive and integrative description of the fish and benthic communities inhabiting different shallow reef habitats of Rocas. We studied two contrasting tide pool habitats: open pools, which communicate with the open ocean even during low tides, thus more exposed to wave action; and closed pools, which remain isolated during low tide and are comparatively less exposed. Reef fish assemblages, benthic cover, algal turfs and fish feeding pressure on the benthos remarkably varied between open and closed pools. The planktivore Thalassoma noronhanum was the most abundant fish species in both habitats. In terms of biomass, the lemon shark Negaprion brevirostris and the omnivore Melichtys niger were dominant in open pools, while herbivorous fishes (mainly Acanthurus spp.) prevailed in closed pools. Overall benthic cover was dominated by algal turfs, composed of articulated calcareous algae in open pools and non-calcified algae in closed pools. Feeding pressure was dominated by acanthurids and was 10-fold lower in open pools than in closed pools. Besides different wave exposure conditions, such pattern could also be related to the presence of sharks in open pools, prompting herbivorous fish to feed more in closed pools. This might indirectly affect the structure of reef fish assemblages and benthic communities. The macroalgae Digenea simplex, which is uncommon in closed pools and abundant in the reef flat, was highly preferred in herbivory assays, indicating that herbivory by fishes might be shaping this distribution pattern. The variations in benthic and reef fish communities, and feeding pressure on the benthos between open and closed pools suggest that the dynamics in open pools is mostly driven by physical factors and the tolerance of organisms to harsh conditions, while in closed pools direct and indirect effects of species interactions also play an important role. Understanding the mechanisms shaping biological communities and how they scale-up to ecosystem functioning is particularly important on isolated near-pristine systems where natural processes can still be studied under limited human impact.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Red cell distribution width (RDW) is a quantitative measure of variability in the size of circulating erythrocytes with higher values reflecting greater heterogeneity in cell sizes. Recent ...studies have shown that higher RDW is associated with increased mortality risk in patients with clinically significant cardiovascular disease (CVD). Whether RDW is prognostic in more representative community-based populations is unclear. Methods Seven relevant community-based studies of older adults with RDW measurement and mortality ascertainment were identified. Cox proportional hazards regression and meta-analysis on individual participant data were performed. Results Median RDW values varied across studies from 13.2% to 14.6%. During 68,822 person-years of follow-up of 11,827 older adults with RDW measured, there was a graded increased risk of death associated with higher RDW values (p < .001). For every 1% increment in RDW, total mortality risk increased by 14% (adjusted hazard ratio HR: 1.14; 95% confidence interval CI: 1.11–1.17). In addition, RDW was strongly associated with deaths from CVD (adjusted HR: 1.15; 95% CI: 1.12–1.25), cancer (adjusted HR: 1.13; 95% CI: 1.07–1.20), and other causes (adjusted HR: 1.13; 95% CI: 1.07–1.18). Furthermore, the RDW–mortality association occurred in all major demographic, disease, and nutritional risk factor subgroups examined. Among the subset of 1,603 older adults without major age-associated diseases, RDW remained strongly associated with total mortality (adjusted HR: 1.32; 95% CI: 1.21–1.44). Conclusions RDW is a routinely reported test that is a powerful predictor of mortality in community-dwelling older adults with and without age-associated diseases. The biologic mechanisms underlying this association merit investigation.
There has been substantial progress in clinical outcomes for patients with multiple myeloma (MM). This encouraging trend derives in large part from the increasing number of effective therapeutic ...options and the ability because of this to achieve higher quality responses to treatment. The approval of both daratumumab and of elotuzumab in combination with lenalidomide and dexamethasone, in late 2015, was a notable achievement in the field, as daratumumab and elotuzumab represent the first monoclonal antibodies available for use in MM. Given their unique mechanisms of action and favorable side effect profiles, daratumumab and elotuzumab have considerable potential as therapeutic partners with agents in other drug classes and in different clinical settings ranging from newly diagnosed to relapsed disease. This review discusses the development of daratumumab and elotuzumab as well as other monoclonal antibodies currently being evaluated for use in MM.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Updated to include the newest drugs and those currently in development, this Fifth Edition is a comprehensive reference on the preclinical and clinical pharmacology of anticancer agents. Organized by ...drug class, the book provides the latest information on all drugs and biological agents-their mechanisms of action, interactions with other agents, toxicities, side effects, and mechanisms of resistance. The authors explain the rationale for use of drugs in specific schedules and combinations and offer guidelines for dose adjustment in particular situations. This edition's introduction includes timely information on general strategies for drug usage, the science of drug discovery and development, economic and regulatory aspects of cancer drug development, and principles of pharmacokinetics. Eight new chapters have been added and more than twenty have been significantly revised. A companion website includes the fully searchable text and an image bank.
The Feline Leukemia Virus Subgroup C Receptor 1a (FLVCR1a) is a transmembrane heme exporter essential for embryonic vascular development. However, the exact role of FLVCR1a during blood vessel ...development remains largely undefined. Here, we show that FLVCR1a is highly expressed in angiogenic endothelial cells (ECs) compared to quiescent ECs. Consistently, ECs lacking FLVCR1a give rise to structurally and functionally abnormal vascular networks in multiple models of developmental and pathologic angiogenesis. Firstly, zebrafish embryos without FLVCR1a displayed defective intersegmental vessels formation. Furthermore, endothelial-specific
Flvcr1a
targeting in mice led to a reduced radial expansion of the retinal vasculature associated to decreased EC proliferation. Moreover,
Flvcr1a
null retinas showed defective vascular organization and loose attachment of pericytes. Finally, adult neo-angiogenesis is severely affected in murine models of tumor angiogenesis. Tumor blood vessels lacking
Flvcr1a
were disorganized and dysfunctional. Collectively, our results demonstrate the critical role of FLVCR1a as a regulator of developmental and pathological angiogenesis identifying FLVCR1a as a potential therapeutic target in human diseases characterized by aberrant neovascularization.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To analyze the perceptions of professionals, caregivers, children, and adolescents with disabilities regarding the implementation of the My Abilities First (MAF) tool in Specialized Child ...Rehabilitation Centers (CERs).
This is a qualitative research based on Reflexive Thematic Analysis (RTA). The study involved twenty-seven intentionally selected individuals, comprising 12 physiotherapists, 4 occupational therapists, 11 caregivers, 9 children and 2 adolescents. Participants completed sociodemographic and clinical questionnaires and took part in semi-structured online interviews, focusing on two themes: Positive health approaches and the MAF tool. The study was approved by the local ethics committee (opinion 4.779.175).
Reflexive Thematic Analysis of the interviews resulted in two themes: (1) Perceptions regarding the MAF tool as an educational and contributory process to enhance the inclusion and participation of children and adolescents with disabilities, and (2) Barriers and facilitators for the implementation process of the MAF tool. The implementation of MAF was identified as a driving factor in promoting equity and increased participation of children and adolescents with disabilities in various settings, including health, education, and leisure. Interviewees highlighted the need to confront attitudinal, communication, and social barriers that may hinder the implementation of the tool.
The implementation of the MAF tool was perceived as an innovation due to its focus on the abilities of individuals with disabilities. However, there is a need to restructure it to broaden its scope and access to different contexts in order to confront barriers and enhance the inclusion and participation of children and adolescents with disabilities.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a ...multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Waist circumference (WC) thresholds derived from western populations continue to be used in sub-Saharan Africa (SSA) despite increasing evidence of ethnic variation in the association between ...adiposity and cardiometabolic disease and availability of data from African populations. We aimed to derive a SSA-specific optimal WC cut-point for identifying individuals at increased cardiometabolic risk.
We used individual level cross-sectional data on 24 181 participants aged ⩾15 years from 17 studies conducted between 1990 and 2014 in eight countries in SSA. Receiver operating characteristic curves were used to derive optimal WC cut-points for detecting the presence of at least two components of metabolic syndrome (MS), excluding WC.
The optimal WC cut-point was 81.2 cm (95% CI 78.5-83.8 cm) and 81.0 cm (95% CI 79.2-82.8 cm) for men and women, respectively, with comparable accuracy in men and women. Sensitivity was higher in women (64%, 95% CI 63-65) than in men (53%, 95% CI 51-55), and increased with the prevalence of obesity. Having WC above the derived cut-point was associated with a twofold probability of having at least two components of MS (age-adjusted odds ratio 2.6, 95% CI 2.4-2.9, for men and 2.2, 95% CI 2.0-2.3, for women).
The optimal WC cut-point for identifying men at increased cardiometabolic risk is lower (⩾81.2 cm) than current guidelines (⩾94.0 cm) recommend, and similar to that in women in SSA. Prospective studies are needed to confirm these cut-points based on cardiometabolic outcomes.International Journal of Obesity advance online publication, 31 October 2017; doi:10.1038/ijo.2017.240.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Objective Maternal protein restriction has been shown to have deleterious effects on placental development, and has long-term consequences for the progeny. We tested the hypothesis that, by ...the use of microarray technology, we could identify specific genes and cellular pathways in the developing placenta that are responsive to maternal protein deprivation, and propose a potential mechanism for observed gene expression changes. Methods We fed pregnant FVB/NJ mice from day post-coitum 10.5 (DPC10.5) to DPC17.5, an isocaloric diet containing 50% less protein than normal chow. We used the Affymetrix Mouse 430A_2.0 array to measure gene expression changes in the placenta. We functionally annotated the regulated genes, and examined over-represented functional categories and performed pathway analysis. For selected genes, we confirmed the microarray results by use of qPCR. Results We observed 244 probe sets, corresponding to 235 genes, regulated by protein restriction ( p < 0.001), with ninety-one genes being up-regulated, and 153 down-regulated. Up-regulated genes included those involved in the p53 pathway, apoptosis, negative regulators of cell growth, negative regulators of cell metabolism and genes related to epigenetic control. Down-regulated genes included those involved in nucleotide metabolism. Conclusions Microarray analysis has allowed us to describe the genetic response to maternal protein deprivation in the mouse placenta. We observed that negative regulators of cell growth and metabolism in conjunction with genes involved in epigenesis were up-regulated, suggesting that protein deprivation may contribute to growth restriction and long-term epigenetic changes in stressed tissues and organs. The challenge will be to understand the cellular and molecular mechanisms of these gene expression responses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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