Transcriptomics reveal an integrative role for maternal thyroid hormones during zebrafish embryogenesis

Thyroid hormones (THs) are essential for embryonic brain development but the genetic mechanisms involved in the action of maternal THs (MTHs) are still largely unknown. As the basis for understanding the underlying genetic mechanisms of MTHs regulation we used an established zebrafish monocarboxylic acid transporter 8 (MCT8) knock-down model and characterised the transcriptome in 25hpf zebrafish embryos. Subsequent mapping of differentially expressed genes using Reactome pathway analysis together with in situ expression analysis and immunohistochemistry revealed the genetic networks and cells under MTHs regulation during zebrafish embryogenesis. We found 4,343 differentially expressed genes and the Reactome pathway analysis revealed that TH is involved in 1681 of these pathways. MTHs regulated the expression of core developmental pathways, such as NOTCH and WNT in a cell specific context. The cellular distribution of neural MTH-target genes demonstrated their cell specific action on neural stem cells and differentiated neuron classes. Taken together our data show that MTHs have a role in zebrafish neurogenesis and suggest they may be involved in cross talk between key pathways in neural development. Given that the observed MCT8 zebrafish knockdown phenotype resembles the symptoms in human patients with Allan-Herndon-Dudley syndrome our data open a window into understanding the genetics of this human congenital condition.Portuguese Fundacao para Ciencia e Tecnologia (FCT) [PTDC/EXPL/MARBIO/0430/2013]; CCMAR FCT Plurianual financing [UID/Multi/04326/2013]; FCT [SFRH/BD/111226/2015, SFRH/BD/108842/2015, SFRH/BPD/89889/2012]; FCT-IF Starting Grant [IF/01274/2014]info:eu-repo/semantics/publishedVersio

HIVAN and medication use in chronic dialysis patients in the United States: analysis of the USRDS DMMS Wave 2 study

BACKGROUND: The use and possible effects of factors known to improve outcomes in patients with human immunodeficiency virus associated nephropathy (HIVAN), namely of angiotensin converting enzyme inhibitors (ACE) and antiretroviral therapy, has not been reported for a national sample of dialysis patients. METHODS: We conducted a historical cohort study of the United States Renal Data System (USRDS) Dialysis Morbidity and Mortality Study (DMMS) Wave 2 to identify risk factors associated with increased mortality in these patients. Data were available for 3374 patients who started dialysis and were followed until March 2000. Cox Regression analysis was used to model adjusted hazard ratios (AHR) with HIVAN as a cause of end stage renal disease (ESRD) and its impact on mortality during the study period, adjusted for potential confounders. RESULTS: Of the 3374 patients who started dialysis, 36 (1.1%) had ESRD as a result of HIVAN. Only 22 (61%) of patients with HIVAN received antiretroviral agents, and only nine patients (25%) received combination antiretroviral therapy, and only 14% received ACE inhibitors. Neither the use of multiple antiretroviral drugs (AHR, 0.62, 95% CI, 0.10, 3.86, p = 0.60), or ACE inhibitors were associated with a survival advantage. Patients with HIVAN had an increased risk of mortality (adjusted hazard ratio, 4.74, 95% Confidence Interval, 3.12, 7.32, p < 0.01) compared to patients with other causes of ESRD. CONCLUSIONS: Medications known to improve outcomes in HIV infected patients were underutilized in patients with HIVAN. Adjusted for other factors, a primary diagnosis of HIVAN was associated with increased mortality compared with other causes of ESRD

Cosmological Simulations with Self-Interacting Dark Matter I: Constant Density Cores and Substructure

We use cosmological simulations to study the effects of self-interacting dark matter (SIDM) on the density profiles and substructure counts of dark matter halos from the scales of spiral galaxies to galaxy clusters, focusing explicitly on models with cross sections over dark matter particle mass \sigma/m = 1 and 0.1 cm^2/g. Our simulations rely on a new SIDM N-body algorithm that is derived self-consistently from the Boltzmann equation and that reproduces analytic expectations in controlled numerical experiments. We find that well-resolved SIDM halos have constant-density cores, with significantly lower central densities than their CDM counterparts. In contrast, the subhalo content of SIDM halos is only modestly reduced compared to CDM, with the suppression greatest for large hosts and small halo-centric distances. Moreover, the large-scale clustering and halo circular velocity functions in SIDM are effectively identical to CDM, meaning that all of the large-scale successes of CDM are equally well matched by SIDM. From our largest cross section runs we are able to extract scaling relations for core sizes and central densities over a range of halo sizes and find a strong correlation between the core radius of an SIDM halo and the NFW scale radius of its CDM counterpart. We construct a simple analytic model, based on CDM scaling relations, that captures all aspects of the scaling relations for SIDM halos. Our results show that halo core densities in \sigma/m = 1 cm^2/g models are too low to match observations of galaxy clusters, low surface brightness spirals (LSBs), and dwarf spheroidal galaxies. However, SIDM with \sigma/m ~ 0.1 cm^2/g appears capable of reproducing reported core sizes and central densities of dwarfs, LSBs, and galaxy clusters without the need for velocity dependence. (abridged)Comment: 26 pages, 16 figures, all figures include colors, submitted for publication in MNRA

Deception in Research on the Placebo Effect

A common feature of research investigating the placebo effect is deception of research participants about the nature of the research. Miller and colleagues examine the ethical issues surrounding such deception

The Cyprinodon variegatus genome reveals gene expression changes underlying differences in skull morphology among closely related species

Genes in durophage intersection set at 15 dpf. This is a comma separated table of the genes in the 15 dpf durophage intersection set. Given are edgeR results for each pairwise comparison. Columns indicating whether a gene is included in the intersection set at a threshold of 1.5 or 2 fold are provided. (CSV 13 kb

Statistical design of personalized medicine interventions: The Clarification of Optimal Anticoagulation through Genetics (COAG) trial

<p>Abstract</p> <p>Background</p> <p>There is currently much interest in pharmacogenetics: determining variation in genes that regulate drug effects, with a particular emphasis on improving drug safety and efficacy. The ability to determine such variation motivates the application of personalized drug therapies that utilize a patient's genetic makeup to determine a safe and effective drug at the correct dose. To ascertain whether a genotype-guided drug therapy improves patient care, a personalized medicine intervention may be evaluated within the framework of a randomized controlled trial. The statistical design of this type of personalized medicine intervention requires special considerations: the distribution of relevant allelic variants in the study population; and whether the pharmacogenetic intervention is equally effective across subpopulations defined by allelic variants.</p> <p>Methods</p> <p>The statistical design of the Clarification of Optimal Anticoagulation through Genetics (COAG) trial serves as an illustrative example of a personalized medicine intervention that uses each subject's genotype information. The COAG trial is a multicenter, double blind, randomized clinical trial that will compare two approaches to initiation of warfarin therapy: genotype-guided dosing, the initiation of warfarin therapy based on algorithms using clinical information and genotypes for polymorphisms in <it>CYP2C9 </it>and <it>VKORC1</it>; and clinical-guided dosing, the initiation of warfarin therapy based on algorithms using only clinical information.</p> <p>Results</p> <p>We determine an absolute minimum detectable difference of 5.49% based on an assumed 60% population prevalence of zero or multiple genetic variants in either <it>CYP2C9 </it>or <it>VKORC1 </it>and an assumed 15% relative effectiveness of genotype-guided warfarin initiation for those with zero or multiple genetic variants. Thus we calculate a sample size of 1238 to achieve a power level of 80% for the primary outcome. We show that reasonable departures from these assumptions may decrease statistical power to 65%.</p> <p>Conclusions</p> <p>In a personalized medicine intervention, the minimum detectable difference used in sample size calculations is not a known quantity, but rather an unknown quantity that depends on the genetic makeup of the subjects enrolled. Given the possible sensitivity of sample size and power calculations to these key assumptions, we recommend that they be monitored during the conduct of a personalized medicine intervention.</p> <p>Trial Registration</p> <p>clinicaltrials.gov: NCT00839657</p

Modern agglutinated foraminifera from the Hovgård ridge, fram strait, west of Spitsbergen: Evidence for a deep bottom current

Deep-water agglutinated foraminifera on the crest of the Hovgârd Ridge, west of Spitsbergen, consist mostly of large tubular astrorhizids. At a boxcore station collected from the crest of Hovgârd Ridge at a water depth of 1169 m, the sediment surface was covered with patches of large (1 mm diameter) tubular forms, belonging mostly to the species Astrorhiza crassatina Brady, with smaller numbers of Saccorhiza, Hyperammina, and Psammosiphonella. Non-tubutar species consisted mainly of opportunistic forms, such as Psammosphaera and Reophax. The presence of large suspension-feeding tubular genera as well as opportunistic forms point to the presence of deep currents at this locality that are strong enough to disturb the benthic fauna. This is confirmed by data obtained from sediment echosounding, which exhibit lateral variation in relative sedimentation rates within the Pleistocene sedimentary drape covering the ridge, indicative of winnowing in a south-easterly direction

The Atlantic Bonito ( Sarda sarda,Bloch 1793) Transcriptome and Detection of Differential Expression during Larvae Development

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Evidence of Increased Muscle Atrophy and Impaired Quality of Life Parameters in Patients with Uremic Restless Legs Syndrome

BACKGROUND: Restless Legs Syndrome is a very common disorder in hemodialysis patients. Restless Legs Syndrome negatively affects quality of life; however it is not clear whether this is due to mental or physical parameters and whether an association exists between the syndrome and parameters affecting survival. METHOD#ENTITYSTARTX003BF;LOGY/PRINCIPAL FINDINGS: Using the Restless Legs Syndrome criteria and the presence of Periodic Limb Movements in Sleep (PLMS/h >15), 70 clinically stable hemodialysis patients were assessed and divided into the RLS (n = 30) and non-RLS (n = 40) groups. Physical performance was evaluated by a battery of tests: body composition by dual energy X ray absorptiometry, muscle size and composition by computer tomography, while depression symptoms, perception of sleep quality and quality of life were assessed through validated questionnaires. In this cross sectional analysis, the RLS group showed evidence of thigh muscle atrophy compared to the non-RLS group. Sleep quality and depression score were found to be significantly impaired in the RLS group. The mental component of the quality of life questionnaire appeared significantly diminished in the RLS group, reducing thus the overall quality of life score. In contrast, there were no significant differences between groups in any of the physical performance tests, body and muscle composition. CONCLUSIONS: The low level of quality of life reported by the HD patients with Restless Legs Syndrome seems to be due mainly to mental health and sleep related aspects. Increased evidence of muscle atrophy is also observed in the RLS group and possibly can be attributed to the lack of restorative sleep

Senescent Cells in Growing Tumors: Population Dynamics and Cancer Stem Cells

Tumors are defined by their intense proliferation, but sometimes cancer cells turn senescent and stop replicating. In the stochastic cancer model in which all cells are tumorigenic, senescence is seen as the result of random mutations, suggesting that it could represent a barrier to tumor growth. In the hierarchical cancer model a subset of the cells, the cancer stem cells, divide indefinitely while other cells eventually turn senescent. Here we formulate cancer growth in mathematical terms and obtain predictions for the evolution of senescence. We perform experiments in human melanoma cells which are compatible with the hierarchical model and show that senescence is a reversible process controlled by survivin. We conclude that enhancing senescence is unlikely to provide a useful therapeutic strategy to fight cancer, unless the cancer stem cells are specifically targeted