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

Search for direct pair production of the top squark in all-hadronic final states in proton-proton collisions at s√=8 TeV with the ATLAS detector

The results of a search for direct pair production of the scalar partner to the top quark using an integrated luminosity of 20.1fb−1 of proton–proton collision data at √s = 8 TeV recorded with the ATLAS detector at the LHC are reported. The top squark is assumed to decay via t˜→tχ˜01 or t˜→ bχ˜±1 →bW(∗)χ˜01 , where χ˜01 (χ˜±1 ) denotes the lightest neutralino (chargino) in supersymmetric models. The search targets a fully-hadronic final state in events with four or more jets and large missing transverse momentum. No significant excess over the Standard Model background prediction is observed, and exclusion limits are reported in terms of the top squark and neutralino masses and as a function of the branching fraction of t˜ → tχ˜01 . For a branching fraction of 100%, top squark masses in the range 270–645 GeV are excluded for χ˜01 masses below 30 GeV. For a branching fraction of 50% to either t˜ → tχ˜01 or t˜ → bχ˜±1 , and assuming the χ˜±1 mass to be twice the χ˜01 mass, top squark masses in the range 250–550 GeV are excluded for χ˜01 masses below 60 GeV

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Inflation and Dark Energy from spectroscopy at z > 2

The expansion of the Universe is understood to have accelerated during two epochs: in its very first moments during a period of Inflation and much more recently, at z < 1, when Dark Energy is hypothesized to drive cosmic acceleration. The undiscovered mechanisms behind these two epochs represent some of the most important open problems in fundamental physics. The large cosmological volume at 2 < z < 5, together with the ability to efficiently target high-$z$ galaxies with known techniques, enables large gains in the study of Inflation and Dark Energy. A future spectroscopic survey can test the Gaussianity of the initial conditions up to a factor of ~50 better than our current bounds, crossing the crucial theoretical threshold of $\sigma(f_{NL}^{\rm local})$ of order unity that separates single field and multi-field models. Simultaneously, it can measure the fraction of Dark Energy at the percent level up to $z = 5$, thus serving as an unprecedented test of the standard model and opening up a tremendous discovery space

The differential effects of ecstasy/polydrug use on executive components: shifting, inhibition, updating and access to semantic memory

Rationale/Objectives Recent theoretical models suggest that the central executive may not be a unified structure. The present study explored the nature of central executive deficits in ecstasy users. Methods In study 1, 27 ecstasy users and 34 non-users were assessed using tasks to tap memory updating (computation span; letter updating) and access to long-term memory (a semantic fluency test and the Chicago Word Fluency Test). In study 2, 51 ecstasy users and 42 non-users completed tasks that assess mental set switching (number/letter and plus/minus) and inhibition (random letter generation). Results MANOVA revealed that ecstasy users performed worse on both tasks used to assess memory updating and on tasks to assess access to long-term memory (C- and S-letter fluency). However, notwithstanding the significant ecstasy group-related effects, indices of cocaine and cannabis use were also significantly correlated with most of the executive measures. Unexpectedly, in study 2, ecstasy users performed significantly better on the inhibition task, producing more letters than non-users. No group differences were observed on the switching tasks. Correlations between indices of ecstasy use and number of letters produced were significant. Conclusions The present study provides further support for ecstasy/polydrug-related deficits in memory updating and in access to long-term memory. The surplus evident on the inhibition task should be treated with some caution, as this was limited to a single measure and has not been supported by our previous work

Concepts of threshold assessment for a first course in control engineering

This paper focuses on the combined challenge of encouraging students to engage with learning and assessment of their competence levels. A core challenge for many staff is the need to distinguish different levels of learning, and to evidence core competence clearly, especially for students with lower marks. This paper proposes a novel assessment strategy which separates core competencies from the more challenging application of the learning in engineering problem solving. The assessment design is efficient for staff and students and allows a reduction in student stress levels while simultaneously giving them strong incentives to adopt good working practices. Evaluation evidence is given to demonstrate the efficacy of the approach

Care for low back pain: can health systems deliver?

Low back pain is the leading cause of years lived with disability globally. In 2018, an international working group called on the World Health Organization to increase attention on the burden of low back pain and the need to avoid excessively medical solutions. Indeed, major international clinical guidelines now recognize that many people with low back pain require little or no formal treatment. Where treatment is required the recommended approach is to discourage use of pain medication, steroid injections and spinal surgery, and instead promote physical and psychological therapies. Many health systems are not designed to support this approach. In this paper we discuss why care for low back pain that is concordant with guidelines requires system-wide changes. We detail the key challenges of low back pain care within health systems. These include the financial interests of pharmaceutical and other companies; outdated payment systems that favour medical care over patients' self-management; and deep-rooted medical traditions and beliefs about care for back pain among physicians and the public. We give international examples of promising solutions and policies and practices for health systems facing an increasing burden of ineffective care for low back pain. We suggest policies that, by shifting resources from unnecessary care to guideline-concordant care for low back pain, could be cost-neutral and have widespread impact. Small adjustments to health policy will not work in isolation, however. Workplace systems, legal frameworks, personal beliefs, politics and the overall societal context in which we experience health, will also need to change

The Bone Morphogenetic Protein 2 Analogue L51P Enhances Spinal Fusion in Combination with BMP2 in an In Vivo Rat Tail Model

INTRODUCTION Non-union and pseudoarthrosis remain major complications after spinal fusion surgery, resulting in unsatisfactory outcomes and high socio-economic costs [1,2]. Several biomaterials and osteobiologics have improved spinal fusion, including bone morphogenetic protein (BMP) 2. However, its necessary high-dose application often leads to adverse effects. L51P, a BMP-2 analogue and inhibitor of BMP antagonists, has been shown to augment BMP-induced bone formation and lower the required doses. The current study, therefore, aimed to demonstrate the effects of L51P and BMP-2 on spinal fusion in vivo. METHODS 46 elderly Wistar rats (~12 months, 52% female, 423±78g) underwent a two-step spinal fusion surgery [3,4]. Firstly, a custom external fixator was applied in the proximal tail. Secondly, discectomy and disc replacement with a β tri-calcium-phosphate (β-TCP) carrier were conducted. Carriers were loaded with the study compounds based on random and blinded allocation into seven groups: g Digital X-rays were performed on day zero, at six weeks, and twelve weeks postoperatively. After twelve weeks, high-resolution µCT scans and histology were obtained. RESULTS At twelve weeks, 10 µg BMP-2, 1 µg BMP-2 + 5 µg L51P and 1 µg BMP-2 + 10 µg L51P showed significantly higher fusion rates compared to the PBS control in X-ray analysis. µCT analysis showed significantly higher fusion rates for all groups than the control group. 1 µg BMP-2 + 1 µg L51P demonstrated significantly higher fusion rates than 1 µg BMP2 alone and equivalent ossification compared to 10 µg BMP-2; higher doses of L51P did not lead to a better fusion outcome. Histological analysis confirmed the radiographical results. Figure 1 provides representative images of the seven experimental groups for each investigated read-outs, i.e., 2D X-rays, µCT and histology

Therapeutic opportunities within the DNA damage response

The DNA damage response (DDR) is essential for maintaining the genomic integrity of the cell, and its disruption is one of the hallmarks of cancer. Classically, defects in the DDR have been exploited therapeutically in the treatment of cancer with radiation therapies or genotoxic chemotherapies. More recently, protein components of the DDR systems have been identified as promising avenues for targeted cancer therapeutics. Here, we present an in-depth analysis of the function, role in cancer and therapeutic potential of 450 expert-curated human DDR genes. We discuss the DDR drugs that have been approved by the US Food and Drug Administration (FDA) or that are under clinical investigation. We examine large-scale genomic and expression data for 15 cancers to identify deregulated components of the DDR, and we apply systematic computational analysis to identify DDR proteins that are amenable to modulation by small molecules, highlighting potential novel therapeutic targets

Measurements of integrated and differential cross sections for isolated photon pair production in pp collisions at √s=8 TeV with the ATLAS detector

A measurement of the production cross section for two isolated photons in proton-proton collisions at a center-of-mass energy of √s=8 TeV is presented. The results are based on an integrated luminosity of 20.2 fb−1 recorded by the ATLAS detector at the Large Hadron Collider. The measurement considers photons with pseudorapidities satisfying |ηγ|40GeV and EγT,2>30 GeV for the two leading photons ordered in transverse energy produced in the interaction. The background due to hadronic jets and electrons is subtracted using data-driven techniques. The fiducial cross sections are corrected for detector effects and measured differentially as a function of six kinematic observables. The measured cross section integrated within the fiducial volume is 16.8 ± 0.8  pb . The data are compared to fixed-order QCD calculations at next-to-leading-order and next-to-next-to-leading-order accuracy as well as next-to-leading-order computations including resummation of initial-state gluon radiation at next-to-next-to-leading logarithm or matched to a parton shower, with relative uncertainties varying from 5% to 20%