Differential impact of LPG-and PG-deficient Leishmania major mutants on the immune response of human dendritic cells

<div><p>Background</p><p><i>Leishmania major</i> infection induces robust interleukin-12 (IL12) production in human dendritic cells (hDC), ultimately resulting in Th1-mediated immunity and clinical resolution. The surface of <i>Leishmania</i> parasites is covered in a dense glycocalyx consisting of primarily lipophosphoglycan (LPG) and other phosphoglycan-containing molecules (PGs), making these glycoconjugates the likely pathogen-associated molecular patterns (PAMPS) responsible for IL12 induction.</p><p>Methodology/Principal Findings</p><p>Here we explored the role of parasite glycoconjugates on the hDC IL12 response by generating <i>L</i>. <i>major</i> Friedlin V1 mutants defective in LPG alone, (FV1 <i>lpg1-</i>), or generally deficient for all PGs, (FV1 <i>lpg2-</i>). Infection with metacyclic, infective stage, <i>L</i>. <i>major</i> or purified LPG induced high levels of <i>IL12B</i> subunit gene transcripts in hDCs, which was abrogated with FV1 <i>lpg1-</i> infections. In contrast, hDC infections with FV1 <i>lpg2-</i> displayed increased <i>IL12B</i> expression, suggesting other PG-related/<i>LPG2</i> dependent molecules may act to dampen the immune response. Global transcriptional profiling comparing WT, FV1 <i>lpg1-</i>, FV1 <i>lpg2-</i> infections revealed that FV1 <i>lpg1-</i> mutants entered hDCs in a silent fashion as indicated by repression of gene expression. Transcription factor binding site analysis suggests that LPG recognition by hDCs induces IL-12 in a signaling cascade resulting in Nuclear Factor κ B (NFκB) and Interferon Regulatory Factor (IRF) mediated transcription.</p><p>Conclusions/Significance</p><p>These data suggest that <i>L</i>. <i>major</i> LPG is a major PAMP recognized by hDC to induce IL12-mediated protective immunity and that there is a complex interplay between PG-baring <i>Leishmania</i> surface glycoconjugates that result in modulation of host cellular IL12.</p></div

Treatments for people who use anabolic androgenic steroids: a scoping review.

BACKGROUND: A growing body of evidence suggests that anabolic androgenic steroids (AAS) are used globally by a diverse population with varying motivations. Evidence has increased greatly in recent years to support understanding of this form of substance use and the associated health harms, but there remains little evidence regarding interventions to support cessation and treat the consequences of use. In this scoping review, we identify and describe what is known about interventions that aim to support and achieve cessation of AAS, and treat and prevent associated health problems. METHODS: A comprehensive search strategy was developed in four bibliographic databases, supported by an iterative citation searching process to identify eligible studies. Studies of any psychological or medical treatment interventions delivered in response to non-prescribed use of AAS or an associated harm in any setting were eligible. RESULTS: In total, 109 eligible studies were identified, which included case reports representing a diverse range of disciplines and sources. Studies predominantly focussed on treatments for harms associated with AAS use, with scant evidence on interventions to support cessation of AAS use or responding to dependence. The types of conditions requiring treatment included psychiatric, neuroendocrine, hepatic, kidney, cardiovascular, musculoskeletal and infectious. There was limited evidence of engagement with users or delivery of psychosocial interventions as part of treatment for any condition, and of harm reduction interventions initiated alongside, or following, treatment. Findings were limited throughout by the case report study designs and limited information was provided. CONCLUSION: This scoping review indicates that while a range of case reports describe treatments provided to AAS users, there is scarce evidence on treating dependence, managing withdrawal, or initiating behaviour change in users in any settings. Evidence is urgently required to support the development of effective services for users and of evidence-based guidance and interventions to respond to users in a range of healthcare settings. More consistent reporting in articles of whether engagement or assessment relating to AAS was initiated, and publication within broader health- or drug-related journals, will support development of the evidence base

Phytoplankton responses to marine climate change – an introduction

Phytoplankton are one of the key players in the ocean and contribute approximately 50% to global primary production. They serve as the basis for marine food webs, drive chemical composition of the global atmosphere and thereby climate. Seasonal environmental changes and nutrient availability naturally influence phytoplankton species composition. Since the industrial era, anthropogenic climatic influences have increased noticeably – also within the ocean. Our changing climate, however, affects the composition of phytoplankton species composition on a long-term basis and requires the organisms to adapt to this changing environment, influencing micronutrient bioavailability and other biogeochemical parameters. At the same time, phytoplankton themselves can influence the climate with their responses to environmental changes. Due to its key role, phytoplankton has been of interest in marine sciences for quite some time and there are several methodical approaches implemented in oceanographic sciences. There are ongoing attempts to improve predictions and to close gaps in the understanding of this sensitive ecological system and its responses

Search for long-lived heavy charged particles using a ring imaging Cherenkov technique at LHCb

A search is performed for heavy long-lived charged particles using 3.0 fb$^{-1}$ of pp collisions collected at $\sqrt{s}$= 7 and 8 TeV with the LHCb detector. The search is mainly based on the response of the ring imaging Cherenkovdetectors to distinguish the heavy, slow-moving particles from muons. No evidence is found for the production of such long-lived states. The results are expressed as limits on the Drell-Yan production of pairs of long-lived particles, with both particles in the LHCb pseudorapidity acceptance, $1.8 < \eta < 4.9$. The mass-dependent cross-section upper limits are in the range 2-4 fb (at 95\% CL) for masses between 124 and 309 GeV/c$^2$

Measurement of the Z plus b-jet cross-section in pp collisions at root s=7 TeV in the forward region

The associated production of a Z boson or an off-shell photon $\gamma^*$ with a bottom quark in the forward region is studied using proton-proton collisions at a centre-of-mass energy of $7{\mathrm{\,Te\kern -0.1em V}}$. The Z bosons are reconstructed in the ${\text{Z}/\gamma^*}\!\rightarrow{\mu^{+}\mu^{-}}$ final state from muons with a transverse momentum larger than $20{\mathrm{\,Ge\kern -0.1em V}}$, while two transverse momentum thresholds are considered for jets ($10{\mathrm{\,Ge\kern -0.1em V}}$ and $20{\mathrm{\,Ge\kern -0.1em V}}$). Both muons and jets are reconstructed in the pseudorapidity range $2.0 < \eta < 4.5$. The results are based on data corresponding to 1.0{\,\mbox{fb}^{-1}} recorded in 2011 with the LHCb detector. The measurement of the Z+b-jet cross-section is normalized to the Z+jet cross-section. The measured cross-sections are \begin{equation*} \sigma(\text{$\text{Z}/\gamma^*(\mu^{+}\mu^{-})$+b-jet}) = 295 \pm 60~(\text{stat}) \pm 51~(\text{syst}) \pm 10~(\text{lumi}) {\,\mbox{fb}} \end{equation*} for ${p_{\rm T}}$(jet)$>10{\mathrm{\,Ge\kern -0.1em V}}$, and \begin{equation*} \sigma(\text{$\text{Z}/\gamma^*(\mu^{+}\mu^{-})$+b-jet}) = 128 \pm 36~(\text{stat}) \pm 22~(\text{syst}) \pm 5~(\text{lumi}) {\,\mbox{fb}} \end{equation*} for ${p_{\rm T}}$(jet)$>20{\mathrm{\,Ge\kern -0.1em V}}$

Uncontrolled Donation After Circulatory Determination of Death: A Systematic Ethical Analysis.

Uncontrolled donation after circulatory determination of death (uDCDD) refers to organ donation after a refractory cardiac arrest. We analyzed ethical issues raised by the uDCDD protocols of France, Madrid, and New York City. We recommend: (1) Termination of resuscitation (TOR) guidelines need refinement, particularly the minimal duration of resuscitation efforts before considering TOR; (2) Before enrolling in an uDCDD protocol, physicians must ascertain that additional resuscitation efforts would be ineffective; (3) Inclusion in an uDCDD protocol should not be made in the outpatient setting to avoid error and conflicts of interest; (4) The patient's condition should be reassessed at the hospital and reversible causes treated; (5) A no-touch period of at least 10 minutes should be respected to avoid the risk of autoresuscitation; (6) Once death has been determined, no procedure that may resume brain circulation should be used, including cardiopulmonary resuscitation, artificial ventilation, and extracorporeal membrane oxygenation; (7) Specific consent is required prior to entry into an uDCDD protocol; (8) Family members should be informed about the goals, risks, and benefits of planned uDCDD procedures; and (9) Public information on uDCDD is desirable because it promotes public trust and confidence in the organ donation system