The role of inflammation in age-related disease.

The National Institutes of Health (NIH) Geroscience Interest Group (GSIG) sponsored workshop, The Role of Inflammation inAge-Related Disease, was held September 6th-7th, 2012 in Bethesda, MD. It is now recognized that a mild pro-inflammatory state is correlated with the major degenerative diseases of the elderly. The focus of the workshop was to better understand the origins and consequences of this low level chronic inflammation in order to design appropriate interventional studies aimed at improving healthspan. Four sessions explored the intrinsic, environmental exposures and immune pathways by which chronic inflammation are generated, sustained, and lead to age-associated diseases. At the conclusion of the workshop recommendations to accelerate progress toward understanding the mechanistic bases of chronic disease were identified

Search for the disappearance of muon antineutrinos in the NuMI neutrino beam

We report constraints on antineutrino oscillation parameters that were obtained by using the two MINOS detectors to measure the 7% muon antineutrino component of the NuMI neutrino beam. In the Far Detector, we select 130 events in the charged-current muon antineutrino sample, compared to a prediction of 136.4 ± 11.7(stat)^(+10.2)_(-8.9)(syst) events under the assumption │Δm^2│ = 2.32 X 10^(-3) eV^2, sin^2(2θ) = 1.0

First Direct Observation of Muon Antineutrino Disappearance

This Letter reports the first direct observation of muon antineutrino disappearance. The MINOS experiment has taken data with an accelerator beam optimized for ν̅ _μ production, accumulating an exposure of 1.71×10^(20) protons on target. In the Far Detector, 97 charged current ν̅ _μ events are observed. The no-oscillation hypothesis predicts 156 events and is excluded at 6.3σ. The best fit to oscillation yields |Δm̅ 2|= [3.36=_(-0.40)^(+0.46)(stat)±0.06(syst)]x10^(-3)eV^2,sin^2(2θ̅)=0.86 _(-0.12)^(+0.11)(stat)±0.01(syst). The MINOS ν̅ _μ and ν̅ _μ measurements are consistent at the 2.0% confidence level, assuming identical underlying oscillation parameters

Metabolic reprogramming of the immune response in the tumor microenvironment

A Division of Cancer Biology, NCI sponsored workshop, Metabolic Reprogramming of the Immune Response in the Tumor Microenvironment, was held October 2nd in Bethesda, MD. The purpose of the workshop was to bring together cancer cell biologists and immunologists to explore the mechanistic relationships between the metabolic pathways used by cancer cells and anti-tumor immune cells and how this information could be used to improve cancer immunotherapy. At the conclusion of the workshop a general discussion focused on defining the major challenges and opportunities concerning the impact of metabolism on anti-tumor immunity and cancer immunotherapy as well as what tools, technologies, resources or community efforts are required to accelerate research in this area. Overall, future studies need to consider how cancer cell metabolic pathways differ from activated lymphocytes in order to define a therapeutic window for cancer therapy. Further, studies aimed at reprogramming the metabolic qualities of T cells with the goal of improving immunotherapy were considered a promising avenue

Uncomfortable truths - teamworking under lean in the UK

A recent contribution in this journal – Procter, S. and Radnor, Z. (2014) ‘Teamworking under Lean in UK public services: lean teams and team targets in Her Majesty’s Revenue and Customs (HMRC)’ International Journal of Human Resource Management, 25:21, 2978–2995 – provides an account of teamworking in the UK Civil Service, specifically Her Majesty’s Revenue and Customs (HMRC), focused on the relationship between recently implemented lean work organisation and teams and teamworking. Procter and Radnor claim in this work that it delivers a ‘more nuanced’ analysis of lean in this government department and, it follows, of the lean phenomenon more generally. Our riposte critiques their article on several grounds. It suffers from problems of logic and construction, conceptual confusion and definitional imprecision. Methodological difficulties and inconsistent evidence contribute additionally to analytical weakness. Included in our response are empirical findings on teamworking at HMRC that challenge Procter and Radnor’s evidential basis and further reveal the shortcomings of their interpretation

In Vivo Expression of MHC Class I Genes Depends on the Presence of a Downstream Barrier Element

Regulation of MHC class I gene expression is critical to achieve proper immune surveillance. In this work, we identify elements downstream of the MHC class I promoter that are necessary for appropriate in vivo regulation: a novel barrier element that protects the MHC class I gene from silencing and elements within the first two introns that contribute to tissue specific transcription. The barrier element is located in intergenic sequences 3′ to the polyA addition site. It is necessary for stable expression in vivo, but has no effect in transient transfection assays. Accordingly, in both transgenic mice and stably transfected cell lines, truncation of the barrier resulted in transcriptional gene silencing, increased nucleosomal density and decreased histone H3K9/K14 acetylation and H3K4 di-methylation across the gene. Significantly, distinct sequences within the barrier element govern anti-silencing and chromatin modifications. Thus, this novel barrier element functions to maintain transcriptionally permissive chromatin organization and prevent transcriptional silencing of the MHC class I gene, ensuring it is poised to respond to immune signaling

Three Novel Downstream Promoter Elements Regulate MHC Class I Promoter Activity in Mammalian Cells

BACKGROUND: MHC CLASS I TRANSCRIPTION IS REGULATED BY TWO DISTINCT TYPES OF REGULATORY PATHWAYS: 1) tissue-specific pathways that establish constitutive levels of expression within a given tissue and 2) dynamically modulated pathways that increase or decrease expression within that tissue in response to hormonal or cytokine mediated stimuli. These sets of pathways target distinct upstream regulatory elements, have distinct basal transcription factor requirements, and utilize discrete sets of transcription start sites within an extended core promoter. METHODOLOGY/PRINCIPAL FINDINGS: We studied regulatory elements within the MHC class I promoter by cellular transfection and in vitro transcription assays in HeLa, HeLa/CIITA, and tsBN462 of various promoter constructs. We have identified three novel MHC class I regulatory elements (GLE, DPE-L1 and DPE-L2), located downstream of the major transcription start sites, that contribute to the regulation of both constitutive and activated MHC class I expression. These elements located at the 3' end of the core promoter preferentially regulate the multiple transcription start sites clustered at the 5' end of the core promoter. CONCLUSIONS/SIGNIFICANCE: Three novel downstream elements (GLE, DPE-L1, DPE-L2), located between +1 and +32 bp, regulate both constitutive and activated MHC class I gene expression by selectively increasing usage of transcription start sites clustered at the 5' end of the core promoter upstream of +1 bp. Results indicate that the downstream elements preferentially regulate TAF1-dependent, relative to TAF1-independent, transcription

Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial

Background: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. Methods: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. Findings: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p<0·0001). Interpretation: Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice

Genetic Diversity and Gene Family Expansions in Members of the Genus Entamoeba

Amoebiasis is the third-most common cause ofmortalityworldwide froma parasitic disease.Although the primary etiological agent of amoebiasis is the obligatehuman parasite Entamoeba histolytica, othermembers of the genus Entamoeba can infecthumans and may be pathogenic. Here, we present the first annotated reference genome for Entamoeba moshkovskii, a species that has been associated with human infections, and compare the genomes of E. moshkovskii, E. histolytica, the human commensal Entamoeba dispar, and the nonhuman pathogen Entamoeba invadens. Gene clustering and phylogenetic analyses show differences in expansion and contraction of families of proteins associated with host or bacterial interactions. They intimate the importance to parasitic Entamoeba species of surface-bound proteins involved in adhesion to extracellular membranes, such as the Gal/GalNAc lectin and members of the BspAandAriel1 families. Furthermore, E. dispar is the only one of the four species to lack a functional copy of the key virulence factor cysteine protease CP-A5, whereas the gene’s presence in E. moshkovskii is consistent with the species’ potentially pathogenicnature. Entamoebamoshkovskiiwas foundtobemore diverse thanE.histolytica across all sequence classes. The former is 200 timesmore diverse than latter,with the four E.moshkovskii strains tested having a most recent common ancestor nearly 500 timesmore ancient than the tested E. histolytica strains. A four-haplotype test indicates that these E.moshkovskii strains are not the same species and should be regarded as a species complex