Shared and distinct transcriptional programs underlie the hybrid nature of iNKT cells

Invariant natural killer T (iNKT) cells are innate-like T lymphocytes that act as critical regulators of the immune response. To better characterize this population, we profiled iNKT cell gene expression during ontogeny and in peripheral subsets as part of the Immunological Genome Project (ImmGen). High-resolution comparative transcriptional analyses defined developmental and subset-specific iNKT cell gene expression programs. In addition, iNKT cells were found to share an extensive transcriptional program with natural killer (NK) cells, similar in magnitude to that shared with major histocompatibility complex (MHC)-restricted T cells. Strikingly, the NK- iNKT program also operated constitutively in γδT cells and in adaptive T cells following activation. Together, our findings highlight a core effector program regulated distinctly in innate and adaptive lymphocytes

A Case Report of Cognitive Processing Therapy Delivered over a Single Week.

Although evidence-based treatments for posttraumatic stress disorder (PTSD), such as Cognitive Processing Therapy (CPT), have been developed and widely disseminated, the rate of veterans engaging in and completing these therapies is low. Alternative methods of delivery may be needed to help overcome key barriers to treatment. Delivering evidence-based therapies intensively may address practical barriers to treatment attendance as well as problems with avoidance. This report details the case of a combat veteran who received 10 sessions of Cognitive Processing Therapy delivered twice per day over a single, five-day work week (CPT-5). Post-treatment, the veteran reported large and clinically meaningful decreases in PTSD and depression symptom severity as well as in guilt cognitions, which is a purported mechanism of successful treatment. These effects persisted six weeks after treatment ended. Despite the intensive nature of the treatment, the veteran found CPT-5 tolerable and could cite many benefits to completing therapy in one work week. In conclusion, CPT-5 holds promise as a way to efficiently deliver an evidence-based therapy that is both clinically effective and acceptable to patients, although more rigorous clinical trials are needed to test this treatment delivery format

Novel image analysis approach for quantifying expression of nuclear proteins assessed by immunohistochemistry: application to measurement of oestrogen and progesterone receptor levels in breast cancer

INTRODUCTION: Manual interpretation of immunohistochemistry (IHC) is a subjective, time-consuming and variable process, with an inherent intra-observer and inter-observer variability. Automated image analysis approaches offer the possibility of developing rapid, uniform indicators of IHC staining. In the present article we describe the development of a novel approach for automatically quantifying oestrogen receptor (ER) and progesterone receptor (PR) protein expression assessed by IHC in primary breast cancer. METHODS: Two cohorts of breast cancer patients (n = 743) were used in the study. Digital images of breast cancer tissue microarrays were captured using the Aperio ScanScope XT slide scanner (Aperio Technologies, Vista, CA, USA). Image analysis algorithms were developed using MatLab 7 (MathWorks, Apple Hill Drive, MA, USA). A fully automated nuclear algorithm was developed to discriminate tumour from normal tissue and to quantify ER and PR expression in both cohorts. Random forest clustering was employed to identify optimum thresholds for survival analysis. RESULTS: The accuracy of the nuclear algorithm was initially confirmed by a histopathologist, who validated the output in 18 representative images. In these 18 samples, an excellent correlation was evident between the results obtained by manual and automated analysis (Spearman\u27s rho = 0.9, P \u3c 0.001). Optimum thresholds for survival analysis were identified using random forest clustering. This revealed 7% positive tumour cells as the optimum threshold for the ER and 5% positive tumour cells for the PR. Moreover, a 7% cutoff level for the ER predicted a better response to tamoxifen than the currently used 10% threshold. Finally, linear regression was employed to demonstrate a more homogeneous pattern of expression for the ER (R = 0.860) than for the PR (R = 0.681). CONCLUSIONS: In summary, we present data on the automated quantification of the ER and the PR in 743 primary breast tumours using a novel unsupervised image analysis algorithm. This novel approach provides a useful tool for the quantification of biomarkers on tissue specimens, as well as for objective identification of appropriate cutoff thresholds for biomarker positivity. It also offers the potential to identify proteins with a homogeneous pattern of expression

Elevated Paracellular Glucose Flux across Cystic Fibrosis Airway Epithelial Monolayers Is an Important Factor for Pseudomonas aeruginosa Growth.

People with cystic fibrosis (CF) who develop related diabetes (CFRD) have accelerated pulmonary decline, increased infection with antibiotic-resistant Pseudomonas aeruginosa and increased pulmonary exacerbations. We have previously shown that glucose concentrations are elevated in airway surface liquid (ASL) of people with CF, particularly in those with CFRD. We therefore explored the hypotheses that glucose homeostasis is altered in CF airway epithelia and that elevation of glucose flux into ASL drives increased bacterial growth, with an effect over and above other cystic fibrosis transmembrane conductance regulator (CFTR)-related ASL abnormalities. The aim of this study was to compare the mechanisms governing airway glucose homeostasis in CF and non-CF primary human bronchial epithelial (HBE) monolayers, under normal conditions and in the presence of Ps. aeruginosa filtrate. HBE-bacterial co-cultures were performed in the presence of 5 mM or 15 mM basolateral glucose to investigate how changes in blood glucose, such as those seen in CFRD, affects luminal Ps. aeruginosa growth. Calu-3 cell monolayers were used to evaluate the potential importance of glucose on Ps. aeruginosa growth, in comparison to other hallmarks of the CF ASL, namely mucus hyperviscosity and impaired CFTR-dependent fluid secretions. We show that elevation of basolateral glucose promotes the apical growth of Ps. aeruginosa on CF airway epithelial monolayers more than non-CF monolayers. Ps. aeruginosa secretions elicited more glucose flux across CF airway epithelial monolayers compared to non-CF monolayers which we propose increases glucose availability in ASL for bacterial growth. In addition, elevating basolateral glucose increased Ps. aeruginosa growth over and above any CFTR-dependent effects and the presence or absence of mucus in Calu-3 airway epithelia-bacteria co-cultures. Together these studies highlight the importance of glucose as an additional factor in promoting Ps. aeruginosa growth and respiratory infection in CF disease

Impact Ionization in ZnS

The impact ionization rate and its orientation dependence in k space is calculated for ZnS. The numerical results indicate a strong correlation to the band structure. The use of a q-dependent screening function for the Coulomb interaction between conduction and valence electrons is found to be essential. A simple fit formula is presented for easy calculation of the energy dependent transition rate.Comment: 9 pages LaTeX file, 3 EPS-figures (use psfig.sty), accepted for publication in PRB as brief Report (LaTeX source replaces raw-postscript file

The social, cosmopolitanism and beyond

First, this article will outline the metaphysics of ‘the social’ that implicitly and explicitly connects the work of lassical and contemporary cosmopolitan sociologists as different as Durkheim, Weber, Beck and Luhmann. In a second step, I will show that the cosmopolitan outlook of classical sociology is driven by exclusive differences. In understanding human affairs, both classical sociology and contemporary cosmopolitan sociology reflect a very modernist outlook of epistemological, conceptual, methodological and disciplinary rigour that separates the cultural sphere from the natural objects of concern. I will suggest that classical sociology – in order to be cosmopolitan – is forced (1) to exclude non-social and non-human objects as part of its conceptual and methodological rigour, and (2) consequently and methodologically to rule out the non-social and the non-human. Cosmopolitan sociology imagines ‘the social’ as a global, universal explanatory device to conceive and describe the non-social and non-human. In a third and final step the article draws upon the work of the French sociologist Gabriel Tarde and offers a possible alternative to the modernist social and cultural other-logics of social sciences. It argues for a inclusive conception of ‘the social’ that gives the non-social and non-human a cosmopolitan voice as well

Preanalytical Processing and Biobanking Procedures of Biological Samples for Metabolomics Research : A White Paper, Community Perspective (for "Precision Medicine and Pharmacometabolomics Task Group"-The Metabolomics Society Initiative)

BACKGROUND: The metabolome of any given biological system contains a diverse range of low molecular weight molecules (metabolites), whose abundances can be affected by the timing and method of sample collection, storage, and handling. Thus, it is necessary to consider the requirements for preanalytical processes and biobanking in metabolomics research. Poor practice can create bias and have deleterious effects on the robustness and reproducibility of acquired data. CONTENT: This review presents both current practice and latest evidence on preanalytical processes and biobanking of samples intended for metabolomics measurement of common biofluids and tissues. It highlights areas requiring more validation and research and provides some evidence-based guidelines on best practices. SUMMARY: Although many researchers and biobanking personnel are familiar with the necessity of standardizing sample collection procedures at the axiomatic level (e.g., fasting status, time of day, "time to freezer," sample volume), other less obvious factors can also negatively affect the validity of a study, such as vial size, material and batch, centrifuge speeds, storage temperature, time and conditions, and even environmental changes in the collection room. Any biobank or research study should establish and follow a well-defined and validated protocol for the collection of samples for metabolomics research. This protocol should be fully documented in any resulting study and should involve all stakeholders in its design. The use of samples that have been collected using standardized and validated protocols is a prerequisite to enable robust biological interpretation unhindered by unnecessary preanalytical factors that may complicate data analysis and interpretation. (C) 2018 American Association for Clinical ChemistryPeer reviewe