Synovial Regulatory T Cells Occupy a Discrete TCR Niche in Human Arthritis and Require Local Signals To Stabilize FOXP3 Protein Expression

Although there is great interest in harnessing the immunosuppressive potential of FOXP3+ regulatory T cells (Tregs) for treating autoimmunity, a sizeable knowledge gap exists regarding Treg fate in human disease. In juvenile idiopathic arthritis (JIA) patients, we have previously reported that atypical CD25+FOXP32 Treg-like cells uniquely populate the inflamed site. Intrigu-ingly, their proportions relative to CD25+FOXP3+ Tregs associate with arthritis course, suggesting a role in disease. The ontogeny of these FOXP32 Treg-like cells is, however, unknown. In this study, we interrogated clonal relationships between CD4+ T cell subsets in JIA, using high-throughput TCR repertoire analysis. We reveal that FOXP3+ Tregs possess highly exclusive TCRb usage from conventional T cells, in blood, and also at the inflamed site, where they are clonally expanded. Intriguingly, the repertoires of FOXP3+ Tregs in synovial fluid are highly overlapping with CD25+FOXP32 Treg-like cells, indicating fluctuations in FOXP3 expression in the inflamed joint. Furthermore, cultured synovial Tregs rapidly downregulated FOXP3 protein (but not mRNA), and this process was prevented by addition of synovial fluid from JIA patients, through an IL-6–independent mechanism. Our findings suggest that most Tregs arise from a separate lineage from conventional T cells, and that this repertoire divergence is largely maintained under chronic inflammatory conditions. We propose that subsequent Treg expansions at the inflamed site creates an environment that leads to competition for limited resources within the synovium, resulting in the destabilization of FOXP3 expression in some Tregs. The Journal of Immunology, 2015, 195: 5616–5624.

High or low? Comparing high and low-variability phonetic training in adult and child second language learners

Background High talker variability (i.e., multiple voices in the input) has been found effective in training nonnative phonetic contrasts in adults. A small number of studies suggest that children also benefit from high-variability phonetic training with some evidence that they show greater learning (more plasticity) than adults given matched input, although results are mixed. However, no study has directly compared the effectiveness of high versus low talker variability in children. Methods Native Greek-speaking eight-year-olds (N = 52), and adults (N = 41) were exposed to the English /i/-/ɪ/ contrast in 10 training sessions through a computerized word-learning game. Pre- and post-training tests examined discrimination of the contrast as well as lexical learning. Participants were randomly assigned to high (four talkers) or low (one talker) variability training conditions. Results Both age groups improved during training, and both improved more while trained with a single talker. Results of a three-interval oddity discrimination test did not show the predicted benefit of high-variability training in either age group. Instead, children showed an effect in the reverse direction—i.e., reliably greater improvements in discrimination following single talker training, even for untrained generalization items, although the result is qualified by (accidental) differences between participant groups at pre-test. Adults showed a numeric advantage for high-variability but were inconsistent with respect to voice and word novelty. In addition, no effect of variability was found for lexical learning. There was no evidence of greater plasticity for phonetic learning in child learners. Discussion This paper adds to the handful of studies demonstrating that, like adults, child learners can improve their discrimination of a phonetic contrast via computerized training. There was no evidence of a benefit of training with multiple talkers, either for discrimination or word learning. The results also do not support the findings of greater plasticity in child learners found in a previous paper (Giannakopoulou, Uther & Ylinen, 2013a). We discuss these results in terms of various differences between training and test tasks used in the current work compared with previous literature

Star formation in the giant HII regions of M101

The molecular components of three giant HII regions (NGC 5461, NGC 5462, NGC 5471) in the galaxy M101 are investigated with new observations from the James Clerk Maxwell Telescope, the NRAO 12-meter, and the Owens Valley millimeter array. Of the three HII regions, only NGC 5461 had previously been detected in CO emission. We calculate preliminary values for the molecular mass of the GMCs in NGC 5461 by assuming a CO-to-H_2 factor (X factor) and then compare these values with the virial masses. We conclude that the data in this paper demonstrate for the first time that the value of X may decrease in regions with intense star formation. The molecular mass for the association of clouds in NGC 5461 is approximately 3x10^7 Mo and is accompanied by 1-2 times as much atomic mass. The observed CO emission in NGC 5461 is an order of magnitude stronger than in NGC 5462, while it was not possible to detect molecular gas toward NGC 5471 with the JCMT. An even larger ratio of atomic to molecular gas in NGC 5471 was observed, which might be attributed to efficient conversion of molecular to atomic gas. The masses of the individual clouds in NGC 5461, which are gravitationally bound, cover a range of (2-8) x 10^5 Mo, comparable with the masses of Galactic giant molecular clouds (GMCs). Higher star forming efficiencies, and not massive clouds, appear to be the prerequisite for the formation of the large number of stars whose radiation is required to produce the giant HII regions in M101.Comment: 32 pages, 5 figures, accepted for publication in the Astrophysical Journa

Abstraction and Assume-Guarantee Reasoning for Automated Software Verification

Compositional verification and abstraction are the key techniques to address the state explosion problem associated with model checking of concurrent software. A promising compositional approach is to prove properties of a system by checking properties of its components in an assume-guarantee style. This article proposes a framework for performing abstraction and assume-guarantee reasoning of concurrent C code in an incremental and fully automated fashion. The framework uses predicate abstraction to extract and refine finite state models of software and it uses an automata learning algorithm to incrementally construct assumptions for the compositional verification of the abstract models. The framework can be instantiated with different assume-guarantee rules. We have implemented our approach in the COMFORT reasoning framework and we show how COMFORT out-performs several previous software model checking approaches when checking safety properties of non-trivial concurrent programs

Large-Area Mapping at 850 Microns. I. Optimum Image Reconstruction from Chop Measurements

We present results on the optimum reconstruction of chop data taken using the Submillimeter Common-User Bolometer Array on the James Clerk Maxwell Telescope. Using an artificial data set with known noise properties, we analyze three techniques for constructing images of the sky from the chop data: Emerson Fourier deconvolution, matrix inversion, and maximum entropy reconstruction. We conclude that a matrix inversion formulation via an iterative procedure produces the best image reconstructions. We apply the three reconstruction techniques to produce maps of the calibration point source CRL 618 and the ? Ophiuchi A core at 850 ?m and use Wiener filtering to remove the high-frequency noise component from the matrix inversion method

Respuestas psicológicas disfuncionales en enfermeros de Unidades de Cuidados Intensivos: una revisión sistemática de la literatura

OBJETIVOBuscar evidencias de respuestas psicológicas disfuncionales en Enfermeros de Unidades de Terapia Intensiva, con enfoque en la ansiedad, síntomas depresivos y factores relacionados.MÉTODORevisión sistemática, con evaluación crítica y síntesis de datos de los estudios, llevada a cabo en las bases de datos CINAHL, PubMed y Scopus, en el período de 1999 hasta el presente, utilizándose los siguientes términos de investigación, individualmente o en combinación: "estado mental", "síntomas depresivos", "ansiedad", "enfermeros de UCI", "estrés post traumático", "burnout", "fatiga por compasión" y "estrés psicológico".RESULTADOFueron incluidos trece estudios cuantitativos en Inglés y Griego. Los resultados sugieren un incremento de la carga psicológica en los Enfermeros de UCI comparativamente con otras especialidades de enfermería, así como con la población en general.CONCLUSIÓNEstudios internacionales de investigación acerca de la respuesta psicológica son limitados. Estudios futuros, longitudinales y de intervención, contribuirán a una mejor comprensión del fenómeno.OBJECTIVETo systematically review evidence on dysfunctional psychological responses of Intensive Care Units nurses (ICUNs), with focus on anxiety and depressive symptoms and related factors.METHODA literature search was performed in CINAHL, PubMed and Scopus databases, from 1999 to present, along with a critical appraisal and synthesis of all relevant data. The following key words, separately and in combination, were used: "mental status" "depressive symptoms" "anxiety" "ICU nurses" "PTSD" "burnout" "compassion fatigue" "psychological distress".RESULTSThirteen quantitative studies in English and Greek were included. The results suggested increased psychological burden in ICUNs compared to other nursing specialties, as well as to the general population.CONCLUSIONSStudies investigating psychological responses of ICUNs are limited, internationally. Future longitudinal and intervention studies will contribute to a better understanding of the phenomenon.OBJETIVORever sistematicamente evidências de respostas psicológicas disfuncionais em Enfermeiros de Unidades de Cuidados Intensivos (EUCI), com foco na ansiedade, sintomas depressivos e fatores relacionados.MÉTODOFoi realizada uma pesquisa bibliográfica, com avaliação crítica e síntese de dados dos estudos, nas bases de dados da CINAHL, PubMed e Scopus, para o período de 1999 até ao presente. Foram utilizados os seguintes termos de pesquisa, individualmente ou em combinação: "estado mental" "sintomas depressivos" "ansiedade" "enfermeiros de UCI" "PTSD" "burnout" "fadiga da compaixão" "stress psicológico".RESULTADOForam incluídos treze estudos quantitativos em Inglês e Grego. Os resultados sugerem um aumento da carga psicológica nos EUCI comparativamente com outras especialidades de enfermagem, assim como com a população em geral.CONCLUSÕESEstudos internacionais de investigação sobre a resposta psicológica de EUCI são limitados. Estudos futuros, longitudinais e de intervenção, irão contribuir para uma melhor compreensão do fenômeno

Parallel and serial mediation analysis between pain, anxiety, depression, fatigue and nausea, vomiting and retching within a randomised controlled trial in patients with breast and prostate cancer

Objective Cancer treatment is a particularly stressful period for the patient. The reasons vary and include fear of treatment outcome as well as treatment induced side effects. The patient frequently experiences simultaneously various side effects resulting in a diminishing of the patient's health-related quality of life (HRQoL). The study provides evidence on the co-occurrence and inter-relations between pain, anxiety, depression and fatigue in patients with breast and prostate cancer. Design This paper presents a secondary analysis of the data from a randomised control trial designed to test the effectiveness of guided imagery and progressive muscle relaxation on pain, fatigue, anxiety and depression. Non-parametric bootstrapping analyses were used to test the mediational model of anxiety, fatigue and depression as parallel mediators of the relationship between pain and HRQoL. Setting The study was undertaken at the home setting. Participants In total 208 patients were included in the study (assigned equally in two groups), referred at the outpatient clinics of the three participating cancer care centres. Results The three mediators fully mediate the relationship between pain and HRQoL indirect effect (IE overall =-0.3839, 95% CI: Lower limit (LL)=-0.5073 to upper limit (UL)=-0.2825) indicating that patients with increased pain are likely to have higher levels of anxiety, fatigue and depression. Gender significantly moderated the mediational effect of Fatigue Index of Moderated Mediation (IMM=-0.2867 SE=0.1526, LL=-0.6127, UL=-0.0226) but did not moderate mediational effect of anxiety (IMM=-0.0709, SE=0.1414, LL=-0.3459, UL=+0.2089). The results show that the three mediators in a serial causal order fully mediate the relationship between pain and HRQoL (IE overall =-0.384, 95% CI: LL=-0.51 to UL=-0.284) and the ratio of the overall indirect effect to the total effect is 0.8315 (95% CI: LL=0.5683 to UL=1.1718). Conclusion This work provides evidence that targeting fatigue, anxiety and depression may have a meaningful effect on pain as a related symptom and potentially have a positive impact on HRQoL of patients with breast and prostate cancer.</p

Adolescent Verbal Memory as a Psychosis Endophenotype: A Genome-Wide Association Study in an Ancestrally Diverse Sample

Verbal memory impairment is one of the most prominent cognitive deficits in psychosis. However, few studies have investigated the genetic basis of verbal memory in a neurodevelopmental context, and most genome-wide association studies (GWASs) have been conducted in European-ancestry populations. We conducted a GWAS on verbal memory in a maximum of 11,017 participants aged 8.9 to 11.1 years in the Adolescent Brain Cognitive Development Study®, recruited from a diverse population in the United States. Verbal memory was assessed by the Rey Auditory Verbal Learning Test, which included three measures of verbal memory: immediate recall, short-delay recall, and long-delay recall. We adopted a mixed-model approach to perform a joint GWAS of all participants, adjusting for ancestral background and familial relatedness. The inclusion of participants from all ancestries increased the power of the GWAS. Two novel genome-wide significant associations were found for short-delay and long-delay recall verbal memory. In particular, one locus (rs9896243) associated with long-delay recall was mapped to the NSF (N-Ethylmaleimide Sensitive Factor, Vesicle Fusing ATPase) gene, indicating the role of membrane fusion in adolescent verbal memory. Based on the GWAS in the European subset, we estimated the SNP-heritability to be 15% to 29% for the three verbal memory traits. We found that verbal memory was genetically correlated with schizophrenia, providing further evidence supporting verbal memory as an endophenotype for psychosis