Mitochondrial and Plasma Membrane Pools of Stomatin-Like Protein 2 Coalesce at the Immunological Synapse during T Cell Activation

Stomatin-like protein 2 (SLP-2) is a member of the stomatin – prohibitin – flotillin – HflC/K (SPFH) superfamily. Recent evidence indicates that SLP-2 is involved in the organization of cardiolipin-enriched microdomains in mitochondrial membranes and the regulation of mitochondrial biogenesis and function. In T cells, this role translates into enhanced T cell activation. Although the major pool of SLP-2 is associated with mitochondria, we show here that there is an additional pool of SLP-2 associated with the plasma membrane of T cells. Both plasma membrane-associated and mitochondria-associated pools of SLP-2 coalesce at the immunological synapse (IS) upon T cell activation. SLP-2 is not required for formation of IS nor for the re-localization of mitochondria to the IS because SLP-2-deficient T cells showed normal re-localization of these organelles in response to T cell activation. Interestingly, upon T cell activation, we found the surface pool of SLP-2 mostly excluded from the central supramolecular activation complex, and enriched in the peripheral area of the IS where signalling TCR microclusters are located. Based on these results, we propose that SLP-2 facilitates the compartmentalization not only of mitochondrial membranes but also of the plasma membrane into functional microdomains. In this latter location, SLP-2 may facilitate the optimal assembly of TCR signalosome components. Our data also suggest that there may be a net exchange of membrane material between mitochondria and plasma membrane, explaining the presence of some mitochondrial proteins in the plasma membrane

Quantum Spacetime Phenomenology

I review the current status of phenomenological programs inspired by quantum-spacetime research. I stress in particular the significance of results establishing that certain data analyses provide sensitivity to effects introduced genuinely at the Planck scale. And my main focus is on phenomenological programs that managed to affect the directions taken by studies of quantum-spacetime theories.Comment: 125 pages, LaTex. This V2 is updated and more detailed than the V1, particularly for quantum-spacetime phenomenology. The main text of this V2 is about 25% more than the main text of the V1. Reference list roughly double

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Expressão de certeza e dúvida na gagueira: estudo dos aspectos temporais da fala Expression of certainty and doubt on stuttering: study of speech's temporal features

OBJETIVO: examinar o papel da organização temporal do discurso na expressão das atitudes de certeza e dúvida em grupo de adultos com gagueira, comparando-a em um grupo de adultos fluentes. MÉTODO: participaram desta pesquisa 24 indivíduos, sendo 12 com gagueira (GE1 e GE2) e 12 sem gagueira (GC). Foram coletadas amostras que teve como base um corpus de 10 frases chave que foram produzidas nas formas neutra, de dúvida e de certeza, totalizando 840 enunciados. A análise acústica foi realizada por meio do programa Praat e os seguintes parâmetros foram analisados: tempos e taxas de elocução e articulação, ocorrência e duração de pausas e disfluências, duração das vogais tônica e pré-tônica e ocorrência da vogal pós-tônica. A análise estatística foi realizada por meio dos testes Kruskall Wallis e qui-quadrado, com índice de significância de 95%. RESULTADOS: a expressão da dúvida apresenta taxa de articulação mais baixa no grupo controle, seguida da forma neutra e de certeza, com diferenças estatisticamente significantes. Ainda no grupo controle, foi observado presença de pausas e disfluências somente na expressão de dúvida. No grupo experimental, a maior diferença encontrada foi na duração da vogal da sílaba tônica. CONCLUSÃO: de uma forma geral, o GC variou mais sua organização temporal a fim de expressar as atitudes. No entanto, é possível observar também uma tendência semelhante no grupo de pessoas com gagueira. Quanto à velocidade de fala, ao retirar as pausas e as disfluências, vemos que tanto GE1 quanto GE2 diferenciam a certeza, articulando cada sílaba de forma mais rápida.<br>PURPOSE: to examine the role of speech temporal organization on the expression as for the attitudes of certainty and doubt in the group of adults who stutter, comparing such analysis with a group of speech-fluent adults. METHOD: we analyzed 24 individuals, 12 with stuttering (SG1 and SG2) and 12 without stuttering (CG). Samples were collected with a corpus of 10 key phrases that were produced in the neutral form, expressing doubt and certainty, totaling 840 utterances. The acoustic analysis was performed using Praat and the following parameters were analyzed: time and speech rate and articulation, presence and duration of pauses and disfluencies, duration of vowels in pre-tonic and tonic syllables and occurrence of post-tonic vowel. Statistical analysis was performed by using Kruskall Wallis and chi-square tests, with a significance level of 95%. RESULTS: the expression of doubt has the lowest rate of articulation in the control group, followed by neutral and certainty expressions, with statistically significant differences. Also in the control group, there was presence of pauses and disfluencies only in the expression of doubt. In the experimental group, the largest difference was found in the vowel duration of the stressed syllable. CONCLUSION: generally speaking, CG varied more its temporal organization in order to express attitudes. However, it is also possible to note a trend in the group of people who stutter. As for the speech rate, by removing the pauses and disfluencies, we see that both GE1 and GE2 differentiate certainty, faster articulating each syllable