Rab27a Regulates the Peripheral Distribution of Melanosomes in Melanocytes

Rab GTPases are regulators of intracellular membrane traffic. We report a possible function of Rab27a, a protein implicated in several diseases, including Griscelli syndrome, choroideremia, and the Hermansky-Pudlak syndrome mouse model, gunmetal. We studied endogenous Rab27a and overexpressed enhanced GFP-Rab27a fusion protein in several cultured melanocyte and melanoma-derived cell lines. In pigmented cells, we observed that Rab27a decorates melanosomes, whereas in nonpigmented cells Rab27a colocalizes with melanosome-resident proteins. When dominant interfering Rab27a mutants were expressed in pigmented cells, we observed a redistribution of pigment granules with perinuclear clustering. This phenotype is similar to that observed by others in melanocytes derived from the ashen and dilute mutant mice, which bear mutations in the Rab27a and MyoVa loci, respectively. We also found that myosinVa coimmunoprecipitates with Rab27a in extracts from melanocytes and that both Rab27a and myosinVa colocalize on the cytoplasmic face of peripheral melanosomes in wild-type melanocytes. However, the amount of myosinVa in melanosomes from Rab27a-deficient ashen melanocytes is greatly reduced. These results, together with recent data implicating myosinVa in the peripheral capture of melanosomes, suggest that Rab27a is necessary for the recruitment of myosinVa, so allowing the peripheral retention of melanosomes in melanocytes

Transcript of The Dory Derby Accident

This story is an excerpt from a longer interview that was collected as part of the Launching through the Surf: The Dory Fleet of Pacific City project. In this story, Don Grotjohn recounts an accident that occurred during a Dory Derby competition

A randomized comparison ofrepeat stenting with balloon angioplasty in patients with in-stent restenosis

AbstractObjectivesThis randomized trial compared repeat stenting with balloon angioplasty (BA) in patients with in-stent restenosis (ISR).BackgroundStent restenosis constitutes a therapeutic challenge. Repeat coronary interventions are currently used in this setting, but the recurrence risk remains high.MethodsWe randomly assigned 450 patients with ISR to elective stent implantation (224 patients) or conventional BA (226 patients). Primary end point was recurrent restenosis rate at six months. Secondary end points included minimal lumen diameter (MLD), prespecified subgroup analyses, and a composite of major adverse events.ResultsProcedural success was similar in both groups, but in-hospital complications were more frequent in the balloon group. After the procedure MLD was larger in the stent group (2.77 ± 0.4 vs. 2.25 ± 0.5 mm, p < 0.001). At follow-up, MLD was larger after stenting when the in-lesion site was considered (1.69 ± 0.8 vs. 1.54 ± 0.7 mm, p = 0.046). However, the binary restenosis rate (38% stent group, 39% balloon group) was similar with the two strategies. One-year event-free survival (follow-up 100%) was also similar in both groups (77% stent vs. 71% balloon, p = 0.19). Nevertheless, in the prespecified subgroup of patients with large vessels (≥3 mm) the restenosis rate (27% vs. 49%, p = 0.007) and the event-free survival (84% vs. 62%, p = 0.002) were better after repeat stenting.ConclusionsIn patients with ISR, repeat coronary stenting provided better initial angiographic results but failed to improve restenosis rate and clinical outcome when compared with BA. However, in patients with large vessels coronary stenting improved the long-term clinical and angiographic outcome

Carvedilol for prevention of restenosis after directional coronary atherectomy : final results of the European carvedilol atherectomy restenosis (EUROCARE) trial

BACKGROUND: In addition to its known properties as a competitive, nonselective beta and alpha-1 receptor blocker, carvedilol directly inhibits vascular myocyte migration and proliferation and exerts antioxidant effects that are considerably greater than those of vitamin E or probucol. This provides the basis for an evaluation of carvedilol for the prevention of coronary restenosis. METHODS AND RESULTS: In a prospective, double-blind, randomized, placebo-controlled trial, 25 mg of carvedilol was given twice daily, starting 24 h

(I)Migrantes, diversidades e desigualdades no sistema educativo português : balanço e perspectivas

O objectivo do presente artigo consiste em procurar transmitir um olhar sociologicamente informado no que concerne à situação portuguesa no domínio das políticas educativas públicas e investigações produzidas relacionadas com o sistema educativo e a (i)migração, ou seja, com a tentativa de construção de uma educação intercultural. Neste sentido, será realizada uma análise descritiva e compreensivo-interpretativa da evolução desta problemática em Portugal desde que a mesma se tornou objecto de reflexão por parte de investigadores/as e políticos nos finais da década de oitenta, início da década de noventa do século XX. Nesta análise, será dada ênfase às investigações e quadros teóricos produzidos e às medidas legislativas e políticas educativas no domínio do tratamento da diferença cultural dentro do sistema educativo português.The aim of this article consists in attempting to transmit a sociologically informed view in what the Portuguese situation in the field of public policies and research related to the educational system and (im)migration are concerned, that is, in attempting to construct an intercultural education. In this way, a descriptive and comprehensiveinterpretative analysis of the evolution of this problem in Portugal will be realized, since the latter became an object of reflection on the part of researchers and politicians towards the end of the 80s, the beginning of the 90s of the XXth century. In this analysis, emphasis will be given on the research and theoretical frameworks produced and on the legislative measures and educational policies in the field of treating cultural difference in the Portuguese educational system

Effectiveness and safety of levosimendan in clinical practice

BACKGROUND: In previous randomized studies levosimendan improved hemodynamics and clinical course, with a still unclear effect on prognosis. There are, however, few data regarding its effects when used in daily practice. AIMS: We evaluated the clinical effectiveness and safety of levosimendan in the treatment of acute systolic heart failure (SHF) in daily practice conditions. METHODS: In this prospective, multicenter, nonrandomized trial, a continuous infusion of levosimendan (0.05 microg/kg/min-0.2 microg/kg/min) was administered for 24 hours. An optional loading dose of 12 microg/kg over 10 minutes was used. The primary combined endpoint of clinical effectiveness (as defined by a eight-variable clinical score) and safety (defined by the absence of serious adverse events) was assessed at 24 hours after the beginning of treatment; a second similar primary combined endpoint was assessed at 5 days. RESULTS: One hundred and twenty-nine consecutive patients requiring inotropes despite optimal oral background heart failure therapy were recruited. The primary endpoint was reached in 80.6% at 24 hours and in 79.7% at 5 days. During the six months before levosimendan the number of patient days of hospitalization for heart failure was 14.9 +/- 14.6 versus 3.1 +/- 7.6 during the six months following levosimendan (p < 0.001). CONCLUSIONS: In daily practice, levosimendan was clinically effective and safe in 80.6% and 79.7% of patients with acute SHF at 24 hours and 5 days respectively after the beginning of treatment. A marked reduction in the number of days of hospitalization for heart failure was also seen during the subsequent six months

Randomized comparison of primary stenting and provisional balloon angioplasty guided by flow velocity measurement.

BACKGROUND: Coronary stenting improves outcomes compared with balloon angioplasty, but it is costly and may have other disadvantages. Limiting stent use to patients with a suboptimal result after angioplasty (provisional angioplasty) may be as effective and less expensive. METHODS AND RESULTS: To analyze the cost-effectiveness of provisional angioplasty, patients scheduled for single-vessel angioplasty were first randomized to receive primary stenting (97 patients) or balloon angioplasty guided by Doppler flow velocity and angiography (523 patients). Patients in the latter group were further randomized after optimization to either additional stenting or termination of the procedure to further investigate what is "optimal." An optimal result was defined as a flow reserve >2.5 and a diameter stenosis <36%. Bailout stenting was needed in 129 patients (25%) who were randomized to balloon angioplasty, and an optimal result was obtained in 184 of the 523 patients (35%). There was no significant difference in event-free survival at 1 year between primary stenting (86.6%) and provisional angioplasty (85.6%). Costs after 1 year were significantly higher for provisional angioplasty (EUR 6573 versus EUR 5885; P:=0.014). Results after the second randomization showed that stenting was also more effective after optimal balloon angioplasty (1-year event free survival, 93.5% versus 84.1%; P:=0. 066). CONCLUSIONS: After 1 year of follow-up, provisional angioplasty was more expensive and without clinical benefit. The beneficial value of stenting is not limited to patients with a suboptimal result after balloon angioplasty

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV