Neurotoxic astrocytes directly converted from sporadic and familial ALS patient fibroblasts reveal signature diversities and miR-146a theragnostic potential in specific subtypes

A lack of stratification methods in patients with amyotrophic lateral sclerosis (ALS) is likely implicated in therapeutic failures. Regional diversities and pathophysiological abnormalities in astrocytes from mice with SOD1 mutations (mSOD1-ALS) can now be explored in human patients using somatic cell reprogramming. Here, fibroblasts from four sporadic (sALS) and three mSOD1-ALS patients were transdifferentiated into induced astrocytes (iAstrocytes). ALS iAstrocytes were neurotoxic toward HB9-GFP mouse motor neurons (MNs) and exhibited subtype stratification through GFAP, CX43, Ki-67, miR-155 and miR-146a expression levels. Up- (two cases) and down-regulated (three cases) miR-146a values in iAstrocytes were recapitulated in their secretome, either free or as cargo in small extracellular vesicles (sEVs). We previously showed that the neuroprotective phenotype of depleted miR-146 mSOD1 cortical astrocytes was reverted by its mimic. Thus, we tested such modulation in the most miR-146a-depleted patient-iAstrocytes (one sALS and one mSOD1-ALS). The miR-146a mimic in ALS iAstrocytes counteracted their reactive/inflammatory profile and restored miR-146a levels in sEVs. A reduction in lysosomal activity and enhanced synaptic/axonal transport-related genes in NSC-34 MNs occurred after co-culture with miR-146a-modulated iAstrocytes. In summary, the regulation of miR-146a in depleted ALS astrocytes may be key in reestablishing their normal function and in restoring MN lysosomal/synaptic dynamic plasticity in disease sub-groups

Alinhamento frontal estático do joelho e cargas plantares durante a marcha de adultos jovens assintomáticos

In physical therapy practice, it is assumed that lower-limb posture changes may influence other complexes' biomechanics or function during movement. However, literature on the relationship between static knee alignment and possible dynamic changes is still scarce and inconclusive. This study assessed the effect of static frontal knee alignment on plantar pressure distribution during gait. At first 44 young asymptomatic adults were evaluated. Front knee angles were measured by digital photogrammetry and classified as normal (170° to 175°), valgus ;175°. Given the low number of valgus found, two groups were analysed: normal knees (n=18) and varus knees (n=23). Plantar pressure distribution was measured during gait in five plantar surface areas. Groups were found to be statistically similar in all kinetic variables assessed in all plantar surface areas. Normal knees showed significant correlation with the contact time at lateral forefoot and midfoot. Varus knees showed correlation with contact area and time at respectively two and three plantar areas, and with full pressure at lateral forefoot. Results thus show that a 3° frontal knee malalignment, though with moderate correlation, does not influence pressure distribution on plantar surface during gait. It is hence suggested that clinical evaluation should not be limited to static knee assessment, but rather include dynamic activities.Na prática fisioterapêutica, pressupõe-se que alterações posturais do membro inferior influenciem a biomecânica e função dos demais complexos durante o movimento. No entanto, a literatura sobre a relação entre desalinhamentos estáticos do joelho e possíveis alterações dinâmicas ainda é escassa e inconclusiva. Assim, buscou-se avaliar o efeito do alinhamento frontal estático do joelho sobre a distribuição da pressão plantar durante a marcha. Foram avaliados inicialmente 44 adultos jovens assintomáticos. Por fotogrametria digital, mediu-se o ângulo frontal do joelho, classificado como normal (170° a 175°), valgo ;175°. Dado o baixo número de valgos, foram analisados dois grupos: de joelhos normais (n=18) e de joelhos varos (n=23). A distribuição da pressão plantar foi avaliada durante a marcha em cinco áreas. Os grupos mostraram-se estatistica-mente semelhantes em todas as variáveis cinéticas avaliadas em todas as áreas plantares. Joelhos normais apresentaram significativa correlação com o tempo de contato no antepé lateral e médio-pé; e os varos, correlação com a área e tempo de contato em duas e três áreas plantares, e com a pressão integral no antepé lateral. Os resultados mostraram que o desalinhamento frontal de 3° do joelho, embora com moderada correlação, não influencia a distribuição de cargas na superfície plantar durante a marcha. Sugere-se pois que a avaliação clínica não se limite à avaliação articular estática do joelho, mas inclua atividades dinâmicas

Stealth monoolein-based nanocarriers for delivery of siRNA to cancer cells

While the delivery of small interfering RNAs (siRNAs) is an attractive strategy to treat several clinical con- ditions, siRNA-nanocarriers stability after intravenous administration is still a major obstacle for the development of RNA-interference based therapies. But, although the need for stability is well recognized, the notion that strong stabilization can decrease nanocarriers efficiency is sometimes neglected. In this work we evaluated two stealth functionalization strategies to stabilize the previously validated dioctade- cyldimethylammonium bromide (DODAB):monoolein (MO) siRNA-lipoplexes. The nanocarriers were pre- and post-pegylated, forming vectors with different stabilities in biological fluids. The stealth nanocarriers behavior was tested under biological mimetic conditions, as the production of stable siRNA-lipoplexes is determinant to achieve efficient intravenous siRNA delivery to cancer cells. Upon incubation in human serum for 2 h, by fluorescence Single Particle Tracking microscopy, PEG-coated lipo- plexes were found to have better colloidal stability as they could maintain a relatively stable size. In addi- tion, using fluorescence fluctuation spectroscopy, post-pegylation also proved to avoid siRNA dissociation from the nanocarriers in human serum. Concomitantly it was found that PEG-coated lipoplexes improved cellular uptake and transfection efficiency in H1299 cells, and had the ability to silence BCR-ABL, affecting the survival of K562 cells. Based on an efficient cellular internalization, good silencing effect, good siRNA retention and good col- loidal stability in human serum, DODAB:MO (2:1) siRNA-lipoplexes coated with PEG-Cer are considered promising nanocarriers for further in vivo validation. Statement of Significance This work describes two stealth functionalization strategies for the stabilization of the previously validated dioctadecyldimethylammonium bromide (DODAB):monoolein (MO) siRNA-lipoplexes. These nanocarriers are capable of efficiently incorporating and delivering siRNA molecules to cells in order to silence genes whose expression is implicated in a pathological condition. The main objective was to functionalize these nanocarriers with a coating conferring protection to siRNA in blood without compromising its efficient delivery to cancer cells, validating the potential of DODAB:MO (2:1) siRNA-lipoplexes as therapeutic vec- tors. We show that the stealth strategy is determinant to achieve a stable and efficient nanocarrier, and that DODAB:MO mixtures have a very promising potential for systemic siRNA delivery to leukemic cells.FEDER through POFC-COMPETE and by national funds from FCT I.P. through the strategic funding UID/BIA/04050/2013 (CBMA) and PEst-C/FIS/UI0607/2013 (CFUM) and PTDC/QUI/69795/2006. We thank the support of the Frame Work Program 7 of the European Commission: BIOCAPS (316265, FP7/REGPOT) and Xunta de Galicia, Spain (Agrupamento INBIOMED, Grupo con potencial crecimiento) reference IF/00498/2012, scholarship SFRH/BD/68588/2010. NanoDelivery-I&D em Bionanotecnologia, Lda. for access to their equipment

Jet size dependence of single jet suppression in lead-lead collisions at sqrt(s(NN)) = 2.76 TeV with the ATLAS detector at the LHC

Measurements of inclusive jet suppression in heavy ion collisions at the LHC provide direct sensitivity to the physics of jet quenching. In a sample of lead-lead collisions at sqrt(s) = 2.76 TeV corresponding to an integrated luminosity of approximately 7 inverse microbarns, ATLAS has measured jets with a calorimeter over the pseudorapidity interval |eta| < 2.1 and over the transverse momentum range 38 < pT < 210 GeV. Jets were reconstructed using the anti-kt algorithm with values for the distance parameter that determines the nominal jet radius of R = 0.2, 0.3, 0.4 and 0.5. The centrality dependence of the jet yield is characterized by the jet "central-to-peripheral ratio," Rcp. Jet production is found to be suppressed by approximately a factor of two in the 10% most central collisions relative to peripheral collisions. Rcp varies smoothly with centrality as characterized by the number of participating nucleons. The observed suppression is only weakly dependent on jet radius and transverse momentum. These results provide the first direct measurement of inclusive jet suppression in heavy ion collisions and complement previous measurements of dijet transverse energy imbalance at the LHC.Comment: 15 pages plus author list (30 pages total), 8 figures, 2 tables, submitted to Physics Letters B. All figures including auxiliary figures are available at http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/HION-2011-02

Measurement of the polarisation of W bosons produced with large transverse momentum in pp collisions at sqrt(s) = 7 TeV with the ATLAS experiment

This paper describes an analysis of the angular distribution of W->enu and W->munu decays, using data from pp collisions at sqrt(s) = 7 TeV recorded with the ATLAS detector at the LHC in 2010, corresponding to an integrated luminosity of about 35 pb^-1. Using the decay lepton transverse momentum and the missing transverse energy, the W decay angular distribution projected onto the transverse plane is obtained and analysed in terms of helicity fractions f0, fL and fR over two ranges of W transverse momentum (ptw): 35 < ptw < 50 GeV and ptw > 50 GeV. Good agreement is found with theoretical predictions. For ptw > 50 GeV, the values of f0 and fL-fR, averaged over charge and lepton flavour, are measured to be : f0 = 0.127 +/- 0.030 +/- 0.108 and fL-fR = 0.252 +/- 0.017 +/- 0.030, where the first uncertainties are statistical, and the second include all systematic effects.Comment: 19 pages plus author list (34 pages total), 9 figures, 11 tables, revised author list, matches European Journal of Physics C versio

Observation of a new chi_b state in radiative transitions to Upsilon(1S) and Upsilon(2S) at ATLAS

The chi_b(nP) quarkonium states are produced in proton-proton collisions at the Large Hadron Collider (LHC) at sqrt(s) = 7 TeV and recorded by the ATLAS detector. Using a data sample corresponding to an integrated luminosity of 4.4 fb^-1, these states are reconstructed through their radiative decays to Upsilon(1S,2S) with Upsilon->mu+mu-. In addition to the mass peaks corresponding to the decay modes chi_b(1P,2P)->Upsilon(1S)gamma, a new structure centered at a mass of 10.530+/-0.005 (stat.)+/-0.009 (syst.) GeV is also observed, in both the Upsilon(1S)gamma and Upsilon(2S)gamma decay modes. This is interpreted as the chi_b(3P) system.Comment: 5 pages plus author list (18 pages total), 2 figures, 1 table, corrected author list, matches final version in Physical Review Letter