MALT1 auto-proteolysis is essential for NF-κB-dependent gene transcription in activated lymphocytes.

Mucosa-associated lymphoid tissue 1 (MALT1) controls antigen receptor-mediated signalling to nuclear factor κB (NF-κB) through both its adaptor and protease function. Upon antigen stimulation, MALT1 forms a complex with BCL10 and CARMA1, which is essential for initial IκBα phosphorylation and NF-κB nuclear translocation. Parallel induction of MALT1 protease activity serves to inactivate negative regulators of NF-κB signalling, such as A20 and RELB. Here we demonstrate a key role for auto-proteolytic MALT1 cleavage in B- and T-cell receptor signalling. MALT1 cleavage occurred after Arginine 149, between the N-terminal death domain and the first immunoglobulin-like region, and did not affect its proteolytic activity. Jurkat T cells expressing an un-cleavable MALT1-R149A mutant showed unaltered initial IκBα phosphorylation and normal nuclear accumulation of NF-κB subunits. Nevertheless, MALT1 cleavage was required for optimal activation of NF-κB reporter genes and expression of the NF-κB targets IL-2 and CSF2. Transcriptome analysis confirmed that MALT1 cleavage after R149 was required to induce NF-κB transcriptional activity in Jurkat T cells. Collectively, these data demonstrate that auto-proteolytic MALT1 cleavage controls antigen receptor-induced expression of NF-κB target genes downstream of nuclear NF-κB accumulation.

Neutral endopeptidase versus angiotensin converting enzyme inhibition in essential hypertension.

OBJECTIVE: To evaluate the antihypertensive efficacy of sinorphan, an orally active inhibitor of neutral endopeptidase EC 3.4.24.11. DESIGN: The ability of sinorphan (100 mg twice a day) to lower blood pressure was compared with that of the angiotensin converting enzyme (ACE) inhibitor captopril (25 mg twice a day) using a randomized-sequence, double-blind crossover design in 16 patients with essential hypertension. Each treatment was administered for 4 weeks and treatments were separated by a 3-week placebo period. At the end of the last phase of treatment sinorphan was combined with captopril for a further 4-week period. The changes in systolic (SBP) and diastolic blood pressure (DBP) were monitored using repeated ambulatory blood pressure monitoring. RESULTS: When given as monotherapy for 4 weeks, neither sinorphan nor captopril significantly reduced the 24-h or the 14-h daytime mean SBP or DBP. However, a significant decrease in DBP was observed during the first 6 h after the morning administration of captopril. With sinorphan only a significant decrease in night-time SBP was found. With the combined therapy of sinorphan and captopril, significant decreases both in SBP and in DBP were observed, which were sustained over 24 h. After 4 weeks of sinorphan alone or in combination with captopril, no change in plasma atrial natriuretic peptide level was found. However, urinary cyclic GMP excretion increased transiently after administration of the neutral endopeptidase inhibitor. CONCLUSIONS: Neutral endopeptidase inhibition with sinorphan has a limited effect on blood pressure in hypertensive patients when given alone. However, simultaneous neutral endopeptidase and ACE inhibition induces a synergistic effect, and might therefore represent an interesting new therapeutic approach to the treatment of essential hypertension.

Factors de creixement autòlegs aplicats a les ferides cròniques amb evolució tòrpida

Les ferides cròniques, especialment les de lenta curació, suposen una carga important pels pacients i pels sistemes de salut. És imprescindible investigar en nous tractaments que redueixin el temps de curació d‟aquestes ferides. L‟objectiu d‟aquest projecte, és avaluar l‟eficàcia dels factors de creixement, obtinguts de plasma ric en plaquetes, en la curació o millora de les ferides cròniques. El projecte s‟ha dissenyat com un estudi d‟una sèrie de casos que compara el tractament convencional amb el tractament amb factors de creixement. La variable resultats és la curació o la disminució del àrea de l‟úlcera. El projecte pretén avaluar uns quants pacients consecutius atesos en l‟ unitat de ferides cròniques del nostre hospital. Els subjectes del estudi han de presentar una ferida de més de 3 mesos d‟evolució nul·la o escassa resposta als tractaments habituals. La tècnica de obtenció dels factors de creixement plaquetar no és complexa i es pot realitzar en l‟entorn d‟un hospital de dia. No s‟han comunicat en la literatura efectes secundaris majors de l‟aplicació dels factors de creixement en ferides cròniques.

Optical counterpart of galactic plane variable radio sources

We present I-band deep CCD exposures of the fields of galactic plane radio variables. An optical counterpart, based on positional coincidence, has been found for 15 of the 27 observed program objects. The Johnson I magnitude of the sources identified is in the range 18-21.

Analysis of warm season thunderstorms using an object-oriented tracking method based on radar and total lightning data

Monitoring thunderstorms activity is an essential part of operational weather surveillance given their potential hazards, including lightning, hail, heavy rainfall, strong winds or even tornadoes. This study has two main objectives: firstly, the description of a methodology, based on radar and total lightning data to characterise thunderstorms in real-time; secondly, the application of this methodology to 66 thunderstorms that affected Catalonia (NE Spain) in the summer of 2006. An object-oriented tracking procedure is employed, where different observation data types generate four different types of objects (radar 1-km CAPPI reflectivity composites, radar reflectivity volumetric data, cloud-to-ground lightning data and intra-cloud lightning data). In the framework proposed, these objects are the building blocks of a higher level object, the thunderstorm. The methodology is demonstrated with a dataset of thunderstorms whose main characteristics, along the complete life cycle of the convective structures (development, maturity and dissipation), are described statistically. The development and dissipation stages present similar durations in most cases examined. On the contrary, the duration of the maturity phase is much more variable and related to the thunderstorm intensity, defined here in terms of lightning flash rate. Most of the activity of IC and CG flashes is registered in the maturity stage. In the development stage little CG flashes are observed (2% to 5%), while for the dissipation phase is possible to observe a few more CG flashes (10% to 15%). Additionally, a selection of thunderstorms is used to examine general life cycle patterns, obtained from the analysis of normalized (with respect to thunderstorm total duration and maximum value of variables considered) thunderstorm parameters. Among other findings, the study indicates that the normalized duration of the three stages of thunderstorm life cycle is similar in most thunderstorms, with the longest duration corresponding to the maturity stage (approximately 80% of the total time).

Radio detections towards unidentified variable EGRET sources

A considerable fraction of the -ray sources discovered with the Energetic Gamma-Ray Experiment Telescope (EGRET) remain unidentified. The EGRET sources that have been properly identified are either pulsars or variable sources at both radio and gamma-ray wavelengths. Most of the variable sources are strong radio blazars. However, some low galactic-latitude EGRET sources, with highly variable -ray emission, lack any evident counterpart according to the radio data available until now. Aims. The primary goal of this paper is to identify and characterise the potential radio counterparts of four highly variable -ray sources in the galactic plane through mapping the radio surroundings of the EGRET confidence contours and determining the variable radio sources in the field whenever possible. Methods. We have carried out a radio exploration of the fields of the selected EGRET sources using the Giant Metrewave Radio Telescope (GMRT) interferometer at 21 cm wavelength, with pointings being separated by months. Results. We detected a total of 151 radio sources. Among them, we identified a few radio sources whose flux density has apparently changed on timescales of months. Despite the limitations of our search, their possible variability makes these objects a top-priority target for multiwavelength studies of the potential counterparts of highly variable, unidentified gamma-ray sources.

Super-resolution of remotely sensed images with variable-pixel linear reconstruction

This paper describes the development and applications of a super-resolution method, known as Super-Resolution Variable-Pixel Linear Reconstruction. The algorithm works combining different lower resolution images in order to obtain, as a result, a higher resolution image. We show that it can make significant spatial resolution improvements to satellite images of the Earth¿s surface allowing recognition of objects with size approaching the limiting spatial resolution of the lower resolution images. The algorithm is based on the Variable-Pixel Linear Reconstruction algorithm developed by Fruchter and Hook, a well-known method in astronomy but never used for Earth remote sensing purposes. The algorithm preserves photometry, can weight input images according to the statistical significance of each pixel, and removes the effect of geometric distortion on both image shape and photometry. In this paper, we describe its development for remote sensing purposes, show the usefulness of the algorithm working with images as different to the astronomical images as the remote sensing ones, and show applications to: 1) a set of simulated multispectral images obtained from a real Quickbird image; and 2) a set of multispectral real Landsat Enhanced Thematic Mapper Plus (ETM+) images. These examples show that the algorithm provides a substantial improvement in limiting spatial resolution for both simulated and real data sets without significantly altering the multispectral content of the input low-resolution images, without amplifying the noise, and with very few artifacts.

Variable Very-High-Energy Gamma-Ray Emission from the Microquasar LS I +61 303

Microquasars are binary star systems with relativistic radio-emitting jets. They are potential sources of cosmic rays and can be used to elucidate the physics of relativistic jets. We report the detection of variable gamma-ray emission above 100 gigaelectron volts from the microquasar LS I 61 + 303. Six orbital cycles were recorded. Several detections occur at a similar orbital phase, which suggests that the emission is periodic. The strongest gamma-ray emission is not observed when the two stars are closest to one another, implying a strong orbital modulation of the emission or absorption processes.

The essential role of radiotherapy in the treatment of Merkel cell carcinoma: a study from the Rare Cancer Network.

PURPOSE: To evaluate the role of postoperative radiotherapy (RT) in Merkel cell carcinoma (MCC). METHODS AND MATERIALS: A retrospective multicenter study was performed in 180 patients with MCC treated between February 1988 and September 2009. Patients who had had surgery alone were compared with patients who received surgery and postoperative RT or radical RT. Local relapse-free survival (LRFS), regional relapse-free survival (RRFS), and distant metastasis-free survival (DMFS) rates were assessed together with disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) rates. RESULTS: Seventy-nine patients were male and 101 patients were female, and the median age was 73 years old (range, 38-93 years). The majority of patients had localized disease (n = 146), and the remaining patients had regional lymph node metastasis (n = 34). Forty-nine patients underwent surgery for the primary tumor without postoperative RT to the primary site; the other 131 patients received surgery for the primary tumor, followed by postoperative RT (n = 118) or a biopsy of the primary tumor followed by radical RT (n = 13). Median follow-up was 5 years (range, 0.2-16.5 years). Patients in the RT group had improved LRFS (93% vs. 64%; p < 0.001), RRFS (76% vs. 27%; p < 0.001), DMFS (70% vs. 42%; p = 0.01), DFS (59% vs. 4%; p < 0.001), and CSS (65% vs. 49%; p = 0.03) rates compared to patients who underwent surgery for the primary tumor alone; LRFS, RRFS, DMFS, and DFS rates remained significant with multivariable Cox regression analysis. However OS was not significantly improved by postoperative RT (56% vs. 46%; p = 0.2). CONCLUSIONS: After multivariable analysis, postoperative RT was associated with improved outcome and seems to be an important component in the multimodality treatment of MCC.

Creació musical i improvisació. Crèdit variable per a primer cicle d'ESO

Document en què es proposen una sèrie d'activitats pràctiques ordenades i agrupades en sessions, per tal de treballar la creativitat i la improvisació musical amb els alumnes de secundària.

Thalamic connectivity in patients with essential tremor treated with MR imaging-guided focused ultrasound: in vivo fiber tracking by using diffusion-tensor MR imaging.

PURPOSE: To use diffusion-tensor (DT) magnetic resonance (MR) imaging in patients with essential tremor who were treated with transcranial MR imaging-guided focused ultrasound lesion inducement to identify the structural connectivity of the ventralis intermedius nucleus of the thalamus and determine how DT imaging changes correlated with tremor changes after lesion inducement. MATERIALS AND METHODS: With institutional review board approval, and with prospective informed consent, 15 patients with medication-refractory essential tremor were enrolled in a HIPAA-compliant pilot study and were treated with transcranial MR imaging-guided focused ultrasound surgery targeting the ventralis intermedius nucleus of the thalamus contralateral to their dominant hand. Fourteen patients were ultimately included. DT MR imaging studies at 3.0 T were performed preoperatively and 24 hours, 1 week, 1 month, and 3 months after the procedure. Fractional anisotropy (FA) maps were calculated from the DT imaging data sets for all time points in all patients. Voxels where FA consistently decreased over time were identified, and FA change in these voxels was correlated with clinical changes in tremor over the same period by using Pearson correlation. RESULTS: Ipsilateral brain structures that showed prespecified negative correlation values of FA over time of -0.5 or less included the pre- and postcentral subcortical white matter in the hand knob area; the region of the corticospinal tract in the centrum semiovale, in the posterior limb of the internal capsule, and in the cerebral peduncle; the thalamus; the region of the red nucleus; the location of the central tegmental tract; and the region of the inferior olive. The contralateral middle cerebellar peduncle and bilateral portions of the superior vermis also showed persistent decrease in FA over time. There was strong correlation between decrease in FA and clinical improvement in hand tremor 3 months after lesion inducement (P < .001). CONCLUSION: DT MR imaging after MR imaging-guided focused ultrasound thalamotomy depicts changes in specific brain structures. The magnitude of the DT imaging changes after thalamic lesion inducement correlates with the degree of clinical improvement in essential tremor.

Common Variable Immunodeficiency: molecular pathways and clinical manifestations

Common variable immunodeficiency (CVID), is a disease that is characterized by hypogammaglobulinemia as well as a defect in T, B and dendritic cells. This leads to recurrent bacterial infection mainly caused by Streptococcus pneumoniae, Klebsiella pneumoniae and Haemophilus influenzae, as well as inflammatory manifestations, i.e. granulomateous disease, gastro-intestinal disorders and chronic lung disease. Intravenous Immunoglobulin (IVIg) therapy reduces CVID susceptibility to bacterial infections to some extend. We analyzed clinical aspects of patients from our database. We recently showed that bacteria-specific CD4 T cells of CVID patients were impaired. We therefor postulated that CVID patients may harbor an acquired T-cell deficiency also called exhaustion. To test this hypothesis, we performed a comprehensive investigation of the functional profiles of bacteria-specific CD4 T cells isolated from 31 healthy individuals and 30 CVID patients. In the present study, we demonstrated that bacteria-specific but not virus-specific CD4 T cells in CVID patients harbored reduced proliferation capacity and expressed high level of PD-1. Interestingly, the blockade of PD-1/PD-1 ligands interactions restored partially bacteria but not virus-specific CD4 T-cell proliferation. Finally, we showed that 1) the level of endotoxins inversely correlates with IgG concentration, 2) IVIG treated CVID patients harbored reduced endotoxemia and 3) IgG concentration exceeding 7 mg/mL strongly reduces both the proportion of CVID patients with detectable endotoxemia and the concentration of endotoxins in plasma. Taken together our observations, suggest that primary B-cell defect(s) in CVID patients leads to recurrent bacterial infections that are associated to an acquired (secondary) impairment of CD4 T cells which may in turn exacerbate the lack of protection against extracellular bacteria.

Cooperation between the transcription factors p63 and IRF6 is essential to prevent cleft palate in mice.

Cleft palate is a common congenital disorder that affects up to 1 in 2,500 live human births and results in considerable morbidity to affected individuals and their families. The etiology of cleft palate is complex, with both genetic and environmental factors implicated. Mutations in the transcription factor-encoding genes p63 and interferon regulatory factor 6 (IRF6) have individually been identified as causes of cleft palate; however, a relationship between the key transcription factors p63 and IRF6 has not been determined. Here, we used both mouse models and human primary keratinocytes from patients with cleft palate to demonstrate that IRF6 and p63 interact epistatically during development of the secondary palate. Mice simultaneously carrying a heterozygous deletion of p63 and the Irf6 knockin mutation R84C, which causes cleft palate in humans, displayed ectodermal abnormalities that led to cleft palate. Furthermore, we showed that p63 transactivated IRF6 by binding to an upstream enhancer element; genetic variation within this enhancer element is associated with increased susceptibility to cleft lip. Our findings therefore identify p63 as a key regulatory molecule during palate development and provide a mechanism for the cooperative role of p63 and IRF6 in orofacial development in mice and humans.