Showing papers by "University of Oviedo published in 2012"

Guidelines for the use and interpretation of assays for monitoring autophagy

Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

Epigenetics and the environment: emerging patterns and implications.

Abstract: Epigenetic phenomena in animals and plants are mediated by DNA methylation and stable chromatin modifications. There has been considerable interest in whether environmental factors modulate the establishment and maintenance of epigenetic modifications, and could thereby influence gene expression and phenotype. Chemical pollutants, dietary components, temperature changes and other external stresses can indeed have long-lasting effects on development, metabolism and health, sometimes even in subsequent generations. Although the underlying mechanisms remain largely unknown, particularly in humans, mechanistic insights are emerging from experimental model systems. These have implications for structuring future research and understanding disease and development.

Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia.

Abstract: Here we perform whole-exome sequencing of samples from 105 individuals with chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults in Western countries. We found 1,246 somatic mutations potentially affecting gene function and identified 78 genes with predicted functional alterations in more than one tumor sample. Among these genes, SF3B1, encoding a subunit of the spliceosomal U2 small nuclear ribonucleoprotein (snRNP), is somatically mutated in 9.7% of affected individuals. Further analysis in 279 individuals with CLL showed that SF3B1 mutations were associated with faster disease progression and poor overall survival. This work provides the first comprehensive catalog of somatic mutations in CLL with relevant clinical correlates and defines a large set of new genes that may drive the development of this common form of leukemia. The results reinforce the idea that targeting several well-known genetic pathways, including mRNA splicing, could be useful in the treatment of CLL and other malignancies.

Combined results of searches for the standard model Higgs boson in pp collisions at √s = 7 TeV

Abstract: Combined results are reported from searches for the standard model Higgs boson in proton-proton collisions at sqrt(s)=7 TeV in five Higgs boson decay modes: gamma pair, b-quark pair, tau lepton pair, W pair, and Z pair. The explored Higgs boson mass range is 110-600 GeV. The analysed data correspond to an integrated luminosity of 4.6-4.8 inverse femtobarns. The expected excluded mass range in the absence of the standard model Higgs boson is 118-543 GeV at 95% CL. The observed results exclude the standard model Higgs boson in the mass range 127-600 GeV at 95% CL, and in the mass range 129-525 GeV at 99% CL. An excess of events above the expected standard model background is observed at the low end of the explored mass range making the observed limits weaker than expected in the absence of a signal. The largest excess, with a local significance of 3.1 sigma, is observed for a Higgs boson mass hypothesis of 124 GeV. The global significance of observing an excess with a local significance greater than 3.1 sigma anywhere in the search range 110-600 (110-145) GeV is estimated to be 1.5 sigma (2.1 sigma). More data are required to ascertain the origin of this excess.

Distinct DNA methylomes of newborns and centenarians

Abstract: Human aging cannot be fully understood in terms of the constrained genetic setting. Epigenetic drift is an alternative means of explaining age-associated alterations. To address this issue, we performed whole-genome bisulfite sequencing (WGBS) of newborn and centenarian genomes. The centenarian DNA had a lower DNA methylation content and a reduced correlation in the methylation status of neighboring cytosine—phosphate—guanine (CpGs) throughout the genome in comparison with the more homogeneously methylated newborn DNA. The more hypomethylated CpGs observed in the centenarian DNA compared with the neonate covered all genomic compartments, such as promoters, exonic, intronic, and intergenic regions. For regulatory regions, the most hypomethylated sequences in the centenarian DNA were present mainly at CpG-poor promoters and in tissue-specific genes, whereas a greater level of DNA methylation was observed in CpG island promoters. We extended the study to a larger cohort of newborn and nonagenarian samples using a 450,000 CpG-site DNA methylation microarray that reinforced the observation of more hypomethylated DNA sequences in the advanced age group. WGBS and 450,000 analyses of middle-age individuals demonstrated DNA methylomes in the crossroad between the newborn and the nonagenarian/centenarian groups. Our study constitutes a unique DNA methylation analysis of the extreme points of human life at a single-nucleotide resolution level.

Prevalence of pathological internet use among adolescents in Europe: demographic and social factors

Abstract: Aims To investigate the prevalence of pathological internet use (PIU) and maladaptive internet use (MIU) among adolescents in 11 European countries in relation to demographic, social factors and internet accessibility. Design Cross-sectional survey. Setting The 7th Framework European Union (EU) funded project, Saving and Empowering Young Lives in Europe (SEYLE), is a randomized controlled trial (RCT) evaluating interventions for risk behavioursamongadolescentsinAustria,Estonia,France,Germany,Hungary,Ireland,Israel,Italy,Romania,Slovenia andSpain,withSwedenservingasthecoordinatingcentre.Participants Atotalof 11 956adolescents(female/male: 6731/5225; mean age: 14.9 0.89) recruited from randomly selected schools within the 11 study sites. Measurements Internet users were classified by gender into three categories: adaptive, maladaptive and pathologi- cal, based on their score in the Young Diagnostic Questionnaire for Internet Addiction (YDQ). Findings The overall prevalence of PIU was 4.4%; it was higher among males than females (5.2% versus 3.8%) and differed between countries (c 2 = 309.98; d.f. = 20; P < 0.001). PIU correlated significantly with mean hours online and male gender. Thehighest-rankedonlineactivitieswerewatchingvideos,frequentingchatroomsandsocialnetworking;significantly higherratesof playingsingle-usergameswerefoundinmalesandsocialnetworkinginfemales.Livinginmetropolitan areas was associated with PIU. Students not living with a biological parent, low parental involvement and parental unemployment showed the highest relative risks of both MIU and PIU. Conclusions Across a range of countries in Europe, using the Young Diagnostic Questionnaire for Internet Addiction yields a prevalence of 'pathological internet use' of 4.4% among adolescents, but varies by country and gender; adolescents lacking emotional and psychological support are at highest risk.

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

Abstract: The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta)<2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.

Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia

Abstract: We have extensively characterized the DNA methylomes of 139 patients with chronic lymphocytic leukemia (CLL) with mutated or unmutated IGHV and of several mature B-cell subpopulations through the use of whole-genome bisulfite sequencing and high-density microarrays. The two molecular subtypes of CLL have differing DNA methylomes that seem to represent epigenetic imprints from distinct normal B-cell subpopulations. DNA hypomethylation in the gene body, targeting mostly enhancer sites, was the most frequent difference between naive and memory B cells and between the two molecular subtypes of CLL and normal B cells. Although DNA methylation and gene expression were poorly correlated, we identified gene-body CpG dinucleotides whose methylation was positively or negatively associated with expression. We have also recognized a DNA methylation signature that distinguishes new clinico-biological subtypes of CLL. We propose an epigenomic scenario in which differential methylation in the gene body may have functional and clinical implications in leukemogenesis.

Vitamin D Therapy and Cardiac Structure and Function in Patients With Chronic Kidney Disease: The PRIMO Randomized Controlled Trial

Abstract: Context Vitamin D is associated with decreased cardiovascular-related morbidity and mortality, possibly by modifying cardiac structure and function, yet firm evidence for either remains lacking. Objective To determine the effects of an active vitamin D compound, paricalcitol, on left ventricular mass over 48 weeks in patients with an estimated glomerular filtration rate of 15 to 60 mL/min/1.73 m 2 . Design, Setting, and Participants Multinational, double-blind, randomized placebo-controlled trial among 227 patients with chronic kidney disease, mild to moderate left ventricular hypertrophy, and preserved left ventricular ejection fraction, conducted in 11 countries from July 2008 through September 2010. Intervention Participants were randomly assigned to receive oral paricalcitol, 2 μg/d (n =115), or matching placebo (n = 112). Main Outcome Measures Change in left ventricular mass index over 48 weeks by cardiovascular magnetic resonance imaging. Secondary end points included echocardiographic changes in left ventricular diastolic function. Results Treatment with paricalcitol reduced parathyroid hormone levels within 4 weeks and maintained levels within the normal range throughout the study duration. At 48 weeks, the change in left ventricular mass index did not differ between treatment groups (paricalcitol group, 0.34 g/m 2.7 [95% CI, −0.14 to 0.83 g/m 2.7 ] vs placebo group, −0.07 g/m 2.7 [95% CI, −0.55 to 0.42 g/m 2.7 ]). Doppler measures of diastolic function including peak early diastolic lateral mitral annular tissue velocity (paricalcitol group, −0.01 cm/s [95% CI, −0.63 to 0.60 cm/s] vs placebo group, −0.30 cm/s [95% CI, −0.93 to 0.34 cm/s]) also did not differ. Episodes of hypercalcemia were more frequent in the paricalcitol group compared with the placebo group. Conclusion Forty-eight week therapy with paricalcitol did not alter left ventricular mass index or improve certain measures of diastolic dysfunction in patients with chronic kidney disease. Trial Registration clinicaltrials.gov Identifier: NCT00497146

Study of high-p(T) charged particle suppression in PbPb compared to pp collisions at root s(NN)=2.76 TeV

Abstract: The transverse momentum spectra of charged particles have been measured in pp and PbPb collisions at sqrt(sNN) = 2.76 TeV by the CMS experiment at the LHC. In the transverse momentum range pt = 5-10 GeV/c, the charged particle yield in the most central PbPb collisions is suppressed by up to a factor of 5 compared to the pp yield scaled by the number of incoherent nucleon-nucleon collisions. At higher pt, this suppression is significantly reduced, approaching roughly a factor of 2 for particles with pt in the range pt=40-100 GeV/c.

A DNA methylation fingerprint of 1628 human samples

Abstract: Most of the studies characterizing DNA methylation patterns have been restricted to particular genomic loci in a limited number of human samples and pathological conditions. Herein, we present a compromise between an extremely comprehensive study of a human sample population with an intermediate level of resolution of CpGs at the genomic level. We obtained a DNA methylation fingerprint of 1628 human samples in which we interrogated 1505 CpG sites. The DNA methylation patterns revealed show this epigenetic mark to be critical in tissue-type definition and stemness, particularly around transcription start sites that are not within a CpG island. For disease, the generated DNA methylation fingerprints show that, during tumorigenesis, human cancer cells underwent a progressive gain of promoter CpG-island hypermethylation and a loss of CpG methylation in non-CpG-island promoters. Although transformed cells are those in which DNA methylation disruption is more obvious, we observed that other common human diseases, such as neurological and autoimmune disorders, had their own distinct DNA methylation profiles. Most importantly, we provide proof of principle that the DNA methylation fingerprints obtained might be useful for translational purposes by showing that we are able to identify the tumor type origin of cancers of unknown primary origin (CUPs). Thus, the DNA methylation patterns identified across the largest spectrum of samples, tissues, and diseases reported to date constitute a baseline for developing higher-resolution DNA methylation maps and provide important clues concerning the contribution of CpG methylation to tissue identity and its changes in the most prevalent human diseases.

Deubiquitinases in cancer: new functions and therapeutic options

Abstract: Deubiquitinases (DUBs) have fundamental roles in the ubiquitin system through their ability to specifically deconjugate ubiquitin from targeted proteins. The human genome encodes at least 98 DUBs, which can be grouped into 6 families, reflecting the need for specificity in their function. The activity of these enzymes affects the turnover rate, activation, recycling and localization of multiple proteins, which in turn is essential for cell homeostasis, protein stability and a wide range of signaling pathways. Consistent with this, altered DUB function has been related to several diseases, including cancer. Thus, multiple DUBs have been classified as oncogenes or tumor suppressors because of their regulatory functions on the activity of other proteins involved in tumor development. Therefore, recent studies have focused on pharmacological intervention on DUB activity as a rationale to search for novel anticancer drugs. This strategy may benefit from our current knowledge of the physiological regulatory mechanisms of these enzymes and the fact that growth of several tumors depends on the normal activity of certain DUBs. Further understanding of these processes may provide answers to multiple remaining questions on DUB functions and lead to the development of DUB-targeting strategies to expand the repertoire of molecular therapies against cancer.

An immunosurveillance mechanism controls cancer cell ploidy

Abstract: Cancer cells accommodate multiple genetic and epigenetic alterations that initially activate intrinsic (cell-autonomous) and extrinsic (immune-mediated) oncosuppressive mechanisms. Only once these barriers to oncogenesis have been overcome can malignant growth proceed unrestrained. Tetraploidization can contribute to oncogenesis because hyperploid cells are genomically unstable. We report that hyperploid cancer cells become immunogenic because of a constitutive endoplasmic reticulum stress response resulting in the aberrant cell surface exposure of calreticulin. Hyperploid, calreticulin-exposing cancer cells readily proliferated in immunodeficient mice and conserved their increased DNA content. In contrast, hyperploid cells injected into immunocompetent mice generated tumors only after a delay, and such tumors exhibited reduced DNA content, endoplasmic reticulum stress, and calreticulin exposure. Our results unveil an immunosurveillance system that imposes immunoselection against hyperploidy in carcinogen- and oncogene-induced cancers.

Neanderthal medics? Evidence for food, cooking, and medicinal plants entrapped in dental calculus

Abstract: Neanderthals disappeared sometime between 30,000 and 24,000 years ago. Until recently, Neanderthals were understood to have been predominantly meat-eaters; however, a growing body of evidence suggests their diet also included plants. We present the results of a study, in which sequential thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS) and pyrolysis-gas chromatography-mass spectrometry (Py-GC-MS) were combined with morphological analysis of plant microfossils, to identify material entrapped in dental calculus from five Neanderthal individuals from the north Spanish site of El Sidron. Our results provide the first molecular evidence for inhalation of wood-fire smoke and bitumen or oil shale and ingestion of a range of cooked plant foods. We also offer the first evidence for the use of medicinal plants by a Neanderthal individual. The varied use of plants that we have identified suggests that the Neanderthal occupants of El Sidron had a sophisticated knowledge of their natural surroundings which included the ability to select and use certain plants.

Observation of sequential Υ suppression in PbPb collisions

Abstract: The suppression of the individual Υ(nS) states in PbPb collisions with respect to their yields in pp data has been measured. The PbPb and pp data sets used in the analysis correspond to integrated luminosities of 150 μb^(-1) and 230 nb^(-1), respectively, collected in 2011 by the CMS experiment at the LHC, at a center-of-mass energy per nucleon pair of 2.76 TeV. The Υ(nS) yields are measured from the dimuon invariant mass spectra. The suppression of the Υ(nS) yields in PbPb relative to the yields in pp, scaled by the number of nucleon-nucleon collisions, R_(AA), is measured as a function of the collision centrality. Integrated over centrality, the R_(AA) values are 0.56±0.08(stat)±0.07(syst), 0.12±0.04(stat)±0.02(syst), and lower than 0.10 (at 95% confidence level), for the Υ(1S), Υ(2S), and Υ(3S) states, respectively. The results demonstrate the sequential suppression of the Υ(nS) states in PbPb collisions at LHC energies.

Correlations between molecular structure and single-junction conductance: a case study with oligo(phenylene-ethynylene)-type wires.

Abstract: The charge transport characteristics of 11 tailor-made dithiol-terminated oligo(phenylene-ethynylene) (OPE)-type molecules attached to two gold electrodes were studied at a solid/liquid interface in a combined approach using an STM break junction (STM-BJ) and a mechanically controlled break junction (MCBJ) setup We designed and characterized 11 structurally distinct dithiol-terminated OPE-type molecules with varied length and HOMO/LUMO energy Increase of the molecular length and/or of the HOMO-LUMO gap leads to a decrease of the single-junction conductance of the linearly conjugate acenes The experimental data and simulations suggest a nonresonant tunneling mechanism involving hole transport through the molecular HOMO, with a decay constant β = 34 ± 01 nm(-1) and a contact resistance R(c) = 40 kΩ per Au-S bond The introduction of a cross-conjugated anthraquinone or a dihydroanthracene central unit results in lower conductance values, which are attributed to a destructive quantum interference phenomenon for the former and a broken π-conjugation for the latter The statistical analysis of conductance-distance and current-voltage traces revealed details of evolution and breaking of molecular junctions In particular, we explored the effect of stretching rate and junction stability We compare our experimental results with DFT calculations using the ab initio code SMEAGOL and discuss how the structure of the molecular wires affects the conductance values

MAX Mutations Cause Hereditary and Sporadic Pheochromocytoma and Paraganglioma

Abstract: PURPOSE: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest-derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL. Design: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics. RESULTS: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine. CONCLUSIONS: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients.

Jet momentum dependence of jet quenching in PbPb collisions at sNN=2.76 TeV

Abstract: Dijet production in PbPb collisions at a nucleon–nucleon center-of-mass energy of 276 TeV is studied with the CMS detector at the LHC A data sample corresponding to an integrated luminosity of 150 μb−1 is analyzed Jets are reconstructed using combined information from tracking and calorimetry, using the anti-kT algorithm with R=03 The dijet momentum balance and angular correlations are studied as a function of collision centrality and leading jet transverse momentum For the most peripheral PbPb collisions, good agreement of the dijet momentum balance distributions with pp data and reference calculations at the same collision energy is found, while more central collisions show a strong imbalance of leading and subleading jet transverse momenta attributed to the jet-quenching effect The dijets in central collisions are found to be more unbalanced than the reference, for leading jet transverse momenta up to the highest values studied

Suppression of non-prompt J/ψ, prompt J/ψ, and Y(1S) in PbPb collisions at √s NN = 2.76 TeV

Abstract: Yields of prompt and non-prompt J/psi, as well as Y(1S) mesons, are measured by the CMS experiment via their dimuon decays in PbPb and pp collisions at sqrt(sNN) = 2.76 TeV for quarkonium rapidity |y|<2.4. Differential cross sections and nuclear modification factors are reported as functions of y and transverse momentum pt, as well as collision centrality. For prompt J/psi with relatively high pt (6.5

Nuclear lamina defects cause ATM-dependent NF-κB activation and link accelerated aging to a systemic inflammatory response

Abstract: Alterations in the architecture and dynamics of the nuclear lamina have a causal role in normal and accelerated aging through both cell-autonomous and systemic mechanisms. However, the precise nature of the molecular cues involved in this process remains incompletely defined. Here we report that the accumulation of prelamin A isoforms at the nuclear lamina triggers an ATM- and NEMO-dependent signaling pathway that leads to NF-kB activation and secretion of high levels of proinflammatory cytokines in two different mouse models of accelerated aging (Zmpste24 –/– and Lmna G609G/G609G mice). Causal involvement of NF-kB in accelerated aging was demonstrated by the fact that both genetic and pharmacological inhibition of NF-kB signaling prevents ageassociated features in these animal models, significantly extending their longevity. Our findings provide in vivo proof of principle for the feasibility of pharmacological modulation of the NF-kB pathway to slow down the progression of physiological and pathological aging.

Search for dark matter and large extra dimensions in monojet events in pp collisions at √s = 7 TeV

Abstract: A search has been made for events containing an energetic jet and an imbalance in transverse momentum using a data sample of pp collisions at a center-of-mass energy of 7 TeV. This signature is common to both dark matter and extra dimensions models. The data were collected by the CMS detector at the LHC and correspond to an integrated luminosity of 5.0 inverse femtobarns. The number of observed events is consistent with the standard model expectation. Constraints on the dark matter-nucleon scattering cross sections are determined for both spin-independent and spin-dependent interaction models. For the spin-independent model, these are the most constraining limits for a dark matter particle with mass below 3.5 GeV, a region unexplored by direct detection experiments. For the spin-dependent model, these are the most stringent constraints over the 0.1-200 GeV mass range. The constraints on the Arkani-Hamed, Dimopoulos, and Dvali model parameter MD determined as a function of the number of extra dimensions are also an improvement over the previous results.

Search for the standard model Higgs boson decaying into two photons in pp collisions at s=7TeV

Abstract: A search for a Higgs boson decaying into two photons is described. The analysis is performed using a dataset recorded by the CMS experiment at the LHC from pp collisions at a centre-of-mass energy of 7 TeV, which corresponds to an integrated luminosity of 4.8 inverse femtobarns. Limits are set on the cross section of the standard model Higgs boson decaying to two photons. The expected exclusion limit at 95% confidence level is between 1.4 and 2.4 times the standard model cross section in the mass range between 110 and 150 GeV. The analysis of the data excludes, at 95% confidence level, the standard model Higgs boson decaying into two photons in the mass range 128 to 132 GeV. The largest excess of events above the expected standard model background is observed for a Higgs boson mass hypothesis of 124 GeV with a local significance of 3.1 sigma. The global significance of observing an excess with a local significance greater than 3.1 sigma anywhere in the search range 110-150 GeV is estimated to be 1.8 sigma. More data are required to ascertain the origin of this excess.

Loss of mitochondrial protease OMA1 alters processing of the GTPase OPA1 and causes obesity and defective thermogenesis in mice

Abstract: Mitochondria are dynamic subcellular organelles that convert nutrient intermediates into readily available energy equivalents. Optimal mitochondrial function is ensured by a highly evolved quality control system, coordinated by protein machinery that regulates a process of continual fusion and fission. In this work, we provide in vivo evidence that the ATP-independent metalloprotease OMA1 plays an essential role in the proteolytic inactivation of the dynamin-related GTPase OPA1 (optic atrophy 1). We also show that OMA1 deficiency causes a profound perturbation of the mitochondrial fusion–fission equilibrium that has important implications for metabolic homeostasis. Thus, ablation of OMA1 in mice results in marked transcriptional changes in genes of lipid and glucose metabolic pathways and substantial alterations in circulating blood parameters. Additionally, Oma1-mutant mice exhibit an increase in body weight due to increased adipose mass, hepatic steatosis, decreased energy expenditure and impaired thermogenenesis. These alterations are especially significant under metabolic stress conditions, indicating that an intact OMA1-OPA1 system is essential for developing the appropriate adaptive response to different metabolic stressors such as a high-fat diet or cold-shock. This study provides the first description of an unexpected role in energy metabolism for the metalloprotease OMA1 and reinforces the importance of mitochondrial quality control for normal metabolic function.

Simultaneous Planck, Swift, and Fermi observations of X-ray and γ-ray selected blazars

Abstract: We present simultaneous Planck, Swift, Fermi, and ground-based data for 105 blazars belonging to three samples with flux limits in the soft X-ray, hard X-ray, and gamma-ray bands, with additional 5 GHz flux-density limits to ensure a good probability of a Planck detection. We compare our results to those of a companion paper presenting simultaneous Planck and multi-frequency observations of 104 radio-loud northern active galactic nuclei selected at radio frequencies. While we confirm several previous results, our unique data set allows us to demonstrate that the selection method strongly influences the results, producing biases that cannot be ignored. Almost all the BL Lac objects have been detected by the Fermi Large Area Telescope (LAT), whereas 30% to 40% of the flat-spectrum radio quasars (FSRQs) in the radio, soft X-ray, and hard X-ray selected samples are still below the gamma-ray detection limit even after integrating 27 months of Fermi-LAT data. The radio to sub-millimetre spectral slope of blazars is quite flat, with (alpha) approx 0 up to about 70GHz, above which it steepens to (alpha) approx -0.65. The BL Lacs have significantly flatter spectra than FSRQs at higher frequencies. The distribution of the rest-frame synchrotron peak frequency (nu(sup s)(sub peak)) in the spectral energy distribution (SED) of FSRQs is the same in all the blazar samples with (nu(sup s)(sub peak)) = 10(exp 13.1 +/- 0.1) Hz, while the mean inverse Compton peak frequency, (nu(sup IC)(sub peak)), ranges from 10(exp 21) to 10(exp 22) Hz. The distributions of nu(sup s)(sub peak) and nu(sup IC)(sub peak) of BL Lacs are much broader and are shifted to higher energies than those of FSRQs; their shapes strongly depend on the selection method. The Compton dominance of blazars. defined as the ratio of the inverse Compton to synchrotron peak luminosities, ranges from less than 0.2 to nearly 100, with only FSRQs reaching values larger than about 3. Its distribution is broad and depends strongly on the selection method, with gamma-ray selected blazars peaking at approx 7 or more, and radio-selected blazars at values close to 1, thus implying that the common assumption that the blazar power budget is largely dominated by high-energy emission is a selection effect. A comparison of our multi-frequency data with theoretical predictions shows that simple homogeneous SSC models cannot explain the simultaneous SEDs of most of the gamma-ray detected blazars in all samples. The SED of the blazars that were not detected by Fermi~LAT may instead be consistent with SSC emission. Our data challenge the correlation between bolometric luminosity and nu(sup s)(sub peak) predicted by the blazar sequence.

Surrounding greenness and pregnancy outcomes in four Spanish birth cohorts.

Abstract: Background: Green spaces have been associated with improved physical and mental health; however, the available evidence on the impact of green spaces on pregnancy is scarce. Objectives: We investigated the association between surrounding greenness and birth weight, head circumference, and gestational age at delivery. Methods: This study was based on 2,393 singleton live births from four Spanish birth cohorts (Asturias, Gipuzkoa, Sabadell, and Valencia) located in two regions of the Iberian Peninsula with distinct climates and vegetation patterns (2003–2008). We defined surrounding greenness as average of satellite-based Normalized Difference Vegetation Index (NDVI) (Landsat 4–5 TM data at 30 m × 30 m resolution) during 2007 in buffers of 100 m, 250 m, and 500 m around each maternal place of residence. Separate linear mixed models with adjustment for potential confounders and a random cohort effect were used to estimate the change in birth weight, head circumference, and gestational age for 1-interquartile range increase in surrounding greenness. Results: Higher surrounding greenness was associated with increases in birth weight and head circumference [adjusted regression coefficients (95% confidence interval) of 44.2 g (20.2 g, 68.2 g) and 1.7 mm (0.5 mm, 2.9 mm) for an interquartile range increase in average NDVI within a 500-m buffer] but not gestational age. These findings were robust against the choice of the buffer size and the season of data acquisition for surrounding greenness, and when the analysis was limited to term births. Stratified analyses indicated stronger associations among children of mothers with lower education, suggesting greater benefits from surrounding greenness. Conclusions: Our findings suggest a beneficial impact of surrounding greenness on measures of fetal growth but not pregnancy length.