Showing papers by "Pierre-and-Marie-Curie University published in 2013"

Richness of human gut microbiome correlates with metabolic markers

Abstract: We are facing a global metabolic health crisis provoked by an obesity epidemic. Here we report the human gut microbial composition in a population sample of 123 non-obese and 169 obese Danish individuals. We find two groups of individuals that differ by the number of gut microbial genes and thus gut bacterial richness. They contain known and previously unknown bacterial species at different proportions; individuals with a low bacterial richness (23% of the population) are characterized by more marked overall adiposity, insulin resistance and dyslipidaemia and a more pronounced inflammatory phenotype when compared with high bacterial richness individuals. The obese individuals among the lower bacterial richness group also gain more weight over time. Only a few bacterial species are sufficient to distinguish between individuals with high and low bacterial richness, and even between lean and obese participants. Our classifications based on variation in the gut microbiome identify subsets of individuals in the general white adult population who may be at increased risk of progressing to adiposity-associated co-morbidities.

Hydrodynamics of soft active matter

Abstract: This review summarizes theoretical progress in the field of active matter, placing it in the context of recent experiments. This approach offers a unified framework for the mechanical and statistical properties of living matter: biofilaments and molecular motors in vitro or in vivo, collections of motile microorganisms, animal flocks, and chemical or mechanical imitations. A major goal of this review is to integrate several approaches proposed in the literature, from semimicroscopic to phenomenological. In particular, first considered are ``dry'' systems, defined as those where momentum is not conserved due to friction with a substrate or an embedding porous medium. The differences and similarities between two types of orientationally ordered states, the nematic and the polar, are clarified. Next, the active hydrodynamics of suspensions or ``wet'' systems is discussed and the relation with and difference from the dry case, as well as various large-scale instabilities of these nonequilibrium states of matter, are highlighted. Further highlighted are various large-scale instabilities of these nonequilibrium states of matter. Various semimicroscopic derivations of the continuum theory are discussed and connected, highlighting the unifying and generic nature of the continuum model. Throughout the review, the experimental relevance of these theories for describing bacterial swarms and suspensions, the cytoskeleton of living cells, and vibrated granular material is discussed. Promising extensions toward greater realism in specific contexts from cell biology to animal behavior are suggested, and remarks are given on some exotic active-matter analogs. Last, the outlook for a quantitative understanding of active matter, through the interplay of detailed theory with controlled experiments on simplified systems, with living or artificial constituents, is summarized.

Discovery and refinement of loci associated with lipid levels

Abstract: Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

Abstract: Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

Impacts of ocean acidification on marine organisms: quantifying sensitivities and interaction with warming

Abstract: Ocean acidification represents a threat to marine species worldwide, and forecasting the ecological impacts of acidification is a high priority for science, management, and policy. As research on the topic expands at an exponential rate, a comprehensive understanding of the variability in organisms' responses and corresponding levels of certainty is necessary to forecast the ecological effects. Here, we perform the most comprehensive meta-analysis to date by synthesizing the results of 228 studies examining biological responses to ocean acidification. The results reveal decreased survival, calcification, growth, development and abundance in response to acidification when the broad range of marine organisms is pooled together. However, the magnitude of these responses varies among taxonomic groups, suggesting there is some predictable trait-based variation in sensitivity, despite the investigation of approximately 100 new species in recent research. The results also reveal an enhanced sensitivity of mollusk larvae, but suggest that an enhanced sensitivity of early life history stages is not universal across all taxonomic groups. In addition, the variability in species' responses is enhanced when they are exposed to acidification in multi-species assemblages, suggesting that it is important to consider indirect effects and exercise caution when forecasting abundance patterns from single-species laboratory experiments. Furthermore, the results suggest that other factors, such as nutritional status or source population, could cause substantial variation in organisms' responses. Last, the results highlight a trend towards enhanced sensitivity to acidification when taxa are concurrently exposed to elevated seawater temperature.

Global carbon dioxide emissions from inland waters

Abstract: Carbon dioxide (CO2) transfer from inland waters to the atmosphere, known as CO2 evasion, is a component of the global carbon cycle. Global estimates of CO2 evasion have been hampered, however, by the lack of a framework for estimating the inland water surface area and gas transfer velocity and by the absence of a global CO2 database. Here we report regional variations in global inland water surface area, dissolved CO2 and gas transfer velocity. We obtain global CO2 evasion rates of 1.8(-0.25)(+0.25) petagrams of carbon (Pg C) per year from streams and rivers and 0.32(-0.26)(+0.52) Pg C yr(-1) from lakes and reservoirs, where the upper and lower limits are respectively the 5th and 95th confidence interval percentiles. The resulting global evasion rate of 2.1 Pg C yr(-1) is higher than previous estimates owing to a larger stream and river evasion rate. Our analysis predicts global hotspots in stream and river evasion, with about 70 per cent of the flux occurring over just 20 per cent of the land surface. The source of inland water CO2 is still not known with certainty and new studies are needed to research the mechanisms controlling CO2 evasion globally.

Large-scale association analysis identifies new risk loci for coronary artery disease

Abstract: Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.

Processes and patterns of oceanic nutrient limitation

Abstract: Microbial activity is a fundamental component of oceanic nutrient cycles. Photosynthetic microbes, collectively termed phytoplankton, are responsible for the vast majority of primary production in marine waters. The availability of nutrients in the upper ocean frequently limits the activity and abundance of these organisms. Experimental data have revealed two broad regimes of phytoplankton nutrient limitation in the modern upper ocean. Nitrogen availability tends to limit productivity throughout much of the surface low-latitude ocean, where the supply of nutrients from the subsurface is relatively slow. In contrast, iron often limits productivity where subsurface nutrient supply is enhanced, including within the main oceanic upwelling regions of the Southern Ocean and the eastern equatorial Pacific. Phosphorus, vitamins and micronutrients other than iron may also (co-)limit marine phytoplankton. The spatial patterns and importance of co-limitation, however, remain unclear. Variability in the stoichiometries of nutrient supply and biological demand are key determinants of oceanic nutrient limitation. Deciphering the mechanisms that underpin this variability, and the consequences for marine microbes, will be a challenge. But such knowledge will be crucial for accurately predicting the consequences of ongoing anthropogenic perturbations to oceanic nutrient biogeochemistry.

Dietary intervention impact on gut microbial gene richness

Abstract: Complex gene-environment interactions are considered important in the development of obesity. The composition of the gut microbiota can determine the efficacy of energy harvest from food and changes in dietary composition have been associated with changes in the composition of gut microbial populations. The capacity to explore microbiota composition was markedly improved by the development of metagenomic approaches, which have already allowed production of the first human gut microbial gene catalogue and stratifying individuals by their gut genomic profile into different enterotypes, but the analyses were carried out mainly in non-intervention settings. To investigate the temporal relationships between food intake, gut microbiota and metabolic and inflammatory phenotypes, we conducted diet-induced weight-loss and weight-stabilization interventions in a study sample of 38 obese and 11 overweight individuals. Here we report that individuals with reduced microbial gene richness (40%) present more pronounced dys-metabolism and low-grade inflammation, as observed concomitantly in the accompanying paper. Dietary intervention improves low gene richness and clinical phenotypes, but seems to be less efficient for inflammation variables in individuals with lower gene richness. Low gene richness may therefore have predictive potential for the efficacy of intervention.

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Abstract: Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 10 × 10(-4)) In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 50 × 10(-8)), 3 of which we found after conditioning on previously identified variants Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals

Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value

Abstract: Background Colon cancer (CC) pathological staging fails to accurately predict recurrence, and to date, no gene expression signature has proven reliable for prognosis stratification in clinical practice, perhaps because CC is a heterogeneous disease. The aim of this study was to establish a comprehensive molecular classification of CC based on mRNA expression profile analyses.

Neurostimulation for Parkinson's Disease with Early Motor Complications

Abstract: A B S T R AC T BACKGROUND Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinson’s disease who have severe levodopa-induced motor complications. We hypothesized that neurostimulation would be beneficial at an earlier stage of Parkinson’s disease. METHODS In this 2-year trial, we randomly assigned 251 patients with Parkinson’s disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone. The primary end point was quality of life, as assessed with the use of the Parkinson’s Disease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100 and higher scores indicating worse function). Major secondary outcomes included parkinsonian motor disability, activities of daily living, levodopa-induced motor com plications (as assessed with the use of the Unified Parkinson’s Disease Rating Scale, parts III, II, and IV, respectively), and time with good mobility and no dyskinesia. RESULTS For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P = 0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P = 0.01). Serious adverse events occurred in 54.8% of the patients in the neuro stimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device oc curred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimula tion group and for 94.5% of those in the medical-therapy group. CONCLUSIONS Subthalamic stimulation was superior to medical therapy in patients with Parkinson’s disease and early motor complications. (Funded by the German Ministry of Research and others; EARLYSTIM ClinicalTrials.gov number, NCT00354133.)

Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial

Abstract: Summary Background Bevacizumab plus fluoropyrimidine-based chemotherapy is standard treatment for first-line and bevacizumab-naive second-line metastatic colorectal cancer. We assessed continued use of bevacizumab plus standard second-line chemotherapy in patients with metastatic colorectal cancer progressing after standard first-line bevacizumab-based treatment. Methods In an open-label, phase 3 study in 220 centres in Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, the Netherlands, Norway, Portugal, Saudi Arabia, Spain, Sweden, and Switzerland, patients (aged ≥18 years) with unresectable, histologically confirmed metastatic colorectal cancer progressing up to 3 months after discontinuing first-line bevacizumab plus chemotherapy were randomly assigned in a 1:1 ratio to second-line chemotherapy with or without bevacizumab 2·5 mg/kg per week equivalent (either 5 mg/kg every 2 weeks or 7·5 mg/kg every 3 weeks, intravenously). The choice between oxaliplatin-based or irinotecan-based second-line chemotherapy depended on the first-line regimen (switch of chemotherapy). A combination of a permuted block design and the Pocock and Simon minimisation algorithm was used for the randomisation. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00700102. Findings Between Feb 1, 2006, and June 9, 2010, 409 (50%) patients were assigned to bevacizumab plus chemotherapy and 411 (50%) to chemotherapy alone. Median follow-up was 11·1 months (IQR 6·4–15·6) in the bevacizumab plus chemotherapy group and 9·6 months (5·4–13·9) in the chemotherapy alone group. Median overall survival was 11·2 months (95% CI 10·4–12·2) for bevacizumab plus chemotherapy and 9·8 months (8·9–10·7) for chemotherapy alone (hazard ratio 0·81, 95% CI 0·69–0·94; unstratified log-rank test p=0·0062). Grade 3–5 bleeding or haemorrhage (eight [2%] vs one [ vs three [ vs 12 [3%]) were more common in the bevacizumab plus chemotherapy group than in the chemotherapy alone group. The most frequently reported grade 3–5 adverse events were neutropenia (65 [16%] in the bevacizumab and chemotherapy group vs 52 [13%] in the chemotherapy alone group), diarrhoea (40 [10%] vs 34 [8%], respectively), and asthenia (23 [6%] vs 17 [4%], respectively). Treatment-related deaths were reported for four patients in the bevacizumab plus chemotherapy group and three in the chemotherapy alone group. Interpretation Maintenance of VEGF inhibition with bevacizumab plus standard second-line chemotherapy beyond disease progression has clinical benefits in patients with metastatic colorectal cancer. This approach is also being investigated in other tumour types, including metastatic breast and non-small cell lung cancers. Funding F Hoffmann-La Roche.

Human-induced nitrogen–phosphorus imbalances alter natural and managed ecosystems across the globe

Abstract: Bioavailable nitrogen is increasing due to human activity, rapidly outpacing increases in another essential nutrient, phosphorous. Penuelas et al. show that this increasing imbalance between these nutrients is likely to significantly affect life and limit carbon storage in this century.

Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study.

Abstract: Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers [PTCs]) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection. Most PTCs lacked the protective HLA B alleles that are overrepresented in spontaneous HIV controllers (HICs); instead, they carried risk-associated HLA alleles that were largely absent among the HICs. Accordingly, the PTCs had poorer CD8+ T cell responses and more severe primary infections than the HICs did. Moreover, the incidence of viral control after the interruption of early antiretroviral therapy was higher among the PTCs than has been reported for spontaneous control. Off therapy, the PTCs were able to maintain and, in some cases, further reduce an extremely low viral reservoir. We found that long-lived HIV-infected CD4+ T cells contributed poorly to the total resting HIV reservoir in the PTCs because of a low rate of infection of naive T cells and a skewed distribution of resting memory CD4+ T cell subsets. Our results show that early and prolonged cART may allow some individuals with a rather unfavorable background to achieve long-term infection control and may have important implications in the search for a functional HIV cure.

CluePedia Cytoscape plugin

Abstract: Summary: The CluePedia Cytoscape plugin is a search tool for new markers potentially associated to pathways. CluePedia calculates linear and non-linear statistical dependencies from experimental data. Genes, proteins and miRNAs can be connected based on in silico and/or experimental information and integrated into a ClueGO network of terms/pathways. Interrelations within each pathway can be investigated, and new potential associations may be revealed through gene/protein/miRNA enrichments. A pathway-like visualization can be created using the Cerebral plugin layout. Combining all these features is essential for data interpretation and the generation of new hypotheses. The CluePedia Cytoscape plugin is user-friendly and has an expressive and intuitive visualization. Availability: http://www.ici.upmc.fr/cluepedia/ and via the Cytoscape plugin manager. The user manual is available at the CluePedia website. Contact: bernhard.mlecnik@crc.jussieu.fr or jerome.galon@crc.jussieu.fr Supplementary information:Supplementary data are available at Bioinformatics online.

Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy: 2013 Update

Abstract: Cytochrome P450 (CYP)2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 loss-of-function alleles impair formation of active metabolites, resulting in reduced platelet inhibition. In addition, CYP2C19 loss-of-function alleles confer increased risks for serious adverse cardiovascular (CV) events among clopidogrel-treated patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI). Guideline updates include emphasis on appropriate indication for CYP2C19 genotype–directed antiplatelet therapy, refined recommendations for specific CYP2C19 alleles, and additional evidence from an expanded literature review (updates at http://www.pharmgkb.org).

Common variants associated with plasma triglycerides and risk for coronary artery disease

Abstract: Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

Emergence of macroscopic directed motion in populations of motile colloids

Abstract: Populations of millions of colloidal rolling particles are shown to self-organize to achieve coherent motion; comparison between experiment and theory based on the microscopic interactions between these ‘rollers’ suggests that hydrodynamic interactions promote the emergence of the collective motion. Collective motion can be observed in the natural world at all scales, from flocking birds to schooling fish and swarming bacteria, but it is difficult to capture such behaviour in simple physical models. Artificial 'active matter' systems that show collective behaviour usually rely on collisions, making the description of interactions complex. Denis Bartolo and colleagues have now developed a unique experimental system consisting of self-propelled rolling spheres that self-organize and move in one direction in a crowd of millions. The spheres 'sense' each other via straightforward hydrodynamic interactions so that all parameters can be easily calculated and tuned. This work demonstrates that genuine physical interactions at the individual level are sufficient to set homogeneous active populations into stable directed motion. The system could be used to model natural collective motion and to design new self-organized materials and swarming microrobots. From the formation of animal flocks to the emergence of coordinated motion in bacterial swarms, populations of motile organisms at all scales display coherent collective motion. This consistent behaviour strongly contrasts with the difference in communication abilities between the individuals. On the basis of this universal feature, it has been proposed that alignment rules at the individual level could solely account for the emergence of unidirectional motion at the group level1,2,3,4. This hypothesis has been supported by agent-based simulations1,5,6. However, more complex collective behaviours have been systematically found in experiments, including the formation of vortices7,8,9, fluctuating swarms7,10, clustering11,12 and swirling13,14,15,16. All these (living and man-made) model systems (bacteria9,10,16, biofilaments and molecular motors7,8,13, shaken grains14,15 and reactive colloids11,12) predominantly rely on actual collisions to generate collective motion. As a result, the potential local alignment rules are entangled with more complex, and often unknown, interactions. The large-scale behaviour of the populations therefore strongly depends on these uncontrolled microscopic couplings, which are extremely challenging to measure and describe theoretically. Here we report that dilute populations of millions of colloidal rolling particles self-organize to achieve coherent motion in a unique direction, with very few density and velocity fluctuations. Quantitatively identifying the microscopic interactions between the rollers allows a theoretical description of this polar-liquid state. Comparison of the theory with experiment suggests that hydrodynamic interactions promote the emergence of collective motion either in the form of a single macroscopic ‘flock’, at low densities, or in that of a homogenous polar phase, at higher densities. Furthermore, hydrodynamics protects the polar-liquid state from the giant density fluctuations that were hitherto considered the hallmark of populations of self-propelled particles2,3,17. Our experiments demonstrate that genuine physical interactions at the individual level are sufficient to set homogeneous active populations into stable directed motion.

New insights into the classification and nomenclature of cortical GABAergic interneurons

Abstract: A systematic classification and accepted nomenclature of neuron types is much needed but is currently lacking. This article describes a possible taxonomical solution for classifying GABAergic interneurons of the cerebral cortex based on a novel, web-based interactive system that allows experts to classify neurons with pre-determined criteria. Using Bayesian analysis and clustering algorithms on the resulting data, we investigated the suitability of several anatomical terms and neuron names for cortical GABAergic interneurons. Moreover, we show that supervised classification models could automatically categorize interneurons in agreement with experts' assignments. These results demonstrate a practical and objective approach to the naming, characterization and classification of neurons based on community consensus.

Proton Structure from the Measurement of 2S-2P Transition Frequencies of Muonic Hydrogen

Abstract: Accurate knowledge of the charge and Zemach radii of the proton is essential, not only for understanding its structure but also as input for tests of bound-state quantum electrodynamics and its predictions for the energy levels of hydrogen. These radii may be extracted from the laser spectroscopy of muonic hydrogen (μp, that is, a proton orbited by a muon). We measured the 2 S 1 / 2 F = 0 - 2 P 3 / 2 F = 1 transition frequency in μp to be 54611.16(1.05) gigahertz (numbers in parentheses indicate one standard deviation of uncertainty) and reevaluated the 2 S 1 / 2 F = 1 - 2 P 3 / 2 F = 2 transition frequency, yielding 49881.35(65) gigahertz. From the measurements, we determined the Zemach radius, rZ = 1.082(37) femtometers, and the magnetic radius, rM = 0.87(6) femtometer, of the proton. We also extracted the charge radius, rE = 0.84087(39) femtometer, with an order of magnitude more precision than the 2010-CODATA value and at 7σ variance with respect to it, thus reinforcing the proton radius puzzle.

MicroRNA-34a regulates cardiac ageing and function

Abstract: Ageing is the predominant risk factor for cardiovascular diseases and contributes to a significantly worse outcome in patients with acute myocardial infarction. MicroRNAs (miRNAs) have emerged as crucial regulators of cardiovascular function and some miRNAs have key roles in ageing. We propose that altered expression of miRNAs in the heart during ageing contributes to the age-dependent decline in cardiac function. Here we show that miR-34a is induced in the ageing heart and that in vivo silencing or genetic deletion of miR-34a reduces age-associated cardiomyocyte cell death. Moreover, miR-34a inhibition reduces cell death and fibrosis following acute myocardial infarction and improves recovery of myocardial function. Mechanistically, we identified PNUTS (also known as PPP1R10) as a novel direct miR-34a target, which reduces telomere shortening, DNA damage responses and cardiomyocyte apoptosis, and improves functional recovery after acute myocardial infarction. Together, these results identify age-induced expression of miR-34a and inhibition of its target PNUTS as a key mechanism that regulates cardiac contractile function during ageing and after acute myocardial infarction, by inducing DNA damage responses and telomere attrition.

Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial

Abstract: Summary Background Few eff ective treatments exist for patients with refractory or relapsed and refractory multiple myeloma not responding to treatment with bortezomib and lenalidomide. Pomalidomide alone has shown limited effi cacy in patients with relapsed multiple myeloma, but synergistic eff ects have been noted when combined with dexamethasone. We compared the effi cacy and safety of pomalidomide plus low-dose dexamethasone with high-dose dexamethasone alone in these patients. Methods This multicentre, open-label, randomised phase 3 trial was undertaken in Australia, Canada, Europe, Russia, and the USA. Patients were eligible if they had been diagnosed with refractory or relapsed and refractory multiple myeloma, and had failed at least two previous treatments of bortezomib and lenalidomide. They were assigned in a 2:1 ratio with a validated interactive voice and internet response system to either 28 day cycles of pomalidomide (4 mg/day on days 1–21, orally) plus low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally) or high-dose dexamethasone (40 mg/day on days 1–4, 9–12, and 17–20, orally) until disease progression or unacceptable toxicity . Stratifi cation factors were age (≤75 years vs >75 years), disease population (refractory vs relapsed and refractory vs bortezomib intolerant), and number of previous treatments (two vs more than two). The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01311687, and with EudraCT, number 2010-019820-30. Findings The accrual for the study has been completed and the analyses are presented. 302 patients were randomly assigned to receive pomalidomide plus low-dose dexamethasone and 153 high-dose dexamethasone. After a median follow-up of 10·0 months (IQR 7·2–13·2), median PFS with pomalidomide plus low-dose dexamethasone was 4·0 months (95% CI 3·6–4·7) versus 1·9 months (1·9–2·2) with high-dose dexamethasone (hazard ratio 0·48 [95% CI 0·39–0·60]; p<0·0001). The most common grade 3–4 haematological adverse events in the pomalidomide plus lowdose dexamethasone and high-dose dexamethasone groups were neutropenia (143 [48%] of 300 vs 24 [16%] of 150, respectively), anaemia (99 [33%] vs 55 [37%], respectively), and thrombocytopenia (67 [22%] vs 39 [26%], respectively). Grade 3–4 non-haematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups included pneumonia (38 [13%] vs 12 [8%], respectively), bone pain (21 [7%] vs seven [5%], respectively), and fatigue (16 [5%] vs nine [6%], respectively). There were 11 (4%) treatment-related adverse events leading to death in the pomalidomide plus low-dose dexamethasone group and seven (5%) in the high-dose dexamethasone group.

Axonal transport deficits and neurodegenerative diseases

Abstract: The intracellular transport of organelles along an axon is crucial for the maintenance and function of a neuron. Anterograde axonal transport has a role in supplying proteins and lipids to the distal synapse and mitochondria for local energy requirements, whereas retrograde transport is involved in the clearance of misfolded and aggregated proteins from the axon and the intracellular transport of distal trophic signals to the soma. Axonal transport can be affected by alterations to various components of the transport machinery. Here, we review the current state of knowledge about axonal transport defects that might contribute to the pathogenesis of particular neurodegenerative diseases.

Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts

Abstract: Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families.