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For even $k$, the matchings connectivity matrix $\mathbf{M}_k$ encodes which pairs of perfect matchings on $k$ vertices form a single cycle. Cygan et al. (STOC 2013) showed that the rank of $\mathbf{M}_k$ over $\mathbb{Z}_2$ is $\Theta(\sqrt 2^k)$ and used this to give an $O^*((2+\sqrt{2})^{\mathsf{pw}})$ time algorithm for counting Hamiltonian cycles modulo $2$ on graphs of pathwidth $\mathsf{pw}$. The same authors complemented their algorithm by an essentially tight lower bound under the Strong Exponential Time Hypothesis (SETH). This bound crucially relied on a large permutation submatrix within $\mathbf{M}_k$, which enabled a "pattern propagation" commonly used in previous related lower bounds, as initiated by Lokshtanov et al. (SODA 2011). We present a new technique for a similar pattern propagation when only a black-box lower bound on the asymptotic rank of $\mathbf{M}_k$ is given; no stronger structural insights such as the existence of large permutation submatrices in $\mathbf{M}_k$ are needed. Given appropriate rank bounds, our technique yields lower bounds for counting Hamiltonian cycles (also modulo fixed primes $p$) parameterized by pathwidth. To apply this technique, we prove that the rank of $\mathbf{M}_k$ over the rationals is $4^k / \mathrm{poly}(k)$. We also show that the rank of $\mathbf{M}_k$ over $\mathbb{Z}_p$ is $\Omega(1.97^k)$ for any prime $p\neq 2$ and even $\Omega(2.15^k)$ for some primes. As a consequence, we obtain that Hamiltonian cycles cannot be counted in time $O^*((6-\epsilon)^{\mathsf{pw}})$ for any $\epsilon>0$ unless SETH fails. This bound is tight due to a $O^*(6^{\mathsf{pw}})$ time algorithm by Bodlaender et al. (ICALP 2013). Under SETH, we also obtain that Hamiltonian cycles cannot be counted modulo primes $p\neq 2$ in time $O^*(3.97^\mathsf{pw})$, indicating that the modulus can affect the complexity in intricate ways. Comment: improved lower bounds modulo primes, improved figures, to appear in SODA 2018

International audience; SIRT1 regulates energy homeostasis by controlling the acetylation status and activity of a number of enzymes and transcriptional regulators. The fact that NAD(+) levels control SIRT1 activity confers a hypothetical basis for the design of new strategies to activate SIRT1 by increasing NAD(+) availability. Here we show that the deletion of the poly(ADP-ribose) polymerase-1 (PARP-1) gene, encoding a major NAD(+)-consuming enzyme, increases NAD(+) content and SIRT1 activity in brown adipose tissue and muscle. PARP-1(-)(/-) mice phenocopied many aspects of SIRT1 activation, such as a higher mitochondrial content, increased energy expenditure, and protection against metabolic disease. Also, the pharmacologic inhibition of PARP in vitro and in vivo increased NAD(+) content and SIRT1 activity and enhanced oxidative metabolism. These data show how PARP-1 inhibition has strong metabolic implications through the modulation of SIRT1 activity, a property that could be useful in the management not only of metabolic diseases, but also of cancer.

The $s$-process nucleosynthesis in Asymptotic Giant Branch (AGB) stars depends on the modeling of convective boundaries. We present models and s-process simulations that adopt a treatment of convective boundaries based on the results of hydrodynamic simulations and on the theory of mixing due to gravity waves in the vicinity of convective boundaries. Hydrodynamics simulations suggest the presence of convective boundary mixing (CBM) at the bottom of the thermal pulse-driven convective zone. Similarly, convection-induced mixing processes are proposed for the mixing below the convective envelope during third dredge-up where the 13C pocket for the s process in AGB stars forms. In this work we apply a CBM model motivated by simulations and theory to models with initial mass $M = 2$ and $M = 3M_\odot$, and with initial metal content Z = 0.01 and Z = 0.02. As reported previously, the He-intershell abundance of 12C and 16O are increased by CBM at the bottom of pulse-driven convection zone. This mixing is affecting the $^{22}Ne(��,n)^{25}Mg$ activation and the s-process effciency in the 13C-pocket. In our model CBM at the bottom of the convective envelope during the third dredgeup represents gravity wave mixing. We take further into account that hydrodynamic simulations indicate a declining mixing efficiency already about a pressure scale height from the convective boundaries, compared to mixing-length theory. We obtain the formation of the 13C-pocket with a mass of $\approx 10^{-4}M_\odot$. The final $s$-process abundances are characterized by 0.36 < [s=Fe] < 0.78 and the heavy-to-light s-process ratio is 0.23 < [hs=ls] < 0.45. Finally, we compare our results with stellar observations, pre-solar grain measurements and previous work. Submitted to ApJ on 11-24-2015. Accepted on 5-17-2016 (Manuscript #: ApJ101257)

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction. B.C.A.C. was funded through a European Community Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS); Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692); the National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), R01 grants (CA128978, CA176785, CA192393), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative); the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Breast Cancer Res. Foundation, and the Ovarian Cancer Research Fund. CIMBA genotyping was supported by National Institutes of Health grant (CA128978); the Department of Defence (W81XWH-10-1-0341); and the Breast Cancer Res. Foundation. CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms11375

WWWforEurope Working Paper No. 11, 35 Pages High inter-country variability characterises the responsiveness of both output to (exogenous) shocks and employment to output contractions. We argue that intercountry differences in firm-size distributions contribute to explaining this variability. Within an open economy model, we show that competitive selection processes are an important channel through which a shock affects aggregate employment. Intra-industry selection is then shown to influence the effectiveness of active labour market policies in countering the employment and welfare effects of a negative shock. We estimate a measure of the shape parameter of firm size distribution and study its effect on the employment-output relationship for a number of OECD countries. Our results confirm the key predictions of the theory.

AbstractThe protein- and/or lipid-mediated association of chaperone proteins to membranes is a widespread phenomenon and implicated in a number of physiological and pathological events that were earlier partially or completely overlooked. A temporary association of certain HSPs with membranes can re-establish the fluidity and bilayer stability and thereby restore the membrane functionality during stress conditions. The fluidity and microdomain organization of membranes are decisive factors in the perception and transduction of stresses into signals that trigger the activation of specific HS genes. Conversely, the membrane association of HSPs may result in the inactivation of membrane-perturbing signals, thereby switch off the heat shock response. Interactions between certain HSPs and specific lipid microdomains (“rafts”) might be a previously unrecognized means for the compartmentalization of HSPs to specific signaling platforms, where key signaling proteins are known to be concentrated. Any modulations of the membranes, especially the raft-lipid composition of the cells can alter the extracellular release and thus the immuno-stimulatory activity of certain HSPs. Reliable techniques, allowing mapping of the composition and dynamics of lipid microdomains and simultaneously the spatio-temporal localization of HSPs in and near the plasma membrane can provide suitable means with which to address fundamental questions, such as how HSPs are transported to and translocated through the plasma membrane. The possession of such information is critical if we are to target the membrane association principles of HSPs for successful drug development in most various diseases.

The n−3 fatty acids are not produced by mammals, although they are essential for hormone synthesis and maintenance of cell membrane structure and integrity. They have recently been shown to inhibit inflammatory reactions and also emerged as potential treatment options for inflammatory diseases, such as rheumatoid arthritis, asthma and inflammatory bowel diseases. Dendritic cells (DC) play a central role in the regulation of both innate and adaptive immunity and upon inflammatory signals they produce various soluble factors among them cytokines and chemokines that act as inflammatory or regulatory mediators. In this study we monitored the effects of α-linoleic acid, eicosapentaenoic acid and docosahexaenoic acid solubilized in a dimethyl sulfoxide (DMSO)/ethanol 1:1 mixture or as complexed by randomly methylated α-cyclodextrin (RAMEA) on the inflammatory response of human monocyte-derived dendritic cells (moDC). The use of RAMEA for enhancing aqueous solubility of n−3 fatty acids has the unambiguous advantage over applying RAMEB (the β-cyclodextrin analog), since there is no interaction with cell membrane cholesterol. In vitro differentiated moDC were left untreated or were stimulated by bacterial lipopolysaccharide and polyinosinic:polycytidylic acid, mimicking bacterial and viral infections, respectively. The response of unstimulated and activated moDC to n−3 fatty acid treatment was tested by measuring the cell surface expression of CD1a used as a phenotypic and CD83 as an activation marker of inflammatory moDC differentiation and activation by using flow cytometry. Monocyte-derived DC activation was also monitored by the secretion level of the pro- and anti-inflammatory cytokines IL-1β, TNF-α, IL-6, IL-10 and IL-12, respectively. We found that RAMEA-complexed n−3 fatty acids reduced the expression of CD1a protein in both LPS and Poly(I:C) stimulated moDC significantly, but most efficiently by eicosapentaenic acid, while no significant change in the expression of CD83 protein was observed. The production of IL-6 by LPS-activated moDC was also reduced significantly when eicosapentaenic acid was added as a RAMEA complex as compared to its DMSO-solubilized form or to the other two n−3 fatty acids either complexed or not. Based on these results n−3 fatty acids solubilized by RAMEA provide with a new tool for optimizing the anti-inflammatory effects of n−3 fatty acids exerted on human moDC and mediated through the GP120 receptor without interfering with the cell membrane structure.

International audience; & Context Projections of species distribution models under future climate are usually based on long-term averages. However, singular extreme drought events presumably con-tribute to the shaping of distribution limits at the retreating low-elevation xeric limits. & Methods The objectives of this study were to set up a distribution model based on extreme drought events (EDM), which uses sanitary logging information as a proxy of vitality response of beech, and compare it with the results of classical species distribution models (SDMs). & Results Predictions of the EDM for 2025 were in agreement with those of the SDM, but EDM predicted a more serious decline in all regions of Hungary towards the end of the century. & Conclusion These results suggest that the predicted increase in frequency and severity of drought events may further limit the distribution of beech in the future.