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The high-precision HERA data allows searches up to TeV scales for beyond the Standard Model contributions to electron-quark scattering. Combined measurements of the inclusive deep inelastic cross sections in neutral and charged current ep scattering corresponding to a luminosity of around 1 fb(-1) have been used in this analysis. A new approach to the beyond the Standard Model analysis of the inclusive ep data is presented; simultaneous fits of parton distribution functions together with contributions of "new physics" processes were performed. Results are presented considering a finite radius of quarks within the quark form-factor model. The resulting 95% C.L. upper limit on the effective quark radius is 0.43.10(-16) cm. (C) 2016 CERN for the benefit of the ZEUS Collaboration. Published by Elsevier B.V.

Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-Guerin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism(22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms(6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis.

During the 1980s, the North Sea plankton community underwent a well-documented ecosystem regime shift, including both spatial changes (northward species range shifts) and temporal changes (increases in the total abundances of warmer water species). This regime shift has been attributed to climate change. Plankton provide a link between climate and higher trophic-level organisms, which can forage on large spatial and temporal scales. It is therefore important to understand not only whether climate change affects purely spatial or temporal aspects of plankton dynamics, but also whether it affects spatiotemporal aspects such as metapopulation synchrony. If plankton synchrony is altered, higher trophic-level feeding patterns may be modified. A second motivation for investigating changes in synchrony is that the possibility of such alterations has been examined for few organisms, in spite of the fact that synchrony is ubiquitous and of major importance in ecology. This study uses correlation coefficients and spectral analysis to investigate whether synchrony changed between the periods 1959-1980 and 1989-2010. Twenty-three plankton taxa, sea surface temperature (SST), and wind speed were examined. Results revealed that synchrony in SST and plankton was altered. Changes were idiosyncratic, and were not explained by changes in abundance. Changes in the synchrony of Calanus helgolandicus and Para-pseudocalanus spp appeared to be driven by changes in SST synchrony. This study is one of few to document alterations of synchrony and climate-change impacts on synchrony. We discuss why climate-change impacts on synchrony may well be more common and consequential than previously recognized.

Spatial synchrony, the tendency of distant populations to fluctuate similarly, is a major concern in ecology(1-8). Except in special circumstances(3,9), researchers historically had difficulty identifying drivers of synchrony in field systems(5,6,10). Perhaps for this reason, the possibility(9,11,12) that changes in large-scale climatic drivers may modify synchrony, thereby impacting ecosystems and human concerns, has been little examined. Here, we use wavelets to determine environmental drivers of phenological synchrony across Britain for 20 aphid species, most major crop pests. Consistently across species, changes in drivers produced large changes in aphid synchrony. Different drivers acted on different timescales: using a new wavelet analogue of the Moran theorem(1), we show that on long timescales (>4 years), 80% of synchrony in aphid first flights is due to synchrony in winter climate; but this explanation accounts for less short-timescale (<= 4 years) synchrony. Changes in aphid synchrony over time also differed by timescale: long-timescale synchrony fell from before 1993 to after, caused by similar changes in winter climate; whereas short-timescale synchrony increased. Shifts in winter climate are attributable to the North Atlantic Oscillation, an important climatic phenomenon(7,11,13), so effects described here may influence other taxa. This study documents a new way that climatic changes influence populations, through altered Moran effects.

The CP-violating weak phase phi(s) of the B-s(0) meson and the decay width difference Delta Gamma(s) of the B-s(0) light and heavy mass eigenstates are measured with the CMS detector at the LHC using a data sample of B-s(0)-> J/psi phi(1020) -> mu(+)mu-K+K- decays. The analysed data set corresponds to an integrated luminosity of 19.7 fb(-1) collected in pp collisions at a centre-of-mass energy of 8 TeV. A total of 49200 reconstructed B-s(0) decays are used to extract the values of phi(s) and Delta Gamma(s) by performing a time dependent and flavour-tagged angular analysis of the mu(+)mu-K+K- final state. The weak phase is measured to be phi(s) =-0.075 +/- 0.097 (stat) +/- 0.031 (syst) rad, and the decay width difference is Delta Gamma(s) = 0.095 +/- 0.013 (stat) +/- 0.007 (syst) ps(-1). (C) 2016 CERN for the benefit of the CMS Collaboration. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Funded by SCOAP(3).

Antimetabolites that affect nucleotide metabolism are frontline chemotherapy agents in several cancers and often successfully target one carbon metabolism. However, the precise mechanisms and resulting determinants of their therapeutic value are unknown. We show that 5-fluorouracil (5-FU), a commonly used antimetabolite therapeutic with varying efficacy, induces specific alterations to nucleotide metabolism by disrupting pyrimidine homeostasis. An integrative metabolomics analysis of the cellular response to 5-FU reveals intracellular uracil accumulation, whereas deoxyuridine levels exhibited increased flux into the extracellular space, resulting in an induction of overflow metabolism. Subsequent analysis from mice bearing colorectal tumors treated with 5-FU show specific secretion of metabolites in tumor-bearing mice into serum that results from alterations in nucleotide flux and reduction in overflowmetabolism. Together, these findings identify a determinant of an antimetabolite response that may be exploited to more precisely define the tumors that could respond to targeting cancer metabolism.

Broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) suppress viremia in animal models of HIV-1 and humans. To achieve potent activity without the emergence of viral escape mutants, co-administration of different bNAbs is necessary to target distinct epitopes essential for viral fitness. Here, we report the development of bispecific anti-Env neutralizing antibodies (biNAbs) with potent activity. Synergistic activity of biNAbs was achieved by combining an engineered hinge domain of IgG3 to increase Fab domain flexibility necessary for hetero-bivalent binding to the Env trimer while retaining the functional properties of the IgG1-Fc. Compared to unmodified biNAbs, hinge domain variants exhibited substantially improved neutralization activity, with particular combinations showing evidence of synergistic neutralization potency in vitro and enhanced in vivo therapeutic activity in HIV-1-infected humanized mice. These findings suggest innovative strategies for generating biNAbs with enhanced neutralization breadth and potency, representing ideal candidate molecules for the control of HIV-1 infection.

The importance of TANK binding kinase-1 (TBK1), a multimeric kinase that modulates inflammation and autophagy, in human health has been highlighted for the first time by the recent discoveries of mutations in TBK1 that underlie amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), normal tension glaucoma (NTG) or childhood herpes simplex encephalitis (HSE). Gain-of-function of TBK1 are associated with NTG, whereas loss-of-function mutations result in ALS/FTD or in HSE. In light of these new findings, we review the role of TBK1 in these seemingly unrelated, yet allelic diseases, and discuss the role of TBK1 in neuroinflammatory diseases. This discovery has the potential to significantly increase our understanding of the molecular basis of these poorly understood diseases.

Biogenesis of the primary cilium, a cellular organelle mediating various signaling pathways, is generally coordinated with cell cycle exit/re-entry. Although the dynamic cell cycle-associated profile of the primary cilium has been largely accepted, the mechanism governing the link between ciliogenesis and cell cycle progression has been poorly understood. Using a human genome-wide RNAi screen, we identify genes encoding subunits of the spliceosome and proteasome as novel regulators of ciliogenesis. We demonstrate that 1) the mRNA processing-related hits are essential for RNA expression of molecules acting in cilia disassembly, such as AURKA and PLK1, and 2) the ubiquitin-proteasome systems (UPS)-involved hits are necessary for proteolysis of molecules acting in cilia assembly, such as IFT88 and CPAP. In particular, we show that these screen hit-associated mechanisms are crucial for both cilia assembly and cell cycle arrest in response to serum withdrawal. Finally, our data suggest that the mRNA processing mechanism may modulate the UPS-dependent decay of cilia assembly regulators to control ciliary resorption-coupled cell cycle re-entry. (C) 2016 The Authors. Published by Elsevier B.V.

During surveillance studies we detected, among over 1500 presumptive pneumococci, 11 isolates displaying conflicting or novel results when characterized by widely accepted phenotypic (optochin susceptibility and bile solubility) and genotypic (lytA-BsaAI-RFLP and MLST) identification methods. We aimed to determine the genetic basis for the unexpected results given by lytA-BsaAl-RFLP and investigate the accuracy of the WHO recommended lytA real-time PCR assay to classify these 11 isolates. Three novel lytA-BsaAI-RFLP signatures were found (one in pneumococcus and two in S. mitts). In addition, one pneumococcus displayed the atypical lytA-BsaAl-RFLP signature characteristic of non-pneumococci and two S. pseudopneumoniae displayed the typical lytA-BsaAl-RFLP pattern characteristic of pneumococci. lytA real-time PCR misidentified these three isolates. In conclusion, identification of pneumococci by lytA real-time PCR, and other lytA-based methodologies, may lead to false results. This is of particular relevance in the increasingly frequent colonization studies relying solely on culture independent methods. (C) 2016 Elsevier Inc. All rights reserved.