Characterizing Quasar C iv Emission-line Measurements from Time-resolved Spectroscopy

We use multi-epoch quasar spectroscopy to determine how accurately single-epoch spectroscopy can locate quasars in emission-line parameter space in order to inform investigations where time-resolved spectroscopy is not available. We explore the improvements in emission-line characterization that result from using non-parametric information from many lines as opposed to a small number of parameters for a single line, utilizing reconstructions based on an independent component analysis applied to the data from the Sloan Digital Sky Survey Reverberation Mapping project. We find that most of the quasars are well described by just two components, while more components signal a quasar likely to yield a successful reverberation mapping analysis. In single-epoch spectroscopy the apparent variability of equivalent width is exaggerated because it is dependent on the continuum. Multi-epoch spectroscopy reveals that single-epoch results do not significantly change where quasars are located in CIV parameter space and do not have a significant impact on investigations of the global Baldwin Effect. Quasars with emission line properties indicative of higher $L/L_{Edd}$ are less variable, consistent with models with enhanced accretion disk density. Narrow absorption features at the systemic redshift may be indicative of orientation (including radio-quiet quasars) and may appear in as much as 20% of the quasar sample. Future work applying these techniques to lower luminosity quasars will be important for understanding the nature of accretion disk winds

Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy

Notch signaling is a highly conserved intercellular pathway with tightly regulated and pleiotropic roles in normal tissue development and homeostasis. Dysregulated Notch signaling has also been implicated in human disease, including multiple forms of cancer, and represents an emerging therapeutic target. Successful development of such therapeutics requires a detailed understanding of potential on-target toxicities. Here, we identify autosomal dominant mutations of the canonical Notch ligand Jagged1 (or JAG1) as a cause of peripheral nerve disease in 2 unrelated families with the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2 (CMT2). Affected individuals in both families exhibited severe vocal fold paresis, a rare feature of peripheral nerve disease that can be life-threatening. Our studies of mutant protein posttranslational modification and localization indicated that the mutations (p.Ser577Arg, p.Ser650Pro) impair protein glycosylation and reduce JAG1 cell surface expression. Mice harboring heterozygous CMT2-associated mutations exhibited mild peripheral neuropathy, and homozygous expression resulted in embryonic lethality by midgestation. Together, our findings highlight a critical role for JAG1 in maintaining peripheral nerve integrity, particularly in the recurrent laryngeal nerve, and provide a basis for the evaluation of peripheral neuropathy as part of the clinical development of Notch pathway–modulating therapeutics

Environmental and Climatic Determinants of Molecular Diversity and Genetic Population Structure in a Coenagrionid Damselfly

Identifying environmental factors that structure intraspecific genetic diversity is of interest for both habitat preservation and biodiversity conservation. Recent advances in statistical and geographical genetics make it possible to investigate how environmental factors affect geographic organisation and population structure of molecular genetic diversity within species. Here we present a study on a common and wide ranging insect, the blue tailed damselfly Ischnuraelegans, which has been the target of many ecological and evolutionary studies. We addressed the following questions: (i) Is the population structure affected by longitudinal or latitudinal gradients?; (ii) Do geographic boundaries limit gene flow?; (iii) Does geographic distance affect connectivity and is there a signature of past bottlenecks?; (iv) Is there evidence of a recent range expansion and (vi) what is the effect of geography and climatic factors on population structure? We found low to moderate genetic sub-structuring between populations (mean FST = 0.06, Dest = 0.12), and an effect of longitude, but not latitude, on genetic diversity. No significant effects of geographic boundaries (e.g. water bodies) were found. FST-and Dest-values increased with geographic distance; however, there was no evidence for recent bottlenecks. Finally, we did not detect any molecular signatures of range expansions or an effect of geographic suitability, although local precipitation had a strong effect on genetic differentiation. The population structure of this small insect has probably been shaped by ecological factors that are correlated with longitudinal gradients, geographic distances, and local precipitation. The relatively weak global population structure and high degree of genetic variation within populations suggest that I. elegans has high dispersal ability, which is consistent with this species being an effective and early coloniser of new habitats

A mechanism for the inhibition of DNA-PK-mediated DNA sensing by a virus

The innate immune system is critical in the response to infection by pathogens and it is activated by pattern recognition receptors (PRRs) binding to pathogen associated molecular patterns (PAMPs). During viral infection, the direct recognition of the viral nucleic acids, such as the genomes of DNA viruses, is very important for activation of innate immunity. Recently, DNA-dependent protein kinase (DNA-PK), a heterotrimeric complex consisting of the Ku70/Ku80 heterodimer and the catalytic subunit DNA-PKcs was identified as a cytoplasmic PRR for DNA that is important for the innate immune response to intracellular DNA and DNA virus infection. Here we show that vaccinia virus (VACV) has evolved to inhibit this function of DNA-PK by expression of a highly conserved protein called C16, which was known to contribute to virulence but by an unknown mechanism. Data presented show that C16 binds directly to the Ku heterodimer and thereby inhibits the innate immune response to DNA in fibroblasts, characterised by the decreased production of cytokines and chemokines. Mechanistically, C16 acts by blocking DNA-PK binding to DNA, which correlates with reduced DNA-PK-dependent DNA sensing. The C-terminal region of C16 is sufficient for binding Ku and this activity is conserved in the variola virus (VARV) orthologue of C16. In contrast, deletion of 5 amino acids in this domain is enough to knockout this function from the attenuated vaccine strain modified vaccinia virus Ankara (MVA). In vivo a VACV mutant lacking C16 induced higher levels of cytokines and chemokines early after infection compared to control viruses, confirming the role of this virulence factor in attenuating the innate immune response. Overall this study describes the inhibition of DNA-PK-dependent DNA sensing by a poxvirus protein, adding to the evidence that DNA-PK is a critical component of innate immunity to DNA viruses

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Deepening Understanding of Certification Adoption and Non-Adoption of International-Supplier Ethical Standards

This study presents a theory of causally complex configurations of antecedent conditions influencing the adoption versus non-adoption of international supplier ethical certification-standards. Using objective measures of antecedents and outcomes, a large-scale study of exporting firms in the cut-flower industry in two South American countries (Colombia and Ecuador) supports the theory. The theory includes the following and additional propositions. No single (simple)-antecedent condition is sufficient for accurately predicting a high membership score in outcome conditions; the outcome conditions include a firm’s adoption or rejection of a product certification. No single (simple)-antecedent condition is necessary for accurately predicting high scores in the outcome condition. A few complex antecedent conditions (configurations) are sufficient but the occurrence of each is not necessary for accurately predicting high scores (e.g., adoption) in an outcome condition. Causal asymmetry of antecedent conditions indicating adoption versus non-adoption of specific ethical standards occurs—that is, causal conditions leading to rejection are not the mirror opposites of causal conditions leading to adoption

Multiple Colonization with S. pneumoniae before and after Introduction of the Seven-Valent Conjugated Pneumococcal Polysaccharide Vaccine

Simultaneous carriage of more than one strain of Streptococcus pneumoniae promotes horizontal gene transfer events and may lead to capsule switch and acquisition of antibiotic resistance. We studied the epidemiology of cocolonization with S. pneumoniae before and after introduction of the seven-valent conjugated pneumococcal vaccine (PCV7)

A Theoretical Analysis of the Feasibility of a Singularity-Induced Micro-Electroporation System

Electroporation, the permeabilization of the cell membrane lipid bilayer due to a pulsed electric field, has important implications in the biotechnology, medicine, and food industries. Traditional macro and micro-electroporation devices have facing electrodes, and require significant potential differences to induce electroporation. The goal of this theoretical study is to investigate the feasibility of singularity-induced micro-electroporation; an electroporation configuration aimed at minimizing the potential differences required to induce electroporation by separating adjacent electrodes with a nanometer-scale insulator. In particular, this study aims to understand the effect of (1) insulator thickness and (2) electrode kinetics on electric field distributions in the singularity-induced micro-electroporation configuration. A non-dimensional primary current distribution model of the micro-electroporation channel shows that while increasing insulator thickness results in smaller electric field magnitudes, electroporation can still be performed with insulators thick enough to be made with microfabrication techniques. Furthermore, a secondary current distribution model of the singularity-induced micro-electroporation configuration with inert platinum electrodes and water electrolyte indicates that electrode kinetics do not inhibit charge transfer to the extent that prohibitively large potential differences are required to perform electroporation. These results indicate that singularity-induced micro-electroporation could be used to develop an electroporation system that consumes minimal power, making it suitable for remote applications such as the sterilization of water and other liquids

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Dynamics of pneumococcal nasopharyngeal carriage in healthy children attending a day care center in northern Spain. influence of detection techniques on the results

<p>Abstract</p> <p>Background</p> <p>Pneumococcal nasopharyngeal carriage precedes invasive infection and is the source for dissemination of the disease. Differences in sampling methodology, isolation or identification techniques, as well as the period (pre -or post-vaccination) when the study was performed, can influence the reported rates of colonization and the distribution of serotypes carried.</p> <p>Objectives</p> <p>To evaluate the prevalence and dynamics of pneumococcal nasopharyngeal colonization in healthy children aged 6-34 months attending a day care center with a high level of hygiene and no overcrowding. The study was performed 3-4 years after the 7-valent pneumococcal vaccine was introduced, using multiple methodologies to detect and characterize the isolates.</p> <p>Methods</p> <p>Over 12 months, 25 children were sampled three times, 53 children twice and 27 children once. Three <it>Streptococcus pneumoniae </it>typing techniques were used: Quellung, Pneumotest-Latex-kit and multiplex-polymerase chain reaction (PCR). The similarity of isolates of the same serotype was established by pulsed field gel electrophoresis (PFGE) and occasionally the multilocus sequence type (ST) was also determined.</p> <p>Results</p> <p>Overall pneumococcal carriage and multiple colonization rates were 89.5% (94/105) and 39%, respectively. Among 218 pneumococci detected, 21 different serotypes and 13 non-typeable isolates were found. The most prevalent serotypes were 19A, 16F and 15B. Serotypes 15B, 19A and 21 were mainly found as single carriage; in contrast serotypes 6B, 11A and 20, as well as infrequent serotypes, were isolated mainly as part of multiple carriage. Most 19A isolates were ST193 but most serotypes showed high genetic heterogeneity. Changes in the pneumococci colonizing each child were frequent and the same serotype detected on two occasions frequently showed a different genotype. By multiplex-PCR, 100% of pneumococci could be detected and 94% could be serotyped versus 80.3% by the Quellung reaction and Pneumotest-Latex in combination (p < 0.001).</p> <p>Conclusions</p> <p>Rates of <it>S. pneumoniae </it>carriage and multiple colonization were very high. Prevalent serotypes differed from those found in similar studies in the pre-vaccination period. In the same child, clearance of a pneumococcal strain and acquisition of a new one was frequent in a short period of time. The most effective technique for detecting pneumococcal nasopharyngeal carriers was multiplex-PCR.</p