bluuebunny/crossref_metadata_2025_split huggingface dataset:
More precisely biased: increasing the number of markers is not a silver bullet in genetic bottleneck testing
Authors: Peery M. Zachariah , Reid Brendan N. , Kirby Rebecca , Stoelting Ricka , Doucet‐Bëer Elena , Robinson Stacie , Vásquez‐Carrillo Catalina , Pauli Jonathan N. , Palsbøll Per J. 
Published: June 2013

In response to our review of the use of genetic bottleneck tests in the conservation literature (Peery et al. 2012, Molecular Ecology, 21, 3403–3418), Hoban et al. (2013, Molecular Ecology, in press) conducted population genetic simulations to show that the statistical power of genetic bottleneck tests can be increased substantially by sampling large numbers of microsatellite loci, as they suggest is now possible in the age of genomics. While we agree with Hoban and co‐workers in principle, sampling large numbers of microsatellite loci can dramatically increase the probability of committing type 1 errors (i.e. detecting a bottleneck in a stable population) when the mutation model is incorrectly assumed. Using conservative values for mutation model parameters can reduce the probability of committing type 1 errors, but doing so can result in significant losses in statistical power. Moreover, we believe that practical limitations associated with developing large numbers of high‐quality microsatellite loci continue to constrain sample sizes, a belief supported by a literature review of recent studies using next generation sequencing methods to develop microsatellite libraries. conclusion, we maintain that researchers employing genetic bottleneck tests should proceed with caution and carefully assess both statistical power and type 1 error rates associated with their study design.
The mobility of two kinase domains in the Escherichia coli chemoreceptor array varies with signalling state
Authors: Briegel Ariane , Ames Peter , Gumbart James C. , Oikonomou Catherine M. , Parkinson John S. , Jensen Grant J. 
Published: June 2013

SummaryMotile bacteria sense their physical and chemical environment through highly cooperative, ordered arrays of chemoreceptors. These signalling complexes phosphorylate a response regulator which in turn governs flagellar motor reversals, driving cells towards favourable environments. The structural changes that translate chemoeffector binding into the appropriate kinase output are not known. Here, we apply high‐resolution electron cryotomography to visualize mutant chemoreceptor signalling arrays in well‐defined kinase activity states. The arrays were well ordered in all signalling states, with no discernible differences in receptor conformation at 2–3 nm resolution. Differences were observed, however, in a keel‐like density that we identify here as CheA kinase domains P1 and P2, the phosphorylation site domain and the binding domain for response regulator target proteins. Mutant receptor arrays with high kinase activities all exhibited small keels and high proteolysis susceptibility, indicative of mobile P1 and P2 domains. In contrast, arrays in kinase‐off signalling states exhibited a range of keel sizes. These findings confirm that chemoreceptor arrays do not undergo large structural changes during signalling, and suggest instead that kinase activity is modulated at least in part by changes in the mobility of key domains.
Effects of Geographic Search on Product Innovation in Industrial Cluster Firms in China
Authors: Wu Aiqi , Wei Jiang 
Published: June 2013

AbstractThe literature suggests that cluster firms may undertake both local and nonlocal geographic searches for knowledge that contributes to their product innovation, and that cluster firms must balance their local and nonlocal searches for product innovation. Yet, previous research has seen local and nonlocal searches as one-dimensional, rather than two-dimensional, activities involving search breadth and depth. In this study, we show that local search and nonlocal search are balanced by jointly considering the breadth and depth of geographic search, and that the optimal balance depends on industry dynamism. Using a sample from two industry clusters in China, we find positive relationships between relative local search depth, relative nonlocal search breadth, and the product innovation of cluster firms. Relative local search depth and relative nonlocal search breadth contribute more to product innovation in stable industries than in dynamic industries.
The Managing Emergencies in Paediatric Anaesthesia global rating scale is a reliable tool for simulation‐based assessment in pediatric anesthesia crisis management
Authors: Everett Tobias C. , Ng Elaine , Power Daniel , Marsh Christopher , Tolchard Stephen , Shadrina Anna , Bould Matthew D. 
Published: June 2013

SummaryIntroductionThe use of simulation‐based assessments for high‐stakes physician examinations remains controversial. The Managing Emergencies in Paediatric Anaesthesia course uses simulation to teach evidence‐based management of anesthesia crises to trainee anesthetists in the United Kingdom (UK) and Canada. In this study, we investigated the feasibility and reliability of custom‐designed scenario‐specific performance checklists and a global rating scale (GRS) assessing readiness for independent practice.MethodsAfter research ethics board approval, subjects were videoed managing simulated pediatric anesthesia crises in a single Canadian teaching hospital. Each subject was randomized to two of six different scenarios. All 60 scenarios were subsequently rated by four blinded raters (two in the UK, two in Canada) using the checklists and GRS. The actual and predicted reliability of the tools was calculated for different numbers of raters using the intraclass correlation coefficient (ICC) and the Spearman–Brown prophecy formula.ResultsAverage measures ICCs ranged from ‘substantial’ to ‘near perfect’ (P ≤ 0.001). The reliability of the checklists and the GRS was similar. Single measures ICCs showed more variability than average measures ICC. At least two raters would be required to achieve acceptable reliability.ConclusionsWe have established the reliability of a GRS to assess the management of simulated crisis scenarios in pediatric anesthesia, and this tool is feasible within the setting of a research study. The global rating scale allows raters to make a judgement regarding a participant's readiness for independent practice. These tools may be used in the future research examining simulation‐based assessment.
Meta‐normative Realism, Evolution, and Our Reasons to Survive
Authors: Behrends Jeff 
Published: June 2013

AbstractIn this article, I articulate and respond to an epistemological challenge to meta‐normative realism. The challenge has it that, if realism about the normative is correct, and if evolutionary forces have significantly influenced our normative judgments, then it would be a remarkable coincidence if the content of the normative facts and our normative judgments were aligned. I criticize David Enoch's recent attempt to meet this challenge, but provide an alternative response that is structurally similar. I argue that if realism is correct, then it would be remarkable if the content of our normative judgments and the normative facts were not significantly aligned.
Reweighting South African National Household Survey Data to Create a Consistent Series Over Time: A Cross‐Entropy Estimation Approach
Authors: Branson Nicola , Wittenberg Martin 
Published: June 2013

AbstractIn the absence of established longitudinal panel surveys in South Africa, national cross‐sectional household survey data are frequently used to analyse change. When these data are stacked side by side, however, inconsistencies both in time trends and between household‐ and person‐level data are found. This study uses a new set of weights calibrated to the Actuarial Society of South Africa 2003 model projected totals using a cross‐entropy estimation approach. These weights are favoured because they produce consistent demographic and geographic trends. The calculated weights are similar to the initial sample weights (and hence retain the survey design benefits) but match to a series of age‐sex‐race and province marginal totals that are consistent over time. The weights are publicly available for the 14‐year period between 1994 and 2007.
Unsociability and Shyness in Chinese Children: Concurrent and Predictive Relations with Indices of Adjustment
Authors: Liu Junsheng , Coplan Robert J. , Chen Xinyin , Li Dan , Ding Xuechen , Zhou Ying 
Published: June 2013

AbstractThe primary goal of this study was to examine the short‐term longitudinal associations between unsociability, shyness, and indices of adjustment among Chinese children. Participants were 787 children (ages 10–14 years) in an urban area in China. Assessments of unsociability, shyness, and adjustment were obtained from multiple sources, including peer nominations, self‐reports, and school records. Results indicated that while controlling for the effects of shyness, unsociability was associated with socioemotional and school difficulties. In particular, unsociability appeared to act as a risk factor for later peer problems and internalizing difficulties across the school year. Some gender differences were also observed in the longitudinal associations between unsociability and indices of adjustment. Results are discussed in terms of the meaning and implication of unsociability in Chinese culture.
Relations Among Gender Typicality, Peer Relations, and Mental Health During Early Adolescence
Authors: Jewell Jennifer A. , Brown Christia Spears 
Published: June 2013

AbstractThe current study examines whether being high in gender typicality is associated with popularity, whether being low in gender typicality is associated with rejection/teasing, and whether teasing due to low gender typicality mediates the association with negative mental health. Middle school children (34 boys and 50 girls) described hypothetical popular and rejected/teased peers, and completed self‐report measures about their own gender typicality, experiences with gender‐based teasing, depressive symptoms, anxiety, self‐esteem, and body image. Participants also completed measures about their peers' gender typicality, popularity, and likeability. Results indicated that popular youth were described as more gender typical than rejected/teased youth. Further, being typical for one's gender significantly predicted being rated as popular by peers, and this relationship was moderated by gender. Finally, low gender typicality predicted more negative mental health outcomes for boys. These relationships were, at times, mediated by experiences with gender‐based teasing, suggesting that negative mental health outcomes may be a result of the social repercussions of being low in gender typicality rather than a direct result of low typicality.
What DoYouThink? The Relationship between Person Reference and Communication About the Mind in Toddlers
Authors: Markova Gabriela , Smolík Filip 
Published: June 2013

AbstractThe present studies examined the relationship between children's use of grammatical structures indicating self–other differentiation (i.e., personal pronouns, verb conjugation) and their ability to use language to express their own and others' mental states (MSL). In Study 1, 104 parents of two‐ to three‐year‐old children filled out online checklists assessing children's vocabulary, their use ofMSL, and first‐ and second‐person pronouns and verb forms. In Study 2, 77 mothers of 1.5‐ to 2.5‐year‐old children filled out theMacArthur–Bates communicative development inventory, and additional checklists forMSLand verb conjugation. Results of both studies showed that children's use of grammatical person reference is strongly related to their level of grammatical abilities. Importantly, pronominal and inflectional references to others were correlated with children's discourse about the mind. Thus, linguistic tools that are used to distinguish self from others are not only indicators of children's grammatical development, but also their level of sociocognitive understanding.
Rhamnogalacturonan II structure shows variation in the side chains monosaccharide composition and methylation status within and across different plant species
Authors: Pabst Martin , Fischl Richard M. , Brecker Lothar , Morelle Willy , Fauland Alexander , Köfeler Harald , Altmann Friedrich , Léonard Renaud 
Published: June 2013

SummaryA paradigm regarding rhamnogalacturonans II (RGII) is their strictly conserved structure within a given plant. We developed and employed a fast structural characterization method based on chromatography and mass spectrometry, allowing analysis of RGII side chains from microgram amounts of cell wall. We found that RGII structures are much more diverse than so far described. In chain A of wild‐type plants, up to 45% of the l–fucose is substituted by l–galactose, a state that is seemingly uncorrelated with RGII dimerization capacity. This led us to completely reinvestigate RGII structures of the Arabidopsis thaliana fucose‐deficient mutant mur1, which provided insights into RGII chain A biosynthesis, and suggested that chain A truncation, rather than l–fucose to l–galactose substitution, is responsible for the mur1 dwarf phenotype. Mass spectrometry data for chain A coupled with NMR analysis revealed a high degree of methyl esterification of its glucuronic acid, providing a plausible explanation for the puzzling RGII antibody recognition. The β–galacturonic acid of chain A exhibits up to two methyl etherifications in an organ‐specific manner. Combined with variation in the length of side chain B, this gives rise to a family of RGII structures instead of the unique structure described up to now. These findings pave the way for studies on the physiological roles of modulation of RGII composition.
Multiple fates of non‐mature lumenal proteins in thylakoids
Authors: Midorikawa Takafumi , Inoue Kentaro 
Published: June 2013

SummaryMost proteins found in the thylakoid lumen are synthesized in the cytosol with an N–terminal extension consisting of transient signals for chloroplast import and thylakoid transfer in tandem. The thylakoid‐transfer signal is required for protein sorting from the stroma to thylakoids, mainly via the cpSEC or cpTAT pathway, and is removed by the thylakoidal processing peptidase in the lumen. An Arabidopsis mutant lacking one of the thylakoidal processing peptidase homologs, Plsp1, contains plastids with anomalous thylakoids and is seedling‐lethal. Furthermore, the mutant plastids accumulate two cpSEC substrates (PsbO and PetE) and one cpTAT substrate (PsbP) as intermediate forms. These properties of plsp1‐null plastids suggest that complete maturation of lumenal proteins is a critical step for proper thylakoid assembly. Here we tested the effects of inhibition of thylakoid‐transfer signal removal on protein targeting and accumulation by examining the localization of non‐mature lumenal proteins in the Arabidopsis plsp1‐null mutant and performing a protein import assay using pea chloroplasts. In plsp1‐null plastids, the two cpSEC substrates were shown to be tightly associated with the membrane, while non‐mature PsbP was found in the stroma. The import assay revealed that inhibition of thylakoid‐transfer signal removal did not disrupt cpSEC‐ and cpTAT‐dependent translocation, but prevented release of proteins from the membrane. Interestingly, non‐mature PetE2 was quickly degraded under light, and unprocessed PsbO1 and PsbP1 were found in a 440‐kDa complex and as a monomer, respectively. These results indicate that the cpTAT pathway may be disrupted in the plsp1‐null mutant, and that there are multiple mechanisms to control unprocessed lumenal proteins in thylakoids.
Identification of MET genomic amplification, protein expression and alternative splice isoforms in neuroblastomas
Authors: Yan Benedict , Lim Malcolm , Zhou Lihan , Kuick Chik Hong , Leong May Ying , Yong Kol Jia , Aung LeLe , Salto-Tellez Manuel , Chang Kenneth T E 
Published: June 2013

BackgroundCrizotinib, a dual anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition (MET) tyrosine kinase inhibitor, is currently being evaluated for the treatment of neuroblastoma. Its effects are thought to be mediated mainly via its activity against ALK. Although MET genomic/protein expression status might conceivably affect crizotinib efficacy, this issue has hitherto not received attention in neuroblastomas.Aims/MethodsMET genomic and protein expression status was characterised by silver in situ hybridisation and immunohistochemistry (IHC) respectively, in a cohort of 54 neuroblastoma samples. MET splice isoforms were characterised in 15 of these samples by quantitative PCR.ResultsOne case (1/54; prevalence 1.85%) displayedMETgenomic amplification, while another case (1/54; prevalence 1.85%) displayed strong membranous MET protein expression (IHC score 3+). Alternative exon 10-deleted and exon 14-deleted MET splice isoforms were identified.ConclusionsMET amplification and protein expression, although low in prevalence, are present in neuroblastomas. This has implications when crizotinib is employed as a therapeutic agent in neuroblastomas. Additionally, the existence of alternatively spliced MET isoforms may have clinical and biological implications in neuroblastomas.
Geomechanical impacts on flow in fractured reservoirs
Authors: Couples Gary D. 
Published: June 2013

Abstract
Flow responses in fractured reservoirs are difficult to predict. Apparent success in predicting flow has been achieved by developing simple rules of thumb based on (i) alterations of effective stress associated with pore pressure changes or (ii) concepts about fracture aperture alterations due to stress changes. Here it is argued that the assumptions underlying these explanations of flow are flawed, as they are based on ideas about stress that are physically wrong. It may be that these simple ideas can be fitted to some observations, but their use in this fashion is highly risky. The role of geomechanics in fractured reservoirs is more complex than suggested by the simple rules of thumb, as illustrated by numerical simulations that demonstrate the occurrence of strong non-linear interactions between the fluids, the geomechanics of blocky systems, and thermal changes. The resulting movements within fractured rock masses can cause major alterations of the upscaled flow properties. Flow performance discrepancies that are often associated with the operation of fractured reservoirs can, and often should, be seen as a consequence of motions occurring within the fractured rock mass. The explanations developed here are phenomenologically correct, and are more holistic than existing simple rules of thumb, improving the reliability of predictions.
p-Adic Fractional Pseudodifferential Equations and Sobolev Type Spaces overp-Adic Fields
Authors: Wu Bo 
Published: June 2013

In this paper, we study the solutions of the pseudodifferential equations of typeDα u=voverp-adic fieldℚp, whereDαis ap-adic fractional pseudodifferential operator. Ifvis a Bruhat-Schwartz function, then there exists a distributionEα, a fundamental solution, such thatu=Eα*vis a solution. We also show that the solutionubelongs to a certain Sobolev space. Furthermore, we give conditions for the continuity and uniqueness ofu.
The CpG Island Methylator Phenotype: What's in a Name?
Authors: Hughes Laura A.E. , Melotte Veerle , de Schrijver Joachim , de Maat Michiel , Smit Vincent T.H.B.M. , Bovée Judith V.M.G. , French Pim J. , van den Brandt Piet A. , Schouten Leo J. , de Meyer Tim , van Criekinge Wim , Ahuja Nita , Herman James G. , Weijenberg Matty P. , van Engeland Manon 
Published: June 2013

Abstract
Although the CpG island methylator phenotype (CIMP) was first identified and has been most extensively studied in colorectal cancer, the term “CIMP” has been repeatedly used over the past decade to describe CpG island promoter methylation in other tumor types, including bladder, breast, endometrial, gastric, glioblastoma (gliomas), hepatocellular, lung, ovarian, pancreatic, renal cell, and prostate cancers, as well as for leukemia, melanoma, duodenal adenocarninomas, adrenocortical carcinomas, and neuroblastomas. CIMP has been reported to be useful for predicting prognosis and response to treatment in a variety of tumor types, but it remains unclear whether or not CIMP is a universal phenomenon across human neoplasia or if there should be cancer-specific definitions of the phenotype. Recently, it was shown that somatic isocitrate dehydrogenase-1 (IDH1) mutations, frequently observed in gliomas, establish CIMP in primary human astrocytes by remodeling the methylome. Interestingly, somatic IDH1 and IDH2 mutations, and loss-of-function mutations in ten-eleven translocation (TET) methylcytosine dioxygenase-2 (TET2) associated with a hypermethylation phenotype, are also found in multiple enchondromas of patients with Ollier disease and Mafucci syndrome, and leukemia, respectively. These data provide the first clues for the elucidation of a molecular basis for CIMP. Although CIMP appears as a phenomenon that occurs in various cancer types, the definition is poorly defined and differs for each tumor. The current perspective discusses the use of the term CIMP in cancer, its significance in clinical practice, and future directions that may aid in identifying the true cause and definition of CIMP in different forms of human neoplasia. Cancer Res; 73(19); 5858–68. ©2013 AACR.
First FDA Approval of Dual Anti-HER2 Regimen: Pertuzumab in Combination with Trastuzumab and Docetaxel for HER2-Positive Metastatic Breast Cancer
Authors: Blumenthal Gideon M. , Scher Nancy S. , Cortazar Patricia , Chattopadhyay Somesh , Tang Shenghui , Song Pengfei , Liu Qi , Ringgold Kimberly , Pilaro Anne M. , Tilley Amy , King Kathryn E. , Graham Laurie , Rellahan Barbara L. , Weinberg Wendy C. , Chi Bo , Thomas Colleen , Hughes Patricia , Ibrahim Amna , Justice Robert , Pazdur Richard 
Published: June 2013

Abstract
On June 8, 2012, the U.S. Food and Drug Administration (FDA) approved pertuzumab (Perjeta, Genentech) for use in combination with trastuzumab (Herceptin, Genentech) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 808 patients with HER2-positive MBC. Patients were randomized (1:1) to receive pertuzumab (n = 402) or placebo (n = 406) in combination with trastuzumab and docetaxel. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). A statistically significant improvement in PFS (difference in medians of 6.1 months) was observed in patients receiving pertuzumab [HR, 0.62; 95% confidence interval (CI), 0.51–0.75; P &lt; 0.0001]. A planned interim analysis suggested an improvement in OS (HR, 0.64; 95% CI, 0.47–0.88; P = 0.0053) but the HR and P value did not cross the stopping boundary. Common adverse reactions (&gt;30%) observed in patients on the pertuzumab arm included diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. No additive cardiac toxicity was observed. Significant manufacturing issues were identified during the review. On the basis of substantial evidence of efficacy for pertuzumab in MBC and the compelling public health need, FDA did not delay availability to patients pending final resolution of all manufacturing concerns. Therefore, FDA approved pertuzumab but limited its approval to lots not affected by manufacturing problems. The applicant agreed to multiple manufacturing and testing postmarketing commitments under third-party oversight to resolve manufacturing issues. Clin Cancer Res; 19(18); 4911–6. ©2013 AACR.