bluuebunny/crossref_metadata_2025 huggingface dataset:
False Discovery Rates: A New Deal
Authors: Stephens Matthew
Published: January 2016

We introduce a new Empirical Bayes approach for large-scale hypothesis testing, including estimating False Discovery Rates (FDRs), and effect sizes. This approach has two key differences from existing approaches to FDR analysis. First, it assumes that the distribution of the actual (unobserved) effects is unimodal, with a mode at 0. This “unimodal assumption” (UA), although natural in many contexts, is not usually incorporated into standard FDR analysis, and we demonstrate how incorporating it brings many benefits. Specifically, the UA facilitates efficient and robust computation – estimating the unimodal distribution involves solving a simple convex optimization problem – and enables more accurate inferences provided that it holds. Second, the method takes as its input two numbers for each test (an effect size estimate, and corresponding standard error), rather than the one number usually used (pvalue, orzscore). When available, using two numbers instead of one helps account for variation in measurement precision across tests. It also facilitates estimation of effects, and unlike standard FDR methods our approach provides interval estimates (credible regions) for each effect in addition to measures of significance. To provide a bridge between interval estimates and significance measures we introduce the term “local false sign rate” to refer to the probability of getting the sign of an effect wrong, and argue that it is a superior measure of significance than the local FDR because it is both more generally applicable, and can be more robustly estimated. Our methods are implemented in an R package ashr available fromhttp://github.com/stephens999/ashr.
Human splicing diversity across the Sequence Read Archive
Authors: Nellore Abhinav , Jaffe Andrew E. , Fortin Jean-Philippe , Alquicira-Hernández José , Collado-Torres Leonardo , Wang Siruo , Phillips Robert A. , Karbhari Nishika , Hansen Kasper D. , Langmead Ben , Leek Jeffrey T.
Published: January 2016

We aligned 21,504 publicly available Illumina-sequenced human RNA-seq samples from the Sequence Read Archive (SRA) to the human genome and compared detected exon-exon junctions with junctions in several recent gene annotations. 56,865 junctions (18.6%) found in at least 1,000 samples were not annotated, and their expression associated with tissue type. Newer samples contributed few novel well-supported junctions, with 96.1% of junctions detected in at least 20 reads across samples present in samples before 2013. Junction data is compiled into a resource calledintropolisavailable athttp://intropolis.rail.bio. We discuss an application of this resource to cancer involving a recently validated isoform of the ALK gene.
Cell re-entry assays do not support models of pathogen-independent translocation of AvrM and AVR3a effectors into plant cells
Authors: Petre Benjamin , Kopischke Michaela , Evrard Alexandre , Robatzek Silke , Kamoun Sophien
Published: January 2016

The cell re-entry assay is widely used to evaluate pathogen effector protein uptake into plant cells. The assay is based on the premise that effector proteins secreted out of a leaf cell would translocate back into the cytosol of the same cell via a yet unknown host-derived uptake mechanism. Here, we critically assess this assay by expressing domains of the effector proteins AvrM-A ofMelampsora liniand AVR3a ofPhytophthora infestansfused to a signal peptide and fluorescent proteins inNicotiana benthamiana. We found that the secreted fusion proteins do not re-enter plant cells from the apoplast and that the assay is prone to false-positives. We therefore emit a cautionary note on the use of the cell re-entry assay for protein trafficking studies.
The genetic architecture of local adaptation II: The QTL landscape of water-use efficiency for foxtail pine (Pinus balfourianaGrev. & Balf.)
Authors: Eckert Andrew J. , Harwood Douglas E. , Lind Brandon M. , Hobson Erin M. , Delfino Mix Annette , Maloney Patricia E. , Friedline Christopher J.
Published: January 2016

Water availability is an important driver of the geographic distribution of many plant species, although its importance relative to other climatic variables varies across climate regimes and species. A common indirect measure of water-use efficiency (WUE) is the ratio of carbon isotopes (δ13C) fixed during photosynthesis, especially when analyzed in conjunction with a measure of leaf-level resource utilization (δ15N). Here, we test two hypotheses about the genetic architecture of WUE for foxtail pine (Pinus balfourianaGrev. & Balf.) using a novel mixture of double digest restriction site associated DNA sequencing, species distribution modeling, and quantitative genetics. First, we test the hypothesis that water availability is an important determinant of the geographical range of foxtail pine. Second, we test the hypothesis that variation in δ13C and δ15N is genetically based, differentiated between regional populations, and has genetic architectures that include loci of large effect. We show that precipitation-related variables structured the geographical range of foxtail pine, climate-based niches differed between regional populations, and δ13C and δ15N were heritable with moderate signals of differentiation between regional populations. A set of large-effect QTLs (n= 11 for δ13C;n= 10 for δ15N) underlying δ13C and δ15N variation, with little to no evidence of pleiotropy, was discovered using multiple-marker, half-sibling regression models. Our results represent a first approximation to the genetic architecture of these phenotypic traits, including documentation of several patterns consistent with δ13C being a fitness-related trait affected by natural selection.
Non-linear tumor-immune interactions arising from spatial metabolic heterogeneity
Authors: Robertson-Tessi Mark , Gillies Robert J. , Gatenby Robert A. , Anderson Alexander R. A.
Published: January 2016

A hybrid multiscale mathematical model of tumor growth is used to investigate how tumoral and microenvironmental heterogeneity affect the response of the immune system. The model includes vascular dynamics and evolution of metabolic tumor phenotypes. Cytotoxic T cells are simulated, and their effect on tumor growth is shown to be dependent on the structure of the microenvironment and the distribution of tumor phenotypes. Importantly, no single immune strategy is best at all stages of tumor growth.
Last-Century Increases in Intrinsic Water-Use Efficiency of Grassland Communities Have Occurred over a Wide Range of Vegetation Composition, Nutrient Inputs, and Soil pH
Authors: Köhler Iris H. , Macdonald Andy J. , Schnyder Hans
Published: January 2016

Last-century climate change has led to variable increases of the intrinsic water-use efficiency (W  i; the ratio of net CO2 assimilation to stomatal conductance for water vapor) of trees and C3 grassland ecosystems, but the causes of the variability are not well understood. Here, we address putative drivers underlying variable W  i responses in a wide range of grassland communities. W  i was estimated from carbon isotope discrimination in archived herbage samples from 16 contrasting fertilizer treatments in the Park Grass Experiment, Rothamsted, England, for the 1915 to 1929 and 1995 to 2009 periods. Changes in W  i were analyzed in relation to nitrogen input, soil pH, species richness, and functional group composition. Treatments included liming as well as phosphorus and potassium additions with or without ammonium or nitrate fertilizer applications at three levels. W  i increased between 11% and 25% (P < 0.001) in the different treatments between the two periods. None of the fertilizers had a direct effect on the change of W  i (ƊW  i). However, soil pH (P < 0.05), species richness (P < 0.01), and percentage grass content (P < 0.01) were significantly related to ƊW  i. Grass-dominated, species-poor plots on acidic soils showed the largest ƊW  i (+14.7 μmol mol−1). The ƊW  i response of these acidic plots was probably related to drought effects resulting from aluminum toxicity on root growth. Our results from the Park Grass Experiment show that W  i in grassland communities consistently increased over a wide range of nutrient inputs, soil pH, and plant community compositions during the last century.
Arabidopsis Pol II-Dependent in Vitro Transcription System Reveals Role of Chromatin for Light-InduciblerbcSGene Transcription
Authors: Ido Ayaka , Iwata Shinya , Iwata Yuka , Igarashi Hisako , Hamada Takahiro , Sonobe Seiji , Sugiura Masahiro , Yukawa Yasushi
Published: January 2016

In vitro transcription is an essential tool to study the molecular mechanisms of transcription. For over a decade, we have developed an in vitro transcription system from tobacco (Nicotiana tabacum)-cultured cells (BY-2), and this system supported the basic activities of the three RNA polymerases (Pol I, Pol II, and Pol III). However, it was not suitable to study photosynthetic genes, because BY-2 cells have lost their photosynthetic activity. Therefore, Arabidopsis (Arabidopsis thaliana) in vitro transcription systems were developed from green and etiolated suspension cells. Sufficient in vitro Pol II activity was detected after the minor modification of the nuclear soluble extracts preparation method; removal of vacuoles from protoplasts and L-ascorbic acid supplementation in the extraction buffer were particularly effective. Surprisingly, all four Arabidopsis Rubisco small subunit (rbcS-1A, rbcS-1B, rbcS-2B, and rbcS-3B) gene members were in vitro transcribed from the naked DNA templates without any light-dependent manner. However, clear light-inducible transcriptions were observed using chromatin template of rbcS-1A gene, which was prepared with a human nucleosome assembly protein 1 (hNAP1) and HeLa histones. This suggested that a key determinant of light-dependency through the rbcS gene transcription was a higher order of DNA structure (i.e. chromatin).
Decreased interleukin‐21 expression in skin and blood in advanced mycosis fungoides
Authors: Kabasawa Miyoko , Sugaya Makoto , Oka Tomonori , Takahashi Naomi , Kawaguchi Makiko , Suga Hiraku , Miyagaki Tomomitsu , Takahashi Takehiro , Shibata Sayaka , Fujita Hideki , Asano Yoshihide , Tada Yayoi , Kadono Takafumi , Okochi Hitoshi , Sato Shinichi
Published: January 2016

Interleukin (IL)‐21 is regarded as a potent antitumor agent, which increases the cytotoxicity of both natural killer (NK) and CD8+ T cells. In this study, we investigated the role of IL‐21 in mycosis fungoides (MF). IL‐21 mRNA expression levels in patch and plaque MF were significantly higher than those in normal skin. IL‐21 mRNA expression levels in tumor MF were significantly decreased compared with those in patch and plaque MF. Interestingly, mRNA expression levels of IL‐21 in MF lesional skin significantly correlated with those of T‐helper type‐1 cytokines/chemokines such as CXCL10, CXCL11 and γ‐interferon. Immunohistochemistry showed that IL‐21 was expressed by keratinocytes in patch and plaque MF. Furthermore, serum IL‐21 levels in patients with tumor MF were significantly lower than those of healthy controls and plaque MF. Thus, IL‐21 expression was significantly downregulated in skin and blood of patients with tumor MF, which may contribute to progression of MF. Our study suggests that recombinant IL‐21 would be a promising therapy for MF.
The Importance of the Mean Platelet Aggregation Degree in Long‐term Dual Antiplatelet Therapy Following Drug‐Eluting Stent Implantation
Authors: Li Quan , Ren Xuejun , Yu Xianpeng , He Jiqiang , Gao Yuechun , Zhang Xiaoling , Wu Changyan , Luo Yawei , Zhang Yuchen , Chen Fang
Published: January 2016

Introduction

The dual antiplatelet therapy (DAPT) and the response of clopidogrel were two pivotal issues in drug‐eluting stent (DES) era.

Aims

To analyze the combined impacts of DAPT and the response to clopidogrel to evaluate their long‐term effect on patients undergoing DES implantation.

Methods

Platelet aggregation was serially measured by light transmission aggregometry in all eligible patients during the course of treatment with DAPT, and the mean platelet aggregation degree of each participant was calculated. Based on the duration of DAPT and the mean platelet aggregation degree, all the enrolled patients were then divided into four groups. The primary endpoint was a composite of major adverse cardiovascular events.

Results

We analyzed 1245 suitable patients in this study. They were divided into four groups: Group A (12‐month DAPT & low platelet aggregation degree) with 233 subjects, Group B (12‐month DAPT & high platelet aggregation degree) with 260 subjects, Group C (>12‐month DAPT & low platelet aggregation degree) with 374 subjects, and Group D (>12‐month DAPT & high platelet aggregation degree) with 378 subjects. Group C was associated with a decreased incidence of primary endpoints [HR 0.512, 95%CI (0.27–0.97); P = 0.040]. The Cox proportional hazard model was further analyzed with Groups A and B combined as the reference category [HR for Group C vs. Group A, 0.84, 95%CI (0.33–2.15); P = 0.719; HR for Group C vs. Group B, 0.45, 95%CI (0.21–0.98); P = 0.043]. Their respective multivariate Cox proportional hazard regressions confirmed these trends.

Conclusions

The mean platelet aggregation degree is of importance in long‐term use of DAPT; extension of DAPT beyond 1 year should be implemented cautiously in patients implanted with DESs.
The Effectiveness of Early Educational Interventions in the Emergency Department to Reduce Incidence or Severity of Postconcussion Syndrome Following a Concussion: A Systematic Review
Authors: Eliyahu Leeor , Kirkland Scott , Campbell Sandy , Rowe Brian H.
Published: January 2016

Objectives

Concussions or mild traumatic brain injury are a major public health concern accounting for 85% of all brain injuries. Postconcussion syndrome (PCS) has been found to affect between 15 and 25% of patients with concussion 1 year after the initial injury. The goal of this review is to assess the effectiveness of early educational information or interventions provided in the emergency department on the onset and/or severity of PCS.

Methods

A comprehensive literature search strategy involving seven electronic databases was developed. A grey literature search of Google Scholar, recent conference proceedings in emergency medicine, bibliographies of included studies, and clinical trial registries was also performed. The citation list was reviewed independently by two reviewers; no restrictions on publication status or language of publication were applied. The Cochrane risk‐of‐bias tool and the Newcastle‐Ottawa scale were used to assess quality.

Results

From 1,325 citations retrieved, four RCTs and one controlled clinical trial met inclusion criteria. Interventions identified in these studies included: educational information sheets, with or without telephone or in‐person follow‐up, and one study on bed rest. While rarely requested, one study offered referrals and additional treatment, if needed. None of the studies were deemed to be high quality. Heterogeneity among outcome reporting, follow‐up dates and interventions used precluded a pooled analysis. Overall, only two of the five included studies involving adult patients receiving early educational interventions reported a significant improvement in PCS symptoms. No reduction in PCS symptoms was found in the study on bed rest interventions.

Conclusion

Limited evidence exists regarding the effectiveness of early educational interventions following concussion. Standardization of the interventions, outcome measures, and follow‐up periods would make quantitative comparisons more valid. Moreover, higher‐quality research in the field of early interventions for patients in the acute care setting is urgently required.
Building a Natural Language Processing Tool to Identify Patients With High Clinical Suspicion for Kawasaki Disease from Emergency Department Notes
Authors: Doan Son , Maehara Cleo K. , Chaparro Juan D. , Lu Sisi , Liu Ruiling , Graham Amanda , Berry Erika , Hsu Chun‐Nan , Kanegaye John T. , Lloyd David D. , Ohno‐Machado Lucila , Burns Jane C. , Tremoulet Adriana H. ,   the Pediatric Emergency Medicine Kawasaki Disease Research Group
Published: January 2016

Objective

Delayed diagnosis of Kawasaki disease (KD) may lead to serious cardiac complications. We sought to create and test the performance of a natural language processing (NLP) tool, the KD‐NLP, in the identification of emergency department (ED) patients for whom the diagnosis of KD should be considered.

Methods

We developed an NLP tool that recognizes the KD diagnostic criteria based on standard clinical terms and medical word usage using 22 pediatric ED notes augmented by Unified Medical Language System vocabulary. With high suspicion for KD defined as fever and three or more KD clinical signs, KD‐NLP was applied to 253 ED notes from children ultimately diagnosed with either KD or another febrile illness. We evaluated KD‐NLP performance against ED notes manually reviewed by clinicians and compared the results to a simple keyword search.

Results

KD‐NLP identified high‐suspicion patients with a sensitivity of 93.6% and specificity of 77.5% compared to notes manually reviewed by clinicians. The tool outperformed a simple keyword search (sensitivity = 41.0%; specificity = 76.3%).

Conclusions

KD‐NLP showed comparable performance to clinician manual chart review for identification of pediatric ED patients with a high suspicion for KD. This tool could be incorporated into the ED electronic health record system to alert providers to consider the diagnosis of KD. KD‐NLP could serve as a model for decision support for other conditions in the ED.
Video‐based Assessment of Peripheral Intravenous Catheter Insertion in the Resuscitation Area of a Pediatric Emergency Department
Authors: Vukovic Adam A. , Frey Mary , Byczkowski Terri , Taylor Regina , Kerrey Benjamin T.
Published: January 2016

Objective

The objective was to describe the frequency of and factors associated with prolonged peripheral intravenous catheter (PIV) insertion in the resuscitation area of a pediatric emergency department (PED).

Methods

Video‐based study of a consecutive sample of nontrauma patients undergoing PIV insertion in the resuscitation area of a PED. Preexisting videos were the main data source. The primary outcome was patients with prolonged duration of PIV insertion (>90 seconds from start of first attempt to successful flush/blood draw). Logistic regression identified variables independently associated with prolonged PIV insertion.

Results

A total of 151 consecutive nontrauma patients underwent PIV insertion during a 2.5‐month period. Sixty‐nine patients (46%) had prolonged PIV insertion, including 14 for whom PED providers failed to insert PIVs. For patients with successful PIV insertion by PED providers, median duration was 48 seconds (interquartile range [IQR] = 23 to 295 seconds). Vascular access was ultimately achieved for 13 patients (93%) with initial insertion failure by the PED team (10 non‐PED personnel, three intraosseous lines), with a median duration of 26.7 minutes (IQR = 19.9 to 34.2 minutes). Age ≤ 2 years (ORadj = 6.9; 95% confidence interval [CI] = 2.9 to 16.1) and musculoskeletal contractures (ORadj = 5.3; 95% CI = 1.6 to 17.2) were independently associated with prolonged PIV insertion.

Conclusions

Prolonged PIV insertion is common in a PED resuscitation area. When PED providers could not insert a PIV, time to insertion was very long. Young patients and those with contractures were at particular risk for prolonged and failed PIV placement. When emergent vascular access is required, alternative approaches should be considered early for these patients.
CURB‐65 Performance Among Admitted and Discharged Emergency Department Patients With Community‐acquired Pneumonia
Authors: Sharp Adam L. , Jones Jason P. , Wu Ivan , Huynh Dan , Kocher Keith E. , Shah Nirav R. , Gould Michael K.
Published: January 2016

Objectives

Pneumonia severity tools were primarily developed in cohorts of hospitalized patients, limiting their applicability to the emergency department (ED). We describe current community ED admission practices and examine the accuracy of the CURB‐65 to predict 30‐day mortality for patients, either discharged or admitted with community‐acquired pneumonia (CAP).

Methods

A retrospective, observational study of adult CAP encounters in 14 community EDs within an integrated healthcare system. We calculated CURB‐65 scores for all encounters and described the use of hospitalization, stratified by each score (0–5). We then used each score as a cutoff to calculate sensitivity, specificity, positive predictive value, negative predictive value (NPV), positive likelihood ratios, and negative likelihood ratios for predicting 30‐day mortality.

Results

The sample included 21,183 ED encounters for CAP (7,952 discharged and 13,231 admitted). The C‐statistic describing the accuracy of CURB‐65 for predicting 30‐day mortality in the full sample was 0.761 (95% confidence interval [CI], 0.747–0.774). The C‐statistic was 0.864 (95% CI, 0.821–0.906) among patients discharged from the ED compared with 0.689 (95% CI, 0.672–0.705) among patients who were admitted. Among all ED encounters a CURB‐65 threshold of ≥1 was 92.8% sensitive and 38.0% specific for predicting mortality, with a 99.9% NPV. Among all encounters, 62.5% were admitted, including 36.2% of those at lowest risk (CURB‐65 = 0).

Conclusions

CURB‐65 had very good accuracy for predicting 30‐day mortality among patients discharged from the ED. This severity tool may help ED providers risk stratify patients to assist with disposition decisions and identify unwarranted variation in patient care.
Geographical disparities in prescription practices of lithium and clozapine: a community‐based study
Authors: Verdoux H. , Pambrun E. , Cortaredona S. , Coldefy M. , Le Neindre C. , Tournier M. , Verger P.
Published: January 2016

Objective

To explore the socioeconomic and health resource characteristics associated with geographical variations of lithium and clozapine dispensing rates in France.

Method

The study was performed using reimbursement data from the French Insurance Healthcare system over the period 2006–2013 in a community‐based sample of persons aged 16 years and over. An ecological design was used to assess whether lithium and clozapine prescribing rates were associated with socioeconomic and health resource characteristics of the zone of residence (n = 95 French administrative subdivisions).

Results

Large geographical disparities were observed in dispensing rates: lithium dispensing rates by zone of residence ranged from 0 to 6.6 per 1000 (mean 2.4 per 1000) and clozapine dispensing rates ranged from 0 to 4.9 per 1000 (mean 0.8 per 1000). Higher density of GPs and regular communication between mental health services and primary care were independently associated with higher rates of lithium and clozapine dispensing and with a higher proportion of lithium users among mood‐stabilizer users.

Conclusion

A sufficient density of GPs and an effective communication and collaboration between mental healthcare services and primary care seems to favor greater access to psychotropic drugs with demonstrated efficacy but often viewed as ‘risky’ to prescribe.
Cannabidiol disrupts the reconsolidation of contextual drug‐associated memories in Wistar rats
Authors: de Carvalho Cristiane Ribeiro , Takahashi Reinaldo Naoto
Published: February 2016

In addicts, craving and relapse are frequently induced by the recall of memories related to a drug experience. Several studies have demonstrated that drug‐related memories are reactivated after exposure to environmental cues and may undergo reconsolidation, a process that can strengthen memories. Thus, reactivation of mnemonic traces provides an opportunity for disrupting memories that contribute to the pathological cycle of addiction. Here we used drug‐induced conditioned place preference (CPP) to investigate whether cannabidiol (CBD), a phytocannabinoid, given just after reactivation sessions, would affect reconsolidation of drug‐reward memory, reinstatement of morphine‐CPP, or conditioned place aversion precipitated by naltrexone in Wistar rats. We found that CBD impaired the reconsolidation of preference for the environment previously paired with both morphine and cocaine. This disruption seems to be persistent, as the preference did not return after further reinstatement induced by priming drug and stress reinstatement. Moreover, in an established morphine‐CPP, an injection of CBD after the exposure to a conditioning session led to a significant reduction of both morphine‐CPP and subsequent conditioned place aversion precipitated by naltrexone in the same context. Thus, established memories induced by a drug of abuse can be blocked after reactivation of the drug experience. Taken together, these results provide evidence for the disruptive effect of CBD on reconsolidation of contextual drug‐related memories and highlight its therapeutic potential to attenuate contextual memories associated with drugs of abuse and consequently to reduce the risk of relapse.
A comparison of neuropsychiatric adverse events during early treatment with varenicline or a nicotine patch
Authors: Cunningham Francesca E. , Hur Kwan , Dong Diane , Miller Donald R. , Zhang Rongping , Wei Xiangming , McCarren Madeline , Mosholder Andrew D. , Graham David J. , Aspinall Sherrie L. , Good Chester B.
Published: January 2016

Aims

We compared the risk of mental health episodes requiring hospitalization (primary aim) or out‐patient clinic visits (secondary aim) associated with varenicline versus the nicotine patch (NP) in an era prior to psychiatric boxed warnings.

Design

Retrospective cohort.

Setting

Department of Veterans Affairs (VA), USA.

Participants

VA patients with or without psychiatric comorbidities and a new prescription for varenicline (15 255) were propensity score‐matched (1 : 2) to new users of NP (123 054) between 1 May 2006 and 30 September 2007, resulting in 11 774 and 23 548 patients in the varenicline and NP groups, respectively.

Measurements

The primary outcomes were hospitalizations with a primary discharge diagnosis of a range of mental health disorders: depression, schizophrenia, bipolar disorder, suicide attempt, post‐traumatic stress disorder, other psychosis and drug‐induced mental disorders. Secondary outcomes were out‐patient clinic visits with a primary diagnosis of the above list of mental health disorders.

Findings

Background characteristics of the treatment groups were similar after matching. There was no statistically significant difference in risk of hospitalization for any of the studied mental health disorders with varenicline compared with NP. Among secondary outcomes there was an increased risk of out‐patient clinic visits for schizophrenia among patients who received varenicline [hazard ratio (HR) = 1.27; 95% confidence interval (CI) = 1.07, 1.51], this increase being evident only in those with a pre‐existing mental health disorder.

Conclusion

In US VA patients studied prior to the boxed warning being implemented, use of varenicline for smoking cessation was not associated with a detectable increase compared with nicotine patches in hospitalization for any mental health outcomes. There was an increased rate of out‐patient attendances with a primary diagnosis of schizophrenia amounting to five per 100 person years of treatment. This increase was found only in patients with a pre‐existing mental health disorder.
Late reproductive analysis in rat male offspring exposed to nicotine during pregnancy and lactation
Authors: Miranda‐Spooner M. , Paccola C. C. , Neves F. M. O. , de Oliva S. U. , Miraglia S. M.
Published: January 2016

We previously observed that nicotine, administered to rats (Wistar) during pregnancy and lactation periods, provokes, in the progeny, late morphofunctional alterations in Leydig cell, body weight increase in adulthood (90 days post partum, dpp) as well as seminiferous epithelium injury. Aiming to investigate whether the spermatogenic damage previously observed in adult progenies from pregnant and lactating nicotine‐exposed rat dams are maintained or whether it is worsened in older rats, we analyzed the morphological testicular alterations after up to two complete periods of spermatogenesis (53 days each), spermatic parameters, and sperm DNA fragmentation. Pregnant and lactating rats were nicotine‐exposed (2 mg/kg/day) through an osmotic minipump implanted on the first day of pregnancy and replaced after birth. Absolute Control (no minipump) and Sham Control (minipump without nicotine) groups were established. The offspring were killed at 90, 143, and 196 dpp. Significant alterations in morphometric and stereological testicular parameters, such as concentration of sperm number, daily sperm production, and plasma and intratesticular levels of cholesterol and testosterone were not observed in nicotine‐exposed rats. Testicular histopathological analysis showed small intraepithelial vacuolization and an accentuated germ cell desquamation in exposed rats. However, the offspring from nicotine‐exposed dams exhibited higher frequency of morphologically abnormal spermatozoa and lower sperm motility in comparison with control groups. In addition, nicotine‐exposed groups showed a significant reduction in sperm mitochondrial activity and an increased sperm DNA fragmentation (Comet assay). These results indicate a late reproductive damage in the male progeny caused by maternal nicotine exposure, related to the decrease in sperm quality.
Light and electron microscopic study of mature spermatozoa from White Pekin duck (Anas platyrhynchos): an ultrastructural and molecular analysis
Authors: Majhi Rakesh Kumar , Kumar Ashutosh , Yadav Manoj , Kumar Pradeep , Maity Apratim , Giri Sunil C. , Goswami Chandan
Published: January 2016

The morphology, ultrastructure, and functions of mature avian spermatozoa have been of immense commercial and scientific interest for several reasons. This is mainly important in case of birds in poultry production, conservation, and in the use of sperm morphometry as phylogenetic evidence. Avian spermatozoa share complex or no correlation of sperm morphometry with respect to testis and/or body size as described before. In this work, we have isolated mature spermatozoa from White Pekin duck (Anas platyrhynchos) by non‐invasive methods and performed several immunostaining analysis as well as cytochemical analysis using electron and light microscopes. Here, we report the presence of different post‐translationally modified tubulin such as tyrosinated‐, detyrosinated‐, acetylated‐, polyglutamylated‐, and glycylated‐tubulin in specific regions of the mature spermatozoa. By using field‐emission scanning electron microscope, we confirm the presence of acrosome‐like structure at the tip of the sperm head. However, this structure remains non‐reactive to common lectins such as Peanut Agglutinin (PNA) and cholesterol‐sensitive dyes such as Filipin. We report that this acrosomal structure is primarily made of lipid‐based structures and is resistant to 0.1% Triton X100. Confocal microscopy and super resolution structured illumination microscopy study indicates that the nucleus is bifurcated at the tip region. By using specific markers, we report that the perforatorium structure present at the tip of the spermatozoa head contains specialized organelles that is similar to atypical mitochondria. We propose that these ultrastructural and molecular parameters can be used as species‐specific features. The bifurcated nucleus and presence of atypical mitochondria within this structure may be relevant for the complex mitochondrial inheritance and mitochondrial heteroplasmy observed in case of avian population.
Notch signaling in the epididymal epithelium regulates sperm motility and is transferred at a distance within epididymosomes
Authors: Murta D. , Batista M. , Silva E. , Trindade A. , Henrique D. , Duarte A. , Lopes‐da‐Costa L.
Published: January 2016

Spermatozoa undergo sequential maturation changes during their transit along the epididymis. These changes are modulated by the epididymal epithelium and require a finely tuned gene expression. The Notch cell signaling pathway is a major regulator of cell fate decisions in several tissues, including the testis. Here, we evaluated the transcription and expression patterns of Notch components (Notch1‐3,Dll1,Dll4,andJagged1) and effectors (Hes1‐2andHes5) in the adult mouse epididymis, and evaluated the role of Notch signaling in the epididymis through its in vivo blockade following administration of an inhibitor (DAPT). Notch components and effectors were dynamically transcribed and expressed in the epididymis andvas deferens, each segment exhibiting a specific combination of epithelial receptor/ligand/effector expression patterns. Nuclear detection of Notch effectors indicates that Notch signaling was active. Notch components (but not effectors) were identified in the cytoplasmic droplet of spermatozoa, in a dynamic and specific pattern along the epididymis. In addition, Notch components were identified within large and small vesicles in the epididymal lumen. A purified population of these membranous vesicles from different epididymal segments was obtained, and through dot blot analysis, it was confirmed that Notch components were carried within these vesicles in a dynamic pattern along the epididymal lumen. We hypothesize that these vesicles (epididymosomes) allow Notch signaling at distance from epididymal epithelial cells to spermatozoa.DAPT‐induced in vivo Notch signaling blockade, although showing a low efficiency, disrupted the expression patterns of Notch components and effectors in the epididymal epithelium and in spermatozoa, and significantly decreased sperm motility, although not affecting male fertility. These results prompt for a regulatory role of Notch signaling in epididymal epithelial function and sperm maturation.
Initiation and exclusivity of breastfeeding: association with mothers' and fathers' prenatal and postnatal depression and marital distress
Authors: Ahlqvist‐Björkroth Sari , Vaarno Jenni , Junttila Niina , Pajulo Marjaterttu , Räihä Hannele , Niinikoski Harri , Lagström Hanna
Published: January 2016

Introduction

This study explored the effects of mothers' and fathers' prenatal and postnatal depressive symptoms and marital distress on breastfeeding initiation and exclusive breastfeeding (EBF) duration.

Material and methods

This was a prospective follow‐up of a cohort sample of 873 families participating to an intensive follow‐up cohort of longitudinal Steps to the Healthy Development and Well‐being of Children study (The STEPS study) in Southwestern Finland. The depressive symptoms were evaluated by The Edinburgh Postpartum Depression Scale and marital distress by the Revised Dyadic Adjustment Scale at 20th gestational week and at 4 months postpartum. EBF was self‐reported real‐time and defined as an infant receiving no food or drink other than mother's breast milk since birth, except occasionally water.

Results

Neither parents' prenatal depressive symptoms predicted breastfeeding initiation or EBF duration. The mothers' prenatal depressive symptoms, in turn, predicted their postnatal depressive symptoms, which were associated with shorter duration of EBF. The EBF duration was shortest amongst the mothers who had depressive symptoms both pre‐ and postnatally compared to mothers who had depressive symptoms only in either time point alone (M = 1.54, 2.06 and 2.04 months, respectively). Higher prenatal maternal marital distress was associated with longer EBF duration.

Conclusions

The findings suggest that the continuity of maternal depressive symptoms throughout the perinatal period has adverse effect on EBF duration. Identification and treatment of mothers' depressive symptoms already during the prenatal period may improve breastfeeding practices. The finding of mothers' marital distress having positive impact on breastfeeding practices requires further investigation.
Enhanced gefitinib‐induced repression of the epidermal growth factor receptor pathway by ataxia telangiectasia‐mutated kinase inhibition in non‐small‐cell lung cancer cells
Authors: Misumi Keizo , Sun Jiying , Kinomura Aiko , Miyata Yoshihiro , Okada Morihito , Tashiro Satoshi
Published: January 2016

The epidermal growth factor receptor (EGFR) tyrosine kinase signaling pathways regulate cellular activities. The EGFR tyrosine kinase inhibitors (EGFR‐TKIs) repress the EGFR pathway constitutively activated by somatic EGFR gene mutations and have drastically improved the prognosis of non‐small‐cell lung cancer (NSCLC) patients. However, some problems, including resistance, remain to be solved. Recently, combination therapy with EGFR‐TKIs and cytotoxic agents has been shown to improve the prognosis of NSCLC patients. To enhance the anticancer effects of EGFR‐TKIs, we examined the cross‐talk of the EGFR pathways with ataxia telangiectasia‐mutated (ATM) signaling pathways. ATM is a key protein kinase in the DNA damage response and is known to phosphorylate Akt, an EGFR downstream factor. We found that the combination of an ATM inhibitor, KU55933, and an EGFR‐TKI, gefitinib, resulted in synergistic cell growth inhibition and induction of apoptosis in NSCLC cell lines carrying the sensitive EGFR mutation. We also found that KU55933 enhanced the gefitinib‐dependent repression of the phosphorylation of EGFR and/or its downstream factors. ATM inhibition may facilitate the gefitinib‐dependent repression of the phosphorylation of EGFR and/or its downstream factors, to exert anticancer effects against NSCLC cells with the sensitive EGFR mutation.
General Ser/Thr Kinases Pharmacophore Approach for Selective Kinase Inhibitors Search as Exemplified by Design of Potent and Selective Aurora A Inhibitors
Authors: Vasilevich Natalya I. , Aksenova Elena A. , Kazyulkin Denis N. , Afanasyev Ilya I.
Published: January 2016

A general pharmachophore model for various types of Ser/Thr kinases was developed. Search for the molecules fitting to this pharmacophore among ASINEX proprietary library revealed a number of compounds, which were tested and appeared to possess some activity against several Ser/Thr kinases such as Aurora A, Aurora B and Haspin. The possibility of performing the fine‐tuning of the general Ser/Thr pharmacophore to desired types of kinase to get active and selective inhibitors was exemplified by Aurora A kinase. As a result, several hits in 3–5 nm range of activity against Aurora A kinase with rather good selectivity and ADME properties were obtained.
Probing the Binding Pocket of the Broadly Tuned Human Bitter Taste Receptor TAS2R14 by Chemical Modification of Cognate Agonists
Authors: Karaman Rafik , Nowak Stefanie , Di Pizio Antonella , Kitaneh Hothaifa , Abu‐Jaish Alaa , Meyerhof Wolfgang , Niv Masha Y. , Behrens Maik
Published: January 2016

Sensing potentially harmful bitter substances in the oral cavity is achieved by a group of ˜25 receptors, named TAS2Rs, which are expressed in specialized sensory cells and recognize individual but overlapping sets of bitter compounds. The receptors differ in their tuning breadths ranging from narrowly to broadly tuned receptors. One of the most broadly tuned human bitter taste receptors is the TAS2R14 recognizing an enormous variety of chemically diverse synthetic and natural bitter compounds, including numerous medicinal drugs. This suggests that this receptor possesses a large readily accessible ligand binding pocket. To allow probing the accessibility and size of the ligand binding pocket, we chemically modified cognate agonists and tested receptor responses in functional assays. The addition of large functional groups to agonists was usually possible without abolishing agonistic activity. The newly synthesized agonist derivatives were modeled in the binding site of the receptor, providing comparison to the mother substances and rationalization of the in vitro activities of this series of compounds.
The Debate Over Single‐Sex Schooling
Authors: Pahlke Erin , Hyde Janet S.
Published: January 2016

Supporters of single‐sex schooling believe that separating boys and girls, by classrooms or schools, increases students' academic achievement. Critics of single‐sex schooling believe that gender segregation increases students' gender stereotypes and has no effect on students' achievement. In this article, we present these rationales, focusing on developmental issues that may affect the effectiveness of single‐sex schooling. We then review the research on the effectiveness of single‐sex schooling. Overall, findings suggest that single‐sex schooling is not more effective than coeducational schooling at improving students' academic achievement or attitudes. More work is needed to explore a broader range of outcomes, examine developmental factors that may influence the effectiveness of various types of schooling, and communicate results to parents, educators, and policymakers.
Developmental bias for number words in the intraparietal sulcus
Authors: Lussier Courtney A. , Cantlon Jessica F.
Published: January 2016

Children and adults show behavioral evidence of psychological overlap between their early, non‐symbolic numerical concepts and their later‐developing symbolic numerical concepts. An open question is to what extent the common cognitive signatures observed between different numerical notations are coupled with physical overlap in neural processes. We show that from 8 years of age, regions of the intraparietal sulcus (IPS) that exhibit a numerical ratio effect during non‐symbolic numerical judgments also show a semantic distance effect for symbolic number words. In both children and adults, the IPS showed a semantic distance effect during magnitude judgments of number words (i.e. larger/smaller number) but not for magnitude judgments of object words (i.e. larger/smaller object size). The results provide novel evidence of conceptual overlap between neural representations of symbolic and non‐symbolic numerical values that cannot be explained by a general process, and present the first demonstration of an early‐developing dissociation between number words and object words in the human brain.
Cultural differences in self‐recognition: the early development of autonomous and related selves?
Authors: Ross Josephine , Yilmaz Mandy , Dale Rachel , Cassidy Rose , Yildirim Iraz , Suzanne Zeedyk M.
Published: January 2016

Fifteen‐ to 18‐month‐old infants from three nationalities were observed interacting with their mothers and during two self‐recognition tasks. Scottish interactions were characterized by distal contact, Zambian interactions by proximal contact, and Turkish interactions by a mixture of contact strategies. These culturally distinct experiences may scaffold different perspectives on self. In support, Scottish infants performed best in a task requiring recognition of the self in an individualistic context (mirror self‐recognition), whereas Zambian infants performed best in a task requiring recognition of the self in a less individualistic context (body‐as‐obstacle task). Turkish infants performed similarly to Zambian infants on the body‐as‐obstacle task, but outperformed Zambians on the mirror self‐recognition task. Verbal contact (a distal strategy) was positively related to mirror self‐recognition and negatively related to passing the body‐as‐obstacle task. Directive action and speech (proximal strategies) were negatively related to mirror self‐recognition. Self‐awareness performance was best predicted by cultural context; autonomous settings predicted success in mirror self‐recognition, and related settings predicted success in the body‐as‐obstacle task. These novel data substantiate the idea that cultural factors may play a role in the early expression of self‐awareness. More broadly, the results highlight the importance of moving beyond the mark test, and designing culturally sensitive tests of self‐awareness.
Predicting writing development in dual language instructional contexts: exploring cross‐linguistic relationships
Authors: Savage Robert , Kozakewich Meagan , Genesee Fred , Erdos Caroline , Haigh Corinne
Published: January 2016

This study examined whether decoding and linguistic comprehension abilities, broadly defined by the Simple View of Reading, in grade 1 each uniquely predicted the grade 6 writing performance of English‐speaking children (n= 76) who were educated bilingually in both English their first language and French, a second language. Prediction was made from (1) English to English; (2) French to French; and (3) English to French. Results showed that both decoding and linguistic comprehension scores predicted writing accuracy but rarely predicted persuasive writing. Within the linguistic comprehension cluster of tests, Formulating Sentences was a strong consistent within‐ and between‐language predictor of writing accuracy. In practical terms, the present results indicate that early screening for later writing ability using measures of sentence formulation early in students’ schooling, in their L1 or L2, can provide greatest predictive power and allow teachers to differentiate instruction in the primary grades. Theoretically, the present results argue that there are correlations between reading‐related abilities and writing abilities not only within the same language but also across languages, adding to the growing body of evidence for facilitative cross‐linguistic relationships between bilinguals’ developing languages.
Papillary Muscle Rupture Following Non‐ST‐Elevation Myocardial Infarction: A Case Report
Authors: Murad Khalil , Missov Emil
Published: January 2016

Papillary muscle rupture is a serious mechanical complication of acute myocardial infarction typically seen within 5–7 days following transmural ST‐elevation myocardial infarction. The incidence of papillary muscle rupture has markedly decreased in the modern era due to improved diagnosis and early coronary revascularization of ST‐elevation myocardial infarction. As a result, papillary muscle rupture is increasingly seen following non‐ST‐elevation myocardial infarction where both diagnosis and revascularization can be delayed. In this report, we describe two cases of papillary muscle rupture following delayed presentation of non‐ST‐elevation myocardial infarction and delayed recognition of papillary muscle rupture.
3D Xplane Echocardiographic Technique for Validation of Mitral Leaflet Separation to Assess Severity of Mitral Stenosis
Authors: Gokhroo Rajendra K. , Ranwa Bhanwar L. , Kishor Kamal , Priti Kumari , Avinash Ananthraj , Gupta Sajal , Bisht Devendra
Published: January 2016

Background

Determining the severity of mitral stenosis (MS) is important for both prognostic and therapeutic implications. Mitral valve area (MVA) calculation techniques have more limitations. Mitral leaflet separation (MLS) is a precise and operator friendly alternative to planimetry. In contrast to previous researchers, we have used a novel 3D Xplane technique to validate MLS for assessing the severity of MS. 3D Xplane is superior for validation of MLS due to simultaneous real time acquisition of MLS in parasternal long‐axis view and corresponding MVA by planimetry in parsternal short‐axis view.

Methods

It was a prospective observational single center study. A total of 174 patients with MS were evaluated for MVA estimation by various echocardiographic modalities. Maximum leaflet separation and corresponding planimetered MVA were measured using novel 3D Xplane technique.

Results

With 3D Xplane technique, there was strong positive correlation between planimetered MVA and MLS (R = 0.925, P < 0.001), irrespective of coexisting MR (R = 0.886, P < 0.001) or AF (R = 0.912, P < 0.001). Receiver operating characteristic curves of MLS demonstrated AUC for mild and severe MS to be 0.966 and 0.995, respectively. MLS less than 8.62 mm predicted severe MS with 95.5% sensitivity and 94.7% specificity and MLS more than 12.23 mm predicted mild MS with 93.2% sensitivity and 91.4% specificity.

Conclusion

In our study, a strong correlation between planimetered MVA and MLS was found using 3D Xplane technique. 3D Xplane thus validates and standardizes MLS by excluding errors due to temporal and spatial variations which are important limitations of 2D echocardiography.