bluuebunny/crossref_metadata_2025_split huggingface dataset:
Large-scale transcriptome-wide association study identifies new prostate cancer risk regions
Authors: Mancuso Nicholas , Gayther Simon , Gusev Alexander , Zheng Wei , Penney Kathryn L. , Kote-Jarai Zsofia , Eeles Rosalind , Freedman Matthew , Haiman Christopher , Pasaniuc Bogdan 
Published: June 2018

AbstractAlthough genome-wide association studies (GWAS) for prostate cancer (PrCa) have identified more than 100 risk regions, most of the risk genes at these regions remain largely unknown. Here, we integrate the largest PrCa GWAS (N=142,392) with gene expression measured in 45 tissues (N=4,458), including normal and tumor prostate, to perform a multi-tissue transcriptomewide association study (TWAS) for PrCa. We identify 235 genes at 87 independent 1Mb regions associated with PrCa risk, 9 of which are regions with no genome-wide significant SNP within 2Mb. 24 genes are significant in TWAS only for alternative splicing models in prostate tumor thus supporting the hypothesis of splicing driving risk for continued oncogenesis. Finally, we use a Bayesian probabilistic approach to estimate credible sets of genes containing the causal gene at pre-defined level; this reduced the list of 235 associations to 120 genes in the 90% credible set. Overall, our findings highlight the power of integrating expression with PrCa GWAS to identify novel risk loci and prioritize putative causal genes at known risk loci.
Downregulation of the central noradrenergic system by Toxoplasma gondii infection
Authors: Alsaady Isra , Tedford Ellen , Alsaad Mohammad , Bristow Greg , Kohli Shivali , Murray Matthew , Reeves Matthew , Vijayabaskar M.S. , Clapcote Steven J. , Wastling Jonathan , McConkey Glenn A. 
Published: June 2018

AbstractThe parasitic protozoan Toxoplasma gondii becomes encysted in brain and muscle tissue during chronic infection, a stage that was previously thought to be dormant but has been found to be active and associated with physiological effects in the host. Dysregulation of catecholamines in the CNS has previously been observed in chronically-infected animals. In the study described here, the noradrenergic system was suppressed with decreased levels of norepinephrine in brains of infected animals and in infected neuronal cells in vitro. Expression of dopamine β-hydroxylase (DBH), essential for synthesis of norepinephrine from dopamine, was the most differentially-expressed gene in infections in vitro and was down-regulated in infected brain tissue, particularly in the prefrontal cortex and dorsal locus coeruleus/pons region. The down-regulated DBH expression in infected rat catecholaminergic and human neuronal cells corresponded with decreased norepinephrine and increased dopamine. As the DBH suppression was observed in vitro, this effect is not caused by neuroinflammation. Silencing of DBH expression was specific for T. gondii infection and was not observed with CMV infection. The noradrenergic-linked behaviors of sociability and arousal were altered in chronically-infected animals, with a high correlation between DBH expression and infection intensity. These findings together provide a plausible mechanism to explain prior discrepancies in changes to CNS neurotransmitters levels with infection. The suppression of norepinephrine synthesis observed here may, in part, explain behavioural effects of infection, associations with mental illness, and neurological consequences of infection such as the loss of coordination and motor impairments associated with human toxoplasmosis.
Recombination between co-infecting herpesviruses occurs where replication compartments coalesce
Authors: Tomer Enosh , Cohen Efrat M. , Drayman Nir , Afriat Amichay , Weitzman Matthew D. , Zaritsky Assaf , Kobiler Oren 
Published: June 2018

AbstractHomologous recombination (HR) is considered a major driving force of evolution since it generates and expands genetic diversity. Evidence of HR between co-infecting herpesvirus DNA genomes can be found frequently, bothin vitroand in clinical isolates. Each herpes simplex virus type 1 (HSV-1) replication compartment (RC) derives from a single incoming genome and maintains a specific territory within the nucleus. This raises intriguing questions about where and when co-infecting viral genomes interact. To study the spatiotemporal requirements for inter-genomic recombination, we developed an assay with dual-color fluorescencein situhybridization which enables detection of HR between different pairs of co-infecting HSV-1 genomes. Our results revealed that when viral RCs enlarge towards each other, there is detectable overlap between territories of genomes from each virus. Infection with paired viruses that allow visualization of HR correlates with increased overlap of RCs. Further, inhibition of RC movement reduces the rate of HR events among co-infecting viruses. Taken together, these findings suggest that inter-genomic HR events take place during replication of HSV-1 DNA and are mainly confined to the periphery of RCs when they coalesce. Our observations have implications on understanding the recombination restrictions of other DNA viruses and cellular DNA.
N1 component of event-related potential evoked by simple composite figures in the lateral occipital cortex
Authors: Uchiyama Hiroyuki , Iwashita Shoichi , Mitsui Takashi 
Published: June 2018

AbstractSince Sugawara and Morotomi (1991) first reported that illusory contour (IC) figures, or Kanizsa square inducers (KSI), evoked a significant N1 component, the first visually evoked negative component of event-related potentials (ERPs), in the lateral occipital cortex (LO), many ERP studies have confirmed their finding, and these studies showed that Kanizsa-type inducers alone evoked a relatively large N1 in the LO, even when the inducers are oriented to not form an IC (see Murray and Herrmann, 2013). In the present study, we used non-IC simple composite figures composed of several elementary shapes (e.g., triplet squares or quadruplet circles) as visual stimuli, and found that the composite figures evoked a significant N1 comparable to that evoked by KSI in the anterior LO, whereas solitary elementary shapes did not. Thus, it appears that the LO is activated by not only an IC but also the compositeness of figures, which implies that the LO might analyze the geometrical relationships among multiple 2D shapes that compose a single composite figure.
Single cell functional genomics reveals the importance of mitochondria in cell-to-cell variation in proliferation, drug resistance and mutation outcome
Authors: Dhar Riddhiman , Missarova Alsu M , Lehner Ben , Carey Lucas B 
Published: June 2018

AbstractMutations frequently have outcomes that differ across individuals, even when these individuals are genetically identical and share a common environment. Moreover, individual microbial and mammalian cells can vary substantially in their proliferation rates, stress tolerance, and drug resistance, with important implications for the treatment of infections and cancer. To investigate the causes of cell-to-cell variation in proliferation, we developed a high-throughput automated microscopy assay and used it to quantify the impact of deleting >1,500 genes in yeast. Mutations affecting mitochondria were particularly variable in their outcome. In both mutant and wild-type cells mitochondria state – but not content – varied substantially across individual cells and predicted cell-to-cell variation in proliferation, mutation outcome, stress tolerance, and resistance to a clinically used anti-fungal drug. These results suggest an important role for cell-to-cell variation in the state of an organelle in single cell phenotypic variation.
Glucose signaling is important for nutrient adaptation during differentiation of pleomorphic African trypanosomes
Authors: Qiu Yijian , Milanes Jillian E. , Jones Jessica A. , Noorai Rooksana E. , Shankar Vijay , Morris James C. 
Published: June 2018

AbstractThe African trypanosome has evolved mechanisms to adapt to changes in nutrient availability that occur during its lifecycle. During transition from mammalian blood to insect vector gut, parasites experience a rapid reduction in environmental glucose. Here we describe how pleomorphic parasites respond to glucose depletion with a focus on parasite changes in energy metabolism and growth. Long slender bloodstream form parasites are rapidly killed as glucose concentrations fall, while the short stumpy bloodstream form parasites persist to differentiate into the insect stage procyclic form parasite. The rate of differentiation was slower than that triggered by other cues but reached physiological rates when combined with cold shock. Both differentiation and growth of resulting procyclic form parasites were inhibited by glucose and its non-metabolizable analogs in a concentration dependent manner. Procyclic form parasites differentiated from short stumpy form parasites in glucose depleted medium significantly upregulated gene expression of amino acid metabolic pathway components when compared to procyclic forms generated by cis-aconitate treatment. Additionally, growth of these parasite was inhibited by the presence of either glucose or 6-deoxyglucose. In summary, glucose transitions from the primary metabolite of the blood stage infection to a negative regulator of cell development and growth in the insect vector, suggesting that the hexose is not only a key metabolic agent but is also an important signaling molecule.Author SummaryAs the African trypanosome, Trypanosoma brucei, completes its lifecycle, it encounters many different environments. Adaptation to these environments includes modulation of metabolic pathways to parallel the availability of nutrients. Here, we describe how the blood-dwelling lifecycle stages of the African trypanosome, which consume glucose to meet their nutritional needs, respond differently to culture in the near absence of glucose. The proliferative long slender parasites rapidly die, while the non-dividing short stumpy remains viable and undergoes differentiation to the next lifecycle stage, the procyclic form parasite. Interestingly a sugar analog that cannot be used as an energy source inhibited the process. Furthermore, the growth of procyclic form parasite that resulted from the event was inhibited by glucose, a behavior that is similar to that of parasites isolated from tsetse flies. Our findings suggest that glucose sensing serves as an important modulator of nutrient adaptation in the parasite.
Sensitive periods for white matter plasticity and reading intervention
Authors: Yeatman Jason D. , Huber Elizabeth 
Published: June 2018

AbstractAs a child matures, some brain circuits stabilize while others remain plastic. However, the literature on maturational changes in the brain’s capacity for experience-dependent plasticity is primarily based on experiments in animals that mature over dramatically different time-scales than humans. Moreover, while principles of plasticity for sensory and motor systems might be conserved across species, the myriad of late-developing and uniquely human cognitive functions such as literacy cannot be studied with animal models. Here we use an intensive reading intervention program, in combination with longitudinal diffusion MRI measurements in school-aged children with dyslexia, to investigate the sensitive period for white matter plasticity and literacy learning. We find that the intervention induces large-scale changes in white matter diffusion properties, and improvements in reading scores, but that the magnitude and time-course of plasticity does not depend on the subject’s age. Thus, we conclude that, for the intensive, one-on-one reading intervention program employed here, if a sensitive period exists, it does not end before middle school.
Resilience of Atlantic Slippersnail Crepidula fornicata Larvae in the Face of Severe Coastal Acidification
Authors: Kriefall Nicola G. , Pechenik Jan A. , Pires Anthony , Davies Sarah W. 
Published: June 2018

AbstractGlobally, average oceanic pH is dropping, and it will continue to decline into the foreseeable future. This ocean acidification (OA) will exacerbate the natural fluctuations in pH that nearshore ecosystems currently experience daily, potentially pushing marine organisms to their physiological limits. Adults of Crepidula fornicata (the Atlantic slippersnail) have proven remarkably resilient to many environmental changes, which is perhaps not surprising considering that they are common intertidally, have a geographically large native range, and have been extremely successful at invading coastal water in many other parts of the world. However, the larvae of C. fornicata have been shown to be somewhat more vulnerable than adults to the effects of reduced pH. Research to date has focused on the physiological impacts of OA on C. fornicata larvae; few studies have explored shifts in gene expression resulting from changes in pH. In the present study, we examined the response of young (4- day old) C. fornicata larvae to two extreme OA treatments (pH 7.5 and 7.6) relative to pH 8.0, documenting both phenotypic and genome-wide gene expression responses. We found that rearing larvae at reduced pH had subtle influences on gene expression, predominantly involving downregulation of genes related to growth and metabolism, accompanied by significantly reduced shell growth rates only for larvae reared at pH 7.5. Additionally, 10-day old larvae that had been reared at the two lower pH levels were far less likely to metamorphose within six hours when exposed to inducer. However, all larvae eventually reached similarly high levels of metamorphosis 24 hours after settlement induction. Finally, there were no observed impacts of OA on larval mortality. Taken together, our results indicate that far future OA levels have observable, but not severe, impacts on C. fornicata larvae, which is consistent with the resilience of this invasive snail across rapidly changing nearshore ecosystems. We propose that future work should delve further into the physiological and transcriptomic responses of all life history stages to gain a more comprehensive understanding of how OA impacts the intertidal gastropod C. fornicata.
A combinatorial extracellular code tunes the intracellular signaling network activity to distinct cellular responses
Authors: Kuchenov Dmitry , Ziebell Frederik , Salopiata Florian , Citir Mevlut , Klingmueller Ursula , Huber Wolfgang , Schultz Carsten 
Published: June 2018

SUMMARYCells constantly survey a complex set of inputs that is processed by the intracellular signaling network, but little is known of how cells integrate input information from more than one cue. We employed a FRET biosensor-based imaging platform to study the effect of combinatorial growth factor levels on the signaling network in human cells. We found that pairwise stimuli caused distinct concentration- and ratio-dependent signaling states through signaling signatures such as antagonism, additivity and synergy. The unique signaling states correlated with differential gene expression and non-additive transcription patterns. We further elucidated how a signal-rich environment can fine-tune the signaling network and adjust physiological outcomes, by kinase and phosphatase activity profiling. We describe how complex extracellular conditions affect phospho-turnover and the basal phosphorylation status. Thus, we provide mechanistic insights into cellular processing of multiple cues and explain part of the complexity of cellular adaptation to changes in the extracellular environment.
Evaluating predictive biomarkers for a binary outcome with linear versus logistic regression – Practical recommendations for the choice of the model
Authors: Gola Damian , Heßler Nicole , Schwaninger Markus , Ziegler Andreas , König Inke R. 
Published: June 2018

AbstractA predictive biomarker can forecast whether a patient benefits from a specific treatment under study. To establish predictiveness of a biomarker, a statistical interaction between the biomarker status and the treatment group concerning the clinical outcome needs to be shown. In clinical trials looking at a binary outcome, linear or logistic regression models may be used to evaluate the interaction, but the effects in the two models are different and differently interpreted. Specifically, the effects are estimated as absolute risk reductions (ARRs) and odds ratios (ORs) in the linear and logistic model, thus measuring the effect on an additive and multiplicative scale, respectively.We derived the relationship between the effects of the linear and the logistic regression model allowing for translations between the effect estimates between both models. In addition, we performed a comprehensive simulation study to compare the power of the two models under a variety of scenarios in different study designs. In general, the differences in power to detect interaction were minor, and visible differences were detected in rather unrealistic scenarios of effect size combinations and were usually in favor of the logistic model.Based on our results and theoretical considerations, we recommend to 1) estimate logistic regression models because of their statistical properties, 2) test for interaction effects and 3) calculate and report both ARRs and ORs from these using the formulae provided.
Measures of Possible Allostatic Load in Comorbid Cocaine and Alcohol Use Disorder: Brain White Matter Integrity, Telomere Length, and Anti-Saccade Performance
Authors: Tannous Jonika , Mwangi Benson , Hasan Khader M. , Narayana Ponnada A. , Steinberg Joel L. , Walss-Bass Consuelo , Moeller F. Gerard , Schmitz Joy M. , Lane Scott D. 
Published: June 2018

AbstractChronic cocaine and alcohol use impart significant stress on biological and cognitive systems, resulting in changes consistent with an allostatic load model of neurocognitive impairment. The present study measured potential markers of allostatic load in individuals with comorbid cocaine/alcohol use disorders (CUD/AUD) and control subjects. Measures of brain white matter (WM) integrity, telomere length, and impulsivity/attentional bias were obtained. WM integrity (CUD/AUD only) was indexed by diffusion tensor imaging metrics, including radial diffusivity (RD) and fractional anisotropy (FA). Telomere length was indexed by T/S ratio. Impulsivity and attentional bias to drug cues were measured via eye-tracking, and were also modeled using the Hierarchical Diffusion Drift Model (HDDM). Average whole-brain RD and FA were associated with years of cocaine use (R2= 0.56 and 0.51, both p < .005) but not years of alcohol use. CUD/AUD subjects showed more anti-saccade errors (p < .01), greater attentional bias scores (p < .001), and higher HDDM drift rates on cocaine-cue trials (Bayesian probability CUD/AUD > control = p > 0.99). Telomere length was shorter in CUD/AUD, but the difference was not statistically significant. Within the CUD/AUD group, exploratory regression using an elastic-net model determined that more years of cocaine use, older age, larger HDDM drift rate differences and shorter telomere length were all predictive of white matter integrity as measured by RD (model R2= 0.79). Collectively, the results provide modest support linking CUD/AUD to putative markers of allostatic load.
TIAM-1/GEF can shape somatosensory dendrites independently of its GEF activity by regulating F-actin localization
Authors: Tang Leo T.H. , Díaz-Balzac Carlos A. , Rahman Maisha , Ramirez-Suarez Nelson J. , Salzberg Yehuda , Lázaro-Peñal María I. , Bülow Hannes E. 
Published: June 2018

SummaryDevelopment of dendritic arbors is crucial for nervous system assembly, but the intracellular mechanisms that govern these processes remain incompletely understood. Here we show that the complex dendritic trees of PVD somatosensory neurons inCaenorhabditis elegansare patterned by distinct pathways downstream of the DMA-1 leucine rich transmembrane (LRR-TM) receptor. The guanine nucleotide exchange factortiam-1/GEFandact-4/Actinfunction with the DMA-1/LRR-TM to pattern 4° higher order branches by localizing F-actin to the distal ends of developing dendrites. Biochemical experiments show that DMA-1/LRR-TM is part of a biochemical complex with TIAM-1/GEF and ACT-4/Actin. Surprisingly, TIAM-1/GEF appears to function independently of Rac1 guanine nucleotide exchange factor activity. Additionally, another pathway dependent on HPO-30/Claudin and TIAM-1/GEF is required for formation of 2° and 3° branches. Collectively, our experiments suggest that the DMA-1/LRR-TM receptor on PVD dendrites may control aspects of dendrite patterning by directly modulating F-actin dynamics, independently of TIAM-1/GEF enzymatic activity.
Investor relations – a systematic literature review
Authors: Hoffmann Christian Pieter , Tietz Sandra , Hammann Kerstin 
Published: June 2018

PurposeThe purpose of this paper is to present a comprehensive, interdisciplinary review of international investor relations (IR) research published since 1990. It highlights the development of IR research, its disciplinary foundations and key areas of inquiry. Research is shown to reflect the rising importance of IR as a corporate communications function, its interdisciplinary character, and the recognition of its contribution to strategic management.Design/methodology/approachFindings are based on an interdisciplinary systematic literature review focusing on peer-reviewed journal articles published in English since 1990.FindingsThe authors differentiate five strands of research focusing on the organization, strategy, instruments, content and effects of IR. IR research is shown to have strong roots in the business and management, accounting and communications literature. The authors document a rising interest in the topic and a steady development beyond descriptive accounts of the function to distinctive lines of inquiry. The authors summarize the state of the field and derive a number of suggestions for future research.Research limitations/implicationsThe review is limited in scope to the applied research process, including the choice of keywords, databases as well as peer-reviewed journal publications published in English since 1990.Originality/valueThis study contributes to the necessary structuration and consolidation of the emergent field of IR research by identify salient perspectives and common subfields. It provides both a comprehensive overview of the state of research and specific suggestions for future endeavors.
The significance of further education for black males
Authors: Peart Sheine 
Published: June 2018

Purpose
The purpose of this paper is to explore the lived educational realities of black male students studying in further education (FE) colleges to understand how these experiences compare to their experiences of statutory education. It describes the way in which students perceived and received education in both sectors and highlights the similarities and variations between the two.

Design/methodology/approach
Ethnographic methods including focus groups, individual interviews and naturalistic observations were used to investigate black male students’ perceptions of FE. These accounts were compared to their memories of compulsory schooling experiences to establish differences and similarities between sectors and to determine which educational approaches black male students identified as most useful.

Findings
The research established black males perceived there were significant differences between the two sectors and these differences had impacted on their ability to learn. These findings provide a useful reference point for educators seeking to evaluate their organisation’s education provision for black male students.

Social implications
This paper provides suggestions on what sorts of educational opportunities are appropriate and accessible for black males and which approaches help to support their educational achievement.

Originality/value
There are little research data which specifically discuss black male students’ experience of the FE sector. This paper will help teachers and managers at all organisational levels in FE (and in schools) review their provision and consider adopting approaches that may help to enhance black students’ educational journeys.