bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nanomechanics and co-transcriptional folding of Spinach and Mango
Authors: Mitra Jaba , Ha Taekjip 
Published: May 2019

AbstractRecent advances in fluorogen-binding RNA aptamers known as “light-up” aptamers provide an avenue for protein-free detection of RNA in cells. Crystallographic studies have revealed a G-Quadruplex (GQ) structure at the core of light-up aptamers such as Spinach, Mango and Corn. Detailed biophysical characterization of folding of such aptamers is still lacking despite the potential implications on their in vivo folding and function. We used single-molecule fluorescence-force spectroscopy that combines fluorescence resonance energy transfer with optical tweezers to examine mechanical responses of Spinach2, iMangoIII and MangoIV. Spinach2 unfolded in four discrete steps as force is increased to 7 pN and refolded in reciprocal steps upon force relaxation. Binding of DFHBI-1T fluorogen preserved the step-wise unfolding behavior although at slightly higher forces. In contrast, GQ core unfolding in iMangoIII and MangoIV occurred in one discrete step at forces > 10 pN and refolding occurred at lower forces showing hysteresis. Binding of the cognate fluorogen, TO1, did not significantly alter the mechanical stability of Mangos. In addition to K+, which is needed to stabilize the GQ cores, Mg2+ was needed to obtain full mechanical stability of the aptamers. Co-transcriptional folding analysis using superhelicases showed that co-transcriptional folding reduces misfolding and allows a folding pathway different from refolding. As the fundamental cellular processes like replication, transcription etc. exert pico-Newton levels of force, these aptamers may unfold in vivo and subsequently misfold.
Quantifying glioblastoma drug penetrance from experimental data
Authors: Massey Susan Christine , Urcuyo Javier , Marin Bianca Maria , Sarkaria Jann , Swanson Kristin R. 
Published: May 2019

AbstractPoor clinical trial outcomes for glioblastoma (GBM) can be attributed to multiple possible causes. GBM is heterogeneous, such that there is a chance of treatment–resistant cells coming to predominate the tumor, and due to the blood brain barrier (BBB) it is also possible that therapy was inadequately delivered to the tumor. Mathematically modeling the dynamics of therapeutic response in patient–derived xenografts (PDX) and fitting the mathematical model to bioluminescence imaging flux data, we may be able to assess the degree to which both drug resistance and drug penetrance are driving varied responses to these therapies.
Using genetic path analysis to control for pleiotropy in a Mendelian randomization study
Authors: Mann Frank D , Shabalin Andrey A , Docherty Anna R , Krueger Robert F 
Published: May 2019

AbstractBackgroundWhen a randomized experimental study is not possible, Mendelian randomization studies use genetic variants or polygenic scores as instrumental variables to control for gene-environment correlation while estimating the association between an exposure and outcome. Polygenic scores have become increasingly potent predictors of their respective phenotypes, satisfying the relevance criteria of an instrumental variable. Evidence for pleiotropy, however, casts doubt on whether the exclusion criteria of an instrumental variable is likely to hold for polygenic scores of complex phenotypes, and a number of methods have been developed to adjust for pleiotropy in Mendelian randomization studies.MethodUsing multiple polygenic scores and path analysis we implement an extension of genetic instrumental variable regression, genetic path analysis, and use it to test whether educational attainment is associated with two health-related outcomes in adulthood, body mass index and smoking initiation, while estimating and controlling for both gene-environment correlations and pleiotropy.ResultsGenetic path analysis provides compelling evidence for a complex set of gene-environment transactions that undergird the relations between educational attainment and health-related outcomes in adulthood. Importantly, results are consistent with education having a protective effect on body mass index and smoking initiation, even after controlling for gene-environment correlations and pleiotropy.ConclusionsThe proposed method is capable of addressing the exclusion criteria for a sound instrumental variable and, consequently, has the potential to help advance Mendelian randomization studies of complex phenotypes.
The roles of Amh in zebrafish gonad development and sex determination
Authors: Yan Yi-Lin , Batzel Peter , Titus Tom , Sydes Jason , Desvignes Thomas , Bremiller Ruth , Draper Bruce , Postlethwait John H. 
Published: May 2019

ABSTRACTFetal mammalian testes secrete Amh (Anti-Müllerian hormone), which inhibits female reproductive tract (Müllerian duct) development. Amh also derives from mature mammalian ovarian follicles, which marks oocyte reserve and characterizes PCOS (polycystic ovarian syndrome). Zebrafish (Danio rerio) lacks Müllerian ducts and the Amh receptor geneamhr2but, curiously, retainsamh. To discover the roles of Amh in the absence of Müllerian ducts and the ancestral receptor gene, we madeamhnull alleles in zebrafish. Results showed that normalamhprevents female-biased sex ratios. Adult maleamhmutants had enormous testes, half of which contained immature oocytes, demonstrating that Amh regulates male germ cell accumulation and inhibits oocyte development or survival. Mutant males formed sperm ducts and some produced a few offspring. Young female mutants laid a few fertile eggs, so they also had functional sex ducts. Olderamhmutants accumulated non-vitellogenic follicles in exceedingly large but sterile ovaries, showing that Amh helps control ovarian follicle maturation and proliferation. RNA-seq data partitioned 21-day post-fertilization (dpf) juveniles into two groups that each contained mutant and wild type fish. Group21-1 up-regulated ovary genes compared to Group21-2, which were likely developing as males. By 35dpf, transcriptomes distinguished males from females and, within each sex, mutants from wild types. In adult mutants, ovaries greatly under-expressed granulosa and theca genes and testes under-expressed Leydig cell genes. These results show that ancestral Amh functions included development of the gonadal soma in ovaries and testes and regulation of gamete proliferation and maturation. A major gap in our understanding is the identity of the gene encoding a zebrafish Amh receptor; we show here that the loss ofamhr2is associated with the breakpoint of a chromosome rearrangement shared among cyprinid fishes.Article SummaryAnti-Müllerian hormone (Amh) inhibits female reproductive duct development, signals oocyte reserve, and marks polycystic ovarian syndrome. Zebrafish lacks Müllerian ducts and the typical Amh receptor, questioning evolving roles of Amh. We made knockout mutations in zebrafishamh. Most mutants were female and the few males often had oocytes in their testes, showing that Amh promotes male development. Mutant reproductive ducts functioned, but testes were enormous and ovaries accumulated immature oocytes, showing that Amh regulates germ cell proliferation and maturation. Transcriptomics revealed that Amh controls development of steroid-producing gonad cells. Amh in zebrafish preserved ancestral roles despite losing Müllerian ducts and the Amh receptor.
Allele-Specific QTL Fine-Mapping with PLASMA
Authors: Wang Austin T. , Shetty Anamay , O’Connor Edward , Bell Connor , Pomerantz Mark M. , Freedman Matthew L. , Gusev Alexander 
Published: May 2019

AbstractAlthough quantitative trait locus (QTL) associations have been identified for many molecular traits such as gene expression, it remains challenging to distinguish the causal nucleotide from nearby variants. In addition to traditional QTLs by association, allele-specific (AS) QTLs are a powerful measure of cis-regulation that are largely concordant with traditional QTLs, and can be less susceptible to technical/environmental noise. However, existing asQTL analysis methods do not produce probabilities of causality for each marker, and do not take into account correlations among markers at a locus in linkage disequilibrium (LD). We introduce PLASMA (PopuLation Allele-Specific MApping), a novel, LD-aware method that integrates QTL and asQTL information to fine-map causal regulatory variants while drawing power from both the number of individuals and the number of allelic reads per individual. We demonstrate through simulations that PLASMA successfully detects causal variants over a wide range of genetic architectures. We apply PLASMA to RNA-Seq data from 524 kidney tumor samples and show that over 17 percent of loci can be fine-mapped to within 5 causal variants, compared less than 2 percent of loci using existing QTL-based fine-mapping. PLASMA furthermore achieves a greater power at 50 samples than conventional QTL fine-mapping does at over 500 samples. Overall, PLASMA achieves a 6.9-fold reduction in median 95% credible set size compared to existing QTL-based fine-mapping. We additionally apply PLASMA to H3K27AC ChIP-Seq from 28 prostate tumor/normal samples and demonstrate that PLASMA is able to prioritize markers even at small samples, with PLASMA achieving a 1.3-fold reduction in median 95% credible set sizes over existing QTL-based fine-mapping. Variants in the PLASMA credible sets for RNA-Seq and ChIP-Seq were enriched for open chromatin and chromatin looping (respectively) at a comparable or greater degree than credible variants from existing methods, while containing far fewer markers. Our results demonstrate how integrating AS activity can substantially improve the detection of causal variants from existing molecular data and at low sample size.
Centrin-anchored hydrodynamic shape changes underpin active nuclear rerouting in branched hyphae of an oomycete pathogen
Authors: Evangelisti Edouard , Shenhav Liron , Yunusov Temur , Le Naour-Vernet Marie , Rink Philipp , Schornack Sebastian 
Published: May 2019

AbstractPolyenergid fungi and oomycetes are phylogenetically distant but structurally similar. To address whether they share similar nuclear dynamics we carried out time-lapse imaging of fluorescently labelledPhytophthora palmivoranuclei. Nuclei underwent coordinated bi-directional movements during plant infection. Within hyphal networks growingin plantaor in axenic culture nuclei are either dragged passively with the cytoplasm or actively become rerouted toward nuclei-depleted hyphal sections and often display a very stretched shape. Benomyl-induced depolymerization of microtubules reduced active movements and the occurrence of stretched nuclei. A centrosome protein localized at the leading end of stretched nuclei, suggesting that like fungi astral microtubule-guided movements contribute to nuclear distribution within oomycete hyphae. The remarkable hydrodynamic shape adaptations ofPhytophthoranuclei contrast those in fungi and likely enable them to migrate over longer distances. Therefore, our work summarises mechanisms which enable a near equal nuclear distribution in an oomycete. We provide a basis for computational modelling of hydrodynamic nuclear deformation within branched tubular networks.
Theta oscillations coincide with sustained hyperpolarization in CA3 pyramidal cells, underlying decreased firing
Authors: Malezieux Meryl , Kees Ashley L. , Mulle Christophe 
Published: May 2019

SummaryBrain-state fluctuations modulate membrane potential dynamics of neurons, influencing the functional repertoire of the network. Pyramidal cells (PCs) in hippocampal CA3 are necessary for rapid memory encoding, preferentially occurring during exploratory behavior in the high-arousal theta state. However, the relationship between the membrane potential dynamics of CA3 PCs and theta has not been explored. Here, we characterize the changes in the membrane potential of PCs in relation to theta using electrophysiological recordings in awake mice. During theta, most PCs behave in a stereotypical manner, consistently hyperpolarizing time-locked to the duration of theta. Additionally, PCs display lower membrane potential variance and reduced firing rate. In contrast, during large irregular activity, a low-arousal state, PCs show heterogeneous changes in membrane potential. This suggests coordinated hyperpolarization of PCs during theta, possibly caused by increased inhibition. This could lead to higher signal-to-noise ratio in the small population of PCs active during theta as observed in ensemble recordings.
Prevalence of coronary artery disease risk factors among fire-fighters in Cape Town, South Africa
Authors: Achmat Ghaleelullah , November Rucia V. , Leach Lloyd L. 
Published: May 2019

AbstractBackgroundCardiovascular disease is a major cause of morbidity and on-duty mortality among fire-fighters. This study investigated the prevalence of coronary artery disease (CAD) risk factors among firefighters in Cape Town, South Africa.MethodsA quantitative, cross-sectional and descriptive study design was used. A convenient sample of 219 male fire-fighters with mean age 37.85±9.80 years was recruited. Eight major CAD risk factors were measured. SPSS (ver. 23) was used with the Pearson correlation and Kruskall-Wallis H test with the Mann Whitney test post hoc and a Bonferroni correction.ResultsThe significance level set at p<0.05. Most fire-fighters (65.29%) were stratified as moderate risk for CAD, with 21.00% as low risk, and 14.15% as high risk. A sedentary lifestyle was the most prevalent CAD risk factor (51.14%), followed by obesity (45.90%). and cigarette smoking (38.30%). Statistically significant correlations were found between waist circumference and body mass index (BMI) (r=0.711; p<0.01), hip circumference and BMI (r=0.673; p<0.01), waist circumference and waist-hip ratio (WHR) (r=0.665; p<0.01), and BMI and body mass (r=0.512; p<0.01).ConclusionThe majority of fire-fighters presented with multiple modifiable CAD risk factors. Fire departments should focus on promoting education on CAD to reduce the risk of fire-fighters developing heart disease.
Presto scales Wilcoxon and auROC analyses to millions of observations
Authors: Korsunsky Ilya , Nathan Aparna , Millard Nghia , Raychaudhuri Soumya 
Published: May 2019

AbstractSummaryThe related Wilcoxon rank sum test and area under the receiver operator curve are ubiquitous in high dimensional biological data analysis. Current implementations do not scale readily to the increasingly large datasets generated by novel high-throughput technologies, such as single cell RNAseq. We introduce a simple and scalable implementation of both analyses, available through the R package Presto. Presto scales to big datasets, with functions optimized for both dense and sparse matrices. On a sparse dataset of 1 million observations, 10 groups, and 1,000 features, Presto performed both rank-sum and auROC analyses in only 17 seconds, compared to 6.4 hours with base R functions. Presto also includes functions to seamlessly integrate with the Seurat single cell analysis pipeline and the Bioconductor SingleCellExperiment class. Presto enables the use of robust classical analyses on big data with a simple interface and optimized implementation.Availability and ImplementationPresto is available as an R package at https://github.com/immunogenomics/presto.Contactsoumya@broadinstitute.orgSupplementary InformationVignettes are available with the Presto package.
Identification of genes required for apical protein trafficking in Drosophila photoreceptor cells
Authors: Laffafian Azadeh , Tepass Ulrich 
Published: May 2019

AbstractDrosophila photoreceptor cells (PRCs) are highly polarized epithelial cells. Their apical membrane is further subdivided into the stalk membrane and the light-sensing rhabdomere. The photo-pigment Rhodopsin1 (Rh1) localizes to the rhabdomere, whereas the apical determinant Crumbs (Crb) is enriched at the stalk membrane. The proteoglycan Eyes shut (Eys) is secreted through the apical membrane into an inter-rhabdomeral space. Rh1, Crb, and Eys are essential for PRC development, normal vision, and PRC survival. Human orthologs of all three proteins have been linked to retinal degenerative diseases. Here, we describe an RNAi-based screen examining the importance of approximately 240 trafficking-related genes in apical trafficking of Eys, Rh1, and Crb. We found 28 genes that have an effect on the localization and/or levels of these apical proteins and analyzed several factors in more detail. We show that the Arf GEF protein Sec71 is required for biosynthetic traffic of both apical and basolateral proteins, that the exocyst complex and the microtubule-based motor proteins dynein and kinesin promote the secretion of Eys and Rh1, and that Syntaxin 7/Avalanche controls the endocytosis of Rh1, Eys, and Crb.Article summeryPhotoreceptor cells (PRCs) rely on polarized vesicle trafficking to deliver key secreted and transmembrane proteins to their correct locations. Failure to do so causes defects in PRC development, function, and survival leading to retinal disease. Using the fruit fly Drosophila as a model we have identified 28 genes that are required for the trafficking of the three apical proteins Rhodopsin 1, Crumbs, and Eyes Shut. Human homologs of all three genes are associated with retinal degeneration. We characterized several genes to reveal novel mechanisms of vesicle trafficking in photoreceptor cells at different points in the biosynthetic or endocytotic pathways.
A novel dimerization module in Gemin5 is critical for protein recruitment and translation control
Authors: Moreno-Morcillo María , Francisco-Velilla Rosario , Embarc-Buh Azman , Fernández-Chamorro Javier , Ramón-Maiques Santiago , Martínez-Salas Encarnación 
Published: May 2019

SUMMARYThe versatile multifunctional protein Gemin5 is involved in small nuclear ribonucleoproteins (snRNPs) assembly, ribosome binding, and translation control through distinct domains located at the protein ends. However, the structure and function of the central moiety of Gemin5 remained unknown. Here, we solved the crystal structure of an extended tetratricopeptide (TPR)-like domain in the middle region of Gemin5, demonstrating that it self-assembles into a canoe-shaped dimer. Mass spectrometry analysis shows that this dimerization module is functional in living cells and drives the interaction between p85, a viral-induced Gemin5 cleavage fragment, and the full-length Gemin5. In contrast, disruption of the dimerization surface by a point mutation in the TPR-like domain prevents this interaction and abrogates the translation enhancement induced by p85. The structural characterization of this unprecedented dimerization domain provides the mechanistic basis for a role of the middle region of Gemin5 as a key mediator of protein-protein interactions.HIGHLIGHTS-The crystal structure of a central region of Gemin5 reveals a novel dimerization domain-The proteolytic product of Gemin5 (p85) recruits the endogenous protein through the dimerization module-The dimerization capability of Gemin5 determines the factors recruited in human cells-Disruption of the dimerization domain impairs p85 ability to stimulate translationGraphical abstract
Technological disruptions in services: lessons from tourism and hospitality
Authors: Buhalis Dimitrios , Harwood Tracy , Bogicevic Vanja , Viglia Giampaolo , Beldona Srikanth , Hofacker Charles 
Published: May 2019

Purpose
Technological disruptions such as the Internet of Things and autonomous devices, enhanced analytical capabilities (artificial intelligence) and rich media (virtual and augmented reality) are creating smart environments that are transforming industry structures, processes and practices. The purpose of this paper is to explore critical technological advancements using a value co-creation lens to provide insights into service innovations that impact ecosystems. The paper provides examples from tourism and hospitality industries as an information dependent service management context.

Design/methodology/approach
The research synthesizes prevailing theories of co-creation, service ecosystems, networks and technology disruption with emerging technological developments.

Findings
Findings highlight the need for research into service innovations in the tourism and hospitality sector at both macro-market and micro-firm levels, emanating from the rapid and radical nature of technological advancements. Specifically, the paper identifies three areas of likely future disruption in service experiences that may benefit from immediate attention: extra-sensory experiences, hyper-personalized experiences and beyond-automation experiences.

Research limitations/implications
Tourism and hospitality services prevail under varying levels of infrastructure, organization and cultural constraints. This paper provides an overview of potential disruptions and developments and does not delve into individual destination types and settings. This will require future work that conceptualizes and examines how stakeholders may adapt within specific contexts.

Social implications
Technological disruptions impact all facets of life. A comprehensive picture of developments here provides policymakers with nuanced perspectives to better prepare for impending change.

Originality/value
Guest experiences in tourism and hospitality by definition take place in hostile environments that are outside the safety and familiarity of one’s own surroundings. The emergence of smart environments will redefine how customers navigate their experiences. At a conceptual level, this requires a complete rethink of how stakeholders should leverage technologies, engage and reengineer services to remain competitive. The paper illustrates how technology disrupts industry structures and stimulates value co-creation at the micro and macro-societal level.
Saxagliptin alters bile acid profiles and yields metabolic benefits in drug‐naïve overweight or obese type 2 diabetes patient
Authors: Li Wen , Liu Ruixin , Li Xuelin , Tao Bei , Zhai Nan , Wang Xiaolin , Li Qi , Zhang Yifei , Gu Weiqiong , Wang Weiqing , Ning Guang 
Published: May 2019

AbstractBackgroundThe aim of the present study was to investigate the metabolic benefits of saxagliptin and its effects on serum bile acids (BAs) in normal weight and overweight/obese drug‐naïve type 2 diabetes (T2D) patients.MethodsIn all, 282 drug‐naïve T2D patients (123 normal weight [NW], with body mass index [BMI] between 19.0 and <25.0 kg/m2; 159 overweight/obese [OW/OB], with BMI ≥25.0 kg/m2) were enrolled in the study and treated with saxagliptin 5 mg daily for 24 weeks. Serum BAs were assayed by liquid chromatography with tandem mass spectrometry.ResultsAt 24 weeks, HbA1c was significantly reduced in both groups, but the HbA1c levels were lower in the OW/OB than NW group. Moreover, significant decreases were seen at 24 weeks in C‐reactive protein (CRP), aspartate aminotransferase, alanine aminotransferase, waist circumference, and systolic blood pressure in the OW/OB group. Interestingly, cholic acid, glycocholic acid, glycochenodeoxycholic acid, glycodeoxycholic acid (GDCA), and glycoursodeoxycholic acid (GUDCA) were increased in both groups after treatment, whereas chenodeoxycholic acid and deoxycholic acid (DCA) were specifically increased in the OW/OB group. Increased DCA and GDCA concentrations were significantly associated with decreased HbA1c or fasting blood glucose and CRP levels, whereas increased GDCA and GUDCA concentrations were associated with decreased waist circumference in the OW/OB group during treatment. In the NW group, increased GUDCA concentrations were significantly associated with a decrease in HbA1c.ConclusionsType 2 diabetes patients with OW/OB exhibited greater improvement in glycemic control and additional metabolic benefits after saxagliptin treatment. Saxagliptin significantly increased the BA pool, and DCA and GDCA were associated with metabolic improvements in OW/OB T2D patients.