bluuebunny/crossref_metadata_2025 huggingface dataset:
Effector-dependent modulation of working memory maintenance in posterior parietal cortex
Authors: Pilacinski Artur , Höller-Wallscheid Melanie S. , Lindner Axel
Published: May 2019

Working memory (WM) is the key process linking perception to action. Several lines of research have, accordingly, highlighted WM’s engagement in sensori-motor associations between retrospective stimuli and future behavior. Using human fMRI we investigated whether prior information about the effector used to report in a WM task would have an impact on the way the same sensory stimulus is maintained in memory – even if a behavioral response could not be readily planned. Specifically, we focused on WM-related activity in posterior parietal cortex during the maintenance of spatial items for a subsequent match-to-sample comparison, which was reported either with a verbal or with a manual response. We expected WM activity to be higher for manual response trials, because of posterior parietal cortex’s engagement in both spatial WM and hand movement preparation. Increased fMRI activity for manual response trials in bilateral anterior intraparietal sulcus confirmed our expectations. These results imply that the maintenance of sensory material in WM is optimized for motor context of the upcoming behavioral responses.
Localized semi-nonnegative matrix factorization (LocaNMF) of widefield calcium imaging data
Authors: Saxena Shreya , Kinsella Ian , Musall Simon , Kim Sharon H. , Meszaros Jozsef , Thibodeaux David N. , Kim Carla , Cunningham John , Hillman Elizabeth , Churchland Anne , Paninski Liam
Published: May 2019

Widefield calcium imaging enables recording of large-scale neural activity across the mouse dorsal cortex. In order to examine the relationship of these neural signals to the resulting behavior, it is critical to demix the recordings into meaningful spatial and temporal components that can be mapped onto well-defined brain regions. However, no current tools satisfactorily extract the activity of the different brain regions in individual mice in a data-driven manner, while taking into account mouse-specific and preparation-specific differences. Here, we introduce Localized semi-Nonnegative Matrix Factorization (LocaNMF), a method that efficiently decomposes widefield video data and allows us to directly compare activity across multiple mice by outputting mouse-specific localized functional regions that are significantly more interpretable than more traditional decomposition techniques. Moreover, it provides a natural subspace to directly compare correlation maps and neural dynamics across different behaviors, mice, and experimental conditions, and enables identification of task- and movement-related brain regions.
Nanomechanics and co-transcriptional folding of Spinach and Mango
Authors: Mitra Jaba , Ha Taekjip
Published: May 2019

Recent 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

Poor 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

Background

When 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.

Method

Using 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.

Results

Genetic 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.

Conclusions

The 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

Fetal 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 Summary

Anti-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

Although 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.
Error-speed correlations in biopolymer synthesis
Authors: Chiuchiú Davide , Tu Yuhai , Pigolotti Simone
Published: May 2019

Synthesis of biopolymers such as DNA, RNA, and proteins are biophysical processes aided by enzymes. Performance of these enzymes is usually characterized in terms of their average error rate and speed. However, because of thermal fluctuations in these single-molecule processes, both error and speed are inherently stochastic quantities. In this paper, we study fluctuations of error and speed in biopolymer synthesis and show that they are in general correlated. This means that, under equal conditions, polymers that are synthesized faster due to a fluctuation tend to have either better or worse errors than the average. The error-correction mechanism implemented by the enzyme determines which of the two cases holds. For example, discrimination in the forward reaction rates tends to grant smaller errors to polymers with faster synthesis. The opposite occurs for discrimination in monomer rejection rates. Our results provide an experimentally feasible way to identify error-correction mechanisms by measuring the error-speed correlations.
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

Polyenergid 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

Brain-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

Background

Cardiovascular 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.

Methods

A 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.

Results

The 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).

Conclusion

The 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

The 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 Implementation

Presto is available as an R package at https://github.com/immunogenomics/presto.

Contact

soumya@broadinstitute.org

Supplementary Information

Vignettes 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

Drosophila 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 summery

Photoreceptor 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

The 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

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The crystal structure of a central region of Gemin5 reveals a novel dimerization domain

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The proteolytic product of Gemin5 (p85) recruits the endogenous protein through the dimerization module

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The dimerization capability of Gemin5 determines the factors recruited in human cells

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Disruption of the dimerization domain impairs p85 ability to stimulate translation

Graphical abstract
Medical contrast media as possible tools for SAXS contrast variation
Authors: Gabel Frank , Engilberge Sylvain , Pérez Javier , Girard Eric
Published: May 2019

Small-angle X-ray scattering (SAXS) is increasingly used to extract structural information from a multitude of soft-matter and biological systems in aqueous solution, including polymers, detergents, lipids, colloids, proteins and RNA/DNA. When SAXS data are recorded at multiple contrasts, i.e. at different electron densities of the solvent, the internal electron-density profile of solubilized molecular systems can be probed. However, contrast-variation SAXS has been limited by the range of electron densities available by conventional agents such as sugars, glycerol and salt, and by the fact that many soft-matter and biological systems are modified in their presence. Here we present a pioneering SAXS contrast-variation study on DDM (n-dodecyl-β-D-maltopyranoside) micelles by using two highly electron-rich contrast agents from biomedical imaging which belong to the families of gadolinium-based and iodinated molecules. The two agents, Gd-HPDO3A and iohexol, were allowed to attain modifications of the solvent electron density that are 50 to 100% higher than those obtained for sucrose, and are located between the electron densities of proteins and RNA/DNA. In the case of Gd-HPDO3A, an analysis of the internal micellar structure was possible and compared with results obtained with sucrose. In conclusion, medical contrast agents represent a promising class of molecules for SAXS contrast-variation experiments with potential applications for numerous soft-matter and biological systems, including membrane proteins and protein–RNA/DNA complexes.
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

Background

The 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.

Methods

In 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.

Results

At 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.

Conclusions

Type 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.
Chronic Intermittent Ethanol and Acute Stress Similarly Modulate BNST CRF Neuron Activity via Noradrenergic Signaling
Authors: Snyder Angela E. , Salimando Gregory J. , Winder Danny G. , Silberman Yuval
Published: May 2019

Background

Relapse is a critical barrier to effective long‐term treatment of alcoholism, and stress is often cited as a key trigger to relapse. Numerous studies suggest that stress‐induced reinstatement to drug‐seeking behaviors is mediated by norepinephrine (NE) and corticotropin‐releasing factor (CRF) signaling interactions in the bed nucleus of the stria terminalis (BNST), a brain region critical to many behavioral and physiologic responses to stressors. Here, we sought to directly examine the effects of NE on BNST CRF neuron activity and determine whether these effects may be modulated by chronic intermittent EtOH (CIE) exposure or a single restraint stress.

Methods

Adult male CRF‐tomato reporter mice were treatment‐naïve, or either exposed to CIE for 2 weeks or to a single 1‐hour restraint stress. Effects of application of exogenous NE on BNST CRF neuron activity were assessed via whole‐cell patch‐clamp electrophysiological techniques.

Results

We found that NE depolarized BNST CRF neurons in naïve mice in a β‐adrenergic receptor (AR)–dependent mechanism. CRF neurons from CIE‐ or stress‐exposed mice had significantly elevated basal resting membrane potential compared to naïve mice. Furthermore, CIE and stress individually disrupted the ability of NE to depolarize CRF neurons, suggesting that both stress and CIE utilize β‐AR signaling to modulate BNST CRF neurons. Neither stress nor CIE altered the ability of exogenous NE to inhibit evoked glutamatergic transmission onto BNST CRF neurons as shown in naïve mice, a mechanism previously shown to be α‐AR–dependent.

Conclusions

Altogether, these findings suggest that stress and CIE interact with β‐AR signaling to modulate BNST CRF neuron activity, potentially disrupting the α/β‐AR balance of BNST CRF neuronal excitability. Restoration of α/β‐AR balance may lead to novel therapies for the alleviation of many stress‐related disorders.
Responses of insectivorous bats and nocturnal insects to local changes in street light technology
Authors: Haddock Joanna K. , Threlfall Caragh G. , Law Bradley , Hochuli Dieter F.
Published: May 2019

Artificial light at night is a pervasive anthropogenic stressor for biodiversity. Many fast‐flying insectivorous bat species feed on insects that are attracted to light‐emitting ultraviolet radiation (10–400 nm). Several countries are currently focused on replacing mercury vapour lamps, which emit ultraviolet light, with more cost‐efficient light‐emitting diode (LED) lights, which emit less ultraviolet radiation. This reduction in ultraviolet light may cause declines in insect densities in cities, predatory fast‐flying bats, and some edge‐foraging and slow‐flying bats. Capitalising on a scheme to update streetlights from high ultraviolet mercury vapour to low ultraviolet LED in Sydney, Australia, we measured the activity of individual bat species, the activity of different functional groups and the bat and insect communities, before and after the change in technology. We also surveyed sites with already LED lights, sites with mercury vapour lights and unlit bushland remnants. Species adapted to foraging in cluttered vegetation, and some edge‐space foraging species, were more active in unlit bushland sites than in all lit sites and decreased in activity at lit sites after the change to LED lights. The change to LED streetlights caused a decrease in the fast‐flying Chalinolobus gouldii but not Miniopterus schreibersii oceanensis, the latter being more influenced by seasonal and environmental variables. Insect biomass was not affected by changing light types, but instead was negatively correlated with the moon's percentage illuminance. Changing streetlights to LEDs could result in a decline in some insectivorous bats in cities. This study confirms that unlit urban bushland remnants are important refuges for high bat diversity, particularly for more clutter‐adapted species and some edge‐space foraging species. Preventing light penetration into unlit bushland patches and corridors remains essential to protect the urban bat community.
Multiple intraguild predators reduce mortality risk of a mutual agricultural pest prey in simple, but not in complex, experimental settings
Authors: Rendon Dalila , Taylor Phillip W. , Whitehouse Mary E. A.
Published: May 2019

Multiple predator species that coexist with each other and their mutual prey can have combined effects on prey mortality that are similar to the sum of each predator's individual impact (linear effects), greater than the sum of each predator's individual impact (risk enhancement), or less than the sum of each predator's individual impact (risk reduction). Understanding multiple predator effects is important to determine the impact of predators on pest prey in agroecosystems. If two predators share the same broad spatial domain and hunting mode and engage in intraguild predation, then their combination is expected to result in risk reduction for a mutual prey. We tested this hypothesis using both additive and replacement experimental designs on two species of generalist wolf spider predators (Tasmanicosa leuckartii and Hogna crispipes) that hunt in the same domain, and a mutual insect prey (cotton bollworm Helicoverpa armigera). We used two types of enclosures: a small simple laboratory enclosure, and a larger more complex cotton plant enclosure. We found that in the small simple laboratory enclosures, the presence of two spiders led to risk reduction of Helicoverpa larva mortality as expected, but in larger more complex cotton plant enclosures the presence of both species resulted in linear effects rather than risk reduction on Helicoverpa mortality. Furthermore, intraguild predation did not change multiple predator effects in laboratory or plant enclosures. This study has implications for managing arthropod predators in agroecosystems; contrary to predictions of ecological frameworks, coexistence of predators that share the same hunting mode and hunting domain may not lead to risk reduction on a mutual prey in more complex environments, where encounters among predators can be lower. Conservation of multiple predators of a single guild can play an essential role on biological control of insect pests.
Developing a quality assurance program for transvaginal cervical length measurement at 18–21 weeks’ gestation
Authors: Filce Casey , Hyett Jon , Sahota Daljit , Wilson Kate , McLennan Andrew
Published: May 2019

Background

Preterm birth is the leading cause of death in children under the age of five years. Transvaginal cervical length (TVCL) assessment can be used to predict preterm delivery risk at the mid‐trimester scan. To optimise the screening tool, developing and maintaining quality standards is important.

Aims

To develop an Australian reference range for TVCL at 18.0–21.0 weeks’ gestation, quality standards for measurement and audit mechanisms for ultrasound operators.

Materials and Methods

A retrospective audit was performed of consecutive patients scanned at 18.0–21.0 weeks’ gestation. Each TVCL measurement ultrasound image was reviewed, and exclusions were made based on a defined set of quality criteria. Fractional polynomial Bayesian methodology was used to establish a reference range. Central tendency, dispersion plots and cumulative sum charts for operators in the original reference range cohort were created. These plots were then applied to a second validation cohort of operators to establish the efficacy of this quality assurance audit tool.

Results

Median TVCL from 1031 participants was 36.0 mm (interquartile range 32.7–40.0 mm), which was independent of gestational age. The quality audit tool was applied to 15 operators from the reference cohort with a mean cervix length multiple of the median of 1.01 and a mean SD log10 cervix length multiple of the median of 0.06. Of the 22 operators in the validation cohort, 20 (90.9%) demonstrated ideal or acceptable central tendency results, and 19 (86.4%) remained in the appropriate cumulative sum zone.

Conclusion

An Australian cervix length measurement reference range at 18.0–21.0 weeks’ gestation has been developed along with a validated quality assurance audit tool for ultrasound operators.
Ranibizumab treatment improves diabetic macular oedema without influencing retinal oximetry parameters
Authors: Takasago Yukari , Fujita Tomoyoshi , Nakano Yuki , Osaka Rie , Miyake Masahiro , Muraoka Yuki , Tsujikawa Akitaka
Published: May 2019

Purpose

To evaluate the effect of ranibizumab on retinal oximetry in eyes with diabetic macular oedema (DME).

Methods

In this prospective interventional study, 30 eyes (30 patients) with DME were treated with three‐monthly intravitreal ranibizumab injections, followed by pro re nata administration for 12 months. Retinal oximetry was performed using an Oxymap T1.

Results

The mean number of injections was 6.6 ± 2.5. No adverse event was observed throughout the study period. Ranibizumab treatments for 12 months improved the macular oedema (p = 0.002) and achieved a recovery of visual acuity (VA; p = 0.011). However, oxygen saturation levels in the major retinal blood vessels, either the arteries or the veins, remained unchanged during the observational period. Arterial oxygen saturation was 100.3 ± 9.4% before treatment and 100.9 ± 10.7% (p = 0.698) at 6 months. Venous oxygen saturation was 56.4 ± 8.9% before treatment and 55.6 ± 8.6% (p = 0.529) at 6 months. In addition, there were no significant changes in diameters of the major retinal arteries and veins. Greater improvement of VA at 12 months was correlated with a smaller number of ranibizumab injections (r = 0.459, p = 0.011). The number of ranibizumab injections during these 12 months correlated with an increased baseline central retinal thickness (r = 0.385, p = 0.035).

Conclusion

Ranibizumab treatments for DME improved the macular oedema and achieved VA recovery, but no changes were noted in the retinal oxygen saturation.
The prevalence of functional constipation in children was unchanged after the Rome IV criteria halved the diagnosis period in Rome III
Authors: Játiva‐Mariño Edgar , Rivera‐Valenzuela Maritza Gisel , Velasco‐Benitez Carlos Alberto , Saps Miguel
Published: May 2019

Aim

The Rome IV criteria for the diagnosis of functional constipation are one month, compared with two months in the Rome III criteria. Our aim was to see whether this altered the prevalence in Ecuador by surveying school children and comparing the results to our previous study.

Methods

A cross‐sectional study was conducted in Quito, Ecuador, in 2013 two randomly selected schools: one private and one public. Children aged 8–15 completed the Spanish version of the Questionnaire of Paediatric Gastrointestinal Symptoms based on the Rome IV criteria. We compared our findings with our previous 2013 study based on the Rome III criteria.

Results

A total of 951 children (61% male) completed the Rome IV questionnaire from June to July 2017 at a mean age of 11.2 ± 1.8 years, and 417 children (52% male) completed the Rome III questionnaire in June 2013 at a mean age of 12.0 ± 1.8 years. We found that 14.4% met the Rome IV criteria for functional constipation compared with 11.8% for the Rome III criteria (p = 0.11).

Conclusion

Modifying the time required for a diagnosis functional constipation from two months to one month did not result in a significant difference in the prevalence.
Obligate anaerobes are abundant in human necrotizing soft tissue infection samples – a metagenomics analysis
Authors: Zhao‐Fleming Hannah H. , Wilkinson Jeremy E. , Larumbe Eneko , Dissanaike Sharmila , Rumbaugh Kendra
Published: May 2019

Necrotizing soft tissue infections (NSTIs) are associated with high morbidity and mortality and are increasing in incidence. Proper identification of the microbial causes of NSTIs is a crucial step in diagnosis and treatment, but the majority of data collected are culture based, which is biased against fastidious organisms, including obligate anaerobes. The goal of this study was to address this gap in knowledge by characterizing NSTI microbial communities through molecular diagnostics. We performed 16S rRNA sequencing on human NSTI samples and identified five genera most commonly found in NSTIs (Prevotella, Bacteroides, Peptoniphilus, Porphyromonas, and Enterococcus). We found that a >70% contribution of obligate anaerobes to the bacterial population distribution was associated with NSTI mortality, and that NSTI samples, from both survivors and non‐survivors, had an increased relative abundance of gram negative bacteria compared to those of abscess patients. Based on our data, we conclude that obligate anaerobes are abundant in NSTIs and a high relative abundance of anaerobes is associated with a worse outcome. We recommend increasing anaerobe antibiotic coverage during the treatment of NSTIs even when anaerobes are not found by traditional clinical microbiology methods, and especially when there is a clinical suspicion for anaerobe involvement.
PD‐L1 expression and deficient mismatch repair in ductal adenocarcinoma of the prostate
Authors: Lindh Claes , Kis Lorand , Delahunt Brett , Samaratunga Hemamali , Yaxley John , Wiklund Nils Peter , Clements Mark , Egevad Lars
Published: May 2019

This study aimed to investigate the expression of programmed death receptor ligand 1 (PD‐L1) and deficient mismatch repair (dMMR) in ductal adenocarcinoma of the prostate. A tissue microarray of 32 ductal and 42 grade‐matched acinar adenocarcinomas was used. Slides were stained for PD‐L1, PD‐L2, MMR proteins, CD4 and CD8. PD‐L1 expression in tumor cells was only seen in 3% (1/34) of ductal and 5% (2/42) of acinar adenocarcinomas (p = 1.0), while PD‐L1 expression in tumor‐infiltrating immune cells was seen in 29% (10/34) of ductal and 14% (6/42) of acinar adenocarcinomas (p = 0.16). dMMR, as defined by loss of one or more of the MMR proteins, was identified in 5% (4/73) of cases, including 1 ductal and 3 acinar adenocarcinomas. There was a suggested association between infiltration of CD8+ lymphocytes and ductal subtype (p = 0.04) but not between CD4+ lymphocytes and tumor type (p = 0.28). The study shows that both dMMR and PD‐L1 expression is uncommon in tumor cells of both ductal and acinar adenocarcinoma of the prostate, while PD‐L1 expression in tumor‐infiltrating immune cells is a more common finding.
An investigation of the effects of conservation incentive programs on management of invasive species by private landowners
Authors: Drescher Michael , Epstein Graham B. , Warriner G. Keith , Rooney Rebecca C.
Published: May 2019

Invasive species are a large and growing threat to biodiversity and ecosystem service provisioning globally as well as in southern Ontario, Canada's most biodiverse region. As in many other world regions, most land in southern Ontario is privately owned and therefore conservation programs that aim at private lands are important. Conservation incentive programs that target private lands are increasingly popular, but little is known about their effectiveness in achieving conservation objectives. To address this knowledge gap, we used a large survey of 1,200 Ontario landowners to investigate how successful conservation incentive programs are at motivating landowners to engage in invasive species management. Utilizing a quasi‐experimental approach, we surveyed landowners participating in the Conservation Lands Tax Incentive Program (CLTIP), the Managed Forest Tax Incentive Program (MFTIP), or in both programs, as well as landowners who were program eligible but did not participate. Our results demonstrate the differential effects of participation in the two programs on specific landowner conservation behaviors: While participation in the MFTIP increased the likelihood of removing invasive species by a factor 2.5 and the planting of native species by a factor 4.3, participants in the CLTIP were no more likely to engage in these behaviors than landowners who did not participate in either program. We suggest that this behavioral disparity is due to the differences in the program designs: The CLTIP does not require a management plan, favors a short planning horizon, and mainly encourages passive management; in doing so it essentially breaks the causal chain that reinforces landowners' environmental awareness and a sense of responsibility for taking conservation actions. Our recommendations include requirements for impact evaluations of private land conservation incentive programs to ensure they achieve stated program outcomes, as well as conservation incentive program designs that oblige landowners to actively manage their land over longer time horizons.
Individual risk tolerance and herding behaviors in financial forecasts
Authors: Christoffersen Jeppe , Stæhr Simone
Published: May 2019

Financial analysts tend to demonstrate herding behavior, which sometimes compromises accuracy. A number of explanations spanning rational economic logic, cognitive biases, and social forces have been suggested. Relying on an experimental setting where participants forecast future earnings from a rich information set, we posit and obtain support for individual risk tolerance (or lack thereof) as an explanatory variable for herding behaviors. Specifically, less risk‐tolerant individuals forecast with less boldness and instead issue forecasts in agreement with the consensus forecast. The results are argued to be at least partially a product of cognitive biases and an intuitive reaction to uncertainty.