bluuebunny/crossref_metadata_2025 huggingface dataset:
Simultaneous measurement of NAD metabolome in aged mice tissue using liquid chromatography tandem‐mass spectrometry
Authors: Yaku Keisuke , Okabe Keisuke , Nakagawa Takashi
Published: February 2018

Nicotinamide adenine dinucleotide (NAD) is a major co‐factor that mediates multiple biological processes including redox reaction and gene expression. Recently, NAD metabolism has received considerable attention because administration of NAD precursors exhibited beneficial effects against aging‐related metabolic disorders in animals. Although numerous studies have reported that NAD levels decline with aging in multiple animal tissues, the pathway and kinetics of NAD metabolism in aged organs are not completely understood. To determine the NAD metabolism upon aging, we developed targeted metabolomics based on an LC/MS/MS system. Our method is simple and applicable to crude biological samples, including culture cells and animal tissues. Unlike a conventional enzymatic cycling assay, our approach can determine NAD and NADH (reduced form of NAD) by performing a single sample preparation. Further, we validated our method using biological samples and investigated the alteration of the NAD metabolome during aging. Consistent with previous reports, the NAD levels in the liver and skeletal muscle decreased with aging. Further, we detected a significant increase in nicotinamide mononucleotide and nicotinamide riboside in the kidney upon aging. The LC/MS/MS‐based NAD metabolomics that we have developed is extensively applicable to biomedical studies, and the results will present innovative ideas for the aging studies, especially for that of NAD metabolism.
Impulse control disorders in Parkinson's: Sleep disorders and nondopaminergic associations
Authors: Carbunaru Samuel , Eisinger Robert S. , Ramirez‐Zamora Adolfo , Bassan Dana , Cervantes‐Arriaga Amin , Rodriguez‐Violante Mayela , Martinez‐Ramirez Daniel
Published: February 2018

Objectives

Impulse control disorders (ICDs) are common among patients with Parkinson's disease (PD). Risk factors identified for developingICDs include young age, family history, and impulsive personality traits. However, the association of these potentially disabling disorders with nondopaminergic drugs and sleep disorders has been understudied. Our objective was to examine the association betweenICDs and nondopaminergic medications and sleep disorders.

Methods

We conducted an observational study of 53 patients withPDfrom the National Institute of Neurology and Neurosurgery.ICDs were diagnosed using the Questionnaire for Impulsive–Compulsive Disorders in Parkinson's Disease Rating Scale (QUIP‐RS). Patients underwent polysomnography screening to diagnose the presence of sleep disorders. We documented the presence of dopaminergic and nondopaminergic medications, including monoamine oxidase type B inhibitors (MAOBIs), antidepressants, sleep inductors, and antipsychotics.

Results

ICDs were reported in 18.9% of the patients (n = 10), and sleep disorders were diagnosed in 81.1% of patients (n = 43). 32.1% of the patients were on antidepressants, 17% onMAOBIs, 15.1% on sleep inductors, and 1.9% on antipsychotics. We observed thatQUIP‐RSA–D subscore depended on the presence of antidepressants (p = .03) and sleep inductors (p = .02). Sleep disorders were not associated with the totalQUIP‐RSscore (p = .93) orQUIP‐RSA–D subscore (p = .81).

Conclusion

Antidepressants and sleep inductors were significant predictors for individualQUIP‐RSitems and subscores. Our results suggest that nondopaminergic drugs commonly used forPDmay be associated with impulse control disorders. We did not identify a relationship betweenICDs and polysomnography‐confirmed sleep disorders in patients withPD. Larger and longitudinal studies are needed to confirm our results.
Discovery of a Short‐Chain Dehydrogenase from Catharanthus roseus that Produces a New Monoterpene Indole Alkaloid
Authors: Stavrinides Anna K. , Tatsis Evangelos C. , Dang Thu‐Thuy , Caputi Lorenzo , Stevenson Clare E. M. , Lawson David M. , Schneider Bernd , O'Connor Sarah E.
Published: February 2018

Plant monoterpene indole alkaloids, a large class of natural products, derive from the biosynthetic intermediate strictosidine aglycone. Strictosidine aglycone, which can exist as a variety of isomers, can be reduced to form numerous different structures. We have discovered a short‐chain alcohol dehydrogenase (SDR) from plant producers of monoterpene indole alkaloids (Catharanthus roseus and Rauvolfia serpentina) that reduce strictosidine aglycone and produce an alkaloid that does not correspond to any previously reported compound. Here we report the structural characterization of this product, which we have named vitrosamine, as well as the crystal structure of the SDR. This discovery highlights the structural versatility of the strictosidine aglycone biosynthetic intermediate and expands the range of enzymatic reactions that SDRs can catalyse. This discovery further highlights how a sequence‐based gene mining discovery approach in plants can reveal cryptic chemistry that would not be uncovered by classical natural product chemistry approaches.
Facilitation of Ca2+‐induced opening of the mitochondrial permeability transition pore either by nicotinamide nucleotide transhydrogenase deficiency or statins treatment
Authors: Busanello Estela N.B. , Figueira Tiago R. , Marques Ana C. , Navarro Claudia D.C. , Oliveira Helena C.F. , Vercesi Anibal E.
Published: February 2018

Mitochondrial redox imbalance and high Ca2+ uptake induce the opening of the permeability transition pore (PTP) that leads to disruption of energy‐linked mitochondrial functions and triggers cell death in many disease states. In this review, we discuss the major results from our studies investigating the consequences of NAD(P)‐transhydrogenase (NNT) deficiency, and of statins treatment for mitochondrial functions and susceptibility to Ca2+‐induced PTP. We highlight the aggravation of high fat diet‐induced fatty liver disease in the context of NNT deficiency and the role of antioxidants in the prevention of statins toxicity to mitochondria.
Angioimmunoblastic T‐cell lymphoma: a rare subtype of peripheral T‐cell lymphoma
Authors: Rai Manoj Ponadka , Bedi Prabhjot Singh , Marinas Edwin B , Khan Nazia Naz S.
Published: February 2018

Key Clinical Message

Angioimmunoblastic T‐cell lymphoma (AITL) is a rare form of NHL and usually presents in the late stage due to the atypical laboratory findings. Immunohistochemistry of the lymph node in AITL is characterized by positive CD2, CD3, CD4, CD10, CXCL‐13, PD1 often BCL‐6 and CD20 positive. Meshworks of follicular dendritic cells are seen outside follicles with CD21 and CD23 stains. EBV can be often positive as well. Autologous transplantation should be offered in the first remission as poor outcome is reported with anthracycline‐containing regimens.
Fe2O+ Cation Mediated Propane Oxidation by Dioxygen in the Gas Phase
Authors: Zhao Yue , Hu Ji‐Chuang , Cui Jia‐Tong , Xu Lin‐Lin , Ma Jia‐Bi
Published: February 2018

The mass‐selected Fe2O+ cation mediated propane oxidation by O2 was investigated by mass spectrometry and density functional theory calculations. In the reaction of Fe2O+ with C3H8, H2 was liberated by C−H bond activation to give Fe2OC3H6+. Interestingly, when a mixture of C3H8/O2 was introduced into the reactor, an intense signal that corresponded to the Fe2O2+ cation was present; the experiments indicated that O2 was activated in its reaction with Fe2O(C3H6)+ to give Fe2O2+and C3H6O (acetone or propanal). A Langmuir–Hinshelwood‐like mechanism was adopted in the propane oxidation reaction by O2 on gas‐phase Fe2O+cations. In comparison with the absence of Fe2O2+ in the reaction of Fe2O+ with O2, the ligand effect of C3H6 on Fe2OC3H6+ is important in the oxygen activation reaction. The theoretical results are consistent with the experimental observations. The propane oxidation by O2 in the presence of Fe2O+ might be applied as a model for alkane and O2 activations over iron oxide catalysts, and the mechanisms and kinetic data are useful for understanding corresponding heterogeneous reactions.
Structure determination of butylone as a new psychoactive substance using chiroptical and vibrational spectroscopies
Authors: Spálovská Dita , Králík František , Kohout Michal , Jurásek Bronislav , Habartová Lucie , Kuchař Martin , Setnička Vladimír
Published: February 2018

Recently, there has been a worldwide substantial increase in the consumption of new psychoactive substances (NPS), compounds that mimic the structure of illicit drugs, such as amphetamines or ecstasy. The producers try to avoid the law by a slight modification of illicit structures, thereby developing dozens of temporarily legal NPS every year. The current trends in the detection and monitoring of such substances demand a fast and reliable analysis. Molecular spectroscopy represents a highly effective tool for the identification of NPS and chiroptical methods can provide further information on their 3D structure, which is the key for the determination of their biological activity. We present the first systematic study of NPS, specifically butylone, combining chiroptical and vibrational spectroscopies with ab initio calculations. According to density functional theory calculations, 6 stable lowest energy conformers of butylone were found and their molecular structure was described. For each conformer, the relative abundance based on the Boltzmann distribution was estimated, their population weighted spectra predicted and compared to the experimental results. Very good agreement between the experimental and the simulated spectra was achieved, which allowed not only the assignment of the absolute configuration, but also a precise description of the molecular structure.
Tetrathiafulvalene‐[2.2]paracyclophanes: Synthesis, crystal structures, and chiroptical properties
Authors: Mézière Cécile , Allain Magali , Oliveras‐Gonzalez Cristina , Cauchy Thomas , Vanthuyne Nicolas , Sarbu Laura G. , Birsa Lucian M. , Pop Flavia , Avarvari Narcis
Published: February 2018

Two racemic tetrathiafulvalene‐[2.2]paracyclophane electron donors EDT‐TTF‐[2.2]paracyclophane 1 and (COOMe)2‐TTF‐[2.2]paracyclophane 2 have been synthesized via the phosphite mediated cross coupling strategy. Chiral HPLC allowed the optical resolution of the (RP) and (SP) enantiomers for both compounds. Solid‐state structures of (RP)‐1 and (rac)‐2 have been determined by single crystal X‐ray analysis. Intermolecular π‐π and S•••S interactions are disclosed in the packing. Single crystal X‐ray analysis of (RP)‐1 combined with experimental and theoretical circular dichroism spectra allowed the assignment of the absolute configuration of the enantiomers of 1 and 2.
Neurotransmitter diversity in pre‐synaptic terminals located in the parvicellular neuroendocrine paraventricular nucleus of the rat and mouse hypothalamus
Authors: Johnson Caroline S. , Bains Jaideep S. , Watts Alan G.
Published: February 2018

Virtually all rodent neuroendocrine corticotropin‐releasing‐hormone (CRH) neurons are in the dorsal medial parvicellular (mpd) part of the paraventricular nucleus of the hypothalamus (PVH). They form the final common pathway for adrenocortical stress responses. Their activity is controlled by sets of GABA‐, glutamate‐, and catecholamine‐containing inputs arranged in an interactive pre‐motor network. Defining the nature and arrangement of these inputs can help clarify how stressor type and intensity information is conveyed to neuroendocrine neurons. Here we use immunohistochemistry with high‐resolution 3‐dimensional image analyses to examine the arrangement of single‐ and co‐occurring GABA, glutamate, and catecholamine markers in synaptophysin‐defined pre‐synaptic terminals in the PVHmpd of unstressed rats and Crh‐IRES‐Cre;Ai14 transgenic mice: respectively, vesicular glutamate transporter 2 (VGluT2), vesicular GABA transporter (VGAT), dopamine β‐hydroxylase (DBH), and phenylethanolamine n‐methyltransferase (PNMT). Just over half of all PVHmpd pre‐synaptic terminals contain VGAT, with slightly less containing VGluT2. The vast majority of terminal appositions with mouse CRH neurons occur non‐somatically. However, there are significantly more somatic VGAT than VGluT2 appositions. In the rat PVHmpd, about five times as many pre‐synaptic terminals contain PNMT than DBH only. However, because epinephrine release has never been detected in the PVH, PNMT terminals may functionally be noradrenergic not adrenergic. PNMT and VGluT2 co‐occur in some pre‐synaptic terminals indicating the potential for co‐transmission of glutamate and norepinephrine. Collectively, these results provide a structural basis for how GABA/glutamate/catecholamine interactions enable adrenocortical responses to fast‐onset interosensory stimuli, and more broadly, how combinations of PVH neurotransmitters and neuromodulators interact dynamically to control adrenocortical activity.
Color appearance rating of familiar real objects under immersive viewing conditions
Authors: Babilon Sebastian , Khanh Tran Quoc
Published: February 2018

With the concept of memory colors being considered to play a crucial role for many imaging and lighting applications, the questions how people assess the color appearance of familiar objects and what kind of fundamental characteristics can be derived from these assessments have extensively been studied in the past. However, all of the previous studies, the authors of this article are aware of, lack in realistic viewing and adaptation conditions. In the attempt of overcoming these deficiencies, a new experiment investigating the impact of long‐term memory on the color appearance ratings of 12 familiar test objects was performed. The pooled observer data were modeled in CIECAM02 color space using bivariate Gaussian functions whose centroids define the corresponding memory color centers for each test object. Comparisons with previous results obtained by Smet et al. revealed no significant differences in the reported memory color centers, but showed distinct deviations in the covariance matrices defining the shape of the fitted distribution functions. It is supposed that this new set of functions will lead to significantly different results when being used for the construction of an updated memory‐based color quality metric.
Simulation for Predicting Effectiveness and Safety of New Cardiovascular Drugs in Routine Care Populations
Authors: Najafzadeh Mehdi , Schneeweiss Sebastian , Choudhry Niteesh K. , Wang Shirley V. , Gagne Joshua J.
Published: February 2018

In the presence of heterogeneity of treatment effect (HTE), the average treatment effect from a randomized controlled trial (RCT) may not be applicable to different patients, such as those in observational settings. Our objective was to develop a novel approach that uses individual‐level simulation to expand RCT results to target patient populations in the presence of HTE. For this purpose, we compared the results of the Randomized Evaluation of Long‐Term Anticoagulation Therapy (RE‐LY) trial, and two observational studies that compared benefits and risks of dabigatran to warfarin in patients with atrial fibrillation. We developed a simulation model that replicates the rates of ischemic stroke and major bleeding observed in RE‐LY using published outcome risk models and participants' baseline characteristics. We used our validated simulation model to predict what the results of the RCT would have been had it been conducted in populations similar to those in the observational studies.
Untangling climate and water chemistry to predict changes in freshwater macrophyte distributions
Authors: Sleith Robin S. , Wehr John D. , Karol Kenneth G.
Published: February 2018

Forecasting changes in the distributions of macrophytes is essential to understanding how aquatic ecosystems will respond to climate and environmental changes. Previous work in aquatic ecosystems has used climate data at large scales and chemistry data at small scales; the consequence of using these different data types has not been evaluated. This study combines a survey of macrophyte diversity and water chemistry measurements at a large regional scale to demonstrate the feasibility and necessity of including ecological measurements, in addition to climate data, in species distribution models of aquatic macrophytes. A survey of 740 water bodies stratified across 327,000 square kilometers was conducted to document Characeae (green macroalgae) species occurrence and water chemistry data. Chemistry variables and climate data were used separately and in concert to develop species distribution models for ten species across the study area. The impacts of future environmental changes on species distributions were modeled using a range of global climate models (GCMs), representative concentration pathways (RCPs), and pollution scenarios. Models developed with chemistry variables generally gave the most accurate predictions of species distributions when compared with those using climate variables. Calcium and conductivity had the highest total relative contribution to models across all species. Habitat changes were most pronounced in scenarios with increased road salt and deicer influences, with two species predicted to increase in range by >50% and four species predicted to decrease in range by >50%. Species of Characeae have distinct habitat ranges that closely follow spatial patterns of water chemistry. Species distribution models built with climate data alone were insufficient to predict changes in distributions in the study area. The development and implementation of standardized, large‐scale water chemistry databases will aid predictions of habitat changes for aquatic ecosystems.
Spatial correlations between browsing on balsam fir by white‐tailed deer and the nutritional value of neighboring winter forage
Authors: Champagne Emilie , Moore Ben D. , Côté Steeve D. , Tremblay Jean‐Pierre
Published: February 2018

Associational effects, that is, the influence of neighboring plants on herbivory suffered by a plant, are an outcome of forage selection. Although forage selection is a hierarchical process, few studies have investigated associational effects at multiple spatial scales. Because the nutritional quality of plants can be spatially structured, it might differently influence associational effects across multiple scales. Our objective was to determine the radius of influence of neighbor density and nutritional quality on balsam fir (Abies balsamea) herbivory by white‐tailed deer (Odocoileus virginianus) in winter. We quantified browsing rates on fir and the density and quality of neighboring trees in a series of 10‐year‐old cutovers on Anticosti Island (Canada). We used cross‐correlations to investigate relationships between browsing rates and the density and nutritional quality of neighboring trees at distances up to 1,000 m. Balsam fir and white spruce (Picea glauca) fiber content and dry matterin vitrotrue digestibility were correlated with fir browsing rate at the finest extra‐patch scale (across distance of up to 50 m) and between cutover areas (300–400 m). These correlations suggest associational effects, that is, low nutritional quality of neighbors reduces the likelihood of fir herbivory (associational defense). Our results may indicate associational effects mediated by intraspecific variation in plant quality and suggest that these effects could occur at scales from tens to hundreds of meters. Understanding associational effects could inform strategies for restoration or conservation; for example, planting of fir among existing natural regeneration could be concentrated in areas of low nutritional quality.
Mechanisms of CD8+ T cell‐mediated suppression of HIV/SIV replication
Authors: McBrien Julia Bergild , Kumar Nitasha A. , Silvestri Guido
Published: February 2018

In this article, we summarize the role of CD8+ T cells during natural and antiretroviral therapy (ART)‐treated HIV and SIV infections, discuss the mechanisms responsible for their suppressive activity, and review the rationale for CD8+ T cell‐based HIV cure strategies. Evidence suggests that CD8+ T cells are involved in the control of virus replication during HIV and SIV infections. During early HIV infection, the cytolytic activity of CD8+ T cells is responsible for control of viremia. However, it has been proposed that CD8+ T cells also use non‐cytolytic mechanisms to control SIV infection. More recently, CD8+ T cells were shown to be required to fully suppress virus production in ART‐treated SIV‐infected macaques, suggesting that CD8+ T cells are involved in the control of virus transcription in latently infected cells that persist under ART. A better understanding of the complex antiviral activities of CD8+ T cells during HIV/SIV infection will pave the way for immune interventions aimed at harnessing these functions to target the HIV reservoir.
Psychological factors not strength deficits are associated with severity of gluteal tendinopathy: A cross‐sectional study
Authors: Plinsinga M.L. , Coombes B.K. , Mellor R. , Nicolson P. , Grimaldi A. , Hodges P. , Bennell K. , Vicenzino B.
Published: February 2018

Background

Gluteal tendinopathy is the most common lower limb tendinopathy presenting to general practice. It has a high prevalence amongst middle‐aged women and impacts on daily activities, work participation and quality of life. The aim was to compare physical and psychological characteristics between subgroups of severity of pain and disability.

Methods

A multicentre cross‐sectional cohort of 204 participants (mean age 55 years, 82% female) who had a clinical diagnosis of gluteal tendinopathy with magnetic resonance imaging confirmation were assessed. A range of physical and psychosocial characteristics were recorded. Pain and disability were measured with the VISA‐G questionnaire. A cluster analysis was used to identify mild, moderate and severe subgroups based on total VISA‐G scores. Between‐group differences were then evaluated with a MANCOVA, including sex and study site as covariates, followed by a Bonferroni post hoc test. Significance was set at 0.05.

Results

There were significantly higher pain catastrophizing and depression scores in the more severe subgroups. Lower pain self‐efficacy scores were found in the severe group compared to the moderate and mild groups. Greater waist girth and body mass index (BMI), lower activity levels and poorer quality of life were reported in the severe group compared to the mild group. Hip abductor muscle strength and hip circumference did not differ between subgroups of severity.

Conclusions

Individuals with severe gluteal tendinopathy present with psychological distress, poorer quality of life, greater BMI and waist girth. Given these features, the consideration of psychological factors in more severe patients may be important to optimize patient outcomes and reduce healthcare utilization.

Significance

Patients with severe gluteal tendinopathy exhibit greater psychological distress, poorer quality of life and greater waist girth and BMI when compared to less severe cases. This implies that clinicians ought to consider psychological factors in the management of more severe gluteal tendinopathy.
Uptake and metabolism of the antidepressants sertraline, clomipramine, and trazodone in a garden cress (Lepidium sativum) model
Authors: Reichl Bernd , Himmelsbach Markus , Emhofer Lisa , Klampfl Christian W. , Buchberger Wolfgang
Published: February 2018

Environmental contamination with pharmaceuticals has received growing attention in recent years. Several studies describe the presence of traces of drugs in water bodies and soils and their impacts on nontarget organisms including plants. Due to these facts investigations of the uptake and metabolism of pharmaceuticals in organisms is an emerging research area. The present study demonstrates the analysis of three selected antidepressants (sertraline, clomipramine, and trazodone) as well as metabolites and transformation products in a cress model (Lepidium sativum). Cress was treated with tap water containing 10 mg/L of the parent drugs. Employing an analytical approach based on high performance liquid chromatography coupled with quadrupole time of flight or Orbitrap mass spectrometry in MS and MS² modes, in total 14 substances were identified in the cress extracts. All three parent drugs were taken up by the cress and translocated from the roots to the leaves in specific patterns. In addition to this, eleven metabolite species were identified. They were generated by hydroxylation, demethylation, conjugation with amino acids, or combinations of these mechanisms. Finally, the inclusion of control cultures in the experimental setup allowed for a differentiation of “true” metabolites generated by the cress and transformation products generated by plant‐independent mechanisms.
Investigation of pumping mechanism for non‐Newtonian blood flow with AC electrothermal forces in a microchannel by hybrid boundary element method and immersed boundary‐lattice Boltzmann method
Authors: Ren Qinlong
Published: February 2018

Efficient pumping of blood flow in a microfluidic device is essential for rapid detection of bacterial bloodstream infections (BSI) using alternating current (AC) electrokinetics. Compared with AC electro‐osmosis (ACEO) phenomenon, the advantage of AC electrothermal (ACET) mechanism is its capability of pumping biofluids with high electrical conductivities at a relatively high AC voltage frequency. In the current work, the microfluidic pumping of non‐Newtonian blood flow using ACET forces is investigated in detail by modeling its multi‐physics process with hybrid boundary element method (BEM) and immersed boundary‐lattice Boltzmann method (IB‐LBM). The Carreau–Yasuda model is used to simulate the realistic rheological behavior of blood flow. The ACET pumping efficiency of blood flow is studied in terms of different AC voltage magnitudes and frequencies, thermal boundary conditions of electrodes, electrode configurations, channel height, and the channel length per electrode pair. Besides, the effect of rheological behavior on the blood flow velocity is theoretically analyzed by comparing with the Newtonian fluid flow using scaling law analysis under the same physical conditions. The results indicate that the rheological behavior of blood flow and its frequency‐dependent dielectric property make the pumping phenomenon of blood flow different from that of the common Newtonian aqueous solutions. It is also demonstrated that using a thermally insulated electrode could enhance the pumping efficiency dramatically. Besides, the results conclude that increasing the AC voltage magnitude is a more economical pumping approach than adding the number of electrodes with the same energy consumption when the Joule heating effect is acceptable.
Conceptual design of a new SF6 abatement technology using a multi‐bed series reactor for the production of valuable chemicals free of toxic wastes
Authors: Lee Boreum , Kim Sehwa , Song Jiseon , Ryi Shin‐Kun , Lim Hankwon
Published: February 2018

Conceptual design using multi‐bed series reactors consisting of catalysts and adsorbent beds was performed for a new SF6 abatement and utilization technology free of toxic chemicals to reduce SF6 emissions and produce valuable products like CaF2 and CaSO4 simultaneously. With process simulation studies using Aspen HYSYS®, comparative studies for a single‐bed reactor (SR‐1), a two‐bed series reactor (SR‐2), and a three‐bed series reactor (SR‐3) revealed that more CaF2 and CaSO4 were produced in multi‐bed series reactors compared to a SR‐1 (SR‐3 > SR‐2 > SR‐1) possibly due to sorption‐enhanced hydrolysis. In addition, lower operating temperatures were observed in multi‐bed series reactors (TSR1 > TSR2 > TSR3) showing the positive effect of using multi‐bed series reactors for a simultaneous SF6 abatement and utilization technology.
Male-biased gene expression resolves sexual conflict through the evolution of sex-specific genetic architecture
Authors: Wright Alison E. , Fumagalli Matteo , Cooney Christopher R. , Bloch Natasha I. , Vieira Filipe G. , Buechel Severine D. , Kolm Niclas , Mank Judith E.
Published: February 2018

Many genes are subject to contradictory selection pressures in males and females, and balancing selection resulting from sexual conflict has the potential to substantially increase standing genetic diversity in populations and thereby act as an important force in adaptation. However, the underlying causes of sexual conflict, and the potential for resolution, remains hotly debated. Using transcriptome-resequencing data from male and female guppies, we use a novel approach, combining patterns of genetic diversity and intersexual divergence in allele frequency, to distinguish the different scenarios that give rise to sexual conflict, and how this conflict may be resolved through regulatory evolution. We show that reproductive fitness is the main source of sexual conflict, and this is resolved via the evolution of male-biased expression. Furthermore, resolution of sexual conflict produces significant differences in genetic architecture between males and females, which in turn lead to specific alleles influencing sex-specific viability. Together, our findings suggest an important role for sexual conflict in shaping broad patterns of genome diversity, and show that regulatory evolution is a rapid and efficient route to the resolution of conflict.
An analytic approach for interpretable predictive models in high‐dimensional data in the presence of interactions with exposures
Authors: Bhatnagar Sahir Rai , Yang Yi , Khundrakpam Budhachandra , Evans Alan C. , Blanchette Mathieu , Bouchard Luigi , Greenwood Celia M.T.
Published: February 2018

Predicting a phenotype and understanding which variables improve that prediction are two very challenging and overlapping problems in the analysis of high‐dimensional (HD) data such as those arising from genomic and brain imaging studies. It is often believed that the number of truly important predictors is small relative to the total number of variables, making computational approaches to variable selection and dimension reduction extremely important. To reduce dimensionality, commonly used two‐step methods first cluster the data in some way, and build models using cluster summaries to predict the phenotype. It is known that important exposure variables can alter correlation patterns between clusters of HD variables, that is, alter network properties of the variables. However, it is not well understood whether such altered clustering is informative in prediction. Here, assuming there is a binary exposure with such network‐altering effects, we explore whether the use of exposure‐dependent clustering relationships in dimension reduction can improve predictive modeling in a two‐step framework. Hence, we propose a modeling framework called ECLUST to test this hypothesis, and evaluate its performance through extensive simulations. With ECLUST, we found improved prediction and variable selection performance compared to methods that do not consider the environment in the clustering step, or to methods that use the original data as features. We further illustrate this modeling framework through the analysis of three data sets from very different fields, each with HD data, a binary exposure, and a phenotype of interest. Our method is available in the eclust CRAN package.
A test for gene–environment interaction in the presence of measurement error in the environmental variable
Authors: Aschard Hugues , Spiegelman Donna , Laville Vincent , Kraft Pete , Wang Molin
Published: February 2018

The identification of gene–environment interactions in relation to risk of human diseases has been challenging. One difficulty has been that measurement error in the exposure can lead to massive reductions in the power of the test, as well as in bias toward the null in the interaction effect estimates. Leveraging previous work on linear discriminant analysis, we develop a new test of interaction between genetic variants and a continuous exposure that mitigates these detrimental impacts of exposure measurement error in ExG testing by reversing the role of exposure and the diseases status in the fitted model, thus transforming the analysis to standard linear regression. Through simulation studies, we show that the proposed approach is valid in the presence of classical exposure measurement error as well as when there is correlation between the exposure and the genetic variant. Simulations also demonstrated that the reverse test has greater power compared to logistic regression. Finally, we confirmed that our approach eliminates bias from exposure measurement error in estimation. Computing times are reduced by as much as fivefold in this new approach. For illustrative purposes, we applied the new approach to an ExGWAS study of interactions with alcohol and body mass index among 1,145 cases with invasive breast cancer and 1,142 controls from the Cancer Genetic Markers of Susceptibility study.
Astrocyte disruption of neurovascular communication is linked to cortical damage in an animal model of multiple sclerosis
Authors: Eilam Raya , Segal Menahem , Malach Rafael , Sela Michael , Arnon Ruth , Aharoni Rina
Published: February 2018

To elucidate mechanisms contributing to cortical pathology in multiple sclerosis (MS), we investigated neurovascular aberrations, in particular the association of astrocytes with cortical neurons and blood vessels, in mice induced with experimental autoimmune encephalomyelitis (EAE). Blood–brain barrier (BBB) dysfunction was evident by leakage of the tracer sodium fluorescein, along with reduced expression of claudin‐5 by endothelial cells and desmin by pericytes. Immunohistological and ultrastructural analyses revealed detachment of the astroglial cell bodies from the blood vessels and loss of their connections with both the blood vessels and the neuronal synapses. Furthermore, examination of individual astrocytic processes at cortical layer IV, where well‐defined neuronal columns (barrels) are linked to functional properties, revealed loss of astrocytic confinement to the functional neuronal boundaries. Thus, in contrast to the highly modulated patches of astrocyte processes in naïve mice overlapping the barrel cores, in EAE‐mice process distribution was uniform ignoring the barrel boundaries. These aberrations are attributed to the surrounding inflammation, indicated by T‐cells presence in the cortex as well as in the subcortical white matter and the meninges. Immunomodulatory treatment with glatiramer acetate partially abrogated the neurovascular damage. These combined findings indicate that under inflammatory conditions, activated perivascular astrocytes fail in neuro‐hemodynamic coupling, resulting in obstructed cross‐talk between the blood vessels and the neurons. We propose that loss of cortical astrocytic regulation and fine‐tuning between the blood supply and the neuronal needs contributes to the neurological impairment and cognitive decline occurring in EAE/MS as well as to the disease progression.
MULTIPLE ECONOMIES AND YOUTH LIVELIHOOD
Authors: McDonnell Liz , Harris Anita , White Rob
Published: February 2018

In this paper we present a model of multiple economic spheres in order to understand and explain the income‐generating activities of young people. These spheres include the formal sector, the informal waged sector, the informal non‐waged sector, the welfare sector and the criminal sector. We conclude that, due to changes in the labour market that affect them in particular ways, young people are engaged in a diverse range of activities within and across each economic sphere.
Asymmetric, nano‐textured surfaces influence neuron viability and polarity
Authors: Belu Andreea , Yilmaz Mehmet , Neumann Elmar , Offenhäusser Andreas , Demirel Gokhan , Mayer Dirk
Published: February 2018

Three dimensional, nanostructured surfaces have attracted considerable attention in biomedical research since they have proven to represent a powerful platform to influence cell fate. In particular, nanorods and nanopillars possess great potential for the control of cell adhesion and differentiation, gene and biomolecule delivery, optical and electrical stimulation and recording, as well as cell patterning. Here, we investigate the influence of asymmetric poly(dichloro‐p‐xylene) (PPX) columnar films on the adhesion and maturation of cortical neurons. We show that nanostructured films with dense, inclined polymer columns can support viable primary neuronal culture. The cell‐nanostructure interface is characterized showing a minimal cell penetration but strong adhesion on the surface. Moreover, we quantify the influence of the nano‐textured surface on the neural development (soma size, neuritogenesis, and polarity) in comparison to a planar PPX sample. We demonstrate that the nanostructures facilitates an enhancement in neurite branching as well as elongation of axons and growth cones. Furthermore, we show for the first time that the asymmetric orientation of polymeric nanocolumns strongly influences the initiation direction of the axon formation. These results evidence that 3D nano‐topographies can significantly change neural development and can be used to engineer axon elongation. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1634–1645, 2018.
Development of zwitterionic sulfobetaine block copolymer conjugation strategies for reduced platelet deposition in respiratory assist devices
Authors: Malkin Alexander D. , Ye Sang‐Ho , Lee Evan J. , Yang Xiguang , Zhu Yang , Gamble Lara J. , Federspiel William J. , Wagner William R.
Published: February 2018

Respiratory assist devices, that utilize ∼2 m2 of hollow fiber membranes (HFMs) to achieve desired gas transfer rates, have been limited in their adoption due to such blood biocompatibility limitations. This study reports two techniques for the functionalization and subsequent conjugation of zwitterionic sulfobetaine (SB) block copolymers to polymethylpentene (PMP) HFM surfaces with the intention of reducing thrombus formation in respiratory assist devices. Amine or hydroxyl functionalization of PMP HFMs (PMP‐A or PMP‐H) was accomplished using plasma‐enhanced chemical vapor deposition. The generated functional groups were conjugated to low molecular weight SB block copolymers with N‐hydroxysuccinimide ester or siloxane groups (SBNHS or SBNHSi) that were synthesized using reversible addition fragmentation chain transfer polymerization. The modified HFMs (PMP‐A‐SBNHS or PMP‐H‐SBNHSi) showed 80–95% reduction in platelet deposition from whole ovine blood, stability under the fluid shear of anticipated operating conditions, and uninhibited gas exchange performance relative to non‐modified HFMs (PMP‐C). Additionally, the functionalization and SBNHSi conjugation technique was shown to reduce platelet deposition on polycarbonate and poly(vinyl chloride), two other materials commonly found in extracorporeal circuits. The observed thromboresistance and stability of the SB modified surfaces, without degradation of HFM gas transfer performance, indicate that this approach is promising for longer term pre‐clinical testing in respiratory assist devices and may ultimately allow for the reduction of anticoagulation levels in patients being supported for extended periods. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2681–2692, 2018.
Evaluation of decellularized xenogenic porcine auricular cartilage as a novel biocompatible filler
Authors: Shin Sung‐Chan , Park Hee Young , Shin Nari , Jung Da‐Woon , Kwon Hyun‐Keun , Kim Ji Min , Wang Soo‐Geun , Lee Jin‐Choon , Sung Eui‐Suk , Park Gi Cheol , Lee Byung‐Joo
Published: February 2018

Fillers are products that fill the space in soft tissues of the human body and actively used in the various medical fields. Unfortunately, most of the cost‐effective commercially available fillers are synthetic and have limitations in terms of their biocompatibility. Here, we evaluated the possible application of decellularized xenogenic cartilage as a long‐lasting material for soft tissue augmentation and compared it with two commercially available fillers Artesense (polymethylmethacrylate microspheres) and Radiesse (calcium hydroxyapatite [CaHa]). To do so, porcine auricular cartilage was harvested, followed by freezing and grinding of the tissue into flakes. Then, we used 1% Triton X‐100 to decellularize the flakes. We then, respectively, injected 0.1 cc of each material (decellularized xenogenic cartilage, Radiesse, and Artesense) into the subcutaneous layer at three different sites per subject in 12 Sprague‐Dawley rats, and evaluated the inflammatory cell infiltration and foreign body reactions of each. Our data indicate that the infiltration of giant cells in the injection area was significantly lower in the decellularized xenogenic cartilage injection group than that in the Radiesse and Artesense injection groups. Further, we observed some neutrophil infiltration in the xenogenic cartilage and Artesense injection groups at 1 month, but these levels were much lower at 3 months (comparable to the Radiesse injection group). Thus, decellularized xenogenic cartilage may have a distinct advantage in terms of biocompatibility compared with other commercial injectable long‐lasting fillers, making it one of the most feasible, natural, and cost effective materials in the market. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2708–2715, 2018.
Analysis and dissociation of anti‐HIV effects of shRNA to CCR5 and the fusion inhibitor C46
Authors: Ledger Scott , Howe Annett , Turville Stuart , Aggarwal Anupriya , Savkovic Borislav , Ong Andrew , Wolstein Orit , Boyd Maureen , Millington Michelle , Gorry Paul R. , Murray John M. , Symonds Geoff
Published: February 2018

Background

The gene therapeutic Cal‐1 comprises the anti‐HIV agents: (i) sh5, a short hairpin RNA to CCR5 that down‐regulates CCR5 expression and (ii) maC46 (C46), a peptide that inhibits viral fusion with the cell membrane. These constructs were assessed for inhibition of viral replication and selective cell expansion in a number of settings.

Methods

HIV replication, selective outgrowth and cell surface viral binding were analysed with a single cycle infection assay of six pseudotyped HIV strains and a static and longitudinal passaging of MOLT4/CCR5 cells with HIV. Pronase digestion of surface virus and fluorescence microscopy assessed interactions between HIV virions and transduced cells.

Results

Cal‐1 reduced CCR5 expression in peripheral blood mononuclear cells to CCR5Δ32 heterozygote levels. Even low level transduction resulted in significant preferential expansion in MOLT4/CCR5 gene‐containing cells over a 3‐week HIV challenge regardless of viral suppression [12.5% to 47.0% (C46), 46.7% (sh5), 62.2% (Dual), respectively]. The sh5 and Dual constructs at > 95% transduction also significantly suppressed virus to day 12 in the passage assay and all constructs, at varying percentage transduction inhibited virus in static culture. No escape mutations were present through 9 weeks of challenge. The Dual construct significantly suppressed infection by a panel of CCR5‐using viruses, with its efficacy being independently determined from the single constructs. Dual and sh5 inhibited virion internalisation, as determined via pronase digestion of surface bound virus, by 70% compared to 13% for C46.

Conclusions

The use of two anti‐HIV genes allows optimal preferential survival and inhibition of HIV replication, with the impact on viral load being dependent on the percentage of gene marked cells.
Amino acid substitutions in the hepatitis C virus core region predict hepatocarcinogenesis following eradication of HCV RNA by all‐oral direct‐acting antiviral regimens
Authors: Ogata Fumihiro , Akuta Norio , Kobayashi Masahiro , Fujiyama Shunichiro , Kawamura Yusuke , Sezaki Hitomi , Hosaka Tetsuya , Kobayashi Mariko , Saitoh Satoshi , Suzuki Yoshiyuki , Suzuki Fumitaka , Arase Yasuji , Ikeda Kenji , Kumada Hiromitsu
Published: February 2018

Impact of substitution of aa70 in the core region (Core aa70) in HCV genotype 1b (HCV‐1b) on hepatocarcinogenesis following eradication of HCV RNA by direct‐acting antiviral therapy is not clear. In a retrospective study, 533 patients with HCV‐related chronic liver disease, with sustained virological response defined as negative HCV RNA at 12 weeks after cessation of direct‐acting antiviral therapy, were examined to evaluate the relationship between Core aa70 substitution and hepatocarcinogenesis. Twelve patients developed hepatocellular carcinoma during the follow‐up period. The cumulative hepatocarcinogenesis rates were 1.7% and 2.4% at the end of 1 and 2 years, respectively. Overall, multivariate analysis identified HCV subgroup (HCV‐1b with Gln70(His70); P = 0.003) and age (>65 years; P = 0.049), as pretreatment predictors of hepatocarcinogenesis. In HCV‐1b patients, multivariate analysis identified post‐treatment Wisteria floribunda agglutinin positive Mac‐2 binding protein (>1.8 COI; P = 0.042) and HCV subgroup (HCV‐1b with Gln70(His70); P = 0.071), as predictors of hepatocarcinogenesis, including post‐treatment parameter. In conclusion, Core aa70 substitution in HCV‐1b at the start of direct‐acting antiviral therapy is an important predictor of hepatocarcinogenesis following eradication of HCV RNA. This study emphasizes the importance of detection of Core aa70 substitution before initiating antiviral therapy.
Prevalence of NS5A resistance associated substitutions in patients with hepatitis C virus genotypes 1a and 3: Impact on current therapeutic strategies
Authors: Grandal Marta , Pernas Berta , Tabernilla Andrés , Mariño Ana , Álvarez Hortensia , Valcarce Nieves , Mena Alvaro , Castro‐Iglesias Angeles , Pérez Ana B. , Delgado Manuel , Poveda Eva
Published: February 2018

The presence of resistance‐associated substitutions (RASs) at NS5A region might compromise the efficacy of Direct Acting Antiviral agents (DAAs). HCV resistance at NS5A region is mainly focused on patients with hepatitis C virus (HCV) genotypes 1a (G1a) and 3 (G3) with other factors of poor treatment response (ie cirrhosis, prior treatment‐exposure, or HCV‐RNA >800 000 IU/mL). Herein, we evaluated in a cohort of HCV G1a and G3 infected patients the prevalence of RASs at domain I NS5A using population‐based sequencing and the impact of RASs on the optimization of current therapeutic strategies. The RASs considered as clinically relevant were: M28A/G/T, Q30D/E/H/G/K/L/R, L31M/V/F, H58D, and Y93C/H/N/S for G1a and Y93H for G3. A total of 232 patients naïve to NS5A inhibitors were included (166 G1a, 66 G3). The overall prevalence of NS5A RASs for G1a and G3 patients was low (5.5%) or null, respectively. A high proportion of patients harbored, at least, one factor of poor response (78.9% for G1a, and 75.8% for G3). Overall, the rates of patients harboring NS5A RASs in combination with any of the other factors were low and the vast majority of patients (G1a> 94% and G3 100%) could be treated with standard treatments of 12 weeks without ribavirin. In conclusion, testing NS5A RASs in specific HCV‐infected populations (ie G1a & G3, cirrhosis, prior treatment experienced, HCV‐RNA >800 000 IU/mL) might be useful to optimize current NS5A‐based therapies avoiding ribavirin‐related toxicities, and shortening treatment duration in the majority of patients.