bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular insights into cell toxicity of a novel familial amyloidogenic variant of β2‐microglobulin
Authors: Leri Manuela , Bemporad Francesco , Oropesa‐Nuñez Reinier , Canale Claudio , Calamai Martino , Nosi Daniele , Ramazzotti Matteo , Giorgetti Sofia , Pavone Francesco S. , Bellotti Vittorio , Stefani Massimo , Bucciantini Monica 
Published: March 2016

AbstractThe first genetic variant of β2‐microglobulin (b2M) associated with a familial form of systemic amyloidosis has been recently described. The mutated protein, carrying a substitution of Asp at position 76 with an Asn (D76N b2M), exhibits a strongly enhanced amyloidogenic tendency to aggregate with respect to the wild‐type protein. In this study, we characterized the D76N b2M aggregation path and performed an unprecedented analysis of the biochemical mechanisms underlying aggregate cytotoxicity. We showed that, contrarily to what expected from other amyloid studies, early aggregates of the mutant are not the most toxic species, despite their higher surface hydrophobicity. By modulating ganglioside GM1 content in cell membrane or synthetic lipid bilayers, we confirmed the pivotal role of this lipid as aggregate recruiter favouring their cytotoxicity. We finally observed that the aggregates bind to the cell membrane inducing an alteration of its elasticity (with possible functional unbalance and cytotoxicity) in GM1‐enriched domains only, thus establishing a link between aggregate‐membrane contact and cell damage.
A randomized controlled trial of cognitive behavioral therapy for ADHD in medication‐treated adolescents
Authors: Sprich Susan E. , Safren Steven A. , Finkelstein Daniel , Remmert Jocelyn E. , Hammerness Paul 
Published: March 2016

ObjectiveTo test cognitive behavioral therapy (CBT) for persistent attention‐deficit hyperactivity disorder (ADHD) symptoms in a sample of medication‐treated adolescents.MethodsForty‐six adolescents (ages 14–18), with clinically significant ADHD symptoms despite stable medication treatment were randomly assigned to receive CBT for ADHD or wait list control in a cross‐over design. Twenty‐four were randomized to CBT, 22 to wait list, and 15 crossed‐over from wait list to CBT. A blind independent evaluator (IE) rated symptom severity on the ADHD Current Symptom Scale, by adolescent and parent report, and rated each subject using the Clinical Global Impression Severity Scale (CGI), a global measure of distress and impairment. These assessments were performed at baseline, 4‐months (post‐CBT or post wait list), and 8‐months (post‐treatment for those originally assigned to the wait list condition and 4‐month follow‐up for those originally assigned to CBT). Trial Registration: http://clinicaltrials.gov/show/NCT01019252.ResultsUsing all available data, mixed effects modeling, and pooling for the wait list cross‐over, participants who received CBT received a mean score 10.93 lower on the IE‐rated parent assessment of symptom severity (95% CI: −12.93, −8.93; p < .0001), 5.24 lower on the IE‐rated adolescent assessment of symptom severity (95% CI: −7.21, −3.28; p < .0001), and 1.17 lower IE‐rated CGI (95% CI: −1.39, −.94; p < .0001). Results were consistent across 100 multiple imputations (all p < .0001). There was a greater proportion of responders after CBT by parent (50% vs. 18%, p = .00) and adolescent (58% vs. 18% p = .02) report.ConclusionsThis study demonstrates initial efficacy of CBT for adolescents with ADHD who continued to exhibit persistent symptoms despite medications.
β‐Cell glutamate signaling: Its role in incretin‐induced insulin secretion
Authors: Yokoi Norihide , Gheni Ghupurjan , Takahashi Harumi , Seino Susumu 
Published: March 2016

AbstractInsulin secretion from the pancreatic β‐cell (referred to as β‐cell hereafter) plays a central role in glucose homeostasis. Impaired insulin secretion is a major factor contributing to the development of diabetes and, therefore, is an important target for treatment of the disease. Cyclic adenosine monophosphate is a key second messenger in β‐cells that amplifies insulin secretion. Incretins released by the gut potentiate insulin secretion through cyclic adenosine monophosphate signaling in β‐cells, which is the basis for the incretin‐based diabetes therapies now being used worldwide. Despite its importance, the interaction between glucose metabolism and incretin/cyclic adenosine monophosphate signaling in β‐cells has long been unknown. A recent study showed that cytosolic glutamate produced by glucose metabolism in β‐cells is a key signal in incretin‐induced insulin secretion. Here we review the physiological and pathophysiological roles of β‐cell glutamate signaling in incretin‐induced insulin secretion.
Glucagon‐like peptide‐1: The missing link in the metabolic clock?
Authors: Brubaker Patricia L , Gil‐Lozano Manuel 
Published: March 2016

AbstractCircadian expression of clock genes in peripheral tissues is critical to the coordinated regulation of intestinal digestive and absorptive functions, insulin secretion, and peripheral tissue nutrient deposition during periods of nutrient ingestion, thereby preventing metabolic dysregulation. As glucagon‐like peptide‐1 is a key incretin hormone that regulates glucose‐dependent insulin secretion, we hypothesized that this intestinal hormone is a player in the peripheral metabolic clock, linking nutrient ingestion to insulin secretion. We have now established that secretion of glucagon‐like peptide‐1 from the intestinal L cell shows a rhythmic pattern in rats and humans in vivo that is altered by circadian disruptors, such as constant light exposure, consumption of a Western diet and feeding at inappropriate times (i.e., during the light period in rodents). Interestingly, the alterations in the rhythm of the glucagon‐like peptide‐1 secretory responses were found to parallel the changes in the pattern of insulin responses in association with significant impairments in glucose tolerance. Furthermore, we have detected circadian clock gene expression, and showed circadian secretion of glucagon‐like peptide‐1 from both the murine and human L cell in vitro. These findings demonstrate that glucagon‐like peptide‐1 is a functional component of the peripheral metabolic clock, and suggest that altered release of glucagon‐like peptide‐1 might play a role in the metabolic perturbations that result from circadian disruption.
Rheological Characterization and CFD Simulation of Soy White Flakes Based Dough in a Single Screw Extruder
Authors: Singh Sushil K. , Muthukumarappan Kasiviswanathan 
Published: March 2016

AbstractUnderstanding the rheological properties such as shear profile, viscosity of a dough inside the extruder is very important for product development, process control, final product quality and scaling up operations. This study aims to characterize the rheological properties of high‐protein dough and perform isothermal flow simulation in a complex geometry for generalized Newtonian fluids. The flow of soy white flakes based dough in a single screw extruder was simulated by using computational fluid dynamics. Process conditions considered were screw speeds (40, 80, 120, 160 and 200 rpm), barrel temperature (100, 120 and 140C) and soy white flakes contents (30, 40 and 50% db). A mesh superposition technique was used to reduce the geometrical complexity. Simulation results were validated quantitatively by experimental data. The results showed good agreement between experimental and computational results. Moreover, the flow profile in the extruder was analyzed by using the influence of screw speed and level of soy white flakes content. Qualitative behavior of local shear rate and viscosity along the screw are analyzed and comparisons of different process conditions are presented. The results of these simulations can be used to optimize processing conditions and also to improve the product quality of extrudates.Practical ApplicationsThe flow of material within the extruder is complicated due to its helical screw configuration and the different zones of solids‐conveying, melting and melts conveying. Shear profile and viscosity of dough within the extruder directly influences the product quality. In the present study, rheological characterization of dough inside the extruder was done by using online capillary die rheometer. The flow of dough during extrusion processing was simulated using computational fluid dynamics. The results of the simulation can be used to optimize the extrusion process influenced by complex flows of relatively high concentration of soy white flakes based dough in an extruder and also to improve the product quality.
Treg subsets in inflammatory bowel disease and colorectal carcinoma: Characteristics, role, and therapeutic targets
Authors: van Herk Egbert H , te Velde Anje A 
Published: March 2016

AbstractT regulatory cells (Tregs) play an important role in the regulation of autoimmunity, autoinflammation, allergic diseases, infection, and the tumor environment. Different subsets are characterized that use a number of regulatory mechanisms. Tregs can influence the progression of inflammatory bowel disease and the development of colorectal cancer. Knowledge of Tregs and their regulatory mechanisms can provide new targets for therapeutic intervention.
Real‐world medical costs of antiviral therapy among patients with chronic HCV infection and advanced hepatic fibrosis
Authors: Maan Raoel , Zaim Remziye , van der Meer Adriaan J , Feld Jordan J , Wedemeyer Heiner , Dufour Jean‐François , Lammert Frank , Manns Michael P , Zeuzem Stefan , Hansen Bettina E , Janssen Harry LA , Veldt Bart J , de Knegt Robert J , Uyl‐de Groot Carin A 
Published: March 2016

AbstractBackground and AimsVery potent direct acting antivirals for the treatment of chronic hepatitis C virus infection were recently introduced into daily clinical practice. Currently, treatment uptake is hampered by their high costs, eliciting prioritization of treatment. We aimed to evaluate the direct medical costs during interferon (IFN)‐based antiviral treatment and the costs per sustained virological response (SVR) among patients with advanced hepatic fibrosis.MethodsThis retrospective cohort study included all consecutive patients with chronic hepatitis C virus infection and biopsy‐proven bridging fibrosis or cirrhosis (Ishak 4–6) treated with IFN‐based regimens in five hepatology units of tertiary care centers in Europe and Canada. Direct medical costs, expressed in 2013 Euros, during therapy were assessed. The components of care were quantified by three distinct categories: treatment, safety/ monitoring, and complications. Cost per SVR was calculated by dividing the mean cost by the SVR rate.ResultsIn total, 672 interferon‐based treatments administered to 455 patients were included. Total medical costs per patient were averaged to €14 559 (95% confidence interval [CI], €13 323–€15 836). The mean cost per SVR was €38 514 (95% CI, €35 244–€41 892). The costs per SVR were €26 105 (95% CI, €23 068–€29 296) for patients with a normal platelet count and €50 907 (95% CI, €44 151–€59 612) for patients with thrombocytopenia, with the costs per SVR of €74 961 (95% CI, €55 463–€103 541) among those patients with a platelet count below 100 * 109/L.ConclusionsBecause of the lower SVR rates, the cost per SVR of IFN‐based treatment increased when patients with more advanced liver disease were treated. Additional costs of IFN‐free therapy could be limited among these patients.
When Comparing Alternative Fuel‐Vehicle Systems, Life Cycle Assessment Studies Should Consider Trends in Oil Production
Authors: Wallington Timothy J. , Anderson James E. , De Kleine Robert D. , Kim Hyung Chul , Maas Heiko , Brandt Adam R. , Keoleian Gregory A. 
Published: March 2016

SummaryPetroleum from unconventional reserves is making an increasingly important contribution to the transportation fuel supply, but is generally more expensive and has greater environmental burdens than petroleum from conventional sources. Life cycle assessments (LCAs) of alternative fuel‐vehicle technologies typically consider conventional internal combustion engine vehicles fueled by gasoline produced from the average petroleum slate used in refineries as a baseline. Large‐scale deployment of alternative fuel‐vehicle technologies will decrease petroleum demand and lead to decreased production at the economic margin (unconventional oil), but this is not considered in most current LCAs. If marginal petroleum resources have larger impacts than average petroleum resources, the environmental benefits of petroleum demand reduction are underestimated by the current modeling approaches. Often, models include some consequential‐based impacts (such as indirect land‐use change for biofuels), but exclude others (such as avoided unconventional oil production). This approach is inconsistent and does not provide a robust basis for public policy and private investment strategy decisions. We provide an example to illustrate the potential scale of these impacts, but further research is needed to establish and quantify these marginal effects and incorporate them into LCAs of both conventional and alternative fuel‐vehicle technologies.
Protein interacting with NIMA (never in mitosis A)‐1 regulates axonal growth cone adhesion and spreading through myristoylated alanine‐rich C kinase substrate isomerization
Authors: Sosa Lucas J. , Malter James S. , Hu Jie , Bustos Plonka Florentyna , Oksdath Mariana , Nieto Guil Alvaro F. , Quiroga Santiago , Pfenninger Karl H. 
Published: March 2016

AbstractAxonal growth cone motility requires precise regulation of adhesion to navigate the complex environment of the nervous system and reach its target. Myristoylated alanine‐rich C kinase substrate (MARCKS) protein is enriched in the developing brain and plays an important, phosphorylation‐dependent role in the modulation of axonal growth cone adhesion. The ratio of phospho‐MARCKS (MARCKS‐P) to total MARCKS controls adhesion modulation and spreading of the axonal growth cone. Pin1, a peptidyl‐prolyl cis/trans isomerase (PPIase) that recognizes and binds to phosphorylated serine/threonine residues preceded by a proline (pSer/Thr‐Pro) is also expressed in the developing brain. Here, we show that Pin1 is present in the growth cone, interacts with MARCKS‐P, and regulates its dephosphorylation. We also described morphological alterations in the corpus callosum and cerebral cortex fibers of the Pin1 knockout mouse brain that may be caused by the misregulation of MARCKS‐P and alterations of neuronal adhesion.
imageWe have shown that MARCKS, a critical protein in the movement of neuronal growth cones, is in turn regulated by both phosphorylation and cis‐trans peptidyl isomerization mediated by Pin1. In the absence of Pin1, MARCKS is hyperphosphorylated, leading to loss of adhesions, and collapse of the growth cone. The Pin1 KO mice exhibited disturbed neuronal projections from the cerebral cortex and reduced white matter tracks such as the corpus callosum. This study highlights a novel function of Pin1 in neurodevelopment.
Sevoflurane prevents stroke‐induced depressive and anxiety behaviors by promoting cannabinoid receptor subtype I‐dependent interaction between β‐arrestin 2 and extracellular signal‐regulated kinases 1/2 in the rat hippocampus
Authors: Zhang Houzhong , Li Li , Sun Yanli , Zhang Xingyi , Zhang Yifan , Xu Shuang , Zhao Peng , Liu Tiecheng 
Published: March 2016

AbstractOne of the most frequent psychological consequences of stroke is depression. Previous animal studies have demonstrated that post‐conditioning with sevoflurane protects against focal cerebral ischemia and reperfusion injury. Thus, we hypothesized that repeated exposure to sevoflurane after transient ischemia can prevent the development of depressive‐like behavior. To test this hypothesis, we induced transient cerebral ischemia via transient occlusion of bilateral common carotid arteries and examined the effects of subsequent repeated exposure to sevoflurane on sucrose preference, locomotor activity, and rearing activity in rats. To explore the putative neurobiological mechanisms, we further investigated the roles of hippocampal CB1 receptor in the behavioral effects of sevoflurane. We found that repeated sevoflurane exposures reversed ischemia‐induced depressive‐like behaviors. Furthermore, CB1 receptor inhibition in the dorsal hippocampus (DH) abolished the effects of sevoflurane exposures on ischemia‐induced depressive‐like behaviors. In addition, repeated sevoflurane exposures increased CB1 receptor expression and endocannabinoids levels in the DH of ischemic rats. Moreover, repeated sevoflurane exposures enhanced the expression of β‐arrestin 2, increased the activation of extracellular signal‐regulated kinases (ERK)1/2, and promoted the interaction of β‐arrestin 2 and ERK1/2 in the DH, and such effects were reversed by CB1 receptor antagonism in the DH. Finally, β‐arrestin 2 expression and ERK1/2 activation in the DH were critical for the preventative effects of sevoflurane exposures on ischemia‐induced depressive‐like behaviors. Taken together, our results suggested that sevoflurane exposure after brain ischemia may prevent the development of depression, and such preventative effects of sevoflurane are likely ascribed to the activation of CB1 receptor‐mediated β‐arrestin 2‐ERK1/2 signaling pathways.
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We propose that the following mechanisms are critical for the preventative effects of sevoflurane against post‐stroke depressive and anxiety behaviors: repeated sevoflurane exposure after transient brain ischemia enhances N‐arachidonoylethanolamine (AEA) and 2‐Arachidonoylglycerol (2‐AG) levels and normalize cannabinoid receptor type 1 (CB1) receptor expression in the dorsal hippocampus, which results in enhanced interaction of β‐arrestin 2 and extracellular signal‐regulated kinases (ERK1/2) and increased ERK1/2 activation, leading to decreased depressive and anxiety behaviors. We think these findings should provide a new strategy for treatment of post‐stroke depression.
Involvement of endogenous antioxidant systems in the protective activity of pituitary adenylate cyclase‐activating polypeptide against hydrogen peroxide‐induced oxidative damages in cultured rat astrocytes
Authors: Douiri Salma , Bahdoudi Seyma , Hamdi Yosra , Cubì Roger , Basille Magali , Fournier Alain , Vaudry Hubert , Tonon Marie‐Christine , Amri Mohamed , Vaudry David , Masmoudi‐Kouki Olfa 
Published: March 2016

AbstractAstroglial cells possess an array of cellular defense mechanisms, including superoxide dismutase (SOD) and catalase antioxidant enzymes, to prevent damages caused by oxidative stress. Nevertheless, astroglial cell viability and functionality can be affected by significant oxidative stress. We have previously shown that pituitary adenylate cyclase‐activating polypeptide (PACAP) is a potent glioprotective agent that prevents hydrogen peroxide (H2O2)‐induced apoptosis in cultured astrocytes. The purpose of this study was to investigate the potential protective effect of PACAP against oxidative‐generated alteration of astrocytic antioxidant systems. Incubation of cells with subnanomolar concentrations of PACAP inhibited H2O2‐evoked reactive oxygen species accumulation, mitochondrial respiratory burst, and caspase‐3 mRNA level increase. PACAP also stimulated SOD and catalase activities in a concentration‐dependent manner, and counteracted the inhibitory effect of H2O2 on the activity of these two antioxidant enzymes. The protective action of PACAP against H2O2‐evoked inhibition of antioxidant systems in astrocytes was protein kinase A, PKC, and MAP‐kinase dependent. In the presence of H2O2, the SOD blocker NaCN and the catalase inhibitor 3‐aminotriazole, both suppressed the protective effects of PACAP on SOD and catalase activities, mitochondrial function, and cell survival. Taken together, these results indicate that the anti‐apoptotic effect of PACAP on astroglial cells can account for the activation of endogenous antioxidant enzymes and reduction in respiration rate, thus preserving mitochondrial integrity and preventing caspase‐3 expression provoked by oxidative stress. Considering its powerful anti‐apoptotic and anti‐oxidative properties, the PACAPergic signaling system should thus be considered for the development of new therapeutical approaches to cure various pathologies involving oxidative neurodegeneration.
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We propose the following cascade for the glioprotective action of Pituitary adenylate cyclase‐activating polypeptide (PACAP) against H2O2‐induced astrocyte damages and cell apoptosis in cultured rat astrocytes. PACAP, through activation of its receptor, PAC1‐R, and the protein kinase A (PKA), protein kinase C (PKC), and MAP‐kinases signaling pathways, prevents accumulation of ROS and inhibition of SOD and catalase activities. This allows the preservation of mitochondrial membrane integrity and the reduction in caspase‐3 activation induced by H2O2. These data may lead to the development of new strategies for cerebral injury treatment. Cat, catalase; Cyt. C, cytochrome C; SOD, superoxide dismutase.
Patients’ experience with intermittent catheterisation in everyday life
Authors: Cobussen‐Boekhorst Hanny , Hermeling Erna , Heesakkers John , van Gaal Betsie 
Published: March 2016

Aims and objectivesThis study reports about the experiences of 11 patients in the Netherlands who use intermittent self‐catheterisation to manage their symptoms. The aim of the study was to get insight in underlying barriers and facilitators for patients dealing with intermittent catheterisation in everyday life.BackgroundStudies show that intermittent catheterisation has an impact on everyday life. A positive effect does not guarantee that patients maintain catheterisation over a longer period of time. After the implementation of a guideline, a quantitative study was performed to determine successful intermittent catheterisation. The patients of this study had previously taken part in this quantitative study.DesignThis is a qualitative multicentre study using semistructured in‐depth interviews with 11 patients between March–May 2013.MethodsInclusion criteria included patients of a quantitative study (n = 124) with a variety of diagnoses referred to the outpatient clinic. Those who received instruction from the researcher and who at start of the study performed catheterisation ≤3 months were excluded. Of the total number that met the inclusion criteria, every fourth patient was invited to participate in an interview. Patients were asked about the introducing of intermittent catheterisation, the incorporation into everyday life, the progress after the instruction and guidance perceived, the cause of the bladder problem and the motivation to start intermittent catheterisation.ResultsEleven interviews were performed (six males/five females). All patients described the instruction and follow‐up care as positive. Barriers were the preparation before the handling, which is more difficult than the catheterisation itself, and the fact that patients felt constrained by the need to plan convenient times to catheterise themselves.ConclusionThis study shows that patients who perform catheterisation are satisfied about the instruction and follow‐up care. Important barriers in everyday life are the preparation and the need to plan convenient times.Relevance to clinical practiceInterviewing patients gave important additional information about dealing with intermittent catheterisation in everyday life. Prescribers and teachers of intermittent catheterisation must realise that they often have to high expectations of patients when it comes to being flexible in frequency of catheterisation. It is important to realise that patients experience barriers of which healthcare workers are not always aware of, such as the preparation before the handling and feeling constrained by the need to plan convenient times to catheterise. The outcome of this study can be used to improve the content of patient information brochures and guidelines for intermittent catheterisation.