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Expectations for safer and sustainable chemicals and products are growing to comply with the United Nations and European strategies for sustainability. The application of Safe(r) by Design (SbD) in nanotechnology implies an iterative process where functionality, human health and safety, environmental and economic impact and cost are assessed and balanced as early as possible in the innovation process and updated at each step. The EU H2020 NanoReg2 project was the first European project to implement SbD in six companies handling and/or manufacturing nanomaterials (NMs) and nano-enabled products (NEP). The results from this experience have been used to develop these guidelines on the practical application of SbD. The SbD approach foresees the identification, estimation, and reduction of human and environmental risks as early as possible in the development of a NM or NEP, and it is based on three pillars: (i) safer NMs and NEP; (ii) safer use and end of life and (iii) safer industrial production. The presented guidelines include a set of information and tools that will help deciding at each step of the innovation process whether to continue, apply SbD measures or carry out further tests to reduce uncertainty. It does not intend to be a prescriptive protocol where all suggested steps have to be followed to achieve a SbD NM/NEP or process. Rather, the guidelines are designed to identify risks at an early state and information to be considered to identify those risks. Each company adapts the approach to its specific needs and circumstances as company decisions influence the way forward., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed Zn 2+ -metallopeptidase that regulates hepatic insulin sensitivity, albeit its regulation in response to the fasting-to-postprandial transition is poorly understood. In this work, we studied the regulation of IDE mRNA and protein levels as well as its proteolytic activity in the liver, skeletal muscle, and kidneys under fasting (18 h) and refeeding (30 min and 3 h) conditions, in mice fed a standard (SD) or high-fat (HFD) diets. In the liver of mice fed an HFD, fasting reduced IDE protein levels (~30%); whereas refeeding increased its activity (~45%) in both mice fed an SD and HFD. Likewise, IDE protein levels were reduced in the skeletal muscle (~30%) of mice fed an HFD during the fasting state. Circulating lactate concentrations directly correlated with hepatic IDE activity and protein levels. Of note, L-lactate in liver lysates augmented IDE activity in a dose-dependent manner. Additionally, IDE protein levels in liver and muscle tissues, but not its activity, inversely correlated ( R 2 = 0.3734 and 0.2951, respectively; p < 0.01) with a surrogate marker of insulin resistance (HOMA index). Finally, a multivariate analysis suggests that circulating insulin, glucose, non-esterified fatty acids, and lactate levels might be important in regulating IDE in liver and muscle tissues. Our results highlight that the nutritional regulation of IDE in liver and skeletal muscle is more complex than previously expected in mice, and that fasting/refeeding does not strongly influence the regulation of renal IDE.

Irrigation water use efficiency, the small size of the orchards, and part-time farmers are major issues for Spanish citriculture. How should irrigation water use efficiency be assessed? Does irrigation water use efficiency improve when increasing the size of the orchards? Are full-time farmers more efficient in irrigation water use than part-time ones? To address these three questions, we propose to apply a new multicriteria approach based on the analytic hierarchy process (AHP) technique and the participation of a group of experts. A new synthetic irrigation efficiency index (IEI) was proposed and tested using data from an irrigation community (IC) and a cooperative of farmers in the East of Spain. The results showed that the size of the orchards had no relation with the IEI scoring but full-time farmers tended to have better IEI scores and, thus, were more efficient. These results were obtained from a sample of 24 orchards of oranges, navelina variety, growing in a very similar environment, and agronomical characteristics. The proposed methodology can be a useful benchmarking tool for improving the irrigation water management in other ICs taking into account the issues related to farm data sharing recorded during the case study.

Hepatic insulin clearance, a physiological process that in response to nutritional cues clears ~50-80% of circulating insulin, is emerging as an important factor in our understanding of the pathogenesis of type 2 diabetes mellitus (T2DM). Insulin-degrading enzyme (IDE) is a highly conserved Zn 2+ -metalloprotease that degrades insulin and several other intermediate-size peptides. Both, insulin clearance and IDE activity are reduced in diabetic patients, albeit the cause-effect relationship in humans remains unproven. Because historically IDE has been proposed as the main enzyme involved in insulin degradation, efforts in the development of IDE inhibitors as therapeutics in diabetic patients has attracted attention during the last decades. In this review, we retrace the path from Mirsky's seminal discovery of IDE to the present, highlighting the pros and cons of the development of IDE inhibitors as a pharmacological approach to treating diabetic patients.

The concept of embodiment has been used in multiple scenarios, but in cognitive neuroscience it normally refers to the comprehension of the role of one's own body in the cognition of everyday situations and the processes involved in that perception. Multisensory research is gradually embracing the concept of embodiment, but the focus has mostly been concentrated upon audiovisual integration. In two experiments, we evaluated how the likelihood of a perceived stimulus to be embodied modulates visuotactile interaction in a Simultaneity Judgement task. Experiment 1 compared the perception of two visual stimuli with and without biological attributes (hands and geometrical shapes) moving towards each other, while tactile stimuli were provided on the palm of the participants' hand. Participants judged whether the meeting point of two periodically-moving visual stimuli was synchronous with the tactile stimulation in their own hands. Results showed that in the hand condition, the Point of Subjective Simultaneity (PSS) was significantly more distant to real synchrony (60 ms after the Stimulus Onset Asynchrony, SOA) than in the geometrical shape condition (45 ms after SOA). In experiment 2, we further explored the impact of biological attributes by comparing performance on two visual biological stimuli (hands and ears), that also vary in their motor and visuotactile properties. Results showed that the PSS was equally distant to real synchrony in both the hands and ears conditions. Overall, findings suggest that embodied visual biological stimuli may modulate visual and tactile multisensory interaction in simultaneity judgements.

Background: Missed adenomas are the main concern for endoscopists. Right colon retroflexion (RCR) seems to increase the adenoma detection rate (ADR), but important variation in success and usefulness of this maneuver has been reported in the literature AIMS: Primary objective: to assess additional adenoma detection rate (AADR) detected during the RCR attempt. Secondary objectives: to assess success rates of RCR, variables associated with it, and safety of RCR., Methods: This is a prospective, unicentric, non-randomized study. Consecutive colonoscopies done by six endoscopists (3 of them with < 3 years of experience and 3 with > 3 years) from March to May 2017 were included. Olympus colonoscopes were used (CF-H190, CF-H180) Demographic, clinical, and endoscopic variables were collected., Results: 463 colonoscopies were included. RCR success rate was 93.1% (431/463 colonoscopies). Forty additional lesions were visualized during RCR in 34/463 colonoscopies (7.3%). Additional adenomas were detected in 31/463 colonoscopies (6.7%; OR 0.07)., Histology: low-grade dysplasia adenomas in 29/40 (72.5%) lesions; 3/40 (7.5%), adenomas with high-grade dysplasia; and 7/40 (17.5%) sessile serrated lesions. Additional adenoma detection contributed to modify the colonoscopy surveillance interval in 25 patients (5.4% of the cohort). Variables associated with RCR success in multivariate analysis were no previous abdominal surgery, length of colonoscope insertion in cecum < 80 cm, and use of Olympus 190 series colonoscopes. No differences between endoscopists' experience were found. RCR was a safe maneuver, with no adverse events in our study., Conclusions: RCR is a feasible and safe maneuver that can increase ADR, so its routine inclusion in colonoscopy practice should be considered.

Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed metalloprotease that degrades insulin and several other intermediate-size peptides. For many decades, IDE had been assumed to be involved primarily in hepatic insulin clearance, a key process that regulates availability of circulating insulin levels for peripheral tissues. Emerging evidence, however, suggests that IDE has several other important physiological functions relevant to glucose and insulin homeostasis, including the regulation of insulin secretion from pancreatic β-cells. Investigation of mice with tissue-specific genetic deletion of Ide in the liver and pancreatic β-cells (L-IDE-KO and B-IDE-KO mice, respectively) has revealed additional roles for IDE in the regulation of hepatic insulin action and sensitivity. In this review, we discuss current knowledge about IDE's function as a regulator of insulin secretion and hepatic insulin sensitivity, both evaluating the classical view of IDE as an insulin protease and also exploring evidence for several non-proteolytic functions. Insulin proteostasis and insulin sensitivity have both been highlighted as targets controlling blood sugar levels in type 2 diabetes, so a clearer understanding the physiological functions of IDE in pancreas and liver could led to the development of novel therapeutics for the treatment of this disease.

Diabetes is one of the most prevalent metabolic diseases and its incidence is increasing throughout the world. Data from World Health Organization (WHO) point-out that diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and lower limb amputation and estimated 1.6 million deaths were directly caused by it in 2016. Population studies show that the incidence of this disease increases in women after menopause, when the production of estrogen is decreasing in them. Knowing the impact that estrogenic signaling has on insulin-secreting β cells is key to prevention and design of new therapeutic targets. This chapter explores the role of estrogen and their receptors in the regulation of insulin secretion and biosynthesis, proliferation, regeneration and survival in pancreatic β cells. In addition, delves into the genetic animal models developed and its application for the specific study of the different estrogen signaling pathways. Finally, discusses the impact of menopause and hormone replacement therapy on pancreatic β cell function., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interest The authors declare no competing interests.

The insulin-degrading enzyme (IDE) is a metalloendopeptidase with a high affinity for insulin. Human genetic polymorphisms in Ide have been linked to increased risk for T2DM. In mice, hepatic Ide ablation causes glucose intolerance and insulin resistance when mice are fed a regular diet., Objective: These studies were undertaken to further investigate its regulatory role in glucose homeostasis and insulin sensitivity in diet-induced obesity., Methods: To this end, we have compared the metabolic effects of loss versus gain of IDE function in mice fed a high-fat diet (HFD)., Results: We demonstrate that loss of IDE function in liver (L-IDE-KO mouse) exacerbates hyperinsulinemia and insulin resistance without changes in insulin clearance but in parallel to an increase in pancreatic β-cell function. Insulin resistance was associated with increased FoxO1 activation and a ~2-fold increase of GLUT2 protein levels in the liver of HFD-fed mice in response to an intraperitoneal injection of insulin. Conversely, gain of IDE function (adenoviral delivery) improves glucose tolerance and insulin sensitivity, in parallel to a reciprocal ~2-fold reduction in hepatic GLUT2 protein levels. Furthermore, in response to insulin, IDE co-immunoprecipitates with the insulin receptor in liver lysates of mice with adenoviral-mediated liver overexpression of IDE., Conclusions: We conclude that IDE regulates hepatic insulin action and whole-body glucose metabolism in diet-induced obesity via insulin receptor levels., Competing Interests: Declaration of competing interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to indentify the involvement of leptin receptors (LepR) in astrocytes in hippocampal synaptic transmission and plasticity and metabolism. To this end we used a genetic mouse model (GFAP-LepR -/- ) of specific LepR ablation in GFAP positive cells and recorded excitatory postsynaptic potentials (fEPSPs) within the CA1 area. Glutamate (Glu) uptake and the expression of Glu transporters (EEAT3, GLT-1 and GLAST) and enzymes involved in Glu metabolism (glutamine synthase, GABA decarboxylase 65 and 67) were quantified. Modifications in the expression of GFAP, the glucose transporter (GLUT)-1, and the monocarboxylate transporters MCT-2 and MCT-4, were also analyzed. The results show that depletion of LepR in GFAP positive cells reduced basal synaptic transmission within the CA1 area and impaired N-methyl-d-aspartate (NMDA)-evoked long-term depression (NMDA-LTD). Hippocampal slices from GFAP-LepR -/- mice displayed lower Glu uptake efficacy together with up-regulation of GLT-1, glutamine synthase, GFAP and GLUT-1. In conclusion, astrocyte LepRs are involved in the maintenance of Glu homeostasis and Glu neurotransmission within the hippocampus. Our findings support a role of hippocampal LepRs in synaptic plasticity, which could have an impact on memory and learning processes., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Examining the processing of others' body-related information in the perceivers' brain (action observation) is a key topic in cognitive neuroscience. However, what happens beyond the perceptual stage, when the body is not within view and it is transformed into an associative form that can be stored, updated, and later recalled, remains poorly understood. Here we examine neurobehavioural evidence on the memory processing of visually perceived bodily stimuli (dynamic actions and images of bodies). The reviewed studies indicate that encoding and maintaining bodily stimuli in memory recruits the sensorimotor system. This process arises when bodily stimuli are either recalled through action recognition or reproduction. Interestingly, the memory capacity for these stimuli is rather limited: only 2 or 3 bodily stimuli can be simultaneously held in memory. Moreover, this process is disrupted by increasing concurrent bodily operations; i.e., moving one's body, seeing or memorising additional bodies. Overall, the evidence suggests that the neural circuitry allowing us to move and feel ourselves supports the encoding, retention, and memory recall of others' visually perceived bodies., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The ability to experience others' emotional states is a key component in social interactions. Uniquely among sensorimotor regions, the somatosensory cortex (SCx) plays an especially important role in human emotion understanding. While distinct emotions are experienced in specific parts of the body, it remains unknown whether the SCx exhibits somatotopic activations to different emotional expressions. In the current study, we investigated if the affective response triggered by observing others' emotional face expressions leads to differential activations in SCx. Participants performed a visual facial emotion discrimination task while we measured changes in SCx topographic EEG activity by tactually stimulating two body-parts representative of the upper and lower limbs, the finger and the toe respectively. The results of the study showed an emotion specific response in the finger SCx when observing angry as opposed to sad emotional expressions, after controlling for carry-over effects of visual evoked activity. This dissociation to observed emotions was not present in toe somatosensory responses. Our results suggest that somatotopic activations of the SCx to discrete emotions might play a crucial role in understanding others' emotions., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Examining the processing of others' body-related information in the perceivers' brain across the neurotypical and clinical population is a key topic in the domain of cognitive neurosciences. We argue that beyond classical neuroimaging techniques and frequency analyses, methods that can be easily adapted to capture the fast processing of body-related information in the brain are needed. Here we introduce a novel method that allows this by measuring event-related potentials recorded with electroencephalography (ERPs-EEG). This method possesses known EEG advantages (low cost, high temporal resolution, established paradigms) plus an improvement of its main limitation; i.e., spatiotemporally smoothed resolution due to mixed neural sources. This occurs when participants are presented and process images of bodies/actions that recruit posterior visual cortices. Such stimulus-evoked activity may spread and mask the recording of simultaneous activity arising from sensorimotor brain areas, which also process body-related information. Therefore, it is difficult to dissociate the contributing role of different brain regions. To overcome this, we propose eliciting a combination of somatosensory, motor, and visual-evoked potentials during processing of body-related information (vs non-body-related). Next, brain activity from sensorimotor and visual systems can be dissociated by subtracting activity from trials containing only visual-evoked potentials to those trials containing either a mixture of visual and somatosensory or visual and motor-cortical potentials. This allows isolating visually driven neural activity in areas other than visual. To introduce this method, we revise recent work using this method, consider the processing of body-related stimuli in the brain, as well as outline key methodological aspects to-be-considered. This work provides a clear guideline to researchers interested or transitioning from behavioural to ERPs studies, offering the possibility to adapt well-established paradigms in the EEG realm to study others' body-related processing in the perceiver's own cortical body representation (e.g., examining classical EEG components in the social and embodiment frameworks)., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The worldwide epidemics of obesity and diabetes have been linked to increased sugar consumption in humans. Here, we review fructose and glucose metabolism, as well as potential molecular mechanisms by which excessive sugar consumption is associated to metabolic diseases and insulin resistance in humans. To this end, we focus on understanding molecular and cellular mechanisms of fructose and glucose transport and sensing in the intestine, the intracellular signaling effects of dietary sugar metabolism, and its impact on glucose homeostasis in health and disease. Finally, the peripheral and central effects of dietary sugars on the gut-brain axis will be reviewed.

Background: post-sphyncterotomy endoscopic retrograde cholangiopancreatography (ERCP) bleeding is an adverse event with an estimated incidence rate of 1.34%. There is no established consensus about how to treat this particular type of gastrointestinal bleed. Placement of fully covered self-expandable biliary metal stents (FCSEBMS) has been evaluated as an alternative treatment with positive outcomes and a low complication rate., Aim: to report the results of a cohort of patients with post-sphyncterotomy bleeding treated in a tertiary care referral hospital with FCSEBMS., Methods: a retrospective cases series study was performed including all post-ERCP bleeds treated with FCSEBMS (immediate or delayed) from January 2015 to June 2017. Clinical data, laboratory results and endoscopic reports were collected in order to evaluate the rebleeding rate after endoscopic treatment. Two different scenarios were considered: a) prophylactic stent placement after effective endoscopic treatment; and b) stents placed for the treatment of an active postsphyncterotomy bleed, refractory to standard endoscopic therapy., Results: twenty-two patients (14 male, eight women) diagnosed with postsphyncterotomy bleeding were treated with FCSEBMS placement. The stents were placed prophylactically in 15 patients, while the stents were placed as a treatment for a refractory bleed in seven patients. No differences were found between both groups except for a higher anticoagulation rate in the treatment group. Clinical success was achieved in all but one patient, with no complications in relation to stent placement. Distal migration was described in two of the 22 patients included in the study., Conclusions: temporary placement of FCSEBMS seems to be a technically feasible treatment option for post-ERCP bleeding with a high clinical success rate. The complication rate was low, although randomized studies are needed.

Inhibition of insulin-degrading enzyme (IDE) has been proposed as a possible therapeutic target for type 2 diabetes treatment. However, many aspects of IDE's role in glucose homeostasis need to be clarified. In light of this, new preclinical models are required to elucidate the specific role of this protease in the main tissues related to insulin handling. To address this, here we generated a novel line of mice with selective deletion of the Ide gene within pancreatic beta-cells, B-IDE-KO mice, which have been characterized in terms of multiple metabolic end points, including blood glucose, plasma C-peptide, and intraperitoneal glucose tolerance tests. In addition, glucose-stimulated insulin secretion was quantified in isolated pancreatic islets and beta-cell differentiation markers and insulin secretion machinery were characterized by RT-PCR. Additionally, IDE was genetically and pharmacologically inhibited in INS-1E cells and rodent and human islets, and insulin secretion was assessed. Our results show that, in vivo, life-long deletion of IDE from beta-cells results in increased plasma C-peptide levels. Corroborating these findings, isolated islets from B-IDE-KO mice showed constitutive insulin secretion, a hallmark of beta-cell functional immaturity. Unexpectedly, we found 60% increase in Glut1 (a high-affinity/low- K m glucose transporter), suggesting increased glucose transport into the beta-cell at low glucose levels, which may be related to constitutive insulin secretion. In parallel, IDE inhibition in INS-1E and islet cells resulted in impaired insulin secretion after glucose challenge. We conclude that IDE is required for glucose-stimulated insulin secretion. When IDE is inhibited, insulin secretion machinery is perturbed, causing either inhibition of insulin release at high glucose concentrations or constitutive secretion.

Background and Purpose: A cholecystokinin (CCK) system has been identified in white adipose tissue (WAT). Nevertheless, the endocrine actions of CCK on WAT remain unknown. Our goal was to investigate the role of CCK in regulating the production of adiponectin, an adipokine expressed in WAT, which is pivotal in preserving energy homeostasis., Experimental Approach: The effect of the bioactive CCK fragment CCK-8 on adiponectin production was studied both in vivo and in vitro. CCK-8 effects were characterized in rats treated with selective CCK 1 and CCK 2 receptor antagonists as well as in pre-adipocytes carrying the selective silencing of either CCK 1 or CCK 2 receptors. The influence of insulin on CCK-8 responses was also analysed., Key Results: In WAT, CCK-8 increased plasma adiponectin levels and the expression of the adiponectin gene (Adipoq). In pre-adipocytes, CCK-8 up-regulated adiponectin production. CCK-8 effects were abolished by L-365,260, a selective CCK 2 receptor antagonist. CCK 2 receptor knockdown also abolished the effects of CCK-8 in pre-adipocytes. Moreover, in vitro CCK-8 effects were blocked by triciribine, a specific inhibitor of protein kinase B (Akt) and by the PPARγ antagonist T0070907. Silencing the expression of the insulin receptor inhibited CCK-8-induced Adipoq expression in pre-adipocytes. Furthermore, insulin potentiated the effect of CCK-8., Conclusion and Implications: CCK-8 stimulates adiponectin production in WAT by acting on CCK 2 receptors, through a mechanism involving both Akt and PPARγ. Moreover, CCK-8 actions are only observed in the presence of insulin. Our results could have translational value in the design of new insulin-sensitizing therapies., (© 2019 The British Pharmacological Society.)

Background: Non-alcoholic fatty liver disease (NAFLD), a condition that leads to fibrosis, is caused by intake of very high-fat diets (HFDs). However, while the negative impact on the liver of these diets has been an issue of interest, systematic research on the effect of HFDs are lacking., Objective: To characterize the overall impact of HFDs on both molecular and morphological signs of liver remodeling., Methods: A study was conducted on male C57BL/6J mice to assess the effect of 4- and 8-week HFDs (60% kcal from fat) on (i) liver steatosis and fibrosis, and (ii) expression of factors involved in inflammation and angiogenesis., Results: After an 8-week HFD, vascular endothelial growth factor type-2 receptor (VEGF-R2) and fatty acid translocase/trombospondin-1 receptor (CD36) were overexpressed in liver tissue of mice given HFDs. These changes suggest impaired liver angiogenesis and occurred together with (i) increased GPR78-BiP and EIF2α phosphorylation, suggesting endoplasmic reticulum stress, (ii) induction of Col1a1 gene expression, a marker of fibrosis, and (iii) increased CD31 immunolabeling, consistent with active angiogenesis and fibrosis., Conclusion: Our data show that very HFDs promote a rapid inflammatory response, as well as deregulation of angiogenesis, both consistent with development of liver fibrosis., (Copyright © 2019 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.)

Purposes: The purpose of this study was to compare the efficacy of a mineral-rich solution vs normal saline solution (0.9% NaCl) following endoscopic complete bilateral ethmoidectomy., Methods: This was a prospective, multicenter, randomized, controlled, open-label trial in subjects suffering from steroid-resistant sinonasal polyposis. Adults performed 4 nasal irrigations of mineral or saline solutions daily for 28 days. Evaluations included subject-reported RHINO quality of life (QoL) and NOSE scores, tolerability, and satisfaction, the Lund-Kennedy endoscopic score and assessments of crusting, secretions and mucociliary clearance (rhinoscintigraphy)., Results: A total of 189 subjects were randomized. Clinically relevant improvements (> 20 points) in RhinoQOL and NOSE scores were measured in both groups without any significant inter-group difference. Among the subjects with impaired RhinoQOL at pre-inclusion, the change in Impact-RhinoQOL score was significantly superior in mineral-rich vs saline solution at day 21 (p = 0.028) and day 28 (p = 0.027). The Lund-Kennedy score continuously improved in both groups earlier with the mineral-rich solution. Crusts were significantly fewer in number and less severe/obstructive in patients receiving mineral-rich vs saline solution at day 7 (p = 0.026) and day 14 (p = 0.016). Furthermore, secretions disappeared significantly more quickly and were less thick/purulent with mineral-rich solution at day 14 (p = 0.002) and day 21 (p = 0.043). Less epistaxis was reported in the mineral vs saline solution (p = 0.008 at day 21)., Conclusions: Our findings indicate that the composition of a nasal irrigation solution influences endoscopic scores and QoL after sinus surgery for patients over 60, those with an initially poor QoL and higher symptom score, and smokers.

Although there is growing evidence that cortistatin regulates several functions in different tissues, its role in the endocrine pancreas is not totally known. Here, we aim to study the effect of cortistatin on pancreatic beta-cells and glucose-stimulated insulin secretion (GSIS). Exposure of isolated mouse islets to cortistatin inhibited GSIS. This effect was prevented using a somatostatin receptor antagonist. Additionally, cortistatin hyperpolarized the membrane potential and reduced glucose-induced action potentials in isolated pancreatic beta-cells. Cortistatin did not modify ATP-dependent K + (K ATP ) channel activity. In contrast, cortistatin increased the activity of a small conductance channel with characteristics of G protein-coupled inwardly rectifying K + (GIRK) channels. The cortistatin effects on membrane potential and GSIS were largely reduced in the presence of a GIRK channel antagonist and by down-regulation of GIRK2 with small interfering RNA. Thus, cortistatin acts as an inhibitory signal for glucose-induced electrical activity and insulin secretion in the mouse pancreatic beta-cell., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The role of insulin-degrading enzyme (IDE), a metalloprotease with high affinity for insulin, in insulin clearance remains poorly understood., Objective: This study aimed to clarify whether IDE is a major mediator of insulin clearance, and to define its role in the etiology of hepatic insulin resistance., Methods: We generated mice with liver-specific deletion of Ide (L-IDE-KO) and assessed insulin clearance and action., Results: L-IDE-KO mice exhibited higher (~20%) fasting and non-fasting plasma glucose levels, glucose intolerance and insulin resistance. This phenotype was associated with ~30% lower plasma membrane insulin receptor levels in liver, as well as ~55% reduction in insulin-stimulated phosphorylation of the insulin receptor, and its downstream signaling molecules, AKT1 and AKT2 (reduced by ~40%). In addition, FoxO1 was aberrantly distributed in cellular nuclei, in parallel with up-regulation of the gluconeogenic genes Pck1 and G6pc. Surprisingly, L-IDE-KO mice showed similar plasma insulin levels and hepatic insulin clearance as control mice, despite reduced phosphorylation of the carcinoembryonic antigen-related cell adhesion molecule 1, which upon its insulin-stimulated phosphorylation, promotes receptor-mediated insulin uptake to be degraded., Conclusion: IDE is not a rate-limiting regulator of plasma insulin levels in vivo., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent studies suggest that brain regions engaged in perception are also recruited during the consolidation interval of the percept in working memory (WM). Evidence for this comes from studies showing that maintaining arbitrary visual, auditory, and tactile stimuli in WM elicits recruitment of the corresponding sensory cortices. Here we investigate if encoding and WM maintenance of visually perceived body-related stimuli engage just visual regions, or additional sensorimotor regions that are classically associated with embodiment processes in studies of body and action perception. We developed a novel WM paradigm in which participants were asked to remember body and control non-body-related images. In half of the trials, visual-evoked activity that was time-locked to the sight of the stimuli allowed us to examine visual processing of the stimuli to-be-remembered (visual-only trials). In the other half of the trials we additionally elicited a task irrelevant key pressing during the consolidation interval of the stimuli in WM. This manipulation elicited motor-cortical potentials (MCPs) concomitant to visual processing (visual-motor trials). This design allowed us to dissociate motor activity depicted in the MCPs from concurrent visual processing by subtracting activity from the visual-only trials to the compound activity found in the visual-motor trials. After dissociating the MCPs from concomitant visual activity, the results show that only the body-related images elicited neural recruitment of sensorimotor regions over and above visual effects. Importantly, the number of body stimuli to-be-remembered (memory load) modulated this later motor cortical activity. The current observations link together research in embodiment and WM by suggesting that neural recruitment is driven by the nature of the information embedded in the percept., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

Quattrocki and Friston (2014) argued that abnormalities in interoception-the process of representing one's internal physiological states-could lie at the heart of autism, because of the critical role interoception plays in the ontogeny of social-affective processes. This proposal drew criticism from proponents of the alexithymia hypothesis, who argue that social-affective and underlying interoceptive impairments are not a feature of autism per se, but of alexithymia (a condition characterized by difficulties describing and identifying one's own emotions), which commonly co-occurs with autism. Despite the importance of this debate for our understanding of autism spectrum disorder (ASD), and of the role of interoceptive impairments in psychopathology, more generally, direct empirical evidence is scarce and inconsistent. Experiment 1 examined in a sample of 137 neurotypical (NT) individuals the association among autistic traits, alexithymia, and interoceptive accuracy (IA) on a standard heartbeat-tracking measure of IA. In Experiment 2, IA was assessed in 46 adults with ASD (27 of whom had clinically significant alexithymia) and 48 NT adults. Experiment 1 confirmed strong associations between autistic traits and alexithymia, but yielded no evidence to suggest that either was associated with interoceptive difficulties. Similarly, Experiment 2 provided no evidence for interoceptive impairments in autistic adults, irrespective of any co-occurring alexithymia. Bayesian analyses consistently supported the null hypothesis. The observations pose a significant challenge to notions that interoceptive impairments constitute a core feature of either ASD or alexithymia, at least as far as the direct perception of interoceptive signals is concerned. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Aim: Cholecystokinin (CCK) participates in the storage of dietary triglycerides in white adipose tissue (WAT). Our goal was to characterize, both in subcutaneous (Sc-WAT) and visceral WAT (Vis-WAT), the functional expression of the two known CCK receptors, CCK-1 (CCK-1R) and CCK-2 (CCK-2R), as well as of CCK., Main Methods: Gene and protein expression was assessed in different cell types of rat and human WAT by means of RT-PCR and western-blot, respectively. The functionality of CCK-Rs was tested by quantifying protein kinase B (Akt) phosphorylation after treatment of pre-adipocytes with the bioactive fragment of CCK, CCK-8. The CCK receptor subtype involved in Akt phosphorylation was investigated by using selective CCK-1R (SR-27,897) and CCK-2R antagonists (L-365,260)., Key Findings: In rats, CCK-1R (Cckar) and CCK-2R (Cckbr) gene expression was detected in the two types of WAT analyzed as well as in isolated adipocytes, mesenchymal stem cells and pre-adipocytes. CCK-1R and CCK-2R proteins were identified in adipocytes and, to a minor extent, in pre-adipocytes. In addition, CCK-2R were detected in subcutaneous mesenchymal stem cells. Gene expression of the CCK precursor preproCCK as well as CCK immunoreactivity were also found in Sc-WAT and Vis-WAT. In human WAT, CCK gene expression as well as CCK-2Rs and CCK were also identified. CCK-8 evoked Akt phosphorylation in rat pre-adipocytes, and this effect was antagonized by SR-27,897 and L-365,260., Significance: Our data show that both human and rat WAT express a complete CCK system, and suggest that CCK may have an autocrine/paracrine role in regulating adipose tissue biology., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This article describes the procedure of definition and design of a process for the continuity care unit to improve the attention to the patient and his/her ecosystem providing a novel alternative to the conventional methods. This work was done under the framework of the MiniQ project, funded by EIT Health to improve the management of poly-medicated patients.

Manufactured nanomaterials (MNMs) are regarded as key components of innovations in various fields with high potential impact (e.g., energy generation and storage, electronics, photonics, diagnostics, theranostics, or drug delivery agents). Widespread use of MNMs raises concerns about their safety for humans and the environment, possibly limiting the impact of the nanotechnology-based innovation. The development of safe MNMs and nanoproducts has to result in a safe as well as functional material or product. Its safe use, and disposal at the end of its life cycle must be taken into account too. However, not all MNMs are similarly useful for all applications, some might bear a higher hazard potential than others, and use scenarios could lead to different exposure probabilities. To improve both safety and efficacy of nanotechnology, we think that a new proactive approach is necessary, based on pre-regulatory safety assessment and dialogue between stakeholders. On the basis of the work carried out in different European Union (EU) initiatives, developing and integrating MNMs Safe-by-Design and Trusted Environments (NANoREG, ProSafe, and NanoReg2), we present our point of view here. This concept, when fully developed, will allow for cost effective industrial innovation, and an exchange of key information between regulators and innovators. Regulators are thus informed about incoming innovations in good time, supporting a proactive regulatory action. The final goal is to contribute to the nanotechnology governance, having faster, cheaper, effective, and safer nano-products on the market., Competing Interests: The authors declare no conflict of interest.

Interoception is the process of perceiving afferent signals arising from within the body including heart rate (HR), gastric signals, etc., and has been described as a mechanism crucially involved in the creation of self-awareness and selfhood. The heartbeat perception task is a tool to measure individuals' interoceptive accuracy (IAcc). IAcc correlates positively with measures of self-awareness and with attributes including emotional sensitivity, empathy, prosocial behavior, and efficient decision making. IAcc is only moderate in the general population, and attempts to identify groups of people who might have higher IAcc due to their specific training (e.g., yoga, meditation) have not been successful. However, a recent study with musicians suggests that those trained in the arts might exhibit high IAcc. Here, we tested IAcc in 20 professional dancers and 20 female control participants on a heartbeat perception task. Dancers had a higher IAcc, and this effect was independent of their lower heart rates (a proxy measure of physical fitness), counting ability, and knowledge about HR. An additional between-groups analysis after a median split in the dancer group (based on years of dance experience) showed that junior dancers' IAcc differed from controls, and senior dancers' IAcc was higher than both junior dancers and controls. General art experience correlated positively with IAcc. No correlations were found between IAcc and questionnaire measures of empathy, emotional experience, and alexithymia. These findings are discussed in the context of current theories of interoception and emotion-highlighting the features of arts training that might be related to IAcc., (© 2017 Society for Psychophysiological Research.)

The incorporation of plasma triglyceride (TG) fatty acids to white adipose tissue (WAT) depends on lipoprotein lipase (LPL), which is regulated by angiopoietin-like protein-4 (ANGPTL-4), an unfolding molecular chaperone that converts active LPL dimers into inactive monomers. The production of ANGPTL-4 is promoted by fasting and repressed by feeding. We hypothesized that the postprandial hormone cholecystokinin (CCK) facilitates the storage of dietary TG fatty acids in WAT by regulating the activity of the LPL/ANGPTL-4 axis and that it does so by acting directly on CCK receptors in adipocytes. We report that administration of CCK-8 (a bioactive fragment of CCK) to rats: (i) reduces plasma ANGTPL-4 levels; (ii) represses Angptl-4 expression in WAT and (iii) simultaneously enhances LPL activity in this tissue without inducing Lpl expression. In vivo CCK-8 effects are specifically antagonized by the CCK-2 receptor (CCK-2R) antagonist, L-365,260. Moreover, CCK-8 downregulates Angptl-4 expression in wild-type pre-adipocytes, an effect that is not observed in engineered pre-adipocytes lacking CCK-2R. These effects have functional consequences as CCK-8 was found to promote the uptake of dietary fatty acids by WAT, as demonstrated by means of proton nuclear magnetic resonance ( 1 H-NMR). The efficacy of acute CCK-8 administration was not reduced after chronic CCK-8 treatment. Moreover, the effects of CCK-8 on WAT were not associated to the increase of circulating insulin. Our results show that cholecystokinin promotes lipid storage in WAT by acting on adipocyte CCK-2R, suggesting a pivotal role for CCK in TG homeostasis., (© 2018 Society for Endocrinology.)

Background: Narrow band imaging (NBI) allows identification of abnormal areas of Barrett's esophagus (BE) and could facilitate targeted biopsies., Aims: We evaluated the diagnostic accuracy for dysplasia prediction using non-magnifying NBI in Evis Exera III processors and high-definition endoscopes using the Barrett International NBI Group (BING) classification, as well as inter/intraobserver agreement for dysplasia prediction and mucosal/vascular patterns., Methods: Eight observers (4 staff endoscopists and 4 trainee endoscopists) evaluated 100 images selected from an anonymized bank of 470 photographs using the BING classification. Observers were to assign their individual assessment of the mucosal and vascular pattern, and prediction for dysplasia. Accuracy for dysplasia prediction and intra/interobserver agreement was calculated., Results: Dysplasia prediction had an accuracy of 81.1%, sensitivity of 48.4%, and a specificity of 91%. Positive predictive value and negative predictive value (NPV) were 61.4 and 85.5%, respectively. Dysplasia prediction done with a high degree of confidence (vs. low degree of confidence) had better diagnostic accuracy (85.8 vs. 70.7%). Interobserver concordance for dysplasia was weak: Κ = 0.40. Agreement for mucosal and vascular patterns was 0.39 and 0.30, respectively. Intraobserver concordance (assessed 6 months after initial test) for mucosal pattern, vascular pattern, and dysplasia prediction was moderate: Κ = 0.56, Κ = 0.47 and Κ = 0.60, respectively., Conclusions: Our results showed that NBI had a significant accuracy in BE assessment for dysplasia prediction, high specificity (>90%), and NPV (>85%), with suboptimal sensitivity. NBI could be a useful additional tool for BE inspection and targeted biopsies, but cannot avoid the need for biopsies following the Seattle protocol.

Introduction: Benign esophageal strictures are relatively frequent and can severely affect the quality of life of a patient. Stenting has been proposed for the treatment of refractory cases. Lesions affecting the cervical esophagus are more difficult to treat, and the placement of stents in this location has traditionally been restricted due to potential adverse events. The aim of this study was to describe the efficacy and safety of endoscopic stenting in the management of refractory benign cervical esophageal strictures (RBCES) in a single-center cohort study., Methods: We analyzed 12 patients with RBCES (Kochman's criteria) and severe dysphagia. We recorded previous endoscopic treatments, stricture characteristics and demographic data. The two types of stents used were fully covered self-expandable metallic stents (FCSEMS) and uncovered biodegradable stents (BDS). FCSEMS were removed eight weeks after placement, and BDS were followed-up until degradation. We assessed technical and clinical success, rate of stricture recurrence and adverse events., Results: The mean age of participants was 64 years (range 30-85). A total of 23 stents (13 FCSEMS and 10 BDS) were placed in 12 patients (median 1.92, range 1-4). The technical success rate was 96% (22/23 stents). Eight patients (66.6%) maintained adequate oral intake at the end of follow-up (median 33.3 months, range 3-84 months). Migration was recorded in 7/23 stents (30.4%) and epithelial hyperplasia in 4/23 stents (17.4%). No severe adverse events were noted. All patients complained of minor cervical pain after placement that was well controlled with mild analgesia., Conclusions: Endoscopic stent therapy seems to be effective and safe in the management of RBCES.

Introduction: Colon capsule endoscopy (CCE) is an alternative approach for the examination of the colon in patients who refuse colonoscopy or after incomplete colonoscopy (IC). We conducted a study to determine the frequency of complete colonoscopy after IC, the diagnostic yield of CCE, the therapeutic impact of lesions found in CCE, the level of colon cleanliness and the safety of the procedure., Methods: We performed a prospective, multicenter study involving ten Spanish hospitals. Consecutive outpatients aged ≥ 18 years with previous IC were invited to participate. The latest version of the CCE device, PillCam™ COLON 2 (CCE-2), was administered to all patients according to the protocol., Results: The study population comprised 96 patients. The most frequent cause of IC was the inability to move past a loop using standard maneuvers (75/96 patients, 78%). Complete visualization of the colon was obtained with CCE-2 in 69 patients (71.9%). Of the 27 patients in whom the CCE-2 did not reach the hemorrhoidal plexus, it passed the colonic segment explored with the previous colonoscopy in 20 cases; therefore, it could be inferred that a combined approach (CCE-2 plus colonoscopy) enabled complete visualization of the colonic mucosa in 92.7% of patients. CCE-2 revealed new lesions in 58 patients (60.4%). Polyps were the most frequent finding (41 patients; 42.7% of the total number of patients). In 43 of the 58 patients (44.8% of the total number of patients), the new lesions observed led to modification of therapy, which included a new colonoscopy for polyp resection or surgery in patients with colonic neoplasm., Conclusions: CCE-2 is a suitable diagnostic procedure that can lead to more frequent diagnosis of significant colonic lesions after IC.

With the growing numbers of nanomaterials (NMs), there is a great demand for rapid and reliable ways of testing NM safety-preferably using in vitro approaches, to avoid the ethical dilemmas associated with animal research. Data are needed for developing intelligent testing strategies for risk assessment of NMs, based on grouping and read-across approaches. The adoption of high throughput screening (HTS) and high content analysis (HCA) for NM toxicity testing allows the testing of numerous materials at different concentrations and on different types of cells, reduces the effect of inter-experimental variation, and makes substantial savings in time and cost. HTS/HCA approaches facilitate the classification of key biological indicators of NM-cell interactions. Validation of in vitro HTS tests is required, taking account of relevance to in vivo results. HTS/HCA approaches are needed to assess dose- and time-dependent toxicity, allowing prediction of in vivo adverse effects. Several HTS/HCA methods are being validated and applied for NM testing in the FP7 project NANoREG, including Label-free cellular screening of NM uptake, HCA, High throughput flow cytometry, Impedance-based monitoring, Multiplex analysis of secreted products, and genotoxicity methods-namely High throughput comet assay, High throughput in vitro micronucleus assay, and γH2AX assay. There are several technical challenges with HTS/HCA for NM testing, as toxicity screening needs to be coupled with characterization of NMs in exposure medium prior to the test; possible interference of NMs with HTS/HCA techniques is another concern. Advantages and challenges of HTS/HCA approaches in NM safety are discussed. WIREs Nanomed Nanobiotechnol 2017, 9:e1413. doi: 10.1002/wnan.1413 For further resources related to this article, please visit the WIREs website., (© 2016 The Authors. WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals, Inc.)

Alterations during development of metabolic key organs such as the endocrine pancreas affect the phenotype later in life. There is evidence that in utero or perinatal exposure to bisphenol-A (BPA) leads to impaired glucose metabolism during adulthood. However, how BPA exposure during pregnancy affects pancreatic β-cell growth and function in offspring during early life has not been explored. We exposed pregnant mice to either vehicle (control) or BPA (10 and 100 μg/kg·d, BPA10 and BPA100) and examined offspring on postnatal days (P) P0, P21, P30, and P120. BPA10 and BPA100 mice presented lower birth weight than control and subsequently gained weight until day 30. At that age, concentration of plasma insulin, C-peptide, and leptin were increased in BPA-exposed animals in the nonfasting state. Insulin secretion and content were diminished in BPA10 and maintained in BPA100 compared with control. A global gene expression analysis indicated that genes related with cell division were increased in islets from BPA-treated animals. This was associated with an increase in pancreatic β-cell mass at P0, P21, and P30 together with increased β-cell proliferation and decreased apoptosis. On the contrary, at P120, BPA-treated animals presented either equal or decreased β-cell mass compared with control and altered fasting glucose levels. These data suggest that in utero exposure to environmentally relevant doses of BPA alters the expression of genes involved in β-cell growth regulation, incrementing β-cell mass/area, and β-cell proliferation during early life. An excess of insulin signaling during early life may contribute to impaired glucose tolerance during adulthood.

The present study shows how motor expertise increases individuals' sensitivity to others' affective body movement. This enhanced sensitivity is evident in the experts' behavior and physiology. Nineteen affective movement experts (professional ballet dancers) and 24 controls watched 96 video clips of emotionally expressive body movements while they performed an affect rating task (subjective response), and their galvanic skin response was recorded (physiological response). The movements in the clips were either sad or happy, and in half of the trials, movements were played in the order in which they are learned (forward presentation), and in the other half, movements were played backward (control condition). Results showed that motor expertise in affective body movement specifically modulated both behavioral and physiological sensitivity to others' affective body movement, and that this sensitivity is particularly strong when movements are shown in the way they are learnt (forward presentation). The evidence is discussed within current theories of proprioceptive arousal feedback and motor simulation accounts. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

Objective: While bile acids are important for the digestion process, they also act as signaling molecules in many tissues, including the endocrine pancreas, which expresses specific bile acid receptors that regulate several cell functions. In this study, we investigated the effects of the conjugated bile acid TUDCA on glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells., Methods: Pancreatic islets were isolated from 90-day-old male mice. Insulin secretion was measured by radioimmunoassay, protein phosphorylation by western blot, Ca(2+) signals by fluorescence microscopy and ATP-dependent K(+) (KATP) channels by electrophysiology., Results: TUDCA dose-dependently increased GSIS in fresh islets at stimulatory glucose concentrations but remained without effect at low glucose levels. This effect was not associated with changes in glucose metabolism, Ca(2+) signals or KATP channel activity; however, it was lost in the presence of a cAMP competitor or a PKA inhibitor. Additionally, PKA and CREB phosphorylation were observed after 1-hour incubation with TUDCA. The potentiation of GSIS was blunted by the Gα stimulatory, G protein subunit-specific inhibitor NF449 and mimicked by the specific TGR5 agonist INT-777, pointing to the involvement of the bile acid G protein-coupled receptor TGR5., Conclusion: Our data indicate that TUDCA potentiates GSIS through the cAMP/PKA pathway., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Encapsulating chemotherapy drugs in targeted nanodelivery systems is one of the most promising approaches to tackle cancer disease, avoiding side effects of common treatment. In the last decade, several nanocarriers with different nature have been tested, but polypeptide-based copolymers have attracted considerable attention for their biocompatibility, controlled and slow biodegradability as well as their low toxicity. In this work, we synthesized, characterized and evaluated poly(trimethylene carbonate)-bock-poly(L-glutamic acid) derived polymersomes, targeted to epidermal growth factor receptor (EGFR), loaded with plitidepsin and ultimately tested in HT29 and LS174T colorectal cancer cell lines for specificity and efficacy. Furthermore, morphology, physico-chemical properties and plitidepsin loading were carefully investigated. A thorough in vitro cytotoxicity analysis of the unloaded polymersomes was carried out for biocompatibility check, studying viability, cell membrane asymmetry and reactive oxygen species levels. Those cytotoxicity assays showed good biocompatibility for plitidepsin-unloaded polymersomes. Cellular uptake and cytotoxic effect of EGFR targeted and plitidepsin loaded polymersome indicated that colorectal cancer cell lines were.more sensitive to anti-EGFR-drug-loaded than untargeted drug-loaded polymersomes. Also, in both cell lines, the use of untargeted polymersomes greatly reduced plitidepsin cytotoxicity as well as the cellular uptake, indicating that the use of this targeted nanocarrier is a promising approach to tackle colorectal cancer disease and avoid the undesired effects of the usual treatment. Furthermore, in vivo assays support the in vitro conclusions that EGFR targeted polymersomes could be a good drug delivery system. This work provides a proof of concept for the use of encapsulated targeted drugs as future therapeutic treatments for cancer.

Current models of emotion simulation propose that intentionally posing a facial expression can change one's subjective feelings, which in turn influences the processing of visual input. However, the underlying neural mechanism whereby one's facial emotion modulates the visual cortical responses to other's facial expressions remains unknown. To understand how one's facial expression affects visual processing, we measured participants' visual evoked potentials (VEPs) during a facial emotion judgment task of positive and neutral faces. To control for the effects of facial muscles on VEPs, we asked participants to smile (adopting an expression of happiness), to purse their lips (incompatible with smiling) or to pose with a neutral face, in separate blocks. Results showed that the smiling expression modulates face-specific visual processing components (N170/vertex positive potential) to watching other facial expressions. Specifically, when making a happy expression, neutral faces are processed similarly to happy faces. When making a neutral expression or pursing the lips, however, responses to neutral and happy face are significantly different. This effect was source localized within multisensory associative areas, angular gyrus, associative visual cortex and somatosensory cortex. We provide novel evidence that one's own emotional expression acts as a top-down influence modulating low-level neural encoding during facial perception., (© The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

This study evaluated the chronotropic and inotropic responses to glucagon in spontaneously beating isolated right atria of rat heart. For comparison, we also investigated the effects resulting from stimulating β-adrenoceptors with isoproterenol in this tissue. Isoproterenol increased both atrial frequency and contractility but glucagon only enhanced atrial rate. The transcript levels of glucagon receptors were about three times higher in sinoatrial node than in the atrial myocardium. Chronotropic responses to glucagon and isoproterenol were blunted by the funny current (If) inhibitor ZD 7288. Inhibitors of protein kinase A, H-89 and KT-5720 reduced the chronotropic response to glucagon but not to isoproterenol. Inhibition of ryanodine receptors and calcium/calmodulin dependent protein kinase II (important regulators of sarcoplasmic reticulum Ca2+ release), with ruthenium red and KN-62 respectively, failed to alter chronotropic responses of either glucagon or isoproterenol. Non selective inhibition of phosphodiesterase (PDE) with 3-isobutylmethylxantine or selective inhibition of PDE3 or PDE4 with cilostamide or rolipram respectively did not affect chronotropic effects of glucagon or isoproterenol. Our results indicate that glucagon increases beating rate but not contractility in rat right atria which could be a consequence of lower levels of glucagon receptors in atrial myocardium than in sinoatrial node. Chronotropic responses to glucagon or isoproterenol are mediated by If current but not by sarcoplasmic reticulum Ca2+ release, neither are regulated by PDE activity.

Obesity is frequently associated with insulin resistance. To compensate for this situation and maintain normoglycaemia, pancreatic beta-cells undergo several morphofunctional adaptations, which result in insulin hypersecretion and hyperinsulinaemia. However, no information exists about pancreatic alpha-cells during this compensatory stage of obesity. Here, we studied alpha-cells in mice fed a high-fat diet (HFD) for 12 weeks. These animals exhibited hyperinsulinaemia and normoglycaemia compared with control animals in addition to hypoglucagonaemia. While the in vivo response of glucagon to hypoglycaemia was preserved in the obese mice, the suppression of glucagon secretion during hyperglycaemia was impaired. Additionally, in vitro glucagon release at low glucose levels and glucagon content in isolated islets were decreased, while alpha-cell exocytosis remained unchanged. Assessment of morphological parameters revealed that alpha-cell area was reduced in the pancreas of the obese mice in association with alpha-cell hypotrophy, increased apoptosis and decreased proliferation. HFD feeding for 24 weeks led to significant deterioration in beta-cell function and glucose homeostasis. Under these conditions, the majority of alpha-cell changes were reversed and became comparable to controls. These findings indicate that pancreatic compensatory adaptations during obesity may also involve pancreatic alpha-cells. Additionally, defects in alpha-cell function during obesity may be implicated in progression to diabetes.

Memory functioning in Autism Spectrum Disorder (ASD) is characterized by impairments in the encoding of relational but not item information and difficulties in the recollection of contextually rich episodic memories but not in the retrieval of relatively context-free memories through processes of familiarity. The neural underpinnings of this profile and the extent to which encoding difficulties contribute to retrieval difficulties in ASD remain unclear. Using a paradigm developed by Addis and McAndrews [2006; Neuroimage, 33, 1194-1206] we asked adults with and without a diagnosis of ASD to study word-triplets during functional Magnetic Resonance Imaging (fMRI) scanning that varied in the number of category relations amongst component words. Performance at test confirmed attenuated recollection in the context of preserved familiarity based retrieval in ASD. The results also showed that recollection but not familiarity based retrieval increases as a function of category relations in word triads for both groups, indicating a close link between the encoding of relational information and recollection. This link was further supported by the imaging results, where blood oxygen level dependent (BOLD) signal responses in overlapping regions of the inferior prefrontal cortex were sensitive to the relational encoding manipulation as well as the contrast between recollection versus familiarity based retrieval. Interestingly, however, there was no evidence of prefrontal signal differentiation for this latter contrast in the ASD group for whom signal changes in a left hippocampal region were also marginally attenuated. Together, these observations suggest that attenuated levels of episodic recollection in ASD are, at least in part, attributable to anomalies in relational encoding processes., (© 2015 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.)

Pancreatic α cells are exposed to metabolic stress during the evolution of type 2 diabetes (T2D), but it remains unclear whether this affects their survival. We used electron microscopy to search for markers of apoptosis and endoplasmic reticulum (ER) stress in α and β cells in islets from T2D or non-diabetic individuals. There was a significant increase in apoptotic β cells (from 0.4% in control to 6.0% in T2D), but no α cell apoptosis. We observed, however, similar ER stress in α and β cells from T2D patients. Human islets or fluorescence-activated cell sorting (FACS)-purified rat β and α cells exposed in vitro to the saturated free fatty acid palmitate showed a similar response as the T2D islets, i.e. both cell types showed signs of ER stress but only β cells progressed to apoptosis. Mechanistic experiments indicate that this α cell resistance to palmitate-induced apoptosis is explained, at least in part, by abundant expression of the anti-apoptotic protein Bcl2l1 (also known as Bcl-xL).

An 87-year-old woman with corticosteroid-resistant polymyalgia rheumatica underwent ¹⁸F-FDG PET/CT for suspected giant cell arteritis or neoplastic disease. FDG uptake in the immediate vicinity of the odontoid process, with a crownlike calcification, was identified on the CT scan on the posterior side of the dens, thus confirming the diagnosis of crowned dens syndrome. Because this rare syndrome is frequently misdiagnosed, nuclear physicians should be aware of the signs and symptoms of this condition, which may call for the use of PET/CT imagery.

It is well established that emotional responses to stimuli presented to one perceptive modality (e.g., visual) are modulated by the concurrent presentation of affective information to another modality (e.g., auditory)-an effect known as the cross-modal bias. However, the affective mechanisms mediating this effect are still not fully understood. It remains unclear what role different dimensions of stimulus valence and arousal play in mediating the effect, and to what extent cross-modal influences impact not only our perception and conscious affective experiences, but also our psychophysiological emotional response. We addressed these issues by measuring participants' subjective emotion ratings and their Galvanic Skin Responses (GSR) in a cross-modal affect perception paradigm employing videos of ballet dance movements and instrumental classical music as the stimuli. We chose these stimuli to explore the cross-modal bias in a context of stimuli (ballet dance movements) that most participants would have relatively little prior experience with. Results showed (i) that the cross-modal bias was more pronounced for sad than for happy movements, whereas it was equivalent when contrasting high vs. low arousal movements; and (ii) that movement valence did not modulate participants' GSR, while movement arousal did, such that GSR was potentiated in the case of low arousal movements with sad music and when high arousal movements were paired with happy music. Results are discussed in the context of the affective dimension of neuroentrainment and with regards to implications for the art community.

Music is an integral part of dance. Over the last 10 years, however, dance stimuli (without music) have been repeatedly used to study action observation processes, increasing our understanding of the influence of observer's physical abilities on action perception. Moreover, beyond trained skills and empathy traits, very little has been investigated on how other observer or spectators' properties modulate action observation and action preference. Since strong correlations have been shown between music and personality traits, here we aim to investigate how personality traits shape the appreciation of dance when this is presented with three different music/sounds. Therefore, we investigated the relationship between personality traits and the subjective esthetic experience of 52 spectators watching a 24 min lasting contemporary dance performance projected on a big screen containing three movement phrases performed to three different sound scores: classical music (i.e., Bach), an electronic sound-score, and a section without music but where the breathing of the performers was audible. We found that first, spectators rated the experience of watching dance without music significantly different from with music. Second, we found that the higher spectators scored on the Big Five personality factor openness, the more they liked the no-music section. Third, spectators' physical experience with dance was not linked to their appreciation but was significantly related to high average extravert scores. For the first time, we showed that spectators' reported entrainment to watching dance movements without music is strongly related to their personality and thus may need to be considered when using dance as a means to investigate action observation processes and esthetic preferences.

Long-term consumption of a high-fat diet (HFD) has been shown to trigger both metabolic and cardiovascular diseases. In contrast, the effect of this type of dietary regime on the central nervous system, particularly outside the hypothalamus, has been investigated poorly. Astrocytes, the most abundant population of glial cells in the brain, are pivotal in regulating glutamatergic transmission as they are responsible for most of the glutamate uptake and metabolism. Mice on an HFD show deficits in learning and memory, together with neurochemical and electrophysiological changes compatible with the impairment in hippocampal glutamatergic activity. Because astrocyte function and morphology have been shown to be interdependent, we speculated whether HFD would trigger changes in astrocyte morphology. For this purpose, we have used a model of diet-induced obesity in mice. We have analyzed astrocyte morphology and density by glial fibrillary acidic protein immunohistochemistry, as well as the expression of the glutamate transporters, GLT-1 (glutamate transporter type-1), and GLAST (astrocyte glutamate transporter), in the CA3 area of the hippocampus. We found that astrocytes from HFD mice showed longer and less abundant projections. These changes were accompanied by the upregulation of both GLT-1 and GLAST. Our data show that the functional impairment detected previously in HFD mice is concomitant with morphological changes within the hippocampus.