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The presence of atherosclerotic plaque vessels is a critical factor in plaque destabilization. This may be attributable to the leaky phenotype of these microvessels, although direct proof for this notion is lacking. In this study, we investigated molecular and cellular patterns of stable and hemorrhaged human plaque to identify novel drivers of intraplaque vessel dysfunction. From transcriptome data of a human atherosclerotic lesion cohort, we reconstructed a co-expression network, identifying a gene module strongly and selectively correlated with both plaque microvascular density and inflammation. Spectrin Beta Non-Erythrocytic 1 (sptbn1) was identified as one of the central hubs of this module (along with zeb1 and dock1) and was selected for further study based on its predominant endothelial expression. Silencing of sptbn1 enhanced leukocyte transmigration and vascular permeability in vitro, characterized by an increased number of focal adhesions and reduced junctional VE-cadherin. In vivo, sptbn1 knockdown in zebrafish impaired the development of the caudal vein plexus. Mechanistically, increased substrate stiffness was associated with sptbn1 downregulation in endothelial cells in vitro and in human vessels. Plaque SPTBN1 mRNA and protein expression were found to correlate with an enhanced presence of intraplaque hemorrhage and future cardiovascular disease (CVD) events during follow-up. In conclusion, we identify SPTBN1 as a central hub gene in a gene program correlating with plaque vascularisation. SPTBN1 was regulated by substrate stiffness in vitro while silencing blocked vascular development in vivo, and compromised barrier function in vitro. Together, SPTBN1 is identified as a new potential regulator of the leaky phenotype of atherosclerotic plaque microvessels. [ABSTRACT FROM AUTHOR]

The importance of guaranteeing accessible Web applications is becoming widely recognised, and supported by national and international legislation. This implies an increasing need for large scale validations, which can be achieved only through automatic support. Thus, there is a need for a new generation of accessibility validation tools able to check against the continuously evolving guidelines and report any issues revealed, considering that their results will be used by many people with varied backgrounds and goals. Such tools should be able to support monitoring of Web sites' accessibility, provide user-friendly information suitable for various purposes, and be transparent in terms of what they are actually able to evaluate in order to elicit the right expectations from their users. They should also consider how the technologies for implementing Web sites have evolved in recent years. In this paper, we provide a description of the requirements and design dimensions that characterise such tools in order to address emerging needs, providing indications on whether and how several existing validation tools support them, and present how we have addressed and implemented them in a specific tool. We also report on a first usability test of such tool, which has provided encouraging feedback. [ABSTRACT FROM AUTHOR]

Introduction: The impact of cardiovascular disease (CVD) risk factors, encompassing various biological determinants and unhealthy lifestyles, on the functional dynamics of circulating monocytes-a pivotal cell type in CVD pathophysiology remains elusive. In this study, we aimed to elucidate the influence of CVD risk factors on monocyte transcriptional responses to an infectious stimulus. Methods: We conducted a comparative analysis of monocyte gene expression profiles from the CTMM - CIRCULATING CELLS Cohort of coronary artery disease (CAD) patients, at baseline and after lipopolysaccharide (LPS) stimulation. Gene co-expression analysis was used to identify gene modules and their correlations with CVD risk factors, while pivotal transcription factors controlling the hub genes in these modules were identified by regulatory network analyses. The identified gene module was subjected to a drug repurposing screen, utilizing the LINCS L1000 database. Results: Monocyte responsiveness to LPS showed a highly significant, negative correlation with blood pressure levels (ρ< -0.4; P<10-80). We identified a ZNF12/ZBTB43-driven gene module closely linked to diastolic blood pressure, suggesting that monocyte responses to infectious stimuli, such as LPS, are attenuated in CAD patients with elevated diastolic blood pressure. This attenuation appears associated with a dampening of the LPS-induced suppression of oxidative phosphorylation. Finally, we identified the serine-threonine inhibitor MW-STK33-97 as a drug candidate capable of reversing this aberrant LPS response. Conclusions: Monocyte responses to infectious stimuli may be hampered in CAD patients with high diastolic blood pressure and this attenuated inflammatory response may be reversed by the serine-threonine inhibitor MW-STK33-97. Whether the identified gene module is a mere indicator of, or causal factor in diastolic blood pressure and the associated dampened LPS responses remains to be determined. [ABSTRACT FROM AUTHOR]

Cognitive developmental disorders are common in children and can affect various abilities. Attention Deficit/Hyperactivity Disorder (ADHD) is the most prevalent childhood psychiatric condition. This work presents PlayToPickUp, a serious game that aims to stimulate children in relevant cognitive domains (attention and error monitoring). A multidisciplinary team of experts and caregivers from two different centers that support therapeutic activities with such children participated from the games's inception to the design and the evaluation of the game. Depending on the characteristics and abilities of the player, therapists can customize the game to provide training that best fits the skills and the needs of the child while maintaining the player's motivation. After its development, the game was used over 2 months "in the wild" by children recruited by the two centers. In one case the children played with it within the regular activities offered by the training center. In the other one, the parents of the children were instructed by caregivers to have the children play the game at home. In the paper, we describe the experience gathered from such two studies run in parallel, discussing the aspects that worked better, those that represented difficulties, and the lesson learnt for future studies. [ABSTRACT FROM AUTHOR]

Type I spiral ganglion neurons (SGNs) are the auditory afferents that transmit sound information from cochlear inner hair cells (IHCs) to the brainstem. These afferents consist of physiological subtypes that differ in their spontaneous firing rate (SR), activation threshold, and dynamic range and have been described as low, medium, and high SR fibers. Lately, single-cell RNA sequencing experiments have revealed three molecularly defined type I SGN subtypes. The extent to which physiological type I SGN subtypes correspond to molecularly defined subtypes is unclear. To address this question, we have generated mouse lines expressing CreERT2 in SGN subtypes that allow for a physiological assessment of molecular subtypes. We show that Lypd1-CreERT2 expressing SGNs represent a well-defined group of neurons that preferentially innervate the IHC modiolar side and exhibit a narrow range of low SRs. In contrast, Calb2-CreERT2 expressing SGNs preferentially innervate the IHC pillar side and exhibit a wider range of SRs, thus suggesting that a strict stratification of all SGNs into three molecular subclasses is not obvious, at least not with the CreERT2 tools used here. Genetically marked neuronal subtypes refine their innervation specificity onto IHCs postnatally during the time when activity is required to refine their molecular phenotype. Type I SGNs thus consist of genetically defined subtypes with distinct physiological properties and innervation patterns. The molecular subtype-specific lines characterized here will provide important tools for investigating the role of the physiologically distinct type I SGNs in encoding sound signals. [ABSTRACT FROM AUTHOR]

In the last few years, several end-user tools have been designed to help people who are not professional developers in programming their smart environments. However, such tools are often based on structured visual editors providing abstract representations of the available connected sensors and objects, which can be problematic for end users, and do not particularly encourage their participation. This work aims to make the end-user experience of creating everyday automations involving various types of connected sensors and objects more engaging by replacing extensive, static, structured and comprehensive abstract visual tools with more narrowed, relevant, context-sensitive, dynamic, augmented reality-based representations. We present a solution for this purpose that mobile users can exploit through their smartphone. End users can use the smartphone camera to frame the relevant sensor or object through the developed prototype, then get the current automations associated with it, edit their definition, create new ones as well as monitor the automations involving the whole current environment. We also report a first user test of the developed prototype deployed in a home equipped with connected sensors and objects, which yielded positive feedback. [ABSTRACT FROM AUTHOR]

This paper presents how the TAREME (Trigger-Action Rule Editing, Monitoring, Executing) platform provides support for executing and analysing personalized automations in Internet of Things scenarios. The platform allows the creation and execution of trigger-action personalization rules that can change the state of connected smart objects and devices, send alarms or reminders, and modify applications' state depending on contextual events. This paper focuses on how the platform supports analytics about the actual use of the rules and provides associated information, which can be useful to better understand users' personalization needs. Such features have been deployed in a first round of six trials, which have shown the feasibility of the approach and reported fruitful feedback. [ABSTRACT FROM AUTHOR]

This work aims to explore the potentialities of an end-user personalisation platform in industrial settings. In such a context, stakeholders with different roles and competencies collaborate to manage and control an environment where legacy machines coexist and interact with newer ones. Our goal is to provide a rule-based tool that allows end-users to build personalised solutions to respond quickly to the dynamic needs of factories. We report on a case study in the paper factory domain, in which the industrial aspects identified with expert stakeholders through interviews have been simulated and addressed through an extension of a personalisation platform. A first user test of the resulting environment has been carried out with a representative set of users, and has provided useful and encouraging feedback in terms of the potentialities of the proposed approach in industrial contexts. [ABSTRACT FROM AUTHOR]

Motivation Agent-based modeling is an indispensable tool for studying complex biological systems. However, existing simulation platforms do not always take full advantage of modern hardware and often have a field-specific software design. Results We present a novel simulation platform called BioDynaMo that alleviates both of these problems. BioDynaMo features a modular and high-performance simulation engine. We demonstrate that BioDynaMo can be used to simulate use cases in: neuroscience, oncology and epidemiology. For each use case, we validate our findings with experimental data or an analytical solution. Our performance results show that BioDynaMo performs up to three orders of magnitude faster than the state-of-the-art baselines. This improvement makes it feasible to simulate each use case with one billion agents on a single server, showcasing the potential BioDynaMo has for computational biology research. Availability and implementation BioDynaMo is an open-source project under the Apache 2.0 license and is available at www.biodynamo.org. Instructions to reproduce the results are available in the supplementary information. Supplementary information Available at https://doi.org/10.5281/zenodo.5121618. [ABSTRACT FROM AUTHOR]

Signal transmission by sensory auditory and vestibular hair cells relies upon Ca2+-dependent exocytosis of glutamate. The Ca2+ current in mammalian inner ear hair cells is predominantly carried through Ca V 1.3 voltage-gated Ca2+ channels. Despite this, Ca V 1.3 deficient mice (Ca V 1.3–/–) are deaf but do not show any obvious vestibular phenotype. Here, we compared the Ca2+ current (I Ca ) in auditory and vestibular hair cells from wild-type and Ca V 1.3–/– mice, to assess whether differences in the size of the residual I Ca could explain, at least in part, the two phenotypes. Using 5 mM extracellular Ca2+ and near-body temperature conditions, we investigated the cochlear primary sensory receptors inner hair cells (IHCs) and both type I and type II hair cells of the semicircular canals. We found that the residual I Ca in both auditory and vestibular hair cells from Ca V 1.3–/– mice was less than 20% (12–19%, depending on the hair cell type and age investigated) compared to controls, indicating a comparable expression of Ca V 1.3 Ca2+ channels in both sensory organs. We also showed that, different from IHCs, type I and type II hair cells from Ca V 1.3–/– mice were able to acquire the adult-like K+ current profile in their basolateral membrane. Intercellular K+ accumulation was still present in Ca V 1.3–/– mice during I K,L activation, suggesting that the K+-based, non-exocytotic, afferent transmission is still functional in these mice. This non-vesicular mechanism might contribute to the apparent normal vestibular functions in Ca V 1.3–/– mice. [ABSTRACT FROM AUTHOR]

Background: While single‐omics analyses on human atherosclerotic plaque have been very useful to map stage‐ or disease‐related differences in expression, they only partly capture the array of changes in this tissue and suffer from scale‐intrinsic limitations. In order to better identify processes associated with intraplaque hemorrhage and plaque instability, we therefore combined multiple omics into an integrated model. Methods: In this study, we compared protein and gene makeup of low‐ versus high‐risk atherosclerotic lesion segments from carotid endarterectomy patients, as judged from the absence or presence of intraplaque hemorrhage, respectively. Transcriptomic, proteomic, and peptidomic data of this plaque cohort were aggregated and analyzed by DIABLO, an integrative multivariate classification and feature selection method. Results: We identified a protein‐gene associated multiomics model able to segregate stable, nonhemorrhaged from vulnerable, hemorrhaged lesions at high predictive performance (AUC >0.95). The dominant component of this model correlated with αSMA−PDGFRα+ fibroblast‐like cell content (p = 2.4E‐05) and Arg1+ macrophage content (p = 2.2E‐04) and was driven by serum response factor (SRF), possibly in a megakaryoblastic leukemia‐1/2 (MKL1/2) dependent manner. Gene set overrepresentation analysis on the selected key features of this model pointed to a clear cardiovascular disease signature, with overrepresentation of extracellular matrix synthesis and organization, focal adhesion, and cholesterol metabolism terms, suggestive of the model's relevance for the plaque vulnerability. Finally, we were able to corroborate the predictive power of the selected features in several independent mRNA and proteomic plaque cohorts. Conclusions: In conclusion, our integrative omics study has identified an intraplaque hemorrhage‐associated cardiovascular signature that provides excellent stratification of low‐ from high‐risk carotid artery plaques in several independent cohorts. Further study revealed suppression of an SRF‐regulated disease network, controlling lesion stability, in vulnerable plaque, which can serve as a scaffold for the design of targeted intervention in plaque destabilization. [ABSTRACT FROM AUTHOR]

We propose a mixed methods approach to digital ethnographic research. Treating online conversational environments as communities that ethnographers engage with as in traditional fieldwork, we represent those conversations and the codes made by researchers thereon in network form. We call these networks "semantic social networks" (SSNs), as they incorporate information on social interaction and their meaning as perceived by informants as a group and use methods from network science to visualize these ethnographic data. We present an application of this method to a large online conversation about community provision of health and social care and discuss its potential for mobilizing collective intelligence. [ABSTRACT FROM AUTHOR]

Recent studies have shown that ionic direct current (iDC) can modulate the vestibular system in-vivo, with potential benefits over conventional pulsed stimulation. In this study, the effects of iDC stimulation on vestibular nerve fiber firing rate was investigated using loose-patch nerve fiber recordings in the acutely excised mouse crista ampullaris of the semicircular canals. Cathodic and anodic iDC steps instantaneously reduced and increased afferent spike rate, with the polarity of this effect dependent on the position of the stimulating electrode. A sustained constant anodic or cathodic current resulted in an adaptation to the stimulus and a return to spontaneous spike rate. Post-adaptation spike rate responses to iDC steps were similar to pre-adaptation controls. At high intensities spike rate response sensitivities were modified by the presence of an adaptation step. Benefits previously observed in behavioral responses to iDC steps delivered after sustained current may be due to post-adaptation changes in afferent sensitivity. These results contribute to an understanding of peripheral spike rate relationships for iDC vestibular stimulation and validate an ex-vivo model for future investigation of cellular mechanisms. In conjunction with previous in-vivo studies, these data help to characterize iDC stimulation as a potential therapy to restore vestibular function after bilateral vestibulopathy. [ABSTRACT FROM AUTHOR]

The advent of the Internet of Things and mobile applications has made the possible contexts of use more and more varied, and creates new challenges for user interface developers. Although model-based approaches aim to support the generation of applications for different implementation technologies, limited attention has been paid to how to exploit them for novel context-dependent applications. We present a model-based framework that allows developers to flexibly customize their mobile apps to react to events not foreseen in the initial versions. It is composed of an authoring environment supporting the definition of model-based descriptions and generating mobile apps from them. The authoring environment allows developers to enrich the dynamic behaviour of the generated applications through trigger-action rules. The resulting versions of the apps can provide customized behaviour according to the actual contexts of use. The authoring environment supports efficient development of such customizations. We show its potential by describing an example application, and report on a first test with developers. [ABSTRACT FROM AUTHOR]

One of the goals of Ambient Assisted Living (AAL) solutions is to extend the time that elderly people can live independently in their preferred environments by using ICT technologies for personal healthcare. However, in order to be optimal, remote monitoring services and health-related interventions should be strongly personalised to specific individuals' requirements, preferences, abilities and motivations, which can vary among the elderly, and even dynamically evolve over time for the same person depending on changing user needs and context-dependent conditions. In this paper we present an End User Development (EUD) tool for the personalisation of context-dependent assistance by non-technical users in the AAL domain. In particular, we have considered applications for remotely monitoring and assisting elderly people at home through sending multimedia messages and reminders, as well as changing the state of various domestic appliances (e.g. lamps, heating system, TV) and devices available in the context surrounding the user. The design and development of the tailoring environment has been carried out in an iterative manner, informed by the feedback that was gathered through empirical evaluations done with older adults and caregivers. [ABSTRACT FROM AUTHOR]

Key points Vestibular type I and type II hair cells and their afferent fibres send information to the brain regarding the position and movement of the head., The characteristic feature of type I hair cells is the expression of a low-voltage-activated outward rectifying K+ current, IK,L, whose biophysical properties and molecular identity are still largely unknown., In vitro, the afferent nerve calyx surrounding type I hair cells causes unstable intercellular K+ concentrations, altering the biophysical properties of IK,L., We found that in the absence of the calyx, IK,L in type I hair cells exhibited unique biophysical activation properties, which were faithfully reproduced by an allosteric channel gating scheme., These results form the basis for a molecular and pharmacological identification of IK,L., Abstract Type I and type II hair cells are the sensory receptors of the mammalian vestibular epithelia. Type I hair cells are characterized by their basolateral membrane being enveloped in a single large afferent nerve terminal, named the calyx, and by the expression of a low-voltage-activated outward rectifying K+ current, IK,L. The biophysical properties and molecular profile of IK,L are still largely unknown. By using the patch-clamp whole-cell technique, we examined the voltage- and time-dependent properties of IK,L in type I hair cells of the mouse semicircular canal. We found that the biophysical properties of IK,L were affected by an unstable K+ equilibrium potential ( VeqK+). Both the outward and inward K+ currents shifted VeqK+ consistent with K+ accumulation or depletion, respectively, in the extracellular space, which we attributed to a residual calyx attached to the basolateral membrane of the hair cells. We therefore optimized the hair cell dissociation protocol in order to isolate mature type I hair cells without their calyx. In these cells, the uncontaminated IK,L showed a half-activation at -79.6 mV and a steep voltage dependence (2.8 mV). IK,L also showed complex activation and deactivation kinetics, which we faithfully reproduced by an allosteric channel gating scheme where the channel is able to open from all (five) closed states. The 'early' open states substantially contribute to IK,L activation at negative voltages. This study provides the first complete description of the 'native' biophysical properties of IK,L in adult mouse vestibular type I hair cells. [ABSTRACT FROM AUTHOR]

Low serum salivary amylase levels have been associated with a range of metabolic abnormalities, including obesity and insulin resistance. We recently suggested that a low copy number at the AMY1 gene, associated with lower enzyme levels, also increases susceptibility to obesity. To advance our understanding of the effect of AMY1 copy number variation on metabolism, we compared the metabolomic signatures of high- and low-copy number carriers. We analyzed, using mass spectrometry and nuclear magnetic resonance (NMR), the sera of healthy normal-weight women carrying either low-AMY1 copies (LAs: four or fewer copies; n = 50) or high-AMY1 copies (HAs: eight or more copies; n = 50). Best-fitting multivariate models (empirical P < 1 × 10-3) of mass spectrometry and NMR data were concordant in showing differences in lipid metabolism between the two groups. In particular, LA carriers showed lower levels of long- and medium-chain fatty acids, and higher levels of dicarboxylic fatty acids and 2-hydroxybutyrate (a known marker of glucose malabsorption). Taken together, these observations suggest increased metabolic reliance on fatty acids in LA carriers through β- and ω-oxidation and reduced cellular glucose uptake with consequent diversion of acetyl-CoA into ketogenesis. Our observations are in line with previously reported delayed glucose uptake in LA carriers after starch consumption. Further functional studies are needed to extrapolate from our findings to implications for biochemical pathways. [ABSTRACT FROM AUTHOR]

Chemokines are involved in the remodeling of the heart; however, their significance as biomarkers in heart failure is unknown. We observed that circulating CXCR3 receptor chemokines CXCL9 and CXCL10 in a rat model of heart failure were increased 1 week after myocardial infarction. CXCL10 was also increased in both remote and infarcted regions of the heart and remained elevated at 16 weeks; CXCL9 was elevated in the remote area at 1 week. In humans, hierarchical clustering and principal component analysis revealed that circulating CXCL10, MIP-1α, and CD40 ligand were the best indicators for differentiating healthy and heart failure subjects. Serum CXCL10 levels were increased in patients with symptomatic heart failure as indexed by NYHA classification II through IV. The presence of CXCL10, MIP-1α, and CD40 ligand appears to be dominant in patients with advanced heart failure. These findings identify a distinct profile of inflammatory mediators in heart failure patients. [ABSTRACT FROM AUTHOR]

The CXC chemokines, CXCL4, -9, -10, -11, CXCL4L1, and the CC chemokine CCL21, activate CXC chemokine receptor 3 (CXCR3), a cell-surface G protein-coupled receptor expressed mainly by Th1 cells, cytotoxic T (Tc) cells and NK cells that have a key role in immunity and inflammation. However, CXCR3 is also expressed by vascular smooth muscle and endothelial cells, and appears to be important in controlling physiological vascular function. In the last decade, evidence from pre-clinical and clinical studies has revealed the participation of CXCR3 and its ligands in multiple cardiovascular diseases (CVDs) of different aetiologies including atherosclerosis, hypertension, cardiac hypertrophy and heart failure, as well as in heart transplant rejection and transplant coronary artery disease (CAD). CXCR3 ligands have also proven to be valid biomarkers for the development of heart failure and left ventricular dysfunction, suggesting an underlining pathophysiological relation between levels of these chemokines and the development of adverse cardiac remodelling. The observation that several of the above-mentioned chemokines exert biological actions independent of CXCR3 provides both opportunities and challenges for developing effective drug strategies. In this review, we provide evidence to support our contention that CXCR3 and its ligands actively participate in the development and progression of CVDs, and may additionally have utility as diagnostic and prognostic biomarkers. [ABSTRACT FROM AUTHOR]

Despite dramatic improvements in short-term mortality rates following myocardial infarction (MI), long-term survival for MI patients who progress to heart failure remains poor. MI occurs when the left ventricle (LV) is deprived of oxygen for a sufficient period of time to induce irreversible necrosis of the myocardium. The LV response to MI involves significant tissue, cellular, and molecular level modifications, as well as substantial hemodynamic changes that feedback negatively to amplify the response. Inflammation to remove necrotic myocytes and fibroblast activation to form a scar are key wound healing responses that are highly variable across individuals. Few biomarkers of early remodeling stages are currently clinically adopted. The discovery of underlying pathophysiological mechanisms and associated novel biomarkers has the potential of improving prognostic capability and therapeutic monitoring. Combining these biomarkers with other prominent ones could constitute a powerful diagnostic and prognostic tool that directly reflects the pathophysiological remodeling of the LV. Understanding temporal remodeling at the tissue, cellular, and molecular level and its link to a well-defined set of biomarkers at early stages post-MI is a prerequisite for improving personalized care and devising more successful therapeutic interventions. Here we summarize the integral mechanisms that occur during early cardiac remodeling in the post-MI setting and highlight the most prominent biomarkers for assessing disease progression. [ABSTRACT FROM AUTHOR]

This paper presents a solution for supporting adaptive user interfaces in work environments that require operators to move about in dynamic contexts for manipulating various physical objects. The solution architecture is built upon the use of logical languages for interactive applications integrated with context aware and adaptive features. The proposed architecture is able to adapt to specific aspects of the context during run-time by communicating with a context server and applying the specified adaptation rules. In order to show the possibilities of the proposed solution, we report on its application in the development of an adaptive user interface for a warehouse picking system, and discuss the results of the associated tests. [ABSTRACT FROM AUTHOR]

Background: Recent clinical studies suggest that inflammatory mediators have huge potential in individualized therapy and in efficacy screening and can be utilized as biomarkers for a plethora of pathological conditions. The standard approach for detecting and measuring these inflammatory mediators is via blood samples. Nevertheless, there is no scientific report providing solid evidence on the most suitable blood compartment that will give the optimal inflammatory mediator measurement, or regarding the diurnal variation of circulating mediators. In this study, we present the biological variability of circulating cytokines and chemokines from healthy individuals (mean age 59 years) assessed by a novel membrane-based assay. Methods: Fifteen males and an equal number of females (all above 50 years) with no known inflammatory condition were selected. Through a planar method, named Proteome Profiler™, improved with fluorescence readout into a semi-quantitative multiplex assay, a screening of 36 inflammatory mediators was performed in serum and plasma of morning and afternoon blood withdrawals. Results: The multiplex analysis revealed that the physiological variability of several circulating inflammatory mediators was relatively small within a cohort of 30 healthy aging subjects. There was no substantial gender effect in the inflammatory mediator profile. On the contrary, most of the cytokine/chemokine values measured in the afternoon collection were found to be higher compared to the morning ones, particularly in plasma. Conclusions: In this study we provide evidence that circulating cytokine and chemokine levels of healthy individuals are elevated when blood is sampled in the afternoon compared to the morning, as influenced by the circulating cortisol levels. Furthermore, we report significant differences between cytokine/chemokine levels measured in serum and plasma. Our results provide essential information for future studies that will focus on examining circulating inflammatory mediator differences between healthy and diseased individuals. [ABSTRACT FROM AUTHOR]

The function of the enzyme glutamate decarboxylase (GAD) is to convert glutamate in γ-aminobutyric acid (GABA). Glutamate decarboxylase exists as two major isoforms, termed GAD65 and GAD67, that are usually expressed in GABA-containing neurons in the central nervous system. GAD65 has been proposed to be associated with GABA exocytosis whereas GAD67 with GABA metabolism. In the present immunofluorescence study, we have investigated the presence of the two GAD isoforms in the semicircular canal cristae of wild type and GAD67-GFP knock-in mice. While no evidence for GAD65 expression was found, GAD67 was detected in a distinct population of peripherally-located supporting cells, but not in hair cells or in centrally-located supporting cells. GABA, on the other hand, was found in all supporting cells. The present result indicate that only a discrete population of supporting cells use GAD67 to synthesize GABA. This is the first report of a marker that allows to distinguish two populations of supporting cells in the vestibular epithelium. On the other hand, the lack of GABA and GAD enzymes in hair cells excludes its involvement in afferent transmission. [ABSTRACT FROM AUTHOR]

Background: Inflammatory mediators can serve as biomarkers for the monitoring of the disease progression or prognosis in many conditions. In the present study we introduce an adaptation of a membrane-based technique in which the level of up to 40 cytokines and chemokines can be determined in both human and rodent blood in a semi-quantitative way. The planar assay was modified using the LI-COR (R) detection system (fluorescence based) rather than chemiluminescence and semi-quantitative outcomes were achieved by normalizing the outcomes using the automated exposure settings of the Odyssey readout device. The results were compared to the gold standard assay, namely ELISA. Results: The improved planar assay allowed the detection of a considerably higher number of analytes (n = 30 and n = 5 for fluorescent and chemiluminescent detection, respectively). The improved planar method showed high sensitivity up to 17 pg/ml and a linear correlation of the normalized fluorescence intensity with the results from the ELISA (r = 0.91). Conclusions: The results show that the membrane-based technique is a semi-quantitative assay that correlates satisfactorily to the gold standard when enhanced by the use of fluorescence and subsequent semi-quantitative analysis. This promising technique can be used to investigate inflammatory profiles in multiple conditions, particularly in studies with constraints in sample sizes and/or budget. [ABSTRACT FROM AUTHOR]

Epidemiological data from the Framingham and other prospective studies suggests an inverse correlation between the plasma concentration of HDL-cholesterol (HDL-C) and the incidence of cardiovascular disease. The relationship between HDL-C and its vascular-protective effects is particularly due to the heterogeneity of these particles and their important role in reverse cholesterol transport. It is well-known that many different factors are involved in metabolic regulation of HDL and can affect their plasma concentration. Apolipoprotein A-I, the principal apolipoprotein of HDL, is synthesized and secreted in the intestine and liver, where several enzymatic processes contribute to the biogenesis and the catabolism of HDLs. In this review we report and analyze the main clinical, genetic and environmental determinants of plasma HDL-C concentration; moreover we underline how different laboratory methods of HDL-C dosage can influence the correct assessment of these plasma values. We present a comparison of HDL-C levels variation among populations and groups of subjects with different and particular characteristics or pathological conditions, considering the genetic and environmental factors that can affect synthesis and metabolism of these lipoproteins. [ABSTRACT FROM AUTHOR]

In the setting of a six-month, open-label clinical trial, 141 consecutively enrolled, hypertensive, overweight patients were randomized to the oral ingestion of psyllium powder or guar gum 3.5 gr t.i.d., to be taken 20 min before the main two meals, or to standard diet. Both fibers improved significantly BMI, FPG, FPI, HOMA Index, HbA1c, LDL-C, and ApoB. Psyllium supplementation only exerted a significant improvement in plasma TG concentration, in SBP and DBP. In our study, six-month supplementation with psyllium fiber, but not with guar fiber nor standard diet, appears to significantly reduce both SBP and DBP in hypertensive overweight subjects. [ABSTRACT FROM AUTHOR]

Recent evidences suggest that modulation of vascular structure by matrix metalloproteinases (MMPs) could be a main determinant of acute cardiovascular events in high-risk subjects. The authors consecutively selected 46 subjects affected by familial combined hyperlipidemia (FCH), 44 by metabolic syndrome (MS), 44 by FCH and MS, and 40 healthy subjects. All these subjects were firstly diagnosed and not treated with lipid-lowering, antihypertensive, or antidiabetic drugs. A 12-h fasting blood sample was obtained from each patient, and plasma levels of MMP-2 and MMP-9 were measured together with their tissue inhibitors and a full set of laboratory cardiovascular disease markers. MMP-2 plasma levels were not significantly different among the considered groups. MMP-9, tissue inhibitor of MMP (TIMP)-1, and TIMP-2 are significantly higher in FCH (p < .001) and MS (p < .001) patients than in healthy controls, and they are also higher in MS patients than in FCH ones (p < .001). TIMP-1 (p < .001) and TIMP-2 (p < .001), but not MMP-9, are also significantly higher in subjects with MS associated to FCH than in patients with MS alone. No specific correlation among MMPs, TIMPs, and the other studied parameters has been observed in the whole sample and in the four above-defined subgroups. MMP-9, TIMP-1, and TIMP-2 plasma levels could be significant determinant and/or diagnostic markers of MS but not of FCH. However, the superposition of MS on FCH further increases the plasma level of these parameters. The prognostic value of this observation has to be evaluated. [ABSTRACT FROM AUTHOR]

Information about several papers discussed during the 14th International Symposium on Atherosclerosis is presented. It gathered attention by various clinicians including sport physiologists, cardiology surgeons and biochemists. The symposium features chairmen Antonio V. Gaddi and Franco Rusticali who discusses the role of physical activity of primary and secondary cardiovascular disease including its prevention and public healthcare improvements.

Current electroencephalogram (EEG) based‐consciousness monitoring technique is vulnerable to specific clinical conditions (eg, epilepsy and dementia). However, hemodynamics is the most fundamental and well‐preserved parameter to evaluate, even under severe clinical situations. In this study, we applied near‐infrared spectroscopy (NIRS) system to monitor hemodynamic change during ketamine‐induced anesthesia to find its correlation with the level of consciousness. Oxy‐hemoglobin (OHb) and deoxy‐hemoglobin concentration levels were continuously acquired throughout the experiment, and the reflectance ratio between 730 and 850 nm was calculated to quantify the hemodynamic changes. The results showed double peaks of OHb concentration change during ketamine anesthesia, which seems to be closely related to the consciousness state of the rat. This finding suggests the possibility of NIRS based‐hemodynamic monitoring as a supplementary parameter for consciousness monitoring, compensating drawbacks of EEG signal based monitoring. To investigate a relationship between ketamine‐induced anesthesia and cerebral hemodynamics, we designed a rat model with intravenous ketamine infusion. Oxy‐hemoglobin and deoxy‐hemoglobin concentration change were continuously measured from the frontal lobe of the rat by using a near‐infrared spectroscopy system. The oxy‐hemoglobin concentration showed a very distinct trend of change during ketamine anesthesia, and the trend was well correlated with the ketamine's pharmacodynamics features. [ABSTRACT FROM AUTHOR]

A correction is presented to the article "Metabolomic Profile of Low-Copy Number Carriers at the Salivary alpha-Amylase Gene Suggests a Metabolic Shift Toward Lipid-Based Energy Production" which appeared in the previous issue.

The authors reflect on the improved method of controlling and understanding various diseases of lipid metabolism which includes divergence of low-density lipoprotein and lysophosphatidic acid metabolic pathways. They tend to recognize its response to therapy including its pleiotropic effects of statins and of omega-3 polyunsaturated fatty acids on heart rate variability. They claim that data should not retained but to be manage to build new theories including methods and inquiries.

A correction to the article "Glutamic acid decarboxylase 67 expression by a distinct population of mouse vestibular supporting cells," by Elisa Tavazzani and colleagues in the 2014 issue is presented.