Gradient attenuation as an emergent property of reset-based Retinex models

The Retinex image filtering algorithms have been inspired by experimental findings on the behavior of the Human Vision System. They are known to locally adjust image color and contrast by preserving edges and attenuating gradients. In a reference formulation of the algorithm by Land and McCann, edge preservation and gradient attenuation are granted by two ad-hoc mechanisms: called respectively reset (the distinctive feature of all the Retinex algorithms) and thresholding. A somehow unanticipated finding is that gradient attenuation is also observed with algorithm variants that do not include the latter mechanism, which was explicitly devised to implement gradient attenuation. In this work, we provide an analytic demonstration of the capability of Retinex models to attenuate gradients using only the "reset" mechanism, combined with the local character of the mutual pixel influences. We show that this capability is an emergent property of all the reset-based Retinex models

Inferring biochemical reaction pathways: the case of the gemcitabine pharmacokinetics.

Background The representation of a biochemical system as a network is the precursor of any mathematical model of the processes driving the dynamics of that system. Pharmacokinetics uses mathematical models to describe the interactions between drug, and drug metabolites and targets and through the simulation of these models predicts drug levels and/or dynamic behaviors of drug entities in the body. Therefore, the development of computational techniques for inferring the interaction network of the drug entities and its kinetic parameters from observational data is raising great interest in the scientic community of pharmacologists. In fact, the network inference is a set of mathematical procedures deducing the structure of a model from the experimental data associated to the nodes of the network of interactions. In this paper, we deal with the inference of a pharmacokinetic network from the concentrations of the drug and its metabolites observed at discrete time points. Results The method of network inference presented in this paper is inspired by the theory of time-lagged correlation inference with regard to the deduction of the interaction network, and on a maximum likelihood approach with regard to the estimation of the kinetic parameters of the network. Both network inference and parameter estimation have been designed specically to identify systems of biotransformations, at the biochemical level, from noisy time-resolved experimental data. We use our inference method to deduce the metabolic pathway of the gemcitabine. The inputs to our inference algorithm are the experimental time series of the concentration of gemcitabine and its metabolites. The output is the set of reactions of the metabolic network of the gemcitabine. Conclusions Time-lagged correlation based inference pairs up to a probabilistic model of parameter inference from metabolites time series allows the identication of the microscopic pharmacokinetics and pharmacodynamics of a drug with a minimal a priori knowledge. In fact, the inference model presented in this paper is completely unsupervised. It takes as input the time series of the concetrations of the parent drug and its metabolites. The method, applied to the case study of the gemcitabine pharmacokinetics, shows good accuracy and sensitivit

Cardiac output monitoring during abdominal aortic cross clamping: a comparison between Vigileo/FloTrac system and transoesophageal Doppler

Cardiac output (CO) monitoring is one of the key points in the hemodynamic evaluation of critically ill patients, and can be useful in various settings of high-risk surgery. There is a lack of evidence that the extensive use of invasive devices in the hemodynamic monitoring has a good impact in terms of outcome [1], and less invasive systems have been proposed. Our aim was to compare the CO estimated by Vigileo/FloTrac with the blood flow in thoracic aorta as measured by transoesophageal Doppler in patients undergoing open abdominal aortic aneurysm repair, during the aortic cross-clamping (AoX) phase. We have measured the Augmentation Index (AI), a parameter related to vascular stiffness, using the applanation tonometry method, in order to have a better understanding of the effect of AoX on blood pressure waves. Methods We enrolled 10 consecutive patients (10 men; age 66 \ub1 6 years) undergoing elective open AAA repair (ASA II to III) under general anesthesia. Radial arterial access was used for semi-invasive determination of blood pressures and CO (APCO) with the Vigileo. An esophageal Doppler was positioned after clinical stabilization. Applanation tonometry was measured just before and after the aortic clamping. Results We found a significant (P < 0.05) increase in CO reported by Vigileo/FloTrac system in the post-clamping phase, when compared with the pre-clamping and basal phases, while the blood flow in thoracic aorta resulted decreased, according with the theory of redistribution of fluids in the splanchnic venous vasculature [2]. There was an important contribution of the wave reflection to the aortic pulse pressure wave after the AoX, as expressed by a significant increase in the AI. Conclusions The Vigileo/FloTrac system appears to overestimate CO after AoX when compared with the measure of blood flow in thoracic aorta, and this result could be influenced by the pulse pressure wave reflection occurring after clamping. In high-risk surgical settings, other situations of rapid change of systemic resistance vessels could be similarly misread, thus suggesting the necessity of a more tailored Vigileo algorithm

Chronic Red Bull Consumption during Adolescence: Effect on Mesocortical and Mesolimbic Dopamine Transmission and Cardiovascular System in Adult Rats

Energy drinks are very popular nonalcoholic beverages among adolescents and young adults for their stimulant effects. Our study aimed to investigate the effect of repeated intraoral Red Bull (RB) infusion on dopamine transmission in the nucleus accumbens shell and core and in the medial prefrontal cortex and on cardiac contractility in adult rats exposed to chronic RB consumption. Rats were subjected to 4 weeks of RB voluntary consumption from adolescence to adulthood. Monitoring of in vivo dopamine was carried out by brain microdialysis. In vitro cardiac contractility was studied on biomechanical properties of isolated left-ventricular papillary muscle. The main finding of the study was that, in treated animals, RB increased shell dopamine via a nonadaptive mechanism, a pattern similar to that of drugs of abuse. No changes in isometric and isotonic mechanical parameters were associated with chronic RB consumption. However, a prolonged time to peak tension and half-time of relaxation and a slower peak rate of tension fall were observed in RB-treated rats. It is likely that RB treatment affects left-ventricular papillary muscle contraction. The neurochemical results here obtained can explain the addictive properties of RB, while the cardiovascular investigation findings suggest a hidden papillary contractility impairment

Mir-125a-3p negatively regulates oligodendrocyte precursor cells maturation and is altered in human multiple sclerosis

In the central nervous system, oligodendrocytes provide support to axons thanks to the production of a myelin sheath. During their maturation oligodendroglial precursors (OPCs) follow a very precise differentiation program, finely orchestrated by transcription factors, epigenetic factors and microRNAs, a class of small non-coding RNAs involved in post-transcriptional regulation. Any alterations in this program can potentially contribute to dysregulated myelination, impaired remyelination and neurodegenerative conditions, as it happens in multiple sclerosis. Recently, we identified miR-125a-3p as a new actor of oligodendroglial maturation, that could also be involved in the pathological consequences of multiple sclerosis, showing that its over-expression impairs, whereas its silencing promotes, oligodendrocyte maturation (Lecca et al., Sci Rep, 2016). To shed light on the mechanism underlying this effect, we performed a microarray analysis on OPCs after miR-125a-3p over-expression. This analysis suggested that miR-125a-3p is indeed involved in the regulation of biological processes important for OPC maturation, such as cell-cell interaction and morphological differentiation. To evaluate whether miR-125a-3p modulation may influence the progression of remyelination in vivo, we overexpressed the miR-125a-3p by lentiviral approach in a focal lysolecithin-mediated demyelinating lesion in the subcortical white matter of adult mice. Interestingly, also in this case, we found that miRNA-overexpressing OPCs persisted in an immature (i.e. PDGR\u3b1+/NG2+) state. Moreover, we found that miR-125a-3p levels are altered in both brain active lesions and cerebrospinal fluid of multiple sclerosis patients, suggesting that it could be a potential biomarker of disease. The identification of a new miRNA modulating oligodendrocyte differentiation provides new findings about the complex regulation of myelination processes and we postulate that an antago-miRNA for miR-125a-3p may help promoting oligodendrocyte maturation in diseases characterized by impaired myelin repair. Sponsored by Fondazione Italiana Sclerosi Multipla 2013/R-1 project to MPA and by Fondazione Cariplo, grant n\ub0 2014-1207 to DL

The ubiquitin ligase Mdm2 controls oligodendrocyte maturation by intertwining mTOR with G protein-coupled receptor kinase 2 in the regulation of GPR17 receptor desensitization

During oligodendrocyte precursor cell (OPC) differentiation, defective control of the membrane receptor GPR17 has been suggested to block cell maturation and impair remyelination under demyelinating conditions. After the immature oligodendrocyte stage, to enable cells to complete maturation, GPR17 is physiologically down-regulated via phosphorylation/desensitization by G protein-coupled receptor kinases (GRKs); conversely, GRKs are regulated by the "mammalian target of rapamycin" mTOR. However, how GRKs and mTOR are connected to each other in modulating GPR17 function and oligodendrogenesis has remained elusive. Here we show, for the first time, a role for Murine double minute 2 (Mdm2), a ligase previously involved in ubiquitination/degradation of the onco-suppressor p53 protein. In maturing OPCs, both rapamycin and Nutlin-3, a small molecule inhibitor of Mdm2-p53 interactions, increased GRK2 sequestration by Mdm2, leading to impaired GPR17 down-regulation and OPC maturation block. Thus, Mdm2 intertwines mTOR with GRK2 in regulating GPR17 and oligodendrogenesis and represents a novel actor in myelination

Mental disorders and drug/alcohol use in patients commencing extensively drug-resistant tuberculosis treatment.

Mental disorders and alcohol/drug use worsen treatment outcomes for multidrug-resistant tuberculosis (TB), but data are lacking for extensively drug-resistant (XDR) TB. We investigated the association of baseline mental disorders and alcohol/drug use on XDR-TB treatment outcomes in a retrospective study of 53 XDR-TB Peruvian patients during 2010-2012. Logistic regression estimated the odds ratios for unfavourable XDR-TB treatment outcomes. Overall treatment success was 25%. Mental disorders and drug/alcohol use were found in respectively 22.4% and 20.4% of patients; neither were associated with unfavourable treatment outcomes. Future research should explore the relationship between mental health and drug/alcohol use in XDR-TB treatment outcomes

Pathophysiological Role of Purines and Pyrimidines in Neurodevelopment: Unveiling New Pharmacological Approaches to Congenital Brain Diseases

In recent years, a substantial body of evidence has emerged demonstrating that purine and pyrimidine synthesis and metabolism play major roles in controlling embryonic and fetal development and organogenesis. Dynamic and time-dependent changes in the expression of purine metabolizing enzymes (such as ectonucleotidases and adenosine deaminase) represent a key checkpoint for the correct sequential generation of the different signaling molecules, that in turn activate their specific membrane receptors. In neurodevelopment, Ca2+ release from radial glia mediated by P2Y1 purinergic receptors is fundamental to allow neuroblast migration along radial glia processes, and their correct positioning in the different layers of the developing neocortex. Moreover, ATP is involved in the development of synaptic transmission and contributes to the establishment of functional neuronal networks in the developing brain. Additionally, several purinergic receptors (spanning from adenosine to P2X and P2Y receptor subtypes) are differentially expressed by neural stem cells, depending on their maturation stage, and their activation tightly regulates cell proliferation and differentiation to either neurons or glial cells, as well as their correct colonization of the developing telencephalon. The purinergic control of neurodevelopment is not limited to prenatal life, but is maintained in postnatal life, when it plays fundamental roles in controlling oligodendrocyte maturation from precursors and their terminal differentiation to fully myelinating cells. Based on the above-mentioned and other literature evidence, it is now increasingly clear that any defect altering the tight regulation of purinergic transmission and of purine and pyrimidine metabolism during pre- and post-natal brain development may translate into functional deficits, which could be at the basis of severe pathologies characterized by mental retardation or other disturbances. This can occur either at the level of the recruitment and/or signaling of specific nucleotide or nucleoside receptors or through genetic alterations in key steps of the purine salvage pathway. In this review, we have provided a critical analysis of what is currently known on the pathophysiological role of purines and pyrimidines during brain development with the aim of unveiling new future strategies for pharmacological intervention in different neurodevelopmental disorders

Gene regulation of GPR17, a checkpoint receptor in oligodendroglial differentiation

GPR17 is a G protein-coupled receptor activated by both uracil nucleotides and cysteinyl-leukotrienes. We have previously demonstrated GPR17 is a key regulator of oligodendroglial differentiation and myelination. The receptor starts to be expressed in early oligodendrocyte precursor cells (OPCs), it reaches its maximal expression in immature oligodendrocytes and is then progressively down-regulated. In late OPCs, GPR17 forced expression led to impaired maturation, suggesting that its expression needs to be tightly time regulated. Based on these evidences, this work was aimed at identifying the signaling molecules regulating GPR17 expression during oligodendroglial differentiation. For this purpose, we cloned a putative promoter region of Gpr17 into a reporter vector upstream to a gene encoding for a luciferase. Then, we transfected this construct in Oli-neu cells, an immortalized oligodendroglial cell line, and we set up a reporter assay to evaluate the bioluminescence produced in response to an array of stimuli. Our results showed that treatment with both dibutyryl-cAMP, an analogue of cAMP, and forskolin, an activator of adenylyl cyclase, led to a significant increase of promoter activity, suggesting that cAMP signaling triggers GPR17 expression. To evaluate if GPR17 could be regulated by neuronal factors, we incubated cells with medium conditioned by cortical neurons. After 48h, we observed a significant induction of promoter activity; this effect was enhanced by heating the medium, suggesting neurons release one or more factors promoting oligodendroglial differentiation via Gpr17 gene, but that an inhibitory thermolabile factor is also present in the neuronal-conditioned medium. In line with this hypothesis, we found that insulin, a component of the medium formulation known to activate the mTOR pathway, strongly inhibited GPR17 promoter activity, whereas rapamycin, an inhibitor of the same pathway, significantly increased it. These data are consistent with the hypothesis that, while a neuronal-derived product activating cAMP is involved in turning GPR17 on, the mTOR pathway, likely activated by insulin-like growth factors, may be responsible for its physiological silencing at later stages of oligodendroglial development. These results may be relevant to the identification of new pharmacological strategies to activate/inhibit GPR17 under dysregulated conditions accompanied by myelination defects

The dark and the light side of the expatriate's cross-cultural adjustment: A novel framework including perceived organizational support, work related stress and innovation

The new context of the Psychology of Sustainability and Sustainable Development has reached the attention of the scientific community in recent years, due to its comprehensive approach aimed at enhancing the sustainability of interpersonal and intrapersonal talent, as well as of groups and communities. In this scenario, research on employee cross-cultural adjustment (CCA) is considered a key theme in human resource management. It is known that psychological support in the host country may alleviate distress and facilitate the integration of the expatriate workers. However, there is a lack of research investigating expatriate adjustment as an antecedent of the perceived organizational support. The aim of the study was to investigate the relationship among cross-cultural adjustment (CCA), perception of organizational support (POS), work-related stress (WRS), and innovation, considering these factors as a part of a unique innovative framework. A cross sectional study was performed using a sample of 234 expatriate workers of a multinational organization. Data were collected through a monitoring survey for the assessment of work-related stress risk factors of their expatriate staff. The results showed a positive correlation between CCA, POS, and innovation. On the other hand, a negative correlational effect of CCA and WRS, CCA and POS on WRS, and POS and WRS was found. Finally, POS was found to be a significant antecedent of CCA. These findings have implications for both international human resource management researchers and practitioners