Block of NMDA receptor channels by endogenous neurosteroids: implications for the agonist induced conformational states of the channel vestibule

N-methyl-D-aspartate receptors (NMDARs) mediate synaptic plasticity, and their dysfunction is implicated in multiple brain disorders. NMDARs can be allosterically modulated by numerous compounds, including endogenous neurosteroid pregnanolone sulfate. Here, we identify the molecular basis of the use-dependent and voltage-independent inhibitory effect of neurosteroids on NMDAR responses. The site of action is located at the extracellular vestibule of the receptor's ion channel pore and is accessible after receptor activation. Mutations in the extracellular vestibule in the SYTANLAAF motif disrupt the inhibitory effect of negatively charged steroids. In contrast, positively charged steroids inhibit mutated NMDAR responses in a voltage-dependent manner. These results, in combination with molecular modeling, characterize structure details of the open configuration of the NMDAR channel. Our results provide a unique opportunity for the development of new therapeutic neurosteroid-based ligands to treat diseases associated with dysfunction of the glutamate system

Fractional modeling dynamics of HIV and CD4+ T-cells during primary infection

In this paper, we introduce fractional-order into a model of HIV-1 infection of CD4+ T cells. We study the effect of the changing the average number of viral particles N with different sets of initial conditions on the dynamics of the presented model. Generalized Euler method (GEM) will be used to find a numerical solution of the HIV-1 infection fractional order model

Magnetic field dependence and bottlenecklike behavior of the ESR spectra in YbRh2Si2

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Electron spin resonance (ESR) experiments at different fields or frequencies (4.1 <=nu <= 34.4 GHz) in the Kondo lattice (T-K similar or equal to 25 K) YbRh2Si2 single-crystal compounds confirmed the observation of a single anisotropic Dysonian resonance with g(perpendicular to c)congruent to 3.55 and no hyperfine components for 4.2 less than or similar to T less than or similar to 20 K. However, our studies differently reveal that (i) the ESR spectra for H-perpendicular to c show strong-field-dependent spin-lattice relaxation, (ii) a weak-field and temperature-dependent effective g value, (iii) a dramatic suppression of the ESR intensity beyond 15% of Lu doping, and (iv) a strong sample and Lu-doping (<= 15%) dependence of the ESR data. These results suggest a different scenario where the ESR signal may be associated to a coupled Yb3+-conduction electron resonant collective mode with a strong bottleneck and dynamiclike behavior.793Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)NSF (USA)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Negative attitudes related to violence against women: gender and ethnic differences among youth living in Serbia

OBJECTIVES: This study aimed to identify to what extent negative attitudes towards intimate partner violence against women are present among young women and men living in Serbia, in Roma and non-Roma settlements. METHODS: We used the data from the 2010 Multiple Indicator Cluster Survey conducted in Serbia, for the respondents who were 15-24 years old. Regression analyses were used to examine the association between judgmental attitudes, socio-demographic factors and life satisfaction. RESULTS: In Roma settlements, 34.8% of men and 23.6% of women believed that under certain circumstances men are justified to be violent towards wives, while among non-Roma it was 5.6 and 4.0%, respectively. These negative attitudes were significantly associated with lower educational level, lower socio-economic status and being married. In multivariate model, in both Roma and non-Roma population women who were not married were less judgmental, while the richest Roma men were least judgmental (OR 0.40, 95% CI 0.18-0.87). CONCLUSIONS: Violence prevention activities have to be focused on promoting gender equality among youth in vulnerable population groups such as Roma, especially through social support, strengthening their education and employment

VEGFR2 Translocates to the Nucleus to Regulate Its Own Transcription

Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) is the major mediator of the angiogenic effects of VEGF. In addition to its well known role as a membrane receptor that activates multiple signaling pathways, VEGFR2 also has a nuclear localization. However, what VEGFR2 does in the nucleus is still unknown. In the present report we show that, in endothelial cells, nuclear VEGFR2 interacts with several nuclear proteins, including the Sp1, a transcription factor that has been implicated in the regulation of genes needed for angiogenesis. By in vivo chromatin immunoprecipitation (ChIP) assays, we found that VEGFR2 binds to the Sp1-responsive region of the VEGFR2 proximal promoter. These results were confirmed by EMSA assays, using the same region of the VEGFR2 promoter. Importantly, we show that the VEGFR2 DNA binding is directly linked to the transcriptional activation of the VEGFR2 promoter. By reporter assays, we found that the region between -300/-116 relative to the transcription start site is essential to confer VEGFR2-dependent transcriptional activity. It was previously described that nuclear translocation of the VEGFR2 is dependent on its activation by VEGF. In agreement, we observed that the binding of VEGFR2 to DNA requires VEGF activation, being blocked by Bevacizumab and Sunitinib, two anti-angiogenic agents that inhibit VEGFR2 activation. Our findings demonstrate a new mechanism by which VEGFR2 activates its own promoter that could be involved in amplifying the angiogenic response

Metabotropic action of postsynaptic kainate receptors triggers hippocampal long-term potentiation

Long-term potentiation (LTP) in the rat hippocampus is the most extensively studied cellular model for learning and memory. Induction of classical LTP involves an NMDA receptor- and calcium-dependent increase in functional synaptic AMPA receptors mediated by enhanced recycling of internalized AMPA receptors back to the postsynaptic membrane. Here we report a novel, physiologically relevant NMDA receptor-independent mechanism that drives increased AMPA receptor recycling and LTP. This pathway requires the metabotropic action of kainate receptors and activation of G-protein, protein kinase C and phospholipase C. Like classical LTP, kainate receptor-dependent LTP recruits recycling endosomes to spines, enhances synaptic recycling of AMPA receptors to increase their surface expression and elicits structural changes in spines, including increased growth and maturation. These data reveal a new and previously unsuspected role for postsynaptic kainate receptors in the induction of functional and structural plasticity in the hippocampus

Factors associated with psychotropic drug use among community-dwelling older persons: A review of empirical studies

BACKGROUND: In the many descriptive studies on prescribed psychotropic drug use by community-dwelling older persons, several sociodemographic and other factors associated with drug use receive inconsistent support. METHOD: Empirical reports with data on at least benzodiazepine or antidepressant drug use in samples of older persons published between 1990 and 2001 (n = 32) were identified from major databases and analyzed to determine which factors are most frequently associated with psychotropic drug use in multivariate analyses. Methodological aspects were also examined. RESULTS: Most reports used probability samples of users and non-users and employed cross-sectional designs. Among variables considered in 5 or more reports, race, proximity to health centers, medical consultations, sleep complaints, and health perception were virtually always associated to drug use. Gender, mental health, and physical health status were associated in about two-thirds of reports. Associations with age, marital status, medication coverage, socioeconomic status, and social support were usually not observed. CONCLUSIONS: The large variety of methods to operationalize drug use, mental health status, and social support probably affected the magnitude of observed relationships. Employing longitudinal designs and distinguishing short-term from long-term use, focusing on samples of drug users exclusively, defining drug use and drug classes more uniformly, and utilizing measures of psychological well-being rather than only of distress, might clarify the nature of observed associations and the direction of causality. Few studies tested specific hypotheses. Most studies focused on individual characteristics of respondents, neglecting the potential contribution of health care professionals to the phenomenon of psychotropic drug use among seniors

An ontology supported risk assessment approach for the intelligent configuration of supply networks

As progress towards globalisation continues, organisations seek ever better ways with which to configure and reconfigure their global production networks so as to better understand and be able to deal with risk. Such networks are complex arrangements of different organisations from potentially diverse and divergent domains and geographical locations. Moreover, greater focus is being put upon global production network systems and how these can be better coordinated, controlled and assessed for risk, so that they are flexible and competitive advantage can be gained from them within the market place. This paper puts forward a reference ontology to support risk assessment for product-service systems applied to the domain of global production networks. The aim behind this is to help accelerate the development of information systems by way of developing a common foundation to improve interoperability and the seamless exchange of information between systems and organisations. A formal common logic based approach has been used to develop the reference ontology, utilising end user information and knowledge from three separate industrial domains. Results are presented which illustrate the ability of the approach, together with areas for further work

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases