Do Different Neurons Age Differently? Direct Genome-Wide Analysis of Aging in Single Identified Cholinergic Neurons

Aplysia californica is a powerful experimental system to study the entire scope of genomic and epigenomic regulation at the resolution of single functionally characterized neurons and is an emerging model in the neurobiology of aging. First, we have identified and cloned a number of evolutionarily conserved genes that are age-related, including components of apoptosis and chromatin remodeling. Second, we performed gene expression profiling of different identified cholinergic neurons between young and aged animals. Our initial analysis indicates that two cholinergic neurons (R2 and LPl1) revealed highly differential genome-wide changes following aging suggesting that on the molecular scale different neurons indeed age differently. Each of the neurons tested has a unique subset of genes differentially expressed in older animals, and the majority of differently expressed genes (including those related to apoptosis and Alzheimer's disease) are found in aging neurons of one but not another type. The performed analysis allows us to implicate (i) cell specific changes in histones, (ii) DNA methylation and (iii) regional relocation of RNAs as key processes underlying age-related changes in neuronal functions and synaptic plasticity. These mechanisms can fine-tune the dynamics of long-term chromatin remodeling, or control weakening and the loss of synaptic connections in aging. At the same time our genomic tests revealed evolutionarily conserved gene clusters associated with aging (e.g., apoptosis-, telomere- and redox-dependent processes, insulin and estrogen signaling and water channels)

Thermoelasticity of Fe2+-bearing bridgmanite

We present LDA+U calculations of high temperature elastic properties of bridgmanite with composition (Mg$_{(1-x)}$Fe$_{x}^{2+}$)SiO$_3$ for $0\le{x}\le0.125$. Results of elastic moduli and acoustic velocities for the Mg-end member (x=0) agree very well with the latest high pressure and high temperature experimental measurements. In the iron-bearing system, we focus particularly on the change in thermoelastic parameters across the state change that occurs in ferrous iron above $\sim$30 GPa, often attributed to a high-spin (HS) to intermediate spin (IS) crossover but explained by first principles calculations as a lateral displacement of substitutional iron in the perovskite cage. We show that the measured effect of this change on the equation of state of this system can be explained by the lateral displacement of substitutional iron, not by the HS to IS crossover. The calculated elastic properties of (Mg$_{0.875}$Fe$_{0.125}^{2+}$)SiO$_3$ along an adiabatic mantle geotherm, somewhat overestimate longitudinal velocities but produce densities and shear velocities quite consistent with Preliminary Reference Earth Model data throughout most of the lower mantle.Comment: Accepted for Geophysical Research Letters (DOI: 10.1002/2014GL062888

Quasiparticle Electronic structure of Copper in the GW approximation

We show that the results of photoemission and inverse photoemission experiments on bulk copper can be quantitatively described within band-structure theory, with no evidence of effects beyond the single-quasiparticle approximation. The well known discrepancies between the experimental bandstructure and the Kohn-Sham eigenvalues of Density Functional Theory are almost completely corrected by self-energy effects. Exchange-correlation contributions to the self-energy arising from 3s and 3p core levels are shown to be crucial.Comment: 4 pages, 2 figures embedded in the text. 3 footnotes modified and 1 reference added. Small modifications also in the text. Accepted for publication in PR

Evidence for a GABAergic system in rodent and human testis: Local GABA production and GABA receptors

The major neurotransmitter of the central nervous system, gamma-aminobutyric acid (GABA), exerts its actions through GABA(A), GABA(B) and GABA(C) receptors. GABA and GABA receptors are, however, also present in several non-neural tissues, including the endocrine organs pituitary, pancreas and testis. In the case of the rat testis, GABA appears to be linked to the regulation of steroid synthesis by Leydig cells via GABA(A) receptors, but neither testicular sources of GABA, nor the precise nature of testicular GABA receptors are fully known. We examined these points in rat, mouse, hamster and human testicular samples. RT-PCR followed by sequencing showed that the GABA-synthesizing enzymes glutamate decarboxylase (GAD) 65 and/or GAD67, as well as the vesicular GABA transporter vesicular inhibitory amino acid transporter (VIAAT/VGAT) are expressed. Testicular GAD in the rat was shown to be functionally active by using a GAD assay, and Western blot analysis confirmed the presence of GAD65 and GAD67. Interstitial cells, most of which are Leydig cells according to their location and morphological characteristics, showed positive immunoreaction for GAD and VIAAT/VGAT proteins. In addition, several GABA(A) receptor subunits (alpha1-3, beta1-3, gamma1-3), as well as GABAB receptor subunits R1 and R2, were detected by RT-PCR. Western blot analysis confirmed the results for GABA(A) receptor subunits beta2/3 in the rat, and immunohistochemistry identified interstitial Leydig cells to possess immunoreactive GABA(A) receptor subunits beta2/3 and alpha1. The presence of GABA(A) receptor subunit alpha1 mRNA in interstitial cells of the rat testis was further shown after laser microdissection followed by RT-PCR analysis. In summary, these results describe molecular details of the components of an intratesticular GABAergic system expressed in the endocrine compartment of rodent and human testes. While the physiological significance of this peripheral neuroendocrine system conserved throughout species remains to be elucidated, its mere presence in humans suggests the possibility that clinically used drugs might be able to interfere with testicular function. Copyright (C) 2003 S. Karger AG, Basel

A Process Calculus for Molecular Interaction Maps

We present the MIM calculus, a modeling formalism with a strong biological basis, which provides biologically-meaningful operators for representing the interaction capabilities of molecular species. The operators of the calculus are inspired by the reaction symbols used in Molecular Interaction Maps (MIMs), a diagrammatic notation used by biologists. Models of the calculus can be easily derived from MIM diagrams, for which an unambiguous and executable interpretation is thus obtained. We give a formal definition of the syntax and semantics of the MIM calculus, and we study properties of the formalism. A case study is also presented to show the use of the calculus for modeling biomolecular networks.Comment: 15 pages; 8 figures; To be published on EPTCS, proceedings of MeCBIC 200

Sunlight-mediated inactivation of health-relevant microorganisms in water: a review of mechanisms and modeling approaches.

Health-relevant microorganisms present in natural surface waters and engineered treatment systems that are exposed to sunlight can be inactivated by a complex set of interacting mechanisms. The net impact of sunlight depends on the solar spectral irradiance, the susceptibility of the specific microorganism to each mechanism, and the water quality; inactivation rates can vary by orders of magnitude depending on the organism and environmental conditions. Natural organic matter (NOM) has a large influence, as it can attenuate radiation and thus decrease inactivation by endogenous mechanisms. Simultaneously NOM sensitizes the formation of reactive intermediates that can damage microorganisms via exogenous mechanisms. To accurately predict inactivation and design engineered systems that enhance solar inactivation, it is necessary to model these processes, although some details are not yet sufficiently well understood. In this critical review, we summarize the photo-physics, -chemistry, and -biology that underpin sunlight-mediated inactivation, as well as the targets of damage and cellular responses to sunlight exposure. Viruses that are not susceptible to exogenous inactivation are only inactivated if UVB wavelengths (280-320 nm) are present, such as in very clear, open waters or in containers that are transparent to UVB. Bacteria are susceptible to slightly longer wavelengths. Some viruses and bacteria (especially Gram-positive) are susceptible to exogenous inactivation, which can be initiated by visible as well as UV wavelengths. We review approaches to model sunlight-mediated inactivation and illustrate how the environmental conditions can dramatically shift the inactivation rate of organisms. The implications of this mechanistic understanding of solar inactivation are discussed for a range of applications, including recreational water quality, natural treatment systems, solar disinfection of drinking water (SODIS), and enhanced inactivation via the use of sensitizers and photocatalysts. Finally, priorities for future research are identified that will further our understanding of the key role that sunlight disinfection plays in natural systems and the potential to enhance this process in engineered systems

Timescales of spike-train correlation for neural oscillators with common drive

We examine the effect of the phase-resetting curve (PRC) on the transfer of correlated input signals into correlated output spikes in a class of neural models receiving noisy, super-threshold stimulation. We use linear response theory to approximate the spike correlation coefficient in terms of moments of the associated exit time problem, and contrast the results for Type I vs. Type II models and across the different timescales over which spike correlations can be assessed. We find that, on long timescales, Type I oscillators transfer correlations much more efficiently than Type II oscillators. On short timescales this trend reverses, with the relative efficiency switching at a timescale that depends on the mean and standard deviation of input currents. This switch occurs over timescales that could be exploited by downstream circuits

Transition Layer for the Heterogeneous Allen-Cahn Equation

We consider the equation \e^{2}\Delta u=(u-a(x))(u^2-1) in $\Omega$, $\frac{\partial u}{\partial \nu} =0$ on $\partial \Omega$, where $\Omega$ is a smooth and bounded domain in $\R^n$, $\nu$ the outer unit normal to \pa\Omega, and $a$ a smooth function satisfying $-1<a(x)<1$ in \ov{\Omega}. We set $K$, $\Omega_+$ and $\Omega_-$ to be respectively the zero-level set of $a$, {a>0} and {a<0}. Assuming $\nabla a \neq 0$ on $K$ and $a\ne 0$ on $\partial \Omega$, we show that there exists a sequence \e_j \to 0 such that the above equation has a solution u_{\e_j} which converges uniformly to $\pm 1$ on the compact sets of \O_{\pm} as $j \to + \infty$.Comment: 25 page

An educational training program for physicians for diagnosis and treatment of depression

OBJECTIVE: The American Regional Office of the WHO has launched a major initiative to reduce the prevalence of affective disorders region-wide that includes focusing on the primary health care system. This study evaluated the results of an educational training program for Brazilian primary care physicians that measured changes in knowledge, attitudes, and practice. METHODS: A total of 17 primary care physicians and 1,224 patients participated in the study. Physician's knowledge, attitudes, and clinical practice were assessed one-month prior and one-month following the training program. In addition, the patients that visited the clinic during a typical week completed depression symptom self-ratings, including the Zung and a DSM-IV/ICD-10 major depression checklist at both times. RESULTS: The training program showed limited benefits in this small sample of physicians. The program was unable to demonstrate benefit in improving knowledge about depression and in changing disorder-related attitudes. There were no changes in the diagnostic rates of major depression. There was some evidence to support improvement in psychopharmacological management. The physicians seemed more confident in treating patients, as there was a reduction of referrals to the specialists. Lack of statistical power prevented the latter two findings from reaching statistical significance. CONCLUSIONS: The inclusion of primary care physicians is a central component of any initiative to reduce the treatment gap and lag of depression. However, more effective methods of training Brazilian primary care physicians in the management of major depression need to be tested.OBJETIVO: Avaliar os resultados da aplicação de programa de treinamento da Organização Mundial de Saúde, voltado para diagnóstico e tratamento da depressão, dirigido a médicos clínicos gerais. MÉTODOS: Dezessete clínicos e 1.224 pacientes da cidade de Campinas, SP, participaram do estudo. Um mês antes e um após o treinamento, foram avaliados o conhecimento dos médicos, suas atitudes e o atendimento prestado aos pacientes; esses, por sua vez, completaram escalas de auto-avaliação de sintomas depressivos: Zung e um checklist para depressão maior do manual para diagnóstico e estatística em saúde mental (DSM-IV/CID-10). A mudança de conhecimento e atitude dos clínicos entre as fases 1 e 2 foi avaliada pelos testes t de Student. Mudanças com relação ao conhecimento de cada indivíduo foram mensuradas pelo teste de qui-quadrado de McNemar. As diferenças entre o modo de atender os pacientes entre as duas fases foram determinadas pelo teste de qui-quadrado de Pearson. A concordância diagnóstica foi analisada utilizando o Kappa, com o intuito de corrigir a concordância ao acaso. RESULTADOS: O programa mostrou benefícios limitados nessa amostra de clínicos gerais. Não foi capaz de mostrar aumento do conhecimento sobre a depressão e nem quanto à atitude dos médicos com relação a esse transtorno. Não houve modificação no número de casos diagnosticados antes ou após o programa. Existiram algumas evidências com relação à melhora no manejo psicofarmacológico. Aparentemente, o programa tornou os clínicos mais confiantes para o tratamento da depressão, diminuindo o número de encaminhamentos feitos aos profissionais da área de saúde mental. Porém, um baixo poder estatístico não permitiu que os dois últimos achados atingissem significância. CONCLUSÕES: A inclusão de clínicos gerais é um componente central de qualquer iniciativa para melhorar a detecção e o tratamento da depressão, porém faz-se necessário testar melhores métodos de treinamento dos clínicos brasileiros no manejo desta.Serviço de Saúde 'Dr. Cândido Ferreira'Ministério da SaúdeBrown University Providence Department of Psychiatry and Human BehaviorOrganização Mundial da Saúde Organização Panamericana de SaúdeUniversidade Federal de São Paulo (UNIFESP)UNIFESP, Departamento de PsiquiatriaSciEL