A translational approach of mouse and human studies to integrate chronobiology into therapies for psychiatric disorders

Background Circadian rhythms are endogenous manifestations of the external 24-hour light-dark cycle that allow the organism to adapt and to anticipate daily temporal changes in the environment. These ~24-hour rhythms, also called circadian clocks, are driven by clock genes in almost each cell throughout our body and are set to 24 hours each day by the external light and dark cycle. Because circadian clocks regulate virtually all of our physiology and behavior, organisms may be susceptible to various types of disorders when circadian rhythms are disrupted. Thus, there is, for example, a bidirectional relationship between the disturbance of circadian clocks and the development of psychiatric disorders, such as anxiety disorders, and alcohol use disorder (AUD), whereby alcohol consumption can influence the circadian system, but conversely, disturbed circadian rhythms are a risk factor for addiction. Results We show that Cryptochrome 1 and 2 (Cry1/2-/-) double knockout mice, which do not express endogenous circadian rhythms, exhibit a pronounced anxiety-like phenotype and are more sensitive to stressful situations. These behavioral effects are confirmed by increased neuronal activity (c-Fos) in the basolateral amygdala. Furthermore, we show that the Cry1/2-/- mice exhibit distinct traits that predispose humans to an increased risk of problematic alcohol consumption. Cry1/2-/- mice show lower alcohol consumption behavior (liking) concomitant with higher motivation to acquire the substance (wanting), a finding that is consistent with the incentive sensitization theory of addiction. These phenotypes are also supported by molecular analyses: In the absence of the Cry genes, the stress hormone corticosterone is continuously elevated, and the level of the orexin precursor prepro-orexin is persistently low, which together represent explanatory factors for an overall altered alcohol preference. In terms of gene-environment interaction, the phenotype of altered alcohol drinking behavior of Cry1/2-/- mice, was enhanced by additional environmental circadian perturbations (shift work model). Outlook Our results underline the importance of stable endogenous and environmental circadian rhythms as well as their interaction for mental health. From our findings, we assume that patients suffering from anxiety disorders, AUD, or both, regardless of whether underlying circadian rhythm disturbances are genetically or environmentally induced, may benefit from chronotherapies. This is why, based on our results, we developed a new adjunctive chronotherapeutic treatment for AUD patients

Fotoreceptores em campo elétrico

Orientadores: Sérgio Santos Mühlen, Richard Hans Wilhelm FunkTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia Elétrica e de ComputaçãoResumo: Estudos anteriores e evidências experimentais sugerem um papel importante dos campos elétricos endógenos no direcionamento da migração celular, no desenvolvimento e na regeneração celular e na cicatrização de feridas. Em culturas de células, campos elétricos de corrente contínua influenciam a divisão celular, a polaridade, a forma e a motilidade das células. As distrofias das células fotoreceptoras são uma das principais causas de cegueira hereditária no mundo ocidental; a aplicação de campo elétrico poderia ser usada como um sinal direcional para o crescimento das células fotoreceptoras na direção do tecido danificado. Neste estudo, investigamos os efeitos do campo elétrico no estabelecimento da polaridade celular de fotoreceptores e na polarização de estruturas intracelulares, a fim de demonstrar que são regulados por um sinal elétrico externo. Utilizando um ensaio de migração bem estabelecido, células fotoreceptoras de retina de camundongos do tipo cone, 661W, foram estimuladas durante 5 horas com campo eléctrico de 5 V/cm. Através de técnicas de imunofluorescência, investigamos mudanças na posição de organelas importantes após a estimulação, como o núcleo e o complexo de Golgi (GA), e também de proteínas do citoesqueleto, tais como actina, microtúbulos e o centro organizador dos microtúbulos (MTOC). Além disso, investigamos também alterações no potencial da membrana plasmática e mitocondrial utilizando corantes específicos, na presença e ausência de campo elétrico aplicado. Em resposta ao estímulo direcional, as células 661W estenderam protuberâncias de membrana no sentido do catodo; elas se alongaram perpendicularmente ao campo elétrico e formaram uma borda frontal. Ocorreu migração significativa na direção do catodo. O centro organizador dos microtúbulos, o complexo de Golgi e actina foram reorientados na direcção da borda frontal das células (catodo), enquanto os microtúbulos se acumularam na borda traseira das células (anodo) e o núcleo foi translocado para a parte de trás das células, também na borda traseira. Após exposição ao campo elétrico, ambos os potenciais de membrana, plasmático e mitocondrial, se despolarizaram, especialmente no lado do catodo das células. Esse estudo contribuiu para uma melhor compreensão dos mecanismos de migração direcional devido ao campo elétrico das células 661W, que depende da despolarização das membranas plasmática e mitocondrial e da polarização induzida do citoequeleto de actina e microtúbulos, com subsequente polarização do núcleo, MTOC e GAAbstract: Previous studies and experimental evidences suggest an important role for endogenous electric fields in directing cell migration in wound healing, development and regeneration. In cultures, applied direct current electric field (dcEF) influences cell division, polarity, shape and motility. Photoreceptors dystrophies are one of the major causes of inherited blindness in the western world; application of EF could be used as a cue to direct photoreceptors cells to growth towards the damaged tissue. In this study we investigate the effects of dcEF in the establishment of photoreceptor cell polarity and polarization of intracellular structures, in order to demonstrate that they are regulated by an extracellular electrical cue. Using a well established migration assay, photoreceptors cone-like 661W mouse retinal cells were stimulated for 5 h with 5 V/cm electric field. Using immunofluorescence techniques we have investigated changes in position of important organelles after the stimulation, like Golgi Apparatus (GA) and nucleus, and also cytoskeletal proteins, such as the Microtubules Organizing Center (MTOC), actin and Microtubules (MT). Furthermore, we investigated changes in plasma and mitochondrial membrane potentials using ion reporter dyes in the presence and absence of an applied dcEF. In response to the directional stimulus, 661W cells have extended membrane protrusions towards cathode; they got elongated perpendicular to the dcEF and have formed a leading edge towards the direction of cues. Directional migration has occurred towards cathode. MTOC, GA and actin were reoriented in the direction of the leading edge of the cells (cathode), while the MT accumulated in the rear edge of the cells (anode) and the nucleus was translocated to the back of the cells, also in the rear edge. After dcEF exposure, both plasma and mitochondrial membranes were depolarized, especially in the cathode side of the cells. This study extended an understanding of the mechanism of the dcEF-directed 661W cell migration, which depends on plasma and mitochondrial membrane depolarization and an induced polarization of actin cytoskeleton and microtubules with subsequent polarization of nucleus, MTOC and GADoutoradoEngenharia BiomedicaDoutora em Engenharia Elétrica34548011846CAPE

Who benefits from aid-for-trade?

Both donors and recipients can benefit from aid, yet aid-for-trade seems to benefit the exports of middle-income countries most, rather than the developing economies for which it was designe

Reversible shift in the superconducting transition for La1.85Sr0.15CuO4 and BaFe1.8Co0.2As2 using piezoelectric substrates

The use of piezoelectric substrates enables a dynamic observation of strain dependent properties of functional materials. Based on studies with La1.85Sr0.15CuO4 we extended this approach to the iron arsenic superconductors represented by BaFe2-xCoxAs2 to investigate strain driven changes in detail. We demonstrate that epitaxial thin films can be prepared on (001)Pb(Mg1/3Nb2/3)0.72Ti0.28O3 substrates using pulsed laser deposition. The structural as well as the electric properties of the grown films were characterized in detail. A reversible shift of the superconducting transition of 0.44 K for La1.85Sr0.15CuO4 and 0.2 K for BaFe1.8Co0.2As2 was observed applying a biaxial strain of 0.022% and 0.017% respectively

Towards a reliable bridge joint between REBCO coated conductors

REBa2Cu3O7-x (REBCO; RE = Y, Gd) coated conductor wires are commercially available up to a length of about 1 km. However, for large-scale devices like superconducting coils for high-field magnets several kilometres of a coated conductors are required. Therefore, it is desirable to use joints, which exhibit similar superconducting properties as the coated conductor itself. In this study, we jointed commercial REBCO coated conductors by a two-step procedure. At first, a superconducting soldering solution was developed and deposited on unstabilized coated conductors via chemical solution deposition. The soldering precursor is based on a Cu-rich solution with a metal cation ratio Y:Ba:Cu of 1:2:4. Secondly, a piece of the coated conductor was delaminated between the superconducting and the buffer layer and used as bridge between two other conductors covered with the soldering layer. Annealing the resulting bridge joint under pressure results in a mechanical stable configuration. © Published under licence by IOP Publishing Ltd

Domain structure of epitaxial Co films with perpendicular anisotropy

Epitaxial hcp Cobalt films with pronounced c-axis texture have been prepared by pulsed lased deposition (PLD) either directly onto Al2O3 (0001) single crystal substrates or with an intermediate Ruthenium buffer layer. The crystal structure and epitaxial growth relation was studied by XRD, pole figure measurements and reciprocal space mapping. Detailed VSM analysis shows that the perpendicular anisotropy of these highly textured Co films reaches the magnetocrystalline anisotropy of hcp-Co single crystal material. Films were prepared with thickness t of 20 nm < t < 100 nm to study the crossover from in-plane magnetization to out-of-plane magnetization in detail. The analysis of the periodic domain pattern observed by magnetic force microscopy allows to determine the critical minimum thickness below which the domains adopt a pure in-plane orientation. Above the critical thickness the width of the stripe domains is evaluated as a function of the film thickness and compared with domain theory. Especially the discrepancies at smallest film thicknesses show that the system is in an intermediate state between in-plane and out-of-plane domains, which is not described by existing analytical domain models