Glycogen synthase kinase 3 (GSK3) in the heart: a point of integration in hypertrophic signalling and a therapeutic target? A critical analysis

Glycogen synthase kinase 3 (GSK3, of which there are two isoforms, GSK3alpha and GSK3beta) was originally characterized in the context of regulation of glycogen metabolism, though it is now known to regulate many other cellular processes. Phosphorylation of GSK3alpha(Ser21) and GSK3beta(Ser9) inhibits their activity. In the heart, emphasis has been placed particularly on GSK3beta, rather than GSK3alpha. Importantly, catalytically-active GSK3 generally restrains gene expression and, in the heart, catalytically-active GSK3 has been implicated in anti-hypertrophic signalling. Inhibition of GSK3 results in changes in the activities of transcription and translation factors in the heart and promotes hypertrophic responses, and it is generally assumed that signal transduction from hypertrophic stimuli to GSK3 passes primarily through protein kinase B/Akt (PKB/Akt). However, recent data suggest that the situation is far more complex. We review evidence pertaining to the role of GSK3 in the myocardium and discuss effects of genetic manipulation of GSK3 activity in vivo. We also discuss the signalling pathways potentially regulating GSK3 activity and propose that, depending on the stimulus, phosphorylation of GSK3 is independent of PKB/Akt. Potential GSK3 substrates studied in relation to myocardial hypertrophy include nuclear factors of activated T cells, beta-catenin, GATA4, myocardin, CREB, and eukaryotic initiation factor 2Bvarepsilon. These and other transcription factor substrates putatively important in the heart are considered. We discuss whether cardiac pathologies could be treated by therapeutic intervention at the GSK3 level but conclude that any intervention would be premature without greater understanding of the precise role of GSK3 in cardiac processes.

Flow-aligned jets in the magnetospheric cusp: Results from the Geospace Environment Modeling Pilot Program

The extended flight of the Airborne Ionospheric Observatory during the Geospace Environment Modeling (GEM) Pilot program on January 16, 1990, allowed continuous all-sky monitoring of the two-dimensional ionospheric footprint of the northward interplanetary magnetic field (IMF) cusp in several wavelengths. Especially important in determining the locus of magnetosheath electron precipitation was the 630.0-nm red line emission. The most striking morphological change in the images was the transient appearance of zonally elongated regions of enhanced 630.0-nm emission which resembled “rays” emanating from the centroid of the precipitation. The appearance of these rays was strongly correlated with the Y component of the IMF: when the magnitude of By was large compared to Bz, the rays appeared; otherwise, the distribution was relatively unstructured. Late in the flight the field of view of the imager included the field of view of flow measurements from the European incoherent scatter radar (EISCAT). The rays visible in 630.0-nm emission exactly aligned with the position of strong flow jets observed by EISCAT. We attribute this correspondence to the requirement of quasi-neutrality; namely, the soft electrons have their largest precipitating fluxes where the bulk of the ions precipitate. The ions, in regions of strong convective flow, are spread out farther along the flow path than in regions of weaker flow. The occurrence and direction of these flow bursts are controlled by the IMF in a manner consistent with newly opened flux tubes; i.e., when |By| > |Bz|, tension in the reconnected field lines produce east-west flow regions downstream of the ionospheric projection of the x line. We interpret the optical rays (flow bursts), which typically last between 5 and 15 min, as evidence of periods of enhanced dayside (or lobe) reconnection when |By| > |Bz|. The length of the reconnection pulse is difficult to determine, however, since strong zonal flows would be expected to persist until the tension force in the field line has decayed, even if the duration of the enhanced reconnection was relatively short.

The fractured lives of German Bohemian children, born 1933-40 in the area known as Sudetenland: a memory study, Nablonz-Neugablonz

At the Paris Peace Conferences of 1918-1919, new states aspiring to be nation-states were created for 60 million people, but at the same time 25 million people found themselves as ethnic minorities. This change of the old order in Europe had a considerable impact on one such group, more than 3 million Bohemian German-speakers, later referred to as Sudeten Germans. After the demise of the Habsburg Empire In 1918, they became part of the new state of Czechoslovakia. In 1938, the Munich Agreement – prelude to the Second World War – integrated them into Hitler’s Reich; in 1945-1946 they were expelled from the reconstituted state of Czechoslovakia. At the centre of this War Child case study are German children from the Northern Bohemian town and district, formerly known as Gablonz an der Neisse, famous for exquisite glass art, now Jablonec nad Nisou in the Czech Republic. After their expulsion they found new homes in the post-war Federal Republic of Germany. In addition, testimonies have been drawn upon of some Czech eyewitnesses from the same area, who provided their perspective from the other side, as it were. It turned out to be an insightful case study of the fate of these communities, previously studied mainly within the context of the national struggle between Germans and Czechs. The inter-disciplinary research methodology adopted here combines history and sociological research to demonstrate the effect of larger political and social developments on human lives, not shying away from addressing sensitive political and historical issues, as far as these are relevant within the context of the study. The expellees started new lives in what became Neugablonz in post-war Bavaria where they successfully re-established the industries they had had to leave behind in 1945-1946. Part 1 of the study sheds light on the complex Czech-German relationship of this important Central European region, addressing issues of democracy, ethnicity, race, nationalism, geopolitics, economics, human geography and ethnography. It also charts the developments leading to the expulsion of the Sudeten Germans from Czechoslovakia after 1945. What is important in this War Child study is how the expellees remember their history while living as children in Sudetenland and later. The testimony data gained indicate that certain stereotypes often repeated within the context of Sudeten issues such as the confrontational nature of inter-ethnic relations are not reflected in the testimonies of the respondents from Gablonz. In Part 2 the War Child Study explores the memories of the former Sudeten war children using sociological research methods. It focuses on how they remember life in their Bohemian homeland and coped with the life-long effects of displacement after their expulsion. The study maps how they turned adversity into success by showing a remarkable degree of resilience and ingenuity in the face of testing circumstances due to the abrupt break in their lives. The thesis examines the reasons for the relatively positive outcome to respondents’ lives and what transferable lessons can be deduced from the results of this study.

Advancements in decadal climate predictability: the role of nonoceanic drivers

We review recent progress in understanding the role of sea ice, land surface, stratosphere, and aerosols in decadal-scale predictability and discuss the perspectives for improving the predictive capabilities of current Earth system models (ESMs). These constituents have received relatively little attention because their contribution to the slow climatic manifold is controversial in comparison to that of the large heat capacity of the oceans. Furthermore, their initialization as well as their representation in state-of-the-art climate models remains a challenge. Numerous extraoceanic processes that could be active over the decadal range are proposed. Potential predictability associated with the aforementioned, poorly represented, and scarcely observed constituents of the climate system has been primarily inspected through numerical simulations performed under idealized experimental settings. The impact, however, on practical decadal predictions, conducted with realistically initialized full-fledged climate models, is still largely unexploited. Enhancing initial-value predictability through an improved model initialization appears to be a viable option for land surface, sea ice, and, marginally, the stratosphere. Similarly, capturing future aerosol emission storylines might lead to an improved representation of both global and regional short-term climatic changes. In addition to these factors, a key role on the overall predictive ability of ESMs is expected to be played by an accurate representation of processes associated with specific components of the climate system. These act as “signal carriers,” transferring across the climatic phase space the information associated with the initial state and boundary forcings, and dynamically bridging different (otherwise unconnected) subsystems. Through this mechanism, Earth system components trigger low-frequency variability modes, thus extending the predictability beyond the seasonal scale.

Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients

Amyotrophic lateral sclerosis (ALS) is an incurable neuromuscular disease that leads to a profound loss of life quality and premature death. Around 10% of the cases are inherited and ALS8 is an autosomal dominant form of familial ALS caused by mutations in the vamp-associated protein B/C (VAPB) gene. The VAPB protein is involved in many cellular processes and it likely contributes to the pathogenesis of other forms of ALS besides ALS8. A number of successful drug tests in ALS animal models could not be translated to humans underscoring the need for novel approaches. The induced pluripotent stem cells (iPSC) technology brings new hope, since it can be used to model and investigate diseases in vitro. Here we present an additional tool to study ALS based on ALS8-iPSC. Fibroblasts from ALS8 patients and their non-carrier siblings were successfully reprogrammed to a pluripotent state and differentiated into motor neurons. We show for the first time that VAPB protein levels are reduced in ALS8-derived motor neurons but, in contrast to over-expression systems, cytoplasmic aggregates could not be identified. Our results suggest that optimal levels of VAPB may play a central role in the pathogenesis of ALS8, in agreement with the observed reduction of VAPB in sporadic ALS.

Transcriptional regulation differs in affected facioscapulohumeral muscular dystrophy patients compared to asymptomatic related carriers

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive muscle disorder that has been associated with a contraction of 3.3-kb repeats on chromosome 4q35. FSHD is characterized by a wide clinical inter- and intrafamilial variability, ranging from wheelchair-bound patients to asymptomatic carriers. Our study is unique in comparing the gene expression profiles from related affected, asymptomatic carrier, and control individuals. Our results suggest that the expression of genes on chromosome 4q is altered in affected and asymptomatic individuals. Remarkably, the changes seen in asymptomatic samples are largely in products of genes encoding several chemokines, whereas the changes seen in affected samples are largely in genes governing the synthesis of GPI-linked proteins and histone acetylation. Besides this, the affected patient and related asymptomatic carrier share the 4qA161 haplotype. Thus, these polymorphisms by themselves do not explain the pathogenicity of the contracted allele. Interestingly, our results also suggest that the miRNAs might mediate the regulatory network in FSHD. Together, our results support the previous evidence that FSHD may be caused by transcriptional dysregulation of multiple genes, in cis and in trans, and suggest some factors potentially important for FSHD pathogenesis. The study of the gene expression profiles from asymptomatic carriers and related affected patients is a unique approach to try to enhance our understanding of the missing link between the contraction in D4Z4 repeats and muscle disease, while minimizing the effects of differences resulting from genetic background.

Synthesis and magnetic characterization of TmCo(2)B(2)C

A new quaternary intermetallic borocarbide TmCo(2)B(2)C has been synthesized via rapid-quench of an arc-melted ingot. Elemental and powder-diffraction analyses established its correct stoichiometry and single-phase character. The crystal structure is isomorphous with that of TmNi(2)B(2)C (I4/mmm) and is stable over the studied temperature range. Above 7 K, the paramagnetic state follows modified Curie-Weiss behavior (chi = C/(T - theta) + chi(0)) wherein chi(0) = 0.008(1) emu mol(-1) with the temperature-dependent term reflecting the paramagnetism of the Tm subsystem: mu(eff) = 7.6(2) mu(B) (in agreement with the expected value for a free Tm(3+) ion) and theta = -4.5(3) K. Long-range ferromagnetic order of the Tm sublattice is observed to develop around similar to 1 K. No superconductivity is detected in TmCo(2)B(2)C down to 20 mK, a feature which is consistent with the general trend in the RCo(2)B(2)C series. Finally, the influence of the rapid-quench process on the magnetism (and superconductivity) of TmNi(2)B(2)C will be discussed and compared to that of TmCo(2)B(2)C.

Structural and magnetic properties and hyperfine interaction in La(3.5)Ru(4)O(13) compound

Structural, magnetic and hyperfine interaction measurements have been carried out on the novel compound La(3.5)Ru(4)O(13) prepared under two different atmospheres (air and oxygen flow). This compound is formed in the orthorhombic structure (space group Pmmm, # 47). The coexistence of the triple-layered perovskite-type planes (quasi-2D structure) and the rutile-like slabs (1D structure) leads to interesting magnetic and electronic properties in this compound. The magnetic susceptibility of this system shows a peak at T similar to 47 K associated with antiferromagnetic interactions. The Curie-Weiss behaviour of the susceptibility provides an effective magnetic moment consistent with Ru ions in low-spin state. Perturbed angular correlation measurements carried out with (111)Cd probe in the temperature range 10-60 K reveal only quadrupole interactions and indicate the occurrence of structural distortions for T<40K. (C) 2009 Elsevier B.V. All rights reserved.

Optical and dielectric relaxor behaviour of Ba(Zr(0.25)Ti(0.75))O(3) ceramic explained by means of distorted clusters

In this work, Ba(Zr(0.25)Ti(0.75))O(3) ceramic was prepared by solid-state reaction. This material was characterized by x-ray diffraction and Fourier transform Raman spectroscopy. The temperature dependent dielectric properties were investigated in the frequency range from 1 kHz to 1 MHz. The dielectric measurements indicated a diffuse phase transition. The broadening of the dielectric permittivity in the frequency range as well as its shifting at higher temperatures indicated a relaxor-like behaviour for this material. The diffusivity and the relaxation strength were estimated using the modified Curie-Weiss law. The optical properties were analysed by ultraviolet-visible (UV-vis) absorption spectroscopy and photoluminescence (PL) measurements at room temperature. The UV-vis spectrum indicated that the Ba(Zr(0.25)Ti(0.75))O(3) ceramic has an optical band gap of 2.98 eV. A blue PL emission was observed for this compound when excited with 350 nm wavelength. The polarity as well as the PL property of this material was attributed to the presence of polar [TiO(6)] distorted clusters into a globally cubic matrix.

Insights into the dynamics and sources of atmospheric lead and particulate matter in Sao Paulo, Brazil, from high temporal resolution sampling

We present the first results of a study investigating the processes that control concentrations and sources of Pb and particulate matter in the atmosphere of Sao Paulo City Brazil Aerosols were collected with high temporal resolution (3 hours) during a four-day period in July 2005 The highest Pb concentrations measured coincided with large fireworks during celebration events and associated to high traffic occurrence Our high-resolution data highlights the impact that a singular transient event can have on air quality even in a megacity Under meteorological conditions non-conducive to pollutant dispersion Pb and particulate matter concentrations accumulated during the night leading to the highest concentrations in aerosols collected early in the morning of the following day The stable isotopes of Pb suggest that emissions from traffic remain an Important source of Pb in Sao Paulo City due to the large traffic fleet despite low Pb concentrations in fuels (C) 2010 Elsevier BV All rights reserved

Accurate and Precise Zinc Isotope Ratio Measurements in Urban Aerosols

We developed an analytical method and constrained procedural boundary conditions that enable accurate and precise Zn isotope ratio measurements in urban aerosols. We also demonstrate the potential of this new isotope system for air pollutant source tracing. The procedural blank is around 5 ng and significantly lower than published methods due to a tailored ion chromatographic separation. Accurate mass bias correction using external correction with Cu is limited to Zn sample content of approximately 50 ng due to the combined effect of blank contribution of Cu and Zn from the ion exchange procedure and the need to maintain a Cu/Zn ratio of approximately 1. Mass bias is corrected for by applying the common analyte internal standardization method approach. Comparison with other mass bias correction methods demonstrates the accuracy of the method. The average precision of delta(66)Zn determinations in aerosols is around 0.05% per atomic mass unit. The method was tested on aerosols collected in Sin Paulo City, Brazil. The measurements reveal significant variations in delta(66)Zn(Imperial) ranging between -0.96 and -0.37% in coarse and between -1.04 and 0.02% in fine particular matter. This variability suggests that Zn isotopic compositions distinguish atmospheric sources. The isotopic light signature suggests traffic as the main source. We present further delta(66)Zn(Imperial) data for the standard reference material NIST SRM 2783 (delta 66Z(Imperial) = 0.26 +/- 0.10%).