Mouse tafazzin is required for male germ cell meiosis and spermatogenesis

Barth syndrome is an X-linked mitochondrial disease, symptoms of which include neutropenia and cardiac myopathy. These symptoms are the most significant clinical consequences of a disease, which is increasingly recognised to have a variable presentation. Mutation in the Taz gene in Xq28 is thought to be responsible for the condition, by altering mitochondrial lipid content and mitochondrial function. Male chimeras carrying a targeted mutation of Taz on their X-chromosome were infertile. Testes from the Taz knockout chimeras were smaller than their control counterparts and this was associated with a disruption of the progression of spermatocytes through meiosis to spermiogenesis. Taz knockout ES cells also showed a defect when differentiated to germ cells in vitro. Mutant spermatocytes failed to progress past the pachytene stage of meiosis and had higher levels of DNA double strand damage and increased levels of endogenous retrotransposon activity. Altogether these data revealed a novel role for Taz in helping to maintain genome integrity in meiosis and facilitating germ cell differentiation. We have unravelled a novel function for the Taz protein, which should contribute to an understanding of how a disruption of the Taz gene results in the complex symptoms underlying Barth Syndrome

Game Over? Geburt, Tod und Renaissance von Arcade-Games

'Game Over' hiess es in den letzten Jahren für sämtliche Spielsalons (engl. Arcades) nicht nur in der Schweiz. Mit dem Sterben des Videospielspielens in einem öffentlich zugänglichen und dazu intendierten Raum verschwanden auch die entsprechenden Computerspiele mitsamt den Automaten aus dem Blickfeld. Die Spielsalons reihten sich nahtlos ein in eine Kulturgeschichte urbanen Vergnügens, welche im 19. Jahrhundert ihren Anfang nahm. Mit dem Betreten eines Spielsalons liess man den Alltag und die ‘Wirklichkeit‘ zurück und war diese Grenze einmal überschritten, fand man sich in einer Welt voller leuchtender und blinkender Automaten wieder. Die Arcades waren jedoch nicht nur soziale Biotope und urbane Kulturräume, sondern es standen auch wirtschaftliche Interessen dahinter. Erst das Einwerfen eines Geldstücks in den Automaten, eröffnete einer Spielerin oder einem Spieler das Vergnügen eines Arcade-Games. Heute findet man die Videospielkästen fast nur noch in den Garagen und Kellern eifriger Sammler/innen und leidenschaftlicher Fans. Die modernen Phänomene der Sammeltätigkeit und Begeisterung für Retro-Spiele haben in den letzten Jahren den Arcade-Games zu einer Art Auferstehung verholfen. Es stellt sich die Frage, was in der Tradition von urbanem Vergnügen zum Aufkommen und Verschwinden von Spielsalons geführt hat. Welche sozialen Aspekte dieses nicht-alltäglichen Ortes sind ersichtlich? Was waren die typischen Charakteristika von Arcade-Games und wie wirkten sich diese auf das Game-Play aus? Was steckt hinter der Motivation jener Menschen, die heute die ausrangierten Spielkästen sammeln, restaurieren und wieder spielen? Diesen Fragen soll im Folgenden nachgegangen werden. Auf der Grundlage der einschlägigen Literatur und einem qualitativen Interview mit Ivo Vasella, einem passionierten Sammler und Restaurator von alten Videospielautomaten, soll gezeigt werden, wie es aus kulturwissenschaftlicher Perspektive zu Geburt, Tod und Renaissance von Arcade-Games gekommen ist

Transcranial Magnetic Stimulation Produces Speech Arrest but Not Song Arrest

Transcranial magnetic stimulation (TMS) is a tool that can be used to disrupt cortical processing for a few tens of milliseconds and, when combined with cognitive paradigms, can be used to look at the role of specific brain regions. TMS can be described as a way of creating virtual neuropsychological patients, but can also extend these findings. It can be delivered focally in time and therefore has the advantage of being able to provide information about the time course of cortical events. In addition, because “virtual lesions” are transient, the interpretation of behavioral effects are not complicated by the functional recovery that results when a damaged brain reorganizes.(Introduction

Indigo : a new tribological substance class for non-toxic and ecological gliding surfaces on ice, snow, and water

The biogenic substance E-indigo can form supramolecular, hydrophobic structures using self-organization. These structures show a low coefficient of friction as a gliding layer against polar surfaces. The formation of primary particles with platelet morphology based on hydrogen-bonded E-indigo molecules is ideal to produce the gliding layer. Structures with excellent gliding properties can be achieved by means of directed friction and high pressure, as well as through tempering. The resulting hard, thin gliding layer of E-indigo does not easily absorb dirt and, thus, prevents a rapid increase in friction. Field tests on snow, with cross-country skis, have shown promising results in comparison to fluorinated and non-fluorinated waxes. Based on quantitative structure–activity relationship (QSAR) data for E-indigo, and its isomers and tautomers, it has been demonstrated that both the application and abrasion of the thin indigo layers are harmless to health, and are ecologically benign and, therefore, sustainable

ATP Analogues for Structural Investigations: Case Studies of a DnaB Helicase and an ABC Transporter.

Nucleoside triphosphates (NTPs) are used as chemical energy source in a variety of cell systems. Structural snapshots along the NTP hydrolysis reaction coordinate are typically obtained by adding stable, nonhydrolyzable adenosine triphosphate (ATP) -analogues to the proteins, with the goal to arrest a state that mimics as closely as possible a physiologically relevant state, e.g., the pre-hydrolytic, transition and post-hydrolytic states. We here present the lessons learned on two distinct ATPases on the best use and unexpected pitfalls observed for different analogues. The proteins investigated are the bacterial DnaB helicase from Helicobacter pylori and the multidrug ATP binding cassette (ABC) transporter BmrA from Bacillus subtilis, both belonging to the same division of P-loop fold NTPases. We review the magnetic-resonance strategies which can be of use to probe the binding of the ATP-mimics, and present carbon-13, phosphorus-31, and vanadium-51 solid-state nuclear magnetic resonance (NMR) spectra of the proteins or the bound molecules to unravel conformational and dynamic changes upon binding of the ATP-mimics. Electron paramagnetic resonance (EPR), and in particular W-band electron-electron double resonance (ELDOR)-detected NMR, is of complementary use to assess binding of vanadate. We discuss which analogues best mimic the different hydrolysis states for the DnaB helicase and the ABC transporter BmrA. These might be relevant also to structural and functional studies of other NTPases

MAP Kinase Phosphatase-2 Plays a Critical Role in Response to Infection by Leishmania mexicana

In this study we generated a novel dual specific phosphatase 4 (DUSP4) deletion mouse using a targeted deletion strategy in order to examine the role of MAP kinase phosphatase-2 (MKP-2) in immune responses. Lipopolysaccharide (LPS) induced a rapid, time and concentration-dependent increase in MKP-2 protein expression in bone marrow-derived macrophages from MKP-2+/+ but not from MKP-2−/− mice. LPS-induced JNK and p38 MAP kinase phosphorylation was significantly increased and prolonged in MKP-2−/− macrophages whilst ERK phosphorylation was unaffected. MKP-2 deletion also potentiated LPS-stimulated induction of the inflammatory cytokines, IL-6, IL-12p40, TNF-α, and also COX-2 derived PGE2 production. However surprisingly, in MKP-2−/− macrophages, there was a marked reduction in LPS or IFNγ-induced iNOS and nitric oxide release and enhanced basal expression of arginase-1, suggesting that MKP-2 may have an additional regulatory function significant in pathogen-mediated immunity. Indeed, following infection with the intracellular parasite Leishmania mexicana, MKP-2−/− mice displayed increased lesion size and parasite burden, and a significantly modified Th1/Th2 bias compared with wild-type counterparts. However, there was no intrinsic defect in MKP-2−/− T cell function as measured by anti-CD3 induced IFN-γ production. Rather, MKP-2−/− bone marrow-derived macrophages were found to be inherently more susceptible to infection with Leishmania mexicana, an effect reversed following treatment with the arginase inhibitor nor-NOHA. These findings show for the first time a role for MKP-2 in vivo and demonstrate that MKP-2 may be essential in orchestrating protection against intracellular infection at the level of the macrophage

Dual-specificity MAP kinase phosphatases in health and disease

Source at https://doi.org/10.1016/j.bbamcr.2018.09.002.It is well established that a family of dual-specificity MAP kinase phosphatases (MKPs) play key roles in the regulated dephosphorylation and inactivation of MAP kinase isoforms in mammalian cells and tissues. MKPs provide a mechanism of spatiotemporal feedback control of these key signalling pathways, but can also mediate crosstalk between distinct MAP kinase cascades and facilitate interactions between MAP kinase pathways and other key signalling modules. As our knowledge of the regulation, substrate specificity and catalytic mechanisms of MKPs has matured, more recent work using genetic models has revealed key physiological functions for MKPs and also uncovered potentially important roles in regulating the pathophysiological outcome of signalling with relevance to human diseases. These include cancer, diabetes, inflammatory and neurodegenerative disorders. It is hoped that this understanding will reveal novel therapeutic targets and biomarkers for disease, thus contributing to more effective diagnosis and treatment for these debilitating and often fatal conditions

Acquired and congenital disorders of sung performance: A review.

Many believe that the majority of people are unable to carry a tune. Yet, this widespread idea underestimates the singing abilities of the layman. Most occasional singers can sing in tune and in time, provided that they perform at a slow tempo. Here we characterize proficient singing in the general population and identify its neuronal underpinnings by reviewing behavioral and neuroimaging studies. In addition, poor singing resulting from a brain injury or neurogenetic disorder (i.e., tone deafness or congenital amusia) is examined. Different lines of evidence converge in indicating that poor singing is not a monolithic deficit. A variety of poor-singing "phenotypes" are described, with or without concurrent perceptual deficits. In addition, particular attention is paid to the dissociations between specific abilities in poor singers (e.g., production of absolute vs. relative pitch, pitch vs. time accuracy). Such diversity of impairments in poor singers can be traced to different faulty mechanisms within the vocal sensorimotor loop, such as pitch perception and sensorimotor integration