Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis

Osteopoikilosis, Buschke-Ollendorff syndrome (BOS) and melorheostosis are disorders characterized by increased bone density. The occurrence of one or more of these phenotypes in the same individual or family suggests that these entities might be allelic. We collected data from three families in which affected individuals had osteopoikilosis with or without manifestations of BOS or melorheostosis. A genome-wide linkage analysis in these families, followed by the identification of a microdeletion in an unrelated individual with these diseases, allowed us to map the gene that is mutated in osteopoikilosis. All the affected individuals that we investigated were heterozygous with respect to a loss-of-function mutation in LEMD3 (also called MAN1), which encodes an inner nuclear membrane protein. A somatic mutation in the second allele of LEMD3 could not be identified in fibroblasts from affected skin of an individual with BOS and an individual with melorheostosis. XMAN1, the Xenopus laevis ortholog, antagonizes BMP signaling during embryogenesis. In this study, LEMD3 interacted with BMP and activin-TGFbeta receptor-activated Smads and antagonized both signaling pathways in human cells.     

Electrical spin injection and accumulation at room temperature in an all-metal mesoscopic spin valve

Finding a means to generate, control and use spin-polarized currents represents an important challenge for spin-based electronics, or 'spintronics'. Spin currents and the associated phenomenon of spin accumulation can be realized by driving a current from a ferromagnetic electrode into a non-magnetic metal or semiconductor. This was first demonstrated over 15 years ago in a spin injection experiment on a single crystal aluminium bar at temperatures below 77 K. Recent experiments have demonstrated successful optical detection of spin injection in semiconductors, using either optical injection by circularly polarized light or electrical injection from a magnetic semiconductor. However, it has not been possible to achieve fully electrical spin injection and detection at room temperature. Here we report room-temperature electrical injection and detection of spin currents and observe spin accumulation in an all-metal lateral mesoscopic spin valve, where ferromagnetic electrodes are used to drive a spin-polarized current into crossed copper strips. We anticipate that larger signals should be obtainable by optimizing the choice of materials and device geometry.     

Temperature excludes N2-fixing heterocystous cyanobacteria in the tropical oceans

Whereas the non-heterocystous cyanobacteria Trichodesmium spp. are the dominant N2-fixing organisms in the tropical oceans, heterocystous species dominate N2 fixation in freshwater lakes and brackish environments such as the Baltic Sea. So far no satisfactory explanation for the absence of heterocystous cyanobacteria in the pelagic of the tropical oceans has been given, even though heterocysts would seem to represent an ideal strategy for protecting nitrogenase from being inactivated by O2, thereby enabling cyanobacteria to fix N2 and to perform photosynthesis simultaneously. Trichodesmium is capable of N2 fixation, apparently without needing to differentiate heterocysts. Here we show that differences in the temperature dependence of O2 flux, respiration and N2 fixation activity explain how Trichodesmium performs better than heterocystous species at higher temperatures. Our results also explain why Trichodesmium is not successful in temperate or cold seas. The absence of heterocystous cyanobacteria in the pelagic zone of temperate and cold seas, however, requires another explanation.     

Civic Meaningfulness ‘Revisited’: A Final Reply to Honohan and Dekker

This final reply responds to Honohan’s invitation to articulate the Arendtian tone of the key-note paper. It spells out the philosophical intuition that the political life of citizens, at least potentially, is capable of making visible what makes human life worthwhile and fully meaningful, and the philosophical curiosity to see whether traces of this deep political awareness can be retrieved in dialogues with volunteers. In response to Dekker’s critical doubts, this final reply clarifies the central stakes of Claes’s paper. The core argument was not to show that the biographical model of meaningfulness is the prevailing approach of meaning in/of volunteering, but to assess the potentials and limits of the model’s interpretive power. Moreover, the paper argues for an alternative, existential model of meaningfulness. This approach refers to deep experiences of meaning that emerge from the practice of volunteering and that shift into powerful political experiences of hope, and a lived sense of equality.     

Structure of a complex between a voltage-gated calcium channel beta-subunit and an alpha-subunit domain

Voltage-gated calcium channels (Ca(V)s) govern muscle contraction, hormone and neurotransmitter release, neuronal migration, activation of calcium-dependent signalling cascades, and synaptic input integration. An essential Ca(V) intracellular protein, the beta-subunit (Ca(V)beta), binds a conserved domain (the alpha-interaction domain, AID) between transmembrane domains I and II of the pore-forming alpha(1) subunit and profoundly affects multiple channel properties such as voltage-dependent activation, inactivation rates, G-protein modulation, drug sensitivity and cell surface expression. Here, we report the high-resolution crystal structures of the Ca(V)beta2a conserved core, alone and in complex with the AID. Previous work suggested that a conserved region, the beta-interaction domain (BID), formed the AID-binding site; however, this region is largely buried in the Ca(V)beta core and is unavailable for protein-protein interactions. The structure of the AID-Ca(V)beta2a complex shows instead that Ca(V)beta2a engages the AID through an extensive, conserved hydrophobic cleft (named the alpha-binding pocket, ABP). The ABP-AID interaction positions one end of the Ca(V)beta near the intracellular end of a pore-lining segment, called IS6, that has a critical role in Ca(V) inactivation. Together, these data suggest that Ca(V)betas influence Ca(V) gating by direct modulation of IS6 movement within the channel pore.     

A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.     

Electrical detection of spin precession in a metallic mesoscopic spin valve

To study and control the behaviour of the spins of electrons that are moving through a metal or semiconductor is an outstanding challenge in the field of 'spintronics', where possibilities for new electronic applications based on the spin degree of freedom are currently being explored. Recently, electrical control of spin coherence and coherent spin precession during transport was studied by optical techniques in semiconductors. Here we report controlled spin precession of electrically injected and detected electrons in a diffusive metallic conductor, using tunnel barriers in combination with metallic ferromagnetic electrodes as spin injector and detector. The output voltage of our device is sensitive to the spin degree of freedom only, and its sign can be switched from positive to negative, depending on the relative magnetization of the ferromagnetic electrodes. We show that the spin direction can be controlled by inducing a coherent spin precession caused by an applied perpendicular magnetic field. By inducing an average precession angle of 180 degrees, we are able to reverse the sign of the output voltage.     

Civic Meaningfulness: The Political Dimension—A Reply to Lena Dominelli

This article argues, firstly, that voluntary civic practices are not doomed to fall prey to a Big Society rhetoric and a cynical politics of cuts in social spending. It all depends on how these civic practices are promoted and what kind of civic discourse is communicated through the channels of social media and public opinion. Secondly, the author highlights the political importance of connecting meaningfulness with citizenship.     

Introduction. Meaningfulness,Volunteers, Citizenship

This introductory article starts by describing the genesis of this special issue and the interconnection of its topics. The editors offer a variety of reading entries into the key-note articles and responses. The article reconstructs the research interests underpinning the idea of integrating meaningfulness, volunteers and citizenship. It highlights the explicit interdisciplinary design of the special issue, and shows how the key-note authors, and their respondents, weave connections between meaningfulness, volunteering and citizenship. And, finally, the editors bring the background understandings of the key-note papers to the foreground, and reconstruct a non-intentional meta-level discussion on two fundamental concepts and their interplay: self and world.