Large magnetoresistance effect due to spin-injection into a non-magnetic semiconductor

A novel magnetoresistance effect, due to the injection of a spin-polarized electron current from a dilute magnetic into a non-magnetic semiconductor, is presented. The effect results from the suppression of a spin channel in the non-magnetic semiconductor and can theoretically yield a positive magnetoresistance of 100%, when the spin flip length in the non-magnetic semiconductor is sufficiently large. Experimentally, our devices exhibit up to 25% magnetoresistance.Comment: 3 figures, submitted for publicatio

Self Assembled II-VI Magnetic Quantum Dot as a Voltage-Controlled Spin-Filter

A key element in the emergence of a full spintronics technology is the development of voltage controlled spin filters to selectively inject carriers of desired spin into semiconductors. We previously demonstrated a prototype of such a device using a II-VI dilute-magnetic semiconductor quantum well which, however, still required an external magnetic field to generate the level splitting. Recent theory suggests that spin selection may be achievable in II-VI paramagnetic semiconductors without external magnetic field through local carrier mediated ferromagnetic interactions. We present the first experimental observation of such an effect using non-magnetic CdSe self-assembled quantum dots in a paramagnetic (Zn,Be,Mn)Se barrier.Comment: 4 pages, 4 figure

Ontogeny of synaptophysin and synaptoporin in the central nervous system

The expression of the synaptic vesicle antigens synaptophysin (SY) and synaptoporin (SO) was studied in the rat striatum, which contains a nearly homogeneous population of GABAergic neurons. In situ hybridization revealed high levels of SY transcripts in the striatal anlage from embryonic day (E) 14 until birth. In contrast. SO hybridization signals were low, and no immunoreactive cell bodies were detected at these stages of development. At E 14, SY-immunoreactivity was restricted to perikarya. In later prenatal stages of development SY-immunoreactivity appeared in puncta (identified as terminals containing immunostained synaptic vesicles), fibers, thick fiber bundles and ‘patches’. In postnatal and adult animals, perikarya of striatal neurons exhibited immunoreaction for SO; ultrastructurally SO antigen was found in the Golgi apparatus and in multivesicular bodies. SO-positive boutons were rare in the striatum. In the neuropil, numerous presynaptic terminals positive for SY were observed. Our data indicate that the expression of synaptic vesicle proteins in GABAergic neurons of the striatum is developmentally regulated. Whereas SY is prevalent during embryonic development, SO is the major synaptic vesicle antigen expressed postnatally by striatal neurons which project to the globus pallidus and the substantia nigra. In contrast synapses of striatal afferents (predominantly from cortex, thalamus and substantia nigra) contain SY

Differential expression of synaptophysin and synaptoporin during pre- and postnatal development of the hippocampal network

The closely related synaptic vesicle membrane proteins synaptophysin and synaptoporin are abundant in the hippocampal formation of the adult rat. But the prenatal hippocampal formation contains only synaptophysin, which is first detected at embryonic day 17 (E17) in perikarya and axons of the pyramidal neurons. At E21 synaptophysin immunoreactivity extends into the apical dendrites of these cells and in newly formed terminals contacting these dendrites. The transient presence of synaptophysin in axons and dendrites suggests a functional involvement of synaptophysin in fibre outgrowth of developing pyramidal neurons. Synaptoporin expression parallels the formation of dentate granule cell synaptic contacts with pyramidal neurons: the amount of hippocampal synaptoporin, determined in immunoblots and by synaptoporin immunostaining of developing mossy fibre terminals, increases during the first postnatal week. Moreover, in the adult, synaptoporin is found exclusively in the mossy fibre terminals present in the hilar region of the dentate gyrus and the regio inferior of the cornu ammonis. In contrast, synaptophysin is present in all synaptic fields of the hippocampal formation, including the mossy fibre terminals, where it colocalizes with synaptoporin in the same boutons. Our data indicate that granule neuron terminals differ from all other terminals of the hippocampal formation by the presence of both synaptoporin and synaptophysin. This difference, observed in the earliest synaptic contacts in the postnatal hippocampus and persisting into adult life, suggests distinct functions of synaptoporin in these nerve terminals

Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy

Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies

Impact of climate change on hydrological regimes and water resource management in the Rhine basin”,

Abstract. The International Commission for the Hydrology of the Rhine basin (CHR) has carried out a research project to assess the impact of climate change on the river flow conditions in the Rhine basin. Along a bottom-up line, different detailed hydrological models with hourly and daily time steps have been developed for representative sub-catchments of the Rhine basin. Along a topdown line, a water balance model for the entire Rhine basin has been developed, which calculates monthly discharges and which was tested on the scale of the major tributaries of the Rhine. Using this set of models, the effects of climate change on the discharge regime in different parts of the Rhine basin were calculated using the results of UKHI and XCCC GCM-experiments. All models indicate the same trends in the changes: higher winter discharge as a result of intensified snow-melt and increased winter precipitation, and lower summer discharge due to the reduced winter snow storage and an increase of evapotranspiration. When the results are considered in more detail, however, several differences show up. These can firstly be attributed to different physical characteristics of the studied areas, but different spatial and temporal scales used in the modelling and different representations of several hydrological processes (e.g., evapotranspiration, snow melt) are responsible for the differences found as well. Climate change can affect various socio-economic sectors. Higher temperatures may threaten winter tourism in the lower winter sport areas. The hydrological changes will increase flood risk during winter, whilst low flows during summer will adversely affect inland navigation, and reduce water availability for agriculture and industry. Balancing the required actions against economic cost and the existing uncertainties in the climate change scenarios, a policy of 'noregret and flexibility' in water management planning and design is recommended, where anticipatory adaptive measures in response to climate change impacts are undertaken in combination with ongoing activities. Present address

Designing stakeholder learning dialogues for effective global governance

A growing scholarship on multistakeholder learning dialogues suggests the importance of closely managing learning processes to help stakeholders anticipate which policies are likely to be effective. Much less work has focused on how to manage effective transnational multistakeholder learning dialogues, many of which aim to help address critical global environmental and social problems such as climate change or biodiversity loss. They face three central challenges. First, they rarely shape policies and behaviors directly, but work to ‘nudge’ or ‘tip the scales’ in domestic settings. Second, they run the risk of generating ‘compromise’ approaches incapable of ameliorating the original problem definition for which the dialogue was created. Third, they run the risk of being overly influenced, or captured, by powerful interests whose rationale for participating is to shift problem definitions or narrow instrument choices to those innocuous to their organizational or individual interests. Drawing on policy learning scholarship, we identify a six-stage learning process for anticipating effectiveness designed to minimize these risks while simultaneously fostering innovative approaches for meaningful and longlasting problem solving: Problem definition assessments; Problem framing; Developing coalition membership; Causal framework development; Scoping exercises; Knowledge institutionalization. We also identify six management techniques within each process for engaging transnational dialogues around problem solving. We show that doing so almost always requires anticipating multiple-step causal pathways through which influence of transnational and/or international actors and institutions might occur

SH3 Domain-Mediated Recruitment of Host Cell Amphiphysins by Alphavirus nsP3 Promotes Viral RNA Replication

Among the four non-structural proteins of alphaviruses the function of nsP3 is the least well understood. NsP3 is a component of the viral replication complex, and composed of a conserved aminoterminal macro domain implicated in viral RNA synthesis, and a poorly conserved carboxyterminal region. Despite the lack of overall homology we noted a carboxyterminal proline-rich sequence motif shared by many alphaviral nsP3 proteins, and found it to serve as a preferred target site for the Src-homology 3 (SH3) domains of amphiphysin-1 and -2. Nsp3 proteins of Semliki Forest (SFV), Sindbis (SINV), and Chikungunya viruses all showed avid and SH3-dependent binding to amphiphysins. Upon alphavirus infection the intracellular distribution of amphiphysin was dramatically altered and colocalized with nsP3. Mutations in nsP3 disrupting the amphiphysin SH3 binding motif as well as RNAi-mediated silencing of amphiphysin-2 expression resulted in impaired viral RNA replication in HeLa cells infected with SINV or SFV. Infection of Balb/c mice with SFV carrying an SH3 binding-defective nsP3 was associated with significantly decreased mortality. These data establish SH3 domain-mediated binding of nsP3 with amphiphysin as an important host cell interaction promoting alphavirus replication

Follow-Up Analysis of Genome-Wide Association Data Identifies Novel Loci for Type 1 Diabetes

OBJECTIVE—Two recent genome-wide association (GWA) studies have revealed novel loci for type 1 diabetes, a common multifactorial disease with a strong genetic component. To fully utilize the GWA data that we had obtained by genotyping 563 type 1 diabetes probands and 1,146 control subjects, as well as 483 case subject–parent trios, using the Illumina HumanHap550 BeadChip, we designed a full stage 2 study to capture other possible association signals

Porcine Sialoadhesin (CD169/Siglec-1) Is an Endocytic Receptor that Allows Targeted Delivery of Toxins and Antigens to Macrophages

Sialoadhesin is exclusively expressed on specific subpopulations of macrophages. Since sialoadhesin-positive macrophages are involved in inflammatory autoimmune diseases, such as multiple sclerosis, and potentially in the generation of immune responses, targeted delivery of drugs, toxins or antigens via sialoadhesin-specific immunoconjugates may prove a useful therapeutic strategy. Originally, sialoadhesin was characterized as a lymphocyte adhesion molecule, though recently its involvement in internalization of sialic acid carrying pathogens was shown, suggesting that sialoadhesin is an endocytic receptor. In this report, we show that porcine sialoadhesin-specific antibodies and F(ab')2 fragments trigger sialoadhesin internalization, both in primary porcine macrophages and in cells expressing recombinant porcine sialoadhesin. Using chemical inhibitors, double immunofluorescence stainings and dominant-negative constructs, porcine sialoadhesin internalization was shown to be clathrin- and Eps15-dependent and to result in targeting to early endosomes but not lysosomes. Besides characterizing the sialoadhesin endocytosis mechanism, two sialoadhesin-specific immunoconjugates were evaluated. We observed that porcine sialoadhesin-specific immunotoxins efficiently kill sialoadhesin-expressing macrophages. Furthermore, porcine sialoadhesin-specific albumin immunoconjugates were shown to be internalized in macrophages and immunization with these immunoconjugates resulted in a rapid and robust induction of albumin-specific antibodies, this compared to immunization with albumin alone. Together, these data expand sialoadhesin functionality and show that it can function as an endocytic receptor, a feature that cannot only be misused by sialic acid carrying pathogens, but that may also be used for specific targeting of toxins or antigens to sialoadhesin-expressing macrophages