High-threshold mechanosensitive ion channels blocked by a novel conopeptide mediate pressure-evoked pain

Little is known about the molecular basis of somatosensory mechanotransduction in mammals. We screened a library of peptide toxins for effects on mechanically activated currents in cultured dorsal root ganglion neurons. One conopeptide analogue, termed NMB-1 for noxious mechanosensation blocker 1, selectively inhibits (IC50 1 µM) sustained mechanically activated currents in a subset of sensory neurons. Biotinylated NMB-1 retains activity and binds selectively to peripherin-positive nociceptive sensory neurons. The selectivity of NMB-1 was confirmed by the fact that it has no inhibitory effects on voltage-gated sodium and calcium channels, or ligand-gated channels such as acid-sensing ion channels or TRPA1 channels. Conversely, the tarantula toxin, GsMTx-4, which inhibits stretch-activated ion channels, had no effects on mechanically activated currents in sensory neurons. In behavioral assays, NMB-1 inhibits responses only to high intensity, painful mechanical stimulation and has no effects on low intensity mechanical stimulation or thermosensation. Unexpectedly, NMB-1 was found to also be an inhibitor of rapid FM1-43 loading (a measure of mechanotransduction) in cochlear hair cells. These data demonstrate that pharmacologically distinct channels respond to distinct types of mechanical stimuli and suggest that mechanically activated sustained currents underlie noxious mechanosensation. NMB-1 thus provides a novel diagnostic tool for the molecular definition of channels involved in hearing and pressure-evoked pain

Pauli Paramagnetic Effects on Vortices in Superconducting TmNi2B2C

The magnetic field distribution around the vortices in TmNi2B2C in the paramagnetic phase was studied experimentally as well as theoretically. The vortex form factor, measured by small-angle neutron scattering, is found to be field independent up to 0.6 Hc2 followed by a sharp decrease at higher fields. The data are fitted well by solutions to the Eilenberger equations when paramagnetic effects due to the exchange interaction with the localized 4f Tm moments are included. The induced paramagnetic moments around the vortex cores act to maintain the field contrast probed by the form factor.Comment: 4 pages, 4 figure

Fermi surface and order parameter driven vortex lattice structure transitions in twin-free YBa2Cu3O7

We report on small-angle neutron scattering studies of the intrinsic vortex lattice (VL) structure in detwinned YBa2Cu3O7 at 2 K, and in fields up to 10.8 T. Because of the suppressed pinning to twin-domain boundaries, a new distorted hexagonal VL structure phase is stabilized at intermediate fields. It is separated from a low-field hexagonal phase of different orientation and distortion by a first-order transition at 2.0(2) T that is probably driven by Fermi surface effects. We argue that another first-order transition at 6.7(2) T, into a rhombic structure with a distortion of opposite sign, marks a crossover from a regime where Fermi surface anisotropy is dominant, to one where the VL structure and distortion is controlled by the order-parameter anisotropy.Comment: 4 pages, 3 figures (2 color), minor change

Phonon-induced quadrupolar ordering of the magnetic superconductor TmNi2_2B2_2C

We present synchrotron x-ray diffraction studies revealing that the lattice of thulium borocarbide is distorted below T_Q = 13.5 K at zero field. T_Q increases and the amplitude of the displacements is drastically enhanced, by a factor of 10 at 60 kOe, when a magnetic field is applied along [100]. The distortion occurs at the same wave vector as the antiferromagnetic ordering induced by the a-axis field. A model is presented that accounts for the properties of the quadrupolar phase and explains the peculiar behavior of the antiferromagnetic ordering previously observed in this compound.Comment: submitted to PR

A Multidomain Adhesion Protein Family Expressed in Plasmodium falciparum Is Essential for Transmission to the Mosquito

The recent sequencing of several apicomplexan genomes has provided the opportunity to characterize novel antigens essential for the parasite life cycle that might lead to the development of new diagnostic and therapeutic markers. Here we have screened the Plasmodium falciparum genome sequence for genes encoding extracellular multidomain putative adhesive proteins. Three of these identified genes, named PfCCp1, PfCCp2, and PfCCp3, have multiple adhesive modules including a common Limulus coagulation factor C domain also found in two additional Plasmodium genes. Orthologues were identified in the Cryptosporidium parvum genome sequence, indicating an evolutionary conserved function. Transcript and protein expression analysis shows sexual stage–specific expression of PfCCp1, PfCCp2, and PfCCp3, and cellular localization studies revealed plasma membrane–associated expression in mature gametocytes. During gametogenesis, PfCCps are released and localize surrounding complexes of newly emerged microgametes and macrogametes. PfCCp expression markedly decreased after formation of zygotes. To begin to address PfCCp function, the PfCCp2 and PfCCp3 gene loci were disrupted by homologous recombination, resulting in parasites capable of forming oocyst sporozoites but blocked in the salivary gland transition. Our results describe members of a conserved apicomplexan protein family expressed in sexual stage Plasmodium parasites that may represent candidates for subunits of a transmission-blocking vaccine

Disease-specific, neurosphere-derived cells as models for brain disorders

There is a pressing need for patient-derived cell models of brain diseases that are relevant and robust enough to produce the large quantities of cells required for molecular and functional analyses. We describe here a new cell model based on patient-derived cells from the human olfactory mucosa, the organ of smell, which regenerates throughout life from neural stem cells. Olfactory mucosa biopsies were obtained from healthy controls and patients with either schizophrenia, a neurodevelopmental psychiatric disorder, or Parkinson's disease, a neurodegenerative disease. Biopsies were dissociated and grown as neurospheres in defined medium. Neurosphere-derived cell lines were grown in serum-containing medium as adherent monolayers and stored frozen. By comparing 42 patient and control cell lines we demonstrated significant disease-specific alterations in gene expression, protein expression and cell function, including dysregulated neurodevelopmental pathways in schizophrenia and dysregulated mitochondrial function, oxidative stress and xenobiotic metabolism in Parkinson's disease. The study has identified new candidate genes and cell pathways for future investigation. Fibroblasts from schizophrenia patients did not show these differences. Olfactory neurosphere-derived cells have many advantages over embryonic stem cells and induced pluripotent stem cells as models for brain diseases. They do not require genetic reprogramming and they can be obtained from adults with complex genetic diseases. They will be useful for understanding disease aetiology, for diagnostics and for drug discovery

Structure and degeneracy of vortex lattice domains in pure superconducting niobium: A small-angle neutron scattering study

High-purity niobium exhibits a surprisingly rich assortment of vortex lattice (VL) structures for fields applied parallel to a fourfold symmetry axis, with all observed VL phases made up of degenerate domains that spontaneously break some crystal symmetry. Yet a single regular hexagonal VL domain is observed at all temperatures and fields parallel to a threefold symmetry axis. We report a detailed investigation of the transition between these lush and barren VL landscapes, discovering new VL structures and phase transitions at high fields. We show that the number and relative population of VL domains is intrinsically tied to the underlying crystal symmetry. We discuss how subtle anisotropies of the crystal may generate the remarkable VLs observed. © 2009 The American Physical Society

Transnational social capital: the socio‐spatialities of civil society

Civil society remains a contested concept, but one that is widely embedded in global development processes. Transnationalism within civil society scholarship is often described dichotomously, either through hierarchical dependency relations or as a more amorphous networked global civil society. These two contrasting spatial imaginaries produce very particular ideas about how transnational relations contribute to civil society. Drawing on empirical material from research with civil society organizations in Barbados and Grenada, in this article I contend that civil society groups use forms of transnational social capital in their work. This does not, however, resonate with the horizontal relations associated with grassroots globalization or vertical chains of dependence. These social relations are imbued with power and agency and are entangled in situated historical, geographical and personal contexts. I conclude that the diverse transnational social relations that are part of civil society activity offer hope and possibilities for continued civil society action in these unexpected spatial arrangements

Secular trends in the initiation of therapy in secondary fracture prevention in Europe : a multi-national cohort study including data from Denmark, Catalonia, and the United Kingdom

Altres ajuts: UCB funded this study. All analyses were conducted independently by the academic researchers involved. MKJ is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC).This paper demonstrates a large post-fracture anti-osteoporosis treatment gap in the period 2005 to 2015. The gap was stable in Denmark at around 88-90%, increased in Catalonia from 80 to 88%, and started to increase in the UK towards the end of our study. Improved post-fracture care is needed. Patients experiencing a fragility fracture are at high risk of subsequent fractures, particularly within the first 2 years after the fracture. Previous studies have demonstrated that only a small proportion of fracture patients initiate therapy with an anti-osteoporotic medication (AOM), despite the proven fracture risk reduction of such therapies. The aim of this paper is to evaluate the changes in this post-fracture treatment gap across three different countries from 2005 to 2015. This analysis, which is part of a multinational cohort study, included men and women, aged 50 years or older, sustaining a first incident fragility fracture. Using routinely collected patient data from three administrative health databases covering Catalonia, Denmark, and the United Kingdom, we estimated the treatment gap as the proportion of patients not treated with AOM within 1 year of their first incident fracture. A total of 648,369 fracture patients were included. Mean age 70.2-78.9 years; 22.2-31.7% were men. In Denmark, the treatment gap was stable at approximately 88-90% throughout the 2005 to 2015 time period. In Catalonia, the treatment gap increased from 80 to 88%. In the UK, an initially decreasing treatment gap-though never smaller than 63%-was replaced by an increasing gap towards the end of our study. The gap was more pronounced in men than in women. Despite repeated calls for improved secondary fracture prevention, an unacceptably large treatment gap remains, with time trends indicating that the problem may be getting worse in recent years. The online version of this article (10.1007/s00198-020-05358-4) contains supplementary material, which is available to authorized users