Identifying Causal Risk Factors for Violence among Discharged Patients

This study was funded by the UK National Institute for Health Research (NIHR) under its Programme Grants for Applied Research funding scheme (RP-PG-0407-10500)

U–Pb Zircon geochronology of the Cambro-Ordovician metagranites and metavolcanic rocks of central and NW Iberia

New U–Pb zircon data from metagranites and metavolcanic rocks of the Schist-Graywacke Complex Domain and the Schistose Domain of Galicia Tras-os-Montes Zone from central and NW Iberia contribute to constrain the timing of the Cambro-Ordovician magmatism from Central Iberian and Galicia Tras-os-Montes Zones which occurred between 498 and 462 Ma. The crystallization ages of the metagranites and metavolcanic rocks from the northern Schist-Graywacke Complex Domain are as follows: (a) in west Salamanca, 489 ± 5 Ma for Vitigudino, 486 ± 6 Ma for Fermoselle and 471 ± 7 Ma for Ledesma; (b) in northern Gredos, 498 ± 4 Ma for Castellanos, 492 ± 4 Ma for San Pelayo and 488 ± 3 Ma for Bercimuelle; (c) in Guadarrama, 490 ± 5 Ma for La Estacion I, 489 ± 9 Ma for La Canada, 484 ± 6 Ma for Vegas de Matute (leucocratic), 483 ± 6 Ma for El Cardoso, 482 ± 8 Ma for La Morcuera, 481 ± 9 Ma for Buitrago de Lozoya, 478 ± 7 Ma for La Hoya, 476 ± 5 Ma for Vegas de Matute (melanocratic), 475 ± 5 Ma for Riaza, 473 ± 8 Ma for La Estacion II and 462 ± 11 Ma for La Berzosa; and (d) in Toledo, 489 ± 7 Ma for Mohares and 480 ± 8 Ma for Polan. The crystallization ages of the metagranites from the Schistose Domain of Galicia Tras-os-Montes Zone are 497 ± 6 Ma for Laxe, 486 ± 8 Ma for San Mamede, 482 ± 7 Ma for Bangueses, 481 ± 5 Ma for Noia, 480 ± 10 for Rial de Sabucedo, 476 ± 9 Ma for Vilanova, 475 ± 6 Ma for Pontevedra, 470 ± 6 Ma for Cherpa and 462 ± 8 Ma for Bande.This magmatism is characterized by an average isotopic composition of (87Sr/86Sr)485Ma ≈ 0.712, (eNd)485Ma ≈ -4.1 and (TDM) ≈ 1.62 Ga, and a high zircon inheritance, composed of Ediacaran–Early Cambrian (65 %) and, to a lesser extent, Cryogenian, Tonian, Mesoproterozoic, Orosirian and Archean pre-magmatic cores. Combining our geochronological and isotopic data with others of similar rocks from the European Variscan Belt, it may be deduced that Cambro-Ordovician magmas from this belt were mainly generated by partial melting of Ediacaran–Early Cambrian igneous rocks

Self-tolerance in multiple sclerosis

During the last decade, several defects in self-tolerance have been identified in multiple sclerosis. Dysfunction in central tolerance leads to the thymic output of antigen-specific T cells with T cell receptor alterations favouring autoimmune reactions. In addition, premature thymic involution results in a reduced export of naïve regulatory T cells, the fully suppressive clone. Alterations in peripheral tolerance concern costimulatory molecules as well as transcriptional and epigenetic mechanisms. Recent data underline the key role of regulatory T cells that suppress Th1 and Th17 effector cell responses and whose immunosuppressive activity is impaired in patients with multiple sclerosis. Those recent observations suggest that a defect in self-tolerance homeostasis might be the primary mover of multiple sclerosis leading to subsequent immune attacks, inflammation and neurodegeneration. The concept of multiple sclerosis as a consequence of the failure of central and peripheral tolerance mechanisms to maintain a self-tolerance state, particularly of regulatory T cells, may have therapeutic implications. Restoring normal thymic output and suppressive functions of regulatory T cells appears an appealing approach. Regulatory T cells suppress the general local immune response via bystander effects rather than through individual antigen-specific responses. Interestingly, the beneficial effects of currently approved immunomodulators (interferons β and glatiramer acetate) are associated with a restored regulatory T cell homeostasis. However, the feedback regulation between Th1 and Th17 effector cells and regulatory T cells is not so simple and tolerogenic mechanisms also involve other regulatory cells such as B cells, dendritic cells and CD56bright natural killer cells

Gene Targeting Implicates Cdc42 GTPase in GPVI and Non-GPVI Mediated Platelet Filopodia Formation, Secretion and Aggregation

Background: Cdc42 and Rac1, members of the Rho family of small GTPases, play critical roles in actin cytoskeleton regulation. We have shown previously that Rac1 is involved in regulation of platelet secretion and aggregation. However, the role of Cdc42 in platelet activation remains controversial. This study was undertaken to better understand the role of Cdc42 in platelet activation. Methodology/Principal Findings: We utilized the Mx-cre;Cdc42 lox/lox inducible mice with transient Cdc42 deletion to investigate the involvement of Cdc42 in platelet function. The Cdc42-deficient mice exhibited a significantly reduced platelet count than the matching Cdc42 +/+ mice. Platelets isolated from Cdc42 2/2, as compared to Cdc42 +/+, mice exhibited (a) diminished phosphorylation of PAK1/2, an effector molecule of Cdc42, (b) inhibition of filopodia formation on immobilized CRP or fibrinogen, (c) inhibition of CRP- or thrombin-induced secretion of ATP and release of P-selectin, (d) inhibition of CRP, collagen or thrombin induced platelet aggregation, and (e) minimal phosphorylation of Akt upon stimulation with CRP or thrombin. The bleeding times were significantly prolonged in Cdc42 2/2 mice compared with Cdc42 +/+ mice. Conclusion/Significance: Our data demonstrate that Cdc42 is required for platelet filopodia formation, secretion an

Equitable and effective area‐based conservation: towards the conserved areas paradigm

In 2018, the Parties to the Convention on Biological Diversity (CBD) adopted a decision on protected areas and other effective area-based conservation measures (OECMs). It contains the definition of an OECM and related scientific and technical advice that has broadened the scope of governance authorities and areas that can be engaged and recognised in global conservation efforts. The voluntary guidance on OECMs and protected areas, also included in the decision, promotes the use of diverse, effective and equitable governance models, the integration of protected areas and OECMs into wider landscapes and seascapes, and mainstreaming of biodiversity conservation across sectors. Taken as a whole, the advice and voluntary guidance provides further clarity about the CBD Parties’ understanding of what constitutes equitable and effective area-based conservation measures within and beyond protected areas and provides standardised criteria with which to measure and report areas’ attributes and performance. This policy perspective suggests that this CBD decision represents further evidence of the evolution from the ‘new paradigm for protected areas’ to a broader ‘conserved areas paradigm’ that embodies good governance, equity and effective conservation outcomes and is inclusive of a diversity of contributions to conservation within and beyond protected areas

Proteome Profiling in Murine Models of Multiple Sclerosis: Identification of Stage Specific Markers and Culprits for Tissue Damage

The identification of new biomarkers is of high interest for the prediction of the disease course and also for the identification of pathomechanisms in multiple sclerosis (MS). To specify markers of the chronic disease phase, we performed proteome profiling during the later phase of myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis (MOG-EAE, day 35 after immunization) as a model disease mimicking many aspects of secondary progressive MS. In comparison to healthy controls, high resolution 2 dimensional gel electrophoresis revealed a number of regulated proteins, among them glial fibrilary acidic protein (GFAP). Phase specific up-regulation of GFAP in chronic EAE was confirmed by western blotting and immunohistochemistry. Protein levels of GFAP were also increased in the cerebrospinal fluid of MS patients with specificity for the secondary progressive disease phase. In a next step, proteome profiling of an EAE model with enhanced degenerative mechanisms revealed regulation of alpha-internexin, syntaxin binding protein 1, annexin V and glutamate decarboxylase in the ciliary neurotrophic factor (CNTF) knockout mouse. The identification of these proteins implicate an increased apoptosis and enhanced axonal disintegration and correlate well the described pattern of tissue injury in CNTF −/− mice which involve oligodendrocyte (OL) apoptosis and axonal injury

Internal strains between grains during creep deformation of an austenitic stainless steel

Internal strains that develop between grains during creep of an austenitic stainless steel were measured using in situ neutron diffraction. The secondary creep pre-strained test specimens were considered. Measurements were undertaken before, during and post creep deformation at 550 °C. There was no measurable change of internal strains between grains during in situ creep for 4 h at 550 °C. In addition, the effect of increasing/reducing temperatures in a range from 470 to 550 °C on the internal strains was measured and interpreted with respect to contributions from thermal expansion/contraction. No further internal misfit strains between grains were created when specimen crept during the dwell time at 530, 510, 490 and 470 °C. Results are discussed with respect to (i) the general structure of self-consistent models and (ii) the optimised use of neutron sources for creep studies

Host Genetics and HIV-1: The Final Phase?

This is a crucial transition time for human genetics in general, and for HIV host genetics in particular. After years of equivocal results from candidate gene analyses, several genome-wide association studies have been published that looked at plasma viral load or disease progression. Results from other studies that used various large-scale approaches (siRNA screens, transcriptome or proteome analysis, comparative genomics) have also shed new light on retroviral pathogenesis. However, most of the inter-individual variability in response to HIV-1 infection remains to be explained: genome resequencing and systems biology approaches are now required to progress toward a better understanding of the complex interactions between HIV-1 and its human host