The Immunometabolomic Interface Receptor Hydroxycarboxylic Acid Receptor 2 Mediates the Therapeutic Effects of Dimethyl Fumarate in Autoantibody-Induced Skin Inflammation

The drug dimethyl fumarate (DMF) is in clinical use for the treatment of psoriasis and multiple sclerosis. In addition, it has recently been demonstrated to ameliorate skin pathology in mouse models of pemphigoid diseases, a group of autoimmune blistering diseases of the skin and mucous membranes. However, the mode of action of DMF in inflammatory skin diseases has remained elusive. Therefore, we have investigated here the mechanisms by which DMF improves skin pathology, using the antibody transfer model of bullous pemphigoid-like epidermolysis bullosa acquisita (EBA). Experimental EBA was induced by transfer of antibodies against collagen VII that triggered the infiltration of immune cells into the skin and led to inflammatory skin lesions. DMF treatment reduced the infiltration of neutrophils and monocytes into the skin explaining the improved disease outcome in DMF-treated animals. Upon ingestion, DMF is converted to monomethyl fumarate that activates the hydroxycarboxylic acid receptor 2 (HCA2). Interestingly, neutrophils and monocytes expressed Hca2. To investigate whether the therapeutic effect of DMF in EBA is mediated by HCA2, we administered oral DMF to Hca2-deficient mice (Hca2−/−) and wild-type littermates (Hca2+/+) and induced EBA. DMF treatment ameliorated skin lesions in Hca2+/+ but not in Hca2−/− animals. These findings demonstrate that HCA2 is a molecular target of DMF treatment in EBA and suggest that HCA2 activation limits skin pathology by inhibiting the infiltration of neutrophils and monocytes into the skin

Handlungsleitfaden zur Entwicklung von klimawandelangepassten Industrie- und Gewerbegebieten

Dieser Leitfaden bündelt Informationsgrundlagen, Kernerkenntnisse, mögliche Vorgehensweisen und Praxistipps aus dem Projekt KlimaWaGe, die dabei helfen sollen, eine Grundlage für Projekte der Bestands- und Neuentwicklung sowie Umplanung von klimawandelangepassten Industrie- und Gewerbegebieten in deutschen Kommunen zu schaffen. Der Fokus liegt dabei einerseits auf methodischen Empfehlungen zur Ermittlung von Klimawandelfolgen in Industrie- und Gewerbegebieten und andererseits auf übertragbaren Maßnahmen für deren Entwicklung. Dabei wird teilweise zwischen Neuentwicklung, Umbau und Bestandsentwicklung unterschieden. Der Leitfaden richtet sich in erster Linie an Akteur*innen in deutschen Städten und Gemeinden sowie in der Forschung und Planung, denn ihnen kommt eine bedeutende Rolle in der Klimaanpassung zu. Er soll Anreiz sein für Anpassungsmaßnahmen zur KIG-Entwicklung und Hilfestellung, diese als sektorübergreifende Prozesse zu verstehen. Im Sinne einer besseren Verständlichkeit und Übertragbarkeit werden konkrete Erkenntnisse aus dem Leuchtturmvorhaben in der Stadt Bottrop beispielhaft vorgestellt und mit allgemeinen Betrachtungen verknüpft

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Feature Selection by User Specific Feature Mask on a Biometric Hash Algorithm for Dynamic Handwriting

Part 1: Research PapersInternational audienceOne of the most important requirements on a biometric verification system, beside others (e.g. biometric template protection), is a high user authentication performance. During the last years a lot of research is done in different domains to improve user authentication performance. In this work we suggest a user specific feature mask vector MV applied on a biometric hash algorithm for dynamic handwriting to improve user authentication and hash generation performance. MV is generated using an additional set of reference data in order to select/deselect certain features used during the verification process. Therefore, this method is considered as a simple feature selection strategy and is applied for every user within the system. In our first experiments we evaluate 5850 raw data samples captured from 39 users for five different semantics. Semantics are alternative written content to conceal the real identity of a user. First results show a noticeable decrease of the equal error rate by approximately three percentage points for each semantic. Lowest equal error rate (5.77%) is achieved by semantic symbol. In the context of biometric hash generation, the reproduction rates (RR) increases by an average of approx. 26%, whereas the highest RR (88.46%) is obtained by semantic symbol along with a collision rate (CR) of 5.11%. The minimal amount of selected features during the evaluation is 81 and the maximum amount is 131 (all available features)

Security of Features Describing the Visual Appearance of Handwriting Samples Using the Bio-hash Algorithm of Vielhauer against an Evolutionary Algorithm Attack

Part 2: Work in ProgressInternational audienceTo improve the security and stability of biometric handwriting samples a Bio-Hash algorithm for handwriting was introduced in [1]. It utilizes features to describe how the sample was written, but the current set of features does not characterize the visual appearance of the sample itself. In this paper we present a set of new features derived from handwriting forensics and OCR algorithms to address this issue. Furthermore, here the security of the old and new sets of features is evaluated for their resilience against a new, fully automated attack trying to compute raw data matching a given hash vector.The main contributions of this paper are: The introduction of new features with a potential to increase the attack resilience of the Bio-Hash algorithm, and, an improvement of the attack approach from [6] to produce more realistic looking synthetic handwriting signals

The Synthesis of Diastereo- and Enantiomerically Pure β-Aminocyclopropane Carboxylic Acids.

The synthesis of diastereo- and enantiomerically pure -aminocyclopropanecarboxylic acids (-ACCs) is described. Starting from pyrrole, (rac)-4 is readily obtained, which was kinetically resolved by enzymatic hydrolysis. Subsequent oxidation of (-)-4 and deformylation gives rise to the cis--ACC derivative (ent)-9, while (+)-10 was converted to the trans--ACC derivative 8. Both 8 and (ent)-9 and their benzyl esters 13 and 16, being conformationally restricted -alanine or -aminobutyric acid (GABA) derivatives, represent useful building blocks for peptides containing unnatural amino acids