Domains of holomorphy for irreducible unitary representations of simple Lie groups

We classify the domains of holomorphy of all Harish-Chandra modules of irreducible unitary representations of simple non-compact Lie groups.Comment: revised version, to appear in Invent. math., 14 page

HLA-DM Stabilizes the Empty MHCII Binding Groove:A Model Using Customized Natural Move Monte Carlo

MHC class II molecules bind peptides derived from extracellular proteins that have been ingested by antigen-presenting cells and display them to the immune system. Peptide loading occurs within the antigen-presenting cell and is facilitated by HLA-DM. HLA-DM stabilises the open conformation of the MHCII binding groove when no peptide is bound. While a structure of the MHCII/HLA-DM complex exists, the mechanism of stabilisation is still largely unknown. Here, we applied customised Natural Move Monte Carlo to investigate this interaction. We found a possible long range mechanism that implicates the configuration of the membrane-proximal globular domains in stabilising the open state of the empty MHCII binding groove

Looming REF deadlines lead to a rush in publication of lower quality research

The increased significance of research assessments and their implications for funding and career prospects has had a knock-on effect on academic publication patterns. Moqi Groen-Xu, Pedro A. Teixeira, Thomas Voigt and Bernhard Knapp report on research that reveals a marked increase in research productivity immediately prior to an evaluation deadline, which quickly reverses once the deadline has passed. Moreoever, the quality of papers published just before deadlines is lower, as measured by citations. Those who design research assessments should consider having cycles of varying lengths across different fields, affording researchers the time and opportunity to pursue more novel, risky projects

Impact of an 0.2 km 3 Rock Avalanche on Lake Eibsee (Bavarian Alps, Germany) – Part II: Catchment Response to Consecutive Debris Avalanche and Debris Flow

The ~0.2 km3 Eibsee rock avalanche impacted Paleolake Eibsee and completely displaced its waters. This study anal- yses the lake impact and the consequences, and the catchment response to the landslide. A quasi‐3D seismic reflection survey, four sediment cores from modern Lake Eibsee, reaching far down into the rock avalanche mass, nine radiocarbon ages, and geomorphic analysis allow us to distinguish the main rock avalanche event from a secondary debris avalanche and debris flow. The highly flu- idized debris avalanche formed a megaturbidite and multiple swashes that are recorded in the lake sediments. The new calibrated age for the Eibsee rock avalanche of ~4080–3970 cal yr BP indicates a coincidence with rockslides in the Fernpass cluster and sub- aquatic landslides in Lake Piburg and Lake Plansee, and raises the possibility that a large regional earthquake triggered these events. We document a complex history of erosion and sedimentation in Lake Eibsee, and demonstrate how the catchment response and rebirth of the lake are revealed through the complementary application of geophysics, sedimentology, radiocarbon dating, and geo- morphology

Outcome differences between PARAMEDIC2 and the German Resuscitation Registry: a secondary analysis of a randomized controlled trial compared with registry data.

BACKGROUND AND IMPORTANCE There has been much discussion of the results of the PARAMEDIC2 trial, as resuscitation outcome rates are considerably lower in this trial than in country-level registries on out-of-hospital cardiac arrest (OHCA). Here, we developed a statistical framework to investigate this gap and to examine possible sources for observed discrepancies in outcome rates. DESIGN Summary data from the PARAMEDIC2 trial were used as available in the publication of this study. We developed a modelling framework based on logistic regression to compare data from this randomized controlled trial and registry data from the German Resuscitation Registry (GRR), where we considered 26 019 patients treated with epinephrine for OHCA in the GRR. To account and adjust for differences in patient characteristics and baseline variables predictive for outcomes after OHCA between the GRR cohort and the PARAMEDIC2 study sample, we included all available variables determined at the arrival of EMS personnel in the modelling framework: age, sex, initial cardiac rhythm, cause of cardiac arrest, witness of cardiac arrest, CPR performed by a bystander, and the interval between emergency call and arrival of the ambulance at the scene (baseline model). In order to find possible explanations for the discrepancies in outcome between PARAMEDIC2 and GRR, in a second (baseline plus treatment) model, we additionally included all available variables related to the interventions of the EMS personnel (type of airway management, type of vascular access, and time to administration of epinephrine). MAIN RESULTS A patient cohort with baseline variables as in the PARAMEDIC2 trial would have survived to hospital discharge in 7.7% and survived with favourable neurological outcome in 5.0% in an EMS and health care system as in Germany, compared with 3.2 and 2.2%, respectively, in the Epinephrine group of the trial. Adding treatment-related variables to our logistic regression model, the rate of survival to discharge would decrease from 7.7 (for baseline variables only) to 5.6% and the rate of survival with favourable neurological outcome from 5.0 to 3.4%. CONCLUSION Our framework helps in the medical interpretation of the PARAMEDIC2 trial and the transferability of the trial's results for other EMS systems. Significantly higher rates of survival and favourable neurological outcome than reported in this trial could be possible in other EMS and health care systems

Protection of aouts monkeys after immunization with recombinant antigens of Plasmodium falciparum

The genus Aotus spp. (owl monkey) is one of the WHO recommended experimental models for Plasmodium falciparum blood stage infection, especially relevant for vaccination studies with asexual blood stage antigens of this parasite. For several immunization trials with purified recombinant merozoite/schizont antigens, the susceptible Aouts kenotypes II, III, IV and VI were immunized with Escherichia coli derived fusion proteins containg partial sequences of the proteins MSAI (merozoite surface antigen I), SERP (serine-strech protein) and HRPII (histidine alanine rich protein II) as well as with a group of recombinant antigens obtained by an antiserum raised against a protective 41 kD protein band. The subcutaneous application (3x) of the antigen preparations was carried out in intact animals followed by splenectomy prior to challange, in order to increase the susceptibility of the experimental hosts to the parasite. A partial sequence of HRPII, the combination of three different fusion proteins of the 41 kD group and mixture of two sequences of SERP in the presence of the modified Al(OH)3 adjuvant conferred significant protection against a challange infection with P. falciparum blood stages (2-5 x 10 (elevado a sexta potência) i. RBC). Monkey immunized with the MS2-fusion protein carrying the N-terminal part of the 195 kD precursor of the major merozoite surface antigens induced only marginal protection showing some correlation between antibody titer and degree of parasitaemia. Based on the protective capacity of these recombinant antigens we have expressed two hybrid proteins (MS2/SERP/HRPII and SERP/MSAI/HRPII) in E. coli containing selected partial sequences of SERP, HRPII and MSAI. Antibodies raised against both hybrid proteins in rabbits and Aotus monkeys recognize the corresponding schizont polypeptides. In two independent immunization trials using 13 animals (age 7 months to 3 years) we could show that immunization of Aotus monkeys with either of the two hybrid proteins administered in an oil-based well tolerated formulation protected the animals frm a severe experimental P. falciparum (strain Palo Alto) infection

Pharmacoproteomic characterisation of human colon and rectal cancer

Most molecular cancer therapies act on protein targets but data on the proteome status of patients and cellular models for proteome-guided pre-clinical drug sensitivity studies are only beginning to emerge. Here, we profiled the proteomes of 65 colorectal cancer (CRC) cell lines to a depth of > 10,000 proteins using mass spectrometry. Integration with proteomes of 90 CRC patients and matched transcriptomics data defined integrated CRC subtypes, highlighting cell lines representative of each tumour subtype. Modelling the responses of 52 CRC cell lines to 577 drugs as a function of proteome profiles enabled predicting drug sensitivity for cell lines and patients. Among many novel associations, MERTK was identified as a predictive marker for resistance towards MEK1/2 inhibitors and immunohistochemistry of 1,074 CRC tumours confirmed MERTK as a prognostic survival marker. We provide the proteomic and pharmacological data as a resource to the community to, for example, facilitate the design of innovative prospective clinical trials. © 2017 The Authors. Published under the terms of the CC BY 4.0 licens

Circulating progranulin levels in women with gestational diabetes mellitus and healthy controls during and after pregnancy

ObjectiveProgranulin (PGRN) was recently introduced as a novel marker of chronic inflammatory response in obesity and type 2 diabetes capable of directly affecting the insulin signaling pathway. This study aimed to investigate the role of PGRN in gestational diabetes mellitus (GDM), which is regarded as a model for early type 2 diabetes.MethodsPGRN serum levels were measured in 90 pregnant women (45 GDM and 45 normal glucose tolerance (NGT)). In addition, PGRN was measured during a 2-h, 75 g oral glucose tolerance test in 20 pregnant women (ten GDM and ten NGT) and in 16 of thempost partum(ten GDM and six NGT).ResultsPGRN concentrations were significantly higher in pregnant women compared withpost partumlevels (536.79±31.81 vs 241.53±8.86,P<0.001). Multivariate regression analyses showed a strong positive correlation of PGRN with estrogen and progesterone. The insulinogenic index, a marker of early insulin secretion, displayed a positive correlation with PGRN, both during and after pregnancy (R=0.47,P=0.034;R=0.63,P=0.012). HbA1c and the oral glucose insulin sensitivity index showed significantpost partumassociations with PGRN (R=0.43,P=0.049;R=−0.65,P=0.009).ConclusionsPGRN concentrations are markedly lower after pregnancy regardless of the gestational glucose tolerance state. PGRN levelsper sedo not discriminate between mild GDM and NGT in pregnant women. Therefore, the development of GDM appears to be due to impaired β-cell function that is not related to PGRN effect

PeptX: Using Genetic Algorithms to optimize peptides for MHC binding

<p>Abstract</p> <p>Background</p> <p>The binding between the major histocompatibility complex and the presented peptide is an indispensable prerequisite for the adaptive immune response. There is a plethora of different <it>in silico </it>techniques for the prediction of the peptide binding affinity to major histocompatibility complexes. Most studies screen a set of peptides for promising candidates to predict possible T cell epitopes. In this study we ask the question vice versa: Which peptides do have highest binding affinities to a given major histocompatibility complex according to certain <it>in silico </it>scoring functions?</p> <p>Results</p> <p>Since a full screening of all possible peptides is not feasible in reasonable runtime, we introduce a heuristic approach. We developed a framework for Genetic Algorithms to optimize peptides for the binding to major histocompatibility complexes. In an extensive benchmark we tested various operator combinations. We found that (1) selection operators have a strong influence on the convergence of the population while recombination operators have minor influence and (2) that five different binding prediction methods lead to five different sets of "optimal" peptides for the same major histocompatibility complex. The consensus peptides were experimentally verified as high affinity binders.</p> <p>Conclusion</p> <p>We provide a generalized framework to calculate sets of high affinity binders based on different previously published scoring functions in reasonable runtime. Furthermore we give insight into the different behaviours of operators and scoring functions of the Genetic Algorithm.</p