Linking stage-resolved population models with field observations: an integrated approach on population dynamics of Pseudocalanus elongatus in the German Bight.

The population dynamics of Pseudocalanus elongatus have been investigated within the framework of the GLOBEC-Germany project to gain a better understanding of its life cycle and population dynamics and to estimate secondary production in the North Sea. During an intensive field study in the German Bight between February and October 2004, experiments on reproduction were performed and data on length of copepodids and abundance were collected to characterize the population in the southern North Sea. This data set was used to update the literature- based parameterization of a population model for P. elongatus to investigate the population dynamics, life history and production in the German Bight. The ability of data to improve population models is also discussed. Pseudocalanus elongatus was found to be a major contributor to carbon uptake contributing about onethird of copepod production. Though the spatial variability in field observations was not reflected by the model, the simulation matched data within one order of magnitude at most stations. The high-resolution field observations and experiments mainly improved the parameterization of the reproductive parameters. Mortality is found to be a critical parameter due to its influence on population size. Using constant rates, though based on observation-derived estimates, seems not to capture realistic variability. Our study confirms the need for experimental and field data to build a robust parameterization for concentration-based population models

Functional characterisation of the mammalian NDR1 and NDR2 protein kinases and their regulation by the mammalian Ste20-like kinase MST3

Protein modification is a common regulatory mechanism in order to transduce a signal from one molecule to another. One of the best-studied protein modifications is phosphorylation. The enzymes that are capable of transferring phosphate groups onto other proteins are called protein kinases. Depending on the acceptor group, kinases can be distinguished into tyrosine, serine/threonine and dual-specificity kinases. This work describes the characterisation of human and mouse NDR1 and NDR2 kinases, members of the AGC group of serine/threonine kinases. The NDR protein kinase family is highly conserved between yeast and human, and several members have been shown to be involved in the regulation of cell morphology and the control of cell cycle progression. For example, the yeast NDR kinases Sid2p (Schizosaccharomyces pombe) and Dbf2p (Saccharomyces cerevisiae) are central components of the septation-initiation network and the mitosis exit network, respectively. The closest yeast relatives Cbk1p and Orb6p, members of the regulation of Ace2p transcription and morphogenesis network and Orb6 signalling pathways, are implicated in the coordination of cell cycle progression and cell morphology. This study, as well as studies using worms and flies, provide evidence that not only NDR is conserved, but also the NDR signalling pathway and regulation. Similar to yeast, NDR kinase activation is regulated by phosphorylation at the activation segment phosphorylation site and the hydrophobic motif phosphorylation site. This phosphorylation is regulated by a conserved signaling module consisting of MOB proteins and a STE20–like kinase. Here we show that the STE20-like kinase MST3 activates NDR by phosphorylation specifically at the hydrophobic motif in vitro and in vivo. Furthermore, MOB1A binding is important for the release of autoinhibition and full kinase activation. The data also indicate that NDR is part of a feedback mechanism, which induces cleavage and nuclear translocation of MST3. The data presented here also show that NDR1 and NDR2 are differentially expressed, but regulated in a similar manner. Mouse Ndr1 mRNA is mainly expressed in spleen, thymus and lung, whereas Ndr2 mRNA is more ubiquitously expressed, with the highest levels in the gastrointestinal tract. Both, NDR1 and NDR2, are activated by S100B protein and okadaic acid stimulated phosphorylation; NDR1 and NDR2 are also indistinguishable in the biochemical assays used: membrane targetting, phosphorylation by MST3, and activation by MOB. Further, this work describes the generation and initial characterisation of a mouse model for NDR1 deficiency. Protein analysis using NDR1 knockout mouse embryonic fibroblasts suggest a compensation of the loss of NDR1 by upregulation of NDR2 expression

Ordinal proof theory of Kripke-Platek set theory augmented by strong reflection principles

Diese Arbeit umfasst vier Teile. Im ersten Teil wird eine Ordinalzahlanalyse der Kripke-Platek Mengenlehre, erweitert um ein Reflexionsschema für erststufige Formeln, erarbeitet. Im zweiten Teil wird diese Ordinalzahlanalyse genutzt, um mit Hilfe subrekursiver Hierarchien eine Charakterisierung der beweisbar rekursiven Funktionen der im ersten Teil untersuchten Theorie zu erhalten. In den letzten beiden Teilen werden die in den ersten beiden Teilen entwickelten Techniken erweitert, um eine Ordinalzahlanalyse, bzw. eine Charakterisierung der beweisbar rekursiven Funktionen, der von M. Rathjen eingeführten Theorie Stabilität zu erhalten. Die Theorie Stabilität umfasst die Theorie KPi, erweitert um das Axiom: zu jeder Ordinalzahl alpha existiert eine Ordinalzahl kappa, so dass kappa kappa+alpha stabil ist. This thesis is divided into four parts. In the first part an ordinal analysis of Kripke-Platek set theory augmented by a first order reflection scheme is given. In the second part a characterization of the provable recursive functions of the above mentioned theory is acquired. These functions are characterized in terms of a subrecursive hierarchy, which is defined by means of the proof-theoretic ordinal established in the first part of this thesis. In the third part the ordinal analysis of the first part is extended to an ordinal analysis of the theory Stability. The theory Stability was introduced by M. Rathjen and denotes the axiom system of KPi augmented by the axiom: for every ordinal alpha there exists an ordinal kappa, such that kappa is kappa+alpha stable. In the last part of this thesis a characterization of the provable recursive functions of Stability is given by an application of the results of the second part to the ordinal analysis of the third part

Prevalence, characteristics, and publication of discontinued randomized trials.

IMPORTANCE: The discontinuation of randomized clinical trials (RCTs) raises ethical concerns and often wastes scarce research resources. The epidemiology of discontinued RCTs, however, remains unclear. OBJECTIVES: To determine the prevalence, characteristics, and publication history of discontinued RCTs and to investigate factors associated with RCT discontinuation due to poor recruitment and with nonpublication. DESIGN AND SETTING: Retrospective cohort of RCTs based on archived protocols approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics and planned recruitment from included protocols. Last follow-up of RCTs was April 27, 2013. MAIN OUTCOMES AND MEASURES: Completion status, reported reasons for discontinuation, and publication status of RCTs as determined by correspondence with the research ethics committees, literature searches, and investigator surveys. RESULTS: After a median follow-up of 11.6 years (range, 8.8-12.6 years), 253 of 1017 included RCTs were discontinued (24.9% [95% CI, 22.3%-27.6%]). Only 96 of 253 discontinuations (37.9% [95% CI, 32.0%-44.3%]) were reported to ethics committees. The most frequent reason for discontinuation was poor recruitment (101/1017; 9.9% [95% CI, 8.2%-12.0%]). In multivariable analysis, industry sponsorship vs investigator sponsorship (8.4% vs 26.5%; odds ratio [OR], 0.25 [95% CI, 0.15-0.43]; P < .001) and a larger planned sample size in increments of 100 (-0.7%; OR, 0.96 [95% CI, 0.92-1.00]; P = .04) were associated with lower rates of discontinuation due to poor recruitment. Discontinued trials were more likely to remain unpublished than completed trials (55.1% vs 33.6%; OR, 3.19 [95% CI, 2.29-4.43]; P < .001). CONCLUSIONS AND RELEVANCE: In this sample of trials based on RCT protocols from 6 research ethics committees, discontinuation was common, with poor recruitment being the most frequently reported reason. Greater efforts are needed to ensure the reporting of trial discontinuation to research ethics committees and the publication of results of discontinued trials

Agreements between Industry and Academia on Publication Rights: A Retrospective Study of Protocols and Publications of Randomized Clinical Trials.

BACKGROUND: Little is known about publication agreements between industry and academic investigators in trial protocols and the consistency of these agreements with corresponding statements in publications. We aimed to investigate (i) the existence and types of publication agreements in trial protocols, (ii) the completeness and consistency of the reporting of these agreements in subsequent publications, and (iii) the frequency of co-authorship by industry employees. METHODS AND FINDINGS: We used a retrospective cohort of randomized clinical trials (RCTs) based on archived protocols approved by six research ethics committees between 13 January 2000 and 25 November 2003. Only RCTs with industry involvement were eligible. We investigated the documentation of publication agreements in RCT protocols and statements in corresponding journal publications. Of 647 eligible RCT protocols, 456 (70.5%) mentioned an agreement regarding publication of results. Of these 456, 393 (86.2%) documented an industry partner's right to disapprove or at least review proposed manuscripts; 39 (8.6%) agreements were without constraints of publication. The remaining 24 (5.3%) protocols referred to separate agreement documents not accessible to us. Of those 432 protocols with an accessible publication agreement, 268 (62.0%) trials were published. Most agreements documented in the protocol were not reported in the subsequent publication (197/268 [73.5%]). Of 71 agreements reported in publications, 52 (73.2%) were concordant with those documented in the protocol. In 14 of 37 (37.8%) publications in which statements suggested unrestricted publication rights, at least one co-author was an industry employee. In 25 protocol-publication pairs, author statements in publications suggested no constraints, but 18 corresponding protocols documented restricting agreements. CONCLUSIONS: Publication agreements constraining academic authors' independence are common. Journal articles seldom report on publication agreements, and, if they do, statements can be discrepant with the trial protocol

A novel, non-canonical mechanism of regulation of MST3 (mammalian Sterile20-related kinase 3)

The canonical pathway of regulation of the germinal centre kinase (GCK) III subgroup member, mammalian Sterile20-related kinase 3 (MST3), involves a caspase-mediated cleavage between N-terminal catalytic and C-terminal regulatory domains with possible concurrent autophosphorylation of the activation loop MST3(Thr178-), induction of Ser-/Thr-protein kinase activity and nuclear localisation. We identified an alternative ‘non-canonical’ pathway of MST3 activation (regulated primarily through dephosphorylation) which may also be applicable to other GCKIII (and GCKVI) subgroup members. In the basal state, inactive MST3 co-immunoprecipitated with the Golgi protein, GOLGA2/gm130. Activation of MST3 by calyculin A (a protein Ser-/Thr- phosphatase 1/2A inhibitor) stimulated (auto)phosphorylation of MST3(Thr178-) in the catalytic domain with essentially simultaneous cis-autophosphorylation of MST3(Thr328-) in the regulatory domain, an event also requiring the MST3(341-376) sequence which acts as a putative docking domain. MST3(Thr178-) phosphorylation increased MST3 kinase activity but this activity was independent of MST3(Thr328-) phosphorylation. Interestingly, MST3(Thr328-) lies immediately C-terminal to a STRAD pseudokinase-like site recently identified as being involved in binding of GCKIII/GCKVI members to MO25 scaffolding proteins. MST3(Thr178- /Thr328-) phosphorylation was concurrent with dissociation of MST3 from GOLGA2/gm130 and association of MST3 with MO25, and MST3(Thr328-) phosphorylation was necessary for formation of the activated MST3-MO25 holocomplex

Co-production in distributed generation:Renewable energy and creating space for fitting infrastructure within landscapes

This review describes the infrastructural elements of the socio-technical system of power supply based on renewables and the role of landscape concerns in decision-making about emerging ‘intelligent grids’. The considerable land areas required for energy infrastructure call for sizable ‘distributed generation’ close to energy consumption. Securing community acceptance of renewables’ infrastructure, perceived impacts on the community, and ‘landscape justice’ requires two types of co-production: in power supply and in making space available. With co-production, landscape issues are prominent, for some options dominant. However, ‘objectification’ of landscape, such as the use of ‘visibility’ as proxy for ‘visual impact’, is part of lingering centralised and hierarchical approaches to the deployment of renewables. Institutional tendencies of centralisation and hierarchy, in power supply management as well as in siting, should be replaced by co-production, as follows from common pool resources theory. Co-production is the key to respecting landscape values, furthering justice, and achieving community acceptance

Management of giant-cell arteritis in Switzerland: an online national survey.

AIMS OF THE STUDY To assess current practices in diagnosing, treating, and following-up giant-cell arteritis by specialists in Switzerland and to identify the main barriers to using diagnostic tools. METHODS We performed a national survey of specialists potentially caring for patients with giant-cell arteritis. The survey was sent by email to all members of the Swiss Societies of Rheumatology and for Allergy and Immunology. A reminder was sent to nonresponders after 4 and 12 weeks. Its questions covered the following dimensions: respondents' main characteristics, diagnosis, treatment, and imaging's role during follow-up. The main study results were summarized using descriptive statistics. RESULTS Ninety-one specialists, primarily aged 46-65 years (n = 53/89; 59%), working in academic or nonacademic hospitals or private practice, and treating a median of 7.5 (interquartile range [IQR]: 3-12) patients with giant-cell arteritis per year participated in this survey. Ultrasound of temporal arteries/large vessels (n = 75/90; 83%) and positron-emission-tomography-computed tomography (n = 52/91; 57%) or magnetic resonance imaging (n = 46/90; 51%) of the aorta/extracranial arteries were the most common techniques used to diagnose giant-cell arteritis with cranial or large vessel involvement, respectively. Most participants reported a short time to obtain imaging tests or arterial biopsy. The glucocorticoid tapering scheme, glucocorticoid-sparing agent, and glucocorticoid-sparing treatment duration varied among the participants. Most physicians did not follow a predefined repeat imaging scheme for follow-up and mainly relied on structural changes (vascular thickening, stenosis, or dilatation) to drive treatment choice. CONCLUSIONS This survey indicates that imaging and temporal biopsy are rapidly accessible for diagnosing giant-cell arteritis in Switzerland but highlights heterogeneous practice in many disease management areas

Subclinical giant cell arteritis in new onset polymyalgia rheumatica:A systematic review and meta-analysis of individual patient data

Objectives: To determine the prevalence and predictors of subclinical giant cell arteritis (GCA) in patients with newly diagnosed polymyalgia rheumatica (PMR). Methods: PubMed, Embase, and Web of Science Core Collection were systematically searched (date of last search July 14, 2021) for any published information on any consecutively recruited cohort reporting the prevalence of GCA in steroid-naïve patients with PMR without cranial or ischemic symptoms. We combined prevalences across populations in a random-effect meta-analysis. Potential predictors of subclinical GCA were identified by mixed-effect logistic regression using individual patient data (IPD) from cohorts screened with PET/(CT). Results: We included 13 cohorts with 566 patients from studies published between 1965 to 2020. Subclinical GCA was diagnosed by temporal artery biopsy in three studies, ultrasound in three studies, and PET/(CT) in seven studies. The pooled prevalence of subclinical GCA across all studies was 23% (95% CI 14%-36%, I2=84%) for any screening method and 29% in the studies using PET/(CT) (95% CI 13%-53%, I2=85%) (n=266 patients). For seven cohorts we obtained IPD for 243 patients screened with PET/(CT). Inflammatory back pain (OR 2.73, 1.32-5.64), absence of lower limb pain (OR 2.35, 1.05-5.26), female sex (OR 2.31, 1.17-4.58), temperature >37° (OR 1.83, 0.90-3.71), weight loss (OR 1.83, 0.96-3.51), thrombocyte count (OR 1.51, 1.05-2.18), and haemoglobin level (OR 0.80, 0.64-1.00) were most strongly associated with subclinical GCA in the univariable analysis but not C-reactive protein (OR 1.00, 1.00-1.01) or erythrocyte sedimentation rate (OR 1.01, 1.00-1.02). A prediction model calculated from these variables had an area under the curve of 0.66 (95% CI 0.55-0.75). Conclusion: More than a quarter of patients with PMR may have subclinical GCA. The prediction model from the most extensive IPD set has only modest diagnostic accuracy. Hence, a paradigm shift in the assessment of PMR patients in favour of implementing imaging studies should be discussed