miRTargetLink—miRNAs, Genes and Interaction Networks

Information on miRNA targeting genes is growing rapidly. For high-throughput experiments, but also for targeted analyses of few genes or miRNAs, easy analysis with concise representation of results facilitates the work of life scientists. We developed miRTargetLink, a tool for automating respective analysis procedures that are frequently applied. Input of the web-based solution is either a single gene or single miRNA, but also sets of genes or miRNAs, can be entered. Validated and predicted targets are extracted from databases and an interaction network is presented. Users can select whether predicted targets, experimentally validated targets with strong or weak evidence, or combinations of those are considered. Central genes or miRNAs are highlighted and users can navigate through the network interactively. To discover the most relevant biochemical processes influenced by the target network, gene set analysis and miRNA set analysis are integrated. As a showcase for miRTargetLink, we analyze targets of five cardiac miRNAs. miRTargetLink is freely available without restrictions at www.ccb.uni-saarland.de/mirtargetlink

Long-term survival after successful out-of-hospital resuscitation

Between 1983 and 1989, 962 patients in Rotterdam were resuscitated outside hospital, of whom 240 (25%) could be discharged alive. A follow-up study was performed to determine prognosis in these patients. Of the 240 survivors of out-of-hospital resuscitation 80% survived after 1 year and 61% after 5 years. During the first year, 9% suffered from myocardial (re)infarction and 13% underwent coronary bypass surgery or angioplasty. Within the first 3 years after resuscitation 60% of the patients were readmitted to hospital. Permanent or temporary neurological deficits were observed in 30 patients (14%). Patients with a primary arrhythmia without myocardial infarction had a worse prognosis than patients with a cardiac arrest in the context of an infarct. Survival was better in patients in whom resuscitation was initiated by physicians or ambulance-nurses, than in patients resuscitated by lay-people. Multivariate analysis revealed that this difference could be explained by a larger proportion of patients with a primary arrhythmia in the latter group. Since long-term prognosis after out-of-hospital resuscitation is satisfactory, programmes for resuscitation courses should be stimulated. Such programmes should aim predominantly at relatives of patients with known heart disease, police officers and children

Coordinating Unions, Wages and Employment

In this paper we consider a two-sector economy in which individual unions are affiliated into a federation of unions. We analyze the consequences of two different types of wage setting. Firstly, individual unions set wages in their own sector without taking into account the effect of their wages on the employment level in the other sector. There may be positive as well as negative externalities. A positive (negative) externality may exist if a higher (lower) wage in one sector implies a higher level of employment in the other sector. Both cases may occur in our model. Secondly, wages in the two sectors are set by the federation of unions. We show that in this case higher (lower) wages result than in the first case if a positive (negative) externality exists

Dynamics of circulating TNF during adalimumab treatment using a drug-tolerant TNF assay

Patients with rheumatoid arthritis (RA) can be successfully treated with tumor necrosis factor (TNF) inhibitors, including the monoclonal antibody adalimumab. Once in remission, a proportion of patients can successfully discontinue treatment, indicating that blocking TNF is no longer required for disease control. To explore the dynamics of circulating TNF during adalimumab treatment, we developed a competition enzyme-linked immunosorbent assay that can quantify TNF in the presence of large amounts of TNF inhibitor, i.e., a “drug-tolerant” assay. In 193 consecutive adalimumab-treated patients with RA, we demonstrated that circulating TNF increased in average of &gt;50-fold upon treatment and reached a stable concentration in time for most patients. A similar increase in TNF was found in 30 healthy volunteers after one dose of adalimumab. This implies that TNF in circulation during anti-TNF treatment is not primarily associated with disease activity. During treatment, TNF was in complex with adalimumab and could be recovered as inactive 3:1 adalimumab-TNF complexes. No quantitative association was found between TNF and adalimumab concentrations. Low TNF concentrations at week 4 were associated with a higher frequency of antidrug antibodies (ADAs) at subsequent time points, less frequent methotrexate use at baseline, and less frequent remission after 52 weeks. Also in healthy volunteers, early low TNF concentrations are associated with ADAs. In conclusion, longitudinal TNF concentrations are mostly stable during adalimumab treatment and may therefore not predict successful treatment discontinuation. However, early low TNF is strongly associated with ADA formation and may be used as timely predictor of nonresponse toward adalimumab treatment.</p

MYND: Unsupervised Evaluation of Novel BCI Control Strategies on Consumer Hardware

Neurophysiological studies are typically conducted in laboratories with limited ecological validity, scalability, and generalizability of findings. This is a significant challenge for the development of brain-computer interfaces (BCIs), which ultimately need to function in unsupervised settings on consumer-grade hardware. We introduce MYND: A framework that couples consumer-grade recording hardware with an easy-to-use application for the unsupervised evaluation of BCI control strategies. Subjects are guided through experiment selection, hardware fitting, recording, and data upload in order to self-administer multi-day studies that include neurophysiological recordings and questionnaires. As a use case, we evaluate two BCI control strategies ("Positive memories" and "Music imagery") in a realistic scenario by combining MYND with a four-channel electroencephalogram (EEG). Thirty subjects recorded 70.4 hours of EEG data with the system at home. The median headset fitting time was 25.9 seconds, and a median signal quality of 90.2% was retained during recordings.Neural activity in both control strategies could be decoded with an average offline accuracy of 68.5% and 64.0% across all days. The repeated unsupervised execution of the same strategy affected performance, which could be tackled by implementing feedback to let subjects switch between strategies or devise new strategies with the platform.Comment: 9 pages, 5 figures. Submitted to PNAS. Minor revisio

Wetenschap met de ramen wijd open: tien lessen voor wie impact wil maken

In tien lessen geven door de wol geverfde sociale en geesteswetenschappers handvatten aan collega’s die impact willen maken met hun onderzoek. In een nieuwe brochure, een uitgave van de Sociaal-Wetenschappelijke Raad van de KNAW, pleiten ze voor meer waardering voor impact en geven ze praktische handvatten om aan de slag te gaan. Wetenschap met de ramen wijd open, tien lessen voor wie impact wil maken is een uitgave van de Sociaal-Wetenschappelijke Raad van de Koninklijke Nederlandse Akademie voor Wetenschappen (KNAW). De brochure is geschreven door Godfried Engbersen, Andrea Evers, Beatrice de Graaf, Paul ’t Hart, Anita Jansen, Lotte Jensen, Leo Lucassen en Maarten Prak, allen hoogleraar in de sociale of geesteswetenschappen. De gedrukte brochure wordt in het Nederlands verspreid over alle faculteiten

Online training courses on Expert Knowledge Elicitation (EKE)

This report summarises the training courses delivered under the contract OC/EFSA/AMU/2021/02 EKE: “Develop and conduct online training courses on Expert Knowledge Elicitation (EKE)”. The objective of the courses was to develop and conduct online training courses on applying the methodology described in the EFSA Guidance on Expert Knowledge Elicitation in Food and Feed Safety Risk Assessment” for EFSA staff and experts, as well as corresponding experts from EU member states. In addition to the three standard EKE methods (Sheffield, Delphi and Cooke), the training included a semi-formal method of EKE. All these methods may be used when EKE is performed within an existing EFSA working group to support uncertainty analysis as outlined in “The principles and methods behind EFSA's Guidance on Uncertainty Analysis in Scientific Assessment”. In total, 12 courses were organised: two on “Steering an Expert Knowledge Elicitation”, two on “Conduct of the Sheffield protocol for an EKE”, one on “Conduct of the Cooke protocol for an EKE”, one on “Conduct of the Delphi protocol for an EKE”, two on “Conduct of a Semi-formal EKE”, two on “Reporting an Expert Knowledge Elicitation” and two on “Writing an Evidence Dossier for an Expert Knowledge Elicitation”. The courses had in total 149 participants and received very good feedback from the participants with a mean value of 4.2 of 5 possible, considering all numerical questions in the feedback questionnaire. Recommendations for future activities on training EKE methodologies are provided

The preclinical pharmacology of the high affinity anti-IL-6R Nanobody (R) ALX-0061 supports its clinical development in rheumatoid arthritis

Introduction: The pleiotropic cytokine interleukin-6 (IL-6) plays an important role in the pathogenesis of different diseases, including rheumatoid arthritis (RA). ALX-0061 is a bispecific Nanobody (R) with a high affinity and potency for IL-6 receptor (IL-6R), combined with an extended half-life by targeting human serum albumin. We describe here the relevant aspects of its in vitro and in vivo pharmacology. Methods: ALX-0061 is composed of an affinity-matured IL-6R-targeting domain fused to an albumin-binding domain representing a minimized two-domain structure. A panel of different in vitro assays was used to characterize the biological activities of ALX-0061. The pharmacological properties of ALX-0061 were examined in cynomolgus monkeys, using plasma levels of total soluble (s)IL-6R as pharmacodynamic marker. Therapeutic effect was evaluated in a human IL-6-induced acute phase response model in the same species, and in a collagen-induced arthritis (CIA) model in rhesus monkeys, using tocilizumab as positive control. Results: ALX-0061 was designed to confer the desired pharmacological properties. A 200-fold increase of target affinity was obtained through affinity maturation of the parental domain. The high affinity for sIL-6R (0.19 pM) translated to a concentration-dependent and complete neutralization of sIL-6R in vitro. In cynomolgus monkeys, ALX-0061 showed a dose-dependent and complete inhibition of hIL-6-induced inflammatory parameters, including plasma levels of C-reactive protein (CRP), fibrinogen and platelets. An apparent plasma half-life of 6.6 days was observed after a single intravenous administration of 10 mg/kg ALX-0061 in cynomolgus monkeys, similar to the estimated expected half-life of serum albumin. ALX-0061 and tocilizumab demonstrated a marked decrease in serum CRP levels in a non-human primate CIA model. Clinical effect was confirmed in animals with active drug exposure throughout the study duration. Conclusions: ALX-0061 represents a minimized bispecific biotherapeutic of 26 kDa, nearly six times smaller than monoclonal antibodies. High in vitro affinity and potency was demonstrated. Albumin binding as a half-life extension technology resulted in describable and expected pharmacokinetics. Strong IL-6R engagement was shown to translate to in vivo effect in non-human primates, demonstrated via biomarker deregulation as well as clinical effect. Presented results on preclinical pharmacological properties of ALX-0061 are supportive of clinical development in RA