Inhibition of peptide aggregation by means of enzymatic phosphorylation

As is the case in numerous natural processes, enzymatic phosphorylation can be used in the laboratory to influence the conformational populations of proteins. In nature, this information is used for signal transduction or energy transfer, but has also been shown to play an important role in many diseases like tauopathies or diabetes. With the goal of determining the effect of phosphorylation on amyloid fibril formation, we designed a model peptide which combines structural characteristics of α-helical coiled-coils and β-sheets in one sequence. This peptide undergoes a conformational transition from soluble structures into insoluble amyloid fibrils over time and under physiological conditions and contains a recognition motif for PKA (cAMP- dependent protein kinase) that enables enzymatic phosphorylation. We have analyzed the pathway of amyloid formation and the influence of enzymatic phosphorylation on the different states along the conformational transition from random-coil to β-sheet-rich oligomers to protofilaments and on to insoluble amyloid fibrils, and we found a remarkable directing effect from β -sheet-rich structures to unfolded structures in the initial growth phase, in which small oligomers and protofilaments prevail if the peptide is phosphorylated

Mena/VASP and αII-Spectrin complexes regulate cytoplasmic actin networks in cardiomyocytes and protect from conduction abnormalities and dilated cardiomyopathy

BACKGROUND: In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks. RESULTS: We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct αII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and β-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, β-actin networks were disrupted and the integrity of Z- and intercalated discs was markedly impaired. CONCLUSIONS: Together, our data suggest that Mena, VASP, and αII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disrupted β-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities

Tierwohlorientierte Bestandsführung: Milchrind: Erarbeitung der fachlichen Grundlagen zur Erfassung und Bewertung von Tierhygiene, Tiergerechtheit und Tiergesundheit für eine tierwohlorientierte Bestandsführung von Milchrindern

Die in dieser Studie erarbeiteten Kennzahlen für die Tierwohlorientierte Bestandsführung beim Milchrind bilden die Grundlage um eine IT-basierte Lösung zu schaffen. Die IT-basierte Lösung soll es den Milchkuhhalterinnen und Milchkuhhaltern ermöglicht, den gesetzlichen Verpflichtungen effizient nachzukommen und das Wohlbefinden ihrer Tiere selbstständig und kontinuierlich nach dem HACCP-Konzept zu optimieren. Redaktionsschluss: 05.06.202

Technical validation of real-world monitoring of gait: a multicentric observational study

Introduction: Existing mobility endpoints based on functional performance, physical assessments and patient self-reporting are often affected by lack of sensitivity, limiting their utility in clinical practice. Wearable devices including inertial measurement units (IMUs) can overcome these limitations by quantifying digital mobility outcomes (DMOs) both during supervised structured assessments and in real-world conditions. The validity of IMU-based methods in the real- world, however, is still limited in patient populations. Rigorous validation procedures should cover the device metrological verification, the validation of the algorithms for the DMOs computation specifically for the population of interest and in daily life situations, and the users’ perspective on the device. Methods and analysis: This protocol was designed to establish the technical validity and patient acceptability of the approach used to quantify digital mobility in the real world by Mobilise-D, a consortium funded by the European Union (EU) as part of the Innovative Medicine Initiative, aiming at fostering regulatory approval and clinical adoption of DMOs. After defining the procedures for the metrological verification of an IMU-based device, the experimental procedures for the validation of algorithms used to calculate the DMOs are presented. These include laboratory and real-world assessment in 120 participants from five groups: healthy older adults; chronic obstructive pulmonary disease, Parkinson’s disease, multiple sclerosis, proximal femoral fracture and congestive heart failure. DMOs extracted from the monitoring device will be compared with those from different reference systems, chosen according to the contexts of observation. Questionnaires and interviews will evaluate the users’ perspective on the deployed technology and relevance of the mobility assessment. Ethics and dissemination: The study has been granted ethics approval by the centre’s committees (London—Bloomsbury Research Ethics committee; Helsinki Committee, Tel Aviv Sourasky Medical Centre; Medical Faculties of The University of Tübingen and of the University of Kiel). Data and algorithms will be made publicly available

Predicting the next pandemic: VACCELERATE ranking of the World Health Organization's Blueprint for Action to Prevent Epidemics

Introduction: The World Health Organization (WHO)'s Research and Development (R&D) Blueprint for Action to Prevent Epidemics, a plan of action, highlighted several infectious diseases as crucial targets for prevention. These infections were selected based on a thorough assessment of factors such as transmissibility, infectivity, severity, and evolutionary potential. In line with this blueprint, the VACCELERATE Site Network approached infectious disease experts to rank the diseases listed in the WHO R&D Blueprint according to their perceived risk of triggering a pandemic. VACCELERATE is an EU-funded collaborative European network of clinical trial sites, established to respond to emerging pandemics and enhance vaccine development capabilities. Methods: Between February and June 2023, a survey was conducted using an online form to collect data from members of the VACCELERATE Site Network and infectious disease experts worldwide. Participants were asked to rank various pathogens based on their perceived risk of causing a pandemic, including those listed in the WHO R&D Blueprint and additional pathogens. Results: A total of 187 responses were obtained from infectious disease experts representing 57 countries, with Germany, Spain, and Italy providing the highest number of replies. Influenza viruses received the highest rankings among the pathogens, with 79 % of participants including them in their top rankings. Disease X, SARS-CoV-2, SARS-CoV, and Ebola virus were also ranked highly. Hantavirus, Lassa virus, Nipah virus, and henipavirus were among the bottom-ranked pathogens in terms of pandemic potential. Conclusion: Influenza, SARS-CoV, SARS-CoV-2, and Ebola virus were found to be the most concerning pathogens with pandemic potential, characterised by transmissibility through respiratory droplets and a reported history of epidemic or pandemic outbreaks

The WORLD6 Integrated System Dynamics Model: Examples of Results from Simulations

The WORLD6 model is a fully integrated dynamic world systems model. It includes a biophysical global economic model, based on first principles of physics and thermodynamics, forcing it to be fully consistent with the underlying mass- and energy balances. The WORLD6 model first creates value from extraction of natural resources, input of human labour, the efficiency effect of mechanization and automation, the effect of innovation and their use in manufacturing of goods and services, and the secondly does monetization through market mechanisms and debt financing. The model includes 7 different capital stocks for: (1) industrial resource extraction, (2) industrial manufacture, (3) social service capital, (4) agricultural capital for land use and food production, (5) military capital, (6) speculative capital tied up in derivatives, real estate, consumer credits, (7) criminal or illegal capital. There are 3 different debt pools; (1) general, (2) speculative and (3) pensions. These are all linked through a number of feedbacks in the system to resource extraction, energy production, population dynamics, food production and phosphorus extraction, manufacture of consumer goods and services. The WORLD6 model connects to environmental pollution with feedbacks and inputs to human health and climate change inside the model. The model includes money flows, stocks as well as debt dynamics and how this is connected to the capital base and the governance. The WORLD6 model has earlier been extensively tested on natural resource extraction rates, resource ore grades, supply volumes and market price for resources with very good success. The WORLD6 model system was tested in its economic aspects against observed GDP for the period 1850 to 2015 and GDP per capita, commodity prices, extraction rates and resource supply rates with good success. These results were obtained from first principles only and without calibrating the model to any type of data time-series

Design and optimization of an energy manager for an office building

Nowadays saving energy in the building sector is more important than ever. To achieve a reduction of energy consumption and also CO2 emissions of buildings, energy efficient Building Energy Management Systems (BEMS), respectively called energy managers, are developed in the research projectenerMAT. Therefore, enerMAT creates a novel approach for simulation, optimization, and verification that will aim to design a new generation of energy aware optimized BEMS which will allow an overall cross-trade automatic control of energy flows to maintain user comfort whilst minimizing energy consumption and CO2 emission. The optimization referenced to energy uses a model-based approach with an overall building system model enabling the assessment of the energy performance for different design and operation alternatives of the energy manager in interaction with the building. This system model allows a simulation-based, energy aware, global, dynamic, multi-criterial optimization of the energy manager. In this paper, the idea, the modeling of an office building and its energy manager and different optimization studies and their results are presented

Modelica based design and optimisation of control systems for solar heat systems and low energy buildings

The goal of the research project enerMAT is the reduction of energy consumption and CO2 emissions of buildings. Especially solar heating systems are installed in more and more buildings. This paper introduces a novel approach for simulation and optimisation that aims to improve the performance of building controllers and especially solar heating controllers by simulation and model-in-the-loop tests. A new generation of energy-aware optimized building energy management system (BEMS) will be discussed and its advantages over the older controllers highlighted. The energy-aware optimisation will be shown on a model-based approach with an overall building system model enabling the assessment of the energy performance for different design and operation alternatives of the building automation system in interaction with the building. This system model will allow a simulation-based, energy-aware, global, dynamic, multi-criterial optimization of BEMS. In this paper, the idea, the approach, and the actual state of the project research is presented with a focus on solar heating controllers