Agrin isoforms and their role in synaptogenesis

Agrin is thought to mediate the motor neuron-induced aggregation of synaptic proteins on the surface of muscle fibers at neuromuscular junctions. Recent experiments provide direct evidence in support of this hypothesis, reveal the nature of agrin immunoreactivity at sites other than neuromuscular junctions, and have resulted in findings that are consistent with the possibility that agrin plays a role in synaptogenesis throughout the nervous system

An antagonism between Spinophilin and Syd-1 operates upstream of memory-promoting presynaptic long-term plasticity

We still face fundamental gaps in understanding how molecular plastic changes of synapses intersect with circuit operation to define behavioral states. Here, we show that an antagonism between two conserved regulatory proteins, Spinophilin (Spn) and Syd-1, controls presynaptic long-term plasticity and the maintenance of olfactory memories in Drosophila. While Spn mutants could not trigger nanoscopic active zone remodeling under homeostatic challenge and failed to stably potentiate neurotransmitter release, concomitant reduction of Syd-1 rescued all these deficits. The Spn/Syd-1 antagonism converged on active zone close F-actin, and genetic or acute pharmacological depolymerization of F-actin rescued the Spn deficits by allowing access to synaptic vesicle release sites. Within the intrinsic mushroom body neurons, the Spn/Syd-1 antagonism specifically controlled olfactory memory stabilization but not initial learning. Thus, this evolutionarily conserved protein complex controls behaviorally relevant presynaptic long-term plasticity, also observed in the mammalian brain but still enigmatic concerning its molecular mechanisms and behavioral relevance

The construct validity of the main student selection tests for medical studies in Germany

Standardized ability tests that are associated with intelligence are often used for student selection. In Germany two different admission procedures to select students for medical studies are used simultaneously; the TMS and the HAM-Nat. Due to this simultaneous use of both a detailed analysis of the construct validity is mandatory. Therefore, the aim of the study is the construct validation of both selection procedures by using data of 4,528 participants (Mage = 20.42, SD = 2.74) who took part in a preparation study under low stakes conditions. This study compares different model specifications within the correlational structure of intelligence factors as well as analysis the g-factor consistency of the admission tests. Results reveal that all subtests are correlated substantially. Furthermore, confirmatory factor analyses demonstrate that both admission tests (and their subtests) are related to g as well as to a further test-specific-factor. Therefore, from a psychometric point of view, the simultaneous use of both student selection procedures appears to be legitimate

ESPEN Guideline: clinical nutrition in inflammatory bowel disease

Crohn’s disease; Ulcerative colitis; Nutritional therapyMalaltia de Crohn; Colitis ulcerosa; Teràpia nutricionalEnfermedad de Crohn; Colitis ulcerosa; Terapia nutricionalIntroduction: the ESPEN Guideline offers a multidisciplinary focus on clinical nutrition in inflammatory bowel disease (IBD). Methodology: the guideline is based on a extensive systematic review of the literature, but relies on expert opinion when objective data are lacking or inconclusive. The conclusions and 64 recommendations have been subject to full peer review and a Delphi process, in which uniformly positive responses (agree or strongly agree) were required. Results: IBD is increasingly common and potential dietary factors in its etiology are briefly reviewed. Malnutrition is highly prevalent in IBD — especially in Crohn’s disease. Increased energy and protein requirements are observed in some patients. The management of malnutrition in IBD is considered within the general context of support for malnourished patients. Treatment of iron deficiency (parenterally, if necessary) is strongly recommended. Routine provision of a special diet in IBD is not, however, supported. Parenteral nutrition is indicated only when enteral nutrition has failed or is impossible. The recommended perioperative management of patients with IBD undergoing surgery accords with general ESPEN guidance for patients having abdominal surgery. Probiotics may be helpful in UC but not in Crohn’s disease. Primary therapy using nutrition to treat IBD is not supported in ulcerative colitis but is moderately well supported in Crohn’s disease, especially in children, where the adverse consequences of steroid therapy are proportionally greater. However, exclusion diets are generally not recommended and there is little evidence to support any particular formula feed when nutritional regimens are constructed. Conclusions: available objective data to guide nutritional support and primary nutritional therapy in IBD are presented as 64 recommendations, of which 9 are very strong recommendations (grade A), 22 are strong recommendations (grade B), and 12 are based only on sparse evidence (grade 0); 21 recommendations are good practice points (GPP).Introducción: la guía ESPEN ofrece un enfoque multidisciplinar de la nutrición clínica en la enfermedad inflamatoria intestinal (EII). Metodología: la guía se basa en una extensa revisión sistemática de la literatura y en la opinión de expertos cuando faltan datos objetivos o estos no son concluyentes. Las conclusiones y las 64 recomendaciones han sido objeto de una revisión completa por pares y de un proceso Delphi en el que se requerían respuestas fuertemente positivas (de acuerdo o totalmente de acuerdo). Resultados: la EII es cada vez más común y se revisan brevemente los posibles factores dietéticos en su etiología. La desnutrición es muy prevalente en la EII, especialmente en la enfermedad de Crohn. En algunos pacientes se observan mayores requerimientos de energía y proteínas. El manejo de la desnutrición en la EII se considera dentro del contexto general de apoyo a los pacientes desnutridos. Se recomienda fuertemente el tratamiento de la deficiencia de hierro (por vía parenteral, si es necesario). Sin embargo, no se aconseja la prescripción de rutina de una dieta especial en la EII. La nutrición parenteral está indicada solo cuando la nutrición enteral ha fallado o es imposible. El manejo perioperatorio recomendado de los pacientes con EII sometidos a cirugía se hace de acuerdo con la guía general de la ESPEN para pacientes sometidos a cirugía abdominal. Los probióticos pueden ser útiles en la CU pero no en la enfermedad de Crohn. El tratamiento primario con nutrición para tratar la EII no está respaldado en la colitis ulcerosa, aunque está moderadamente bien soportado en la enfermedad de Crohn, especialmente en los niños, donde las consecuencias adversas de la terapia con esteroides son proporcionalmente mayores. Sin embargo, las dietas de exclusión generalmente no se recomiendan y hay poca evidencia que respalde cualquier fórmula de nutrición en particular cuando se realizan regímenes nutricionales. Conclusiones: los datos objetivos disponibles para guiar el apoyo nutricional y la terapia nutricional primaria en la EII se presentan como 64 recomendaciones, de las cuales 9 son recomendaciones muy fuertes (grado A), 22 son recomendaciones fuertes (grado B) y 12 se basan solo en evidencia escasa (grado 0); 21 recomendaciones son recomendaciones de buenas prácticas (GPP).El proceso de la guía ha sido financiado exclusivamente por la ESPEN

ESPEN Guideline: Clinical Nutrition in inflammatory bowel disease

Introduction: The ESPEN guideline presents a multidisciplinary focus on clinical nutrition in inflammatory bowel disease (IBD). Methodology: The guideline is based on extensive systematic review of the literature, but relies on expert opinion when objective data were lacking or inconclusive. The conclusions and 64 recommendations have been subject to full peer review and a Delphi process in which uniformly positive responses (agree or strongly agree) were required. Results: IBD is increasingly common and potential dietary factors in its aetiology are briefly reviewed. Malnutrition is highly prevalent in IBD – especially in Crohn's disease. Increased energy and protein requirements are observed in some patients. The management of malnu-trition in IBD is considered within the general context of support for malnourished patients. Treatment of iron deficiency (parenterally if necessary) is strongly recommended. Routine provision of a special diet in IBD is not however supported. Parenteral nutrition is indicated only when enteral nutrition has failed or is impossible. The recommended perioperative man-agement of patients with IBD undergoing surgery accords with general ESPEN guidance for patients having abdominal surgery. Probiotics may be helpful in UC but not Crohn's disease. Primary therapy using nutrition to treat IBD is not supported in ulcerative colitis, but is mod-erately well supported in Crohn's disease, especially in children where the adverse conse-quences of steroid therapy are proportionally greater. However, exclusion diets are generally not recommended and there is little evidence to support any particular formula feed when nutritional regimens are constructed. Conclusions: Available objective data to guide nutritional support and primary nutritional therapy in IBD are presented as 64 recommendations, of which 9 are very strong recom-mendations (grade A), 22 are strong recommendations (grade B) and 12 are based only on sparse evidence (grade 0); 21 recommendations are good practice points (GPP)

Abschlussbericht

Die Herausforderungen des Klimawandels erfordern eine beschleunigte Transformation der Energiesysteme bei der Einbindung erneuerbarer Energien zur Erreichung der Klimaziele, insbesondere auf regionaler Ebene. Neben Strom werden zukünftig auch weiterhin Brennstoffe wie Wasserstoff und kohlenstoffbasierte Energieträger wie z.B. Biomethan bedeutend sein. Im Rahmen des Forschungsvorhabens wurde ein hochaufgelöstes multimodales Energiesystemmodell zur Analyse der sektorübergreifenden Energiewende in vier Landkreisen Baden-Württembergs (Biberach, Sigmaringen, Alb-Donau-Kreis, Ravensburg) entwickelt. Die Langfristszenarien 3 des BMWK wurden als methodisch fundierte Referenz identifiziert, da sie sowohl Szenarien mit Ausprägungen von Strom bis Wasserstoff als auch sektorspezifische Transformationspfade für das Zieljahr 2045 quantifizieren. Darauf aufbauend wurden die Szenarien O45-Strom und O45-H2 als Basis für die regionale Herunterskalierung gewählt. Das auf Modelica und Python basierende Modell simuliert Strom-, Gas- und Wärmesektoren zeitgleich mit hoher räumlicher und zeitlicher Auflösung für die Transformationsjahre 2022-2045. Die Datenbasis umfasst Primärdaten regionaler Energieversorger, öffentliche Datensätze und detaillierte Netzmodelle mit über 24 Mittelspannungsnetzen und mehr als 9.000 Leitungen. Die Stromnetzanalyse zeigt bereits für das Jahr 2022 kritische Überlastungen in 8 % der Mittelspannungsleitungen, hauptsächlich durch PV-Mittagsspitzen verursacht. Bis 2045 werden 50-70 % aller 5.500 km Mittelspannungsleitungen überlastet, was einen hohen Investitionsbedarf bedeutet. Im Gassektor erweist sich die bestehende Infrastruktur eines Beispielnetzes als nahezu vollständig wasserstoffkompatibel. Nur etwa ein Kilometer kritische Abschnitte müssten angepasst werden, wenn die gleiche Energiemenge wie aktuell als Erdgas in 2045 als Wasserstoff transportiert werden soll. Regionale Elektrolyseure könnten bilanziell 1,7 TWh Wasserstoff jährlich erzeugen und damit ohne Speichereinsatz 70 % des regionalen Industriebedarfs decken. Zusätzlich besteht ein Exportpotenzial von 1,4 TWh pro Jahr zum geplanten Wasserstoff-Backbone. Durch Biomethanproduktion über Biogas-Cluster könnten weitere 0,6 TWh grüne Gase jährlich in den vier Landkreisen bereitgestellt werden. Der Wärmesektor zeigt begrenzte Netzausbaupotentiale in 2045, da nur jede achte Gemarkung teilweise die für Wärmenetze erforderliche Wärmedichte von mindestens 415 MWh/(ha a) laut KEA BW Leitlinien erreicht. Aufgrund niedriger Siedlungsdichte gekoppelt mit fortschreitender Sanierung der Gebäude bleiben dezentrale Lösungen die dominierenden Optionen im ländlichen Raum. Die Energiewende in ländlich-industriellen Räumen wird primär durch Stromnetzkapazitäten limitiert, nicht durch fehlende Erzeugungspotenziale. Ein massiver Ausbau der erneuerbaren Energien, insbesondere der PV-Ausbau, erfordert ab 2025 erhebliche Investitionen in den Netzausbau. Erste Untersuchungen zeigen, dass die Produktion grüner Gase unter der Voraussetzung, dass sich die Elektrolyseure in der Nähe des H2-Kernnetzes bzw. des regionalen Wasserstoffnetzes befinden und dort einspeisen, erhebliche Export- und Wertschöpfungspotenziale mit geringem Infrastrukturanpassungsbedarf bieten. Gleichwohl könnte die Sektorkopplung Chancen für einen schnelleren Hochlauf der Erneuerbaren Erzeugung bieten, die andernfalls durch den Ausbau des Stromnetzes limitiert würde. Das entwickelte modulare Modell weist Potenzial für die Übertragbarkeit auf und kann eine belastbare Grundlage zur Ausarbeitung regionaler Energie- und Klimaschutzstrategien bieten. Eine integrierte Betrachtung von Netzausbau, Erzeugungskapazitäten sowie Power-to-Gas-Strategien erscheint dabei als ein zentraler Aspekt für die Ermittlung kosteneffizienter Transformationspfade zur Klimaneutralität. Gleichwohl verbleiben offene Fragen, insbesondere im Hinblick auf die dynamische Abbildung von Preisen, saisonaler Effekte, die eingehende Analyse der netzdienlichen Sektorkopplung, die Potenzialabschätzung für Demand-Side-Management sowie die vertiefte sozioökonomische Bewertung von Geschäftsmodellen. Zudem ist die abschließende Überprüfung von THG-Minderungspotentialen für optimale Transformationspfade offen.The challenges posed by climate change necessitate an accelerated transformation of energy systems, particularly through the integration of renewable energy sources, to meet climate targets—especially at the regional level. In addition to electricity, fuels such as hydrogen and carbon-based energy carriers like biomethane will continue to play a significant role in the future energy landscape. As part of this research project, a high-resolution, multimodal energy system model was developed to analyze the cross-sectoral energy transition in four districts of Baden-Württemberg (Biberach, Sigmaringen, Alb-Donau-Kreis, and Ravensburg). The long-term scenarios (Scenario Set 3) of the German Federal Ministry for Economic Affairs and Climate Action (BMWK) were identified as a methodologically robust reference, as they quantify sector-specific transformation pathways for the target year 2045, encompassing electricity and hydrogen scenarios. Based on this, the scenarios O45-Electricity and O45-Hydrogen were selected as the foundation for regional downscaling. The model, implemented in Modelica and Python, simulates the electricity, gas, and heat sectors concurrently with high spatial and temporal resolution for the transformation period from 2022 to 2045. The data foundation includes primary data from regional energy providers, public datasets, and detailed grid models comprising over 24 medium-voltage networks and more than 9,000 lines. The electricity grid analysis reveals that as early as 2022, 8% of medium-voltage lines experienced critical overloads, primarily due to midday photovoltaic peaks. By 2045, 50–70% of the 5,500 km of medium-voltage lines are projected to be overloaded, indicating a substantial need for investment. In the gas sector, the existing infrastructure of a sample network proves to be almost entirely compatible with hydrogen. Only about one kilometer of critical segments would require modification if the same energy volume currently transported as natural gas were to be conveyed as hydrogen in 2045. Regional electrolyzers could theoretically produce 1.7 TWh of hydrogen annually, covering 70% of regional industrial demand without the need for storage. Additionally, there is an export potential of 1.4 TWh per year to the planned hydrogen backbone. Through biomethane production via biogas clusters, a further 0.6 TWh of green gases could be supplied annually within the four districts. The heat sector shows limited potential for network expansion by 2045, as only one in eight cadastral areas partially meets the heat density threshold of 415 MWh/(ha·a) required for district heating networks, according to KEA BW guidelines. Due to low settlement density and ongoing building renovations, decentralized solutions remain the dominant option in rural areas. The energy transition in rural-industrial regions is primarily constrained by electricity grid capacities rather than generation potential. A massive expansion of renewable energy, particularly photovoltaics, will require significant grid investments starting in 2025. Initial analyses indicate that the production of green gases—provided electrolyzers are located near the hydrogen core network or regional hydrogen infrastructure—offers substantial export and value creation potential with minimal infrastructure adaptation. Moreover, sector coupling could accelerate the deployment of renewable generation, which would otherwise be limited by grid expansion. The modular model developed in this study demonstrates strong potential for transferability and can serve as a robust foundation for the development of regional energy and climate protection strategies. An integrated assessment of grid expansion, generation capacities, and power-to-gas strategies emerges as a key element in identifying cost-efficient transformation pathways toward climate neutrality. Nevertheless, several open questions remain, particularly regarding the dynamic modeling of prices, seasonal effects, in-depth analysis of grid-supportive sector coupling, potential for demand-side management, and comprehensive socio-economic evaluation of business models. Furthermore, the final assessment of greenhouse gas mitigation potentials for optimal transformation pathways is still pending

Small business owners’ success criteria, a values approach to personal differences

This study of 150 Dutch small business owners, identified through business/ network directories, investigated relationships between owners’ understanding of success and their personal values. Business owners ranked 10 success criteria. Per- sonal satisfaction, profitability, and satisfied stakeholders ranked highest. Multidi- mensional scaling techniques revealed two dimensions underlying the rank order of success criteria: person-oriented (personal satisfaction versus business growth) and business-oriented (profitability versus contributing back to society). Furthermore, business growth, profitability, and innovativeness were guided by self-enhancing value orientations (power and achievement). Softer success criteria, such as having satisfied stakeholders and a good work–life balance, were guided by self-transcendent value orientations (benevolence and universalism)

Building ProteomeTools based on a complete synthetic human proteome.

We describe ProteomeTools, a project building molecular and digital tools from the human proteome to facilitate biomedical research. Here we report the generation and multimodal liquid chromatography-tandem mass spectrometry analysis of \u3e330,000 synthetic tryptic peptides representing essentially all canonical human gene products, and we exemplify the utility of these data in several applications. The resource (available at http://www.proteometools.org) will be extended to \u3e1 million peptides, and all data will be shared with the community via ProteomicsDB and ProteomeXchange

LHCb upgrade software and computing : technical design report

This document reports the Research and Development activities that are carried out in the software and computing domains in view of the upgrade of the LHCb experiment. The implementation of a full software trigger implies major changes in the core software framework, in the event data model, and in the reconstruction algorithms. The increase of the data volumes for both real and simulated datasets requires a corresponding scaling of the distributed computing infrastructure. An implementation plan in both domains is presented, together with a risk assessment analysis