Structural Insights into TIR Domain Specificity of the Bridging Adaptor Mal in TLR4 Signaling

MyD88 adaptor-like protein (Mal) is a crucial adaptor that acts as a bridge to recruit the MyD88 molecule to activated TLR4 receptors in response to invading pathogens. The specific assembly of the Toll/interleukin-1 receptor (TIR) domains of TLR4, Mal and MyD88 is responsible for proper signal transduction in the TLR4 signaling pathway. However, the molecular mechanism for the specificity of these TIR domains remains unclear. Here, we present the crystal structure of the TIR domain of the human Mal molecule (Mal-TIR) at a resolution of 2.4 Å. Unexpectedly, Mal-TIR exhibits an extraordinarily long AB loop, but no αB helix or BB loop, distinguishing it from other TIR domains. More importantly, the Mal-TIR AB loop is capable of mediating direct binding to the TIR domains of TLR4 and MyD88 simultaneously. We also found that Mal-TIR can form a back-to-back dimer that may resemble the dimeric assembly of the entire Mal molecule. Our data demonstrate the bridge role of the Mal-TIR domain and provide important information about TIR domain specificity

Construction of a large scale integrated map of macrophage pathogen recognition and effector systems

<p>Abstract</p> <p>Background</p> <p>In an effort to better understand the molecular networks that underpin macrophage activation we have been assembling a map of relevant pathways. Manual curation of the published literature was carried out in order to define the components of these pathways and the interactions between them. This information has been assembled into a large integrated directional network and represented graphically using the modified Edinburgh Pathway Notation (mEPN) scheme.</p> <p>Results</p> <p>The diagram includes detailed views of the toll-like receptor (TLR) pathways, other pathogen recognition systems, NF-kappa-B, apoptosis, interferon signalling, MAP-kinase cascades, MHC antigen presentation and proteasome assembly, as well as selected views of the transcriptional networks they regulate. The integrated pathway includes a total of 496 unique proteins, the complexes formed between them and the processes in which they are involved. This produces a network of 2,170 nodes connected by 2,553 edges.</p> <p>Conclusions</p> <p>The pathway diagram is a navigable visual aid for displaying a consensus view of the pathway information available for these systems. It is also a valuable resource for computational modelling and aid in the interpretation of functional genomics data. We envisage that this work will be of value to those interested in macrophage biology and also contribute to the ongoing Systems Biology community effort to develop a standard notation scheme for the graphical representation of biological pathways.</p

Die zukünftige Entwicklung intensivmedizinischer Qualitätsindikatoren - ein Methodenpapier

Introduction: Medical quality indicators (QI) are important tools in the evaluation of medical quality. Their development is subject to specific methodological requirements, which include practical applicability. This is especially true for intensive care medicine with its complex processes and their interactions. This methods paper presents the status quo and shows necessary methodological developments for intensive care QI. For this purpose, a cooperation with the Association of the Scientific Medical Societies' Institute for Medical Knowledge Management (AWMF-IMWi) was established.Methodology: Review of published German manuals for QI development from guidelines and narrative review of quality indicators with a focus on evidence and consensus-based guideline recommendations. Future methodological adaptations of indicator development for improved operationalization, measurability and pilot testing are presented, and a development process is proposed.Results: The development of intensive care quality indicators in Germany is based on an established process. In the future, additional evaluation criteria (QUALIFY criteria) will be applied to assess the evidence base. In addition, a continuous exchange between the national steering committee of the DIVI responsible for QI development and guideline development groups involved in intensive care medicine is planned.Conclusion: Intensive care quality indicators will have to meet improved methodological requirements in the future by means of an improved development process. Future QI development is intended to improve the structure of the development process, with a focus on scientific evidence and a link to guideline projects. This is intended to achieve the goal of a broad application of QI and to further evaluate its relevance for patient outcome and performance of institutions.Einleitung: Medizinische Qualitätsindikatoren (QI) stellen ein wichtiges Werkzeug bei der Betrachtung medizinischer Qualität dar. Ihre Entwicklung unterliegt methodischen Anforderungen, die auch ihre praktische Anwendbarkeit einschließen. Dies gilt insbesondere für die Intensivmedizin mit ihren komplexen Prozessen und Interaktionen. Dieses Methodenpapier dient der Darstellung des Status quo und zeigt erforderliche methodische Weiterentwicklungen intensivmedizinischer QI auf. Dazu erfolgte eine Kooperation mit dem Institut für Medizinisches Wissensmanagement der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF-IMWi).Methodik: Rückgriff auf publizierte deutsche Manuale zur QI-Ableitung aus Leitlinien und narratives Review zu Qualitätsindikatoren mit Fokus auf die Beziehung zu evidenz- und konsensbasierten Leitlinienempfehlungen. Die notwendigen methodischen Anpassungen der Indikatorentwicklung wie Operationalisierbarkeit, Messbarkeit und Pilotierung werden dargestellt, und ein Vorschlag für einen Entwicklungsprozess wird erarbeitet.Ergebnisse: Die Entwicklung intensivmedizinischer Qualitätsindikatoren in Deutschland geschieht in einem etablierten Verfahren. Dieses soll künftig durch die Aufnahme zusätzlicher Bewertungskriterien (QUALIFY-Kriterien) u.a. zur Beurteilung der Evidenzbasierung erweitert werden. Ergänzend ist ein kontinuierlicher Austausch der für die QI verantwortlichen nationalen Steuerungsgruppe der DIVI mit den Leitliniengruppen geplant, die intensivmedizinische Fragestellungen bearbeiten.Schlussfolgerung: Intensivmedizinische Qualitätsindikatoren können durch einen verbesserten Entwicklungsprozess in Zukunft gestiegenen methodischen Anforderungen genügen. Die beschriebenen Weiterentwicklungen sollen den Erstellungsprozess besser strukturieren, wissenschaftlicher gestalten und in Zukunft mit Leitlinienprojekten vernetzen. Dadurch soll das Ziel einer flächendeckenden Anwendung der QI erreicht werden und schließlich ihre Relevanz für das Outcome bezogen auf Patienten und Einrichtungen geprüft werden

Das Angehörigengespräch in der Intensivmedizin

Family members of adult intensive care patients are partners of the interdisciplinary team. Family members provide important contributions to patient-centered care in the intensive care unit (ICU) and beyond. At the same time, family members are stressed and are themselves in need of support ("family-centered care"). This is mainly provided through family conferences. Family members must always be treated respectfully and with consideration for their acute stress syndrome. A structured communication is recommended as well as written standard operating procedures (SOPs) or guidelines for the ICU team and brochures and written guidelines for relatives. Documentation of structured family conferences is an established quality indicator of intensive care