Lis1 is an initiation factor for dynein-driven organelle transport

The molecular motor cytoplasmic dynein is responsible for most minus-end–directed, microtubule-based transport in eukaryotic cells. It is especially important in neurons, where defects in microtubule-based motility have been linked to neurological diseases. For example, lissencephaly is caused by mutations in the dynein-associated protein Lis1. In this paper, using the long, highly polarized hyphae of the filamentous fungus Aspergillus nidulans, we show that three morphologically and functionally distinct dynein cargos showed transport defects in the genetic absence of Lis1/nudF, raising the possibility that Lis1 is ubiquitously used for dynein-based transport. Surprisingly, both dynein and its cargo moved at normal speeds in the absence of Lis1 but with reduced frequency. Moreover, Lis1, unlike dynein and dynactin, was absent from moving dynein cargos, further suggesting that Lis1 is not required for dynein-based cargo motility once it has commenced. Based on these observations, we propose that Lis1 has a general role in initiating dynein-driven motility

Beurteilung des Therapieerfolgs – konventionelle versus neue Methoden

New ways of evaluating treatment success among thoracic tumour patients are increasingly being used alongside more conventional methods. These new approaches include tumour regression grading, CAD volumetry (computer-assisted volumetry), determination of the tumour density and tumour perfusion as well as the use of positron emission tomography (PET) using (18)F-FDG (fluorodeoxyglucose) or other tracers. Increasingly, endpoints that impact directly on the patient's quality of life and tumour-related symptoms are becoming more relevant factors together with the objectively measurable parameters used for assessing treatment response. This contribution describes the potential value of new methods and end-points from the point of view of a pathologist, radiologist, nuclear medicine specialist, radiotherapist, thoracic surgeon, medical and pneumology oncologist, and general practitioner

Aktuelle Entwicklungen und Perspektiven zielgerichteter Therapien

Current Developments and Perspectives in Targeted Therapies Many different approaches for improving the prognosis of patients with advanced non-small-cell lung cancer (NSCLC) are currently being investigated. This article discusses the significance of maintenance therapy after primary chemotherapy and reviews study data on second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), inhibitors of insulin-like growth factor receptors (IGFR), vascular-disrupting agents (VDAs) and multi-TKIs of vascular endothelial growth factor receptors (VEGFR). The article also looks at the future prospects of using genetic markers in the field of NSCLC

Kreativität des Findens – Figurationen des Zitats

Manche Zitate sucht man nicht, sondern sie werden gefunden, wie man unversehens über einen Stein oder eine Baumwurzel stolpert. Solche Zufälle der Zitation ergeben Figuren des Ein- und Verrückens von Bedeutung, insofern Zitate immer zwischen Aussagekontexten, zwischen Texten stehen. Denn nicht der Urheber, den die Zitation zuschreibt, spricht, sondern der Zitierende, indem er seine eigene Autorschaft einklammert. Von hier aus ist der Titel einer ›Kreativität des Findens‹ gedacht. Theoretische oder systematische Aspekte einer Kreatologie sind weniger intendiert, wenngleich der Ansatz bei der konkreten Figur fürs Grundsätzliche offen ist – zumal bei ›ästhetischen Objekten‹, dem Gegenstandsbereich dieses Bandes. Das was Robert Musil ›induktive Gesinnung‹ nannte, ist hier Voraussetzung der Erschließung, denn ohne Insistenz des Beispiels gegenüber dem Gesetz entfällt die Relevanz des ästhetischen Objekts. – Drei Bereiche strukturieren den Band nach grundständigen Figuren des Zitats, Perspektiven einer Philologie des Zitats mit Blick auf literarische Zitation und nach Randgängen des Zitats mit medienspezifischen Problemstellungen; der Popliterat Thomas Meinecke erläutert seine Kreativität des Findens als literarisches Sampling

The status of transgender persons in civil law

The status of transgender persons in civil law Abstract The thesis focuses on the legal regulation of gender reassignment in the Czech Republic, both in terms of civil law and constitutional law. The thesis initially focuses mainly on the correct definition of important terms and their essential meaning. Attention is paid not only to transsexuality itself and its forms, but also to related conditions such as intersexuality and transvestitism. After discussing the human rights foundations of gender reassignment, the thesis briefly discusses the historical genesis of the legal regulation of gender reassignment. This is followed by a description of the currently effective legislation, including its shortcomings with regard not only to domestic law but also to the Czech Republic's international obligations under international human rights treaties. In this area, the greatest emphasis is then placed on the decision-making of the European Court of Human Rights, which is more advanced than Czech national courts in this area. Apart from transsexuality and the process of gender reassignment, the thesis also focuses on the opposite phenomenon, namely detransition. This topic is often neglected, even though it is a topic essentially inseparable from gender reassignment and offers many interesting legal issues. The...Postavení transgender osob v civilním právu Abstrakt Diplomová práce se zaměřuje na právní úpravu změny pohlaví v České republice, a to jak v rovině civilněprávní, tak ústavněprávní. Práce se zprvu soustřeďuje zejména na správnou definici významných pojmů a na jejich základní obsah. Pozornost je věnována nejen samotné transsexualitě a jejím formám, ale také souvisejícím stavům jako je intersexualita a transvestitismus. Po rozebrání lidskoprávních základů změny pohlaví se práce stručně zaobírá historickou genezí zákonné právní úpravy změny pohlaví. Následuje popis aktuálně účinné právní úpravy včetně jejích nedostatků s ohledem nejen na vnitrostátní právo, ale také na mezinárodní závazky České republiky plynoucí z mezinárodních smluv o lidských právech. V této oblasti je pak největší důraz kladen na rozhodovací činnost Evropského soudu pro lidská práva, který je v této oblasti pokrokovější než vnitrostátní soudy. Kromě samotné transsexuality a procesu změny pohlaví se práce věnuje také v podstatě opačnému jevu, a to detranzici. Toto téma je často opomíjeno, ačkoliv se jedná o téma od změny pohlaví v podstatě neoddělitelné a nabízející spoustu zajímavých právních otázek. Předmětem posledních dvou obsahových částí této diplomové práce je pak vnitrostátní i zahraniční judikatura. Rozhodovací činnost českých...Department of Civil LawKatedra občanského právaFaculty of LawPrávnická fakult

2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer

To complement the existing treatment guidelines, ESMO organises consensus conferences to focus on specific issues. The 2nd ESMO Consensus Conference on Lung Cancer included 35 experts who met to address several questions on non-small-cell lung cancer (NSCLC). Recommendations were made with reference to grade of recommendation and level of evidence. This paper focuses on locally advanced diseas

A microscopy-based screen employing multiplex genome sequencing identifies cargo-specific requirements for dynein velocity

The timely delivery of membranous organelles and macromolecules to specific locations within the majority of eukaryotic cells depends on microtubule-based transport. Here, we describe a screening method to identify mutations that have a critical effect on intracellular transport and its regulation using mutagenesis, multicolor-fluorescence microscopy, and multiplex genome sequencing. This screen exploits the filamentous fungus Aspergillus nidulans, which has many of the advantages of yeast molecular genetics, but uses long-range microtubule-based transport in a manner more similar to metazoan cells. Using this method, we identified 7 mutants that represent novel alleles of components of the intracellular transport machinery: specifically, kinesin-1, cytoplasmic dynein, and the dynein regulators Lis1 and dynactin. The two dynein mutations identified in our screen map to dynein's AAA+ catalytic core. Single-molecule studies reveal that both mutations reduce dynein's velocity in vitro. In vivo these mutants severely impair the distribution and velocity of endosomes, a known dynein cargo. In contrast, another dynein cargo, the nucleus, is positioned normally in these mutants. These results reveal that different dynein functions have distinct velocity requirements