Charakterisierung von Pathogenese und Prävention des zerebralen Vasospasmus mittels Durchmesseranalyse zerebraler Arteriolen im akuten Hirnschnittmodell der Maus

Eine der häufigsten Komplikationen der Subarachnoidalblutung (SAB) ist der zerebrale Vasospasmus. Die daraus resultierenden Veränderungen der zerebralen Mikrozirkulation begünstigen neurologische Defizite und erhöhen die Letalität von Patienten nach einer SAB. Die Behandlungs- und Präventionsmöglichkeiten des Vasospasmus sind unzureichend; die Pathogenese ist nur lückenhaft aufgeklärt. Ein ätiologischer Ansatzpunkt sind die Abbauprodukte des Hämoglobins (HDPs). Hierzu zählen Propentdyopents (PDPs) und Bilirubin-Oxidations-Endprodukte (BOXes), welche vermutlich inhibitorisch auf Gefäßtonus-regulierende BK-Kanäle wirken. Im Rahmen dieser Arbeit wurden pathophysiologische Faktoren der HDPs untersucht, welche als Grundlage für zukünftige präventive Therapieansätze fungieren sollen. In einem in vitro-Modell wurden Maushirnschnitte mittels DIC-Mikroskopie visualisiert und Änderungen des Gefäßdurchmessers intrakortikaler Arteriolen unter dem Einfluss vasoaktiver Substanzen analysiert. Die Testung von HDPs in Mäusen unterschiedlichen Alters resultierte in einer abgeschwächten Vasokonstriktion, was im Einklang mit der niedrigeren Inzidenz des Vasospasmus bei Patienten höheren Alters steht und auf eine abnehmende Gefäßvitalität zurückzuführen ist. Erstmalig getestete HDPs (Dihydro-BOX A und MVM) zeigten keine Vasoaktivität. Bei der Testung von BK-Kanal-Aktivatoren konnte BMS 204352 den gefäßverengenden Effekt von PDP A verhindern. Zudem konnte der PKC-Inhibitor Gö 6983 die PDP A-Wirkung aufheben. Das Ergebnis deutet auf eine Involvierung der PKC in die Pathophysiologie von PDP A hin und ist ein möglicher Ansatz für zukünftige Präventionsstrategien. Die Ergebnisse der getesteten BK Kanal-Inhibitoren lassen vermuten, dass PDPs vorwiegend auf astrozytäre BK Kanäle inhibitorisch wirken. Diese Inhibition konnte im Rahmen von elektrischen Stimulationsversuchen zur Untersuchung der Beeinflussung der neurovaskulären Kopplung nur bedingt gezeigt, jedoch nicht ausgeschlossen werden

Solid-state NMR evidence for inequivalent GvpA subunits in gas vesicles

Gas vesicles are organelles that provide buoyancy to the aquatic microorganisms that harbor them. The gas vesicle shell consists almost exclusively of the hydrophobic 70-residue gas vesicle protein A, arranged in an ordered array. Solid-state NMR spectra of intact collapsed gas vesicles from the cyanobacterium Anabaena flos-aquae show duplication of certain gas vesicle protein A resonances, indicating that specific sites experience at least two different local environments. Interpretation of these results in terms of an asymmetric dimer repeat unit can reconcile otherwise conflicting features of the primary, secondary, tertiary, and quaternary structures of the gas vesicle protein. In particular, the asymmetric dimer can explain how the hydrogen bonds in the β-sheet portion of the molecule can be oriented optimally for strength while promoting stabilizing aromatic and electrostatic side-chain interactions among highly conserved residues and creating a large hydrophobic surface suitable for preventing water condensation inside the vesicle.National Institutes of Health (U.S.) (Grant EB002175)National Institutes of Health (U.S.) (Grant EB003151)National Institutes of Health (U.S.) (Grant EB002026

PaLI-X: On Scaling up a Multilingual Vision and Language Model

We present the training recipe and results of scaling up PaLI-X, a multilingual vision and language model, both in terms of size of the components and the breadth of its training task mixture. Our model achieves new levels of performance on a wide-range of varied and complex tasks, including multiple image-based captioning and question-answering tasks, image-based document understanding and few-shot (in-context) learning, as well as object detection, video question answering, and video captioning. PaLI-X advances the state-of-the-art on most vision-and-language benchmarks considered (25+ of them). Finally, we observe emerging capabilities, such as complex counting and multilingual object detection, tasks that are not explicitly in the training mix

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe