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Molecular analysis of the ribosome recycling factor ABCE1 bound to the 30S post-splitting complex
(2020)
Ribosome recycling by the twin-ATPase ABCE1 is a key regulatory process in mRNA translation and surveillance and in ribosome-associated protein quality control in Eukarya and Archaea. Here, we captured the archaeal 30S ribosome post-splitting complex at 2.8 Å resolution by cryo-electron microscopy. The structure reveals the dynamic behavior of structural motifs unique to ABCE1, which ultimately leads to ribosome splitting. More specifically, we provide molecular details on how conformational rearrangements of the iron–sulfur cluster domain and hinge regions of ABCE1 are linked to closure of its nucleotide-binding sites. The combination of mutational and functional analyses uncovers an intricate allosteric network between the ribosome, regulatory domains of ABCE1, and its two structurally and functionally asymmetric ATP-binding sites. Based on these data, we propose a refined model of how signals from the ribosome are integrated into the ATPase cycle of ABCE1 to orchestrate ribosome recycling.
Diese Arbeit untersucht die mitteldeutschen Vorkommen von Luzula divulgata, einer Sippe aus der Artengruppe um Luzula campestris und L. multiflora, deren ökologische Ansprüche und soziologisches Verhalten in Deutschland bisher kaum bekannt waren. Die östlich verbreitete Art wächst in Mitteldeutschland im oberen Bodetal, unteren Unstruttal, mittleren Saaletal und im Kyffhäusergebirge. Die isolierten Vorkommen bilden den nordwestlichen Arealrand der Art. L. divulgata ist im Gebiet an Eichen-Trockenwälder des Luzulo luzuloidis-Quercetum petraeae und Potentillo albae-Quercetum petraeae gebunden. Mitunter wächst sie auch in waldnahen Heiden, Säumen und Magerrasen. Das Klima der Wuchsgebiete ist sommerwarm und relativ trocken. Die Böden sind nahezu kalkfrei, mäßig sauer bis sauer und meist oligotroph. Das standortökologische Verhalten von L. divulgata wird mit Hilfe von Ellenberg-Zeigerwerten zusammengefasst; das Verbreitungsbild und die soziologische Bindung der Art werden diskutiert.
Introduction: Prophylaxis with factor VIII (FVIII) concentrates in children with haemophilia A (HA) is current standard of care. The benefit of prophylactic treatment for adult HA patients is not commonly accepted.
Aim: To investigate the benefit of prophylaxis over on‐demand treatment in adult and elderly patients with severe or non‐severe HA in a real‐life setting.
Methods: Data from 163 patients comprising 1202 patient‐years were evaluated for 7.5 (±5.3) years. The effects on the annual bleeding rate (ABR, including spontaneous and traumatic bleeds) of treatment with a plasma‐derived FVIII concentrate, the patient's age and disease severity were investigated. The effect of changing the treatment from on demand to continuous prophylaxis on the patients’ ABRs was further analysed.
Results: Prophylaxis had the greatest effect on the ABRs of patients of any age with severe or non‐severe HA. The difference in ABR of all patients treated on demand (median 31.4; interquartile range (IQR) 27.6; N = 83) compared with those treated prophylactically (median 1.3; IQR 3.6; N = 122) was statistically significant (P < .05), even for patients with non‐severe HA (median 8.4; IQR 15.5; N = 11) vs median 1.5; IQR 4.2 (N = 17), P < .05). Patients, aged up to 88 years, switching from on demand to continuous prophylaxis showed the lowest median ABR (1.1; N = 51) after their regimen change.
Conclusion: Any (even low‐frequency) prophylaxis results in lower ABR than on‐demand treatment. Patients switching to prophylaxis benefitted the most, irrespective of age or HA severity. Prophylactic treatment—even tertiary—is the regimen of choice for patients of any age, including elderly patients, with severe or non‐severe HA.
Ligand stimulation of CD95 induces activation of Plk3 followed by phosphorylation of caspase-8
(2016)
Upon interaction of the CD95 receptor with its ligand, sequential association of the adaptor molecule FADD (MORT1), pro-forms of caspases-8/10, and the caspase-8/10 regulator c-FLIP leads to the formation of a death-inducing signaling complex. Here, we identify polo-like kinase (Plk) 3 as a new interaction partner of the death receptor CD95. The enzymatic activity of Plk3 increases following interaction of the CD95 receptor with its ligand. Knockout (KO) or knockdown of caspase-8, CD95 or FADD prevents activation of Plk3 upon CD95 stimulation, suggesting a requirement of a functional DISC for Plk3 activation. Furthermore, we identify caspase-8 as a new substrate for Plk3. Phosphorylation occurs on T273 and results in stimulation of caspase-8 proapoptotic function. Stimulation of CD95 in cells expressing a non-phosphorylatable caspase-8-T273A mutant in a rescue experiment or in Plk3-KO cells generated by CRISPR/Cas9 reduces the processing of caspase-8 prominently. Low T273 phosphorylation correlates significantly with low Plk3 expression in a cohort of 95 anal tumor patients. Our data suggest a novel mechanism of kinase activation within the Plk family and propose a new model for the stimulation of the extrinsic death pathway in tumors with high Plk3 expression.
Die Steppenrasen des NSG „Badraer Lehde–Großer Eller“ werden hier erstmalig beschrieben und analysiert. 156 Originalaufnahmen wurden über eine Clusteranalyse in sieben Assoziationen und zwei ranglose Gesellschaften innerhalb der Verbände Alysso-Sedion, Seslerio-Festucion pallentis, Festucion valesiacae, Xerobromion und Cirsio-Brachypodion gegliedert. Die Auswertung alter Luftbilder zeigt, dass die beiden ranglosen Gesellschaften junge Steppenrasen auf ehemaligen Ackerflächen darstellen, während die Assoziationen überwiegend alte Steppenrasen repräsentieren. Der erste floristische Gradient nach einer NMDS in der Vegetation wird durch Variablen erklärt, die die Temperatur und die Wasserversorgung der Standorte anzeigen. Der zweite floristische Gradient kann durch das Alter der Flächen erklärt werden. Alte Steppenrasen enthalten signifikant mehr gefährdete Pflanzenarten als junge Steppenrasen, während sich der Gesamtartenreichtum zwischen jungen und alten Beständen nicht signifikant unterscheidet. Ein CSR-Strategietypenspektrum zeigt in einer Gesellschaft auf ehemaligen Ackerflächen eine höhere Bedeutung der C-Strategie, sonst aber kaum Unterschiede zwischen den Syntaxa. Die beiden Xerobromion-Assoziationen sind besonders artenreich und enthalten überdurchschnittlich viele gefährdete Pflanzenarten. Eine Gesellschaft auf ehemaligen Ackerflächen enthält durchschnittlich viele und die andere fast keine gefährdeten Arten. Der Artenreichtum der Gefäßpflanzen ist am stärksten positiv mit der Bodengründigkeit, der Deckung der Krautschicht und dem Ellenberg-Zeigerwert für Bodenreaktion und negativ mit dem Zeigerwert für Temperatur korreliert. Unsere Studie zeigt die hohe Bedeutung des NSG für den Trockenrasenschutz. Diese beruht vor allem auf der allgemein hohen Artenvielfalt und Diversität an Gesellschaften sowie auf der sehr hohen Zahl gefährdeter Arten.
Background: Available data on the incidence and outcome of invasive fungal diseases (IFD) in children with hematological malignancies or after allogeneic hematopoietic stem cell transplantation (HSCT) are mostly based on monocenter, retrospective studies or on studies performed prior to the availability of newer triazoles or echinocandins.
Procedure: We prospectively collected clinical data on incidence, diagnostic procedures, management and outcome of IFD in children treated for hematological malignancies or undergoing HSCT in three major European pediatric cancer centers.
Results: A total of 304 children (median age 6.0 years) who underwent 360 therapies (211 chemotherapy treatments, 138 allogeneic HSCTs and/or 11 investigational chemotherapeutic treatments) were included in the analysis. Nineteen children developed proven/probable IFD, mostly due to Aspergillus (n = 10) and Candida spp. (n = 5), respectively. In patients receiving chemotherapy, 11 IFDs occurred, all during induction or re-induction therapy. None of these patients died due to IFD, whereas IFD was lethal in 3 of the 8 HSCT recipients with IFD. Significant differences among centers were observed with regard to the use of imaging diagnostics and the choice, initiation and duration of antifungal prophylaxis.
Conclusion: This prospective multicenter study provides information on the current incidence and outcome of IFD in the real life setting. Practice variation between the centers may help to ultimately improve antifungal management in children at highest risk for IFDs.
Background: To evaluate the impact of time to castration resistance (TTCR) in metastatic hormone-sensitive prostate cancer (mHSPC) patients on overall survival (OS) in the era of combination therapies for mHSPC.
Material and Methods: Of 213 mHSPC patients diagnosed between 01/2013-12/2020 who subsequently developed metastatic castration resistant prostate cancer (mCRPC), 204 eligible patients were analyzed after having applied exclusion criteria. mHSPC patients were classified into TTCR <12, 12-18, 18-24, and >24 months and analyzed regarding OS. Moreover, further OS analyses were performed after having developed mCRPC status according to TTCR. Logistic regression models predicted the value of TTCR on OS.
Results: Median follow-up was 34 months. Among 204 mHSPC patients, 41.2% harbored TTCR <12 months, 18.1% for 12-18 months, 15.2% for 18-24 months, and 25.5% for >24 months. Median age was 67 years and median PSA at prostate cancer diagnosis was 61 ng/ml. No differences in patient characteristics were observed (all p>0.05). According to OS, TTCR <12 months patients had the worst OS, followed by TTCR 12-18 months, 18-24 months, and >24 months, in that order (p<0.001). After multivariable adjustment, a 4.07-, 3.31-, and 6.40-fold higher mortality was observed for TTCR 18-24 months, 12-18 months, and <12 months patients, relative to TTCR >24 months (all p<0.05). Conversely, OS after development of mCRPC was not influenced by TTCR stratification (all p>0.05).
Conclusion: Patients with TTCR <12 months are at the highest OS disadvantage in mHSPC. This OS disadvantage persisted even after multivariable adjustment. Interestingly, TTCR stratified analyses did not influence OS in mCRPC patients.
In an ongoing clinical phase I/II study, 16 pediatric patients suffering from high risk leukemia/tumors received highly purified donor natural killer (NK) cell immunotherapy (NK-DLI) at day (+3) +40 and +100 post haploidentical stem cell transplantation. However, literature about the influence of NK-DLI on recipient's immune system is scarce. Here we present concomitant results of a noninvasive in vivo monitoring approach of recipient's peripheral blood (PB) cells after transfer of either unstimulated (NK-DLI(unstim)) or IL-2 (1000 U/ml, 9–14 days) activated NK cells (NK-DLI(IL-2 stim)) along with their ex vivo secreted cytokine/chemokines. We performed phenotypical and functional characterizations of the NK-DLIs, detailed flow cytometric analyses of various PB cells and comprehensive cytokine/chemokine arrays before and after NK-DLI. Patients of both groups were comparable with regard to remission status, immune reconstitution, donor chimerism, KIR mismatching, stem cell and NK-DLI dose. Only after NK-DLI(IL-2 stim) was a rapid, almost complete loss of CD56(bright)CD16(dim/−) immune regulatory and CD56(dim)CD16(+) cytotoxic NK cells, monocytes, dendritic cells and eosinophils from PB circulation seen 10 min after infusion, while neutrophils significantly increased. The reduction of NK cells was due to both, a decrease in patients' own CD69(−) NCR(low)CD62L(+) NK cells as well as to a diminishing of the transferred cells from the NK-DLI(IL-2 stim) with the CD56(bright)CD16(+/−)CD69(+)NCR(high)CD62L(−) phenotype. All cell counts recovered within the next 24 h. Transfer of NK-DLI(IL-2 stim) translated into significantly increased levels of various cytokines/chemokines (i.e. IFN-γ, IL-6, MIP-1β) in patients' PB. Those remained stable for at least 1 h, presumably leading to endothelial activation, leukocyte adhesion and/or extravasation. In contrast, NK-DLI(unstim) did not cause any of the observed effects. In conclusion, we assume that the adoptive transfer of NK-DLI(IL-2 stim) under the influence of ex vivo and in vivo secreted cytokines/chemokines may promote NK cell trafficking and therefore might enhance efficacy of immunotherapy.
Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.
GrassVeg.DE – die neue kollaborative Vegetationsdatenbank für alle Offenlandhabitate Deutschlands
(2017)
Der Bericht stellt die neue kollaborative Vegetationsdatenbank GrassVeg.DE (EU-DE-020; http://bit.ly/2qgX208) vor, die Vegetationsaufnahmen von Grasländern und anderen nicht-aquatischen Offenlandhabitaten Deutschlands sammelt, um sie national und international für die vegetationsökologische Forschung zur Verfügung zu stellen. GrassVeg.DE trägt die Daten zum European Vegetation Archive (EVA) und künftig auch zur globalen Vegetationsdatenbank „sPlot“ bei. Datenlieferanten von GrassVeg.DE behalten volle Verfügungsgewalt über ihre Daten und werden Mitglied des GrassVeg.DE-Konsortiums. Dadurch profitieren sie durch Co-Autorenschaften und Zitate von ihren Beiträgen und erlangen zugleich die Möglichkeit, selbst Projekte zu beantragen, die GrassVeg.DE- oder EVA-Daten nutzen. Die schnell wachsende GrassVeg.DE-Datenbank umfasste im Juli 2017 3.181 Vegetationsaufnahmen aus acht deutschen Bundesländern. Perspektivisch kann GrassVeg.DE dazu beitragen, eine konsistente Neuklassifikation der Graslandvegetationstypen Deutschlands im Rahmen der Synopsis der Pflanzengesellschaften Deutschlands zu ermöglichen. Wir schließen den Beitrag mit einem Aufruf, eigene und aus der Literatur digitalisierte Vegetationsaufnahmen zu GrassVeg.DE beizutragen.