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Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the Xchromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10-9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10-9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
Background: Intensive Care Resources are heavily utilized during the COVID-19 pandemic. However, risk stratification and prediction of SARS-CoV-2 patient clinical outcomes upon ICU admission remain inadequate. This study aimed to develop a machine learning model, based on retrospective & prospective clinical data, to stratify patient risk and predict ICU survival and outcomes. Methods: A Germany-wide electronic registry was established to pseudonymously collect admission, therapeutic and discharge information of SARS-CoV-2 ICU patients retrospectively and prospectively. Machine learning approaches were evaluated for the accuracy and interpretability of predictions. The Explainable Boosting Machine approach was selected as the most suitable method. Individual, non-linear shape functions for predictive parameters and parameter interactions are reported. Results: 1039 patients were included in the Explainable Boosting Machine model, 596 patients retrospectively collected, and 443 patients prospectively collected. The model for prediction of general ICU outcome was shown to be more reliable to predict “survival”. Age, inflammatory and thrombotic activity, and severity of ARDS at ICU admission were shown to be predictive of ICU survival. Patients’ age, pulmonary dysfunction and transfer from an external institution were predictors for ECMO therapy. The interaction of patient age with D-dimer levels on admission and creatinine levels with SOFA score without GCS were predictors for renal replacement therapy. Conclusions: Using Explainable Boosting Machine analysis, we confirmed and weighed previously reported and identified novel predictors for outcome in critically ill COVID-19 patients. Using this strategy, predictive modeling of COVID-19 ICU patient outcomes can be performed overcoming the limitations of linear regression models. Trial registration “ClinicalTrials” (clinicaltrials.gov) under NCT04455451.
Background: Cytogenetic aberrations such as deletion of chromosome 5q (del(5q)) represent key elements in routine clinical diagnostics of haematological malignancies. Currently established methods such as metaphase cytogenetics, FISH or array-based approaches have limitations due to their dependency on viable cells, high costs or semi-quantitative nature. Importantly, they cannot be used on low abundance DNA. We therefore aimed to establish a robust and quantitative technique that overcomes these shortcomings.
Methods: For precise determination of del(5q) cell fractions, we developed an inexpensive multiplex-PCR assay requiring only nanograms of DNA that simultaneously measures allelic imbalances of 12 independent short tandem repeat markers.
Results: Application of this method to n=1142 samples from n=260 individuals revealed strong intermarker concordance (R²=0.77–0.97) and reproducibility (mean SD: 1.7%). Notably, the assay showed accurate quantification via standard curve assessment (R²>0.99) and high concordance with paired FISH measurements (R²=0.92) even with subnanogram amounts of DNA. Moreover, cytogenetic response was reliably confirmed in del(5q) patients with myelodysplastic syndromes treated with lenalidomide. While the assay demonstrated good diagnostic accuracy in receiver operating characteristic analysis (area under the curve: 0.97), we further observed robust correlation between bone marrow and peripheral blood samples (R²=0.79), suggesting its potential suitability for less-invasive clonal monitoring.
Conclusions: In conclusion, we present an adaptable tool for quantification of chromosomal aberrations, particularly in problematic samples, which should be easily applicable to further tumour entities.
UV-B radiation represents a potentially selective, yet little studied environmental factor for plant invasions, especially with respect to germination characteristics and seedling establishment in areas of high UV-B exposure such as New Zealand. To explain invasive potential of plant species pre-adaptation and local adaptation to selection factors in the invaded range are two frequently consulted concepts. To test for the relevance of these mechanisms, it is necessary to compare both invasive and non-invasive species, as well as native and exotic origins of invasive species. In the present study, germination success of two congeneric species pairs of the genera Verbascum (Scrophulariaceae) and Echium (Boraginaceae) were investigated under high UV-B intensities. Each genus comprised one species that has successfully invaded New Zealand grasslands and one species that was introduced but has not been invasive in New Zealand. In an among-species approach, pre-adaptation was tested by comparing germination success of native (European) origins of all four species in relation to their different invasive success in New Zealand. In a within-species comparison, native (European) and exotic (New Zealand) origins of the two invasive species were compared to test for local adaptation to UV-B in the invaded range. In both approaches, UV-B radiation inhibited the germination success of all study species. However, the comparison of invasive and non-invasive species of the two genera showed no UV-B-specific pre-adaptation of invasive species to high UV-B intensities. Higher germination success of invasive species probably led to an establishment advantage during colonization of the invaded range. Although local adaptation of exotic populations to UV-B could not be demonstrated in the within-species approach, a genetic shift in germination velocity between native and exotic origins was found. These differences may be ascribed to other relevant environmental factors, e.g. overall irradiation and drought, inducing similar plant responses as under UV-B radiation.
Background Endothelium-derived nitric oxide plays an important role for the bone marrow microenvironment. Since several important effects of nitric oxide are mediated by cGMP-dependent pathways, we investigated the role of the cGMP downstream effector cGMP-dependent protein kinase I (cGKI) on postnatal neovascularization. Methodology/Principal Findings In a disc neovascularization model, cGKI -/- mice showed an impaired neovascularization as compared to their wild-type (WT) littermates. Infusion of WT, but not cGKI -/- bone marrow progenitors rescued the impaired ingrowth of new vessels in cGKI-deficient mice. Bone marrow progenitors from cGKI -/- mice showed reduced proliferation and survival rates. In addition, we used cGKI alpha leucine zipper mutant (LZM) mice as model for cGKI deficiency. LZM mice harbor a mutation in the cGKI alpha leucine zipper that prevents interaction with downstream signaling molecules. Consistently, LZM mice exhibited reduced numbers of vasculogenic progenitors and impaired neovascularization following hindlimb ischemia compared to WT mice. Conclusions/Significance Our findings demonstrate that the cGMP-cGKI pathway is critical for postnatal neovascularization and establish a new role for cGKI in vasculogenesis, which is mediated by bone marrow-derived progenitors.
Hyperhomocysteinemia has been suggested potentially to contribute to a variety of pathologies, such as Alzheimer’s disease (AD). While the impact of hyperhomocysteinemia on AD has been investigated extensively, there are scarce data on the effect of AD on hyperhomocysteinemia. The aim of this in vivo study was to investigate the kinetics of homocysteine (HCys) and homocysteic acid (HCA) and effects of AD-like pathology on the endogenous levels. The mice received a B-vitamin deficient diet for eight weeks, followed by the return to a balanced control diet for another eight weeks. Serum, urine, and brain tissues of AppNL-G-F knock-in and C57BL/6J wild type mice were analyzed for HCys and HCA using LC-MS/MS methods. Hyperhomocysteinemic levels were found in wild type and knock-in mice due to the consumption of the deficient diet for eight weeks, followed by a rapid normalization of the levels after the return to control chow. Hyperhomocysteinemic AppNL-G-F mice had significantly higher HCys in all matrices, but not HCA, compared to wild type control. Higher serum concentrations were associated with elevated levels in both the brain and in urine. Our findings confirm a significant impact of AD-like pathology on hyperhomocysteinemia in the AppNL-G-F mouse model. The immediate normalization of HCys and HCA after the supply of B-vitamins strengthens the idea of a B-vitamin intervention as a potentially preventive treatment option for HCys-related disorders such as AD.
Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (~ 90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.
Background: The epidermal growth factor receptor (EGFR) signaling pathway is genetically activated in approximately 50% of glioblastomas (GBs). Its inhibition has been explored clinically but produced disappointing results, potentially due to metabolic effects that protect GB cells against nutrient deprivation and hypoxia. Here, we hypothesized that EGFR activation could disable metabolic adaptation and define a GB cell population sensitive to starvation.
Methods: Using genetically engineered GB cells to model different types of EGFR activation, we analyzed changes in metabolism and cell survival under conditions of the tumor microenvironment.
Results: We found that expression of mutant EGFRvIII as well as EGF stimulation of EGFR-overexpressing cells impaired physiological adaptation to starvation and rendered cells sensitive to hypoxia-induced cell death. This was preceded by adenosine triphosphate (ATP) depletion and an increase in glycolysis. Furthermore, EGFRvIII mutant cells had higher levels of mitochondrial superoxides potentially due to decreased metabolic flux into the serine synthesis pathway which was associated with a decrease in the NADPH/NADP+ ratio.
Conclusions: The finding that EGFR activation renders GB cells susceptible to starvation could help to identify a subgroup of patients more likely to benefit from starvation-inducing therapies.
Die folgenden Ausführungen beleuchten anhand ausgewählter Beispiele die Art und Weise, wie Smyrna/Izmir, die Ägäis und "Kleinasien" in der deutschen Literatur dargestellt werden. Sie stehen damit zunächst im Kontext der Imagologie, die sie aber im Sinne einer kritischen interkulturellen Literaturwissenschaft erweitern. Denn es geht hier nicht (nur) darum, "Bilder" des ägäischen Raums und seiner Metropole nachzuzeichnen, sondern der Frage nachzugehen, wie die Diskurse über den fremden Ort und die fremde Region mit Fragen und Problemen des Eigenen, des Deutschen, zusammenhängen, das heißt, welche Funktion die Bilder des Fremden im Hinblick auf das Eigene haben. Die Stichproben, die ich vornehme, bezieht sich nach einem kurzen Blick auf Wielands 'Agathon' (erste Fassung 1766/67), den wichtigsten Roman der deutschen Aufklärung, zunächst vornehmlich auf Hölderlins 'Hyperion' (1797/99). Weder Wieland noch Hölderlin […] haben […] das Objekt ihrer Beschreibung niemals in Augenschein nehmen können. Insofern ist klar, dass vor allem das Bild Wieland auf Stereotypen beruht, die aber ihrerseits von einem nicht unerheblichen Interesse sind. Wie wir zeigen werden, ist Hölderlin mehr als Wieland auf eine solide Dokumentation bedacht, und er schöpft aus zeitgenössischen Reiseberichten, zumal er ja nicht wie Wieland das antike Smyrna, sondern das Smyrna/Izmir seiner Epoche darstellt. Als reizvollen Kontrast zu den Klassikern der deutschen Literatur wenden wir uns dann Feridun Zaimoglu zu, dem "Star" und enfant terrible der deutsch-türkischen Gegenwartsliteratur, der in seinem Roman 'Liebesmale scharlachrot' (2000) seinen Protagonisten Serdar von Kiel an die türkische Ägäisküste versetzt. Dabei ist sowohl beim Protagonisten als auch beim Autor die Konstellation Eigenes-Fremdes in Bezug auf die Ägäis und die Region komplex, denn für beide ist die Türkei und damit auch "Kleinasien" fremd und eigen zugleich: Sie sind nämlich in Deutschland aufgewachsen und eher mit den deutschen Verhältnissen vertraut und kommen einerseits durchaus als Fremde in das Land ihrer Vorfahren, dem sie dennoch in spezifischer Weise verbunden sind.