@article{CarstenAGorskiLietal.2011, author = {Carsten A., B{\"o}ger and Gorski, Mathias and Li, Man and Hoffmann, Michael M. and Huang, Chunmei and Yang, Qiong and Teumer, Alexander and Krane, Vera and O'Seaghdha, Conall M. and Kutalik, Zolt{\´a}n and Wichmann, H.-Erich and Haak, Thomas and Boes, Eva and Coassin, Stefan and Coresh, Josef and Kollerits, Barbara and Haun, Margot and Paulweber, Bernhard and K{\"o}ttgen, Anna and Li, Guo and Shlipak, Michael G. and Powe, Neil and Hwang, Shih-Jen and Dehghan, Abbas and Rivadeneira, Fernando and Uitterlinden, Andr{\´e} and Hofman, Albert and Beckmann, Jacques S. and Kr{\"a}mer, Bernhard K. and Witteman, Jacqueline and Bochud, Murielle and Siscovick, David and Rettig, Rainer and Kronenberg, Florian and Wanner, Christoph and Thadhani, Ravi I. and Heid, Iris M. and Fox, Caroline S. and Kao, W.H.}, title = {Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD}, series = {PLoS Genetics}, volume = {7}, journal = {PLoS Genetics}, number = {9}, doi = {10.1371/journal.pgen.1002292}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133758}, pages = {e1002292}, year = {2011}, abstract = {Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR < 60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.}, language = {en} } @article{HoppAlbertWeissenbergerMencletal.2016, author = {Hopp, Sarah and Albert-Weissenberger, Christiane and Mencl, Stine and Bieber, Michael and Schuhmann, Michael K. and Stetter, Christian and Nieswandt, Bernhard and Schmidt, Peter M. and Monoranu, Camelia-Maria and Alafuzoff, Irina and Marklund, Niklas and Nolte, Marc W. and Sir{\´e}n, Anna-Leena and Kleinschnitz, Christoph}, title = {Targeting coagulation factor XII as a novel therapeutic option in brain trauma}, series = {Annals of Neurology}, volume = {79}, journal = {Annals of Neurology}, number = {6}, doi = {10.1002/ana.24655}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-188800}, pages = {970-982}, year = {2016}, abstract = {Objective: Traumatic brain injury is a major global public health problem for which specific therapeutic interventions are lacking. There is, therefore, a pressing need to identify innovative pathomechanism-based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury. Methods: We investigated the impact of genetic deficiency of factor XII and acute inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused infestin-4 (rHA-Infestin-4) on trauma-induced microvascular thrombus formation and the subsequent outcome in 2 mouse models of traumatic brain injury. Results: Our study showed that both genetic deficiency of factor XII and an inhibition of activated factor XII in mice minimize trauma-induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human factor XII in factor XII-deficient mice fully restored injury-induced microvascular thrombus formation and brain damage. Interpretation: The robust protective effect of rHA-Infestin-4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies.}, language = {en} } @article{AlbertBerningBurschkaetal.1984, author = {Albert, Bernhard and Berning, Wilfried and Burschka, Christian and H{\"u}nig, Siegfried and Prokschy, Frank}, title = {Azobr{\"u}cken aus Azinen, IV. Intramolekulare [2 + 2]-Photocycloaddition zwischen parallelen C = C- und N = N-Bindungen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-31314}, year = {1984}, abstract = {In den starren Molek{\"u}len 1- 10 reagieren die benachbarten parallelen C = C- und N = N-Bindungen nahezu quantitativ unter Photocyclisierung lU den l,2-Diazetidinen 11-10, deren Struktur spektroskopisch und f{\"u}r 13 durch Kristallstrukturanalyse bewiesen wird. Die in Abwesenheit der C = C-Bindung beobachtete Photo-Denitrogenierung unterbleibt selbst bei den empfindlichen Derivaten des 2,3-Diazabicyclo[2.2.11heptens. Photocyclisierung von 6 mit lwei zur N=N· Bindung benachbarten C=C-Bindungen tritt nur mit der Norbornendoppelbindung ein.}, subject = {Chemie}, language = {de} } @article{AlbertBerningBurschkaetal.1981, author = {Albert, Bernhard and Berning, Wilfried and Burschka, Christian and H{\"u}nig, Siegfried and Martin, Hans-Dieter and Prokschy, Frank,}, title = {Transanulare Wechselwirkung des Azo-Chromophors inisodrinanalogen Systemen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-31328}, year = {1981}, abstract = {No abstract available}, subject = {Chemie}, language = {de} } @article{LombardiMayerSemleretal.2021, author = {Lombardi, Jolina and Mayer, Benjamin and Semler, Elisa and Anderl-Straub, Sarah and Uttner, Ingo and Kassubek, Jan and Diehl-Schmid, Janine and Danek, Adrian and Levin, Johannes and Fassbender, Klaus and Fliessbach, Klaus and Schneider, Anja and Huppertz, Hans-J{\"u}rgen and Jahn, Holger and Volk, Alexander and Kornhuber, Johannes and Landwehrmeyer, Bernhard and Lauer, Martin and Prudlo, Johannes and Wiltfang, Jens and Schroeter, Matthias L. and Ludolph, Albert and Otto, Markus}, title = {Quantifying progression in primary progressive aphasia with structural neuroimaging}, series = {Alzheimer's \& Dementia}, volume = {17}, journal = {Alzheimer's \& Dementia}, number = {10}, doi = {10.1002/alz.12323}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262605}, pages = {1595 -- 1609}, year = {2021}, abstract = {Introduction The term primary progressive aphasia (PPA) sums up the non-fluent (nfv), the semantic (sv), and the logopenic (lv) variant. Up to now, there is only limited data available concerning magnetic resonance imaging volumetry to monitor disease progression. Methods Structural brain imaging and an extensive assessment were applied at baseline and up to 4-year(s) follow-up in 269 participants. With automated atlas-based volumetry 56 brain regions were assessed. Atrophy progression served to calculate sample sizes for therapeutic trials. Results At baseline highest atrophy appeared in parts of the left frontal lobe for nfvPPA (-17\%) and of the left temporal lobe for svPPA (-34\%) and lvPPA (-24\%). Severest progression within 1-year follow-up occurred in the basal ganglia in nfvPPA (-7\%), in the hippocampus/amygdala in svPPA (-9\%), and in (medial) temporal regions in lvPPA (-6\%). Conclusion PPA presents as a left-dominant, mostly gray matter sensitive disease with considerable atrophy at baseline that proceeds variant-specific.}, language = {en} } @article{SchanbacherBieberReindersetal.2022, author = {Schanbacher, Constanze and Bieber, Michael and Reinders, Yvonne and Cherpokova, Deya and Teichert, Christina and Nieswandt, Bernhard and Sickmann, Albert and Kleinschnitz, Christoph and Langhauser, Friederike and Lorenz, Kristina}, title = {ERK1/2 activity is critical for the outcome of ischemic stroke}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {2}, issn = {1422-0067}, doi = {10.3390/ijms23020706}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-283991}, year = {2022}, abstract = {Ischemic disorders are the leading cause of death worldwide. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are thought to affect the outcome of ischemic stroke. However, it is under debate whether activation or inhibition of ERK1/2 is beneficial. In this study, we report that the ubiquitous overexpression of wild-type ERK2 in mice (ERK2\(^{wt}\)) is detrimental after transient occlusion of the middle cerebral artery (tMCAO), as it led to a massive increase in infarct volume and neurological deficits by increasing blood-brain barrier (BBB) leakiness, inflammation, and the number of apoptotic neurons. To compare ERK1/2 activation and inhibition side-by-side, we also used mice with ubiquitous overexpression of the Raf-kinase inhibitor protein (RKIP\(^{wt}\)) and its phosphorylation-deficient mutant RKIP\(^{S153A}\), known inhibitors of the ERK1/2 signaling cascade. RKIP\(^{wt}\) and RKIP\(^{S153A}\) attenuated ischemia-induced damages, in particular via anti-inflammatory signaling. Taken together, our data suggest that stimulation of the Raf/MEK/ERK1/2-cascade is severely detrimental and its inhibition is rather protective. Thus, a tight control of the ERK1/2 signaling is essential for the outcome in response to ischemic stroke.}, language = {en} } @article{BeckStegnerLorochetal.2021, author = {Beck, Sarah and Stegner, David and Loroch, Stefan and Baig, Ayesha A. and G{\"o}b, Vanessa and Schumbutzki, Cornelia and Eilers, Eva and Sickmann, Albert and May, Frauke and Nolte, Marc W. and Panousis, Con and Nieswandt, Bernhard}, title = {Generation of a humanized FXII knock-in mouse-A powerful model system to test novel anti-thrombotic agents}, series = {Journal of Thrombosis and Haemostasis}, volume = {19}, journal = {Journal of Thrombosis and Haemostasis}, number = {11}, doi = {10.1111/jth.15488}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259567}, pages = {2835-2840}, year = {2021}, abstract = {Background Effective inhibition of thrombosis without generating bleeding risks is a major challenge in medicine. Accumulating evidence suggests that this can be achieved by inhibition of coagulation factor XII (FXII), as either its knock-out or inhibition in animal models efficiently reduced thrombosis without affecting normal hemostasis. Based on these findings, highly specific inhibitors for human FXII(a) are under development. However, currently, in vivo studies on their efficacy and safety are impeded by the lack of an optimized animal model expressing the specific target, that is, human FXII. Objective The primary objective of this study is to develop and functionally characterize a humanized FXII mouse model. Methods A humanized FXII mouse model was generated by replacing the murine with the human F12 gene (genetic knock-in) and tested it in in vitro coagulation assays and in in vivo thrombosis models. Results These hF12\(^{KI}\) mice were indistinguishable from wild-type mice in all tested assays of coagulation and platelet function in vitro and in vivo, except for reduced expression levels of hFXII compared to human plasma. Targeting FXII by the anti-human FXIIa antibody 3F7 increased activated partial thromboplastin time dose-dependently and protected hF12\(^{KI}\) mice in an arterial thrombosis model without affecting bleeding times. Conclusion These data establish the newly generated hF12\(^{KI}\) mouse as a powerful and unique model system for in vivo studies on anti-FXII(a) biologics, supporting the development of efficient and safe human FXII(a) inhibitors.}, language = {en} } @article{SemlerAnderlStraubUttneretal.2018, author = {Semler, Elisa and Anderl-Straub, Sarah and Uttner, Ingo and Diehl-Schmid, Janine and Danek, Adrian and Einsiedler, Beate and Fassbender, Klaus and Fliessbach, Klaus and Huppertz, Hans-J{\"u}rgen and Jahn, Holger and Kornhuber, Johannes and Landwehrmeyer, Bernhard and Lauer, Martin and Muche, Rainer and Prudlo, Johannes and Schneider, Anja and Schroeter, Matthias L. and Ludolph, Albert C. and Otto, Markus}, title = {A language-based sum score for the course and therapeutic intervention in primary progressive aphasia}, series = {Alzheimer's Research \& Therapy}, volume = {10}, journal = {Alzheimer's Research \& Therapy}, organization = {FLTD consortium}, doi = {10.1186/s13195-018-0345-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236277}, year = {2018}, abstract = {Background With upcoming therapeutic interventions for patients with primary progressive aphasia (PPA), instruments for the follow-up of patients are needed to describe disease progression and to evaluate potential therapeutic effects. So far, volumetric brain changes have been proposed as clinical endpoints in the literature, but cognitive scores are still lacking. This study followed disease progression predominantly in language-based performance within 1 year and defined a PPA sum score which can be used in therapeutic interventions. Methods We assessed 28 patients with nonfluent variant PPA, 17 with semantic variant PPA, 13 with logopenic variant PPA, and 28 healthy controls in detail for 1 year. The most informative neuropsychological assessments were combined to a sum score, and associations between brain atrophy were investigated followed by a sample size calculation for clinical trials. Results Significant absolute changes up to 20\% in cognitive tests were found after 1 year. Semantic and phonemic word fluency, Boston Naming Test, Digit Span, Token Test, AAT Written language, and Cookie Test were identified as the best markers for disease progression. These tasks provide the basis of a new PPA sum score. Assuming a therapeutic effect of 50\% reduction in cognitive decline for sample size calculations, a number of 56 cases is needed to find a significant treatment effect. Correlations between cognitive decline and atrophy showed a correlation up to r = 0.7 between the sum score and frontal structures, namely the superior and inferior frontal gyrus, as well as with left-sided subcortical structures. Conclusion Our findings support the high performance of the proposed sum score in the follow-up of PPA and recommend it as an outcome measure in intervention studies.}, language = {en} }