1-20 von 3274 Publikationen

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      TFClass: expanding the classification of human transcription factors to their mammalian orthologs 

      Wingender, Edgar; Schoeps, Torsten; Haubrock, Martin; Krull, Mathias; Dönitz, Jürgen
      Nucleic Acids Research 2018; 46(D1) p.D343-D347
      TFClass is a resource that classifies eukaryotic transcription factors (TFs) according to their DNA-binding domains (DBDs), available online at http://tfclass.bioinf.med.uni-goettingen.de. The classification scheme of TFClass was originally derived for human TFs and is expanded here to the whole taxonomic class of mammalia. Combining information from different resources, checking manually the retrieved mammalian TFs sequences and applying extensive phylogenetic analyses, >39 000 TFs from up to 41 mammalian species were assigned to the Superclasses, Classes, Families and Subfamilies of TFClass. As a result, TFClass now provides the corresponding sequence collection in FASTA format, sequence logos and phylogenetic trees at different classification levels, predicted TF binding sites for human, mouse, dog and cow genomes as well as links to several external databases. In particular, all those TFs that are also documented in the TRANSFAC® database (FACTOR table) have been linked and can be freely accessed. TRANSFAC® FACTOR can also be queried through an own search interface.
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      Predictors of mortality and ICD shock therapy in primary prophylactic ICD patients-A systematic review and meta-analysis 

      Bergau, Leonard; Tichelbäcker, Tobias; Kessel, Barbora; Lüthje, Lars; Fischer, Thomas H.; Friede, Tim; Zabel, Markus
      PloS one 2017; 12(10): Art. e0186387
      BACKGROUND: There is evidence that the benefit of a primary prophylactic ICD therapy is not equal in all patients. PURPOSE: To evaluate risk factors of appropriate shocks and all- cause mortality in patients with a primary prophylactic ICD regarding contemporary studies. DATA SOURCE: PubMed, LIVIVO, Cochrane CENTRAL between 2010 and 2016. STUDY SELECTION: Studies were eligible if at least one of the endpoints of interest were reported. DATA EXTRACTION: All abstracts were independently reviewed by at least two authors. The full text of all selected studies was then analysed in detail. DATA SYNTHESIS: Our search strategy retrieved 608 abstracts. After exclusion of unsuitable studies, 36 papers with a total patient number of 47282 were included in our analysis. All-cause mortality was significantly associated with increasing age (HR 1.41, CI 1.29-1.53), left ventricular function (LVEF; HR 1.21, CI 1.14-1.29), ischemic cardiomyopathy (ICM; HR 1.37, CI 1.14-1.66) and co-morbidities such as impaired renal function (HR 2.30, CI 1.97-2.69). Although, younger age (HR 0.96, CI 0.85-1.09), impaired LVEF (HR 1.26, CI 0.89-1.78) and ischemic cardiomyopathy (HR 2.22, CI 0.83-5.93) were associated with a higher risk of appropriate shocks, none of these factors reached statistical significance. LIMITATIONS: Individual patient data were not available for most studies. CONCLUSION: In this meta-analysis of contemporary clinical studies, all-cause mortality is predicted by a variety of clinical characteristics including LVEF. On the other hand, the risk of appropriate shocks might be associated with impaired LVEF and ischemic cardiomyopathy. Further prospective studies are required to verify risk factors for appropriate shocks other than LVEF to help select appropriate patients for primary prophylactic ICD-therapy.
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      Magnetically Controlled Devices Parallel to the Spine in Children with Spinal Muscular Atrophy 

      Lorenz, Heiko M.; Badwan, Batoul; Hecker, Marina M.; Tsaknakis, Konstantinos; Groenefeld, Katharina; Braunschweig, Lena; Hell, Anna K.
      JBJS Open Access 2017; 2(4): Art. e0036
      Background: Children with severe spinal deformity frequently are managed with growth-friendly implants. After initial surgery, externally controlled magnetic rods allow spinal deformity correction during growth without further surgical intervention. The ability to lengthen the spine without additional surgical procedures is especially beneficial in high-risk children, such as those with spinal muscular atrophy (SMA). The purpose of the present study was to assess the level of control of spinal deformity in a homogeneous group of patients with SMA who were managed with magnetically controlled implants for 2 years. Methods: This prospective, nonrandomized study included 21 non-ambulatory children with type-II SMA and progressive scoliosis who were managed bilaterally with a magnetically controlled implant that was inserted parallel to the spine with use of rib-to-pelvis hook fixation. Radiographic measurements of scoliotic curves, kyphosis, lordosis, pelvic obliquity, and spinal length were performed before and after implantation of the magnetically controlled device and during external lengthening. The mean duration of follow-up was 2 years. Results: The mean main curve of patients without prior vertical expandable prosthetic titanium rib (VEPTR) treatment decreased from 70° before implantation of the magnetically controlled device to 30° after implantation of the device. Correction was maintained during the follow-up period, with a mean curve of 31° at the time of the latest follow-up at 2.2 years. Pelvic obliquity was surgically corrected by 76% (from 17° to 4°) and remained stable during follow-up. Thoracic kyphosis could not be corrected within the follow-up period. Spinal length of children without prior spinal surgery increased by >50 mm immediately after device implantation and steadily increased at a rate of 13.5 mm/yr over the course of treatment. During treatment, 4 general complications occurred and 6 lengthening procedures failed, with 3 patients requiring surgical revision. Conclusions: Bilateral implantation of an externally controlled magnetic rod with rib-to-pelvis fixation represents a safe and efficient method to control spinal deformity in children with SMA, achieving sufficient and stable curve correction as well as increased spinal length. The complication rate was lower than those that have been described for VEPTR and other growing rod instrumentation strategies. Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
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      YKL-40 in the brain and cerebrospinal fluid of neurodegenerative dementias 

      Llorens, Franc; Thüne, Katrin; Tahir, Waqas; Kanata, Eirini; Diaz-Lucena, Daniela; Xanthopoulos, Konstantinos; Kovatsi, Eleni; Pleschka, Catharina; Garcia-Esparcia, Paula; Schmitz, Matthias; et al.
      Ozbay, DuruCorreia, SusanaCorreia, ÂngelaMilosevic, IraAndréoletti, OlivierFernández-Borges, NataliaVorberg, Ina M.Glatzel, MarkusSklaviadis, TheodorosTorres, Juan MariaKrasemann, SusanneSánchez-Valle, RaquelFerrer, IsidroZerr, Inga
      Molecular Neurodegeneration 2017; 12(1): Art. 83
      Background YKL-40 (also known as Chitinase 3-like 1) is a glycoprotein produced by inflammatory, cancer and stem cells. Its physiological role is not completely understood but YKL-40 is elevated in the brain and cerebrospinal fluid (CSF) in several neurological and neurodegenerative diseases associated with inflammatory processes. Yet the precise characterization of YKL-40 in dementia cases is missing. Methods In the present study, we comparatively analysed YKL-40 levels in the brain and CSF samples from neurodegenerative dementias of different aetiologies characterized by the presence of cortical pathology and disease-specific neuroinflammatory signatures. Results YKL-40 was normally expressed in fibrillar astrocytes in the white matter. Additionally YKL-40 was highly and widely expressed in reactive protoplasmic cortical and perivascular astrocytes, and fibrillar astrocytes in sporadic Creutzfeldt-Jakob disease (sCJD). Elevated YKL-40 levels were also detected in Alzheimer’s disease (AD) but not in dementia with Lewy bodies (DLB). In AD, YKL-40-positive astrocytes were commonly found in clusters, often around β-amyloid plaques, and surrounding vessels with β-amyloid angiopathy; they were also distributed randomly in the cerebral cortex and white matter. YKL-40 overexpression appeared as a pre-clinical event as demonstrated in experimental models of prion diseases and AD pathology. CSF YKL-40 levels were measured in a cohort of 288 individuals, including neurological controls (NC) and patients diagnosed with different types of dementia. Compared to NC, increased YKL-40 levels were detected in sCJD (p < 0.001, AUC = 0.92) and AD (p < 0.001, AUC = 0.77) but not in vascular dementia (VaD) (p > 0.05, AUC = 0.71) or in DLB/Parkinson’s disease dementia (PDD) (p > 0.05, AUC = 0.70). Further, two independent patient cohorts were used to validate the increased CSF YKL-40 levels in sCJD. Additionally, increased YKL-40 levels were found in genetic prion diseases associated with the PRNP-D178N (Fatal Familial Insomnia) and PRNP-E200K mutations. Conclusions Our results unequivocally demonstrate that in neurodegenerative dementias, YKL-40 is a disease-specific marker of neuroinflammation showing its highest levels in prion diseases. Therefore, YKL-40 quantification might have a potential for application in the evaluation of therapeutic intervention in dementias with a neuroinflammatory component.
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      Magnetically Controlled Devices Parallel to the Spine in Children with Spinal Muscular Atrophy 

      Lorenz, Heiko M.; Badwan, Batoul; Hecker, Marina M.; Tsaknakis, Konstantinos; Groenefeld, Katharina; Braunschweig, Lena; Hell, Anna K.
      JBJS Open Access 2017; 2(4): Art. e0036
      Background: Children with severe spinal deformity frequently are managed with growth-friendly implants. After initial surgery, externally controlled magnetic rods allow spinal deformity correction during growth without further surgical intervention. The ability to lengthen the spine without additional surgical procedures is especially beneficial in high-risk children, such as those with spinal muscular atrophy (SMA). The purpose of the present study was to assess the level of control of spinal deformity in a homogeneous group of patients with SMA who were managed with magnetically controlled implants for 2 years. Methods: This prospective, nonrandomized study included 21 non-ambulatory children with type-II SMA and progressive scoliosis who were managed bilaterally with a magnetically controlled implant that was inserted parallel to the spine with use of rib-to-pelvis hook fixation. Radiographic measurements of scoliotic curves, kyphosis, lordosis, pelvic obliquity, and spinal length were performed before and after implantation of the magnetically controlled device and during external lengthening. The mean duration of follow-up was 2 years. Results: The mean main curve of patients without prior vertical expandable prosthetic titanium rib (VEPTR) treatment decreased from 70° before implantation of the magnetically controlled device to 30° after implantation of the device. Correction was maintained during the follow-up period, with a mean curve of 31° at the time of the latest follow-up at 2.2 years. Pelvic obliquity was surgically corrected by 76% (from 17° to 4°) and remained stable during follow-up. Thoracic kyphosis could not be corrected within the follow-up period. Spinal length of children without prior spinal surgery increased by >50 mm immediately after device implantation and steadily increased at a rate of 13.5 mm/yr over the course of treatment. During treatment, 4 general complications occurred and 6 lengthening procedures failed, with 3 patients requiring surgical revision. Conclusions: Bilateral implantation of an externally controlled magnetic rod with rib-to-pelvis fixation represents a safe and efficient method to control spinal deformity in children with SMA, achieving sufficient and stable curve correction as well as increased spinal length. The complication rate was lower than those that have been described for VEPTR and other growing rod instrumentation strategies. Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
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      RNF40 regulates gene expression in an epigenetic context-dependent manner 

      Xie, Wanhua; Nagarajan, Sankari; Baumgart, Simon J.; Kosinsky, Robyn Laura; Najafova, Zeynab; Kari, Vijayalakshmi; Hennion, Magali; Indenbirken, Daniela; Bonn, Stefan; Grundhoff, Adam; et al.
      Wegwitz, FlorianMansouri, AhmedJohnsen, Steven A.
      Genome Biology 2017; 18(1): Art. 32
      Background: Monoubiquitination of H2B (H2Bub1) is a largely enigmatic histone modification that has been linked to transcriptional elongation. Because of this association, it has been commonly assumed that H2Bub1 is an exclusively positively acting histone modification and that increased H2Bub1 occupancy correlates with increased gene expression. In contrast, depletion of the H2B ubiquitin ligases RNF20 or RNF40 alters the expression of only a subset of genes. Results: Using conditional Rnf40 knockout mouse embryo fibroblasts, we show that genes occupied by low to moderate amounts of H2Bub1 are selectively regulated in response to Rnf40 deletion, whereas genes marked by high levels of H2Bub1 are mostly unaffected by Rnf40 loss. Furthermore, we find that decreased expression of RNF40-dependent genes is highly associated with widespread narrowing of H3K4me3 peaks. H2Bub1 promotes the broadening of H3K4me3 to increase transcriptional elongation, which together lead to increased tissue-specific gene transcription. Notably, genes upregulated following Rnf40 deletion, including Foxl2, are enriched for H3K27me3, which is decreased following Rnf40 deletion due to decreased expression of the Ezh2 gene. As a consequence, increased expression of some RNF40-“suppressed” genes is associated with enhancer activation via FOXL2. Conclusion: Together these findings reveal the complexity and context-dependency whereby one histone modification can have divergent effects on gene transcription. Furthermore, we show that these effects are dependent upon the activity of other epigenetic regulatory proteins and histone modifications.
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      TORC1-mediated sensing of chaperone activity alters glucose metabolism and extends lifespan. 

      Perić, Matea; Lovrić, Anita; Šarić, Ana; Musa, Marina; Bou Dib, Peter; Rudan, Marina; Nikolić, Andrea; Sobočanec, Sandra; Mikecin, Ana-Matea; Dennerlein, Sven; et al.
      Milošević, IraVlahoviček, KristianRaimundo, NunoKriško, Anita
      Aging Cell 2017; 16(5) p.994-1005
      Protein quality control mechanisms, required for normal cellular functioning, encompass multiple functions related to protein production and maintenance. However, the existence of communication between proteostasis and metabolic networks and its underlying mechanisms remain elusive. Here, we report that enhanced chaperone activity and consequent improved proteostasis are sensed by TORC1 via the activity of Hsp82. Chaperone enrichment decreases the level of Hsp82, which deactivates TORC1 and leads to activation of Snf1/AMPK, regardless of glucose availability. This mechanism culminates in the extension of yeast replicative lifespan (RLS) that is fully reliant on both TORC1 deactivation and Snf1/AMPK activation. Specifically, we identify oxygen consumption increase as the downstream effect of Snf1 activation responsible for the entire RLS extension. Our results set a novel paradigm for the role of proteostasis in aging: modulation of the misfolded protein level can affect cellular metabolic features as well as mitochondrial activity and consequently modify lifespan. The described mechanism is expected to open new avenues for research of aging and age-related diseases.
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      Polygenic risk has an impact on the structural plasticity of hippocampal subfields during aerobic exercise combined with cognitive remediation in multi-episode schizophrenia. 

      Papiol, S; Popovic, D.; Keeser, D.; Hasan, A.; Schneider-Axmann, T.; Degenhardt, F.; Rossner, M. J.; Bickeböller, H.; Schmitt, A.; Falkai, P.; et al.
      Malchow, B.
      Translational psychiatry 2017-06-27; 7(6): Art. e1159
      Preliminary studies suggest that, besides improving cognition, aerobic exercise might increase hippocampal volume in schizophrenia patients; however, results are not consistent. Individual mechanisms of volume changes are unknown but might be connected to the load of risk genes. Genome-wide association studies have uncovered the polygenic architecture of schizophrenia. The secondary analysis presented here aimed to determine the modulatory role of schizophrenia polygenic risk scores (PRSs) on volume changes in the total hippocampus and cornu ammonis (CA) 1, CA2/3, CA4/dentate gyrus (DG) and subiculum over time. We studied 20 multi-episode schizophrenia patients and 23 healthy controls who performed aerobic exercise (endurance training) combined with cognitive remediation for 3 months and 21 multi-episode schizophrenia patients allocated to a control intervention (table soccer) combined with cognitive remediation. Magnetic resonance imaging-based assessments were performed at baseline and after 3 months with FreeSurfer. No effects of PRSs were found on total hippocampal volume change. Subfield analyses showed that the volume changes between baseline and 3 months in the left CA4/DG were significantly influenced by PRSs in schizophrenia patients performing aerobic exercise. A larger genetic risk burden was associated with a less pronounced volume increase or a decrease in volume over the course of the exercise intervention. Results of exploratory enrichment analyses reinforced the notion of genetic risk factors modulating biological processes tightly related to synaptic ion channel activity, calcium signaling, glutamate signaling and regulation of cell morphogenesis. We hypothesize that a high polygenic risk may negatively influence neuroplasticity in CA4/DG during aerobic exercise in schizophrenia.
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      Protection of Mice from Acute Graft-versus-Host Disease Requires CD28 Co-stimulation on Donor CD4+ Foxp3+ Regulatory T Cells. 

      Uri, Anna; Werner, Sandra; Lühder, Fred; Hünig, Thomas; Kerkau, Thomas; Beyersdorf, Niklas
      Frontiers in immunology 2017; 8: Art. 721
      Acute graft-versus-host disease (aGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell plus T cell transplantation (allo-HSCT). In this study, we investigated the requirement for CD28 co-stimulation of donor CD4+ conventional (CD4+CD25-Foxp3-, Tconv) and regulatory (CD4+CD25+Foxp3+, Treg) T cells in aGvHD using tamoxifen-inducible CD28 knockout (iCD28KO) or wild-type (wt) littermates as donors of CD4+ Tconv and Treg. In the highly inflammatory C57BL/6 into BALB/c allo-HSCT transplantation model, CD28 depletion on donor CD4+ Tconv reduced clinical signs of aGvHD, but did not significantly prolong survival of the recipient mice. Selective depletion of CD28 on donor Treg did not abrogate protection of recipient mice from aGvHD until about day 20 after allo-HSCT. Later, however, the pool of CD28-depleted Treg drastically declined as compared to wt Treg. Consequently, only wt, but not CD28-deficient, Treg were able to continuously suppress aGvHD and induce long-term survival of the recipient mice. To our knowledge, this is the first study that specifically evaluates the impact of CD28 expression on donor Treg in aGvHD. Moreover, the delayed kinetics of aGvHD lethality after transplantation of iCD28KO Treg provides a novel animal model for similar disease courses found in patients after allo-HSCT.
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      Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia. 

      Witt, S. H.; Streit, F.; Jungkunz, M.; Frank, J.; Awasthi, S.; Reinbold, C. S.; Treutlein, J.; Degenhardt, F.; Forstner, A. J.; Heilmann-Heimbach, S.; et al.
      Dietl, L.Schwarze, C. E.Schendel, D.Strohmaier, J.Abdellaoui, A.Adolfsson, R.Air, T. M.Akil, H.Alda, M.Alliey-Rodriguez, N.Andreassen, O. A.Babadjanova, G.Bass, N. J.Bauer, M.Baune, B. T.Bellivier, F.Bergen, S.Bethell, A.Biernacka, J. M.Blackwood, D. H. R.Boks, M. P.Boomsma, D. I.Børglum, A. D.Borrmann-Hassenbach, M.Brennan, P.Budde, M.Buttenschøn, H. N.Byrne, E. M.Cervantes, P.Clarke, T.-K.Craddock, N.Cruceanu, C.Curtis, D.Czerski, P. M.Dannlowski, U.Davis, T.de Geus, E. J. C.Di Florio, A.Djurovic, S.Domenici, E.Edenberg, H. J.Etain, B.Fischer, S. B.Forty, L.Fraser, C.Frye, M. A.Fullerton, J. M.Gade, K.Gershon, E. S.Giegling, I.Gordon, S. D.Gordon-Smith, K.Grabe, H. J.Green, E. K.Greenwood, T. A.Grigoroiu-Serbanescu, M.Guzman-Parra, J.Hall, L. S.Hamshere, M.Hauser, J.Hautzinger, M.Heilbronner, U.Herms, S.Hitturlingappa, S.Hoffmann, P.Holmans, P.Hottenga, J.-J.Jamain, S.Jones, I.Jones, L. A.Juréus, A.Kahn, R .S.Kammerer-Ciernioch, J.Kirov, G.Kittel-Schneider, S.Kloiber, S.Knott, S. V.Kogevinas, M.Landén, M.Leber, M.Leboyer, M.Li, Q. S.Lissowska, J.Lucae, S.Martin, N. G.Mayoral-Cleries, F.McElroy, S. L.McIntosh, A. M.McKay, J. D.McQuillin, A.Medland, S. E.Middeldorp, C. M.Milaneschi, Y.Mitchell, P. B.Montgomery, G. W.Morken, G.Mors, O.Mühleisen, T. W.Müller-Myhsok, B.Myers, R. M.Nievergelt, C. M.Nurnberger, J. I.O'Donovan, M. C.Loohuis, L. M. O.Ophoff, R.Oruc, L.Owen, M. J.Paciga, S. A.Penninx, B. W. J. H.Perry, A.Pfennig, A.Potash, J. B.Preisig, M.Reif, A.Rivas, F.Rouleau, G. A.Schofield, P. R.Schulze, T. G.Schwarz, M.Scott, L.Sinnamon, G. C. B.Stahl, E. A.Strauss, J.Turecki, G.Van der Auwera, S.Vedder, H.Vincent, J. B.Willemsen, G.Witt, C. C.Wray, N. R.Xi, H. S.Tadic, A.Dahmen, N.Schott, B. H.Cichon, S.Nöthen, M. M.Ripke, S.Mobascher, A.Rujescu, D.Lieb, K.Roepke, S.Schmahl, C.Bohus, M.Rietschel, M.
      Translational psychiatry 2017-06-20; 7(6): Art. e1155
      Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10-7) and PKP4 (P=8.67 × 10-7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10-3]), SCZ (rg=0.34 [P=4.37 × 10-5]) and MDD (rg=0.57 [P=1.04 × 10-3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.
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      Types and Strains: Their Essential Role in Understanding Protein Aggregation in Neurodegenerative Diseases. 

      Wemheuer, Wiebke M.; Wrede, Arne; Schulz-Schaeffer, Walter J.
      Frontiers in aging neuroscience 2017; 9: Art. 187
      Protein misfolding and aggregation is a key event in diseases like Alzheimer's disease (AD) or Parkinson's disease (PD) and is associated with neurodegeneration. Factors that initiate protein misfolding and the role of protein aggregation in the pathophysiology of disease pose major challenges to the neuroscientific community. Interestingly, although the accumulation of the same misfolded protein, e.g., α-synuclein is detectable in all idiopathic PD patients, the disease spectrum covers a variety of different clinical presentations and disease courses. In a more recent attempt this clinical variance is being explained in analogy to prion diseases by different protein aggregate conformations. In prion diseases a relationship between protein aggregate conformation properties and the clinical disease course was shown by relating different prion types to a dementia and an ataxic disease course in Creutzfeldt-Jakob patients. This principle is currently transferred to AD, PD and other neurodegenerative diseases with protein aggregation. However, differences in protein aggregate conformation are frequently addressed as disease strains. The term "strain" also derives from prion research and evolved by adopting the virus terminology at a time when transmissible spongiform encephalopathies (TSEs; later called prion diseases) were assumed to be caused by a virus. The problem is that in virus taxonomy the term "type" refers to properties of the disease agent itself and the term "strain" refers to host associated factors that interact with the disease agent and may moderately modify the clinical disease presentation. Strain factors can be discovered only after transmission and passaging of the agent in a host of a different species. The incorrect use of the terminology confuses disease agent and host factors and hampers the understanding of the pathophysiology of protein aggregate-associated neurodegenerative diseases. In this review article the discoveries are reviewed that explain how the terms "type" and "strain" emerged for unconventional disease agents. This may help to avoid confusion in the terminology of protein aggregation diseases and to reflect correctly the impact of protein aggregate conformation as well as host factor contribution on different clinical variations of AD, PD and other neurodegenerative diseases.
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      Rab Interacting Molecules 2 and 3 Directly Interact with the Pore-Forming CaV1.3 Ca2+ Channel Subunit and Promote Its Membrane Expression. 

      Picher, Maria M; Oprişoreanu, Ana-Maria; Jung, SangYong; Michel, Katrin; Schoch, Susanne; Moser, Tobias
      Frontiers in cellular neuroscience 2017; 11: Art. 160
      Rab interacting molecules (RIMs) are multi-domain proteins that positively regulate the number of Ca2+ channels at the presynaptic active zone (AZ). Several molecular mechanisms have been demonstrated for RIM-binding to components of the presynaptic Ca2+ channel complex, the key signaling element at the AZ. Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). Co-expressing full-length RIM2α with a Ca2+ channel complex closely resembling that of IHCs (CaV1.3α1-CaVß2a) in HEK293 cells doubled the Ca2+-current and shifted the voltage-dependence of Ca2+ channel activation by approximately +3 mV. Co-expression of the short RIM isoform RIM3γ increased the CaV1.3α1-CaVß2a-mediated Ca2+-influx in HEK293 cells, but disruption of RIM3γ in mice left Ca2+-influx in IHCs and hearing intact. In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells.
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      Immune and myodegenerative pathomechanisms in inclusion body myositis. 

      Keller, Christian W.; Schmidt, Jens; Lünemann, Jan D.
      Annals of clinical and translational neurology 2017-06; 4(6) p.422-445
      Inclusion Body Myositis (IBM) is a relatively common acquired inflammatory myopathy in patients above 50 years of age. Pathological hallmarks of IBM are intramyofiber protein inclusions and endomysial inflammation, indicating that both myodegenerative and inflammatory mechanisms contribute to its pathogenesis. Impaired protein degradation by the autophagic machinery, which regulates innate and adaptive immune responses, in skeletal muscle fibers has recently been identified as a potential key pathomechanism in IBM. Immunotherapies, which are successfully used for treating other inflammatory myopathies lack efficacy in IBM and so far no effective treatment is available. Thus, a better understanding of the mechanistic pathways underlying progressive muscle weakness and atrophy in IBM is crucial in identifying novel promising targets for therapeutic intervention. Here, we discuss recent insights into the pathomechanistic network of mutually dependent inflammatory and degenerative events during IBM.
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      Hepatic gene therapy rescues high-fat diet responses in circadian Clock mutant mice. 

      Meyer-Kovac, Judit; Kolbe, Isa; Ehrhardt, Lea; Leliavski, Alexei; Husse, Jana; Salinas, Gabriela; Lingner, Thomas; Tsang, Anthony H.; Barclay, Johanna L.; Oster, Henrik
      Molecular metabolism 2017-06; 6(6) p.512-523
      OBJECTIVE: Circadian Clock gene mutant mice show dampened 24-h feeding rhythms and an increased sensitivity to high-fat diet (HFD) feeding. Restricting HFD access to the dark phase counteracts its obesogenic effect in wild-type mice. The extent to which altered feeding rhythms are causative for the obesogenic phenotype of Clock mutant mice, however, remains unknown. METHODS: Metabolic parameters of wild-type (WT) and ClockΔ19 mutant mice (MT) were investigated under ad libitum and nighttime restricted HFD feeding. Liver circadian clock function was partially rescued by hydrodynamic tail vein delivery of WT-Clock DNA vectors in mutant mice and transcriptional, metabolic, endocrine and behavioral rhythms studied. RESULTS: Nighttime-restricted feeding restored food intake, but not body weight regulation in MT mice under HFD, suggesting Clock-dependent metabolic dysregulation downstream of circadian appetite control. Liver-directed Clock gene therapy partially restored liver circadian oscillator function and transcriptome regulation without affecting centrally controlled circadian behaviors. Under HFD, MT mice with partially restored liver clock function (MT-LR) showed normalized body weight gain, rescued 24-h food intake rhythms, and WT-like energy expenditure. This was associated with decreased nighttime leptin and daytime ghrelin levels, reduced hepatic lipid accumulation, and improved glucose tolerance. Transcriptome analysis revealed that hepatic Clock rescue in MT mice affected a range of metabolic pathways. CONCLUSION: Liver Clock gene therapy improves resistance against HFD-induced metabolic impairments in mice with circadian clock disruption. Restoring or stabilizing liver clock function might be a promising target for therapeutic interventions in obesity and metabolic disorders.
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      Condensed versus standard schedule of high-dose cytarabine consolidation therapy with pegfilgrastim growth factor support in acute myeloid leukemia. 

      Jaramillo, S.; Benner, A.; Krauter, J.; Martin, H.; Kindler, T.; Bentz, M.; Salih, H. R.; Held, G.; Köhne, C.-H.; Götze, K.; et al.
      Lübbert, M.Kündgen, A.Brossart, P.Wattad, M.Salwender, H.Hertenstein, B.Nachbaur, D.Wulf, G.Horst, H.-A.Kirchen, H.Fiedler, W.Raghavachar, A.Russ, G.Kremers, S.Koller, E.Runde, V.Heil, G.Weber, D.Göhring, G.Döhner, K.Ganser, A.Döhner, H.Schlenk, R. F.
      Blood cancer journal 2017-05-26; 7(5): Art. e564
      The aim of this cohort study was to compare a condensed schedule of consolidation therapy with high-dose cytarabine on days 1, 2 and 3 (HDAC-123) with the HDAC schedule given on days 1, 3 and 5 (HDAC-135) as well as to evaluate the prophylactic use of pegfilgrastim after chemotherapy in younger patients with acute myeloid leukemia in first complete remission. One hundred and seventy-six patients were treated with HDAC-135 and 392 patients with HDAC-123 with prophylactic pegfilgrastim at days 10 and 8, respectively, in the AMLSG 07-04 and the German AML Intergroup protocol. Time from start to chemotherapy until hematologic recovery with white blood cells >1.0 G/l and neutrophils >0.5 G/l was in median 4 days shorter in patients receiving HDAC-123 compared with HDAC-135 (P<0.0001, each), and further reduced by 2 days (P<0.0001) by pegfilgrastim. Rates of infections were reduced by HDAC-123 (P<0.0001) and pegfilgrastim (P=0.002). Days in hospital and platelet transfusions were significantly reduced by HDAC-123 compared with HDAC-135. Survival was neither affected by HDAC-123 versus HDAC-135 nor by pegfilgrastim. In conclusion, consolidation therapy with HDAC-123 leads to faster hematologic recovery and less infections, platelet transfusions as well as days in hospital without affecting survival.
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      Primary Progressive Multiple Sclerosis: Putting Together the Puzzle. 

      Abdelhak, Ahmed; Weber, Martin S.; Tumani, Hayrettin
      Frontiers in neurology 2017; 8: Art. 234
      The focus of multiple sclerosis research has recently turned to the relatively rare and clearly more challenging condition of primary progressive multiple sclerosis (PPMS). Many risk factors such as genetic susceptibility, age, and Epstein-Barr virus (EBV) infection may interdepend on various levels, causing a complex pathophysiological cascade. Variable pathological mechanisms drive disease progression, including inflammation-associated axonal loss, continuous activation of central nervous system resident cells, such as astrocytes and microglia as well as mitochondrial dysfunction and iron accumulation. Histological studies revealed diffuse infiltration of the gray and white matter as well as of the meninges with inflammatory cells such as B-, T-, natural killer, and plasma cells. While numerous anti-inflammatory agents effective in relapsing remitting multiple sclerosis basically failed in treatment of PPMS, the B-cell-depleting monoclonal antibody ocrelizumab recently broke the dogma that PPMS cannot be treated by an anti-inflammatory approach by demonstrating efficacy in a phase 3 PPMS trial. Other treatments aiming at enhancing remyelination (MD1003) as well as EBV-directed treatment strategies may be promising agents on the horizon. In this article, we aim to summarize new advances in the understanding of risk factors, pathophysiology, and treatment of PPMS. Moreover, we introduce a novel concept to understand the nature of the disease and possible treatment strategies in the near future.
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      Experimental Porcine Toxoplasma gondii Infection as a Representative Model for Human Toxoplasmosis. 

      Nau, Julia; Eller, Silvia Kathrin; Wenning, Johannes; Spekker-Bosker, Katrin Henrike; Schroten, Horst; Schwerk, Christian; Hotop, Andrea; Groß, Uwe; Däubener, Walter
      Mediators of inflammation 2017; 2017: Art. 3260289
      Porcine infections are currently not the state-of-the-art model to study human diseases. Nevertheless, the course of human and porcine toxoplasmosis is much more comparable than that of human and murine toxoplasmosis. For example, severity of infection, transplacental transmission, and interferon-gamma-induced antiparasitic effector mechanisms are similar in pigs and humans. In addition, the severe immunosuppression during acute infection described in mice does not occur in the experimentally infected ones. Thus, we hypothesise that porcine Toxoplasma gondii infection data are more representative for human toxoplasmosis. We therefore suggest that the animal model chosen must be critically evaluated for its assignability to human diseases.
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      The ribosome biogenesis factor yUtp23/hUTP23 coordinates key interactions in the yeast and human pre-40S particle and hUTP23 contains an essential PIN domain. 

      Wells, Graeme R.; Weichmann, Franziska; Sloan, Katherine E.; Colvin, David; Watkins, Nicholas J.; Schneider, Claudia
      Nucleic acids research 2017-05-05; 45(8) p.4796-4809
      Two proteins with PIN endonuclease domains, yUtp24(Fcf1)/hUTP24 and yUtp23/hUTP23 are essential for early pre-ribosomal (r)RNA cleavages at sites A0, A1/1 and A2/2a in yeast and humans. The yUtp24/hUTP24 PIN endonuclease is proposed to cleave at sites A1/1 and A2/2a, but the enzyme cleaving at site A0 is not known. Yeast yUtp23 contains a degenerate, non-essential PIN domain and functions together with the snR30 snoRNA, while human hUTP23 is associated with U17, the human snR30 counterpart. Using in vivo RNA-protein crosslinking and gel shift experiments, we reveal that yUtp23/hUTP23 makes direct contacts with expansion sequence 6 (ES6) in the 18S rRNA sequence and that yUtp23 interacts with the 3΄ half of the snR30 snoRNA. Protein-protein interaction studies further demonstrated that yeast yUtp23 and human hUTP23 directly interact with the H/ACA snoRNP protein yNhp2/hNHP2, the RNA helicase yRok1/hROK1(DDX52), the ribosome biogenesis factor yRrp7/hRRP7 and yUtp24/hUTP24. yUtp23/hUTP23 could therefore be central to the coordinated integration and release of ES6 binding factors and likely plays a pivotal role in remodeling this pre-rRNA region in both yeast and humans. Finally, studies using RNAi-rescue systems in human cells revealed that intact PIN domain and Zinc finger motifs in human hUTP23 are essential for 18S rRNA maturation.
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      Collapsin response mediator protein-2 plays a major protective role in acute axonal degeneration. 

      Zhang, Jian-Nan; Koch, Jan C
      Neural regeneration research 2017-05; 12(5) p.692-695
      Axonal degeneration is a key pathological feature in many neurological diseases. It often leads to persistent deficits due to the inability of axons to regenerate in the central nervous system. Therefore therapeutic approaches should optimally both attenuate axonal degeneration and foster axonal regeneration. Compelling evidence suggests that collapsin response mediator protein-2 (CRMP2) might be a molecular target fulfilling these requirements. In this mini-review, we give a compact overview of the known functions of CRMP2 and its molecular interactors in neurite outgrowth and in neurodegenerative conditions. Moreover, we discuss in detail our recent findings on the role of CRMP2 in acute axonal degeneration in the optic nerve. We found that the calcium influx induced by the lesion activates the protease calpain which cleaves CRMP2, leading to impairment of axonal transport. Both calpain inhibition and CRMP2 overexpression effectively protected the proximal axons against acute axonal degeneration. Taken together, CRMP2 is further characterized as a central molecular player in acute axonal degeneration and thus evolves as a promising therapeutic target to both counteract axonal degeneration and foster axonal regeneration in neurodegenerative and neurotraumatic diseases.
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      p53 loss-of-heterozygosity is a necessary prerequisite for mutant p53 stabilization and gain-of-function in vivo. 

      Alexandrova, Evguenia M.; Mirza, Safia A.; Xu, Sulan; Schulz-Heddergott, Ramona; Marchenko, Natalia D.; Moll, Ute M.
      Cell death & disease 2017-03-09; 8(3): Art. e2661
      Missense mutations in TP53 comprise >75% of all p53 alterations in cancer, resulting in highly stabilized mutant p53 proteins that not only lose their tumor-suppressor activity, but often acquire oncogenic gain-of-functions (GOFs). GOF manifests itself in accelerated tumor onset, increased metastasis, increased drug resistance and shortened survival in patients and mice. A known prerequisite for GOF is mutant p53 protein stabilization, which itself is linked to aberrant protein conformation. However, additional determinants for mutant p53 stabilization likely exist. Here we show that in initially heterozygous mouse tumors carrying the hotspot GOF allele R248Q (p53Q/+), another necessary prerequisite for mutant p53 stabilization and GOF in vivo is loss of the remaining wild-type p53 allele, termed loss-of-heterozygosity (LOH). Thus, in mouse tumors with high frequency of p53 LOH (osteosarcomas and fibrosarcomas), we find that mutant p53 protein is stabilized (16/17 cases, 94%) and tumor onset is significantly accelerated compared with p53+/- tumors (GOF). In contrast, in mouse tumors with low frequency of p53 LOH (MMTV-Neu breast carcinomas), mutant p53 protein is not stabilized (16/20 cases, 80%) and GOF is not observed. Of note, human genomic databases (TCGA, METABRIC etc.) show a high degree of p53 LOH in all examined tumor types that carry missense p53 mutations, including sarcomas and breast carcinomas (with and without HER2 amplification). These data - while cautioning that not all genetic mouse models faithfully represent the human situation - demonstrate for the first time that p53 LOH is a critical prerequisite for missense mutant p53 stabilization and GOF in vivo.
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