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    WDR1 is a novel EYA3 substrate and its dephosphorylation induces modifications of the cellular actin cytoskeleton 

    Mentel, Mihaela; Ionescu, Aura E; Puscalau-Girtu, Ioana; Helm, Martin S; Badea, Rodica A; Rizzoli, Silvio O; Szedlacsek, Stefan E
    Scientific Reports 2018; 8(1) p.2910-2910: Art.
    Eyes absent (EYA) proteins are unusual proteins combining in a single polypeptide chain transactivation, threonine phosphatase, and tyrosine phosphatase activities. They play pivotal roles in organogenesis and are involved in a variety of physiological and pathological processes including innate immunity, DNA damage repair or cancer metastasis. The molecular targets of EYA tyrosine phosphatase activity are still elusive. Therefore, we sought to identify novel EYA substrates and also to obtain further insight into the tyrosine-dephosphorylating role of EYA proteins in various cellular processes. We show here that Src kinase phosphorylates tyrosine residues in two human EYA family members, EYA1 and EYA3. Both can autodephosphorylate these residues and their nuclear and cytoskeletal localization seems to be controlled by Src phosphorylation. Next, using a microarray of phosphotyrosine-containing peptides, we identified a phosphopeptide derived from WD-repeat-containing protein 1 (WDR1) that is dephosphorylated by EYA3. We further demonstrated that several tyrosine residues on WDR1 are phosphorylated by Src kinase, and are efficiently dephosphorylated by EYA3, but not by EYA1. The lack of phosphorylation generates major changes to the cellular actin cytoskeleton. We, therefore, conclude that WDR1 is an EYA3-specific substrate, which implies that EYA3 is a key modulator of the cytoskeletal reorganization.
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    Whither systems medicine? 

    Apweiler, Rolf; Beissbarth, Tim; Berthold, Michael R.; Blüthgen, Nils; Burmeister, Yvonne; Dammann, Olaf; Deutsch, Andreas; Feuerhake, Friedrich; Franke, Andre; Hasenauer, Jan; et al.
    Hoffmann, SteveHöfer, ThomasJansen, Peter L. M.Kaderali, LarsKlingmüller, UrsulaKoch, InaKohlbacher, OliverKuepfer, LarsLammert, FrankMaier, DieterPfeifer, NicoRadde, NicoleRehm, MarkusRoeder, IngoSaez-Rodriguez, JulioSax, UlrichSchmeck, BerndSchuppert, AndreasSeilheimer, BerndTheis, Fabian J.Vera, JulioWolkenhauer, Olaf
    Experimental & Molecular Medicine 2018; 50(3): Art. e453
    New technologies to generate, store and retrieve medical and research data are inducing a rapid change in clinical and translational research and health care. Systems medicine is the interdisciplinary approach wherein physicians and clinical investigators team up with experts from biology, biostatistics, informatics, mathematics and computational modeling to develop methods to use new and stored data to the benefit of the patient. We here provide a critical assessment of the opportunities and challenges arising out of systems approaches in medicine and from this provide a definition of what systems medicine entails. Based on our analysis of current developments in medicine and healthcare and associated research needs, we emphasize the role of systems medicine as a multilevel and multidisciplinary methodological framework for informed data acquisition and interdisciplinary data analysis to extract previously inaccessible knowledge for the benefit of patients.
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    COX16 promotes COX2 metallation and assembly during respiratory complex IV biogenesis 

    Aich, Abhishek; Wang, Cong; Chowdhury, Arpita; Ronsör, Christin; Pacheu-Grau, David; Richter-Dennerlein, Ricarda; Dennerlein, Sven; Rehling, Peter
    eLife 2018; 7: Art. e32572
    Cytochrome c oxidase of the mitochondrial oxidative phosphorylation system reduces molecular oxygen with redox equivalent-derived electrons. The conserved mitochondrial-encoded COX1- and COX2-subunits are the heme- and copper-center containing core subunits that catalyze water formation. COX1 and COX2 initially follow independent biogenesis pathways creating assembly modules with subunit-specific, chaperone-like assembly factors that assist in redox centers formation. Here, we find that COX16, a protein required for cytochrome c oxidase assembly, interacts specifically with newly synthesized COX2 and its copper center-forming metallochaperones SCO1, SCO2, and COA6. The recruitment of SCO1 to the COX2-module is COX16- dependent and patient-mimicking mutations in SCO1 affect interaction with COX16. These findings implicate COX16 in CuA-site formation. Surprisingly, COX16 is also found in COX1-containing assembly intermediates and COX2 recruitment to COX1. We conclude that COX16 participates in merging the COX1 and COX2 assembly lines.
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    Rescue of hyperexcitability in hippocampal CA1 neurons from Mecp2 (-/y) mouse through surface potential neutralization 

    Balakrishnan, Saju; Mironov, Sergej L.
    PlOS ONE 2018; 13(4): Art. e0195094
    Hyperventilation is a known feature of Rett syndrome (RTT). However, how hyperventilation is related to other RTT symptoms such as hyperexcitability is unknown. Intense breathing during hyperventilation induces hypocapnia and culminates in respiratory alkalosis. Alkalinization of extracellular milieu can trigger epilepsy in patients who already have neuronal hyperexcitability. By combining patch-clamp electrophysiology and quantitative glutamate imaging, we compared excitability of CA1 neurons of WT and Mecp2 (-/y) mice, and analyzed the biophysical properties of subthreshold membrane channels. The results show that Mecp2 (-/y) CA1 neurons are hyperexcitable in normal pH (7.4) and are increasingly vulnerable to alkaline extracellular pH (8.4), during which their excitability increased further. Under normal pH conditions, an abnormal negative shift in the voltage-dependencies of HCN (hyperpolarization-activated cyclic nucleotide-gated) and calcium channels in the CA1 neurons of Mecp2 (-/y) mice was observed. Alkaline pH also enhanced excitability in wild-type (WT) CA1 neurons through modulation of the voltage dependencies of HCN- and calcium channels. Additionally alkaline pH augmented spontaneous glutamate release and burst firing in WT CA1 neurons. Conversely, acidic pH (6.4) and 8 mM Mg2+ exerted the opposite effect, and diminished hyperexcitability in Mecp2 (-/y) CA1 neurons. We propose that the observed effects of pH and Mg2+ are mediated by changes in the neuronal membrane surface potential, which consecutively modulates the gating of HCN and calcium channels. The results provide insight to pivotal cellular mechanisms that can regulate neuronal excitability and help to devise treatment strategies for hyperexcitability induced symptoms of Rett syndrome.
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    Inter-vendor reproducibility of left and right ventricular cardiovascular magnetic resonance myocardial feature-tracking 

    Gertz, Roman Johannes; Lange, Torben; Kowallick, Johannes Tammo; Backhaus, Sören Jan; Steinmetz, Michael; Staab, Wieland; Kutty, Shelby; Hasenfuß, Gerd; Lotz, Joachim; Schuster, Andreas
    PLOS ONE 2018; 13(3): Art. e0193746
    AIM: Since cardiovascular magnetic resonance feature-tracking (CMR-FT) has been demonstrated to be of incremental clinical merit we investigated the interchangeability of global left and right ventricular strain parameters between different CMR-FT software solutions. MATERIAL AND METHODS: CMR-cine images of 10 patients without significant reduction in LVEF and RVEF and 10 patients with a significantly impaired systolic function were analyzed using two different types of FT-software (TomTec, Germany; QStrain, Netherlands). Global longitudinal strains (LV GLS, RV GLS), global left ventricular circumferential (GCS) and radial strains (GRS) were assessed. Differences in intra- and inter-observer variability within and between software types based on single and up to three repeated and subsequently averaged measurements were evaluated. RESULTS: Inter-vendor agreement was highest for GCS followed by LV GLS. GRS and RV GLS showed lower inter-vendor agreement. Variability was consistently higher in healthy volunteers as compared to the patient group. Intra-vendor reproducibility was excellent for GCS, LV GLS and RV GLS, but lower for GRS. The impact of repeated measurements was most pronounced for GRS and RV GLS on an intra-vendor level. CONCLUSION: Cardiac pathology has no influence on CMR-FT reproducibility. LV GLS and GCS qualify as the most robust parameters within and between individual software types. Since both parameters can be interchangeably assessed with different software solutions they may enter the clinical arena for optimized diagnostic and prognostic evaluation of cardiovascular morbidity and mortality in various pathologies.
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    Cognitive deficits including executive functioning in relation to clinical parameters in paediatric MS patients 

    Wuerfel, Eva; Weddige, Almuth; Hagmayer, York; Jacob, Rebecca; Wedekind, Lisa; Stark, Wiebke; Gärtner, Jutta
    PLOS ONE 2018; 13(3): Art. e0194873
    BACKGROUND: A number of studies have investigated cognitive impairment in paediatric patients with multiple sclerosis (MS) but deficits regarding executive functions have not been comprehensively assessed up to now. This study was meant to explore cognitive impairment in German paediatric MS patients with a focus on deficits in executive functions and relate these to clinical disease parameters. METHODS AND FINDINGS: Forty paediatric MS patients, which presented at the German centre for MS in childhood and adolescence, were assessed for cognitive deficits applying a very comprehensive battery of cognitive tests including the Wechsler Intelligence scale and subtests of the D-KEFS for executive functions. The performance of MS patients was compared with a group of age and sex matched healthy controls using between-subjects ANOVAs. Paediatric MS patients performed worse in tests assessing verbal comprehension and fluency, processing speed, memory, calculation skills and other executive functions. Arranged by the cognitive domain, group differences were most pronounced regarding verbal comprehension and fluency for the WISC subtests Comprehension (p = 0.000), Vocabulary (p = 0.003) and Information (p = 0.005); regarding processing speed for the written SDMT (p = 0.001) and the WISC subtest Coding (p = 0.005); regarding memory for the VLMT training (p = 0.007) and the BASIC MLT pattern learning training (p = 0.009); regarding executive functions including working memory for the WISC subtest Arithmetics (p = 0.002), the D-KEFS Design Fluency (p = 0.003) and the Corsi block tapping backward task (p = 0.003). Fluid reasoning was largely intact. Relations of cognitive performance and clinical parameters were assessed in MS patients. Disease duration was associated with a reduced performance in tests belonging to the domains verbal comprehension and fluency (WISC Vocabulary: p = 0.034, WISC Information: p = 0.015) and fluid reasoning (WISC Picture Completion: p = 0.003) as well as the WISC Working Memory Index (p = 0.047). Patients with a disease onset between 11 and 14 years performed better in fluid reasoning (WISC matrix reasoning: p = 0.024) than patients with a disease onset at an age above 14. The number of relapses negatively influenced the visual spatial memory performance (BASIC MLT pattern learning training: p = 0.009). CONCLUSIONS: The distribution of cognitive deficits in a representative group German of paediatric MS patients was similar to the pattern known from other European and North-American cohorts. Paediatric MS patients do have cognitive deficits in executive functions and key qualities necessary for successful school performance. Disease duration, age of onset and the number of relapses influence cognitive performance. Cognitive screenings should be implemented on a regular basis for paediatric MS patients, enabling early intervention.
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    OTTO: a new strategy to extract mental disease-relevant combinations of GWAS hits from individuals. 

    Ehrenreich, H.; Mitjans, M.; Van der Auwera, S.; Centeno, T. P.; Begemann, M.; Grabe, H. J.; Bonn, S.; Nave, K.-A.
    Molecular Psychiatry 2018; 23(2) p.476-486
    Despite high heritability of schizophrenia, genome-wide association studies (GWAS) have not yet revealed distinct combinations of single-nucleotide polymorphisms (SNPs), relevant for mental disease-related, quantifiable behavioral phenotypes. Here we propose an individual-based model to use genome-wide significant markers for extracting first genetic signatures of such behavioral continua. 'OTTO' (old Germanic=heritage) marks an individual characterized by a prominent phenotype and a particular load of phenotype-associated risk SNPs derived from GWAS that likely contributed to the development of his personal mental illness. This load of risk SNPs is shared by a small squad of 'similars' scattered under the genetically and phenotypically extremely heterogeneous umbrella of a schizophrenia end point diagnosis and to a variable degree also by healthy subjects. In a discovery sample of >1000 deeply phenotyped schizophrenia patients and several independent replication samples, including the general population, a gradual increase in the severity of 'OTTO's phenotype' expression is observed with an increasing share of 'OTTO's risk SNPs', as exemplified here by autistic and affective phenotypes. These data suggest a model in which the genetic contribution to dimensional behavioral traits can be extracted from combinations of GWAS SNPs derived from individuals with prominent phenotypes. Even though still in the 'model phase' owing to a world-wide lack of sufficiently powered, deeply phenotyped replication samples, the OTTO approach constitutes a conceptually novel strategy to delineate biological subcategories of mental diseases starting from GWAS findings and individual subjects.
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    Endothelial dysfunction is a superinducer of syndecan-4: fibrogenic role of its ectodomain. 

    Lipphardt, Mark; Song, Jong W; Ratliff, Brian B; Dihazi, Hassan; Müller, Gerhard A; Goligorsky, Michael S
    American Journal of Physiology. Heart and Circulatory Physiology 2018; 314(3) p.H484-H496
    Syndecan-4 (Synd4) is a member of the membrane-spanning, glycocalyx-forming proteoglycan family. It has been suggested that Synd4 participates in renal fibrosis. We compared wild-type and fibrosis-prone endothelial sirtuin 1-deficient (Sirt1endo-/-) mice, the latter being a model of global endothelial dysfunction. We performed mass spectrometry analysis, which revealed that Synd4 was highly enriched in the secretome of renal microvascular endothelial cells obtained from Sirt1endo-/- mice upon stimulation with transforming growth factor-β1; notably, all detectable peptides were confined to the ectodomain of Synd4. Elevated Synd4 was due to enhanced NF-κB signaling in Sirt1endo-/- mice, while its shedding occurred as a result of oxidative stress in Sirt1 deficiency. Synd4 expression was significantly enhanced after unilateral ureteral obstruction compared with contralateral kidneys. Furthermore, hyperplasia of renal myofibroblasts accompanied by microvascular rarefaction and overexpression of Synd4 were detected in Sirt1endo-/- mice. The ectodomain of Synd4 acted as a chemoattractant for monocytes with higher levels of macrophages and higher expression levels of Synd4 in the extracellular matrix of Sirt1endo-/- mice. In vitro, ectodomain application resulted in generation of myofibroblasts from cultured renal fibroblasts, while in vivo, subcapsular injection of ectodomain increased interstitial fibrosis. Moreover, the endothelial glycocalyx was reduced in Sirt1endo-/- mice, highlighting the induction of Synd4 occurring in parallel with the depletion of its intact form and accumulation of its ectodomain in Sirt1endo-/- mice. On the basis of our experimental results, we propose that it is the Synd4 ectodomain per se that is partially responsible for fibrosis in unilateral ureteral obstruction, especially when it is combined with endothelial dysfunction. NEW & NOTEWORTHY Our findings suggest that endothelial dysfunction induces the expression of syndecan-4 via activation of the NF-κB pathway. Furthermore, we show that syndecan-4 is shed to a greater amount because of increased oxidative stress in dysfunctional endothelial cells and that the release of the syndecan-4 ectodomain leads to tubulointerstitial fibrosis.
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    IL-6, IL-1β, and TNF-α only in combination influence the osteoporotic phenotype in Crohn's patients via bone formation and bone resorption. 

    Blaschke, Martina; Koepp, Regine; Cortis, Julia; Komrakova, Marina; Schieker, Matthias; Hempel, Ute; Siggelkow, Heide
    Advances in clinical and experimental medicine : official organ Wroclaw Medical University 2018; 27(1) p.45-56
    BACKGROUND: Crohn´s disease (CD) is associated with a higher prevalence of osteoporosis. The pathogenesis of bone affliction remains controversial, especially if inflammatory cytokines or glucocorticoid therapy are the main contributors. In postmenopausal osteoporosis, bone resorption is induced by IL-6, IL-1β and TNF-α. In contrast, in children with CD, IL-6 exclusively decreased bone formation without affecting bone resorption. OBJECTIVES: The objective of this study was to further clarify the pathophysiology of bone affliction in adult patients with CD with the use of an osteoblast and osteoclast cell model. MATERIAL AND METHODS: Inflammatory cytokines IL-6, IL-1β, and TNF-α were measured in adult CD patients' serum. Mean values of these cytokines were applied with or without dexamethasone to the human cell line SCP-1 (osteoblastic cell model). Also, the effect of cytokines on primary human osteoclast differentiation and activity was determined. RESULTS: The combined cytokine application increased the receptor activator of NF-κB ligand/osteoprotegerin (RANKL/OPG) ratio 2-fold after 2 and 14 days. Additional application of dexamethasone to SCP-1 cells further increased the RANKL/OPG ratio 3-fold, but decreased IL-6 and IL-1β expression to 10% and 50%, respectively. TNF-α expression was maximally suppressed to 16% by dexamethasone in the presence of cytokines. In osteoclasts, the combined cytokine treatment decreased expression of characteristic genes to approx. 30%, while increasing osteoclast resorption activity to 148%. In addition, a cytokine stimulated osteoblast cell culture-generated supernatant stimulated osteoclast resorption activity by 170%. CONCLUSIONS: Our results suggest that IL-6, IL-1β, and TNF-α only in combination induced osteoclaststimulating activity represented by the RANKL/OPG ratio in osteoblasts. Dexamethasone further increased this effect in osteoblasts, while decreasing cytokine expression. The results in osteoclasts support a direct and osteoblast-mediated effect on bone resorption. Our in vitro results differentiate for the first time the effect of cytokines on bone turnover as measured in adult CD patients from the additional dexamethasone effect on osteoblasts as part of the pathophysiology of osteoporosis.
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    Biologicals and small molecules in psoriasis: A systematic review of economic evaluations. 

    Kromer, Christian; Celis, Daniel; Sonntag, Diana; Peitsch, Wiebke K.
    PLOS ONE 2018; 13(1): Art. e0189765
    Biological therapy for moderate-to-severe psoriasis is highly effective but cost-intensive. This systematic review aimed at analyzing evidence on the cost-effectiveness of biological treatment of moderate-to-severe psoriasis. A literature search was conducted until 30/06/2017 in PubMed, Cochrane Library, LILACS, and EconLit. The quality of identified studies was assessed with the checklist by the Centre for Reviews and Dissemination guidance. Out of 482 records, 53 publications were eligible for inclusion. Half of the studies met between 20 and 25 of the quality checklist items, displaying moderate quality. Due to heterogeneity of studies, a qualitative synthesis was conducted. Cost ranges per outcome were enormous across different studies due to diversity in assumptions and model design. Pairwise comparisons of biologicals revealed conflicting results. Overall, adalimumab appeared to be most cost-effective (100% of all aggregated pairwise comparisons), followed by ustekinumab (66.7%), and infliximab (60%). However, in study conclusions most recent publications favored secukinumab and apremilast (75% and 60% of the studies investigating these medications). Accepted willingness-to-pay thresholds varied between 30,000 and 50,000 USD/Quality-Adjusted Life Year (QALY). Three-quarters of studies were financially supported, and in 90% of those, results were consistent with the funder's interest. Economic evaluation of biologicals is crucial for responsible allocation of health care resources. In addition to summarizing the actual evidence this review highlights gaps and needs for future research.
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    Cooperative STAT/NF-κB signaling regulates lymphoma metabolic reprogramming and aberrant GOT2 expression. 

    Feist, Maren; Schwarzfischer, Philipp; Heinrich, Paul; Sun, Xueni; Kemper, Judith; von Bonin, Frederike; Perez-Rubio, Paula; Taruttis, Franziska; Rehberg, Thorsten; Dettmer, Katja; et al.
    Gronwald, WolframReinders, JörgEngelmann, Julia C.Dudek, JanKlapper, WolframTrümper, LorenzSpang, RainerOefner, Peter J.Kube, Dieter
    Nature communications 2018; 9(1): Art. 1514
    Knowledge of stromal factors that have a role in the transcriptional regulation of metabolic pathways aside from c-Myc is fundamental to improvements in lymphoma therapy. Using a MYC-inducible human B-cell line, we observed the cooperative activation of STAT3 and NF-κB by IL10 and CpG stimulation. We show that IL10 + CpG-mediated cell proliferation of MYClow cells depends on glutaminolysis. By 13C- and 15N-tracing of glutamine metabolism and metabolite rescue experiments, we demonstrate that GOT2 provides aspartate and nucleotides to cells with activated or aberrant Jak/STAT and NF-κB signaling. A model of GOT2 transcriptional regulation is proposed, in which the cooperative phosphorylation of STAT3 and direct joint binding of STAT3 and p65/NF-κB to the proximal GOT2 promoter are important. Furthermore, high aberrant GOT2 expression is prognostic in diffuse large B-cell lymphoma underscoring the current findings and importance of stromal factors in lymphoma biology.
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    Preventive Services Utilization Among Cancer Survivors Compared to Cancer-free Controls 

    Uhlig, Annemarie; Uhlig, Johannes; Strauss, Arne; Trojan, Lutz; Lotz, Joachim; Hosseini, Ali Seif Amir
    The Open Public Health Journal 2018; 11(1) p.122-133
    Purpose: To summarize the current evidence on preventive services utilization in cancer survivors. Methods: A systematic literature review and meta-analysis was conducted in February 2016. Studies were included if they compared the utilization of influenza vaccination, cholesterol/lipid testing, bone densitometry, or blood pressure measurement among survivors of adulthood cancer to cancer-free controls. Random effects meta-analyses were conducted to pool estimates. Results: Literature search identified 3740 studies of which 10 fulfilled the inclusion criteria. Cancer survivors were significantly more likely to utilize bone densitometry (OR=1.226, 95% CI: 1.114 – 1.350, p<0.001) and influenza vaccination (OR=1.565, 95% CI: 1.176 – 2.082, p=0.002) than cancer-free controls. No statistically significant differences were detected for blood pressure measurement and cholesterol/lipid testing (OR=1.322, 95% CI: 0.812 – 2.151, p=0.261; OR=1.046, 95% CI: 0.96 – 1.139, p=0.304). Conclusions: Cancer survivors were more likely to receive influenza vaccinations and bone densitometry. Future studies should evaluate underlying mechanisms and whether the utilization of preventive services translates into prolonged survival of cancer survivors. Implications for Cancer Survivors: Our meta-analysis demonstrated cancer survivors to be more likely to receive the preventive services such as influenza vaccination and bone densitometry than cancer free controls. Still, these results should be interpreted in the context of suboptimal utilization of preventive services in general, and for cancer survivors in specific. Future research should evaluate the underlying mechanisms and whether utilization of preventive services is associated with overall survival in cancer survivors.
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    Current Methods for Skeletal Muscle Tissue Repair and Regeneration 

    Liu, Juan; Saul, Dominik; Böker, Kai Oliver; Ernst, Jennifer; Lehman, Wolfgang; Schilling, Arndt F.
    BioMed Research International 2018; 2018 p.1-11
    Skeletal muscle has the capacity of regeneration after injury. However, for large volumes of muscle loss, this regeneration needs interventional support. Consequently, muscle injury provides an ongoing reconstructive and regenerative challenge in clinical work. To promote muscle repair and regeneration, different strategies have been developed within the last century and especially during the last few decades, including surgical techniques, physical therapy, biomaterials, and muscular tissue engineering as well as cell therapy. Still, there is a great need to develop new methods and materials, which promote skeletal muscle repair and functional regeneration. In this review, we give a comprehensive overview over the epidemiology of muscle tissue loss, highlight current strategies in clinical treatment, and discuss novel methods for muscle regeneration and challenges for their future clinical translation.
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    Synaptic Alterations in Mouse Models for Alzheimer Disease—A Special Focus on N-Truncated Abeta 4-42 

    Dietrich, Katharina; Bouter, Yvonne; Müller, Michael; Bayer, Thomas
    Molecules 2018; 23(4) p.1-14: Art. 718
    This commentary reviews the role of the Alzheimer amyloid peptide Aβ on basal synaptic transmission, synaptic short-term plasticity, as well as short- and long-term potentiation in transgenic mice, with a special focus on N-terminal truncated Aβ4-42. Aβ4-42 is highly abundant in the brain of Alzheimer’s disease (AD) patients. It demonstrates increased neurotoxicity compared to full length Aβ, suggesting an important role in the pathogenesis of AD. Transgenic Tg4-42 mice, a model for sporadic AD, express human Aβ4-42 in Cornu Ammonis (CA1) neurons, and develop age-dependent hippocampal neuron loss and neurological deficits. In contrast to other transgenic AD mouse models, the Tg4-42 model exhibits synaptic hyperexcitability, altered synaptic short-term plasticity with no alterations in short- and long-term potentiation. The outcomes of this study are discussed in comparison with controversial results from other AD mouse models.
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    Testosterone metabolites inhibit proliferation of castration- and therapy-resistant prostate cancer 

    Bremmer, Felix; Jarry, Hubertus; Unterkircher, Valerie; Kaulfuss, Silke; Burfeind, Peter; Radzun, Heinz-Joachim; Ströbel, Philipp; Thelen, Paul
    Oncotarget 2018; 9(24) p.16951-16961
    Novel treatments for castration-resistant prostate cancer (CRPC) such as abiraterone acetate (AA) or enzalutamide effectively target the androgen pathway to arrest aberrant signalling and cell proliferation. Testosterone is able to inhibit tumour cell growth in CRPC. Estrogen receptor-beta (ERβ) binds the testosteronemetabolites 3β-androstanediol and 3α-androstanediol in parallel to the canonical estradiol. In the prostate it is widely accepted that ERβ regulates estrogen signalling, mediating anti-proliferative effects. We used the prostate cancer cell lines LNCaP, PC-3, VCaP, and the non-neoplastic BPH-1. VCaP cells were treated with 1 nmol/L testosterone over 20 passages, yielding the cell line VCaPrev, sensitive to hormone therapies. In contrast, LNCaP cells were grown for more than 100 passages yielding a high passage therapy resistant cell line (hiPLNCaP). VCaP and hiPLNCaP cell lines were treated with 5 μmol/L AA for more than 20 passages, respectively, generating the AAtolerant- subtypes VCaPAA and hiPLNCaPAA. Cell lines were treated with testosterone, dihydrotestosterone (DHT), R1881, and the androgen-metabolites 3β-androstanediol and 3α-androstanediol. 3β-androstanediol or 3α-androstanediol significantly reduced proliferation in all cell lines except the BPH-1 and androgen receptor-negative PC-3 and markedly downregulated AR and estrogen receptor alpha (ERα). Whereas ERβ expression was increased in all cell lines except BPH-1 or PC-3. In summary, 3β-adiol or 3α-adiol, as well as DHT and R1881, significantly reduced tumour cell growth in CRPC cells. Thus, these compounds represent novel potential therapeutic approaches to overcome drug-resistance in CRPC, especially with regard to AR-V7 function in therapy resistance. Furthermore, these data confirm the tumour suppressor properties of ERβ in CRPC.
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    Influence of Material Selection on the Marginal Accuracy of CAD/CAM-Fabricated Metal- and All-Ceramic Single Crown Copings 

    Rödiger, Matthias; Schneider, Lea; Rinke, Sven
    BioMed Research International 2018; 2018 p.1-8: Art. 2143906
    This study evaluated the marginal accuracy of CAD/CAM-fabricated crown copings from four different materials within the same processing route. Twenty stone replicas of a metallic master die (prepared upper premolar) were scanned and divided into two groups. Group 1 (𝑛� = 10) was used for a pilot test to determine the design parameters for best marginal accuracy. Group 2 (𝑛� = 10) was used to fabricate 10 specimens from the following materials with one identical CAD/CAM system (GAMMA 202, Wissner GmbH, Goettingen, Germany): A = commercially pure (cp) titanium, B = cobalt-chromium alloy, C = yttria-stabilized zirconia (YSZ), and D = leucite-reinforced glass-ceramics. Copings from group 2 were evaluated for the mean marginal gap size (MeanMG) and average maximum marginal gap size (AMaxMG) with a light microscope in the “as-machined” state. The effect of the material on the marginal accuracy was analyzed by multiple pairwise comparisons (Mann–Whitney, 𝑈�-test, 𝛼� = 0.05, adjusted by Bonferroni-Holmes method). MeanMG values were as follows: A: 46.92 ± 23.12 𝜇�m, B: 48.37 ± 29.72 𝜇�m, C: 68.25 ± 28.54 𝜇�m, and D: 58.73 ± 21.15 𝜇�m. The differences in the MeanMG values proved to be significant for groups A/C (𝑝� = 0.0024), A/D (𝑝� = 0.008), and B/C (𝑝� = 0.0332). AMaxMG values (A: 91.54 ± 23.39 𝜇�m, B: 96.86 ± 24.19 𝜇�m, C: 120.66 ± 32.75 𝜇�m, and D: 100.22 ± 10.83 𝜇�m) revealed no ignificant differences. The material had a significant impact on the marginal accuracy of CAD/CAM-fabricated copings.
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    Synergistic Effect on Neurodegeneration by N-Truncated Aβ4-42 and Pyroglutamate Aβ3-42 in a Mouse Model of Alzheimer's Disease. 

    Lopez-Noguerola, Jose S.; Giessen, Nicolai M. E.; Ueberück, Maximilian; Meißner, Julius N.; Pelgrim, Charlotte E.; Adams, Johnathan; Wirths, Oliver; Bouter, Yvonne; Bayer, Thomas A.
    Frontiers in aging neuroscience 2018; 10 p.1-12: Art. 64
    The N-terminally truncated pyroglutamate Aβ3-42 (AβpE3-42) and Aβ4-42 peptides are known to be highly abundant in the brain of Alzheimer's disease (AD) patients. Both peptides show enhanced aggregation and neurotoxicity in comparison to full-length Aβ, suggesting that these amyloid peptides may play an important role in the pathogenesis of AD. The aim of the present work was to study the direct effect of the combination of AβpE3-42 and Aβ4-42 on ongoing AD-related neuron loss, pathology, and neurological deficits in transgenic mice. Bigenic mice were generated by crossing the established TBA42 and Tg4-42 mouse models expressing the N-truncated Aβ peptides AβpE3-42 and Aβ4-42, respectively. After generation of the bigenic mice, detailed phenotypical characterization was performed using either immunostainings to evaluate amyloid pathology or quantification of neuron numbers using design-based stereology. The elevated plus maze was used to study anxiety levels. In order to evaluate sensori-motor deficits, the inverted grid, the balance beam and the string suspension tasks were applied. We could demonstrate that co-expression of AβpE3-42 and Aβ4-42 accelerates neuron loss in the CA1 pyramidal layer of young bigenic mice as seen by reduced neuron numbers in comparison to single transgenic homozygous mice expressing either AβpE3-42 or Aβ4-42. This observation coincides with the robust intraneuronal Aβ accumulation observed in the bigenic mice. In addition, loss of anxiety and motor deficits were enhanced in an age-dependent manner. The sensori-motor deficits correlate with the abundant spinal cord pathology, as demonstrated by robust intracellular Aβ accumulation within motor neurons and extracellular Aβ deposition. Our observations demonstrate that a combination of AβpE3-42 and Aβ4-42 has a stronger effect on ongoing AD pathology than the peptides alone. Therefore, AβpE3-42 and Aβ4-42 might represent excellent potential therapeutic targets and diagnostic markers for AD.
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    Small bowel capsule endoscopy: Indications, results, and clinical benefit in a University environment. 

    Flemming, Juliane; Cameron, Silke
    Medicine 2018; 97(14): Art. e0148
    Capsule endoscopy (CE) opened a new method for visualization of the small intestine. We here further explore its clinical implications.We retrospectively analyzed the clinical benefit of CE in view of medical history, diagnostics, and therapy. Our patient collective consisted of 203 patients. CE was investigated in the context of bleeding, anemia, abdominal pain, diarrhea, Crohn's disease, and suspected tumors.The study collective consisted of 118 male and 85 female patients with a mean age of 58 years (range 8-90 years). Complete bowel transit took place in 82% of the patients. The diagnostic yield in the detection of obscure gastrointestinal bleeding was 80% and for anemia 78%. Mucosal lesions were the most common finding (43%). Unclear abdominal pain had the lowest diagnostic yield (41%). Ensuing therapeutic interventions were mostly medical (66%), and to a minor extent surgical (4.4%) as well as endoscopic (4%).In conclusion, small intestinal CE is a secure method to clarify small intestinal diseases, especially obscure gastrointestinal bleeding, even in pre-operated patients without stenosis symptoms. Our study emphasizes in a collective of patients with extensive prior diagnostics that due to CE therapeutic measures resulted in 73%.
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    Practical and Ethical Aspects of Advance Research Directives for Research on Healthy Aging: German and Israeli Professionals’ Perspectives 

    Werner, Perla; Schicktanz, Silke
    Frontiers in Medicine 2018; 5 p.1-10: Art. 81
    Background: Healthy aging is the development and maintenance of optimal cognitive, social and physical well-being, and function in older adults. Preventing or minimizing disease is one of the main ways of achieving healthy aging. Dementia is one of the most prevalent and life-changing diseases of old age. Thus, dementia prevention research is defined as one of the main priorities worldwide. However, conducting research with persons who lack the capacity to give consent is a major ethical issue. Objective: Our study attempts to explore if and how advance research directives (ARDs) may be used as a future tool to deal with the ethical and practical issues in dementia research. Method: We conducted focus groups and in-depth interviews with German and Israeli professional stakeholders from the fields of gerontology, ethics, medical law, psychiatry, neurology and policy advice (n = 16), and analyzed the main topics discussed regarding cross-national similarities and controversies within the groups, as well as across the two national contexts. Results: While both countries are in the midst of a developmental process and have recognized the importance and need for ARD as a tool for expanding healthy aging, Germany is in a more advanced stage than Israel because of the EU regulation process, which indicates the influence of international harmonization on these research-related ethical issues. Consensual themes within the qualitative material were identified: the need for a broader debate on ARD, the ethical importance of autonomy and risk–benefit assessment for ARD implementation, the role of the proxy and the need for the differentiation of types of dementia research. Controversies and dilemmas aroused around themes such as the current role of IRBs in each country, the need for limits, and how to guaranty safeguarding and control. Discussion: Implementing a new tool is a step-by-step procedure requiring a thorough understanding of the current state of knowledge as well as of the challenges and hurdles ahead. As long as improving quality of life and promoting autonomy continue to be core elements in the process of healthy aging, efforts to advance knowledge and solve dilemmas associated with the implementation of ARD is of the utmost importance.
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    ATP-Dependent Chromatin Remodeling During Cortical Neurogenesis 

    Sokpor, Godwin; Castro-Hernandez, Ricardo; Rosenbusch, Joachim; Staiger, Jochen F.; Tuoc, Tran
    Frontiers in Neuroscience 2018; 12 p.1-25: Art. 226
    The generation of individual neurons (neurogenesis) during cortical development occurs in discrete steps that are subtly regulated and orchestrated to ensure normal histogenesis and function of the cortex. Notably, various gene expression programs are known to critically drive many facets of neurogenesis with a high level of specificity during brain development. Typically, precise regulation of gene expression patterns ensures that key events like proliferation and differentiation of neural progenitors, specification of neuronal subtypes, as well as migration and maturation of neurons in the developing cortex occur properly. ATP-dependent chromatin remodeling complexes regulate gene expression through utilization of energy fromATP hydrolysis to reorganize chromatin structure. These chromatin remodeling complexes are characteristically multimeric, with some capable of adopting functionally distinct conformations via subunit reconstitution to perform specific roles in major aspects of cortical neurogenesis. In this review, we highlight the functions of such chromatin remodelers during cortical development. We also bring together various proposed mechanisms by which ATP-dependent chromatin remodelers function individually or in concert, to specifically modulate vital steps in cortical neurogenesis.
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