Recent Submissions

  • Journal Article

    Judgments of effort exerted by others are influenced by received rewards 

    Rollwage, Max; Pannach, Franziska; Stinson, Caedyn; Toelch, Ulf; Kagan, Igor; Pooresmaeili, Arezoo
    Scientific Reports 2020; 10(1) p.1-14: Art. 1868
    Estimating invested effort is a core dimension for evaluating own and others’ actions, and views on the relationship between effort and rewards are deeply ingrained in various societal attitudes. Internal representations of effort, however, are inherently noisy, e.g. due to the variability of sensorimotor and visceral responses to physical exertion. The uncertainty in effort judgments is further aggravated when there is no direct access to the internal representations of exertion – such as when estimating the effort of another person. Bayesian cue integration suggests that this uncertainty can be resolved by incorporating additional cues that are predictive of effort, e.g. received rewards. We hypothesized that judgments about the effort spent on a task will be influenced by the magnitude of received rewards. Additionally, we surmised that such influence might further depend on individual beliefs regarding the relationship between hard work and prosperity, as exemplified by a conservative work ethic. To test these predictions, participants performed an effortful task interleaved with a partner and were informed about the obtained reward before rating either their own or the partner’s effort. We show that higher rewards led to higher estimations of exerted effort in self-judgments, and this effect was even more pronounced for other-judgments. In both types of judgment, computational modelling revealed that reward information and sensorimotor markers of exertion were combined in a Bayes-optimal manner in order to reduce uncertainty. Remarkably, the extent to which rewards influenced effort judgments was associated with conservative world-views, indicating links between this phenomenon and general beliefs about the relationship between effort and earnings in society.
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  • Journal Article

    Long‐term human IgG treatment improves heart and muscle function in a mouse model of Duchenne muscular dystrophy 

    Zschüntzsch, Jana; Jouvenal, Pia Vanessa; Zhang, Yaxin; Klinker, Florian; Tiburcy, Malte; Liebetanz, David; Malzahn, Dörthe; Brinkmeier, Heinrich; Schmidt, Jens
    Journal of Cachexia, Sarcopenia and Muscle p.1-14
    Background: Duchenne muscular dystrophy (DMD) is a progressive muscle‐wasting disease caused by mutations in the dystrophin gene, which leads to structural instability of the dystrophin–glycoprotein‐complex with subsequent muscle degeneration. In addition, muscle inflammation has been implicated in disease progression and therapeutically addressed with glucocorticosteroids. These have numerous adverse effects. Treatment with human immunoglobulin G (IgG) improved clinical and para‐clinical parameters in the early disease phase in the well‐established mdx mouse model. The aim of the present study was to confirm the efficacy of IgG in a long‐term pre‐clinical study in mdx mice. Methods: IgG (2 g/kg body weight) or NaCl solution as control was administered monthly over 18 months by intraperitoneal injection in mdx mice beginning at 3 weeks of age. Several clinical outcome measures including endurance, muscle strength, and echocardiography were assessed. After 18 months, the animals were sacrificed, blood was collected for analysis, and muscle samples were obtained for ex vivo muscle contraction tests, quantitative PCR, and histology. Results: IgG significantly improved the daily voluntary running performance (1.9 m more total daily running distance, P < 0.0001) and slowed the decrease in grip strength by 0.1 mN, (P = 0.018). IgG reduced fatigability of the diaphragm (improved ratio to maximum force by 0.09 ± 0.04, P = 0.044), but specific tetanic force remained unchanged in the ex vivo muscle contraction test. Cardiac function was significantly better after IgG, especially fractional area shortening (P = 0.012). These results were accompanied by a reduction in cardiac fibrosis and the infiltration of T cells (P = 0.0002) and macrophages (P = 0.0027). In addition, treatment with IgG resulted in a significant reduction of the infiltration of T cells (P ≤ 0.036) in the diaphragm, gastrocnemius, quadriceps, and a similar trend in tibialis anterior and macrophages (P ≤ 0.045) in gastrocnemius, quadriceps, tibialis anterior, and a similar trend in the diaphragm, as well as a decrease in myopathic changes as reflected by a reduced central nuclear index in the diaphragm, tibialis anterior, and quadriceps (P ≤ 0.002 in all). Conclusions: The present study underscores the importance of an inflammatory contribution to the disease progression of DMD. The data demonstrate the long‐term efficacy of IgG in the mdx mouse. IgG is well tolerated by humans and could preferentially complement gene therapy in DMD. The data call for a clinical trial with IgG in DMD.
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  • Journal Article

    Seven Myths on Crowding and Peripheral Vision 

    Strasburger, Hans
    i-Perception 2020; 11(3) p.1-46
    Crowding has become a hot topic in vision research, and some fundamentals are now widely agreed upon. For the classical crowding task, one would likely agree with the following statements. (1) Bouma’s law can be stated, succinctly and unequivocally, as saying that critical distance for crowding is about half the target’s eccentricity. (2) Crowding is predominantly a peripheral phenomenon. (3) Peripheral vision extends to at most 90° eccentricity. (4) Resolution threshold (the minimal angle of resolution) increases strongly and linearly with eccentricity. Crowding increases at an even steeper rate. (5) Crowding is asymmetric as Bouma has shown. For that inner-outer asymmetry, the peripheral flanker has more effect. (6) Critical crowding distance corresponds to a constant cortical distance in primary visual areas like V1. (7) Except for Bouma’s seminal article in 1970, crowding research mostly became prominent starting in the 2000s. I propose the answer is “not really” or “not quite” to these assertions. So should we care? I think we should, before we write the textbook chapters for the next generation.
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  • Journal Article

    CARASIL with coronary artery disease and distinct cerebral microhemorrhage: A case report and literature review 

    Müller, Sebastian J; Khadhraoui, Eya; Allam, Ibrahim; Argyriou, Loukas; Hehr, Ute; Liman, Jan; Hasenfuß, Gerd; Bähr, Mathias; Riedel, Christian H; Koch, Jan C
    Clinical and Translational Neuroscience 2020; 4(1) p.1-5
    Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL, Maedasyndrome) is an extremely rare autosomal-recessive genetic disorder with a serious arteriopathy causing subcorticalinfarcts and leukoencephalopathy. In less than 20 cases, a genetic mutation was proven. Patients suffer from alopecia, discherniations, and spondylosis. Between the age of 30 and 40, the patients typically develop severe cerebral infarcts. Clinicalsymptoms, genetic study, magnetic resonance imaging (MRI), and coronary angiography of a patient with proven CARASILare presented. The patient showed the typical phenotype with cerebral small-vessel disease, cerebral infarcts, spondylosis,and abnormal hair loss. Additionally, distinct cerebral microhemorrhage and a severe coronary artery disease (CAD)were found, which have not been reported before for CARASIL. Mutation screening revealed the presence of ahomozygous c.1022G > T substitution in the HTRA1 gene. Evidence from other publications supports a pathogenetic linkbetween the HTRA1 mutation and CAD as a new feature of CARASIL. This is the first report about CARASIL with aconcomitant severe CAD. Thus, in patients with CARASIL, other vessel diseases should also be considered.
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  • Journal Article

    Probing the Environment of Emerin by Enhanced Ascorbate Peroxidase 2 (APEX2)-Mediated Proximity Labeling 

    Müller, Marret; James, Christina; Lenz, Christof; Urlaub, Henning; Kehlenbach, Ralph H.
    Cells 2020; 9(3) p.1-18: Art. 605
    Emerin is one of the best characterized proteins of the inner nuclear membrane, but can also occur at the level of the endoplasmic reticulum. We now use enhanced ascorbate peroxidase 2 (APEX2) to probe the environment of emerin. APEX2 can be used as a genetic tag that produces short-lived yet highly reactive biotin species, allowing the modification of proteins that interact with or are in very close proximity to the tagged protein. Biotinylated proteins can be isolated using immobilized streptavidin and analyzed by mass spectrometry. As an alternative to the standard approach with a genetic fusion of APEX2 to emerin, we also used RAPIDS (rapamycin- and APEX-dependent identification of proteins by SILAC), a method with improved specificity, where the peroxidase interacts with the protein of interest (i.e., emerin) only upon addition of rapamycin to the cells. We compare these di erent approaches, which, together, identify well-known interaction partners of emerin like lamin A and the lamina associated polypeptide 1 (LAP1), as well as novel proximity partners.
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  • Journal Article

    Re-exploration Early after Cardiac Surgery in Adults: The Importance of Bleeding-Related Complications 

    Tirilomis, Theodor; Bougioukas, Ioannis G.; Friedrich, Martin G.; Danner, Bernhard C.; Schoendube, Friedrich A.
    The Heart Surgery Forum 2020; 23(2) p.E174-E177
    Background: Re-explorations soon after cardiac surgery are mostly related to bleeding or unclear hemodynamic situations possibly related to heart compression resulting from pericardial hematoma. This condition has a significant impact on mortality, morbidity, and costs. The aim of this study was to analyze indications and outcomes of re-exploration for bleeding or pericardial tamponade early after cardiac surgery in adults. Methods: The clinical data of 4790 consecutive adult patients who underwent cardiac surgery in our institution from January 2011 to May 2016 were retrospectively analyzed. Results: We identified 331 re-explorations performed in 231 patients. Sixty-seven of these patients had >1 re- exploration. In most cases (88%), repeat sternotomy was performed. Most procedures (57%) were performed within the first 48 hours. In two-thirds of re-explorations, active bleeding or pericardial hematoma was verified. In the remaining cases, neither bleeding nor significant pericardial hematoma leading to tamponade was found. Among the cases with active bleeding causes, the most bleeding sites were found to be at the coronary anastomosis and the epicardial exposure harvesting site, as well as from the side branches of bypass grafts and intercostal arteries. Conclusions: The incidence of re-exploration after cardiac surgery in adults was low (4.8%). In about two-thirds of the cases, active bleeding or significant pericardial hematoma was found. The most common bleeding causes were the easiest to treat.
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  • Journal Article

    Functions of Vertebrate Ferlins 

    Bulankina, Anna V.; Thoms, Sven
    Cells 2020; 9(3) p.1-31: Art. 534
    Ferlins are multiple-C2-domain proteins involved in Ca2+-triggered membrane dynamics within the secretory, endocytic and lysosomal pathways. In bony vertebrates there are six ferlin genes encoding, in humans, dysferlin, otoferlin, myoferlin, Fer1L5 and 6 and the long noncoding RNA Fer1L4. Mutations in DYSF (dysferlin) can cause a range of muscle diseases with various clinical manifestations collectively known as dysferlinopathies, including limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy. A mutation in MYOF (myoferlin) was linked to a muscular dystrophy accompanied by cardiomyopathy. Mutations in OTOF (otoferlin) can be the cause of nonsyndromic deafness DFNB9. Dysregulated expression of any human ferlin may be associated with development of cancer. This review provides a detailed description of functions of the vertebrate ferlins with a focus on muscle ferlins and discusses the mechanisms leading to disease development.
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  • Journal Article

    Endophilin-A coordinates priming and fusion of neurosecretory vesicles via intersectin 

    Gowrisankaran, Sindhuja; Houy, Sébastien; del Castillo, Johanna G. Peña; Steubler, Vicky; Gelker, Monika; Kroll, Jana; Pinheiro, Paulo S.; Schwitters, Dirk; Halbsgut, Nils; Pechstein, Arndt; et al.
    van Weering, Jan R. T.Maritzen, TanjaHaucke, VolkerRaimundo, NunoSørensen, Jakob B.Milosevic, Ira
    Nature Communications 2020; 11(1) p.1-18: Art. 1266
    Endophilins-A are conserved endocytic adaptors with membrane curvature-sensing and -inducing properties. We show here that, independently of their role in endocytosis, endophilin-A1 and endophilin-A2 regulate exocytosis of neurosecretory vesicles. The number and distribution of neurosecretory vesicles were not changed in chromaffin cells lacking endophilin-A, yet fast capacitance and amperometry measurements revealed reduced exocytosis, smaller vesicle pools and altered fusion kinetics. The levels and distributions of the main exocytic and endocytic factors were unchanged, and slow compensatory endocytosis was not robustly affected. Endophilin-A’s role in exocytosis is mediated through its SH3-domain, specifically via a direct interaction with intersectin-1, a coordinator of exocytic and endocytic traffic. Endophilin-A not able to bind intersectin-1, and intersectin-1 not able to bind endophilin-A, resulted in similar exocytic defects in chromaffin cells. Altogether, we report that two endocytic proteins, endophilin-A and intersectin-1, are enriched on neurosecretory vesicles and regulate exocytosis by coordinating neurosecretory vesicle priming and fusion.
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  • Journal Article

    Application of Campylobacter jejuni Phages: Challenges and Perspectives 

    Ushanov, Leonid; Lasareishvili, Besarion; Janashia, Irakli; Zautner, Andreas E.
    Animals 2020; 10(2) p.1-21: Art. 279
    Bacteriophages (phages) are the most abundant and diverse biological entities in the biosphere. Due to the rise of multi-drug resistant bacterial strains during the past decade, phages are currently experiencing a renewed interest. Bacteriophages and their derivatives are being actively researched for their potential in the medical and biotechnology fields. Phage applications targeting pathogenic food-borne bacteria are currently being utilized for decontamination and therapy of live farm animals and as a biocontrol measure at the post-harvest level. For this indication, the United States Food and Drug Administration (FDA) has approved several phage products targeting Listeria sp., Salmonella sp. and Escherichia coli. Phage-based applications against Campylobacter jejuni could potentially be used in ways similar to those against Salmonella sp. and Listeria sp.; however, only very few Campylobacter phage products have been approved anywhere to date. The research on Campylobacter phages conducted thus far indicates that highly diverse subpopulations of C. jejuni as well as phage isolation and enrichment procedures influence the specificity and efficacy of Campylobacter phages. This review paper emphasizes conclusions from previous findings instrumental in facilitating isolation of Campylobacter phages and improving specificity and efficacy of the isolates.
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  • Journal Article

    The ESAS-score: A histological severity grading system of subarachnoid hemorrhage using the modified double hemorrhage model in rats 

    Mielke, Dorothee; Bleuel, Kim; Stadelmann, Christine; Rohde, Veit; Malinova, Vesna
    PLOS ONE 2020; 15(2) p.1-14: Art. e0227349
    Objective: The amount of extravasated blood is an established surrogate marker for subarachnoid hemorrhage (SAH) severity, which varies in different experimental SAH (eSAH) models. A comprehensive eSAH grading system would allow a more reliable correlation of outcome parameters with SAH severity. The aim of this study was to define a severity score for eSAH related to the Fisher-Score in humans. Material and methods: SAH was induced in 135 male rats using the modified double hemorrhage model. A sham group included 8 rats, in which saline solution instead of blood was injected. Histological analysis with HE(hematoxylin-eosin)-staining for the visualization of blood was performed in all rats on day 5. The amount and distribution of blood within the subarachnoid space and ventricles (IVH) was analyzed. Results: The mortality rate was 49.6% (71/143). In all except five SAH rats, blood was visible within the subarachnoid space. As expected, no blood was detected in the sham group. The following eSAH severity score was established (ESAS-score): grade I: no SAH visible; grade II: local or diffuse thin SAH, no IVH; grade III: diffuse / thick layers of blood, no IVH; grade IV: additional IVH. Grade I was seen in five rats (7.9%), grade II in 28.6% (18/63), grade III in 41.3% (26/63) and grade IV in 22.2% (14/63) of the rats with eSAH. Conclusion: The double hemorrhage model allows the induction of a high grade SAH in more than 60% of the rats, making it suitable for the evaluation of outcome parameters in severe SAH.
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  • Journal Article

    Diagnostic Accuracy of Prion Disease Biomarkers in Iatrogenic Creutzfeldt-Jakob Disease 

    Llorens, Franc; Villar-Piqué, Anna; Hermann, Peter; Schmitz, Matthias; Calero, Olga; Stehmann, Christiane; Sarros, Shannon; Moda, Fabio; Ferrer, Isidre; Poleggi, Anna; et al.
    Pocchiari, MaurizioCatania, MarcellaKlotz, SigridO’Regan, CarlBrett, FrancescaHeffernan, JosephineLadogana, AnnaCollins, Steven J.Calero, MiguelKovacs, Gabor G.Zerr, Inga
    Biomolecules 2020; 10(2) p.1-13: Art. 290
    Human prion diseases are classified into sporadic, genetic, and acquired forms. Within this last group, iatrogenic Creutzfeldt–Jakob disease (iCJD) is caused by human-to-human transmission through surgical and medical procedures. After reaching an incidence peak in the 1990s, it is believed that the iCJD historical period is probably coming to an end, thanks to lessons learnt from past infection sources that promoted new prion prevention and decontamination protocols. At this point, we sought to characterise the biomarker profile of iCJD and compare it to that of sporadic CJD (sCJD) for determining the value of available diagnostic tools in promptly recognising iCJD cases. To that end, we collected 23 iCJD samples from seven national CJD surveillance centres and analysed the electroencephalogram and neuroimaging data together with a panel of seven CSF biomarkers: 14-3-3, total tau, phosphorylated/total tau ratio, alpha-synuclein, neurofilament light, YKL-40, and real-time quaking induced conversion of prion protein. Using the cut-off values established for sCJD, we found the sensitivities of these biomarkers for iCJD to be similar to those described for sCJD. Given the limited relevant information on this issue to date, the present study validates the use of current sCJD biomarkers for the diagnosis of future iCJD cases.
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  • Journal Article

    How to intervene in the caries process: proximal caries in adolescents and adults—a systematic review and meta-analysis 

    Splieth, Christian H.; Kanzow, Philipp; Wiegand, Annette; Schmoeckel, Julian; Jablonski-Momeni, Anahita
    Clin Oral Investig(24) p.1623-1636: Art. 5
    Objectives: For an ORCA/EFCD consensus, this systematic review assessed the question "How to intervene in the caries process in proximal caries in adolescents and adults". Material and methods: Separating between the management of initial and cavitated proximal caries lesions, Medline via PubMed was searched regarding non-operative/non-invasive, minimally/micro-invasive and restorative treatment. First priority was systematic reviews or randomized controlled trials (RCTs), otherwise cohort studies. After extraction of data, the potential risk of bias was estimated depending on the study type, and the emerging evidence for conclusions was graded. Results: Regarding non-invasive/non-operative care (NOC), no systematic reviews or RCTs were found. In cohort studies (n = 12) with a low level of evidence, NOC like biofilm management and fluoride was associated with a low proportion and slow speed of progression of initial proximal lesions. Minimally/micro-invasive (MI) treatments such as proximal sealants or resin infiltration (four systematic reviews/meta-analyses) were effective compared with a non-invasive/placebo control at a moderate level of evidence. Data on restorative treatment came with low evidence (5 systematic reviews, 13 RCTs); with the limitation of no direct comparative studies, sample size-weighted mean annual failure rates of class II restorations varied between 1.2 (bulk-fill composite) and 3.8% (ceramic). Based on one RCT, class II composite restorations may show a higher risk of failure compared with amalgam. Conclusions: Proximal caries lesions can be managed successfully with non-operative, micro-invasive and restorative treatment according to lesion stage and caries activity. Clinical relevance: Proximal caries treatment options like non-operative, micro-invasive and restorative care should be considered individually.
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  • Journal Article

    Clinical effectiveness of primary prevention implantable cardioverter-defibrillators: results of the EU-CERT-ICD controlled multicentre cohort study 

    Zabel, Markus; Willems, Rik; Lubinski, Andrzej; Bauer, Axel; Brugada, Josep; Conen, David; Flevari, Panagiota; Hasenfuß, Gerd; Svetlosak, Martin; Huikuri, Heikki V; et al.
    Malik, MarekPavlović, NikolaSchmidt, GeorgSritharan, RajevaaSchlögl, SimonSzavits-Nossan, JankoTraykov, VassilTuinenburg, Anton EWillich, Stefan NHarden, MarkusFriede, TimSvendsen, Jesper HastrupSticherling, ChristianMerkely, BélaMerkely, BélaPerge, PeterSallo, ZoltanSzeplaki, GaborSzegedi, NandorNagy, Klaudia VivienZabel, MarkusLüthje, LarsSchlögl, SimonSritharan, RHaarmann, HelgeBergau, LeonardSeegers, JoachimHasenfuß, GerdMunoz-Exposito, PascalTichelbäcker, TobiasKirova, AleksandraHasenfuß, GerdFriede, TimZabel, MarkusSchlögl, SimonFriede, TimHarden, MarkusMalik, MarekHnatkova, KaterinaVos, Marc AWillich, Stefan NReinhold, ThomasWillems, RikVandenberk, BertKlinika, MagdalenaSzavits-Nossan, JankoRotkvić, LFlevari, PanayotaKatsimardos, AndreasKatsaras, DimitriosHatala, RobertSvetlosak, MartinLubinski, AndrzejKuczejko, TomaszHansen, JimSticherling, ChristianConen, DavidPavlović, NikolaManola, ŠimeVinter, OzrenBenko, IvicaTuinenburg, AntonSprenkeler, DavidSmoczynska, AVos, M ABauer, AxelMeyer-Zürn, ChristineEick, ChristianSvendsen, Jesper HastrupBrugada, JosepArbelo, ElenaKaliska, GabrielaMartinek, JozefSchmidt, GeorgDommasch, MichaelSteger, AlexanderKääb, StefanBauer, AxelSinner, Moritz FRizas, Konstantinos DHamm, WolfgangTraykov, VCygankiewicz, IwonaPtaszyński, PawelKaczmarek, KPoddebska, IIovev, SvetoslavNovotný, TomášKozak, MilanHuikuri, HeikkiKenttä, TuomasPelli, AriKasprzak, Jaroslaw DQavoq, DariuszBrusich, SandroAvdovic, ErvinKlasan, MarinaGaluszka, JanTaborsky, MilosVelchev, VasilDissmann, RüdigerShalganov, TGuzik, PKrauze, TBimmel, DieterLieberz, ChristianeLudwigsburg, KlinikumStefanow, StefanRüb, NormanWolpert, ChristianSeegers, JoachimMeier, Lars SBehrens, SteffenJurisic, ZrinkaBraunschweig, FriederBlaschke, FlorianPieske, BurkertBakotic, ZoranAnic, AnteWeiden, KlinikumSchwinger, Robert H GPlatonov, PyotrGrönefeld, GerianKlingenheben, Thomas
    European Heart Journal 2020; 2020(0) p.1-12
    Aims: The EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter-Defibrillators (EU-CERT-ICD), a prospective investigator-initiated, controlled cohort study, was conducted in 44 centres and 15 European countries. It aimed to assess current clinical effectiveness of primary prevention ICD therapy. Methods and results: We recruited 2327 patients with ischaemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM) and guideline indications for prophylactic ICD implantation. Primary endpoint was all-cause mortality. Clinical characteristics, medications, resting, and 12-lead Holter electrocardiograms (ECGs) were documented at enrolment baseline. Baseline and follow-up (FU) data from 2247 patients were analysable, 1516 patients before first ICD implantation (ICD group) and 731 patients without ICD serving as controls. Multivariable models and propensity scoring for adjustment were used to compare the two groups for mortality. During mean FU of 2.4 ± 1.1 years, 342 deaths occurred (6.3%/years annualized mortality, 5.6%/years in the ICD group vs. 9.2%/years in controls), favouring ICD treatment [unadjusted hazard ratio (HR) 0.682, 95% confidence interval (CI) 0.537–0.865, P = 0.0016]. Multivariable mortality predictors included age, left ventricular ejection fraction (LVEF), New York Heart Association class <III, and chronic obstructive pulmonary disease. Adjusted mortality associated with ICD vs. control was 27% lower (HR 0.731, 95% CI 0.569–0.938, P = 0.0140). Subgroup analyses indicated no ICD benefit in diabetics (adjusted HR = 0.945, P = 0.7797, P for interaction = 0.0887) or those aged ≥75 years (adjusted HR 1.063, P = 0.8206, P for interaction = 0.0902). Conclusion: In contemporary ICM/DCM patients (LVEF ≤35%, narrow QRS), primary prophylactic ICD treatment was associated with a 27% lower mortality after adjustment. There appear to be patients with less survival advantage, such as older patients or diabetics.
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  • Journal Article

    Distinct molecular patterns of TDP-43 pathology in Alzheimer’s disease: relationship with clinical phenotypes 

    Tomé, Sandra O; Vandenberghe, Rik; Ospitalieri, Simona; Van Schoor, Evelien; Tousseyn, Thomas; Otto, Markus; von Arnim, Christine A F; Thal, Dietmar R
    Acta Neuropathologica Communications. 2020 Apr 29;8(1):61
    Abstract The co-existence of multiple pathologies and proteins is a common feature in the brains of cognitively impaired elderly individuals. Transactive response DNA-binding protein (TDP-43) has been discovered to accumulate in limbic brain regions of a portion of late-onset Alzheimer’s disease (AD) patients, in addition to amyloid-β and τ protein. However, it is not yet known whether the TDP-43 species in the AD brain differ in their composition, when compared among different AD cases and to frontotemporal lobar degeneration cases with TDP-43 inclusions (FTLD-TDP). Furthermore, it is not known whether TDP-43 pathology in AD is related to symptoms of the frontotemporal dementia (FTD) spectrum. In this study, we investigated the molecular pattern of TDP-43 lesions with five different antibodies against different phosphorylated (pTDP-43) and non-phosphorylated TDP-43 epitopes. We analyzed a cohort of 97 autopsy cases, including brains from 20 non-demented individuals, 16 cognitively normal pathologically-defined preclinical AD (p-preAD), 51 neuropathologically-confirmed AD cases and 10 FTLD-TDP cases as positive controls. We observed distinct neuropathological patterns of TDP-43 among AD cases. In 11 neuropathologically-confirmed AD cases we found dystrophic neurites (DNs), neuronal cytoplasmic inclusions (NCIs) and/or neurofibrillary tangle (NFT)-like lesions not only positive for pTDP-43409/410, but also for pTDP-43 phosphorylated at serines 403/404 (pTDP-43403/404) and non-phosphorylated, full-length TDP-43, as seen with antibodies against C-terminal TDP-43 and N-terminal TDP-43. These cases were referred to as ADTDP + FL because full-length TDP-43 was presumably present in the aggregates. FTLD-TDP cases showed a similar molecular TDP-43 pattern. A second pattern, which was not seen in FTLD-TDP, was observed in most of p-preAD, as well as 30 neuropathologically-confirmed AD cases, which mainly exhibited NFTs and NCIs stained with antibodies against TDP-43 phosphorylated at serines 409/410 (pTDP-43409, pTDP-43409/410). Because only phosphorylated C-terminal species of TDP-43 could be detected in the lesions we designated these AD cases as ADTDP + CTF. Ten AD cases did not contain any TDP-43 pathology and were referred to as ADTDP-. The different TDP-43 patterns were associated with clinically typical AD symptoms in 80% of ADTDP + CTF cases, 63,6% of ADTDP + FL and 100% of the ADTDP- cases. On the other hand, clinical symptoms characteristic for FTD were observed in 36,4% of ADTDP + FL, in 16,6% of the ADTDP + CTF, and in none of the ADTDP- cases. Our findings provide evidence that TDP-43 aggregates occurring in AD cases vary in their composition, suggesting the distinction of different molecular patterns of TDP-43 pathology ranging from ADTDP- to ADTDP + CTF and ADTDP + FL with possible impact on their clinical picture, i.e. a higher chance for FTD-like symptoms in ADTDP + FL cases.
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  • Journal Article

    Establishment and characterization of stable red, far-red (fR) and near infra-red (NIR) transfected canine prostate cancer cell lines 

    Liu, Wen; Sender, Sina; Kong, Weibo; Beck, Julia; Sekora, Anett; Bornemann-Kolatzki, Kirsten; Schuetz, Ekkehart; Junghanss, Christian; Brenig, Bertram; Nolte, Ingo; et al.
    Murua Escobar, Hugo
    Cancer Cell International. 2020 Apr 29;20(1):139
    Abstract Background Canine prostate cancer represents a unique model for human prostate cancer. In vitro systems offer various possibilities but Xenograft in vivo imaging allows studying complex tasks as tumor progression and drug intervention longitudinal. Herein, we established three canine prostate carcinoma cell lines stably expressing fluorescent proteins allowing deep tissue in vivo imaging. Methods Three canine prostate carcinoma (cPC) cell lines were stably transfected with fluorescent proteins in red, far-red and near infra-red spectrum, followed by G418 selection. Fluorescent protein expression was demonstrated by microscopy, flow cytometry and a NightOWL LB 983 in vivo imaging system. Cellular and molecular characteristics of the generated cell lines were compared to the parental cell line CT1258. Cell proliferation, metabolic activity and sphere formation capacity were analyzed. Stem cell marker expression was examined by qPCR and genomic copy number variation by genomic DNA whole genome sequencing. Results Three stably fluorescent protein transfected cPC cell lines were established and characterized. Compared to the parental cell line, no significant difference in cell proliferation and metabolic activity were detected. Genomic copy number variation analyses and stem cell marker gene expression revealed in general no significant changes. However, the generated cell line CT1258-mKate2C showed uniquely no distal CFA16 deletion and an elevated metabolic activity. The introduced fluorescencent proteins allowed highly sensitive detection in an in vivo imaging system starting at cell numbers of 0.156 × 106. Furthermore, we demonstrated a similar sphere formation capacity in the fluorescent cell lines. Interestingly, the clone selected CT1258-mKate2C, showed increased sphere formation ability. Discussion Starting from a well characterized cPC cell line three novel fluorescent cell lines were established showing high cellular and molecular similarity to the parental cell line. The introduction of the fluorescent proteins did not alter the established cell lines significantly. The red fluorescence allows deep tissue imaging, which conventional GFP labeling is not able to realize. Conclusion As no significant differences were detected between the established cell lines and the very well characterized parental CT1258 the new fluorescent cell lines allow deep tissue in vivo imaging for perspective in vivo evaluation of novel therapeutic regimens.
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  • Journal Article

    Psychometric characterization of incidental feedback sources during grasping with a hand prosthesis 

    Wilke, Meike Annika; Niethammer, Christian; Meyer, Britta; Farina, Dario; Dosen, Strahinja
    Journal of NeuroEngineering and Rehabilitation 2019; 16(1)
    Background:A prosthetic system should ideally reinstate the bidirectional communication between the user’sbrain and its end effector by restoring both motor and sensory functions lost after an amputation. However, currentcommercial prostheses generally do not incorporate somatosensory feedback. Even without explicit feedback,grasping using a prosthesis partly relies on sensory information. Indeed, the prosthesis operation is characterized byvisual and sound cues that could be exploited by the user to estimate the prosthesis state. However, the quality ofthis incidental feedback has not been objectively evaluated.Methods:In this study, the psychometric properties of the auditory and visual feedback of prosthesis motion wereassessed and compared to that of a vibro-tactile interface. Twelve able-bodied subjects passively observed prosthesisclosing and grasping an object, and they were asked to discriminate (experiment I)or estimate (experiment II) the closingvelocity of the prosthesis using visual (VIS), acoustic (SND), or combined (VIS + SND) feedback. In experiment II, the subjectsperformed the task also with a vibrotactile stimulus (VIB) delivered using a single tactor. The outcome measures for thediscrimination and estimation experiments were just noticeabledifference(JND)andmedian absolute estimation error(MAE), respectively.Results:The results demonstrated that the incidental sources provided a remarkably good discrimination and estimationof the closing velocity, significantly outperforming the vibrotactile feedback. Using incidental sources, the subjects coulddiscriminate almost the minimum possible increment/decrement in velocity that could be commanded to the prosthesis(median JND < 2% forSNDandVIS + SND). Similarly, the median MAE in estimating the prosthesis velocity randomlycommanded from the full working range was also low, i.e., approximately 5% inSNDandVIS + SND.Conclusions:Since the closing velocity is proportional to grasping force in state-of-the-art myoelectric prostheses, theresults of the present study imply that the incidental feedback, when available, could be usefully exploited for graspingforce control. Therefore, the impact of incidental feedback needs to be considered when designing a feedback interface inprosthetics, especially since the quality of estimation usingsupplemental sources (e.g., vibration) can be worse comparedto that of the intrinsic cues.
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  • Journal Article

    Bayesian random-effects meta-analysis using the bayesmeta R package 

    Röver, Christian
    Journal of Statistical Software 2020; 93(6) p.1-51
    The random-effects or normal-normal hierarchical model is commonly utilized in a wide range of meta-analysis applications. A Bayesian approach to inference is very attractive in this context, especially when a meta-analysis is based only on few studies. The bayesmeta R package provides readily accessible tools to perform Bayesian meta-analyses and generate plots and summaries, without having to worry about computational details. It allows for flexible prior specification and instant access to the resulting posterior distributions, including prediction and shrinkage estimation, and facilitating for example quick sensitivity checks. The present paper introduces the underlying theory and showcases its usage.
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  • Journal Article

    Altering microtubule dynamics is synergistically toxic with spindle assembly checkpoint inhibition 

    Schukken, Klaske M.; Lin, Yu-Chih; Bakker, Petra L.; Schubert, Michael; Preuss, Stephanie F.; Simon, Judith E.; van den Bos, Hilda; Storchova, Zuzana; Colomé-Tatché, Maria; Bastians, Holger; et al.
    Spierings, Diana C. J.Foijer, Floris
    Life Science Alliance 2020; 3(2): Art. e201900499
    Chromosomal instability (CIN) and aneuploidy are hallmarks of cancer. As most cancers are aneuploid, targeting aneuploidy or CIN may be an effective way to target a broad spectrum of cancers. Here, we perform two small molecule compound screens to identify drugs that selectively target cells that are aneuploid or exhibit a CIN phenotype. We find that aneuploid cells are much more sensitive to the energy metabolism regulating drug ZLN005 than their euploid counterparts. Furthermore, cells with an ongoing CIN phenotype, induced by spindle assembly checkpoint (SAC) alleviation, are significantly more sensitive to the Src kinase inhibitor SKI606. We show that inhibiting Src kinase increases microtubule polymerization rates and, more generally, that deregulating microtubule polymerization rates is particularly toxic to cells with a defective SAC. Our findings, therefore, suggest that tumors with a dysfunctional SAC are particularly sensitive to microtubule poisons and, vice versa, that compounds alleviating the SAC provide a powerful means to treat tumors with deregulated microtubule dynamics.
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  • Journal Article

    Quality of Information Regarding Repair Restorations on Dentist Websites: Systematic Search and Analysis 

    Kanzow, Philipp; Büttcher, Amelie Friederike; Wiegand, Annette; Schwendicke, Falk
    Journal of Medical Internet Research 2020; 22(4): Art. e17250
    Background: Repairing instead of replacing partially defective dental restorations represents a minimally invasive treatment concept, and repairs are associated with advantages over complete restoration replacement. To participate in the shared decision-making process when facing partially defective restorations, patients need to be aware of the indications, limitations, and advantages or disadvantages of repairs. Patients are increasingly using the internet to gain health information like this online. Objective: We aimed to assess the quality of German-speaking dentist websites on repairs of partially defective restorations. Methods: Three electronic search engines were used to identify German-speaking websites of dental practices mentioning repairs. Regarding information on repairs, websites were assessed for (1) technical and functional aspects, (2) comprehensiveness of information, and (3) generic quality and risk of bias. Domains 1 and 3 were scored using validated tools (LIDA and DISCERN). Comprehensiveness was assessed using a criterion checklist related to evidence, advantages and disadvantages, restorations and defects suitable for repairs, and information regarding technical implementation. Generalized linear modeling was used to assess the impact of practice-specific parameters (practice location, practice setting, dental society membership, and year of examination or license to practice dentistry) on the quality of information. An overall quality score was calculated by averaging the quality scores of all three domains and used as primary outcome parameter. Quality scores of all three domains were also assessed individually and used as secondary outcomes. Results: Fifty websites were included. The median score of quality of information was 23.2% (interquartile range [IQR] 21.7%-26.2%). Technical and functional aspects (55.2% [IQR 51.7%-58.6%]) showed significantly higher quality than comprehensiveness of information (8.3% [IQR 8.3%-16.7%]) and generic quality and risk of bias (3.6% [IQR 0.0%-7.1%]; P<.001/Wilcoxon). Quality scores were not related to practice-specific parameters (P>.05/generalized linear modeling). Conclusions: The quality of German-speaking dentist websites on repairs was limited. Despite sufficient technical and functional quality, the provided information was neither comprehensive nor trustworthy. There is great need to improve the quality of information to fully and reliably inform patients, thereby allowing shared decision making.
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  • Journal Article

    Modes of phase separation affecting chromatin regulation 

    Palikyras, Spiros; Papantonis, Argyris
    Open Biology 2019; 9(10): Art. 190167
    It has become evident that chromatin in cell nuclei is organized at multiple scales. Significant effort has been devoted to understanding the connection between the nuclear environment and the diverse biological processes taking place therein. A fundamental question is how cells manage to orchestrate these reactions, both spatially and temporally. Recent insights into phase-separated membraneless organelles may be the key for answering this. Of the two models that have been proposed for phase-separated entities, one largely depends on chromatin-protein interactions and the other on multivalent protein-protein and/or protein-RNA ones. Each has its own characteristics, but both would be able to, at least in part, explain chromatin and transcriptional organization. Here, we attempt to give an overview of these two models and their studied examples to date, before discussing the forces that could govern phase separation and prevent it from arising unrestrainedly.
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