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https://www.readbyqxmd.com/read/28098782/auranofin-inhibits-the-enzyme-activity-of-pasteurella-multocida-toxin-pmt-in-human-cells-and-protects-cells-from-intoxication
#1
Stefan Carle, Thorsten Brink, Joachim H C Orth, Klaus Aktories, Holger Barth
The AB-type protein toxin from Pasteurella multocida (PMT) contains a functionally important disulfide bond within its catalytic domain, which must be cleaved in the host cell cytosol to render the catalytic domain of PMT into its active conformation. Here, we found that the reductive potential of the cytosol of target cells, and more specifically, the activity of the thioredoxin reductase (TrxR) is crucial for this process. This was demonstrated by the strong inhibitory effect of the pharmacological TrxR inhibitor auranofin, which inhibited the intoxication of target cells with PMT, as determined by analyzing the PMT-catalyzed deamidation of GTP-binding proteins (G-proteins) in the cytosol of cells...
January 13, 2017: Toxins
https://www.readbyqxmd.com/read/28068668/the-hippo-kinases-lats1-and-2-control-human-breast-cell-fate-via-crosstalk-with-er%C3%AE
#2
Adrian Britschgi, Stephan Duss, Sungeun Kim, Joana Pinto Couto, Heike Brinkhaus, Shany Koren, Duvini De Silva, Kirsten D Mertz, Daniela Kaup, Zsuzsanna Varga, Hans Voshol, Alexandra Vissieres, Cedric Leroy, Tim Roloff, Michael B Stadler, Christina H Scheel, Loren J Miraglia, Anthony P Orth, Ghislain M C Bonamy, Venkateshwar A Reddy, Mohamed Bentires-Alj
Cell fate perturbations underlie many human diseases, including breast cancer. Unfortunately, the mechanisms by which breast cell fate are regulated are largely unknown. The mammary gland epithelium consists of differentiated luminal epithelial and basal myoepithelial cells, as well as undifferentiated stem cells and more restricted progenitors. Breast cancer originates from this epithelium, but the molecular mechanisms that underlie breast epithelial hierarchy remain ill-defined. Here, we use a high-content confocal image-based short hairpin RNA screen to identify tumour suppressors that regulate breast cell fate in primary human breast epithelial cells...
January 9, 2017: Nature
https://www.readbyqxmd.com/read/28054333/bmp-2-coated-mineral-coated-microparticles-improve-bone-repair-in-atrophic-non-unions
#3
M Orth, N J Kruse, B J Braun, C Scheuer, J H Holstein, A Khalil, X Yu, W L Murphy, T Pohlemann, M W Laschke, M D Menger
Atrophic non-unions are a major clinical problem. Mineral coated microparticles (MCM) are electrolyte-coated hydroxyapatite particles that have been shown in vitro to bind growth factors electrostatically and enable a tuneable sustained release. Herein, we studied whether MCM can be used in vivo to apply Bone Morphogenetic Protein-2 (BMP-2) to improve bone repair of atrophic non-unions. For this purpose, atrophic non-unions were induced in femurs of CD-1 mice (n = 48). Animals either received BMP-2-coated MCM (MCM + BMP; n = 16), uncoated MCM (MCM; n = 16) or no MCM (NONE; n = 16)...
January 2, 2017: European Cells & Materials
https://www.readbyqxmd.com/read/27996032/targeting-bacterial-adherence-inhibits-multidrug-resistant-pseudomonas-aeruginosa-infection-following-burn-injury
#4
Ryan M Huebinger, Daniel H Stones, Marcela de Souza Santos, Deborah L Carlson, Juquan Song, Diana Pereira Vaz, Emma Keen, Steven E Wolf, Kim Orth, Anne Marie Krachler
Classical antimicrobial drugs target proliferation and therefore place microbes under extreme selective pressure to evolve resistance. Alternative drugs that target bacterial virulence without impacting survival directly offer an attractive solution to this problem, but to date few such molecules have been discovered. We previously discovered a widespread group of bacterial adhesins, termed Multivalent Adhesion Molecules (MAMs) that are essential for initial binding of bacteria to host tissues and virulence...
December 20, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27983563/important-but-not-enough-information-about-hd-related-topics-and-peer-and%C3%A2-professional-support-for-young-adults-from-hd-families
#5
Ulrike Braisch, Saul Martinez-Horta, Marcy MacDonald, Michael Orth
BACKGROUND: The number of people affected by Huntington's disease (HD) is far greater than those with manifest HD because it also includes those at risk, both HD gene mutation carriers and family members not carrying the HD mutation. Many relevant needs of young adults from HD families may not be met at present. This includes advice on important life decisions e.g. family planning and having children, psychological support and treatment of medical conditions. OBJECTIVE: To survey the opinion of young adults from HD families about relevance and availability of information and support regarding several aspects of HD...
December 15, 2016: Journal of Huntington's Disease
https://www.readbyqxmd.com/read/27933948/discovery-of-the-3-imino-1-2-4-thiadiazinane-1-1-dioxide-derivative-verubecestat-mk-8931-a-%C3%AE-site-amyloid-precursor-protein-cleaving-enzyme-1-inhibitor-for-the-treatment-of-alzheimer-s-disease
#6
Jack D Scott, Sarah W Li, Andrew P J Brunskill, Xia Chen, Kathleen Cox, Jared N Cumming, Mark Forman, Eric J Gilbert, Robert A Hodgson, Lynn A Hyde, Qin Jiang, Ulrich Iserloh, Irina Kazakevich, Reshma Kuvelkar, Hong Mei, John Meredith, Jeffrey Misiaszek, Peter Orth, Lana M Rossiter, Meagan Slater, Julie Stone, Corey O Strickland, Johannes H Voigt, Ganfeng Wang, Hongwu Wang, Yusheng Wu, William J Greenlee, Eric M Parker, Matthew E Kennedy, Andrew W Stamford
Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Aβ levels in rats and nonhuman primates and CSF Aβ levels in humans...
December 8, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27929302/age-time-period-and-birth-cohort-differences-in-self-esteem-reexamining-a-cohort-sequential-longitudinal-study
#7
Jean M Twenge, Nathan T Carter, W Keith Campbell
Orth, Trzesniewski, and Robins (2010) concluded that the nationally representative Americans' Changing Lives (ACL) cohort-sequential study demonstrated moderate to large age differences in self-esteem, and no birth cohort (generational) differences in the age trajectory. In a reanalysis of these data using 2 different statistical techniques, we find significant increases in self-esteem that could be attributed to birth cohort or time period. First, hierarchical linear modeling analyses with birth cohort as a continuous variable (vs...
December 8, 2016: Journal of Personality and Social Psychology
https://www.readbyqxmd.com/read/27889468/mitochondrial-cristae-remodelling-is-associated-with-disrupted-opa1-oligomerisation-in-the-huntington-s-disease-r6-2-fragment-model
#8
Tanja Hering, Kerstin Kojer, Nathalie Birth, Jaqueline Hallitsch, Jan-Willem Taanman, Michael Orth
There is evidence of an imbalance of mitochondrial fission and fusion in patients with Huntington's disease (HD) and HD animal models. Fission and fusion are important for mitochondrial homeostasis including mitochondrial DNA (mtDNA) maintenance and may be relevant for the selective striatal mtDNA depletion that we observed in the R6/2 fragment HD mouse model. We aimed to investigate the fission/fusion balance and the integrity of the mitochondrial membrane system in cortex and striatum of end-stage R6/2 mice and wild-type animals...
February 2017: Experimental Neurology
https://www.readbyqxmd.com/read/27884336/predictive-value-of-clinical-scoring-and-simplified-gait-analysis-for-acetabulum-fractures
#9
Benedikt J Braun, Julian Wrona, Nils T Veith, Mika Rollman, Marcel Orth, Steven C Herath, Jörg H Holstein, Tim Pohlemann
BACKGROUND: Fractures of the acetabulum show a high, long-term complication rate. The aim of the present study was to determine the predictive value of clinical scoring and standardized, simplified gait analysis on the outcome after these fractures. METHODS: Forty-one patients with acetabular fractures treated between 2008 and 2013 and available, standardized video recorded aftercare were identified from a prospective database. A visual gait score was used to determine the patients walking abilities 6-m postoperatively...
December 2016: Journal of Surgical Research
https://www.readbyqxmd.com/read/27868347/identification-of-extreme-motor-phenotypes-in-huntington-s-disease
#10
Ulrike Braisch, Birgit Hay, Rainer Muche, Dietrich Rothenbacher, G Bernhard Landwehrmeyer, Jeffrey D Long, Michael Orth
The manifestation of motor signs in Huntington's disease (HD) has a well-known inverse relationship with HTT CAG repeat length, but the prediction is far from perfect. The probability of finding disease modifiers is enhanced in individuals with extreme HD phenotypes. We aimed to identify extreme HD motor phenotypes conditional on CAG and age, such as patients with very early or very late onset of motor manifestation. Retrospective data were available from 1,218 healthy controls and 9,743 HD participants with CAG repeats ≥40, and a total of about 30,000 visits...
November 21, 2016: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
https://www.readbyqxmd.com/read/27867017/genomic-amplification-of-fanconi-anemia-complementation-group-a-fanca-in-head-and-neck-squamous-cell-carcinoma-hnscc-cellular-mechanisms-of-radioresistance-and-clinical-relevance
#11
Julia Hess, Kristian Unger, Michael Orth, Ulrike Schötz, Lars Schüttrumpf, Verena Zangen, Igor Gimenez-Aznar, Agata Michna, Ludmila Schneider, Ramona Stamp, Martin Selmansberger, Herbert Braselmann, Ludwig Hieber, Guido A Drexler, Sebastian Kuger, Diana Klein, Verena Jendrossek, Anna A Friedl, Claus Belka, Horst Zitzelsberger, Kirsten Lauber
Radio (chemo) therapy is a crucial treatment modality for head and neck squamous cell carcinoma (HNSCC), but relapse is frequent, and the underlying mechanisms remain largely elusive. Therefore, novel biomarkers are urgently needed. Previously, we identified gains on 16q23-24 to be associated with amplification of the Fanconi anemia A (FancA) gene and to correlate with reduced progression-free survival after radiotherapy. Here, we analyzed the effects of FancA on radiation sensitivity in vitro, characterized the underlying mechanisms, and evaluated their clinical relevance...
February 1, 2017: Cancer Letters
https://www.readbyqxmd.com/read/27852003/the-neuropsychology-of-first-impressions-evidence-from-huntington-s-disease
#12
Reiner Sprengelmeyer, Andrew W Young, Eva-Maria Baldas, Iris Ratheiser, Clare A M Sutherland, Hans-Peter Müller, Georg Grön, Sigurd D Süssmuth, G Bernhard Landwehrmeyer, Michael Orth
Impairments of emotion recognition have been widely documented in Huntington's disease (HD), but little is known concerning how these relate to other aspects of social cognition, including first impressions of traits such as trustworthiness and dominance. Here, we introduce a novel and sensitive method to investigate the ability to evaluate trustworthiness and dominance from facial appearance, with control tasks measuring ability to perceive differences between comparable stimuli. We used this new method together with standard tests of face perception to investigate social cognition in HD...
October 21, 2016: Cortex; a Journal Devoted to the Study of the Nervous System and Behavior
https://www.readbyqxmd.com/read/27800150/immunoglobulin-detection-in-wild-birds-effectiveness-of-three-secondary-anti-avian-igy-antibodies-in-direct-elisas-in-41-avian-species
#13
Carol A Fassbinder-Orth, Travis E Wilcoxen, Tiffany Tran, Raoul K Boughton, Jeanne M Fair, Erik K Hofmeister, Jennifer L Grindstaff, Jen C Owen
Immunological reagents for wild, non-model species are limited or often non-existent for many species.In this study, we compare the reactivity of a new anti-passerine IgY secondary antibody with existing secondary antibodies developed for use with birds. Samples from 41 species from the following six avian orders were analysed: Anseriformes (1 family, 1 species), Columbiformes (1 family, 2 species), Galliformes (1 family, 1 species), Passeriformes (16 families, 34 species), Piciformes (1 family, 2 species) and Suliformes (1 family, 1 species)...
October 2016: Methods in Ecology and Evolution
https://www.readbyqxmd.com/read/27797677/diagnostic-performance-of-us-for-differentiating-perforated-from-nonperforated-pediatric-appendicitis-a-prospective-cohort-study
#14
Jennifer L Carpenter, Robert C Orth, Wei Zhang, Monica E Lopez, Kate L Mangona, R Paul Guillerman
Purpose To prospectively evaluate the diagnostic performance of ultrasonography (US) for differentiating perforated from nonperforated pediatric appendicitis and to investigate the association between specific US findings and perforation. Materials and Methods This HIPAA-compliant study had institutional review board approval, and the need for informed consent was waived. All abdominal US studies performed for suspected pediatric appendicitis at one institution from July 1, 2013, to July 9, 2014, were examined prospectively...
October 31, 2016: Radiology
https://www.readbyqxmd.com/read/27789340/macroscopic-cartilage-repair-scoring-of-defect-fill-integration-and-total-points-correlate-with-corresponding-items-in-histological-scoring-systems-a-study-in-adult-sheep
#15
Lars Goebel, Patrick Orth, Magali Cucchiarini, Dietrich Pape, Henning Madry
OBJECTIVE: To correlate osteochondral repair assessed by validated macroscopic scoring systems with established semiquantitative histological analyses in an ovine model and to test the hypothesis that important macroscopic individual categories correlate with their corresponding histological counterparts. METHODS: In the weight-bearing portion of medial femoral condyles (n = 38) of 19 female adult Merino sheep (age 2 to 4 years; weight 70 ± 20 kg) full-thickness chondral defects were created (size 4 x 8 mm; ICRS grade 3C) and treated with Pridie drilling...
October 24, 2016: Osteoarthritis and Cartilage
https://www.readbyqxmd.com/read/27743426/14-3-3-proteins-regulate-k2p-5-1-surface-expression-on-t-lymphocytes
#16
Juncal Fernández-Orth, Petra Ehling, Tobias Ruck, Susann Pankratz, Majella-Sophie Hofmann, Peter Landgraf, Daniela C Dieterich, Karl-Heinz Smalla, Thilo Kähne, Guiscard Seebohm, Thomas Budde, Heinz Wiendl, Stefan Bittner, Sven G Meuth
K2P 5.1 channels (also called TASK-2 or Kcnk5) have already been shown to be relevant in the pathophysiology of autoimmune disease because they are known to be upregulated on peripheral and central T lymphocytes of multiple sclerosis (MS) patients. Moreover, overexpression of K2P 5.1 channels in vitro provokes enhanced T-cell effector functions. However, the molecular mechanisms regulating intracellular K2P 5.1 channel trafficking are unknown so far. Thus, the aim of the study is to elucidate the trafficking of K2P 5...
January 2017: Traffic
https://www.readbyqxmd.com/read/27732858/breast-cancer-derived-lung-metastases-show-increased-pyruvate-carboxylase-dependent-anaplerosis
#17
Stefan Christen, Doriane Lorendeau, Roberta Schmieder, Dorien Broekaert, Kristine Metzger, Koen Veys, Ilaria Elia, Joerg Martin Buescher, Martin Franz Orth, Shawn Michael Davidson, Thomas Georg Philipp Grünewald, Katrien De Bock, Sarah-Maria Fendt
Cellular proliferation depends on refilling the tricarboxylic acid (TCA) cycle to support biomass production (anaplerosis). The two major anaplerotic pathways in cells are pyruvate conversion to oxaloacetate via pyruvate carboxylase (PC) and glutamine conversion to α-ketoglutarate. Cancers often show an organ-specific reliance on either pathway. However, it remains unknown whether they adapt their mode of anaplerosis when metastasizing to a distant organ. We measured PC-dependent anaplerosis in breast-cancer-derived lung metastases compared to their primary cancers using in vivo (13)C tracer analysis...
October 11, 2016: Cell Reports
https://www.readbyqxmd.com/read/27699957/the-vulnerability-of-study-participants-in-the-context-of-transnational-biomedical-research-from-conceptual-considerations-to-practical-implications
#18
Helen Grete Orth, Silke Schicktanz
Outsourcing clinical trials sponsored by pharmaceutical companies from industrialized countries to low- (middle)-income countries - summarized as transnational biomedical research (TBR) - has lead to many concerns about ethical standards. Whether study participants are particularly vulnerable is one of those concerns. However, the concept of vulnerability is still vague and varies in its definition. Despite the fact that important international ethical guidelines such as the Declaration of Helsinki by the World Medical Association or the Ethical Guidelines for Biomedical Research Involving Human Subjects by the Council of International Organizations of Medical Sciences refer to vulnerability as ethical principle, each of their approaches are different...
October 4, 2016: Developing World Bioethics
https://www.readbyqxmd.com/read/27649498/high-throughput-random-mutagenesis-and-single-molecule-real-time-sequencing-of-the-muscle-nicotinic-acetylcholine-receptor
#19
Paul J Groot-Kormelink, Sandrine Ferrand, Nicholas Kelley, Anke Bill, Felix Freuler, Pierre-Eloi Imbert, Anthony Marelli, Nicole Gerwin, Lucia G Sivilotti, Loren Miraglia, Anthony P Orth, Edward J Oakeley, Ulrich Schopfer, Sandra Siehler
High throughput random mutagenesis is a powerful tool to identify which residues are important for the function of a protein, and gain insight into its structure-function relation. The human muscle nicotinic acetylcholine receptor was used to test whether this technique previously used for monomeric receptors can be applied to a pentameric ligand-gated ion channel. A mutant library for the α1 subunit of the channel was generated by error-prone PCR, and full length sequences of all 2816 mutants were retrieved using single molecule real time sequencing...
2016: PloS One
https://www.readbyqxmd.com/read/27624438/basic-science-of-osteoarthritis
#20
Magali Cucchiarini, Laura de Girolamo, Giuseppe Filardo, J Miguel Oliveira, Patrick Orth, Dietrich Pape, Pascal Reboul
Osteoarthritis (OA) is a prevalent, disabling disorder of the joints that affects a large population worldwide and for which there is no definitive cure. This review provides critical insights into the basic knowledge on OA that may lead to innovative end efficient new therapeutic regimens. While degradation of the articular cartilage is the hallmark of OA, with altered interactions between chondrocytes and compounds of the extracellular matrix, the subchondral bone has been also described as a key component of the disease, involving specific pathomechanisms controlling its initiation and progression...
December 2016: Journal of Experimental Orthopaedics
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