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https://www.readbyqxmd.com/read/28917824/parkinson-s-disease-susceptibility-variants-and-severity-of-lewy-body-pathology
#1
Michael G Heckman, Koji Kasanuki, Nancy N Diehl, Shunsuke Koga, Alexandra Soto, Melissa E Murray, Dennis W Dickson, Owen A Ross
INTRODUCTION: Meta-analyses of genome-wide association studies (GWAS) have established common genetic risk factors for clinical Parkinson's disease (PD); however, associations between these risk factors and quantitative neuropathologic markers of disease severity have not been well-studied. This study evaluated associations of nominated variants from the most recent PD GWAS meta-analysis with Lewy body disease (LBD) subtype (brainstem, transitional, or diffuse) and pathologic burden of LB pathology as measured by LB counts in five cortical regions in a series of LBD cases...
September 11, 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/28901275/reverse-induced-fit-driven-mas-downstream-transduction-looking-for-metabotropic-agonists
#2
Larissa Pernomian, Mayara Santos Gomes, Carlos Henrique Tomich de Paula da Silva, Joaquin Campos
The protective effects assigned to MAS receptors activation have spurred a great interest in the development of MAS agonists for clinical purposes. However, the current bases that drive the design of these ligands preclude important concepts recently addressed for MAS activation. Emerging data confirmed that physiological concentrations of peptide MAS agonists induce an atypical signaling that does not reach the metabotropic efficacy of constitutive MAS activation. The canonical activation of MAS-coupled G proteins is only achieved by supraphysiological concentrations of peptide MAS agonists or physiological concentrations of chemically modified analogues...
September 11, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28894088/a-de-novo-substructure-generation-algorithm-for-identifying-the-privileged-chemical-fragments-of-liver-x-receptor%C3%AE-agonists
#3
He Peng, Zhihong Liu, Xin Yan, Jian Ren, Jun Xu
Liver X receptorβ (LXRβ) is a promising therapeutic target for lipid disorders, atherosclerosis, chronic inflammation, autoimmunity, cancer and neurodegenerative diseases. Druggable LXRβ agonists have been explored over the past decades. However, the pocket of LXRβ ligand-binding domain (LBD) is too large to predict LXRβ agonists with novel scaffolds based on either receptor or agonist structures. In this paper, we report a de novo algorithm which drives privileged LXRβ agonist fragments by starting with individual chemical bonds (de novo) from every molecule in a LXRβ agonist library, growing the bonds into substructures based on the agonist structures with isomorphic and homomorphic restrictions, and electing the privileged fragments from the substructures with a popularity threshold and background chemical and biological knowledge...
September 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28840137/uptake-index-of-123-i-metaiodobenzylguanidine-myocardial-scintigraphy-for-diagnosing-lewy-body-disease
#4
Yoshito Kamiya, Satoru Ota, Shintaro Okumiya, Kosuke Yamashita, Akihiro Takaki, Shigeki Ito
OBJECTIVES: Iodine-123 metaiodobenzylguanidine ((123)I-MIBG) myocardial scintigraphy has been used to evaluate cardiac sympathetic denervation in Lewy body disease (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The heart-to-mediastinum ratio (H/M) in PD and DLB is significantly lower than that in Parkinson's plus syndromes and Alzheimer's disease. Although this ratio is useful for distinguishing LBD from non-LBD, it fluctuates depending on the system performance of the gamma cameras...
2017: Asia Oceania Journal of Nuclear Medicine & Biology
https://www.readbyqxmd.com/read/28838802/literature-based-discovery-models-methods-and-trends
#5
REVIEW
M S Sam Henry, Bridget T McInnes
OBJECTIVES: This paper provides an introduction and overview of literature based discovery (LBD) in the biomedical domain. It introduces the reader to modern and historical LBD models, key system components, evaluation methodologies, and current trends. After completion, the reader will be familiar with the challenges and methodologies of LBD. The reader will be capable of distinguishing between recent LBD systems and publications, and be capable of designing an LBD system for a specific application...
August 21, 2017: Journal of Biomedical Informatics
https://www.readbyqxmd.com/read/28838607/structural-and-biochemical-characterization-of-ligand-recognition-by-cysb-the-master-regulator-of-sulfate-metabolism
#6
Monica Mittal, Appu Kumar Singh, S Kumaran
CysB, a member of LysR-type transcriptional regulators, up-regulates the expression of genes associated with sulfate metabolism and cysteine biosynthesis. CysB is activated under sulfur limiting conditions by O-acetylserine (OAS) and N-acetylserine (NAS), but the activation mechanism of CysB remain unknown. Here, we report four crystal structures of ligand binding domains of CysB (CysB-LBD) in apo form and in complex with sulfate, OAS, and NAS. Our results show that CysB has two distinct allosteric ligand binding sites; a sulfate and NAS specific site-1 and a second, NAS and OAS specific site-2...
August 21, 2017: Biochimie
https://www.readbyqxmd.com/read/28836490/unawareness-for-motor-impairment-and-distorted-perception-of-task-difficulty
#7
Gianna Cocchini, Nicoletta Beschin, Sergio Della Sala
OBJECTIVES: Anosognosia for motor impairment is a complex syndrome that can manifest itself under different forms, guiding patients' behavior and task decisions. However, current diagnostic tools tend to evaluate only more explicit aspects of anosognosia (asking the patients about their motor abilities) and fail to address more subtle features of awareness. We have developed a new assessment measure, the ECT (Errand Choice Test), where patients are asked to judge task difficulty rather than estimate their own impairment...
August 24, 2017: Journal of the International Neuropsychological Society: JINS
https://www.readbyqxmd.com/read/28833672/a-large-scale-expression-strategy-for-multimeric-extracellular-protein-complexes-using-drosophila-s2-cells-and-its-application-to-the-recombinant-expression-of-heterodimeric-ligand-binding-domains-of-taste-receptor
#8
Atsuko Yamashita, Eriko Nango, Yuji Ahikawa
Many of the extracellular proteins or extracellular domains of plasma membrane proteins exist or function as homo- or heteromeric multimer protein complexes. Successful recombinant production of such proteins is often achieved by co-expression of the components using eukaryotic cells via the secretory pathway. Here we report a strategy addressing large-scale expression of hetero-multimeric extracellular domains of plasma membrane proteins and its application to the extracellular domains of a taste receptor...
August 19, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28832499/a-molecular-modeling-study-of-the-hydroxyflutamide-resistance-mechanism-induced-by-androgen-receptor-mutations
#9
Hong-Li Liu, Hai-Yang Zhong, Tian-Qing Song, Jia-Zhong Li
Hydroxyflutamide (HF), an active metabolite of the first generation antiandrogen flutamide, was used in clinic to treat prostate cancer targeting androgen receptor (AR). However, a drug resistance problem appears after about one year's treatment. AR T877A is the first mutation that was found to cause a resistance problem. Then W741C_T877A and F876L_T877A mutations were also reported to cause resistance to HF, while W741C and F876L single mutations cannot. In this study, molecular dynamics (MD) simulations combined with the molecular mechanics generalized Born surface area (MM-GBSA) method have been carried out to analyze the interaction mechanism between HF and wild-type (WT)/mutant ARs...
August 23, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28819159/identification-of-boric-acid-as-a-novel-chemoattractant-and-elucidation-of-its-chemoreceptor-in-ralstonia-pseudosolanacearum-ps29
#10
Akiko Hida, Shota Oku, Yutaka Nakashimada, Takahisa Tajima, Junichi Kato
Chemotaxis enables bacteria to move toward more favorable environmental conditions. We observed chemotaxis toward boric acid by Ralstonia pseudosolanacearum Ps29. At higher concentrations, the chemotactic response of R. pseudosolanacearum toward boric acid was comparable to or higher than that toward L-malate, indicating that boric acid is a strong attractant for R. pseudosolanacearum. Chemotaxis assays under different pH conditions suggested that R. pseudosolanacearum recognizes B(OH)3 (or B(OH3) + B(OH)4(-)) but not B(OH)4(-) alone...
August 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28811268/antecedent-adhd-dementia-and-metabolic-dysregulation-a-u-s-based-cohort-analysis
#11
Keith Fluegge, Kyle Fluegge
INTRODUCTION: Epidemiological and genetic studies have reported a link between antecedent ADHD and dementia. The underpinning mechanisms of these associations are not known and have generated considerable speculation. METHODS: We have extracted hospitalization discharge data on dementia and ADHD (representing a severe phenotype) from the Healthcare Cost and Utilization Project (HCUPnet) and utilized a Poisson regression with two-ways fixed effects to investigate this association...
August 12, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28808912/molecular-imaging-and-updated-diagnostic-criteria-in-lewy-body-dementias
#12
REVIEW
Nicolaas I Bohnen, Martijn L T M Müller, Kirk A Frey
PURPOSE OF REVIEW: The aims of the study were to review recent advances in molecular imaging in the Lewy body dementias (LBD) and determine if these may support the clinical but contested temporal profile distinction between Parkinson disease (PD) with dementia (PDD) versus dementia with Lewy bodies (DLB). RECENT FINDINGS: There do not appear to be major regional cerebral metabolic or neurotransmitter distinctions between PDD and DLB. However, recent studies highlight the relative discriminating roles of Alzheimer proteinopathies...
August 14, 2017: Current Neurology and Neuroscience Reports
https://www.readbyqxmd.com/read/28801984/low-dose-bortezomib-and-dexamethasone-as-primary-therapy-in-elderly-patients-with-waldenstr%C3%B3-m-macroglobulinemia
#13
Ya-Ping Zhang, Xi Yang, Zeng-Hua Lin, Xin-Feng Wang, Xin Cao, Xue-Fen You, Hong-Ming Huang, Wen-Yu Shi, Hong Liu
OBJECTIVE: This retrospective study was designed to determine the efficacy and safety of low-dose bortezomib and dexamethasone (lBD) in elderly Chinese patients with Waldenstrӧm macroglobulinemia (WM). METHODS: Ten WM patients aged over 60 years received first-line treatment with lBD. RESULTS: The median age was 70 years (range, 61-77 years). The overall response rate was 80%, including 1 patient who achieved a complete response, 1 patient with very good partial response, and 6 patients with a partial response...
August 12, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28775145/bypassing-drug-resistance-mechanisms-of-prostate-cancer-with-small-molecules-that-target-androgen-receptor-chromatin-interactions
#14
Kush Dalal, Meixia Che, Nanette S Que, Aishwariya Sharma, Rendong Yang, Nada Lallous, Hendrik Borgmann, Deniz Ozistanbullu, Ronnie Tse, Fuqiang Ban, Huifang Li, Kevin J Tam, Mani Roshan-Moniri, Eric Leblanc, Martin E Gleave, Daniel T Gewirth, Scott M Dehm, Artem Cherkasov, Paul S Rennie
Human androgen receptor (AR) is a hormone-activated transcription factor that is an important drug-target in the treatment of prostate cancer. Current small molecule AR-antagonists, such as enzalutamide, compete with androgens that bind to the steroid binding pocket of the AR ligand binding domain (LBD). In castration-resistant prostate cancer (CRPC), drug-resistance can manifest through AR-LBD mutations that convert AR-antagonists into agonists, or by expression of AR-variants lacking the LBD. Such treatment resistance underscores the importance of novel ways of targeting the AR...
August 3, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28766014/high-temperature-promotion-of-callus-formation-requires-the-bin2-arf-lbd-axis-in-arabidopsis
#15
Kyounghee Lee, Pil Joon Seo
The auxin-brassinosteroid interaction involving the BIN2-ARF-LBD axis plays a key role in temperature-dependent callus formation in Arabidopsis. An extensive web of multiple hormone signaling pathways underlies callus formation. Here, we report that a brassinosteroid (BR) signaling component, BR-INSENSITIVE 2 (BIN2), positively regulates callus formation. The BIN2 kinase promotes transcriptional activities of AUXIN RESPONSE FACTOR 7 (ARF7) and ARF19 and subsequently activates expression of LATERAL ORGAN BOUNDARIES-DOMAIN 16 (LBD16) and LBD29 during callus formation...
August 1, 2017: Planta
https://www.readbyqxmd.com/read/28761055/a-single-channel-mechanism-for-pharmacological-potentiation-of-glun1-glun2a-nmda-receptors
#16
Divyan A Chopra, Kiran Sapkota, Mark W Irvine, Guangyu Fang, David E Jane, Daniel T Monaghan, Shashank M Dravid
NMDA receptors (NMDARs) contribute to several neuropathological processes. Novel positive allosteric modulators (PAMs) of NMDARs have recently been identified but their effects on NMDAR gating remain largely unknown. To this end, we tested the effect of a newly developed molecule UBP684 on GluN1/GluN2A receptors. We found that UBP684 potentiated the whole-cell currents observed under perforated-patch conditions and slowed receptor deactivation. At the single channel level, UBP684 produced a dramatic reduction in long shut times and a robust increase in mean open time...
July 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28753698/complete-endoscopic-sphincterotomy-with-vs-without-large-balloon-dilation-for-the-removal-of-large-bile-duct-stones-randomized-multicenter-study
#17
David Karsenti, Emmanuel Coron, Geoffroy Vanbiervliet, Jocelyn Privat, Eric Kull, Philippe Bichard, Bastien Perrot, Vincent Quentin, Arnaud Duriez, Franck Cholet, Clément Subtil, Jean Christophe Duchmann, Christine Lefort, Hervé Hudziak, Stéphane Koch, Philippe Granval, Stéphane Lecleire, Antoine Charachon, Karl Barange, Elodie Metivier Cesbron, Axel De Widerspach, Yann Le Baleur, Marc Barthet, Laurent Poincloux
Background and study aims Endoscopic sphincterotomy plus large-balloon dilation (ES-LBD) has been reported as an alternative to endoscopic sphincterotomy for the removal of bile duct stones. This multicenter study compared complete endoscopic sphincterotomy with vs. without large-balloon dilation for the removal of large bile duct stones. This is the first randomized multicenter study to evaluate these procedures in patients with exclusively large common bile duct (CBD) stones. Methods Between 2010 and 2015, 150 patients with one or more common bile duct stones ≥ 13 mm were randomized to two groups: 73 without balloon dilation (conventional group), 77 with balloon dilation (ES-LBD group)...
July 28, 2017: Endoscopy
https://www.readbyqxmd.com/read/28753664/validation-of-a-novel-mho-microarray-for-a-comprehensive-characterisation-of-the-mycoplasma-hominis-action-in-hela-cell-infection
#18
Birgit Henrich, Freya Kretzmer, René Deenen, Karl Köhrer
Mycoplasma hominis is the second smallest facultative pathogen of the human urogenital tract. With less than 600 protein-encoding genes, it represents an ideal model organism for the study of host-pathogen interactions. For a comprehensive characterisation of the M. hominis action in infection a customized Mho microarray, which was based on two genome sequences (PG21 and LBD-4), was designed to analyze the dynamics of the mycoplasma transcriptome during infection and validated for M. hominis strain FBG. RNA preparation was evaluated and adapted to ensure the highest recovery of mycoplasmal mRNAs from in vitro HeLa cell infection assays...
2017: PloS One
https://www.readbyqxmd.com/read/28741230/new-therapeutic-strategies-for-lewy-body-dementias
#19
REVIEW
Latha Velayudhan, Dominic Ffytche, Clive Ballard, Dag Aarsland
This article reviews current treatment strategies and recent advances for the Lewy body dementias (LBDs). Current available symptom treatment strategies are based on monoaminergic, cholinergic and glutaminergic neurotransmitter systems. Relatively robust evidence exists for cholinesterase inhibitors for cognitive impairment in LBD and in Parkinson's disease for antidepressants, clozapine and recently pimavanserin for psychosis. interpidine (RVT 101) and nelotanserin are currently under investigation. Non-pharmacological interventions, such as cognitive stimulation, physical exercises and neuromodulation strategies, may be useful in Parkinson's disease but have not yet been tested in dementias...
September 2017: Current Neurology and Neuroscience Reports
https://www.readbyqxmd.com/read/28739805/functional-insights-into-the-mode-of-dna-and-ligand-binding-of-the-tetr-family-regulator-tylp-from-streptomyces-fradiae
#20
Shamayeeta Ray, Anwesha Maitra, Anwesha Biswas, Santosh Panjikar, Jagannath Mondal, Ruchi Anand
Tetracycline Repressors (TetRs) modulate multi-drug efflux pathways in several pathogenic bacteria. In Streptomyces, they additionally regulate secondary metabolic pathways like antibiotic production. For instance, in the antibiotic producer Streptomyces fradiae, a layered network of TetRs regulate the levels of commercially important antibiotic tylosin, with TylP occupying the top of this cascading network. TetRs exist in two functional states; the DNA-bound and the ligand-bound form, which are allosterically regulated...
July 24, 2017: Journal of Biological Chemistry
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