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Geetha Rani Yuvaraj, Baddrireddi Subhadra Lakshmi
Estrogen receptor α (ER α) is an important therapeutic target in the regulation of ligand dependent signaling in breast cancer. The current study investigates the anti-estrogenic potential of the Diarylheptanoid, 5-hydroxy-7-(4-hydroxy-3 methoxyphenyl)-1-phenyl-3-heptanone (DAH) in silico. Rigid Docking analysis of DAH at the ligand binding domain (LBD) of ER α showed hydrogen bond interactions with Arg394 and Glu353 at the active site, similar to the positive controls 4 - Hydroxy Tamoxifen (4-OHT) and Fulvestrant (FUL)...
March 20, 2018: Journal of Biomolecular Structure & Dynamics
Susanna Nuvoli, Barbara Palumbo, Simona Malaspina, Giuseppe Madeddu, Angela Spanu
Nuclear medicine procedures are widely used as "in vivo" biomarkers in a large number of brain diseases, especially in the diagnosis of Parkinson's disease (PD) and of parkinsonian disorders (pD). Furthermore, nuclear medicine is used in the differential diagnosis of dementias especially Alzheimer's disease (AD) and dementia with Lewy's bodies (LBD) which share many clinical symptoms and often LBD is misdiagnosed as AD. The differential diagnosis between these clinical entities is crucial for treatment since LBD also shares some clinical symptoms with parkinsonian disorders...
March 20, 2018: Hellenic Journal of Nuclear Medicine
Nicolas Daffern, Zhonglei Chen, Yongbo Zhang, Leslie Pick, Ishwar Radhakrishnan
The ligand-binding domains (LBD) of the NR5A subfamily of nuclear receptors activate transcription via ligand-dependent and ligand-independent mechanisms. The Drosophila Ftz-F1 receptor (NR5A3) belongs to the latter category and its ligand-independence is attributed to a short helical segment (6) within the protein that resides in the canonical ligand-binding pocket (LBP) in the crystalline state. Here, we show that the 6 helix is dynamic in solution when Ftz-F1 is bound to the LxxLL motif of its cofactor Ftz, undergoing motions on the fast (picosecond-nanosecond) as well as slow (microsecond-millisecond) timescales...
March 16, 2018: Biochemistry
Jessica Tulloch, Lesley Leong, Sunny Chen, C Dirk Keene, Steven P Millard, Andrew Shutes-David, Oscar L Lopez, Julia Kofler, Jeffrey A Kaye, Randy Woltjer, Peter T Nelson, Janna H Neltner, Gregory A Jicha, Douglas Galasko, Eliezer Masliah, James B Leverenz, Chang-En Yu, Debby Tsuang
INTRODUCTION: Inheritance of the ε4 allele of apolipoprotein E (APOE) increases a person's risk of developing both Alzheimer's disease (AD) and Lewy body dementia (LBD), yet the underlying mechanisms behind this risk are incompletely understood. The recent identification of reduced APOE DNA methylation in AD postmortem brains prompted this study to investigate APOE methylation in LBD. METHODS: Genomic DNA from postmortem brain tissues (frontal lobe and cerebellum) of neuropathological pure (np) controls and npAD, LBD + AD, and npLBD subjects were bisulfite pyrosequenced...
March 12, 2018: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
Po-Chi Chan, Cheng-Yu Wei, Guang-Uei Hung, Pai-Yi Chiu
Objectives: The association of vascular risk factors (VRFs) with incidence of Alzheimer's disease (AD) and vascular dementia (VaD) has been well studied. However, the association between VRFs and non-AD dementia is seldom investigated. In this study, we aim to compare the concurrence of VRFs of Lewy body dementia (LBD) to AD. Materials & Methods: We consecutively enrolled patients with dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), and AD, and the prevalence of arterial hypertension, diabetes mellitus, hypercholesterolemia, hyperlipidemia, smoking, and obesity was assessed and compared...
March 2018: Brain and Behavior
Hiroshige Fujishiro, Masato Okuda, Kunihiro Iwamoto, Seiko Miyata, Youta Torii, Shuji Iritani, Norio Ozaki
AIMS: REM sleep behavior disorder (RBD) and psychiatric symptoms often antedate the clinical diagnosis of Parkinson's disease / dementia with Lewy bodies. The purpose of this study is to investigate RBD and its relevance to Lewy body disease (LBD) in patients with late-onset psychiatric disorders. METHODS: Study subjects included 19 patients with late-onset psychiatric disorders who exhibited REM sleep without atonia (RWA), which is a hallmark of RBD on polysomnography, at our psychiatric ward...
March 14, 2018: Psychiatry and Clinical Neurosciences
Emma Robson, Clare Tweedy, Nelson Manzanza, John-Paul Taylor, Peter Atkinson, Fiona Randall, Amy Reeve, Gavin J Clowry, Fiona E N LeBeau
Intracellular accumulation of alpha-synuclein (α-syn) is a key pathological process evident in Lewy body dementias (LBD), including Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). LBD results in marked cognitive impairments and changes in cortical networks. To assess the impact of abnormal α-syn expression on cortical network oscillations relevant to cognitive function, we studied changes in fast beta/gamma network oscillations in the hippocampus in a mouse line that over-expresses human mutant α-syn (A30P)...
March 7, 2018: Neuroscience
Mohamed I Radwan, Mohamed H Emara, Ibrahim M Ibrahim, Mahmoud E Moursy
BACKGROUND AND STUDY AIM: Removal of large common bile duct (CBD) stones is one of the challenges faced during endoscopic retrograde cholangiopancreatography, and it seems more difficult in cirrhotic patients because of suspected higher rates of adverse events, especially bleeding diathesis. This study aimed at comparing the success rate and complications between mechanical lithotripsy (ML) and large balloon dilation (LBD) after endoscopic sphincterotomy in patients with liver cirrhosis...
March 7, 2018: Journal of Clinical Gastroenterology
Kyounghee Lee, Ok-Sun Park, Pil Joon Seo
Tissue identity is plastically regulated in plants, and chromatin modifiers/remodelers are main players of cell fate changes. Callus formation is an intriguing example of cell fate transition. Leaf explants can form callus tissues, which resemble lateral root primordium, on callus-inducing medium (CIM). We recently demonstrated that the ARABIDOPSIS TRITHORAX-RELATED 2 (ATXR2) protein, which deposits H3K36me3 at genomic level, regulates callus formation on CIM. Consistent with the role of ATXR2 in conferring root identity, lateral root formation was significantly reduced in atxr2-deficient mutants...
March 8, 2018: Plant Signaling & Behavior
Paul L Wood, Soumya Tippireddy, Joshua Feriante, Randall L Woltjer
BACKGROUND: Research from our laboratory, and that of other investigators, has demonstrated augmented levels of diacylglycerols (DAG) in the frontal cortex and plasma of subjects with Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI). We have extended these observations to investigate the frontal cortex of subjects with Parkinson's disease (PD) and Lewy Body Disease (LBD), with and without coexisting pathologic features of AD. METHODS/PRINCIPAL FINDINGS: Utilizing a high-resolution mass spectrometry analytical platform, we clearly demonstrate that DAG levels are significantly increased in the frontal cortex of subjects with PD, LBD with intermediate neocortical AD neuropathology, and in LBD with established neocortical AD neuropathology...
2018: PloS One
Nicolaas I Bohnen, Michel J Grothe, Nicola J Ray, Martijn L T M Müller, Stefan J Teipel
Purpose of review: Although the cholinergic hypothesis of dementia provided a successful paradigm for the development of new drugs for dementia, this hypothesis has waned in popularity. Cholinergic brain imaging may provide novel insights into the viability of this hypothesis. Recent findings: Cholinergic receptor and forebrain volumetric studies suggest an important role of the cholinergic system in maintaining brain network integrity that may deteriorate with cognitive decline in Alzheimer disease (AD) and Lewy body disorders (LBD)...
March 2018: Current Geriatrics Reports
Ana Gámez-Valero, Alex Iranzo, Monica Serradell, Dolores Vilas, Joan Santamaria, Carles Gaig, Ramiro Álvarez, Aurelio Ariza, Eduardo Tolosa, Katrin Beyer
INTRODUCTION: Glucocerebrosidase (GBA) gene variants are associated with the development of the Lewy body disorders (LBD) Parkinson disease (PD) and dementia with Lewy bodies (DLB). Idiopathic REM sleep behavior disorder (IRBD) represents prodromal LBD in most instances. We investigated whether GBA variants are overrepresented in IRBD and if their presence shortens the time to conversion to clinically-defined LBD. METHODS: All GBA coding exons from 69 polysomnography-confirmed IRBD patients and 84 matched controls were sequenced by the Sanger method...
February 21, 2018: Parkinsonism & related Disorders
David J Irwin, Sharon X Xie, David Coughlin, Naomi Nevler, Rizwan S Akhtar, Corey T McMillan, Edward B Lee, David A Wolk, Daniel Weintraub, Alice Chen-Plotkin, John E Duda, Meredith Spindler, Andrew Siderowf, Howard I Hurtig, Leslie M Shaw, Murray Grossman, John Q Trojanowski
OBJECTIVE: To test the association of antemortem CSF biomarkers with postmortem pathology in Lewy body disorders (LBD). METHODS: Patients with autopsy-confirmed LBD (n = 24) and autopsy-confirmed Alzheimer disease (AD) (n = 23) and cognitively normal (n = 36) controls were studied. In LBD, neuropathologic criteria defined Lewy body α-synuclein (SYN) stages with medium/high AD copathology (SYN + AD = 10) and low/no AD copathology (SYN - AD = 14). Ordinal pathology scores for tau, β-amyloid (Aβ), and SYN pathology were averaged across 7 cortical regions to obtain a global cerebral score for each pathology...
February 21, 2018: Neurology
Yonghui Wang, Wei Cai, Ting Tang, Qian Liu, Ting Yang, Liuqing Yang, Yingli Ma, Guifeng Zhang, Yafei Huang, Xiaoxia Song, Lisa A Orband-Miller, Qianqian Wu, Ling Zhou, Zhijun Xiang, Jia-Ning Xiang, Stewart Leung, Liming Shao, Xichen Lin, Mercedes Lobera, Feng Ren
Biaryl amides as new RORγt modulators were discovered. The crystal structure of biaryl amide agonist 6 in complex with RORγt ligand binding domain (LBD) was resolved, and both "short" and "long" inverse agonists were obtained by removing from 6 or adding to 6 a proper structural moiety. While "short" inverse agonist ( 8 ) recruits a corepressor peptide and dispels a coactivator peptide, "long" inverse agonist ( 9 ) dispels both. The two types of inverse agonists can be utilized as potential tools to study mechanisms of Th17 transcriptional network inhibition and related disease biology...
February 8, 2018: ACS Medicinal Chemistry Letters
Simone Brogi, Margherita Brindisi, Stefania Butini, Giridhar Uttam Kshirsagar, Samuele Maramai, Giulia Chemi, Sandra Gemma, Giuseppe Campiani, Ettore Novellino, Paolo Fiorenzani, Jessica Pinassi, Anna Maria Aloisi, Mikko Gynther, Raminta Venskutonyte, Liwei Han, Karla Frydenvang, Jette Sandholm Kastrup, Darryl S Pickering
Starting from 1-4 and 7 structural templates, analogues based on bioisosteric replacements (5a-c vs 1, 2 and 6 vs 7) were synthesized for completing the SAR analysis. Interesting binding properties at GluA2, GluK1 and GluK3 receptors were discovered. The requirements for GluK3 interaction were elucidated determining the X-ray structures of the GluK3-LBD with 2 and 5c and by computational studies. Antinociceptive potential was demonstrated for GluK1 partial agonist 3 and antagonist 7 (2 mg/kg ip).
February 16, 2018: Journal of Medicinal Chemistry
Matilde Fernández, Álvaro Ortega, Miriam Rico-Jiménez, David Martín-Mora, Abdelali Daddaoua, Miguel A Matilla, Tino Krell
The majority of bacterial chemoreceptors remain functionally un-annotated. The knowledge of chemoreceptor function, however, is indispensable to understanding the evolution of the chemotaxis system in bacteria with different lifestyles. Significant progress in the annotation of chemoreceptor function has been made using experimental strategies that are based on the individual, genetically engineered ligand binding domain (LBD) of chemoreceptors. There is now evidence that all major classes of LBDs can be produced as individual domains that retain their ligand binding activity...
2018: Methods in Molecular Biology
David Martín-Mora, Álvaro Ortega, Francisco J Pérez-Maldonado, Tino Krell, Miguel A Matilla
Chemotaxis toward organic acids has been associated with colonization fitness and virulence and the opportunistic pathogen Pseudomonas aeruginosa exhibits taxis toward several tricarboxylic acid intermediates. In this study, we used high-throughput ligand screening and isothermal titration calorimetry to demonstrate that the ligand binding domain (LBD) of the chemoreceptor PA2652 directly recognizes five C4-dicarboxylic acids with KD values ranging from 23 µM to 1.24 mM. In vivo experimentation showed that three of the identified ligands act as chemoattractants whereas two of them behave as antagonists by inhibiting the downstream chemotaxis signalling cascade...
February 1, 2018: Scientific Reports
Wen-Jing You, Xiao-Ying Tan, Guang-Hui Chen, Chuan-Chuan Wei, Dan-Dan Li
Peroxisome proliferator-activated receptor beta (PPARβ) is a ligand-activated transcription factor that plays critical roles in the regulation of many important physiological processes. In this study, PPARβ was cloned and characterized in yellow catfish Pelteobagrus fulvidraco. PPARβ cDNA was 2350 bp in length with an open reading frame (ORF) of 1530 bp, encoding 509 amino acids, a 5'-untranslated region (UTR) of 474 bp, and a 3'-UTR of 346 bp. Similar to mammals, PPARβ protein was predicted to consist of four domains, the A/B domain, DNA-binding domain (DBD), D domain, and ligand-binding domain (LBD)...
February 1, 2018: Fish Physiology and Biochemistry
Chul Hyoung Lyoo, Hanna Cho, Jae Yong Choi, Young Hoon Ryu, Myung Sik Lee
In recent years, several radiotracers that selectively bind to pathological tau proteins have been developed. Evidence is emerging that binding patterns of in vivo tau positron emission tomography (PET) studies in Alzheimer's disease (AD) patients closely resemble the distribution patterns of known neurofibrillary tangle pathology, with the extent of tracer binding reflecting the clinical and pathological progression of AD. In Lewy body diseases (LBD), tau PET imaging has clearly revealed cortical tau burden with a distribution pattern distinct from AD and increased cortical binding within the LBD spectrum...
January 2018: Journal of Movement Disorders
Nan Li, Han Wu, Qiangqiang Ding, Huihui Li, Zhifei Li, Jing Ding, Yi Li
Anthocyanins are naturally occurring secondary metabolites, responsible for the color of many plants. The Arabidopsis thaliana MYB90/PAP2 (production of anthocyanin pigment 2) was introduced into tomato to study its effect on anthocyanin accumulation. The transgenic tomato displayed much greater anthocyanin accumulation than wild type in all plant organs, but the organs were not fully purple in color except for the stamen. The expression of anthocyanin biosynthetic genes and an anthocyanin-related basic helix-loop-helix (bHLH) gene SlAN1 was significantly increased in the transgenic line, suggesting that ectopic expression of AtPAP2 increases the expression of anthocyanin-related structural and regulatory genes to enhance anthocyanin content...
January 26, 2018: Functional & Integrative Genomics
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