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https://www.readbyqxmd.com/read/28741230/new-therapeutic-strategies-for-lewy-body-dementias
#1
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
#2
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
https://www.readbyqxmd.com/read/28723656/inhibitor-of-h3k27-demethylase-jmjd3-utx-gsk-j4-is-a-potential-therapeutic-option-for-castration-resistant-prostate-cancer
#3
Viacheslav M Morozov, Ying Li, Matthew M Clowers, Alexander M Ishov
Androgen receptor (AR) mediates initiation and progression of prostate cancer (PCa); AR-driven transcription is activated by binding of androgens to the ligand-binding domain (LBD) of AR. Androgen ablation therapy offers only a temporary relief of locally advanced and metastatic PCa, and the disease eventually recurs as a lethal castration-resistant PCa (CRPC) as there is no effective treatment for CRPC patients. Thus, it is critical to identify novel targeted and combinatorial regimens for clinical management of CRPC...
July 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28723234/flexible-small-molecular-anti-estrogens-with-n-n-dialkylated-2-5-diethoxy-4-morpholinoaniline-scaffold-targets-multiple-estrogen-receptor-conformations
#4
Bethany K Asare, Emmanuel Yawson, Rajendram V Rajnarayanan
Estrogen mediates various cellular processes including cell proliferation, differentiation, growth and mammary gland function. Estrogen Receptors (ERs) are expressed in 70% of breast cancers. Consequently, estrogen mediated ER signaling plays a critical role in breast cancer diagnosis, prognosis, and treatment. Estrogen Receptors are ligand-triggered transcription factors. However, in the absence of a cognate estrogenic ligand, ERs can be activated by a variety of other extracellular signals. Tamoxifen, an anti-estrogen that selectively targets ER, induces substantial regression of breast tumors and an increase in disease-free survival...
July 19, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28714891/structural-and-functional-neuroimaging-of-visual-hallucinations-in-lewy-body-disease-a-systematic-literature-review
#5
REVIEW
Stefania Pezzoli, Annachiara Cagnin, Oliver Bandmann, Annalena Venneri
Patients with Lewy body disease (LBD) frequently experience visual hallucinations (VH), well-formed images perceived without the presence of real stimuli. The structural and functional brain mechanisms underlying VH in LBD are still unclear. The present review summarises the current literature on the neural correlates of VH in LBD, namely Parkinson's disease (PD), and dementia with Lewy bodies (DLB). Following a systematic literature search, 56 neuroimaging studies of VH in PD and DLB were critically reviewed and evaluated for quality assessment...
July 15, 2017: Brain Sciences
https://www.readbyqxmd.com/read/28711817/selection-and-application-of-familiar-and-novel-tools-in-patients-with-left-and-right-hemispheric-stroke-psychometrics-and-normative-data
#6
Ilka Buchmann, Jennifer Randerath
Frequently left brain damage (LBD) leads to limb apraxia, a disorder that can affect tool-use. Despite its impact on daily life, classical tests examining the pantomime of tool-use and imitation of gestures are seldom applied in clinical practice. The study's aim was to present a diagnostic approach which appears more strongly related to actions in daily life in order to sensitize applicants and patients about the relevance of the disorder before patients are discharged. Two tests were introduced that evaluate actual tool selection and tool-object-application: the Novel Tools (NTT) and the Familiar Tools (FTT) Test (parts of the DILA-S: Diagnostic Instrument for Limb Apraxia - Short Version)...
June 23, 2017: Cortex; a Journal Devoted to the Study of the Nervous System and Behavior
https://www.readbyqxmd.com/read/28709671/mechanism-and-properties-of-positive-allosteric-modulation-of-n-methyl-d-aspartate-receptors-by-6-alkyl-2-naphthoic-acid-derivatives
#7
Kiran Sapkota, Mark W Irvine, Guangyu Fang, Erica S Burnell, Neil Bannister, Arturas Volianskis, Georgia R Culley, Shashank M Dravid, Graham L Collingridge, David E Jane, Daniel T Monaghan
The theory that N-methyl-d-aspartate receptor (NMDAR) hypofunction is responsible for the symptoms of schizophrenia is well supported by many pharmacological and genetic studies. Accordingly, positive allosteric modulators (PAMs) that augment NMDAR signaling may be useful for treating schizophrenia. Previously we have identified several NMDAR PAMs containing a carboxylic acid attached to naphthalene, phenanthrene, or coumarin ring systems. In this study, we describe several functional and mechanistic properties of UBP684, a 2-naphthoic acid derivative, which robustly potentiates agonist responses at each of the four GluN1a/GluN2 receptors and at neuronal NMDARs...
July 11, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28698609/functional-analyses-of-a-novel-missense-and-other-mutations-of-the-vitamin-d-receptor-in-association-with-alopecia
#8
Mayuko Tamura, Michiyasu Ishizawa, Tsuyoshi Isojima, Samim Özen, Akira Oka, Makoto Makishima, Sachiko Kitanaka
Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is a rare disorder, caused by bialellic mutations of the vitamin D receptor (VDR) gene, sometimes associated with alopecia. The aim of this study is to elucidate the mechanism of functional disruption of a novel mutation, detected in a patient with HVDRR, comparing to other mutations with or without alopecia. The patient was a 2-year-old girl with alopecia, who was clinically diagnosed as HVDRR. Genetic analysis revealed a novel homozygous mutation, S360P, located in ligand binding domain (LBD)...
July 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28696695/structure-based-approach-to-identify-5-4-hydroxyphenyl-pyrrole-2-carbonitrile-derivatives-as-potent-and-tissue-selective-androgen-receptor-modulators
#9
Ray Unwalla, James J Mousseau, Olugbeminiyi O Fadeyi, Chulho Choi, Kevin Parris, Baihua Hu, Thomas Kenney, Susan Chippari, Christopher McNally, Karthick Vishwanathan, Edward Kilbourne, Catherine Thompson, Sunil Nagpal, Jay Wrobel, Matthew Yudt, Carl A Morris, Dennis Powell, Adam M Gilbert, Eugene L Piatnitski Chekler
In an effort to find new and safer treatments for osteoporosis and frailty, we describe a novel series of selective androgen receptor modulators (SARMs). Using a structure-based approach, we identified compound 7, a potent AR (ARE EC50 = 0.34 nM) and selective (N/C interaction EC50 = 1206 nM) modulator. In vivo data, an AR LBD X-ray structure of 7, and further insights from modeling studies of ligand receptor interactions are also presented.
July 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28695853/crystal-structure-of-the-n-terminal-domain-of-vqsr-from-pseudomonas-aeruginosa-at-2-1%C3%A2-%C3%A3-resolution
#10
Qing He, Kang Wang, Tiantian Su, Feng Wang, Lichuan Gu, Sujuan Xu
VqsR is a quorum-sensing (QS) transcriptional regulator which controls QS systems (las, rhl and pqs) by directly downregulating the expression of qscR in Pseudomonas aeruginosa. As a member of the LuxR family of proteins, VqsR shares the common motif of a helix-turn-helix (HTH)-type DNA-binding domain at the C-terminus, while the function of its N-terminal domain remains obscure. Here, the crystal structure of the N-terminal domain of VqsR (VqsR-N; residues 1-193) was determined at a resolution of 2.1 Å...
July 1, 2017: Acta Crystallographica. Section F, Structural Biology Communications
https://www.readbyqxmd.com/read/28692816/unique-oestrogen-receptor-ligand-binding-domain-sequence-of-native-parrots-a-possible-link-between-phytoestrogens-and-breeding-success
#11
Catherine E J Davis, Adrian H Bibby, Kevin M Buckley, Kenneth P McNatty, Janet L Pitman
The New Zealand (NZ) native parrots kākāpō, kākā and kea are classified as critically endangered, endangered and vulnerable respectively. Successful reproduction of kākāpō and kākā is linked to years of high levels of fruiting in native flora (mast years). To assess a possible hormonal link between native plants and reproductive success in these parrots in mast years, we examined the ligand-binding domains (LBD) of the progesterone receptor (PR), androgen receptor (AR), estrogen receptor 1 (ESR1) and estrogen receptor 2 (ESR2) in NZ native (kākāpō, kākā, kea and kākāriki) and non-native (Australian cockatiel) parrots and compared them with those in the chicken...
July 11, 2017: Reproduction, Fertility, and Development
https://www.readbyqxmd.com/read/28691798/structure-and-affinity-of-two-bicyclic-glutamate-analogues-at-ampa-and-kainate-receptors
#12
Stine Møllerud, Andrea Pinto, Laura Marconi, Karla Frydenvang, Thor S Thorsen, Saara K Laulumaa, Raminta Venskutonyte, Sebastian Winther, Ana M C Moral, Lucia Tamborini, Paola Conti, Darryl S Pickering, Jette Sandholm Kastrup
Ionotropic glutamate receptors (iGluRs) are involved in most of the fast excitatory synaptic transmission in the central nervous system. These receptors are important for learning and memory formation, but are also involved in the development of diseases such as Alzheimer's disease, epilepsy and depression. In order to understand the function of different types of iGluRs, selective agonists are invaluable as pharmacological tool compounds. Here, we report binding affinities of two bicyclic, conformationally restricted analogues of glutamate (CIP-AS and LM-12b) at AMPA (GluA2 and GluA3) and kainate receptor subunits (GluK1-3 and GluK5)...
July 10, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28689508/social-inappropriateness-in-neurodegenerative-disorders
#13
Philippe Desmarais, Krista L Lanctôt, Mario Masellis, Sandra E Black, Nathan Herrmann
BACKGROUND: New onset of mood and behavioral changes in middle-aged patients are frequently the first manifestations of an unrecognized neurocognitive disorder. Impairment of social cognition, the cognitive ability to process social information coming from others, such as emotions, to attribute mental states to others, and to respond appropriately to them, is often at the origin of behavioral manifestations in neurodegenerative disorders. METHODS: This paper reviews the current literature on social cognition impairment in neurocognitive disorders, particularly in prodromal stages of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer's disease (AD), idiopathic Parkinson's disease (IPD), and Lewy body dementia (LBD)...
July 10, 2017: International Psychogeriatrics
https://www.readbyqxmd.com/read/28672400/comparison-of-alternative-tumor-size-classifications-for-posterior-uveal-melanomas
#14
COMPARATIVE STUDY
Cassandra C Skinner, James J Augsburger, Bret D Augsburger, Zelia M Correa
Purpose: Determine which posterior uveal melanoma (PUM) size classification with three categories has the best prognostic discrimination. Methods: Single-institution study of 424 consecutive patients with PUM. The tumor's largest basal diameter (LBD), smallest basal diameter (SBD), and thickness (TH) were estimated by fundus mapping and ultrasonography. Tumors were assigned to "small," "medium," or "large" size categories defined by 11 different classifications (Linear LBD, Rectangular LBD × TH, Cubic LBD × SBD × TH, Warren Original, Warren Modified, Augsburger, COMS Original, COMS Revised, TNM 2002, and modified TNM 2010 classification [a,b])...
July 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28636281/aryl-and-heteroaryl-substituted-phenylalanines-as-ampa-receptor-ligands
#15
Ewa Szymańska, Paulina Chałupnik, Tommy N Johansen, Birgitte Nielsen, Ana Maria Cuñado Moral, Darryl S Pickering, Anna Więckowska, Katarzyna Kieć-Kononowicz
A series of racemic unnatural amino acids was rationally designed on the basis of recently published X-ray structures of the GluA2 LBD with bound phenylalanine-based antagonists. Twelve new diaryl- or aryl/heteroaryl-substituted phenylalanine derivatives were synthesized and evaluated in vitro in radioligand binding assays at native rat ionotropic glutamate receptors. The most interesting compound in this series, (RS)-2-amino-3-(3'-hydroxy-5-(1H-pyrazol-4-yl)-[1,1'-biphenyl]-3-yl)propanoic acid 7e, showed the binding affinity of 4...
June 21, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28633425/androgen-receptor-mutations-in-patients-with-castration-resistant-prostate-cancer-treated-with-apalutamide
#16
D E Rathkopf, M R Smith, C J Ryan, W R Berry, N D Shore, G Liu, C S Higano, J J Alumkal, R Hauke, R F Tutrone, M Saleh, E Chow Maneval, S Thomas, D S Ricci, M K Yu, C J de Boer, A Trinh, T Kheoh, R Bandekar, H I Scher, E S Antonarakis
Background: : Mutations in the androgen receptor (AR) ligand-binding domain (LBD), such as F877L and T878A, have been associated with resistance to next-generation AR-directed therapies. ARN-509-001 was a phase I/II study that evaluated apalutamide activity in castration-resistant prostate cancer (CRPC). Here we evaluated the type and frequency of 11 relevant AR-LBD mutations in apalutamide-treated CRPC patients. Patients and methods: : Blood samples from men with non-metastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC) pre- or post abiraterone acetate and prednisone (AAP) treatment (≥6 months' exposure) were evaluated at baseline and disease progression in trial ARN-509-001...
June 15, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28631183/comprehension-of-idioms-in-turkish-aphasic-participants
#17
Burcu Aydin, Muzaffer Barin, Oktay Yagiz
Brain damaged participants offer an opportunity to evaluate the cognitive and linguistic processes and make assumptions about how the brain works. Cognitive linguists have been investigating the underlying mechanisms of idiom comprehension to unravel the ongoing debate on hemispheric specialization in figurative language comprehension. The aim of this study is to evaluate and compare the comprehension of idiomatic expressions in left brain damaged (LBD) aphasic, right brain damaged (RBD) and healthy control participants...
June 19, 2017: Journal of Psycholinguistic Research
https://www.readbyqxmd.com/read/28624954/ar-mutations-in-28-patients-with-androgen-insensitivity-syndrome-prader-grade-0-3
#18
Yi Wang, Chunxiu Gong, Xiou Wang, Miao Qin
We investigated the androgen receptor (AR) gene mutation profiles of Chinese patients exhibiting severe androgen insensitivity syndrome (AIS) phenotypes. The present study enrolled 28 patients with genetically diagnosed AIS, who presented with severe phenotypes (Prader grade 0-3). Patients and some family members were screened via amplification and sequencing of their AR exons 1-8, including the corresponding intronic flanking regions. Luteinizing (LH), follicle-stimulating (FSH), and testosterone (T) hormone levels were found to be slightly, but not significantly, higher in patients with complete androgen insensitivity syndrome (CAIS) than in patients with partial androgen insensitivity syndrome (PAIS) (P>0...
June 14, 2017: Science China. Life Sciences
https://www.readbyqxmd.com/read/28623334/novel-complex-of-hat-protein-tip60-and-nuclear-receptor-pxr-promotes-cell-migration-and-adhesion
#19
Karishma Bakshi, B Ranjitha, Shraddha Dubey, Jaisri Jagannadham, Bharti Jaiswal, Ashish Gupta
PXR is a member of nuclear receptor superfamily and a well-characterized mediator of xenobiotic metabolism. The classical mode of PXR activation involves its binding to appropriate ligand and subsequent heterodimerization with its partner RXR. However, various factors such as post-translational modifications and crosstalk with different cellular factors may also regulate the functional dynamics and behavior of PXR. In the present study, we have identified that TIP60, an essential lysine acetyltransferase protein interacts with unliganded PXR and together this complex promotes cell migration & adhesion...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28620365/metabolic-value-chemoattractants-are-preferentially-recognized-at-broad-ligand-range-chemoreceptor-of-pseudomonas-putida-kt2440
#20
Matilde Fernández, Miguel A Matilla, Álvaro Ortega, Tino Krell
Bacteria have evolved a wide range of chemoreceptors with different ligand specificities. Typically, chemoreceptors bind ligands with elevated specificity and ligands serve as growth substrates. However, there is a chemoreceptor family that has a broad ligand specificity including many compounds that are not of metabolic value. To advance the understanding of this family, we have used the PcaY_PP (PP2643) chemoreceptor of Pseudomonas putida KT2440 as a model. Using Isothermal Titration Calorimetry we showed here that the recombinant ligand binding domain (LBD) of PcaY_PP recognizes 17 different C6-ring containing carboxylic acids with KD values between 3...
2017: Frontiers in Microbiology
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