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https://www.readbyqxmd.com/read/28062571/performance-of-a-condensed-protocol-that-reduces-effort-and-cost-of-nia-aa-guidelines-for-neuropathologic-assessment-of-alzheimer-disease
#1
Margaret E Flanagan, Desiree A Marshall, Jane B Shofer, Kathleen S Montine, Peter T Nelson, Thomas J Montine, C Dirk Keene
Concerns regarding resource expenditures have been expressed about the 2012 NIA-AA Sponsored Guidelines for neuropathologic assessment of Alzheimer disease (AD) and related dementias. Here, we investigated a cost-reducing Condensed Protocol and its effectiveness in maintaining the diagnostic performance of Guidelines in assessing AD, Lewy body disease (LBD), microvascular brain injury, hippocampal sclerosis (HS), and congophilic amyloid angiopathy (CAA). The Condensed Protocol consolidates the same 20 regions into 5 tissue cassettes at ∼75% lower cost...
January 6, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28051871/modulating-mineralocorticoid-receptor-with-non-steroid-antagonists-new-opportunities-for-the-development-of-potent-and-selective-ligands-without-off-target-side-effects
#2
Mercedes Martín-Martínez, Felipe Luis Pérez-Gordillo, Diego Alvarez De la Rosa, Yoel Rodríguez, Guillermo Gerona-Navarro, Rosario González-Muñiz, Ming-Ming Zhou
Steroidal mineralocorticoid receptor (MR) antagonists are used for treatment of a range of human diseases, but present challenging issues of complex chemical synthesis, undesirable physical properties and poor selectivity along with unwanted side effects. Therefore, there is a great interest in the discovery of non-steroidal ligands able to bind to the ligand-binding domain (LBD) of the MR, and recruit different coregulators to produce tissue-specific therapeutic effects. Several academic groups and pharmaceutical companies have been developing a series of non-steroidal ligands that consist of different chemical scaffolds, yielding MR antagonists currently evaluated in clinical studies for the treatment of congestive heart failure, hypertension or diabetic nephropathy...
January 4, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28036278/a-novel-nonsense-mutation-in-androgen-receptor-confers-resistance-to-cyp17-inhibitor-treatment-in-prostate-cancer
#3
Dong Han, Shuai Gao, Kevin Valencia, Jude Owiredu, Wanting Han, Eric de Waal, Jill A Macoska, Changmeng Cai
The standard treatment for prostate cancer (PCa) is androgen deprivation therapy (ADT) that blocks transcriptional activity of androgen receptor (AR). However, ADT invariably leads to the development of castration-resistant PCa (CRPC) with restored activity of AR. CRPC can be further treated with CYP17 inhibitors to block androgen synthesis pathways, but most patients still relapse after a year of such treatment. The mechanisms that drive this progression are not fully understood, but AR activity, at least in a subset of cancers, appears to be restored again...
December 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/28035932/effect-of-vascular-risk-factors-on-the-progression-of-mild-alzheimer-s-disease-and-lewy-body-dementia
#4
Anne Katrine Bergland, Ingvild Dalen, Alf Inge Larsen, Dag Aarsland, Hogne Soennesyn
BACKGROUND: Vascular risk factors (VRF) are associated with an increased risk of neurodegenerative disease. OBJECTIVE: To examine the association between VRF and cognitive decline in patients with Alzheimer's disease (AD) and Lewy body dementia (LBD). METHODS: We included consecutive referrals with mild AD or LBD to dementia clinics in western Norway from 2005 to 2013. The Mini-Mental Status Exam (MMSE) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) were administered at baseline and then annually for up to five years...
December 30, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28027508/quizalofop-p-ethyl-exposure-increases-estrogen-axis-activity-in-male-and-slightly-decreases-estrogen-axis-activity-in-female-zebrafish-danio-rerio
#5
Li-Zhen Zhu, Su-Zhen Qi, Fang-Jie Cao, Xi-Yan Mu, Yang Yang, Chengju Wang
The herbicide Quizalofop-P-ethyl (QpE) exerts toxic effects in fish, but limited information is currently available on its effects on the endocrine system. In the current study, adult zebrafish (Danio rerio) were exposed to different concentrations (0, 2, 20, 200μg/L) of QpE for 30days. In males, QpE exposure significantly increased plasma estradiol (E2) and vitellogenin (VTG) levels, concomitant with up-regulation of hepatic esr1 and vtg gene expression. In females, plasma sex hormone levels and VTG concentrations were not altered significantly, but an increased expression of hepatic esr1 in addition to decreased expression of hepatic vtg, esr2a and esr2b was observed...
December 12, 2016: Aquatic Toxicology
https://www.readbyqxmd.com/read/27965656/identification-of-a-chemoreceptor-in-pseudomonas-aeruginosa-that-specifically-mediates-chemotaxis-toward-%C3%AE-ketoglutarate
#6
David Martín-Mora, Alvaro Ortega, José A Reyes-Darias, Vanina García, Diana López-Farfán, Miguel A Matilla, Tino Krell
Pseudomonas aeruginosa is an ubiquitous pathogen able to infect humans, animals, and plants. Chemotaxis was found to be associated with the virulence of this and other pathogens. Although established as a model for chemotaxis research, the majority of the 26 P. aeruginosa chemoreceptors remain functionally un-annotated. We report here the identification of PA5072 (named McpK) as chemoreceptor for α-ketoglutarate (αKG). High-throughput thermal shift assays and isothermal titration calorimetry studies (ITC) of the recombinant McpK ligand binding domain (LBD) showed that it recognizes exclusively α-ketoglutarate...
2016: Frontiers in Microbiology
https://www.readbyqxmd.com/read/27937122/rational-screening-of-peroxisome-proliferator-activated-receptor-%C3%AE-agonists-from-natural-products-potential-therapeutics-for-heart-failure
#7
Rui Chen, Jing Wan, Jing Song, Yan Qian, Yong Liu, Shuiming Gu
CONTEXT: Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. Activation of PPARγ pathway has been shown to enhance fatty acid oxidation, improve endothelial cell function, and decrease myocardial fibrosis in heart failure. Thus, the protein has been raised as an attractive target for heart failure therapy. OBJECTIVE: This work attempted to discover new and potent PPARγ agonists from natural products using a synthetic strategy of computer virtual screening and transactivation reporter assay...
December 2017: Pharmaceutical Biology
https://www.readbyqxmd.com/read/27928840/development-of-assessment-toolkits-for-improving-the-diagnosis-of-the-lewy-body-dementias-feasibility-study-within-the-diamond-lewy-study
#8
Alan J Thomas, John Paul Taylor, Ian McKeith, Claire Bamford, David Burn, Louise Allan, John O'Brien
OBJECTIVE: The Lewy body dementias (LBD, dementia with Lewy bodies and Parkinson's disease dementia) are the second most common cause of neurodegenerative dementia but remain under-recognised, with long delays from initial assessment to diagnosis. Whilst validated instruments have been developed for key symptoms, there is no brief instrument for overall diagnostic assessment suitable for routine practice. We here report the development of such assessment toolkits. METHODS: We developed the LBD assessment toolkits in three stages...
December 8, 2016: International Journal of Geriatric Psychiatry
https://www.readbyqxmd.com/read/27919657/synthesis-of-novel-steroidal-agonists-partial-agonists-and-antagonists-for-the-glucocorticoid-receptor
#9
Zhuang Jin, Hua Lin, Sathish Srinivasan, Jerome C Nwachukwu, Nelson Bruno, Patrick R Griffin, Kendall W Nettles, Theodore M Kamenecka
Adverse effects of glucocorticoids could be limited by developing new compounds that selectively modulate anti-inflammatory activity of the glucocorticoid receptor (GR). We have synthesized a novel series of steroidal GR ligands, including potent agonists, partial agonists and antagonists with a wide range of effects on inhibiting secretion of interleukin-6. Some of these new ligands were designed to directly impact conformational stability of helix-12, in the GR ligand-binding domain (LBD). These compounds modulated GR activity and glucocorticoid-induced gene expression in a manner that was inversely correlated to the degree of inflammatory response...
January 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27918994/importance-of-5-6-aryl-substitution-on-the-pharmacological-profile-of-4-2-propyl-1h-benzo-d-imidazol-1-yl-methyl-1-1-biphenyl-2-carboxylic-acid-derived-ppar%C3%AE-agonists
#10
Victoria Obermoser, Robert Mauersberger, Daniela Schuster, Monika Czifersky, Marina Lipova, Monika Siegl, Ulrich Kintscher, Ronald Gust
In this structure-activity relationship study, the influence of aryl substituents at position 5 or 6 on the pharmacological profile of the partial PPARγ agonist 4'-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid was investigated. This lead was previously identified as the essential part of telmisartan to induce PPARγ activation. Para-OCH3-phenyl substitution strongly increased potency and efficacy independent of the position. Both compounds represent full agonists because of strong hydrophobic contacts with the amino acid Phe363 in the ligand binding domain...
November 25, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27911312/increased-transforming-growth-factor-%C3%AE-2-in-the-neocortex-of-alzheimer-s-disease-and-dementia-with-lewy-bodies-is%C3%A2-correlated-with-disease-severity-and%C3%A2-soluble-a%C3%AE-42-load
#11
Joyce R Chong, Yuek Ling Chai, Jasinda H Lee, David Howlett, Johannes Attems, Clive G Ballard, Dag Aarsland, Paul T Francis, Christopher P Chen, Mitchell K P Lai
BACKGROUND: Of the three transforming growth factor (TGF)-β isoforms known, TGFβ1 deficits have been widely reported in Alzheimer's disease (AD) and studied as a potential therapeutic target. In contrast, the status of TGFβ2, which has been shown to mediate amyloid-β (Aβ)-mediated neuronal death, are unclear both in AD and in Lewy body dementias (LBD) with differential neuritic plaque and neurofibrillary tangle burden. OBJECTIVE: To measure neocortical TGFβ2 levels and their correlations with neuropathological and clinical markers of disease severity in a well-characterized cohort of AD as well as two clinical subtypes of LBD, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), known to manifest relatively high and low Aβ plaque burden, respectively...
November 28, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/27903893/identification-of-a-novel-k311-ubiquitination-site-critical-for-androgen-receptor-transcriptional-activity
#12
Urszula L McClurg, David M W Cork, Steven Darby, Claudia A Ryan-Munden, Sirintra Nakjang, Leticia Mendes Côrtes, Achim Treumann, Luke Gaughan, Craig N Robson
The androgen receptor (AR) is the main driver of prostate cancer (PC) development and progression, and the primary therapeutic target in PC. To date, two functional ubiquitination sites have been identified on AR, both located in its C-terminal ligand binding domain (LBD). Recent reports highlight the emergence of AR splice variants lacking the LBD that can arise during disease progression and contribute to castrate resistance. Here, we report a novel N-terminal ubiquitination site at lysine 311. Ubiquitination of this site plays a role in AR stability and is critical for its transcriptional activity...
November 29, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27895202/the-lbd12-1-transcription-factor-suppresses-apical-meristem-size-by-repressing-argonaute-10-expression
#13
Weiwei Ma, Fuqing Wu, Peike Sheng, Xiaole Wang, Zhe Zhang, Kunneng Zhou, Huan Zhang, Jinlong Hu, Qibin Lin, Zhijun Cheng, Jiulin Wang, Shanshan Zhu, Xin Zhang, Xiuping Guo, Haiyang Wang, Chuanyin Wu, Huqu Zhai, Jianmin Wan
The shoot apical meristem (SAM) consists of a population of multipotent cells that generates all aerial structures and regenerates itself. SAM maintenance and lateral organ development are regulated by several complex signaling pathways, in which the Argonaute gene-mediated pathway plays a key role. One Argonaute gene, AGO10, functions as a microRNA locker that attenuates miR165/166 activity and positively regulates shoot apical meristem development, but little is known about when and how AGO10 is regulated at the transcriptional level...
January 2017: Plant Physiology
https://www.readbyqxmd.com/read/27890717/ecdysone-receptor-ecr-and-ultraspiracle-usp-genes-from-the-cyclopoid-copepod-paracyclopina-nana-identification-and-expression-in-response-to-water-accommodated-fractions-wafs
#14
Jayesh Puthumana, Min-Chul Lee, Jeonghoon Han, Hui-Su Kim, Dae-Sik Hwang, Jae-Seong Lee
Ecdysteroid hormones are pivotal in the development, growth, and molting of arthropods, and the hormone pathway is triggered by binding ecdysteroid to a heterodimer of the two nuclear receptors; ecdysone receptors (EcR) and ultraspiracle (USP). We have characterized EcR and USP genes, and their 5'-untranslated region (5'-UTR) from the copepod Paracyclopina nana, and studied mRNA transcription levels in post-embryonic stages and in response to water accommodated fractions (WAFs) of crude oil. The open reading frames (ORF) of EcR and USP were 1470 and 1287bp that encoded 490 and 429 amino acids with molecular weight of 121...
February 2017: Comparative Biochemistry and Physiology. Toxicology & Pharmacology: CBP
https://www.readbyqxmd.com/read/27890450/src2-3-binds-to-vitamin-d-receptor-with-high-sensitivity-and-strong-affinity
#15
Daichi Egawa, Toshimasa Itoh, Akira Kato, Saori Kataoka, Yasuaki Anami, Keiko Yamamoto
Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily and regulates the expression of target genes through ligand binding. To express the target gene, coactivator binding to the VDR/ligand complex is essential. Although there are many coactivators in living cells, precise interactions between coactivators and VDR have not been clarified. Here, we synthesized two coactivator peptides, DRIP205-2 and SRC2-3, evaluated their affinity for the ligand-binding domain (LBD) of VDR using 1α,25-dihydroxyvitamin D3, partial agonist 1, and antagonist 2 by surface plasmon resonance (SPR), and assessed their interaction modes with VDR-LBD using X-ray crystallographic analysis...
January 15, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27870939/mixed-neuropathologies-and-estimated-rates-of-clinical-progression-in-a-large-autopsy-sample
#16
Willa D Brenowitz, Rebecca A Hubbard, C Dirk Keene, Stephen E Hawes, W T Longstreth, Randy L Woltjer, Walter A Kukull
INTRODUCTION: Whether co-occurring neuropathologies interact or independently affect clinical disease progression is uncertain. We estimated rates of clinical progression and tested whether associations between clinical progression and Alzheimer's disease neuropathology (ADNP) were modified by co-occurring Lewy body disease (LBD) or vascular brain injury (VBI). METHODS: Linear mixed effects models evaluated longitudinal trends in the Clinical Dementia Rating Scale Sum of Boxes on 2046 autopsied participants seen at a U...
November 19, 2016: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
https://www.readbyqxmd.com/read/27868177/-early-use-of-memantine-in-the-treatment-of-lewy-body-dementia
#17
H Vanhaute, P Persoons
Early use of memantine in the treatment of Lewy body dementia (LBD) is a common type of major neurocognitive disorder (NCD), which is difficult to treat. The use of memantine can be an early treatment strategy. This is illustrated by a case of an 80-year-old patient whose cognition, motor skills and perception disorders reacted favourably to treatment with memantine. The beneficial effect, however, was soon lost after the treatment was discontinued, but reappeared after the medication was reintroduced.
2016: Tijdschrift Voor Psychiatrie
https://www.readbyqxmd.com/read/27864003/novel-screening-system-for-high-affinity-ligand-of-heredity-vitamin-d-resistant-rickets-associated-vitamin-d-receptor-mutant-r274l-using-bioluminescent-sensor
#18
Hiroki Mano, Miyu Nishikawa, Kaori Yasuda, Shinichi Ikushiro, Nozomi Saito, Daisuke Sawada, Shinobu Honzawa, Masashi Takano, Atsushi Kittaka, Toshiyuki Sakaki
Hereditary vitamin D-resistant rickets (HVDRR) is caused by mutations in the vitamin D receptor (VDR) gene. Arg274 located in the ligand binding domain (LBD) of VDR is responsible for anchoring 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) by forming a hydrogen bond with the 1α-hydroxyl group of 1α,25(OH)2D3. The Arg274Leu (R274L) mutation identified in patients with HVDRR causes a 1000-fold decrease in the affinity for 1α,25(OH)2D3, and dramatically reduces vitamin D- related gene expression. Recently, we successfully constructed fusion proteins consisting of split-luciferase and LBD of the VDR...
November 15, 2016: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/27860026/medical-specialists-care-and-hospital-costs-for-low-back-pain-in-the-netherlands
#19
C J Itz, B L T Ramaekers, M van Kleef, C D Dirksen
BACKGROUND: To examine the organization of medical specialist care and hospital costs for low back pain (LBP) in the Netherlands. METHODS: Aggregated health insurance claims data were provided on all diagnosis treatment combination (DTC) declarations for LBP patients first referred to the hospital in the 2nd half of 2008 and retrieved from Vektis, an organization that collects health insurance claims data. Data were available up to 1 January 2012. The data included patient characteristics, DTC-specific information including: neurology, neurosurgery, orthopaedic surgery, anaesthesiology and radiology...
November 8, 2016: European Journal of Pain: EJP
https://www.readbyqxmd.com/read/27849622/novel-mutations-of-the-srd5a2-and-ar-genes-in-thai-patients-with-46-xy-disorders-of-sex-development
#20
Chupong Ittiwut, Jaturong Pratuangdejkul, Vichit Supornsilchai, Sasipa Muensri, Yodporn Hiranras, Taninee Sahakitrungruang, Suttipong Watcharasindhu, Kanya Suphapeetiporn, Vorasuk Shotelersuk
BACKGROUND: Abnormalities of dihydrotestosterone conversion [5α-reductase deficiency: online Mendelian inheritance in man (OMIM) 607306] or actions of androgens [partial androgen insensitivity syndrome (PAIS): OMIM 312300] during the 8th-12th weeks of gestation cause varying degrees of undervirilized external genitalia in 46, XY disorders of sex development (DSD) with increased testosterone production. The objective of the study was to determine clinical and genetic characteristics of Thai patients with 46, XY DSD...
January 1, 2017: Journal of Pediatric Endocrinology & Metabolism: JPEM
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