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https://www.readbyqxmd.com/read/28636886/sirt1-enzymatically-potentiates-1-25-dihydroxyvitamin-d3-signaling-via-vitamin-d-receptor-deacetylation
#1
Marya S Sabir, Chengcheng Hu, Zainab Khan, Michael A Galligan, Christopher M Dussik, Sanchita Mallick, Angelika Dampf Stone, Shane F Batie, Elizabeth T Jacobs, G Kerr Whitfield, Mark R Haussler, Michael C Heck, Peter W Jurutka
The hormonal metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D), binds to the vitamin D receptor (VDR) and promotes heterodimerization of VDR with a retinoid-X-receptor (RXR) to genomically regulate diverse cellular processes. Herein, it is revealed for the first time that VDR is post-translationally acetylated, and that VDR immunoprecipitated from human embryonic kidney (HEK293) cells displays a dramatic decrease in acetylated receptor in the presence of 1,25D-ligand, sirtuin-1 (SIRT1) deacetylase, or the resveratrol activator of SIRT1...
June 18, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28636641/development-of-a-range-of-fluorescent-reagentless-biosensors-for-atp-based-on-malonyl-coenzyme-a-synthetase
#2
Renée Vancraenenbroeck, Simone Kunzelmann, Martin R Webb
The range of ATP concentrations that can be measured with a fluorescent reagentless biosensor for ATP has been increased by modulating its affinity for this analyte. The ATP biosensor is an adduct of two tetramethylrhodamines with MatB from Rhodopseudomonas palustris. Mutations were introduced into the binding site to modify ATP binding affinity, while aiming to maintain the concomitant fluorescence signal. Using this signal, the effect of mutations in different parts of the binding site was measured. This mutational analysis revealed three variants in particular, each with a single mutation in the phosphate-binding loop, which had potentially beneficial changes in ATP binding properties but preserving a fluorescence change of ~3-fold on ATP binding...
2017: PloS One
https://www.readbyqxmd.com/read/28632973/molecular-modeling-study-on-the-tubulin-binding-modes-of-epothilone-derivatives-insight-into-the-structural-basis-for-epothilones-activity
#3
Verónica A Jiménez, Joel B Alderete, Karen R Navarrete
Molecular dynamics (MD) simulations were employed to study the tubulin-binding modes of 20 epothilone derivatives spanning a wide range of antitumor activity. Trajectory analysis revealed that active ligands shared a common region of association and similar binding poses compared to the high-resolution crystal structure of the tubulin complex with epothilone A, the stathmin-like protein RB3, and tubulin tyrosine ligase (PDB code 4I50). Conformational analysis of epothilones in aqueous solution and tubulin-bound states indicated that the bound conformations of active species can be found to a significant extent within the ensemble of conformers available in aqueous solution...
June 20, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28631849/experiences-of-closed-loop-insulin-delivery-among-pregnant-women-with-type-1-diabetes
#4
C Farrington, Z A Stewart, K Barnard, R Hovorka, H R Murphy
AIMS: To explore the experiences of pregnant women with Type 1 diabetes, and the relationships between perceptions of glucose control, attitudes to technology and glycaemic responses with regard to closed-loop insulin delivery. METHODS: We recruited 16 pregnant women with Type 1 diabetes [mean ± sd age 34.1 ± 4.6 years, duration of diabetes 23.6 ± 7.2 years, baseline HbA1c 51±5 mmol/mol (6.8 ± 0.6%)] to a randomized crossover trial of sensor-augmented pump therapy vs automated closed-loop therapy...
June 20, 2017: Diabetic Medicine: a Journal of the British Diabetic Association
https://www.readbyqxmd.com/read/28628118/oncoppi-informed-discovery-of-mitogen-activated-protein-kinase-kinase-3-as-a-novel-binding-partner-of-c-myc
#5
A A Ivanov, V Gonzalez-Pecchi, L F Khuri, Q Niu, Y Wang, Y Xu, Y Bai, X Mo, E V Prochownik, M A Johns, Y Du, F R Khuri, H Fu
Mitogen-activated protein kinase kinase 3 (MKK3) is a dual threonine/tyrosine protein kinase that regulates inflammation, proliferation and apoptosis through specific phosphorylation and activation of the p38 mitogen-activated protein kinase. However, the role of MKK3 beyond p38-signaling remains elusive. Recently, we reported a protein-protein interaction (PPI) network of cancer-associated genes, termed OncoPPi, as a resource for the scientific community to generate new biological models. Analysis of the OncoPPi connectivity identified MKK3 as one of the major hub proteins in the network...
June 19, 2017: Oncogene
https://www.readbyqxmd.com/read/28627025/novel-rankl-de-loop-mutants-antagonize-rank-mediated-osteoclastogenesis
#6
Yizhou Wang, Aart H G van Assen, Carlos R Reis, Rita Setroikromo, Ronald van Merkerk, Ykelien L Boersma, Robbert H Cool, Wim J Quax
Bone is a dynamic tissue that is maintained by continuous renewal. An imbalance in bone resorption and bone formation can lead to a range of disorders, such as osteoporosis. The Receptor Activator of NF-κB (RANK)-RANK ligand (RANKL) pathway plays a major role in bone remodeling. Here, we investigated the effect of mutations at position I248 in the DE-loop of murine RANKL on the interaction of RANKL with RANK, and subsequent activation of osteoclastogenesis. Two single mutants, RANKL I248Y and I248K, were found to maintain binding and have the ability to reduce wild type RANKL-induced osteoclastogenesis...
June 19, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28626906/behavioural-implications-of-traditional-treatment-and-closed-loop-automated-insulin-delivery-systems-in-type-1-diabetes-applying-a-cognitive-restraint-theory-framework
#7
REVIEW
A R Kahkoska, E J Mayer-Davis, K K Hood, D M Maahs, K S Burger
As the prevalence of obesity in Type 1 diabetes rises, the effects of emerging therapy options should be considered in the context of both weight and glycaemic control outcomes. Artificial pancreas device systems will 'close the loop' between blood glucose monitoring and automated insulin delivery and may transform day-to-day dietary management for people with Type 1 diabetes in multiple ways. In the present review, we draw directly from cognitive restraint theory to consider unintended impacts that closed-loop systems may have on ingestive behaviour and food intake...
June 19, 2017: Diabetic Medicine: a Journal of the British Diabetic Association
https://www.readbyqxmd.com/read/28624612/human-mast-cells-present-antigen-to-autologous-cd4-t-cells
#8
Sahar Lotfi-Emran, Brant R Ward, Quang T Le, Andrea L Pozez, Masoud H Manjili, Judith Woodfolk, Lawrence B Schwartz
BACKGROUND: Mast cells (MCs), the primary effector cell of the atopic response, participate in immune defense at host/environment interfaces, yet the mechanisms by which they interact with CD4(+)-T cells has been controversial. OBJECTIVE: We utilize in situ-matured primary human MCs and matched CD4(+)-T cells to diligently assess the ability of MCs to act as antigen-presenting cells. METHODS: We examined mature human skin-derived MCs by flow cytometry for expression of antigen-presenting molecules; for their ability to stimulate CD4(+)-T cells to express CD25 and proliferate when exposed to superantigen or to CMV antigen using matched T cells and MCs from CMV seropositive or seronegative donors; and for uptake of antigens...
June 14, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28624566/4d-phase-contrast-mri-protocol-optimization-using-patient-specific-3d-printed-replicas-for-in-vivo-imaging-before-and-after-flow-diverter-placement
#9
Christof Karmonik, Jeff R Anderson, Saba Elias, Richard Klucznik, Orlando Diaz, Y Jonathan Zhang, Robert G Grossman, Gavin W Britz
PURPOSE: Hemodynamics in cerebral aneurysms is currently investigated towards its clinical efficacy using non-standardized computational simulation techniques. At the same time, flow patterns and velocities are accessible by 4D phase contrast magnetic resonance imaging (4D pcMRI). Complexity of protocol design and imaging duration has limited the use of this technique in clinical imaging. A new approach is presented to overcome these limitations. MATERIAL AND METHODS: 3D replicas of two cerebral aneurysms were fabricated by fused deposition prototyping (3D printing) and imaged using 4D pcMRI while connected to an MRI compatible continuous flow loop...
June 14, 2017: World Neurosurgery
https://www.readbyqxmd.com/read/28621526/orthogonal-mass-spectrometry-based-footprinting-for-epitope-mapping-and-structural-characterization-the-il-6-receptor-upon-binding-of-protein-therapeutics
#10
Ke Sherry Li, Guodong Chen, Jingjie Mo, Richard Y-C Huang, Ekaterina G Deyanova, Brett R Beno, Steve O'Neil, Adrienne A Tymiak, Michael L Gross
Higher order structure (HOS) is a crucial determinant for the biological functions and quality attributes of protein therapeutics. Mass spectrometry (MS)-based protein footprinting approaches play an important role in elucidating the relationship between protein biophysical properties and structure. Here, we describe the use of a combined method including hydrogen-deuterium exchange (HDX), fast photochemical oxidation of proteins (FPOP) and site-specific carboxyl group footprinting to investigate the HOS of protein and protein complexes...
June 16, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28620051/the-role-of-the-m20-loop-in-the-hydride-transfer-in-e-coli-dihydrofolate-reductase
#11
Anil R Mhashal, Alexandra Vardi-Kilshtain, Amnon Kohen, Dan Thomas Major
A key question concerning the catalytic cycle of E. Coli Dihydrofolate Reductase (ecDHFR) is whether the M20 loop is dynamically coupled to the chemical step during catalysis. A more basic, yet unanswered question is whether the M20 loop adopts a closed conformation during the chemical hydride transfer step. To examine the most likely conformation of the M20 loop during the chemical step, we studied the hydride transfer in wild type (WT) ecDHFR using hybrid quantum mechanics-molecular mechanics free energy simulations with the M20 loop in a closed and disordered conformation...
June 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28619716/ratchet-like-polypeptide-translocation-mechanism-of-the-aaa-disaggregase-hsp104
#12
Stephanie N Gates, Adam L Yokom, JiaBei Lin, Meredith E Jackrel, Alexandrea N Rizo, Nathan M Kendsersky, Courtney E Buell, Elizabeth A Sweeny, Korrie L Mack, Edward Chuang, Mariana P Torrente, Min Su, James Shorter, Daniel R Southworth
Hsp100 polypeptide translocases are conserved AAA+ machines that maintain proteostasis by unfolding aberrant and toxic proteins for refolding or proteolytic degradation. The Hsp104 disaggregase from S. cerevisiae solubilizes stress-induced amorphous aggregates and amyloid. The structural basis for substrate recognition and translocation is unknown. Using a model substrate (casein), we report cryo-EM structures at near-atomic resolution of Hsp104 in different translocation states. Substrate interactions are mediated by conserved, pore-loop tyrosines that contact an 80 Å-long unfolded polypeptide along the axial channel...
June 15, 2017: Science
https://www.readbyqxmd.com/read/28619664/nailfold-capillaroscopic-changes-in-patients-with-idiopathic-pulmonary-arterial-hypertension-and-systemic-sclerosis-related-pulmonary-arterial-hypertension
#13
A Corrado, M Correale, N Mansueto, I Monaco, A Carriero, A Mele, R Colia, M Di Biase, F P Cantatore
Pulmonary arterial hypertension (PAH) represents one of the main clinical expressions of the vascular changes in systemic sclerosis (SSc). Lung microvascular changes can play a role in the pathogenesis of idiopathic PAH (IPAH) also. The aim of this study is to investigate the presence of capillaroscopic abnormalities in patients with IPAH and to evaluate the differences in capillary nailfold changes between patients with IPAH and patients with SSc with and without PAH. METHODS: 39 SSc patients (19 with PAH - SSc-PAH and 20 without - SSc-noPAH), 21 subjects with IPAH and 20 healthy subjects were recruited...
June 12, 2017: Microvascular Research
https://www.readbyqxmd.com/read/28619589/isolation-of-sutherlandins-a-b-c-and-d-from-sutherlandia-frutescens-l-r-br-by-counter-current-chromatography-using-spiral-tubing-support-rotors
#14
Cuiping Chen, William R Folk, Rodrigo Lazo-Portugal, Thomas M Finn, Martha Knight
Spiral countercurrent-chromatography has great potential for improving the capacity and efficiency of purification of secondary metabolites, and here we describe applications useful for the isolation of flavonoids from the widely used South African medicinal plant, Sutherlandia frutescens (L.) R. Br. In the spiral tubing support rotor, STS-4 for high-speed counter-current chromatography, several polar butanol aqueous solvent systems were selected using a logK plot, and the novel flavonol glycosides (sutherlandins A-D) were well separated by the optimized solvent system (ethyl acetate:n-butanol:acetic acid:water; 5:1:0...
May 22, 2017: Journal of Chromatography. A
https://www.readbyqxmd.com/read/28617590/structure-and-dynamics-of-rna-repeat-expansions-that-cause-huntington-s-disease-and-myotonic-dystrophy-type-1
#15
Jonathan L Chen, Damian M VanEtten, Matthew A Fountain, Ilyas Yildirim, Matthew D Disney
RNA repeat expansions cause a host of incurable, genetically-defined diseases. The most common class of RNA repeats are trinucleotide repeats. These long, repeating transcripts fold into hairpins containing 1 × 1 internal loops that can mediate disease via a variety of mechanism(s) in which RNA is the central player. Two of these disorders are Huntington's disease and myotonic dystrophy type 1, which are caused by r(CAG) and r(CUG) repeats, respectively. We report the structures of two RNA constructs containing three copies of a r(CAG) [r(3×CAG)] or r(CUG) [r(3×CUG)] motif that were modeled with nuclear magnetic resonance spectroscopy and simulated annealing with restrained molecular dynamics...
June 15, 2017: Biochemistry
https://www.readbyqxmd.com/read/28617533/cervical-carcinogenesis-bacterial-vaginosis-hpv-mrna-test-and-relapse-of-cin2-after-loop-electrosurgical-excision-procedure-leep
#16
A Frega, G Lavini, A Guarino, V Giovanale, A Lukic, P Bianchi, G Cozza, R Marziani, A D'Ambrosio, D French, D Caserta
OBJECTIVE: The aim of the study was to evaluate the relationship between bacterial vaginosis (BV) and relapse of cervical intraepithelial neoplasia grade 2 or more (CIN2+) after Loop electrosurgical excision procedure (LEEP). PATIENTS AND METHODS: One hundred four patients who underwent LEEP for CIN2+ were followed up every six months for three years. Fifty-three were negative for BV and fifty-one were positive. Each clinical control included Pap test, colposcopy, Amsel criteria test, HPV-DNA, and HPV-mRNA test...
May 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28617332/dynamic-allostery-modulates-catalytic-activity-by-modifying-the-hydrogen-bonding-network-in-the-catalytic-site-of-human-pin1
#17
Jing Wang, Ryosuke Kawasaki, Jun-Ichi Uewaki, Arif U R Rashid, Naoya Tochio, Shin-Ichi Tate
Allosteric communication among domains in modular proteins consisting of flexibly linked domains with complimentary roles remains poorly understood. To understand how complementary domains communicate, we have studied human Pin1, a representative modular protein with two domains mutually tethered by a flexible linker: a WW domain for substrate recognition and a peptidyl-prolyl isomerase (PPIase) domain. Previous studies of Pin1 showed that physical contact between the domains causes dynamic allostery by reducing conformation dynamics in the catalytic domain, which compensates for the entropy costs of substrate binding to the catalytic site and thus increases catalytic activity...
June 15, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28615206/plasticity-and-epitope-exposure-of-the-hiv-1-envelope-trimer
#18
Rebecca L R Powell, Maxim Totrov, Vincenza Itri, Xiaomei Liu, Alisa Fox, Susan Zolla-Pazner
We recently showed that mutations in the HIV-1 Envelope (Env) destabilize the V3 loop, rendering neutralization-resistant viruses sensitive to V3-directed monoclonal antibodies (mAbs). Here we investigated the propagation of this effect on other Env epitopes, with special emphasis on V2 loop exposure. Wildtype JR-FL and 19 mutant JR-FL pseudoviruses were tested for neutralization sensitivity to 21 mAbs specific for epitopes in V2, the CD4 binding site (CD4bs), and the CD4-induced (CD4i) region. Certain glycan mutants, mutations in the gp120 hydrophobic core, and mutations in residues involved in intra-protomer interactions exposed epitopes in the V2i region (overlays the α4β7 integrin binding site) and the V3 crown, suggesting a general destabilization of the distal region of the trimer apex...
June 14, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28614118/the-renal-response-to-potassium-stress-integrating-past-with-present
#19
Cary R Boyd-Shiwarski, Arohan R Subramanya
PURPOSE OF REVIEW: The current review combines past findings with recent advances in our understanding of the homeostatic response to potassium imbalance. RECENT FINDINGS: Following the ingestion of a dietary potassium load, a combination of extrarenal and renal mechanisms act to maintain extracellular K+ within a tight window. Through hormonal regulation and direct K+ sensing, the nephron is ideally suited to respond to wide shifts in external K+ balance. Current evidence indicates that dietary K+ loading triggers a coordinated kaliuretic response that appears to involve voltage-dependent changes in sodium transport across multiple nephron segments, including the proximal tubule, medullary loop of Henle, and distal tubule...
June 12, 2017: Current Opinion in Nephrology and Hypertension
https://www.readbyqxmd.com/read/28614008/the-role-of-electronic-feedback-loops-in-the-continuous-quality-improvement-of-thyroid-nodule-and-thyroid-cancer-care
#20
Mark L Urken, Gregory Randolph, Lisa Orloff, Bruce M Wenig, Rosalie Machado, Marcela Osorio, Martha Griffin, R Michael Tuttle
No abstract text is available yet for this article.
June 14, 2017: Endocrine Practice
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