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https://www.readbyqxmd.com/read/28453552/specific-blockade-of-rictor-mtor-association-inhibits-mtorc2-activity-and-is-cytotoxic-in-glioblastoma
#1
Angelica Benavides-Serrato, Jihye Lee, Brent Holmes, Kenna A Landon, Tariq Bashir, Michael E Jung, Alan Lichtenstein, Joseph Gera
A small molecule which specifically blocks the interaction of Rictor and mTOR was identified utilizing a high-throughput yeast two-hybrid screen and evaluated as a potential inhibitor of mTORC2 activity in glioblastoma multiforme (GBM). In vitro, CID613034 inhibited mTORC2 kinase activity at submicromolar concentrations and in cellular assays specifically inhibited phosphorylation of mTORC2 substrates, including AKT (Ser-473), NDRG1 (Thr-346) and PKCα (Ser-657), while having no appreciable effects on the phosphorylation status of the mTORC1 substrate S6K (Thr-389) or mTORC1-dependent negative feedback loops...
2017: PloS One
https://www.readbyqxmd.com/read/28448495/dysregulation-of-inf2-mediated-mitochondrial-fission-in-spop-mutated-prostate-cancer
#2
Xiaofeng Jin, Jie Wang, Kun Gao, Pingzhao Zhang, Longfang Yao, Yan Tang, Lisha Tang, Jian Ma, Jiantao Xiao, Enceng Zhang, Jie Zhu, Bin Zhang, Shi-Min Zhao, Yao Li, Shancheng Ren, Haojie Huang, Long Yu, Chenji Wang
Next-generation sequencing of the exome and genome of prostate cancers has identified numerous genetic alternations. SPOP (Speckle-type POZ Protein) was one of the most frequently mutated genes in primary prostate cancer, suggesting SPOP is a potential driver of prostate cancer development and progression. However, how SPOP mutations contribute to prostate cancer pathogenesis remains poorly understood. SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation...
April 27, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28447315/neglected-hip-dislocation-an-unusual-presentation-its-management-and-review-of-the-literature
#3
Sandeep Kumar, Anshul Dahuja, M S Narula, Sangam Garg, Rashmeet Kaur
Neglected traumatic posterior hip dislocation is not an uncommon condition seen in developing countries. Its treatment is fraught with great difficulties and controversies. Here we present a 31-year-old female patient presented to our hospital 2 years after sustaining an accident. She had gone through multiple treatments for her dislocated hip without any success. After arrival to our hospital, patient managed by constrained total hip replacement (THR). Her Harris hip score improved from 48 (preoperative) to 81 (postoperative)...
April 26, 2017: Strategies in Trauma and Limb Reconstruction
https://www.readbyqxmd.com/read/28447047/replacement-of-threonine-55-with-glycine-decreases-the-reduction-rate-of-ostrx20-by-glutathione
#4
Mitra Roodgar-Nashta, Azar Shahpiri
Thioredoxins (Trxs) are small ubiquitous oxidoreductase proteins with two redox-active Cys residues in a conserved active site (WCG/PPC) that regulate numerous target proteins via thiol/disulfide exchanges in the cells of prokaryotes and eukaryotes. The isoforms OsTrx23 with a typical active site (WCGPC) and OsTrx20 with an atypical active site (WCTPC) are two Trx h- type isoforms in rice that were previously found to be reduced by NADPH-dependent thioredoxin reductase and GSH/Grx system, respectively. In the present work the reduction of mutants G41TOsTrx23, T55GOsTrx20, K48DOsTrx20 and T55G-K48D OsTrx20 as well as wild types OsTrx23 and OsTrx20 were tested in the reaction containing either NADPH/NTR or glutathione (GSH)...
March 2017: Molecular Biology Research Communications
https://www.readbyqxmd.com/read/28446154/effects-of-escitalopram-and-paroxetine-on-mtorc1-signaling-in-the-rat-hippocampus-under-chronic-restraint-stress
#5
Mi Kyoung Seo, Cheol Min Choi, Roger S McIntyre, Hye Yeon Cho, Chan Hong Lee, Rodrigo B Mansur, Yena Lee, Jae-Hon Lee, Young Hoon Kim, Sung Woo Park, Jung Goo Lee
BACKGROUND: Recent studies have suggested that the activation of mammalian target of rapamycin (mTOR) signaling may be related to antidepressant action. Therefore, the present study evaluated whether antidepressant drugs would exert differential effects on mTOR signaling in the rat hippocampus under conditions of chronic restraint stress. Male Sprague-Dawley rats were subjected to restraint stress for 6 h/days for 21 days with either escitalopram (10 mg/kg) or paroxetine (10 mg/kg) administered after the chronic stress procedure...
April 26, 2017: BMC Neuroscience
https://www.readbyqxmd.com/read/28445123/changes-in-the-free-energy-landscape-of-p38%C3%AE-map-kinase-through-its-canonical-activation-and-binding-events-as-studied-by-enhanced-molecular-dynamics-simulations
#6
Antonija Kuzmanic, Ludovico Sutto, Giorgio Saladino, Angel R Nebreda, Francesco L Gervasio, Modesto Orozco
p38α is a Ser/Thr protein kinase involved in a variety of cellular processes and pathological conditions, which makes it a promising pharmacological target. Although the activity of the enzyme is highly regulated, its molecular mechanism of activation remains largely unexplained, even after decades of research. By using state-of-the-art molecular dynamics simulations, we decipher the key elements of the complex molecular mechanism refined by evolution to allow for a fine tuning of p38α kinase activity. Our study describes for the first time the molecular effects of different regulators of the enzymatic activity, and provides an integrative picture of the activation mechanism that explains the seemingly contradictory X-ray and NMR data...
April 26, 2017: ELife
https://www.readbyqxmd.com/read/28443077/molecular-dynamics-simulation-of-the-influenza-a-h3n2-hemagglutinin-trimer-reveals-the-structural-basis-for-adaptive-evolution-of-the-recent-epidemic-clade-3c-2a
#7
Masaru Yokoyama, Seiichiro Fujisaki, Masayuki Shirakura, Shinji Watanabe, Takato Odagiri, Kimito Ito, Hironori Sato
Influenza A(H3N2) has been a major cause of seasonal influenza in humans since 1968, and has evolved by antigenic drift under the constantly changing human herd immunity. Increasing evidence suggests that the antigenic change occasionally occurred concomitant with the alterations of the N-glycosylation site profile and hemagglutination activity of the virion surface protein hemagglutinin (HA). However, the structural basis of these changes remains largely unclear. To address this issue, we performed molecular dynamics simulations of the glycosylated HA trimers of the A(H3N2), which has a novel pattern of Asn-X-Ser/Thr sequons unique in the new A(H3N2) epidemic clade 3C...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28442161/zurich-cementless-total-hip-replacement
#8
REVIEW
David Hummel
Total hip replacement (THR) is the gold standard treatment of intractable pain from hip dysplasia. THR procedures are divided into 2 main categories: cemented and cementless, with hybrid a combination. The Zurich Cementless THR system uses a combination of press-fit (acetabular component) and locking screw (femoral component) fixation designed to address the main challenge facing cemented systems (aseptic loosening) while providing the benefit of immediate stability with its novel locking screw implantation system for the femoral stem...
April 22, 2017: Veterinary Clinics of North America. Small Animal Practice
https://www.readbyqxmd.com/read/28438942/the-correlation-between-gyra-and-cmer-box-polymorphism-and-fluoroquinolones-resistance-in-campylobacter-jejuni-isolates-in-china
#9
Tengfei Zhang, Yiluo Cheng, Qingping Luo, Qin Lu, Jun Dong, Rongrong Zhang, Guoyuan Wen, Honglin Wang, Ling Luo, Hongcai Wang, Guoping Liu, Huabin Shao
Sequence analysis of 79 ciprofloxacin-resistant Campylobacter jejuni isolates collected in China showed resistance-related sequence variations in gyrA and CmeR-Box. All the isolates contain an identical Thr-86-Ile substitution in GyrA. Several novel CmeR-Box variations were identified, including point substitutions, deletion and insertion. The point insertion or deletion led to dramatically reduced binding of CmeR to the cmeABC promoter, which significantly increase the expression of cmeABC and contribute to the high fluoroquinolone resistance...
April 24, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28437432/genome-wide-identification-and-expression-analysis-of-calcium%C3%A2-dependent-protein-kinase-and-its-related-kinase-gene-families-in-melon-cucumis-melo-l
#10
Haifei Zhang, Chunhua Wei, Xiaozhen Yang, Hejie Chen, Yongchao Yang, Yanling Mo, Hao Li, Yong Zhang, Jianxiang Ma, Jianqiang Yang, Xian Zhang
The calcium-dependent protein kinase (CDPK) is a ser/thr protein kinase that plays vital roles in plant growth, development, and responses to multiple stresses. Despite an important member of the stress responsive gene family, little is known about the evolutionary history and expression patterns of CDPK genes in melon. Herein, a total of 18 CDPK genes and 7 CDPK-related protein kinases (CRK) genes were identified in the melon genome via bioinformatic analysis, which were unevenly distributed across eleven chromosomes with an apparent exception for chromosome 3...
2017: PloS One
https://www.readbyqxmd.com/read/28435965/conformational-and-hydration-properties-modulate-ice-recognition-by-type-i-antifreeze-protein-and-its-mutants
#11
Sandipan Chakraborty, Biman Jana
The mechanism of ice recognition by antifreeze protein (AFP) is a topic of recent interest. Here, using equilibrium simulations and free energy calculations, we provide structural rationale to the observed experimental anomalies on type I AFP (wfAFP isoform HPLC6) and its mutants as well as probe the molecular origin of ice recognition by them. Our results clearly demonstrate that the interplay between the conformational and hydration properties dictates the ice binding ability of type I AFP and its mutants...
April 24, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28435566/functional-outcome-of-bipolar-prosthesis-versus-total-hip-replacement-in-the-treatment-of-femoral-neck-fracture-in-elderly-patients
#12
R Shukla, M Singh, R K Jain, P Mahajan, R Kumar
INTRODUCTION: The present study was performed to compare cemented total hip replacement (THR) with cemented bipolar prosthesis in the treatment of displaced fracture neck of femur in elderly patients. MATERIALS AND METHODS: This prospective study included 47 patients of greater than 60 years of age and having fracture of neck of femur, out of which 25 patients were managed by cemented bipolar prosthesis and remaining 22 were managed by cemented THR between June 2011 and June 2013...
March 2017: Malaysian Orthopaedic Journal
https://www.readbyqxmd.com/read/28433761/a-glycoproteomic-approach-reveals-that-the-s-layer-glycoprotein-of-lactobacillus-kefiri-cidca-83111-is-o-and-n-glycosylated
#13
Gustavo J Cavallero, Mariano Malamud, Adriana C Casabuono, M de Los Ángeles Serradell, Alicia S Couto
In Gram-positive bacteria, such as lactic acid bacteria, general glycosylation systems have not been documented so far. The aim of this work was to characterize in detail the glycosylation of the S-layer protein of Lactobacillus kefiri CIDCA 83111. A reductive β-elimination treatment followed by anion exchange high performance liquid chromatography analysis was useful to characterize the O-glycosidic structures. MALDI-TOF mass spectrometry analysis confirmed the presence of oligosaccharides bearing from 5 to 8 glucose units carrying galacturonic acid...
April 19, 2017: Journal of Proteomics
https://www.readbyqxmd.com/read/28431929/effects-of-naturally-occurring-charged-mutations-on-the-structure-stability-and-binding-of-the-pin1-ww-domain
#14
Xiaoya Qiao, Ying Liu, Liting Luo, Lei Chen, Caixian Zhao, Xuanjun Ai
Pin1 is a peptidyl-prolyl cis-trans isomerase, whose WW domain specifically recognizes the pSer/Thr-Pro motif. Pin1 is involved in multiple phosphorylation events that regulate the activities of various substrates, and Pin1 deregulation has been reported in various diseases, including cancer and Alzheimer's disease. The WW domain of Pin1 has been used as a small model protein to investigate the folding mechanisms of the β-sheet structure by studying the effect of mutations or its naturally occurring variants...
April 19, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28431381/zeaxanthin-ameliorates-high-glucose-induced-mesangial-cell-apoptosis-through-inhibiting-oxidative-stress-via-activating-akt-signalling-pathway
#15
Changjiang Ying, Lei Chen, Shanshan Wang, Yizhen Mao, Hongwei Ling, Wei Li, Xiaoyan Zhou
Oxidative stress is a critical factor in the pathophysiology of diabetic kidney disease. Previous study shows that hyperglycaemia aggravates renal injury through oxidative stress in diabetic model, and antioxidants have beneficial effect on diabetic kidney disease. However, the role of antioxidants in the progression of diabetic kidney disease is poorly understood. The aim of this study was to clarify whether zeaxanthin, an antioxidant, could ameliorate mesangial cell injury and if so, identify the related mechanism underlying this protective effect...
April 18, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28431241/akt-pkb-signaling-navigating-the-network
#16
REVIEW
Brendan D Manning, Alex Toker
The Ser and Thr kinase AKT, also known as protein kinase B (PKB), was discovered 25 years ago and has been the focus of tens of thousands of studies in diverse fields of biology and medicine. There have been many advances in our knowledge of the upstream regulatory inputs into AKT, key multifunctional downstream signaling nodes (GSK3, FoxO, mTORC1), which greatly expand the functional repertoire of AKT, and the complex circuitry of this dynamically branching and looping signaling network that is ubiquitous to nearly every cell in our body...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431078/effect-of-threonine-on-secretory-immune-system-using-a-chicken-intestinal-ex%C3%A2-vivo-model-with-lipopolysaccharide-challenge
#17
Q Zhang, X Chen, S D Eicher, K M Ajuwon, T J Applegate
Secretory IgA (sIgA) and its transcytosis receptor, polymeric immunoglobulin receptor (pIgR), along with mucus, form the first lines of intestinal defense. Threonine (Thr) is a major component of intestinal mucins and IgA, which are highly secreted under lipopolysaccharide (LPS) induced inflammation. In the current study, the effect of Thr on the secretory immune system was determined in an ex vivo chicken ileal explant model. Results showed that a 2-hour Thr-deprivation of culture medium induced a compensatory increase in the mRNA expression of interleukin-8 (IL-8), mucin 2 ( ), and IgA during LPS challenge, and this increase was suppressed with Thr addition to the media ( P  ≤ 0...
April 18, 2017: Poultry Science
https://www.readbyqxmd.com/read/28428613/differential-regulation-of-pkd-isoforms-in-oxidative-stress-conditions-through-phosphorylation-of-a-conserved-tyr-in-the-p-1-loop
#18
Mathias Cobbaut, Rita Derua, Heike Döppler, Hua Jane Lou, Sandy Vandoninck, Peter Storz, Benjamin E Turk, Thomas Seufferlein, Etienne Waelkens, Veerle Janssens, Johan Van Lint
Protein kinases are essential molecules in life and their crucial function requires tight regulation. Many kinases are regulated via phosphorylation within their activation loop. This loop is embedded in the activation segment, which additionally contains the Mg(2+) binding loop and a P + 1 loop that is important in substrate binding. In this report, we identify Abl-mediated phosphorylation of a highly conserved Tyr residue in the P + 1 loop of protein kinase D2 (PKD2) during oxidative stress. Remarkably, we observed that the three human PKD isoforms display very different degrees of P + 1 loop Tyr phosphorylation and we identify one of the molecular determinants for this divergence...
April 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28427860/differential-mtor-pathway-profiles-in-bladder-cancer-cell-line-subtypes-to-predict-sensitivity-to-mtor-inhibition
#19
Andrew M Hau, Manando Nakasaki, Kazufumi Nakashima, Goutam Krish, Donna E Hansel
BACKGROUND: Molecular classification of bladder cancer has been increasingly proposed as a potential tool to predict clinical outcomes and responses to chemotherapy. Here we focused on mechanistic target of rapamycin (mTOR) inhibition as a chemotherapeutic strategy and characterized the expression profile of mTOR signaling targets in representative bladder cancer cell lines from basal, luminal, and either basal/luminal ("non-type") molecular subtypes. MATERIALS AND METHODS: Protein and mRNA expression of mTOR signaling components from representative luminal (RT4 and RT112), basal (SCaBER and 5637), and nontype (T24 and J82) bladder cancer cell line subtypes were determined by Western blot and database mining analysis of the Cancer Cell Line Encyclopedia...
April 18, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28427014/chemical-and-biological-properties-of-a-supramolecular-complex-of-tuftsin-and-cucurbit-7-uril
#20
Ekaterina A Kovalenko, Ekaterina A Pashkina, Lyubov Y Kanazhevskaya, Alexey N Masliy, Vladimir A Kozlov
Cucurbit[7]uril (CB7) is an uncharged and water-soluble macrocyclic host. CB7 binds to doubly protonated tuftsin, which is the tetrapeptide Thr-Lys-Pro-Arg, with moderate affinity (Ka=2.1×10(3)M(-1)). In this study, the host-guest complexation was confirmed by fluorescence titration. This affinity would allow for easy release of the peptide under physiological conditions. According to density functional theory calculations, the structural binding motif involves hydrogen bonding. The most energetically stable form had the Arg side chain inside the CB7 cavity...
April 17, 2017: International Immunopharmacology
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