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https://www.readbyqxmd.com/read/28647489/a-high-throughput-assay-to-identify-substrate-selective-inhibitors-of-the-erk-protein-kinases
#1
Chad J Miller, Yagmur Muftuoglu, Benjamin E Turk
Extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylate a variety of substrates important for survival and proliferation, and their activity is frequently deregulated in tumors. ERK pathway inhibitors have shown clinical efficacy as anti-cancer drugs, but most patients eventually relapse due to reactivation of the pathway. One factor limiting the efficacy of current therapeutics is the difficulty in reaching clinically effective inhibition of the ERK pathway in the absence of on-target toxicities...
June 21, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28647433/targeted-release-of-transcription-factors-for-human-cell-reprogramming-by-zebra-cell-penetrating-peptide
#2
Benjamin Caulier, Lionel Berthoin, Helène Coradin, Frédéric Garban, Marie Claire Dagher, Benoît Polack, Bertrand Toussaint, Jean Luc Lenormand, David Laurin
Transcription factors (TFs) are key actors of the control of gene expression and consequently of every major process within cells, ranging from cell fate determination, cell cycle control and response to environment. Their ectopic expression has proven high potential in reprogramming cells for regenerative medicine; ontogenesis studies and cell based modelling. Direct delivery of proteins could represent an alternative to current reprogramming methods using gene transfer but still needs technological improvements...
June 21, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28647362/farnesoid-x-receptor-agonist-gw4064-ameliorates-lipopolysaccharide-induced-ileocolitis-through-tlr4-myd88-pathway-related-mitochondrial-dysfunction-in-mice
#3
Hsuan-Miao Liu, Jyh-Fe Liao, Tzung-Yan Lee
Inflammatory bowel disease (IBD) is a complex and relapsing inflammatory condition of the gastro intestinal tract characterized by diarrhea and abdominal pain. Farnesoid X receptor (FXR) plays an important role in enteroprotection and mucosal injury by regulating inflammatory responses and barrier function in the intestinal tract. Here we show the mechanisms of FXR agonist, GW4064, inhibits mucosal injury in ileum caused by lipopolysaccharides (LPS). Ileum injury was induced by intraperitoneal injection of LPS in Wild-type (WT) and FXR knockout (KO) mice...
June 21, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28647360/structure-of-an-unconventional-sh3-domain-from-the-postsynaptic-density-protein-shank3-at-ultrahigh-resolution
#4
Srinivas Kumar Ponna, Matti Myllykoski, Tobias M Boeckers, Petri Kursula
The Shank family comprises three large multi-domain proteins playing central roles as protein scaffolds in the neuronal postsynaptic density. The Shank proteins are closely linked to neuropsychiatric diseases, such as autism spectrum disorders. One characteristic domain in the Shank family is the SH3 domain, assumed to play a role in protein-protein interactions; however, no specific ligand binding to any Shank SH3 domain has been described. We solved the crystal structure of the SH3 domain from Shank3 at sub-atomic resolution...
June 21, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28647345/cutaneous-nod2-expression-regulates-the-skin-microbiome-and-wound-healing-in-a-murine-model
#5
Helen Williams, Rachel A Crompton, Helen A Thomason, Laura Campbell, Gurdeep Singh, Andrew J McBain, Sheena M Cruickshank, Matthew J Hardman
The skin microbiome exists in dynamic equilibrium with the host but when the skin is compromised, bacteria can colonise the wound and impair wound healing. Thus the interplay between normal skin-microbial interactions versus pathogenic-microbial interactions in wound repair is important. Bacteria are recognised by innate host pattern recognition receptors (PRRs) and we previously demonstrated an important role for the PRR NOD2 (nucleotide-binding oligomerisation domains-containing protein 2) in skin wound repair...
June 21, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28647124/putative-protein-vc0395_0300-from-vibrio-cholerae-is-a-diguanylate-cyclase-with-a-role-in-biofilm-formation
#6
Divya Bandekar, Om Prakash Chouhan, Swati Mohapatra, Mousumi Hazra, Saugata Hazra, Sumit Biswas
The hallmark of the lifecycle of Vibrio cholerae is its ability to switch between two lifestyles - the sessile, non-pathogenic form and the motile, infectious form in human hosts. One of these changes is in the formation of surface biofilms, when in sessile aquatic habitats. The cell-cell interactions within a V. cholerae biofilm are stabilized by the production of an exopolysachharide (EPS) matrix, which in turn is regulated by the ubiquitous secondary messenger, cyclic di-GMP (c-di-GMP), synthesized by proteins containing GGD(/E)EF domains in all prokaryotic systems...
September 2017: Microbiological Research
https://www.readbyqxmd.com/read/28646905/mechanistic-understanding-of-nanoparticles-interactions-with-extracellular-matrix-the-cell-and-immune-system
#7
REVIEW
Ayse Basak Engin, Dragana Nikitovic, Monica Neagu, Petra Henrich-Noack, Anca Oana Docea, Mikhail I Shtilman, Kirill Golokhvast, Aristidis M Tsatsakis
Extracellular matrix (ECM) is an extraordinarily complex and unique meshwork composed of structural proteins and glycosaminoglycans. The ECM provides essential physical scaffolding for the cellular constituents, as well as contributes to crucial biochemical signaling. Importantly, ECM is an indispensable part of all biological barriers and substantially modulates the interchange of the nanotechnology products through these barriers. The interactions of the ECM with nanoparticles (NPs) depend on the morphological characteristics of intercellular matrix and on the physical characteristics of the NPs and may be either deleterious or beneficial...
June 24, 2017: Particle and Fibre Toxicology
https://www.readbyqxmd.com/read/28646885/comparison-of-the-protective-efficacy-between-single-and-combination-of-recombinant-adenoviruses-expressing-complete-and-truncated-glycoprotein-and-nucleoprotein-of-the-pathogenic-street-rabies-virus-in-mice
#8
Ha-Hyun Kim, Dong-Kun Yang, Jin-Ju Nah, Jae-Young Song, In-Soo Cho
BACKGROUND: Rabies is an important viral zoonosis that causes acute encephalitis and death in mammals. To date, several recombinant vaccines have been developed based on G protein, which is considered to be the main antigen, and these vaccines are used for rabies control in many countries. Most recombinant viruses expressing RABV G protein retain the G gene from attenuated RABV. Not enough is currently known about the protective effect against RABV of a combination of recombinant adenoviruses expressing the G and N proteins of pathogenic street RABV...
June 24, 2017: Virology Journal
https://www.readbyqxmd.com/read/28646872/role-of-p2x7r-in-the-development-and-progression-of-pulmonary-hypertension
#9
Jie Yin, Shuling You, Haopeng Liu, Li Chen, Chengdong Zhang, Hesheng Hu, Mei Xue, Wenjuan Cheng, Ye Wang, Xinran Li, Yugen Shi, Nannan Li, Suhua Yan, Xiaolu Li
BACKGROUND: Pulmonary arterial hypertension (PAH) is a devastating disease that lacks sufficient treatment. Studies have shown that the Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome contributes to PAH pathogenesis, but the role of the upstream molecular P2X7 receptor (P2X7R) has remained unexplored. We investigated the role of P2X7R in the pathogenesis of PAH. METHODS AND RESULTS: PH was induced by a single subcutaneous injection of monocrotaline (MCT) (60 mg/kg) on left pneumonectomised Sprague-Dawley rats, as validated by significant increases in pulmonary artery pressure and vessel wall thickness...
June 24, 2017: Respiratory Research
https://www.readbyqxmd.com/read/28646547/a-dual-fluorescence-reporter-in-the-eomes-locus-for-live-imaging-and-medium-term-lineage-tracing
#10
Simone Probst, Ray A Daza, Natalie Bader, Jonas F Hummel, Matthias Weiß, Yakup Tanriver, Robert F Hevner, Sebastian J Arnold
The T-box transcription factor Eomes (also known as Tbr2) shows short-lived expression in various localized domains of the embryo, including epiblast cells during gastrulation and intermediate progenitor cells in the cerebral cortex. In these tissues Eomes fulfills crucial roles for lineage specification of progenitors. To directly observe Eomes-dependent cell lineages in the living embryo, we generated a novel dual-fluorescence reporter allele that expresses a membrane-bound tdTomato protein for investigation of cell morphology and a nuclear GFP for cell tracing...
June 24, 2017: Genesis: the Journal of Genetics and Development
https://www.readbyqxmd.com/read/28646525/preliminary-characterization-of-putative-structural-cuticular-proteins-in-the-malaria-vector-anopheles-sinensis
#11
Dan Zhou, Baiyun Duan, Yan Sun, Lei Ma, Changliang Zhu, Bo Shen
BACKGROUND: The insect cuticle protects against environmental stresses such as insecticides, physical injury, dehydration and pathogenic microorganisms. Structural cuticular proteins (CPs) are the primary components, and are of interest for physiology-based pest management methods. Anopheles sinensis CPs are poorly characterised at present, therefore we performed whole genome sequence analysis and re-analysed available transcriptome data to identify potential insecticide resistance-associated CPs...
June 23, 2017: Pest Management Science
https://www.readbyqxmd.com/read/28646429/decoupled-side-chain-and-backbone-dynamics-for-proton-translocation-m2-of-influenza-a
#12
Monoj Mon Kalita, Wolfgang B Fischer
The 97 amino acid bitopic membrane protein M2 of influenza A forms a tetrameric bundle in which two of the monomers are covalently linked via a cysteine bridge. In its tetrameric assembly the protein conducts protons across the viral envelope and within intracellular compartments during the infectivity cycle of the virus. A key residue in the translocation of the protons is His-37 which forms a planar tetrad in the configuration of the bundle accepting and translocating the incoming protons from the N terminal side, exterior of the virus, to the C terminal side, inside the virus...
July 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28646426/eftrenonacog-alfa-a-review-in-haemophilia-b
#13
Sheridan M Hoy
Eftrenonacog alfa (Alprolix™) is a recombinant fusion protein comprising human factor IX (FIX) covalently linked to the constant region (Fc) domain of human IgG1 (i.e. rFIXFc). The presence of the Fc domain extends the terminal half-life (t½) of rFIXFc, permitting prolonged treatment intervals. rFIXFc is available for intravenous use for the prophylaxis and treatment of bleeding in patients with haemophilia B. In two multinational, phase III studies in previously treated children, adolescents and adults with severe haemophilia B, rFIXFc prophylaxis resulted in low median annualized bleeding rates (ABRs), and was associated with reductions in median weekly factor consumption and dosing frequency compared with pre-study FIX regimens...
June 23, 2017: Drugs
https://www.readbyqxmd.com/read/28646413/integrated-in-silico-in-vitro-identification-and-characterization-of-the-sh3-mediated-interaction-between-human-pttg-and-its-cognate-partners-in-medulloblastoma
#14
Jiangang Liu, Dapeng Wang, Yanyan Li, Hui Yao, Nan Zhang, Xuewen Zhang, Fangping Zhong, Yulun Huang
The human pituitary tumor-transforming gene is an oncogenic protein which serves as a central hub in the cellular signaling network of medulloblastoma. The protein contains two vicinal PxxP motifs at its C terminus that are potential binding sites of peptide-recognition SH3 domains. Here, a synthetic protocol that integrated in silico analysis and in vitro assay was described to identify the SH3-binding partners of pituitary tumor-transforming gene in the gene expression profile of medulloblastoma. In the procedure, a variety of structurally diverse, non-redundant SH3 domains with high gene expression in medulloblastoma were compiled, and their three-dimensional structures were either manually retrieved from the protein data bank database or computationally modeled through bioinformatics technique...
June 24, 2017: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28646145/the-calmodulin-fused-kinase-novel-gene-family-is-the-major-system-in-plants-converting-ca-2-signals-to-protein-phosphorylation-responses
#15
Fei Chen, Liangsheng Zhang, Zong-Ming Max Cheng
Eukaryotes utilize Ca(2+) as a universal second messenger to convert and multiply environmental and developmental signals to downstream protein phosphorylation responses. However, the phylogenetic relationships of the genes that convert Ca(2+) signal (CS) to protein phosphorylation responses (PPRs) remain highly controversial, and their origin and evolutionary trajectory are unclear, which greatly hinders functional studies. Here we examined the deep phylogeny of eukaryotic CS converter gene families and identified a phylogenetically and structurally distinctive monophyly in Archaeplastida...
June 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28646141/human-sialidase-neu3-is-s-acylated-and-behaves-like-an-integral-membrane-protein
#16
Macarena Rodriguez-Walker, Jose L Daniotti
Membrane-bound sialidase Neu3 is involved in the catabolism of glycoconjugates, and plays crucial roles in numerous biological processes. Since the mechanism of its association with membranes is still not completely understood, the aim of this work was to provide further information regarding this aspect. Human Neu3 was found to be associated with the plasma membrane and endomembranes, and it was not released from the lipid bilayer under conditions that typically release peripheral membrane proteins. By different experimental approaches, we demonstrated that its C-terminus is exposed to the cytosol while another portion of the protein is exposed to the extracellular space, suggesting that Neu3 possesses the features of a transmembrane protein...
June 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28646110/the-mcm2-7-interacting-domain-of-human-mini-chromosome-maintenance-10-mcm10-protein-is-important-for-stable-chromatin-association-and-origin-firing
#17
Masako Izumi, Takeshi Mizuno, Ken-Ichiro Yanagi, Kazuto Sugimura, Katsuzumi Okumura, Naoko Imamoto, Tomoko Abe, Fumio Hanaoka
The protein mini-chromosome maintenance 10 (Mcm10) was originally identified as an essential yeast protein in the maintenance of mini-chromosome plasmids. Subsequently, Mcm10 has been shown to be required for both initiation and elongation during chromosomal DNA replication. However, it is not fully understood how the multiple functions of Mcm10 are coordinated or how Mcm10 interacts with other factors at replication forks. Here, we identified and characterized the Mcm2-7-interacting domain in human Mcm10. The interaction with Mcm2-7 required the Mcm10 domain that contained amino acids 530-655, which overlapped with the domain required for the stable retention of Mcm10 on chromatin...
June 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28646092/deletion-analysis-of-agd1-reveals-domains-crucial-for-its-plasma-membrane-recruitment-and-function-in-root-hair-polarity
#18
Cheol-Min Yoo, Satoshi Naramoto, J Alan Sparks, Bibi Rafeiza Khan, Jin Nakashima, Hiroo Fukuda, Elison B Blancaflor
AGD1, a plant ACAP-type ADP-ribosylation factor-GTPase activating protein (ARF-GAP), functions in specifying root hair polarity in Arabidopsis thaliana To better understand how AGD1 modulates root hair growth, we generated full length and domain-deleted AGD1-green fluorescent protein (GFP) constructs, and followed their localization during root hair development. AGD1-GFP localized to the cytoplasm and was recruited to specific regions of the root hair plasma membrane (PM). Distinct PM AGD1-GFP signal was first detected along the site of root hair bulge formation...
June 23, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28646018/the-amyloid-precursor-protein-modulates-%C3%AE-2a-adrenergic-receptor-endocytosis-and-signaling-through-disrupting-arrestin-3-recruitment
#19
Fang Zhang, Mary Gannon, Yunjia Chen, Lufang Zhou, Kai Jiao, Qin Wang
The amyloid precursor protein (APP) has long been appreciated for its role in Alzheimer's disease (AD) pathology. However, less is known about the physiologic function of APP outside of AD. Particularly, whether and how APP may regulate functions of cell surface receptors, including GPCRs, remains largely unclear. In this study, we identified a novel direct interaction between APP and the α2A adrenergic receptor (α2AAR) that occurs at the intracellular domains of both proteins. The APP interaction with α2AAR is promoted by agonist stimulation and competes with arrestin 3 binding to the receptor...
June 23, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28645932/a-functional-nav1-7-navab-chimera-with-a-reconstituted-high-affinity-protx-ii-binding-site
#20
Ramkumar Rajamani, Sophie Wu, Iyoncy Rodrigo, Mian Gao, Simon Low, Lisa Megson, David Wensel, Rick Pieschl, Debra Post-Munson, John Watson, David R Langley, Michael Ahlijanian, Linda Bristow, James Herrington
NaV1.7 is genetically implicated in human pain perception. Rare gain of function mutations in NaV1.7 lead to spontaneous pain in humans whereas loss of function mutations result in congenital insensitivity to pain (CIP). Hence, agents that specifically modulate the function of NaV1.7 have the potential to yield novel therapeutics to treat pain. The complexity of the channel and the challenges to generate recombinant cell lines with high NaV1.7 expression have led to a templated target strategy approach employing chimeras with the bacterial channel, NavAb...
June 23, 2017: Molecular Pharmacology
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