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https://www.readbyqxmd.com/read/28107624/tocilizumab-alendronate-conjugate-for-treatment-of-rheumatoid-arthritis
#1
Hwiwon Lee, Suk Ho Bhang, Jeong Ho Lee, Hyemin Kim, Sei Kwang Hahn
An autoimmune disease of rheumatoid arthritis (RA) causes severe inflammation on the synovial membrane, which results in the destruction of articular cartilage and bone. Here, Tocilizumab (TCZ) - Alendronate (ALD) conjugate is synthesized for the early intervention of RA. A humanized monoclonal antibody of TCZ shows an immunosuppressive effect, targeting interleukin-6 (IL-6) receptor in the RA pathogenesis. ALD is an anti-inflammatory bisphosphonate drug which can bind to the exposed bone surface. ALD is conjugated selectively to N-glycan on Fc region of TCZ using a chemical linker of 3-(2-pyridyldithio) propionyl hydrazide (PDPH) - poly(ethylene glycol) - N-hydroxysuccinimide (PDPH-PEG-NHS)...
January 20, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28106467/follicular-lymphoma-a-b-cell-malignancy-addicted-to-epigenetic-mutations
#2
Koorosh Korfi, Sara Ali, James A Heward, Jude Fitzgibbon
While follicular lymphoma (FL) is exquisitely responsive to immuno-chemotherapy, many patients follow a relapsing remitting clinical course driven in part by a common precursor cell (CPC) population. Advances in next generation sequencing have provided valuable insights into the genetic landscape of FL and its clonal evolution in response to therapy, implicating perturbations of epigenetic regulators as a hallmark of the disease. Recurrent mutations of histone modifiers KMT2D, CREBBP, EP300, EZH2, ARIDIA, and linker histones are likely early events arising in the CPC pool, rendering epigenetic based therapies conceptually attractive for treatment of indolent and transformed FL...
January 20, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/28106385/substituent-effects-on-the-ph-sensitivity-of-acetals-and-ketals-and-their-correlation-with-encapsulation-stability-in-polymeric-nanogels
#3
Bin Liu, Sankaran Thayumanavan
Effect of structural variations in acetal- and ketal- based linkers upon their degradation kinetics is studied through the design, synthesis and study of six series of molecules, comprising a total of eighteen different molecules. Through this systematic study, we show that the structural fine-tuning of the linkers allow access to variations in kinetics of degradation of more than six orders of magnitude. Hammett correlations show that the ρ value for the hydrolysis of benzylidene acetals is about -4.06, which is comparable to an SN1-like process...
January 20, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28106194/connectivity-pattern-modifies-excited-state-relaxation-dynamics-of-fluorophore-photoswitch-molecular-dyads
#4
F Schweighöfer, J Moreno, S Bobone, S Chiantia, A Herrmann, S Hecht, J Wachtveitl
In order to modulate the emission of BODIPY fluorophores, they were connected to a diarylethene (DAE) photoswitch via phenylene-ethynylene linkers of different lengths and orientations. The latter allowed for modulation of the electronic coupling in the prepared four BODIPY-DAE dyads, which were compared also to appropriate BODIPY and DAE model compounds by steady state as well as time-resolved spectroscopies. In their open isomers, all dyads show comparable luminescence behavior indicative of an unperturbed BODIPY fluorophore...
January 20, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28105892/molecularly-imprinted-cryogel-membranes-for-mitomycin-c-delivery
#5
Pınar Öncel, Kemal Çetin, Aykut Arif Topçu, Handan Yavuz, Adil Denizli
In this study, cryogel-based implantable molecularly imprinted drug delivery systems were designed for the delivery of antineoplastic agent. Mitomycin C imprinted poly(2-hydroxyethyl methacrylate-N-methacryloyl-l-glutamic acid) cryogel membranes were produced by free-radical bulk polymerization under partially frozen conditions. The membranes were characterized by swelling tests, Fourier transform infrared spectroscopy, scanning electron microscopy, surface area measurements and in vitro hemocompatibility tests...
January 20, 2017: Journal of Biomaterials Science. Polymer Edition
https://www.readbyqxmd.com/read/28105486/immobilization-of-alkaline-polygalacturonate-lyase-from-bacillus-subtilis-on-the-surface-of-bacterial-polyhydroxyalkanoate-nano-granules
#6
GanQiao Ran, Dan Tan, WeiEr Dai, XinLiang Zhu, JiPing Zhao, Qi Ma, XiaoYun Lu
Alkaline polygalacturonate lyase (PGL), one of the pectinolytic enzymes, has been widely used for the bioscouring of cotton fibers, biodegumming, and biopulp production. In our study, PGL from Bacillus subtilis was successfully immobilized on the surface of polyhydroxyalkanoate (PHA) nanogranules by fusing PGL to the N-terminal of PHA synthase from Ralstonia eutropha via a designed linker. The PGL-decorated PHA beads could be simply achieved by recombinant fermentation and consequent centrifugation. The fused PGL occupied 0...
January 20, 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28105278/hydrazone-linker-as-a-useful-tool-for-preparing-chimeric-peptide-nonpeptide-bifunctional-compounds
#7
Jolanta Dyniewicz, Piotr F J Lipiński, Piotr Kosson, Anna Leśniak, Marta Bochyńska-Czyż, Adriana Muchowska, Dirk Tourwé, Steven Ballet, Aleksandra Misicka, Andrzej W Lipkowski
The area of multitarget compounds, joining two pharmacophores within one molecule, is a vivid field of research in medicinal chemistry. Not only pharmacophoric elements are essential for the design and activity of such compounds, but the type and length of linkers used to connect them are also crucial. In the present contribution, we describe compound 1 in which a typical opioid peptide sequence is combined with a fragment characteristic for neurokinin-1 receptor (NK1R) antagonists through a hydrazone bridge...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28104471/the-intracellular-delivery-of-plasmid-dna-using-cationic-reducible-carbon-nanotube-disulfide-conjugates-ofpolyethylenimine
#8
Azadeh Hashem Nia, Hossein Eshghi, Kalil Abnous, Mohammad Ramezani
A series of polyethylenimine conjugates of single-walled carbon nanotube (PEI-SWNT) containing bioreducible disulfide bonds was synthesized and evaluated for their transfection efficiency. Different molecular weights of polyethylenimine (PEI) were thiolated with different mole ratio of 2-iminothiolane (2-IT). Single-walled carbon nanotube (SWNT) was first carboxylated and then three different cysteine-functionalized SWNT formulations were synthesized via introduced linkers: a) carbonyl group b) spermidine c) 1,8-diamino 3,6-dioxo octane...
January 16, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28104372/insights-on-the-structural-dynamics-of-leishmania-braziliensis-hsp90-molecular-chaperone-by-small-angle-x-ray-scattering
#9
Thiago V Seraphim, Kelly P Silva, Paulo R Dores-Silva, Leandro R S Barbosa, Júlio C Borges
Heat shock protein of 90kDa (Hsp90) is an essential molecular chaperone involved in a plethora of cellular activities which modulate protein homeostasis. During the Hsp90 mechanochemical cycle, it undergoes large conformational changes, oscillating between open and closed states. Although structural and conformational equilibria of prokaryotic and some eukaryotic Hsp90s are known, some protozoa Hsp90 structures and dynamics are poorly understood. In this study, we report the solution structure and conformational dynamics of Leishmania braziliensis Hsp90 (LbHsp90) investigated by small angle X-ray scattering (SAXS)...
January 16, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28103592/influences-of-various-peptide-linkers-on-the-thermotoga-maritima-msb8-nitrilase-displayed-on-the-spore-surface-of-bacillus-subtilis
#10
Huayou Chen, Zhi Chen, Bangguo Wu, Jawad Ullah, Tianxi Zhang, Jinru Jia, Hongcheng Wang, Tianwei Tan
In the present study, fusion genes composed of Thermotoga maritima MSB8 nitrilase and Bacillus subtilis 168 outer coat protein CotG were constructed with various peptide linkers and displayed on B. subtilis DB 403 spores. The successful display of CotG-nit fusion proteins on the spore surface of B. subtilis was verified by Western blot analysis and activity measurement. It was demonstrated that the fusion with linker GGGGSEAAAKGGGGS presented the highest thermal and pH stability, which is 2.67- and 1.9-fold of the fusion without linker...
January 20, 2017: Journal of Molecular Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28103440/carbon-nanotubes-mediate-fusion-of-lipid-vesicles
#11
Ramachandra Moorthy Bhaskara, Stephanie M Linker, Martin Vögele, Juergen Koefinger, Gerhard Hummer
The fusion of lipid membranes is opposed by high energetic barriers. In living organisms, complex protein machineries carry out this biologically essential process. Here we show that membrane-spanning carbon nanotubes (CNTs) can trigger spontaneous fusion of small lipid vesicles. In coarse-grained molecular dynamics simulations, we find that a CNT bridging between two vesicles locally perturbs their lipid structure. Their outer leaflets merge as the CNT pulls lipids out of the membranes, creating an hourglass-shaped fusion intermediate with still intact inner leaflets...
January 19, 2017: ACS Nano
https://www.readbyqxmd.com/read/28103013/building-nanoporous-metal-organic-frameworks-armour-on-fibers-for-high-performance-composite-materials
#12
Xiaobin Yang, Xu Jiang, Yudong Huang, Zhanhu Guo, Lu Shao
The nanoporous Metal-Organic Frameworks (MOFs) "armour" is in situ intergrown onto the surfaces of carbon fibers (CFs) by nitric acid oxidization to supply nucleation sites, and serves as a novel interfacial linker between the fiber and polymer matrix and a smart cushion to release interior and exterior applied forces. Simultaneous enhancements of the interfacial and interlaminar shear strength as well as the tensile strength of CFs were achieved. With the aid of an ultrasonic "cleaning" process, the optimized surface energy and tensile strength of CFs with a MOF "armour" are 83...
January 19, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28102754/enhancement-of-antibody-functions-through-fc-multiplications
#13
Qun Wang, Yan Chen, Mark Pelletier, Romana Cvitkovic, Jessica Bonnell, Chien-Ying Chang, Adem C Koksal, Ellen O'Connor, Xizhe Gao, Xiang-Qing Yu, Herren Wu, C Kendall Stover, William F Dall'Acqua, Xiaodong Xiao
Antibodies carry out a plethora of functions through their crystallizable fragment (Fc) regions, which can be naturally tuned by the adoption of several isotypes and post-translational modifications. Protein engineering enables further Fc function modulations through modifications of the interactions between the Fc and its functional partners, including FcγR, FcRn, complement complex, and additions of auxiliary functional units. Due to the many functions embedded within the confinement of an Fc, a suitable balance must be maintained for a therapeutic antibody to be effective and safe...
January 19, 2017: MAbs
https://www.readbyqxmd.com/read/28102353/cofilin-regulates-nuclear-architecture-through-a-myosin-ii-dependent-mechanotransduction-module
#14
O'Neil Wiggan, Bryce Schroder, Diego Krapf, James R Bamburg, Jennifer G DeLuca
Structural features of the nucleus including shape, size and deformability impact its function affecting normal cellular processes such as cell differentiation and pathological conditions such as tumor cell migration. Despite the fact that abnormal nuclear morphology has long been a defining characteristic for diseases such as cancer relatively little is known about the mechanisms that control normal nuclear architecture. Mounting evidence suggests close coupling between F-actin cytoskeletal organization and nuclear morphology however, mechanisms regulating this coupling are lacking...
January 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28101951/rigidity-and-flexibility-in-the-tetrasaccharide-linker-of-proteoglycans-from-atomic-resolution-molecular-simulation
#15
Cathy Ng, Padmavathy Nandha Premnath, Olgun Guvench
Proteoglycans (PGs) are covalent conjugates between protein and carbohydrate (glycosaminoglycans). Certain classes of glycosaminoglycans such as chondroitin sulfate/dermatan sulfate and heparan sulfate utilize a specific tetrasaccharide linker for attachment to the protein component: GlcAβ1-3Galβ1-3Galβ1-4Xylβ1-O-Ser. Toward understanding the conformational preferences of this linker, the present work used all-atom explicit-solvent molecular dynamics (MD) simulations combined with Adaptive Biasing Force (ABF) sampling to determine high-resolution, high-precision conformational free energy maps ΔG(φ, ψ) for each glycosidic linkage between constituent disaccharides, including the variant where GlcA is substituted with IdoA...
January 19, 2017: Journal of Computational Chemistry
https://www.readbyqxmd.com/read/28101862/crystallographic-studies-of-intermediate-filament-proteins
#16
Dmytro Guzenko, Anastasia A Chernyatina, Sergei V Strelkov
Intermediate filaments (IFs), together with microtubules and actin microfilaments, are the three main cytoskeletal components in metazoan cells. IFs are formed by a distinct protein family, which is made up of 70 members in humans. Most IF proteins are tissue- or organelle-specific, which includes lamins, the IF proteins of the nucleus. The building block of IFs is an elongated dimer, which consists of a central α-helical 'rod' domain flanked by flexible N- and C-terminal domains. The conserved rod domain is the 'signature feature' of the IF family...
2017: Sub-cellular Biochemistry
https://www.readbyqxmd.com/read/28101692/the-assembly-and-function-of-perinuclear-actin-cap-in-migrating-cells
#17
Miloslava Maninova, Josef Caslavsky, Tomas Vomastek
Stress fibers are actin bundles encompassing actin filaments, actin-crosslinking, and actin-associated proteins that represent the major contractile system in the cell. Different types of stress fibers assemble in adherent cells, and they are central to diverse cellular processes including establishment of the cell shape, morphogenesis, cell polarization, and migration. Stress fibers display specific cellular organization and localization, with ventral fibers present at the basal side, and dorsal fibers and transverse actin arcs rising at the cell front from the ventral to the dorsal side and toward the nucleus...
January 18, 2017: Protoplasma
https://www.readbyqxmd.com/read/28101578/a-22q11-2-amplification-in-the-region-encoding-microrna-650-correlates-with-the-epithelial-to-mesenchymal-transition-in-breast-cancer-primary-cultures-of-mexican-patients
#18
M Lango-Chavarría, G K Chimal-Ramírez, M E Ruiz-Tachiquín, N A Espinoza-Sánchez, M C Suárez-Arriaga, E M Fuentes-Pananá
Breast cancer ranks first in incidence and mortality in working age women. Cancer initiation and progression relies on accumulation of genetic and epigenetic aberrations that alter cellular processes, among them, epithelial to mesenchymal transition (EMT) denotes particularly aggressive neoplasias given its capacity to invade and metastasize. Several microRNAs (miRNA) have been found able to regulate gene expression at the core of EMT. In this study, the Affymetrix CytoScan HD array was used to analyze three different primary tumor cell isolates from Mexican breast cancer patients...
February 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28100636/centriole-splitting-caused-by-loss-of-the-centrosomal-linker-protein-c-nap1-reduces-centriolar-satellite-density-and-impedes-centrosome-amplification
#19
Anne-Marie Flanagan, Elena Stavenschi, Shivakumar Basavaraju, David Gaboriau, David A Hoey, Ciaran G Morrison
Duplication of the centrosomes is a tightly regulated process. Abnormal centrosome numbers can impair cell division and cause changes in how cells migrate. Duplicated centrosomes are held together by a proteinaceous linker made up of rootletin filaments anchored to the centrioles by C-NAP1. This linker is removed in a NEK2A kinase-dependent manner as mitosis begins. To explore C-NAP1 activities in regulating centrosome activities, we used genome editing to ablate it. C-NAP1 null cells were viable and had an increased frequency of premature centriole separation, accompanied by reduced density of the centriolar satellites, with re-expression of C-NAP1 rescuing both these phenotypes...
January 18, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28100492/dynamic-assembly-of-ultrasoft-colloidal-networks-enables-cell-invasion-within-restrictive-fibrillar-polymers
#20
Alison M Douglas, Alexandros A Fragkopoulos, Michelle K Gaines, L Andrew Lyon, Alberto Fernandez-Nieves, Thomas H Barker
In regenerative medicine, natural protein-based polymers offer enhanced endogenous bioactivity and potential for seamless integration with tissue, yet form weak hydrogels that lack the physical robustness required for surgical manipulation, making them difficult to apply in practice. The use of higher concentrations of protein, exogenous cross-linkers, and blending synthetic polymers has all been applied to form more mechanically robust networks. Each relies on generating a smaller network mesh size, which increases the elastic modulus and robustness, but critically inhibits cell spreading and migration, hampering tissue regeneration...
January 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
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