Biomolecular condensation of the microtubule-associated protein tau.

Cells contain multiple compartments dedicated to the regulation and control of biochemical reactions. Cellular compartments that are not surrounded by membranes can rapidly form and dissolve in response to changes in the cellular environment. The physicochemical processes that underlie the formation of non-membrane-bound compartments in vivo are connected to liquid-liquid phase separation of proteins and nucleic acids in vitro. Recent evidence suggests that the protein tau, which plays an important role in Alzheimer's disease and other neurodegenerative disorders, phase separates in solution, forms tau phases with microtubules, and associates with phase-separated RNA-binding protein granules in cells. Here we review the experimental evidence that supports the ability of tau to phase separate in solution and form biomolecular condensates in cells. As for other disease-relevant proteins, the physiological and pathological functions of tau are tightly connected - through loss of normal function or gain of toxic function - and we therefore discuss how tau phase separation plays a role for both, and with respect to different cellular functions of tau

Interactions of the potent synthetic AT1 antagonist analog BV6 with membrane bilayers and mesoporous silicate matrices

The present work describes the drug:membrane interactions and a drug delivery system of the novel potent AT1 blocker BV6. This designed analog has most of the pharmacological segments of losartan and an additional biphenyltetrazole moiety resulting in increased lipophilicity. We found that BV6:membrane interactions lead to compact bilayers that may in part explain its higher in vitro activity compared to losartan since such environment may facilitate its approach to AT1 receptor. Its high docking score to AT1 receptor stems from more hydrophobic interactions compared to losartan. X-ray powder diffraction (XRPD) and thermogravimetric analysis (TGA) have shown that BV6 has a crystalline form that is not decomposed completely up to 600 °C. These properties are desirable for a drug molecule. BV6 can also be incorporated into a mesoporous silicate drug-delivery matrix SBA-15. The properties of the obtained drug-delivery system have been inspected by XRD, 13C CP/MAS, TGA and nitrogen sorption experiments

Lysine/RNA-interactions drive and regulate biomolecular condensation.

Cells form and use biomolecular condensates to execute biochemical reactions. The molecular properties of non-membrane-bound condensates are directly connected to the amino acid content of disordered protein regions. Lysine plays an important role in cellular function, but little is known about its role in biomolecular condensation. Here we show that protein disorder is abundant in protein/RNA granules and lysine is enriched in disordered regions of proteins in P-bodies compared to the entire human disordered proteome. Lysine-rich polypeptides phase separate into lysine/RNA-coacervates that are more dynamic and differ at the molecular level from arginine/RNA-coacervates. Consistent with the ability of lysine to drive phase separation, lysine-rich variants of the Alzheimer's disease-linked protein tau undergo coacervation with RNA in vitro and bind to stress granules in cells. Acetylation of lysine reverses liquid-liquid phase separation and reduces colocalization of tau with stress granules. Our study establishes lysine as an important regulator of cellular condensation

A study of some fundamental physicochemical variables on the morphology of mesoporous silica nanoparticles MCM-41 type

[EN] All variables affecting the morphology of mesoporous silica nanoparticles (MSN) should be carefully analyzed in order to truly tailored design their mesoporous structure according to their final use. Although complete control on MCM-41 synthesis has been already claimed, reproducibility and repeatability of results remain a big issue due to the lack of information reported in literature. Stirring rate, reaction volume, and system configuration (i.e., opened or closed reactor) are three variables that are usually omitted, making the comparison of product characteristics difficult. Specifically, the rate of solvent evaporation is seldom disclosed, and its influence has not been previously analyzed. These variables were systematically studied in this work, and they were proven to have a fundamental impact on final particle morphology. Hence, a high degree of circularity (C = 0.97) and monodispersed particle size distributions were only achieved when a stirring speed of 500 rpm and a reaction scale of 500 mL were used in a partially opened system, for a 2 h reaction at 80 degrees C. Well-shaped spherical mesoporous silica nanoparticles with a diameter of 95 nm, a pore size of 2.8 nm, and a total surface area of 954 m(2) g(-1) were obtained. Final characteristics made this product suitable to be used in biomedicine and nanopharmaceutics, especially for the design of drug delivery systems.This study was funded partially by Departamento Administrativo de Ciencia Tecnología e Innovación–COLCIENCIAS (recipient, Angela A. Beltrán-Osuna); Ministerio de Economía y Competitividad, MINECO, research number MAT2016-76039-C4-1-R (Recipient, José L. Gómez-Ribelles); and Universidad Nacional de Colombia, grant number DIB201010021438 (Recipient, Jairo E. Perilla).Beltrán-Osuna, A.; Gómez Ribelles, JL.; Perilla-Perilla, JE. (2017). A study of some fundamental physicochemical variables on the morphology of mesoporous silica nanoparticles MCM-41 type. Journal of Nanoparticle Research. 19(12):1-14. https://doi.org/10.1007/s11051-017-4077-2S1141912Barrabino A (2011) Synthesis of mesoporous silica particles with control of both pore diameter and particle size. Master Thesis, Chalmers University of Technology, SwedenBastos FS, Lima OA, Filho CR, Fernandes LD (2011) Mesoporous molecular sieve MCM-41 synthesis from fluoride media. Brazilian. J Chem Eng 28:649–658Beck JS, Vartuli JC, Roth WJ, Leonowicz ME, Kresge CT, Schmitt KD, Chu CTW, Olson DH, Sheppard EW, McCullen SB, Higgins JB, Schlenker JL (1992) A new family of mesoporous molecular sieves prepared with liquid crystal templates. J Am Chem Soc 114(27):10834–10843. https://doi.org/10.1021/ja00053a020Beltrán-Osuna AA, Perilla JE (2016) Colloidal and spherical mesoporous silica particles: synthesis and new technologies for delivery applications. J Sol-Gel Sci Technol 77(2):480–496. https://doi.org/10.1007/s10971-015-3874-2Bernardos A, Mondragón L, Aznar E et al (2010) Enzyme-responsive intracellular controlled release using nanometric silica mesoporous supports capped with “saccharides”. ACS Nano 4(11):6353–6368. https://doi.org/10.1021/nn101499dBharti C, Nagaich U, Pal AK, Gulati N (2015) Mesoporous silica nanoparticles in target drug delivery system: a review. Int J Pharm Investig 5(3):124–133. https://doi.org/10.4103/2230-973X.160844Brevet D, Hocine O, Delalande A, Raehm L, Charnay C, Midoux P, Durand JO, Pichon C (2014) Improved gene transfer with histidine-functionalized mesoporous silica nanoparticles. Int J Pharm 471(1-2):197–205. https://doi.org/10.1016/j.ijpharm.2014.05.020Cai Q, Luo Z, Pang W et al (2001) Dilute solution routes to various controllable morphologies of MCM-41 silica with a basic medium. Chem Mater 13(2):258–263. https://doi.org/10.1021/cm990661zChakraborty I, Mascharak PK (2016) Mesoporous silica materials and nanoparticles as carriers for controlled and site-specific delivery of gaseous signaling molecules. Microporous Mesoporous Mater 234:409–419. https://doi.org/10.1016/j.micromeso.2016.07.028Chen L, Zhang Z, Yao X, Chen X, Chen X (2015a) Intracellular pH-operated mechanized mesoporous silica nanoparticles as potential drug carries. Microporous Mesoporous Mater 201:169–175. https://doi.org/10.1016/j.micromeso.2014.09.023Chen X, Yao X, Wang C, Chen L, Chen X (2015b) Mesoporous silica nanoparticles capped with fluorescence-conjugated cyclodextrin for pH-activated controlled drug delivery and imaging. Microporous Mesoporous Mater 217:46–53. https://doi.org/10.1016/j.micromeso.2015.06.012Chen Y, Chen H, Shi J (2013) In vivo bio-safety evaluations and diagnostic / therapeutic applications of chemically designed mesoporous silica nanoparticles. Adv Mater 25(23):3144–3176. https://doi.org/10.1002/adma.201205292Chen Y, Shi X, Han B, Qin H, Li Z, Lu Y, Wang J, Kong Y (2012) The complete control for the nanosize of spherical MCM-41. J Nanosci Nanotechnol 12(9):7239–7249. https://doi.org/10.1166/jnn.2012.6459Cheng Y-J, Zeng X, Cheng D-B, Xu XD, Zhang XZ, Zhuo RX, He F (2016) Functional mesoporous silica nanoparticles (MSNs) for highly controllable drug release and synergistic therapy. Colloids Surfaces B Biointerfaces 145:217–225. https://doi.org/10.1016/j.colsurfb.2016.04.051Crommelin DJA, Florence AT (2013) Towards more effective advanced drug delivery systems. Int J Pharm 454(1):496–511. https://doi.org/10.1016/j.ijpharm.2013.02.020Edler KJ (1997) Synthesis and characterisation of the mesoporous molecular sieve, MCM-41. Doctoral dissertation, The Australian National University, AustraliaGuo Z, Liu X-M, Ma L, Li J, Zhang H, Gao YP, Yuan Y (2013) Effects of particle morphology, pore size and surface coating of mesoporous silica on naproxen dissolution rate enhancement. Colloids Surf B Biointerfaces 101:228–235. https://doi.org/10.1016/j.colsurfb.2012.06.026Han N, Wang Y, Bai J, Liu J, Wang Y, Gao Y, Jiang T, Kang W, Wang S (2016) Facile synthesis of the lipid bilayer coated mesoporous silica nanocomposites and their application in drug delivery. Microporous Mesoporous Mater 219:209–218. https://doi.org/10.1016/j.micromeso.2015.08.006Hu X, Wang Y, Peng B (2014) Chitosan-capped mesoporous silica nanoparticles as pH-responsive nanocarriers for controlled drug release. Chem - An Asian J 9(1):319–327. https://doi.org/10.1002/asia.201301105Huh S, Wiench JW, Yoo J et al (2003) Organic functionalization and morphology control of mesoporous silicas via a co-condensation synthesis method. Chem Mater 15(22):4247–4256. https://doi.org/10.1021/cm0210041Ikari K, Suzuki K, Imai H (2006) Structural control of mesoporous silica nanoparticles in a binary surfactant system. Langmuir 22(2):802–806. https://doi.org/10.1021/la0525527Iliade P, Miletto I, Coluccia S, Berlier G (2012) Functionalization of mesoporous MCM-41 with aminopropyl groups by co-condensation and grafting: a physico-chemical characterization. Res Chem Intermed 38(3-5):785–794. https://doi.org/10.1007/s11164-011-0417-5IUPAC (1985) Reporting physisorption data for gas/solid systems. Pure Appl Chem 57:603–619IUPAC (2014) Compendium of chemical terminology-gold book, 2.3.3. International Union of Pure and Applied ChemistryKhezri K, Roghani-Mamaqani H, Sarsabili M, Sobani M, Mirshafiei-Langari SA (2014) Spherical mesoporous silica nanoparticles/tailor-made polystyrene nanocomposites by in situ reverse atom transfer radical polymerization. Polym Sci Ser B 56(6):909–918. https://doi.org/10.1134/S1560090414660026Kresge CT, Leonowicz ME, Roth WJ, Vartuli JC, Beck JS (1992) Ordered mesoporous molecular sieves synthesized by a liquid-crystal template mechanism. Nature 359(6397):710–712. https://doi.org/10.1038/359710a0Lelong G, Bhattacharyya S, Kline S, Cacciaguerra T, Gonzalez MA, Saboungi ML (2008) Effect of surfactant concentration on the morphology and texture of MCM-41 materials. J Phys Chem C 112(29):10674–10680. https://doi.org/10.1021/jp800898nLv X, Zhang L, Xing F, Lin H (2016) Controlled synthesis of monodispersed mesoporous silica nanoparticles: particle size tuning and formation mechanism investigation. Microporous Mesoporous Mater 225:238–244. https://doi.org/10.1016/j.micromeso.2015.12.024Mamaeva V, Sahlgren C, Lindén M (2013) Mesoporous silica nanoparticles in medicine: recent advances. Adv Drug Deliv Rev 65(5):689–702. https://doi.org/10.1016/j.addr.2012.07.018Manzano M, Aina V, Areán CO, Balas F, Cauda V, Colilla M, Delgado MR, Vallet-Regí M (2008) Studies on MCM-41 mesoporous silica for drug delivery: effect of particle morphology and amine functionalization. Chem Eng J 137(1):30–37. https://doi.org/10.1016/j.cej.2007.07.078Merkus HG (2009) Particle size measurements: fundamentals, practice, quality. Springer Science +Businees Media B.V, The NetherlandsMorishige K, Fujii H, Uga M, Kinukawa D (1997) Capillary critical point of argon, nitrogen, oxygen, ethylene, and carbon dioxide in MCM-41. Langmuir 13(13):3494–3498. https://doi.org/10.1021/la970079ude Padua Oliveira DC, de Barros ALB, Belardi RM et al (2016) Mesoporous silica nanoparticles as a potential vaccine adjuvant against Schistosoma mansoni. J Drug Deliv Sci Technol 35:234–240. https://doi.org/10.1016/j.jddst.2016.07.002Phillips E, Penate-Medina O, Zanzonico PB, Carvajal RD, Mohan P, Ye Y, Humm J, Gonen M, Kalaigian H, Schoder H, Strauss HW, Larson SM, Wiesner U, Bradbury MS (2014) Clinical translation of an ultrasmall inorganic optical-PET imaging nanoparticle probe. Sci Transl Med 6(260):260ra149. https://doi.org/10.1126/scitranslmed.3009524Qu F, Zhu G, Lin H, Zhang W, Sun J, Li S, Qiu S (2006) A controlled release of ibuprofen by systematically tailoring the morphology of mesoporous silica materials. J Solid State Chem 179(7):2027–2035. https://doi.org/10.1016/j.jssc.2006.04.002Rafi AA, Mahkam M, Davaran S, Hamishehkar H (2016) A smart pH-responsive nano-carrier as a drug delivery system: a hybrid system comprised of mesoporous nanosilica MCM-41 (as a nano-container) & a pH-sensitive polymer (as smart reversible gatekeepers): preparation, characterization and in vitro releas. Eur J Pharm Sci 93:64–73. https://doi.org/10.1016/j.ejps.2016.08.005Rouquerol J, Rouquerol F, Llewellyn P, et al (2014) Adsorption by powders and porous solids: principles, methodology and applications. Elsevier Ltd.Selvam P, Bhatia SK, Sonwane CG (2001) Recent advances in processing and characterization of periodic mesoporous MCM-41 silicate molecular sieves. Ind Eng Chem Res 40(15):3237–3261. https://doi.org/10.1021/ie0010666Shi YT, Cheng HY, Geng Y, Nan HM, Chen W, Cai Q, Chen BH, Sun XD, Yao YW, Li HD (2010) The size-controllable synthesis of nanometer-sized mesoporous silica in extremely dilute surfactant solution. Mater Chem Phys 120(1):193–198. https://doi.org/10.1016/j.matchemphys.2009.10.045Shibata H, Chiba Y, Kineri T, Matsumoto M, Nishio K (2010) The effect of heat treatment on the interplanar spacing of the mesostructure during the synthesis of mesoporous MCM-41 silica. Colloids Surfaces A Physicochem Eng Asp 358(1-3):1–5. https://doi.org/10.1016/j.colsurfa.2009.12.020Slowing II, Vivero-Escoto JL, Wu C-W, Lin VSY (2008) Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers. Adv Drug Deliv Rev 60(11):1278–1288. https://doi.org/10.1016/j.addr.2008.03.012Sun R, Wang W, Wen Y, Zhang X (2015) Recent advance on mesoporous silica nanoparticles-based controlled release system: intelligent switches open up. Nano 5(4):2019–2053. https://doi.org/10.3390/nano5042019U.S. Department of Health & Human Services (2015) Cancer Nanotechnology PlanUkmar T, Maver U, Planinšek O, Kaučič V, Gaberšček M, Godec A (2011) Understanding controlled drug release from mesoporous silicates: theory and experiment. J Control Release 155(3):409–417. https://doi.org/10.1016/j.jconrel.2011.06.038Vallet-Regi M, Arcos Navarrete D (2016) Nanoceramics in clinical use, 1st edn. The Royal Society of Chemistry, CambridgeVallet-Regi M, Rámila A, Del Real RP, Pérez-Pariente J (2001) A new property of MCM-41: drug delivery system. Chem Mater 13(2):308–311. https://doi.org/10.1021/cm0011559Varga N, Benko M, Sebok D et al (2015) Mesoporous silica core-shell composite functionalized with polyelectrolytes for drug delivery. Microporous Mesoporous Mater 213:134–141. https://doi.org/10.1016/j.micromeso.2015.02.008Wang Y, Zhao Q, Han N, Bai L, Li J, Liu J, Che E, Hu L, Zhang Q, Jiang T, Wang S (2015) Mesoporous silica nanoparticles in drug delivery and biomedical applications. Nanomed Nanotechnol Biol Med 11(2):313–327. https://doi.org/10.1016/j.nano.2014.09.014Wanyika H, Gatebe E, Kioni P et al (2011) Synthesis and characterization of ordered mesoporous silica nanoparticles with tunable physical properties by varying molar composition of reagents. African J Pharm Pharmacol 5(21):2402–2410. https://doi.org/10.5897/AJPP11.592Wu SH, Mou CY, Lin HP (2013) Synthesis of mesoporous silica nanoparticles. Chem Soc Rev 42(9):3862–3875. https://doi.org/10.1039/c3cs35405aXu X, Lü S, Gao C, Wang X, Bai X, Gao N, Liu M (2015a) Facile preparation of pH-sensitive and self-fluorescent mesoporous silica nanoparticles modified with PAMAM dendrimers for label-free imaging and drug delivery. Chem Eng J 266:171–178. https://doi.org/10.1016/j.cej.2014.12.075Xu X, Lü S, Gao C, Wang X, Bai X, Duan H, Gao N, Feng C, Liu M (2015b) Polymeric micelle-coated mesop orous silica nanoparticle for enhanced fluorescent imaging and pH-responsive drug delivery. Chem Eng J 279:851–860. https://doi.org/10.1016/j.cej.2015.05.085Xu X, Lü S, Gao C, Feng C, Wu C, Bai X, Gao N, Wang Z, Liu M (2016) Self-fluorescent and stimuli-responsive mesoporous silica nanoparticles using a double-role curcumin gatekeeper for drug delivery. Chem Eng J 300:185–192. https://doi.org/10.1016/j.cej.2016.04.087Yang Y, Yu C (2015) Advances in silica based nanoparticles for targeted cancer therapy. Nanomedicine nanotechnology. Biol Med 12(2):317–332. https://doi.org/10.1016/j.nano.2015.10.018Zhang H, Tong C, Sha J, Liu B, Lü C (2015) Fluorescent mesoporous silica nanoparticles functionalized graphene oxide: a facile FRET-based ratiometric probe for Hg2+. Sensors Actuators B Chem 206:181–189. https://doi.org/10.1016/j.snb.2014.09.051Zhou C, Yan C, Zhao J, Wang H, Zhou Q, Luo W (2016) Rapid synthesis of morphology-controlled mesoporous silica nanoparticles from silica fume. J Taiwan Inst Chem Eng 62:307–312. https://doi.org/10.1016/j.jtice.2016.01.03

Challenges and approaches to understand cholesterol-binding impact on membrane protein function: An NMR view.

Experimental evidence for a direct role of lipids in determining the structure, dynamics, and function of membrane proteins leads to the term 'functional lipids'. In particular, the sterol molecule cholesterol modulates the activity of many membrane proteins. The precise nature of cholesterol-binding sites and the consequences of modulation of local membrane micro-viscosity by cholesterol, however, is often unknown. Here, we review the current knowledge of the interaction of cholesterol with transmembrane proteins, with a special focus on structural aspects of the interaction derived from nuclear magnetic resonance approaches. We highlight examples of the importance of cholesterol modulation of membrane protein function, discuss the specificity of cholesterol binding, and review the proposed binding motifs from a molecular perspective. We conclude with a short perspective on what could be future trends in research efforts targeted towards a better understanding of cholesterol/membrane protein interactions

Challenges and approaches to understand cholesterol-binding impact on membrane protein function: An NMR view.

Experimental evidence for a direct role of lipids in determining the structure, dynamics, and function of membrane proteins leads to the term 'functional lipids'. In particular, the sterol molecule cholesterol modulates the activity of many membrane proteins. The precise nature of cholesterol-binding sites and the consequences of modulation of local membrane micro-viscosity by cholesterol, however, is often unknown. Here, we review the current knowledge of the interaction of cholesterol with transmembrane proteins, with a special focus on structural aspects of the interaction derived from nuclear magnetic resonance approaches. We highlight examples of the importance of cholesterol modulation of membrane protein function, discuss the specificity of cholesterol binding, and review the proposed binding motifs from a molecular perspective. We conclude with a short perspective on what could be future trends in research efforts targeted towards a better understanding of cholesterol/membrane protein interactions

Inversion of pore size dependence of solute transport kinetics from increasingly attractive ordered porous matrix.

The problem of solute transport in interacting ordered porous media is addressed by numerically solving the 2D Fokker-Planck equation using 4-step operator splitting. The subtle interplay between drift and diffusion is shown to result in a nontrivial dependence of solute transport kinetics on pore size. Depending on the strength of attraction to pore walls distinct regimes of pore size dependence of transport kinetics are found. The results suggest a decoupling of local dynamics from large-scale transport