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Medicinal treatments for Idiopathic Lung Fibrosis: existing and emerging choices.
Gene therapy holds great promise for the treatment of acquired genetic disorders such as cancer with reduced side effects compared to chemotherapy. For gene therapy to be successful, it is crucial to develop efficient and nontoxic gene carriers to overcome the poor in vivo stability and low cellular uptake of nucleic acid-based therapeutic agents. Here, we report a new and versatile approach exploring a combination of hydrophobic modifications and dual-stimuli-responsive degradation (SRD) for controlled gene delivery with amphiphilic block copolymer-based nanocarriers. The block copolymer, synthesized by atom transfer radical polymerization, is designed with an acid-labile acetal linkage at the block junction and a pendant disulfide group in the hydrophobic block. The incorporation of labile linkages enables both disulfide-core-cross-linking and dual-location dual-acid/reduction-responsive degradation (DL-DSRD). Furthermore, the disulfide linkages integrated as hydrophobic moieties facilitate the nucleic acids to condense into nanometer-sized micelleplexes through electrostatic interactions of pendant dimethylamino groups with the anionic phosphate groups of the nucleic acids. Our preliminary results demonstrate that the DL-DSRD approach through hydrophobic modification is a robust platform in the development of gene delivery systems with enhanced colloidal stability, reduced cytotoxicity, and improved gene transfection efficiency.The temperature derivative of the infrared (IR) spectrum of HOD/D2O is directly calculated from simulations at a single temperature using a fluctuation theory approach. It is demonstrated, on the basis of an energetic decomposition of the derivative, that the blue shift with increasing temperature is associated with the competition between electrostatic and Lennard-Jones interactions. The same competition gives rise, where their contributions cancel, to a near isosbestic point. The derivative is further used to define an effective internal energy (and entropy) associated with the IR spectrum, and it is shown how a van't Hoff relation can be used to accurately predict the spectrum over a wide range of temperatures. These predictions also explain why a precise isosbestic point is not observed.In the last few years, hybrid lipid-copolymer assemblies have attracted increasing attention as possible two-dimensional (2D) membrane platforms, combining the biorelevance of the lipid building blocks with the stability and chemical tunability of copolymers. The relevance of these systems varies from fundamental studies on biological membrane-related phenomena to the construction of 2D complex devices for material science and biosensor technology. Both the fundamental understanding and the application of hybrid lipid-copolymer-supported bilayers require thorough physicochemical comprehension and structural control. Herein, we report a comprehensive physicochemical and structural characterization of hybrid monolayers at the air/water interface and of solid-supported hybrid membranes constituted by 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and the block copolymer poly(butadiene-b-ethyleneoxide) (PBD-b-PEO). Hybrid lipid-copolymer supported bilayers (HSLBs) with variable copolymer contents were prepared through spontaneous rupture and fusion of hybrid vesicles onto a hydrophilic substrate. The properties of the thin films and the parent vesicles were probed through dynamic light scattering (DLS), differential scanning calorimetry (DSC), optical ellipsometry, quartz crystal microbalance with dissipation monitoring (QCM-D), and confocal scanning laser microscopy (CSLM). Stable, hybrid lipid/copolymer systems were obtained for a copolymer content of 10-65 mol %. In particular, DSC and CSLM show lateral phase separation in these hybrid systems. These results improve our fundamental understanding of HSLBs, which is necessary for future applications of hybrid systems as biomimetic membranes or as drug delivery systems, with additional properties with respect to phospholipid liposomes.To identify the molecular composition of the low-energy states in cyanobacterial Photosystem I (PSI) of Synechocystis PCC6803, we focus on high-resolution (low-temperature) absorption, emission, resonant, and nonresonant hole-burned spectra obtained for wild-type (WT) PSI and three PSI mutants. In the Red_a mutant, the B33 chlorophyll (Chl) is added to the B31-B32 dimer; in Red_b, histidine 95 (His95) on PsaB (which coordinates Mg in the B7 Chl within the His95-B7-A31-A32-cluster) is replaced with glutamine (Gln), while in the Red_ab mutant, both mutations are made. We show that the C706 state (B31-B32) changes to the C710 state (B31-B32-B33) in both Red_a and Red_ab mutants, while the C707 state in WT Synechocystis (localized on the His95-B7-A31-A32 cluster) is modified to C716 in both Red_b and Red_ab. Excitation energy transfer from C706 to the C714 trap in the WT PSI and Red_b mutant is hampered as reflected by a weak emission at 712 nm. Large electron-phonon coupling strength (exposed via resonant hole-burned spectra) is consistent with a strong mixing of excited states with intermolecular charge transfer states leading to significantly red-shifted emission spectra. We conclude that excitation energy transfer in PSI is controlled by fine-tuning the electronic states of a small number of highly conserved red states. Finally, we show that mutations modify the protein potential energy landscape as revealed by different shapes and shifts of the blue- and red-shifted antiholes.Heterofunctional dendrimers with internal and external representations of functionalities are considered as the ultimate dendritic frameworks. This is reflected by their unprecedented scaffolding, such as precise control over the structure, molecular weight, number, and location of different cargos across the whole dendritic skeleton. Consequently, these dendrimers with multipurpose characters are the pinnacle of precision polymers and thereof are highly attractive to the scientific community as they can find use in a great number of cutting-edge applications, especially as discrete unimolecular carriers for therapeutic exploitation. Unfortunately, most established dendrimer families display external functionalities but lack internal scaffolding ability, which leads to inherent limitations to their full potential use as precision carriers. Consequently, here, we embark on a novel synthetic strategy facilitating the introduction of internal functionalization of established dendrimers. As a proof of concept, a new class of internally and externally functionalized multipurpose dendrimers based on the established 2,2-bis(methylol)propionic acid (bis-MPA) was successfully obtained by the elegant and simple design of AB2C monomers, amalgamated from two traditional AB2 monomers. Utilizing fluoride-promoted esterification (FPE), straightforward layer-by-layer divergent growth up to the fourth generation was successful in less than one day of reaction time, with a molecular weight of 15 kDa, and displaying 93 reactive groups divided by 45 internal and 48 external functionalities. The feasibility of postfunctionalization through click reactions is demonstrated, where the fast and effective attachment of drugs, dyes, and PEG chains is achieved, as well as cross-linking into multifunctional hydrogels. The simplicity and versatility of the presented strategy can easily be transferred to generate a myriad of functional materials such as polymers, surfaces, nanoparticles, or biomolecules.The most basic site of 4-aminobenzoic acid in aqueous solution is the amino nitrogen, while the carbonyl oxygen is calculated to be the most basic site in the gas phase. However, the preferred protonation site of 4-aminobenzoic acid upon electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) depends upon the ionization solvent and ion source parameters. The influence of the concentration of the analyte on the manifested protonation sites upon APCI has not been investigated and is reported here. Gas-phase ion-molecule reactions of trimethoxymethylsilane were used to identify the protonation sites of 4-aminobenzoic acid ionized using APCI with methanol or acetonitrile-water as the solvent. The nitrogen-protomer was found to be about twice as abundant as the oxygen-protomer at low analyte concentrations (10-9-10-6 M) in methanol solvent. This finding was rationalized on the basis of a previous finding that when the O-protomer is surrounded by more than eight methanol molecules in the gas phase it starts behaving as if it were in an aqueous solution and converts to the N-protomer. At greater analyte concentrations (≥10-4 M), the amino group was predominantly protonated, which was rationalized based on the formation of a particularly stable proton-bound dimer of 4-aminobenzoic acid that preferentially dissociates to form the N-protomer. The above findings suggest that solution processes are much more important in APCI than commonly assumed, in agreement with recent literature. Indeed, when 11 (v/v) acetonitrile-water was used as the solvent system for 4-aminobenzoic acid, the N-protomer was predominantly generated at all analyte concentrations.Pulsed laser photolysis coupled with infrared (IR) wavelength modulation spectroscopy and ultraviolet (UV) absorption spectroscopy was used to study the kinetics and branching fractions for the acetonyl peroxy (CH3C(O)CH2O2) self-reaction and its reaction with hydro peroxy (HO2) at a temperature of 298 K and pressure of 100 Torr. Near-IR and mid-IR lasers simultaneously monitored HO2 and hydroxyl, OH, respectively, while UV absorption measurements monitored the CH3C(O)CH2O2 concentrations. The overall rate constant for the reaction between CH3C(O)CH2O2 and HO2 was found to be (5.5 ± 0.5) × 10-12 cm3 molecule-1 s-1, and the branching fraction for OH yield from this reaction was directly measured as 0.30 ± 0.04. The CH3C(O)CH2O2 self-reaction rate constant was measured to be (4.8 ± 0.8) × 10-12 cm3 molecule-1 s-1, and the branching fraction for alkoxy formation was inferred from secondary chemistry as 0.33 ± 0.13. An increase in the rate of the HO2 self-reaction was also observed as a function of acetone (CH3C(O)CH3) concentration which is interpreted as a chaperone effect, resulting from hydrogen-bond complexation between HO2 and CH3C(O)CH3. The chaperone enhancement coefficient for CH3C(O)CH3 was determined to be kA″ = (4.0 ± 0.2) × 10-29 cm6 molecule-2 s-1, and the equilibrium constant for HO2·CH3C(O)CH3 complex formation was found to be Kc(R14) = (2.0 ± 0.89) × 10-18 cm3 molecule-1; from these values, the rate constant for the HO2 + HO2·CH3C(O)CH3 reaction was estimated to be (2 ± 1) × 10-11 cm3 molecule-1 s-1. Results from UV absorption cross-section measurements of CH3C(O)CH2O2 and prompt OH radical yields arising from possible oxidation of the CH3C(O)CH3-derived alkyl radical are also discussed. Using theoretical methods, no likely pathways for the observed prompt OH radical formation have been found and the prompt OH radical yields thus remain unexplained.We studied NaSCN(H2O)n- clusters in the gas phase using size-selected anion photoelectron spectroscopy. Vertical detachment energies (VDEs) of NaSCN(H2O)n- (n = 0-6) clusters were obtained in the experiment. Structures of NaSCN(H2O)n- (n = 0-6) clusters and their corresponding neutral counterparts were investigated by theoretical calculations. Our studies show that the Na-NCS type of structures rather than the Na-SCN type of structures are dominant in the gas phase for both anionic and neutral NaSCN(H2O) n clusters. For NaSCN(H2O)n- anions, the contact ion pair (CIP) and solvent-separated ion pair (SSIP) type of structures coexist at n = 2 and 3, the SSIP type of structures become dominant at n ≥ 4. For neutral NaSCN(H2O) n , the CIP type of structures are dominant from n = 1 to 6 and the SSIP type of structures start to appear at n = 6. The gas phase structures in this work support the existence of ion clustering in concentrated NaSCN aqueous solutions.
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