Systemic Brain Delivery of Antisense Oligonucleotides across the Blood–Brain Barrier with a Glucose-Coated Polymeric Nanocarrier

Current antisense oligonucleotide (ASO) therapies for the treatment of central nervous system (CNS) disorders are performed through invasive administration, thereby placing a major burden on patients. To alleviate this burden, we herein report systemic ASO delivery to the brain by crossing the blood–brain barrier using glycemic control as an external trigger. Glucose-coated polymeric nanocarriers, which can be bound by glucose transporter-1 expressed on the brain capillary endothelial cells, are designed for stable encapsulation of ASOs, with a particle size of about 45 nm and an adequate glucose-ligand density. The optimized nanocarrier efficiently accumulates in the brain tissue 1 h after intravenous administration and exhibits significant knockdown of a target long non-coding RNA in various brain regions, including the cerebral cortex and hippocampus. These results demonstrate that the glucose-modified polymeric nanocarriers enable noninvasive ASO administration to the brain for the treatment of CNS disorders.     

On‐line sample preconcentration by polarity switching in floating electrode‐integrated microchannel

In this study, we found that the polarity switching was effective to enrich and separate fluorescent analytes which have weakly‐dissociated groups in a floating platinum electrode (width, 50 µm; thickness, 2.5 µm)‐integrated straight‐channel in microchip electrophoresis (MCE). In the straight channel filled with an Alexa Flour 488 (AF488) solution, a sharp peak was observed after the polarity inversion with a 530‐fold enhancement of the sensitivity relative to the conventional MCE analysis. By using a fluorescent pH indicator, we verified that a sharp high‐pH zone was generated nearby the floating electrode and moved toward the anode with maintaining the high pH, which induced the sample enrichment like a dynamic pH junction mechanism. In the floating electrode‐embedded channel, the mixture of AF488‐labeled proteins was also well concentrated and separated within 100 s.     

Biopharmaceutical Study on Nobiletin-Loaded Amorphous Solid Dispersion with Improved Hypouricemic Effect

The present study aimed to develop an amorphous solid dispersion of nobiletin (ASD/NOB) using hydroxypropyl cellulose-SSL (HPC-SSL) to improve the pharmacokinetic properties and hypouricemic effect of NOB. ASD/NOB was prepared by the freeze-drying method (ASD/NOB). ASD/NOB was characterized with a focus on crystallinity, dissolution, pharmacokinetic behavior, and hypouricemic action in a rat model of hyperuricemia. ASD/NOB showed significant improvement in dissolution behavior, as evidenced by a 4.4-fold higher dissolved NOB concentration than crystalline NOB at 2 h in distilled water. After the oral administration of ASD/NOB (50 mg NOB/kg) in rats, higher systemic exposure to NOB was observed with an 18-fold enhancement in oral bioavailability, and the T_max value of orally administered ASD/NOB was 60% shorter than that of orally administered crystalline NOB. In a rat model of hyperuricemia, orally dosed ASD/NOB showed an improved hypouricemic effect by a 16% reduction in the plasma uric acid level compared with orally administered crystalline NOB. Based on these findings, ASD/NOB may be an efficacious dosage option to improve the nutraceutical potential of NOB for the treatment of hyperuricemia.     

Studies of human hair by friction force microscopy with the hair-model-probe

We employed a cantilever modified with a self-assembled monolayer (SAM) as a “hair-model-probe” for friction force microscopy (FFM) to measure friction acting between hair and hair-like surfaces. The “hair-model-probe” was prepared by forming a SAM of octadecanethiol on a gold-coated cantilever. We investigated frictional properties of human hair at both root and tip, and the dependency on applied load, influence of scanning direction, and local frictional distribution. The friction coefficient of the hair tip was greater than that of the hair root. Load dependency of friction at the hair tip was clearly observed, while friction at the hair root was less dependent on applied load. At the hair root, an anisotropic frictional property was observed: friction force along the long axis of the hair fiber was about 1.5–2 times larger than that along the short axis. Atomic force microscopy (AFM) images showed striations on the cuticle cells that have about 6 nm depth and their long axis oriented in the direction of the hair fiber. The frictional distribution images revealed that the local areas showing strong shear corresponded to striations. Since such distribution of friction was not observed at the hair tip, it is suggested that the anisotropic frictional property at the hair root was caused mainly by the striations. The frictional distribution in regions that excluded the striations also showed the anisotropic frictional property that friction parallel to the long axis of the hair fiber is greater than that along the short axis. This result suggests that the orientation of fatty acid molecules comprising the fat layer (F-layer) may also contribute to the anisotropic frictional property. We have concluded that loss of the F-layer is a dominant cause of strong friction detected at the hair tip, and at the striations of the hair root.     

The first total synthesis and absolute stereochemistry of plakortone G from the Jamaican sponge Plakortis sp.

Total synthesis of plakortone G (1), a secondary metabolite of the Jamaican sponge Plakortis sp., was successfully achieved. The absolute configuration of this molecule was determined by comparison of the synthetic diastereomers with reported data to possess the (4R,8R)-configuration 14.     

Isolation and characterization of a carbene derivative of La@C82

The photochemical reaction of La@C82 with 2-adamantane-2,3-[3H]-diazirine affords adduct 2, La@C82(Ad), in a quantitative and highly selective manner. The structure of compound 2 is confirmed by ESR, MS, and UV-vis-NIR spectroscopies, and the first X-ray crystallographic characterization of an endohedral monometallofullerene derivative is reported.     

Photodissociation of gas-phase I3-: comprehensive understanding of nonadiabatic dissociation dynamics

Photodissociation of the gas-phase tri-iodide anion, I3-, was investigated using photofragment time of flight (TOF) mass spectrometry combined with the core extraction method. An analysis of the TOF profiles provided the kinetic energy and angular distributions of photofragment ions and photoneutrals, from which the photoproduct branching fractions were determined in the excitation energy range of 3.26-4.27 eV. The measurement has revealed that (1) in the entire energy range investigated, three-body dissociation occurs preferentially as the "charge-asymmetric" process I-(1S)+I(2P3/2)+I(2P3/2) with the yield of approximately 30%-40%, where the excess charge is localized on the end atoms of the dissociating I3-, and that (2) two-body dissociation via the 3Piu(0u+)<--1Sigmag+(0g+) excitation proceeds as I-(1S)+I2(X 1Sigmag+)/I2(A 3Pi1u) or I(2P3/2)+I2-(X 2Sigmau+) with the yield of approximately 60%, while that via the 1Sigmau+(0u+)<--1Sigmag+(0g+) excitation alternatively as I*(2P1/2)+I2-(X 2Sigmau+) or I-(1S)+I2(B 3Piu) with the yield of approximately 60%. Ab initio calculations including spin-orbit configuration interactions were also performed to gain precise information on the potential energy surfaces relevant to the I3- photodissociation. The calculations have shown the presence of conical intersections and avoided crossings located along the symmetric stretch coordinate near the ground-state equilibrium geometry of I3-, which play key roles for the two-body and the three-body product branching. The nonadiabatic nature of the I3- photodissociation dynamics is discussed by combining the experimental findings and the ab initio results.     

Relationship between Perceived Leg Length Discrepancy at One Month and Preoperative Hip Abductor Muscle Elasticity in Patients after Total Hip Arthroplasty

Objective: Preoperative factors related to perceived leg length discrepancy (PLLD) after total hip arthroplasty (THA) are not well studied. This study aimed to examine the preoperative factors, including hip abductor modulus, related to PLLD one month after THA. Methods: The study included 73 patients diagnosed with osteoarthritis secondary to developmental dysplasia of the hip and a posterior approach to surgery. Multiple logistic regression analysis was performed using the presence or absence of PLLD as the dependent variable and preoperative hip abductor''s modulus of elasticity, pain, hip abduction range of motion, hip abductor muscle strength and pelvic obliquity as the independent variable. Additionally, receiver operating characteristic curves were used for the extracted variables for calculating the cutoffs, sensitivity, specificity and area under the curve (AUC) to determine the presence or absence of PLLD. The significance level was set at p<0.05. Results: The hip abductor modulus (odds ratio=1.13; 95% confidence interval=1.06-1.21; p<0.001) was selected as a preoperative factor. The cutoff value to determine the presence or absence of a PLLD was 16.32 kPa. The sensitivity and specificity were 81.8% and 72.5%, respectively, and the AUC was 0.8137. Conclusion: The hip abductor muscle elastic modulus affected PLLD one month after THA. If the preoperative hip abductor elastic modulus is higher than the cutoff value, it may affect the appearance of PLLD at one month postoperatively.     

Cross-Section Molecular Imaging of Supramolecular Microtubes with Contact Atomic Force Microscopy

Bent molecules, distorted layers, columnar domains, and tube membranes (shown schematically in the picture): These hierarchical layers were directly visualized by contact atomic force microscopy along the long axes of the molecules aligned within microtubes made up of bolaamphiphile 1 by self-assembly.