Tailored Solid-State Carbohydrate Nanostructures Based on Star-Shaped Discrete Block Co-Oligomers.

Carbohydrates are key building blocks for advanced functional materials owing to their biological functions and unique material properties. Here, we propose a star-shaped discrete block co-oligomer (BCO) platform to access carbohydrate nanostructures in bulk and thin-film states via the microphase separation of immiscible carbohydrate and hydrophobic blocks (maltooligosaccharides with 1-4 glucose units and solanesol, respectively). BCOs with various star-shaped architectures and saccharide volume fractions were synthesized using a modular approach. In the bulk, the BCOs self-assembled into common lamellar, cylindrical, and spherical carbohydrate microdomains as well as double gyroid, hexagonally perforated lamellar, and Fddd network morphologies with domain spacings of ∼7 nm. In thin films, long-range-ordered periodic carbohydrate microdomains were fabricated via spin coating. Such controlled spatial arrangements of functional carbohydrate moieties on the nanoscale have great application potential in biomedical and nanofabrication fields.

Synthesis of Electromagnetic Wave-Absorbing Co-Ni Alloys and Co-Ni Core-Shell Structured Nanoparticles.

Co-Ni alloy nanoparticles, a potential candidate for microwave absorption material, were successfully synthesized by tuning the reduction timing of Co and Ni ions by introducing oleylamine as a complexing agent and 1-heptanol as a reducing solvent. The formation mechanism elucidated using time-resolved sampling and in situ X-ray absorption spectroscopy (XAS) and ultraviolet-visible (UV-vis) spectrophotometry measurements suggested that the delay in the reduction of Co ions via complexation with oleylamine facilitated the co-reduction of Co with Ni ions and led to the formation of Co-Ni alloys. The successful synthesis of Co-Ni alloys experimentally confirmed the differences in magnetic properties between alloy and core-shell structured Co50Ni50 particles. Further, the syntheses of Co-Ni alloys with different compositions were also possible using the above technique. In addition, the microwave absorption properties were measured using the free-space method utilizing a vector network analyzer of Co50Ni50─polyethylene composite with different sheet thicknesses. A reflection loss (RL) value of -25.7 dB at 13.6 GHz for the alloy structure was more significant than the core-shell counterpart. The above values are high compared to results reported in the past. The validity of the measurements was confirmed by utilizing the parameter retrieval method to extract permittivity and permeability from the scattering parameter (S) and recalculation of the RL as a function of frequency.

Materials informatics approach to understand aluminum alloys.

The relations between the mechanical properties, heat treatment, and compositions of elements in aluminum alloys are extracted by a materials informatics technique. In our strategy, a machine learning model is first trained by a prepared database to predict the properties of materials. The dependence of the predicted properties on explanatory variables, that is, the type of heat treatment and element composition, is searched using a Markov chain Monte Carlo method. From the dependencies, a factor to obtain the desired properties is investigated. Using targets of 5000, 6000, and 7000 series aluminum alloys, we extracted relations that are difficult to find via simple correlation analysis. Our method is also used to design an experimental plan to optimize the materials properties while promoting the understanding of target materials.

Stress mapping reveals extrinsic toughening of brittle carbon fiber in polymer matrix.

We conducted an in situ study on CFRP fracturing process using atomic-force-microscopy-based stress-sensitive indentation. Tensile stress distribution during fracture initiation and propagation was directly observed quantitatively. It led to a discovery that previously believed catastrophic fracture of individual carbon fiber develops in a controllable manner in the polymer matrix, exhibiting 10 times increase of fracture toughness. Plastic deformation in crack-bridging polymer matrix was accounted for the toughening mechanism. The model was applied to explain low temperature strength weakening of CFRP bulk material when matrix plasticity was intentionally 'shut down' by cryogenic cooling.

Stress dependence of indentation modulus for carbon fiber in polymer composite.

Elastic modulus measured through atomic force microscopy (AFM)-based indentation on single carbon fiber (CF) is found with dependence on lateral applied stress. An in situ indentation experiment inside a high-resolution transmission electron microscope was performed to quantitatively understand this phenomenon by observing microstructure change in the indented area. Change of graphitic basal plane misalignment angle during indentation was linked to a continuous change of modulus with the help of finite element simulation. The established relationship between modulus and indentation force was further used to calculate residual stress distribution in CF imbedded in a CF reinforced polymer composite using the AFM indentation technique. The stress-induced formation of nanoscale defects in the CF and their transformation into fracture were directly characterized.

Sprayable tissue adhesive microparticle-magnetic nanoparticle composites for local cancer hyperthermia.

Incomplete removal of early-stage gastrointestinal cancers by endoscopic treatments often leads to recurrence induced by residual cancer cells. To completely remove or kill cancer tissues and cells and prevent recurrence, chemotherapy, radiotherapy, and hyperthermia using biomaterials with drugs or nanomaterials are usually administered following endoscopic treatments. However, there are few biomaterials that can be applied using endoscopic devices to locally kill cancer tissues and cells. We previously reported that decyl group-modified Alaska pollock gelatin-based microparticles (denoted C10MPs) can adhere to gastrointestinal tissues under wet conditions through the formation of a colloidal gel driven by hydrophobic interactions. In this study, we combined C10MPs with superparamagnetic iron oxide nanoparticles (SPIONs) to develop a sprayable heat-generating nanomaterial (denoted SP/C10MP) for local hyperthermia of gastrointestinal cancers. The rheological property, tissue adhesion strength, burst strength, and underwater stability of SP/C10MP were improved through decyl group modification and SPION addition. Moreover, SP/C10MP that adhered to gastrointestinal tissues formed a colloidal gel, which locally generated heat in response to an alternating magnetic field. SP/C10MP successfully killed cancer tissues and cells in colon cancer-bearing mouse models in vitro and in vivo. Therefore, SP/C10MP has the potential to locally kill residual cancer tissues and cells after endoscopic treatments.

Neutron imaging for magnetization inside an operating inductor.

Magnetic components are key parts of energy conversion systems, such as electric generators, motors, power electric devices, and magnetic refrigerators. Toroidal inductors with magnetic ring cores can be found inside such electric devices that are used daily. For such inductors, magnetization vector M is believed to circulate with/without distribution inside magnetic cores as electric power was used in the late nineteenth century. Nevertheless, notably, the distribution of M has never been directly verified. Herein, we measured a map of polarized neutron transmission spectra for a ferrite ring core assembled on a familiar inductor device. The results showed that M circulates inside the ring core with a ferrimagnetic spin order when power is supplied to the coil. In other words, this method enables the multiscale operando imaging of magnetic states, allowing us to evaluate the novel architectures of high-performance energy conversion systems using magnetic components with complex magnetic states.

Impact of reimbursement restriction on drug market sales under the National Health Insurance in Japan.

AIM: National health care expenditures have been increasing each year, although the Japanese government has annually revised official drug prices. Managing the health care system to pay for expensive drugs is a major concern. The reimbursement restriction, which is the only way that a drug can be implemented before market entry in Japan, is crucial for managing expenditures. Therefore, this study identifies the impact of the reimbursement restriction on drug market sales in Japan, particularly in the situation where health technology assessment or other market access regulations are not applicable before market entry. METHOD: All new drugs listed in fiscal years 2011-2019, along with their market size forecast, were identified using the materials from the Central Social Insurance Medical Council. We then calculated the percentage rate of reimbursement amounts based on the National Database of Health Insurance Claims relative to the predicted market size as a dependent variable. Using the reimbursement restriction for each drug as an independent variable, we performed descriptive and univariate analyses on each variable, followed by generalized linear mixed-effects model regression analysis. RESULTS: We identified 211 drugs. The mean rates of drugs that required physicians, facilities, and patients to meet criteria for use were 30.85% (n = 2), 31.42% (n = 2), and 72.11% (n = 6), respectively. The mean rate of drugs that required diagnostic testing was 22.99% (n = 7), which was 3.7 times lower than the rate of drugs that did not require such testing (p < .05). CONCLUSION: Our results indicate that the reimbursement restriction requiring diagnostic testing has a substantial impact on decreasing market sales. As the number of cases for each requirement is small, further study is needed to measure the impact of the other reimbursement restrictions.

Determinants of market prices for drugs under Japan's national health insurance.

AIMS: The Japanese government reimburses patients for drugs at prices specified in the Drug Price Standard (DPS) published by the National Health Insurance (NHI) scheme. It revises reimbursements for most drugs on the basis of their market prices. This study thereby identifies factors related to drugs or disease that impact market prices for drugs using the DPS list. MATERIALS AND METHODS: This study first examined the 2018 DPS list to identify all listed drugs, their prices, and their stipulated reimbursements. We then excluded from this study all the drugs for which prices are set per alternate rules. We calculated the percentage divergence between market prices and DPS prices and designated it our dependent variable. We performed descriptive and a univariate analysis on each variable and constructed multivariate regression models featuring independent variables for drug characteristics that might affect market prices. RESULTS: We identified 1,775 drugs with prices revised only by the market. We observed higher percentage divergences between DPS and market prices for drugs with generic alternatives (p < 0.001), drugs listed in the Japanese Pharmacopoeia (p < 0.001), and drugs for which at least two new drugs entered the same therapeutic category (p < 0.001). Injectable drugs exhibited a more significant and negative correlation with percentage divergences (p = 0.009) than ingestible drugs. Drugs that treat specific organs (p < 0.001), affect metabolism (p = 0.001), and those prescribed for non-therapeutic purposes (p < 0.001) display significantly higher percentage divergence than drugs affecting the nervous system and sensory organs. Divergences are less for narcotics (p < 0.001) and drugs that counter pathologic microorganisms and parasites (p = 0.004). CONCLUSIONS: Factors that elevate competition among pharmaceutical companies likely lower market prices for drugs, and the direction of prices under NHI in Japan is affected by the category of diseases a drug treats.

High-efficiency magnetic refrigeration using holmium.

Magnetic refrigeration (MR) is a method of cooling matter using a magnetic field. Traditionally, it has been studied for use in refrigeration near room temperature; however, recently MR research has also focused on a target temperature as low as 20 K for hydrogen liquefaction. Most research to date has employed high magnetic fields (at least 5 T) to obtain a large entropy change, which requires a superconducting magnet and, therefore, incurs a large energy cost. Here we propose an alternative highly efficient cooling technique in which small magnetic field changes, Δµ0H ≤ 0.4 T, can obtain a cooling efficiency of -ΔSM/Δµ0H = 32 J kg-1K-1T-1, which is one order of magnitude higher than what has been achieved using typical magnetocaloric materials. Our method uses holmium, which exhibits a steep magnetization change with varying temperature and magnetic field. The proposed technique can be implemented using permanent magnets, making it a suitable alternative to conventional gas compression-based cooling for hydrogen liquefaction.

Studies on a Tyr residue critical for the binding of coenzyme and substrate in mouse 3(17)alpha-hydroxysteroid dehydrogenase (AKR1C21): structure of the Y224D mutant enzyme.

Mouse 3(17)alpha-hydroxysteroid dehydrogenase (AKR1C21) is the only aldo-keto reductase that catalyzes the stereospecific reduction of 3- and 17-ketosteroids to the corresponding 3(17)alpha-hydroxysteroids. The Y224D mutation of AKR1C21 reduced the K(m) value for NADP(H) by up to 80-fold and completely reversed the 17alpha stereospecificity of the enzyme. The crystal structure of the Y224D mutant at 2.3 A resolution revealed that the mutation resulted in a change in the conformation of the flexible loop B, including the V-shaped groove, which is a unique feature of the active-site architecture of wild-type AKR1C21 and is formed by the side chains of Tyr224 and Trp227. Furthermore, mutations (Y224F and Q222N) of residues involved in forming the safety belt for binding of the coenzyme showed similar alterations in kinetic constants for 3alpha-hydroxy/3-ketosteroids and 17-hydroxy/ketosteroids compared with the wild type.

Estimation of Magnetic Anisotropy of Individual Magnetite Nanoparticles for Magnetic Hyperthermia.

Ideal interaction-free magnetite nanoparticles were prepared, and their magnetic properties were measured to clarify the true nature of magnetic anisotropy of individual magnetite nanoparticles at the nanoscale and to analyze the shape, surface, and crystalline anisotropy contributions. Spherical (17.7 nm), cubic (10.6 nm), and octahedral-shaped magnetite nanoparticles with average sizes ranging from 7.6 to 23.4 nm were synthesized using solution techniques. Then, these nanoparticles were coated with silica at appropriate shell thicknesses to prepare magnetic interaction-free samples, and their noninteractive nature was confirmed through first-order reversal curve diagrams. For these well-isolated nanoparticles, remanent magnetizations of the hysteresis loops are just equal to a half of the saturation magnetization. This result clearly indicates that uniaxial magnetic anisotropy is predominant in each nanoparticle. In order to clarify the details of the uniaxial magnetic anisotropy, the analysis of blocking temperature-switching field distribution diagrams is constructed based on thermal decay curves of isothermal remanent magnetization at various applied fields. The obtained effective magnetic anisotropy constant Keff is distributed around 10-20 kJ/m3 and has insignificant size dependence. This result seems inconsistent with the inverse proportion relation of Keff with size predicted for surface magnetic anisotropy. The theoretical calculation suggested that the crystalline magnetic anisotropy plays a major role in magnetic properties of the magnetite nanoparticles at lower temperatures. However, it should be noted that Keff seems slightly different for the different shapes. The above study indicates that control size, shape, and interparticle interactions is required to strictly discuss such delicate differences of magnetic anisotropy of individual magnetite nanoparticles for the design of thermal seeds for magnetic hyperthermia.

Highly asymmetric lamellar nanostructures from nanoparticle-linear hybrid block copolymers.

The highly asymmetric lamellar (A-LAM) nanostructure is one of the most important template geometries for block copolymer (BCP) lithography. However, A-LAM is unattainable from conventional BCPs, and there is no general molecular design strategy for A-LAM-forming BCP. Herein, a nanoparticle-linear hybrid BCP system is reported, which is designed based on the intramolecular crosslinking technique, as a remarkably effective platform to obtain the A-LAM morphology. The hybrid BCPs consisting of polystyrene single-chain nanoparticles and linear polylactide segments show a remarkable capability to form the A-LAM morphology in bulk, where a maximum width ratio of 4.1 between the two domains is obtained. This unusual phase behavior is attributed to the bulky and rigid characteristics of the nanoparticle block. Furthermore, the thin films of these hybrid BCPs show perpendicularly oriented A-LAM morphology on a chemically modified Si substrate, allowing promising application in the fabrication of asymmetric line-and-space nanopatterns.

Rapid access to discrete and monodisperse block co-oligomers from sugar and terpenoid toward ultrasmall periodic nanostructures.

Discrete block co-oligomers (BCOs) are gaining considerable attention due to their potential to form highly ordered ultrasmall nanostructures suitable for lithographic templates. However, laborious synthetic routes present a major hurdle to the practical application. Herein, we report a readily available discrete BCO system that is capable of forming various self-assembled nanostructures with ultrasmall periodicity. Click coupling of propargyl-functionalized sugars (containing 1-7 glucose units) and azido-functionalized terpenoids (containing 3, 4, and 9 isoprene units) afforded the discrete and monodisperse BCOs with a desired total degree of polymerization and block ratio. These BCOs microphase separated into lamellar, gyroid, and cylindrical morphologies with the domain spacing (d) of 4.2-7.5 nm. Considering easy synthesis and rich phase behavior, presented BCO systems could be highly promising for application to diverse ~4-nm nanofabrications.

Structure of the G225P/G226P mutant of mouse 3(17)alpha-hydroxysteroid dehydrogenase (AKR1C21) ternary complex: implications for the binding of inhibitor and substrate.

3(17)alpha-Hydroxysteroid dehydrogenase (AKR1C21) is a unique member of the aldo-keto reductase (AKR) superfamily owing to its ability to reduce 17-ketosteroids to 17alpha-hydroxysteroids, as opposed to other members of the AKR family, which can only produce 17beta-hydroxysteroids. In this paper, the crystal structure of a double mutant (G225P/G226P) of AKR1C21 in complex with the coenzyme NADP(+) and the inhibitor hexoestrol refined at 2.1 A resolution is presented. Kinetic analysis and molecular-modelling studies of 17alpha- and 17beta-hydroxysteroid substrates in the active site of AKR1C21 suggested that Gly225 and Gly226 play an important role in determining the substrate stereospecificity of the enzyme. Additionally, the G225P/G226P mutation of the enzyme reduced the affinity (K(m)) for both 3alpha- and 17alpha-hydroxysteroid substrates by up to 160-fold, indicating that these residues are critical for the binding of substrates.

Kinetic studies of AKR1B10, human aldose reductase-like protein: endogenous substrates and inhibition by steroids.

A human member of the aldo-keto reductase (AKR) superfamily, AKR1B10, was identified as a biomarker of lung cancer, exhibiting high sequence identity with human aldose reductase (AKR1B1). Using recombinant AKR1B10 and AKR1B1, we compared their substrate specificity for biogenic compounds and inhibition by endogenous compounds and found the following unique features of AKR1B10. AKR1B10 efficiently reduced long-chain aliphatic aldehydes including farnesal and geranylgeranial, which are generated from degradation of prenylated proteins and metabolism of farnesol and geranylgeraniol derived from the mevalonate pathway. The enzyme oxidized aliphatic and aromatic alcohols including 20alpha-hydroxysteroids. In addition, AKR1B10 was inhibited by steroid hormones, bile acids and their metabolites, showing IC(50) values of 0.03-25 microM. Kinetic analyses of the alcohol oxidation and inhibition by the steroids and tolrestat, together with the docked model of AKR1B10-inhibitor complex, suggest that the inhibitory steroids and tolrestat bind to overlapping sites within the active site of the enzyme-coenzyme complex. Thus, we propose a novel role of AKR1B10 in controlling isoprenoid homeostasis that is important in cholesterol synthesis and cell proliferation through salvaging isoprenoid alcohols, as well as its metabolic regulation by endogenous steroids.

Downsizing feature of microphase-separated structures via intramolecular crosslinking of block copolymers.

A novel strategy for downsizing the feature of microphase-separated structures was developed via the intramolecular crosslinking reaction of block copolymers (BCPs) without changing the molecular weight. A series of BCPs consisting of poly[styrene-st-(p-3-butenyl styrene)] and poly(rac-lactide) (SBS-LA) was subjected to Ru-catalyzed olefin metathesis under highly diluted conditions to produce intramolecularly crosslinked BCPs (SBS(cl)-LAs). Small-angle X-ray scattering measurement and transmission electron microscopy observation of the SBS(cl)-LAs revealed feature size reduction in lamellar (LAM) and hexagonally close-packed cylinder (HEX) structures in the bulk state, which was surely due to the restricted chain dimensions of the intramolecularly crosslinked SBS block. Notably, the degree of size reduction was controllable by varying the crosslink density, with a maximum decrease of 22% in the LAM spacing. In addition, we successfully observed the downsizing of the HEX structure in the thin film state using atomic force microscopy, indicating the applicability of the present methodology to next-generation lithography technology.

Magnetic Bragg dip and Bragg edge in neutron transmission spectra of typical spin superstructures.

Neutron diffractometry has been a critical tool for clarifying spin structures. In contrast, little attention has been paid to neutron transmission spectroscopy, even though they are different types of the same phenomenon. Soon, it will be possible to measure the wavelength dependence of transmissions easily using accelerator-driven neutron facilities. Therefore, we have started studying the potential of spectroscopy in magnetism, and in this paper, we report the first observation of a magnetic Bragg dip and Bragg edge in the neutron transmission spectra of a typical spin superstructure; clear antiferromagnetic Bragg dips and Bragg edges are found for a single crystal and powder of nickel oxide, respectively. The obtained results show that transmission spectroscopy is a promising tool for measurements under multi-extreme conditions and for the precise analyses of spin structures, not only in MW-class pulsed spallation source facilities but also in compact neutron source facilities.

Nonequilibrium magnetic response of anisotropic superparamagnetic nanoparticles and possible artifacts in magnetic particle imaging.

Magnetic responses of superparamagnetic nanoparticles to high-frequency AC magnetic fields with sufficiently large amplitudes are numerically simulated to exactly clarify the phenomena occurring in magnetic particle imaging. When the magnetic anisotropy energy inevitable in actual nanoparticles is taken into account in considering the magnetic potential, larger nanoparticles exhibit a delayed response to alternations of the magnetic fields. This kind of delay is rather remarkable in the lower-amplitude range of the field, where the assistance by the Zeeman energy to thermally activated magnetization reversal is insufficient. In some cases, a sign inversion of the third-order harmonic response was found to occur at some specific amplitude, despite the lack in DC bias magnetic field strength. Considering the attenuation of the AC magnetic field generated in the human body, it is possible that the phases of the signals from nanoparticles deep inside the body and those near the body surface are completely different. This may lead to artifacts in the reconstructed image. Furthermore, when the magnetic/thermal torque-driven rotation of the anisotropic nanoparticles as well as the magnetic anisotropy energy are taken into account, the simulated results show that, once the easy axes are aligned toward the direction of the DC bias magnetic field, it takes time to randomize them at the field-free point. During this relaxation, the third-order harmonic response depends highly upon the history of the magnetic field. This is because non-linearity of the anhysteretic magnetization curve for the superparamagnetic nanoparticles varies with the orientations of the easy axes. This history dependence may also lead to another artifact in magnetic particle imaging, when the scanning of the field-free point is faster than the Brownian relaxations.

Cellular effects of magnetic nanoparticles explored by atomic force microscopy.

The investigation of subtle change of cells exposed to nanomaterials is extremely essential but also challenging for nanomaterial-based biological applications. In this study, atomic force microscopy (AFM) was employed to investigate the effects of iron-iron oxide core-shell magnetic nanoparticles on the mechanical properties of bovine articular chondrocytes (BACs). After being exposed to the nanoparticles even at a high nanoparticle-concentration (50 µg mL(-1)), no obvious difference was observed by using conventional methods, including the WST-1 assay and live/dead staining. However a significant difference of Young's modulus of the cells was detected by AFM even when the concentration of nanoparticles applied in the cell culture medium was low (10 µg mL(-1)). The difference of cellular Young's modulus increased with the increase of nanoparticle concentration. AFM was demonstrated to be a useful tool to identify the subtle change of cells when they were exposed to nanomaterials even at a low concentration.