Effects of the Molecular Structure of Malodor Substances and Their Masking on 1,2-Dioleoyl-sn-glycero-3-phosphocholine Molecular Layers.

Certain odors have been shown not only to cause health problems and stress but also to affect skin barrier function. Therefore, it is important to understand olfactory masking to develop effective fragrances to mask malodors. However, olfaction and olfactory masking mechanisms are not yet fully understood. To understand the mechanism of the masking effect that has been studied, the responses of several target substance (TS) molecules-1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) mixed molecular layers to odorant (OD) molecules were examined as a simple experimental model of epithelial cellular membranes injured by TS molecules. Here, we examined trans-2-nonenal, 1-nonanal, trans-2-decenal, and 1-decanal as TS molecules to clarify the effects of double bonds and hydrocarbon chain lengths on the phospholipid molecular layer. In addition, benzaldehyde and cyclohexanecarboxaldehyde were utilized as OD molecules to clarify the masking effect of the aromatic ring. Surface pressure (Π)-area (A) isotherms were measured to clarify the adsorption or desorption of TS and OD molecules on the DOPC molecular layer. In addition, Fourier transform infrared spectroscopy was performed to clarify the interactions among DOPC, TS, and OD molecules. We found that TS molecules with and without double bonds had different effects on the DOPC molecular layer and that molecules with shorter chain lengths had greater effects on the DOPC molecular layer. Furthermore, OD molecules with aromatic rings counteracted the effects of the TS molecules. On the basis of this research, not only a detailed mechanism by which odor molecules affect lipid membranes without mediating olfactory receptors is elucidated but also more effective OD molecules with masking effects are proposed.

Can self-propelled objects escape from compression stimulation?

We studied circular papers impregnated with camphor (CPs) and CPs with magnets (MCPs) as self-propelled objects floating on water under the compression of the water surface as an inanimate system for evacuation in an emergency. Two water chambers-Cin and Cout-were connected via a plastic gate, and eight CPs or eight MCPs were placed on Cin. We monitored the movement of the CPs or MCPs from Cin to Cout when the gate was opened and the area of Cin (Ain) was decreased using a barrier. When Ain was large, CPs moved stochastically from Cin to Cout while exhibiting random motion. The escape probability from Cin to Cout (P) at time t = 20 s increased with a decrease in Ain, and the rate of increase in P increased depending on the width of the gate (Wg). By contrast, clustering was observed for MCPs. Consequently, P of MCPs was lower than that of CPs. The difference in the surface tension between Cin and Cout (Δγ) increased with a decrease in Ain. P is discussed in relation to Δγ as the driving force for emergencies and the repulsive forces between CPs or attractive forces between MCPs. These results suggest that the repulsive force enhances the self-propulsion of objects towards the gate, that is, as a result, higher values of P are obtained.

Self-propelled motion controlled by ionic liquids.

We studied the self-propulsion of a camphor disk floating on a water surface using two types of ionic liquids (hexylammonium-trifluoroacetate (HHexam-TFA) and hexylethylenediaminium-trifluoroacetate (HHexen-TFA)). Bifurcation between continuous, oscillatory, and no motion was observed depending on the concentration of the ionic liquid. The bifurcation concentration between oscillatory and no motion for HHexam-TFA was lower than that for HHexen-TFA. The different bifurcation concentrations are discussed in relation to the surface tension and Fourier transform infrared spectra of the mixtures of camphor and ionic liquids. These results suggest that the interaction between the ionic liquid molecules at the air/water interface is weakened by the addition of camphor molecules and the features of self-propulsion vary due to the change in the driving force.

Sequentially Selective Coalescence of Binary Self-Propelled Droplets upon Collective Motion.

Subsequent synthesis and detection using droplets as microreactors have shown promise in the development of novel materials and drugs because microreactors enable small-scale synthesis and detection of covalent/non-covalent intermolecular interactions. Self-organization exhibited by autonomous droplets under non-equilibrium conditions is beneficial for manipulating the sequentiality and selectivity of droplet coalescence because expensive equipment or elaborate techniques are not required with the autonomy of droplets. However, to our knowledge, selective coalescence caused by the collective motion of self-propelled droplets has not been demonstrated in inanimate systems. Here, we report sequentially selective coalescence based on the dynamic collective pattern of self-propelled droplets composed of ethyl salicylate (ES) or butyl salicylate (BS). When ES and BS droplets were placed on an aqueous sodium dodecyl sulfate (SDS) solution, the collective motion of droplets resulted in three stages of selective coalescence on the time development. Initially, coalescence was observed only between different types of self-propelled droplets. Subsequently, the formed droplets selectively coalesced with ES droplets. Finally, mature droplets merged with BS droplets. The sequentially selective coalescence was discussed from the dynamic pattern formation of swarming droplets and the collapse of the SDS monolayer at the o/w interface caused by the difference in Laplace pressure and the interfacial instability at the contact point between droplets. Thus, this study formulates a strategy of sequentially selective coalescence of droplets via the collective motion of non-identical self-propelled droplets, promoting a new type of powerful and efficient automation technology based on an autonomous inanimate manner of spatiotemporal pattern formation under non-equilibrium conditions for the droplet manipulation.

Height-dependent oscillatory motion of a plastic cup with a camphor disk floated on water.

We have developed a self-propelled object, which is composed of a plastic cup and a camphor disk, on water to reflect its three-dimensional shape in the nature of motion. The self-propelled object, of which the driving force of motion is the difference in the surface tension, exhibited oscillatory motion between motion and rest. The period and the maximum speed of oscillatory motion increased and decreased depending on the height of the cup, h, respectively. Two types of diffusion coefficients were estimated based on the diffusion of camphor molecules which were indirectly visualized using 7-hydroxycoumarin. The experimental result on the period of oscillatory motion depending on h could be reproduced by the numerical calculation based on the diffusion of camphor molecules around the object and the diffusion coefficients which were experimentally estimated. The experimental results suggest that characteristic features of motion can be created based on the three-dimensional shape of the object.

Characteristic growth of chemical gardens from mixtures of two salts.

Chemical gardens formed from two metal salts (MCl2 or MSO4) have been investigated to understand the effects of mixing on the growth of precipitate tubes. The growth of tubes can be classified into three types, i.e., collaborative, inhibited, and individual growth, depending on the combination of the two metal salts. Characteristic features of tube growth are discussed in relation to the flow near the tip of the tube controlled by osmotic pressure and the solubility product, Ksp, for M(OH)2. The present study can be interpreted as an inanimate model system of symbiosis among different species, such as mixed cropping systems and survival among different kinds of microbial cells.

Therapeutic Drug Monitoring of Golimumab for the Prediction of Long-Term Clinical Remission in Patients with Ulcerative Colitis.

BACKGROUND AND AIMS: A considerable number of patients with ulcerative colitis (UC) who initially respond to golimumab (GLM), an anti-TNF-α antibody, gradually lose clinical response. Therapeutic drug monitoring has been proposed to optimize serum anti-TNF-α antibody concentrations before the loss of response; however, little is known about ideal serum GLM concentrations. We aimed to evaluate whether the serum GLM trough levels (TLs) early after the initiation of induction therapy affect the long-term outcomes in UC and to identify the early GLM TLs that should be targeted for better long-term outcomes. METHODS: Thirty-one patients were prospectively evaluated. The primary outcome was clinical remission at 54 weeks, and we measured the serum GLM TLs at weeks 6, 10, and 14. Receiver operating characteristic (ROC) curves were constructed to identify optimal GLM TL thresholds early after induction therapy that were associated with clinical remission at week 54. RESULTS: The GLM TL at week 14, but not at weeks 6 or 10, was significantly associated with clinical remission at week 54 (median [IQR] 1.6 [1.3-1.6] µg/mL vs. 0.9 [0.6-1.3] µg/mL; p = 0.04). The area under the ROC curve for GLM TLs at week 14 was 0.78. We identified a week-14 GLM TL of 1.1 µg/mL as the target threshold for achieving clinical remission at week 54. CONCLUSION: Our results demonstrate the value of early serum GLM TLs in predicting the long-term outcomes of GLM for patients with UC.

Risk Factors for Nephrotoxicity due to Tacrolimus Therapy for Ulcerative Colitis.

BACKGROUND AND AIMS: The calcineurin inhibitor tacrolimus is reportedly effective for moderate/severe ulcerative colitis (UC); however, it is also reportedly associated with nephrotoxicity. We investigated the risk factors for tacrolimus-induced nephrotoxicity and whether renal impairment adversely affected the outcomes of tacrolimus treatment in patients with UC. METHODS: We conducted a retrospective study of 93 patients with UC who were administered tacrolimus leading to high trough levels (10-15 ng/mL) for 2 weeks and low trough levels (5-10 ng/mL) for 3 months. RESULTS: Acute kidney injury (AKI) occurred in 44 patients (47.3%) during tacrolimus treatment. Of these patients, 34 (36.6%) developed AKI during the high trough phase and 17 (18.3%) developed AKI when the trough value exceeded the original target value of 15 ng/mL. Multivariate logistic regression analysis revealed that the male sex was significantly associated with AKI (p = 0.002, AOR = 4.38, 95% CI [1.69-11.3]). Clinical remission rate after 4, 8, 12, and 24 weeks of tacrolimus treatment in patients with AKI was lower than that in patients without AKI. Six patients (6.5%) had chronic kidney disease (CKD) after tacrolimus treatment completion, and all patients with CKD developed AKI during treatment. The median duration of treatment with no improvement in AKI was significantly longer in patients with CKD than in those without CKD (p = 0.016). CONCLUSION: We revealed the risk factors for tacrolimus-induced nephrotoxicity. Renal impairment occurrence adversely affected the tacrolimus treatment outcome; therefore, it is important to carefully administer tacrolimus to prevent renal impairment.

Coexistence of oscillatory and reduced states on a spherical field controlled by electrical potential.

The Belousov-Zhabotinsky (BZ) reaction was investigated to elucidate features of oscillations depending on the applied electrical potential, E. A cation-exchange resin bead loaded with the catalyst of the BZ reaction was placed on a platinum plate as a working electrode and then E was applied. We found that global oscillations (GO) and a reduced state coexisted on the bead at a negative value of E and that the source point of GO changed depending on E. The thickness of the reduced state was determined by a yellow colored region which corresponded to the distribution of Br2. The present studies suggest that the distribution of the inhibitor, Br-, which is produced from Br2, plays an important role in the existence of the reduced state and GO, and the source point of GO.

Alternate Route Selection of Self-Propelled Filter Papers Impregnated with Camphor for Two-Branched Water Channels.

The route selection of self-propelled filter papers impregnated with camphor for two-branched water channels was investigated. The two-branched water channel was composed of a stem channel and two branch channels, and the branch channels were connected to the stem channel at a junction. When a single camphor paper reached the junction from the stem channel, it selected one of the two routes equivalently. Three or five camphor papers which were placed on a stem channel exhibited either alternate or random route selection depending on the characteristic length between the leading and following papers, Lc. That is, the alternate route selection of the camphor papers for the two-branched water channels was observed at Lc ≤ 25 mm. By contrast, the alternate route selection was broken at Lc > 25 mm. The physicochemical meaning of the threshold value, Lth ∼ 26 mm, between the alternate and random route selections was discussed based on the experimental results. In addition, the distribution length of camphor molecules developed from the leading camphor paper and the change in the spatial gradient of surface tension around the junction supports the value of Lth. These results suggest that autonomous phenomena using inanimate self-propelled objects are important to understand collective motion in living organisms.

A surfactant reaction model for the reciprocating motion of a self-propelled droplet.

We report herein experimental observations of the reciprocating motion of a self-propelled droplet floating on the surface of an aqueous surfactant solution and a simple reaction model capable of reproducing the observed behavior of the droplet. The reciprocating motion was observed in a quasi-one-dimensional annular channel, so the reciprocation was not caused by reflections at boundaries. To understand the reciprocation, our model assumes a reaction between the surface active substance emitted from the droplet and surfactants dissolved in the aqueous solution. This reaction invokes an inversion of the surface tension gradient and thus the droplet's reciprocation. We show that the model can reproduce experimental results semi-quantitatively using numerical simulations with realistic parameters.

Traveling waves propagating through coupled microbeads in the Belousov-Zhabotinsky reaction.

Spatio-temporal patterns, namely global oscillations (GO) and traveling waves (TW), were investigated in spherical microbeads loaded with a catalyst for the Belousov-Zhabotinsky (BZ) reaction onto the surface (2D-loaded) or the entire volume of the bead (3D-loaded). GO and TW selectively appeared in the 2D- and 3D-loaded beads, respectively, placed on a polyethylene terephthalate (PET) sheet in the catalyst-free BZ solution. We examined two types of coupling of the two beads: 2D-3D and 3D-3D couplings. In both cases, synchronization occurred when the minimum distance between the two beads, l, was shorter than the threshold. Herein, we reported not only temporal information, that is, phase difference, but also spatial information, that is, the directions of the TW propagating through the coupled BZ beads. In the synchronization for the 2D-3D coupling, TW in the 3D-loaded bead were initiated from the point near the 2D-loaded bead as a pacemaker and propagated in the opposite direction. By contrast, the directions of the TW in the 3D-loaded bead changed depending on l in the synchronization for the 3D-3D coupling. These experimental results can be quantitatively reproduced by numerical calculations based on the diffusion dynamics of an activator of the BZ reaction. Our results suggest that the features of spatio-temporal wave propagation are indicative of the configuration of the oscillators.

BCOR Internal Tandem Duplication Expression in Neural Stem Cells Promotes Growth, Invasion, and Expression of PRC2 Targets.

Central nervous system tumor with BCL6-corepressor internal tandem duplication (CNS-BCOR ITD) is a malignant entity characterized by recurrent alterations in exon 15 encoding the essential binding domain for the polycomb repressive complex (PRC). In contrast to deletion or truncating mutations seen in other tumors, BCOR expression is upregulated in CNS-BCOR ITD, and a distinct oncogenic mechanism has been suggested. However, the effects of this change on the biology of neuroepithelial cells is poorly understood. In this study, we introduced either wildtype BCOR or BCOR-ITD into human and murine neural stem cells and analyzed them with quantitative RT-PCR and RNA-sequencing, as well as growth, clonogenicity, and invasion assays. In human cells, BCOR-ITD promoted derepression of PRC2-target genes compared to wildtype BCOR. A similar effect was found in clinical specimens from previous studies. However, no growth advantage was seen in the human neural stem cells expressing BCOR-ITD, and long-term models could not be established. In the murine cells, both wildtype BCOR and BCOR-ITD overexpression affected cellular differentiation and histone methylation, but only BCOR-ITD increased cellular growth, invasion, and migration. BCOR-ITD overexpression drives transcriptional changes, possibly due to altered PRC function, and contributes to the oncogenic transformation of neural precursors.

Can simple physicochemical studies predict the effects of molecules on epidermal water-impermeable barrier function?

Improvement of the water-impermeable barrier function of skin is clinically important, because barrier abnormality is associated with various skin diseases, such as psoriasis or atopic dermatitis. We have shown that topical application of fatty acids, sex hormones, hexoses, polyols and polymers influences barrier homeostasis, but the effects are highly dependent on even small variations of molecular structure. Moreover, the effects appear within one hour after application and thus are likely to be non-genomic (physicochemical) phenomena. Secretion of lipids from lamellar bodies into the intercellular space between stratum granulosum and stratum corneum is a crucial step in epidermal water-impermeable barrier homeostasis, especially at the early stage of barrier recovery after damage, and phase transition of the lipid lamellar structure in the epidermis is an important part of this process. Therefore, we evaluated the effects of the above molecules on the physicochemical properties of phospholipid monolayers and liposomes as models of the lamellar body membrane and cell membrane. Molecules that influenced the barrier recovery process also altered the stability of liposomes and the air-water surface pressure of phospholipid monolayers. Studies using attenuated total reflection Fourier-transform infrared spectroscopy (ATR FT-IR), differential scanning calorimetry (DSC) and 13 C nuclear magnetic resonance (NMR) spectrometry suggested that molecules influencing barrier recovery interact specifically with phospholipids. The idea that molecules interacting with phospholipids may influence barrier homeostasis should open up new approaches to the treatment of a variety of skin diseases.

Inversion probability of three-bladed self-propelled rotors after forced stops of different durations.

We investigated self-propelled rotation of a symmetric three-bladed rotor on water under periodic halt and release operations. The rotation was driven by the difference in the surface tension around the blades of the rotor because camphor molecules developed from three camphor disks glued at the blade ends. Spontaneous inversion of rotation direction was observed after a forced stop of the rotor and the subsequent release. The probability of such inversion decreased with an increase in the halting time. The asymmetric distribution of camphor molecules around the blades was also inverted after the forced stop and the degree of asymmetry increased with an increase in the angular velocity characterizing the stationary rotation of the rotor. Our experimental results for rotors with different shapes indicate that there is a strong correlation between the stationary angular velocity of the rotor and the maximum time duration of the forced stop for which a high probability of inversion is observed.

Oligodendroglioma showing pleomorphic xanthoastrocytoma-like perivascular microlesion: With IDH1, TERT promoter mutation and 1p/19q codeletion detected in both components.

We report a histological and genetic study of concurrent oligodendroglioma and a microscopic pleomorphic xanthoastrocytoma (PXA)-like lesion in a 48-year-old male. He presented with generalized seizure, and magnetic resonance imaging revealed a nonenhanced left frontal lobe mass suggesting low-grade glioma. The patient underwent craniotomy and tumor resection. Histopathological examination of the surgical specimen showed an oligodendroglioma with a PXA-like element; the latter measured 0.9 mm and occupied a Virchow-Robin space of the superficial cortex. The whole tumor had no elevated mitotic activity, microvascular proliferation or necrosis. Each component was immunohistochemically isocitrate dehydrogenase (IDH1)-R132H positive, p53 negative and ATRX positive. Genetic analyses clarified identical IDH1 G395A mutation, promoter C228T mutation and 1p/19q codeletion in both elements. Careful integration of histology and telomerase reverse transcriptase (TERT) molecular parameters revealed that this case was an oligodendroglioma showing PXA-like features, rather than a collision tumor. This case provides further insights into the gliomagenesis.

On a simple model that explains inversion of a self-propelled rotor under periodic stop-and-release-operations.

We propose a simple mathematical model that describes the time evolution of a self-propelled object on a liquid surface using variables such as object location, surface concentration of active molecules, and hydrodynamic surface flow. The model is applied to simulate the time evolution of a rotor composed of a polygonal plate with camphor pills at its corners. We have qualitatively reproduced results of experiments, in which the inversion of rotational direction under periodic stop-and-release-operations was investigated. The model correctly describes the probability of the inversion as a function of the duration of the phase when the rotor is stopped. Moreover, the model allows to introduce the rotor asymmetry unavoidable in real experiments and study its influence on the studied phenomenon. Our numerical simulations have revealed that the probability of the inversion of rotational direction is determined by the competition among the transport of the camphor molecules by the flow, the intrinsic asymmetry of the rotor, and the noise amplitude.

Self-Propelled Motion of a Camphor Disk on a Photosensitive Amphiphilic Molecular Layer.

We have studied the self-propelled motion of a camphor disk on a 2,2'-bis(2-chlorophenyl)-4,4',5,5'-tetraphenyl-1,2'-biimidazole ( o-Cl-HABI) molecular layer, which was developed on water, as a photomechanical sensing system. The o-Cl-HABI dimer changed to its monomeric form upon UV light irradiation, and as a result, the surface pressure of the o-Cl-HABI molecular layer decreased. The reciprocating motion of a camphor disk in the absence of UV light irradiation was observed at A = 45 Å2 molecule-1, of which the surface pressure was ∼10 mN m-1. Random motion was observed under UV light irradiation at A = 45 Å2 molecule-1, of which the surface pressure was ∼5 mN m-1. Therefore, the nature of motion of a camphor disk changes depending on the photosensitivity of the o-Cl-HABI molecular layer. We have discussed the mechanism of the change in the motion of the camphor disk in relation to the photoreaction of the o-Cl-HABI molecular layer with the surface pressure acting as the driving force.

Chemical Wave Propagation in the Belousov-Zhabotinsky Reaction Controlled by Electrical Potential.

The Belousov-Zhabotinsky (BZ) reaction is an important experimental model for the study of chemical oscillations and waves far from the thermodynamic equilibrium. Earlier studies had observed that individual BZ microbeads can show both global oscillations and traveling waves, but failed to select these different dynamic states. Here, we report experiments, in which this control was achieved by an externally applied electrical potential. The spherical microbeads were first loaded with the catalyst, then immersed into a catalyst-free BZ solution, and finally placed onto a planar platinum electrode. For positive electrical potentials, we observed global oscillations, whereas negative potentials resulted in traveling waves. The spatio-temporal characteristics of these phenomena are discussed in relation to the activator, HBrO2, which is produced by an electrochemical reaction.

Inhibition of enhancer of zest homologue 2 is a potential therapeutic target for high-MYC medulloblastoma.

MYC amplification is common in Group 3 medulloblastoma and is associated with poor survival. Group 3 and Group 4 medulloblastomas are also known to have elevated levels of histone H3-lysine 27-tri-methylation (H3K27me3), at least in part due to high expression of the H3K27 methyltransferase enhancer of zest homologue 2 (EZH2), which can be regulated by MYC. We therefore examined whether MYC expression is associated with elevated EZH2 and H3K27me3 in medulloblastoma, and if high-MYC medulloblastomas are particularly sensitive to pharmacological EZH2 blockade. Western blot analysis of low (DAOY, UW228, CB SV40) and high (DAOY-MYC, UW228-MYC, CB-MYC, D425) MYC cell lines showed that higher levels of EZH2 and H3K27me3 were associated with elevated MYC. In fixed medulloblastoma samples examined using immunohistochemistry, most MYC positive tumors also had high H3K27me3, but many MYC negative ones did as well, and the correlation was not statistically significant. All high MYC lines tested were sensitive to the EZH2 inhibitor EPZ6438. Many low MYC lines also grew more slowly in the presence of EPZ6438, although DAOY-MYC cells responded more strongly than parent DAOY cultures with lower MYC levels. We find that higher MYC levels are associated with increased EZH2, and pharmacological blockade of EZH2 is a potential therapeutic strategy for aggressive medulloblastoma with elevated MYC.