Implications of Incorporating Plasma Lipoprotein Binding into a Physiologically-Based Pharmacokinetic Model: A Simulation Study with Amiodarone.

Although various lipophilic drugs are bound to lipoproteins, lipoprotein binding in plasma is not usually considered in current physiologically-based pharmacokinetic (PBPK) models. Amiodarone is extensively bound to serum triglyceride-rich lipoproteins. Total plasma amiodarone concentration, which is the sum of both unbound and bound concentrations, increases with increasing serum triglyceride levels. We investigated the impact of lipoprotein binding on amiodarone pharmacokinetics using PBPK modeling and simulations. An amiodarone PBPK model that incorporates plasma lipoprotein binding (LPP model) was developed based on the correlation between serum triglyceride levels and lipoprotein-bound amiodarone. The predicted unbound fraction of amiodarone in plasma and systemic clearance in the LPP and base models (with albumin binding only) were similar, but the coefficients of variation for the LPP model were greater than those for the base model and were closer to the observed data. The total plasma amiodarone concentration predicted using the LPP model increased with higher levels of plasma lipoprotein binding and serum albumin. In contrast, changes in plasma lipoprotein binding and serum albumin levels did not influence the predicted unbound plasma amiodarone concentration at steady-state. This study demonstrates that incorporating plasma lipoprotein binding into a PBPK model improves the accuracy of predicting interindividual variabilities in amiodarone clearance by more reliably predicting the interindividual variability in the plasma unbound fraction of amiodarone. Plasma lipoprotein binding should be considered in PBPK modeling and simulations for lipoprotein-associated drugs if there is available information on the relationship between plasma lipoprotein binding and hyperlipidemia.

InGaN/GaN superlattice underlayer for fabricating of red nanocolumnµ-LEDs with (10-11) plane InGaN/AlGaN MQWs.

In this study, the growth behavior of Indium gallium nitride (InGaN)-based nanocolumn arrays was investigated, and red emission nanocolumn micro-light emitting diodes (µ-LEDs) were fabricated. The internal structure of the InGaN/GaN superlattice (SL) layer under the multiple-quantum-well (MQW) active layers was evaluated using scanning transmission electron microscopy (STEM) analysis. It was revealed that the InGaN crystal plane at the top of the nanocolumn changed from the c-plane, (1-102) plane, to the (10-11) plane as the number of SL pairs increased. A semipolar (10-11) plane was completely formed on top of the nanocolumn by growing InGaN/GaN SLs over 15-20 pairs, where the InGaN/GaN SL layers were uniformly piled up, maintaining the (10-11) plane. Therefore, when InGaN/AlGaN MQWs were grown on the (10-11) plane InGaN/GaN SL layer, the growth of the (10-11) plane semipolar InGaN active layers was observed in the high-angle annular dark field (HAADF)-STEM image. Moreover, the acute nanocolumn top of the (10-11) plane of the InGaN/GaN SL underlayer did not contribute to the formation of the c-plane InGaN core region. Red nanocolumnµ-LEDs with anφ12µm emission window were fabricated using the (10-11) plane MQWs to obtain the external quantum efficiency of 1.01% at 51 A cm-2. The process of nanocolumnµ-LEDs suitable for the smaller emission windows was provided, where the flat p-GaN contact layer contributed to forming a fine emission window ofφ5µm.

Donor-π-Acceptor-Type Fluorinated Tolane Containing a Semifluoroalkoxy Chain as a Condensed-Phase Luminophore.

Photoluminescent liquid-crystalline (PLLC) molecules, which can easily tune the PL behavior through the crystal (Cry)-LC phase transition, have attracted significant attention. Previously, we have demonstrated that the incorporation of a semifluoroalkoxy chain into π-conjugated mesogen is a promising approach for developing PLLC molecules with PL and SmA LC characteristics. We focused on the LC and PL characteristics of the molecules induced by the semifluoroalkoxy chain and fluorinated tolanes in the condensed phase. In this study, we developed cyano- or ethoxycarbonyl-terminated donor-π-acceptor-type fluorinated tolanes containing a semifluoroalkoxy flexible chain. The cyano-terminated fluorinated tolanes exhibited intense light-blue photoluminescence in the crystalline phase and did not exhibit any LC phase. In contrast, blue photoluminescence in the ethoxycarbonyl-terminated analogs was slightly weak; however, they exhibited Cry-SmA phase transition during the heating and cooling processes. The PL intensity of the ethoxycarbonyl-terminated fluorinated tolanes significantly decreased in the SmA phase; however, their PL colors changed during the Cry-SmA phase transition. This indicates that the developed tolanes are promising temperature-dependent PL materials, such as PL thermosensors or PL thermometers.

Janus faced fluorocyclohexanes for supramolecular assembly: synthesis and solid state structures of equatorial mono-, di- and tri alkylated cyclohexanes and with tri-axial C-F bonds to impart polarity.

Concise and general synthesis protocols are reported to generate all-syn mono-, di- and tri-alkylated cyclohexanes where a single fluorine is located on the remaining carbons of the ring. The alkyl groups are positioned to lie equatorially and to have triaxial C-F bonds imparting polarity to these ring systems. Intermolecular electrostatic interactions in the solid-state structure of the trialkylated systems are explored and the resultant supramolecular order opens up prospects for design in soft materials.

Zebrafish can regenerate endoskeleton in larval pectoral fin but the regenerative ability declines.

We show for the first time endoskeletal regeneration in the developing pectoral fin of zebrafish. The developing pectoral fin contains an aggregation plate of differentiated chondrocytes (endochondral disc; primordium for endoskeletal components, proximal radials). The endochondral disc can be regenerated after amputation in the middle of the disc. The regenerated disc sufficiently forms endoskeletal patterns. Early in the process of regenerating the endochondral disc, epithelium with apical ectodermal ridge (AER) marker expression rapidly covers the amputation plane, and mesenchymal cells start to actively proliferate. Taken together with re-expression of a blastema marker gene, msxb, and other developmental genes, it is likely that regeneration of the endochondral disc recaptures fin development as epimorphic limb regeneration does. The ability of endoskeletal regeneration declines during larval growth, and adult zebrafish eventually lose the ability to regenerate endoskeletal components such that amputated endoskeletons become enlarged. Endoskeletal regeneration in the zebrafish pectoral fin will serve as a new model system for successful appendage regeneration in mammals.

Insights regarding skin regeneration in non-amniote vertebrates: Skin regeneration without scar formation and potential step-up to a higher level of regeneration.

Skin wounds are among the most common injuries in animals and humans. Vertebrate skin is composed of an epidermis and dermis. After a deep skin injury in mammals, the wound heals, but the dermis cannot regenerate. Instead, collagenous scar tissue forms to fill the gap in the dermis, but the scar does not function like the dermis and often causes disfiguration. In contrast, in non-amniote vertebrates, including fish and amphibians, the dermis and skin derivatives are regenerated after a deep skin injury, without a recognizable scar remaining. Furthermore, skin regeneration can be compared with a higher level of organ regeneration represented by limb regeneration in these non-amniotes, as fish, anuran amphibians (frogs and toads), and urodele amphibians (newts and salamanders) have a high capacity for organ regeneration. Comparative studies of skin regeneration together with limb or other organ regeneration could reveal how skin regeneration is stepped up to a higher level of regeneration. The long history of regenerative biology research has revealed that fish, anurans, and urodeles have their own strengths as models for regeneration studies, and excellent model organisms of these non-amniote vertebrates that are suitable for molecular genetic studies are now available. Here, we summarize the advantages of fish, anurans, and urodeles for skin regeneration studies with special reference to three model organisms: zebrafish (Danio rerio), African clawed frog (Xenopus laevis), and Iberian ribbed newt (Pleurodele waltl). All three of these animals quickly cover skin wounds with the epidermis (wound epidermis formation) and regenerate the dermis and skin derivatives as adults. The availability of whole genome sequences, transgenesis, and genome editing with these models enables cell lineage tracing and the use of human disease models in skin regeneration phenomena, for example. Zebrafish present particular advantages in genetics research (e.g., human disease model and Cre-loxP system). Amphibians (X. laevis and P. waltl) have a skin structure (keratinized epidermis) common with humans, and skin regeneration in these animals can be stepped up to limb regeneration, a higher level of regeneration.

Psychometric properties of a Japanese version of Composite Scale of Morningness.

This study aimed to assess the factor structure and validity of the Composite Scale of Morningness (CSM) in Japanese samples. A sample of 348 Japanese university students (196 men, 152 women) and 170 adults from the community (50 men, 120 women) completed a questionnaire including the CSM, the Diurnal Type Scale (DTS) and questions regarding sleeping and waking times. Four measurement models were compared, and a two-factor measurement model with Morningness/Time of day preference (α = 0.78) and Morning Affect/Alertness (α = 0.80) factors yielded the closest fit. Both Morningness/Time of day preference and Morning Affect/Alertness were positively correlated with DTS score. Morningness/Ttime of day preference was negatively correlated with the midpoint of sleep on weekdays and free days. The measurement model was invariant across the university and community groups. The community group, which was older, was characterized by greater morningness. The results provide evidence of the validity of the Japanese CSM, thus opening up the possibility of including Japanese samples in cross-cultural research on morningness.

Effect of passengers' active head tilt and opening/closure of eyes on motion sickness in lateral acceleration environment of cars.

This study examined the effect of passengers' active head-tilt and eyes-open/eyes-closed conditions on the severity of motion sickness in the lateral acceleration environment of cars. In the centrifugal head-tilt condition, participants intentionally tilted their heads towards the centrifugal force, whereas in the centripetal head-tilt condition, the participants tilted their heads against the centrifugal acceleration. The eyes-open and eyes-closed cases were investigated for each head-tilt condition. In the experimental runs, the sickness rating in the centripetal head-tilt condition was significantly lower than that in the centrifugal head-tilt condition. Moreover, the sickness rating in the eyes-open condition was significantly lower than that in the eyes-closed condition. The results suggest that an active head-tilt motion against the centrifugal acceleration reduces the severity of motion sickness both in the eyes-open and eyes-closed conditions. They also demonstrate that the eyes-open condition significantly reduces the motion sickness even when the head-tilt strategy is used. Practitioner Summary: Little is known about the effect of head-tilt strategies on motion sickness. This study investigated the effects of head-tilt direction and eyes-open/eyes-closed conditions on motion sickness during slalom automobile driving. Passengers' active head tilt towards the centripetal direction and the eyes-open condition greatly reduce the severity of motion sickness.

Linear regression models predicting strength of transcriptional activity of promoters.

We developed linear regression models which predict strength of transcriptional activity of promoters from their sequences. Intrinsic transcriptional strength data of 451 human promoter sequences in three cell lines (HEK293, MCF7 and 3T3), which were measured by systematic luciferase reporter gene assays, were used to build the models. The models sum up contributions of CG dinucleotide content and transcription factor binding sites (TFBSs) to transcriptional strength. We evaluated prediction accuracies of the models by cross validation tests and found that they have adequate ability for predicting transcriptional strength of promoters in spite of their simple formalization. We also evaluated statistical significance of the contributions and proposed a picture of regulatory code hidden in promoter sequences. That is, CG dinucleotide content and TFBSs mainly determine strength of transcriptional activity under ubiquitous and specific environments, respectively.

Total syntheses of natural tubelactomicins B, D, and E: establishment of their stereochemistries.

Total syntheses of the antimicrobial tricyclic 16-membered macrolides, (+)-tubelactomicin B, (+)-tubelactomicin D, and (+)-tubelactomicin E, have been accomplished for the first time with common synthetic approaches. These total syntheses established the relative and absolute configurations of the three tubelactomicins, for which planar structures had solely been reported. The total synthesis of (+)-tubelactomicin D included a newly developed stereoselective intramolecular Diels-Alder reaction for constructing the highly functionalized octahydronaphthalene substructures.

Total synthesis of (+)-tubelactomicin A. 1. Stereoselective synthesis of the lower-half segment by an intramolecular Diels-Alder approach.

[reaction: see text]. Starting from diethyl (R)-malate, synthesis of the lower-half segment of (+)-tubelactomicin A, a 16-membered macrolide antibiotic, has been achieved. The synthesis involved the highly endo- and pi-facial selective intramolecular Diels-Alder reaction achieved using a trisubstituted methacrolein derivative tethering a 10-carbon dienyne unit at the beta-carbon, which in turn was prepared from a known allylated malic acid derivative.

Total synthesis of (+)-tubelactomicin A. 2. Synthesis of the upper-half segment and completion of the total synthesis.

[reaction: see text]. We have completed the total synthesis of natural (+)-tubelactomicin A (1), a 16-membered macrolide antibiotic. This Letter presents a highly efficient synthesis of the upper-half segment (C14-C24) and the completion of the total synthesis featuring a high-yielding Stille coupling for the connection of the upper-half and lower-half segments and Mukaiyama macrolactonization for the construction of the entire structure of 1.