Identification and Total Synthesis of Two Previously Unreported Odd-Chain Bis-Methylene-Interrupted Fatty Acids with a Terminal Olefin that Activate Protein Phosphatase, Mg2+/Mn2+-Dependent 1A (PPM1A) in Ovaries of the Limpet Cellana toreuma.

Diverse non-methylene-interrupted (NMI) fatty acids (FAs) with odd-chain lengths have been recognized in triacylglycerols and polar lipids from the ovaries of the limpet Cellana toreuma, however their biological properties remain unclear. In this study, two previously unreported odd-chain NMI FAs, (12Z)-12,16-heptadecadienoic (1) and (14Z)-14,18-nonadecadienoic (2) acids, from the ovary lipids of C. toreuma were identified by a combination of equivalent chain length (ECL) values of their methyl esters and capillary gas chromatography-mass spectrometry (GC-MS) of their 3-pyridylcarbinol derivatives. On the basis of the experimental results, both 1 and 2 were synthesized to prove their structural assignments and to test their biological activity. The ECL values and electron impact-mass (EI-MS) spectra of naturally occurring 1 and 2 were in agreement with those of the synthesized 1 and 2. In an in vitro assay, both 1 and 2 activated protein phosphatase, Mg2+/Mn2+-dependent 1A (PPM1A) up to 100 µM in a dose-dependent manner.

Safety and Efficacy of FIT039 for Verruca Vulgaris: A Placebo-Controlled, Phase I/II Randomized Controlled Trial.

TRIAL DESIGN: Human papillomavirus infection causes verruca vulgaris. CDK9 inhibitor FIT039 inhibits DNA virus proliferation in animal models. We conducted a multicenter, single-blind, placebo-controlled, randomized phase I/II clinical trial evaluating the safety and efficacy of FIT039 against verruca vulgaris. METHODS: Target lesions were treated with liquid nitrogen once, and a FIT039 patch or placebo patch was applied for 14 days. The primary endpoint was lesion disappearance. The secondary endpoints were safety and changes in dimension, cross-sectional area, and the number of petechial lesions. RESULTS: A total of 24 participants were randomly allocated to the FIT039 (n = 13, median age, 54 years) and placebo (n = 11, median age, 62 years) groups. Verruca vulgaris did not disappear. FIT039 decreased the dimension to 76% of the initial value on day 29, followed by an increase to 98% on day 57. Placebo showed a monotonic increase to 107% on day 57. Changes in the cross-sectional area and petechiae number were comparable between the groups. CONCLUSIONS: No drug-related adverse reactions occurred. FIT039 efficacy was not determined in this study.

Numerical simulations of particle behaviour in a realistic human airway model with varying inhalation patterns.

OBJECTIVES: For dry powder inhalers, the airflow properties in the airways could affect the deposition of inhaled particles; the flow patterns vary inherently between patients. This paper provides an evaluation of the effects of six airflow patterns on the behaviour of inhaled particles, as determined by using numerical simulations. METHODS: Constant-velocity and unsteady inhalation flows were employed. The unsteady inhalation flow was set as an inhalation curve with a peak inspiratory flow rate. Under a constant flow of 28.3 l/min, the total flow rates were calculated to confirm the validity of the numerical simulation. The effects of different inhalation patterns on the particle behaviour in a realistic human airway model were revealed via numerical simulation. KEY FINDINGS: Different flow rates affected the behaviour and deposition of the inhaled particles. Under an inhalation flow pattern, different airflow tendencies were observed between the right and left bronchi. Particle deposition in the airways was promoted by a vortex following terminal-velocity-like breath-holding. The inhalation flow pattern affected the behaviour and deposition of inhaled particles in the airway. CONCLUSIONS: Our results indicated that particle deposition in a realistic human airway model was promoted by a vortex formation following the terminal-velocity-like breath-holding. Moreover, the inhalation flow pattern significantly influenced the behaviour and deposition of inhaled particles in the airways. Additionally, the effect of flow patterns on the particle deposition in each airway position was quantitatively evaluated by numerical simulations for a realistic human airway model.

Phylogenetic characterization of rabies virus isolates from Carnivora in Brazil.

The incidence of canine rabies has been widely reported in Brazil, and new rabies virus (RV) variants, genetically similar to canine RV, have recently been isolated from foxes. In order to derive the epidemiological characteristics of Brazilian Carnivora RV, Brazilian RVs isolated from dogs, cats, and foxes were genetically analyzed. Brazilian Carnivora RV isolates were divided into 2 main lineages. The predominant lineage was found in dogs and cats, which included the Argentinean and Bolivian Carnivora RV isolates, and was extensively distributed throughout Brazil and surrounding countries. The other lineage consisted of three sublineages containing Brazilian dog and fox RV isolates, with the dog sublineages located on an internal branch of 2 fox sublineages, suggesting that RV transmission events might have occurred between foxes and dogs in the past. These results suggest that contact between dogs and wildlife has the potential to generate new rabies variants and that it is important to control RV infection cycles in both dogs and wildlife to prevent spread of rabies infection.

CARD14 Glu138 mutation in familial pityriasis rubra pilaris does not warrant differentiation from familial psoriasis.

Some familial cases of pityriasis rubra pilaris (PRP) have the CARD14 gene mutations that are also detected in familial psoriasis vulgaris. However, genotype-phenotype correlation in these two entities is poorly understood. Here, we report a case of PRP with a new mutation in CARD14. Genomic analysis of a 40-year-old female patient with sporadic PRP type V identified a heterozygous dominant c.412G>A mutation (p.Glu138Lys) in CARD14. Two types of CARD14 mutations causing Glu138 substitutions have been reported in cases of familial PRP and pustular psoriasis. All three types, including the present case, are predicted to cause similar loss of the negative charges at this site. This suggests that the difference in molecular charge and the resulting change in molecular interaction around the N-terminal end of the coiled-coil region of CARD14 molecule do not determine the phenotypic differences between psoriasis and PRP.

Dissolving microneedles to obtain rapid local anesthetic effect of lidocaine at skin tissue.

Dissolving microneedles (DMs) were applied to lidocaine for local anesthesia of the skin. Three DM array chips were prepared where lidocaine was localized at the acral portion of DMs (type 1), loaded in whole DMs (type 2), and lidocaine was loaded both in whole DMs and the chip (type 3). DM chips were 15-mm diameter with 225 DMs, each 500-µm long with a 300-µm diameter base. The lidocaine contents were (type 1) 0.08 ± 0.01 mg, (type 2) 0.22 ± 0.01 mg and (type 3) 8.52 ± 0.49 mg. Lidocaine was released from type 1 and 2 DM array chips within 10 min. Pharmacological activity of DMs were compared to lidocaine cream by the suppression of idiospasm of hair-removed rat skin. Type 1, 2 and 3 DMs showed faster onset time, 5 min, than lidocaine cream. Type 2 and 3 DMs showed stronger anti-idioplasmic activity than type 1 DMs. Pharmacokinetic study showed that tissue lidocaine levels, 62.8 ± 3.6 (type 1), 89.1 ± 9.9 (type 2) and 131.2 ± 10.2(type 3) µg/g wet weight at 5 min after the removal of DM were obtained higher than lidocaine cream, 26.2 ± 12.5 µg/g wet weight. Those results suggest the usefulness of type 2 DMs to obtain fast onset time for the local anesthesia in the skin.