Compressive frequency-difference direction-of-arrival estimation.

Direction-of-arrival estimation is difficult for signals spatially undersampled by more than half the wavelength. Frequency-difference beamforming [Abadi, Song, and Dowling (2012). J. Acoust. Soc. Am. 132, 3018-3029] offers an alternative approach to avoid such spatial aliasing by using multifrequency signals and processing them at a lower frequency, the difference-frequency. As with the conventional beamforming method, lowering the processing frequency sacrifices spatial resolution due to a beam broadening. Thus, unconventional beamforming is detrimental to the ability to distinguish between closely spaced targets. To overcome spatial resolution deterioration, we propose a simple yet effective method by formulating the frequency-difference beamforming as a sparse signal reconstruction problem. Similar to compressive beamforming, the improvement (compressive frequency-difference beamforming) promotes sparse nonzero elements to obtain a sharp estimate of the spatial direction-of-arrival spectrum. Analysis of the resolution limit demonstrates that the proposed method outperforms the conventional frequency-difference beamforming in terms of separation if the signal-to-noise ratio exceeds 4 dB. Ocean data from the FAF06 experiment support the validity.

Estimation of the Complex Dynamic Stiffness of Inflated Rubber Diaphragms in Pneumatic Springs Using Finite Element Method.

The accurate modeling of the complex dynamic stiffness of inflated rubber diaphragms in pneumatic springs is necessary for an efficient design of vibration isolation tables for precision instruments, such as optical devices and nano-scale equipment. In addition to pressurized air, rubber diaphragms, essentially employed for the prevention of air leakage, make a significant contribution to the total complex stiffness. To reflect the effect of the dynamic stiffness of the inflated rubber diaphragm on the total complex stiffness during the initial design or design improvement stage, it is desirable to predict the complex stiffness of the inflated rubber diaphragm beforehand. In this paper, an estimation method for the complex stiffness of inflated rubber diaphragms using the commercial finite element method (e.g., ABAQUS) is proposed. The proposed method reflects their dynamic characteristics under the large static deformation by the Mooney-Rivlin and Morman's constitutive equations. The results of comparison with experimental results indicate that the predictions obtained by the proposed method are congruent with the experimental values of the diaphragm.

KLF4 suppresses the tumor activity of cutaneous squamous cell carcinoma (SCC) cells via the regulation of SMAD signaling and SOX2 expression.

Kruppel-like factor 4 (KLF4) is a zinc-finger transcription factor that plays a role in terminal differentiation of epidermal keratinocytes. There are conflicting reports regarding the role of KLF4 in tumor development, with both the tumor suppressive and/or oncogenic properties depending on different conditions and cell types. In this study, we investigated the functional importance of KLF4 in cutaneous squamous cell carcinoma (SCC). Immunohistochemistry showed that KLF4 expression was relatively low in SCC lesion compared to normal epidermis. To examine the effects of KFL4, we transduced SCC lines (SCC12 and SCC13 cells) with the KLF4-expressing recombinant adenovirus. Overexpression of KLF4 significantly decreased cell proliferation and colony forming activity. In addition, overexpression of KLF4 markedly reduced invasive potential, along with the downregulation of epithelial-mesenchymal transition (EMT)-related molecules. In a mechanistic study, KLF4 inhibited SOX2, of which expression is critical for tumor initiation and growth of SCC. Further investigations indicated that SOX2 expression is induced by TGF-ß/SMAD signaling, and that overexpression of KLF4 inhibited SMAD signaling via upregulation of SMAD7, an important inhibitory SMAD molecule. Based on these data, KLF4 plays a tumor suppressive role in cutaneous SCC cells.

Induction of pigmentation by a small molecule tyrosine kinase inhibitor nilotinib.

Skin color is determined by the melanin pigments that are produced in melanocytes then transferred to surrounding keratinocytes. Despite the growing number of commercial products claiming the pigmentation-regulatory effects, there is still a demand for the development of new materials that are safe and more efficacious. We tried to screen the pigmentation-regulatory materials using a commercially available drugs, and found that nilotinib could induce pigmentation in melanoma cells. When HM3KO melanoma cells were treated with nilotinib, melanin content was increased together with increase of tyrosinase activity. Nilotinib increased the expression of pigmentation-related genes such as MITF, tyrosinase and TRP1. Consistent with these results, the protein level for MITF, tyrosinase, and TRP1 was significantly increased by nilotinib. To delineate the action mechanism of nilotinib, we investigated the effects of nilotinib on intracellular signaling. As a result, nilotinib decreased the phosphorylation of AKT, while increased the phosphorylation of CREB. The pretreatment of PKA inhibitor H89 markedly blocked the nilotinib-induced phosphorylation of CREB. In accordance with, pretreatment of H89 significantly inhibited the nilotinib-induced pigmentation, indicating that nilotinib induces pigmentation via the activation of PKA signaling. Together, our data suggest that nilotinib can be developed for the treatment of hypopigmentary disorder such as vitiligo.

Sea-trial verification of ultrasonic antifouling control.

An ultrasonic antifouling treatment was applied to a 96,000 m3 class drill-ship to verify its feasibility through a sea-trial. Soon after the hull cleaning had been performed, six ultrasonic projectors were evenly deployed around the starboard shell plate. Driven by a 23 kHz sinusoidal ultrasound in an intermittent manner, the projectors emitted a high-intensity sound reaching 214 dB at the source level causing cavitation around the adjacent water and eventually deterring the settlement of marine fouling organisms. Underwater photographs acquired after four months showed fairly clean slabs on the starboard side, but heavy fouling on the port side. This experiment revealed that ultrasound treatment is a promising method for inhibiting fouling accumulation, even for large-scale ship applications.

Destructive frequency of oblate spheroidal air-balloon for suppression of propeller cavitation induced hull excitation.

The air-balloon can effectively neutralize hull excitations induced by the propeller cavitation. For the design, it is essential to derive the destructive frequency of an oblate spheroidal air-bubble, which is elaborated on in this paper. Beginning with the exact modal-series solution proposed by Yeh [Ann. Phys. 468, 53-61 (1964)], an approximated form of the scattered pressure is set up by assuming that the acoustic wavelength is much larger than the size of the balloon in the low frequency ranges. An algebraic formula for the destructive frequency can then be written as a function of the resonance frequency and a spatial variable. It is well known that the resonance frequency of a deformed bubble is higher than that of an ideal spherical one with the same volume. In addition to this, the current investigation puts an emphasis on the fact that asphericity induces a more severe shift of the destructive frequency than the resonance frequency, and that its effect needs to be reflected in the balloon design.

Effects of Brn2 overexpression on eccrine sweat gland development in the mouse paw.

Eccrine sweat glands regulate body temperature by secreting water and electrolytes. In humans, eccrine sweat glands are ubiquitous in the skin, except in the lips and external genitalia. In mice, eccrine sweat glands are present only in the paw pad. Brn2 is a protein belonging to a large family of transcription factors. A few studies have examined Brn2 in melanoma cells and epidermal keratinocytes. This study investigated changes in the skin in the K5-Brn2 transgenic mouse, which overexpresses Brn2 and contains the keratin 5 promotor. Interestingly, the volume of eccrine sweat glands was reduced markedly in the K5-Brn2 transgenic mouse compared with the wild-type, while the expression of aquaporin 5, important molecule in sweat secretion, was increased in each sweat gland cell, probably to compensate for the reduction in gland development. However, sweating response to a pilocarpine injection in the hind paw was significantly decreased in the K5-Brn2 transgenic mouse compared with the wild-type. The paw epidermis was thicker in the K5-Brn2 transgenic mouse compared with the wild-type. Taken together, eccrine sweat gland development and sweat secretion were suppressed markedly in the K5-Brn2 transgenic mouse. These results may be associated with dominant development of the epidermis by Brn2 overexpression in the paw skin.

Inhibitory effect of 5-iodotubercidin on pigmentation.

Melanin pigments are the primary contributors for the skin color. They are produced in melanocytes and then transferred to keratinocytes, eventually giving various colors on skin surface. Although many depigmenting and/or skin-lightening agents have been developed, there is still a growing demand on materials for reducing pigmentation. We attempted to find materials for depigmentation and/or skin-lightening using the small molecule compounds commercially available, and found that 5-iodotubercidin had inhibitory potential on pigmentation. When HM3KO melanoma cells were treated with 5-iodotubercidin, pigmentation was dramatically reduced. The 5-iodotubercidin decreased the protein level for pigmentation-related molecules such as MITF, tyrosinase, and TRP1. In addition, 5-iodotubercidin decreased the phosphorylation of CREB, while increased the phosphorylation of AKT and ERK. These data suggest that 5-iodotubercidin inhibits melanogenesis via the regulation of intracellular signaling related with pigmentation. Finally, 5-iodotubercidin markedly inhibited the melanogenesis of zebrafish embryos, an in vivo evaluation model for pigmentation. Together, these data suggest that 5-iodotubercidin can be developed as a depigmenting and/or skin-lightening agent.

Comparative Efficacy of Radiofrequency and Pulsed Dye Laser in the Treatment of Rosacea.

BACKGROUND: Laser and light-based therapies have been used successfully in the treatment of rosacea; however, evidence is lacking regarding the efficacy of radiofrequency (RF). OBJECTIVE: This study evaluated the efficacy of RF in the treatment of rosacea compared with pulsed dye laser (PDL). METHODS: Thirty patients with rosacea (erythematotelangiectatic rosacea [ETR], n = 20; papulopustular rosacea [PPR], n = 10) were enrolled in a randomized, controlled, split-face study. The patients were treated with RF on one side and PDL on the other side. Each treatment consisted of 3 sessions at 4-week intervals and followed up until 4 weeks after the last treatment. Efficacy was assessed by rosacea severity score, erythema index, lesion counts, physician's subjective evaluation, and patient's satisfaction. RESULTS: Radiofrequency and PDL resulted in significant improvement in severity scores and erythema and 70% of the patients receiving RF treatment showed a clinical improvement of >50%. No significant difference was noted between RF and PDL treatment in ETR. However, RF treatment led to a significantly greater decrease in papulopustular lesion count and rosacea severity score in PPR compared with PDL treatment. CONCLUSION: RF therapy was effective in the treatment of rosacea. It should be considered an alternative therapeutic option, especially in PPR.

A multicenter, randomized, open-label pilot trial assessing the efficacy and safety of etanercept 50 mg twice weekly followed by etanercept 25 mg twice weekly, the combination of etanercept 25 mg twice weekly and acitretin, and acitretin alone in patients with moderate to severe psoriasis.

BACKGROUND: Etanercept, a soluble tumor necrosis factor receptor, and acitretin have been shown to be effective in treating psoriasis. Acitretin is widely used in Korea. However, the combination of etanercept plus acitretin has not been evaluated among Korean patients with psoriasis. The objective of this study was to investigate the efficacy and safety of combination therapy with etanercept and acitretin in patients with moderate to severe plaque psoriasis. METHODS: Sixty patients with psoriasis were randomized to receive etanercept 50 mg twice weekly (BIW) for 12 weeks followed by etanercept 25 mg BIW for 12 weeks (ETN-ETN); etanercept 25 mg BIW plus acitretin 10 mg twice daily (BID) for 24 weeks (ETN-ACT); or acitretin 10 mg BID for 24 weeks (ACT). The primary efficacy measurement was the proportion of patients achieving 75 % improvement in Psoriasis Area and Severity Index (PASI 75) at week 24. Secondary end points included 50 % improvement in PASI (PASI 50) at week 24 and clear/almost-clear by Physician Global Assessment (PGA) at each visit through week 24. RESULTS: The proportions of patients achieving PASI 75, PASI 50, and PGA clear/almost-clear at week 24 in the ETN-ETN (52.4, 71.4, and 52.4 %, respectively) and ETN-ACT groups (57.9, 84.2, and 52.6 %, respectively) were higher than in the ACT group (22.2, 44.4, and 16.7 %, respectively). The incidence of adverse events was similar across all arms. This was an open-label study with a small number of patients. CONCLUSION: In Korean patients with moderate to severe plaque psoriasis, etanercept alone or in combination with acitretin was more effective than acitretin. All treatments were well tolerated throughout the study. TRIAL REGISTRATION: This study was registered on July 7, 2009 at ClinicalTrials.gov, NCT00936065 .

Traditional herbal prescription LASAP-C inhibits melanin synthesis in B16F10 melanoma cells and zebrafish.

BACKGROUND: In this study, the anti-melanogenesis efficacy of clinically used herbal prescription LASAP-C, which consists of four herbal medicines-Rehmanniae Radix Crudus, Lycii Fructus, Scutellariae Radix, and Angelicae Dahuricae Radix, was investigated. METHODS: The chemical profile of LASAP-C was established by conducting ultra-performance liquid chromatography-electrospray ionization-mass spectrometry. Anti-melanogenic efficacy was evaluated by tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2 expression in B16F10 melanoma cells. In vivo evaluation was performed by using zebrafish model. RESULTS: Molecular evidences suggested that melanin synthesis was inhibited via the down-regulation of tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2 expression in B16F10 melanoma cells treated with LASAP-C. The anti-melanogenesis efficacy was also confirmed in vivo by using the zebrafish model. CONCLUSION: The results of this study provide strong evidences that LASAP-C can be used as an active component in cosmeceutical products for reducing excess pigmentation in the human skin.

Inhibitory effect of cucurbitacin B on imiquimod-induced skin inflammation.

Psoriasis is a common skin disease, of which pathogenesis involves the increase of inflammatory reaction in epidermal cells. In an attempt to find therapeutics for psoriasis, we found that cucurbitacin B has an inhibitory potential on imiquimod-induced inflammation of keratinocytes. Cucurbitacin B significantly inhibited imiquimod-induced expression of crucial psoriatic cytokines, such as IL-8 and CCL20, via down-regulation of NF-κB and STAT3 signaling pathway in human keratinocytes. In addition, keratinocyte proliferation was markedly inhibited by cucurbitacin B. The potential beneficial effect of cucurbitacin B on psoriasis was further validated in imiquimod-induced psoriasiform dermatitis of experimental animal. Topical application of cucurbitacin B resulted in significant reduction of epidermal hyperplasia and inflammatory cytokines production, and ameliorated the psoriatic symptom. Taken together, these results suggest that cucurbitacin B may be a potential candidate for the treatment of psoriasis.

Identification of a possible susceptibility locus for UVB-induced skin tanning phenotype in Korean females using genomewide association study.

A two-stage genomewide association (GWA) analysis was conducted to investigate the genetic factors influencing ultraviolet (UV)-induced skin pigmentation in Korean females after UV exposure. Previously, a GWA study evaluating ~500 000 single nucleotide polymorphisms (SNPs) in 99 Korean females identified eight SNPs that were highly associated with tanning ability. To confirm these associations, we genotyped the SNPs in an independent replication study (112 Korean females). We found that a novel SNP in the intron of the WW domain-containing oxidoreductase (WWOX) gene yielded significant replicated associations with skin tanning ability (P-value = 1.16 × 10(-4) ). To understand the functional consequences of this locus located in the non-coding region, we investigated the role of WWOX in human melanocytes using a recombinant adenovirus expressing a microRNA specific for WWOX. Inhibition of WWOX expression significantly increased the expression and activity of tyrosinase in human melanocytes. Taken together, our results suggest that genetic variants in the intronic region of WWOX could be determinants in the UV-induced tanning ability of Korean females. WWOX represents a new candidate gene to evaluate the molecular basis of the UV-induced tanning ability in individuals.

A low-fluence 1064-nm Q-switched neodymium-doped yttrium aluminium garnet laser for the treatment of café-au-lait macules.

BACKGROUND: Café-au-lait macules (CALMs) are a common pigmentary disorder. Although a variety of laser modalities have been used to treat CALMs, their efficacies vary and dyspigmentation may develop. OBJECTIVE: We evaluated the clinical efficacy and safety of a low-fluence 1064-nm Q-switched neodymium-doped yttrium aluminium garnet (Nd:YAG) laser for the treatment of CALMs. METHODS: In a preliminary investigation, 6 patients underwent a split-lesion comparative study with 532- and 1064-nm Q-switched Nd:YAG laser treatment. In total, 32 patients with 39 CALMs were enrolled in a subsequent prospective trial to evaluate the treatment with a low-fluence 1064-nm Q-switched Nd:YAG laser. RESULTS: In the preliminary study, the 1064-nm treatment group had a more favorable response and a shorter recovery time. In a subsequent prospective trial of a 1064-nm laser, 74.4% of the lesions showed a clinical response with clearance of ≥50.0%. The treatment regimen was well tolerated; 15.4% of patients experienced adverse events. LIMITATIONS: The study participants were followed for 6 months, and there were no relevant treatment controls in the prospective trial group. CONCLUSION: Low-fluence 1064-nm Q-switched Nd:YAG laser therapy afforded good clinical improvement for treating CALMs.

Inhibitory role of Id1 on TGF-ß-induced collagen expression in human dermal fibroblasts.

Inhibitor of DNA binding 1 (Id1) is a basic helix-loop-helix (bHLH) protein that has a variety of functional roles in cellular events including differentiation, cell cycle and cancer development. In addition, it has been demonstrated that Id1 is related with TGF-ß and Smad signaling in various biological conditions. In this study, we investigated the effect of Id1 on TGF-ß-induced collagen expression in human dermal fibroblasts. When Id1-b isoform was overexpressed, TGF-ß-induced collagen expression was markedly inhibited. Consistent with this result, Id1-b significantly inhibited TGF-ß-induced collagen gel contraction. In addition, Id1-b inhibited TGF-ß-induced phosphorylation of Smad2 and Smad3. Finally, immunohistochemistry showed that Id1 expression was decreased in fibrotic skin diseases while TGF-ß signaling was increased. Together, these results suggest that Id1 is an inhibitory regulator on TGF-ß-induced collagen expression in dermal fibroblasts.

Genkwadaphnin induces reactive oxygen species (ROS)-mediated apoptosis of squamous cell carcinoma (SCC) cells.

Genkwadaphnin is a daphnane diterpene ester molecule isolated from the flower buds of Daphne genkwa. In the present study, we investigated the apoptosis-inducing effect of genkwadaphnin in squamous cell carcinoma (SCC) cells. Apoptosis was triggered in SCC12 cells following genkwadaphnin treatment in a time- and concentration-dependent manner. Genkwadaphnin treatment increased phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Knockdown of JNK and p38 MAPK by recombinant adenovirus expressing microRNA (miR) resulted in significant inhibition of genkwadaphnin-induced apoptosis in SCC12 cells. Finally, pretreatment with the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) markedly reduced SCC12 cell apoptosis, concomitant with significant inhibition of MAPK activation. These results indicate that genkwadaphnin has the potential to induce apoptosis in SCC cells, providing information on which to base further research with the aim of developing a cure for SCC.

DAMP molecules S100A9 and S100A8 activated by IL-17A and house-dust mites are increased in atopic dermatitis.

S100A9 and S100A8 are called damage-associated molecular pattern (DAMP) molecules because of their pro-inflammatory properties. Few studies have evaluated S100A9 and S100A8 function as DAMP molecules in atopic dermatitis (AD). We investigated how house-dust mites affect S100A9 and S100A8 expression in Th2 cytokine- and Th17 cytokine-treated keratinocytes, and how secretion of these molecules affects keratinocyte-derived cytokines. Finally, we evaluated expression of these DAMP molecules in AD patients. S100A9 expression and S100A8 expression were strongly induced in IL-17A- and Dermatophagoides (D.) farinae-treated keratinocytes, respectively. Furthermore, co-treatment with D. farinae and IL-17A strongly increased expression of S100A9 and S100A8 compared with D. farinae-Th2 cytokine co-treatment. The IL-33 mRNA level increased in a dose-dependent manner in S100A9-treated keratinocytes, but TSLP expression did not change. S100A8/A9 levels were also higher in the lesional skin and serum of AD patients, and correlated with disease severity. Taken together, S100A9 and S100A8 may be involved in inducing DAMP-mediated inflammation in AD triggered by IL-17A and house-dust mites.

Regional difference in sebum production by androgen susceptibility in human facial skin.

Androgens are important hormones that influence sebum production from the sebaceous glands. Human facial skin can be categorized as T- and U-zones, which are areas with high and low levels of sebum secretion, respectively. This study was performed to investigate whether there are topographical differences in androgen receptor (AR) expression related to regional variations in facial sebum secretion. The results of in vivo analysis indicated a statistically significant increase in AR expression in the sebaceous gland T-zones compared with the U-zones. In vitro experiments using human primary sebocytes also yielded similar results, with higher levels of AR protein and mRNA expression in T-zones. The results of this study suggested that differences in androgen susceptibility may be an important factor influencing regional differences in sebum production in human facial skin.

Glucocorticoid receptor enhances involucrin expression of keratinocyte in a ligand-independent manner.

In this study, we investigated the role of glucocorticoid receptor (GR) in epidermal keratinocytes. In adult normal human skin, GR was highly expressed in the upper layers of the epidermis. Consistent with normal skin, GR expression was increased after calcium treatment of HaCaT keratinocytes cultured in vitro, suggesting that GR is involved in keratinocyte differentiation process. Overexpression of GR using an adenovirus showed that expression of involucrin, an early differentiation marker of keratinocytes, was markedly increased due to GR overexpression. However, treatment with dexamethasone, a GR agonist, did not increase involucrin expression. Overexpression of GR led to phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinases (ERK) in the absence of glucocorticoid, suggesting that the GR effect on involucrin expression is related to activation of intracellular signaling cascades. This idea was supported by the fact that GR-mediated involucrin induction was abolished after treatment with JNK and ERK inhibitors. In addition, GR mutants lacking the ligand-binding domain increased involucrin expression concomitantly with increase of ERK phosphorylation. Together, these results suggest that GR modulates involucrin expression of keratinocytes by regulating the intracellular signaling network in a ligand-independent manner.

Toenail onychomycosis treated with a fractional carbon-dioxide laser and topical antifungal cream.

BACKGROUND: Traditional pharmacotherapy for onychomycosis has low to moderate efficacy and may be associated with adverse reactions and medication interactions limiting its use in many patients. OBJECTIVE: We evaluated the clinical efficacy and safety of a fractional carbon-dioxide laser with topical antifungal therapy in the treatment of onychomycosis. METHODS: In all, 24 patients were treated with fractional carbon-dioxide laser therapy and a topical antifungal cream. The laser treatment consisted of 3 sessions at 4-week intervals. Efficacy was assessed based on the response rate from standardized photographs, a microscopic examination of subungual debris, and subjective evaluations. RESULTS: Among the patients, 92% showed a clinical response and 50% showed a complete response with a negative microscopic result. The factors that influenced a successful outcome were the type of onychomycosis and the thickness of the nail plate before treatment. The treatment regimen was well tolerated and there was no recurrence 3 months after the last treatment episode. LIMITATIONS: The study followed up only 24 patients and there were no relevant treatment controls. CONCLUSIONS: Fractional carbon-dioxide laser therapy, combined with a topical antifungal agent, was effective in the treatment of onychomycosis. It should be considered an alternative therapeutic option in patients for whom systemic antifungal agents are contraindicated.