An interaction between eIF4A3 and eIF3g drives the internal initiation of translation.

An RNA structure or modified RNA sequences can provide a platform for ribosome loading and internal translation initiation. The functional significance of internal translation has recently been highlighted by the discovery that a subset of circular RNAs (circRNAs) is internally translated. However, the molecular mechanisms underlying the internal initiation of translation in circRNAs remain unclear. Here, we identify eIF3g (a subunit of eIF3 complex) as a binding partner of eIF4A3, a core component of the exon-junction complex (EJC) that is deposited onto spliced mRNAs and plays multiple roles in the regulation of gene expression. The direct interaction between eIF4A3-eIF3g serves as a molecular linker between the eIF4A3 and eIF3 complex, thereby facilitating internal ribosomal entry. Protein synthesis from in vitro-synthesized circRNA demonstrates eIF4A3-driven internal translation, which relies on the eIF4A3-eIF3g interaction. Furthermore, our transcriptome-wide analysis shows that efficient polysomal association of endogenous circRNAs requires eIF4A3. Notably, a subset of endogenous circRNAs can express a full-length intact protein, such as ß-catenin, in an eIF4A3-dependent manner. Collectively, our results expand the understanding of the protein-coding potential of the human transcriptome, including circRNAs.

Phase 1/2 trials of human bone marrow-derived clonal mesenchymal stem cells for treatment of adults with moderate to severe atopic dermatitis.

BACKGROUND: Mesenchymal stem cells (MSCs) play important roles in therapeutic applications by regulating immune responses. OBJECTIVE: We investigated the safety and efficacy of allogenic human bone marrow-derived clonal MSCs (hcMSCs) in subjects with moderate to severe atopic dermatitis (AD). METHODS: The study included a phase 1 open-label trial followed by a phase 2 randomized, double-blind, placebo-controlled trial that involved 72 subjects with moderate to severe AD. RESULTS: In phase 1, intravenous administration of hcMSCs at 2 doses (1 × 106 and 5 × 105 cells/kg) was safe and well tolerated in 20 subjects. Because there was no difference between the 2 dosage groups (P = .9), it was decided to administer low-dose hcMSCs only for phase 2. In phase 2, subjects receiving 3 weekly intravenous infusions of hcMSCs at 5 × 105 cells/kg showed a higher proportion of an Eczema Area and Severity Index (EASI)-50 response at week 12 compared to the placebo group (P = .038). The differences between groups in the Dermatology Life Quality Index and pruritus numeric rating scale scores were not statistically significant. Most adverse events were mild or moderate and resolved by the end of the study period. CONCLUSIONS: The hcMSC treatment resulted in a significantly higher rate of EASI-50 at 12 weeks compared to the control group in subjects with moderate to severe AD. The safety profile of hcMSC treatment was acceptable. Further larger-scale studies are necessary to confirm these preliminary findings.

Zinc penetration through the skin barrier in atopic dermatitis and rosacea using reflectance confocal microscopy.

Atopic dermatitis (AD) is a chronic, recurrent eczematous disorder with a complex pathophysiology caused by skin barrier abnormalities. Rosacea is a common chronic immune-mediated inflammatory disorder that results in diminished skin barrier function. Reflectance confocal microscopy (RCM) is a non-invasive method for visualizing the dynamic status of epidermal and upper dermal structures. In this study, we compared skin barrier permeability among normal, AD and rosacea groups. To assess skin barrier permeability, zinc was applied to lesional skin and the RCM reflectance intensity of zinc penetration was measured. Reflectance confocal microscopy revealed that the intensity in patients with rosacea and AD was higher than that in the normal group at depths of 8-24 µm in both the face and forearm, which were considered as the stratum corneum (SC) and tight junction (TJ) level (p < 0.0001). When comparing AD and rosacea, the intensity of rosacea was higher than that of AD at a depth of 8 µm in the face (p < 0.0001). The intensity of AD was higher than that of rosacea at a depth of 24 µm (p = 0.009). This suggests that skin barrier permeability is increased in the upper epidermis of patients with AD and rosacea. On the face, patients with rosacea had more SC weakness than did those with AD, whereas patients with AD had more TJ weakness than those with rosacea.

Proposal of facial pigmentary unit and facial hyperpigmentation type for Fitzpatrick skin types II-IV.

BACKGROUND: Studies on facial hyperpigmentation across different facial units are limiting. We aimed to analyze melanin pigmentation images to observe facial pigmentary demarcation lines (FPDLs) and suggest facial hyperpigmentation types for normal individuals. MATERIALS AND METHODS: 3D facial melanin pigmentation images of 173 volunteers were obtained and analyzed for the presence of FPDLs. Pigmentation severity was assessed for each of the thirteen facial pigment units. The images were then grouped according to a pattern of hyperpigmentation to suggest three facial hyperpigmentation types-dark spot, photoaging and post-inflammatory hyperpigmentation. RESULTS: Four groups of FPDLs including a novel group I were observed. Nasal, frontal, auricular were the darkest pigmented facial pigment unit, and the anterior neck was the least pigmented. The dark spot type was the most common facial hyperpigmentation type. The photoaging type and the PIH type showed age-dependent distribution, as the photoaging type was more common among the subjects over 40s, and the PIH type was more common in younger subjects. CONCLUSION: Facial hyperpigmentation among healthy individuals with Fitzpatrick skin types II-IV is often accompanied by FPDLs and categorized into three types. Each type is modeled after the pattern of pigmentation associated with certain dermatological disorders. The practical implications of facial hyperpigmentation types can be resourceful in various fields including prevention and treatment of pigmentary disorders.

Analysis of facial vascular pattern characteristics in the Korean population.

BACKGROUND: Facial erythema is a common problem among patients visiting dermatologists. However, data on the clinical characteristics of facial erythema in healthy people are lacking. We aimed to compare and analyze the severity and pattern of facial vascularity in healthy subjects based on their age and gender. MATERIALS AND METHODS: This study included 198 Korean volunteers (126 females and 72 males) with Fitzpatrick skin types II, III, or IV. Fourteen different anatomical areas on the face were divided into facial erythema units. Each unit was scored from one (least erythematous) to five (most erythematous) according to the observed level of erythema on the red images implemented as hemoglobin content. We also evaluated the presence of facial telangiectatic macules. RESULTS: On average, the perinasal, nasal, and cheek units were the most hypervascular regions. In contrast, the degree of facial erythema was lowest in the labial (perioral), neck, and temporal regions. The average value of erythema was higher in males than in females. Additionally, the severity of erythema tended to increase with age. In both males and females, the number of telangiectatic macules increased with age. CONCLUSIONS: We analyzed the clinical characteristics of erythema in healthy subjects with Fitzpatrick skin types II, III, or IV in the Korean population. This study is expected to be used to identify the neurovascular pathogenesis of the most common regions of facial dermatosis in the future.

Pigmented contact dermatitis and hair dyes: A retrospective case-control multicentre study in Korea.

BACKGROUND: Pigmented contact dermatitis (PCD), a rare variant of non-eczematous contact dermatitis, is clinically characterized by sudden-onset brown or grey pigmentation on the face and neck. It is hypothesized to be caused by repeated contact with low levels of allergens. OBJECTIVES: This study evaluated the risk of using hair dyes in patients with PCD in Korea. METHODS: A total of 1033 PCD patients and 1366 controls from 31 university hospitals were retrospectively recruited. We collected and analysed the data from the patient group, diagnosed through typical clinical findings of PCD and the control group, which comprised age/sex-matched patients who visited the participating hospitals with pre-existing skin diseases other than current allergic disease or PCD. RESULTS: Melasma and photosensitivity were significantly more common in the control group, and a history of contact dermatitis was more common in the PCD group. There were significantly more Fitzpatrick skin type V participants in the PCD group than in the control group. There was no significant difference in sunscreen use between the groups. Using dermatologic medical history, Fitzpatrick skin type and sunscreen use as covariates, we showed that hair dye use carried a higher PCD risk (odds ratio [OR] before adjustment: 2.06, confidence interval [CI]: 1.60-2.65; OR after adjustment: 2.74, CI: 1.88-4.00). Moreover, henna users had a higher risk of PCD (OR before adjustment: 5.51, CI: 4.07-7.47; OR after adjustment: 7.02, CI: 4.59-10.74), indicating a significant increase in the risk of PCD with henna dye use. Contact dermatitis history was more prevalent in henna users than in those using other hair dyes in the PCD group (17.23% vs. 11.55%). CONCLUSION: Hair dye use is a risk factor for PCD. The risk significantly increased when henna hair dye was used by those with a history of contact dermatitis.

Nine cases of chronic hand and foot eczema treated with baricitinib.

Chronic hand and foot eczema (CHFE) is a common inflammatory disorder that generally lasts for over 3 months. If it is intractable to topical agents, systemic immunomodulators can be considered; however, they are not suitable for long-term management because of their adverse effects. Baricitinib is an oral Janus kinase inhibitor that has been approved for the treatment of moderate-to-severe atopic dermatitis. However, its effect on CHFE has rarely been described. Herein, we report nine cases of recalcitrant CHFE that were treated with baricitinib after an inadequate response to low-dose ciclosporin. All patients had more than moderate improvement within 2-8 weeks without serious adverse effects.

Serum 25-Hydroxy Vitamin D Levels and Association of Vitamin D Receptor Gene Polymorphisms in Vitiligo.

BACKGROUND: The role of vitamin D deficiency and vitamin D receptor (VDR) gene polymorphisms has been established in many autoimmune diseases, including vitiligo, but the result is still controversial. OBJECTIVES: The aim of this study was to investigate the serum vitamin D levels in vitiligo patients and to compare the association of VDR gene polymorphisms in vitiligo patients and healthy controls. METHODS: We collected the data of age, sex, serum 25-hydroxy vitamin D (25[OH]D) level, thyroid autoantibodies, disease duration, types of vitiligo, family history and the affected body surface area of vitiligo from 172 patients. And we analyzed the VDR gene polymorphisms in 130 vitiligo and 453 age-sex-matched control subjects. RESULTS: The mean serum level of 25(OH)D in 172 vitiligo patients was 18.75 ± 0.60 ng/mL, which had no significant difference with a mean serum value of 25(OH)D in the Korean population. However, there were significant differences according to the duration of the disease and family history. Also, there were no significant differences in the genotypic and allelic distributions of 37 examined SNPs of VDR gene between vitiligo patients and healthy controls. CONCLUSION: Serum level of 25(OH)D in vitiligo patients was not significantly different from the mean serum value of the Korean population. Also, there were no significant differences in the genotypic distributions of VDR gene between vitiligo patients and healthy controls.

A Phase 3, Randomized, Multi-center Clinical Trial to Evaluate the Efficacy and Safety of Neu-BoNT/A in Treatment of Primary Axillary Hyperhidrosis.

BACKGROUND: Botulinum toxin type A is widely used to treat primary axillary hyperhidrosis and has proven to be an effective and safe approach. Onabotulinumtoxin A was approved by the FDA as a treatment for primary axillary hyperhidrosis. This study aimed to evaluate the efficacy and safety of Neu-BoNT/A in subjects diagnosed with primary axillary hyperhidrosis. METHODS: The Hyperhidrosis Disease Severity Scale, gravimetric measurement of sweat, and Global Assessment Scale were analyzed at weeks 4, 8, 12, and 16 to determine the effect of treatment. Adverse events, physical examination, and vital signs were monitored. RESULTS: Subjects treated with Neu-BoNT/A showed statistically significant improvement by all 3 methods at weeks 4, 8, 12, and 16 (P value = 0.00). There were no severe adverse events or significant changes in vital signs, physical examination, or laboratory tests. CONCLUSION: Neu-BoNT/A can be effectively and safely used for primary axillary hyperhidrosis. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

A Neglected Acne Scar Type: Papular Acne Scars and Their Correlations With Keloid Scars.

BACKGROUND: Acne scarring can be divided into 2 types: atrophic and hypertrophic scars. Papular acne scars are commonly encountered, skin-colored papules on the chin and back. OBJECTIVE: This study aimed to estimate the prevalence of each acne scar type and to investigate the clinical manifestations of papular acne scars. METHODS: This retrospective study included 416 patients with acne scars. Dermatologists classified the scars into 3 types (atrophic, papular, and keloid type) based on clinical photographs and analyzed the clinical and histologic features of papular acne scars. RESULTS: Among 416 patients with acne scars, 410 patients (98.56%) had atrophic scars, 53 patients (12.74%) had keloid scars, and 46 patients (11.06%) had papular acne scars. Twenty patients (4.81%) had both papular and keloid acne scars. Histologic analysis showed fibrotic tissue in both keloid and papular acne scars. Fibrosis of the papular scar was limited to the upper dermis. CONCLUSION: Papular acne scars were significantly more prevalent in patients with keloid scars than in those without keloid scars. These results provide a basis for understanding papular acne scars, which have been under-recognized. The association between papular and keloid acne scars can suggest the decision for scar treatment.

Objective assessment of facial laxity changes after monopolar radiofrequency treatment by using moiré topography.

Radiofrequency (RF) has been widely used as a noninvasive technique for skin tightening and rejuvenation. Moiré is a type of interference pattern corresponding to the shape of the face. We aimed to objectively evaluate the effect of RF on facial skin laxity using moiré. Ten subjects participated and were treated with a monopolar RF on the face. Clinical photographs and moiré images were obtained at the baseline and after treatment. The periorbital angle from the upper third of the face, zygomatic length ratio (L1/L2), angle from the middle third, perioral perpendicular length, and angle from the lower third were analyzed. After one session of RF treatment, the mean zygomatic length ratio (L1/L2) from the middle third of the face significantly increased in the 4th week (by 49.68%, P = .047). The L1/L2 ratio increased to nearly one, which were not significant after 8 weeks. The mean perioral perpendicular length decreased to 282.25 ± 84.069 pixels (px) after 4 weeks, and to 281.38 ± 76.03 px after 24 weeks; these differences were statistically significant. The parameters of zygomatic length ratio and perioral perpendicular length extracted from illuminated moiré images can be useful for objectively assessing various facial tightening treatments in clinical settings.

Oligomers of α-ABpeptoid/ß3 -peptide hybrid.

Peptoids, oligomers of N-substituted glycines, have been attracting increasing interest due to their advantageous properties as peptidomimetics. However, due to the lack of chiral centers and amide hydrogen atoms, peptoids, in general, do not form folding structures except that they have α-chiral side chains. We have recently developed "peptoids with backbone chirality" as a new class of peptoid foldamers called α-ABpeptoids and demonstrated that they could have folding conformations owing to the methyl groups on chiral α-carbons in the backbone structure. Here we report α-ABpeptoid/ß3 -peptide oligomers as a unique peptidomimetic structure with a heterogeneous backbone. This hybrid structure contains a mixed α-ABpeptoid and ß3 -peptide residues arranged in an alternate manner. These α-ABpeptoid/ß3 -peptide oligomers could form intramolecular hydrogen bonding and have better cell permeability relative to pure peptide sequences. These oligomers were shown to adopt ordered folding structures based on circular dichroism studies. Overall, α-ABpeptoid/ß3 -peptide oligomers may represent a novel class of peptidomimetic foldamers and will find a wide range of applications in biomedical and material sciences.

Identification of a closed cutaneous injury after mechanical trauma caused by collision.

PURPOSE: Robotics has evolved rapidly in terms of mechanical design and control in the past few years. Collaborative robots that have direct contact with humans are being introduced in various fields, including industrial and medical services. Because collaborative robot systems are being introduced rapidly, the safety of the humans who work with them is becoming an important issue. In this study, we investigated skin injuries resulting from a collision between robots and humans using a freefall experiment system. METHODS: We particularly focused on closed skin injuries caused by a collision. To induce a closed injury, we struck mini-pigs with cubic-edge square and semi-sphere impactors at collision speeds of 1 and 3 m/s. We did not observe any open injuries with those conditions. Closed injuries were observed in the dermal layer of the skin after the collision test at both speeds and with both impactors. RESULTS: The collagen fiber in the dermal layer was separated and fragmented, and the subcutaneous fat layer became dense as a result of the collision. CONCLUSIONS: We closely observed and analyzed the histopathologic changes in the dermal and subcutaneous layers with intact epidermis after mechanical trauma to the inner skin layers.

Using reflectance confocal microscopy to observe in vivo melanolysis after treatment with the picosecond alexandrite laser and Q-switched Nd:YAG laser in melasma.

OBJECTIVES: Melasma is an acquired type of hyperpigmentation that is characterized by the appearance of scattered light- to dark-brown macules and patches on the face. Recently, several lasers have been proposed as treatment options for melasma. In particular, the picosecond alexandrite laser is an ideal laser for selective photothermal melanolysis. The aim of our study was to compare the effectiveness in melanolysis of a single treatment of the picosecond alexandrite laser with that of the Q-switched Nd:YAG laser using reflectance confocal microscopy imaging of the melasma lesions. MATERIALS AND METHODS: We performed a spilt-face study using the picosecond alexandrite laser and Q-switched Nd:YAG laser in eight patients with melasma. Both melasma lesions and surrounding normal skin were examined under reflectance confocal microscopy 1 and 24 hours after treatment. The melanin intensity of each skin layer was investigated. RESULTS: At baseline, melasma has irregular melanin distribution and a higher melanin density than surrounding normal skin under reflectance confocal microscopy. After a single treatment with either the picosecond alexandrite laser or the Q-switched Nd:YAG laser, both melanin-induced reflectance and melanin index decreased. CONCLUSION: Our findings suggest that it is feasible to assess the distribution of melanin by reflectance confocal microscopy and observe the melanolysis in melasma lesion after laser treatment. Lasers Surg. Med. 51:423-429, 2019. © 2018 Wiley Periodicals, Inc.

Superficial intense focused ultrasound on periorbital wrinkle.

The periorbital wrinkles are easily perceived evidence of aging, so become a major concern for many patients. Various treatments have been attempted to improve periorbital wrinkles, but the need for new treatments that are less invasive and more effective is still high. In this study, we evaluated the safety, clinical and histological effects of intense focused ultrasound using only a 1.5 mm transducer in the management of periorbital wrinkles. Ten adult Korean females were enrolled. The treatment effect and safety profile were evaluated up to 3 months after 1 session of IFUS treatment on the periorbital wrinkles. The mean subjective satisfaction score was 3.2 ± 0.79 (mean ± standard deviation) by 5- point scale. The mean objective clinical improvement score was highest in the fine wrinkle on the crow's feet area and lowest in the deep wrinkles of the infraorbital and crow's feet area. Histometrically, increase of collagen and elastic fiber density was observed in the all layers of dermis. No serious side effects occurred after the treatment. In conclusion, intense focused ultrasound treatment using a 1.5-mm transducer alone can significantly improve periocular wrinkles after a single treatment with a good safety profile.

Manifestation of atopic dermatitis-like skin in TNCB-induced NC/Nga mice is ameliorated by topical treatment of substance P, possibly through blockade of allergic inflammation.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by intense pruritus and eczematous lesion. In this study, topically applied substance P (SP) significantly alleviated AD-like clinical symptoms in 2, 4, 6-trinitrochlorobenzene (TNCB)-induced dermatitis in NC/Nga mice. This effect was nullified by pretreatment of the neurokinin-1 receptor (NK-1R) antagonist CP99994. SP treatment significantly reduced the infiltration of mast cells and CD3-positive T cells as well as inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and thymic stromal lymphopoietin (TSLP), in AD-like skin lesions and decreased the levels of IgE and thymus and activation-regulated chemokine in serum. This SP-induced alleviation of allergic inflammatory responses was also confirmed as reduced activation in the axillary lymph nodes (aLN) and spleen, suggesting the systemic effect of SP on immune responses in TNCB-induced NC/Nga mice. Furthermore, SP-mediated TSLP reduction was confirmed in human keratinocyte culture under pro-inflammatory TNF-α stimulation. Taken together, these results suggest that topically administered SP may have potential as a medication for atopic dermatitis.

Efficacy and durability of hyaluronic acid fillers for malar enhancement: A prospective, randomized, split-face clinical controlled trial.

Various hyaluronic acid fillers can be used for facial attenuation and rejuvenation. The efficacy and durability of hyaluronic acid fillers are of major concern to dermatologists and patients. This study aimed to evaluate three-dimensional morphology, tissue distribution, and changes in volume after injection of two different hyaluronic acid fillers. Ten Korean women were enrolled in this study. Each subject was injected with monophasic hyaluronic acid filler in one malar area and biphasic filler in the other. Clinical outcome was measured before and after injection, and after 2, 4, 6, 8, 12, and 24 weeks, using the Global Aesthetic Improvement Scale, photographs and Moire's topography. Facial magnetic resonance imaging (MRI) was performed twice over six months. Both products showed good results after injection and demonstrated good durability over time. MRI was a useful modality for assessing tissue distribution and volume changes. The effects and durability after injection of monophasic hyaluronic acid filler and biphasic hyaluronic acid filler are generally comparable.

Targeted Inhibition of the NCOA1/STAT6 Protein-Protein Interaction.

The complex formation between transcription factors (TFs) and coactivator proteins is required for transcriptional activity, and thus disruption of aberrantly activated TF/coactivator interactions could be an attractive therapeutic strategy. However, modulation of such protein-protein interactions (PPIs) has proven challenging. Here we report a cell-permeable, proteolytically stable, stapled helical peptide directly targeting nuclear receptor coactivator 1 (NCOA1), a coactivator required for the transcriptional activity of signal transducer and activator of transcription 6 (STAT6). We demonstrate that this stapled peptide disrupts the NCOA1/STAT6 complex, thereby repressing STAT6-mediated transcription. Furthermore, we solved the first crystal structure of a stapled peptide in complex with NCOA1. The stapled peptide therefore represents an invaluable chemical probe for understanding the precise role of the NCOA1/STAT6 interaction and an excellent starting point for the development of a novel class of therapeutic agents.