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Microtubules (MTs) are dynamic components of the cytoskeleton and play essential roles in morphogenesis and maintenance of tissue and cell integrity. Despite recent advances in understanding MT ultrastructure, organization, and growth control, how cells regulate MT organization at the cell cortex remains poorly understood. The EFA-6/EFA6 proteins are recently identified membrane-associated proteins that inhibit cortical MT dynamics. Here, combining visualization of endogenously tagged C. elegans EFA-6 with genetic screening, we uncovered tubulin-dependent regulation of EFA-6 patterning. In the mature epidermal epithelium, EFA-6 forms punctate foci in specific regions of the apical cortex, dependent on its intrinsically disordered region (IDR). We further show the EFA-6 IDR is sufficient to form biomolecular condensates in vitro. In screens for mutants with altered GFP::EFA-6 localization, we identified a novel gain-of-function (gf) mutation in an α-tubulin tba-1 that induces ectopic EFA-6 foci in multiple cell types. tba-1(gf) animals exhibit temperature-sensitive embryonic lethality, which is partially suppressed by efa-6(lf), indicating the interaction between tubulins and EFA-6 is important for normal development. TBA-1(gf) shows reduced incorporation into filamentous MTs but has otherwise mild effects on cellular MT organization. The ability of TBA-1(gf) to trigger ectopic EFA-6 foci formation requires β-tubulin TBB-2 and the chaperon EVL-20/Arl2. The tba-1(gf)-induced EFA-6 foci display slower turnover, contain the MT-associated protein TAC-1/TACC, and require the EFA-6 MTED. Our results reveal a novel crosstalk between cellular tubulins and cortical MT regulators in vivo.

IL-17C is an epithelial cell-derived proinflammatory cytokine whose transcriptional regulation remains unclear. Analysis of the IL17C promoter region identified TCF4 as putative regulator, and siRNA knockdown of TCF4 in human keratinocytes (KCs) increased IL17C. IL-17C stimulation of KCs (along with IL-17A and TNF-α stimulation) decreased TCF4 and increased NFKBIZ and ZC3H12A expression in an IL-17RA/RE-dependent manner, thus creating a feedback loop. ZC3H12A (MCPIP1/Regnase-1), a transcriptional immune-response regulator, also increased following TCF4 siRNA knockdown, and siRNA knockdown of ZC3H12A decreased NFKBIZ, IL1B, IL36G, CCL20, and CXCL1, revealing a proinflammatory role for ZC3H12A. Examination of lesional skin from the KC-Tie2 inflammatory dermatitis mouse model identified decreases in TCF4 protein concomitant with increases in IL-17C and Zc3h12a that reversed following the genetic elimination of Il17c, Il17ra, and Il17re and improvement in the skin phenotype. Conversely, interference with Tcf4 in KC-Tie2 mouse skin increased Il17c and exacerbated the inflammatory skin phenotype. Together, these findings identify a role for TCF4 in the negative regulation of IL-17C, which, alone and with TNF-α and IL-17A, feed back to decrease TCF4 in an IL-17RA/RE-dependent manner. This loop is further amplified by IL-17C-TCF4 autocrine regulation of ZC3H12A and IL-17C regulation of NFKBIZ to promote self-sustaining skin inflammation.

Tik Tok is an emerging social media platform that provides a novel opportunity for health practitioners such as dermatologists to disseminate accurate health information.

Single‐cell RNA sequencing and spatial transcriptomics enable unprecedented insight into cellular and molecular pathways implicated in human skin aging and regeneration. Senescent cells are individual cells that are irreversibly cell cycle arrested and can accumulate across the human lifespan due to cell‐intrinsic and ‐extrinsic stressors. With an atlas of single‐cell RNA‐sequencing and spatial transcriptomics, epidermal and dermal senescence and its effects were investigated, with a focus on melanocytes and fibroblasts. Photoaging due to ultraviolet light exposure was associated with higher burdens of senescent cells, a sign of biological aging, compared to chronological aging. A skin‐specific cellular senescence gene set, termed SenSkin™, was curated and confirmed to be elevated in the context of photoaging, chronological aging, and non‐replicating CDKN1A+ (p21) cells. In the epidermis, senescent melanocytes were associated with elevated melanin synthesis, suggesting haphazard pigmentation, while in the dermis, senescent reticular dermal fibroblasts were associated with decreased collagen and elastic fiber synthesis. Spatial analysis revealed the tendency for senescent cells to cluster, particularly in photoaged skin. This work proposes a strategy for characterizing age‐related skin dysfunction through the lens of cellular senescence and suggests a role for senescent epidermal cells (i.e., melanocytes) and senescent dermal cells (i.e., reticular dermal fibroblasts) in age‐related skin sequelae. [ABSTRACT FROM AUTHOR]

Persistent inflammation, characterized by the intense interplay of inflammatory chemokine secretion and immune cell infiltration, is a hallmark of many skin disorders including diabetic wounds and psoriasis with inadequate therapeutic interventions. Monocyte chemotactic protein‐1 (MCP‐1) is an inflammatory chemokine that plays a key role in recruiting and polarizing monocytes into pro‐inflammatory macrophages to establish a vicious cycle that worsens the inflamed tissue microenvironment. Here, the sponge‐like microneedles (HPMN) technology is described to alleviate inflammatory skin disorders. Heparin/4‐arm PEG‐NH2 network crosslinked onto microneedle surface spatially attracted and sequestered multiple inflammatory chemokines including MCP‐1. Enrichment of MCP‐1 on microneedles recruits and traps inflammatory monocytes within the porous structure of microneedles. Subsequent removal of microneedles not only depletes inflammatory chemokine, MCP‐1, but also its cellular source. As a result, HPMN treatment facilitates 47.1% smaller open wound area in mice and 27.2% shorter wound length in pigs. To demonstrate the versatility of the HPMN technology, it is also shown that combining the method with standard‐of‐care immunosuppressants reduces 45.1% epidermis thickening and attenuated immune cell influx in a mouse psoriasis model. Overall, the HPMN technology is a novel demonstration of employing inflammatory chemokine and cell extraction to treat a broad range of inflammatory skin disorders. [ABSTRACT FROM AUTHOR]

Neurons are highly polarized cells with dendrites and axons. Dendrites, which receive sensory information or input from other neurons, often display elaborately branched morphologies. While mechanisms that promote dendrite branching have been widely studied, less is known about the mechanisms that restrict branching. Using the nematode Caenorhabditis elegans , we identify rabr-1 (for Rab - related gene 1) as a factor that restricts branching of the elaborately branched dendritic trees of PVD and FLP somatosensory neurons. Animals mutant for rabr-1 show excessively branched dendrites throughout development and into adulthood in areas where the dendrites overlay epidermal tissues. Phylogenetic analyses show that RABR-1 displays similarity to small GTPases of the Rab - type, although based on sequence alone, no clear vertebrate ortholog of RABR-1 can be identified. We find that rabr-1 is expressed and can function in epidermal tissues, suggesting that rabr-1 restricts dendritic branching cell-nonautonomously. Genetic experiments further indicate that for the formation of ectopic branches rabr-1 mutants require the genes of the Menorin pathway, which have been previously shown to mediate dendrite morphogenesis of somatosensory neurons. A translational reporter for RABR-1 reveals a subcellular localization to punctate, perinuclear structures, which correlates with endosomal and autophagosomal markers, but anticorrelates with lysosomal markers suggesting an amphisomal character. Point mutations in rabr-1 analogous to key residues of small GTPases suggest that rabr-1 functions in a GTP-bound form independently of GTPase activity. Taken together, rabr-1 encodes for an atypical small GTPase of the Rab - type that cell-nonautonomously restricts dendritic branching of somatosensory neurons, likely independently of GTPase activity. [ABSTRACT FROM AUTHOR]

Background: Conspicuous facial pores are benign but represent a cosmetic concern for men and women. Recent works described dermal and epidermal impairments as clinical causes of enlarged pores. Morphological modifications of skin at the site of pores were associated with collagen density loss, possible alteration of extracellular matrix and abnormal differentiation of keratinocytes. Aims: A composition containing mannose‐6‐phosphate (Active Complex) was designed to address these different aspects of pore enlargement. In vitro and ex vivo evaluations were conducted in different models mimicking disturbance of dermal and epidermal functions. The pore refining activity of Active Complex was assessed in two clinical trials studying a Caucasian women cohort and an Asian men cohort. Results: At the dermal level, Active Complex upregulated collagen I and decorin synthesis, and genes encoding collagens I, III, V, VII, XVII; suggesting its ability to favor collagen fiber organization and anchorage. The downregulation of matrix metalloprotease, involved in extracellular matrix degradation, reinforced the protective effect of Active Complex in the dermis. Active Complex down modulated differentiation markers in keratinocytes as well as genes involved in cell renewal. Study of reconstructed human epidermis modeling keratinocyte hyperproliferation revealed that Active Complex mitigated two markers of this state: number of nuclei in the stratum corneum and involucrin expression. Clinical trials confirmed the pore refining activity of Active Complex on men and women of different ages and ethnicities; −24% total skin pore area after 56 days of application on women, and −30.2% on men after 7 days. Conclusions: This work demonstrates the interest to target dermal and epidermal modifications described in conspicuous pore area, especially dermis fiber organization, to address this cosmetic concern. [ABSTRACT FROM AUTHOR]

The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. Pododermatitis aseptica hemorrhagica circumscripta is associated with metalloproteinase 2 weakening of distal phalangeal suspensory structures and sinkage of the distal phalanx in the claw capsule. Pressure from the tuberculum flexorium on the sole epidermis and dermis produces hemorrhagic tissue injury and defective horn production appearing as yellow-red, softened claw horn in region 4 of the sole. A model of the MAPK/ERK signal cascade orchestrating epidermal-dermal homeostasis was employed to determine if sterile inflammatory responses are linked to disturbed signal transduction for epidermal homeostasis in sole epidermis and dermis. The objective was to assess shifts in target genes of inflammation, up- and downstream MAPK/ERK signal elements, and targeted genes supporting epidermal proliferation and differentiation. Sole epidermis and dermis were removed from lateral claws bearing lesions of PAHC, medial claws from the same limb and lateral claws from completely normal limbs of multiparous, lactating Holstein cows. The abundance levels of targeted transcripts were evaluated by real-time PCR. Lesion effects were assessed by ANOVA, and mean comparisons were performed with t -tests to assess variations between mean expression in ulcer-bearing or medial claw dermis and epidermis and completely normal lateral claw dermis and epidermis or between ulcer-bearing dermis and epidermis and medial claw dermis and epidermis. The lesions were sterile and showed losses across multiple growth factors, their receptors, several downstream AP1 transcription components, CMYC, multiple cell-cycle and terminal differentiation elements conducted by MAPK/ERK signals and β 4, α 6, and collagen 17A hemidesmosome components. These losses coincided with increased cytokeratin 6, β 1 integrin, proinflammatory metalloproteinases 2 and 9, IL1B and physiologic inhibitors of IL1B, the decoy receptor, and receptor antagonist. Medial claw epidermis and dermis from limbs with lateral claws bearing PAHC showed reductions in upstream MAPK/ERK signal elements and downstream targets that paralleled those in hemorrhagic lesions. Inhibitors of IL1B increased in the absence of real increases in inflammatory targets in the medial claw dermis and epidermis. Losses across multiple signal path elements and downstream targets were associated with negative effects on targeted transcripts supporting claw horn production and wound repair across lesion-bearing lateral claws and lesion-free medial claw dermis and epidermis. It was unclear if the sterile inflammation was causative or a consequence of these perturbations. [ABSTRACT FROM AUTHOR]

Vitiligo is an autoimmune disorder characterized by epidermal melanocyte damage, with the typical clinical manifestation of white patches of skin. Keratinocytes, which work in concert with melanocytes to maintain the structural and functional integrity of the skin, are implicated in the progression of vitiligo. Recent studies have reported abnormal keratinocyte proliferation and epidermal thickening in some patients with vitiligo; however, the relationship between these changes and the clinical characteristics of vitiligo remains unclear. We assessed the changes in epidermal thickness in patients with vitiligo and their correlation with clinical characteristics. Compared to the non-lesional skins, the stratum corneum, viable epidermis, and full epidermis in the lesional skins were all significantly thicker. The thickness of the stratum corneum in the head, neck, and trunk was greatly lower than that in the extremities. The thickness of the stratum corneum in the sun-exposed area was higher than that in the sun-protected area, whereas the thickness of the viable epidermis decreased. In conclusion, our study found that the epidermis in the lesional skins of patients with vitiligo was significantly thickened, especially in the sun-exposed areas and extremities. [ABSTRACT FROM AUTHOR]

Tardigrades possess the ability to enter an almost completely dehydrated state, anhydrobiosis. The CAHS (cytosolic abundant heat‐soluble) protein family has been identified as one of the anhydrobiosis‐related proteins. In particular, CAHS3 protein from an anhydrobiotic tardigrade, Ramazzottius varieornatus, shows heat‐solubility and reversible condensation and is one of the most highly expressed among the CAHS paralogs. A recently developed tardigrade‐specific vector showed tissue‐specific expression of RvCAHS3 most pronounced in the epidermis in vivo, contrary to the idea that anhydrobiotic genes are uniformly expressed in all tardigrade cells. In this study, we investigated the regulation of RvCAHS3 gene expression through in vivo expression experiments using tardigrade vectors with a series of truncated upstream regions coupled with in silico analysis to identify the anhydrobiosis‐related genes that are expressed under the same regulatory system as RvCAHS3. As a result, the 300–350 bp region upstream of RvCAHS3 is critical for regulating gene expression in tardigrade vector experiments, and three motifs conserved between two species of anhydrobiotic tardigrades were identified within a 500 bp region directly upstream of RvCAHS3 start codon. These motifs, which have also been identified upstream of other CAHS genes, could be associated with the regulatory system of anhydrobiosis‐related genes in tardigrades. [ABSTRACT FROM AUTHOR]

Background: Epidermal remodeling and hypertrophy are hallmarks of skin fibrotic disorders, and keratinocyte to mesenchymal (EMT)-like transformations drive epidermis alteration in skin fibrosis such as keloids and hypertrophic scars (HTS). While phosphodiesterase 4 (PDE4) inhibitors have shown effectiveness in various fibrotic disorders, their role in skin fibrosis is not fully understood. This study aimed to explore the specific role of PDE4B in epidermal remodeling and hypertrophy seen in skin fibrosis. Methods: In vitro experiments examined the effects of inhibiting PDE4A-D (with Roflumilast) or PDE4B (with siRNA) on TGFβ1-induced EMT differentiation and dedifferentiation in human 3D epidermis. In vivo studies investigated the impact of PDE4 inhibition on HOCl-induced skin fibrosis and epidermal hypertrophy in mice, employing both preventive and therapeutic approaches. Results: The study found increased levels of PDE4B (mRNA, protein) in keloids > HTS compared to healthy epidermis, as well as in TGFβ-stimulated 3D epidermis. Keloids and HTS epidermis exhibited elevated levels of collagen Iα1, fibronectin, αSMA, N-cadherin, and NOX4 mRNA, along with decreased levels of E-cadherin and ZO-1, confirming an EMT process. Inhibition of both PDE4A-D and PDE4B prevented TGFβ1-induced Smad3 and ERK1/2 phosphorylation and mesenchymal differentiation in vitro. PDE4A-D inhibition also promoted mesenchymal dedifferentiation and reduced TGFβ1-induced ROS and keratinocyte senescence by rescuing PPM1A, a Smad3 phosphatase. In vivo, PDE4 inhibition mitigated HOCl-induced epidermal hypertrophy in mice in both preventive and therapeutic settings. Conclusions: Overall, the study supports the potential of PDE4 inhibitors, particularly PDE4B, in treating skin fibrosis, including keloids and HTS, shedding light on their functional role in this condition. [ABSTRACT FROM AUTHOR]

Introduction With similar prevalence to injuries from fires, stings, and natural disasters, soft tissue injuries may occur from fireworks, industrial accidents, or other explosives. Surgeons are less familiar with treating high-velocity penetration from small debris, which may increase the chance of infection and subsequent fatality. Penetration risk curves have been developed to predict V50, the velocity with 50% probability of penetration, for various sized projectiles. However, there has been limited research using nonmetallic materials to achieve lower density projectiles less than 1 g cm−2, such as sand or rocks. Material and Methods To emulate the size and density of these energized particles, 14 ball bearings of stainless steel, silicon nitride, or Delrin acetal plastic ranging from 1.59 mm (1/16") to 9.53 mm (3/8") with sectional densities between 0.3 g cm−2 and 5  g cm−2 were launched toward porcine legs at a range of velocities to determine the penetration thresholds. High-speed videography was captured laterally at 40 kHz and impact velocity was captured using a physics-based tracking software. A generalized linear model with repeated measures and a logit link function was used to predict probability of penetration for each projectile. A total of 600 impacts were conducted to achieve at least 15 penetrating impacts for each projectile over a range of velocities. Results Higher impact velocities were required to penetrate the skin as sectional density of the projectile decreased, and the relationship between velocity and sectional density exhibited an exponential relationship (V 50, |$ = 184.6*S{D^{ - 0.385}}$|⁠ , R 2 = 0.95) with substantial change for nonlinearity in sectional densities ranging from 0.3 g cm−2 to 1  g cm−2. Compared to previous studies, the empirical relationship was consistent in the linear region (2-5  g cm−2), and novel experimentation filled in the gaps for sectional densities less than 1  g cm−2, which expressed more nonlinearity than previously estimated. For low-density projectiles with diameters of 1.59 (1/16") or 3.18 (1/8"), 32 impacts were lodged into the epidermis but did not penetrate through the dermis; however, penetration was defined as displacement into or through the dermis. Conclusions These experimental results may be used to develop and validate finite element simulations of low-density projectile impacts to address complex, multivariate loading conditions for the development of protective clothing to reduce wounding and subsequent infection rates. [ABSTRACT FROM AUTHOR]

Chronic skin wounds are estimated to affect 6.5 million patients in the US, at a cost of over USD 25 billion. Efforts to prevent and/or treat such wounds will result in reduced morbidity and economic losses. This project is focused on the role of vitamin D signaling in the epidermis in the control of stem cell (SC) activation and function during the initial response to the wounding of the skin, a response that, if defective, contributes to poor wound healing or cancer. In this review, I first describe the anatomy of the skin, focusing first on the epidermis, describing the different cell layers which in a spatial way also represent the differentiation process of the interfollicular epidermis (IFE) as it undergoes continuous regeneration. I then describe the other components of the skin, particularly the hair follicle (HF), which undergoes a cyclic pattern of regeneration. Adult SCs residing in these regenerative tissues play essential roles in the maintenance of these tissues. However, when the skin is wounded, the progeny of SCs from all regions of the HF and IFE contribute to the healing process by changing their initial cell fate to take on an epithelial genotype/phenotype to heal the wound. Although earlier lineage tracing studies helped to define the contributions SCs from the different niches made to wound healing, scRNAseq studies have demonstrated a considerably more nuanced picture. The role of vitamin D signaling will be introduced by reviewing the unique role played by the epidermal keratinocyte first in producing vitamin D and then in metabolizing it into its active form 1,25(OH)2D. 1,25(OH)2D is the principal ligand for the vitamin D receptor (VDR), a transcription factor that helps to mediate the genomic changes in the stem cells in their response to wounding. In these actions, the VDR is regulated by coregulators, of which the steroid receptor coactivator complexes SRC 2 and 3 and the mediator complex (MED) play essential roles. The VDR generally acts in association with other transcription factors such as p63 and β-catenin that can colocalize with the VDR in the genes it regulates. Although much remains to be understood, the role of the VDR in the stem cell response to wounding is clearly essential and quite different from its classic roles in regulating calcium metabolism, although calcium is essential for the actions of vitamin D signaling in the skin. [ABSTRACT FROM AUTHOR]

The epidermal differentiation complex (EDC) is a cluster of genes that code for protein components of cornified cells on the skin surface of amniotes. Squamates are the most species-rich clade of reptiles with skin adaptations to many different environments. As the genetic regulation of the skin epidermis and its evolution has been characterized for only a few species so far, we aimed to determine the organization of the EDC in a model species of squamates, the common wall lizard (Podarcis muralis). By comparative genomics, we identified EDC genes of the wall lizard and compared them with homologs in other amniotes. We found that the EDC of the wall lizard has undergone a major rearrangement leading to a unique order of three ancestral EDC segments. Several subfamilies of EDC genes, such as those encoding epidermal differentiation proteins containing PCCC motifs (EDPCCC) and loricrins, have expanded by gene duplications. Most of the EDPCCC proteins have cysteine contents higher than 50%, whereas glycine constitutes more than 50% of the amino acid residues of loricrin 1. The extremely biased amino acid compositions indicate unique structural properties of these EDC proteins. This study demonstrates that cornification proteins of the common wall lizard differ from homologous proteins of other reptiles, illustrating the evolutionary dynamics of diversifying evolution in squamates. [ABSTRACT FROM AUTHOR]

Background: The emergence of horizontal neck wrinkles is increasingly becoming a focal point for both cosmetic professionals and clients. Various treatment approaches must be considered to address this issue effectively, owing to its diverse underlying causes. The study explores the potential of utilizing the Endolift laser in conjunction with nanofat injection as a viable treatment option. Methods: Twenty patients with horizontal neck wrinkles involved in the study. Ten patients underwent treatment with a combination of Endolift laser and nanofat injection and 10 patients treated with nanofat injection alone. The participants were monitored for 6 months post‐treatment. Biometric measurements were utilized to assess outcomes, including changes in volume, depth, and area of the wrinkles, skin elasticity, as well as the diameter and density of the epidermis and dermis in the treated area. Skin improvement was evaluated by two independent dermatologists, who compared before and after photos in a blinded manner. Patient satisfaction levels were also documented. Results: The Visioface analysis showed a notable decrease in neck wrinkle depth and area in both groups. However, the group receiving the combination treatment of Endolift laser and nanofat exhibited a significantly greater improvement compared to the group treated with nanofat alone. Skin ultrasonography results demonstrated an increase in thickness and density of the dermis and epidermis in both groups. Particularly, the group treated with Endolift laser‐nanofat displayed significant enhancements in dermis and epidermis density and thickness when contrasted with the nanofat‐only group. Analysis with Cutometer revealed a marked enhancement in skin elasticity in the Endolift‐nanofat treated group in comparison to the nanofat‐only treated group. Furthermore, in the Endolift‐nanofat treated group, a substantial majority (90%) of patients exhibited improvement. Patient evaluations highlighted significant distinctions between the two groups, with 95% of patients in the Endolift‐nanofat treated group demonstrating enhancement. Conclusion: Both methods notably enhance horizontal neck wrinkles; nevertheless, the combination of endolift laser and nanofat seems to be more efficient for treating horizontal neck wrinkles. [ABSTRACT FROM AUTHOR]

Background: Bipolar microneedling radiofrequency (RF) treatment generates different patterns of thermal reactions, depending on the skin impedance and RF treatment parameters, including the frequency, power, conduction time, settings of sub‐pulse packs, and penetrating depth and type of microneedles used. We compared the effect of sequential delivery of 1‐ and 2‐MHz bipolar RF energy to in vivo minipig skin on thermal tissue reaction. Methods: RF treatments at frequencies of 1 and 2 MHz were sequentially delivered to minipigs' skin in vivo. A histological study was performed to analyze RF‐induced skin reactions at 1‐h and at 3‐, 7‐, and 14‐days post‐treatment. Results: The skin specimens demonstrated that the two different frequencies of RF treatment generated mixed patterns of the peri‐electrode coagulative necrosis (PECN) according to the experimental settings and tissue impedance. In the PECN zone, the tissue coagulation induced by the first RF treatment was surrounded by the effect of the later RF treatment at the other RF frequency. In the inter‐electrode non‐necrotic thermal reaction zone, the effect of the latter RF treatment was widespread and deep through the dermis, which had received RF treatment at the other frequency first. The delivery of pulsed‐type RF energy at sub‐pulse packs of 6 or 10 provided effective RF delivery over long conduction time without excessive thermal damage of the epidermis. Nonetheless, by sequential delivery of two different RF frequencies, RF‐induced tissue reactions were found to be markedly enhanced. Conclusion: The sequential delivery of 1‐ and 2‐MHz RF energy induces novel histological patterns of tissue reactions, which can synergistically enhance the thermostimulatory effects of each RF setting. Moreover, variations in patterns of tissue reactions can be generated by regulating the order of frequencies and the number of sub‐pulse packs of RF used. [ABSTRACT FROM AUTHOR]

Objective: This study explores the application of Line‐field Confocal Optical Coherence Tomography (LC‐OCT) imaging coupled with artificial intelligence (AI)‐based algorithms to investigate atopic dermatitis (AD), a common inflammatory dermatosis. Materials and methods: AD acute and chronic lesions (ADL) were compared to clinically healthy‐looking skin (ADNL). LC‐OCT was used noninvasively and in real‐time to image the skin of AD patients during flare‐ups and monitor remissions under topical steroid treatment for 2 weeks. Quantitative parameters were extracted from the images, including morphological and cellular‐level markers of epidermal architecture. A novel cellular‐level parameter, nuclei "atypia," which quantifies the orderliness of epidermal renewal, was used to highlight abnormal maturation processes. Results: Compared to healthy skin, AD lesions exhibited significant increases in both epidermal and stratum corneum (SC) thickness, along with a more undulated dermo‐epidermal junction (DEJ). Additionally, keratinocyte nuclei (KN) were larger, less compact, and less organized in lesional areas, as indicated by the atypia parameter. A higher degree of atypia was observed in chronic lesions compared to acute ones. Following treatment, all the parameters normalized to levels observed in healthy skin within 2 weeks, mirroring clinical improvements. Conclusion: This study provides insights into the quantification of epidermal renewal using a noninvasive imaging technique, highlighting differences between ADL/ADNL and acute/chronic lesions. It also presents the AD treatment mechanism, paving the way for future investigations on AD and other skin barrier function‐related conditions. [ABSTRACT FROM AUTHOR]

Local gene therapies, including in vivo genome editing, are highly anticipated for the treatment of genetic diseases in skin, especially the epidermis. While the adeno-associated virus (AAV) is a potent vector for in vivo gene delivery, the lack of efficient gene delivery methods has limited its clinical applications. To optimize the AAV gene delivery system with higher gene delivery efficiency and specificity for epidermis and keratinocytes (KCs), using AAV capsid and promoter engineering technologies. AAV variants with mutations in residues reported to be critical to determine the tropism of AAV2 for KCs were generated by site-directed mutagenesis of AAVDJ. The infection efficiency and specificity for KCs of these variants were compared with those of previously reported AAVs considered to be suitable for gene delivery to KCs in vitro and in vivo. Additionally, we generated an epidermis-specific promoter using the most recent short-core promoter and compared its specificity with existing promoters. A novel AAVDJ variant capsid termed AAVDJK2 was superior to the existing AAVs in terms of gene transduction efficiency and specificity for epidermis and KCs in vitro and in vivo. A novel tissue-specific promoter, termed the K14 SCP3 promoter, was superior to the existing promoters in terms of gene transduction efficiency and specificity for KCs. The combination of the AAVDJK2 capsid and K14 SCP3 promoter improves gene delivery to epidermis in vivo and KCs in vitro. The novel AAV system may benefit experimental research and development of new epidermis-targeted gene therapies. • A novel AAV capsid termed AAVDJK2 was developed and was superior to existing AAVs in terms of gene transduction efficiency and specificity for keratinocytes in vitro and in vivo. • A novel tissue-specific promotor termed K14 SCP3 promotor was developed and was superior to existing promoters in terms of gene transduction efficiency and specificity for keratinocytes in vitro and in vivo. • The novel AAV system benefits experimental research and development of new epidermis-targeted gene therapies. [ABSTRACT FROM AUTHOR]

The elongation of Caenorhabditis elegans embryos allows examination of mechanical interactions between adjacent tissues. Muscle contractions during late elongation induce the remodeling of epidermal circumferential actin filaments through mechanotransduction. Force inputs from the muscles deform circumferential epidermal actin filament, which causes them to be severed, eventually reformed, and shortened. This squeezing force drives embryonic elongation. We investigated the possible role of the nonmuscle myosins NMY-1 and NMY-2 in this process using nmy-1 and nmy-2 thermosensitive alleles. Our findings show these myosins act redundantly in late elongation, since double nmy-2(ts); nmy-1(ts) mutants immediately stop elongation when raised to 25°C. Their inactivation does not reduce muscle activity, as measured from epidermis deformation, suggesting that they are directly involved in the multistep process of epidermal remodeling. Furthermore, NMY-1 and NMY-2 inactivation is reversible when embryos are kept at the nonpermissive temperature for a few hours. However, after longer exposure to 25°C double mutant embryos fail to resume elongation, presumably because NMY-1 was seen to form protein aggregates. We propose that the two C. elegans nonmuscle myosin II act during actin remodeling either to bring severed ends or hold them. [ABSTRACT FROM AUTHOR]

Background Early studies showed promise of combined anti-epidermal growth factor receptor (EGFR) plus anti–vascular endothelial growth factor (VEGF) antibodies for advanced colorectal cancer (CRC), yet this was later rejected as toxic and ineffective in studies not selected for RAS status. We studied advanced KRAS wild-type CRC, as second-line treatment, using irinotecan-cetuximab with or without the anti-VEGF receptor antibody ramucirumab. Methods Patients with 1 prior regimen including fluoropyrimidine, oxaliplatin, and bevacizumab, with KRAS wild-type tumors were stratified by Eastern Cooperative Oncology Group Performance Score, time since last chemotherapy, and progression on oxaliplatin to irinotecan-cetuximab (IC) (180 mg/m2 and 500 mg/m2 every 2 weeks) vs modified ICR (irinotecan-cetuximab with ramucirumab 150 mg/m2 and 400 mg/m2 plus 6 mg/kg, respectively). A total of 102 patients were compared for progression-free survival (PFS) as primary endpoint (85% power for 70% improvement in median PFS from 4.5 to 7.65 months). Results Of the 102 enrolled, 44 treated with irinotecan-cetuximab and 45 with modified ramucirumab were evaluable. Median PFS was 6.0 months vs 9.2 months, respectively (hazard ratio = 0.75, P = .07; statistically significant by study design for P  < .128). Response rate was 23% vs 36% (P = .27), and disease-control rate was 52% vs 73% (P  = .05). Grade 3 or higher toxicity was equivalent. Overall survival was not significantly different at approximately 19 months. Conclusion Previous phase 3 trials without RAS genotyping rejected combining anti-epidermal growth factor receptor and anti-VEGF drugs. In this randomized multicenter phase 2 study for KRAS wild-type CRC (all previously bevacizumab treated), the addition of ramucirumab to irinotecan and cetuximab improved PFS and disease control rate, showing the combination is feasible and effective. Further, phase 3 trials with appropriate patient-selection are required. (NCT01079780) [ABSTRACT FROM AUTHOR]

Aims: To develop a standardised, automated protocol for detecting protein gene product 9.5 (PGP9.5) positive intra‐epidermal nerve fibres (IENFs) in skin biopsies, transitioning from the established manual technique to an automated platform. This automated method, although currently intended for research applications, may improve the accessibility of this diagnostic test for small fibre neuropathy in clinical settings. Methods: Skin biopsies (n = 274) from 100 participants (fibromyalgia syndrome n = 62; idiopathic small fibre neuropathy: n = 16; healthy volunteers: n = 22) were processed using an automated immunohistochemistry platform. IENF quantification was performed by blinded examiners, with reliability assessed via a two‐way mixed‐effects model to evaluate inter‐ and intra‐observer variability. Results: The automated staining system reproduced intra‐epidermal nerve fibre density (IENFD) counts consistent with free‐floating sections (mean ± standard deviation: free‐floating: 5.6 ± 3.4 fibres/mm; automated: 5.9 ± 3.2 fibres/mm). A median difference of 0.3 with a lower bound 95% Confidence Interval (CI) at −0.00005 established non‐inferiority against a margin of −0.4 (p =.08). Specifically, the inter‐class correlation coefficient (class denotes consistency in measured observations) was 99% (95% CI: 0.9–1), indicating excellent agreement between free‐floating and automated methods. The inter‐ and intra‐class coefficient between examiners were both 99% (95% CI: 0.9–0.1) for IENFD, demonstrating high reliability using sections stained using the automated method. Interpretation: Automated immunohistochemistry provides high‐throughput reliable and reproducible intra‐epidermal nerve fibre quantification. This method, although currently proof‐of‐concept, for research use only, may be more widely deployed in histopathology laboratories to increase the adoption of IENFD assessment for the diagnosis of peripheral neuropathies. [ABSTRACT FROM AUTHOR]

The ultrastructure of the leaf epidermis and the localization and content of silicon in epidermal cells of the psammophyte Alyssum desertorum Stapf (Brassicaceae) were investigated using electron microscopy and laser confocal microscopy. The study aimed to examine the effect of flooding on the epidermal structure of the leaves, study the presence, localization, and content of silicon in the epidermal cells and determine whether changes in soil moisture affect the silicon content in the leaf epidermis. Silicon inclusions were observed in trichomes and typical epidermal cells on both leaf surfaces, with varying content depending on the cell type, leaf surface, and conditions growth. Soil flooding was found to influence the leaf epidermis ultrastructure and the silicon content in the epidermal cells of A. desertorum. Trichomes and pavement cells were identified as the main accumulators of silicon inclusions and wax-like structures. These findings suggest that changes in leaf microstructure and silicon content contribute to the normal functioning of psammophyte plants and can be considered signs of plant phenotypic plasticity and adaptive markers depending on water supply conditions. [ABSTRACT FROM AUTHOR]

Haematomas of the lower limb are traumatic wounds that can have serious and often debilitating consequences; especially in the aged. Wound healing may be protracted due to multiple factors including disruptive consumer behaviours from poor cognition from dementia. This case study describes the management of an elderly consumer with dementia in a nursing home who sustained an extensive haematoma that resulted in a complex wound. Wound management was provided under local restrictions imposed by COVID-19. The importance of using holistic wound assessment frameworks and evidence-based approaches to wound management to achieve positive wound healing outcomes are emphasised. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) is the largest organelle in terms of membrane content, occupying the entire cytoplasmic volume. It is tethered to the cell cortex through ER‐plasma membrane contact sites (EPCS). Previous studies have shown that EPCSs labelled by VAP27 align with cortical microtubules, and that ER tubules elongate along microtubules. Here, we addressed the question whether this relationship is bidirectional, with EPCSs influencing microtubule organisation. Using TIRF microscopy to track EPCSs and microtubule dynamics simultaneously, we demonstrate that while EPCSs remain stable, microtubules are highly dynamic and can adjust their positioning based on nearby EPCS in Arabidopsis cotyledon epidermis. In lobes of epidermal cells enclosed by two indentations, where microtubules bundle together, EPCSs flank the bundles and exhibit a distinctive arrangement, forming symmetric arcs in relation to the lobe axis. In guard cells, transversely oriented ER tubules co‐align with microtubules. Disrupting microtubules with the drug oryzalin leads to transient guard cells‐ER remodelling, followed by its reorganisation into transverse tubules before microtubule recovery. Taken together our observations suggest, that the positioning of EPCSs and cortical microtubules, can affect each other and the organisation of cortical ER. [ABSTRACT FROM AUTHOR]

Photoallergic contact dermatitis is a skin disease caused by combined exposure to photoreactive chemicals and sunlight. Exposure to allergens and the risk of skin sensitization is an essential regulatory issue within the industry. Yet, only few non‐validated assays for photoallergy assessment exist as the pathogenesis is not fully deciphered. Improving such assays and/or developing new ones require an understanding of the chemical mechanisms involved. The first key event in the photosensitization process, namely chemical binding of the photoallergen to endogenous proteins, is thought to proceed via photo‐mediated radicals arising from the photoallergen. Moreover, the mechanism of action of these radicals if formed in the epidermis is not known and far from being unraveled. We present here an original proof‐of‐concept methodology to probe radical generation from allergens in contact with photoexposed skin, using electron paramagnetic resonance and spin trapping in a reconstructed human epidermis model mimicking real‐life exposure scenarios. [ABSTRACT FROM AUTHOR]

Tremendous popularity is observed for multifunctional flexible electronics with appealing applications in intelligent electronic skins, human–machine interfaces, and healthcare sensing. However, the reported sensing electronics, mostly can hardly provide ultrasensitive sensing sensitivity, wider sensing range, and robust cycling stability simultaneously, and are limited of efficient heat conduction out from the contacted skin interface after wearing flexible electronics on human skin to satisfy thermal comfort of human skin. Inspired from the ultrasensitive tactile perception microstructure (epidermis/spinosum/signal transmission) of human skin, a flexible comfortably wearable ultrasensitive electronics is hereby prepared from thermal conductive boron nitride nanosheets‐incorporated polyurethane elastomer matrix with MXene nanosheets‐coated surface microdomes as epidermis/spinosum layers assembled with interdigitated electrode as sensing signal transmission layer. It demonstrates appealing sensing performance with ultrasensitive sensitivity (≈288.95 kPa−1), up to 300 kPa sensing range, and up to 20 000 sensing cycles from obvious contact area variation between microdome microstructures and the contact electrode under external compression. Furthermore, the bioinspired electronics present advanced thermal management by timely efficient thermal dissipation out from the contacted skin surface to meet human skin thermal comfort with the incorporated thermal conductive boron nitride nanosheets. Thus, it is vitally promising in wearable artificial electronic skins, intelligent human‐interactive sensing, and personal health management. [ABSTRACT FROM AUTHOR]

Psoriasis is a common chronic inflammatory skin disease that significantly impacts the patients' quality of life. Recent studies highlighted the function of the interleukin (IL)-1 family member IL-38 in skin homeostasis and suggested an anti-inflammatory role for this cytokine in psoriasis. In this study, we generated mice specifically overexpressing the IL-38 protein in epidermal keratinocytes. We confirmed IL-38 overexpression in the skin by Western blotting. We further detected the protein by ELISA in the plasma, as well as in conditioned media of skin explants isolated from IL-38 overexpressing mice, indicating that IL-38 produced in the epidermis is released from keratinocytes and can be found in the circulation. Unexpectedly, epidermal IL-38 overexpression did not impact the global severity of imiquimod (IMQ)-induced skin inflammation, Similarly, keratinocyte activation and differentiation in IMQ-treated skin were not affected by increased IL-38 expression and there was no global effect on local or systemic inflammatory responses. Nevertheless, we observed a selective inhibition of CXCL1 and IL-6 production in response to IMQ in IL-38 overexpressing skin, as well as reduced Ly6g mRNA levels, suggesting decreased neutrophil infiltration. Epidermal IL-38 overexpression also selectively affected the desquamation process during IMQ-induced psoriasis, as illustrated by reduced plaque formation. Taken together, our results validate the generation of a new mouse line allowing for tissue-specific IL-38 overexpression. Interestingly, epidermal IL-38 overexpression selectively affected specific disease-associated readouts during IMQ-induced psoriasis, suggesting a more complex role of IL-38 in the inflamed skin than previously recognized. In particular, our data highlight a potential involvement of IL-38 in the regulation of skin desquamation. [ABSTRACT FROM AUTHOR]

A 3-dimensional culture system of keratinocytes achieves cornification as a terminal differentiation that can mimic the formation of stratified epidermis. At the onset of keratinocyte differentiation, air-exposure treatment is essential for promotion. We have previously reported that the stimulation of differentiation is accompanied by downregulation of the transcriptional activity of the hypoxia-inducible factor (HIF) and also found that rocking treatment of cultured keratinocytes in the submerged condition restored their differentiation. A comparative study of cultured keratinocytes with and without rocking was then carried out to investigate the characteristics of the recovered differentiation by morphological and biochemical analyses. In addition, transcriptome analysis revealed the expected similar pattern between air-exposed and rocking cultures, including HIF-regulating transcripts. Furthermore, the promotive effect of rocking treatment was impaired under hypoxic culture conditions (1% O2). We showed that the restored promotion of differentiation by rocking culture is mainly due to the abrogation of transcriptional events by hypoxia. [ABSTRACT FROM AUTHOR]

Apical extracellular matrices (aECMs) coat the exposed surfaces of animal bodies to shape tissues, influence social interactions, and protect against pathogens and other environmental challenges. In the nematode Caenorhabditis elegans , collagenous cuticle and zona pellucida protein-rich precuticle aECMs alternately coat external epithelia across the molt cycle and play many important roles in the worm's development, behavior, and physiology. Both these types of aECMs contain many matrix proteins related to those in vertebrates, as well as some that are nematode-specific. Extensive differences observed among tissues and life stages demonstrate that aECMs are a major feature of epithelial cell identity. In addition to forming discrete layers, some cuticle components assemble into complex substructures such as ridges, furrows, and nanoscale pillars. The epidermis and cuticle are mechanically linked, allowing the epidermis to sense cuticle damage and induce protective innate immune and stress responses. The C. elegans model, with its optical transparency, facilitates the study of aECM cell biology and structure/function relationships and all the myriad ways by which aECM can influence an organism. [ABSTRACT FROM AUTHOR]

Introduction: Complexities of robotic distal gastrectomy (RDG) give reason to assess physician's surgical skill. Varying levels in surgical skill affect patient outcomes. We aim to investigate how a novel artificial intelligence (AI) model can be used to evaluate surgical skill in RDG by recognizing surgical instruments. Methods: Fifty‐five consecutive robotic surgical videos of RDG for gastric cancer were analyzed. We used Deeplab, a multi‐stage temporal convolutional network, and it trained on 1234 manually annotated images. The model was then tested on 149 annotated images for accuracy. Deep learning metrics such as Intersection over Union (IoU) and accuracy were assessed, and the comparison between experienced and non‐experienced surgeons based on usage of instruments during infrapyloric lymph node dissection was performed. Results: We annotated 540 Cadiere forceps, 898 fenestrated bipolars, 359 suction tubes, 307 Maryland bipolars, 688 harmonic scalpels, 400 staplers, and 59 large clips. The average IoU and accuracy were 0.82 ± 0.12% and 87.2 ± 11.9% respectively. Moreover, the percentage of each instrument's usage to overall infrapyloric lymphadenectomy duration predicted by AI were compared. The use of stapler and large clip were significantly shorter in the experienced group compared to the non‐experienced group. Conclusions: This study is the first to report that surgical skill can be successfully and accurately determined by an AI model for RDG. Our AI gives us a way to recognize and automatically generate instance segmentation of the surgical instruments present in this procedure. Use of this technology allows unbiased, more accessible RDG surgical skill. [ABSTRACT FROM AUTHOR]

Significance: Aquaporins and ion channels establish and regulate gradients of calcium, sodium, potassium, chloride, water, and protons in the epidermis. These elements have been found to play significant roles in skin biology and wound healing. In this study, we review our understanding of these channels and ion gradients, with a special emphasis on their role in acute wound healing. Recent Advances: Specifically, we assess the temporal and spatial arrangements of ions and their respective channels in the intact skin and during wound and healing to provide a novel perspective of the role of ionic gradients through the various stages of wound healing. Critical Issues: The roles of gradients of ions and channels in wound healing are currently not well understood. A collective analysis of their traits and arrangements in the skin during wound healing may provide a new perspective and understanding of the functionality of gradients of ions and channels in skin biology and wound healing. Future Directions: It is important to elucidate how the gradients of ions and ion channels regulate and facilitate wound healing. A better understanding of the ionic environments may identify novel therapeutic targets and improved strategies to promote wound healing and possibly treat other cutaneous diseases.

Skin expands and regenerates in response to mechanical stretch. This important homeostasis process is critical for skin biology and can be exploited to generate extra skin for reconstructive surgery. Atmospheric oxygen uptake is important in skin homeostasis. However, whether and how cutaneous atmospheric oxygen uptake changes during mechanical stretch remains unclear, and relevant research tools to quantify oxygen flux are limited. Herein, we used the scanning micro-optrode technique (SMOT), a non-invasive self-referencing optical fiber microsensor, to achieve real-time measurement of cutaneous oxygen uptake from the atmosphere. An in vivo mechanical stretch-induced skin expansion model was established, and an in vitro Flexcell Tension system was used to stretch epidermal cells. We found that oxygen influx of skin increased dramatically after stretching for 1 to 3 days and decreased to the non-stretched level after 7 days. The enhanced oxygen influx of stretched skin was associated with increased epidermal basal cell proliferation and impaired epidermal barrier. In conclusion, mechanical stretch increases cutaneous oxygen uptake with spatial-temporal characteristics, correlating with cell proliferation and barrier changes, suggesting a fundamental mechanistic role of oxygen uptake in the skin in response to mechanical stretch. Optical fiber microsensor-based oxygen uptake detection provides a non-invasive approach to understand skin homeostasis.

The human body exhibits complex, spatially distributed chemo-electro-mechanical processes that must be properly captured for emerging applications in virtual/augmented reality, precision health, activity monitoring, bionics, and more. A key factor in enabling such applications involves the seamless integration of multipurpose wearable sensors across the human body in different environments, spanning from indoor settings to outdoor landscapes. Here, we report a versatile epidermal body area network ecosystem that enables wireless power and data transmission to and from battery-free wearable sensors with continuous functionality from dry to underwater settings. This is achieved through an artificial near field propagation across the chain of biocompatible, magneto-inductive metamaterials in the form of stretchable waterborne skin patches-these are fully compatible with pre-existing consumer electronics. Our approach offers uninterrupted, self-powered communication for human status monitoring in harsh environments where traditional wireless solutions (such as Bluetooth, Wi-Fi or cellular) are unable to communicate reliably.

Peucedanum L. (Apiaceae) is broadly distributed in the Old World, and 11 taxa, including five endemic species, have been reported in Korea. In this study, we used scanning electron microscopy to describe petal epidermal cell patterns and evaluated their systematic implications for all Korean Peucedanum species except for one. This included two recently reported endemic species, P. miroense and P. tongkangense, which are closely associated with Heracleum moellendorffii. The epidermal characteristics of the petals, including cell type (papillose conical, papillose knobby rugose, tabular conical, or tabular rugose), anticlinal wall shape (straight, sinuous, or curved), cuticle sculpture (striate or wrinkled), and stomata (presence or absence) were observed. The petal epidermis could be categorized into three types and two subtypes. We concluded that petal epidermal characteristics provide evidence supporting the recent robust phylogeny that suggests the non-monophyly of the genus Peucedanum. In particular, P. japonicum and P. praeruptorum, which are positioned in different clades to the other species in the recent phylogeny, had different types of petal epidermis among the studied species. These petal epidermal micro-characteristics were evaluated as possible consistent parameters for the taxonomic delimitation of species of the genus Peucedanum.

Triphenyl phosphate (TPHP) - a widely used organophosphate-based flame retardant - blocks cardiac looping during zebrafish development in a concentration-dependent manner, a phenotype that is dependent on disruption of embryonic osmoregulation and pericardial edema formation. However, its currently unclear whether (1) TPHP-induced effects on osmoregulation are driven by direct TPHP-induced injury to the embryonic epidermis and (2) whether TPHP-induced pericardial edema is reversible or irreversible following cessation of exposure. Therefore, the objectives of this study were to determine whether TPHP-induced pericardial edema is reversible and whether TPHP causes injury to the embryonic epidermis by quantifying the number of DAPI-positive epidermal cells and analyzing the morphology of the yolk sac epithelium using scanning electron microscopy. First, we found that exposure to 5 μM TPHP from 24-72 h post-fertilization (hpf) did not increase prolactin - a hormone that regulates ions and water levels - in embryonic zebrafish, whereas high ionic strength exposure media was associated with elevated levels of prolactin. Second, we found that exposure to 5 μM TPHP from 24-72 hpf did not decrease DAPI-positive epidermal cells within the embryonic epithelium, and that co-exposure with 2.14 μM fenretinide - a synthetic retinoid that promotes epithelial wound repair - from 24-72 hpf did not mitigate the prevalence of TPHP-induced epidermal folds within the yolk sac epithelium when embryos were exposed within high ionic strength exposure media. Finally, we found that the pericardial area and body length of embryos exposed to 5 μM TPHP from 24-72 hpf were similar to vehicle-treated embryos at 120 hpf following transfer to clean water and depuration of TPHP from 72-120 hpf. Overall, our findings suggest that (1) the ionic strength of exposure media may influence the baseline physiology of zebrafish embryos; (2) TPHP does not cause direct injury to the embryonic epidermis; and (3) TPHP-induced effects on pericardial area and body length are reversible 48 h after transferring embryos to clean water.

Lipid synthesis is necessary for formation of epithelial barriers and homeostasis with external microbes. An analysis of the response of human keratinocytes to several different commensal bacteria on the skin revealed that Cutibacterium acnes induced a large increase in essential lipids including triglycerides, ceramides, cholesterol, and free fatty acids. A similar response occurred in mouse epidermis and in human skin affected with acne. Further analysis showed that this increase in lipids was mediated by short-chain fatty acids produced by Cutibacterium acnes and was dependent on increased expression of several lipid synthesis genes including glycerol-3-phosphate-acyltransferase-3. Inhibition or RNA silencing of peroxisome proliferator-activated receptor-α (PPARα), but not PPARβ and PPARγ, blocked this response. The increase in keratinocyte lipid content improved innate barrier functions including antimicrobial activity, paracellular diffusion, and transepidermal water loss. These results reveal that metabolites from a common commensal bacterium have a previously unappreciated influence on the composition of epidermal lipids.

Enfortumab vedotin (EV), a nectin‐4‐binding agent that affects microtubules, has become standard therapy for advanced urothelial carcinoma. The agent, now given in combination with pembrolizumab, frequently induces cutaneous reactions. Here, we report a severe EV‐induced cutaneous eruption. A 58‐year‐old woman with metastatic urothelial carcinoma developed a rash after receiving simultaneous first doses of EV and pembrolizumab. The eruption began on the flank and spread to involve her trunk and extremities with prominent involvement of folds, including the axillae and medial thighs. Skin biopsy revealed extensive vacuolar alteration of the basal epidermis and numerous epidermal keratinocytic mitotic figures, often suprabasilar, including ring and "starburst" forms. The findings supported a diagnosis of EV‐induced eruption. With EV cessation and systemic corticosteroids, the rash resolved over a few weeks. Pembrolizumab was restarted as monotherapy, and the patient's cancer showed a significant radiographic treatment response at 3 months. An emerging literature of small series and case reports, largely from oncologic literature, presents the histopathology of EV‐induced cutaneous eruption as a vacuolar interface dermatitis with the inconsistently reported feature of arrested mitotic figures. This case study demonstrates distinctive clinical and histopathologic features of EV‐induced eruption, which may inform dermatologic and oncologic management. [ABSTRACT FROM AUTHOR]

In this review we discuss how the mammalian interfollicular epidermis forms during development, maintains homeostasis, and is repaired following wounding. Recent studies have provided new insights into the relationship between the stem cell compartment and the differentiating cell layers; the ability of differentiated cells to dedifferentiate into stem cells; and the epigenetic memory of epidermal cells following wounding. [Display omitted] • Switch between planar and perpendicular cell divisions during development. • Epidermal signalling is integrated at the cellular and supracellular levels. • Epigenetic environmental and lineage memory of wounding. [ABSTRACT FROM AUTHOR]

Terminal differentiation of epithelial cells is critical for the barrier function of the skin, the growth of skin appendages, such as hair and nails, and the development of the skin of amniotes. Here, we present the hypothesis that the differentiation of cells in the embryonic periderm shares characteristic features with the differentiation of epithelial cells that support the morphogenesis of cornified skin appendages during postnatal life. The periderm prevents aberrant fusion of adjacent epithelial sites during early skin development. It is shed off when keratinocytes of the epidermis form the cornified layer, the stratum corneum. A similar role is played by epithelia that ensheath cornifying skin appendages until they disintegrate to allow the separation of the mature part of the skin appendage from the adjacent tissue. These epithelia, exemplified by the inner root sheath of hair follicles and the epithelia close to the free edge of nails or claws, are referred to as scaffolding epithelia. The periderm and scaffolding epithelia are similar with regard to their transient functions in separating tissues and the conserved expression of trichohyalin and trichohyalin-like genes in mammals and birds. Thus, we propose that parts of the peridermal differentiation program were coopted to a new postnatal function during the evolution of cornified skin appendages in amniotes. [Display omitted] • The periderm prevents adhesion of adjacent stratified epithelia during development • Cornified skin appendages require scaffolding epithelia for morphogenesis • The inner root sheath of the hair follicle is an example a scaffolding epithelium • Scaffoldin is a marker of the periderm and scaffolding epithelia of birds • Trichohyalin is the mammalian homolog of scaffoldin [ABSTRACT FROM AUTHOR]

Skin stem cells (SCs) play a pivotal role in supporting tissue homeostasis. Several types of SCs are responsible for maintaining and regenerating skin tissue. These include bulge SCs and others residing in the interfollicular epidermis, infundibulum, isthmus, sebaceous glands, and sweat glands. The emergence of skin SCs commences during embryogenesis, where multipotent SCs arise from various precursor populations. These early events set the foundation for the diverse pool of SCs that will reside in the adult skin, ready to respond to tissue repair and regeneration demands. A network of molecular cues regulates skin SC behavior, balancing quiescence, self-renewal, and differentiation. The disruption of this delicate equilibrium can lead to SC exhaustion, impaired wound healing, and pathological conditions such as skin cancer. The present review explores the intricate mechanisms governing the development, activation, and differentiation of skin SCs, shedding light on the molecular signaling pathways that drive their fate decisions and skin homeostasis. Unraveling the complexities of these molecular drivers not only enhances our fundamental knowledge of skin biology but also holds promise for developing novel strategies to modulate skin SC fate for regenerative medicine applications, ultimately benefiting patients with skin disorders and injuries.

Skin, the largest organ in the human body, is a crucial protective barrier that plays essential roles in thermoregulation, sensation, and immune defence. This complex organ undergoes intricate processes of development. Skin development initiates during the embryonic stage, orchestrated by molecular cues that control epidermal specification, commitment, stratification, terminal differentiation, and appendage growth. Key signalling pathways are integral in coordinating the development of the epidermis, hair follicles, and sweat glands. The complex interplay among these pathways is vital for the appropriate formation and functionality of the skin. Disruptions in multiple molecular pathways can give rise to a spectrum of skin diseases, from congenital skin disorders to cancers. By delving into the molecular mechanisms implicated in developmental processes, as well as in the pathogenesis of diseases, this narrative review aims to present a comprehensive understanding of these aspects. Such knowledge paves the way for developing innovative targeted therapies and personalised treatment approaches for various skin conditions.

Abstract Zinc oxide nanoparticles (ZNPs) are widely used in sunscreens and nanomedicines, and it was recently confirmed that ZNPs can penetrate stratum corneum into deep epidermis. Therefore, it is necessary to determine the impact of ZNPs on epidermis. In this study, ZNPs were applied to mouse skin at a relatively low concentration for one week. As a result, desmosomes in epidermal tissues were depolymerized, epidermal mechanical strain resistance was reduced, and the levels of desmosomal cadherins were decreased in cell membrane lysates and increased in cytoplasmic lysates. This finding suggested that ZNPs promote desmosomal cadherin endocytosis, which causes desmosome depolymerization. In further studies, ZNPs were proved to decrease mammalian target of rapamycin complex 1 (mTORC1) activity, activate transcription factor EB (TFEB), upregulate biogenesis of lysosome-related organelle complex 1 subunit 3 (BLOC1S3) and consequently promote desmosomal cadherin endocytosis. In addition, the key role of mTORC1 in ZNP-induced decrease in mechanical strain resistance was determined both in vitro and in vivo. It can be concluded that ZNPs reduce epidermal mechanical strain resistance by promoting desmosomal cadherin endocytosis via the mTORC1-TFEB-BLOC1S3 axis. This study helps elucidate the biological effects of ZNPs and suggests that ZNPs increase the risk of epidermal fragmentation. Graphical abstract

Polymicrobial infections are the leading causes of complications incurred from injuries that burn patients develop. Such patients admitted to the hospital have a high risk of developing hospital-acquired infections, with longer patient stays leading to increased chances of acquiring such drug-resistant infections. Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis are the most common multidrug-resistant (MDR) Gram-negative bacteria identified in burn wound infections (BWIs). BWIs caused by viruses, like herpes simplex and varicella zoster, and fungi-like Candida species appear to occur occasionally. However, the preponderance of infection by opportunistic pathogens is very high in burn patients. Variations in the causative agents of BWIs are due to differences in geographic location and infection control measures. Overall, burn injuries are characterized by elevated serum cytokine levels, systemic immune response, and immunosuppression. Hence, early detection and treatment can accelerate the wound-healing process and reduce the risk of further infections at the site of injury. A multidisciplinary collaboration between burn surgeons and infectious disease specialists is also needed to properly monitor antibiotic resistance in BWI pathogens, help check the super-spread of MDR pathogens, and improve treatment outcomes as a result.

Abstract Mesotrypsin, encoded by the PRSS3 gene, is a distinctive trypsin isoform renowned for its exceptional resistance to traditional trypsin inhibitors and unique substrate specificity. Within the skin epidermis, this protein primarily expresses in the upper layers of the stratified epidermis and plays a crucial role in processing pro-filaggrin (Pro-FLG). Although prior studies have partially elucidated its functions using primary cultured keratinocytes, challenges persist due to these cells' differentiation-activated cell death program. In the present study, HaCaT keratinocytes, characterized by minimal endogenous mesotrypsin expression and sustained proliferation in differentiated states, were utilized to further scrutinize the function of mesotrypsin. Despite the ready degradation of the intact form of active mesotrypsin in these cells, fusion with Venus, flanked by a peptide linker, enables evasion from the protein elimination machinery, thus facilitating activation of the Pro-FLG processing system. Inducing Venus-mesotrypsin expression in the cells resulted in a flattened phenotype and reduced proliferative capacity. Moreover, these cells displayed altered F-actin assembly, enhanced E-cadherin adhesive activity, and facilitated tight junction formation without overtly influencing epidermal differentiation. These findings underscore mesotrypsin's potentially pivotal role in shaping the characteristic cellular morphology of upper epidermal layers.

The senescence‐associated protein p16INK4A acts as a limiter element in cell‐cycle progression. The loss of p16INK4A function is causally related to cellular immortalization. The increase in p16INK4A levels with advancing age was demonstrated in melanocytes. However, the characteristic difference between young and senescent melanocytes affecting immortalization of melanocytes remains unclear. In this study, we generated 10 different cell lines in total from newborn (NB) and adult (AD) primary normal human epidermal melanocytes (NHEM) using four different methods, transduction of CDK4R24C and cyclin D1 (K4D), K4D with TERT (K4DT), SV40 T‐antigen (SV40T), and HPV16 E6 and E7 (E6/E7) and performed whole transcriptome sequencing analysis (RNA‐Seq) to elucidate the differences of genome‐wide expression profiles among cell lines. The analysis data revealed distinct differences in expression pattern between cell lines from NB and AD although no distinct biological differences were detected in analyses such as comparison of cell morphology, evaluation of cell proliferation, and cell cycle profiles. This study may provide useful in vitro models to benefit the understanding of skin‐related diseases. [ABSTRACT FROM AUTHOR]

This case report presents the clinical scenario of a 22 years old female patient with decade long history of seizure disorder and is on chronic anti-seizure management therapy. The patient's initial symptoms manifested as lesions over the oral cavity, over the period of time the lesions progressed to scalp, chest and buttocks. Pemphigus is a rare heterogeneous group of autoimmune disease that affects the skin and the mucous membrane. A combination of inappropriate activation of host B lymphocytes producing intracellular ImmunoglobulinG antibodies and biochemical interactions results in the drug-induced pemphigus. Acantholypsia is the term for the process by which these auto antibodies target the desmogleins and split the cells in the epidermis. This case emphasizes the requisite for further research on understanding the effect of anti-seizure therapy. [ABSTRACT FROM AUTHOR]

The epidermis of the skin provides a barrier between the organism and the external environment. It is constantly subjected to physical and chemical insults, and thus susceptible to wounding and to neoplastic transformation. Long-lasting epigenetic modifications in epidermal stem cells are now shown to link responses to skin injuries with cell priming for carcinoma development, through regulation of histone H2A ubiquitylation. [ABSTRACT FROM AUTHOR]

Wearable alcohol monitoring devices demand noninvasive, real-time measurement of blood alcohol content (BAC) reliably and continuously. A few commercial devices are available to determine BAC noninvasively by detecting transcutaneous diffused alcohol. However, they suffer from a lack of accuracy and reliability in the determination of BAC in real time due to the complex scenario of the human skin for transcutaneous alcohol diffusion and numerous factors (e.g., skin thickness, kinetics of alcohol, body weight, age, sex, metabolism rate, etc.). In this work, a transcutaneous alcohol diffusion model has been developed from real-time captured data from human wrists to better understand the kinetics of diffused alcohol from blood to different skin epidermis layers. Such a model will be a footprint to determine a base computational model in larger studies. Eight anonymous volunteers participated in this pilot study. A laboratory-built wearable blood alcohol content (BAC) monitoring device collected all the data to develop this diffusion model. The proton exchange membrane fuel cell (PEMFC) sensor was fabricated and integrated with an nRF51822 microcontroller, LMP91000 miniaturized potentiostat, 2.4 GHz transceiver supporting Bluetooth low energy (BLE), and all the necessary electronic components to build this wearable BAC monitoring device. The %BAC data in real time were collected using this device from these volunteers' wrists and stored in the end device (e.g., smartphone). From the captured data, we demonstrate how the volatile alcohol concentration on the skin varies over time by comparing the alcohol concentration in the initial stage (= 10 min) and later time (= 100 min). We also compare the experimental results with the outputs of three different input profiles: piecewise linear, exponential linear, and Hoerl, to optimize the developed diffusion model. Our results demonstrate that the exponential linear function best fits the experimental data compared to the piecewise linear and Hoerl functions. Moreover, we have studied the impact of skin epidermis thickness within ±20% and demonstrate that a 20% decrease in this thickness results in faster dynamics compared to thicker skin. The model clearly shows how the diffusion front changes within a skin epidermis layer with time. We further verified that 60 min was roughly the time to reach the maximum concentration, Cmax, in the stratum corneum from the transient analysis. Lastly, we found that a more significant time difference between BACmax and Cmax was due to greater alcohol consumption for a fixed absorption time. [ABSTRACT FROM AUTHOR]

• Upcycled canola meal extract (CME) showed anti-photoaging effects in hairless mice. • CME reduced the number, mean length, and mean depth of wrinkles. • CME inhibited the increase of epidermal thickness induced by UVB radiation. • CME increased catalase activity and hydroxyproline content in mouse skin. • CME inhibited the phosphorylation of MAPKs such as ERK, JNK, and p38. • CME reduced MMP-2, -9, and -13 production in mice in response to UVB radiation. Canola meal, a by-product of processing canola into oil, reportedly contains high amounts of phenolic compounds and proteins. However, as canola meal is primarily used as feed for livestock, advances in multiple research fields are required to broaden its potential applications. Photoaging is caused by continuous exposure to ultraviolet (UV) radiation from sunlight. UV radiation generates reactive oxygen species and destroys collagen in the skin, thickening the epidermis, reducing elasticity, and causing wrinkles. We hypothesized that canola meal extract (CME) can mitigate the damage to skin associated with wrinkles induced by exposure to UVB radiation. To evaluate the anti-wrinkle effect, we administered CME orally to 40 female Hos:HR-1 hairless mice divided into 5 groups: (1) control mice, (2) a UVB group, and (3−5) CME-treated groups (CME−250, 500, and 1000 mg/kg body weight/day, respectively). All groups except the controls were irradiated with UVB 3 times a week to create wrinkles due to photoaging. CME administration inhibited the increase of the number, mean length, and mean depth of wrinkles induced by UVB radiation as assessed using a skin replica. Histopathological image analysis revealed that CME administration resulted in a decrease in epidermal thickness and an increase in collagen content, while increasing catalase activity and hydroxyproline content in skin tissues. CME administration inhibited the phosphorylation of mitogen-activated protein kinase and decreased the production of collagenase and gelatinase. These results suggest that CME, an upcycled material, has the potential to develop into a healthful and functional food ingredient with anti-wrinkling effects. Administration of CME to hairless mouse decreased the number, length, and depth of wrinkles and epidermal thickness. CME administration also increased antioxidant enzyme activity and hydroxyproline content in skin tissue and inhibited phosphorylation of MAPKs, reducing the production of collagenase and gelatinase. These results suggest that CME mitigates skin wrinkles caused by UVB radiation. CME, canola meal extract; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; UVB, ultraviolet B. [Display omitted] [ABSTRACT FROM AUTHOR]