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A fundamental characteristic of living organisms is their ability to separate the internal and external environments, a function achieved in large part through the different physiological barrier systems and their component junctional molecules. Barrier integrity is subject to multiple influences, but one that has received comparatively little attention to date is the role of the commensal microbiota. These microbes, which represent approximately 50% of the cells in the human body, are increasingly recognized as powerful physiological modulators in other systems, but their role in regulating barrier function is only beginning to be addressed. Through comparison of the impact commensal microbes have on cell–cell junctions in three exemplar physiological barriers—the gut epithelium, the epidermis and the blood–brain barrier—this review will emphasize the important contribution microbes and microbe-derived mediators play in governing barrier function. By extension, this will highlight the critical homeostatic role of commensal microbes, as well as identifying the puzzles and opportunities arising from our steadily increasing knowledge of this aspect of physiology. [ABSTRACT FROM AUTHOR]

The goal of this inquiry activity is to evaluate a variety of skin-care products on simulated skin cells using Orbeez, a brand of superabsorbent polymers. These small beads can quickly absorb water but will dry out in the air, thus perfectly representing our own skin cells. This property makes Orbeez an acceptable model for human skin, and test material for evaluating various skin-care products. Students will observe the quantitative changes that happened to the mass of the samples to determine the percent change. They will also observe the qualitative changes that happened throughout the lab investigation and record their observations in a lab notebook. After completing the experiment, students will create a presentation of the quantitative and qualitative results. [ABSTRACT FROM AUTHOR]

Summary: The endodermis surrounds and protects the vasculature partly by depositing hydrophobic suberin in the cell walls. Yet, some cells remain unsuberised. These historically termed 'passage cells' are assumed to provide a low‐resistance pathway to the xylem. Only recently have we started to gain molecular insights into these cells, which allow us to probe how roots coordinate communication with the environment across barriers with single‐cell precision. Increased understanding of root physiology at a high‐resolution is intriguing, as it is likely to provide us with new tools to improve overall plant health. With this in mind, we here provide a brief overview of passage cells, their presence across plant species, as well as a molecular update and future directions for passage cell‐related research. [ABSTRACT FROM AUTHOR]

The stereotyped floral morphology of Neotropical Malpighiaceae species—zygomorphic and calyx with oil glands—is correlated with oil-bee pollination. In contrast, the floral trends of the Paleotropical lineages are actinomorphy and lack of calyx glands, probably due to the absence of oil-collecting bees. The Paleotropical genus Acridocarpus is an exception because of its zygomorphic, gland-bearing flowers. Glands throughout Acridocarpus inflorescences were morphoanatomically evaluated to verify the occurrence of patterns related to species and geographic distribution. Herbarium (25 species) and fresh samples of A. longifolius were processed according to standard anatomical techniques. To verify the presence of glucose and protein, strip tests were applied to the exudate. Fresh samples were fixed and submitted to histochemical tests. Based on the occurrence, number and placement of glands, three distribution patterns were recognized on the bracteole and ten on the calyx. Bract, bracteole and sepal glands have a typical nectary structure with a palisade-like epidermis and vascularized parenchyma. Glands were classified as short-stalked, sessile or immersed. Histochemical tests performed on bract and sepal glands of A. longifolius were positive for proteins, polysaccharides and phenolic compounds, and negative for oil compounds. Glucose and protein were detected in the exudate. These results allow us to recognize the glands in Acridocarpus inflorescences as nectaries. This comprehensive morphoanatomical study helps to clarify the correlation between patterns of floral morphology and secretion consumers, as well as to better understand floral evolution in Malpighiaceae across their dispersal events. [ABSTRACT FROM AUTHOR]

Migration of cells from both local and systemic sources is essential for the inflammatory and regenerative processes that occur during normal wound healing. CXCL12 is considered a critical regulator of CXCR4-positive cell migration during tissue regeneration. In this study, we investigated the expression of Cxcl12 and Cxcr4 during healing of a murine full thickness ear wound. We also investigated the expression of angiopoietin-like 4, which has been shown to participate in wound angiogenesis and reepithelialization. At time points up to 48hrs, complete blood counts were performed using automated hematology analysis, and the numbers of circulating stem and progenitor cells quantified using flow cytometry. Expression of both Cxcr4 and Angptl4 was significantly elevated within 3 days of wounding, and both were strongly expressed in cells of the epidermis. ANGPTL4 protein expression remained elevated in the epithelium through day 14. Cxcl12 expression was increased significantly at day 3, and remained elevated through day 21. Faint Cxcl12 staining was detectable in the epithelium at day 1, and thereafter staining was faint and more generalized. There were significantly fewer circulating total white blood cells and lymphocytes 1hr following ear punching. Similarly, there was a significant early (1hr) reduction in the number of circulating endothelial progenitor cells. Further studies are warranted to investigate whether ANGPTL4 and CXCL12/CXCR4 interact or synergize to facilitate cell recruitment and migration, and to potentiate reepithelialization and wound healing. [ABSTRACT FROM AUTHOR]

Eumelanin is the major pigment responsible for human skin color. This black/brown pigment is localized in membrane-bound organelles (melanosomes) found in specialized cells (melanocytes) in the basal layer of the epidermis. This review highlights the steps involved in melanogenesis in the epidermis and the disorders in skin pigmentation that occur when specific steps critical for this process are defective. Melanosomes, which contain tyrosinase, a major enzyme involved in melanin synthesis, develop through a series of steps in the melanocyte. They are donated from the melanocyte dendrites to the surrounding keratinocytes in the epidermis. In the keratinocytes, the melanosomes are found singly or packaged into groups, and as the keratinocytes move upward in the epidermis, the melanosomes start to degrade. This sequence of events is critical for melanin pigmentation in the skin and can be influenced by genetic, hormonal, and environmental factors, which all play a role in levels of melanization of the epidermis. The effects these factors have on skin pigmentation can be due to different underlying mechanisms involved in the melanization process leading to either hypo- or hyperpigmentary disorders. These disorders highlight the importance of mechanistic studies on the specific steps involved in the melanization process. [ABSTRACT FROM AUTHOR]

p63 is a transcriptional regulator of ectodermal development that is required for basal cell proliferation and stem cell maintenance. p73 is a closely related p53 family member that is expressed in select p63-positive basal cells and can heterodimerize with p63. p73-/- mice lack multiciliated cells and have reduced numbers of basal epithelial cells in select tissues; however, the role of p73 in basal epithelial cells is unknown. Herein, we show that p73-deficient mice exhibit delayed wound healing despite morphologically normal-appearing skin. The delay in wound healing is accompanied by decreased proliferation and increased levels of biomarkers of the DNA damage response in basal keratinocytes at the epidermal wound edge. In wild-type mice, this same cell population exhibited increased p73 expression after wounding. Analyzing single-cell transcriptomic data, we found that p73 was expressed by epidermal and hair follicle stem cells, cell types required for wound healing. Moreover, we discovered that p73 isoforms expressed in the skin (ΔNp73) enhance p63-mediated expression of keratinocyte genes during cellular reprogramming from a mesenchymal to basal keratinocyte-like cell. We identified a set of 44 genes directly or indirectly regulated by ΔNp73 that are involved in skin development, cell junctions, cornification, proliferation, and wound healing. Our results establish a role for p73 in cutaneous wound healing through regulation of basal keratinocyte function. [ABSTRACT FROM AUTHOR]

Growth differentiation factor 11 (GDF11) belongs to the TGF-β superfamily of proteins and is closely related to myostatin. Recent findings show that GDF11 has rejuvenating properties with pronounced effects on the cardiovascular system, brain, skeletal muscle, and skeleton in mice. Several human studies were also conducted, some implicating decreasing levels of circulating GDF11 with age. To date, however, there have not been any reports on its role in human skin. This study examined the impact of GDF11 on human skin, specifically related to skin aging. The effect of recombinant GDF11 on the function of various skin cells was examined in human epidermal keratinocytes, dermal fibroblasts, melanocytes, dermal microvascular endothelial cells and 3D skin equivalents, as well as in ex vivo human skin explants. GDF11 had significant effects on the production of dermal matrix components in multiple skin models in vitro and ex vivo. In addition, it had a pronounced effect on expression of multiple skin related genes in full thickness 3D skin equivalents. This work, for the first time, demonstrates an important role for GDF11 in skin biology and a potential impact on skin health and aging. [ABSTRACT FROM AUTHOR]

Delayed wound healing and reduced barrier function with an increased risk of cancer are characteristics of aged skin and one possible mechanism is misregulation or dysfunction of epidermal stem cells during aging. Recent studies have identified heterogeneous stem cell populations within the mouse interfollicular epidermis that are defined by territorial distribution and cell division frequency; however, it is unknown whether the individual stem cell populations undergo distinct aging processes. Here we provide comprehensive characterization of age-related changes in the mouse epidermis within the specific territories of slow-cycling and fast-dividing stem cells using old wild-type, senescence-accelerated mouse prone 1 (SAMP1) and SAMP8 mice. During aging, the epidermis exhibits structural changes such as irregular micro-undulations and overall thinning of the tissue. We also find that, in the old epidermis, proliferation is preferentially decreased in the region where fast-dividing stem cells reside whereas the lineage differentiation marker appears to be more affected in the slow-cycling stem cell region. Furthermore, SAMP8, but not SAMP1, exhibits precocious aging similar to that of aged wild-type mice, suggesting a potential use of this model for aging study of the epidermis and its stem cells. Taken together, our study reveals distinct aging processes governing the two epidermal stem cell populations and suggests a potential mechanism in differential responses of compartmentalized stem cells and their niches to aging. [ABSTRACT FROM AUTHOR]

Objectives: Soft tissue wounds with exposed bone often require extended healing times and can be associated with severe complications. We describe the ability of artificial dermis with autogenic adipose-derived stem cells (ADSCs) to promote the healing of wounds with exposed bone in a rat model. Methods: Adipose tissues harvested from the bilateral inguinal regions of Wistar rats were used as ADSCs. Rats were randomly divided into control and ADSC groups to investigate the efficacy of ADSC transplantation for wound healing (n = 20 per group). Soft tissue defects were created on the heads of the rats and were covered with artificial dermis with or without the seeded ADSCs. Specimens from these rats were evaluated using digital image analysis, histology, immunohistochemistry, cell labeling, and real-time reverse-transcription polymerase chain reaction (real-time RT-PCR). Results: The average global wound area was significantly smaller in the ADSC group than in the control group on days 3, 7, and 14 after surgery (p<0.05). After 14 days, the blood vessel density in the wound increased by 1.6-fold in the ADSC group compared with that in the control group (p<0.01). Real-time RT-PCR results showed higher Fgfb and Vegf expression levels at all time points, and higher Tgfb1 and Tgfb3 expression levels until 14 days after surgery in the ADSC group than in the control group (p<0.05). Conclusions: In wounds with exposed bone, autogenic ADSCs can promote vascularization and wound healing. Use of this cell source has multiple benefits, including convenient clinical application and lack of ethical concerns. [ABSTRACT FROM AUTHOR]

There is a pressing need for improved preclinical model systems in which to study human skin wound healing. Here, we report the development and application of a serum-free full thickness human skin wound healing model. Not only can re-epithelialization (epidermal repair) and angiogenesis be studied in this simple and instructive model, but the model can also be used to identify clinically relevant wound-healing promoting agents, and to dissect underlying candidate mechanisms of action in the target tissue. We present preliminary ex vivo data to suggest that Thyroxine (T4), which reportedly promotes skin wound healing in rodents in vivo, may promote key features of human skin wound healing. Namely, T4 stimulates re-epithelialisation and angiogenesis, and modulates both wound healing-associated epidermal keratin expression and energy metabolism in experimentally wound human skin. Functionally, the wound healing-promoting effects of T4 are at least partially mediated via fibroblast growth factor/fibroblast growth factor receptor-mediated signalling, since they could be significantly antagonized by bFGF-neutralizing antibody. Thus, this pragmatic, easy-to-use full-thickness human skin wound healing model provides a useful preclinical research tool in the search for clinically relevant candidate wound healing-promoting agents. These ex vivo data encourage further pre-clinical testing of topical T4 as a cost-efficient, novel agent in the management of chronic human skin wounds. [ABSTRACT FROM AUTHOR]

We developed a novel skin regeneration therapy combining nevus tissue inactivated by high hydrostatic pressure (HHP) in the reconstruction of the dermis with a cultured epidermal autograft (CEA). The issue with this treatment is the unstable survival of CEA on the inactivated dermis. In this study, we applied collagen/gelatin sponge (CGS), which can sustain the release of basic fibroblast growth factor (bFGF), to the inactivated skin in order to accelerate angiogenesis. Murine skin grafts from C57BL6J/Jcl mice (8 mm in diameter) were prepared, inactivated by HHP and cryopreserved. One month later, the grafts were transplanted subcutaneously onto the back of other mice and covered by CGS impregnated with saline or bFGF. Grafts were harvested after one, two and eight weeks, at which point the engraftment was evaluated through the histology and angiogenesis-related gene expressions were determined by real-time polymerase chain reaction. Histological sections showed that the dermal cellular density and newly formed capillaries in the bFGF group were significantly higher than in the control group. The relative expression of FGF-2, PDGF-A and VEGF-A genes in the bFGF group was significantly higher than in the control group at Week 1. This study suggested that the angiogenesis into grafts was accelerated, which might improve the engraftment of inactivated dermis in combination with the sustained release of bFGF by CGSs. [ABSTRACT FROM AUTHOR]

Feathers are arranged in a precise pattern in avian skin. They first arise during development in a row along the dorsal midline, with rows of new feather buds added sequentially in a spreading wave. We show that the patterning of feathers relies on coupled fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) signalling together with mesenchymal cell movement, acting in a coordinated reaction-diffusion-taxis system. This periodic patterning system is partly mechanochemical, with mechanical-chemical integration occurring through a positive feedback loop centred on FGF20, which induces cell aggregation, mechanically compressing the epidermis to rapidly intensify FGF20 expression. The travelling wave of feather formation is imposed by expanding expression of Ectodysplasin A (EDA), which initiates the expression of FGF20. The EDA wave spreads across a mesenchymal cell density gradient, triggering pattern formation by lowering the threshold of mesenchymal cells required to begin to form a feather bud. These waves, and the precise arrangement of feather primordia, are lost in the flightless emu and ostrich, though via different developmental routes. The ostrich retains the tract arrangement characteristic of birds in general but lays down feather primordia without a wave, akin to the process of hair follicle formation in mammalian embryos. The embryonic emu skin lacks sufficient cells to enact feather formation, causing failure of tract formation, and instead the entire skin gains feather primordia through a later process. This work shows that a reaction-diffusion-taxis system, integrated with mechanical processes, generates the feather array. In flighted birds, the key role of the EDA/Ectodysplasin A receptor (EDAR) pathway in vertebrate skin patterning has been recast to activate this process in a quasi-1-dimensional manner, imposing highly ordered pattern formation. [ABSTRACT FROM AUTHOR]

Targeted therapies and immunotherapies are associated with a wide range of dermatologic adverse events (dAEs) resulting from common signaling pathways involved in malignant behavior and normal homeostatic functions of the epidermis and dermis. Dermatologic toxicities include damage to the skin, oral mucosa, hair, and nails. Acneiform rash is the most common dAE, observed in 25-85% of patients treated by epidermal growth factor receptor and mitogen-activated protein kinase kinase inhibitors. BRAF inhibitors mostly induce secondary skin tumors, squamous cell carcinoma and keratoacanthomas, changes in pre-existing pigmented lesions, as well as hand-foot skin reactions and maculopapular hypersensitivity-like rash. Immune checkpoint inhibitors (ICIs) most frequently induce nonspecific maculopapular rash, but also eczema-like or psoriatic lesions, lichenoid dermatitis, xerosis, and pruritus. Of the oral mucosal toxicities observed with targeted therapies, oral mucositis is the most frequent with mammalian target of rapamycin (mTOR) inhibitors, followed by stomatitis associated to multikinase angiogenesis and HER inhibitors, geographic tongue, oral hyperkeratotic lesions, lichenoid reactions, and hyperpigmentation. ICIs typically induce oral lichenoid reactions and xerostomia. Targeted therapies and endocrine therapy also commonly induce alopecia, although this is still underreported with the latter. Finally, targeted therapies may damage nail folds, with paronychia and periungual pyogenic granuloma distinct from chemotherapy-induced lesions. Mild onycholysis, brittle nails, and a slower nail growth rate may also be observed. Targeted therapies and immunotherapies often profoundly diminish patients’ quality of life, which impacts treatment outcomes. Close collaboration between dermatologists and oncologists is therefore essential. [ABSTRACT FROM AUTHOR]

Extensive apoptosis is often seen in patterning mutants, suggesting that tissues can detect and eliminate potentially harmful mis-specified cells. Here, we show that the pattern of apoptosis in the embryonic epidermis of Drosophila is not a response to fate mis-specification but can instead be explained by the limiting availability of prosurvival signaling molecules released from locations determined by patterning information. In wild-type embryos, the segmentation cascade elicits the segmental production of several epidermal growth factor receptor (EGFR) ligands, including the transforming growth factor Spitz (TGFα), and the neuregulin, Vein. This leads to an undulating pattern of signaling activity, which prevents expression of the proapoptotic gene head involution defective (hid) throughout the epidermis. In segmentation mutants, where specific peaks of EGFR ligands fail to form, gaps in signaling activity appear, leading to coincident hid up-regulation and subsequent cell death. These data provide a mechanistic understanding of how cell survival, and thus appropriate tissue size, is made contingent on correct patterning. [ABSTRACT FROM AUTHOR]

Sweet cherry ( Prunus avium L.) is highly perishable and is greatly affected by orchard management and environmental conditions, such as excess rainfall before harvest. Rain-induced cracking is the major cause of crop loss in sweet cherry in most production areas of the world. Advances in understanding the physiological and molecular mechanisms involved in cracking physiology in combination with orchard management strategies to limit cherry cracking are discussed. The current opinions to explain fruit cracking is that the process initiates with water uptake by the fruit surface that results in localised bursting of cells that release malic acid into the apoplast. This results in swelling of the epidermis and weakening of the epidermal and hypodermal cells until macroscopic fruit cracking. This review focusses on management strategies such as rain cover protection, mineral sprays, anti-transpirants and growth regulators. Tree responses to growth regulators and biostimulants vary with cultivar, application frequency, concentration and type, making it hard to generalize their effects. New approaches to limit cracking are presented, including the development of tolerant cultivars, candidate mineral sprays, biostimulants and technologies for rainwater removal such as orchard air-blast sprayers or creating downwash by helicopters. [ABSTRACT FROM AUTHOR]

Background and objectives: Microneedling therapy is a widely used technique in dermatology. However, little is known about the underlying molecular effects of this therapy on extracellular matrix remodeling, wound healing, and inflammation. The aim of this study was to examine morphological and molecular changes caused by microneedling treatment in a standardized in vitro full-thickness 3D model of human skin. Materials and methods: A microneedling device was used to treat full-thickness 3D skin models. Specimens were harvested at specified time points and qRT-PCR and microarray studies were performed. Frozen sections were examined histologically. Results: Microneedling treatment caused morphological changes in the skin model resulting in an almost complete recovery of the epidermis five days after treatment. Microarray analysis identified an upregulation of genes that are associated with tissue remodeling and wound healing (e.g. COL3A1, COL8A1, TIMP3), epithelial proliferation and differentiation (KRT13, IGF1), immune cell recruitment (CCL11), and a member of the heat shock protein family (HSPB6). On the other hand, we detected a downregulation of pro-inflammatory cytokines (e.g. IL1α, IL1β, IL24, IL36γ, IL36RN), and antimicrobial peptides (e.g. S100A7A, DEFB4). These data were confirmed by independent RT-PCR analyses. Conclusion: We present for the first time the direct molecular effects of microneedling therapy on epidermal keratinocytes and dermal fibroblasts using a standardized 3D skin model. Treatment resulted in histological alterations and changed the expression of various genes related to epidermal differentiation, inflammation, and dermal remodeling. This data suggests that skin microneedling plays a role in dermal remodeling, increases epidermal differentiation, and might also have a direct effect on collagen synthesis. These findings may increase our understanding of the molecular mechanisms of human skin repair induced by microneedling therapy and will allow comparisons with competing applications, such as ablative laser therapies. [ABSTRACT FROM AUTHOR]

Keratinocytes are the most abundant cell type in the epidermis. They prevent desiccation and provide immunological and barrier defense against potential pathogens such as Staphylococcus aureus and Candida albicans. The study of this first line of immune defense may be hindered by invasive isolation methods and/or improper culture conditions to support stem cell maintenance and other potential mechanisms contributing to long-term subcultivation in vitro. Primary keratinocytes have been successfully isolated from blister roofs induced by negative pressure, which separates the epidermis from the dermis in vivo in human subjects. This method allows collection of pure epidermal cells without dermal contamination in a minimally invasive manner. However, the isolated keratinocytes differentiate and senesce when cultured in vitro beyond five passages. Here, we present evidence that the Rho kinase (ROCK) inhibitor Y-27632 can be used to effectively increase the proliferative capabilities of keratinocytes isolated using the suction blister method, similar to what has been previously reported for primary keratinocytes isolated using alternative methods. We show that the increase in passage number is directly correlated to delayed differentiation, and that cells passaged long term with the inhibitor retain their ability to stratify in organotypic raft cultures and respond to cytokine treatment; additionally, the late passage cells have a heterogeneous mix of differentiated and non-differentiated cells which may be predicted by a ratio of select differentiation markers. The described method presents a minimally invasive procedure for keratinocyte isolation and prolonged culture that allows analysis of keratinocyte function in both healthy volunteers and patients with dermatologic diseases. [ABSTRACT FROM AUTHOR]

The epidermis undergoes constant renewal during its lifetime. This is possible due to a special population of keratinocyte stem cells (KSCs) located at the basal layer. These cells are surrounded by their direct progeny, keratinocyte progenitors or transient amplifying cells (TAs), which arise from cell division. Skin is exposed every day to sun radiation; in particular, UVA radiation penetrates through the epidermis and induces damage to KSCs and TAs. Although keratinocytes in the basal layer are the most likely skin carcinomas and/or photoaging cells of origin, surprisingly few studies have addressed the specific responses of these cells to UV radiation. In this study, we showed for the first time that keratinocyte stem cells were more resistant to UVA irradiation than their direct progeny, transient amplifying cells. Using both the MTT assay and clonogenic assay, we found that KSCs were more photo-resistant compared to TAs after exposure to different doses of UVA (from 0 to 50 J/cm2). Moreover, KSCs had a greater ability to reconstruct human epidermis (RHE) after UVA exposure compared with TAs. Finally, investigations of DNA repair using the comet assay showed that DNA single-strand breaks and thymine dimers were repaired quicker and more efficiently in KSCs compared with TAs. In a previous work, we showed that the same stem cell population was more resistant to ionizing radiation, another carcinogenic agent. Collectively, our results combined with other observations demonstrate that keratinocyte stem cells, which are responsible for epidermal renewal throughout life, are equipped with an efficient arsenal against several genotoxic agents. Our future work will try to identify the factors or signaling pathways that are responsible for this differential photo-sensitivity and DNA repair capacity between KSCs and TAs. [ABSTRACT FROM AUTHOR]

The biology and behavior of adults differ substantially from those of developing animals, and cell-specific information is critical for deciphering the biology of multicellular animals. Thus, adult tissue-specific transcriptomic data are critical for understanding molecular mechanisms that control their phenotypes. We used adult cell-specific isolation to identify the transcriptomes of C. elegans’ four major tissues (or “tissue-ome”), identifying ubiquitously expressed and tissue-specific “enriched” genes. These data newly reveal the hypodermis’ metabolic character, suggest potential worm-human tissue orthologies, and identify tissue-specific changes in the Insulin/IGF-1 signaling pathway. Tissue-specific alternative splicing analysis identified a large set of collagen isoforms. Finally, we developed a machine learning-based prediction tool for 76 sub-tissue cell types, which we used to predict cellular expression differences in IIS/FOXO signaling, stage-specific TGF-β activity, and basal vs. memory-induced CREB transcription. Together, these data provide a rich resource for understanding the biology governing multicellular adult animals. [ABSTRACT FROM AUTHOR]

This article presents the first empirical experimental data on the skin absorption of methyl chloride gas using an in vitro technique and human skin. Methyl chloride is a commonly used industrial agent that is known to be an inhalational hazard but is also reported to be absorbed through human skin in amounts that contribute substantially to systemic intoxication. As a result, is has been assigned a skin notation by the ACGIH. Other than predictive models, there is a general paucity of experimental data on the skin absorption of methyl chloride and therefore a distinct lack of empirical evidence in the open literature to support the assignment of a skin notation for this chemical. This study found that methyl chloride permeates through human epidermis when exposed at high atmospheric concentrations within relatively short timeframes. Therefore, providing important initial empirical evidence in support of the assignment of a skin notation. [ABSTRACT FROM AUTHOR]

Cultured keratinocytes play important roles in burn wound healing and scientific research studies. We aimed to modify the isolation method to avoid over-digestion, maximize the number of isolated epidermal cells and establish a more efficient and innocuous way of cell isolation. Compared to the conventional method, the modified method combines the more dynamic process of enzymatic digestion with multiple harvestings of dissociated cells via digestion. The cells from each harvesting were immediately re-suspended in culture medium with serum to avoid extended trypsinization and then pooled for further analysis. The number of viable cells isolated per gram of adult foreskin epidermis was (18.88±13.22)×106 cells in the control group and (67.34±30.66)×106 cells in the modified group (p<0.001). No significant differences were observed in the proportion of CD49f-positive cells between the two groups (p>0.05). The modified method was significantly more efficient in dissociating keratinocytes from each unit of skin biopsy, which is particularly important for treating severe burns when donor skin is limited. [ABSTRACT FROM AUTHOR]

We previously reported elevated oxidative stress-related mechanical vulnerabilities of the skin as sparse distributions of hyperechoic areas. Although this helped establish a personalized skin care system to prevent skin disorders related to mechanical stress, obesity-related skin vulnerability involves individual differences. Here, we hypothesized that individual differences are caused by polymorphisms of GT repetitive sequences in the heme oxygenase1 (HMOX1) promoter region, which encodes an antioxidant enzyme. This cross-sectional study enrolled healthy male volunteers in a walking classroom aimed at weight control. Subjects with a body mass index <25 kg/m2 were classified as non-obese and those with body mass index ≥25 kg/m2 were classified as obese. Subject skin was categorized into sparse dermis or normal groups according to the distribution of hyperechoic areas by high-resolution skin ultrasonography (20 MHz). Genomic DNA and mRNA extracted from three body hairs with attached follicle cells were used to analyze GT repetitive sequences of the HMOX1 promoter, HMOX1 mRNA expression levels, and oxidative stress levels (8-hydroxy-2’-deoxyguanosine). Classifications of GT repetitive sequence of HMOX1 promoter were Short (<27 times) and Long (≥27 times). Higher numbers of subjects with sparse dermis were in the obese group compared with the non-obese group. In obese subjects, the number of subjects that had the Long allele of the HMOX1 promoter with sparse dermis was significantly higher compared with the normal group, whereas no association was observed between the polymorphism and ultrasonographic features in non-obese subjects. Thus, HMOX1 polymorphisms detected a risk of low collagen density in Japanese obese male subjects. [ABSTRACT FROM AUTHOR]

Skin physiology is dynamically changing over the first years of postnatal life; however, ethnic variations are still unclear. The aim of this study was to characterize infant skin barrier function, epidermal structure, and desquamation-related enzymatic activity as compared to that of adult skin in an East Asian population. The skin properties of 52 infants (3-24 months) and 27 adults (20-40 years) were assessed by noninvasive methods at the dorsal forearm and upper inner arm. Transepidermal water loss and skin surface conductance values were higher and more dispersed for infants compared to adults. Infant skin surface pH was slightly lower than adult on the dorsal forearm. The infant SC and viable epidermis were thinner compared to adults with differences that were site-specific. Although the chymotrypsin-like activity for infant skin was comparable to adult level, the caseinolytic specific activity was significantly higher for the infant cohort. These observations indicate a differently controlled pattern of corneocyte desquamation in infants. In conclusion, structural and functional differences exist between infant and adult skin in the East Asian population pointing to dynamic maturation of the epidermal barrier early in life. [ABSTRACT FROM AUTHOR]

Objective. Over the years, several techniques have been proposed for soft tissue augmentation around dental implants in order to improve keratinized mucosa width (KMW). Recently, a porcine derived acellular dermal matrix (Mucoderm®) has been proposed as autogenous graft substitute in order to avoid palatal harvesting and obtain comparable results to connective tissue grafts, in terms of aesthetics and function. The aim of this study is to present the one-year follow-up results of this matrix in peri-implant soft tissue augmentation procedures. Material and Methods. Twelve patients were enrolled in this pilot prospective study: a dental implant was placed in the upper premolar area and, at implant uncovering after eight weeks, the matrix was inserted. KMW gain was considered as primary outcome variable. Results. After one month from matrix insertion, mean KMW was 7.86±3.22 mm (100%), with no statistically significant intragroup variations (p>0.05). No membrane exposures or wound healing complications occurred during postoperative phase and, after one year, mean KMW was 5.67±2.12 mm (72.13%). Conclusions. The results of the present pilot study indicate that by placing a Mucoderm membrane during implant surgery the keratinized tissue width can be augmented, and the width remains stable for the assessment period of 12 months. Further studies with greater power and longer investigation period are needed to confirm the suggestion for clinical use. Clinical trial registration number is EudraCT number 2018-000147-16. [ABSTRACT FROM AUTHOR]

Summary: During secondary growth in most eudicots and gymnosperms, the periderm replaces the epidermis as the frontier tissue protecting the vasculature from biotic and abiotic stresses. Despite its importance, the mechanisms underlying periderm establishment and formation are largely unknown. The herbaceous Arabidopsis thaliana undergoes secondary growth, including periderm formation in the root and hypocotyl. Thus, we focused on these two organs to establish a framework to study periderm development in a model organism. We identified a set of characteristic developmental stages describing periderm growth from the first cell division in the pericycle to the shedding of the cortex and epidermis. We highlight that two independent mechanisms are involved in the loosening of the outer tissues as the endodermis undergoes programmed cell death, whereas the epidermis and the cortex are abscised. Moreover, the phellem of Arabidopsis, as in trees, is suberized, lignified and peels off. In addition, putative regulators from oak and potato are also expressed in the Arabidopsis periderm. Collectively, the periderm of Arabidopsis shares many characteristics/features of woody and tuberous periderms, rendering Arabidopsis thaliana an attractive model for cork biology. [ABSTRACT FROM AUTHOR]

Abstract: Ultraviolet radiation (UVR) and ionizing radiation (IR) are common genotoxic stresses that damage human skin, although the specific damages to the genomic DNA are different. Here, we show that in the mouse glabrous skin, both UVR and IR induce DNA damage, cell cycle arrest, and condensed cell nuclei. However, only IR induces mitotic catastrophe (MC) in the epidermis. This is because UVR induces a complete blockage of pRB phosphorylation and cell cycle arrest in the G1 phase, whereas pRB phosphorylation remains positive in a significant portion of the epidermal keratinocytes following IR exposure. Furthermore, Cyclin B1 expression is significantly downregulated only by IR but not UVR. Finally, there are more MC cells in the epidermis of p53‐/‐ mice after IR exposure as compared to wild‐type mice. Our results suggest that although both IR and UVR are genotoxic, they show distinct impacts on the cell cycle machinery and thus damage the epidermal keratinocytes via different mechanisms. [ABSTRACT FROM AUTHOR]

Lysyl oxidase-like 2 (LOXL2) is a copper-dependent monoamine oxidase that contributes to the remodelling of the extracellular matrix (ECM) by cross linkage of collagen and elastin fibres and has emerged as a potential therapeutic target in cancer and fibrosis. In the skin, LOXL2 is essential for epidermal cell polarity and differentiation. However, its role in the dermis has not been evaluated. We found that Loxl2 is dispensable for mouse dermal development, maturation and homeostasis, yet affects dermal stiffness. Neither loss of Loxl2 nor increased Loxl2 expression affected dermal architecture following treatment with the phorbol ester TPA. Furthermore, Loxl2 expression did not alter the stroma of DMBA-TPA-induced tumours. We conclude that, although Loxl2 is expressed in both dermis and epidermis, its function appears largely confined to the epidermis. [ABSTRACT FROM AUTHOR]

Cutaneous ganglioneuromas (CGNs) are exceptional. We aim to describe the anatomico‐clinical profile of primary CGN and report 4 cases. Patients were 2 men and 2 women aged 53 to 76 years, who had flesh‐colored nodules on the back, associated with adjacent keratotic changes, that is, epidermal nevus (1 case) or seborrheic keratosis (3 cases). Histopathology showed ganglion cells within a proliferation of Schwann cells. The epidermis was acanthotic, associated with sebaceous induction in 2 cases, with follicular hyperplasia as in fibroepithelial tumors (1 case) or with tricholemmoma (2 cases). Cytokeratin‐20 immunostaining showed Merkel cells in the epidermis. A higher density of Merkel cells was observed in BerEP4+ follicular structures. Along with 16 published cases, our study indicates that a nodule associated with seborrheic keratosis on the back may represent a CGN, a complex mesenchymal and epidermal/follicular lesion of neuroectodermal lineage, associating neuronal proliferation and Merkel cell hyperplasia with follicular induction. [ABSTRACT FROM AUTHOR]

Hemidesmosomes are epithelial-specific attachment structures that maintain tissue integrity and resist tension. Despite their importance, how hemidesmosomes are regulated at the post-transcriptional level is poorly understood. Caenorhabditis elegans hemidesmosomes (CeHDs) have a similar structure and composition to their mammalian counterparts, making C. elegans an ideal model for studying hemidesmosomes. Here, we focus on the transcription regulator CCAR-1, identified in a previous genetic screen searching for enhancers of mutations in the conserved hemidesmosome component VAB-10A (known as plectin in mammals). Loss of CCAR-1 function in a vab-10(e698) background results in CeHD disruption and muscle detachment from the epidermis. CCAR-1 regulates CeHD biogenesis, not by controlling the transcription of CeHD-related genes, but by affecting the alternative splicing of unc-52 (known as perlecan or HSPG2 in mammals), the predicted basement extracellular matrix (ECM) ligand of CeHDs. CCAR-1 physically interacts with HRP-2 (hnRNPR in mammals), a splicing factor known to mediate unc-52 alternative splicing to control the proportions of different UNC-52 isoforms and stabilize CeHDs. Our discovery underlines the importance of post-transcriptional regulation in hemidesmosome reorganization. It also uncovers previously unappreciated roles of CCAR-1 in alternative splicing and hemidesmosome biogenesis, shedding new light on the mechanisms through which mammalian CCAR1 functions in tumorigenesis. [ABSTRACT FROM AUTHOR]

Bletilla striata (Thunb.), an ornamental and medicinal plant, is on the list of endangered plants in China. Its pseudobulb is abundant in polysaccharide and has been used for centuries as a herbal remedy. However, a recent rise in demand has placed it at risk of extinction, and therefore, research on its propagation and genetic improvement is essential. Since polyploids tend to possess advantageous qualities, we incubated B. striata seeds with colchicine with the aim of creating tetraploid plantlets. Aseptic seeds treated with 0.1% colchicine for 7 days showed the highest tetraploid induction rate of 40.67 ± 0.89%. Compared with the wild-type, the tetraploids could be identified by their morphological characteristics including larger stomata at a lower density, larger leaf blades, and a thicker petiole. Contents of polysaccharide and phenolic compounds were also determined in the tetraploid pseudobulbs, revealing significantly higher values than in the wild-type. In vitro colchicine treatment can therefore be used to successfully produce B. striata tetraploids with superior pseudobulbs. [ABSTRACT FROM AUTHOR]

Tissues and organs undergo extensive remodelling to reach their final morphology and physiological activity. The genetic programs underlying tissue formation are well studied, but less is known about how this formation is influenced by extrinsic forces derived from other concomitant morphogenetic events. Here we address this question in Drosophila melanogaster . We analyse tissue organisation in the embryonic epidermis at stage 10 by computational tissue segmentation methods to provide a quantitative description of packing. We find that the epidermis adopts different organisations along the dorso-ventral axis that correlate with differences in cell density. We analyse the contribution of three morphogenetic events that take place right before or concomitant to this period of embryogenesis, neuroblast delamination, asynchronous postblastoderm cell divisions and germ band extension, and we find that they all exert an influence on the packing of the epidermis. We previously described that the apical determinant Crumbs accumulates differentially in the epidermis along the dorso-ventral axis. Here we find that this differential accumulation of Crumbs correlates with the differential tissue packing. Perturbation of the three mentioned morphogenetic events also modulate Crumbs differential accumulation, suggesting that Crb could act as a read-out of tissue organisation. We also previously showed that Crb plays a role in regulating cell architecture. Now we find that it is also required for proper packing of the embryonic epidermis. In summary, here we uncover an intimate relationship between morphogenetic events and cell packing within a tissue that is dependent on surrounding cell density. Furthermore we find that this morphogenetically-regulated tissue packing modulates the key cell polarity protein Crumbs, which in turn is required for tissue packing, suggesting that it may participate in the molecular mechanism/s underlying the described tissue organisation. [ABSTRACT FROM AUTHOR]

Abstract: Background/Objectives: Water‐filtered broad‐spectrum near‐infrared irradiation can induce various biological effects, as our previous clinical, histological, and biochemical investigations have shown. However, few studies that examined the changes thus induced in gene expression. The aim was to investigate the changes in gene expression in a 3‐dimensional reconstructed epidermal tissue culture exposed to water‐filtered broad‐spectrum near‐infrared irradiation. Methods: DNA microarray and quantitative real‐time polymerase chain reaction (PCR) analysis was used to assess gene expression levels in a 3‐dimensional reconstructed epidermal model composed of normal human epidermal cells exposed to water‐filtered broad‐spectrum near‐infrared irradiation. The water filter allowed 1000–1800 nm wavelengths and excluded 1400–1500 nm wavelengths, and cells were exposed to 5 or 10 rounds of near‐infrared irradiation at 10 J/cm2. Results: A DNA microarray with over 50 000 different probes showed 18 genes that were upregulated or downregulated by at least twofold after irradiation. Quantitative real‐time PCR revealed that, relative to control cells, the gene encoding La ribonucleoprotein domain family member 6 (LARP6), which regulates collagen expression, was significantly and dose‐dependently upregulated (P < 0.05) by water‐filtered broad‐spectrum near‐infrared exposure. Gene encoding transcripts of collagen type I were significantly upregulated compared with controls (P < 0.05). Conclusions: This study demonstrates the ability of water‐filtered broad‐spectrum near‐infrared irradiation to stimulate the production of type I collagen. [ABSTRACT FROM AUTHOR]

Abstract: Ageing is a complex multifaceted process affecting skin functionality and structure. Several 3D organotypic skin culture models have reproduced ageing by inducing replicative senescence, glycation or oxidative stress. Yet, very few models have focused on hormonal ageing and especially the insulin‐like growth factor 1 (IGF‐1) signalling pathway, which has been associated with longevity in animal studies and is necessary for the early stages of skin development. In this study, we built an organotypic epidermis model with targeted IGF‐1 receptor knockdown to reproduce some aspects of hormonal ageing on skin. Our model displayed morphological and functional features of aged epidermis, which were mostly attributed to a loss of function of the Stratum basale. IGF‐1 receptor knockdown keratinocytes depicted an extended cell cycle, reduced proliferation potential and reduced adhesion capacities and greater sensitivity to oxidative stress than control cells. Altogether, this model represents an essential tool for further investigations into the mechanisms linked to some aspects of hormonal decline or when screening for potent anti‐ageing compounds. [ABSTRACT FROM AUTHOR]

The Onchidiidae family is ideal for studying the evolution of marine invertebrate species from sea to wetland environments. However, comparative studies of Onchidiidae species are rare. A total of 40 samples were collected from four species (10 specimens per onchidiid), and their histological and molecular differences were systematically evaluated to elucidate the morphological foundations underlying the adaptations of these species. A histological analysis was performed to compare the structures of respiratory organs (gill, lung sac, dorsal skin) among onchidiids, and transcriptome sequencing of four representative onchidiids was performed to investigate the molecular mechanisms associated with their respective habitats. Twenty-six SNP markers of Onchidium reevesii revealed some DNA polymorphisms determining visible traits. Non-muscle myosin heavy chain II (NMHC II) and myosin heavy chain (MyHC), which play essential roles in amphibian developmental processes, were found to be differentially expressed in different onchidiids and tissues. The species with higher terrestrial ability and increased integrated expression of Os-MHC (NMHC II gene) and the MyHC gene, illustrating that the expression levels of these genes were associated with the evolutionary degree. This study provides a comprehensive analysis of the adaptions of a diverse and widespread group of invertebrates, the Onchidiidae. Some onchidiids can breathe well through gills and skin when under seawater, and some can breathe well through lung sacs and skin when in wetlands. A histological comparison of respiratory organs and the relative expression levels of two genes provided insights into the adaptions of onchidiids that allowed their transition from shallow seas to wetlands. This work provides a valuable reference and might encourage further study. [ABSTRACT FROM AUTHOR]

Introduction: Although it is important to know the normal values of dermis, epidermis, or total skin thicknesses (ST) for some drugs and vaccine research, skin-related clinical investigations, and skin transfer operations used in plastic surgery, it would not be ethical to take new biopsies from healthy volunteers to measure their ST. This study aims to describe a new ethical histometric technique for the measurement of skin layers and to determine the mean ST of some major body regions in the people living in our region. Materials and Methods: A total of 180 skin samples from six major body regions of 90 males and 90 females were enrolled in the study. The measurements were performed histometrically from appropriate skin samples obtained from the pathology archive. The samples were classified according to the six different parts of the body (scalp, abdomen, back, dorsum of foot, dorsum of hand, and the breast). Results: The mean epidermal thickness ranged from 76.9 ± 26.2 to 267.4 ± 120.6 µm. The thickest epidermis was found in the dorsum of foot in women (267.4 ± 120.6 µm) while the thinnest was found in the breast in women (76.9 ± 26.2 µm). The mean dermal thickness ranged from 2115 ± 946.4 to 5888 ± 2422.3 µm. The thickest dermis was found in the breast in men (5888 ± 2422.3 µm), while the thinnest dermis was found in the dorsum of hand in women (2115 ± 946.4 µm). Conclusions: Human ST varies according to ethnic origin. It was determined that the dermis and epidermis of Anatolian people are thicker than that of the previously reported other ethnic groups. The skin pathology archive can be used to create maps of the body's skin structure. [ABSTRACT FROM AUTHOR]

Molting is an essential process in the nematode Caenorhabditis elegans during which the epidermal apical extracellular matrix, termed the cuticle, is detached and replaced at each larval stage. The conserved NIMA-related kinases NEKL-2/NEK8/NEK9 and NEKL-3/NEK6/NEK7, together with their ankyrin repeat partners, MLT-2/ANKS6, MLT-3/ANKS3, and MLT-4/INVS, are essential for normal molting. In nekl and mlt mutants, the old larval cuticle fails to be completely shed, leading to entrapment and growth arrest. To better understand the molecular and cellular functions of NEKLs during molting, we isolated genetic suppressors of nekl molting-defective mutants. Using two independent approaches, we identified CDC-42, a conserved Rho-family GTPase, and its effector protein kinase, SID-3/ACK1. Notably, CDC42 and ACK1 regulate actin dynamics in mammals, and actin reorganization within the worm epidermis has been proposed to be important for the molting process. Inhibition of NEKL–MLT activities led to strong defects in the distribution of actin and failure to form molting-specific apical actin bundles. Importantly, this phenotype was reverted following cdc-42 or sid-3 inhibition. In addition, repression of CDC-42 or SID-3 also suppressed nekl-associated defects in trafficking, a process that requires actin assembly and disassembly. Expression analyses indicated that components of the NEKL–MLT network colocalize with both actin and CDC-42 in specific regions of the epidermis. Moreover, NEKL–MLT components were required for the normal subcellular localization of CDC-42 in the epidermis as well as wild-type levels of CDC-42 activation. Taken together, our findings indicate that the NEKL–MLT network regulates actin through CDC-42 and its effector SID-3. Interestingly, we also observed that downregulation of CDC-42 in a wild-type background leads to molting defects, suggesting that there is a fine balance between NEKL–MLT and CDC-42–SID-3 activities in the epidermis. [ABSTRACT FROM AUTHOR]

The IL-1 cytokine family includes eleven members, among which Il-36α, β and γ, IL-36Ra and IL-38. The IL-36 cytokines are involved in the pathogenesis of psoriasis. IL-38 is also expressed in the skin and was previously proposed to act as an IL-36 antagonist. In this study, we thus examined expression and function of Il-38 in a mouse model of imiquimod (IMQ)-induced skin inflammation. Il-38 mRNA was detected in the epidermis and in primary mouse keratinocytes, but not in dermal fibroblasts. At the peak of IMQ-induced inflammation, skin Il-38 mRNA levels were reduced, whereas Il-36ra mRNA expression increased. The severity of IMQ-induced skin inflammation, as assessed by recording ear thickness and histological changes, was similar in Il-38 KO and WT littermate control mice, while, in contrast, Il-36ra-deficient mice displayed more severe skin pathology than their WT littermates. Il-38-deficiency had no impact on IMQ-induced expression of proinflammatory mediators in the skin in vivo, on the basal expression of various cytokines or chemokines by cultured primary keratinocytes and dermal fibroblasts in vitro, or on the response of these cells to Il-36β. Finally, after cessation of topical IMQ application, the resolution of skin inflammation was also not altered in Il-38 KO mice. In conclusion, Il-38-deficiency did not impact the development or resolution of IMQ-induced skin inflammation. Our observations further suggest that endogenous Il-38 does not exert Il-36 inhibitory activity in this model, or in cultured skin cells. A potential anti-inflammatory function of Il-38 in mouse skin thus still remains to be demonstrated. [ABSTRACT FROM AUTHOR]

The epidermis of the thick skin on the flexor sides of hands and feet has a very complex superficial relief, known as dermatoglyphics, constantly maintained by precise, spatially coordinated regeneration and differentiation, whose potential lies within the deeper epidermal parts - rete ridges. One of the proliferative markers, AgNORs, represents neucleolar organizing regions, that after histochemical staining with silver ions can be observed as black dots in the nucleus. The aim of this study was to estimate morphometric properties of AgNORs in different micro-topographical compartments of thick skin epidermis, such as deep intermediate and limiting epidermal ridges. Necropsy samples of thick skin were taken from the tips of big toes of fifteen cadavers, and routinely processed to paraffinized microtome sections, which were stained with hematoxylin-eosin, and silver-based method for staining nucleolar organizing regions. Morphometric analysis was performed separately on basal keratinocytes of intermediate and limiting epidermal ridges. Suprabasal layer of tips, as well as basal layer of intermediate ridge sides, as a sign of higher proliferative status, showed a higher number of silver-stained nucleolar organizer regions with small average values of the area. According to AgNORs morphology, proliferation was sporadically and diffusely present in basal, as well as in suprabasal layer of tips, and sides of limiting ridges. [ABSTRACT FROM AUTHOR]

The airway epithelium in human plays a central role as the first line of defense against environmental contaminants. Most respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, and respiratory infections, disturb normal muco-ciliary functions by stimulating the hypersecretion of mucus. Several muco-active agents have been used to treat hypersecretion symptoms in patients. Current muco-active reagents control mucus secretion by modulating either airway inflammation, cholinergic parasympathetic nerve activities or by reducing the viscosity by cleaving crosslinking in mucin and digesting DNAs in mucus. However, none of the current medication regulates mucus secretion by directly targeting airway goblet cells. The major hurdle for screening potential muco-active agents that directly affect the goblet cells, is the unavailability of in vivo model systems suitable for high-throughput screening. In this study, we developed a high-throughput in vivo model system for identifying muco-active reagents using Xenopus laevis embryos. We tested mucus secretion under various conditions and developed a screening strategy to identify potential muco-regulators. Using this novel screening technique, we identified narasin as a potential muco-regulator. Narasin treatment of developing Xenopus embryos significantly reduced mucus secretion. Furthermore, the human lung epithelial cell line, Calu-3, responded similarly to narasin treatment, validating our technique for discovering muco-active reagents. [ABSTRACT FROM AUTHOR]

Abstract: Skin mechanical properties are usually measured considering the entire skin thickness and very little is known about the mechanical behaviour of individual skin layers. We propose atomic force microscopy (AFM) as a tool to quantify nanoscale changes in the biomechanical properties and ultrastructure of human papillary dermis exposed to different mechanical and physical stimuli. Samples from 3 human skin biopsies were studied: one stretched by obesity, one subjected to a high level of sun exposure and normal skin as control. Slices of the papillary dermis layer were harvested at controlled depths from each skin biopsy and 25 μm2 areas of each slice were imaged and D‐periodicity of collagen fibres measured by AFM, together with their stiffness. Standard histological analysis was also carried out to correlate biochemical properties and their distribution with stiffness and topography. We obtained similar stiffness values between the sample affected by obesity and the control sample at any depth level into the dermis, while the sun‐exposed sample presented a significantly lower stiffness. Additionally, all samples presented an increase in the stiffness at higher depths into the papillary dermis layer. Collagen fibres close to the epidermis of sample affected either by obesity and sun exposure—the former even more than the latter—are thicker and present a larger D‐period than those in the control sample. Our results open the possibility to use structural and mechanical analysis based on AFM as a complementary tool for medical diagnosis and therapy monitoring. [ABSTRACT FROM AUTHOR]

Dermal delivery of hydrophobic drugs by microemulsion (ME) formulations and effect from ME microstructures were studied. Anti-fungal drug, clotrimazole (CLOT), was used as the model compound. ME formulations possessing different microstructures were prepared using a ME system that contains isopropyl myristate as oil, Labrasol and Cremophor EL as surfactant and co-surfactant, and water. Permeation experiments on human cadaver skin were conducted for ME and the control formulations of different CLOT concentrations. Dermal delivery of CLOT assessed by the dermal tissue drug concentration was found to be significantly higher for MEs when compared with the control formulation, evidenced by dermal retention Enhancement Ratio (ER D ) of 5.1, 2.8, and 3.0 for tested O/W, bi-continuous, and W/O MEs, respectively. The highest concentration was observed with O/W ME, suggesting the ME microstructure is an important formulation variable for enhancing dermal delivery efficiency. ME gel formulations prepared by incorporating 1.0%(w/w) of Carbopol980 showed comparable dermal CLOT concentration to MEs, but up to 2.4 fold higher than the commercial CLOT cream product, Lotrimin ® . Furthermore, Fluorescein Isothiocynate (FITC), used as a model compound for highly hydrophobic drugs, was also studied for dermal delivery by MEs, and results show consistent ME microstructure effect, suggested by significantly higher FITC concentrations in all skin layers, SC, viable epidermis, and dermis, from O/W ME over bi-continuous and W/O MEs. [ABSTRACT FROM AUTHOR]

Activation of progenitor cells is crucial to promote tissue repair following injury in adult animals. In the context of successful limb regeneration following amputation, progenitor cells residing within the stump must re-enter the cell cycle to promote regrowth of the missing limb. We demonstrate that in axolotls, amputation is sufficient to induce cell-cycle activation in both the amputated limb and the intact, uninjured contralateral limb. Activated cells were found throughout all major tissue populations of the intact contralateral limb, with internal cellular populations (bone and soft tissue) the most affected. Further, activated cells were additionally found within the heart, liver, and spinal cord, suggesting that amputation induces a common global activation signal throughout the body. Among two other injury models, limb crush and skin excisional wound, only limb crush injuries were capable of inducing cellular responses in contralateral uninjured limbs but did not achieve activation levels seen following limb loss. We found this systemic activation response to injury is independent of formation of a wound epidermis over the amputation plane, suggesting that injury-induced signals alone can promote cellular activation. In mammals, mTOR signaling has been shown to promote activation of quiescent cells following injury, and we confirmed a subset of activated contralateral cells is positive for mTOR signaling within axolotl limbs. These findings suggest that conservation of an early systemic response to injury exists between mammals and axolotls, and propose that a distinguishing feature in species capable of full regeneration is converting this initial activation into sustained and productive growth at the site of regeneration. [ABSTRACT FROM AUTHOR]

Abstract: Leaf anatomical traits may reflect plants adaption to environmental changes and influence ecosystem functions, as they regulate light absorption and gas exchange to some extent. Here, we hypothesized that leaf anatomical traits were closely related to gross primary productivity (GPP) because photosynthesis commonly occurs in the chloroplasts of palisade and spongy tissues in leaf. Eight leaf anatomical traits were measured in 916 plant species inhabiting from tropical to cold‐temperate forests in eastern China: adaxial epidermis thickness (AD), abaxial epidermis thickness (AB), leaf thickness (LT), palisade tissue thickness (PT), and spongy tissue thickness (ST), palisade–spongy tissue ratio (PT/ST), palisade tissue–leaf thickness ratio (PT/LT), and spongy tissue–leaf thickness ratio (ST/LT). Leaf anatomical traits showed significant latitudinal patterns at species, plant functional group (PFG), and community levels (p < .05), and they differed between PFG and community. Temperature and precipitation were the main factors influencing AD, AB, PT/ST, and PT/LT, explaining 33–72% of the total variation at large scale. Furthermore, AB, LT, PT/ST, and PT/LT were significantly correlated with the aridity index. Our findings filled the data gap of plant anatomical traits at regional scales, and broadened current knowledge on the adaptation strategies of plant anatomical traits, which also provided new evidence for linkages of plant traits and functioning across natural communities. A plain language summary is available for this article. [ABSTRACT FROM AUTHOR]

Trace element accumulation in the epidermis of cetaceans has been less studied. This study explored the feasibility of using epidermis as a surrogate tissue to evaluate internal contaminant burdens in Indo-Pacific humpback dolphin ( Sousa chinensis ). Eleven trace elements were analyzed in the epidermis, muscle and liver tissues from 46 individuals of dolphins stranded along the Pearl River Estuary (PRE) coast between 2007 and 2013. Trace elemental concentrations varied among the three tissues, generally with the highest concentrations found in liver tissues and lowest in the epidermis (except Zn, As, and Pb). Zn concentration in the epidermis was the highest among all tissues, indicating that Zn could be an important element for the epidermis physiology. High concentrations of Hg and Cr in liver were likely due to an excessive intake by dolphins which consumed high Hg and Cr contaminated fishes in the PRE. Hg concentrations in epidermis and muscle tissues were significantly higher in the females than in males. Concentrations of V and Pb in liver, Se and Cd in both muscle and liver, and As and Hg in all tissue samples showed significantly positive relationships with body length. Hepatic Cu concentrations were significantly negatively correlated with the body length. Hg and As concentrations in epidermis showed significantly positive correlations with those in liver tissues. Thus this study proposed that epidermis could be used as a non-invasive monitoring tissue to evaluate Hg and As bioaccumulation in internal tissues of Indo-Pacific humpback dolphins populations. [ABSTRACT FROM AUTHOR]

The feeling of touch is an essential human sensation. Four types of mechanoreceptors (i.e., FA-I, SA-I, FA-II, and SA-II) in human skin signalize physical properties, such as shape, size, and texture, of an object that is touched and transmit the signal to the brain. Previous studies attempted to investigate the mechanical properties of skin microstructure and their effect on mechanoreceptors by using finite element modeling. However, very few studies have focused on the three-dimensional microstructure of dermal papillae, and this is related to that of FA-I receptors. A gap exists between conventional 2D models of dermal papillae and the natural configuration, which corresponds to a complex and uneven structure with depth. In this study, the three-dimensional microstructure of dermal papillae is modeled, and the differences between two-dimensional and three-dimensional aspects of dermal papillae on the strain energy density at receptor positions are examined. The three-dimensional microstructure has a focalizing effect and a localizing effect. Results also reveal the potential usefulness of these effects for tactile sensor design, and this may improve edge discrimination. [ABSTRACT FROM AUTHOR]

Protein phosphatase 2A (PP2A) is a ubiquitously expressed Serine-Threonine phosphatase mediating 30–50% of protein phosphatase activity. PP2A functions as a heterotrimeric complex, with the B subunits directing target specificity to regulate the activity of many key pathways that control cellular phenotypes. PP2A-B56α has been shown to play a tumor suppressor role and to negatively control c-MYC stability and activity. Loss of B56α promotes cellular transformation, likely at least in part through its regulation of c-MYC. Here we report generation of a B56α hypomorph mouse with very low B56α expression that we used to study the physiologic activity of the PP2A-B56α phosphatase. The predominant phenotype we observed in mice with B56α deficiency in the whole body was spontaneous skin lesion formation with hyperproliferation of the epidermis, hair follicles and sebaceous glands. Increased levels of c-MYC phosphorylation on Serine62 and c-MYC activity were observed in the skin lesions of the B56αhm/hm mice. B56α deficiency was found to increase the number of skin stem cells, and consistent with this, papilloma initiation was accelerated in a carcinogenesis model. Further analysis of additional tissues revealed increased inflammation in spleen, liver, lung, and intestinal lymph nodes as well as in the skin lesions, resembling elevated extramedullary hematopoiesis phenotypes in the B56αhm/hm mice. We also observed an increase in the clonogenicity of bone marrow stem cells in B56αhm/hm mice. Overall, this model suggests that B56α is important for stem cells to maintain homeostasis and that B56α loss leading to increased activity of important oncogenes, including c-MYC, can result in aberrant cell growth and increased stem cells that can contribute to the initiation of malignancy. [ABSTRACT FROM AUTHOR]

While all 2-methylene-19-nor analogs of 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) tested produce an increase in epidermal thickness in the rhino mouse, only a subset reduce utricle size (comedolysis). All-trans retinoic acid (atRA) also causes epidermal thickening and a reduction in utricle size in the rhino mouse. We now report that 2-methylene-19-nor-(20S)-1α-hydroxybishomopregnacalciferol (2MbisP), a comedolytic analog, increases epidermal thickening more rapidly than does atRA, while both reduce utricle area at an equal rate. Whereas unlike atRA, 2MbisP does not alter the epidermal growth factor receptor ligand, heparin-binding epidermal growth factor-like growth factor, it does increase the expression of both amphiregulin and epigen mRNA, even after a single dose. In situ hybridization reveals an increase in these transcripts throughout the closing utricle as well as in the interfollicular epidermis. The mRNAs for other EGFR ligands including betacellulin and transforming growth factor-α, as well as the epidermal growth factor receptor are largely unaffected by 2MbisP. Another analog, 2-methylene-19-nor-(20S)-26,27-dimethylene-1α,25-dihydroxyvitamin D3 (CAGE-3), produces epidermal thickening but fails to reduce utricle size or increase AREG mRNA levels. CAGE-3 modestly increases epigen mRNA levels, but only after 5 days of dosing. Thus, 2-MbisP produces unique changes in epidermal growth factor receptor ligand mRNAs that may be responsible for both epidermal proliferation and a reduction in utricle size. [ABSTRACT FROM AUTHOR]

Bowhead whales (Balaena mysticetus) have a nearly circumpolar distribution, and occasionally occupy warmer shallow coastal areas during summertime that may facilitate molting. However, relatively little is known about the occurrence of molting and associated behaviors in bowhead whales. We opportunistically observed whales in Cumberland Sound, Nunavut, Canada with skin irregularities consistent with molting during August 2014, and collected a skin sample from a biopsied whale that revealed loose epidermis and sloughing. During August 2016, we flew a small unmanned aerial system (sUAS) over whales to take video and still images to: 1) determine unique individuals; 2) estimate the proportion of the body of unique individuals that exhibited sloughing skin; 3) determine the presence or absence of superficial lines representative of rock-rubbing behavior; and 4) measure body lengths to infer age-class. The still images revealed that all individuals (n = 81 whales) were sloughing skin, and that nearly 40% of them had mottled skin over more than two-thirds of their bodies. The video images captured bowhead whales rubbing on large rocks in shallow, coastal areas—likely to facilitate molting. Molting and rock rubbing appears to be pervasive during late summer for whales in the eastern Canadian Arctic. [ABSTRACT FROM AUTHOR]

Dengue virus (DENV) is the most prevalent, medically important mosquito-borne virus. Disease ranges from uncomplicated dengue to life-threatening disease, characterized by endothelial dysfunction and vascular leakage. Previously, we demonstrated that DENV nonstructural protein 1 (NS1) induces endothelial hyperpermeability in a systemic mouse model and human pulmonary endothelial cells, where NS1 disrupts the endothelial glycocalyx-like layer. NS1 also triggers release of inflammatory cytokines from PBMCs via TLR4. Here, we examined the relative contributions of inflammatory mediators and endothelial cell-intrinsic pathways. In vivo, we demonstrated that DENV NS1 but not the closely-related West Nile virus NS1 triggers localized vascular leak in the dorsal dermis of wild-type C57BL/6 mice. In vitro, we showed that human dermal endothelial cells exposed to DENV NS1 do not produce inflammatory cytokines (TNF-α, IL-6, IL-8) and that blocking these cytokines does not affect DENV NS1-induced endothelial hyperpermeability. Further, we demonstrated that DENV NS1 induces vascular leak in TLR4- or TNF-α receptor-deficient mice at similar levels to wild-type animals. Finally, we blocked DENV NS1-induced vascular leak in vivo using inhibitors targeting molecules involved in glycocalyx disruption. Taken together, these data indicate that DENV NS1-induced endothelial cell-intrinsic vascular leak is independent of inflammatory cytokines but dependent on endothelial glycocalyx components. [ABSTRACT FROM AUTHOR]