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Degenerative Suspensory Ligament Desmitis (DSLD) negatively impacts connective tissues in horses, which often leads to progressive chronic pain and lameness. DSLD has been shown to be a systemic disorder that affects multiple body systems, including tendons, sclerae, and the aorta. Currently, the diagnosis is confirmed by post mortem histological examination of a tendon or suspensory ligament. Histology reveals inappropriate accumulations of proteoglycans in the tendons and other tissues in DSLD-affected horses. Unfortunately, there is no reliable method to diagnose DSLD in living horses. Recently, bone morphogenetic protein 2 (BMP2) was identified in active DSLD lesions. In addition, recent data from RNA sequencing (RNA-seq) showed overexpression of numerous genes, among them BMP2, FOS and genes for keratins in DSLD skin biopsies-derived RNA. We hypothesized that some of these genes can be used as biomarkers for diagnosis of DSLD in a panel. Overexpression of some of them was verified in quantitative real time PCR. Immunohistochemistry and RNAscope in-situ hybridization (ISH) assays were used to determine the level of overexpression of specific genes in skin biopsies from control and DSLD-affected horses. The RNAscope ISH assay has shown to be more reliable and more specific that immunohistochemistry. ISH confirmed a significant increase in KRT83 and BMP-2 in hair follicles in DSLD cases, as well as abnormally high expression of FOS in the epidermis, especially in aging horses. Because statistically relevant specificity and sensitivity was documented only for FOS and BMP2, but not KRT83 we recommend the use of FOS and BMP2 panel to diagnose DSLD. We conclude that a panel of two markers from the studied group (BMP2 and FOS) can serve as an additional diagnostic tool for DSLD in living horses, especially in older animals. Further studies are necessary to confirm if this biomarker panel could be used as a prospective tool to identify DSLD in horses as they age.

Social touch is an important form of interpersonal emotion regulation. In recent years, the emotion regulation effects of two types of touch have been studied extensively: handholding and stroking (specifically of skin with C-tactile afferents on the forearm, i.e. C-touch). While some studies compare their effectiveness, with mixed results, no study to date has examined which type of touch is subjectively preferred. Given the potential bidirectional communication provided by handholding, we hypothesized that to regulate intense emotions, participants would prefer handholding. In four pre-registered online studies (total N = 287), participants rated handholding and stroking, presented in short videos, as emotion regulation methods. Study 1 examined touch reception preference in hypothetical situations. Study 2 replicated Study 1 while also examining touch provision preferences. Study 3 examined touch reception preferences of participants with blood/injection phobia in hypothetical injection situations. Study 4 examined types of touch participants who have recently given birth recalled receiving during childbirth and their hypothetical preferences. In all studies, participants preferred handholding over stroking; participants who have recently given birth reported receiving handholding more than stroking. This was especially evident in Studies 1-3 in emotionally intense situations. These results demonstrate that handholding is preferred over stroking as a form of emotion regulation, especially in intense situations, and support the importance of two-way sensory communication for emotion regulation via touch. We discuss the results and possible additional mechanisms, including top-down processing and cultural priming.

Protein profiling offers an effective approach to characterizing how far epidermis departs from normal in disease states. The present pilot investigation tested the hypothesis that protein expression in epidermal corneocytes is perturbed in the forehead of subjects exhibiting frontal fibrosing alopecia. To this end, samples were collected by tape stripping from subjects diagnosed with this condition and compared to those from asymptomatic control subjects and from those exhibiting androgenetic alopecia. Unlike the latter, which exhibited only 3 proteins significantly different from controls in expression level, forehead samples from frontal fibrosing alopecia subjects displayed 72 proteins significantly different from controls, nearly two-thirds having lower expression. The results demonstrate frontal fibrosing alopecia exhibits altered corneocyte protein expression in epidermis beyond the scalp, indicative of a systemic condition. They also provide a basis for quantitative measures of departure from normal by assaying forehead epidermis, useful in monitoring response to treatment while avoiding invasive biopsy.

Collagen is the major structural protein in the skin. Fragmentation and disorganization of the collagen fibrils are the hallmarks of the aged human skin dermis. These age-related alterations of collagen fibrils impair skin structural integrity and make the tissue microenvironment more prone to skin disorders. As the biological function of collagen lies predominantly in its physical properties, we applied atomic force microscopy (AFM) and nanoindentation to evaluate the physical properties (surface roughness, stiffness, and hardness) of dermal collagen in young (25±5 years, N = 6) and aged (75±6 years, N = 6) healthy sun-protected hip skin. We observed that in the aged dermis, the surface of collagen fibrils was rougher, and fiber bundles were stiffer and harder, compared to young dermal collagen. Mechanistically, the age-related elevation of matrix metalloproteinase-1 (MMP-1) and advanced glycation end products (AGEs) are responsible for rougher and stiffer/harder dermal collagen, respectively. Analyzing the physical properties of dermal collagen as a function of age revealed that alterations of the physical properties of collagen fibrils changed with age (22–89 years, N = 18). We also observed that the reticular dermis is rougher and mechanically stiffer and harder compared to the papillary dermis in human skin. These data extend the current understanding of collagen beyond biological entities to include biophysical properties. [ABSTRACT FROM AUTHOR]

Clinical testing typically relies on invasive blood draws and biopsies. Alternative methods of sample collection are continually being developed to improve patient experience; swabbing the skin is one of the least invasive sampling methods possible. To show that skin swabs in combination with untargeted mass spectrometry (metabolomics) can be used for non-invasive monitoring of an oral drug, we report the kinetics and metabolism of diphenhydramine in healthy volunteers (n = 10) over the course of 24 hours in blood and three regions of the skin. Diphenhydramine and its metabolites were observed on the skin after peak plasma levels, varying by compound and skin location, and is an illustrative example of how systemically administered molecules can be detected on the skin surface. The observation of diphenhydramine directly from the skin supports the hypothesis that both parent drug and metabolites can be qualitatively measured from a simple non-invasive swab of the skin surface. The mechanism of the drug and metabolites pathway to the skin's surface remains unknown.

Keratinocyte migration into skin wounds is the step of the healing process that correlates with the wound closure rate. Keratinocyte migration, and wound epithelialization are decreased when beta 2-adrenergic receptors (B2AR) are activated by 1 μM epinephrine/adrenaline, resulting in delayed wound healing in human and mouse skin. In the present study, we found paradoxically, that in a subset of keratinocyte strains exposure to low concentrations of epinephrine (0.1 nM) increased, rather than decreased, their migratory rate. We find that both the alpha- and the beta-adrenergic receptors are expressed in human keratinocytes, and expression of alpha-2 AR subtypes demonstrated for the first time. Therefore, we tested if the alpha-AR could be modulating the increased migratory response observed in these cell strains. By using specific inhibitors to alpha-AR, we demonstrated that blocking A2B-AR could reverse the rapid cell migration induced by the 0.1 nM epinephrine. Phosphorylation of ERK was elevated after 1-10 minutes of the low epinephrine treatment and the A2B-AR inhibitor blocked the ERK phosphorylation. The results suggest that both the A2B-AR and B2AR mediate keratinocyte migration, in which with a low level of epinephrine treatment, A2B-AR could alter the B2AR signals and regulate the migration rate.

Wound healing is a multi-step process to rapidly restore the barrier function. This process is often impaired in diabetic patients resulting in chronic wounds and amputation. We previously found that paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway via topical administration of the BRAF inhibitor vemurafenib accelerates wound healing by activating keratinocyte proliferation and reepithelialization pathways in healthy mice. Herein, we investigated whether this wound healing acceleration also occurs in impaired diabetic wounds and found that topical vemurafenib not only improves wound healing in a murine diabetic wound model but unexpectedly promotes hair follicle regeneration. Hair follicles expressing Sox-9 and K15 surrounded by CD34+ stroma were found in wounds of diabetic and non-diabetic mice, and their formation can be prevented by blocking downstream MEK signaling. Thus, topically applied BRAF inhibitors may accelerate wound healing, and promote the restoration of improved skin architecture in both normal and impaired wounds.

We devised a surgical tape that prevents skin tears while maintaining adhesive strength. Under the assumption that microscopic damage to the skin is reflected in pain felt on the skin, we statistically analyzed skin pain when the tape was peeled off to show the skin protection effect of the mesh on the new tape. This tape has a three-layer structure consisting of a tape substrate, adhesive, and mesh. When the tape is applied to the skin, a mesh is located between the adhesive and the skin. The adhesive contacts the skin through the mesh holes and fixes the substrate to the skin; it does not come into contact with the skin at the mesh body; therefore, the adhesive-skin contact area is reduced. In this experiment, we used surgical tape with and without mesh. At 8 hours after the application of each tape to the forearm of five adult males, it was removed. All tapes were peeled off while maintaining an angle of approximately 120° between the skin and tape substrate. For the tape with mesh, the tape substrate was peeled off in two ways: peeling off the substrate together with the mesh and peeling off the substrate, leaving the mesh on the skin. A perception and pain quantification analyzer (Pain Vision™) was used to quantify pain. The data were compared and examined statistically (Friedman's test and Wilcoxon's coded rank test). The least pain was experienced while peeling off the tape substrate, leaving the mesh on the skin. There was a significant difference in pain levels among the three tape removal methods. There was also a significant difference between the two peeling methods in the experimental group. The skin protection effect of the mesh reduced pain when the surgical tape was removed. [ABSTRACT FROM AUTHOR]

Ion channels have recently attracted attention as potential mediators of skin disease. Here, we explored the consequences of genetically encoded induction of the cell volume-regulating Ca2+-activated KCa3.1 channel (Kcnn4) for murine epidermal homeostasis. Doxycycline-treated mice harboring the KCa3.1+-transgene under the control of the reverse tetracycline-sensitive transactivator (rtTA) showed 800-fold channel overexpression above basal levels in the skin and solid KCa3.1-currents in keratinocytes. This overexpression resulted in epidermal spongiosis, progressive epidermal hyperplasia and hyperkeratosis, itch and ulcers. The condition was accompanied by production of the pro-proliferative and pro-inflammatory cytokines, IL-β1 (60-fold), IL-6 (33-fold), and TNFα (26-fold) in the skin. Treatment of mice with the KCa3.1-selective blocker, Senicapoc, significantly suppressed spongiosis and hyperplasia, as well as induction of IL-β1 (-88%) and IL-6 (-90%). In conclusion, KCa3.1-induction in the epidermis caused expression of pro-proliferative cytokines leading to spongiosis, hyperplasia and hyperkeratosis. This skin condition resembles pathological features of eczematous dermatitis and identifies KCa3.1 as a regulator of epidermal homeostasis and spongiosis, and as a potential therapeutic target.

Epidermal lineages and injury induced regeneration are controlled by transcriptional programs coordinating cellular signaling and epigenetic regulators, but the mechanism remains unclear. Previous studies showed that conditional deletion of the transcriptional coactivator Mediator 1 (Med1) changes epidermal lineages and accelerates wound re-epithelialization. Here, we studied a molecular mechanism by which Med1 facilitates these processes, in particular, by focusing on TGFβ signaling through genome wide transcriptome analysis. The expression of the TGF ligands (Tgfβ1/β2) and their downstream target genes is decreased in both normal and wounded Med1 null skin. Med1 silencing in cultured keratinocytes likewise reduces the expression of the ligands (TGFβ1/β2) and diminishes activity of TGFβ signaling as shown by decreased p-Smad2/3. Silencing Med1 increases keratinocyte proliferation and migration in vitro. Epigenetic studies using chromatin immuno-precipitation and next generation DNA sequencing reveals that Med1 regulates transcription of TGFβ components by forming large clusters of enhancers called super-enhancers at the regulatory regions of the TGFβ ligand and SMAD3 genes. These results demonstrate that Med1 is required for the maintenance of the TGFβ signaling pathway. Finally, we show that pharmacological inhibition of TGFβ signaling enhances epidermal lineages and accelerates wound re-epithelialization in skin similar to that seen in the Med1 null mice, providing new insights into epidermal regeneration.

We recently used EPA databases to identify that isocyanates, most notably toluene diisocyanate (TDI), were the pollutant class with the strongest spatiotemporal and epidemiologic association with atopic dermatitis (AD). Our findings demonstrated that isocyanates like TDI disrupted lipid homeostasis and modeled benefit in commensal bacteria like Roseomonas mucosa through disrupting nitrogen fixation. However, TDI has also been established to activate transient receptor potential ankyrin 1 (TRPA1) in mice and thus could directly contribute to AD through induction of itch, rash, and psychological stress. Using cell culture and mouse models, we now demonstrate that TDI induced skin inflammation in mice as well as calcium influx in human neurons; each of these findings were dependent on TRPA1. Furthermore, TRPA1 blockade synergized with R. mucosa treatment in mice to improve TDI-independent models of AD. Finally, we show that the cellular effects of TRPA1 are related to shifting the balance of the tyrosine metabolites epinephrine and dopamine. This work provides added insight into the potential role, and therapeutic potential, or TRPA1 in the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory skin disease manifested as painful inflamed lesions including deep-seated nodules, abscesses and sinus tracts. The exact aetiology of HS is unclear. Recent evidence suggests that immune dysregulation plays a crucial role in pathogenesis and disease progression. Innate lymphoid cells (ILC) are a recently identified immune cell subset involved in mediating immunity, however their role in HS has not yet been investigated. Three distinct subsets of ILC- ILC1, ILC2 and ILC3 have been described, and these are involved in skin tissue homeostasis and pathologic inflammation associated with autoimmunity and allergic diseases. In this study, we analysed by multiparameter flow cytometry the frequencies of ILC subsets in skin and peripheral blood mononuclear cells (PBMC) of HS patients and compared these to healthy control subjects and psoriasis patients. The absolute numbers of total ILC and subsets thereof were significantly reduced in the blood of HS patients relative to healthy controls. However, when patients were stratified according to treatment, this reduction was no longer observed in patients undergoing anti-TNF treatment. In HS lesional skin the absolute numbers of ILC were significantly increased relative to control skin. Furthermore, the frequencies of total ILC as well as ILC2 and ILC3 were significantly higher in non-lesional than lesional HS skin. This study analysed for the first time the presence of ILC subsets in the blood and skin of HS patients. Our findings suggest that ILC may participate in HS pathogenesis. [ABSTRACT FROM AUTHOR]

Poison frogs acquire chemical defenses from the environment for protection against potential predators. These defensive chemicals are lipophilic alkaloids that are sequestered by poison frogs from dietary arthropods and stored in skin glands. Despite decades of research focusing on identifying poison frog alkaloids, we know relatively little about how environmental variation and subsequent arthropod availability impacts alkaloid loads in poison frogs. We investigated how seasonal environmental variation influences poison frog chemical profiles through changes in the diet of the Climbing Mantella (Mantella laevigata). We collected M. laevigata females on the Nosy Mangabe island reserve in Madagascar during the wet and dry seasons and tested the hypothesis that seasonal differences in rainfall is associated with changes in diet composition and skin alkaloid profiles of M. laevigata. The arthropod diet of each frog was characterized into five groups (i.e. ants, termites, mites, insect larvae, or other) using visual identification and cytochrome oxidase 1 DNA barcoding. We found that frog diet differed between the wet and dry seasons, where frogs had a more diverse diet in the wet season and consumed a higher percentage of ants in the dry season. To determine if seasonality was associated with variation in frog defensive chemical composition, we used gas chromatography / mass spectrometry to quantify alkaloids from individual skin samples. Although the assortment of identified alkaloids was similar across seasons, we detected significant differences in the abundance of certain alkaloids, which we hypothesize reflects seasonal variation in the diet of M. laevigata. We suggest that these variations could originate from seasonal changes in either arthropod leaf litter composition or changes in frog behavioral patterns. Although additional studies are needed to understand the consequences of long-term environmental shifts, this work suggests that alkaloid profiles are relatively robust against short-term environmental perturbations.

Background: Pain is a common non-motor symptom of Parkinson's disease (PD), however, its pathomechanism remains elusive. Objective: We aimed to investigate the local gene expression of selected proinflammatory mediators in patients with PD and correlated our data with patients'pain phenotype. Methods: We recruited 30 patients with PD and 30 healthy controls. Pain intensity of patients was assessed using the Numeric Rating Scale (NRS) and patients were stratified into PD pain (NRS≥4) and PD No Pain (NRS<4) subgroups. Skin punch biopsies were immunoassayed for protein-gene product 9.5 as a pan-neuronal marker and intraepidermal nerve fiber density (IEFND). Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was performed to assess the gene expression of inflammatory mediators in the skin compared to controls. Results: Patients with PD had lower distal IENFD compared to healthy controls. In skin samples, IL-2 (p<0.001) and TNF-α (p<0.01) were expressed higher in PD patients compared to controls. IL-1β (p<0.05) was expressed higher in the PD pain group compared to healthy controls. PD patients with pain receiving analgesics had a lower expression of TNF-α (p<0.05) in the skin compared to those not receiving treatment. Conclusions: Our data suggest the occurrence of a local, peripheral inflammatory response in the skin in PD, but do not support this being a relevant factor contributing to pain in PD. [ABSTRACT FROM AUTHOR]

Research on visually driven behavior in anurans has often focused on Dendrobatoidea, a clade with extensive variation in skin reflectance, which is perceived to range from cryptic to conspicuous coloration. Because these skin patterns are important in intraspecific and interspecific communication, we hypothesized that the visual spectral sensitivity of dendrobatids should vary with conspecific skin spectrum. We predicted that the physiological response of frog retinas would be tuned to portions of the visible light spectrum that match their body reflectance. Using wavelength-specific electroretinograms (ERGs; from 350-650 nm), spectrometer measurements, and color-calibrated photography of the skin, we compared retinal sensitivity and reflectance of two cryptic species (Allobates talamancae and Silverstoneia flotator), two intermediate species (Colostethus panamansis and Phyllobates lugubris), and two conspicuous aposematic species (Dendrobates tinctorius and Oophaga pumilio). Consistent with the matched filter hypothesis, the retinae of cryptic and intermediate species were sensitive across the spectrum, without evidence of spectral tuning to specific wavelengths, yielding low-threshold broadband sensitivity. In contrast, spectral tuning was found to be different between morphologically distinct populations of O. pumilio, where frogs exhibited retinal sensitivity better matching their morph's reflectance. This sensory specialization is particularly interesting given the rapid phenotypic divergence exhibited by this species and their behavioral preference for sympatric skin reflectances. Overall, this study suggests that retinal sensitivity is coevolving with reflective strategy and spectral reflectance in dendrobatids., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Walkowski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Understanding trophic relationships among marine predators in remote environments is challenging, but it is critical to understand community structure and dynamics. In this study, we used stable isotope analysis of skin biopsies to compare the isotopic, and thus, trophic niches of three sympatric delphinids in the waters surrounding Palmyra Atoll, in the Central Tropical Pacific: the melon-headed whale (Peponocephala electra), Gray's spinner dolphin (Stenella longirostris longirostris), and the common bottlenose dolphin (Tursiops truncatus). δ15N values suggested that T. truncatus occupied a significantly higher trophic position than the other two species. δ13C values did not significantly differ between the three delphinds, potentially indicating no spatial partitioning in depth or distance from shore in foraging among species. The dietary niche area-determined by isotopic variance among individuals-of T. truncatus was also over 30% smaller than those of the other species taken at the same place, indicating higher population specialization or lower interindividual variation. For P. electra only, there was some support for intraspecific variation in foraging ecology across years, highlighting the need for temporal information in studying dietary niche. Cumulatively, isotopic evidence revealed surprisingly little evidence for trophic niche partitioning in the delphinid community of Palmyra Atoll compared to other studies. However, resource partitioning may happen via other behavioral mechanisms, or prey abundance or availability may be adequate to allow these three species to coexist without any such partitioning. It is also possible that isotopic signatures are inadequate to detect trophic partitioning in this environment, possibly because isotopes of prey are highly variable or insufficiently resolved to allow for differentiation.

BackgroundIntrauterine infection is a primary cause of preterm birth and fetal injury. The pro-inflammatory role of the fetal skin in the setting of intrauterine infection remains poorly characterized. Whether or not inflammation of the fetal skin occurs in primates remains unstudied. Accordingly, we hypothesized that: i) the fetal primate skin would mount a pro-inflammatory response to preterm birth associated pro-inflammatory agents (lipopolysaccharides from Escherichia coli, live Ureaplasma parvum, interleukin-1β) and; ii) that inhibiting interleukin-1 signaling would decrease the skin inflammatory response.MethodsRhesus macaques with singleton pregnancies received intraamniotic injections of either sterile saline (control) or one of three pro-inflammatory agonists: E. coli lipopolysaccharides, interluekin-1β or live U. parvum under ultrasound guidance. A fourth group of animals received both E. coli lipopolysaccharide and interleukin-1 signaling inhibitor interleukin-1 receptor antagonist (Anakinra) prior to delivery. Animals were surgically delivered at approximately 130 days' gestational age.ResultsIntraamniotic lipopolysaccharide caused an inflammatory skin response characterized by increases in interluekin-1β,-6 and -8 mRNA at 16 hours. There was a modest inflammatory response to U. parvum, but interleukin-1β alone caused no inflammatory response in the fetal skin. Intraamniotic Anakinra treatment of lipopolysaccharide-exposed animals significantly reduced skin inflammation.ConclusionsIntraamniotic lipopolysaccharide and U. parvum were associated with modest increases in the expression of inflammatory mediators in primate fetal skin. Although administration of Interleukin-1β alone did not elicit an inflammatory response, lipopolysaccharide-driven skin inflammation was decreased following intraamniotic Anakinra therapy. These findings provide support for the role of the fetal skin in the development of the fetal inflammatory response.

BackgroundThere are no effective treatments or validated clinical response markers in systemic sclerosis (SSc). We assessed imaging biomarkers and performed gene expression profiling in a single-arm open-label clinical trial of tyrosine kinase inhibitor dasatinib in patients with SSc-associated interstitial lung disease (SSc-ILD).MethodsPrimary objectives were safety and pharmacokinetics. Secondary outcomes included clinical assessments, quantitative high-resolution computed tomography (HRCT) of the chest, serum biomarker assays and skin biopsy-based gene expression subset assignments. Clinical response was defined as decrease of >5 or >20% from baseline in the modified Rodnan Skin Score (MRSS). Pulmonary function was assessed at baseline and day 169.ResultsDasatinib was well-tolerated in 31 patients receiving drug for a median of nine months. No significant changes in clinical assessments or serum biomarkers were seen at six months. By quantitative HRCT, 65% of patients showed no progression of lung fibrosis, and 39% showed no progression of total ILD. Among 12 subjects with available baseline and post-treatment skin biopsies, three were improvers and nine were non-improvers. Improvers mapped to the fibroproliferative or normal-like subsets, while seven out of nine non-improvers were in the inflammatory subset (p = 0.0455). Improvers showed stability in forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), while both measures showed a decline in non-improvers (p = 0.1289 and p = 0.0195, respectively). Inflammatory gene expression subset was associated with higher baseline HRCT score (p = 0.0556). Non-improvers showed significant increase in lung fibrosis (p = 0.0313).ConclusionsIn patients with SSc-ILD dasatinib treatment was associated with acceptable safety profile but no significant clinical efficacy. Patients in the inflammatory gene expression subset showed increase in skin fibrosis, decreasing pulmonary function and worsening lung fibrosis during the study. These findings suggest that target tissue-specific gene expression analyses can help match patients and therapeutic interventions in heterogeneous diseases such as SSc, and quantitative HRCT is useful for assessing clinical outcomes.Trial registrationClinicaltrials.gov NCT00764309.

This study was conceived to detect skin mites in social mammals through real-time qPCR, and to estimate taxonomic Demodex and further Prostigmata mite relationships in different host species by comparing sequences from two genes: mitochondrial 16S rRNA and nuclear 18S rRNA. We determined the mite prevalence in the hair follicles of marmots (13%) and bats (17%). The high prevalence found in marmots and bats by sampling only one site on the body may indicate that mites are common inhabitants of their skin. Since we found three different mites (Neuchelacheles sp, Myobia sp and Penthaleus sp) in three bat species (Miotis yumanensis, Miotis californicus and Corynorhinus townsendii) and two different mites (both inferred to be members of the Prostigmata order) in one marmot species (Marmota flaviventris), we tentatively concluded that these skin mites 1) cannot be assigned to the same genus based only on a common host, and 2) seem to evolve according to the specific habitat and/or specific hair and sebaceous gland of the mammalian host. Moreover, two M. yumanensis bats harbored identical Neuchelacheles mites, indicating the possibility of interspecific cross-infection within a colony. However, some skin mites species are less restricted by host species than previously thought. Specifically, Demodex canis seems to be more transmissible across species than other skin mites. D. canis have been found mostly in dogs but also in cats and captive bats. In addition, we report the first case of D. canis infestation in a domestic ferret (Mustela putorius). All these mammalian hosts are related to human activities, and D. canis evolution may be a consequence of this relationship. The monophyletic Demodex clade showing closely related dog and human Demodex sequences also supports this likely hypothesis.

While much is known about genes that promote aging, little is known about genes that protect against or prevent aging, particularly in human skin. The main objective of this study was to perform an unbiased, whole transcriptome search for genes that associate with intrinsic skin youthfulness. To accomplish this, healthy women (n = 122) of European descent, ages 18-89 years with Fitzpatrick skin type I/II were examined for facial skin aging parameters and clinical covariates, including smoking and ultraviolet exposure. Skin youthfulness was defined as the top 10% of individuals whose assessed skin aging features were most discrepant with their chronological ages. Skin biopsies from sun-protected inner arm were subjected to 3'-end sequencing for expression quantification, with results verified by quantitative reverse transcriptase-polymerase chain reaction. Unbiased clustering revealed gene expression signatures characteristic of older women with skin youthfulness (n = 12) compared to older women without skin youthfulness (n = 33), after accounting for gene expression changes associated with chronological age alone. Gene set analysis was performed using Genomica open-access software. This study identified a novel set of candidate skin youthfulness genes demonstrating differences between SY and non-SY group, including pleckstrin homology like domain family A member 1 (PHLDA1) (p = 2.4x10-5), a follicle stem cell marker, and hyaluronan synthase 2-anti-sense 1 (HAS2-AS1) (p = 0.00105), a non-coding RNA that is part of the hyaluronan synthesis pathway. We show that immunologic gene sets are the most significantly altered in skin youthfulness (with the most significant gene set p = 2.4x10-5), suggesting the immune system plays an important role in skin youthfulness, a finding that has not previously been recognized. These results are a valuable resource from which multiple future studies may be undertaken to better understand the mechanisms that promote skin youthfulness in humans.

Many skin diseases show circular red lesions on the skin, called erythema. Erythema is characterized by the expansion of its circular area solely from local stimulation. A pathological inflammatory response caused by the stimulation persistently increases inflammatory mediators in the dermis, whereas a normal inflammatory response transiently increases mediators, resulting in the shrinkage of the erythema. Although the diffusion of mediators theoretically reproduces the expansion, how the inflammatory response expands or shrinks the erythema remains unknown. A possibility is positive feedback, which affects mediator production and can generate two distinct stable states (i.e., inflamed and noninflamed), referred to as bistability. Bistability causes a state transition either from the noninflamed to inflamed state or the reverse direction by suprathreshold stimulation. Additionally, the diffusion selectively causes state transition in either direction, resulting in spatial spread of the transited state, known as the traveling wave. Therefore, we hypothesize that the traveling wave of the inflammatory response can account for both the expansion and shrinkage. Using a reaction-diffusion model with bistability, we theoretically show a possible mechanism in which the circular inflamed area expands via the traveling wave from the noninflamed to the inflamed state. During the expansion, the boundary between the inflamed and noninflamed areas moves at a constant velocity while maintaining its concentration gradient. Moreover, when the positive feedback is weak, the traveling wave selectively occurs from the inflamed to noninflamed state, shrinking the inflamed area. Whether the inflamed area expands or shrinks is mainly controlled by the balance of mediator concentration between the noninflamed and inflamed states, relative to the threshold. The traveling wave of the inflammatory response provides an experimentally testable framework for erythema expansion and shrinkage, thereby contributing to the development of effective treatments, including probiotics. [ABSTRACT FROM AUTHOR]

Burn is a common case in developing countries, with over half of fire-related deaths reported in Southeast Asia and full-thickness burns as a high mortality risk. Human amnion has been used as a wound dressing for centuries. In this study, a decellularised amnion overlaid with fibrin, "amnion bilayer (AB)," was used as a dressing immediately after burn and as a graft to replace the scar in Sprague-Dawley rats subjected to full-thickness burn model. The aim was to observe whether amnion bilayer can reduce damages in third-grade burn when skin replacement is deemed impossible. The burn was induced using an electrical solder, heated for 5 mins, and contacted on the rat's bare skin for 20 s. AB was applied as a (i) dressing immediately after induction and graft after eschar removal. Two groups (n = 6) were compared: AB and Sofra-Tulle ®, the National Hospital of Indonesia (NHI) protocol. Sections were stained with hematoxylin and eosin and Masson trichrome stains. Immunohistochemistry labelling was used to indicate scars (α-smooth muscle actin [α-SMA] and collagen-1) and angiogenesis (von Willebrand factor). Also, the macrophages inflammatory protein-3α (MIP-3α) indicates an early inflammatory process. The post dressing of the AB group demonstrated hair follicle remains and adipose tissue development. The NHI group appeared with a denatured matrix. Complete healing was seen in the AB group after 28 days with skin appendages similar to normal, while the NHI group showed no appendages in the centre of the actively inflamed area. The α-SMA was found in both groups. Collagen-1 was highly expressed in the NHI group, which led to a scar. Angiogenesis was found more in the AB group. The AB group had shown the capacity to accelerate complete healing and recover skin appendages better than the current protocol. [ABSTRACT FROM AUTHOR]

Background: Although deep neural networks have shown promising results in the diagnosis of skin cancer, a prospective evaluation in a real-world setting could confirm these results. This study aimed to evaluate whether an algorithm (http://b2019.modelderm.com) improves the accuracy of nondermatologists in diagnosing skin neoplasms. Methods: A total of 285 cases (random series) with skin neoplasms suspected of malignancy by either physicians or patients were recruited in two tertiary care centers located in South Korea. An artificial intelligence (AI) group (144 cases, mean [SD] age, 57.0 [17.7] years; 62 [43.1%] men) was diagnosed via routine examination with photographic review and assistance by the algorithm, whereas the control group (141 cases, mean [SD] age, 61.0 [15.3] years; 52 [36.9%] men) was diagnosed only via routine examination with a photographic review. The accuracy of the nondermatologists before and after the interventions was compared. Results: Among the AI group, the accuracy of the first impression (Top-1 accuracy; 58.3%) after the assistance of AI was higher than that before the assistance (46.5%, P =.008). The number of differential diagnoses of the participants increased from 1.9 ± 0.5 to 2.2 ± 0.6 after the assistance (P <.001). In the control group, the difference in the Top-1 accuracy between before and after reviewing photographs was not significant (before, 46.1%; after, 51.8%; P =.19), and the number of differential diagnoses did not significantly increase (before, 2.0 ± 0.4; after, 2.1 ± 0.5; P =.57). Conclusions: In real-world settings, AI augmented the diagnostic accuracy of trainee doctors. The limitation of this study is that the algorithm was tested only for Asians recruited from a single region. Additional international randomized controlled trials involving various ethnicities are required. [ABSTRACT FROM AUTHOR]

Differences in the bacterial community structure associated with 7 skin sites in 71 healthy people over five days showed significant correlations with age, gender, physical skin parameters, and whether participants lived in urban or rural locations in the same city. While body site explained the majority of the variance in bacterial community structure, the composition of the skin-associated bacterial communities were predominantly influenced by whether the participants were living in an urban or rural environment, with a significantly greater relative abundance of Trabulsiella in urban populations. Adults maintained greater overall microbial diversity than adolescents or the elderly, while the intragroup variation among the elderly and rural populations was significantly greater. Skin-associated bacterial community structure and composition could predict whether a sample came from an urban or a rural resident ~5x greater than random.

Immune prophylaxis and treatment of transplanted tissue rejection act indiscriminately, risking serious infections and malignancies. Although animal data suggest that cellular immune responses causing rejection may be rather narrow and predictable based on genetic background, there are only limited data regarding the clonal breadth of anti-donor responses in humans after allogeneic organ transplantation. We evaluated the graft-infiltrating CD8+ T lymphocytes in skin punch biopsies of a transplanted hand over 178 days. Profiling of T cell receptor (TCR) variable gene usage and size distribution of the infiltrating cells revealed marked skewing of the TCR repertoire indicating oligoclonality, but relatively normal distributions in the blood. Although sampling limitation prevented complete assessment of the TCR repertoire, sequencing further identified 11 TCR clonal expansions that persisted through varying degrees of clinical rejection and immunosuppressive therapy. These 11 clones were limited to three TCR beta chain variable (BV) gene families. Overall, these data indicate significant oligoclonality and likely restricted BV gene usage of alloreactive CD8+ T lymphocytes, and suggest that changes in rejection status are more due to varying regulation of their activity or number rather than shifts in the clonal populations in the transplanted organ. Given that controlled animal models produce predictable BV usage in T lymphocytes mediating rejection, understanding the determinants of TCR gene usage associated with rejection in humans may have application in specifically targeted immunotherapy.

UnlabelledMigalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT) with either agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme). Based on preclinical data, migalastat HCl in combination with agalsidase is expected to result in the pharmacokinetic (PK) enhancement of agalsidase in plasma by increasing the systemic exposure of active agalsidase, thereby leading to increased cellular levels in disease-relevant tissues. This Phase 2a study design consisted of an open-label, fixed-treatment sequence that evaluated the effects of single oral doses of 150 mg or 450 mg migalastat HCl on the PK and tissue levels of intravenously infused agalsidase (0.2, 0.5, or 1.0 mg/kg) in male Fabry patients. As expected, intravenous administration of agalsidase alone resulted in increased α-Gal A activity in plasma, skin, and peripheral blood mononuclear cells (PBMCs) compared to baseline. Following co-administration of migalastat HCl and agalsidase, α-Gal A activity in plasma was further significantly increased 1.2- to 5.1-fold compared to agalsidase administration alone, in 22 of 23 patients (95.6%). Importantly, similar increases in skin and PBMC α-Gal A activity were seen following co-administration of migalastat HCl and agalsidase. The effects were not related to the administered migalastat HCl dose, as the 150 mg dose of migalastat HCl increased α-Gal A activity to the same extent as the 450 mg dose. Conversely, agalsidase had no effect on the plasma PK of migalastat. No migalastat HCl-related adverse events or drug-related tolerability issues were identified.Trial registrationClinicalTrials.gov NCT01196871.

Trial designThis analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomatic untreated young patients with Fabry disease enrolled in an ongoing randomized, open-label, parallel-group, phase 3B clinical trial.MethodsMales aged 5-18 years with complete α-galactosidase A deficiency, without symptoms of major organ damage, were enrolled in a phase 3B trial evaluating two doses of agalsidase beta. Baseline disease characteristics of 31 eligible patients (median age 12 years) were studied, including cellular globotriaosylceramide (GL-3) accumulation in skin (n = 31) and kidney biopsy (n = 6; median age 15 years; range 13-17 years), renal function, and glycolipid levels (plasma, urine).ResultsPlasma and urinary GL-3 levels were abnormal in 25 of 30 and 31 of 31 patients, respectively. Plasma lyso-GL-3 was elevated in all patients. GL-3 accumulation was documented in superficial skin capillary endothelial cells (23/31 patients) and deep vessel endothelial cells (23/29 patients). The mean glomerular filtration rate (GFR), measured by plasma disappearance of iohexol, was 118.1 mL/min/1.73 m(2) (range 90.4-161.0 mL/min/1.73 m(2)) and the median urinary albumin/creatinine ratio was 10 mg/g (range 4.0-27.0 mg/g). On electron microscopy, renal biopsy revealed GL-3 accumulation in all glomerular cell types (podocytes and parietal, endothelial, and mesangial cells), as well as in peritubular capillary and non-capillary endothelial, interstitial, vascular smooth muscle, and distal tubules/collecting duct cells. Lesions indicative of early Fabry arteriopathy and segmental effacement of podocyte foot processes were found in all 6 patients.ConclusionsThese data reveal that in this small cohort of children with Fabry disease, histological evidence of GL-3 accumulation, and cellular and vascular injury are present in renal tissues at very early stages of the disease, and are noted before onset of microalbuminuria and development of clinically significant renal events (e.g. reduced GFR). These data give additional support to the consideration of early initiation of enzyme replacement therapy, potentially improving long-term outcome.Trial registrationClinicalTrials.gov NCT00701415.

BackgroundSkin fibrosis is a significant medical problem that leads to a functional, aesthetic, and psychosocial impact on quality-of-life. Light-emitting diode-generated 633-nm red light (LED-RL) is part of the visible light spectrum that is not known to cause DNA damage and is considered a safe, non-invasive, inexpensive, and portable potential alternative to ultraviolet phototherapy that may change the treatment paradigm of fibrotic skin disease.ObjectiveThe goal of our study was to investigate the how reactive oxygen species (ROS) free radicals generated by high fluence LED-RL inhibit the migration of skin fibroblasts, the main cell type involved in skin fibrosis. Fibroblast migration speed is increased in skin fibrosis, and we studied cellular migration speed of cultured human skin fibroblasts as a surrogate measure of high fluence LED-RL effect on fibroblast function. To ascertain the inhibitory role of LED-RL generated ROS on migration speed, we hypothesized that resveratrol, a potent antioxidant, could prevent the photoinhibitory effects of high fluence LED-RL on fibroblast migration speed.MethodsHigh fluence LED-RL generated ROS were measured by flow cytometry analysis using dihydrorhodamine (DHR). For purposes of comparison, we assessed the effects of ROS generated by hydrogen peroxide (H2O2) on fibroblast migration speed and the ability of resveratrol, a well known antioxidant, to prevent LED-RL and H2O2 generated ROS-associated changes in fibroblast migration speed. To determine whether resveratrol could prevent the high fluence LED-RL ROS-mediated photoinhibition of human skin fibroblast migration, treated cells were incubated with resveratrol at concentrations of 0.0001% and 0.001% for 24 hours, irradiated with high fluences LED-RL of 480, 640, and 800 J/cm2.ResultsHigh fluence LED-RL increases intracellular fibroblast ROS and decreases fibroblast migration speed. LED-RL at 480, 640 and 800 J/cm2 increased ROS levels to 132.8%, 151.0%, and 158.4% relative to matched controls, respectively. These LED-RL associated increases in ROS were prevented by pretreating cells with 0.0001% or 0.001% resveratrol. Next, we quantified the effect of hydrogen peroxide (H2O2)-associated ROS on fibroblast migration speed, and found that while H2O2-associated ROS significantly decreased relative fibroblast migration speed, pretreatment with 0.0001% or 0.001% resveratrol significantly prevented the decreases in migration speed. Furthermore, we found that LED-RL at 480, 640 and 800 J/cm2 decreased fibroblast migration speed to 83.0%, 74.4%, and 68.6% relative to matched controls, respectively. We hypothesized that these decreases in fibroblast migration speed were due to associated increases in ROS generation. Pretreatment with 0.0001% and 0.001% resveratrol prevented the LED-RL associated decreases in migration speed.ConclusionHigh fluence LED-RL increases ROS and is associated with decreased fibroblast migration speed. We provide mechanistic support that the decreased migration speed associated with high fluence LED-RL is mediated by ROS, by demonstrating that resveratrol prevents high fluence LED-RL associated migration speed change. These data lend support to an increasing scientific body of evidence that high fluence LED-RL has anti-fibrotic properties. We hypothesize that our findings may result in a greater understanding of the fundamental mechanisms underlying visible light interaction with skin and we anticipate clinicians and other researchers may utilize these pathways for patient benefit.

The mechanisms that lead to variation in human skin and hair color are not fully understood. To better understand the molecular control of skin and hair color variation, we modulated the expression of Tyrosinase (Tyr), which controls the rate-limiting step of melanogenesis, by expressing a single-copy, tetracycline-inducible shRNA against Tyr in mice. Moderate depletion of TYR was sufficient to alter the appearance of the mouse coat in black, agouti, and yellow coat color backgrounds, even though TYR depletion did not significantly inhibit accumulation of melanin within the mouse hair. Ultra-structural studies revealed that the reduction of Tyr inhibited the accumulation of terminal melanosomes, and inhibited the expression of genes that regulate melanogenesis. These results indicate that color in skin and hair is determined not only by the total amount of melanin within the hair, but also by the relative accumulation of mature melanosomes.

A newly-discovered foot disease of unknown origin in captive European Bison (Bison bonasus) was recently detected at Berne Animal Park. Dermatitis of the interdigital cleft of varying degrees of severity was diagnosed in all animals (n = 10). The aim of this study was to describe the gross and histological lesions of the interdigital cleft found in 10 captive European bison and to identify involved potential pathogens in affected feet using molecular-based methods for Treponema spp., Dichelobacter nodosus and Fusobacterium necrophorum. Lesions were scored according to the degree of gross pathology at limb level. In a single animal, the gross lesions were restricted to focal lesions on the dorsal aspect of the digital skin of each foot (score 1), whereas all other animals showed at least one foot with extended lesions including the interdigital cleft (score 2). The presence of viable spirochaetes was observed in all animals using dark field microscopy. Applying fluorescence in situ hybridisation (FISH) on biopsies, Treponema spp. were identified, infiltrating the skin lesions in varying numbers in nine animals. Nested PCRs for Treponema medium, Treponema phagedenis and Treponema pedis of swab samples showed three positive animals out of ten for the latter two, whereas pooled biopsy samples were positive in all ten animals for at least T. phagedenis (9/10) and/or T. pedis (7/10), while all samples were negative for T. medium. However, none of these Treponema species could be isolated and sequence analysis of the amplified products showed 100% match of 365 base pairs (bp) to Treponema phylotype PT3 and almost full match (530 of 532 bp, 99.6%) to Treponema phylotype PT13. The presence of T. phagedenis, PT3 and PT13 phylotypes was confirmed by FISH analyses. The phylotypes of T. phagedenis were present in all hybridized positive biopsies of Treponema spp., and PT13 and PT3 were less abundant. Neither D. nodosus nor F. necrophorum were detected. The histological Treponema score was mostly mild. Digital dermatitis in captive European Bison is contagious and differs from bovine digital dermatitis, concerning associated pathogens as well as gross appearance. [ABSTRACT FROM AUTHOR]

Background: Sneddon syndrome (SS) is defined by widespread livedo reticularis (LR) and stroke. There is no single diagnostic test for SS and diagnosis can be solely based on clinical features. This cross-sectional case-control study aimed to determine the diagnostic value of skin biopsies in SS patients. Materials and methods: We studied skin biopsies from patients with a clinical diagnosis of SS or isolated LR. We also studied controls with vitiligo or normal skin. Biopsies were considered standardized if 3 biopsies were taken from the white centre of the livedo and reached until the dermis-subcutis border. Biopsies were scored for features of an occlusive microangiopathy without knowledge of the clinical features. Sensitivity and specificity of the biopsy findings were calculated with the clinical criteria as the reference standard. Results: We included 34 SS patients, 14 isolated LR patients and 41 control patients. Biopsies of 17 patients with SS (50%), 4 with isolated LR (31%) and 10 control patients (24%) showed at least one artery in the deep dermis with a thickened vessel wall combined with recanalization or neovascularization (sensitivity 50% and specificity 69% with LR as reference). Standardized biopsies increased the sensitivity to 70%. In a post hoc analysis the combination of an occlusive microangiopathy and the presence of a livedo pattern in the superficial dermis increased the specificity to 92%. Conclusions: Standardized skin biopsies can support the clinical diagnosis of SS. An occlusive microangiopathy as the only positive criterion for the diagnosis of SS had insufficient specificity for a definite diagnosis. [ABSTRACT FROM AUTHOR]

This study aimed to assess the biophysical parameters of the skin in Polish Konik horses (Polish primitive horses). According to the authors, this is the first assessment performed on such a wide scale in this group of animals. The evaluation carried out is innovative both with regards to the breed of the animals and the wide scope of the physicochemical skin assessment. The study group comprised mares, stallions and geldings, and the evaluations concerned transepidermal water loss, corneometry, pH, skin temperature assessment and mexametry. These parameters were assessed in five skin regions: the lips, the right ear, the prosternum, the right side of the neck and the chest. The measurements were taken after spreading the hair apart, with the use of a Multiprobe Adapter System (MPA®) and dedicated probes (Courage + Khazaka electronic GmbH, Cologne, Germany). The measurements revealed statistically significant differences in the values of transepidermal water loss in the lips in mares compared with stallions (P = 0.023) and also in stallions compared with geldings (P = 0.009). Corneometry showed significantly higher results in the neck region in mares compared with stallions (P = 0.037) and the prosternum areas in mares and geldings compared with stallions (P = 0.037 and P = 0.018). Skin pH measurement on the right side of the neck rendered significantly higher values in stallions than in mares (P = 0.037). In geldings, the skin temperature was significantly higher than in stallions (P = 0.049). Once the appropriate physicochemical values for specific animal species and breeds are determined, non-invasive methods of skin examination in many diseases and also methods of evaluation of the efficacy and/or adverse effects of applied medications can be established. [ABSTRACT FROM AUTHOR]

Prior studies suggest that the impaired healing seen in diabetic wounds derives from a state of persistent hyper-inflammation characterized by harmful increases in inflammatory leukocytes including macrophages. However, such studies have focused on wounds at later time points (day 10 or older), and very little attention has been given to the dynamics of macrophage responses in diabetic wounds early after injury. Given the importance of macrophages for the process of healing, we studied the dynamics of macrophage response during early and late phases of healing in diabetic wounds. Here, we report that early after injury, the diabetic wound exhibits a significant delay in macrophage infiltration. The delay in the macrophage response in diabetic wounds results from reduced Chemokine (C-C motif) ligand 2 (CCL2) expression. Importantly, one-time treatment with chemoattractant CCL2 significantly stimulated healing in diabetic wounds by restoring the macrophage response. Our data demonstrate that, rather than a hyper-inflammatory state; the early diabetic wound exhibits a paradoxical and damaging decrease in essential macrophage response. Our studies suggest that the restoration of the proper kinetics of macrophage response may be able to jumpstart subsequent healing stages. CCL2 chemokine-based therapy may be an attractive strategy to promote healing in diabetic wounds.

Data suggest that clinical applications of human induced pluripotent stem cells (hiPSCs) will be realized. Nonetheless, clinical applications will require hiPSCs that are free of exogenous DNA and that can be manufactured through Good Manufacturing Practice (GMP). Optimally, derivation of hiPSCs should be rapid and efficient in order to minimize manipulations, reduce potential for accumulation of mutations and minimize financial costs. Previous studies reported the use of modified synthetic mRNAs to reprogram fibroblasts to a pluripotent state. Here, we provide an optimized, fully chemically defined and feeder-free protocol for the derivation of hiPSCs using synthetic mRNAs. The protocol results in derivation of fully reprogrammed hiPSC lines from adult dermal fibroblasts in less than two weeks. The hiPSC lines were successfully tested for their identity, purity, stability and safety at a GMP facility and cryopreserved. To our knowledge, as a proof of principle, these are the first integration-free iPSCs lines that were reproducibly generated through synthetic mRNA reprogramming that could be putatively used for clinical purposes.

An estimated 2.3 million disability-adjusted life years are lost globally from leishmaniasis. In Peru's Amazon region, the department of Madre de Dios (MDD) rises above the rest of the country in terms of the annual incidence rates of human leishmaniasis. Leishmania (Viannia) braziliensis is the species most frequently responsible for the form of disease that results in tissue destruction of the nose and mouth. However, essentially nothing is known regarding the reservoirs of this vector-borne, zoonotic parasite in MDD. Wild rodents have been suspected, or proven, to be reservoirs of several Leishmania spp. in various ecosystems and countries. Additionally, people who live or work in forested terrain, especially those who are not regionally local and whose immune systems are thus naïve to the parasite, are at most risk for contracting L. (V.) braziliensis. Hence, the objective of this study was to collect tissues from wild rodents captured at several study sites along the Amazonian segment of the newly constructed Transoceanic Highway and to use molecular laboratory techniques to analyze samples for the presence of Leishmania parasites. Liver tissues were tested via polymerase chain reaction from a total of 217 rodents; bone marrow and skin biopsies (ear and tail) were also tested from a subset of these same animals. The most numerous rodent species captured and tested were Oligoryzomys microtis (40.7%), Hylaeamys perenensis (15.7%), and Proechimys spp. (12%). All samples were negative for Leishmania, implying that although incidental infections may occur, these abundant rodent species are unlikely to serve as primary reservoirs of L. (V.) braziliensis along the Transoceanic Highway in MDD. Therefore, although these rodent species may persist and even thrive in moderately altered landscapes, we did not find any evidence to suggest they pose a risk for L. (V.) braziliensis transmission to human inhabitants in this highly prevalent region.

Climatic variation alters biochemical and ecological processes, but it is difficult both to quantify the magnitude of such changes, and to differentiate long-term shifts from inter-annual variability. Here, we simultaneously quantify decade-scale isotopic variability at the lowest and highest trophic positions in the offshore California Current System (CCS) by measuring δ15N and δ13C values of amino acids in a top predator, the sperm whale (Physeter macrocephalus). Using a time series of skin tissue samples as a biological archive, isotopic records from individual amino acids (AAs) can reveal the proximate factors driving a temporal decline we observed in bulk isotope values (a decline of ≥1 ‰) by decoupling changes in primary producer isotope values from those linked to the trophic position of this toothed whale. A continuous decline in baseline (i.e., primary producer) δ15N and δ13C values was observed from 1993 to 2005 (a decrease of ∼4‰ for δ15N source-AAs and 3‰ for δ13C essential-AAs), while the trophic position of whales was variable over time and it did not exhibit directional trends. The baseline δ15N and δ13C shifts suggest rapid ongoing changes in the carbon and nitrogen biogeochemical cycling in the offshore CCS, potentially occurring at faster rates than long-term shifts observed elsewhere in the Pacific. While the mechanisms forcing these biogeochemical shifts remain to be determined, our data suggest possible links to natural climate variability, and also corresponding shifts in surface nutrient availability. Our study demonstrates that isotopic analysis of individual amino acids from a top marine mammal predator can be a powerful new approach to reconstructing temporal variation in both biochemical cycling and trophic structure.

Pathogenesis is strongly dependent on microbial context, but development of probiotic therapies has neglected the impact of ecological interactions. Dynamics among microbial communities, host immune responses, and environmental conditions may alter the effect of probiotics in human and veterinary medicine, agriculture and aquaculture, and the proposed treatment of emerging wildlife and zoonotic diseases such as those occurring on amphibians or vectored by mosquitoes. Here we use a holistic measure of amphibian mucosal defenses to test the effects of probiotic treatments and to assess disease risk under different ecological contexts. We developed a non-invasive assay for antifungal function of the skin mucosal ecosystem (mucosome function) integrating host immune factors and the microbial community as an alternative to pathogen exposure experiments. From approximately 8500 amphibians sampled across Europe, we compared field infection prevalence with mucosome function against the emerging fungal pathogen Batrachochytrium dendrobatidis. Four species were tested with laboratory exposure experiments, and a highly susceptible species, Alytes obstetricans, was treated with a variety of temperature and microbial conditions to test the effects of probiotic therapies and environmental conditions on mucosome function. We found that antifungal function of the amphibian skin mucosome predicts the prevalence of infection with the fungal pathogen in natural populations, and is linked to survival in laboratory exposure experiments. When altered by probiotic therapy, the mucosome increased antifungal capacity, while previous exposure to the pathogen was suppressive. In culture, antifungal properties of probiotics depended strongly on immunological and environmental context including temperature, competition, and pathogen presence. Functional changes in microbiota with shifts in temperature provide an alternative mechanistic explanation for patterns of disease susceptibility related to climate beyond direct impact on host or pathogen. This nonlethal management tool can be used to optimize and quickly assess the relative benefits of probiotic therapies under different climatic, microbial, or host conditions.

The search for significantly overrepresented and co-occurring transcription factor binding sites in the promoter regions of the most differentially expressed genes in microarray data sets could be a powerful approach for finding key regulators of complex biological processes. To test this concept, two previously published independent data sets on wounded human epidermis were re-analyzed. The presence of co-occurring transcription factor binding sites for FOXO1, FOXO3 and FOXO4 in the majority of the promoter regions of the most significantly differentially expressed genes between non-wounded and wounded epidermis implied an important role for FOXO transcription factors during wound healing. Expression levels of FOXO transcription factors during wound healing in vivo in both human and mouse skin were analyzed and a decrease for all FOXOs in human wounded skin was observed, with FOXO3 having the highest expression level in non wounded skin. Impaired re-epithelialization was found in cultures of primary human keratinocytes expressing a constitutively active variant of FOXO3. Conversely knockdown of FOXO3 in keratinocytes had the opposite effect and in an in vivo mouse model with FOXO3 knockout mice we detected significantly accelerated wound healing. This article illustrates that the proposed approach is a viable method for identifying important regulators of complex biological processes using in vivo samples. FOXO3 has not previously been implicated as an important regulator of wound healing and its exact function in this process calls for further investigation.

Topical application of platelet-derived growth factor-BB (PDGF-BB) is considered to accelerate tissue repair of impaired chronic wounds. However, the vast literature is plagued with conflicting reports of its efficacy in animal models and this is often influenced by a wide array of experimental variables making it difficult to compare the results across the studies. To mitigate the confounding variables that influence the efficacy of topically applied PDGF-BB, we used a controlled full thickness splinted excisional wound model in db/db mice (type 2 diabetic mouse model) for our investigations. A carefully-defined silicone-splinted wound model, with reduced wound contraction, controlled splint and bandage maintenance, allowing for healing primarily by reepithelialization was employed. Two splinted 8 mm dorsal full thickness wounds were made in db/db mice. Wounds were topically treated once daily with either 3 µg PDGF-BB in 30 µl of 5% PEG-PBS vehicle or an equal volume of vehicle for 10 days. Body weights, wound contraction, wound closure, reepithelialization, collagen content, and wound bed inflammation were evaluated clinically and histopathologically. The bioactivity of PDGF-BB was confirmed by in vitro proliferation assay. PDGF-BB, although bioactive in vitro, failed to accelerate wound healing in vivo in the db/db mice using the splinted wound model. Considering that the predominant mechanism of wound healing in humans is by re-epithelialization, the most appropriate model for evaluating therapeutics is one that uses splints to prevent excessive wound contraction. Here, we report that PDGF-BB does not promote wound closure by re-epithelialization in a murine splinted wound model. Our results highlight that the effects of cytoactive factors reported in vivo ought to be carefully interpreted with critical consideration of the wound model used.

BACKGROUND: The immunopathogenic mechanisms leading to psoriasis remain unresolved. CD57 is a marker of replicative inability and immunosenescence on CD8+ T cells and the proportion of CD57 expressing CD8+ T cells is increased in a number of inflammatory conditions. METHODOLOGY: We examined the expression of CD57 on T cells in the skin of patients affected with psoriasis, comparing lesional and unaffected skin. We also assessed functionality of the T cells by evaluating the secretion of several inflammatory cytokines (IL-17A, IFN-gamma, IL-2, IL-33, TNF-alpha, IL-21, IL-22, and IL-27), from cell-sorted purified CD4+ and CD8+ T cells isolated from lesional and unaffected skin biopsies of psoriasis patients. PRINCIPAL FINDINGS: We observed that the frequency of CD57+CD4+ and CD57+CD8+ T cells was significantly higher in unaffected skin of psoriasis patients compared to lesional skin. Sorted CD4+ T cells from psoriatic lesional skin produced higher levels of IL-17A, IL-22, and IFN-gamma compared to unaffected skin, while sorted CD8+ T cells from lesional skin produced higher levels of IL-17, IL-22, IFN-gamma, TNF-alpha, and IL-2 compared to unaffected skin. CONCLUSIONS/SIGNIFICANCE: These findings suggest that T cells in unaffected skin from psoriasis patients exhibit a phenotype compatible with replicative inability. As they have a lower replicative capacity, CD57+ T cells are less frequent in lesional tissue due to the high cellular turnover.

The predominant hypothesis regarding the composition of microbial assemblages in indoor environments is that fungal assemblages are structured by outdoor air with a moderate contribution by surface growth, whereas indoor bacterial assemblages represent a mixture of bacteria entered from outdoor air, shed by building inhabitants, and grown on surfaces. To test the fungal aspect of this hypothesis, we sampled fungi from three surface types likely to support growth and therefore possible contributors of fungi to indoor air: drains in kitchens and bathrooms, sills beneath condensation-prone windows, and skin of human inhabitants. Sampling was done in replicated units of a university-housing complex without reported mold problems, and sequences were analyzed using both QIIME and the new UPARSE approach to OTU-binning, to the same result. Surfaces demonstrated a mycological profile similar to that of outdoor air from the same locality, and assemblages clustered by surface type. Weedy genera typical of indoor air, such as Cladosporium and Cryptococcus, were abundant on sills, as were a diverse set of fungi of likely outdoor origin. Drains supported more depauperate assemblages than the other surfaces and contained thermotolerant genera such as Exophiala, Candida, and Fusarium. Most surprising was the composition detected on residents foreheads. In addition to harboring Malassezia, a known human commensal, skin also possessed a surprising richness of non-resident fungi, including plant pathogens such as ergot (Claviceps purperea). Overall, fungal richness across indoor surfaces was high, but based on known autecologies, most of these fungi were unlikely to be growing on surfaces. We conclude that while some endogenous fungal growth on typical household surfaces does occur, particularly on drains and skin, all residential surfaces appear - to varying degrees - to be passive collectors of airborne fungi of putative outdoor origin, a view of the origins of the indoor microbiome quite different from bacteria.

Nurses continue to disinfect the skin before administering subcutaneous injections as a standard process in clinical settings; despite evidence that disinfection is not necessary. To implement evidence-based practice, it is critical to explore why this gap between "evidence" and "practice" exists. This study aimed to describe the reasons offered by Certified Nurses in Infection Control (CNIC) in Japan for performing skin disinfection before subcutaneous injection. Adopting an inductive qualitative design, interviews were conducted with 10 CNIC in 2013. According to the participants, skin disinfection before subcutaneous injection: (a) was common practice; (b) may have been beneficial if it was omitted; (c) adhered to hospital norms; (d) prevented persistent suspicion of infection; (e) had no detrimental effect; (f) was an ingrained custom; and (g) involved a tacit approval for not disinfecting in home care settings. The themes (c) and (g) were cited as the main reasons affecting decision-making. The CNIC administered injections following skin disinfection in hospitals in accordance with hospital norms. On the contrary, outside the hospital, they administered subcutaneous injections without skin disinfection. All themes except (b) and (g) reflect the barriers and resistance to omitting skin disinfection, while (g) shows that it is already partly implemented in home care settings. It is necessary to create a guideline for skin disinfection before subcutaneous injection that considers the quality of life of patients at home, their physical conditions, and the surrounding environment at the time of injection, in addition to the guidelines applicable in hospitals. [ABSTRACT FROM AUTHOR]

Parchment, the skins of animals prepared for use as writing surfaces, offers a valuable source of genetic information. Many have clearly defined provenance, allowing for the genetic findings to be evaluated in temporal and spatial context. While these documents can yield evidence of the animal sources, the DNA contained within these aged skins is often damaged and fragmented. Previously, genetic studies targeting parchment have used destructive sampling techniques and so the development and validation of non-destructive sampling methods would expand opportunities and facilitate testing of more precious documents, especially those with historical significance. Here we present genetic data obtained by non-destructive sampling of eight parchments spanning the 15th century to the modern day. We define a workflow for enriching the mitochondrial genome (mtGenome), generating next-generation sequencing reads to permit species identification, and providing interpretation guidance. Using sample replication, comparisons to destructively sampled controls, and by establishing authentication criteria, we were able to confidently assign full/near full mtGenome sequences to 56.3% of non-destructively sampled parchments, each with greater than 90% of the mtGenome reference covered. Six of eight parchments passed all four established thresholds with at least one non-destructive sample, highlighting promise for future studies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Scheible et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

An age-old hypothesis proposes that object motion across the receptor surface organizes sensory maps (Lotze, 19th century). Skin patches learn their relative positions from the order in which they are stimulated during motion events. We propose that reversing the local motion within a global motion sequence ('motion scrambling') provides a good test for this idea, and present results of the first experiment implementing the paradigm. We used 6-point apparent motion along the forearm. In the Scrambled sequence, two middle locations were touched in reversed order (1-2-4-3-5-6, followed by 6-5-3-4-2-1, in a continuous loop). This created a double U-turn within an otherwise constant-velocity motion, as if skin patches 3 and 4 physically swapped locations. The control condition, Orderly, proceeded at constant velocity at inter-stimulus onset interval of 120 ms. The 26.4-minute conditioning (delivered in twenty-four 66-s bouts) was interspersed with testing of perceived motion direction between the two middle tactors presented on their own (sequence 3–4 or 4–3). Our twenty participants reported motion direction. Direction discrimination was degraded following exposure to Scrambled pattern and was 0.31 d' weaker than following Orderly conditioning (p =.007). Consistent with the proposed role of motion, this could be the beginning of re-learning of relative positions. An alternative explanation is that greater speed adaptation occurred in the Scrambled pattern, raising direction threshold. In future studies, longer conditioning should tease apart the two explanations: our re-mapping hypothesis predicts an overall reversal in perceived motion direction between critical locations (for either motion direction), whereas the speed adaptation alternative predicts chance-level performance at worst, without reversing. [ABSTRACT FROM AUTHOR]

The main ingredient of sunless tanning products is dihydroxyacetone (DHA). DHA reacts with the protein and amino acid composition in the surface layers of the skin, producing melanoidins, which changes the skin colour, imitating natural skin tan caused by melanin. The purpose of this study was to characterise DHA-induced skin colour changes and to test whether we can predict the outcome of DHA application on skin tone changes. To assess the DHA-induced skin colour shift quantitatively, colorimetric and spectral measurements of the inner forearm were obtained before, four hours and 24 hours after application of a 7.5% concentration DHA gel in the experimental group (n = 100). In a control group (n = 60), the same measurements were obtained on both the inner forearm (infrequently sun-exposed) and the outer forearm (frequently sun-exposed); the difference between these two areas was defined as the naturally occurring tan. Skin colour shifts caused by DHA tanning and by natural tanning were compared in terms of lightness (L*), redness (a*) and yellowness (b*) in the standard CIELAB colour space. Naturalness of the DHA-induced skin tan was evaluated by comparing the trajectory of the chromaticity distribution in (L*, b*) space with that of naturally occurring tan. Twenty-four hours after DHA application, approximately 20% of the skin colour samples became excessively yellow, with chromaticities outside the natural range in (L*, b*) space. A principal component analysis was used to characterise the tanning pathway. Skin colour shifts induced by DHA were predicted by a multiple regression on the chromaticities and the skin properties. The model explained up to 49% of variance in colorimetric components with a median error of less than 2 ΔE. We conclude that the control of both the magnitude and the direction of the colour shift is a critical factor to achieve a natural appearance. [ABSTRACT FROM AUTHOR]

Bradykinin-related peptides (BRPs) family is one of the most significant myotropic peptide families derived from frog skin secretions. Here, a novel BRP callitide was isolated and identified from the red-eyed leaf frog, Agalychnis callidryas, with atypical primary structure FRPAILVRPK-NH2. The mature peptide was cleaved N-terminally at a classic propeptide convertase cleavage site (-KR-) and at the C-terminus an unusual -GKGKGK sequence was removed using the first G residue as an amide donor for the C-terminally-located K residue. Thereafter, the synthetic replicates of callitide were assessed the myotropic activity and showed a significant contraction of balder, with the 0.63 nM EC50 value, more potent than most discovered myotropic peptides. The binding mode was further speculated by molecular docking and stimulation. The result indicated that the C-terminal of callitide might selectively bind to bradykinin receptor B2 (BKRB2). Further investigation of the callitide needs to be done in the future to be exploited as potential future drug leads. [ABSTRACT FROM AUTHOR]

Udder cleft dermatitis (UCD) is a skin condition affecting the fore udder attachment of dairy cows. UCD may be defined as mild (eczematous skin changes) or severe (open wounds, large skin changes). Our aims were to compare the microbiota of mild and severe UCD lesions with the microbiota of healthy skin from the fore udder attachment of control cows, and to investigate whether mastitis-causing pathogens are present in UCD lesions. Samples were obtained from cows in six dairy herds. In total, 36 UCD samples categorized as mild (n = 17) or severe (n = 19) and 13 control samples were sequenced using a shotgun metagenomic approach and the reads were taxonomically classified based on their k-mer content. The Wilcoxon rank sum test was used to compare the abundance of different taxa between different sample types, as well as to compare the bacterial diversity between samples. A high proportion of bacteria was seen in all samples. Control samples had a higher proportion of archaeal reads, whereas most samples had low proportions of fungi, protozoa and viruses. The bacterial microbiota differed between controls and mild and severe UCD samples in both composition and diversity. Subgroups of UCD samples were visible, characterized by increased proportion of one or a few bacterial genera or species, e.g. Corynebacterium, Staphylococcus, Brevibacterium luteolum, Trueperella pyogenes and Fusobacterium necrophorum. Bifidobacterium spp. were more common in controls compared to UCD samples. The bacterial diversity was higher in controls compared to UCD samples. Bacteria commonly associated with mastitis were uncommon. In conclusion, a dysbiosis of the microbiota of mild and severe UCD samples was seen, characterized by decreased diversity and an increased proportion of certain bacteria. There was no evidence of a specific pathogen causing UCD or that UCD lesions are important reservoirs for mastitis-causing bacteria. [ABSTRACT FROM AUTHOR]

Because tactile perception relies on the response of large populations of receptors distributed across the skin, we seek to characterize how a mechanical deformation of the skin at one location affects the skin at another. To this end, we introduce a novel non-contact method to characterize the surface waves produced in the skin under a variety of stimulation conditions. Specifically, we deliver vibrations to the fingertip using a vibratory actuator and measure, using a laser Doppler vibrometer, the surface waves at different distances from the locus of stimulation. First, we show that a vibration applied to the fingertip travels at least the length of the finger and that the rate at which it decays is dependent on stimulus frequency. Furthermore, the resonant frequency of the skin matches the frequency at which a subpopulation of afferents, namely Pacinian afferents, is most sensitive. We show that this skin resonance can lead to a two-fold increase in the strength of the response of a simulated afferent population. Second, the rate at which vibrations propagate across the skin is dependent on the stimulus frequency and plateaus at 7 m/s. The resulting delay in neural activation across locations does not substantially blur the temporal patterning in simulated populations of afferents for frequencies less than 200 Hz, which has important implications about how vibratory frequency is encoded in the responses of somatosensory neurons. Third, we show that, despite the dependence of decay rate and propagation speed on frequency, the waveform of a complex vibration is well preserved as it travels across the skin. Our results suggest, then, that the propagation of surface waves promotes the encoding of spectrally complex vibrations as the entire neural population is exposed to essentially the same stimulus. We also discuss the implications of our results for biomechanical models of the skin.

Determining the mechanisms of host-pathogen interaction is critical for understanding and mitigating infectious disease. Mechanisms of fungal pathogenicity are of particular interest given the recent outbreaks of fungal diseases in wildlife populations. Our study focuses on Batrachochytrium dendrobatidis (Bd), the chytrid pathogen responsible for amphibian declines around the world. Previous studies have hypothesized a role for several specific families of secreted proteases as pathogenicity factors in Bd, but the expression of these genes has only been evaluated in laboratory growth conditions. Here we conduct a genome-wide study of Bd gene expression under two different nutrient conditions. We compare Bd gene expression profiles in standard laboratory growth media and in pulverized host tissue (i.e., frog skin). A large proportion of genes in the Bd genome show increased expression when grown in host tissue, indicating the importance of studying pathogens on host substrate. A number of gene classes show particularly high levels of expression in host tissue, including three families of secreted proteases (metallo-, serine- and aspartyl-proteases), adhesion genes, lipase-3 encoding genes, and a group of phylogenetically unusual crinkler-like effectors. We discuss the roles of these different genes as putative pathogenicity factors and discuss what they can teach us about Bds metabolic targets, host invasion, and pathogenesis.