Skin barrier, phenotypic and genotypic characterisation of autosomal recessive ichthyosis in TGM1-deficient Jack Russell Terriers and response to topical ceramide.

BACKGROUND: Autosomal recessive ichthyosis leads to structural or biochemical changes that impair skin barrier function. HYPOTHESIS/OBJECTIVES: To assess (1) the phenotype and genotype in a litter of Jack Russell Terriers with autosomal recessive congenital ichthyosis (ARCI), and (2) the defective skin barrier and determine if a topical ceramide can modulate the barrier. ANIMALS: A healthy dam and litter of Jack Russell Terrier puppies (healthy male, affected male and female), one affected adult Jack Russell Terrier and one unrelated healthy Jack Russell Terrier. MATERIALS AND METHODS: A severe cornification defect was identified via examination of affected puppies. As the phenotype worsened, the affected puppies received a topical application of ω-0-acylceramide for 10 days. Before humane euthanasia, the skin barrier was evaluated via transepidermal water loss (TEWL), corneometry and pH in affected dogs. Genomic testing was performed, and skin samples were analysed by light and electron microscopy. RESULTS: Affected puppies were homozygous for the 1980 bp LINE-1 insertion in the TGM1 (transglutaminase 1) gene; the unaffected littermate and the dam were heterozygous carriers. ARCI puppies were underweight and had a severe hyperkeratotic phenotype that impaired mobility. TEWL was markedly higher in affected dogs. The cutaneous pH of affected puppies was higher than the normal littermate. Treatment of the skin with ω-0-acylceramide normalised the pH to match the littermate and decreased TEWL. Electron microscopy revealed marked attenuation of the cornified envelope. CONCLUSIONS AND CLINICAL RELEVANCE: Dogs with TGM1-deficient ARCI have an impaired skin barrier. Topical therapy can partially repair the barrier defect.

Skin Barrier in Atopic Dermatitis.

A compromised permeability barrier is a hallmark of atopic dermatitis (AD). Localized to the outermost skin layer, the stratum corneum (SC) is critically dependent on terminal differentiation of epidermal keratinocytes, which transform into protein-rich corneocytes surrounded by extracellular lamellae of unique epidermal lipids, conferring permeability barrier function. These structures are disrupted in AD. A leaky barrier is prone to environmental insult, which in AD elicits type 2-dominant inflammation, in turn resulting in a vicious cycle further impairing the SC structure. Therapies directed at enforcing SC structure and anti-inflammatory strategies administered by topical and systemic route as well as UV therapy have differential effects on the permeability barrier. The expanding armamentarium of therapeutic modalities for AD treatment warrants optimization of their effects on permeability barrier function.

Phase-Dependent Phonon Heat Transport in Nanoscale Gallium Oxide Thin Films.

Different phases of Ga2O3 have been regarded as superior platforms for making new-generation high-performance electronic devices. However, understanding of thermal transport in different phases of nanoscale Ga2O3 thin-films remains challenging, owing to the lack of phonon transport models and systematic experimental investigations. Here, thermal conductivity (TC) and thermal boundary conductance (TBC) of the ( 1 ¯ 010 ) $( {\bar 1010} )$ α-, ( 2 ¯ 01 ) $( {\bar 201} )\;$ ß-, and (001) κ-Ga2O3 thin films on sapphire are investigated. At ≈80 nm, the measured TC of α (8.8 W m-1 K-1) is ≈1.8 times and ≈3.0 times larger than that of ß and κ, respectively, consistent with model based on density functional theory (DFT), whereas the model reveals a similar TC for the bulk α- and ß-Ga2O3. The observed phase- and size-dependence of TC is discussed thoroughly with phonon transport properties such as phonon mean free path and group velocity. The measured TBC at Ga2O3/sapphire interface is analyzed with diffuse mismatch model using DFT-derived full phonon dispersion relation. Phonon spectral distribution of density of states, transmission coefficients, and group velocity are studied to understand the phase-dependence of TBC. This study provides insight into the fundamental phonon transport mechanism in Ga2O3 thin films and paves the way for improved thermal management of high-power Ga2O3-based devices.

"Outside-to-inside," "inside-to-outside," and "intrinsic" endogenous pathogenic mechanisms in atopic dermatitis: keratinocytes as the key functional cells involved in both permeability barrier dysfunction and immunological alterations.

Permeability barrier disruption has been shown to induce immunological alterations (i.e., an "outside-to-inside" pathogenic mechanism). Conversely, several inflammatory and immunological mechanisms reportedly interrupt permeability barrier homeostasis (i.e., an "inside-to-outside" pathogenic mechanism). It is now widely recognized that alterations of even a single molecule in keratinocytes can lead to not only permeability barrier dysfunction but also to immunological alterations. Such a simultaneous, bidirectional functional change by keratinocytes is herein named an "intrinsic" pathogenic mechanism. Molecules and/or pathways involved in this mechanism could be important not only as factors in disease pathogenesis but also as potential therapeutic targets for inflammatory cutaneous diseases, such as atopic dermatitis, psoriasis, and prurigo nodularis. Elevation of skin surface pH following permeability barrier abrogation comprises one of the key pathogenic phenomena of the "outside-to-inside" mechanism. Not only type 2 cytokines (e.g., IL-4, IL-13, IL-31) but also type 1 (e.g. IFN-γ), and type 3 (e.g., IL-17, IL-22) as well as several other inflammatory factors (e.g. histamine) can disrupt permeability barrier homeostasis and are all considered part of the "inside-to-outside" mechanism. Finally, examples of molecules relevant to the "intrinsic" pathogenic mechanism include keratin 1, filaggrin, and peroxisome proliferator-activated receptor-α (PPARα).

Link between obesity and atopic dermatitis: Does obesity predispose to atopic dermatitis, or vice versa?

Two serious health conditions, obesity and atopic dermatitis (AD), share some pathological features such as insulin resistance, leptin resistance and inflammation, and a growing body of evidence suggests a link between obesity and AD. Obesity predisposes an individual to and/or worsens AD, whereas AD increases the risk of obesity. Obesity and AD's interactions are mediated by cytokines, chemokines and immune cells. Obese individuals with AD are more resistant to anti-inflammatory therapy, while weight loss can alleviate AD. In this review, we summarize the evidence linking AD and obesity. We also discuss the pathogenic role of obesity in AD, and vice versa. Because of the connection between these two conditions, mitigation of one could possibly prevent the development of or alleviate the other condition. Effective management of AD and weight loss can enhance the wellness of individuals with both of these conditions. However, proper clinical studies are warranted to validate this speculation.

Targeting Skin Barrier Function in Atopic Dermatitis.

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in the general population. Skin barrier dysfunction is the central abnormality leading to AD. The cause of skin barrier dysfunction is complex and rooted in genetic mutations, interactions between the immune pathway activation and epithelial cells, altered host defense mechanisms, as well as environmental influences that cause epithelial cell activation and release of alarmins (such as thymic stromal lymphopoietin) that can activate the type 2 immune pathway, including generation of interleukins 4 and 13, which induces defects in the skin barrier and increased allergic inflammation. These inflammatory pathways are further influenced by environmental factors including the microbiome (especially Staphylococcus aureus), air pollution, stress, and other factors. As such, AD is a syndrome involving multiple phenotypes, all of which have in common skin barrier dysfunction as a key contributing factor. Understanding mechanisms leading to skin barrier dysfunction in AD is pointing to the development of new topical and systemic treatments in AD that helps keep skin borders secure and effectively treat the disease.

Excess psoriasis and psoriatic arthritis mortality during the COVID-19 pandemic in the United States: A nationwide population-based study from 2010 to 2021.

BACKGROUND: Little is known about mortality trends among patients with psoriasis (PsO) and psoriatic arthritis (PsA) in the United States. OBJECTIVES: To ascertain mortality trends of PsO and PsA between 2010 and 2021, focusing on the effects of the COVID-19 pandemic. METHODS: We collected data from the National Vital Statistic System and calculated age-standardized mortality rates (ASMR) and cause-specific mortality for PsO/PsA. We evaluated observed versus predicted mortality for 2020-2021 based on trends from 2010 to 2019 with joinpoint and prediction modelling analysis. RESULTS: Among 5810 and 2150 PsO- and PsA-related deaths between 2010 and 2021, ASMR for PsO dramatically increased between 2010-2019 and 2020-2021 (annual percentage change [APC] 2.07% vs. 15.26%; p < 0.01), leading to a higher observed ASMR (per 100,000 persons) than predicted for 2020 (0.27 vs. 0.22) and 2021 (0.31 vs. 0.23). The excess mortality of PsO was 22.7% and 34.8% higher than that in the general population in 2020 (16.4%, 95% CI: 14.9%-17.9%) and 2021 (19.8%, 95% CI: 18.0%-21.6%) respectively. Notably, the ASMR rise for PsO was most pronounced in the female (APC: 26.86% vs. 12.19% in males) and the middle-aged group (APC: 17.67% vs. 12.47% in the old-age group). ASMR, APC and excess mortality for PsA were similar to PsO. SARS-CoV-2 infection contributed to more than 60% of the excess mortality for PsO and PsA. CONCLUSIONS: Individuals living with PsO and PsA were disproportionately affected during the COVID-19 pandemic. Both ASMRs increased at an alarming rate, with the most pronounced disparities among the female and middle-aged groups.

Stratum corneum hydration inversely correlates with certain serum cytokine levels in the elderly, possibly contributing to inflammaging.

BACKGROUND: Chronic, low-grade inflammation, also termed 'inflammaging', has been linked to the development of some aging-associated disorders. Recent studies suggest that inflammaging is attributable to aging-associated epidermal dysfunction. However, abnormality in which epidermal function contributes to inflammaging is not clear. OBJECTIVE: We delineated the correlation of epidermal functions with circulating levels of proinflammatory cytokines in the elderly. METHODS: Blood sample was collected from a total of 255 participants aged ≥ 65 years. Epidermal biophysical properties were measured on the left forearm and the right shin. Serum cytokine levels were measured by Multiplex Luminex Assays. RESULTS: Neither skin surface pH nor transepidermal water loss rates (TEWL) correlated with serum cytokine levels except TEWL on the right shin for TNFa (p < 0.05). In contrast, stratum corneum hydration levels on both the forearm and the shin correlated negatively with serum cytokine levels (p < 0.05). CONCLUSION: Reduced stratum corneum hydration likely contributes to inflammaging.

Citizen Science as an Approach for Responding to the Threat of Anopheles stephensi in Africa.

Even as novel technologies emerge and medicines advance, pathogen-transmitting mosquitoes pose a deadly and accelerating public health threat. Detecting and mitigating the spread of Anopheles stephensi in Africa is now critical to the fight against malaria, as this invasive mosquito poses urgent and unprecedented risks to the continent. Unlike typical African vectors of malaria, An. stephensi breeds in both natural and artificial water reservoirs, and flourishes in urban environments. With An. stephensi beginning to take hold in heavily populated settings, citizen science surveillance supported by novel artificial intelligence (AI) technologies may offer impactful opportunities to guide public health decisions and community-based interventions. Coalitions like the Global Mosquito Alert Consortium (GMAC) and our freely available digital products can be incorporated into enhanced surveillance of An. stephensi and other vector-borne public health threats. By connecting local citizen science networks with global databases that are findable, accessible, interoperable, and reusable (FAIR), we are leveraging a powerful suite of tools and infrastructure for the early detection of, and rapid response to, (re)emerging vectors and diseases.

In(Ga)N 3D Growth on GaN-Buffered On-Axis and Off-Axis (0001) Sapphire Substrates by MOCVD.

In(Ga)N epitaxial layers were grown on on-axis and off-axis (0001) sapphire substrates with an about 1100 nm-thick GaN buffer layer stack using organometallic chemical vapor deposition at 600 °C. The In(Ga)N layers consisted of a thin (~10-25 nm) continuous layer of small conical pyramids in which large conical pyramids with an approximate height of 50-80 nm were randomly distributed. The large pyramids were grown above the edge-type dislocations which originated in the GaN buffer; the dislocations did not penetrate the large, isolated pyramids. The large pyramids were well crystallized and relaxed with a small quantity of defects, such as dislocations, preferentially located at the contact zones of adjacent pyramids. The low temperature (6.5 K) photoluminescence spectra showed one clear maximum at 853 meV with a full width at half maximum (FWHM) of 75 meV and 859 meV with a FWHM of 80 meV for the off-axis and on-axis samples, respectively.

Alterations in epidermal function in type 2 diabetes: Implications for the management of this disease.

Epidermal function is regulated by numerous exogenous and endogenous factors, including age, psychological stress, certain skin disorders, ultraviolet irradiation and pollution, and epidermal function itself can regulate cutaneous and extracutaneous functions. The biophysical properties of the stratum corneum reflect the status of both epidermal function and systemic conditions. Type 2 diabetes in both murine models and humans displays alterations in epidermal functions, including reduced levels of stratum corneum hydration and increased epidermal permeability as well as delayed permeability barrier recovery, which can all provoke and exacerbate cutaneous inflammation. Because inflammation plays a pathogenic role in type 2 diabetes, a therapy that improves epidermal functions could be an alternative approach to mitigating type 2 diabetes and its associated cutaneous disorders.

Cetacean epidermal specialization: A review.

Cetacean skin continues to be the investigative focus of researchers from several different scientific disciplines. Yet, most research on the basic functions of lipo-keratinocytes, which constitute most of the cetacean epidermis, providing the first layer of protection against various environmental aggressors (including an ever-increasing level of pollutants), is restricted to specialized literature on the permeability barrier only. In this review, we have attempted to bring together much of the recent research on the functional biology of cetacean skin, including special adaptations at the cellular, genetic and molecular level. We have correlated these data with the cetacean permeability barrier's unique structural and metabolic adaptations to fully aquatic life, including the development of secondary barriers to ward off challenges such as biofouling as well as exposure to extreme cold for the epidermis, which is outside of the insulation provided by blubber. An apparent contradiction exists between some of the reported gene loss for lipogenic enzymes in cetacean skin and the high degree of cetacean epidermal lipogenesis, as well as loss of desmocollin 1 and desmoplakin genes [while immunolocalization of these proteins is reported (Journal of Anatomy, 234, 201)] warrants a re-evaluation of the gene loss data.

Mitochondrial Activity Is Upregulated in Nonlesional Atopic Dermatitis and Amenable to Therapeutic Intervention.

Previous work has shown increased expression of genes related to oxidative stress in nonlesional atopic dermatitis (ADNL) skin. Although mitochondria are key regulators of ROS production, their function in AD has never been investigated. Energy metabolism and the oxidative stress response were studied in keratinocytes (KCs) from patients with ADNL or healthy controls. Moreover, ADNL human epidermal equivalents were treated with tigecycline or MitoQ. We found that pyruvate and glucose were used as energy substrates by ADNL KCs. Increased mitochondrial oxidation of (very) long-chain fatty acids, associated with enhanced complexes I and II activities, was observed in ADNL KCs. Metabolomic analysis revealed increased tricarboxylic acid cycle turnover. Increased aerobic metabolism generated oxidative stress in ADNL KCs. ADNL human epidermal equivalents displayed increased mitochondrial function and an enhanced oxidative stress response compared with controls. Treatment of ADNL human epidermal equivalents with tigecycline or MitoQ largely corrected the AD profile, including high p-65 NF-κB, abnormal lamellar bodies, and cellular damage. Furthermore, we found that glycolysis supports but does not supersede mitochondrial metabolism in ADNL KCs. Thus, aerobic metabolism predominates in ADNL but leads to oxidative stress. Therefore, mitochondria could be a reservoir of potential therapeutic targets in atopic dermatitis.

Integron detection for prediction of trimethoprim/sulfamethoxazole susceptibility in children with Enterobacterales urinary tract infections.

OBJECTIVES: In some countries, third-generation cephalosporins (3GCs) serve as first-line therapy in children with urinary tract infections (UTIs). However, their use may contribute to the emergence of antibiotic resistance, notably among Gram-negative bacteria (GNB). Integrons are bacterial genetic elements involved in antibiotic resistance in GNB. Their absence is associated with >97% susceptibility to trimethoprim/sulfamethoxazole in adults infected with GNB. The objective of this study was to examine the value of integron detection directly from urine samples as a predictive marker of resistance to trimethoprim/sulfamethoxazole in children with GNB-related UTIs. METHODS: Children admitted to the Limoges University Hospital's paediatric emergency department between February 2018 and March 2019 with a suspicion of UTI were eligible for the study. Only confirmed cases presenting a positive urine culture with unique GNB were retained for further study analyses. Integrons were detected directly from urines using real-time PCR. RESULTS: The data of 72 patients were analysed and integrons were detected in 15 urine samples. The negative predictive value of integron detection for resistance to trimethoprim/sulfamethoxazole was 100% as all of the GNB (all were Enterobacterales) isolated from patients with no integrons detected in their urine samples were susceptible to trimethoprim/sulfamethoxazole. CONCLUSIONS: The detection of integrons in cases of paediatric patients with suspected UTI could help limit 3GC empirical use and empower an empirical first-line strategy better tailored to the needs of each patient.

Atopic Dermatitis: The Fate of the Fat.

Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease in which dry and itchy skin may develop into skin lesions. AD has a strong genetic component, as children from parents with AD have a two-fold increased chance of developing the disease. Genetic risk loci and epigenetic modifications reported in AD mainly locate to genes involved in the immune response and epidermal barrier function. However, AD pathogenesis cannot be fully explained by (epi)genetic factors since environmental triggers such as stress, pollution, microbiota, climate, and allergens also play a crucial role. Alterations of the epidermal barrier in AD, observed at all stages of the disease and which precede the development of overt skin inflammation, manifest as: dry skin; epidermal ultrastructural abnormalities, notably anomalies of the lamellar body cargo system; and abnormal epidermal lipid composition, including shorter fatty acid moieties in several lipid classes, such as ceramides and free fatty acids. Thus, a compelling question is whether AD is primarily a lipid disorder evolving into a chronic inflammatory disease due to genetic susceptibility loci in immunogenic genes. In this review, we focus on lipid abnormalities observed in the epidermis and blood of AD patients and evaluate their primary role in eliciting an inflammatory response.

Optimizing emollient therapy for skin barrier repair in atopic dermatitis.

OBJECTIVE: We compared the principal characteristics of over-the-counter moisturizers with physiological lipid-based barrier repair therapy (BRT). DATA SOURCES: An extended literature reported that moisturizers are considered standard ancillary therapy for anti-inflammatory skin disorders such as atopic dermatitis (AD). Additional studies have found that physiological lipid-based BRT can comprise effective, stand-alone therapy for pediatric AD. RESULTS: Not all moisturizers are beneficial-some negatively impact skin function, and in doing so, they risk inducing or exacerbating inflammation in patients with AD. The frequent self-reported occurrences of sensitive skin in patients with AD could reflect the potential toxicity of such formulations. A still unanswered question is whether improper formulations could also prove to be counterproductive in other types of sensitive skin, such as rosacea. In contrast, we found how physiological lipid-based BRT (when comprised of the 3 key stratum corneum lipids in sufficient quantities and at an appropriate molar ratio) can correct the barrier abnormality, thereby reducing inflammation in AD and possibly in other inflammatory dermatoses, such as adult eczemas and possibly even psoriasis. CONCLUSION: We provide guidelines for the appropriate dispensation of moisturizers and physiological lipid-based, BRT for the treatment of AD. Both over-the-counter (Atopalm) and prescription (EpiCeram) products are available in the United States with these characteristics.