Skin barrier and autoimmunity - mechanisms and novel therapeutic approaches for autoimmune blistering diseases of the skin

One of the most important functions of the skin besides regulating internal body temperature includes formation of the barrier between the organism and the external environment, hence protecting against pathogen invasion, chemical and physical assaults and unregulated loss of water and solutes. Disruption of the protective barrier is observed clinically in blisters and erosions of the skin that form in autoimmune blistering diseases where the body produces autoantibodies against structural proteins of the epidermis or the epidermal-dermal junction. Although there is no cure for autoimmune skin blistering diseases, immune suppressive therapies currently available offer opportunities for disease management. In cases where no treatment is sought, these disorders can lead to life threatening complications and current research efforts have focused on developing therapies that target autoantibodies which contribute to disease symptoms. This review will outline the involvement of the skin barrier in main skin-specific autoimmune blistering diseases by describing the mechanisms underpinning skin autoimmunity and review current progress in development of novel therapeutic approaches targeting the underlying causes of autoimmune skin blistering diseases.Natalie E. Stevens, Allison J. Cowin and Zlatko Kopeck

A framework for realistic 3D tele-immersion

Meeting, socializing and conversing online with a group of people using teleconferencing systems is still quite differ- ent from the experience of meeting face to face. We are abruptly aware that we are online and that the people we are engaging with are not in close proximity. Analogous to how talking on the telephone does not replicate the experi- ence of talking in person. Several causes for these differences have been identified and we propose inspiring and innova- tive solutions to these hurdles in attempt to provide a more realistic, believable and engaging online conversational expe- rience. We present the distributed and scalable framework REVERIE that provides a balanced mix of these solutions. Applications build on top of the REVERIE framework will be able to provide interactive, immersive, photo-realistic ex- periences to a multitude of users that for them will feel much more similar to having face to face meetings than the expe- rience offered by conventional teleconferencing systems

Flightless I alters the inflammatory response and autoantibody profile in an OVA-induced atopic dermatitis skin-like disease

Atopic dermatitis (AD) is a chronic pruritic inflammatory skin disease characterized by excessive inflammation and disrupted skin barrier function. Although the etiology of AD is not completely understood, clinical and basic studies suggest increasing involvement of autoantibodies against intracellular proteins. An actin remodeling protein, Flightless I (Flii), has been shown to promote development of inflammatory mediated skin conditions and impairment of skin barrier development and function. Here, we sought to determine the effect of altering Flii expression on the development of AD and its contribution to autoimmune aspects of inflammatory skin conditions. Ovalbumin (OVA)-induced AD skin-like disease was induced in Flii heterozygous (Flii+/- ), wild-type (Flii+/+ ), and Flii transgenic (FliiTg/Tg ) mice by epicutaneous exposure to OVA for 3 weeks; each week was separated by 2-week resting period. Reduced Flii expression resulted in decreased disease severity and tissue inflammation as determined by histology, lymphocytic, and mast cell infiltrate and increased anti-inflammatory IL-10 cytokine levels and a marked IFN-γ Th1 response. In contrast, Flii over-expression lead to a Th2 skewed response characterized by increased pro-inflammatory TNF-α cytokine production, Th2 chemokine levels, and Th2 cell numbers. Sera from OVA-induced AD skin-like disease Flii+/- mice showed a decreased level of autoreactivity while sera from FliiTg/Tg mice counterparts showed an altered autoantibody profile with strong nuclear localization favoring development of a more severe disease. These findings demonstrate autoimmune responses in this model of OVA-induced AD-like skin disease and suggest that Flii is a novel target, whose manipulation could be a potential approach for the treatment of patients with AD.Zlatko Kopecki, Natalie E. Stevens, Heng T. Chong, Gink N. Yang and Allison J. Cowi

Taking eDNA underground: factors affecting eDNA detection of subterranean fauna in groundwater

First published: 31 March 2023. OnlinePublStygofauna are aquatic fauna that have evolved to live underground. The impacts of anthropogenic climate change, extraction and pollution on groundwater pose major threats to groundwater health, prompting the need for efficient and reliable means to detect and monitor stygofaunal communities. Conventional survey techniques for these species rely on morphological identification and can be biased, labour intensive, and often indeterminate to lower taxonomic levels. By contrast, environmental DNA (eDNA)-based methods have the potential to dramatically improve on existing stygofaunal survey methods in a large range of habitats and for all life stages, reducing the need for the destructive manual collection of often critically endangered species or specialized taxonomic expertise. We compared eDNA and haul-net samples collected in 2020 and 2021 from 19 groundwater bores and a cave on Barrow Island, located north-west of Western Australia, and assessed how sampling factors influenced the quality of eDNA detection of stygofauna. The two detection methods were complementary, eDNA metabarcoding was able to detect soft-bodied taxa and fish often missed by nets, but only detected seven of the nine stygofaunal crustacean orders identified from haul-net specimens. Our results also indicated that eDNA metabarcoding could detect 54-100% of stygofauna from shallow water samples and 82-90% from sediment samples. However, there was significant variation in stygofaunal diversity between sample years and sampling types. The findings of this study demonstrate that haul net sampling has a tendency to underestimate stygofaunal diversity and that eDNA metabarcoding of groundwater can substantially improve efficiency of stygofaunal surveys.Mieke van der Heyde, Nicole E. White, Paul Nevill, Andrew D. Austin, Nicholas Stevens, Matt Jones, Michelle T. Guzi

Electron self-trapping in intermediate-valent SmB6

SmB6 exhibits intermediate valence in the ground state and unusual behaviour at low temperatures. The resistivity and the Hall effect cannot be explained either by conventional sf-hybridization or by hopping transport in an impurity band. At least three different energy scales determine three temperature regimes of electron transport in this system. We consider the ground state properties, the soft valence fluctuations and the spectrum of band carriers in n-doped SmB6. The behaviour of excess conduction electrons in the presence of soft valence fluctuations and the origin of the three energy scales in the spectrum of elementary excitations is discussed. The carriers which determine the low-temperature transport in this system are self-trapped electron-polaron complexes rather than simply electrons in an impurity band. The mechanism of electron trapping is the interaction with soft valence fluctuations.Comment: 12 pages, 3 figure

Magnetic Anisotropy in the Molecular Complex V15

We apply degenerate perturbation theory to investigate the effects of magnetic anisotropy in the magnetic molecule V15. Magnetic anisotropy is introduced via Dzyaloshinskii-Moriya (DM) interaction in the full Hilbert space of the system. Our model provides an explanation for the rounding of transitions in the magnetization as a function of applied field at low temperature, from which an estimate for the DM interaction is found. We find that the calculated energy differences of the lowest energy states are consistent with the available data. Our model also offers a novel explanation for the hysteretic nature of the time-dependent magnetization data.Comment: Final versio

Multicomponent obesity prevention intervention in low-income preschoolers: Primary and subgroup analyses of the NET-works randomized clinical trial, 2012-2017

Objectives. To evaluate a multicomponent obesity prevention intervention among diverse, low-income preschoolers. Methods. Parent-child dyads (n = 534) were randomized to the Now Everybody Together for Amazing and Healthful Kids (NET-Works) intervention or usual care in Minneapolis, MN (2012-2017). The intervention consisted of home visits, parenting classes, and telephone check-ins. The primary outcomes were adjusted 24- and 36-month body mass index (BMI). Results. Compared with usual care, the NET-Works intervention showed no significant difference in BMI change at 24 (-0.12 kg/m2; 95% confidence interval [CI] = -0.44, 0.19) or 36 months (-0.19 kg/m2; 95% CI = -0.64, 0.26). Energy intake was significantly lower in the NET-Works group at 24 (-90 kcal/day; 95% CI = -164, -16) and 36 months (-101 kcal/day; 95% CI = -164, -37). Television viewing was significantly lower in the NET-Works group at 24 (rate ratio = 0.84; 95% CI = 0.75, 0.93) and 36 months (rate ratio = 0.88; 95% CI = 0.78, 0.99). Children with baseline overweight or obesity had lower BMI in the NET-Works group than those in usual care at 36 months (-0.71 kg/m2; 95% CI = -1.30, -0.12). Hispanic children had lower BMI in the NET-Works group than those in usual care at 36 months (-0.59 kg/m2; 95% CI = -1.14, -0.04). Conclusions. In secondary analyses, NET-Works significantly reduced BMI over 3 years among Hispanic children and children with baseline overweight or obesity. Trial Registration: ClinicalTrials.gov Identifier: NCT01606891

Tomato: a crop species amenable to improvement by cellular and molecular methods

Tomato is a crop plant with a relatively small DNA content per haploid genome and a well developed genetics. Plant regeneration from explants and protoplasts is feasable which led to the development of efficient transformation procedures. In view of the current data, the isolation of useful mutants at the cellular level probably will be of limited value in the genetic improvement of tomato. Protoplast fusion may lead to novel combinations of organelle and nuclear DNA (cybrids), whereas this technique also provides a means of introducing genetic information from alien species into tomato. Important developments have come from molecular approaches. Following the construction of an RFLP map, these RFLP markers can be used in tomato to tag quantitative traits bred in from related species. Both RFLP's and transposons are in the process of being used to clone desired genes for which no gene products are known. Cloned genes can be introduced and potentially improve specific properties of tomato especially those controlled by single genes. Recent results suggest that, in principle, phenotypic mutants can be created for cloned and characterized genes and will prove their value in further improving the cultivated tomato.

The immunotoxicity, but not anti-tumor efficacy, of anti-CD40 and anti-CD137 immunotherapies is dependent on the gut microbiota

Immune agonist antibodies (IAAs) are promising immunotherapies that target co-stimulatory receptors to induce potent anti-tumor immune responses, particularly when combined with checkpoint inhibitors. Unfortunately, their clinical translation is hampered by serious dose-limiting, immune-mediated toxicities, including high-grade and sometimes fatal liver damage, cytokine release syndrome (CRS), and colitis. We show that the immunotoxicity, induced by the IAAs anti-CD40 and anti-CD137, is dependent on the gut microbiota. Germ-free or antibiotic-treated mice have significantly reduced colitis, CRS, and liver damage following IAA treatment compared with conventional mice or germ-free mice recolonized via fecal microbiota transplant. MyD88 signaling is required for IAA-induced CRS and for anti-CD137-induced, but not anti-CD40-induced, liver damage. Importantly, antibiotic treatment does not impair IAA anti-tumor efficacy, alone or in combination with anti-PD1. Our results suggest that microbiota-targeted therapies could overcome the toxicity induced by IAAs without impairing their anti-tumor activity.Stephen J. Blake, Jane James, Feargal J. Ryan, Jose Caparros-Martin, Georgina L. Eden, Yee C. Tee, John R. Salamon, Saoirse C. Benson, Damon J. Tumes, Anastasia Sribnaia, Natalie E. Stevens, John W. Finnie, Hiroki Kobayashi, Deborah L. White, Steve L. Wesselingh, Fergal O’Gara, Miriam A. Lynn, and David J. Lyn

Applying the Behavior Change Technique Taxonomy to Four Multicomponent Childhood Obesity Interventions

Applying the Behavior Change Technique Taxonomy has the potential to facilitate identification of effective childhood obesity intervention components. This article evaluates the feasibility of coding Childhood Obesity Prevention and Treatment Consortium interventions and compares reliability between external taxonomy-familiar coders and internal intervention-familiar coders. After training, coder pairs independently coded prespecified portions of intervention materials. An adjudication process was used to explore coding discrepancies. Reliability between internal and external coders was moderate (prevalence and bias-adjusted kappa.38 to.55). Reliability for specific target behaviors varied with substantial agreement for physical activity (.63 to.76) and moderate for dietary intake (.44 to.63). Applying the taxonomy to these interventions was feasible, but agreement was modest. Coding discrepancies highlight the importance of refining coding to capture the complexities of childhood obesity interventions, which often engage multiple recipients (e.g., parents and/or children) and address multiple behaviors (e.g., diet, physical activity, screen time)