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The two cell-adhesion molecules, Neurexin-1 and Neuroligin-1, are essential for synapse function in neural networks. Interruptions to the function of these two proteins are associated with predestination for cognitive disorders, such as Autism spectrum disorder (ASD). In this paper, we study the effects of genetic missense mutations located on the cell interface between NRXN-1 and NLGN-1 on the development of neurodevelopmental disorders by identifying and determining the effects of mutations on bond strengths between NRXN-1 and NLGN-1 on the synaptic interface by building a computational platform. This was done by mapping all ASD-associated point mutations found in a web-based database on the computationally modeled structure of NRXN-1, then determining which mutations interact with NLGN-1. Then, the binding strength of the two proteins without the influence of the mutations was compared to the binding strength with the mutations so that the effects of the mutation were established. Based on our structural models and calculations of binding free energy, we found that these mutations can change the binding affinity of Neurexin-neuroligin interaction. Thus, we suggest that the changes in bond strength between Neurexin and Neuroligin at neural synapses can affect neural circuits, leading to autism-associated symptoms. [ABSTRACT FROM AUTHOR]

Chronic or delayed healing wounds constitute an ever‐increasing burden on healthcare providers and patients alike. Thus, therapeutic modalities that are tailored to particular deficiencies in the delayed wound healing response are of critical importance to improve clinical outcomes. Human amnion‐derived viable and devitalized allografts have demonstrated clinical efficacy in promoting the closure of delayed healing wounds, but the mechanisms responsible for this efficacy and the specific wound healing processes modulated by these tissues are not fully understood. Here, we utilized a diabetic murine excisional wound model in which healing is driven by granulation and re‐epithelialization, and we applied viable (vHAMA) or devitalized (dHAMA) amnion‐derived allografts to the wound bed in order to determine their effects on wound healing processes. Compared to control wounds that were allowed to heal in the absence of treatment, wounds to which vHAMA or dHAMA were applied demonstrated enhanced deposition of granulation tissue accompanied by increased cellular proliferation and increased de novo angiogenesis, while vHAMA‐treated wounds also demonstrated accelerated re‐epithelialization. Taken together, these data suggest that both vHAMA and dHAMA facilitate wound healing through promoting processes critical to granulation tissue formation. Further understanding of the cellular and tissue mechanisms underlying the effects of tissue‐derived matrices on wound healing will enable tailored prescription of their use in order to maximize clinical benefit. [ABSTRACT FROM AUTHOR]

Background: Hypertrophic scars (HTS) result from injury to the skin and represent a clinical burden with limited treatment options. Previously, we demonstrated that statin drugs could attenuate HTS formation, but convenient topical delivery and retention of these drugs at the wound site remains a challenge. Aims: Here, we aimed to develop a topical cream formulation that can deliver statin drugs simply and conveniently to reduce scar hypertrophy. Methods: We formulated creams containing 10% pravastatin, 2% simvastatin, and 10% simvastatin. We tested these creams for their ability to reduce scar hypertrophy and attenuate dermal fibrosis in a clinically relevant HTS wound model performed in rabbit ear skin. We also monitored trans‐epidermal water loss (TEWL) over the course of wound healing in order to understand the effects of statin treatment on epidermal barrier recovery. Results: Of the three creams formulated, only application of 10% simvastatin cream significantly attenuated hypertrophy of resultant scars compared with vehicle cream application. Application of 10% simvastatin cream resulted in a decrease in macrophage and myofibroblast density at post‐operative day 28 (POD28) harvest. Application of 10% simvastatin cream resulted in visible symptoms of dryness and increased TEWL at POD28, but subsequent withdrawal of statin cream treatment resulted in rapid alleviation of dryness and decrease in TEWL back to normal levels. Conclusions: Our data demonstrate that topical administration of 10% simvastatin cream antagonizes dermal fibrosis and reduces hypertrophy in an HTS model, and withdrawal of the cream enables recovery of epidermal barrier and resolution of skin dryness. [ABSTRACT FROM AUTHOR]

Dermal fibrosis is a consequence of damage to skin and is accompanied by dysfunction and cosmetic disfigurement. Improved understanding of the pathological factors driving skin fibrosis is critical to development of therapeutic modalities. Here, we describe that the Wnt signalling antagonist SFRP2 is upregulated in organotypic keratinocyte cultures upon experimental reduced hydration, a model that simulates the aberrant epidermal barrier state characteristic of several skin pathologies, including those that manifest in development of fibrosis. Consistent with this, we find that SFRP2 is overexpressed in both the dermis and epidermis of human hypertrophic scar tissue and lesional tissue of a mouse scleroderma model. Knockdown of SFRP2 expression in human fibroblasts antagonises proliferation and myofibroblast differentiation, including deposition of type I collagen, suggesting that SFRP2 signalling in fibroblasts may contribute to propagation of fibrosis in hypertrophic scar, as well as in other clinical indications characterised by skin fibrosis. [ABSTRACT FROM AUTHOR]