Alopecia areata is a common cause of non-scaring autoimmune hair loss, associated with substantial psychosocial burden. Alopecia areata is an autoimmune disease in which loss of immune privilege in hair follicles leads to local hair follicle-associated inflammation. A chronic disease with uncertain course that is estimated to affect 2% of people over their lifetime, alopecia areata can present with a range of clinical features, from a single small round patch of hair loss to full scalp and body hair loss, and is associated with atopic, autoimmune and psychological comorbidities. Alopecia areata also has a major negative impact on quality of life, with a greater mental burden than physical burden. Since the 2010s, advances in understanding of disease pathogenesis have led to the identification of inflammatory pathways that can be successfully inhibited to produce substantial clinical responses. The therapeutic landscape has been transformed, with FDA approval of the first treatment for adults with severe alopecia areata in 2022 and for adolescents with severe alopecia areata in 2023, with multiple investigational treatments currently in phase II and phase III clinical trials. This Primer by Guttman-Yassky and colleagues reviews the epidemiology, pathophysiology, diagnosis and treatment of alopecia areata. This Primer also discusses the quality of life issues faced by patients and future research avenues.

Importance:The results of small studies suggest that off-label use of low-dose oral minoxidil (LDOM) may be safe and effective for patients with hair loss, but larger trials and standardized guidelines are lacking. Objective:To create an expert consensus statement for LDOM prescribing for patients with hair loss. Evidence Review:The current literature on the pharmacological properties, adverse effect profile, and use of LDOM for patients with hair loss was reviewed. Topics of interest were identified, and a modified Delphi consensus process was created. A total of 43 hair loss specialist dermatologists from 12 countries participated in a modified Delphi process. Consensus was reached if at least 70% agreed or strongly agreed on a 5-point Likert scale. Findings:Over 4 survey rounds, 180 items in the first round, 121 items in the second round, 16 items in the third round, and 11 items in the fourth round were considered and revised. A total of 76 items achieved consensus including diagnoses for which LDOM may provide direct or supportive benefit, indications for LDOM compared to topical minoxidil, dosing for adults (18 years and older) and adolescents (aged 12 to 17 years), contraindications, precautions, baseline evaluation, monitoring, adjunctive therapy, and specialty consultation. Pediatric use and dosing items for children younger than 12 years, and LDOM titration protocols fell short of consensus. Conclusions and Relevance:This international expert consensus statement regarding the off-label prescribing of LDOM for patients with hair loss can help guide clinical practice until more data emerge. Hair loss experts with experience treating pediatric patients were underrepresented on this expert panel. Future research should investigate best practices for LDOM use in pediatric patients. Other critical topics for further investigation include the comparative efficacy of topical minoxidil vs oral minoxidil, the safety of oral minoxidil for patients with a history of allergic contact dermatitis to topical minoxidil, the long-term safety of LDOM, and the use of other off-label forms of minoxidil, such as compounded formulations of oral minoxidil and sublingual minoxidil. As additional evidence-based data emerge, these recommendations should be updated.

ImportanceThe results of small studies suggest that off-label use of low-dose oral minoxidil (LDOM) may be safe and effective for patients with hair loss, but larger trials and standardized guidelines are lacking.ObjectiveTo create an expert consensus statement for LDOM prescribing for patients with hair loss.Evidence ReviewThe current literature on the pharmacological properties, adverse effect profile, and use of LDOM for patients with hair loss was reviewed. Topics of interest were identified, and a modified Delphi consensus process was created. A total of 43 hair loss specialist dermatologists from 12 countries participated in a modified Delphi process. Consensus was reached if at least 70% agreed or strongly agreed on a 5-point Likert scale.FindingsOver 4 survey rounds, 180 items in the first round, 121 items in the second round, 16 items in the third round, and 11 items in the fourth round were considered and revised. A total of 76 items achieved consensus including diagnoses for which LDOM may provide direct or supportive benefit, indications for LDOM compared to topical minoxidil, dosing for adults (18 years and older) and adolescents (aged 12 to 17 years), contraindications, precautions, baseline evaluation, monitoring, adjunctive therapy, and specialty consultation. Pediatric use and dosing items for children younger than 12 years, and LDOM titration protocols fell short of consensus.Conclusions and RelevanceThis international expert consensus statement regarding the off-label prescribing of LDOM for patients with hair loss can help guide clinical practice until more data emerge. Hair loss experts with experience treating pediatric patients were underrepresented on this expert panel. Future research should investigate best practices for LDOM use in pediatric patients. Other critical topics for further investigation include the comparative efficacy of topical minoxidil vs oral minoxidil, the safety of oral minoxidil for patients with a history of allergic contact dermatitis to topical minoxidil, the long-term safety of LDOM, and the use of other off-label forms of minoxidil, such as compounded formulations of oral minoxidil and sublingual minoxidil. As additional evidence-based data emerge, these recommendations should be updated.

Alopecia areata (AA) is an autoimmune non-scarring hair loss that arises in genetically susceptible individuals, potentially in combination with environmental triggers or inciting events, of which the exact mechanism is not yet fully understood. Genome wide association studies have demonstrated an association between AA and variants in HLA haplotypes on chromosome 6 which correlate with other autoimmune conditions as well as other gene variants. Familial and twin studies also confer additional evidence to a genetic component. AA pathogenesis relies on immune privilege collapse at the hair follicle (HF) bulb in the anagen hair cycle phase. Immune privilege collapse is associated with upregulation of IFN-γ, ultimately activating JAK-STAT pathway resulting in upregulation of MHC class I and II in the HF and subjecting it to attack by NKG2D+ CD8 T cells. The complex interplay between pro-inflammatory cytokines such as IFN-γ, IL-2, IL-15 and their use of JAK-STAT signaling are important in perpetuation of AA.

High fat diet (HFD)-induced obesity increases the risk and severity of psoriasis. However, the immunoregulatory effects of different HFD-induced obesity on psoriasis pathogenesis remains poorly understood. Here, mimicking human dietary fat profiles, four HFDs ꟷ saturated, monounsaturated, omega-6 and omega-3 fats ꟷ were designed and used to induce obesity in mice. Despite comparable obesity levels across groups, only the saturated HFD exacerbated imiquimod (IMQ)-induced psoriasis. This exacerbation correlated with elevated levels of IL-1β-producing macrophages, IL-17A-producing γδ T cells, and neutrophils within psoriatic lesions. Mechanistically, saturated fatty acids (FAs) promoted IL-1β/IL-17 signaling via fatty acid-binding protein 5 (FABP5)-mediated mitochondrial FA oxidation and extracellular ATP release in skin macrophages. Deletion of FABP5, either globally or specifically in macrophages, attenuated IL-1β/IL-17A signaling and alleviated IMQ-induced psoriasis. These findings identify FABP5 as a key mediator of saturated HFD-driven psoriasis via the IL-1β/IL-17 axis, offering insights into the interplay between dietary fats, obesity and psoriasis. ### Competing Interest Statement The authors have declared no competing interest.

The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure can lead to development of inflammatory skin lesions. We have previously shown that Langerhans cells (LCs) limit keratinocyte apoptosis and photosensitivity via a disintegrin and metalloprotease 17 (ADAM17)-mediated release of epidermal growth factor receptor (EGFR) ligands and that LC ADAM17 sheddase activity is reduced in lupus. Here, we sought to understand how the lupus skin environment contributes to LC ADAM17 dysfunction and, in the process, differentiate between effects on LC ADAM17 sheddase function, LC ADAM17 expression, and LC numbers. We show through transcriptomic analysis a shared IFN-rich environment in non-lesional skin across human lupus and three murine models: MRL/lpr, B6.Sle1yaa, and imiquimod (IMQ) mice. IFN-I inhibits LC ADAM17 sheddase activity in murine and human LCs, and IFNAR blockade in lupus model mice restores LC ADAM17 sheddase activity, all without consistent effects on LC ADAM17 protein expression or LC numbers. Anti-IFNAR-mediated LC ADAM17 sheddase function restoration is associated with reduced photosensitive responses that are dependent on EGFR signaling and LC ADAM17. Reactive oxygen species (ROS) is a known mediator of ADAM17 activity; we show that UVR-induced LC ROS production is reduced in lupus model mice, restored by anti-IFNAR, and is cytoplasmic in origin. Our findings suggest that IFN-I promotes photosensitivity at least in part by inhibiting UVR-induced LC ADAM17 sheddase function and raise the possibility that anifrolumab ameliorates lupus skin disease in part by restoring this function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a potential mechanism of action for anifrolumab in lupus.

Abstract Alopecia areata (AA) is an autoimmune disease with a 2% lifetime incidence. Commonly presenting as defined patches of hair loss on the scalp, AA is characterized by the presence of T cells surrounding the hair bulb and is thought to result as a consequence of the breakdown of immune privilege of the hair follicle. IL-27 is a cytokine with context-dependent pro- and anti-inflammatory properties that has been used as a potential therapy in models of autoimmune diseases and cancer. The objective of this study was to determine if IL-27 has therapeutic potential in AA. To address this, we used an adeno-associated virus that drives the overexpression of IL-27 (AAV-IL27) in our skin-graft induction model of AA. We found that mice that received AAV-IL27 were fully protected from disease development and had minimal CD8 T cell infiltration into the hair follicles. Further, we saw an increase in IL-10 producing CD4 T cells, supporting a potential mechanism by which IL-27 prevents disease development. Interestingly, we found that mice treated with AAV-IL27 generated a robust population of NKG2D expressing CD8 T cells, which has previously been associated with the presence of disease. These results suggest that IL-27 may act in an immunoregulatory manner in AA, by promoting immunosuppressive T cells in the SDLNs. Further studies are needed to further define the specific mechanisms by which IL-27 contributes to the prevention of AA and its utility as a treatment for AA.

Abstract Air‐cored axial‐flux permanent‐magnet synchronous generators (AFPMSGs) are potential candidates for gearless direct‐coupled wind turbines (DCWTs) owing to providing high efficiency and power density. The design of a DCWT generator is so complicated since the generator cost, dimension, and weight affected by gear elimination. Therefore, it is essential to find an optimal AFPMSG design at rated conditions. In this paper, an accurate procedure for the optimal design of an air‐cored AFPMSG applicable for DCWTs is proposed. The genetic algorithm (GA) is used for multi‐objective design optimization to reach the optimal configuration as well as system dimension in order to decrease the weight, increase the power density and enhance the effectiveness of the generator. To validate the efficiency of the suggested optimization proceducer, a 30 kW AFPMSG has been considered as a case study. The results of optimization have been investigated by finite element analysis (FEA). A prototype generator is also fabricated, and the test results are offered and compared with the numerical study. The outcomes show that there exists an acceptable agreement between FEA and experimental outcomes with the error percentage about of 1.35%.

Background The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure inflames skin. Beneficial effects of anifrolumab (anti-interferon α/βreceptor (anti-IFNAR)) on lupus skin disease support a pathogenic role for IFN-I , but mechanistic understanding is limited. We have shown that Langerhans cell (LC) dysfunction contributes to photosensitivity. Healthy LCs act via a disintegrin and metalloprotease 17 (ADAM17) to release epidermal growth factor receptor (EGFR) ligands that limit UVR-induced keratinocyte apoptosis and photosensitivity. However, LC ADAM17 activity is reduced in non-lesional lupus model skin, and data point to reduced LC- mediated protection in human lupus. Here, we asked about the role of the IFN-rich lupus skin environment in LC dysfunction and the implications of this regulation for photosensitivity. Methods Gene expression patterns in non-lesional skin from human lupus and multiple murine models were examined. We used MRL/lpr, B6.Sle1yaa, and imiquimod models of lupus in in vivo studies to assess the role of IFN-I in LC ADAM17 dysfunction and photosensitivity. Results We show a shared IFN-rich environment in non-lesional skin across human and murine model systems, that IFN-I inhibits LC ADAM17 activity, and that anti-IFNAR in lupus models restores LC ADAM17 function and reduces photosensitivity in EGFR and LC ADAM17- dependent manners. Reactive oxygen species (ROS) can mediate ADAM17 activity, and we show reduced LC ROS expression in lupus models that is restored by anti-IFNAR. Conclusions Our findings suggest that IFN-I promotes photosensitivity by causing LC ADAM17 dysfunction and that anifrolumab ameliorates lupus skin disease at least in part by restoring LC function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a mechanism of action for anifrolumab in lupus.

Inactivating mutations of Foxp3, the master regulator of regulatory T cell development and function, lead to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in mice and humans. IPEX is a fatal autoimmune disease, with allogeneic stem cell transplant being the only available therapy. In this study, we report that a single dose of adeno-associated virus (AAV)-IL-27- IL-27 to young mice with naturally occurring Foxp3 mutation (Scurfy mice) substantially ameliorates clinical symptoms, including growth retardation and early fatality. Correspondingly, AAV-IL-27- IL-27 gene therapy significantly prevented naive T cell activation, as manifested by downregulation of CD62L and upregulation of CD44, and immunopathology typical of IPEX. Because IL-27 is known to induce IL-10, a key effector molecule of regulatory T cells, we evaluated the contribution of IL-10 induction by crossing IL-10- null allele to Scurfy mice. Although IL-10 deficiency does not affect the survival of Scurfy mice, it largely abrogated the therapeutic effect of AAV-IL-27.- IL-27. Our study revealed a major role for IL-10 in AAV-IL-27- IL-27 gene therapy and demonstrated that IPEX is amenable to gene therapy. The Journal of Immunology, , 2024, 213: 559-566.- 566.

Abstract Alopecia Areata (AA) is a prevalent autoimmune disease that presents as nonscarring hair loss. AA is associated with the loss of immune tolerance to the hair follicle and marked by a robust immune cell infiltration and production of pro-inflammatory cytokines. In AA, CD8 T cells accumulate around and within the hair follicle and have been identified as pathogenic effectors of disease. The close spatial relationship between cytotoxic CD8 T cells and the hair follicle end-organ target invites further study of the interactions between them. Our transcriptional analysis has revealed CD8 T cells infiltrating AA skin exhibit increased gene expression of perforin and granzymes, which are key mediators of cytolysis. However, the contributions of these cytolytic molecules in AA are currently unknown. Our objective was to investigate the role of perforin in the onset of AA by using C3H/HeJ mice globally deficient in Prf1 (PKO). Interestingly, PKO mice were capable of developing spontaneous AA. Using a skin-graft induction model, we observed that wild type (WT) and PKO recipient mice showed equivalent onset and progression of AA. However, when a CD8-induction model was used, we found CD8 T cells from PKO AA mice were inferior at inducing disease when compared to CD8 T cells from WT AA mice. Overall, our findings suggest that perforin-mediated cytolysis is not required for the autoimmune attack of the hair follicle, and that other effector mechanisms of CD8 T cells are drivers of AA.

In this study, the effect of preheating on the quality of the joint created by simultaneous friction drilling of aluminum alloy AA6061T6 and stainless steel AISI304L sheets was experimentally investigated. Preheating temperatures of 250 , 300, and 350 °C were applied to the components, and the resulting joints were compared to those formed at ambient temperature (39 °C). The tensile test results indicated a reduction of 13

Along with the development of hybrid electric vehicles, researchers are trying to reduce existing limitations such as noise and environmental concerns and improve the efficiency and reliability of these systems. The use of magnetic gear technology is one of the solutions that have been recently proposed to remove these limitations and achieve higher benefits. In this paper, a mechanically coupled magnetic geared (MCMG) machine has been introduced. An accurate analytical model based on the subdomain method is presented to calculate the magnetic machine performance. To do this, first, a pseudo-Cartesian coordinate system is specified, and then the constitutive equations, i.e. Laplace’s and Poisson’s equations are rewritten for different regions of the machine. The separation of variables method was used to determine the general solution of the equations. Then by applying appropriate interface and boundary conditions, the Fourier coefficients of the equations were determined. To verify the analytical results, the performance of the proposed magnetic machine is numerically simulated using the finite element method in commercial software, and then a prototype is built and tested in three distinct modes. By comparing the analysis results with numerical simulation results and experimental tests, the high accuracy of the proposed analytical model can be confirmed.