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Pigmentation evolved in ancestral humans to protect against toxic, ultraviolet B irradiation, but the question remains: "what is being protected?" Because humans with dark pigmentation display a suite of superior epidermal functions in comparison with their more lightly pigmented counterparts, we hypothesized and provided evidence that dark pigmentation evolved in Africa to support cutaneous function. Because our prior clinical studies also showed that a restoration of a competent barrier dampens cutaneous inflammation, we hypothesized that resistance to inflammation could have provided pigmented hominins with yet another, important evolutionary benefit. We addressed this issue here in two closely related strains of hairless mice, endowed with either moderate (Skh2/J) or absent (Skh1) pigmentation. In these models, we showed that (a) pigmented mice display a markedly reduced propensity to develop inflammation after challenges with either a topical irritant or allergen in comparison with their nonpigmented counterparts; (b) visible and histologic evidence of inflammation was paralleled by reduced levels of pro-inflammatory cytokines (i.e., IL-1α and INFα); (c) because depigmentation of Skh2/J mouse skin enhanced both visible inflammation and pro-inflammatory cytokine levels after comparable pro-inflammatory challenges, the reduced propensity to develop inflammation was directly linked to the presence of pigmentation; and (d) furthermore, in accordance with our prior work showing that pigment production endows benefits by reducing the surface pH of skin, acidification of albino (Skh1) mouse skin also protected against inflammation, and equalized cytokine levels to those found in pigmented skin. In summary, pigmentation yields a reduced propensity to develop inflammation, consistent with our hypothesis that dark pigmentation evolved in ancestral humans to provide a suite of barrier-linked benefits that now include resistance to inflammation.

Mutations in the progranulin gene cause frontotemporal dementia (FTD), a debilitating neurodegenerative disease that involves atrophy of the frontal and temporal lobes and affects personality, behavior, and language. Progranulin-deficient mouse models of FTD exhibit deficits in compulsive and social behaviors reminiscent of patients with FTD, and develop excessive microgliosis and increased release of inflammatory cytokines. Activation of nicotinic acetylcholine receptors (nAChRs) by nicotine or specific α7 nAChR agonists reduces neuroinflammation. Here, we investigated whether activation of nAChRs by nicotine or α7 agonists improved the excessive inflammatory and behavioral phenotypes of a progranulin-deficient FTD mouse model. We found that treatment with selective α7 agonists, PHA-568487 or ABT-107, strongly suppressed the activation of NF-κB in progranulin-deficient cells. Treatment with ABT-107 also reduced microgliosis, decreased TNFα levels, and reduced compulsive behavior in progranulin-deficient mice. Collectively, these data suggest that targeting activation of the α7 nAChR pathway may be beneficial in decreasing neuroinflammation and reversing some of the behavioral deficits observed in progranulin-deficient FTD.

Background: Blurry images in teledermatology and consultation increased the diagnostic difficulty for both deep learning models and physicians. We aim to determine the extent of restoration in diagnostic accuracy after blurry images are deblurred by deep learning models. Methods: We used 19,191 skin images from a public skin image dataset that includes 23 skin disease categories, 54 skin images from a public dataset of blurry skin images, and 53 blurry dermatology consultation photos in a medical center to compare the diagnosis accuracy of trained diagnostic deep learning models and subjective sharpness between blurry and deblurred images. We evaluated five different deblurring models, including models for motion blur, Gaussian blur, Bokeh blur, mixed slight blur, and mixed strong blur. Main Outcomes and Measures: Diagnostic accuracy was measured as sensitivity and precision of correct model prediction of the skin disease category. Sharpness rating was performed by board-certified dermatologists on a 4-point scale, with 4 being the highest image clarity. Results: The sensitivity of diagnostic models dropped 0.15 and 0.22 on slightly and strongly blurred images, respectively, and deblurring models restored 0.14 and 0.17 for each group. The sharpness ratings perceived by dermatologists improved from 1.87 to 2.51 after deblurring. Activation maps showed the focus of diagnostic models was compromised by the blurriness but was restored after deblurring. Conclusions: Deep learning models can restore the diagnostic accuracy of diagnostic models for blurry images and increase image sharpness perceived by dermatologists. The model can be incorporated into teledermatology to help the diagnosis of blurry images. [ABSTRACT FROM AUTHOR]

Background: Generalized pustular psoriasis (GPP) is an uncommon variant of psoriasis. Clinical characteristics of GPP are limited due to its relatively low prevalence worldwide. Thus, the region-specific phenotypic differences between GPP and severe plaque psoriasis (SPP) remained not fully clarified. Objectives: This study aimed to compare the gender distribution, disease onset, clinical features, medical comorbidities, associated symptoms, laboratory findings, and potential precipitating factors of GPP and SPP in a single center in tropical Taiwan. Methods: A retrospective review was conducted for GPP and SPP in a tertiary medical center from 2003 to 2023. The GPP Area and Severity Index (GPPASI) and GPP Physician Global Assessment (GPPGA) score were used to measure the severity of GPP. Results: A total of 26 patients with GPP (mean age: 48.2 years) and 50 patients with SPP (defined as psoriasis area and severity index over 20 and undergoing biological agents more than 1 year, mean age: 41.3 years) were included in this study. Forty-six percentage of the GPP patients had a preceding history of psoriasis. While there was no gender or age predominance, patients with GPP tended to develop fever, hypertension, upper respiratory tract infection, leukocytosis, elevated C-reactive protein (CRP) levels, scalp involvement, be hospitalized and for a long time, along with allergy history of medications (diclofenac, ampicillin, and ceftriaxone), as compared to those with SPP. Hepatitis B virus and hepatitis C virus infections were less prevalent in GPP patients (with 15.4% and 3.8%, compared to 30.0% and 8.0% in SPP, respectively, although not statistically significant). The highest GPPASI and GPPGA scores occurred in young patients of GPP, but they are not associated with diseases of hypertension, hyperglycemia, or hyperlipidemia. Conclusion: Patients with GPP in Taiwan tended to have a higher hospitalization rate and longer mean hospitalization time along with increased occurrence of fever, leukocytosis, elevated CRP levels, and drug allergy. The younger patients of GPP tended to have higher GPPASI and GPPGA scores than the elder ones. [ABSTRACT FROM AUTHOR]

Introduction There remains an unmet medical need for a diverse array of allergic diseases, of which the combined disease prevalence has substantially increased to affect more than 30% of the [...], Over the last 2 decades, omalizumab is the only anti-IgE antibody that has been approved for asthma and chronic spontaneous urticaria (CSU). Ligelizumab, a higher-affinity anti-IgE mAb and the only rival viable candidate in late-stage clinical trials, showed anti-CSU efficacy superior to that of omalizumab in phase IIb but not in phase III. This report features the antigenic-functional characteristics of UB-221, an anti-IgE mAb of a newer class that is distinct from omalizumab and ligelizumab. UB-221, in free form, bound abundantly to CD23-occupied IgE and, in oligomeric mAb-IgE complex forms, freely engaged CD23, while ligelizumab reacted limitedly and omalizumab stayed inert toward CD23; these observations are consistent with UB- 221 outperforming ligelizumab and omalizumab in CD23-mediated downregulation of IgE production. UB-221 bound IgE with a strong affinity to prevent Fc[epsilon]RI-mediated basophil activation and degranulation, exhibiting superior IgE-neutralizing activity to that of omalizumab. UB-221 and ligelizumab bound cellular IgE and effectively neutralized IgE in sera of patients with atopic dermatitis with equal strength, while omalizumab lagged behind. A single UB-221 dose administered to cynomolgus macaques and human IgE ([epsilon], [kappa])-knockin mice could induce rapid, pronounced serum-IgE reduction. A single UB-221 dose administered to patients with CSU in a first-in-human trial exhibited durable disease symptom relief in parallel with a rapid reduction in serum free-IgE level.