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Pemphigoid diseases refer to a group of severe autoimmune skin blistering diseases characterized by subepidermal blistering and loss of dermal-epidermal adhesion induced by autoantibody and immune cell infiltrate at the dermal-epidermal junction and upper dermis. Here, we explore the role of the immune cell-secreted serine protease, granzyme B, in pemphigoid disease pathogenesis using three independent murine models. In all models, granzyme B knockout or topical pharmacological inhibition significantly reduces total blistering area compared to controls. In vivo and in vitro studies show that granzyme B contributes to blistering by degrading key anchoring proteins in the dermal-epidermal junction that are necessary for dermal-epidermal adhesion. Further, granzyme B mediates IL-8/macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity. Clinically, granzyme B is elevated and abundant in human pemphigoid disease blister fluids and lesional skin. Collectively, granzyme B is a potential therapeutic target in pemphigoid diseases. Pemphigoid diseases involve autoimmune mediated blistering and immunopathology of the upper dermis. Here, the authors implicate granzyme B in the immunopathology in multiple in vivo models of pemphigoid diseases and utilise a topical granzyme B inhibitor that attenuates disease phenotypes in vivo.

Abstract Background Nonthyroidal illness syndrome (NTIS) can result in thyroid function test alterations that mimic hypothyroidism. The duration of NTIS-induced changes in dogs is not well-described. Objectives Document alterations in thyroid function tests during NTIS and recovery, and the time necessary for their resolution. Animals From 103 dogs sampled, 25 euthyroid dogs with acute, resolvable illness having a low serum total thyroxine (TT4) concentration on admission were analyzed. Methods Prospective observational study. Serum TT4 concentration was measured in 103 dogs within 4 hours of admission. If below the reference interval (RI), subsequent serum samples were obtained every 24 hours from admission until discharge (acute phase) and at 2 weeks and 4 weeks after discharge (recovery phase). Serum samples were submitted for batch measurement of serum TT4, free thyroxine (fT4), total 3,5,3′-triiodothyronine (TT3), and thyroid-stimulating hormone (TSH) concentrations. Results In the cohort of dogs analyzed, serum TT4, TT3, and fT4 concentrations were below the RI in 100%, 80%, and 16% at admission; 20%, 80%, and 0% at discharge; 4%, 8%, and 0% at 2 weeks; and 0%, 0%, and 0% at 4 weeks, respectively. Serum TSH concentration was within the RI in 100% at admission and discharge, and above the RI in 4% and 12% at 2 weeks and 4 weeks, respectively. Conclusions and Clinical Importance Naturally occurring NTIS in dogs induces alterations in thyroid function tests during acute illness and recovery. Measurement of serum TT4 concentration 2 to 4 weeks after discharge or serum fT4 concentration by ED during illness is recommended for accurate assessment of thyroid function in acutely ill dogs.

Neural stem and progenitor cell (NSPC) maintenance is essential for ensuring that organisms are born with proper brain volumes and head sizes. Microcephaly is a disorder in which babies are born with significantly smaller head sizes and cortical volumes. Mutations in subunits of the DNA organizing complex condensin have been identified in microcephaly patients. However, the molecular mechanisms by which condensin insufficiency causes microcephaly remain elusive. We previously identified conserved roles for condensins in repression of retrotransposable elements (RTEs). Here, we show that condensin subunit knockdown in NSPCs of the Drosophila larval central brain increases RTE expression and mobility which causes cell death, and significantly decreases adult head sizes and brain volumes. These findings suggest that unrestricted RTE expression and activity may lead to improper brain development in condensin insufficient organisms, and lay the foundation for future exploration of causative roles for RTEs in other microcephaly models. Mutations in condensin subunits cause microcephaly, but the underlying molecular mechanisms remain elusive. Here, the authors show that unrestricted retrotransposable element activity impairs brain development in condensin insufficient organisms.

Type Ia supernovae are important cosmological distance indicators. Each of these bright supernovae supposedly results from the thermonuclear explosion of a white dwarf star that, after accreting material from a companion star, exceeds some mass limit, but the true nature of the progenitor star system remains controversial. Here we report the spectroscopic detection of circumstellar material in a normal type Ia supernova explosion. The expansion velocities, densities, and dimensions of the circumstellar envelope indicate that this material was ejected from the progenitor system. In particular, the relatively low expansion velocities suggest that the white dwarf was accreting material from a companion star that was in the red-giant phase at the time of the explosion.

Total bacteria, fungal spore and yeast counts were compared with ultraviolet-light-induced fluorescence (UV-LIF) measurements of ambient aerosol at the summit of the Puy de Dôme (PdD) mountain in central France (1465 m a.s.l), which represents a background elevated site. Bacteria, fungal spores and yeast were enumerated by epifluorescence microscopy (EFM) and found to number 2.2 to 23 L−1 and 0.8 to 2 L−1, respectively. Bacteria counts on two successive nights were an order of magnitude larger than in the intervening day. A wide issue bioaerosol spectrometer, version 3 (WIBS-3) was used to perform UV-LIF measurements on ambient aerosol sized 0.8 to 20 μm. Mean total number concentration was 270 L−1 (σ = 66 L−1), found predominantly in a size mode at 2 μm for most of the campaign. Total concentration (fluorescent + non-fluorescent aerosol) peaked at 500 L−1 with a size mode at 1 μm because of a change in air mass origin lasting around 48 h. The WIBS-3 features two excitation and fluorescence detection wavelengths corresponding to different biological molecules, although non-biological interferents also contribute. The mean fluorescent particle concentration after short-wave (280 nm; associated with tryptophan) excitation was 12 L−1 (σ = 6 L−1), and did not vary much throughout the campaign. In contrast, the mean concentration of particles fluorescent after long-wave (370 nm; associated with NADH) excitation was 95 L−1 (σ = 25 L−1), and a nightly rise and subsequent fall of up to 100 L−1 formed a strong diurnal cycle in the latter. The two fluorescent populations exhibited size modes at 3 μm and 2 to 3 μm, respectively. A hierarchical agglomerative cluster analysis algorithm was applied to the data and used to extract different particle factors. A cluster concentration time series representative of bacteria was identified. This was found to exhibit a diurnal cycle with a maximum peak appearing during the day. Analysis of organic mass spectra recorded using an aerosol mass spectrometer (AMS; Aerodyne Inc.) suggests that aerosol reaching the site at night was more aged than that during the day, indicative of sampling the residual layer at night. Supplementary meteorological data and previous work also show that PdD lies in the residual layer/free troposphere at night, and this is thought to cause the observed diurnal cycles in organic-type and fluorescent aerosol particles. Based on the observed disparity between bacteria and fluorescent particle concentrations, fluorescent non-PBA is likely to be important in the WIBS-3 data and the surprisingly high fluorescent concentration in the residual layer/free troposphere raises questions about a ubiquitous background in continental air during the summer.

Patients with breast cancer which lack molecular targets, such as human epidermal growth factor receptor 2 (HER2) or hormone receptors, have limited access to targeted therapies. Somatostatin receptor 2 (SSTR2) is overexpressed in some cancers, and SSTR2-targeted radiopharmaceuticals are FDA-approved for theranostic targeted imaging and therapy in neuroendocrine tumors (NETs). Importantly, histone deacetylase (HDAC) inhibitors can epigenetically modulate SSTR2 expression in NETs with low or variable basal expression. The goal of this study is to characterize SSTR2 basal expression and induction via HDAC inhibition as a potential target for imaging and therapy in preclinical models of triple-negative breast cancer (TNBC). SSTR2 expression in mouse samples was assessed via Western blot and immunohistochemistry. Real-time quantitative PCR (qRT-PCR), flow cytometry, and cell binding assays were utilized to determine if HDAC inhibition can upregulate SSTR2 expression. [ 68 Ga]Ga-DOTATATE positron emission tomography (PET) imaging, which targets SSTR2, was used to non-invasively characterize SSTR2 expression and variability in the EO771 and 4T1 TNBC models before and after HDAC inhibition. These studies demonstrate that HDAC inhibition can upregulate SSTR2 at the transcriptional, translational, and functional levels in breast cancer. Importantly, SSTR2 expression can be characterized non-invasively via PET imaging and modulation with HDAC inhibitors can be monitored longitudinally. Our findings highlight SSTR2 as a promising therapeutic molecular target in TNBC.

Keloid scars (KS) and hypertrophic scars (HS) are fibroproliferative wound healing defects characterized by excessive accumulation of extracellular matrix (ECM) in the dermis of affected individuals. Although transforming growth factor (TGF)-β is known to be involved in the formation of KS and HS, the molecular mechanisms responsible for its activation remain unclear. In this study we investigated Granzyme B (GzmB), a serine protease with established roles in fibrosis and scarring through the cleavage of ECM proteins, as a potential new mediator of TGF-β activation in KS and HS. Increased GzmB-positive mast cells were identified in the dermis of KS and HS but not healthy skin controls. Elevated levels of substance P, a neuropeptide involved in mast cell degranulation, suggest that GzmB is released extracellularly, as confirmed by the significant reduction of the established extracellular GzmB substrate decorin in KS and HS. Similarly, presence of latent TGF-β binding protein 1 (LTBP1), a protein involved in the extracellular tethering of latent TGF-β, was disrupted proximal to the dermal-epidermal junction (DEJ) of GzmB high KS and HS lesions. Using LTBP1-enriched medium as well as purified LTBP1, its cleavage by GzmB was confirmed in vitro . Increased TGF-β/Smad signaling pathway was observed in keratinocytes treated with GzmB-digested LTBP1 and was abolished by the addition of a pan-TGF-β inhibitor, suggesting that GzmB cleavage of LTBP1 contributes to TGF-β activation. In dermal fibroblasts, GzmB also cleaved cell-derived LTBP1 and induced TGF-β activation through the cleavage of one or more unidentified fibroblast-secreted proteins. Altogether, the present results suggest that GzmB contributes to KS and HS through ECM remodeling and TGF-β activation.

In healthy skin, epidermis and dermis are anchored together at the dermal-epidermal junction (DEJ), a specialized basement membrane pivotal for skin integrity and function. However, increased inflammation in the DEJ is associated with the disruption and separation of this junction and sub-epidermal blistering. Granzyme B (GzmB) is a serine protease secreted by immune cells. Dysregulated inflammation may lead to increased GzmB accumulation and proteolysis in the extracellular milieu. Although elevated GzmB is observed at the level of the DEJ in inflammatory and blistering skin conditions, the present study is the first to explore GzmB in the context of DEJ degradation in autoimmune sub-epidermal blistering. In the present study, GzmB induced separation of the DEJ in healthy human skin. Subsequently, α6/β4 integrin, collagen VII, and collagen XVII were identified as extracellular substrates for GzmB through western blot, and specific cleavage sites were identified by mass spectrometry. In human bullous pemphigoid, dermatitis herpetiformis, and epidermolysis bullosa acquisita, GzmB was elevated at the DEJ when compared to healthy samples, while α6/β4 integrin, collagen VII, and collagen XVII were reduced or absent in the area of blistering. In summary, our results suggest that regardless of the initial causation of sub-epidermal blistering, GzmB activity is a common final pathway that could be amenable to a single targeted treatment approach.

Psoriasis is an inflammatory disease with systemic manifestations that most commonly presents as itchy, erythematous, scaly plaques on extensor surfaces. Activation of the IL-23/IL-17 pro-inflammatory signaling pathway is a hallmark of psoriasis and its inhibition is key to clinical management. Granzyme K (GzmK) is an immune cell-secreted serine protease elevated in inflammatory and proliferative skin conditions. In the present study, human psoriasis lesions exhibited elevated GzmK levels compared to non-lesional psoriasis and healthy control skin. In an established murine model of imiquimod (IMQ)-induced psoriasis, genetic loss of GzmK significantly reduced disease severity, as determined by delayed plaque formation, decreased erythema and desquamation, reduced epidermal thickness, and inflammatory infiltrate. Molecular characterization in vitro revealed that GzmK contributed to macrophage secretion of IL-23 as well as PAR-1-dependent keratinocyte proliferation. These findings demonstrate that GzmK enhances IL-23-driven inflammation as well as keratinocyte proliferation to exacerbate psoriasis severity.