Interleukin-1β Interferes with Epidermal Homeostasis through Induction of Insulin Resistance: Implications for Psoriasis Pathogenesis

Response pathways of the metabolic and the immune system have been evolutionary conserved, resulting in a high degree of integrated regulation. Insulin is a central player in the metabolic system and potentially also in the homeostasis of the skin. Psoriasis is a frequent and often severe autoimmune skin disease, clinically characterized by altered epidermal homeostasis, of which the molecular pathomechanisms are only little understood. In this study, we have examined a potential role for insulin signaling in the pathogenesis of this disease. We show that IL-1β is present in high quantities in tissue fluid collected via microdialysis from patients with psoriasis; these levels are reduced under successful anti-psoriatic therapy. Our results suggest that IL-1β contributes to the disease by dual effects. First, it induces insulin resistance through p38MAPK (mitogen-activated protein kinase), which blocks insulin-dependent differentiation of keratinocytes, and at the same time IL-1β drives proliferation of keratinocytes, both being hallmarks of psoriasis. Taken together, our findings point toward insulin resistance as a contributing mechanism to the development of psoriasis; this not only drives cardiovascular comorbidities, but also its cutaneous phenotype. Key cytokines inducing insulin resistance in keratinocytes and kinases mediating their effects may represent attractive targets for novel anti-psoriatic therapies

Antiviral Activity of the G-Quadruplex Ligand TMPyP4 against Herpes Simplex Virus-1

The herpes simplex virus 1 (HSV-1) genome is extremely rich in guanine tracts that fold into G-quadruplexes (G4s), nucleic acid secondary structures implicated in key biological functions. Viral G4s were visualized in HSV-1 infected cells, with massive virus cycle-dependent G4-formation peaking during viral DNA replication. Small molecules that specifically interact with G4s have been shown to inhibit HSV-1 DNA replication. We here investigated the antiviral activity of TMPyP4, a porphyrin known to interact with G4s. The analogue TMPyP2, with lower G4 affinity, was used as control. We showed by biophysical analysis that TMPyP4 interacts with HSV-1 G4s, and inhibits polymerase progression in vitro; in infected cells, it displayed good antiviral activity which, however, was independent of inhibition of virus DNA replication or entry. At low TMPyP4 concentration, the virus released by the cells was almost null, while inside the cell virus amounts were at control levels. TEM analysis showed that virus particles were trapped inside cytoplasmatic vesicles, which could not be ascribed to autophagy, as proven by RT-qPCR, western blot, and immunofluorescence analysis. Our data indicate a unique mechanism of action of TMPyP4 against HSV-1, and suggest the unprecedented involvement of currently unknown G4s in viral or antiviral cellular defense pathways

Impact of Altered Mineral Metabolism on Pathological Cardiac Remodeling in Elevated Fibroblast Growth Factor 23

Clinical and experimental studies indicate a possible link between high serum levels of fibroblast growth factor 23 (FGF23), phosphate, and parathyroid hormone (PTH), deficiency of active vitamin D (1,25D) and klotho with the development of pathological cardiac remodeling, i.e., left ventricular hypertrophy and myocardial fibrosis, but a causal link has not been established so far. Here, we investigated the cardiac phenotype in klotho hypomorphic (kl/kl) mice and Hyp mice, two mouse models of elevated FGF23 levels and klotho deficiency, but differing in parameters of mineral metabolism, by using histology, quantitative real-time PCR, immunoblot analysis, and serum and urine biochemistry. Additionally, the specific impact of calcium, phosphate, PTH, and 1,25D on hypertrophic growth of isolated neonatal rat cardiac myocytes was investigated in vitro. Kl/kl mice displayed high serum Fgf23 levels, increased relative heart weight, enhanced cross-sectional area of individual cardiac myocytes, activated cardiac Fgf23/Fgf receptor (Fgfr) 4/calcineurin/nuclear factor of activated T cell (NFAT) signaling, and induction of pro-hypertrophic NFAT target genes including Rcan1, bMHC, brain natriuretic peptide (BNP), and atrial natriuretic peptide (ANP) as compared to corresponding wild-type (WT) mice. Investigation of fibrosis-related molecules characteristic for pathological cardiac remodeling processes demonstrated ERK1/2 activation and enhanced expression of Tgf-β1, collagen I, and Mmp2 in kl/kl mice than in WT mice. In contrast, despite significantly elevation of serum and cardiac Fgf23, and reduced renal klotho expression, Hyp mice showed no signs of pathological cardiac remodeling. Kl/kl mice showed enhanced serum calcium and phosphate levels, while Hyp mice showed unchanged serum calcium levels, lower serum phosphate, and elevated serum iPTH concentrations compared to corresponding WT mice. In cultured cardiac myocytes, treatment with both calcium or phosphate significantly upregulated endogenous Fgf23 mRNA expression and stimulated hypertrophic cell growth and expression of pro-hypertrophic genes. The treatment with PTH induced hypertrophic cell growth only, and stimulation with 1,25D had no significant effects. In conclusion, our data indicate that Hyp mice, in contrast to kl/kl mice appear to be protected from pathological cardiac remodeling during conditions of high FGF23 levels and klotho deficiency, which may be due, at least in part, to differences in mineral metabolism alterations, i.e., hypophosphatemia and lack of hypercalcemia

Lithospheric erosion in the Patagonian slab window, and implications for glacial isostasy

Author Posting. © American Geophysical Union, 2022. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geophysical Research Letters 49(2), (2022): e2021GL096863, https://doi.org/10.1029/2021GL096863.The Patagonian slab window has been proposed to enhance the solid Earth response to ice mass load changes in the overlying Northern and Southern Patagonian Icefields (NPI and SPI, respectively). Here, we present the first regional seismic velocity model covering the entire north-south extent of the slab window. A slow velocity anomaly in the uppermost mantle indicates warm mantle temperature, low viscosity, and possibly partial melt. Low velocities just below the Moho suggest that the lithospheric mantle has been thermally eroded over the youngest part of the slab window. The slowest part of the anomaly is north of 49°S, implying that the NPI and the northern SPI overlie lower viscosity mantle than the southern SPI. This comprehensive seismic mapping of the slab window provides key evidence supporting the previously hypothesized connection between post-Little Ice Age anthropogenic ice mass loss and rapid geodetically observed glacial isostatic uplift (≥4 cm/yr).The facilities of the IRIS Consortium are supported by the National Science Foundation’s SAGE Award under Cooperative Support Agreement EAR-1851048. The GUANACO project is funded by the National Science Foundation under grants EAR-1714154 to WUSTL and EAR-1714662 to SMU, and Erik R. Ivins was supported by NASA under grant NNH19ZDA001N-GRACEFO.2022-07-1

Integrin αE(CD103) Is Involved in Regulatory T-Cell Function in Allergic Contact Hypersensitivity

Murine contact hypersensitivity (CHS) is a dendritic cell (DC)-dependent T-cell-mediated inflammation with CD8+ T cells as effectors and CD4+ T cells as regulators (Treg cells) that models human allergic contact dermatitis. The integrin αE(CD103) is expressed by some T-cell and DC subsets and has been implicated in epithelial lymphocyte localization, but its role in immune regulation remains enigmatic. We have identified a function for CD103 in the development of cutaneous allergic immune responses. CHS responses, but not irritant contact dermatitis, were significantly augmented in CD103-deficient mice in hapten-challenged skin. Phenotype and function of skin DCs during sensitization were normal, whereas adoptive transfer experiments revealed that the elevated CHS response in CD103-deficient mice is transferred by primed T cells and is independent of resident cells in recipient mice. While T-cell counts were elevated in challenged skin of CD103-deficient mice, the FoxP3 expression level of CD4+CD25+ Treg cells was significantly reduced, indicating impaired functionality. Indeed, Treg cells from CD103-deficient mice were not able to suppress CHS reactions during the elicitation phase. Further, CD103 on FoxP3+ Treg cells was involved in Treg retention to inflamed skin. These findings indicate an unexpected dichotomous functional role for CD103 on Treg cells by modulating FoxP3 expression

The Grizzly, October 25, 1994

Service: It\u27s Not Greek to Them • Ursinus Cross Country Team Involved in Accident • Five Lives Claimed at Bloomsburg Frat House • Pi Omega Delta Captures Banner for Blood Drive • Democrats in Danger: Election for House and Senate too Close to Call • United States and North Korean Timetable for Nuclear Disarmament • Freshman Class Officers Ready to Make a Difference • Lopate Shares Humor and Insight • Berman Museum Celebrates its Fifth Anniversary • Choir to Sing on Saturday • An Open Letter to All Greeks • Basketball Woes • A Few Inches From Drowning • A Philly Fan • UC Soccer Gets Back on Track • Intramural Updatehttps://digitalcommons.ursinus.edu/grizzlynews/1344/thumbnail.jp

Diagnostic yield of renal biopsies: a retrospective single center review

<p>Abstract</p> <p>Background</p> <p>Previous studies have examined the spectrum of diseases identified with a kidney biopsy and the complications of the procedure. However, few studies have examined the utility of the test to clarify the diagnosis and guide treatment of pediatric patients. This retrospective, single-center chart review was performed to test the hypothesis that at least 80% of native kidney biopsies provide clinically valuable information that rationally guides diagnosis and patient management.</p> <p>Methods</p> <p>200 biopsies performed between January 1, 2000 and June 30, 2008 were reviewed. A scheme composed of six categories was devised to classify the utility of each kidney biopsy.</p> <p>Results</p> <p>196 complete case files were available for review. Twenty-four (12.2%) biopsies did not shed light on the diagnosis and were unhelpful in patient management – 21 biopsies (10.7%) were non-diagnostic and 3 (1.5%) failed to yield enough tissue for examination. The number of unhelpful biopsies did not cluster in any specific disease entity.</p> <p>Conclusion</p> <p>Our findings provide guidance to nephrologists about the total risk of a kidney biopsy, including uninformative results, when seeking informed consent for the procedure. The results suggest an appropriate balance has been reached which maximizes the use of kidney biopsies while minimizing the risk of this invasive procedure (word count: 202).</p

Lens epithelial cell apoptosis and intracellular Ca(2+) increase in the presence of xanthurenic acid

BACKGROUND: Xanthurenic acid is an endogenous product of tryptophan degradation by indoleamine 2,3-dioxygenase (IDO). We have previously reported that IDO is present in mammalian lenses, and xanthurenic acid is accumulated in the lenses with aging. Here, we studied the involvement of xanthurenic acid in the human lens epithelial cell physiology. METHODS: Human lens epithelial cells primary cultures were used. Control cells, and cells in the presence of xanthurenic acid grow in the dark. Western blot analysis and immunofluorescence studies were performed. RESULTS: In the presence of xanthurenic acid human lens epithelial cells undergo apoptosis-like cell death. In the control cells gelsolin stained the perinuclear region, whereas in the presence of 10 μM xanthurenic acid gelsolin is translocated to the cytoskeleton, but does not lead to cytoskeleton breakdown. In the same condition caspase-3 activation, and DNA fragmentation was observed. At low (5 to 10 μM) of xanthurenic acid concentration, the elongation of the cytoskeleton was associated with migration of mitochondria and cytochrome c release. At higher concentrations xanthurenic acid (20 μM and 40 μM) damaged mitochondria were observed in the perinuclear region, and nuclear DNA cleavage was observed. We observed an induction of calpain Lp 82 and an increase of free Ca(2+) in the cells in a xanthurenic acid concentration-dependent manner. CONCLUSIONS: The results show that xanthurenic acid accumulation in human lens epithelial cells disturbs the normal cell physiology and leads to a cascade of pathological events. Xanthurenic acid induces calpain Lp82 and caspases in the cells growing in the dark and can be involved in senile cataract development

Система автоматического регулирования температуры в производственном помещении

САР температуры в помещении необходима для быстрого восстановления температурного режима в помещении чего не обеспечивает существующее центральное отопление.Позволяет улучшить качество регулирования температурного баланса. Цель работы – Оснащение воздушного отопительного агрегата системой автоматического управления. В процессе исследования проводились Анализ работы САУ вентиляционных систем, анализ построения САР температуры вентиляционных систем. В результате исследования Была разработана структурная и функциональная схемы САР температуры отопительного агрегата, а также алгоритм управления САР.ACS of temperature is indoors necessary for fast restoration of temperature condition in what doesn't provide the existing central heating. Allows to improve quality of regulation of temperature balance. The aim of the work is Vehicle air heating unit automatic control system. In the process of investigation the Analysis of the work of the ACS ventilation systems, analysis of building SAR temperature ventilation systems. The study was developed by structural and functional scheme of the SAR temperature of the heating unit and the control algorithm of the SAR

A highly invasive human glioblastoma pre-clinical model for testing therapeutics

Animal models greatly facilitate understanding of cancer and importantly, serve pre-clinically for evaluating potential anti-cancer therapies. We developed an invasive orthotopic human glioblastoma multiforme (GBM) mouse model that enables real-time tumor ultrasound imaging and pre-clinical evaluation of anti-neoplastic drugs such as 17-(allylamino)-17-demethoxy geldanamycin (17AAG). Clinically, GBM metastasis rarely happen, but unexpectedly most human GBM tumor cell lines intrinsically possess metastatic potential. We used an experimental lung metastasis assay (ELM) to enrich for metastatic cells and three of four commonly used GBM lines were highly metastatic after repeated ELM selection (M2). These GBM-M2 lines grew more aggressively orthotopically and all showed dramatic multifold increases in IL6, IL8, MCP-1 and GM-CSF expression, cytokines and factors that are associated with GBM and poor prognosis. DBM2 cells, which were derived from the DBTRG-05MG cell line were used to test the efficacy of 17AAG for treatment of intracranial tumors. The DMB2 orthotopic xenografts form highly invasive tumors with areas of central necrosis, vascular hyperplasia and intracranial dissemination. In addition, the orthotopic tumors caused osteolysis and the skull opening correlated to the tumor size, permitting the use of real-time ultrasound imaging to evaluate antitumor drug activity. We show that 17AAG significantly inhibits DBM2 tumor growth with significant drug responses in subcutaneous, lung and orthotopic tumor locations. This model has multiple unique features for investigating the pathobiology of intracranial tumor growth and for monitoring systemic and intracranial responses to antitumor agents