CARD14 Gain-of-Function Mutation Alone Is Sufficient to Drive IL-23/IL-17-Mediated Psoriasiform Skin Inflammation In Vivo.

Rare autosomal dominant mutations in the gene encoding the keratinocyte signaling molecule CARD14, have been associated with an increased susceptibility to psoriasis, but the physiological impact of CARD14 gain-of-function mutations remains to be fully determined in vivo. Here, we report that heterozygous mice harboring a CARD14 gain-of-function mutation (Card14ΔE138) spontaneously develop a chronic psoriatic phenotype with characteristic scaling skin lesions, epidermal thickening, keratinocyte hyperproliferation, hyperkeratosis, and immune cell infiltration. Affected skin of these mice is characterized by elevated expression of anti-microbial peptides, chemokines, and cytokines (including T helper type 17 cell-signature cytokines) and an immune infiltrate rich in neutrophils, myeloid cells, and T cells, reminiscent of human psoriatic skin. Disease pathogenesis was driven by the IL-23/IL-17 axis, and neutralization of IL-23p19, the key cytokine in maintaining T helper type 17 cell polarization, significantly reduced skin lesions and the expression of antimicrobial peptides and proinflammatory cytokines. Therefore, hyperactivation of CARD14 alone is sufficient to orchestrate the complex immunopathogenesis that drives T helper type 17-mediated psoriasis skin disease in vivo

Drilling-induced and logging-related features illustrated from IODP-ICDP Expedition 364 downhole logs and borehole imaging tools

Expedition 364 was a joint IODP and ICDP mission-specific platform (MSP) expedition to explore the Chicxulub impact crater buried below the surface of the Yucatán continental shelf seafloor. In April and May 2016, this expedition drilled a single borehole at Site M0077 into the crater's peak ring. Excellent quality cores were recovered from ~ 505 to ~1335m below seafloor (m b.s.f.), and high-resolution open hole logs were acquired between the surface and total drill depth. Downhole logs are used to image the borehole wall, measure the physical properties of rocks that surround the borehole, and assess borehole quality during drilling and coring operations. When making geological interpretations of downhole logs, it is essential to be able to distinguish between features that are geological and those that are operation-related. During Expedition 364 some drilling-induced and logging-related features were observed and include the following: effects caused by the presence of casing and metal debris in the hole, logging-tool eccentering, drilling-induced corkscrew shape of the hole, possible re-magnetization of low-coercivity grains within sedimentary rocks, markings on the borehole wall, and drilling-induced changes in the borehole diameter and trajectory

Early paleocene paleoceanography and export productivity in the Chicxulub crater

The Chicxulub impact caused a crash in productivity in the world''s oceans which contributed to the extinction of ~75% of marine species. In the immediate aftermath of the extinction, export productivity was locally highly variable, with some sites, including the Chicxulub crater, recording elevated export production. The long-term transition back to more stable export productivity regimes has been poorly documented. Here, we present elemental abundances, foraminifer and calcareous nannoplankton assemblage counts, total organic carbon, and bulk carbonate carbon isotope data from the Chicxulub crater to reconstruct changes in export productivity during the first 3 Myr of the Paleocene. We show that export production was elevated for the first 320 kyr of the Paleocene, declined from 320 kyr to 1.2 Myr, and then remained low thereafter. A key interval in this long decline occurred 900 kyr to 1.2 Myr post impact, as calcareous nannoplankton assemblages began to diversify. This interval is associated with fluctuations in water column stratification and terrigenous flux, but these variables are uncorrelated to export productivity. Instead, we postulate that the turnover in the phytoplankton community from a post-extinction assemblage dominated by picoplankton (which promoted nutrient recycling in the euphotic zone) to a Paleocene pelagic community dominated by relatively larger primary producers like calcareous nannoplankton (which more efficiently removed nutrients from surface waters, leading to oligotrophy) is responsible for the decline in export production in the southern Gulf of Mexico. © 2021. American Geophysical Union. All Rights Reserved

Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis

Aims/hypothesis The innate immune cells, invariant natural killer T cells (iNKT cells), are implicated in the pathogenesis of psoriasis, an inflammatory condition associated with obesity and other metabolic diseases, such as diabetes and dyslipidaemia. We observed an improvement in psoriasis severity in a patient within days of starting treatment with an incretin-mimetic, glucagon-like peptide-1 (GLP-1) receptor agonist. This was independent of change in glycaemic control. We proposed that this unexpected clinical outcome resulted from a direct effect of GLP-1 on iNKTcells. Methods We measured circulating and psoriatic plaque iNKT cell numbers in two patients with type 2 diabetes and psoriasis before and after commencing GLP-1 analogue therapy. In addition, we investigated the in vitro effects of GLP-1 on iNKT cells and looked for a functional GLP-1 receptor on these cells. Results The Psoriasis Area and Severity Index improved in both patients following 6 weeks of GLP-1 analogue therapy. This was associated with an alteration in iNKT cell number, with an increased number in the circulation and a decreased number in psoriatic plaques. The GLP-1 receptor was expressed on iNKT cells, and GLP-1 induced a dose-dependent inhibition of iNKT cell cytokine secretion, but not cytolytic degranulation in vitro. Conclusions/interpretation The clinical effect observed and the direct interaction between GLP-1 and the immune system raise the possibility of therapeutic applications for GLP-1 in inflammatory conditions such as psoriasis

Intravesical Treatments of Bladder Cancer: Review

For bladder cancer, intravesical chemo/immunotherapy is widely used as adjuvant therapies after surgical transurethal resection, while systemic therapy is typically reserved for higher stage, muscle-invading, or metastatic diseases. The goal of intravesical therapy is to eradicate existing or residual tumors through direct cytoablation or immunostimulation. The unique properties of the urinary bladder render it a fertile ground for evaluating additional novel experimental approaches to regional therapy, including iontophoresis/electrophoresis, local hyperthermia, co-administration of permeation enhancers, bioadhesive carriers, magnetic-targeted particles and gene therapy. Furthermore, due to its unique anatomical properties, the drug concentration-time profiles in various layers of bladder tissues during and after intravesical therapy can be described by mathematical models comprised of drug disposition and transport kinetic parameters. The drug delivery data, in turn, can be combined with the effective drug exposure to infer treatment efficacy and thereby assists the selection of optimal regimens. To our knowledge, intravesical therapy of bladder cancer represents the first example where computational pharmacological approach was used to design, and successfully predicted the outcome of, a randomized phase III trial (using mitomycin C). This review summarizes the pharmacological principles and the current status of intravesical therapy, and the application of computation to optimize the drug delivery to target sites and the treatment efficacy

The effects of long-term saturated fat enriched diets on the brain lipidome

The brain is highly enriched in lipids, where they influence neurotransmission, synaptic plasticity and inflammation. Non-pathological modulation of the brain lipidome has not been previously reported and few studies have investigated the interplay between plasma lipid homeostasis relative to cerebral lipids. This study explored whether changes in plasma lipids induced by chronic consumption of a well-tolerated diet enriched in saturated fatty acids (SFA) was associated with parallel changes in cerebral lipid homeostasis. Male C57Bl/6 mice were fed regular chow or the SFA diet for six months. Plasma, hippocampus (HPF) and cerebral cortex (CTX) lipids were analysed by LC-ESI-MS/MS. A total of 348 lipid species were determined, comprising 25 lipid classes. The general abundance of HPF and CTX lipids was comparable in SFA fed mice versus controls, despite substantial differences in plasma lipid-class abundance. However, significant differences in 50 specific lipid species were identified as a consequence of SFA treatment, restricted to phosphatidylcholine (PC), phosphatidylethanolamine (PE), alkyl-PC, alkenyl-PC, alkyl-PE, alkenyl-PE, cholesterol ester (CE), diacylglycerol (DG), phosphatidylinositol (PI) and phosphatidylserine (PS) classes. Partial least squares regression of the HPF/CTX lipidome versus plasma lipidome revealed the plasma lipidome could account for a substantial proportion of variation. The findings demonstrate that cerebral abundance of specific lipid species is strongly associated with plasma lipid homeostasis