Dietary magnesium, not calcium, prevents vascular calcification in a mouse model for pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by ectopic calcification of connective tissue in skin, Bruch’s membrane of the eye, and walls of blood vessels. PXE is caused by mutations in the ABCC6 gene, but the exact etiology is still unknown. While observations on patients suggest that high calcium intake worsens the clinical symptoms, the patient organization PXE International has published the dietary advice to increase calcium intake in combination with increased magnesium intake. To obtain more data on this controversial issue, we examined the effect of dietary calcium and magnesium in the Abcc6−/− mouse, a PXE mouse model which mimics the clinical features of PXE. Abcc6−/− mice were placed on specific diets for 3, 7, and 12 months. Disease severity was measured by quantifying calcification of blood vessels in the kidney. Raising the calcium content in the diet from 0.5% to 2% did not change disease severity. In contrast, simultaneous increase of both calcium (from 0.5% to 2.0%) and magnesium (from 0.05% to 0.2%) slowed down the calcification significantly. Our present findings that increase in dietary magnesium reduces vascular calcification in a mouse model for PXE should stimulate further studies to establish a dietary intervention for PXE

Combinatorial effects of environmental parameters on transcriptional regulation in Saccharomyces cerevisiae: A quantitative analysis of a compendium of chemostat-based transcriptome data

<p>Abstract</p> <p>Background</p> <p>Microorganisms adapt their transcriptome by integrating multiple chemical and physical signals from their environment. Shake-flask cultivation does not allow precise manipulation of individual culture parameters and therefore precludes a quantitative analysis of the (combinatorial) influence of these parameters on transcriptional regulation. Steady-state chemostat cultures, which do enable accurate control, measurement and manipulation of individual cultivation parameters (e.g. specific growth rate, temperature, identity of the growth-limiting nutrient) appear to provide a promising experimental platform for such a combinatorial analysis.</p> <p>Results</p> <p>A microarray compendium of 170 steady-state chemostat cultures of the yeast <it>Saccharomyces cerevisiae </it>is presented and analyzed. The 170 microarrays encompass 55 unique conditions, which can be characterized by the combined settings of 10 different cultivation parameters. By applying a regression model to assess the impact of (combinations of) cultivation parameters on the transcriptome, most <it>S. cerevisiae </it>genes were shown to be influenced by multiple cultivation parameters, and in many cases by combinatorial effects of cultivation parameters. The inclusion of these combinatorial effects in the regression model led to higher explained variance of the gene expression patterns and resulted in higher function enrichment in subsequent analysis. We further demonstrate the usefulness of the compendium and regression analysis for interpretation of shake-flask-based transcriptome studies and for guiding functional analysis of (uncharacterized) genes and pathways.</p> <p>Conclusion</p> <p>Modeling the combinatorial effects of environmental parameters on the transcriptome is crucial for understanding transcriptional regulation. Chemostat cultivation offers a powerful tool for such an approach.</p

Do Biofilm Formation and Interactions with Human Cells Explain the Clinical Success of Acinetobacter baumannii?

BACKGROUND: The dramatic increase in antibiotic resistance and the recent manifestation in war trauma patients underscore the threat of Acinetobacter baumannii as a nosocomial pathogen. Despite numerous reports documenting its epidemicity, little is known about the pathogenicity of A. baumannii. The aim of this study was to obtain insight into the factors that might explain the clinical success of A. baumannii. METHODOLOGY/PRINCIPAL FINDINGS: We compared biofilm formation, adherence to and inflammatory cytokine induction by human cells for a large panel of well-described strains of A. baumannii and compared these features to that of other, clinically less relevant Acinetobacter species. Results revealed that biofilm formation and adherence to airway epithelial cells varied widely within the various species, but did not differ among the species. However, airway epithelial cells and cultured human macrophages produced significantly less inflammatory cytokines upon exposure to A. baumannii strains than to strains of A. junii, a species infrequently causing infection. CONCLUSION/SIGNIFICANCE: The induction of a weak inflammatory response may provide a clue to the persistence of A. baumannii in patients

Super Resolution Microscopy Reveals that Caveolin-1 Is Required for Spatial Organization of CRFB1 and Subsequent Antiviral Signaling in Zebrafish

10.1371/journal.pone.0068759PLoS ONE87-POLN

Galectin-3C Inhibits Tumor Growth and Increases the Anticancer Activity of Bortezomib in a Murine Model of Human Multiple Myeloma

Galectin-3 is a human lectin involved in many cellular processes including differentiation, apoptosis, angiogenesis, neoplastic transformation, and metastasis. We evaluated galectin-3C, an N-terminally truncated form of galectin-3 that is thought to act as a dominant negative inhibitor, as a potential treatment for multiple myeloma (MM). Galectin-3 was expressed at varying levels by all 9 human MM cell lines tested. In vitro galectin-3C exhibited modest anti-proliferative effects on MM cells and inhibited chemotaxis and invasion of U266 MM cells induced by stromal cell-derived factor (SDF)-1α. Galectin-3C facilitated the anticancer activity of bortezomib, a proteasome inhibitor approved by the FDA for MM treatment. Galectin-3C and bortezomib also synergistically inhibited MM-induced angiogenesis activity in vitro. Delivery of galectin-3C intravenously via an osmotic pump in a subcutaneous U266 cell NOD/SCID mouse model of MM significantly inhibited tumor growth. The average tumor volume of bortezomib-treated animals was 19.6% and of galectin-3C treated animals was 13.5% of the average volume of the untreated controls at day 35. The maximal effect was obtained with the combination of galectin-3C with bortezomib that afforded a reduction of 94% in the mean tumor volume compared to the untreated controls at day 35. In conclusion, this is the first study to show that inhibition of galectin-3 is efficacious in a murine model of human MM. Our results demonstrated that galectin-3C alone was efficacious in a xenograft mouse model of human MM, and that it enhanced the anti-tumor activity of bortezomib in vitro and in vivo. These data provide the rationale for continued testing of galectin-3C towards initiation of clinical trials for treatment of MM

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Risk limits for PFOA in soil and groundwater : Elaboration for generic and land use specific policy

In opdracht van de gemeente Dordrecht heeft het RIVM risicogrenzen voor perfluoroctaanzuur (PFOA) in grond en grondwater afgeleid. De gemeente kan hiermee bepalen of de kwaliteit van de grond en het grondwater een risico vormt voor mens en milieu, en of maatregelen nodig zijn. De verontreiniging door PFOA is naar verwachting eind vorige eeuw ontstaan. PFOA werd door de Dupont/Chemours fabriek in Dordrecht tot 2012 gebruikt bij de productie van polymeren. In het huidige rapport zijn generieke risicogrenzen afgeleid voor grond en grondwater volgens de interventiewaardenmethodiek, waarbij rekening gehouden wordt met blootstelling van mens en milieu vanuit grond en grondwater. Daarnaast zijn locatiespecifieke of bodemgebruik-specifieke risicogrenzen afgeleid voor grond en grondwater voor verschillende bodemgebruiksvormen. Deze zijn toegespitst op de bestemming wonen en industrie, rekening houdend met de relevante blootstellingsroutes. In deze herziene versie zijn enkele risicogrenzen voor de mens aangepast vanwege nieuwe informatie en een correctie in de doorwerking van plantopname in de risicogrenzen. De gemeente kan de afgeleide risicogrenzen gebruiken om, indien gewenst, gebiedsspecifiek beleid te maken voor het bodemgebruik en grondverzet.The municipality of Dordrecht commissioned the RIVM to derive risk limits for perfluorooctanoic acid (PFOA) in soil and groundwater. The local government can determine if the quality of the soil and groundwater can cause risks to humans and the environment, and if measures are needed. The contamination with PFOA is probably caused in the end of the last Century. PFOA was used by Dupont/Chemours in Dordrecht up to 2012 for the production of polymers. This report derives generic risk limits for soil and groundwater according the method for deriving Intervention Values. This approach takes into account exposure of men and the environment from contamination in soil and groundwater. Additionally site-specific (or soil use specific risk limits have been derived for soil and groundwater for different types of land use. It is focusing on residential and industrial areas, taking into account the relevant exposure routes. In this revised version some human risk limits have been revised, because of new informatio and a correction of the calculation of the plantuptake in the risk limits. The municipality can use the derived risk limits to develop a policy depending on the land use and for the reuse of soil in the municipality.Gemeente Dordrech

Risicogrenzen PFOA voor grond en grondwater : Uitwerking voor generiek en gebiedsspecifiek beleid (herziene versie)

In opdracht van de gemeente Dordrecht heeft het RIVM risicogrenzen voor perfluoroctaanzuur (PFOA) in grond en grondwater afgeleid. De gemeente kan hiermee bepalen of de kwaliteit van de grond en het grondwater een risico vormt voor mens en milieu, en of maatregelen nodig zijn. De verontreiniging door PFOA is naar verwachting eind vorige eeuw ontstaan. PFOA werd door de Dupont/Chemours fabriek in Dordrecht tot 2012 gebruikt bij de productie van polymeren. In het huidige rapport zijn generieke risicogrenzen afgeleid voor grond en grondwater volgens de interventiewaardenmethodiek, waarbij rekening gehouden wordt met blootstelling van mens en milieu vanuit grond en grondwater. Daarnaast zijn locatiespecifieke of bodemgebruik-specifieke risicogrenzen afgeleid voor grond en grondwater voor verschillende bodemgebruiksvormen. Deze zijn toegespitst op de bestemming wonen en industrie, rekening houdend met de relevante blootstellingsroutes. In deze herziene versie zijn enkele risicogrenzen voor de mens aangepast vanwege nieuwe informatie en een correctie in de doorwerking van plantopname in de risicogrenzen. De gemeente kan de afgeleide risicogrenzen gebruiken om, indien gewenst, gebiedsspecifiek beleid te maken voor het bodemgebruik en grondverzet