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Large agglomerates of 17 nm TiO2 induced stronger responses than small agglomerates for glutathione depletion, IL-8 and IL-1β increase, and DNA damage in THP-1, while no effect of agglomeration was observed with 117 nm TiO2. In vivo, C57BL/6JRj mice were exposed via oropharyngeal aspiration or oral gavage to TiO2 suspensions and, after 3 days, biological parameters including cytotoxicity, inflammatory cell recruitment, DNA damage and biopersistence were measured. Mainly, we observed that large agglomerates of 117 nm TiO2 induced higher pulmonary responses in aspirated mice and blood DNA damage in gavaged mice compared to small agglomerates. CONCLUSION Agglomeration of TiO2 NPs influences their toxicity/biological responses and, large agglomerates do not appear less active than small agglomerates. This study provides a deeper insight on the toxicological relevance of NP agglomerates and contributes to the establishment of a toxicologically relevant definition for NMs.The original version of this article [1], published on 28 November 2019, contained incorrect title. In this Correction the affected part of the article is shown.Following publication of the original article [1], the authors flagged that the article had gone to publishing with errors in Tables 1-3.BACKGROUND In a real-world setting, the effect of pulse rate measured at the time of diagnosis and serially during follow-up and management, on outcomes in heart failure with reduced ejection fraction (HFrEF), has not been well-studied. Furthermore, how beta-blockade use in a real-world situation modifies this relation between pulse rate and outcomes in HFrEF is not well-known. Hence, we identified a large, national, real-world cohort of HFrEF to examine the association of pulse rate and outcomes. METHODS Using Veterans Affairs (VA) national electronic health records we identified incident HFrEF cases between 2006 and 2012. We examined the associations of both baseline and serially measured pulse rates, with mortality and days hospitalized per year for heart failure and for any cause, using crude and multivariable Cox proportional hazards and Poisson or negative binomial models, respectively. The exposure was examined as continuous, dichotomous, and categorical. Post-hoc analyses addressed the interaction of llow-up, is strongly associated with increased risk of adverse outcomes in HFrEF patients, independent of the use of beta-blockers. In a real-world setting, the majority of HFrEF patients do not achieve target dose of beta-blockade; greater use of strategies to reduce heart rate may improve outcomes in HFrEF.BACKGROUND Calcific Uremic Arteriolopathy (CUA) is a rare disease, causing painful skin ulcers in patients with end stage renal disease. Recommendations for CUA management and treatment are lacking. METHODS We conducted a retrospective cohort study on CUA cases identified in western France, in order to describe its management and outcome in average clinical practices. Selection was based on the Hayashi diagnosis criteria (2013) extended to patients with eGFR less then  30 mL/min/1.73m2. Dialyzed CUA cases were compared with 2 controls, matched for age, gender, region of treatment and time period. RESULTS Eighty-nine CUA cases were identified between 2006 and 2016, including 19 non dialyzed and 70 dialyzed patients. Females with obesity (55.1%) were predominant. Bone mineral disease abnormalities, inflammation and malnutrition (weight loss, serum albumin decrease) preceded CUA onset for 6 months. The multimodal treatment strategy included wound care (98.9%), antibiotherapy (77.5%), discontinuation of Vitamin K antagonists (VKA) (70.8%) and intravenous sodium thiosulfate (65.2%). 40.4% of the patients died within the year after lesion onset, mainly under palliative care. Surgical debridement, distal CUA, localization to the lower limbs and non calcium-based phosphate binders were associated with better survival. Risks factors of developing CUA among dialysis patients were obesity, VKA, weight loss, serum albumin decrease or high serum phosphate in the 6 months before lesion onset. CONCLUSION CUA involved mainly obese patients under VKA. Malnutrition and inflammation preceded the onset of skin lesions and could be warning signs among dialysis patients at risk. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT02854046, registered August 3, 2016.BACKGROUND The lumen of the endoplasmic reticulum (ER) acts as a cellular Ca2+ store and a site for oxidative protein folding, which is controlled by the reduced glutathione (GSH) and glutathione-disulfide (GSSG) redox pair. Although depletion of luminal Ca2+ from the ER provokes a rapid and reversible shift towards a more reducing poise in the ER, the underlying molecular basis remains unclear. RESULTS We found that Ca2+ mobilization-dependent ER luminal reduction was sensitive to inhibition of GSH synthesis or dilution of cytosolic GSH by selective permeabilization of the plasma membrane. A glutathione-centered mechanism was further indicated by increased ER luminal glutathione levels in response to Ca2+ efflux. Inducible reduction of the ER lumen by GSH flux was independent of the Ca2+-binding chaperone calreticulin, which has previously been implicated in this process. However, opening the translocon channel by puromycin or addition of cyclosporine A mimicked the GSH-related effect of Ca2+ mobilization. While the action of puromycin was ascribable to Ca2+ leakage from the ER, the mechanism of cyclosporine A-induced GSH flux was independent of calcineurin and cyclophilins A and B and remained unclear. CONCLUSIONS Our data strongly suggest that ER influx of cytosolic GSH, rather than inhibition of local oxidoreductases, is responsible for the reductive shift upon Ca2+ mobilization. We postulate the existence of a Ca2+- and cyclosporine A-sensitive GSH transporter in the ER membrane. These findings have important implications for ER redox homeostasis under normal physiology and ER stress.Despite their small numbers, cancer stem cells play a central role in driving cancer cell growth, chemotherapeutic resistance, and distal metastasis. Previous studies mainly focused on how DNA or histone modification determines cell fate in cancer. However, it is still largely unknown how RNA modifications orchestrate cancer cell fate decisions. More than 170 distinct RNA modifications have been identified in the RNA world, while only a few RNA base modifications have been found in mRNA. Growing evidence indicates that three mRNA modifications, inosine, 5-methylcytosine, and N6-methyladenosine, are essential for the regulation of spatiotemporal gene expression during cancer stem cell fate transition. Apitolisib Furthermore, transcriptome-wide mapping has found that the aberrant deposition of mRNA modification, which can disrupt the gene regulatory network and lead to uncontrollable cancer cell growth, is widespread across different cancers. In this review, we try to summarize the recent advances of these three mRNA modifications in maintaining the stemness of cancer stem cells and discuss the underlying molecular mechanisms, which will shed light on the development of novel therapeutic approaches for eradicating cancer stem cells.