Notes

Modelling mothering: the roll-out of a great new technique throughout neurobiology.
Significant attention has been given to the potential of environmental chemicals to disrupt lipid homeostasis at the cellular level. These chemicals, classified as obesogens, are abundantly used in a wide variety of consumer products. However, there is a significant lack of information regarding the mechanisms by which environmental exposure can contribute to the onset of obesity and non-alcoholic fatty liver disease (NAFLD). Several studies have described the interaction of potential obesogens with lipid-related peroxisome proliferator-activated receptors (PPAR). However, no studies have quantified the degree of modification to lipidomic profiles in relevant human models, making it difficult to directly link PPAR agonists to the onset of lipid-related diseases. A quantitative metabolomic approach was used to examine the dysregulation of lipid metabolism in human liver cells upon exposure to potential obesogenic compounds. The chemicals rosiglitazone, perfluorooctanoic acid, di-2-ethylexylphthalate, and tributyltin significantly increased total lipids in liver cells, being diglycerides, triglycerides and phosphatidylcholines the most prominent. Contrarily, perfluorooctane sulfonic acid and the pharmaceutical fenofibrate appeared to lower total lipid concentrations, especially those belonging to the acylcarnitine, ceramide, triglyceride, and phosphatidylcholine groups. Fluorescence microscopy analysis for cellular neutral lipids revealed significant lipid bioaccumulation upon exposure to obesogens at environmentally relevant concentrations. This integrated omics analysis provides unique mechanistic insight into the potential of these environmental pollutants to promote diseases like obesity and NAFLD. Furthermore, this study provides a significant contribution to advance the understanding of molecular signatures related to obesogenic chemicals and to the development of alternatives to in vivo experimentation. Human adenoviruses (HAdVs) often cause mild respiratory infections. Novobiocin concentration These infections, however, can potentially become fatal in immunosuppressive patients. Unfortunately, there has been no specific anti-HAdV drug approved for treatment of HAdV infections. In this study, a time-course transcriptome of HAdV-infected human lung epithelial cells (A549 cells) was performed and compared with perturbation datasets of 890 drug-treated A549 cells from the library of integrated network-based cellular signatures (LINCS) database to predict previously unknown therapeutic drug-HAdV relationships using a characteristic direction (CD) algorithm. We performed experiments to validate a prediction for the anti-diabetic drug rosiglitazone as a candidate drug for treatment of anti-HAdV both in vivo and in vitro. The Type I interferon (IFNs) signaling pathway was negatively regulated during the course of HAdV infection and rosiglitazone increased STAT1 phosphorylation for antiviral IFN response induction. Taken together, this study confirmed the prospect for re-exploitation of this FDA-approved drug as a potential therapeutic for HAdV infections. PURPOSE To determine if female hormonal therapy (FHT) increases the incidence of non-infectious uveitis. DESIGN Retrospective cohort study PARTICIPANTS FHT-exposed women and matched unexposed women enrolled in a national insurance plan. METHODS Estimation of non-infectious uveitis incidence used multivariable Cox proportional hazards regression. To account for differences between the exposed and unexposed cohorts, a propensity score for being prescribed FHT was created using logistic regression, and inverse probability of treatment weighting was performed. MAIN OUTCOME MEASURES Incidence of non-infectious uveitis. For the primary outcome, incident non-infectious uveitis was defined as a new diagnosis code for non-infectious uveitis followed by a second instance of a non-infectious uveitis code within 120 days. For the alternative outcome definition, a corticosteroid prescription or code for an ocular corticosteroid injection within 120 days of the uveitis diagnosis code was used instead of the second uveitis osure to FHT increases the rate of incident non-infectious uveitis when uveitis is defined based on both diagnostic codes and documentation of corticosteroid treatment. The neuromuscular junction (NMJ) is the vehicle for fast, reliable and robust communication between motor neuron and muscle. The unparalleled accessibility of this synapse to morphological, electrophysiological and genetic analysis has yielded an in depth understanding of many molecular components mediating its formation, maturation and stability. However, key questions surrounding the signaling pathways mediating these events and how they play out across the lifetime of the synapse remain unanswered. Such information is critical since the NMJ is necessary for normal movement and is compromised in several settings including Myasthenia Gravis, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), muscular dystrophy, sarcopenia and aging. Muscle specific kinase (MuSK) is a central player in most if not all contexts of NMJ formation and stability. However, elucidating the function of this receptor in this range of settings is challenging since MuSK participates in at least three signaling pathways as a tyrosine kinase-dependent receptor for agrin-LRP4 and Wnts; and, as a kinase-independent BMP co-receptor. Here we focus on NMJ stability during aging and discuss open questions regarding the molecular mechanisms that govern active maintenance of the NMJ, with emphasis on MuSK and the potential role of its multiple signaling contexts. V.Release of aqueous contents from model lipid vesicles has been a standard procedure to evaluate pore formation efficiency by actinoporins, such as sticholysin II (StnII), for the last few decades. However, regardless of the probe of choice, the results reported that StnII action was never able to empty the vesicles completely. This was hard to explain if StnII pores were to be stable and always leaky for the probes used. To address this question, we have used a variety of probes, including rhodamine 6G or Tb3+, to test the permeability of StnII's pores. Our results indicate that calcein was in fact too large to fit through StnII's pores, and that the standard method in the field is actually reporting StnII-induced transient permeation of the membrane rather than the passage of solutes through the stable assembled pores. In order to evaluate the permeability of these structures, we used a dithionite-based assay, which showed that the final pores were in fact open. Thus, our results indicate that the stable actinoporins' pores are open in spite of plateaued classic release curves.
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