N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide (EPPTB) prevents 3-iodothyronamine (T1AM)-induced neuroprotection against kainic acid toxicity

Thyroid hormone and thyroid hormone metabolites, including 3-iodothyronamine (T1AM) and 3-iodothyroacetic acid (TA1), activate AKT signaling in hippocampal neurons affording protection from excitotoxic damage. We aim to explore whether the mechanism of T1AM neuroprotection against kainic acid (KA)-induced excitotoxicity included the activation of the trace amine associated receptor isoform 1 (TAAR1), one of T1AM targets. Rat organotypic hippocampal slices were exposed to vehicle (Veh) or to 5 μM kA for 24 h in the absence or presence of 0.1, 1 and 10 μM T1AM or to 0.1, 1 and 10 μM T1AM and 1 μM N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide (EPPTB), the only available TAAR1 antagonist, or to 1 μM T1AM in the absence or in the presence of 10 μM LY294002, an inhibitor of phosphoinositide 3-kinases (PI3Ks). Cell death was evaluated by measuring propidium iodide (PI) levels of fluorescence 24 h after treatment. In parallel, the expression levels of p-AKT and p-PKA were evaluated by Western blot analysis of slice lysates. The activity of mitochondrial monoamine oxidases (MAO) was assayed fluorimetrically. 24 h exposure of slices to T1AM resulted in the activation of AKT and PKA. KA exposure induced cell death in the CA3 region and significantly reduced p-AKT and p-PKA levels. The presence of 1 and 10 μM T1AM significantly protected neurons from death and conserved both kinase levels with the essential role of AKT in neuroprotection. Furthermore, EPPTB prevented T1AM-induced neuroprotection, activation of PKA and AKT. Of note, in the presence of EPPTB T1AM degradation by MAO was reduced. Our results indicate that the neuroprotection offered by T1AM depends, as for TA1, on AKT activation but do not allow to conclusively indicate TAAR1 as the target implicated. Graphical abstrac

3-iodothyronamine affects thermogenic substrates’ mobilization in brown adipocytes

We investigated the effect of 3-iodothyronamine (T1AM) on thermogenic substrates in brown adipocytes (BAs). BAs isolated from the stromal fraction of rat brown adipose tissue were exposed to an adipogenic medium containing insulin in the absence (M) or in the presence of 20 nM T1AM (M+T1AM) for 6 days. At the end of the treatment, the expression of p-PKA/PKA, p-AKT/AKT, p-AMPK/AMPK, p-CREB/CREB, p-P38/P38, type 1 and 3 beta adrenergic receptors (β1–β3AR), GLUT4, type 2 deiodinase (DIO2), and uncoupling protein 1 (UCP-1) were evaluated. The effects of cell conditioning with T1AM on fatty acid mobilization (basal and adrenergic-mediated), glucose uptake (basal and insulin-mediated), and ATP cell content were also analyzed in both cell populations. When compared to cells not exposed, M+T1AM cells showed increased p-PKA/PKA, p-AKT/AKT, p-CREB/CREB, p-P38/P38, and p-AMPK/AMPK, downregulation of DIO2 and β1AR, and upregulation of glycosylated β3AR, GLUT4, and adiponectin. At basal conditions, glycerol release was higher for M+T1AM cells than M cells, without any significant differences in basal glucose uptake. Notably, in M+T1AM cells, adrenergic agonists failed to activate PKA and lipolysis and to increase ATP level, but the glucose uptake in response to insulin exposure was more pronounced than in M cells. In conclusion, our results suggest that BAs conditioning with T1AM promote a catabolic condition promising to fight obesity and insulin resistance

Role of CD8+ cells in controlling replication of nonpathogenic Simian Immunodeficiency Virus SIVmac1A11

Infection of macaques with the avirulent molecular clone SIVmac1A11 results in transient low viremia and no disease. To investigate if this low viremia is solely due to intrinsic poor replication fitness or is mediated by efficient immune-mediated control, 5 macaques were inoculated intravenously with SIVmac1A11. Three animals that were depleted of CD8+ cells at the start of infection had more prolonged viremia with peak virus levels 1 to 2 logs higher than those of 2 animals that received a non-depleting control antibody. Thus, CD8+ cell-mediated immune responses play an important role in controlling SIVmac1A11 replication during acute viremia

Weekly paclitaxel plus capecitabine in advanced breast cancer patients: dose-finding trial of GOIRC and GOL

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approach to a water safety plan for recreational waters disinfection of a drainage pumping station as an unconventional point source of fecal contamination

Abstract In the context of the management of bathing water quality, the intermittent contamination of rainwater drainage pumps (unconventional point sources) could be controlled by peracetic acid disinfection. Thus, a field experimental study was carried out to set up a water safety plan, determining the monitoring parameters and the critical limit for corrective actions. With a 0.5 mg/l dosage, the average logarithmic microbial reduction was 0.50 ± 0.48 for Escherichia coli (EC) and 0.43 ± 0.54 for intestinal enterococci. Among the chemical and physical parameters that could be monitored in real time, the oxidation–reduction potential was the only one able to predict the microbial concentration discharged from a drainage pump and the logarithmic abatement of EC. Considering the possible impact of this source on bathing waters in terms of additional risk of gastrointestinal infections, the critical limit for continuous monitoring was established using a quantitative microbial risk assessment (QMRA) model

Development of fragility models for process equipment affected by physical security attacks

The vulnerability of chemical and process facilities toward physical security attacks depends on the equipment resistance against such attacks and on the performance of Physical Protection Systems (PPS) in place. To enhance the protection against intentional attacks, the development of quantitative vulnerability metrics is essential, nevertheless current standard approaches only offer qualitative or semi-quantitative evaluations. The aim of the present work is to develop a quantitative methodology for the assessment of chemical and process facilities vulnerability towards external acts of interference. The proposed methodology is based both on the evaluation of equipment structural integrity in response to different types of specific impact vectors characterizing intentional attacks and on the quantitative performance assessment of related PPS. In particular, specific fragility models were developed for impact vectors associated with improvised explosive devices, firearms, and incendiary weapons. The novel fragility models were implemented in a comprehensive security vulnerability assessment (SVA) based on Bayesian Networks, in which the contribution of PPS performance was also considered. A case study was defined and analyzed to exemplify the application of the proposed approach. The results obtained allowed for the identification of the most critical security-related escalation scenarios and thus for an improved quantitative SVA.Seventh Framework Programme (FP7)LIFE20 ENV/IT/000436Security and Global Affair

Incremental value of 3D echocardiography and two-dimensional speckle tracking in the early detection of cardiotoxicity linked to chemotherapy and trastuzumab in patients with HER-2 positive breast cancer

Abstract not availabl