Perinatal S-Adenosylmethionine Supplementation Represses PSEN1 Expression by the Cellular Epigenetic Memory of CpG and Non-CpG Methylation in Adult TgCRD8 Mice

DNA methylation, the main epigenetic modification regulating gene expression, plays a role in the pathophysiology of neurodegeneration. Previous evidence indicates that 50 -flanking hypomethylation of PSEN1, a gene involved in the amyloidogenic pathway in Alzheimer’s dis- ease (AD), boosts the AD-like phenotype in transgenic TgCRND8 mice. Supplementation with S-adenosylmethionine (SAM), the methyl donor in the DNA methylation reactions, reverts the patho- logical phenotype. Several studies indicate that epigenetic signatures, driving the shift between normal and diseased aging, can be acquired during the first stages of life, even in utero, and manifest phenotypically later on in life. Therefore, we decided to test whether SAM supplementation during the perinatal period (i.e., supplementing the mothers from mating to weaning) could exert a protec- tive role towards AD-like symptom manifestation. We therefore compared the effect of post-weaning vs. perinatal SAM treatment in TgCRND8 mice by assessing PSEN1 methylation and expression and the development of amyloid plaques. We found that short-term perinatal supplementation was as effective as the longer post-weaning supplementation in repressing PSEN1 expression and amyloid deposition in adult mice. These results highlight the importance of epigenetic memory and methyl donor availability during early life to promote healthy aging and stress the functional role of non-CpG methylation

Printed Electrochemical Strip for the Detection of miRNA-29a: A Possible Biomarker Related to Alzheimer's Disease

The development of electrochemical strips, as extremely powerful diagnostic tools, has received much attention in the field of sensor analysis and, in particular, the detection of nucleic acids in complex matrixes is a hot topic in the electroanalytical area, especially when directed toward the development of emerging technologies, for the purpose of facilitating personal healthcare. One of the major diseases for which early diagnosis is crucial is represented by Alzheimer's disease (AD). AD is a progressive neurodegenerative disease, and it is the most common cause of dementia worldwide. In this context microRNAs (miRNAs), which are small noncoding RNAs, have recently been highlighted for their promising role as biomarkers for early diagnosis. In particular, miRNA-29 represents a class of miRNAs known to regulate pathogenesis of AD. In this work we developed an electrochemical printed strip for the detection of miRNA-29a at low levels. The architecture was characterized by the presence of gold nanoparticles (AuNPs) and an anti-miRNA-29a probe labeled with a redox mediator. The novel analytical tool has been characterized with microscale thermophoresis and electrochemical methods, and it has been optimized by selection of the most appropriate probe density to detect low target concentration. The present tool was capable to detect miRNA-29a both in standard solution and in serum, respectively, down to 0.15 and 0.2 nM. The platform highlighted good repeatability (calculated as the relative standard deviation) of ca. 10% and satisfactory selectivity in the presence of interfering species. This work has the objective to open a way for the study and possible early diagnosis of a physically and socially devastating disease such as Alzheimer's. The results demonstrate the suitability of this approach in terms of ease of use, time of production, sensitivity, and applicability

Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure.

Although supraphysiological concentrations of urea are known to increase oxidative stress in cultured cells, it is generally thought that the elevated levels of urea in chronic renal failure patients have negligible toxicity. We previously demonstrated that ROS increase intracellular protein modification by O-linked β-N-acetylglucosamine (O-GlcNAc), and others showed that increased modification of insulin signaling molecules by O-GlcNAc reduces insulin signal transduction. Because both oxidative stress and insulin resistance have been observed in patients with end-stage renal disease, we sought to determine the role of urea in these phenotypes. Treatment of 3T3-L1 adipocytes with urea at disease-relevant concentrations induced ROS production, caused insulin resistance, increased expression of adipokines retinol binding protein 4 (RBP4) and resistin, and increased O-GlcNAc–modified insulin signaling molecules. Investigation of a mouse model of surgically induced renal failure (uremic mice) revealed increased ROS production, modification of insulin signaling molecules by O-GlcNAc, and increased expression of RBP4 and resistin in visceral adipose tissue. Uremic mice also displayed insulin resistance and glucose intolerance, and treatment with an antioxidant SOD/catalase mimetic normalized these defects. The SOD/catalase mimetic treatment also prevented the development of insulin resistance in normal mice after urea infusion. These data suggest that therapeutic targeting of urea-induced ROS may help reduce the high morbidity and mortality caused by end-stage renal disease

NEMO-SN1 Abyssal Cabled Observatory in the Western Ionian Sea

The NEutrinoMediterranean Observatory—Submarine Network 1 (NEMO-SN1) seafloor observatory is located in the central Mediterranean Sea, Western Ionian Sea, off Eastern Sicily (Southern Italy) at 2100-m water depth, 25 km from the harbor of the city of Catania. It is a prototype of a cabled deep-sea multiparameter observatory and the first one operating with real-time data transmission in Europe since 2005. NEMO-SN1 is also the first-established node of the European Multidisciplinary Seafloor Observatory (EMSO), one of the incoming European large-scale research infrastructures included in the Roadmap of the European Strategy Forum on Research Infrastructures (ESFRI) since 2006. EMSO will specifically address long-term monitoring of environmental processes related to marine ecosystems, marine mammals, climate change, and geohazards

Nuclear FGFR2 Interacts with the MLL-AF4 Oncogenic Chimera and Positively Regulates HOXA9 Gene Expression in t(4;11) Leukemia Cells

The chromosomal translocation t(4;11) marks an infant acute lymphoblastic leukemia associated with dismal prognosis. This rearrangement leads to the synthesis of the MLL-AF4 chimera, which exerts its oncogenic activity by upregulating transcription of genes involved in hematopoietic differentiation. Crucial for chimera’s aberrant activity is the recruitment of the AF4/ENL/P-TEFb protein complex. Interestingly, a molecular interactor of AF4 is fibroblast growth factor receptor 2 (FGFR2). We herein analyze the role of FGFR2 in the context of leukemia using t(4;11) leukemia cell lines. We revealed the interaction between MLL-AF4 and FGFR2 by immunoprecipitation, western blot, and immunofluorescence experiments; we also tested the effects of FGFR2 knockdown, FGFR2 inhibition, and FGFR2 stimulation on the expression of the main MLL-AF4 target genes, i.e., HOXA9 and MEIS1. Our results show that FGFR2 and MLL-AF4 interact in the nucleus of leukemia cells and that FGFR2 knockdown, which is associated with decreased expression of HOXA9 and MEIS1, impairs the binding of MLL-AF4 to the HOXA9 promoter. We also show that stimulation of leukemia cells with FGF2 increases nuclear level of FGFR2 in its phosphorylated form, as well as HOXA9 and MEIS1 expression. In contrast, preincubation with the ATP-mimetic inhibitor PD173074, before FGF2 stimulation, reduced FGFR2 nuclear amount and HOXA9 and MEIS1 transcript level, thereby indicating that MLL-AF4 aberrant activity depends on the nuclear availability of FGFR2. Overall, our study identifies FGFR2 as a new and promising therapeutic target in t(4;11) leukemia

MiR‐27a downregulates 14‐3‐3θ, RUNX1, AF4, and MLL‐AF4, crucial drivers of blast transformation in t(4;11) leukemia cells

The chromosomal translocation t(4;11)(q21;q23), a hallmark of an aggressive form of acute lymphoblastic leukemia (ALL), encodes mixed-lineage leukemia (MLL)-AF4 oncogenic chimera that triggers aberrant transcription of genes involved in lymphocyte differentiation, including HOXA9 and MEIS1. The scaffold protein 14-3-3θ, which promotes the binding of MLL-AF4 to the HOXA9 promoter, is a target of MiR-27a, a tumor suppressor in different human leukemia cell types. We herein study the role of MiR-27a in the pathogenesis of t(4;11) ALL. Reverse transcription quantitative PCR (qPCR) reveals that MiR-27a and 14-3-3θ expression is inversely correlated in t(4;11) ALL cell lines; interestingly, MiR-27a relative expression is significantly lower in patients affected by t(4;11) ALL than in patients affected by the less severe t(12;21) leukemia. In t(4;11) leukemia cells, ectopic expression of MiR-27a decreases protein level of 14-3-3θ and of the key transcription factor RUNX1. We show for the first time that MiR-27a also targets AF4 and MLL-AF4; in agreement, MiR-27a overexpression strongly reduces AF4 and MLL-AF4 protein levels in RS4;11 cells. Consequent to AF4 and MLL-AF4 downregulation, MiR-27a overexpression negatively affects transcription of HOXA9 and MEIS1 in different t(4;11) leukemia cell lines. In agreement, we show through chromatin immunoprecipitation experiments that MiR-27a overexpression impairs the binding of MLL-AF4 to the HOXA9 promoter. Lastly, we found that MiR-27a overexpression decreases viability, proliferation, and clonogenicity of t(4;11) cells, whereas it enhances their apoptotic rate. Overall, our study identifies the first microRNAthat strikes in one hit four crucial drivers of blast transformation in t(4;11) leukemia. Therefore, MiR-27a emerges as a new promising therapeutic target for this aggressive and poorly curable form of leukemia

Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure

Although supraphysiological concentrations of urea are known to increase oxidative stress in cultured cells, it is generally thought that the elevated levels of urea in chronic renal failure patients have negligible toxicity. We previously demonstrated that ROS increase intracellular protein modification by O-linked β-N-acetylglucosamine (O-GlcNAc), and others showed that increased modification of insulin signaling molecules by O-GlcNAc reduces insulin signal transduction. Because both oxidative stress and insulin resistance have been observed in patients with end-stage renal disease, we sought to determine the role of urea in these phenotypes. Treatment of 3T3-L1 adipocytes with urea at disease-relevant concentrations induced ROS production, caused insulin resistance, increased expression of adipokines retinol binding protein 4 (RBP4) and resistin, and increased O-GlcNAc–modified insulin signaling molecules. Investigation of a mouse model of surgically induced renal failure (uremic mice) revealed increased ROS production, modification of insulin signaling molecules by O-GlcNAc, and increased expression of RBP4 and resistin in visceral adipose tissue. Uremic mice also displayed insulin resistance and glucose intolerance, and treatment with an antioxidant SOD/catalase mimetic normalized these defects. The SOD/catalase mimetic treatment also prevented the development of insulin resistance in normal mice after urea infusion. These data suggest that therapeutic targeting of urea-induced ROS may help reduce the high morbidity and mortality caused by end-stage renal disease

NEMO-SN1 (Western Ionian Sea, off Eastern Sicily): Example of architecture of a cabled observatory

NEMO-SN1, located in the central Mediterranean Sea, Western Ionian Sea, off Eastern Sicily Island (Southern Italy) at 2100 m water depth, 25 km from the harbour of the city of Catania, is a prototype of a cabled deep-sea multiparameter observatory and the first operating with real-time data transmission in Europe since 2005. NEMO-SN1 is also the first-established node of EMSO (European Multidisciplinary Seafloor Observatory, http://emso-eu.org), one of the incoming European large-scale research infrastructure included since 2006 in the Roadmap of the ESFRI (European Strategy Forum on Research Infrastructures, http://cordis.europa.eu/esfri/roadmap.htm), which will specifically address long-term monitoring of environmental processes related to Marine Ecosystems, Climate Change and Geo-hazards. NEMO-SN1 has been deployed and developed over the last decade thanks to Italian resources and to the EC project ESONET-NoE (European Seas Observatory NETwork Network of Excellence, 20072011) that funded the LIDO-DM (Listening to the Deep Ocean Demonstration Mission) and a technological interoperability test (http://www.esonet-emso.org/ esonet-noe/). NEMO-SN1 is performing geophysical and environmental long-term monitoring by acquiring seismological, geomagnetic, gravimetric, accelerometric, physico-oceanographic, hydro-acoustic, bio-acoustic measurements specifically related to earthquakes and tsunamis generation and ambient noise characterisation in term of marine mammal sounds, environmental and anthropogenic sources. A further main feature of NEMO-SN1 is to be an important test-site for the construction of KM3NeT (Kilometre-Cube Underwater Neutrino Telescope, http://www.km3net.org/), another large-scale research infrastructure included in the ESFRI Roadmap constituted by a large volume neutrino telescope. The description of the observatory and the most recent data acquired will be presented and framed in the general objectives of EMSO. © 2011 IEEE

Salvate Eva in Sicilia: indagine conoscitiva 2016 sull’adesione allo screening organizzato del cervicocarcinoma.

In Sicilia, a fronte di un incremento dell’estensione dello screening organizzato del cervicocarcinoma, non corrisponde un aumento dell’adesione. Nei mesi di gennaio-giugno 2016 è stata condotta un’indagine trasversale somministrando un questionario standardizzato a un campione di 365 donne, per descrivere le ragioni del fenomeno e promuovere interventi mirati. Per le variabili di atteggiamento e conoscenza è stato utilizzato l’Health Belief Model, che ha esplorato la percezione della donna della suscettibilità (rischio di sviluppare il cancro), della gravità della patologia e dei benefici derivanti dal pap-test. Dai risultati emerge che il 66,6% delle intervistate ha effettuato un pap- test nell’ultimo triennio (valore nazionale 79,2%); il consiglio da parte di un operatore sanitario e la suscettibilità percepita sono associati a una maggiore adesione allo screening. Il potenziamento dei programmi organizzati di screening e l’intervento attivo del medico di medicina generale rappresentano strategie efficaci di promozione dello screening