Effects of Fifty-Hertz Electromagnetic Fields on Granulocytic Differentiation of ATRA-Treated Acute Promyelocytic Leukemia NB4 Cells

Background/Aims: Life on Earth is constantly exposed to electromagnetic fields (EMFs) and the effects induced by EMFs on biological systems have been extensively studied producing different and sometimes contradictory results. Extremely low-frequency electromagnetic fields (ELF-EMFs) have shown to play a role in regulating cell proliferation and differentiation, although how EMFs influence these processes remains unclear. Human acute promyelocytic leukemia (APL) cells are characterized by the arrest of differentiation at the promyelocytic stage due to epigenetic perturbations induced by PML/RARα fusion protein (Promyelocytic Leukemia protein - PML/Retinoic Acid Receptor alpha - RARα). Therapeutic administration of all-trans retinoic acid (ATRA) re-establishes the leukemogenic mechanism re-inducing the normal differentiation processes. Methods: We studied the effects of ELF-EMFs (50 Hz, 2 mT) on the ATRA-mediated granulocytic differentiation process of APL NB4 cells (a cell line established from the bone marrow of a patient affected by the acute promyelocytic leukemia) by monitoring cellular proliferation and morphology, nitrob lue tetrazolium (NBT) reduction and the expression of differentiation surface markers. Finally, we investigated mechanisms focusing on reactive oxygen species (ROS) generation and related molecular pathways. Results: ELF-EMF exposure decreases cellular proliferation potential and helps ATRA-treated NB4 cells to mature. Furthermore, the analysis of ROS production and the consequent extracellular signal regulated kinases (ERK1/2) phosphorylation suggest that a changed intracellular oxidative balance may influence the biological effects of ELF-EMFs. Conclusions: These results indicate that the exposure to ELF-EMF promotes ATRA-induced granulocytic differentiation of APL cells

Towards Naples Ecological REsearch for Augmented Observatories (NEREA): The NEREA-Fix module, a stand-alone platform for long-term deep-sea ecosystem monitoring

Deep-sea ecological monitoring is increasingly recognized as indispensable for the comprehension of the largest biome on Earth, but at the same time it is subjected to growing human impacts for the exploitation of biotic and abiotic resources. Here, we present the Naples Ecological REsearch (NEREA) stand-alone observatory concept (NEREA-fix), an integrated observatory with a modular, adaptive structure, characterized by a multiparametric video-platform to be deployed in the Dohrn canyon (Gulf of Naples, Tyrrhenian Sea) at ca. 650 m depth. The observatory integrates a seabed platform with optoacoustic and oceanographic/geochemical sensors connected to a surface transmission buoy, plus a mooring line (also equipped with depth-staged environmental sensors). This reinforced high-frequency and long-lasting ecological monitoring will integrate the historical data conducted over 40 years for the Long-Term Ecological Research (LTER) at the station “Mare Chiara”, and ongoing vessel-assisted plankton (and future environmental DNA-eDNA) sampling. NEREA aims at expanding the observational capacity in a key area of the Mediterranean Sea, representing a first step towards the establishment of a bentho-pelagic network to enforce an end-to-end transdisciplinary approach for the monitoring of marine ecosystems across a wide range of animal sizes (from bacteria to megafauna).This research was funded by PON “Iniziative in supporto al consolidamento e potenziamento dell’infrastruttura EMSO e delle sue attività (InSEA)” - European Union - Italian Ministry of University and Research, grant number PIR01_00030.Peer ReviewedPostprint (published version

Generation of induced pluripotent stem cell line CSSi008-A (4698) from a patient affected by advanced stage of Dentato-Rubral-Pallidoluysian atrophy (DRPLA)

Abstract Dentato-Rubral-pallidoluysian atrophy (DRPLA) is a rare autosomal, dominant, progressive neurodegenerative disease that causes involuntary movements, mental and emotional problems. DRPLA is caused by a mutation in the ATN1 gene that encodes for an abnormal polyglutamine stretch in the atrophin-1 protein. DRPLA is most common in the Japanese population, where it has an estimated incidence of 2 to 7 per million people. This condition has also been seen in families from North America and Europe. We obtained a reprogrammed iPSC line from a Caucasian patient with a juvenile onset of the disease, carrying 64 CAG repeat expansion in the ATN1 gene

Targeted cancer exome sequencing reveals recurrent mutations in myeloproliferative neoplasms

With the intent of dissecting the molecular complexity of Philadelphia-negative myeloproliferative neoplasms (MPN), we designed a target enrichment panel to explore, using next-generation sequencing (NGS), the mutational status of an extensive list of 2,000 cancer-associated genes and microRNAs. The genomic DNA of granulocytes and in-vitro-expanded CD3+ T-lymphocytes, as a germline control, was target-enriched and sequenced in a learning cohort of 20 MPN patients using Roche 454 technology. We identified 141 genuine somatic mutations, most of which were not previously described. To test the frequency of the identified variants, a larger validation cohort of 189 MPN patients was additionally screened for these mutations using Ion Torrent AmpliSeq NGS. Excluding the genes already described in MPN, for 8 genes (SCRIB, MIR662, BARD1, TCF12, FAT4, DAP3, POLG, and NRAS), we demonstrated a mutation frequency between 3 and 8%. We also found that mutations at codon 12 of NRAS (NRASG12V and NRASG12D) were significantly associated, for primary myelofibrosis (PMF), with highest DIPSS-plus score categories. This association was then confirmed in 66 additional PMF patients composing a final dataset of 168 PMF showing an NRAS mutation frequency of 4.7%, which was associated with a worse outcome, as defined by the DIPSS plus score

miRNA-mRNA integrative analysis in primary myelofibrosis CD34+ cells: role of miR-155/JARID2 axis in abnormal megakaryopoiesis

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by megakaryocyte (MK) hyperplasia, bone marrow fibrosis, and abnormal stem cell trafficking. PMF may be associated with somatic mutations in JAK2, MPL, or CALR. Previous studies have shown that abnormal MKs play a central role in the pathophysiology of PMF. In this work, we studied both gene and microRNA (miRNA) expression profiles in CD34(+) cells from PMF patients. We identified several biomarkers and putative molecular targets such as FGR, LCN2, and OLFM4. By means of miRNA-gene expression integrative analysis, we found different regulatory networks involved in the dysregulation of transcriptional control and chromatin remodeling. In particular, we identified a network gathering several miRNAs with oncogenic potential (eg, miR-155-5p) and targeted genes whose abnormal function has been previously associated with myeloid neoplasms, including JARID2, NR4A3, CDC42, and HMGB3. Because the validation of miRNA-target interactions unveiled JARID2/miR-155-5p as the strongest relationship in the network, we studied the function of this axis in normal and PMF CD34(+) cells. We showed that JARID2 downregulation mediated by miR-155-5p overexpression leads to increased in vitro formation of CD41(+) MK precursors. These findings suggest that overexpression of miR-155-5p and the resulting downregulation of JARID2 may contribute to MK hyperplasia in PMF

Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males

Background: While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome. Methods: We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects. Findings: Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men <60 years of age (p = 0.014). Testosterone was higher in subjects with AR long-polyQ, possibly indicating receptor resistance (p = 0.042 Mann-Whitney U test). Inappropriately low serum testosterone level among carriers of the long-polyQ alleles (p = 0.0004 Mann-Whitney U test) predicted the need for intensive care in COVID-19 infected men. In agreement with the known anti-inflammatory action of testosterone, patients with long-polyQ and age ≥60 years had increased levels of CRP (p = 0.018, not accounting for multiple testing). Interpretation: We identify the first genetic polymorphism that appears to predispose some men to develop more severe disease. Failure of the endocrine feedback to overcome AR signaling defects by increasing testosterone levels during the infection leads to the polyQ tract becoming dominant to serum testosterone levels for the clinical outcome. These results may contribute to designing reliable clinical and public health measures and provide a rationale to test testosterone as adjuvant therapy in men with COVID-19 expressing long AR polyQ repeats. Funding: MIUR project "Dipartimenti di Eccellenza 2018-2020" to Department of Medical Biotechnologies University of Siena, Italy (Italian D.L. n.18 March 17, 2020) and "Bando Ricerca COVID-19 Toscana" project to Azienda Ospedaliero-Universitaria Senese. Private donors for COVID-19 research and charity funds from Intesa San Paolo

Motivations for collaborating with industry: has public policy influenced new academics in Argentina?

Between 2005 and 2015 a series of science, technology and innovation policies were deployed in Argentina among which academic research collaborations with industry was particularly fostered. This paper studies the effect of those policies on newer researchers, defined as those with PhD or postdoctoral scholarships, looking at their motivations to collaborate and, to some extent, at their actual collaborations with Industry. Our hypothesis is that those policies had a positive effect on young academics’ perception of collaborations with industry, now conceived as a dimension of their job, and also on actual collaborations. To conduct our study, we used an original database constructed from an online survey answered by more than 600 newer researchers. Empirical results partly confirm our hypothesis: a direct policy encouraging collaborations by providing collaborative grants was not associated with actual collaborations, while orienting research towards strategic areas–defined by the Science and Technology Ministry- is

Política latinoamericana comparada

La política latinoamericana desde una perspectiva comparada ha adquirido en los últimos tiempos una mayor centralidad e importancia dentro de las ciencias sociales, generando la necesidad de reflexionar acerca de su desarrollo histórico, su estado actual y su derrotero futuro. Política Latinoamericana Comparada es un libro que busca realizar un aporte en este sentido, acercando múltiples vías de entrada y análisis de la temática, ya que conjuga miradas panorámicas, diagnósticos regionales y perspectivas ancladas en la observación de realidades nacionales, proponiendo un escenario común en el cual dialogar, debatir y encontrar puntos de encuentro y de fuga entre especialistas.Fil: Geary, Mirta. Universidad Nacional de Rosario. Facultad de Ciencia Política y Relaciones Internacionales; Argentina.Fil: Lucca, Juan Bautista. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Universidad Nacional de Rosario; Argentina.Fil: Pinillos, Cintia. Universidad Nacional de Rosario. Facultad de Ciencia Política y Relaciones Internacionales; Argentina.Fil: Fanelli, Lucrecia. Universidad Nacional de Rosario. Facultad de Ciencia Política y Relaciones Internacionales.Fil: Schreiner, Federico. Universidad Nacional de Rosario. Facultad de Ciencia Política y Relaciones Internacionales; Argentina.Fil: Perbellini, Melina. Universidad Nacional de Rosario. Facultad de Ciencia Política y Relaciones Internacionales; Argentina.Fil: Fernández, Elías. Universidad Nacional de Rosario. Facultad de Ciencia Política y Relaciones Internacionales; Argentina.Fil: Ruiz, Valeria. Universidad Nacional de Rosario. Facultad de Ciencia Política y Relaciones Internacionales; Argentina.Fil: Orta, Melisa. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Universidad Nacional de Rosario; Argentina.Fil: Kestler, Thomas. Würzburg University; Germany.Fil: Lauth, Hans-Joachim. Würzburg University; Germany.Fil: Mohamad-Klotzbach, Christoph. Würzburg University; Germany.Fil: Borrell, Mariana. Universidad Nacional de Rosario. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); ArgentinaFil: Heinisch, Reinhard. Universidad de Salzburgo; Austria.Fil: Gugliano, Alfredo Alejandro. Universidade Federal do Rio Grande do Sul; Brasil.Fil: Rodrigues, Priscila. Universidade Federal do Rio Grande do Sul; Brasil.Fil: Batlle, Margarita. Universidad Externado, Colombia.Fil: Cascante, María José. Universidad de Costa Rica.Fil: Basabe-Serrano, Santiago. Facultad Latinoamericana de Ciencias Sociales (FLACSO), Ecuador.Fil: Caballero Santos, Sergio. Universidad Autónoma de Madrid; España.Fil: Graziano, Paolo. Universidad Bocconi, Italia.Fil: Vidal de la Rosa: Godofredo. Universidad Autónoma Metropolitana; México.Fil: Duarte Recalde, Liliana Rocío. Universidad Católica “Nuestra Señora de la Asunción”; Paraguay.Fil: Camerlo, Marcelo. Universidad de Lisboa; Portugal.Fil: Malamud, Andrés. Universidad de Lisboa; Portugal.Fil: Chasquetti, Daniel. Universidad de la República; Uruguay.Fil: Castiglioni, Rossana. Universidad Diego Portales; Chile

Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise: the TRUFFLE 2 randomised trial protocol

Introduction: Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years. Methods and analysis: Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is &lt;10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire. Ethics and dissemination: The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy. Trial registration number: Main sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical &amp; Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200