CALCAREOUS NANNOFOSSILS AT THE TRIASSIC/JURASSIC BOUNDARY: STRATIGRAPHIC AND PALEOCEANOGRAPHIC CHARACTERIZATION

In this work, calcareous nannofossils are identified for the first time in the uppermost Triassic sequence of the Lombardy Basin (Southern Calcareous Alps, Italy). Two zones are recognized, namely the NT2b (latest Triassic) and the NJT1 (earliest Jurassic). Two species resulted to be good markers to constrain the TJB interval: Prinsiosphaera triassica and Schizosphaerella punctulata. Nannofossil data are calibrated with C isotopic chemostratigraphy obtained for carbonate and organic matter. Size reduction of P. triassica and a decline in the abundance of Triassic nannofossils are detected soon after the “precursor Carbon Isotope Excursion (CIE) and culminated during the “initial negative CIE” characterized by lowest nannofossil abundances and small-sized P. triassica. The extinction of Triassic nannofossils occurred in distinctive steps within the “initial negative CIE”, while the Jurassic S. punctulata is first observed at the base of the “main negative CIE”. The latest Triassic nannofossil decline in abundance, size reduction and extinctions, represent a progressive deterioration associated to the Central Atlantic Magmatic Province (CAMP) volcanism. Our findings are consistent with nannofossil changes at supraregional scale and indicate that the massive CAMP flood basalts were preceded by initial volcanic pulses. We speculate that a combination of climate change, fertilization and ocean acidification started to influence the calcification process prior to the “initial negative CIE”. Nannoplankton extinctions were not simultaneous and might imply limited capacity for adaptation in the early stages of evolutionary history. However, originations of new taxa soon after the disappearance of Triassic forms suggest the ability to rapidly overcame extreme stressing conditions

BID and the α-bisabolol-triggered cell death program: converging on mitochondria and lysosomes

\u3b1-Bisabolol (BSB) is a plant-derived sesquiterpene alcohol able to trigger regulated cell death in transformed cells, while deprived of the general toxicity in several mouse models. Here, we investigated the involvement of lysosomal and mitochondrial compartments in the cytotoxic effects of BSB, with a specific focus on the BH3-only activator protein BID. We found that BSB particularly accumulated in cancer cell lines, displaying a higher amount of lipid rafts as compared to normal blood cells. By means of western blotting and microscopy techniques, we documented rapid BSB-induced BID translocation to lysosomes and mitochondria, both of them becoming dysfunctional. Lysosomal membranes were permeabilized, thus blocking the cytoprotective autophagic flux and provoking cathepsin B leakage into the cytosol. Multiple flow cytometry-based experiments demonstrated the loss of mitochondrial membrane potential due to pore formation across the lipid bilayer. These parallel events converged on neoplastic cell death, an outcome significantly prevented by BID knockdown. Therefore, BSB promoted BID redistribution to the cell death executioner organelles, which in turn activated anti-autophagic and proapoptotic mechanisms. This is an example of how xenohormesis can be exploited to modulate basic cellular programs in cancer

Distal left circumflex coronary artery flow reserve recorded by transthoracic Doppler echocardiography: a comparison with Doppler-wire

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Il curricolo verticale nella scuola del primo ciclo. Analisi, percorsi, strumenti

Un Istituto comprensivo è composto da tre ordini di scuola (dell'infanzia, primaria e secondaria di primo grado) con caratteristiche molto diverse, talvolta difficili da raccordare. Ciò nonostante, il curricolo d’Istituto (o verticale) va costruito insieme, con l'apporto di tutti gli insegnanti. Su quali basi? Il gruppo Università-Scuola del Laboratorio RED (Ricerca Educativa e Didattica) dell’Università Ca’ Foscari di Venezia, ha studiato e sperimentato, nelle pratiche formative, modelli aperti di progettazione del curricolo verticale per competenze, come proposto dalle Indicazioni nazionali, centrato sui nodi concettuali formativi, ovvero sui processi che sovrintendono agli apprendimenti nelle interconnessioni tra i multiformi potenziali formativi degli allievi e la ricchezza dei processi di conoscenza nei diversi ambiti disciplinari. Questo volume testimonia le analisi e i percorsi di ricerca-forma-azione nelle scuole, con gli insegnanti sperimentatori in classe

Elucidating the 3D Structure of a Surface Membrane Antigen from Trypanosoma cruzi as a Serodiagnostic Biomarker of Chagas Disease

Chagas disease (CD) is a vector-borne parasitosis, caused by the protozoan parasite Trypanosoma cruzi, that affects millions of people worldwide. Although endemic in South America, CD is emerging throughout the world due to climate change and increased immigratory flux of infected people to non-endemic regions. Containing of the diffusion of CD is challenged by the asymptomatic nature of the disease in early infection stages and by the lack of a rapid and effective diagnostic test. With the aim of designing new serodiagnostic molecules to be implemented in a microarray-based diagnostic set-up for early screening of CD, herein, we report the recombinant production of the extracellular domain of a surface membrane antigen from T. cruzi (TcSMP) and confirm its ability to detect plasma antibodies from infected patients. Moreover, we describe its high-resolution (1.62 angstrom) crystal structure, to which in silico epitope predictions were applied in order to locate the most immunoreactive regions of TcSMP in order to guide the design of epitopes that may be used as an alternative to the full-length antigen for CD diagnosis. Two putative, linear epitopes, belonging to the same immunogenic region, were synthesized as free peptides, and their immunological properties were tested in vitro. Although both peptides were shown to adopt a structural conformation that allowed their recognition by polyclonal antibodies raised against the recombinant protein, they were not serodiagnostic for T. cruzi infections. Nevertheless, they represent good starting points for further iterative structure-based (re)design cycles

Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis

There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention

Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis

There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention. 201