A NEW BRANCH of the ANIO NOVUS AQUEDUCT (ROME, ITALY) REVEALED by ARCHAEOLOGY and GEOPHYSICS

The area south-east of Rome is characterised by the presence of several roman aqueducts which brought water to the eternal city from the Apennine and Alban Hills springs. In the last 40 years, several pieces of evidence about these aqueducts were acquired during the realisation of archaeological test trenches before building activities. In 2019, a small branch of a subterranean aqueduct unknown to the Latin sources was unearthed in Via dei Sette Metri. Here we show that this aqueduct is a lateral branch of the Anio Novus, a major imperial aqueduct built between 38 and 52 CE. To achieve this result, we employed detailed photogrammetric restitution of the new aqueduct and an integrated geophysical survey focused in the area where the Anio Novus was supposed to pass. Electrical Resistivity Tomography (ERT) and Ground Penetrating Radar (GPR) methods were used to reconstruct aqueduct paths and their relative heights. Different light conditions were tested during the picture acquisition step to determine the best practice in the photogrammetric restitution. The results obtained in this study confirmed the great effectiveness of the integration between geophysical investigation methods and the modern archaeology approach in detecting buried ancient structures

N6L pseudopeptide interferes with nucleophosmin protein-protein interactions and sensitizes leukemic cells to chemotherapy.

Abstract NPM1 is a multifunctional nucleolar protein implicated in several processes such as ribosome maturation and export, DNA damage response and apoptotic response to stress stimuli. The NPM1 gene is involved in human tumorigenesis and is found mutated in one third of acute myeloid leukemia patients, leading to the aberrant cytoplasmic localization of NPM1. Recent studies indicated that the N6L multivalent pseudopeptide, a synthetic ligand of cell–surface nucleolin, is also able to bind NPM1 with high affinity. N6L inhibits cell growth with different mechanisms and represents a good candidate as a novel anticancer drug for a number of malignancies of different histological origin. In this study we investigated whether N6L treatment could drive antitumor effect in acute myeloid leukemia cell lines. We found that N6L binds NPM1 at the N-terminal domain, co-localizes with cytoplasmic, mutated NPM1, and interferes with its protein-protein associations. N6L toxicity appears to be p53 dependent but interestingly, the leukemic cell line harbouring the mutated form of NPM1 is more resistant to treatment, suggesting that NPM1 cytoplasmic delocalization confers protection from p53 activation. Moreover, we show that N6L sensitizes AML cells to doxorubicin and cytarabine treatment. These studies suggest that N6L may be a promising option in combination therapies for acute myeloid leukemia treatment

p73: A Multifunctional Protein in Neurobiology

p73, a transcription factor of the p53 family, plays a key role in many biological processes including neuronal development. Indeed, mice deficient for both TAp73 and ΔNp73 isoforms display neuronal pathologies, including hydrocephalus and hippocampal dysgenesis, with defects in the CA1-CA3 pyramidal cell layers and the dentate gyrus. TAp73 expression increases in parallel with neuronal differentiation and its ectopic expression induces neurite outgrowth and expression of neuronal markers in neuroblastoma cell lines and neural stem cells, suggesting that it has a pro-differentiation role. In contrast, ΔNp73 shows a survival function in mature cortical neurons as selective ΔNp73 null mice have reduced cortical thickness. Recent evidence has also suggested that p73 isoforms are deregulated in neurodegenerative pathologies such as Alzheimer’s disease, with abnormal tau phosphorylation. Thus, in addition to its increasingly accepted contribution to tumorigenesis, the p73 subfamily also plays a role in neuronal development and neurodegeneration

Deciphering and modelling remyelinating mechanisms induced by clinically-used azole antifungals with exploitable repurposing properties

Recent evidence demonstrated the ability of some antifungals to induce (re)myelination in speci c experimental models. These compounds, already marketed for di erent pathologies, are interesting candidates for a repurposing strategy in neurodegenerative diseases, like multiple sclerosis (MS), characterized by strong demyelination. Our preliminary results show that the inhibition of enzymes involved in retinoic acid (RA) catabolism (CYP26), by miconazole and other azole antifungals, induces an increase of cellular RA concentration and that this increase may be behind the observed oligodendrocyte precursor cell (OPC) maturation and di erentiation. On this basis, our proposal is aimed at studying the molecular mechanisms of azole antifungals used in human pharmacology, both in silico and in vitro, and at identifying the most promising ones according to their ability to increase Myelin Basic Protein (MBP) expression on OPCs and to promote their di erentiation and myelination. In our investigation, the ability of 7 azoles to inhibit CYP26 isozymes was evaluated through molecular docking: in silico results were the basis for the selection of the drugs for the in vitro experiments. The selected azoles were tested in three di erent cell models, characterized by increasing complexity: i) OPC cultures, a maturation assay for myelin-producing cells; ii) OPC-dorsal root ganglion (DRG) neuron co-cultures, a myelination assay; iii) cerebral micromass cultures, a cell di erentiation assay for CNS. In parallel, the e ects of exogenous RA and of an inhibitor of the synthesis of RA (citral), were evaluated as well. In the next phase of the project, the outcomes from the di erent in vitro models will be statistically correlated with the pharmacological treatments. Our results will be useful: 1) for identifying the most promising azole antifungals with respect to their pro-myelinating activity, 2) for clarifying the molecular mechanisms underlying their reparative e ect and 3) for formalizing mathematical models to identify the most active concentrations for the most potent azoles

An efficient algorithm for the stochastic simulation of the hybridization of DNA to microarrays

<p>Abstract</p> <p>Background</p> <p>Although oligonucleotide microarray technology is ubiquitous in genomic research, reproducibility and standardization of expression measurements still concern many researchers. Cross-hybridization between microarray probes and non-target ssDNA has been implicated as a primary factor in sensitivity and selectivity loss. Since hybridization is a chemical process, it may be modeled at a population-level using a combination of material balance equations and thermodynamics. However, the hybridization reaction network may be exceptionally large for commercial arrays, which often possess at least one reporter per transcript. Quantification of the kinetics and equilibrium of exceptionally large chemical systems of this type is numerically infeasible with customary approaches.</p> <p>Results</p> <p>In this paper, we present a robust and computationally efficient algorithm for the simulation of hybridization processes underlying microarray assays. Our method may be utilized to identify the extent to which nucleic acid targets (e.g. cDNA) will cross-hybridize with probes, and by extension, characterize probe robustnessusing the information specified by MAGE-TAB. Using this algorithm, we characterize cross-hybridization in a modified commercial microarray assay.</p> <p>Conclusions</p> <p>By integrating stochastic simulation with thermodynamic prediction tools for DNA hybridization, one may robustly and rapidly characterize of the selectivity of a proposed microarray design at the probe and "system" levels. Our code is available at <url>http://www.laurenzi.net</url>.</p

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death

Delivery of hepato-pancreato-biliary surgery during the COVID-19 pandemic: an European-African Hepato-Pancreato-Biliary Association (E-AHPBA) cross-sectional survey

Background: The extent of the COVID-19 pandemic and the resulting response has varied globally. The European and African Hepato-Pancreato-Biliary Association (E-AHPBA), the premier representative body for practicing HPB surgeons in Europe and Africa, conducted this survey to assess the impact of COVID-19 on HPB surgery. Methods: An online survey was disseminated to all E-AHPBA members to assess the effects of the pandemic on unit capacity, management of HPB cancers, use of COVID-19 screening and other aspects of service delivery. Results: Overall, 145 (25%) members responded. Most units, particularly in COVID-high countries (>100,000 cases) reported insufficient critical care capacity and reduced HPB operating sessions compared to COVID-low countries. Delayed access to cancer surgery necessitated alternatives including increased neoadjuvant chemotherapy for pancreatic cancer and colorectal liver metastases, and locoregional treatments for hepatocellular carcinoma. Other aspects of service delivery including COVID-19 screening and personal protective equipment varied between units and countries. Conclusion: This study demonstrates that the COVID-19 pandemic has had a profound adverse impact on the delivery of HPB cancer care across the continents of Europe and Africa. The findings illustrate the need for safe resumption of cancer surgery in a “new” normal world with screening of patients and staff for COVID-19

Activation and Inhibition of Transglutaminase 2 in Mice

Transglutaminase 2 (TG2) is an allosterically regulated enzyme with transamidating, deamidating and cell signaling activities. It is thought to catalyze sequence-specific deamidation of dietary gluten peptides in the small intestines of celiac disease patients. Because this modification has profound consequences for disease pathogenesis, there is considerable interest in the design of small molecule TG2 inhibitors. Although many classes of TG2 inhibitors have been reported, thus far an animal model for screening them to identify promising celiac drug candidates has remained elusive. Using intraperitoneal administration of the toll-like receptor 3 (TLR3) ligand, polyinosinic-polycytidylic acid (poly(I∶C)), we induced rapid TG2 activation in the mouse small intestine. Dose dependence was observed in the activation of TG2 as well as the associated villous atrophy, gross clinical response, and rise in serum concentration of the IL-15/IL-15R complex. TG2 activity was most pronounced in the upper small intestine. No evidence of TG2 activation was observed in the lung mucosa, nor were TLR7/8 ligands able to elicit an analogous response. Introduction of ERW1041E, a small molecule TG2 inhibitor, in this mouse model resulted in TG2 inhibition in the small intestine. TG2 inhibition had no effect on villous atrophy, suggesting that activation of this enzyme is a consequence, rather than a cause, of poly(I∶C) induced enteropathy. Consistent with this finding, administration of poly(I∶C) to TG2 knockout mice also induced villous atrophy. Our findings pave the way for pharmacological evaluation of small molecule TG2 inhibitors as drug candidates for celiac disease

The politics of vibrant matter: consistency, containment and the concrete of Mussolini’s bunker

This article explores the idea of how vibrancy can be produced. Specifically, the attempt is to investigate the multiplicities of vibrancy by considering one of Mussolini’s bunkers. The author examines the location of the bunker in the EUR (Esposizione Universale Romana) neighbourhood in Rome, the bunker’s materiality, and the context and social meaning of the bunker through a contemporary art exhibition called ‘Confronti’ (Confrontations) that took place in the bunker in 2009. The article argues that while emphasizing matter’s inherent vibrancy may be useful in some cases, there is also merit in further unpacking the ways in which vibrancy is produced. In this example, the concrete bunker expresses vibrancy through the processes involved in the emergent material form, and in the sustained politics and social considerations embedded in valuing tangible urban heritage