Comparative analysis of rigidity across protein families

We present a comparative study in which 'pebble game' rigidity analysis is applied to multiple protein crystal structures, for each of six different protein families. We find that the main-chain rigidity of a protein structure at a given hydrogen bond energy cutoff is quite sensitive to small structural variations, and conclude that the hydrogen bond constraints in rigidity analysis should be chosen so as to form and test specific hypotheses about the rigidity of a particular protein. Our comparative approach highlights two different characteristic patterns ('sudden' or 'gradual') for protein rigidity loss as constraints are removed, in line with recent results on the rigidity transitions of glassy networks

Design and Initial Performance of the Askaryan Radio Array Prototype EeV Neutrino Detector at the South Pole

We report on studies of the viability and sensitivity of the Askaryan Radio Array (ARA), a new initiative to develop a Teraton-scale ultra-high energy neutrino detector in deep, radio-transparent ice near Amundsen-Scott station at the South Pole. An initial prototype ARA detector system was installed in January 2011, and has been operating continuously since then. We report on studies of the background radio noise levels, the radio clarity of the ice, and the estimated sensitivity of the planned ARA array given these results, based on the first five months of operation. Anthropogenic radio interference in the vicinity of the South Pole currently leads to a few-percent loss of data, but no overall effect on the background noise levels, which are dominated by the thermal noise floor of the cold polar ice, and galactic noise at lower frequencies. We have also successfully detected signals originating from a 2.5 km deep impulse generator at a distance of over 3 km from our prototype detector, confirming prior estimates of kilometer-scale attenuation lengths for cold polar ice. These are also the first such measurements for propagation over such large slant distances in ice. Based on these data, ARA-37, the 200 km^2 array now under construction, will achieve the highest sensitivity of any planned or existing neutrino detector in the 10^{16}-10^{19} eV energy range.Comment: 25 pages, 37 figures, this version with improved ice attenuation length analysis; for submission to Astroparticle Physic

Performance of two Askaryan Radio Array stations and first results in the search for ultra-high energy neutrinos

Ultra-high energy neutrinos are interesting messenger particles since, if detected, they can transmit exclusive information about ultra-high energy processes in the Universe. These particles, with energies above $10^{16}\mathrm{eV}$, interact very rarely. Therefore, detectors that instrument several gigatons of matter are needed to discover them. The ARA detector is currently being constructed at South Pole. It is designed to use the Askaryan effect, the emission of radio waves from neutrino-induced cascades in the South Pole ice, to detect neutrino interactions at very high energies. With antennas distributed among 37 widely-separated stations in the ice, such interactions can be observed in a volume of several hundred cubic kilometers. Currently 3 deep ARA stations are deployed in the ice of which two have been taking data since the beginning of the year 2013. In this publication, the ARA detector "as-built" and calibrations are described. Furthermore, the data reduction methods used to distinguish the rare radio signals from overwhelming backgrounds of thermal and anthropogenic origin are presented. Using data from only two stations over a short exposure time of 10 months, a neutrino flux limit of $3 \cdot 10^{-6} \mathrm{GeV} / (\mathrm{cm^2 \ s \ sr})$ is calculated for a particle energy of 10^{18}eV, which offers promise for the full ARA detector.Comment: 21 pages, 34 figures, 1 table, includes supplementary materia

An observational study on the expression levels of MDM2 and MDMX proteins, and associated effects on P53 in a series of human liposarcomas

Background: Inactivation of wild type P53 by its main cellular inhibitors (MDM2 and MDMX) is a well recognised feature of tumour formation in liposarcomas. MDM2 over-expression has been detected in approximately 80% of liposarcomas but only limited information is available about MDMX over-expression. To date, we are not aware of any study that has described the patterns of MDM2 and MDMX co-expression in liposarcomas. Such information has become more pertinent as various novel MDM2 and/or MDMX single and dual affinity antagonist compounds are emerging as an alternative approach for potential targeted therapeutic strategies. Methods. We analysed a case series of 61 fully characterized liposarcomas of various sub-types by immunohistochemistry, to assess the expression levels of P53, MDM2 and MDMX, simultaneously. P53 sequencing was performed in all cases that expressed P53 protein in 10% or more of cells to rule out mutation-related over-expression. Results: 50 cases over-expressed MDM2 and 42 of these co-expressed MDMX at varying relative levels. The relative expression levels of the two proteins with respect to each other were subtype-dependent. This apparently affected the detected levels of P53 directly in two distinct patterns. Diminished levels of P53 were observed when MDM2 was significantly higher in relation to MDMX, suggesting a dominant role for MDM2 in the degradation of P53. Higher levels of P53 were noted with increasing MDMX levels suggesting an interaction between MDM2 and MDMX that resulted in a reduced efficiency of MDM2 in degrading P53. Of the 26 cases of liposarcoma with elevated P53 expression, 5 were found to have a somatic mutation in the P53 gene. Conclusions: The results suggest that complex dynamic interactions between MDM2 and MDMX proteins may directly affect the cellular levels of P53. This therefore suggests that careful characterization of both these markers will be necessary in tumours when considering in vivo evaluation of novel blocker compounds for MDM proteins, as a therapeutic strategy to restore wild type P53 function

Hospitalization for acute cerebellitis in children affected by varicella: how much does it cost?

Background Chickenpox is a highly contagious airborne disease caused by the varicella zoster virus. It is generally benign and self-limiting, but it may be responsible of life-threatening complications. Acute cerebellitis (AC) is the most common neurological complication and is associated with prolonged hospitalization in the acute phase (HAP). Aim of the study To estimate the costs of AC HAP in children affected by varicella. Materials and methods We retrospectively reviewed the medical records of a pediatric cohort hospitalized for chickenpox AC over a period of 15 years (from October 2003 to October 2018) and we analyzed acute care costs. For any patient the HAP has been calculated. The final value includes cost of hospital accommodation and management at the Pediatric and Infectious Diseases Unit. To this cost, the price of procedures (imaging, laboratory exams, medical and paramedical evaluations) and medical treatments was added. Results In the study period, 856 children had been hospitalized for varicella. Out of them, 65 met a diagnosis of AC and were included in the study. The hospitalization length was of 10 days (range 3-20 days). The median cost of HAP for each patient was of 5366 euro, with an average annual cost of 23,252 euro. The most significant part of HAP is due to the cost of hospital accommodation and management at the Pediatric Infectious Diseases Unit, which was about euro 537.78 for a single day. Discussion Although AC post-varicella is rare, its HAP cost is not negligible resulting in substantial economic burden. Vaccination would have probably prevented varicella and AC complication, avoiding hospitalization. Conclusions Financial studies are important for evaluate the cost saving in order to influence public funding decisions. Further studies are necessary to investigate the economic burden of the disease

Identification of a 2-propanol analogue modulating the non-enzymatic function of indoleamine 2,3-dioxygenase 1

Abstract Indoleamine 2,3 dioxygenase 1 (IDO1) is a metabolic enzyme that catalyzes the conversion of the essential amino acid tryptophan (Trp) into a series of immunoactive catabolites, collectively known as kynurenines. Through the depletion of Trp and the generation of kynurenines, IDO1 represents a key regulator of the immune responses involved in physiologic homeostasis as well as in neoplastic and autoimmune pathologies. The IDO1 enzyme has been described as an important immune checkpoint to be targeted by catalytic inhibitors in the treatment of cancer. In contrast, a defective expression/activity of the enzyme has been demonstrated in autoimmune diseases. Beside its catalytic activity, the IDO1 protein is endowed with an additional function associated with the presence of two immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which, once phosphorylated, bind SHP phosphatases and mediate a long-term immunoregulatory activity of IDO1. Herein, we report the screening of a focused library of molecules bearing a propanol core by a protocol combining microscale thermophoresis (MST) analysis and a cellular assay. As a result, the combined screening identified a 2-propanolol analogue, VIS351, as the first potent activator of the ITIM-mediated function of the IDO1 enzyme. VIS351 displayed a good dissociation constant (Kd = 1.90 μM) for IDO1 and a moderate cellular inhibitor activity (IC50 = 11.463 μM), although it did not show any catalytic inhibition of the recombinant IDO1 enzyme. Because we previously demonstrated that the enzymatic and non-enzymatic (i.e., ITIM-mediated) functions of IDO1 reside in different conformations of the protein, we hypothesized that in the cellular system VIS351 may shift the dynamic conformational balance towards the ITIM-favoring folding of IDO1, resulting in the activation of the signaling rather than catalytic activity of IDO1. We demonstrated that VIS351 activated the ITIM-mediated signaling of IDO1 also in mouse plasmacytoid dendritic cells, conferring those cells an immunosuppressive phenotype detectable in vivo. Thus the manuscript describes for the first time a small molecule as a positive modulator of IDO1 signaling function, paving the basis for an innovative approach to develop first-in-class drugs acting on the IDO1 target

Design, synthesis and biological evaluation of novel bicyclo[1.1.1]pentane-basedx-acidic amino acids as glutamate receptors ligands

A novel series of bicyclo[1.1.1]pentane-based x-acidic amino acids, including (2S)- and (2R)-3-(30-carboxybicyclo[ 1.1.1]pentyl)alanines (8 and 9), (2S)- and (2R)-2-(30-carboxymethylbicyclo[1.1.1]pentyl)glycines (10 and 11), and (2S)- and (2R)-3-(30-phosphonomethylbicyclo[1.1.1]pentyl)glycines (12 and 13), were synthesized and evaluated as glutamate receptor ligands. Among them, (2R)-3-(30-phosphonomethylbicyclo[ 1.1.1]pentyl)glycine (13) showed relatively high affinity and selectivity at the NMDA receptor. The results are also discussed in light of pharmacophoric modelling studies of NMDA agonists and antagonists

Lessons for Remote Post-earthquake Reconnaissance from the 14 August 2021 Haiti Earthquake

On 14th August 2021, a magnitude 7.2 earthquake struck the Tiburon Peninsula in the Caribbean nation of Haiti, approximately 150 km west of the capital Port-au-Prince. Aftershocks up to moment magnitude 5.7 followed and over 1,000 landslides were triggered. These events led to over 2,000 fatalities, 15,000 injuries and more than 137,000 structural failures. The economic impact is of the order of US$1.6 billion. The on-going Covid pandemic and a complex political and security situation in Haiti meant that deploying earthquake engineers from the UK to assess structural damage and identify lessons for future building construction was impractical. Instead, the Earthquake Engineering Field Investigation Team (EEFIT) carried out a hybrid mission, modelled on the previous EEFIT Aegean Mission of 2020. The objectives were: to use open-source information, particularly remote sensing data such as InSAR and Optical/Multispectral imagery, to characterise the earthquake and associated hazards; to understand the observed strong ground motions and compare these to existing seismic codes; to undertake remote structural damage assessments, and to evaluate the applicability of the techniques used for future post-disaster assessments. Remote structural damage assessments were conducted in collaboration with the Structural Extreme Events Reconnaissance (StEER) team, who mobilised a group of local non-experts to rapidly record building damage. The EEFIT team undertook damage assessment for over 2,000 buildings comprising schools, hospitals, churches and housing to investigate the impact of the earthquake on building typologies in Haiti. This paper summarises the mission setup and findings, and discusses the benefits, and difficulties, encountered during this hybrid reconnaissance mission