Preclinical discovery and development of fingolimod for the treatment of multiple sclerosis

ABSTRACTIntroduction: Fingolimod, the first oral disease-modifying treatment (DMT) in multiple sclerosis (MS), is a sphingosine 1-phosphate receptor (S1PR) ligand. Approved in 2010, fingolimod has ..

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

Combining remote sensing techniques and field surveys for post‑earthquake reconnaissance missions

Remote reconnaissance missions are promising solutions for the assessment of earthquake induced structural damage and cascading geological hazards. Space-borne remote sensing can complement in-field missions when safety and accessibility concerns limit post-earthquake operations on the ground. However, the implementation of remote sensing techniques in post-disaster missions is limited by the lack of methods that combine different techniques and integrate them with field survey data. This paper presents a new approach for rapid post-earthquake building damage assessment and landslide mapping, based on Synthetic Aperture Radar (SAR) data. The proposed texture-based building damage classification approach exploits very high resolution post-earthquake SAR data integrated with building survey data. For landslide mapping, a backscatter intensity-based landslide detection approach, which also includes the separation between landslides and flooded areas, is combined with optical-based manual inventories. The approach was implemented during the joint Structural Extreme Event Reconnaissance, GeoHazards International and Earthquake Engineering Field Investigation Team mission that followed the 2021 Haiti Earthquake and Tropical Cyclone Grace

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

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

Combining remote sensing techniques and field surveys for post-earthquake reconnaissance missions

Copyright © The Author(s) 2023. Remote reconnaissance missions are promising solutions for the assessment of earthquake-induced structural damage and cascading geological hazards. Space-borne remote sensing can complement in-field missions when safety and accessibility concerns limit post-earthquake operations on the ground. However, the implementation of remote sensing techniques in post-disaster missions is limited by the lack of methods that combine different techniques and integrate them with field survey data. This paper presents a new approach for rapid post-earthquake building damage assessment and landslide mapping, based on Synthetic Aperture Radar (SAR) data. The proposed texture-based building damage classification approach exploits very high resolution post-earthquake SAR data integrated with building survey data. For landslide mapping, a backscatter intensity-based landslide detection approach, which also includes the separation between landslides and flooded areas, is combined with optical-based manual inventories. The approach was implemented during the joint Structural Extreme Event Reconnaissance, GeoHazards International and Earthquake Engineering Field Investigation Team mission that followed the 2021 Haiti Earthquake and Tropical Cyclone Grace.VM was supported by the Dutch Research Council (NWO), project OCENW.XS5.114. StEER and GHI Data collection was supported by the National Science Foundation (NSF) under Grant CMMI-1841667, the U.S. Geological Survey (USGS) and the U.S. Agency for International Development (USAID), under USGS Cooperative Agreement No. G21AC10343-00 and USAID Award AID-OFDA-T-16-00001, under lead investigator Janise Rodgers

First Test Results of the Trans-Impedance Amplifier Stage of the Ultra-fast HPSoC ASIC

We present the first results from the HPSoC ASIC designed for readout of Ultra-fast Silicon Detectors. The 4-channel ASIC manufactured in 65 nm CMOS by TSMC has been optimized for 50 um thick AC-LGAD. The evaluation of the analog front end with \b{eta}-particles impinging on 3x3 AC-LGAD arrays (500 um pitch, 200x200 um2 metal) confirms a fast output rise time of 600 ps and good timing performance with a jitter of 45 ps. Further calibration experiments and TCT laser studies indicate some gain limitations that are being investigated and are driving the design of the second-generation pre-amplification stages to reach a jitter of 15 ps.Comment: 7 pages, 6 figure

Dancing With Parkinson's Disease: The SI-ROBOTICS Study Protocol

Introduction: Parkinson's disease (PD) is one of the most frequent causes of disability among older people, characterized by motor disorders, rigidity, and balance problems. Recently, dance has started to be considered an effective exercise for people with PD. In particular, Irish dancing, along with tango and different forms of modern dance, may be a valid strategy to motivate people with PD to perform physical activity. The present protocol aims to implement and evaluate a rehabilitation program based on a new system called “SI-ROBOTICS,” composed of multiple technological components, such as a social robotic platform embedded with an artificial vision setting, a dance-based game, environmental and wearable sensors, and an advanced AI reasoner module. Methods and Analysis: For this study, 20 patients with PD will be recruited. Sixteen therapy sessions of 50 min will be conducted (two training sessions per week, for 8 weeks), involving two patients at a time. Evaluation will be primarily focused on the acceptability of the SI-ROBOTICS system. Moreover, the analysis of the impact on the patients' functional status, gait, balance, fear of falling, cardio-respiratory performance, motor symptoms related to PD, and quality of life, will be considered as secondary outcomes. The trial will start in November 2021 and is expected to end by April 2022. Discussions: The study aims to propose and evaluate a new approach in PD rehabilitation, focused on the use of Irish dancing, together with a new technological system focused on helping the patient perform the dance steps and on collecting kinematic and performance parameters used both by the physiotherapist (for the evaluation and planning of the subsequent sessions) and by the system (to outline the levels of difficulty of the exercise). Ethics and Dissemination: The study was approved by the Ethics Committee of the IRCCS INRCA. It was recorded in ClinicalTrials.gov on the number NCT05005208. The study findings will be used for publication in peer-reviewed scientific journals and presentations in scientific meetings