Anti-IL5 Drugs in COVID-19 Patients: Role of Eosinophils in SARS-CoV-2-Induced Immunopathology

SARS-CoV-2 infection stimulates a complex activation of the immune system. Eosinophils belong to the host’s defense equipment against respiratory viruses. In the first phase of the infection, eosinophils contribution is probably appropriate and beneficial, as they facilitate the suppression of the viral replication. However, in severe COVID-19 patients, during the second and third phases of the disease, eosinophils may participate in a maladaptive immune response and directly contribute to immunopathology. In fact, in severe patients, the immune response is prevalently T helper 1 type, but T helper 2 is also present. Eosinophils’ expansion and activation are stimulated by Type 2 cytokines, especially IL-5. Moreover, bronchial asthma, in which eosinophils play a central role, seems not to be a major risk factor for severe COVID-19. Among possible explanations, asthmatic patients are often treated with corticosteroids, which have been demonstrated to reduce the progression to critical COVID-19 in hospitalized patients. In addition to steroids, severe asthmatic patients are currently treated with biological drugs that target Type 2 immune response. Because IL-5 is necessary for the growth, survival, and activation of eosinophils, IL-5 inhibitors, such as mepolizumab, decrease the peripheral blood count of eosinophils, but do not influence eosinophils activation in the airway. In severe COVID-19 patients, the blockade of eosinophils’ activation might contrast harmful immunity

Dynamic Assessment of Personal Exposure to Air Pollution for Everyone: a Smartphone-Based Approach

Abstract. In Epidemiology, exposure assessment is the process of measuring or estimating the intensity of human exposures to an environmental agent such as air pollution. Healthcare agencies typically take into consideration yearly averaged pollution values and apply them to all citizens, in risk models. However distinct parts of cities can have significantly different levels of pollution and individual habits can influence exposure, too. Consequently, in epidemiology and public health, there is an increasing interest for personal exposure assessment, i.e. the capability of measuring the exposure of individuals. Within the EU H2020 PULSE project, an innovative mechanism for the individual and dynamic assessment of exposure to air pollution has been implemented. The present paper illustrates its technological and scientific components. The system has already been deployed to several pilot cities of the project and Pavia, Italy, has been the first one. In that city several hundreds of tracks have already been acquired and processed. Therefore, the paper thoroughly illustrates the assessment procedure with examples

Metadynamics Simulations Distinguish Short- and Long-Residence-Time Inhibitors of Cyclin-Dependent Kinase 8.

The duration of drug efficacy in vivo is a key aspect primarily addressed during the lead optimization phase of drug discovery. Hence, the availability of robust computational approaches that can predict the residence time of a compound at its target would accelerate candidate selection. Nowadays the theoretical prediction of this parameter is still very challenging. Starting from methods reported in the literature, we set up and validated a new metadynamics (META-D)-based protocol that was used to rank the experimental residence times of 10 arylpyrazole cyclin-dependent kinase 8 (CDK8) inhibitors for which target-bound X-ray structures are available. The application of reported methods based on the detection of the escape from the first free energy well gave a poor correlation with the experimental values. Our protocol evaluates the energetics of the whole unbinding process, accounting for multiple intermediates and transition states. Using seven collective variables (CVs) encoding both roto-translational and conformational motions of the ligand, a history-dependent biasing potential is deposited as a sum of constant-height Gaussian functions until the ligand reaches an unbound state. The time required to achieve this state is proportional to the integral of the deposited potential over the CV hyperspace. Average values of this time, for replicated META-D simulations, provided an accurate classification of CDK8 inhibitors spanning short, medium, and long residence times

Metadynamics for perspective drug design: Computationally driven synthesis of new protein-protein interaction inhibitors targeting the EphA2 receptor

Metadynamics (META-D) is emerging as a powerful method for the computation of the multidimensional freeenergy surface (FES) describing the protein-ligand binding process. Herein, the FES of unbinding of the antagonist N-(3α-hydroxy-5β-cholan-24-oyl)-L-β-homotryptophan (UniPR129) from its EphA2 receptor was reconstructed by META-D simulations. The characterization of the free-energy minima identified on this FES proposes a binding mode fully consistent with previously reported and new structure-activity relationship data. To validate this binding mode, new N-(3α-hydroxy-5β-cholan-24-oyl)-L-β-homotryptophan derivatives were designed, synthesized, and tested for their ability to displace ephrin-A1 from the EphA2 receptor. Among them, two antagonists, namely compounds 21 and 22, displayed high affinity versus the EphA2 receptor and resulted endowed with better physicochemical and pharmacokinetic properties than the parent compound. These findings highlight the importance of free-energy calculations in drug design, confirming that META-D simulations can be used to successfully design novel bioactive compounds

Transfer Learning for Urban Landscape Clustering and Correlation with Health Indexes

Within the EU-funded Pulse project, we are implementing a data analytic platform designed to provide public health decision makers with advanced approaches to jointly analyze maps and geospatial information with health care data and air pollution measurements. In this paper we describe a component of such platform, designed to couple deep learning analysis of geospatial images of cities and some healthcare and behavioral indexes collected by the 500 cities US project, showing that, in New York City, urban landscape significantly correlates with the access to healthcare services

Spatial Enablement to Support Environmental, Demographic, Socioeconomics, and Health Data Integration and Analysis for Big Cities: A Case Study With Asthma Hospitalizations in New York City

The percentage of the world's population living in urban areas is projected to increase in the next decades. Big cities are heterogeneous environments in which socioeconomic and environmental differences among the neighborhoods are often very pronounced. Each individual, during his/her life, is constantly subject to a mix of exposures that have an effect on their phenotype but are frequently difficult to identify, especially in an urban environment. Studying how the combination of environmental and socioeconomic factors which the population is exposed to influences pathological outcomes can help transforming public health from a reactive to a predictive system. Thanks to the application of state-of-the-art spatially enabled methods, patients can be stratified according to their characteristics and the geographical context they live in, optimizing healthcare processes and the reducing its costs. Some public health studies focusing specifically on urban areas have been conducted, but they usually consider a coarse spatial subdivision, as a consequence of scarce availability of well-integrated data regarding health and environmental exposure at a sufficient level of granularity to enable meaningful statistical analyses. In this paper, we present an application of highly fine-grained spatial resolution methods to New York City data. We investigated the link between asthma hospitalizations and a combination of air pollution and other environmental and socioeconomic factors. We first performed an explorative analysis using spatial clustering methods that shows that asthma is related to numerous factors whose level of influence varies considerably among neighborhoods. We then performed a Geographically Weighted Regression with different covariates and determined which environmental and socioeconomic factors can predict hospitalizations and how they vary throughout the city. These methods showed to be promising both for visualization and analysis of demographic and epidemiological urban dynamics, that can be used to organize targeted intervention and treatment policies to address the single citizens considering the factors he/she is exposed to. We found a link between asthma and several factors such as PM2.5, age, health insurance coverage, race, poverty, obesity, industrial areas, and recycling. This study has been conducted within the PULSE project, funded by the European Commission, briefly presented in this paper

Evaluation of vacuum packaging for extending the shelf life of Sardinian fermented sausage

Salsiccia sarda or Sardinian fermented sausage is a traditional dry-fermented sausage included in the list of traditional food products of Sardinia (Italy). At the request of some producing plants, the possibility of extending the shelf life of the vacuum-packed product up to 120 days was evaluated. Manufacturing of 90 samples, representing 3 different batches of Sardinian fermented sausage was carried out in two producing plants (A and B). In the packaged product and subsequently every 30 days for four months (T0, T30, T60, T120), the following analyses were conducted on all samples: physicochemical characteristics, total aerobic mesophilic count, Enterobacteriaceae count, detection of Listeria monocytogenes, Salmonella spp., mesophilic lactic acid bacteria, and coagulase-positive Staphylococci. Moreover, surfaces in contact and surfaces not in contact with food were sampled in both producing plants. Sensory profile analysis was also performed for every analysis time. At the end of the extended shelf life, pH values were equal to 5.90±0.11 (producing plant A) and 5.61±0.29 (producing plant B). Water activity mean values at T120 were 0.894±0.02 (producing plant A) and 0.875±0.01 (producing plant B). L. monocytogenes was detected in 73.3% (33/45) of the samples from producing plant A, with mean levels of 1.12±0.76 log10 CFU/g. In producing plant B, L. monocytogenes was never detected. Enterobacteriaceae were detected in 91.1% (41/45) of samples in producing plant A with mean values of 3.15±1.21 log10 CFU/g, and in 35.5% (16/45) samples in producing plant B samples with mean values of 0.72±0.86 log10 CFU/g. Salmonella and Staphylococcus aureus were never detected. Regarding environmental samples, the sites that were most contaminated by L. monocytogenes were the bagging table (contact surface) and processing room floor drains (non-contact surface) with a prevalence of 50% each (8/16 positive samples for both sampling sites). Sensory analysis results showed that at T30 the overall sensory quality was at its highest; moreover, the visual-tactile aspect, the olfactory characteristics, the gustatory aspects, and the texture showed significant differences in samples throughout the shelf life, with a decreased intensity at 120 days of storage. Overall, the quality and sensory acceptance of the vacuum-packed Sardinian fermented sausage were not affected until 120 days of shelf-life. However, the possible contamination by L. monocytogenes calls attention to the hygienic management of the entire technological process. The environmental sampling was confirmed as a useful verification tool during control

Uniparental markers in Italy reveal a sex-biased genetic structure and different historical strata

University of Adelaide Genographic Consortium contributers: Christina J. Adler, Alan Cooper, Clio S. I. Der Sarkissian, Wolfgang Haak.Located in the center of the Mediterranean landscape and with an extensive coastal line, the territory of what is today Italy has played an important role in the history of human settlements and movements of Southern Europe and the Mediterranean Basin. Populated since Paleolithic times, the complexity of human movements during the Neolithic, the Metal Ages and the most recent history of the two last millennia (involving the overlapping of different cultural and demic strata) has shaped the pattern of the modern Italian genetic structure. With the aim of disentangling this pattern and understanding which processes more importantly shaped the distribution of diversity, we have analyzed the uniparentally-inherited markers in ~900 individuals from an extensive sampling across the Italian peninsula, Sardinia and Sicily. Spatial PCAs and DAPCs revealed a sex-biased pattern indicating different demographic histories for males and females. Besides the genetic outlier position of Sardinians, a North West–South East Y-chromosome structure is found in continental Italy. Such structure is in agreement with recent archeological syntheses indicating two independent and parallel processes of Neolithisation. In addition, date estimates pinpoint the importance of the cultural and demographic events during the late Neolithic and Metal Ages. On the other hand, mitochondrial diversity is distributed more homogeneously in agreement with older population events that might be related to the presence of an Italian Refugium during the last glacial period in Europe.Alessio Boattini, Begoña Martinez-Cruz, Stefania Sarno, Christine Harmant, Antonella Useli, Paula Sanz, Daniele Yang-Yao, Jeremy Manry, Graziella Ciani, Donata Luiselli, Lluis Quintana- Murci, David Comas, Davide Pettener, the Genographic Consortiu