Drug research, therapy development, and other areas of pharmacology and medicine can benefit from simula- tions and optimization of mathematical models that contain a mathematical description of interactions between systems elements at the cellular, tissue, organ, body, and population level. This approach is the foundation of systems medicine and precision medicine. Here, simulated experiments are performed with computers (in silico) first, and they are then replicated through lab experiments (in vivo or in vitro) or clinical studies. In turn, these experiments and studies can be used to validate or improve the models. This iterative loop of dry and wet lab work is successful when biomedical researchers tightly collaborate with data scientists and modelers. From an educational point of view, the interdisciplinary research in systems biology can be sustained most ef- fectively when specialists have been trained to have both a strong background in the disciplines of biology or modeling and strong communication skills, which make them able to communicate with other specialists. This overview addresses possible interdisciplinary communication gaps. Focusing our attention on biomedical re- searchers, we describe the reasons for using modeling and ways to collaborate with modelers, including their needs for specific biological expertise and data. This review includes an introduction to the principles of several widely used mechanistic modeling methods, focusing on their areas of applicability as well as their limitations. A potential complementary role of machine-learning methods in the development of mechanistic models is also discussed. The descriptions of the methods also include links to corresponding modeling software tools as well as practical examples of their application. Finally, we also explicitly address different aspects of multiscale mod- eling approaches that allow a more complete and holistic perspective of the human body.

Background: The aim of a recent research project was the investigation of the mechanisms involved in the onset of type 2 diabetes in the absence of familiarity. This has led to the development of a computational model that recapitulates the aetiology of the disease and simulates the immunological and metabolic alterations linked to type-2 diabetes subjected to clinical, physiological, and behavioural features of prototypical human individuals. Results: We analysed the time course of 46,170 virtual subjects, experiencing different lifestyle conditions. We then set up a statistical model able to recapitulate the simulated outcomes. Conclusions: The resulting machine learning model adequately predicts the synthetic dataset and can, therefore, be used as a computationally-cheaper version of the detailed mathematical model, ready to be implemented on mobile devices to allow self-assessment by informed and aware individuals. The computational model used to generate the dataset of this work is available as a web-service at the following address: http://kraken.iac.rm.cnr.it/T2DM.

Unsupervised learning approaches are frequently employed to stratify patients into clinically relevant subgroups and to identify biomarkers such as disease-associated genes. However, clustering and biclustering techniques are oblivious to the functional relationship of genes and are thus not ideally suited to pinpoint molecular mechanisms along with patient subgroups.We developed the network-constrained biclustering approach BiCoN (Biclustering Constrained by Networks) which (i) restricts biclusters to functionally related genes connected in molecular interaction networks and (ii) maximizes the difference in gene expression between two subgroups of patients. This allows BiCoN to simultaneously pinpoint molecular mechanisms responsible for the patient grouping. Network-constrained clustering of genes makes BiCoN more robust to noise and batch effects than typical clustering and biclustering methods. BiCoN can faithfully reproduce known disease subtypes as well as novel, clinically relevant patient subgroups, as we could demonstrate using breast and lung cancer datasets. In summary, BiCoN is a novel systems medicine tool that combines several heuristic optimization strategies for robust disease mechanism extraction. BiCoN is well-documented and freely available as a python package or a web interface.PyPI package: https://pypi.org/project/biconhttps://exbio.wzw.tum.de/biconSupplementary data are available at Bioinformatics online.

Invasive species cause huge amounts of environmental, economic, social and cultural damage in Europe and worldwide. Improving measures to control them is an ongoing challenge, and mathematical modeling and optimization are becoming increasingly popular as a tool to assist management (1; 2; 4). We analyse an optimal control model for the control of invasive species which aims to find the best temporal resource allocation strategy for the population reduction, under a budget constraint (3). We derive the optimality system in the state and control variables and we use the phase-space analysis to provide qualitative insights about the behaviour of the optimal solution. We pay special attention to the nature of the optimal trajectories in long time intervals and the explore the Turnpike property of the problem (5). Finally, we introduce a numerical scheme for the solution of the state-costate nearly-Hamiltonian system, based on exponential-Lawson symplectic Runge-Kutta schemes applied in a forward-backward procedure.

We analyse the lower ionosphere disturbances in the time period around the Mw 5.4 Kraljevo earthquake (EQ), which occurred on 3 November 2010 in Serbia. The results presented herein are based on analysis of the amplitudes of three VLF signals emitted in Italy, UK, and Germany and recorded in Serbia whose variations primarily result from changes in the electrical properties of the lower ionosphere at a distance more than 120 km from the epicentre of the EQ. The primary goals of this study are to reveal specific variations as possible EQ precursors as well as disturbances following the EQ event recorded by the observational equipment, and to investigate whether better time resolution data can affect the analysis of the lower ionosphere disturbances possibly connected to the EQ. We process two sets of data with sampling periods of 1 min and 0.1 s. As the first analysis indicates the absence of long-term disturbances, which can clearly be connected to the Kraljevo EQ, our attention is focused on the study of short-period noise amplitude and the excitation and attenuation of acoustic and gravity waves in the lower ionosphere. Processing of the amplitudes of three VLF signals during the nights of the four EQs with magnitude greater than 4 that occurred in Serbia, as well as EQs of all magnitudes during the three days of 3, 4, and 9 November, indicates that the detected ICV radio signal noise amplitude reduction starting before the Kaljevo EQ is also observed for 13 additional EQ events near the signal propagation path, and occurred during all three days (for all EQs with magnitude greater than 4 and several less intensive events). Excitation and attenuation of acoustic waves are also found for all these EQ events with a magnitude greater than 4.

This study describes a semi-empirical model developed to estimate volumetric soil moisture (theta v) in bare soils during the dry season (March-May) using C-band (5.42 GHz) synthetic aperture radar (SAR) imagery acquired from the Sentinel-1 European satellite platform at a 20 m spatial resolution. The semi-empirical model was developed using backscatter coefficient (sigma degrees dB) and in situ soil moisture collected from Siruguppa taluk (sub-district) in the Karnataka state of India. The backscatter coefficients sigma VV0 and sigma VH0 were extracted from SAR images at 62 geo-referenced locations where ground sampling and volumetric soil moisture were measured at a 10 cm (0-10 cm) depth using a soil core sampler and a standard gravimetric method during the dry months (March-May) of 2017 and 2018. A linear equation was proposed by combining sigma VV0 and sigma VH0 to estimate soil moisture. Both localized and generalized linear models were derived. Thirty-nine localized linear models were obtained using the 13 Sentinel-1 images used in this study, considering each polarimetric channel Co-Polarization (VV) and Cross-Polarization (VH) separately, and also their linear combination of VV + VH. Furthermore, nine generalized linear models were derived using all the Sentinel-1 images acquired in 2017 and 2018; three generalized models were derived by combining the two years (2017 and 2018) for each polarimetric channel; and three more models were derived for the linear combination of sigma VV0 and sigma VH0. The above set of equations were validated and the Root Mean Square Error (RMSE) was 0.030 and 0.030 for 2017 and 2018, respectively, and 0.02 for the combined years of 2017 and 2018. Both localized and generalized models were compared with in situ data. Both kind of models revealed that the linear combination of sigma VV0 + sigma VH0 showed a significantly higher R-2 than the individual polarimetric channels.

This work presents a methodology to monitor the dynamic behaviour of tall metallic towers based on ground-based radar interferometry, and apply it to the case of telecommunication towers. Ground-based radar displacement measurements of metallic towers are acquired without installing any Corner Reflector (CR) on the structure. Each structural element of the tower is identified based on its range distance with respect to the radar. The interferometric processing of a time series of radar profiles is used to measure the vibration frequencies of each structural element and estimate the amplitude of its oscillation. A methodology is described to visualize the results and provide a useful tool for the real-time analysis of the dynamic behaviour of metallic towers.

The Global Navigation Satellite System (GNSS) meteorology contribution to the comprehension of the Earth's atmosphere's global and regional variations is essential. In GNSS processing, the zenith wet delay is obtained using the difference between the zenith total delay and the zenith hydrostatic delay. The zenith wet delay can also be converted into precipitable water vapor by knowing the atmospheric weighted mean temperature profiles. Improving the accuracy of the zenith hydrostatic delay and the weighted mean temperature, normally obtained using modeled surface meteorological parameters at coarse scales, leads to a more accurate and precise zenith wet delay estimation, and consequently, to a better precipitable water vapor estimation. In this study, we developed an hourly global pressure and temperature (HGPT) model based on the full spatial and temporal resolution of the new ERA5 reanalysis produced by the European Centre for Medium-Range Weather Forecasts (ECMWF). The HGPT model provides information regarding the surface pressure, surface air temperature, zenith hydrostatic delay, and weighted mean temperature. It is based on the time-segmentation concept and uses the annual and semi-annual periodicities for surface pressure, and annual, semi-annual, and quarterly periodicities for surface air temperature. The amplitudes and initial phase variations are estimated as a periodic function. The weighted mean temperature is determined using a 20-year time series of monthly data to understand its seasonality and geographic variability. We also introduced a linear trend to account for a global climate change scenario. Data from the year 2018 acquired from 510 radiosonde stations downloaded from the National Oceanic and Atmospheric Administration (NOAA) Integrated Global Radiosonde Archive were used to assess the model coefficients. Results show that the GNSS meteorology, hydrological models, Interferometric Synthetic Aperture Radar (InSAR) meteorology, climate studies, and other topics can significantly benefit from an ERA5 full-resolution model.

This article presents a methodology for the monitoring of tall structures based on the joint use of a terrestrial laser scanner (TLS), configured in line scanner mode, and a ground-based real aperture radar (GB-RAR) interferometer. The methodology provides both natural frequencies and oscillation amplitudes of tall structures. Acquisitions of the surface of the tall structure are performed by the TLS with a high sampling rate: each line scan provides an instantaneous longitudinal section. By interpolating the points of each line, oscillation profiles are estimated with a much better precision than each single point. The amplitude and frequency of the main oscillation mode of the whole structure are derived from the TLS profiles. GB-RAR measurements are used to measure the vibration frequencies of higher oscillation modes which are not caught by the TLS due its lower precision in the measurement of displacements. In contrast, the high spatial resolution of TLS measurements provides an accurate description of oscillation amplitude along the tower, which cannot be caught by the GB-RAR, due to its poorer spatial resolution. TLS and GB-RAR acquisitions are simultaneous. The comparison with the analytical solution for oscillation modes demonstrates that the proposed methodology can provide useful information for structural health monitoring (SHM). The methodology does not require the use of targets on the structure and it can be applied during its normal use, even in presence of dynamic loads (wind, traffic vibrations, etc.). A test was carried out on a wind tower where the synergistic use of TLS and GB-RAR made it possible to fully describe the spectral properties of the tower and at the same time measure the amplitude of the first oscillation mode along the tower with a high spatial resolution.

Global mean sea level rise associated with global warming has a major impact on coastal areas and represents one of the significant natural hazards. The Asia-Pacific region, which has the highest concentration of human population in the world, represents one of the larger areas on Earth being threatened by the rise of sea level. Recent studies indicate a global sea level of 3.2 mm/yr as measured from 20 years of satellite altimetry. The combined effect of sea level rise and local land subsidence, can be overwhelming for coastal areas. The Synthetic Aperture Radar (SAR) interferometry technique is used to process a time series of TerraSAR-X images and estimate the land subsidence in the urban area of Singapore. Interferometric SAR (InSAR) measurements are merged to the Representative Concentration Pathway (RCP) 4.5 and RCP 8.5 sea-level rise scenarios to identify projected inundated areas and provide a map of flood vulnerability. Subsiding rates larger than 5 mm/year are found near the shore on the low flat land, associated to areas recently reclaimed or built. The projected flooded map of Singapore are provided for different sea-level rise scenarios. In this study, we show that local land subsidence can increase the flood vulnerability caused by sea level rise by 2100 projections. This can represent an increase of 25% in the flood area in the central area of Singapore for the RCP4.5 scenario.

In this article, a methodology to retrieve the precipitable water vapor (PWV) from a differential interferometric time series is presented. We used external data provided by atmospheric weather models (e.g., ERA-Interim reanalysis) to constrain the initial state and by Global Navigation Satellite System (GNSS) to phase ambiguities elimination introduced by phase unwrapping algorithm. An iterative least-square is then used to solve the optimization problem. We applied the presented methodology to two time series of differential PWV maps estimated from synthetic aperture radar (SAR) images acquired by the Sentinel-1A, over the southwest part of the Appalachian Mountains (USA). The results were validated using an independent GNSS data set and also compared with atmospheric weather prediction data. The GNSS PWV observations show a strong correlation with the estimated PWV maps with a root-mean-square error less than 1 mm. These results are very encouraging, particularly for the meteorology community, providing crucial information to assimilate into numerical weather models and potentially improve the forecasts.

We investigate the influence of the perturbed (by a solar X-ray flare) ionospheric D-region on the global navigation satellite systems (GNSS) and synthetic aperture radar (SAR) signals. We calculate a signal delay in the D-region based on the low ionospheric monitoring by very-low-frequency (VLF) radio waves. The results show that the ionospheric delay in the perturbed D-region can be important and, therefore, should be taken into account in modeling the ionospheric influence on the GNSS and SAR signal propagation and in calculations relevant for space geodesy. This conclusion is significant because numerous existing models ignore the impact of this ionospheric part on the GNSS and SAR signals due to its small electron density which is true only in quiet conditions and can result in significant errors in space geodesy during intensive ionospheric disturbances.

Online social networks are nowadays one of the most effective and widespread tools used to share information. In addition to being employed by individuals for communicating with friends and acquaintances, and by brands for marketing and customer service purposes, they constitute a primary source of daily news for a significant number of users. Unfortunately, besides legit news, social networks also allow to effectively spread inaccurate or even entirely fabricated ones. Also due to sensationalist claims, misinformation can spread from the original sources to a large number of users in a very short time, with negative consequences that, in extreme cases, can even put at risk public safety or health. In this work we discuss and propose methods to limit the spread of misinformation over online social networks. The issue is split in two separate sub-problems. We first aim to identify the most probable sources of the misinformation among the subset of users that have been reached by it. In the second step, assuming to know the misinformation sources, we want to locate a minimum number of monitors (that is, entities able to identify and block false information) in the network in order to prevent that the misinformation campaign reaches some "critical" nodes while maintaining low the number of nodes exposed to the infection. For each of the two issues, we provide both heuristics and mixed integer programming formulations. To verify the quality and efficiency of our suggested solutions, we conduct experiments on several real-world networks. The results of this extensive experimental phase validate our heuristics as effective tools to contrast the spread of misinformation in online social networks. Regarding the source identification step, our approach showed success rates above 80% in most of the considered settings, and above 60% in almost all of them. With respect to the second issue, our heuristic proved to be able to obtain solutions that exceeded (in terms of number of required monitors) the ones obtained through our MILP-based approach of more than 20% in only few test scenarios. Our heuristics for both problems also proved to outperform significantly some previously proposed algorithms.

In this paper we introduce and study the Knapsack Problem with Forfeits. With respect to the classical definition of the problem, we are given a collection of pairs of items, such that the inclusion of both in the solution involves a reduction of the profit. We propose a mathematical formulation and two heuristic algorithms for the problem. Computational results validate the effectiveness of our approaches.

Science et BD, comme sauvagarder la rigueur en situations extrêmes

L'Intelligenza Artificiale nasce come disciplina negli anni Cinquanta e negli ultimi anni ha avuto una vera e propria esplosione: nei cellulari, nei computer, nell'analisi delle immagini biomediche e nel riconoscimento del linguaggio naturale, tra le tantissime applicazioni. Ma come si è arrivati a questo? Cosa ci si aspetta? Questa storia di Diego Cajelli disegnata da Andrea Scoppetta è nata grazie alla collaborazione con l'AIxIA (Associazione Italiana per l'Intelligenza Artificiale) e ci parla di N3well. Che è anche una macchina.

Impossibile sopravvalutare l'importanza di Leonardo Pisano, detto "il Fibonacci". Agli inizi del XIII secolo il suo Liber Abbaci porta in Occidente i numeri indo-arabi e la notazione posizionale che usiamo ancora oggi. Descrive inoltre numerosi problemi pratici di grande importanza per i mercanti dell'epoca, spiegando come risolverli con "i nuovi numeri" e i raffinati metodi di calcolo (oggi diremmo "algoritmi") da lui importati. Negli 850 anni dalla nascita, Comics&Science lo ricorda in collaborazione con il Museo degli Strumenti per il Calcolo, l'Università di Pisa, e naturalmente con Il libro di Leonardo, la storia a fumetti che Claudia Flandoli ambienta nella Pisa dell'epoca che accoglie il suo Figliol Prodigo, carico di entusiamo e nuove conoscenze.

SARS-CoV-2 is highly contagious, rapidly turned into a pandemic, and is causing a relevant number of critical to severe life-threatening COVID-19 patients. However, robust statistical studies of a large cohort of patients, potentially useful to implement a vaccination campaign, are rare. We analyzed public data of about 19,000 patients for the period 28 February to 15 May 2020 by several mathematical methods. Precisely, we describe the COVID-19 evolution of a number of variables that include age, gender, patient's care location, and comorbidities. It prompts consideration of special preventive and therapeutic measures for subjects more prone to developing life-threatening conditions while affording quantitative parameters for predicting the effects of an outburst of the pandemic on public health structures and facilities adopted in response. We propose a mathematical way to use these results as a powerful tool to face the pandemic and implement a mass vaccination campaign. This is done by means of priority criteria based on the influence of the considered variables on the probability of both death and infection.

We report on the Covid-19 epidemic in Italy in relation to the extraordinary measures implemented by the Italian Government between the 24th of February and the 12th of March. We analysed the Covid-19 cumulative incidence (CI) using data from the 1st to the 31st of March. We estimated that in Lombardy, the worst hit region in Italy, the observed Covid-19 CI diverged towards values lower than the ones expected in the absence of government measures approximately 7-10 days after the measures implementation. The Covid-19 CI growth rate peaked in Lombardy the 22nd of March and in other regions between the 24th and the 27th of March. The CI growth rate peaked in 87 out of 107 Italian provinces on average 13.6 days after the measures implementation. We projected that the CI growth rate in Lombardy should substantially slow by mid-May 2020. Other regions should follow a similar pattern. Our projections assume that the government measures will remain in place during this period. The evolution of the epidemic in different Italian regions suggests that the earlier the measures were taken in relation to the stage of the epidemic, the lower the total cumulative incidence achieved during this epidemic wave. Our analyses suggest that the government measures slowed and eventually reduced the Covid-19 CI growth where the epidemic had already reached high levels by mid-March (Lombardy, Emilia-Romagna and Veneto) and prevented the rise of the epidemic in regions of central and southern Italy where the epidemic was at an earlier stage in mid-March to reach the high levels already present in northern regions. As several governments indicate that their aim is to "push down" the epidemic curve, the evolution of the epidemic in Italy supports the WHO recommendation that strict containment measures should be introduced as early as possible in the epidemic curve.

In this paper we establish the higher differentiability of solutions to the Dirichlet problem {div(A(x,Du))+b(x)u(x)=fin?u=0on??under a Sobolev assumption on the partial map x-> A(x, ?). The novelty here is that we take advantage from the regularizing effect of the lower order term to deal with bounded solutions.