Computational Models for Clinical Applications in Personalized Medicine—Guidelines and Recommendations for Data Integration and Model Validation

The future development of personalized medicine depends on a vast exchange of data from different sources, as well as harmonized integrative analysis of large-scale clinical health and sample data. Computational-modelling approaches play a key role in the analysis of the underlying molecular processes and pathways that characterize human biology, but they also lead to a more profound understanding of the mechanisms and factors that drive diseases; hence, they allow personalized treatment strategies that are guided by central clinical questions. However, despite the growing popularity of computational-modelling approaches in different stakeholder communities, there are still many hurdles to overcome for their clinical routine implementation in the future. Especially the integration of heterogeneous data from multiple sources and types are challenging tasks that require clear guidelines that also have to comply with high ethical and legal standards. Here, we discuss the most relevant computational models for personalized medicine in detail that can be considered as best-practice guidelines for application in clinical care. We define specific challenges and provide applicable guidelines and recommendations for study design, data acquisition, and operation as well as for model validation and clinical translation and other research areas

Detection and Investigation of Atypical Porcine Pestivirus within a Breed-to-Finish Farm and Off-Site Nursery and Finisher Locations

Atypical porcine pestivirus (APPV) has been associated with congenital tremors (CT) and splay leg (SL) in piglets of infected dams. The major cost of this virus is the increased pre-weaning mortality due to CT or SL interfering with the piglet’s ability to nurse and move around the farrowing stall. A commercial farrow-to-finish farm with replacement gilts coming from an off-site genetic multiplier farm, and semen delivery from a commercial boar stud began to see an increase of CT and SL in the farrowing room in early 2020. Diagnostics on clinically affected pigs’ samples identified APPV RNA and no other suspected pathogen. At this point, the origin of the virus and means of introduction into the farm was unknown since the farm had no previous clinical cases of CT or SL prior to this investigation. The two hypothesized routes were the introduction of replacement gilts or incoming semen doses. Therefore, the objectives of this investigation were to determine the prevalence of clinical APPV cases at the farrow-to-finish farm, understand the route of introduction of APPV into the farrowto- finish farm, and understand the prevalence of APPV viremia within a population of offspring from a gilt multiplication farm through an off-site nursery and finisher barn. Farrowing records from the farm were analyzed for the presence of CT or SL and parities of females with affected litters. Blood samples were collected at two different times from the new group of replacement gilts and maternal barrows at the isolation nursery barn. Serum and oral fluids were collected from the same pigs at an off-site finisher barn to determine APPV persistence. The APPV sequencing was conducted on a serum sample from a gilt housed at the isolation nursery intended as a replacement gilt for the farrow-to-finish farm, semen dose utilized at the farrow-to-finish farm, and serum of a clinically affected piglet in the farrowing room of the farrow-to-finish farm. Overall, the prevalence of affected litters within batch farrowing groups ranged from 0 to 31%. The prevalence of APPV within samples pooled by pens (5 pigs) ranged from 37.5 to 77.5%, while individual prevalence ranged from 20 to 40%. When followed to the finisher, the same group of pigs had an APPV prevalence in serum ranging from 0 to 26%, while oral fluid prevalence was 100%. Sequencing results indicated that the virus circulating in clinically affected piglets was the most similar to an incoming semen dose. In summary, introduction of APPV into a naïve herd is associated with an increase in clinical CT and SL. While APPV is present in herds previously exposed to APPV, the APPV RNA remains detectable in serum and oral fluids with no clinical disease. To decrease the chance of infection to a naïve herd, quarantines should be implemented for all introductions. Additionally, semen should be screened for APPV presence if there is a recent onset of clinically affected piglets with CT or SL with no other explanation. The APPV RNA was detected in group oral fluids, suggesting the technique may be used to screen incoming animals

Continuum Halos in Nearby Galaxies -- an EVLA Survey (CHANG-ES) -- I: Introduction to the Survey

We introduce a new survey to map the radio continuum halos of a sample of 35 edge-on spiral galaxies at 1.5 GHz and 6 GHz in all polarization products. The survey is exploiting the new wide bandwidth capabilities of the Karl G. Jansky Very Large Array (i.e. the Expanded Very Large Array, or EVLA) in a variety of array configurations (B, C, and D) in order to compile the most comprehensive data set yet obtained for the study of radio halo properties. This is the first survey of radio halos to include all polarization products. In this first paper, we outline the scientific motivation of the survey, the specific science goals, and the expected improvements in noise levels and spatial coverage from the survey. Our goals include investigating the physical conditions and origin of halos, characterizing cosmic ray transport and wind speed, measuring Faraday rotation and mapping the magnetic field, probing the in-disk and extraplanar far-infrared - radio continuum relation, and reconciling non-thermal radio emission with high-energy gamma-ray models. The sample size allows us to search for correlations between radio halos and other properties, including environment, star formation rate, and the presence of AGNs. In a companion paper (Paper II) we outline the data reduction steps and present the first results of the survey for the galaxy, NGC 4631.Comment: 17 pages, 1 figure, accepted to the Astronomical Journal, Version 2 changes: added acknowledgement to NRA

The Birth of a Galaxy. II. The Role of Radiation Pressure

Massive stars provide feedback that shapes the interstellar medium of galaxies at all redshifts and their resulting stellar populations. Here we present three adaptive mesh refinement radiation hydrodynamics simulations that illustrate the impact of momentum transfer from ionising radiation to the absorbing gas on star formation in high-redshift dwarf galaxies. Momentum transfer is calculated by solving the radiative transfer equation with a ray tracing algorithm that is adaptive in spatial and angular coordinates. We find that momentum input partially affects star formation by increasing the turbulent support to a three-dimensional rms velocity equal to the circular velocity of early haloes. Compared to a calculation that neglects radiation pressure, the star formation rate is decreased by a factor of five to 1.8 x 10^{-2} Msun/yr in a dwarf galaxy with a dark matter and stellar mass of 2.0 x 10^8 and 4.5 x 10^5 solar masses, respectively, when radiation pressure is included. Its mean metallicity of 10^{-2.1} Z_sun is consistent with the observed dwarf galaxy luminosity-metallicity relation. However, what one may naively expect from the calculation without radiation pressure, the central region of the galaxy overcools and produces a compact, metal-rich stellar population with an average metallicity of 0.3 Z_sun, indicative of an incorrect physical recipe. In addition to photo-heating in HII regions, radiation pressure further drives dense gas from star forming regions, so supernovae feedback occurs in a warmer and more diffuse medium, launching metal-rich outflows. Capturing this aspect and a temporal separation between the start of radiative and supernova feedback are numerically important in the modeling of galaxies to avoid the "overcooling problem". We estimate that dust in early low-mass galaxies is unlikely to aid in momentum transfer from radiation to the gas.Comment: 18 pages, 11 figures, replaced with accepted version, MNRAS. Minor changes with the conclusions unaffecte

A Brightest Cluster Galaxy with an Extremely Large Flat Core

Hubble Space Telescope images of the galaxy cluster Abell 2261, obtained as part of the Cluster Lensing And Supernova survey with Hubble, show that the brightest galaxy in the cluster, A2261-BCG, has the largest core yet detected in any galaxy. The cusp radius of A2261-BCG is 3.2 kpc, twice as big as the next largest core known, and ~3x bigger than those typically seen in the most luminous BCGs. The morphology of the core in A2261-BCG is also unusual, having a flat or even slightly-depressed interior surface brightness profile, rather than the typical shallow cusp. This implies that the galaxy has a core with constant or even centrally decreasing stellar density. Interpretation of the core as an end product of the "scouring" action of a binary supermassive black hole implies a total black hole mass ~1E+10 M_sun from the extrapolation of most relationships between core structure and black hole mass. The core falls 1-sigma above the cusp-radius versus galaxy luminosity relation. Its large size in real terms, and the extremely large black hole mass required to generate it, raise the possibility that the core has been enlarged by additional processes, such as the ejection of the black holes that originally generated the core. The flat central stellar density profile is consistent with this hypothesis. The core is also displaced by 0.7 kpc from the center of the surrounding envelope, consistent with a local dynamical perturbation of the core.Comment: 11 pages, 7 figures, accepted for publication in the Astrophysical Journa

Phenomenological analysis of ATP dependence of motor protein

In this study, through phenomenological comparison of the velocity-force data of processive motor proteins, including conventional kinesin, cytoplasmic dynein and myosin V, we found that, the ratio between motor velocities of two different ATP concentrations is almost invariant for any substall, superstall or negative external loads. Therefore, the velocity of motor can be well approximated by a Michaelis-Menten like formula V=\atp k(F)L/(\atp +K_M), with $L$ the step size, and $k(F)$ the external load $F$ dependent rate of one mechanochemical cycle of motor motion in saturated ATP solution. The difference of Michaelis-Menten constant $K_M$ for substall, superstall and negative external load indicates, the ATP molecule affinity of motor head for these three cases are different, though the expression of $k(F)$ as a function of $F$ might be unchanged for any external load $F$. Verifications of this Michaelis-Menten like formula has also been done by fitting to the recent experimental data

Suppression of star formation in early-type galaxies by feedback from supermassive black holes

Detailed high-resolution observations of the innermost regions of nearby galaxies have revealed the presence of supermassive black holes1. These black holes may interact with their host galaxies by means of 'feedback' in the form of energy and material jets; this feedback affects the evolution of the host and gives rise to observed relations between the black hole and the host. Here we report observations of the ultraviolet emissions of massive early-type galaxies. We derive an empirical relation for a critical black-hole mass (as a function of velocity dispersion) above which the outflows from these black holes suppress star formation in their hosts by heating and expelling all available cold gas. Supermassive black holes are negligible in mass compared to their hosts but nevertheless seem to play a critical role in the star formation history of galaxies.Comment: Nature, in press. 27 pages, 4 Figures. Article & supplements with high-resolution figures can be downloaded at: http://www-astro.physics.ox.ac.uk/~kevins/PAPERS/AGN_feedback.pd

Constraint-based modeling analysis of the metabolism of two Pelobacter species

BACKGROUND: Pelobacter species are commonly found in a number of subsurface environments, and are unique members of the Geobacteraceae family. They are phylogenetically intertwined with both Geobacter and Desulfuromonas species. Pelobacter species likely play important roles in the fermentative degradation of unusual organic matters and syntrophic metabolism in the natural environments, and are of interest for applications in bioremediation and microbial fuel cells. RESULTS: In order to better understand the physiology of Pelobacter species, genome-scale metabolic models for Pelobacter carbinolicus and Pelobacter propionicus were developed. Model development was greatly aided by the availability of models of the closely related Geobacter sulfurreducens and G. metallireducens. The reconstructed P. carbinolicus model contains 741 genes and 708 reactions, whereas the reconstructed P. propionicus model contains 661 genes and 650 reactions. A total of 470 reactions are shared among the two Pelobacter models and the two Geobacter models. The different reactions between the Pelobacter and Geobacter models reflect some unique metabolic capabilities such as fermentative growth for both Pelobacter species. The reconstructed Pelobacter models were validated by simulating published growth conditions including fermentations, hydrogen production in syntrophic co-culture conditions, hydrogen utilization, and Fe(III) reduction. Simulation results matched well with experimental data and indicated the accuracy of the models. CONCLUSIONS: We have developed genome-scale metabolic models of P. carbinolicus and P. propionicus. These models of Pelobacter metabolism can now be incorporated into the growing repertoire of genome scale models of the Geobacteraceae family to aid in describing the growth and activity of these organisms in anoxic environments and in the study of their roles and interactions in the subsurface microbial community

Corporate Entrepreneurship in Complex Organisations: Towards a Holistic Decision Aid Tool Set to Analyse and Plan Innovative Design Projects

International audienceCorporate innovative design projects (IDP) in large and complex organizations are characterized by a high level of both uncertainty and dynamics of needs, insights, and solution approaches. This article proposes a holistic decision aid tool supporting IDP managers and teams in both the prospective planning and retrospective analysis of IDP's. This tool is essentially based on the classification of work packages according to their uncertainty levels with respect to the design problem and the design solution. Furthermore, the success of work packages can be assessed against pre-defined output criteria. This methodological support is complemented by the stakeholder dimension, which adds the involved stakeholders as well as their relationships and influences in the project. The analysis of an ongoing IDP at a leading global industrial player in the pharmaceutical and chemical industry serves as validation platform for the presented tool set

Corporate Entrepreneurship in Complex Organisations: Towards a Holistic Decision Aid Tool Set to Analyse and Plan Innovative Design Projects

International audienceCorporate innovative design projects (IDP) in large and complex organizations are characterized by a high level of both uncertainty and dynamics of needs, insights, and solution approaches. This article proposes a holistic decision aid tool supporting IDP managers and teams in both the prospective planning and retrospective analysis of IDP's. This tool is essentially based on the classification of work packages according to their uncertainty levels with respect to the design problem and the design solution. Furthermore, the success of work packages can be assessed against pre-defined output criteria. This methodological support is complemented by the stakeholder dimension, which adds the involved stakeholders as well as their relationships and influences in the project. The analysis of an ongoing IDP at a leading global industrial player in the pharmaceutical and chemical industry serves as validation platform for the presented tool set