Agent-based and continuum models for spatial dynamics of infection by oncolytic viruses

The use of oncolytic viruses as cancer treatment has received considerable attention in recent years, however the spatial dynamics of this viral infection is still poorly understood. We present here a stochastic agent-based model describing infected and uninfected cells for solid tumours, which interact with viruses in the absence of an immune response. Two kinds of movement, namely undirected random and pressure-driven movements, are considered: the continuum limit of the models is derived and a systematic comparison between the systems of partial differential equations and the individual-based model, in one and two dimensions, is carried out. In the case of undirected movement, a good agreement between agent-based simulations and the numerical and well-known analytical results for the continuum model is possible. For pressure-driven motion, instead, we observe a wide parameter range in which the infection of the agents remains confined to the center of the tumour, even though the continuum model shows traveling waves of infection; outcomes appear to be more sensitive to stochasticity and uninfected regions appear harder to invade, giving rise to irregular, unpredictable growth patterns. Our results show that the presence of spatial constraints in tumours' microenvironments limiting free expansion has a very significant impact on virotherapy. Outcomes for these tumours suggest a notable increase in variability. All these aspects can have important effects when designing individually tailored therapies where virotherapy is included.Comment: 29 pages, 10 figures. Supplementary material available at https://tinyurl.com/5c5nxss

Non-exhaustive DNA methylation-mediated transposon silencing in the black truffle genome, a complex fungal genome with massive repeat element content

Background: We investigated how an extremely transposon element (TE)-rich organism such as the plant-symbiotic ascomycete truffle Tuber melanosporum exploits DNA methylation to cope with the more than 45,000 repeated elements that populate its genome. Results: Whole-genome bisulfite sequencing performed on different developmental stages reveals a high fraction of methylated cytosines with a strong preference for CpG sites. The methylation pattern is highly similar among samples and selectively targets TEs rather than genes. A marked trend toward hypomethylation is observed for TEs located within a 1 kb distance from expressed genes, rather than segregated in TE-rich regions of the genome. Approximately 300 hypomethylated or unmethylated TEs are transcriptionally active, with higher expression levels in free-living mycelium compared to fruitbody. Indeed, multiple TE-enriched, copy number variant regions bearing a significant fraction of hypomethylated and expressed TEs are found almost exclusively in free-living mycelium. A reduction of DNA methylation, restricted to non-CpG sites and accompanied by an increase in TE expression, is observed upon treatment of free-living mycelia with 5-azacytidine. Conclusions: Evidence derived from analysis of the T. melanosporum methylome indicates that a non-exhaustive, partly reversible, methylation process operates in truffles. This allows for the existence of hypomethylated, transcriptionally active TEs that are associated with copy number variant regions of the genome. Non-exhaustive TE methylation may reflect a role of active TEs in promoting genome plasticity and the ability to adapt to sudden environmental changes

Determinants of Slow-Wave Activity in Overweight and Obese Adults: Roles of Sex, Obstructive Sleep Apnea and Testosterone Levels

Background: Slow-wave activity (SWA) in non-rapid eye movement (NREM) sleep, obtained by spectral analysis of the electroencephalogram, is a marker of the depth or intensity of NREM sleep. Higher levels of SWA are associated with lower arousability during NREM sleep and protect against sleep fragmentation. Multiple studies have documented that SWA levels are higher in lean women, compared to age-matched lean men, but whether these differences persist in obese subjects is unclear. Obstructive sleep apnea (OSA), a condition associated with obesity, is more prevalent in men than in women. Sex differences in SWA could therefore be one of the factors predisposing men to OSA. Furthermore, we hypothesized that higher levels of testosterone may be associated with lower levels of SWA.Objective: The aim of the current study was to identify sex differences in the determinants of SWA in young and middle-aged overweight and obese adults.Methods: We enrolled 101 overweight and obese but otherwise healthy participants from the community (44 men, 57 women) in this cross-sectional study. Participants underwent an overnight in-laboratory polysomnogram. The recordings were submitted to sleep staging and spectral analysis. Sex differences and the potential contribution of testosterone levels were evaluated after adjusting for age, body mass index and race/ethnicity.Results: OSA was present in 66% of men and in 44% of women. After adjustment for differences in age, race/ethnicity and BMI, the odds ratio for OSA in men vs. women was 3.17 (95% CI 1.14–9.43, p = 0.027). There was a graded inverse relationship between the apnea-hypopnea index (AHI) and SWA in men (β = −0.21, p = 0.018) but not in women (β = 0.10, p = 0.207). In a multivariate regression model, higher testosterone levels were independently associated with lower SWA in men after controlling for age, race/ethnicity and apnea-hypopnea index (β = −0.56, p = 0.025).Conclusion: Increasing severity of OSA was associated with significant decrease in sleep intensity in men but not in women. Higher testosterone levels were associated with lower sleep intensity in men. Men with higher testosterone levels may therefore have lower arousal thresholds and higher ventilatory instability in NREM sleep, and be at greater risk of OSA

Sex Differences in the Impact of Obstructive Sleep Apnea on Glucose Metabolism

Objectives: Obstructive sleep apnea (OSA) is more prevalent in men and is an independent risk factor for type 2 diabetes. We aimed to determine if there are sex differences in the impact of OSA on glucose metabolism in nondiabetic overweight and obese adults.Methods: One hundred and forty-five men and women (age 33.4 ± 0.6, BMI 37.2 ± 0.7, 70.3% blacks) from the community underwent in-laboratory polysomnography. Severity of OSA was assessed by the apnea-hypopnea index (AHI). Glucose tolerance was assessed using fasting glucose, 1-h glucose, 2-h glucose and the area under the curve (AUC) during the 2-h oral glucose tolerance test (OGTT). Fasting insulin resistance was assessed by HOMA-IR, and insulin sensitivity during the OGTT was assessed by the Matsuda Index. Pancreatic beta-cell function was assessed by fasting HOMA-%B and by AUCinsulin/glucose, insulinogenic index, and oral disposition index (DIoral) during the OGTT. All comparisons were adjusted for age, BMI, race and severity of OSA.Results: There were no significant demographic differences between men and women without OSA. Men and women with OSA were similar in age, BMI, and severity of OSA, but there were more black women with OSA. Compared to women with OSA, men with OSA had significantly higher fasting glucose, 1-h glucose levels, AUCglucose, and AUC for insulin secretion rate (AUCISR) but similar 2-h glucose levels. These differences persisted in adjusted analyses. Men with OSA secreted significantly more insulin than women with OSA in order to achieve similar glucose levels. Men with OSA had significantly worse beta cell function as measured by the DIoral than women with OSA. In contrast, there were no significant sex differences in measures of glucose tolerance and beta-cell function in participants without OSA.Conclusion: Men with OSA secreted more insulin compared to women with OSA in order to maintain glucose homeostasis. The adverse impact of OSA on beta-cell responsiveness was larger in men, which may result in an overall greater risk of type 2 diabetes compared to women

A comprehensive resource of genomic, epigenomic and transcriptomic sequencing data for the black truffle Tuber melanosporum

Abstract Background: Tuber melanosporum, also known in the gastronomic community as "truffle", features one of the largest fungal genomes (125 Mb) with an exceptionally high transposable element (TE) and repetitive DNA content (>58%). The main purpose of DNA methylation in fungi is TE silencing. As obligate outcrossing organisms, truffles are bound to a sexual mode of propagation, which together with TEs is thought to represent a major force driving the evolution of DNA methylation. Thus, it was of interest to examine if and how T. melanosporum exploits DNA methylation to maintain genome integrity. Findings: We performed whole-genome DNA bisulfite sequencing and mRNA sequencing on different developmental stages of T. melanosporum; namely, fruitbody ("truffle"), free-living mycelium and ectomycorrhiza. The data revealed a high rate of cytosine methylation (>44%), selectively targeting TEs rather than genes with a strong preference for CpG sites. Whole genome DNA sequencing uncovered multiple TE-enriched, copy number variant regions bearing a significant fraction of hypomethylated and expressed TEs, almost exclusively in free-living mycelium propagated in vitro. Treatment of mycelia with 5-azacytidine partially reduced DNA methylation and increased TE transcription. Our transcriptome assembly also resulted in the identification of a set of novel transcripts from 614 genes

Health impact assessment of waste management facilities in three European countries

<p>Abstract</p> <p>Background</p> <p>Policies on waste disposal in Europe are heterogeneous and rapidly changing, with potential health implications that are largely unknown. We conducted a health impact assessment of landfilling and incineration in three European countries: Italy, Slovakia and England.</p> <p>Methods</p> <p>A total of 49 (Italy), 2 (Slovakia), and 11 (England) incinerators were operating in 2001 while for landfills the figures were 619, 121 and 232, respectively. The study population consisted of residents living within 3 km of an incinerator and 2 km of a landfill. Excess risk estimates from epidemiological studies were used, combined with air pollution dispersion modelling for particulate matter (PM₁₀) and nitrogen dioxide (NO₂). For incinerators, we estimated attributable cancer incidence and years of life lost (YoLL), while for landfills we estimated attributable cases of congenital anomalies and low birth weight infants.</p> <p>Results</p> <p>About 1,000,000, 16,000, and 1,200,000 subjects lived close to incinerators in Italy, Slovakia and England, respectively. The additional contribution to NO₂levels within a 3 km radius was 0.23, 0.15, and 0.14 μg/m³, respectively. Lower values were found for PM₁₀. Assuming that the incinerators continue to operate until 2020, we are moderately confident that the annual number of cancer cases due to exposure in 2001-2020 will reach 11, 0, and 7 in 2020 and then decline to 0 in the three countries in 2050. We are moderately confident that by 2050, the attributable impact on the 2001 cohort of residents will be 3,621 (Italy), 37 (Slovakia) and 3,966 (England) YoLL. The total exposed population to landfills was 1,350,000, 329,000, and 1,425,000 subjects, respectively. We are moderately confident that the annual additional cases of congenital anomalies up to 2030 will be approximately 2, 2, and 3 whereas there will be 42, 13, and 59 additional low-birth weight newborns, respectively.</p> <p>Conclusions</p> <p>The current health impacts of landfilling and incineration can be characterized as moderate when compared to other sources of environmental pollution, e.g. traffic or industrial emissions, that have an impact on public health. There are several uncertainties and critical assumptions in the assessment model, but it provides insight into the relative health impact attributable to waste management.</p

Fermi Large Area Telescope Constraints on the Gamma-ray Opacity of the Universe

The Extragalactic Background Light (EBL) includes photons with wavelengths from ultraviolet to infrared, which are effective at attenuating gamma rays with energy above ~10 GeV during propagation from sources at cosmological distances. This results in a redshift- and energy-dependent attenuation of the gamma-ray flux of extragalactic sources such as blazars and Gamma-Ray Bursts (GRBs). The Large Area Telescope onboard Fermi detects a sample of gamma-ray blazars with redshift up to z~3, and GRBs with redshift up to z~4.3. Using photons above 10 GeV collected by Fermi over more than one year of observations for these sources, we investigate the effect of gamma-ray flux attenuation by the EBL. We place upper limits on the gamma-ray opacity of the Universe at various energies and redshifts, and compare this with predictions from well-known EBL models. We find that an EBL intensity in the optical-ultraviolet wavelengths as great as predicted by the "baseline" model of Stecker et al. (2006) can be ruled out with high confidence.Comment: 42 pages, 12 figures, accepted version (24 Aug.2010) for publication in ApJ; Contact authors: A. Bouvier, A. Chen, S. Raino, S. Razzaque, A. Reimer, L.C. Reye

A population of gamma-ray emitting globular clusters seen with the Fermi Large Area Telescope

Globular clusters with their large populations of millisecond pulsars (MSPs) are believed to be potential emitters of high-energy gamma-ray emission. Our goal is to constrain the millisecond pulsar populations in globular clusters from analysis of gamma-ray observations. We use 546 days of continuous sky-survey observations obtained with the Large Area Telescope aboard the Fermi Gamma-ray Space Telescope to study the gamma-ray emission towards 13 globular clusters. Steady point-like high-energy gamma-ray emission has been significantly detected towards 8 globular clusters. Five of them (47 Tucanae, Omega Cen, NGC 6388, Terzan 5, and M 28) show hard spectral power indices $(0.7 < \Gamma <1.4)$ and clear evidence for an exponential cut-off in the range 1.0-2.6 GeV, which is the characteristic signature of magnetospheric emission from MSPs. Three of them (M 62, NGC 6440 and NGC 6652) also show hard spectral indices $(1.0 < \Gamma < 1.7)$, however the presence of an exponential cut-off can not be unambiguously established. Three of them (Omega Cen, NGC 6388, NGC 6652) have no known radio or X-ray MSPs yet still exhibit MSP spectral properties. From the observed gamma-ray luminosities, we estimate the total number of MSPs that is expected to be present in these globular clusters. We show that our estimates of the MSP population correlate with the stellar encounter rate and we estimate 2600-4700 MSPs in Galactic globular clusters, commensurate with previous estimates. The observation of high-energy gamma-ray emission from a globular cluster thus provides a reliable independent method to assess their millisecond pulsar populations that can be used to make constraints on the original neutron star X-ray binary population, essential for understanding the importance of binary systems in slowing the inevitable core collapse of globular clusters.Comment: Accepted for publication in A&A. Corresponding authors: J. Kn\"odlseder, N. Webb, B. Pancraz

Zinc Polyaleuritate Ionomer Coatings as a Sustainable, Alternative Technology for Bisphenol A-Free Metal Packaging

Sustainable coatings for metal food packaging were prepared from ZnO nanoparticles (obtained by the thermal decomposition of zinc acetate) and a naturally occurring polyhydroxylated fatty acid named aleuritic (or 9,10,16-trihydroxyhexadecanoic) acid. Both components reacted, originating under specific conditions zinc polyaleuritate ionomers. The polymerization of aleuritic acid into polyaleuritate by a solvent-free, melt polycondensation reaction was investigated at different times (15, 30, 45, and 60 min), temperatures (140, 160, 180, and 200 °C), and proportions of zinc oxide and aleuritic acid (0:100, 5:95, 10:90, and 50:50, w/w). Kinetic rate constants calculated by infrared spectroscopy decreased with the amount of Zn due to the consumption of reactive carboxyl groups, while the activation energy of the polymerization decreased as a consequence of the catalyst effect of the metal. The adhesion and hardness of coatings were determined from scratch tests, obtaining values similar to robust polymers with high adherence. Water contact angles were typical of hydrophobic materials with values ≥94°. Both mechanical properties and wettability were better than those of bisphenol A (BPA)-based resins and most likely are related to the low migration values determined using a hydrophilic food simulant. The presence of zinc provided a certain degree of antibacterial properties. The performance of the coatings against corrosion was studied by electrochemical impedance spectroscopy at different immersion times in an aqueous solution of NaCl. Considering the features of these biobased lacquers, they can be potential materials for bisphenol A-free metal packagingPeer reviewe

Épisodes d’inactivité et revenus criminels dans une trajectoire de délinquance

L’instabilité de l’activité criminelle dans le temps est déjà bien documentée. On connaît toutefois peu les circonstances qui expliquent ces variations à court terme. Une meilleure connaissance de ces facteurs est souhaitable puisqu’il est possible que les transitions et les changements à court terme précèdent les points tournants des carrières criminelles. Les conditions qui rendent compte d’une interruption temporaire des activités peuvent, par exemple, contribuer à expliquer un désistement définitif. L’étude se fonde sur les trajectoires de 172 délinquants impliqués dans des crimes à but lucratif et analyse les variations mensuelles de leurs revenus criminels ainsi que les épisodes d’inactivité criminelle à l’intérieur d’une période fenêtre de 36 mois. La méthode des calendriers d’histoire de vie combinée aux modèles hiérarchiques permet d’examiner conjointement le rôle de facteurs statiques (les caractéristiques individuelles des sujets) et dynamiques (les circonstances de vie). Les résultats mettent en évidence l’importance des événements qui marquent le style de vie des délinquants et des paramètres qui caractérisent l’engagement criminel dans la compréhension des variations dans les trajectoires à l’étude. Ils soulignent également l’importance de la finalité derrière les activités criminelles pour expliquer la décision des délinquants de cesser temporaire leurs activités illicites