Why we should use topological data analysis in ageing: Towards defining the “topological shape of ageing”

Living systems are subject to the arrow of time; from birth, they undergo complex transformations (self-organization) in a constant battle for survival, but inevitably ageing and disease trap them to death. Can ageing be understood and eventually reversed? What tools can be employed to further our understanding of ageing? The present article is an invitation for biologists and clinicians to consider key conceptual ideas and computational tools (known to mathematicians and physicists), which potentially may help dissect some of the underlying processes of ageing and disease. Specifically, we first discuss how to classify and analyse complex systems, as well as highlight critical theoretical difficulties that make complex systems hard to study. Subsequently, we introduce Topological Data Analysis - a novel Big Data tool – which may help in the study of complex systems since it extracts knowledge from data in a holistic approach via topological considerations. These conceptual ideas and tools are discussed in a relatively informal way to pave future discussions and collaborations between mathematicians and biologists studying ageing.Basque Government under the grant “Artificial Intelligence in BCAM number EXP. 2019/00432” Inria associated team "NeuroTransSF

Lymphoma and Myeloma Cell Resistance to Cytotoxic Agents and Ionizing Radiations Is Not Affected by Exposure to Anti–IL-6 Antibody

Background: Production of high levels of IL-6 is often correlated with resistance to cytotoxics or ionizing radiations, in cancer cell lines as in various cancer patients. We investigated whether monoclonal antibodies directed against IL-6 may enable to reverse resistance of cancer cell lines. Methodology/Principal Findings: We exposed ten haematological cancer cells from lymphoma, myeloma, or leukemia origins to cytotoxics or ionizing radiations and assessed the effects of anti–IL-6 antibody addition on cell proliferation, apoptosis, or IL-6 signaling. A strong correlation between IL-6 secretion, measured by ELISA, and resistance to doxorubicin as ionizing radiations was observed in the multiple myeloma U266 and the Burkitt’s lymphoma Daudi and Namalwa cells. Although an anti–IL-6 antibody combined to both treatments efficiently blocked IL-6 signaling in U266 cells, expressing the IL-6 receptor gp80, it did not increase treatment-induced anti-proliferative and pro-apoptotic effects on these cells, as well as on Daudi and Namalwa cells. This lack of effect could be related to diverse factors: 1) a higher release of the soluble form of IL-6 receptor gp80 in response to doxorubicin and irradiation from all cell lines, 2) an impaired level of the IL-6 pathway inhibitor SOCS3 in Daudi cells, and 3) an increased release of IL-10 and TNFa, two cytokines involved in cell radio- and chemoresistance. Conclusions/Significance: These data support the fact that IL-6 is not the preponderant actor of cell resistance to cytotoxic

Correlated X-ray/Ultraviolet/Optical variability in the very low mass AGN NGC 4395

We report the results of a one year Swift X-ray/UV/optical programme monitoring the dwarf Seyfert nucleus in NGC 4395 in 2008-2009. The UV/optical flux from the nucleus was found to vary dramatically over the monitoring period, with a similar pattern of variation in each of the observed UV/optical bands (spanning 1900 - 5500 {\AA}). In particular, the luminosity of NGC 4395 in the 1900 {\AA} band changed by more than a factor of eight over the monitoring period. The fractional variability was smaller in the UV/optical bands than that seen in the X-rays, with the X-ray/optical ratio increasing with increasing flux. Pseudo-instantaneous flux measurements in the X-ray and each UV/optical band were well correlated, with cross correlation coefficients of >0.7, significant at 99.9 per cent confidence. Archival Swift observations from 2006 sample the intra-day X-ray/optical variability on NGC 4395. These archival data show a very strong correlation between the X-ray and b bands, with a cross-correlation coefficient of 0.84 (significant at >99 per cent confidence). The peak in the cross correlation function is marginally resolved and asymmetric, suggesting that X-rays lead the b band, but by 1 hour. In response to recent (August 2011) very high X-ray flux levels from NGC4395 we triggered Swift ToO observations, which sample the intra-hour X-ray/UV variability. These observations indicate, albeit with large uncertainties, a lag of the 1900 {\AA} band behind the X-ray flux of ~400 s. The tight correlation between the X-ray and UV/optical lightcurves, together with the constraints we place on lag time-scale are consistent with the UV/optical variability of NGC 4395 being primarily due to reprocessing of X-ray photons by the accretion disc.Comment: 11 pages, 9 figures, 3 tables. Accepted for publication in MNRA

X-Ray Properties of Narrow-Line Seyfert 1 Galaxies with Very Small Broad-Line Widths

Narrow-line Seyfert\,1 galaxies (NLS1s) with very small broad-line widths (say, FWHM(\hb) \la 1200\,\kms) represent the extreme type of Seyfert\,1 galaxies that have small black hole masses (\mbh) and/or high Eddington ratios (\redd). Here we study the X-ray properties of a homogeneously and optically selected sample of 13 such objects, termed as very narrow line Seyfert\,1 galaxies (VNLS1s), using archival \xmm\ data. It is found that the Fe K$\alpha$ emission line is at most weak in these objects. A soft X-ray excess is ubiquitous, with the thermal temperatures falling within a strict range of 0.1--0.2\,keV. Our result highlights the puzzling independence of the thermal temperature by extending the relations to even smaller FWHM(\hb), i.e., smaller \mbh\ ($\sim 10^6$ \msun) and/or higher \redd. The excess emission can be modeled by a range of viable models, though the disk reflection and Comptonization models generally give somewhat better fits over the smeared absorption and the $p$-free models. At the Eddington ratios around unity and above, the X-ray spectral slopes in the 2--10\,keV band are systematically flatter than the Risaliti et al.'s predictions of the relationship with \redd\ suggested previously. Short timescale (1--2 hours) X-ray variability is common, which, together with the variability amplitude computed for some of the objects, are supportive of the scenario that NLS1s are indeed AGN with relatively small \mbh.Comment: 11 figures and 4 table. Accepted for publication in the Astrophysical Journa

Development and formative evaluation of the e-Health implementation toolkit

<b>Background</b> The use of Information and Communication Technology (ICT) or e-Health is seen as essential for a modern, cost-effective health service. However, there are well documented problems with implementation of e-Health initiatives, despite the existence of a great deal of research into how best to implement e-Health (an example of the gap between research and practice). This paper reports on the development and formative evaluation of an e-Health Implementation Toolkit (e-HIT) which aims to summarise and synthesise new and existing research on implementation of e-Health initiatives, and present it to senior managers in a user-friendly format.<p></p> <b>Results</b> The content of the e-HIT was derived by combining data from a systematic review of reviews of barriers and facilitators to implementation of e-Health initiatives with qualitative data derived from interviews of "implementers", that is people who had been charged with implementing an e-Health initiative. These data were summarised, synthesised and combined with the constructs from the Normalisation Process Model. The software for the toolkit was developed by a commercial company (RocketScience). Formative evaluation was undertaken by obtaining user feedback. There are three components to the toolkit - a section on background and instructions for use aimed at novice users; the toolkit itself; and the report generated by completing the toolkit. It is available to download from http://www.ucl.ac.uk/pcph/research/ehealth/documents/e-HIT.xls<p></p> <b>Conclusions</b> The e-HIT shows potential as a tool for enhancing future e-Health implementations. Further work is needed to make it fully web-enabled, and to determine its predictive potential for future implementations

Targeting Impaired Antimicrobial Immunity in the Brain for the Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia and aging is the most common risk factor for developing the disease. The etiology of AD is not known but AD may be considered as a clinical syndrome with multiple causal pathways contributing to it. The amyloid cascade hypothesis, claiming that excess production or reduced clearance of amyloid-beta (Aβ) and its aggregation into amyloid plaques, was accepted for a long time as the main cause of AD. However, many studies showed that Aβ is a frequent consequence of many challenges/pathologic processes occurring in the brain for decades. A key factor, sustained by experimental data, is that low-grade infection leading to production and deposition of Aβ, which has antimicrobial activity, precedes the development of clinically apparent AD. This infection is chronic, low grade, largely clinically silent for decades because of a nearly efficient antimicrobial immune response in the brain. A chronic inflammatory state is induced that results in neurodegeneration. Interventions that appear to prevent, retard or mitigate the devel- opment of AD also appear to modify the disease. In this review, we conceptualize further that the changes in the brain antimicrobial immune response during aging and especially in AD sufferers serve as a foundation that could lead to improved treatment strategies for preventing or decreasing the progression of AD in a disease-modifying treatment

A method for the reconstruction of unknown non-monotonic growth functions in the chemostat

We propose an adaptive control law that allows one to identify unstable steady states of the open-loop system in the single-species chemostat model without the knowledge of the growth function. We then show how one can use this control law to trace out (reconstruct) the whole graph of the growth function. The process of tracing out the graph can be performed either continuously or step-wise. We present and compare both approaches. Even in the case of two species in competition, which is not directly accessible with our approach due to lack of controllability, feedback control improves identifiability of the non-dominant growth rate.Comment: expansion of ideas from proceedings paper (17 pages, 8 figures), proceedings paper is version v

The Collision Between The Milky Way And Andromeda

We use a N--body/hydrodynamic simulation to forecast the future encounter between the Milky Way and the Andromeda galaxies, given current observational constraints on their relative distance, relative velocity, and masses. Allowing for a comparable amount of diffuse mass to fill the volume of the Local Group, we find that the two galaxies are likely to collide in a few billion years - within the Sun's lifetime. During the the interaction, there is a chance that the Sun will be pulled away from its present orbital radius and reside in an extended tidal tail. The likelihood for this outcome increases as the merger progresses, and there is a remote possibility that our Sun will be more tightly bound to Andromeda than to the Milky Way before the final merger. Eventually, after the merger has completed, the Sun is most likely to be scattered to the outer halo and reside at much larger radii (>30 kpc). The density profiles of the stars, gas and dark matter in the merger product resemble those of elliptical galaxies. Our Local Group model therefore provides a prototype progenitor of late--forming elliptical galaxies.Comment: accepted to MNRA