Common Host Responses in Murine Aerosol Models of Infection Caused by Highly Virulent Gram-Negative Bacteria from the Genera Burkholderia, Francisella and Yersinia

This is the final version. Available on open access from MDPI via the DOI in this recordContent includes material subject to © Crown copyright (2019), Dstl. This material is licensed under the terms of the Open Government Licence except where otherwise stated. To view this licence, visit: http://www.nationalarchives.gov.uk/doc/open-government-licence/version/3 or write to the Information Policy Team, The National Archives, Kew, London TW9 4DU, or email: [email protected] virulent bacterial pathogens cause acute infections which are exceptionally difficult to treat with conventional antibiotic therapies alone. Understanding the chain of events that are triggered during an infection of a host has the potential to lead to new therapeutic strategies. For the first time, the transcriptomic responses within the lungs of Balb/C mice have been compared during an acute infection with the intracellular pathogens Burkholderia pseudomallei, Francisella tularensis and Yersinia pestis. Temporal changes were determined using RNAseq and a bioinformatics pipeline; expression of protein was also studied from the same sample. Collectively it was found that early transcriptomic responses within the infected host were associated with the (a) slowing down of critical cellular functions, (b) production of circulatory system components, (c) lung tissue integrity, and (d) intracellular regulatory processes. One common molecule was identified, Errfi1 (ErbB receptor feedback inhibitor 1); upregulated in response to all three pathogens and a potential novel marker of acute infection. Based upon the pro-inflammatory responses observed, we sought to synchronise each infection and report that 24 h p.i. of B. pseudomallei infection closely aligned with 48 h p.i. of infection with F. tularensis and Y. pestis. Post-transcriptional modulation of RANTES expression occurred across all pathogens, suggesting that these infections directly or indirectly modulate cell trafficking through chemokine expression/detection. Collectively, this unbiased NGS approach has provided an in-depth characterisation of the host transcriptome following infection with these highly virulent pathogens ultimately aiding in the development of host-directed therapies as adjuncts or alternatives to antibiotic treatment

Short-term monitoring of the Spanish government balance

We construct multivariate, state-space mixed-frequencies models for the main components of the Spanish General Government sector made up of blocks for each one of its subsectors: Central Government, Social Security and aggregate of Regional and Local government sectors. Each block is modelled through its total revenue and expenditure categories, and encompasses a number of indicators, depending on data availability. The mixed-frequencies approach is particularly relevant for the case of Spain, given its institutional set-up and the specific data availability for the different subsectors. All in all, we provide models detailed enough in coverage, while at the same time manageable, to be used: (1) for real-time monitoring of fiscal policies with a focus on quarterly developments of the General Government sector, (2) for the monitoring of general government sub-sectors for which intra-annual data coverage is limited (Regional and Local governments), (3) to bridge (translate) into National Accounts availablemonthly information for the subsectors of the general government

Small Scattered Fragments Do Not a Dwarf Make: Biological and Archaeological Data Indicate that Prehistoric Inhabitants of Palau Were Normal Sized

Current archaeological evidence from Palau in western Micronesia indicates that the archipelago was settled around 3000–3300 BP by normal sized populations; contrary to recent claims, they did not succumb to insular dwarfism

Wide-Scale Analysis of Human Functional Transcription Factor Binding Reveals a Strong Bias towards the Transcription Start Site

We introduce a novel method to screen the promoters of a set of genes with shared biological function, against a precompiled library of motifs, and find those motifs which are statistically over-represented in the gene set. The gene sets were obtained from the functional Gene Ontology (GO) classification; for each set and motif we optimized the sequence similarity score threshold, independently for every location window (measured with respect to the TSS), taking into account the location dependent nucleotide heterogeneity along the promoters of the target genes. We performed a high throughput analysis, searching the promoters (from 200bp downstream to 1000bp upstream the TSS), of more than 8000 human and 23,000 mouse genes, for 134 functional Gene Ontology classes and for 412 known DNA motifs. When combined with binding site and location conservation between human and mouse, the method identifies with high probability functional binding sites that regulate groups of biologically related genes. We found many location-sensitive functional binding events and showed that they clustered close to the TSS. Our method and findings were put to several experimental tests. By allowing a "flexible" threshold and combining our functional class and location specific search method with conservation between human and mouse, we are able to identify reliably functional TF binding sites. This is an essential step towards constructing regulatory networks and elucidating the design principles that govern transcriptional regulation of expression. The promoter region proximal to the TSS appears to be of central importance for regulation of transcription in human and mouse, just as it is in bacteria and yeast.Comment: 31 pages, including Supplementary Information and figure

Exploring hypotheses of the actions of TGF-beta 1 in epidermal wound healing using a 3D computational multiscale model of the human epidermis

In vivo and in vitro studies give a paradoxical picture of the actions of the key regulatory factor TGF-beta 1 in epidermal wound healing with it stimulating migration of keratinocytes but also inhibiting their proliferation. To try to reconcile these into an easily visualized 3D model of wound healing amenable for experimentation by cell biologists, a multiscale model of the formation of a 3D skin epithelium was established with TGF-beta 1 literature-derived rule sets and equations embedded within it. At the cellular level, an agent-based bottom-up model that focuses on individual interacting units ( keratinocytes) was used. This was based on literature-derived rules governing keratinocyte behavior and keratinocyte/ECM interactions. The selection of these rule sets is described in detail in this paper. The agent-based model was then linked with a subcellular model of TGF-beta 1 production and its action on keratinocytes simulated with a complex pathway simulator. This multiscale model can be run at a cellular level only or at a combined cellular/subcellular level. It was then initially challenged ( by wounding) to investigate the behavior of keratinocytes in wound healing at the cellular level. To investigate the possible actions of TGF-beta 1, several hypotheses were then explored by deliberately manipulating some of these rule sets at subcellular levels. This exercise readily eliminated some hypotheses and identified a sequence of spatial-temporal actions of TGF-beta 1 for normal successful wound healing in an easy-to-follow 3D model. We suggest this multiscale model offers a valuable, easy-to-visualize aid to our understanding of the actions of this key regulator in wound healing, and provides a model that can now be used to explore pathologies of wound healing

Gender perspectives on views and preferences of older people on exercise to prevent falls: a systematic mixed studies review

Background: To offer fall prevention exercise programs that attract older people of both sexes there is a need to understand both womens and mens views and preferences regarding these programs. This paper aims to systematically review the literature to explore any underlying gender perspectives or gender interpretations on older peoples views or preferences regarding uptake and adherence to exercise to prevent falls. Methods: A review of the literature was carried out using a convergent qualitative design based on systematic searches of seven electronic databases (PubMed, CINAHL, Amed, PsycINFO, Scopus, PEDro, and OTseeker). Two investigators identified eligible studies. Each included article was read by at least two authors independently to extract data into tables. Views and preferences reported were coded and summarized in themes of facilitators and barriers using a thematic analysis approach. Results: Nine hundred and nine unique studies were identified. Twenty five studies met the criteria for inclusion. Only five of these contained a gender analysis of mens and womens views on fall prevention exercises. The results suggests that both women and men see women as more receptive to and in more need of fall prevention messages. The synthesis from all 25 studies identified six themes illustrating facilitators and six themes describing barriers for older people either starting or adhering to fall prevention exercise. The facilitators were: support from professionals or family; social interaction; perceived benefits; a supportive exercise context; feelings of commitment; and having fun. Barriers were: practical issues; concerns about exercise; unawareness; reduced health status; lack of support; and lack of interest. Considerably more women than men were included in the studies. Conclusion: Although there is plenty of information on the facilitators and barriers to falls prevention exercise in older people, there is a distinct lack of studies investigating differences or similarities in older womens and mens views regarding fall prevention exercise. In order to ensure that fall prevention exercise is appealing to both sexes and that the inclusion of both men and women are encouraged, more research is needed to find out whether gender differences exists and whether practitioners need to offer a range of opportunities and support strategies to attract both women and men to falls prevention exercise.Funding Agencies|Swedish Research Council [2015-03481]; Strategic Research Programme in Care Sciences, Umea University; Karolinska Institute, Sweden; Umea University</p

A patient with Melorheostosis manifesting with features similar to tricho-dento-osseous syndrome: a case report

<p>Abstract</p> <p>Introduction</p> <p>A case of melorheostosis in association with tricho-dento-osseous (TDO) syndrome has been encountered.</p> <p>Case presentation</p> <p>The clinical and the radiographic manifestations of melorheostosis have been encountered in a 41-year-old man. Mutations in the 13 exons and flanking intronic regions of the LEMD3-gene have not been detected. His phenotypic features were consistent but not completely diagnostic for tricho-dento-osseous syndrome (TDO). We report what might be a novel syndromic association.</p> <p>Conclusion</p> <p>Melorheostosis has not previously been reported to be a part of TDO and an extensive review of the literature suggests that the constellation of hair, tooth and bone abnormalities found in our patient either represents an unusual variant of tricho-dento-osseous syndrome or a new syndrome.</p

The National Tumor Association Foundation (ANT): A 30 year old model of home palliative care

<p>Abstract</p> <p>Background</p> <p>Models of palliative care delivery develop within a social, cultural, and political context. This paper describes the 30-year history of the National Tumor Association (ANT), a palliative care organization founded in the Italian province of Bologna, focusing on this model of home care for palliative cancer patients and on its evaluation.</p> <p>Methods</p> <p>Data were collected from the 1986-2008 ANT archives and documents from the Emilia-Romagna Region Health Department, Italy. Outcomes of interest were changed in: number of patients served, performance status at admission (Karnofsky Performance Status score [KPS]), length of participation in the program (days of care provided), place of death (home vs. hospital/hospice), and satisfaction with care. Statistical methods included linear and quadratic regressions. A linear and a quadratic regressions were generated; the independent variable was the year, while the dependent one was the number of patients from 1986 to 2008. Two linear regressions were generated for patients died at home and in the hospital, respectively. For each regression, the R square, the unstandardized and standardized coefficients and related P-values were estimated.</p> <p>Results</p> <p>The number of patients served by ANT has increased continuously from 131 (1986) to a cumulative total of 69,336 patients (2008), at a steady rate of approximately 121 additional patients per year and with no significant gender difference. The annual number of home visits increased from 6,357 (1985) to 904,782 (2008). More ANT patients died at home than in hospice or hospital; this proportion increased from 60% (1987) to 80% (2007). The rate of growth in the number of patients dying in hospital/hospice was approximately 40 patients/year (p < 0.01), vs. approximately 177 patients/year for patients who died at home. The percentage of patients with KPS < 40 at admission decreased from 70% (2003) to 30% (2008); the percentage of patients with KPS > 40 increased. Mean days of care for patients with KPS > 40 exceeded mean days for patients with KPS < 40 (p < 0.001). Patients and caregivers reported high satisfaction with care in each year of assessment; in 2008, among 187 interviewed caregivers, 95% judged the quality of doctors' assistance, and 91% judged the quality of nurses' assistance, to be "optimal."</p> <p>Conclusions</p> <p>The ANT home care model of palliative care delivery has been well-received, with progressively growing numbers of patients served. It has resulted in a greater proportion of home deaths and in patients' accessing palliative care at an earlier point in the disease trajectory. Changes in ANT chronicle palliative care trends in general.</p