\u3ci\u3eSalmonella enterica\u3c/i\u3e induces biogeography-specific changes in the gut microbiome of pigs

Swine are a major reservoir of an array of zoonotic Salmonella enterica subsp. enterica lineage I serovars including Derby, Typhimurium, and 4,[5],12:i:- (a.k.a. Monophasic Typhimurium). In this study, we assessed the gastrointestinal (GI) microbiome composition of pigs in different intestinal compartments and the feces following infection with specific zoonotic serovars of S. enterica (S. Derby, S. Monophasic, and S. Typhimurium). 16S rRNA based microbiome analysis was performed to assess for GI microbiome changes in terms of diversity (alpha and beta), community structure and volatility, and specific taxa alterations across GI biogeography (small and large intestine, feces) and days post-infection (DPI) 2, 4, and 28; these results were compared to disease phenotypes measured as histopathological changes. As previously reported, only S. Monophasic and S. Typhimurium induced morphological alterations that marked an inflammatory milieu restricted to the large intestine in this experimental model. S. Typhimurium alone induced significant changes at the alpha- (Simpson’s and Shannon’s indexes) and beta-diversity levels, specifically at the peak of inflammation in the large intestine and feces. Increased community dispersion and volatility in colonic apex and fecal microbiomes were also noted for S. Typhimurium. All three Salmonella serovars altered community structure as measured by co-occurrence networks; this was most prominent at DPI 2 and 4 in colonic apex samples. At the genus taxonomic level, a diverse array of putative short-chain fatty acid (SCFA) producing bacteria were altered and often decreased during the peak of inflammation at DPI 2 and 4 within colonic apex and fecal samples. Among all putative SCFA producing bacteria, Prevotella showed a broad pattern of negative correlation with disease scores at the peak of inflammation. In addition, Prevotella 9 was found to be significantly reduced in all Salmonella infected groups compared to the control at DPI 4 in the colonic apex. In conclusion, this work further elucidates that distinct swine-related zoonotic serovars of S. enterica can induce both shared (high resilience) and unique (altered resistance) alterations in gut microbiome biogeography, which helps inform future investigations of dietary modifications aimed at increasing colonization resistance against Salmonella through GI microbiome alterations

Salmonella enterica induces biogeography-specific changes in the gut microbiome of pigs

Swine are a major reservoir of an array of zoonotic Salmonella enterica subsp. enterica lineage I serovars including Derby, Typhimurium, and 4,[5],12:i:- (a.k.a. Monophasic Typhimurium). In this study, we assessed the gastrointestinal (GI) microbiome composition of pigs in different intestinal compartments and the feces following infection with specific zoonotic serovars of S. enterica (S. Derby, S. Monophasic, and S. Typhimurium). 16S rRNA based microbiome analysis was performed to assess for GI microbiome changes in terms of diversity (alpha and beta), community structure and volatility, and specific taxa alterations across GI biogeography (small and large intestine, feces) and days post-infection (DPI) 2, 4, and 28; these results were compared to disease phenotypes measured as histopathological changes. As previously reported, only S. Monophasic and S. Typhimurium induced morphological alterations that marked an inflammatory milieu restricted to the large intestine in this experimental model. S. Typhimurium alone induced significant changes at the alpha- (Simpson’s and Shannon’s indexes) and beta-diversity levels, specifically at the peak of inflammation in the large intestine and feces. Increased community dispersion and volatility in colonic apex and fecal microbiomes were also noted for S. Typhimurium. All three Salmonella serovars altered community structure as measured by co-occurrence networks; this was most prominent at DPI 2 and 4 in colonic apex samples. At the genus taxonomic level, a diverse array of putative short-chain fatty acid (SCFA) producing bacteria were altered and often decreased during the peak of inflammation at DPI 2 and 4 within colonic apex and fecal samples. Among all putative SCFA producing bacteria, Prevotella showed a broad pattern of negative correlation with disease scores at the peak of inflammation. In addition, Prevotella 9 was found to be significantly reduced in all Salmonella infected groups compared to the control at DPI 4 in the colonic apex. In conclusion, this work further elucidates that distinct swine-related zoonotic serovars of S. enterica can induce both shared (high resilience) and unique (altered resistance) alterations in gut microbiome biogeography, which helps inform future investigations of dietary modifications aimed at increasing colonization resistance against Salmonella through GI microbiome alterations

Development of the Malocclusion Impact Questionnaire (MIQ) to measure the oral health-related quality of life of young people with malocclusion: part 1 - qualitative inquiry

OBJECTIVES: To seek the views of adolescents with malocclusion about how the appearance and arrangement of their teeth affects their everyday life and to incorporate these views into a new Malocclusion Impact Questionnaire (MIQ). METHODS: Semi-structured interviews were undertaken with a purposive sample of 30 young people (10-16 years) referred for orthodontic treatment to two dental teaching hospitals. The interviews were recorded, transcribed and analysed using framework analysis. Several themes and sub themes were identified and these were used to identify items to include in the new measure. RESULTS: Three themes emerged which were: concerns about the appearance of their teeth, effect on social interactions and oral health/function. Participants expressed the view that their teeth did not look normal, causing them embarrassment and a lack of confidence, particularly when they were with their peers or having their photograph taken. Concerns regarding the potential effect of a malocclusion on oral health, in terms of food becoming stuck between crooked teeth, interferences when chewing and increased risk of damaging the teeth were also identified. The themes were used to generate individual items for inclusion in the questionnaire. CONCLUSIONS: Common themes relating to the impact of malocclusion on the lives of young people were identified and generated items for the new MIQ to measure the oral health-related quality of life of young people with malocclusion. Part 2 outlines the further development and testing of the MIQ

Species-specific differences in the Pro-Ala rich region of cardiac myosin binding protein-C

Cardiac myosin binding protein-C (cMyBP-C) is an accessory protein found in the A-bands of vertebrate sarcomeres and mutations in the cMyBP-C gene are a leading cause of familial hypertrophic cardiomyopathy. The regulatory functions of cMyBP-C have been attributed to the N-terminus of the protein, which is composed of tandem immunoglobulin (Ig)-like domains (C0, C1, and C2), a region rich in proline and alanine residues (the Pro-Ala rich region) that links C0 and C1, and a unique sequence referred to as the MyBP-C motif, or M-domain, that links C1 and C2. Recombinant proteins that contain various combinations of the N-terminal domains of cMyBP-C can activate actomyosin interactions in the absence of Ca2+, but the specific sequences required for these effects differ between species; the Pro-Ala region has been implicated in human cMyBP-C whereas the C1 and M-domains appear important in mouse cMyBP-C. To investigate whether species-specific differences in sequence can account for the observed differences in function, we compared sequences of the Pro-Ala rich region in cMyBP-C isoforms from different species. Here we report that the number of proline and alanine residues in the Pro-Ala rich region varies significantly between different species and that the number correlates directly with mammalian body size and inversely with heart rate. Thus, systematic sequence differences in the Pro-Ala rich region of cMyBP-C may contribute to observed functional differences in human versus mouse cMyBP-C isoforms and suggest that the Pro-Ala region may be important in matching contractile speed to cardiac function across species

Tumor Endothelial Cells with Distinct Patterns of TGF -Driven Endothelial-to-Mesenchymal Transition

Endothelial-to-mesenchymal transition (EndMT) occurs during development and underlies the pathophysiology of multiple diseases. In tumors, unscheduled EndMT generates cancer-associated myofibroblasts that fuel inflammation and fibrosis, and may contribute to vascular dysfunction that promotes tumor progression. We report that freshly isolated subpopulations of tumor-specific endothelial cells (TEC) from a spontaneous mammary tumor model undergo distinct forms of EndMT in response to TGFβ stimulation. Whereas some TEC strikingly up-regulate alpha smooth muscle actin (SMA), a principal marker of EndMT and activated myofibroblasts, counterpart normal mammary gland endothelial cells (NEC) showed little change in SMA expression after TGFβ treatment. Compared with NEC, SMA+ TEC were 40 % less motile in wound healing assays and formed more stable vascular-like networks in vitro when challenged with TGFβ. Lineage tracing using ZsGreenCdh5-Cre reporter mice confirmed that only a fraction of vessels in breast tumors contain SMA+ TEC, suggesting that not all endothelial cells (EC) respond identically to TGFβ in vivo. Indeed, examination of 84 TGFβ-regulated target genes revealed entirely different genetic signatures in TGFβ-stimulated NEC and TEC cultures. Finally, we found that basic FGF (bFGF) exerts potent inhibitory effects on many TGFβ-regulated genes but operates in tandem with TGFβ to up-regulate others. EC challenged with TGFβ secrete bFGF which blocks SMA expression in secondary cultures suggesting a cell-autonomous or lateral-inhibitory mechanism for impeding mesenchymal differentiation. Together, our results suggest that TGFβ-driven EndMT produces a spectrum of EC phenotypes with different functions that could underlie the plasticity and heterogeneity of the tumor vasculature

RASOnD - A comprehensive resource and search tool for RAS superfamily oncogenes from various species

<p>Abstract</p> <p>Background</p> <p>The Ras superfamily plays an important role in the control of cell signalling and division. Mutations in the Ras genes convert them into active oncogenes. The Ras oncogenes form a major thrust of global cancer research as they are involved in the development and progression of tumors. This has resulted in the exponential growth of data on Ras superfamily across different public databases and in literature. However, no dedicated public resource is currently available for data mining and analysis on this family. The present database was developed to facilitate straightforward accession, retrieval and analysis of information available on Ras oncogenes from one particular site.</p> <p>Description</p> <p>We have developed the RAS Oncogene Database (RASOnD) as a comprehensive knowledgebase that provides integrated and curated information on a single platform for oncogenes of Ras superfamily. RASOnD encompasses exhaustive genomics and proteomics data existing across diverse publicly accessible databases. This resource presently includes overall 199,046 entries from 101 different species. It provides a search tool to generate information about their nucleotide and amino acid sequences, single nucleotide polymorphisms, chromosome positions, orthologies, motifs, structures, related pathways and associated diseases. We have implemented a number of user-friendly search interfaces and sequence analysis tools. At present the user can (i) browse the data (ii) search any field through a simple or advance search interface and (iii) perform a BLAST search and subsequently CLUSTALW multiple sequence alignment by selecting sequences of Ras oncogenes. The Generic gene browser, GBrowse, JMOL for structural visualization and TREEVIEW for phylograms have been integrated for clear perception of retrieved data. External links to related databases have been included in RASOnD.</p> <p>Conclusions</p> <p>This database is a resource and search tool dedicated to Ras oncogenes. It has utility to cancer biologists and cell molecular biologists as it is a ready source for research, identification and elucidation of the role of these oncogenes. The data generated can be used for understanding the relationship between the Ras oncogenes and their association with cancer. The database updated monthly is freely accessible online at <url>http://202.141.47.181/rasond/</url> and <url>http://www.aiims.edu/RAS.html</url>.</p

Mismatches in Scale Between Highly Mobile Marine Megafauna and Marine Protected Areas

Marine protected areas (MPAs), particularly large MPAs, are increasing in number and size around the globe in part to facilitate the conservation of marine megafauna under the assumption that large-scale MPAs better align with vagile life histories; however, this alignment is not well established. Using a global tracking dataset from 36 species across five taxa, chosen to reflect the span of home range size in highly mobile marine megafauna, we show most MPAs are too small to encompass complete home ranges of most species. Based on size alone, 40% of existing MPAs could encompass the home ranges of the smallest ranged species, while only \u3c 1% of existing MPAs could encompass those of the largest ranged species. Further, where home ranges and MPAs overlapped in real geographic space, MPAs encompassed \u3c 5% of core areas used by all species. Despite most home ranges of mobile marine megafauna being much larger than existing MPAs, we demonstrate how benefits from MPAs are still likely to accrue by targeting seasonal aggregations and critical life history stages and through other management techniques

Mismatches in Scale Between Highly Mobile Marine Megafauna and Marine Protected Areas

Marine protected areas (MPAs), particularly large MPAs, are increasing in number and size around the globe in part to facilitate the conservation of marine megafauna under the assumption that large-scale MPAs better align with vagile life histories; however, this alignment is not well established. Using a global tracking dataset from 36 species across five taxa, chosen to reflect the span of home range size in highly mobile marine megafauna, we show most MPAs are too small to encompass complete home ranges of most species. Based on size alone, 40% of existing MPAs could encompass the home ranges of the smallest ranged species, while only \u3c 1% of existing MPAs could encompass those of the largest ranged species. Further, where home ranges and MPAs overlapped in real geographic space, MPAs encompassed \u3c 5% of core areas used by all species. Despite most home ranges of mobile marine megafauna being much larger than existing MPAs, we demonstrate how benefits from MPAs are still likely to accrue by targeting seasonal aggregations and critical life history stages and through other management techniques

FOXP3 Expression Is Upregulated in CD4+T Cells in Progressive HIV-1 Infection and Is a Marker of Disease Severity

Understanding the role of different classes of T cells during HIV infection is critical to determining which responses correlate with protective immunity. To date, it is unclear whether alterations in regulatory T cell (Treg) function are contributory to progression of HIV infection.FOXP3 expression was measured by both qRT-PCR and by flow cytometry in HIV-infected individuals and uninfected controls together with expression of CD25, GITR and CTLA-4. Cultured peripheral blood mononuclear cells were stimulated with anti-CD3 and cell proliferation was assessed by CFSE dilution.HIV infected individuals had significantly higher frequencies of CD4(+)FOXP3(+) T cells (median of 8.11%; range 1.33%-26.27%) than healthy controls (median 3.72%; range 1.3-7.5%; P = 0.002), despite having lower absolute counts of CD4(+)FOXP3(+) T cells. There was a significant positive correlation between the frequency of CD4(+)FOXP3(+) T cells and viral load (rho = 0.593 P = 0.003) and a significant negative correlation with CD4 count (rho = -0.423 P = 0.044). 48% of our patients had CD4 counts below 200 cells/microl and these patients showed a marked elevation of FOXP3 percentage (median 10% range 4.07%-26.27%). Assessing the mechanism of increased FOXP3 frequency, we found that the high FOXP3 levels noted in HIV infected individuals dropped rapidly in unstimulated culture conditions but could be restimulated by T cell receptor stimulation. This suggests that the high FOXP3 expression in HIV infected patients is likely due to FOXP3 upregulation by individual CD4(+) T cells following antigenic or other stimulation.FOXP3 expression in the CD4(+) T cell population is a marker of severity of HIV infection and a potential prognostic marker of disease progression

ARIA 2016:Care pathways implementing emerging technologies for predictive medicine in rhinitis and asthma across the life cycle

The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative commenced during a World Health Organization workshop in 1999. The initial goals were (1) to propose a new allergic rhinitis classification, (2) to promote the concept of multi-morbidity in asthma and rhinitis and (3) to develop guidelines with all stakeholders that could be used globally for all countries and populations. ARIA-disseminated and implemented in over 70 countries globally-is now focusing on the implementation of emerging technologies for individualized and predictive medicine. MASK [MACVIA (Contre les Maladies Chroniques pour un Vieillissement Actif)-ARIA Sentinel NetworK] uses mobile technology to develop care pathways for the management of rhinitis and asthma by a multi-disciplinary group and by patients themselves. An app (Android and iOS) is available in 20 countries and 15 languages. It uses a visual analogue scale to assess symptom control and work productivity as well as a clinical decision support system. It is associated with an inter-operable tablet for physicians and other health care professionals. The scaling up strategy uses the recommendations of the European Innovation Partnership on Active and Healthy Ageing. The aim of the novel ARIA approach is to provide an active and healthy life to rhinitis sufferers, whatever their age, sex or socio-economic status, in order to reduce health and social inequalities incurred by the disease