Complex microbiota targeted rederivation (CMTR) as an alternative method to study effect of gut microbiota on host physiology /

Includes vita.Rodent models are invaluable tools to study the effects of differing gut microbiota (GM) on health and disease. Our laboratory has demonstrated that mouse GM profiles vary among animal vendors suggesting that subtle differences in GM may be an important experimental variable influencing reproducibility. To assess the role of microbiota on model phenotypes, complex microbiota targeted rederivation (CMTR) can be used. With CMTR, mice of the desired model are rederived using embryo transfer into surrogate dams with one or more desired GM profiles. Unfortunately, differing GM are often present in inbred strains of mice complicating CMTR as these strains frequently have poor reproductive indices and variations in maternal care which can add unwanted experimental variables. To overcome this, we exploited the benefits of outbred mice as surrogates by establishing colonies of CD1 mice with differing GM profiles. CD1 embryos were transferred into CD1 or C57BL/6 surrogate dams that varied by GM composition and complexity to establish three separate colonies. Using targeted next generation sequencing, female offspring were shown to have similar GM profiles to surrogate dams. Furthermore, breeding colonies of CD1 mice with distinct GM profiles were maintained for four generations, demonstrating stability of GM profiles within these colonies. We then compared changes in the phenotype of B6 IL-10-/- and C3H IL-10-/- mice rederived by CMTR using either CD1 colonies or the inbred strains from which the colonies were derived. Cecal and colonic histologic lesion scores differed significantly between groups, but no differences were seen when surrogate source of GM (CD1 vs inbred strain) was compared. These findings underscore that CMTR using outbred CD1 colonies will be an invaluable experimental resource for experiments desiring to assess the role of complex microbiota on model phenotypes.Dr. Craig L. Franklin, Dissertation co-mentor.|Aaron C. Ericsson, Dissertation co-mentor.|Includes vita.Includes bibliographical references (pages 125-132)

Development of outbred CD1 mouse colonies with distinct standardized gut microbiota profiles for use in complex microbiota targeted studies.

Studies indicate that the gut microbiota (GM) can significantly influence both local and systemic host physiologic processes. With rising concern for optimization of experimental reproducibility and translatability, it is essential to consider the GM in study design. However, GM profiles can vary between rodent producers making consistency between models challenging. To circumvent this, we developed outbred CD1 mouse colonies with stable, complex GM profiles that can be used as donors for a variety of GM transfer techniques including rederivation, co-housing, cross-foster, and fecal microbiota transfer (FMT). CD1 embryos were surgically transferred into CD1 or C57BL/6 surrogate dams that varied by GM composition and complexity to establish four separate mouse colonies harboring GM profiles representative of contemporary mouse producers. Using targeted 16S rRNA amplicon sequencing, subsequent female offspring were found to have similar GM profiles to surrogate dams. Furthermore, breeding colonies of CD1 mice with distinct GM profiles were maintained for nine generations, demonstrating GM stability within these colonies. To confirm GM stability, we shipped cohorts of these four colonies to collaborating institutions and found no significant variation in GM composition. These mice are an invaluable experimental resource that can be used to investigate GM effects on mouse model phenotype

Activity-Dependent Exocytosis of Lysosomes Regulates the Structural Plasticity of Dendritic Spines

Lysosomes have traditionally been viewed as degradative organelles, though a growing body of evidence suggests that they can function as Ca2+ stores. Here, we examined the function of these stores in hippocampal pyramidal neurons. We found that back-propagating action potentials (bpAPs) could elicit Ca2+ release from lysosomes in the dendrites. This Ca2+ release triggered the fusion of lysosomes with the plasma membrane, resulting in the release of Cathepsin B. Cathepsin B increased the activity of matrix metalloproteinase 9 (MMP-9), an enzyme involved in extracellular matrix (ECM) remodelling and synaptic plasticity. Inhibition of either lysosomal Ca2+ signalling or Cathepsin B release prevented the maintenance of dendritic spine growth induced by Hebbian activity. This impairment could be rescued by exogenous application of active MMP-9. Our findings suggest that activity-dependent exocytosis of Cathepsin B from lysosomes regulates the long-term structural plasticity of dendritic spines by triggering MMP-9 activation and ECM remodelling

Inequalities in public water supply fluoridation in Brazil: An ecological study

Background. The literature is scarce on the social and geographic inequalities in the access to and implementation of the fluoridation of public water supplies. This study adds knowledge to the Brazilian experience of the chronic privation of water and wastewater policies, access to potable water and fluoridation in the country. Thus, the aim of this study was to verify possible inequalities in the population's access to fluoridated drinking water in 246 Brazilian municipalities. Methods. The information on the process of water fluoridation in the municipalities and in the macro region in which each municipality is located was obtained from the national epidemiological survey which was concluded in 2003. The data relating to the human development index at municipal level (HDI-M) and access to mains water came from the Brazilian Human Development Atlas, whilst the size of the population was obtained from a governmental source. The Fisher exact test (P < 0.05) was employed to identify significant associations between the explanatory variables and their ability to predict the principal outcomes of interest to this study, namely the presence or absence of the water fluoridation process in the municipalities as well as the length of time during which this measure has been implemented. Linear regression was used to observe the associations between the relevant variables in a multivariate environment. Results. The results clearly showed that there is a relationship between municipalities with larger populations, located in more socio-economically advantaged regions and with better HDI-M, and where fluoridation is both present and has been implemented for a longer period of time (started before 1990). Conclusion. The findings suggest that the aim of treating water with fluoride may not be being adequately achieved, requiring more effective strategies so that access to this measure can be expanded equitably.81Hart, J.T., The inverse care law (1971) Lancet, 1 (7696), pp. 405-12. , 4100731Victora, C.G., Vaughan, J.P., Barros, F.C., Silva, A.C., Tomasi, E., Explaining trends in inequities: Evidence from Brazilian child health studies (2000) Lancet, 356 (9235), pp. 1093-98. , 10.1016/S0140-6736(00)02741-0 11009159Basting, R.T., Pereira, A.C., Meneghim, M.C., Evaluation of dental caries prevalence in students from Piracicaba, SP, Brazil, after 25 years of fluoridation of the public water supply (1997) Rev Odontol Univ São Paulo, 11 (4), pp. 287-92. , 10.1590/S0103-06631997000400010Lawrence, H.P., Sheiham, A., Caries progression in 12 to 16-year-old schoolchildren in fluoridated and fluoride-deficient areas in Brazil (1997) Community Dent Oral Epidemiol, 25 (6), pp. 402-11. , 10.1111/j.1600-0528.1997.tb01730.x 9429812Pereira, A.C., Mialhe, F.L., Bianchini, F.L.C., Prevalence of caries and dental floozies in scholars from cities with different fluoride concentrations in drinking water (2001) Rev Bras Odontol Sade Coletiva, 2 (1), pp. 34-9For Disease Control, C., Prevention, Achievementsin Public Health, 1900-1999: Fluoridation of drinking water to prevent dental caries (1999) Morbidity and Mortality Weekly Report, 48 (41), pp. 933-40For Disease Control, C., Prevention, Ten great public health achievements -United Sates, 1900-1999 (1999) Morbidity and Mortality Weekly Report, 48 (12), pp. 241-3. , 10220250American Health Organization, P., XV Directing Council of the Pan American Health Organization - Resolutions, 1964, , http://www.paho.org/English/GOV/CD/ftcd_15.htm(2003) The World Oral Health Report 2003, , http://www.who.int/oral_health, Geneva: WHOMcDonagh, M.S., Whiting, P.F., Wilson, P.M., Sutton, A.J., Chestnutt, I., Cooper, J., Misso, K., Kleijnen, J., Systematic review of water fluoridation (2000) BMJ, 321 (7265), pp. 855-9. , 11021861 10.1136/bmj.321.7265.855Bratthall, D., Hänsel-Petersson, G., Sundberg, H., Reasons for the caries decline: What do the experts believe? (1996) Eur J Oral Sci, 104 (4 PART 2), pp. 416-22. , 10.1111/j.1600-0722.1996.tb00104.x 8930592Narvai, P.C., Dental caries and fluorine: A twentieth century relation (2000) Cinc Sade Coletiva, 5 (2), pp. 381-92. , 10.1590/S1413-81232000000200011Peres, M.A., Fernandes, L.S., Peres, K.G., Inequality of water fluoridation in Southern Brazil - The inverse equity hypothesis revisited (2004) Soc Sci Med, 58 (6), pp. 1181-9. , 10.1016/S0277-9536(03)00289-2 14723912Peres, M.A., Antunes, J.L.F., Peres, K.G., Is water fluoridation effective in reducing inequalities in dental caries distribution in developing countries? (2006) Sozial und Präventiv Medizin, 51 (5), pp. 1-9Peres, K.G., Bastos, J.R., Mrdo, L., Relationship between severity of dental caries and social and behavioral factors in children (2000) Rev Saude Publica, 34 (4), pp. 402-8. , 10973161Maltz, M., Barbachan Silva, E.B., Relationship between caries, gingivitis and fluorosis and the socioeconomic status among school children (2001) Rev Saude Publica, 35 (2), pp. 170-6. , 11359204Moysés, S.J., Desigualdades em Sade Bucal e Desenvolvimento Humano: Um ensaio em preto, branco e alguns tons de cinza (2001) Rev Bras Odontol Sade Coletiva, 1 (1), pp. 7-17Patussi, M.P., Marcenes, W., Croucher, R., Sheiham, A., Social deprivation, income inequality, social cohesion and dental caries in Brazilian school children (2001) Soc Sci Med, 53 (7), pp. 915-25. , 10.1016/S0277-9536(00)00391-9 11522137Antunes, J.L.F., Frazão, P., Narvai, P.C., Bispo, C.M., Pegoretti, T., Spatial analysis to identify differentials in dental needs by area-based measures (2002) Community Dent Oral Epidemiol, 30 (2), pp. 133-42. , 10.1034/j.1600-0528.2002.300207.x 12000354Peres, M.A., Peres, K.G., Antunes, J.L.F., Junqueira, S.R., Frazão, P., Narvai, P.C., The association between socioeconomic development at the town level and the distribution of dental caries in Brazilian children (2003) Rev Panam Salud Publica, 14 (3), pp. 149-57. , 10.1590/S1020-49892003000800001 14653902Antunes, J.L.F., Narvai, P.C., Nugent, Z.J., Measuring inequalities in the distribution of dental caries (2004) Community Dent Oral Epidemiol, 32 (1), pp. 41-8. , 10.1111/j.1600-0528.2004.00125.x 14961839Antunes, J.L.F., Peres, M.A., De Campos Mello, T.R., Waldman, E.A., Multilevel assessment of determinants of dental caries experience in Brazil (2006) Community Dent Oral Epidemiol, 34 (2), pp. 146-152. , 10.1111/j.1600-0528.2006.00274.x 16515679Narvai, P.C., Frazão, P., Roncalli, A.G., Antunes, J.L.F., Dental caries in Brazil: Decline, polarization, inequality and social exclusion (2006) Rev Panam Salud Publica, 19 (6), pp. 385-93. , 10.1590/S1020-49892006000600004 16968593Projeto, S.B., Brasil, Condiçes de sade bucal da população brasileira 2002-2003. 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The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure