Expression of ZebrafishragGenes during Early Development Identifies the Thymus

AbstractRecent experiments have demonstrated that zebrafish is a vertebrate in which it is possible to carry out large-scale mutagenic screens to identify genes involved in specific developmental pathways. To follow development of the immune system in zebrafish, we have analyzed the expression of the recombination activating genes,rag1andrag2,which we have previously isolated and characterized. These genes catalyze the rearrangement of immunoglobulin genes in immature B lymphocytes and of T cell receptor genes in immature T lymphocytes and are therefore appropriate markers to follow the development of organs containing these cells. By whole-mountin situhybridization, we detected expression of bothraggenes in a paired organ in the head, beginning on the fourth day after fertilization. Histological examination of this organ indicated that it corresponds to the thymus, as described for other fish, an organ that has not previously been identified in zebrafish. By histological analysis, the thymus primordium appears at 54 hr but does not enlarge significantly until 30 hr later. The thymus continues to enlarge and reaches its mature histological organization at 1 month. The pronephros, the major hematopoietic organ in the adult fish, begins to develop hematopoietic tissue about 2 weeks after fertilization. By 1 month, mature lymphocytes are distinguishable in the tissue surrounding renal tubules. Lymphocytes appear in the kidney too late for screening by whole-mountin situhybridization; however, the pattern ofrag1expression in the thymus forms the basis of an assay for mutations affecting development of the thymus or its constituent lymphocytes

Pathway-Based Toxicity: History, Current Approaches and Liver Fibrosis and Steatosis as Prototypes

The Human Toxicology Project Consortium (HTPC) was created to accelerate implementation of the science and policies required to achieve a pathway-based foundation for toxicology as articulated in the 2007 National Research Council report, Toxicity Testing in the 21st Century: a Vision and a Strategy. The HTPC held a workshop, “Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology: Liver Toxicity Mode-of-Action,” in January, 2013, in Baltimore, MD, to further the science of pathway-based approaches to liver toxicity. This review was initiated as a thought-starter for this workshop and has since been updated to include insights from the workshop and other activities occurring in 2013. The report of the workshop has been published elsewhere in this journal (Willett, 2014).JRC.I.5-Systems Toxicolog

An Interdisciplinary Approach to Community-Engaged Research Surrounding Lead in Drinking Water in the Mississippi Delta

Childhood lead poisoning is a problem requiring interdisciplinary attention from toxicology, public health, social sciences, environmental law, and policy. In the U.S., Mississippi was ranked as one of the worst states for lead poisoning with limited childhood screening measures. We conducted community-engaged research by working with leaders in the largely rural Mississippi Delta region from 2016-2019 to collect household water samples and questionnaires and involve their communities in lead poisoning risk awareness and outreach. Drinking water from 213 homes was collected and analyzed for pH and lead concentrations. Highest lead concentrations were from households served by private wells, and detectable concentrations at or above 0.09 ppb were found in 66.2 percent of all samples. Nine samples exceeded 5 ppb, and these households received certified sink filters. Findings indicated that community-engaged research and outreach could be used to address data gaps relating to lead in drinking water in rural decentralized water systems

Phobic Anxiety is Associated with Higher Serum Concentrations of Adipokines and Cytokines in Women with Diabetes

OBJECTIVE: Phobic anxiety has been associated with increased risk of cardiovascular disease (CVD), but the underlying mechanisms are poorly understood. We aimed to determine whether associations of phobic anxiety with several known markers of CVD might be contributors. RESEARCH DESIGN AND METHODS: We used a 16-point validated index (Crown-Crisp) measured in 1988 to categorize 984 women with type 2 diabetes from the Nurses' Health Study as having low, moderate, or high phobic anxiety. Groups were then compared for differences in adipokines (adiponectin and leptin), inflammatory markers (C-reactive protein and tumor necrosis factor [TNF]-α receptor II), and markers of endothelial function (sE-selectin, soluble intercellular adhesion molecule [sICAM]-1) measured on blood samples provided between 1989 and 1990. RESULTS: Higher levels of phobic anxiety were associated with higher BMI and lower education. Higher levels of phobic anxiety were also associated with higher leptin and soluble TNF-α receptor II in both crude analyses and after adjustment for potential confounders. sICAM and sE-selectin were higher in the highest tertile compared with the middle tertile, but there was no significant trend across tertiles. We found no association between phobic anxiety and adiponectin. CONCLUSIONS: High levels of phobic anxiety are associated with increased levels of leptin and inflammatory markers, which may in part explain the previously observed relationship between anxiety and other psychosocial disorders with CVD

Alcohol Intake Between Menarche and First Pregnancy: A Prospective Study of Breast Cancer Risk

Background: Adult alcohol consumption during the previous year is related to breast cancer risk. Breast tissue is particularly susceptible to carcinogens between menarche and first full-term pregnancy. No study has characterized the contribution of alcohol consumption during this interval to risks of proliferative benign breast disease (BBD) and breast cancer. Methods: We used data from 91005 parous women in the Nurses’ Health Study II who had no cancer history, completed questions on early alcohol consumption in 1989, and were followed through June 30, 2009, to analyze breast cancer risk. A subset of 60093 women who had no history of BBD or cancer in 1991 and were followed through June 30, 2001, were included in the analysis of proliferative BBD. Relative risks (RRs) were estimated using Cox proportional hazard regression. Results: We identified 1609 breast cancer cases and 970 proliferative BBD cases confirmed by central histology review. Alcohol consumption between menarche and first pregnancy, adjusted for drinking after first pregnancy, was associated with risks of breast cancer (RR = 1.11 per 10g/day intake; 95% confidence interval [CI] = 1.00 to 1.23) and proliferative BBD (RR = 1.16 per 10g/day intake; 95% CI = 1.02 to 1.32). Drinking after first pregnancy had a similar risk for breast cancer (RR = 1.09 per 10g/day intake; 95% CI = 0.96 to 1.23) but not for BBD. The association between drinking before first pregnancy and breast neoplasia appeared to be stronger with longer menarche to first pregnancy intervals. Conclusions: Alcohol consumption before first pregnancy was consistently associated with increased risks of proliferative BBD and breast cancer

Peste des petits ruminants virus transmission scaling and husbandry practices that contribute to increased transmission risk: an investigation among sheep, goats, and cattle in Northern Tanzania

Peste des petits ruminants virus (PPRV) causes an infectious disease of high morbidity and mortality among sheep and goats which impacts millions of livestock keepers globally. PPRV transmission risk varies by production system, but a deeper understanding of how transmission scales in these systems and which husbandry practices impact risk is needed. To investigate transmission scaling and husbandry practice-associated risk, this study combined 395 household questionnaires with over 7115 cross-sectional serosurvey samples collected in Tanzania among agropastoral and pastoral households managing sheep, goats, or cattle (most managed all three, n = 284, 71.9%). Although self-reported compound-level herd size was significantly larger in pastoral than agropastoral households, the data show no evidence that household herd force of infection (FOI, per capita infection rate of susceptible hosts) increased with herd size. Seroprevalence and FOI patterns observed at the sub-village level showed significant spatial variation in FOI. Univariate analyses showed that household herd FOI was significantly higher when households reported seasonal grazing camp attendance, cattle or goat introduction to the compound, death, sale, or giving away of animals in the past 12 months, when cattle were grazed separately from sheep and goats, and when the household also managed dogs or donkeys. Multivariable analyses revealed that species, production system type, and goat or sheep introduction or seasonal grazing camp attendance, cattle or goat death or sales, or goats given away in the past 12 months significantly increased odds of seroconversion, whereas managing pigs or cattle attending seasonal grazing camps had significantly lower odds of seroconversion. Further research should investigate specific husbandry practices across production systems in other countries and in systems that include additional atypical host species to broaden understanding of PPRV transmission

Adolescent diet and risk of breast cancer

BACKGROUND: Early life exposures, including diet, have been implicated in the etiology of breast cancer. METHODS: A nested case-control study was conducted among participants in the Nurses' Health Study who completed a 24-item questionnaire about diet during high school. There were 843 eligible cases diagnosed between onset of study (1976) and before the return of the high school diet questionnaire (1986), who were matched 10:1 with controls on the basis of age. RESULTS: Women who had, during adolescence, a higher consumption of eggs, vegetable fat and fiber had a lower risk of breast cancer, whereas risk of breast cancer was increased among women who consumed more butter. CONCLUSIONS: A possible association of elements of adolescent diet with risk of breast cancer is reported, but the findings require confirmation in prospective study

Identifying Age Cohorts Responsible for Peste Des Petits Ruminants Virus Transmission among Sheep, Goats, and Cattle in Northern Tanzania.

This research article published by MDPI, 2020Peste des petits ruminants virus (PPRV) causes a contagious disease of high morbidity and mortality in global sheep and goat populations. To better control this disease and inform eradication strategies, an improved understanding of how PPRV transmission risk varies by age is needed. Our study used a piece-wise catalytic model to estimate the age-specific force of infection (FOI, per capita infection rate of susceptible hosts) among sheep, goats, and cattle from a cross-sectional serosurvey dataset collected in 2016 in Tanzania. Apparent seroprevalence increased with age, reaching 53.6%, 46.8%, and 11.6% (true seroprevalence: 52.7%, 52.8%, 39.2%) for sheep, goats, and cattle, respectively. Seroprevalence was significantly higher among pastoral animals than agropastoral animals across all ages, with pastoral sheep and goat seroprevalence approaching 70% and 80%, respectively, suggesting pastoral endemicity. The best fitting piece-wise catalytic models merged age groups: two for sheep, three for goats, and four for cattle. The signal of these age heterogeneities were weak, except for a significant FOI peak among 2.5-3.5-year-old pastoral cattle. The subtle age-specific heterogeneities identified in this study suggest that targeting control efforts by age may not be as effective as targeting by other risk factors, such as production system type. Further research should investigate how specific husbandry practices affect PPRV transmission

Towards a 21st-century roadmap for biomedical research and drug discovery:consensus report and recommendations

Decades of costly failures in translating drug candidates from preclinical disease models to human therapeutic use warrant reconsideration of the priority placed on animal models in biomedical research. Following an international workshop attended by experts from academia, government institutions, research funding bodies, and the corporate and nongovernmental organisation (NGO) sectors, in this consensus report, we analyse, as case studies, five disease areas with major unmet needs for new treatments. In view of the scientifically driven transition towards a human pathway-based paradigm in toxicology, a similar paradigm shift appears to be justified in biomedical research. There is a pressing need for an approach that strategically implements advanced, human biology-based models and tools to understand disease pathways at multiple biological scales. We present recommendations to help achieve this