Redlining and Lead Poisoning: Causes and Consequences.

In 1934, the Federal Housing Authority precluded mortgage loans to residents of neighborhoods with non-White families or where housing was deteriorated; these were declared "hazardous" and labeled red on maps. In 1962 three redlined north Brooklyn neighborhoods had 41 children, all Black and Puerto Rican, with lead levels >60ug/dL. A review of public polices in the U.S. from 1898 to the present revealed that lead poisoning followed an income gradient with multiple disproportionate effects on non-White children in redlined neighborhoods. The poisonings diminished when federal and local regulations prevented lead exposure. While redlining had profound influences on both likelihood and severity of lead poisoning and its consequences, it was a mediator of effects. The principal causes were federal policies failing to prevent environmental contamination and local governments failing to prevent exposure.

Perspective: Dietary Biomarkers of Intake and Exposure-Exploration with Omics Approaches.

While conventional nutrition research has yielded biomarkers such as doubly labeled water for energy metabolism and 24-h urinary nitrogen for protein intake, a critical need exists for additional, equally robust biomarkers that allow for objective assessment of specific food intake and dietary exposure. Recent advances in high-throughput MS combined with improved metabolomics techniques and bioinformatic tools provide new opportunities for dietary biomarker development. In September 2018, the NIH organized a 2-d workshop to engage nutrition and omics researchers and explore the potential of multiomics approaches in nutritional biomarker research. The current Perspective summarizes key gaps and challenges identified, as well as the recommendations from the workshop that could serve as a guide for scientists interested in dietary biomarkers research. Topics addressed included study designs for biomarker development, analytical and bioinformatic considerations, and integration of dietary biomarkers with other omics techniques. Several clear needs were identified, including larger controlled feeding studies, testing a variety of foods and dietary patterns across diverse populations, improved reporting standards to support study replication, more chemical standards covering a broader range of food constituents and human metabolites, standardized approaches for biomarker validation, comprehensive and accessible food composition databases, a common ontology for dietary biomarker literature, and methodologic work on statistical procedures for intake biomarker discovery. Multidisciplinary research teams with appropriate expertise are critical to moving forward the field of dietary biomarkers and producing robust, reproducible biomarkers that can be used in public health and clinical research.

Considerations for best practices in studies of fiber or other dietary components and the intestinal microbiome.

A 2-day workshop organized by the National Institutes of Health and U.S. Department of Agriculture included 16 presentations focused on the role of diet in alterations of the gastrointestinal microbiome, primarily that of the colon. Although thousands of research projects have been funded by U.S. federal agencies to study the intestinal microbiome of humans and a variety of animal models, only a minority addresses dietary effects, and a small subset is described in sufficient detail to allow reproduction of a study. Whereas there are standards being developed for many aspects of microbiome studies, such as sample collection, nucleic acid extraction, data handling, etc., none has been proposed for the dietary component; thus this workshop focused on the latter specific point. It is important to foster rigor in design and reproducibility of published studies to maintain high quality and enable designs that can be compared in systematic reviews. Speakers addressed the influence of the structure of the fermentable carbohydrate on the microbiota and the variables to consider in design of studies using animals, in vitro models, and human subjects. For all types of studies, strengths and weaknesses of various designs were highlighted, and for human studies, comparisons between controlled feeding and observational designs were discussed. Because of the lack of published, best-diet formulations for specific research questions, the main recommendation is to describe dietary ingredients and treatments in as much detail as possible to allow reproduction by other scientists.

The Death of Burghardt Du Bois, 1899; Implications for Today.

ACKNOWLEDGEMENTS: Laura Dattner, John Krai and Linda Oppenheim provided assistance in obtaining archival material and manuscript review. Edwin Rosenthal's decedents, Robert, Eleanore Jane and Edwin Rosenthal II, provided information about their distinguished grandfather's life and commitments. Linda Oppenheim, Michael Angelo, Jessica Lydon, and Sofie Serada, archivists at Princeton University, Thomas Jefferson University, Temple University, and the College of Physicians of Philadelphia provided access to material on Edwin Rosenthal and medical care in Philadelphia at the turn of the 20th century. We thanks Laura Dattner, John Krai and Linda Oppenheim for their manuscript review. BACKGROUND: The Souls of Black Folks, W. E. B. Du Bois' compelling narrative from 1903, includes a description of the death of his only son, Burghardt. His death was caused by diphtheria and occurred in Atlanta, GA in the year 1899. Mortality from diphtheria had fallen precipitously in the mid-1890s, but neither city of Atlanta nor Philadelphia, from which the family had recently moved, had made the diphtheria antitoxin available for general use. OBJECTIVES: To identify factors affecting availability diphtheria treatment in the two cities the Du Bois family lived in and to address implications for immunization policies today. METHODS: We reviewed data and observations from medical texts and articles from the turn of the 20th century, health department records, archives of newspapers and Du Bois' writings. RESULTS: Mortality from diphtheria dropped precipitously at the end of the 19th century with the introduction of laryngecostomy and a diphtheria antitoxin. However these measures required action by health departments and was dependent on the availability of physicians and medical facilities. Lack of Public Health Departments put all southerners at risk for infectious illnesses. With respect to diphtheria, there was neither an available supply of antitoxin nor physician care available. Philadelphia may have been too mired in corruption to provide antitoxin. Burghardt lived in close proximity to a facility where antitoxin was available, data suggests he would have received appropriate treatment there and was likely to have survived. Similar phenomena-disinterest and dysfunction-affect provision of immunization for children today. Currently, availability of immunization is affected by ethnicity, income levels and immigration status.

Bifurcation analysis of single-cell gene expression data reveals epigenetic landscape.

We present single-cell clustering using bifurcation analysis (SCUBA), a novel computational method for extracting lineage relationships from single-cell gene expression data and modeling the dynamic changes associated with cell differentiation. SCUBA draws techniques from nonlinear dynamics and stochastic differential equation theories, providing a systematic framework for modeling complex processes involving multilineage specifications. By applying SCUBA to analyze two complementary, publicly available datasets we successfully reconstructed the cellular hierarchy during early development of mouse embryos, modeled the dynamic changes in gene expression patterns, and predicted the effects of perturbing key transcriptional regulators on inducing lineage biases. The results were robust with respect to experimental platform differences between RT-PCR and RNA sequencing. We selectively tested our predictions in Nanog mutants and found good agreement between SCUBA predictions and the experimental data. We further extended the utility of SCUBA by developing a method to reconstruct missing temporal-order information from a typical single-cell dataset. Analysis of a hematopoietic dataset suggests that our method is effective for reconstructing gene expression dynamics during human B-cell development. In summary, SCUBA provides a useful single-cell data analysis tool that is well-suited for the investigation of developmental processes.

Demonstrating Nutrient Cost Gradients: A Brooklyn Case Study.

INTRODUCTION: Foods dense in micronutrients are generally more expensive than those with higher energy content. These cost-differentials may put low-income families at risk of diminished micronutrient intake. OBJECTIVES: We sought to determine differences in the cost for iron, folate, and choline in foods available for purchase in a low-income community when assessed for energy content and serving size. METHODS: Sixty-nine foods listed in the menu plans provided by the United States Department of Agriculture (USDA) for low-income families were considered, in 10 domains. The cost and micronutrient content for-energy and per-serving of these foods were determined for the three micronutrients. Exact Kruskal-Wallis tests were used for comparisons of energy costs; Spearman rho tests for comparisons of micronutrient content. Ninety families were interviewed in a pediatric clinic to assess the impact of food cost on food selection. RESULTS: Significant differences between domains were shown for energy density with both cost-for-energy (p < 0.001) and cost-per-serving (p < 0.05) comparisons. All three micronutrient contents were significantly correlated with cost-for-energy (p < 0.01). Both iron and choline contents were significantly correlated with cost-per-serving (p < 0.05). Of the 90 families, 38 (42 %) worried about food costs; 40 (44 %) had chosen foods of high caloric density in response to that fear, and 29 of 40 families experiencing both worry and making such food selection. CONCLUSION: Adjustments to USDA meal plans using cost-for-energy analysis showed differentials for both energy and micronutrients. These differentials were reduced using cost-per-serving analysis, but were not eliminated. A substantial proportion of low-income families are vulnerable to micronutrient deficiencies.

Complex-linear invariants of biochemical networks.

The nonlinearities found in molecular networks usually prevent mathematical analysis of network behaviour, which has largely been studied by numerical simulation. This can lead to difficult problems of parameter determination. However, molecular networks give rise, through mass-action kinetics, to polynomial dynamical systems, whose steady states are zeros of a set of polynomial equations. These equations may be analysed by algebraic methods, in which parameters are treated as symbolic expressions whose numerical values do not have to be known in advance. For instance, an "invariant" of a network is a polynomial expression on selected state variables that vanishes in any steady state. Invariants have been found that encode key network properties and that discriminate between different network structures. Although invariants may be calculated by computational algebraic methods, such as Gröbner bases, these become computationally infeasible for biologically realistic networks. Here, we exploit Chemical Reaction Network Theory (CRNT) to develop an efficient procedure for calculating invariants that are linear combinations of "complexes", or the monomials coming from mass action. We show how this procedure can be used in proving earlier results of Horn and Jackson and of Shinar and Feinberg for networks of deficiency at most one. We then apply our method to enzyme bifunctionality, including the bacterial EnvZ/OmpR osmolarity regulator and the mammalian 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase glycolytic regulator, whose networks have deficiencies up to four. We show that bifunctionality leads to different forms of concentration control that are robust to changes in initial conditions or total amounts. Finally, we outline a systematic procedure for using complex-linear invariants to analyse molecular networks of any deficiency.

Relation of growth rate from birth to three months and four to six months to body mass index at ages four to six years.

Background. While rapid early weight gain are common in children who become obese later in life, so is growth faltering in the first 3 months of life. Objective. We seek to determine what relationship weight gain in the first six months of age, separated into two 3-month periods, have with the BMI of children ages 4 to 6 years in an inner-city community. Subjects. A convenience sample cohort of 154 children attending an inner-city clinic. Methods. Consecutive charts were reviewed retrospectively. Age, gender, birth weight and weight change in the first and second 3 months of life were introduced as fixed factors using mixed linear models with BMI in years 4 to 6 as the dependent variable. Results. Weight change quartile in the first 3 months of life did not predict of BMI in years 4 to 6; however, weight changes quartiles during months 4 to 6 were significant predictors for subsequent overweight. Conclusion. The data presented herein suggest that, for this specific population, weight gain can be promoted when it is most essential. It is necessary, however, to identify intermediary variables that could affect outcomes in this and other communities.

Diet and social disadvantage: the 'Medical Home' improves nutrition in childhood and diminishes likelihood of disease in adult life.

It is well appreciated that malnutrition in early life has an adverse impact on the overall health of adults. In this review, we address the impact of malnutrition, social disadvantages, and poverty on the lives of children. An integrated response to these difficulties associated in the lives of children, families and the communities in which they live - the "Medical Home" - is suggested as a means to promote health for all ages. The four types of malnutrition delineated by the World Health Organization are discussed, as are differences between "socioeconomic status" and "social gradient." The latter construct is more meaningful from a health care standpoint as differences within each of the socioeconomic groupings are greater than differences between them. Poverty affects food choices with a profound impact on nutritional status. This review suggests how providing a "Medical Home" can improve dietary habits, improve overall nutrition and prevent disease.

Review and application of group theory to molecular systems biology.

In this paper we provide a review of selected mathematical ideas that can help us better understand the boundary between living and non-living systems. We focus on group theory and abstract algebra applied to molecular systems biology. Throughout this paper we briefly describe possible open problems. In connection with the genetic code we propose that it may be possible to use perturbation theory to explore the adjacent possibilities in the 64-dimensional space-time manifold of the evolving genome. With regards to algebraic graph theory, there are several minor open problems we discuss. In relation to network dynamics and groupoid formalism we suggest that the network graph might not be the main focus for understanding the phenotype but rather the phase space of the network dynamics. We show a simple case of a C6 network and its phase space network. We envision that the molecular network of a cell is actually a complex network of hypercycles and feedback circuits that could be better represented in a higher-dimensional space. We conjecture that targeting nodes in the molecular network that have key roles in the phase space, as revealed by analysis of the automorphism decomposition, might be a better way to drug discovery and treatment of cancer.

The NIH Human Microbiome Project.

The Human Microbiome Project (HMP), funded as an initiative of the NIH Roadmap for Biomedical Research (http://nihroadmap.nih.gov), is a multi-component community resource. The goals of the HMP are: (1) to take advantage of new, high-throughput technologies to characterize the human microbiome more fully by studying samples from multiple body sites from each of at least 250 "normal" volunteers; (2) to determine whether there are associations between changes in the microbiome and health/disease by studying several different medical conditions; and (3) to provide both a standardized data resource and new technological approaches to enable such studies to be undertaken broadly in the scientific community. The ethical, legal, and social implications of such research are being systematically studied as well. The ultimate objective of the HMP is to demonstrate that there are opportunities to improve human health through monitoring or manipulation of the human microbiome. The history and implementation of this new program are described here.

Fostering translation of genetics research: an NIDDK perspective.

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the NIH, supports a large and varied portfolio of genetic research grants and contracts. As a funding agency, the NIDDK aims to support research that can be translated into discoveries that help to reduce the burden of genetic diseases. Except for the major advances in diagnostics for Mendelian diseases and a few disease-specific therapies, there has only been modest clinical benefit from the investment in human genetics research. For genetically complex, multifactorial diseases, including many of the common diseases in the USA, the risk genes are harder to find than for Mendelian diseases, and translation seems even further off. How can NIDDK make its investment in human genetics research pay off? This report describes the challenges in human genetics research and NIDDK's fivefold funding strategy to support science that will eventually lead to meaningful translation.