Global food systems transitions have enabled affordable diets but had less favourable outcomes for nutrition, environmental health, inclusion and equity.

Over the past 50 years, food systems worldwide have shifted from predominantly rural to industrialized and consolidated systems, with impacts on diets, nutrition and health, livelihoods, and environmental sustainability. We explore the potential for sustainable and equitable food system transformation (ideal state of change) by comparing countries at different stages of food system transition (changes) using food system typologies. Historically, incomes have risen faster than food prices as countries have industrialized, enabling a simultaneous increase in the supply and affordability of many nutritious foods. These shifts are illustrated across five food system typologies, from rural and traditional to industrial and consolidated. Evolving rural economies, urbanization and changes in food value chains have accompanied these transitions, leading to changes in land distribution, a smaller share of agri-food system workers in the economy and changes in diets. We show that the affordability of a recommended diet has improved over time, but food systems of all types are falling short of delivering optimal nutrition and health outcomes, environmental sustainability, and inclusion and equity for all. Six 'outlier' case studies (Tajikistan, Egypt, Albania, Ecuador, Bolivia and the United States of America) illustrate broad trends, trade-offs and deviations. With the integrated view afforded by typologies, we consider how sustainable transitions can be achieved going forward.

A review of global progress toward the Millennium Development Goal 1 Hunger Target.

BACKGROUND: The hunger component of the first Millennium Development Goal (MDG) aims to reduce the proportion of people who suffer from hunger by half between 1990 and 2015. In low- and middle-income countries, progress has been mixed, with approximately 925 million people hungry and 125 million and 195 million children underweight and stunted, respectively. OBJECTIVE: To assess global progress on the hunger component of MDG1 and evaluate the success of interventions and country programs in reducing undernutrition. METHODS: We review global progress on the hunger component of MDG1, examining experience from 40 community-based programs as well as national efforts to move interventions to scale drawn from the published and gray literature, alongside personal interviews with representatives of governments and development agencies. RESULTS: Based on this review, most strategies being implemented and scaled are focusing on treatment of malnutrition and rooted within the health sector. While critical, these programs generally address disease-related effects and emphasize the immediate determinants of undernutrition. Other major strategies to tackle undernutrition rely on the production of staple grains within the agriculture sector. These programs address hunger, as opposed to improving the quality of diets within communities. Strategies that adopt multisectoral programming as crucial to address longer-term determinants of undernutrition, such as poverty, gender equality, and functioning food and health systems, remain underdeveloped and under-researched. CONCLUSIONS: This review suggests that accelerating progress toward the MDG1 targets is less about the development of novel innovations and new technologies and more about putting what is already known into practice. Success will hinge on linking clear policies with effective delivery systems in working towards an evidence-based and contextually relevant multisectoral package of interventions that can rapidly be taken to scale.

Balancing a sustained pursuit of nutrition, health, affordability and climate goals: exploring the case of Indonesia.

BACKGROUND: To guide the transformation of food systems to provide for healthy and sustainable diets, countries need to assess their current diet and food supply in comparison to nutrition, health, affordability, and environmental goals. OBJECTIVES: We sought to compare Indonesia's food utilization to diets optimized for nutritional value and cost and to diets that are increasingly plant-based in order to meet further health and environmental goals, including the EAT-Lancet planetary health diet, to explore whether multiple goals could be achieved simultaneously. METHODS: We compared 13 dietary scenarios (2 current, 7 optimized, 3 increasingly plant-based, 1 EAT-Lancet) for nutrient content, cost, greenhouse gas emissions (GHGe), and water footprints, using the FAO food balance sheet, Indonesia Household Income and Expenditure Survey household food expenditure, food composition, life cycle assessment, food losses, and trade data. RESULTS: The diversity of modeled scenarios was higher than that of current consumption, reflecting nutritional deficiencies underlying Indonesia's burden of different forms of malnutrition. Nutrient intake targets were met best by nutrient- and cost-optimized diets, followed by the EAT-Lancet diet. Those diets also had high GHGe, although less than 40% of a scenario in which Indonesia would adopt a typical high-income country's diet. Only the low food chain diet had a GHGe below the 2050 target set by the EAT-Lancet commission. Its nutrient content was comparable to that of a no-dairy diet, slightly above those of fish-and-poultry and current diets, and somewhat below those of the EAT-Lancet diets. To meet nutrient needs, some animal-source foods had to be included. Costs of all except the optimized diets were above the current national average food expenditure. No scenario met all goals simultaneously. CONCLUSIONS: Indonesia's consumption of rice and unhealthy foods should decrease; food production, trade, and processing should prioritize diversification, (bio)fortification, and limiting environmental impacts; and consumer and institutional demands for healthy, nutritious, and sustainable foods should be stimulated. More granular data and tools are required to develop and assess more detailed scenarios to achieve multiple goals simultaneously.

Regulation of lymphocyte apoptosis by interferon regulatory factor 4 (IRF-4).

To ensure that homeostasis of the immune system is maintained, the sensitivity of lymphocytes to Fas-mediated apoptosis is differentially regulated during their activation. The molecular mechanisms that link the activation program of lymphocytes to changes in sensitivity to Fas-mediated apoptosis have, however, not been fully characterized. In these studies, we have investigated whether Fas-mediated apoptosis can be regulated by interferon regulatory factor 4 (IRF-4), a lymphoid-restricted member of the IRF family of transcription factors. IRF-4 expression is upregulated during lymphocyte activation and IRF-4-deficient mice have defects in both lymphocyte activation and homeostasis. Here, we show that stable expression of IRF-4 in a human lymphoid cell line that normally lacks IRF-4 leads to a significantly enhanced apoptotic response on Fas receptor engagement. A systematic examination of the downstream effectors of Fas signaling in IRF-4-transfected cells demonstrates an increased activation of caspase-8, as well as an increase in Fas receptor polarization. We demonstrate that IRF-4-deficient mice display defects in activation-induced cell death, as well as superantigen-induced deletion, and that these defects are accompanied by impairments in Fas receptor polarization. These data suggest that IRF-4, by modulating the efficiency of the Fas-mediated death signal, is a novel participant in the regulation of lymphoid cell apoptosis.

Loss of IRF-4-binding protein leads to the spontaneous development of systemic autoimmunity.

IFN regulatory factor 4-binding (IRF-4-binding) protein (IBP) is a novel type of activator of Rho GTPases that is recruited to the immunological synapse upon TCR stimulation. Here we demonstrate that loss of IBP leads to the spontaneous development of a systemic autoimmune disorder characterized by the accumulation of effector/memory T cells and IgG+ B cells, profound hypergammaglobulinemia, and autoantibody production. Similar to human SLE, this syndrome primarily affects females. T cells from IBP-deficient mice are resistant to death in vitro as well as in vivo and exhibit selective defects in effector function. In the absence of IBP, T cells respond suboptimally to TCR engagement, as demonstrated by diminished ERK1/2 activation, decreased c-Fos induction, impaired immunological synapse formation, and defective actin polymerization. Transduction of IBP-deficient T cells with a WT IBP protein, but not with an IBP mutant lacking the Dbl-like domain required for Rho GTPase activation, rescues the cytoskeletal defects exhibited by these cells. Collectively, these findings indicate that IBP, a novel regulator of Rho GTPases, is required for optimal T cell effector function, lymphocyte homeostasis, and the prevention of systemic autoimmunity.

Educating and training a workforce for nutrition in a post-2015 world.

Nearly all countries in the world today are burdened with malnutrition, manifesting as undernutrition, micronutrient deficiencies, and/or overweight and obesity. Despite some progress, efforts to alleviate malnutrition are hampered by a shortage in number, skills, and geographic coverage, of a workforce for nutrition. Here, we report the findings of the Castel Gandolfo workshop, a convening of experts from diverse fields in March 2014 to consider how to develop the capacity of a global cadre of nutrition professionals for the post-2015 development era. Workshop participants identified several requirements for developing a workforce for nutrition, including an ability to work as part of a multisectoral team; communication, advocacy, and leadership skills to engage decision makers; and a set of technical skills to address future challenges for nutrition. Other opportunities were highlighted that could immediately contribute to capacity development, including the creation of a consortium to link global North and South universities, online training modules for middle managers, and practical, hands-on experiences for frontline nutrition workers. Institutional and organizational support is needed to enable workshop recommendations on education and training to be effectively implemented and sustained. The findings from the Castel Gandolfo workshop can contribute to the delivery of successful nutrition-relevant actions in the face of mounting external pressures and informing and attaining the forthcoming Sustainable Development Goals.

CD95 rapidly clusters in cells of diverse origins.

We have shown that CD95-mediated cell death requires a clustering of the receptor in distinct sphingolipid-rich domains of the cell membrane (Grassme et al., 2000, Cremesti et al., 2000). These domains form in response to acid sphingomyelinase (ASM)-induced ceramide generation. However, recent studies challenged the finding of early CD95 clustering (Algeciras-Schimnich et al., 2002). Here, six independent groups tested clustering of CD95 in diverse cell type including primary cells ex vivo and established cell lines. The studies show clustering of CD95 within seconds to minutes in all cell types tested by the different groups. In addition, clustering of CD95 was detected after stimulation of cells using three agonistic anti-CD95 antibodies (CH11, APO-1-3 and JO2), CD95 ligand and stimuli that induce an upregulation and activation of the endogenous CD95/CD95 ligand system. The data confirm our previous studies and suggest rapid, i.e., within seconds to minutes, CD95 clustering as a general phenomenon occurring in many cell types.

Understanding sustainable diets: a descriptive analysis of the determinants and processes that influence diets and their impact on health, food security, and environmental sustainability.

The confluence of population, economic development, and environmental pressures resulting from increased globalization and industrialization reveal an increasingly resource-constrained world in which predictions point to the need to do more with less and in a "better" way. The concept of sustainable diets presents an opportunity to successfully advance commitments to sustainable development and the elimination of poverty, food and nutrition insecurity, and poor health outcomes. This study examines the determinants of sustainable diets, offers a descriptive analysis of these areas, and presents a causal model and framework from which to build. The major determinants of sustainable diets fall into 5 categories: 1) agriculture, 2) health, 3) sociocultural, 4) environmental, and 5) socioeconomic. When factors or processes are changed in 1 determinant category, such changes affect other determinant categories and, in turn, the level of "sustainability" of a diet. The complex web of determinants of sustainable diets makes it challenging for policymakers to understand the benefits and considerations for promoting, processing, and consuming such diets. To advance this work, better measurements and indicators must be developed to assess the impact of the various determinants on the sustainability of a diet and the tradeoffs associated with any recommendations aimed at increasing the sustainability of our food system.

Multisector intervention to accelerate reductions in child stunting: an observational study from 9 sub-Saharan African countries.

BACKGROUND: In sub-Saharan Africa, ~ 40% of children <5 y old are stunted, with levels that have remained largely unchanged over the past 2 decades. Although the complex determinants of undernutrition are well recognized, few studies have evaluated strategies that combine nutrition-specific, health-based approaches with food system- and livelihood-based interventions. OBJECTIVE: We examined changes in childhood stunting and its determinants after 3 y of exposure to an integrated, multisector intervention and compared these changes with national trends. DESIGN: A prospective observational trial was conducted across rural sites in 9 sub-Saharan African countries with baseline levels of childhood stunting >20%. A stratified random sample of households and resident children <2 y old from villages exposed to the program were enrolled in the study. Main outcome measures included principal determinants of undernutrition and childhood stunting, which was defined as a height-for-age z score less than -2. National trends in stunting were generated from demographic and health surveys. RESULTS: Three years after the start of the program in 2005-2006, consistent improvements were observed in household food security and diet diversity, whereas coverage with child care and disease-control interventions improved for most outcomes. The prevalence of stunting in children <2 y old at year 3 of the program (2008-2009) was 43% lower (adjusted OR: 0.57; 95% CI: 0.38, 0.83) than at baseline. The average national stunting prevalence for the countries included in the study had remained largely unchanged over the past 2 decades. CONCLUSION: These findings provide encouraging evidence that a package of multisector interventions has the potential to produce reductions in childhood stunting.

p53 protein and p21 mRNA levels and caspase-3 activity are altered by zinc status in aortic endothelial cells.

The influence of zinc status on the levels of p53, as well as downstream targets of p53 in cell repair and survival, was examined in human aortic endothelial cells (HAECs). A serum-reduced low-zinc medium (ZD) was used to deplete zinc over one passage. Other treatments included zinc-normal control (ZN), zinc-adequate (ZA), and zinc-supplemented (ZS) treatment with 3.0, 16.0, and 32.0 microM zinc, respectively. Cellular zinc levels in the ZD cells were 64% of ZN controls; levels in the ZA cells were not different, but levels in ZS cells were significantly higher (40%) than in ZN cells. No difference in p53 mRNA abundance was detected among all treatments; however, p53 nuclear protein levels were >100% higher in the ZD and ZS cells and almost 200% higher in the ZA cells than in ZN controls. In addition, p21 mRNA abundance, a downstream target of p53 protein, was increased in the ZS cells compared with both the ZN control and ZD cells. In the ZS cells, bax and mcl-1 were also approximately 50% higher compared with ZN controls, whereas bcl-2 mRNA was increased compared with ZA cells. Moreover, caspase-3 activity of ZD cells was not different from that of ZN controls but was reduced to 83 and 69% of ZN controls in ZA and ZS cells, respectively. Thus p53 protein and p53 downstream target genes appeared to be modulated by intracellular zinc status in HAECs.

Modulation of T cell cytokine production by interferon regulatory factor-4.

Production of cytokines is one of the major mechanisms employed by CD4(+) T cells to coordinate immune responses. Although the molecular mechanisms controlling T cell cytokine production have been extensively studied, the factors that endow T cells with their ability to produce unique sets of cytokines have not been fully characterized. Interferon regulatory factor (IRF)-4 is a lymphoid-restricted member of the interferon regulatory factor family of transcriptional regulators, whose deficiency leads to a profound impairment in the ability of mature CD4(+) T cells to produce cytokines. In these studies, we have investigated the mechanisms employed by IRF-4 to control cytokine synthesis. We demonstrate that stable expression of IRF-4 in Jurkat T cells not only leads to a strong enhancement in the synthesis of interleukin (IL)-2, but also enables these cells to start producing considerable amounts of IL-4, IL-10, and IL-13. Transient transfection assays indicate that IRF-4 can transactivate luciferase reporter constructs driven by either the human IL-2 or the human IL-4 promoter. A detailed analysis of the effects of IRF-4 on the IL-4 promoter reveals that IRF-4 binds to a site adjacent to a functionally important NFAT binding element and that IRF-4 cooperates with NFATc1. These studies thus support the notion that IRF-4 represents one of the lymphoid-specific components that control the ability of T lymphocytes to produce a distinctive array of cytokines.

Zinc depletion reduced Egr-1 and HNF-3beta expression and apolipoprotein A-I promoter activity in Hep G2 cells.

We examined the influence of zinc status on expression of certain transcription factors involved in regulation of apolipoprotein A-I (apoAI) expression in human hepatoblastoma Hep G2 cells. A low zinc basal medium (zinc deficient, ZD) consisting of DMEM and 10% Chelex100-treated fetal bovine serum was used to deplete cellular zinc over one passage. Cells were also cultured for one passage in medium supplemented with 0.4 (ZD0.4), 4.0 (zinc normal, ZN), 16.0 (zinc adequate, ZA), or 32.0 microM zinc (zinc supplemented, ZS). Compared with ZN cells, cellular zinc levels were 43 and 31% lower in ZD and ZD0.4 cells but 70 and 146% higher in ZA and ZS cells, respectively. Supplementation of 0.4 microM zinc significantly increased DNA contents per plate, from 65% in ZD cells to 83% in ZD0.4 cells compared with ZN cells. Addition of >4 microM zinc in medium did not further increase DNA contents. The proportion of cells in G(1)/S and S phase was about fourfold higher and threefold lower, respectively, in ZD cells compared with ZN and other groups. Nuclear Egr-1 protein was markedly decreased in ZD and ZD0.4 cells. Moreover, hepatocyte nuclear factor (HNF)-3beta was severely degraded in ZD and ZD0.4 cells. In contrast, HNF-4alpha remained stable in all groups and was not significantly lower in ZD and ZD0.4 cells. Furthermore, downregulation of trans-acting factor Egr-1 and cleavage of HNF-3beta were associated with reduction of apoAI promoter activity in zinc-deficient Hep G2 cells. Thus zinc is critical in transcriptional regulation of apoAI gene expression in hepatocytes.

T cell receptor engagement leads to the recruitment of IBP, a novel guanine nucleotide exchange factor, to the immunological synapse.

Reorganization of the actin cytoskeleton is crucial to the formation and function of the immunological synapse. Rho GTPases are critical mediators of cytoskeletal reorganization, and their activity at the synapse is likely to be stringently regulated. Guanine nucleotide exchange factors (GEFs) belonging to the Dbl family of proteins represent one major class of proteins that regulate the activity of Rho GTPases. Here we demonstrate that IBP, a homologue of SWAP-70, is a novel GEF for Rac1 and Cdc42 in T lymphocytes, which is recruited to the immunological synapse upon engagement of the antigen receptor. Mutational analysis supports a model whereby IBP is inactive in unstimulated cells. Upon engagement of the T cell receptor, its GEF activity is enhanced by tyrosine phosphorylation, as well as by binding newly generated phosphatidylinositol 3,4,5-trisphosphate. Although it is known that T cell receptor engagement leads to the recruitment of Vav to the immunological synapse, these findings indicate that other GEFs, such as IBP, also relocalize to this intercellular region. The recruitment and activation of distinct classes of GEFs may allow for precise control of Rho GTPase function at the crucial interface between T cells and antigen presenting cells.