The role of metabolic compartmentation in spatially organizing metabolic enzymes into pathways, regulating flux through metabolic pathways, and controlling the partitioning of metabolic intermediates among pathways is appreciated, but our understanding of the mechanisms that establish metabolic architecture and mediate communication and regulation among interconnected metabolic pathways and networks is still incomplete. This review discusses recent advancements in our understanding of metabolic compartmentation within the pathways that constitute the folate-mediated one-carbon metabolic network and emerging evidence for a need to regulate the trafficking of folates among compartmentalized metabolic pathways.

Folate, an essential nutrient found naturally in foods in a reduced form, is present in dietary supplements and fortified foods in an oxidized synthetic form (folic acid). There is widespread agreement that maintaining adequate folate status is critical to prevent diseases due to folate inadequacy (e.g., anemia, birth defects, and cancer). However, there are concerns of potential adverse effects of excess folic acid intake and/or elevated folate status, with the original concern focused on exacerbation of clinical effects of vitamin B-12 deficiency and its role in neurocognitive health. More recently, animal and observational studies have suggested potential adverse effects on cancer risk, birth outcomes, and other diseases. Observations indicating adverse effects from excess folic acid intake, elevated folate status, and unmetabolized folic acid (UMFA) remain inconclusive; the data do not provide the evidence needed to affect public health recommendations. Moreover, strong biological and mechanistic premises connecting elevated folic acid intake, UMFA, and/or high folate status to adverse health outcomes are lacking. However, the body of evidence on potential adverse health outcomes indicates the need for comprehensive research to clarify these issues and bridge knowledge gaps. Three key research questions encompass the additional research needed to establish whether high folic acid or total folate intake contributes to disease risk. 1) Does UMFA affect biological pathways leading to adverse health effects? 2) Does elevated folate status resulting from any form of folate intake affect vitamin B-12 function and its roles in sustaining health? 3) Does elevated folate intake, regardless of form, affect biological pathways leading to adverse health effects other than those linked to vitamin B-12 function? This article summarizes the proceedings of an August 2019 NIH expert workshop focused on addressing these research areas.

Abstract.The basic properties of vector fields and diffeomorphisms invariant under the action of a compact Lie group are presented. A Kupka-Smale density theorem for equivariant dynamical systems and an existence theorem for equivariant Morse-Smale systems on an arbitrary compact G-manifold are proved.Introduction. In this work we develop the basic properties of vector fields and diffeomorphisms invariant under the action of a compact Lie group. Earlier versions of this theory were announced in [7], [8] though these results are weaker in certain significant respects than those presented here.We prove two fundamental theorems: A Kupka-Smale density theorem for equivariant dynamical systems (Theorem B of §9) and an existence theorem for equivariant Morse-Smale vector fields on a compact G-manifold (Theorem D of §10). The latter theorem has interesting implications for the theories of equivariant dynamical systems and equivariant differential topology, notably for a generalisation of the C° isotopy and approximation theorems of Shub and Smale [23], [27] to equivariant maps and we intend to pursue these matters elsewhere. We hope also to make applications of part of our theory to bifurcation problems involving a loss of symmetry (cf. S. Schecter, Bifurcations with symmetry [17, pp. 224-249]). The definition of Í2G in §10 is particularly relevant here as is the theory of equivariant general position or G-transversality for the invariant manifolds of elementary critical elements (see §9 and also below). In § §1, 2 we outline the basic properties of smooth G-manifolds and equivariant flows and diffeomorphisms that we need. In §3 we define elementary invariant (7-orbits in terms of the normal hyperbolicity conditions of Hirsh, Pugh and Shub [15] and then give a spectral characterisation of such orbits. In §4 we make a similar discussion of periodic orbits followed in § §5, 6 by the basic local theory of equivariant dynamical systems. In §7, we prove that Cr 1-generic (resp. 2-generic) equivariant vector fields and diffeomorphisms form an open dense set (resp. residual set), r > 1. Apart from the complications introduced by the presence of the G-action, the proofs follow Peixoto [20]. Stable manifold theory is discussed in §8. In §9, we prove a Kupka-Smale density theorem for C°° equivariant dynamical systems. As there is yet no Cr-theory of equivariant general position, r < oo, we have no C density theorem. It should be pointed out that the theory of equivariant

There is a large body of literature demonstrating the efficacy of maternal folic acid intake in preventing birth defects, as well as investigations into potential adverse consequences of consuming folic acid above the upper level of intake (UL). Recently, two authoritative bodies convened expert panels to assess risks from high intakes of folic acid: the United States’ National Toxicology Program (NTP) and the United Kingdom’s Scientific Advisory Committee on Nutrition (SACN). Overall, the totality of the evidence examined by these panels, as well as studies published since the release of their reports, have not established risks for adverse consequences resulting from existing mandatory folic acid fortification programs that have been implemented in many countries. Current folic acid fortification programs have been shown to support public health in populations, and the exposure levels are informed by and adherent to the precautionary principle. Additional research is needed to assess the health effects of folic acid supplement use when the current upper limit for folic acid is exceeded.