Individual and community-level risk factors for maternal morbidity and mortality among Native American women in the USA: protocol for systematic review.

INTRODUCTION: Incidents of maternal morbidity and mortality (MMM) continue to rise in the USA. Significant racial and ethnic health inequities exist, with Native American (NA) women being three to four times more likely to die than white, non-Hispanic women, and three to five times more likely to experience an incident of severe maternal morbidity. Few studies have identified individual and community-level risk factors of MMM experienced by NA women. Therefore, this systematic review will identify said risk factors of MMM experienced by NA women in the USA. METHODS AND ANALYSIS: This systematic review will be conducted according to the Cochrane Handbook for Systematic Reviews, and the findings will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA). The search strategy will include searches from electronic databases: PUBMED, EMBASE, CINAHL and SCOPUS, from 1 January 2012 to 10 October 2022. The search strategy will include terms related to the search concepts: 'maternal', 'Native American' and 'MMM'. Bibliographies of selected articles, previously published reviews and high-yield journals will also be searched. All included papers will be evaluated for quality and bias using NIH Quality Assessment Tools for Observational Studies. A description of the study findings will be presented in a tabular format organised by outcome of interest along with study characteristics. ETHICS AND DISSEMINATION: There are no formal ethics approvals needed for this protocol. The findings of this systematic review will be shared with academic, governmental, community-based, institutes and NA (tribal) entities via a published peer-reviewed article, informational brief, poster and oral presentations. PROSPERO REGISTRATION NUMBER: CRD42022363405.

Recent evolution of a TET-controlled and DPPA3/STELLA-driven pathway of passive DNA demethylation in mammals.

Genome-wide DNA demethylation is a unique feature of mammalian development and naïve pluripotent stem cells. Here, we describe a recently evolved pathway in which global hypomethylation is achieved by the coupling of active and passive demethylation. TET activity is required, albeit indirectly, for global demethylation, which mostly occurs at sites devoid of TET binding. Instead, TET-mediated active demethylation is locus-specific and necessary for activating a subset of genes, including the naïve pluripotency and germline marker Dppa3 (Stella, Pgc7). DPPA3 in turn drives large-scale passive demethylation by directly binding and displacing UHRF1 from chromatin, thereby inhibiting maintenance DNA methylation. Although unique to mammals, we show that DPPA3 alone is capable of inducing global DNA demethylation in non-mammalian species (Xenopus and medaka) despite their evolutionary divergence from mammals more than 300 million years ago. Our findings suggest that the evolution of Dppa3 facilitated the emergence of global DNA demethylation in mammals.

Anabolic SIRT4 Exerts Retrograde Control over TORC1 Signaling by Glutamine Sparing in the Mitochondria.

Anabolic and catabolic signaling mediated via mTOR and AMPK (AMP-activated kinase) have to be intrinsically coupled to mitochondrial functions for maintaining homeostasis and mitigate cellular/organismal stress. Although glutamine is known to activate mTOR, whether and how differential mitochondrial utilization of glutamine impinges on mTOR signaling has been less explored. Mitochondrial SIRT4, which unlike other sirtuins is induced in a fed state, is known to inhibit catabolic signaling/pathways through the AMPK-PGC1α/SIRT1-peroxisome proliferator-activated receptor α (PPARα) axis and negatively regulate glutamine metabolism via the tricarboxylic acid cycle. However, physiological significance of SIRT4 functions during a fed state is still unknown. Here, we establish SIRT4 as key anabolic factor that activates TORC1 signaling and regulates lipogenesis, autophagy, and cell proliferation. Mechanistically, we demonstrate that the ability of SIRT4 to inhibit anaplerotic conversion of glutamine to α-ketoglutarate potentiates TORC1. Interestingly, we also show that mitochondrial glutamine sparing or utilization is critical for differentially regulating TORC1 under fed and fasted conditions. Moreover, we conclusively show that differential expression of SIRT4 during fed and fasted states is vital for coupling mitochondrial energetics and glutamine utilization with anabolic pathways. These significant findings also illustrate that SIRT4 integrates nutrient inputs with mitochondrial retrograde signals to maintain a balance between anabolic and catabolic pathways.