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The biological mechanism(s) linking changes in environmental factors to health and disease are incompletely understood. We propose a TNF\u2010hypersecreting phenotype described in rheumatoid arthritis patients also has a role in the inflammatory response differences observed between rural and urban populations living in Africa. The mechanism involves insufficient mitochondrial aspartate production, failed NAD\n                    <jats:sup>+<\/jats:sup>\n                    regeneration, ER membrane expansion, and enhanced biogenesis of TNF\u2010\u03b1. Supporting data show serum and stool aspartate levels decline with urbanization, and TNF\u2010\u03b1 production inversely correlates with stool aspartate levels across a spectrum of socioeconomic development. These findings suggest a new hypothesis for the inflammatory differences between rural and urban populations and their role in noncommunicable diseases like atherosclerosis.\n                  <\/jats:p>","DOI":"10.1096\/fj.202500738r","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T11:36:32Z","timestamp":1749468992000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Aspartate Is A Determinant of TNF\u2010\u03b1 Biogenesis in Sub\u2010Saharan Africa: Insight Into the Pathogenesis of Noncommunicable Diseases"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2626-2407","authenticated-orcid":false,"given":"Stephen W.","family":"Bickler","sequence":"first","affiliation":[{"name":"Department of Surgery, Division of Pediatric Surgery UC San Diego  San Diego California USA"},{"name":"Division of Pediatric Surgery Rady Children's Hospital  San Diego USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M.","family":"Cauvi","sequence":"additional","affiliation":[{"name":"Division of Pediatric Surgery Rady Children's Hospital  San Diego USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jack A.","family":"Gilbert","sequence":"additional","affiliation":[{"name":"University of California, San Diego, Scripps Institution of Oceanography  La Jolla California USA"},{"name":"Department of Pediatrics UC San Diego  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Romeo C.","family":"Ignacio","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Pediatric Surgery UC San Diego  San Diego California USA"},{"name":"Division of Pediatric Surgery Rady Children's Hospital  San Diego USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuel A.","family":"Ameh","sequence":"additional","affiliation":[{"name":"Division of Pediatric Surgery, Department of Surgery National Hospital  Abuja Nigeria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert T.","family":"Schooley","sequence":"additional","affiliation":[{"name":"Department of Medicine UC San Diego  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilia V.","family":"Noormahomed","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Faculty of Medicine Universidade Eduardo Mondlane (UEM)  Maputo Mozambique"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,6,9]]},"reference":[{"key":"e_1_2_11_2_1","first-page":"159","article-title":"Population Health in Transition","volume":"79","author":"Caldwell J. 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