Cloning of Dimethylglycine Dehydrogenase and a New Human Inborn Error of Metabolism, Dimethylglycine Dehydrogenase Deficiency

Dimethylglycine dehydrogenase (DMGDH) (E.C. number 1.5.99.2) is a mitochondrial matrix enzyme involved in the metabolism of choline, converting dimethylglycine to sarcosine. Sarcosine is then transformed to glycine by sarcosine dehydrogenase (E.C. number 1.5.99.1). Both enzymes use flavin adenine dinucleotide and folate in their reaction mechanisms. We have identified a 38-year-old man who has a lifelong condition of fishlike body odor and chronic muscle fatigue, accompanied by elevated levels of the muscle form of creatine kinase in serum. Biochemical analysis of the patient’s serum and urine, using 1H-nuclear magnetic resonance NMR spectroscopy, revealed that his levels of dimethylglycine were much higher than control values. The cDNA and the genomic DNA for human DMGDH (hDMGDH) were then cloned, and a homozygous A→G substitution (326 A→G) was identified in both the cDNA and genomic DNA of the patient. This mutation changes a His to an Arg (H109R). Expression analysis of the mutant cDNA indicates that this mutation inactivates the enzyme. We therefore confirm that the patient described here represents the first reported case of a new inborn error of metabolism, DMGDH deficiency

North Atlantic Drift Sediments Constrain Eocene Tidal Dissipation and the Evolution of the Earth-Moon System

Cyclostratigraphy and astrochronology are now at the forefront of geologic timekeeping. While this technique heavily relies on the accuracy of astronomical calculations, solar system chaos limits how far back astronomical calculations can be performed with confidence. High-resolution paleoclimate records with Milankovitch imprints now allow reversing the traditional cyclostratigraphic approach: Middle Eocene drift sediments from Newfoundland Ridge are well-suited for this purpose, due to high sedimentation rates and distinct lithological cycles. Per contra, the stratigraphies of Integrated Ocean Drilling Program Sites U1408–U1410 are highly complex with several hiatuses. Here, we built a two-site composite and constructed a conservative age-depth model to provide a reliable chronology for this rhythmic, highly resolved (<1 kyr) sedimentary archive. Astronomical components (g-terms and precession constant) are extracted from proxy time-series using two different techniques, producing consistent results. We find astronomical frequencies up to 4% lower than reported in astronomical solution La04. This solution, however, was smoothed over 20-Myr intervals, and our results therefore provide constraints on g-term variability on shorter, million-year timescales. We also report first evidence that the g4–g3 “grand eccentricity cycle” may have had a 1.2-Myr period around 41 Ma, contrary to its 2.4-Myr periodicity today. Our median precession constant estimate (51.28 ± 0.56″/year) confirms earlier indicators of a relatively low rate of tidal dissipation in the Paleogene. Newfoundland Ridge drift sediments thus enable a reliable reconstruction of astronomical components at the limit of validity of current astronomical calculations, extracted from geologic data, providing a new target for the next generation of astronomical calculations

Middle Eocene greenhouse climate instability

Understanding warm climate states is increasingly important as projections of anthropogenic climate change indicate atmospheric carbon dioxide concentrations in the coming century not previously seen on Earth for tens of millions of years. The Eocene (~56-34 Ma) is a critical period in the long-term Cenozoic climate evolution, encompassing the transition from widespread greenhouse warmth and high atmospheric carbon dioxide levels pervasive during the early Eocene to an icehouse world with major Antarctic ice sheets and cooler temperatures. Increasingly, it has become apparent that global climate during this transition was not gradual; the middle Eocene is characterized by significant short-term climate variability with recent findings including both transient warming and cooling events. However, the timing, and nature of many of the climate fluctuations during this interval are poorly constrained. To this end, this thesis aims to better characterize the long-term background trends and investigate the nature of short-term transient perturbations during the greenhouse climate of the middle Eocene. In Chapter 2, new nine million year long benthic foraminiferal stable isotope records (~46 to 38 Ma) generated from recently drilled equatorial Pacific sediments with excellent age control are presented. These are the first records to document that the seven enigmatic equatorial Pacific Carbon Accumulation Events (CAEs) are not associated with transient global cooling and/or glaciation events, as previously hypothesized. Further, new carbonate accumulation records in Chapter 3 provide the first robust evidence for the presence of CAEs 3 and 4 in the Atlantic basin. Together, these findings constrain the feasibility of potential CAE forcing mechanisms and imply that there are only two viable mechanisms; (1) solute flux from continental weathering, and (2) increased organic carbon burial from marine assemblage changes. A new compilation (including new and published records) of carbonate accumulation records from a paleodepth transect (2-4 km) in the Atlantic and Pacific basins provides the first multi-basin look at deep-sea carbonate burial at high temporal resolution across the Middle Eocene Climatic Optimum global warming event (~40 Ma). New CCD and lysocline interpretations reveal for the first time that multiple rapid fluctuations (&lt;100 kyrs) and extreme lysocline shoaling (reaching &gt;2 km water depth) are superimposed on long-term trends. This finding implies multiple pulses of carbon input to the ocean–atmosphere system during the MECO and provides critical time constraints to potential forcing mechanisms, which have so far remained elusive. In the final Chapter 4, new lithological and geochemical data from the Atlantic and Pacific Basins are presented which reveal the global nature of the transient ‘C19r event’ (~41.5 Ma) and confirm that the event meets the criteria to be defined as a ‘hyperthermal’. Further, analyses of the stable isotope datasets suggests that the C19r event was not exceptional and is one (albeit the most extreme) of a large number of transient ‘warming’ events throughout the middle Eocene, adding to the growing body of data implying that hyperthermal occurrence is pervasive outside of the very warm late Paleocene and early Eocene.<br/