We review Phanerozoic sea-level changes [543 million years ago (Ma) to the present] on various time scales and present a new sea-level record for the past 100 million years (My). Long-term sea level peaked at 100 ± 50 meters during the Cretaceous, implying that ocean-crust production rates were much lower than previously inferred. Sea level mirrors oxygen isotope variations, reflecting ice-volume change on the 10 4 - to 10 6 -year scale, but a link between oxygen isotope and sea level on the 10 7 -year scale must be due to temperature changes that we attribute to tectonically controlled carbon dioxide variations. Sea-level change has influenced phytoplankton evolution, ocean chemistry, and the loci of carbonate, organic carbon, and siliciclastic sediment burial. Over the past 100 My, sea-level changes reflect global climate evolution from a time of ephemeral Antarctic ice sheets (100 to 33 Ma), through a time of large ice sheets primarily in Antarctica (33 to 2.5 Ma), to a world with large Antarctic and large, variable Northern Hemisphere ice sheets (2.5 Ma to the present).

/pdf/the-phanerozoic-record-of-global-sea-level-change-14696qrujw.pdf

The Phanerozoic Record of Global Sea-Level Change

Assessing mitochondrial dysfunction requires definition of the dysfunction to be investigated. Usually, it is the ability of the mitochondria to make ATP appropriately in response to energy demands. Where other functions are of interest, tailored solutions are required. Dysfunction can be assessed in isolated mitochondria, in cells or in vivo, with different balances between precise experimental control and physiological relevance. There are many methods to measure mitochondrial function and dysfunction in these systems. Generally, measurements of fluxes give more information about the ability to make ATP than do measurements of intermediates and potentials. For isolated mitochondria, the best assay is mitochondrial respiratory control: the increase in respiration rate in response to ADP. For intact cells, the best assay is the equivalent measurement of cell respiratory control, which reports the rate of ATP production, the proton leak rate, the coupling efficiency, the maximum respiratory rate, the respiratory control ratio and the spare respiratory capacity. Measurements of membrane potential provide useful additional information. Measurement of both respiration and potential during appropriate titrations enables the identification of the primary sites of effectors and the distribution of control, allowing deeper quantitative analyses. Many other measurements in current use can be more problematic, as discussed in the present review.

/pdf/assessing-mitochondrial-dysfunction-in-cells-3j64pz5jhm.pdf

Assessing mitochondrial dysfunction in cells

The "fetal" or "early" origins of adult disease hypothesis was originally put forward by David Barker and colleagues and stated that environmental factors, particularly nutrition, act in early life to program the risks for adverse health outcomes in adult life. This hypothesis has been supported by a worldwide series of epidemiological studies that have provided evidence for the association between the perturbation of the early nutritional environment and the major risk factors (hypertension, insulin resistance, and obesity) for cardiovascular disease, diabetes, and the metabolic syndrome in adult life. It is also clear from experimental studies that a range of molecular, cellular, metabolic, neuroendocrine, and physiological adaptations to changes in the early nutritional environment result in a permanent alteration of the developmental pattern of cellular proliferation and differentiation in key tissue and organ systems that result in pathological consequences in adult life. This review focuses on those experimental studies that have investigated the critical windows during which perturbations of the intrauterine environment have major effects, the nature of the epigenetic, structural, and functional adaptive responses which result in a permanent programming of cardiovascular and metabolic function, and the role of the interaction between the pre- and postnatal environment in determining final health outcomes.

https://www.physiology.org/doi/pdf/10.1152/physrev.00053.2003

Developmental Origins of the Metabolic Syndrome: Prediction, Plasticity, and Programming

Partitioning of Nutrients During Pregnancy and Lactation: A Review of Mechanisms Involving Homeostasis and Homeorhesis

Knowledge of the evolution of atmospheric carbon dioxide concentrations throughout the Earth's history is important for a
reconstruction of the links between climate and radiative forcing of the Earth's surface temperatures. Although atmospheric
carbon dioxide concentrations in the early Cenozoic era (about 60Myr ago) are widely believed to have been higher than at present,
there is disagreement regarding the exact carbon dioxide levels, the timing of the decline and the mechanisms that are most
important for the control of CO2 concentrations over geological timescales. Here we use the boron-isotope ratios of ancient
planktonic foraminifer shells to estimate the pH of surface-layer sea water throughout the past 60 million years, which can be used
to reconstruct atmospheric CO2 concentrations. We estimate CO2 concentrations of more than 2,000 p.p.m. for the late Palaeocene
and earliest Eocene periods (from about 60 to 52 Myr ago), and ®nd an erratic decline between 55 and 40 Myr ago that may have
been caused by reduced CO2 outgassing from ocean ridges, volcanoes and metamorphic belts and increased carbon burial. Since
the early Miocene (about 24Myr ago), atmospheric CO2 concentrations appear to have remained below 500 p.p.m. and were more
stable than before, although transient intervals of CO2 reduction may have occurred during periods of rapid cooling approximately
15 and 3 Myr ago.

Atmospheric carbon dioxide concentrations over the past 60 million years

Climate modes of the phanerozoic

Greater protein intakes are required than have been commonly used to achieve fetal in utero protein accretion rates in preterm neonates. To study the efficacy and safety of more aggressive amino acid intake, we performed a prospective randomized study in 28 infants [mean wt, 946 +/- 40 g (SEM)] of 1 (low amino acid intake, LAA) versus 3 g.kg(-1).d(-1) (high amino acid intake, HAA) at 52.0 +/- 3.0 h of life. After a minimum of 12 h of parenteral nutrition, efficacy was determined by protein balance and was significantly lower in the LAA versus HAA groups by both nitrogen balance (-0.26 +/- 0.11 versus 1.16 +/- 0.15 g.kg(-1).d(-1), p < 0.00005) and leucine stable isotope (0.184 +/- 0.17 versus 1.63 +/- 0.20 g.kg(-1).d(-1), p < 0.0005) methods. Leucine flux and oxidation and nonoxidative leucine disposal rates were all significantly higher in the HAA versus LAA groups (249 +/- 13 versus 164 +/- 8, 69 +/- 5 versus 32 +/- 3, and 180 +/- 10 versus 132 +/- 8 micro mol.kg(-1).h(-1), respectively, p < 0.005), but leucine appearance from protein breakdown was not (140 +/- 15 in HAA versus 128 +/- 8 micro mol.kg(-1).h(-1)). In terms of possible toxicity with HAA, there were no significant differences between groups in the amount of sodium bicarbonate administered, degree of acidosis as determined by base deficit, or blood urea nitrogen concentration. Parenteral HAA versus LAA intake resulted in increased protein accretion, primarily by increasing protein synthesis versus suppressing protein breakdown, and appeared to be well tolerated by very preterm infants in the first days of life.

/pdf/effect-of-low-versus-high-intravenous-amino-acid-intake-on-2ix0zy44yb.pdf

Effect of low versus high intravenous amino acid intake on very low birth weight infants in the early neonatal period.

According to many experts in neonatal nutrition, the goal for nutrition of the preterm infant should be to achieve a postnatal growth rate approximating that of the normal fetus of the same gestationa

/pdf/strategies-for-feeding-the-preterm-infant-30fuf4z4kw.pdf

Strategies for Feeding the Preterm Infant

Fetal glucose metabolism depends on additive effects of fetal plasma glucose and insulin. Glucose-stimulated insulin secretion increases over gestation, is down-regulated by constant hyperglycemia, but enhanced by pulsatile hyperglycemia. Insulin production is diminished in fetuses with intrauterine growth restriction (IUGR) by inhibition of pancreatic β-cell replication, but not by mechanisms that regulate insulin production or secretion, while the opposite occurs with hypoglycemia alone, despite its common occurrence in IUGR. Chronic hyperglycemia down-regulates glucose tolerance and insulin sensitivity with decreased expression of skeletal muscle and hepatic Glut 1 and 4 glucose transporters, while chronic hypoglycemia up-regulates these transporters. The opposite occurs for signal transduction proteins that regulate amino acid synthesis into protein. These results demonstrate the mixed phenotype of the IUGR fetus with enhanced glucose utilization capacity, but diminished protein synthesis and growth. Such adaptations might underlie childhood and adult metabolic disorders of insulin resistance, obesity, and diabetes mellitus.

Placental-fetal glucose exchange and fetal glucose metabolism.

We determined in vivo and in vitro pancreatic islet insulin secretion and glucose metabolism in fetuses with intrauterine growth restriction (IUGR) caused by chronic placental insufficiency to identify functional deficits in the fetal pancreas that might be caused by nutrient restriction. Plasma insulin concentrations in the IUGR fetuses were 69% lower at baseline and 76% lower after glucose-stimulated insulin secretion (GSIS). Similar deficits were observed with arginine-stimulated insulin secretion. Fetal islets, immunopositive for insulin and glucagon, secreted insulin in response to increasing glucose and KCl concentrations. Insulin release as a fraction of total insulin content was greater in glucose-stimulated IUGR islets, but the mass of insulin released per IUGR islet was lower because of their 82% lower insulin content. A deficiency in islet glucose metabolism was found in the rate of islet glucose oxidation at maximal stimulatory glucose concentrations (11 mmol/liter). Thus, pancreatic islets from nutritionally deprived IUGR fetuses caused by chronic placental insufficiency have impaired insulin secretion caused by reduced glucose-stimulated glucose oxidation rates, insulin biosynthesis, and insulin content. This impaired GSIS occurs despite an increased fractional rate of insulin release that results from a greater proportion of releasable insulin as a result of lower insulin stores. Because this animal model recapitulates the human pathology of chronic placental insufficiency and IUGR, the beta-cell GSIS dysfunction in this model might indicate mechanisms that are developmentally adaptive for fetal survival but in later life might predispose offspring to adult-onset diabetes that has been previously associated with IUGR.

/pdf/attenuated-insulin-release-and-storage-in-fetal-sheep-3ngs0hymbr.pdf

William W. Hay

Papers

Climate modes of the phanerozoic

Effect of low versus high intravenous amino acid intake on very low birth weight infants in the early neonatal period.

Strategies for Feeding the Preterm Infant

Placental-fetal glucose exchange and fetal glucose metabolism.

Attenuated insulin release and storage in fetal sheep pancreatic islets with intrauterine growth restriction.