Abrupt reversal in ocean overturning during the Palaeocene/Eocene warm period

An exceptional analogue for the study of the causes and consequences of global warming occurs at the Palaeocene/Eocene Thermal Maximum, 55 million years ago. A rapid rise of global temperatures during this event accompanied turnovers in both marine and terrestrial biota, as well as significant changes in ocean chemistry and circulation. Here we present evidence for an abrupt shift in deep-ocean circulation using carbon isotope records from fourteen sites. These records indicate that deep-ocean circulation patterns changed from Southern Hemisphere overturning to Northern Hemisphere overturning at the start of the Palaeocene/Eocene Thermal Maximum. This shift in the location of deep-water formation persisted for at least 40,000 years, but eventually recovered to original circulation patterns. These results corroborate climate model inferences that a shift in deep-ocean circulation would deliver relatively warmer waters to the deep sea, thus producing further warming. Greenhouse conditions can thus initiate abrupt deep-ocean circulation changes in less than a few thousand years, but may have lasting effects; in this case taking 100,000 years to revert to background conditions.     

Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene

Lysinuric protein intolerance (LPI; OMIM 222700) is a rare, recessive disorder with a worldwide distribution, but with a high prevalence in the Finnish population; symptoms include failure to thrive, growth retardation, muscle hypotonia and hepatosplenomegaly. A defect in the plasma membrane transport of dibasic amino acids has been demonstrated at the baso-lateral membrane of epithelial cells in small intestine and in renal tubules and in plasma membrane of cultured skin fibroblasts from LPI patients. The gene causing LPI has been assigned by linkage analysis to 14q11-13. Here we report mutations in SLC7A7 cDNA (encoding y+L amino acid transporter-1, y+LAT-1), which expresses dibasic amino-acid transport activity and is located in the LPI region, in 31 Finnish LPI patients and 1 Spanish patient. The Finnish patients are homozygous for a founder missense mutation leading to a premature stop codon. The Spanish patient is a compound heterozygote with a missense mutation in one allele and a frameshift mutation in the other. The frameshift mutation generates a premature stop codon, eliminating the last one-third of the protein. The missense mutation abolishes y+LAT-1 amino-acid transport activity when co-expressed with the heavy chain of the cell-surface antigen 4F2 (4F2hc, also known as CD98) in Xenopus laevis oocytes. Our data establish that mutations in SLC7A7 cause LPI.     

Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass

Genetic and pharmacological studies have defined a role for the melanocortin-4 receptor (Mc4r) in the regulation of energy homeostasis. The physiological function of Mc3r, a melanocortin receptor expressed at high levels in the hypothalamus, has remained unknown. We evaluated the potential role of Mc3r in energy homeostasis by studying Mc3r-deficient (Mc3r(-/-)) mice and compared the functions of Mc3r and Mc4r in mice deficient for both genes. The 4-6-month Mc3r-/- mice have increased fat mass, reduced lean mass and higher feed efficiency than wild-type littermates, despite being hypophagic and maintaining normal metabolic rates. (Feed efficiency is the ratio of weight gain to food intake.) Consistent with increased fat mass, Mc3r(-/-) mice are hyperleptinaemic and male Mc3r(-/-) mice develop mild hyperinsulinaemia. Mc3r(-/-) mice did not have significantly altered corticosterone or total thyroxine (T4) levels. Mice lacking both Mc3r and Mc4r become significantly heavier than Mc4r(-/-) mice. We conclude that Mc3r and Mc4r serve non-redundant roles in the regulation of energy homeostasis.     

Tauroursodeoxycholic acid prevents E22Q Alzheimer’s Aβ toxicity in human cerebral endothelial cells

The vasculotropic E22Q mutant of the amyloid-β (Aβ) peptide is associated with hereditary cerebral hemorrhage with amyloidosis Dutch type. The cellular mechanism(s) of toxicity and nature of the AβE22Q toxic assemblies are not completely understood. Comparative assessment of structural parameters and cell death mechanisms elicited in primary human cerebral endothelial cells by AβE22Q and wild-type Aβ revealed that only AβE22Q triggered the Bax mitochondrial pathway of apoptosis. AβE22Q neither matched the fast oligomerization kinetics of Aβ42 nor reached its predominant β-sheet structure, achieving a modest degree of oligomerization with a secondary structure that remained a mixture of β and random conformations. The endogenous molecule tauroursodeoxycholic acid (TUDCA) was a strong modulator of AβE22Q-triggered apoptosis but did not significantly change the secondary structures and fibrillogenic propensities of Aβ peptides. These data dissociate the pro-apoptotic properties of Aβ peptides from their distinct mechanisms of aggregation/fibrillization in vitro, providing new perspectives for modulation of amyloid toxicity. Received 20 November 2008; received after revision 12 December 2008; accepted 12 January 2009     

Nowcasting quarterly GDP growth in a monthly coincident indicator model

This paper presents an extension of the Stock and Watson coincident indicator model that allows one to include variables available at different frequencies while taking care of missing observations at any time period. The proposed procedure provides estimates of the unobserved common coincident component, of the unobserved monthly series underlying any included quarterly indicator, and of any missing values in the series. An application to a coincident indicator model for the Portuguese economy is presented. We use monthly indicators from business surveys whose results are published with a very short delay. By using the available data for the monthly indicators and for quarterly real GDP, it becomes possible to produce simultaneously a monthly composite index of coincident indicators and an estimate of the latest quarter real GDP growth well ahead of the release of the first official figures. Copyright © 2005 John Wiley & Son, Ltd.     

Identification of receptors for neuromedin U and its role in feeding

Neuromedin U (NMU) is a neuropeptide with potent activity on smooth muscle which was isolated first from porcine spinal cord and later from other species. It is widely distributed in the gut and central nervous system. Peripheral activities of NMU include stimulation of smooth muscle, increase of blood pressure, alteration of ion transport in the gut, control of local blood flow and regulation of adrenocortical function. An NMU receptor has not been molecularly identified. Here we show that the previously described orphan G-protein-coupled receptor FM-3 (ref. 15) and a newly discovered one (FM-4) are cognate receptors for NMU. FM-3, designated NMU1R, is abundantly expressed in peripheral tissues whereas FM-4, designated NMU2R, is expressed in specific regions of the brain. NMU is expressed in the ventromedial hypothalamus in the rat brain, and its level is significantly reduced following fasting. Intracerebroventricular administration of NMU markedly suppresses food intake in rats. These findings provide a molecular basis for the biochemical activities of NMU and may indicate that NMU is involved in the central control of feeding.     

Dark-recovery in a petite mutant ofSaccharomyces cerevisiae irradiated with ultraviolet light

Zusammenfassung Erholung nach UV-Bestrahlung wurde bei diploiden atmungsdefekten Hefezellen nach Zugabe eines Energiesubstrats (Glukose) im Aufbewahrungsmedium festgestellt. Die Erholungsraten hängen von der UV-Dosis und von der Glukose-Konzentration im Aufbewahrungsmedium ab. Ein Erholungsmaximum wurde bei einer Glukose-Konzentration von 0.15% beobachtet.

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We thank MissEnida Borsani for her expert technical assistance. We also wish to express our thanks to Prof. Dr.W. Pohlit for providing the yeast strain.

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This work was partially supported by the International Atomic Energy Agency (Research Contract No. 785 RB) and by the Fondo de Investigacion Cientifica de la Universidad de la Republica (Uruguay).     

Gene-culture coevolution between cattle milk protein genes and human lactase genes

Milk from domestic cows has been a valuable food source for over 8,000 years, especially in lactose-tolerant human societies that exploit dairy breeds. We studied geographic patterns of variation in genes encoding the six most important milk proteins in 70 native European cattle breeds. We found substantial geographic coincidence between high diversity in cattle milk genes, locations of the European Neolithic cattle farming sites (>5,000 years ago) and present-day lactose tolerance in Europeans. This suggests a gene-culture coevolution between cattle and humans.