Synthesis of the heterocyclic core of the alkaloids martinelline and martinellic acid

The tricyclic core of martinelline and martinellic acid was rapidly assembled utilising an imino Diels-Alder reaction of an imine derived from cinnamaldehyde with a cyclic enamide. The cycloaddition was completely regioselective though the exo endo selectivity was poor. These diastercoisomers were readily separated by flash chromatography and the relative stereochemistry of the exo-isomer confirmed by single crystal X-ray crystallography. This intermediate was converted to the central core of the aforementioned alkaloids in five additional synthetic operations. (C) 2001 Elsevier Science Ltd. All rights reserved.

A mutation in the transmembrane/luminal domain of the ryanodine receptor is associated with abnormal Ca2+ release channel function and severe central core disease

Central core disease is a rare, nonprogressive myopathy that is characterized by hypotonia and proximal muscle weakness. In a large Mexican kindred with an unusually severe and highly penetrant form of the disorder, DNA sequencing identified an I4898T mutation in the C-terminal transmembrane/luminal region of the RyR1 protein that constitutes the skeletal muscle ryanodine receptor. All previously reported RYR1 mutations are located either in the cytoplasmic N terminus or in a central cytoplasmic region of the 5,038-aa protein. The I4898T mutation was introduced into a rabbit RYR1 cDNA and expressed in HEK-293 cells. The response of the mutant RyR1 Ca2+ channel to the agonists halothane and caffeine in a Ca2+ photometry assay was completely abolished. Coexpression of normal and mutant RYR1 cDNAs in a 1:1 ratio, however, produced RyR1 channels with normal halothane and caffeine sensitivities, but maximal levels of Ca2+ release were reduced by 67%. [3H]Ryanodine binding indicated that the heterozygous channel is activated by Ca2+ concentrations 4-fold lower than normal. Single-cell analysis of cotransfected cells showed a significantly increased resting cytoplasmic Ca2+ level and a significantly reduced luminal Ca2+ level. These data are indicative of a leaky channel, possibly caused by a reduction in the Ca2+ concentration required for channel activation. Comparison with two other coexpressed mutant/normal channels suggests that the I4898T mutation produces one of the most abnormal RyR1 channels yet investigated, and this level of abnormality is reflected in the severe and penetrant phenotype of affected central core disease individuals.

Excitation–contraction uncoupling by a human central core disease mutation in the ryanodine receptor

Central core disease (CCD) is a human congenital myopathy characterized by fetal hypotonia and proximal muscle weakness that is linked to mutations in the gene encoding the type-1 ryanodine receptor (RyR1). CCD is thought to arise from Ca2+-induced damage stemming from mutant RyR1 proteins forming “leaky” sarcoplasmic reticulum (SR) Ca2+ release channels. A novel mutation in the C-terminal region of RyR1 (I4898T) accounts for an unusually severe and highly penetrant form of CCD in humans [Lynch, P. J., Tong, J., Lehane, M., Mallet, A., Giblin, L., Heffron, J. J., Vaughan, P., Zafra, G., MacLennan, D. H. & McCarthy, T. V. (1999) Proc. Natl. Acad. Sci. USA 96, 4164–4169]. We expressed in skeletal myotubes derived from RyR1-knockout (dyspedic) mice the analogous mutation engineered into a rabbit RyR1 cDNA (I4897T). Here we show that homozygous expression of I4897T in dyspedic myotubes results in a complete uncoupling of sarcolemmal excitation from voltage-gated SR Ca2+ release without significantly altering resting cytosolic Ca2+ levels, SR Ca2+ content, or RyR1-mediated enhancement of dihydropyridine receptor (DHPR) channel activity. Coexpression of both I4897T and wild-type RyR1 resulted in a 60% reduction in voltage-gated SR Ca2+ release, again without altering resting cytosolic Ca2+ levels, SR Ca2+ content, or DHPR channel activity. These findings indicate that muscle weakness suffered by individuals possessing the I4898T mutation involves a functional uncoupling of sarcolemmal excitation from SR Ca2+ release, rather than the expression of overactive or leaky SR Ca2+ release channels.

A high-resolution sedimentology and age determination of core PS2185 from the central Arctic Ocean

A high-resolution multiparameter stratigraphy allows the identification of late Quaternary glacial and interglacial cycles in a central Arctic Ocean sediment core. Distinct sandy layers in the upper part of the otherwise fine-grained sediment core from the Lomonosov Ridge (lat 87.5°N) correlate to four major glacials since ca. 0.7 Ma. The composition of these ice-rafted terrigenous sediments points to a glaciated northern Siberia as the main source. In contrast, lithic carbonates derived from North America are also present in older sediments and indicate a northern North American glaciation since at least 2.8 Ma. We conclude that large-scale northern Siberian glaciation began much later than other Northern Hemisphere ice sheets.

Planktic foraminifera isotopes, temperature and d18O of seawater at the central Walvis Ridge for Termination II (MIS 6 to 5), sediment core 64PE-174P13

Salty and warm Indian Ocean waters enter the South Atlantic via the Agulhas leakage, south of Africa. Model simulations and proxy evidence of Agulhas leakage strengthening during glacial terminations led to the hypothesis that it was an important modulator of the Atlantic Ocean circulation. Yet, the fate of the leakage salinity and temperature anomalies remains undocumented beyond the southern tip of Africa. Downstream of the leakage, new paleoceanographic evidence from the central Walvis Ridge (southeast Atlantic) shows that salinity increased at the thermocline, and less so at the surface, during glacial termination II. Thermocline salinity change coincided with higher frequency of Agulhas rings passage at the core location and with salinity maxima in the Agulhas leakage area, suggesting that leakage waters were incorporated in the Atlantic circulation through the thermocline. Hydrographic changes at the Walvis Ridge and in the leakage area display a distinct two-step structure, with a reversal at ca. 134 ka. This matched a wet interlude within the East Asia weak monsoon interval of termination II, and a short-lived North Atlantic warming. Such concurrence points to a Bølling-Allerød-like recovery of the Atlantic circulation amidst termination II, with a northward shift of the Intertropical Convergence Zone and Southern Hemisphere westerlies, and attendant curtailment of the interocean connection south of Africa.