Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice

A fundamental question about the pathogenesis of spontaneous autoimmune diabetes is whether there are primary autoantigens. For type 1 diabetes it is clear that multiple islet molecules are the target of autoimmunity in man and animal models. It is not clear whether any of the target molecules are essential for the destruction of islet beta cells. Here we show that the proinsulin/insulin molecules have a sequence that is a primary target of the autoimmunity that causes diabetes of the non-obese diabetic (NOD) mouse. We created insulin 1 and insulin 2 gene knockouts combined with a mutated proinsulin transgene (in which residue 16 on the B chain was changed to alanine) in NOD mice. This mutation abrogated the T-cell stimulation of a series of the major insulin autoreactive NOD T-cell clones. Female mice with only the altered insulin did not develop insulin autoantibodies, insulitis or autoimmune diabetes, in contrast with mice containing at least one copy of the native insulin gene. We suggest that proinsulin is a primary autoantigen of the NOD mouse, and speculate that organ-restricted autoimmune disorders with marked major histocompatibility complex (MHC) restriction of disease are likely to have specific primary autoantigens.     

A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis

Genetic susceptibility to multiple sclerosis is associated with genes of the major histocompatibility complex (MHC), particularly HLA-DRB1 and HLA-DQB1 (ref. 1). Both locus and allelic heterogeneity have been reported in this genomic region. To clarify whether HLA-DRB1 itself, nearby genes in the region encoding the MHC or combinations of these loci underlie susceptibility to multiple sclerosis, we genotyped 1,185 Canadian and Finnish families with multiple sclerosis (n = 4,203 individuals) with a high-density SNP panel spanning the genes encoding the MHC and flanking genomic regions. Strong associations in Canadian and Finnish samples were observed with blocks in the HLA class II genomic region (P < 4.9 x 10(-13) and P < 2.0 x 10(-16), respectively), but the strongest association was with HLA-DRB1 (P < 4.4 x 10(-17)). Conditioning on either HLA-DRB1 or the most significant HLA class II haplotype block found no additional block or SNP association independent of the HLA class II genomic region. This study therefore indicates that MHC-associated susceptibility to multiple sclerosis is determined by HLA class II alleles, their interactions and closely neighboring variants.     

Increased marine production of N2O due to intensifying anoxia on the Indian continental shelf

Eutrophication of surface waters and hypoxia in bottom waters has been increasing in many coastal areas, leading to very large depletions of marine life in the affected regions. These areas of high surface productivity and low bottom-water oxygen concentration are caused by increasing runoff of nutrients from land. Although the local ecological and socio-economic effects have received much attention, the potential contribution of increasing hypoxia to global-change phenomena is unknown. Here we report the intensification of one of the largest low-oxygen zones in the ocean, which develops naturally over the western Indian continental shelf during late summer and autumn. We also report the highest accumulations yet observed of hydrogen sulphide (H2S) and nitrous oxide (N2O) in open coastal waters. Increased N2O production is probably caused by the addition of anthropogenic nitrate and its subsequent denitrification, which is favoured by hypoxic conditions. We suggest that a global expansion of hypoxic zones may lead to an increase in marine production and emission of N2O, which, as a potent greenhouse gas, could contribute significantly to the accumulation of radiatively active trace gases in the atmosphere.     

导弹制导和控制系统

虽然导弹制导和控制系统的出现源自军事目的，但是这项技术已经应用于很多领域，比如机器人、工业过程控制和全球定位系统（GPS，Global Positioning System）。本书详细的阐述了这项技术的最新幕后，战略和战术导弹及其对给定目标的制导、控制和采取的策略。     

Alkaloid studies XXV. The structure of the Aspidosperma alkaloids cylindrocarpine and cylindrocarpidine

Zusammenfassung Die Strukturaufklärung von Cylindrocarpin (II) und Cylindrocarpidin (IV) zeigt, dass diese zwei Alkaloide die ersten Mitglieder der Aspidosperminfamilie (I) sind, in denen eine sauerstoffhaltige Seitenkette anstatt der gewöhnlichen C-5-Äthylgruppe vorliegt.

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Paper XXIV,T. Nakano, C. Djerassi, R. A. Corral, andO. O. Orazi, J. org. Chem., in press.

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Postdoctorate research fellow, 1958–1960.     

Comparison of the effects of atropine sulfate and procaine hydrochloride on nerve conduction

Zusammenfassung Die lokalanästhetische Wirksamkeit des Atropinsulfats wurde mit der des Novokains mittels Messung der Kinetik des Nervenimpulsblocks am isolierten Nervus ischiadicus des Frosches verglichen. Die relative Wirksamkeit des Atropinsulfats ist weniger als 120.     

Methods for determining ploidy in amphibians: Nucleolar number and erythrocyte size

Summary Diploid and triploidXenopus can be easily and reliably distinguished by the size of their erythrocytes. This method has several advantages over other methods, such as counting metaphase chromosomes and counting nucleoli. One problem with the latter method is the reduction in cells with a full complement of nucleoli when regenerating tissue is used.Research supported by NIH grant EY 01662.     

Respiratory control in liver mitochondria of rats hosting the walker 256 carcinoma tumor.

The decrease in the respiratory control ratio of mitochondria is a first order process when these organelles are incubated in isotonic sucrose. Furthermore, the initial respiratory control ratios and the rates of loss in respiratory control in liver mitochondria from rats hosting the Walker 256 carcinoma are not significantly different form the same properties of mitochondria from untreated animals.