Activation of two signal-transduction systems in hepatocytes by glucagon

The ability of glucagon to stimulate glycogen breakdown in liver played a key part in the classic identification of cyclic AMP and hormonally stimulated adenylate cyclase. But several observations indicate that glucagon can exert effects independent of elevating intracellular cAMP concentrations. These effects are probably mediated by an elevation of the intracellular concentration of free Ca2+ although the mechanism by which this occurs is unknown. We show here that glucagon, at the low concentrations found physiologically, causes both a breakdown of inositol phospholipids and the production of inositol phosphates. Indeed, we show that the glucagon analogue, (1-N-alpha-trinitrophenylhistidine,12-homoarginine)glucagon (TH-glucagon), which does not activate adenylate cyclase or cause any increase in cAMP in hepatocytes yet can fully stimulate glycogenolysis, gluconeogenesis and urea synthesis, stimulates the production of inositol phosphates. This stimulation of inositol phospholipid metabolism by low concentrations of glucagon provides a mechanism whereby glucagon can exert cAMP-independent actions on target cells. We suggest that hepatocytes possess two distinct receptors for glucagon, a GR-1 receptor coupled to stimulate inositol phospholipid breakdown and a GR-2 receptor coupled to stimulate adenylate cyclase activity.     

TM-Zn金属间化合物结构稳定性的第一性原理研究

基于能带结构,提出Jahn-Teller效应的诱发条件.基于声子色散曲线,揭示晶格动态稳定性和简并振动模式产生劈裂的物理特征.基于电子局域化函数和束缚能,揭示原子成键特性.结果表明,TM-Zn(TM=Ni,Pd,Pt,Cu,Ag,Au)金属间化合物发生立方到四方的相变变形过程中,结构保持稳定.     

Variable stoichiometry of proton pumping by the mitochondrial respiratory chain

The proton/oxygen stoichiometry and the mechanism of the proton pumping respiratory complexes in the mitochondrial respiratory chain have been central issues in bioenergetics for several years. Recently, a number of disagreements about stoichiometry have been resolved, and H+/O ratios of 6 (refs 1-3) or perhaps 8 (refs 4 and 5) for succinate oxidation are now accepted. Suggestions that the stoichiometry in mitochondria is intrinsically variable ('slip' in the pumps) have been made but the evidence has been neither strong nor direct. We now show by direct measurement in steady-state conditions that the H+/O ratio (measured as the charge/O ratio) for isolated mitochondria respiring on succinate varies from 6 at low membrane potential to 2.5-3 at membrane potentials of about 170 mV.     

Bilateral amblyopia after a short period of reverse occlusion in kittens

The majority of neurones in the visual cortex of both adult cats and kittens can be excited by visual stimulation of either eye. Nevertheless, if one eye is deprived of patterned vision early in life, most cortical cells can only be activated by visual stimuli presented to the nondeprived eye and behaviourally the deprived eye is apparently useless. Although the consequences of monocular deprivation can be severe, they can in many circumstances be rapidly reversed with the early implementation of reverse occlusion which forces the use of the initially deprived eye. However, by itself reverse occlusion does not restore a normal distribution of cortical ocular dominance and only promotes visual recovery in one eye. In an effort to find a procedure that might restore good binocular vision, we have examined the effects on acuity and cortical ocular dominance of a short, but physiologically optimal period of reverse occlusion, followed by a period of binocular vision beginning at 7.5 weeks of age. Surprisingly, despite the early introduction of binocular vision, both eyes attained acuities that were only approximately 1/3 of normal acuity levels. Despite the severe bilateral amblyopia, cortical ocular dominance appeared similar to that of normal cats. This is the first demonstration of severe bilateral amblyopia following consecutive periods of monocular occlusion.     

Maternal involvement in the development of cardiovascular phenotype

Over the past 20 years, laboratory studies of genetically defined animal models of human essential hypertension have provided valuable information on the pathophysiology of this disturbance in cardiovascular regulation. Relatively fewer studies have examined the impact of preweaning factors on the developing cardiovascular system of hypertensive animals. In our laboratory studies, we have utilized two inbred genetically hypertensive models: the spontaneously hypertensive (SHR) rat and its Wistar/Kyoto (WKY) normotensive control strain as well as the Dahl hypertension-sensitive (SS/Jr) and hypertension-resistant (SR/Jr) strains. To manipulate the preweaning maternal environment, we have employed the technique of reciprocal cross-fostering of litters between hypertensive and matched normotensive mothers. Our findings to date point to the maternal environment as a powerful influence on the development of high blood pressure in genetically hypertensive rats. In general, hypertensive rats reared by normotensive foster mothers have significant reductions in arterial blood pressure in adulthood. Thus, the progression of hypertinsive disease is not strictly predtermined by genotypic factors. Rather, a genetic predisposition to hypertension interacts with preweaning environmental factors to determine an animal's cardiovascular phenotype in adulthood.     

Biochemistry: biosynthesis of an organofluorine molecule

Although fluorine in the form of fluoride minerals is the most abundant halogen in the Earth's crust, only 12 naturally occurring organofluorine compounds have so far been found, and how these are biosynthesized remains a mystery. Here we describe an enzymatic reaction that occurs in the bacterium Streptomyces cattleya and which catalyses the conversion of fluoride ion and S-adenosylmethionine (SAM) to 5'-fluoro-5'-deoxyfluoroadenosine (5'-FDA). To our knowledge, this is the first fluorinase enzyme to be identified, a discovery that opens up a new biotechnological opportunity for the preparation of organofluorine compounds.     

Sequence of Plasmodium falciparum chromosomes 1, 3-9 and 13

Since the sequencing of the first two chromosomes of the malaria parasite, Plasmodium falciparum, there has been a concerted effort to sequence and assemble the entire genome of this organism. Here we report the sequence of chromosomes 1, 3-9 and 13 of P. falciparum clone 3D7--these chromosomes account for approximately 55% of the total genome. We describe the methods used to map, sequence and annotate these chromosomes. By comparing our assemblies with the optical map, we indicate the completeness of the resulting sequence. During annotation, we assign Gene Ontology terms to the predicted gene products, and observe clustering of some malaria-specific terms to specific chromosomes. We identify a highly conserved sequence element found in the intergenic region of internal var genes that is not associated with their telomeric counterparts.     

Massive gene decay in the leprosy bacillus

Leprosy, a chronic human neurological disease, results from infection with the obligate intracellular pathogen Mycobacterium leprae, a close relative of the tubercle bacillus. Mycobacterium leprae has the longest doubling time of all known bacteria and has thwarted every effort at culture in the laboratory. Comparing the 3.27-megabase (Mb) genome sequence of an armadillo-derived Indian isolate of the leprosy bacillus with that of Mycobacterium tuberculosis (4.41 Mb) provides clear explanations for these properties and reveals an extreme case of reductive evolution. Less than half of the genome contains functional genes but pseudogenes, with intact counterparts in M. tuberculosis, abound. Genome downsizing and the current mosaic arrangement appear to have resulted from extensive recombination events between dispersed repetitive sequences. Gene deletion and decay have eliminated many important metabolic activities including siderophore production, part of the oxidative and most of the microaerophilic and anaerobic respiratory chains, and numerous catabolic systems and their regulatory circuits.     

Enhanced expression of H-2K and H-2D antigens on reticulocytes infected with Plasmodium yoelii

The 17XNL strain of Plasmodium yoelii induces a highly effective and permanent T-cell dependent immunity in mice of the CBA strain; the lethal variant P. yoelii 17XL and P. berghei (ANKA) fail to activate an effective immune response in the same host. These differences in immunogenicity are unexplained. We recently observed that in CBA/CaJ mice the intracellular blood stages of P. yoelii 17XNL were almost exclusively within reticulocytes whereas lethal P. yoelii 17XL and P. berghei (ANKA), at comparable stages of infection, were predominantly erythrocytic. Induction of a reticulocytosis converted the normally lethal P. yoelii 17XL infection into a nonlethal one, and reticulocytic P. yoelii was shown to be more immunogenic than the erythrocytic form. Since one of the differences between reticulocytes and erythrocytes that might have influenced the development of immunity was greater expression of MHC antigens of the former cell type we examined the expression of H-2K, H-2D and Ia on reticulocytes infected with P. yoelii 17XNL. These cells showed a very marked increase in H-2K and D antigen expression compared to normal reticulocytes or erythrocytes. No Ia was detected. Red blood cells (RBC) infected with lethal P. yoelii 17XL or P. berghei showed no increase in H-2K or H-2D antigen expression. Finally, the level of expression of H-2K on P. yoelii 17XNL parasitized red blood cells from different strains of mice correlated closely with the ability of these strains to control the infection.