The imidazoline RX871024 induces death of proliferating insulin-secreting cells by activation of c-jun N-terminal kinase

An insufficient number of insulin-producing β-cells is a major cause of defective control of blood glucose in both type 1 and type 2 diabetes. The aim of this study was to clarify whether the insulinotropic imidazolines can affect the survival of highly proliferating insulin-secreting cells, here exemplified by the MIN6 cell line. Our data demonstrate that RX871024, but not efaroxan, triggered MIN6 cell death and potentiated death induced by a combination of the pro-inflammatory cytokines interleukin-1β, interferon- γ and tumor necrosis factor-α. These effects did not involve changes in nitric oxide production but correlated with stimulation of c-jun N-terminal kinase (JNK) activity and activation of caspases-1, -3, -8 and -9. Our results suggest that the imidazoline RX871024 causes death of highly proliferating insulin-secreting cells, putatively via augmentation of JNK activity, a finding that may impact on the possibility of using compounds of similar activity in the treatment of diabetes. Received 13 December 2007; received after revision 5 February 2008; accepted 6 February 2008     

健美操动作节奏与音乐的探讨

健美操动作具有强烈的节奏性,是通过音乐充分地表现出来.因此音乐是健美操运动不可缺少的组成部分.音乐是健美操练习的口令,是运动的节拍,音乐对健美操练习起重要的支配作用.音乐的旋律、速度能使健美操练习更具有感染力.健美操运动之所以深受人们的喜爱,很重要的因素之一是现代音乐给健美操带来了活力.     

Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction

Dysfunction of the exocrine pancreas is observed in diabetes, but links between concurrent exocrine and endocrine pancreatic disease and contributing genetic factors are poorly characterized. We studied two families with diabetes and exocrine pancreatic dysfunction by genetic, physiological and in vitro functional studies. A genome-wide screen in Family 1 linked diabetes to chromosome 9q34 (maximal lod score 5.07). Using fecal elastase deficiency as a marker of exocrine pancreatic dysfunction refined the critical chromosomal region to 1.16 Mb (maximal lod score 11.6). Here, we identified a single-base deletion in the variable number of tandem repeats (VNTR)-containing exon 11 of the carboxyl ester lipase (CEL) gene, a major component of pancreatic juice and responsible for the duodenal hydrolysis of cholesterol esters. Screening subjects with maturity-onset diabetes of the young identified Family 2, with another single-base deletion in CEL and a similar phenotype with beta-cell failure and pancreatic exocrine disease. The in vitro catalytic activities of wild-type and mutant CEL protein were comparable. The mutant enzyme was, however, less stable and secreted at a lower rate. Furthermore, we found some evidence for an association between common insertions in the CEL VNTR and exocrine dysfunction in a group of 182 unrelated subjects with diabetes (odds ratio 4.2 (1.6, 11.5)). Our findings link diabetes to the disrupted function of a lipase in the pancreatic acinar cells.     

Citrate kills tumor cells through activation of apical caspases

Most tumor cells exhibit a glycolytic phenotype. Thus, inhibition of glycolysis might be of therapeutic value in antitumor treatment. Among the agents that can suppress glycolysis is citrate, a member of the Krebs cycle and an inhibitor of phosphofructokinase. Here, we show that citrate can trigger cell death in multiple cancer cell lines. The lethal effect of citrate was found to be related to the activation of apical caspases-8 and -2, rather than to the inhibition of cellular energy metabolism. Hence, increasing concentrations of citrate induced characteristic manifestations of apoptosis, such as caspase-3 activation, and poly-ADP-ribose polymerase cleavage, as well as the release of cytochrome c. Apoptosis induction did not involve the receptor-mediated pathway, since the processing of caspase-8 was not attenuated in cells deficient in Fas-associated protein with Death Domain. We propose that the activation of apical caspases by citrate could be explained by its kosmotropic properties. Caspase-8 is activated by proximity-induced dimerization, which might be facilitated by citrate through the stabilization of intermolecular interactions between the proteins.     

An integrated approach to characterize genetic interaction networks in yeast metabolism

Although experimental and theoretical efforts have been applied to globally map genetic interactions, we still do not understand how gene-gene interactions arise from the operation of biomolecular networks. To bridge the gap between empirical and computational studies, we i, quantitatively measured genetic interactions between ～185,000 metabolic gene pairs in Saccharomyces cerevisiae, ii, superposed the data on a detailed systems biology model of metabolism and iii, introduced a machine-learning method to reconcile empirical interaction data with model predictions. We systematically investigated the relative impacts of functional modularity and metabolic flux coupling on the distribution of negative and positive genetic interactions. We also provide a mechanistic explanation for the link between the degree of genetic interaction, pleiotropy and gene dispensability. Last, we show the feasibility of automated metabolic model refinement by correcting misannotations in NAD biosynthesis and confirming them by in vivo experiments.     

The “Unknown Heritage”: trace of a forgotten locus of mathematical sophistication

The “unknown heritage” is the name usually given to a problem type in whose archetype a father leaves to his first son 1 monetary unit and \({\frac{1}{n}}\) (n usually being 7 or 10) of what remains, to the second 2 units and \({\frac{1}{n}}\) of what remains, and so on. In the end, all sons get the same, and nothing remains. The earliest known occurrence is in Fibonacci’s Liber abbaci, which also contains a number of much more sophisticated versions, together with a partial algebraic solution for one of these and rules for all which do not follow from his algebraic calculation. The next time the problem turns up is in Planudes’s late thirteenth century Calculus according to the Indians, Called the Great. After that the simple problem type turns up regularly in Provençal, Italian and Byzantine sources. It seems never to appear in Arabic or Indian writings, although two Arabic texts (one from c. 1190) contain more regular problems where the number of shares is given; they are clearly derived from the type known from European and Byzantine works, not its source. The sophisticated versions turn up again in Barthélemy de Romans’ Compendy de la praticque des nombres (c. 1467) and, apparently inspired from there, in the appendix to Nicolas Chuquet’s Triparty (1484). Apart from a single trace in Cardano’s Practica arithmetice et mensurandi singularis, the sophisticated versions never surface again, but the simple version spreads for a while to German practical arithmetic and, more persistently, to French polite recreational mathematics. Close examination of the texts shows that Barthélemy cannot have drawn his familiarity with the sophisticated rules from Fibonacci. It also suggests that the simple version is originally either a classical, strictly Greek or Hellenistic, or a medieval Byzantine invention; and that the sophisticated versions must have been developed before Fibonacci within an environment (located in Byzantium, Provence, or possibly in Sicily?) of which all direct traces has been lost, but whose mathematical level must have been quite advanced.     

Single-copy insertion of transgenes in Caenorhabditis elegans

At present, transgenes in Caenorhabditis elegans are generated by injecting DNA into the germline. The DNA assembles into a semistable extrachromosomal array composed of many copies of injected DNA. These transgenes are typically overexpressed in somatic cells and silenced in the germline. We have developed a method that inserts a single copy of a transgene into a defined site. Mobilization of a Mos1 transposon generates a double-strand break in noncoding DNA. The break is repaired by copying DNA from an extrachromosomal template into the chromosomal site. Homozygous single-copy insertions can be obtained in less than 2 weeks by injecting approximately 20 worms. We have successfully inserted transgenes as long as 9 kb and verified that single copies are inserted at the targeted site. Single-copy transgenes are expressed at endogenous levels and can be expressed in the female and male germlines.     

S-phase-coupled apoptosis in tumor suppression

DNA replication is essential for accurate transmission of genomic information from parental to daughter cells. DNA replication is licensed once per cell division cycle. This process is highly regulated by both positive and negative regulators. Over-replication, under-replication, as well as DNA damage in a cell all induce the activation of checkpoint control pathways such as ATM/ATR, CHK kinases, and the tumor suppressor protein p53, which provide “damage controls” via either DNA repairs or apoptosis. This review focuses on accumulating evidence, with the emphasis on recently discovered Killin, that S-phase checkpoint control is crucial for a mammalian cell to make a life and death decision in order to safeguard genome integrity.