Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer

The fraction of pyruvate dehydrogenase complex (PDC) in the active form is reduced by the activities of dedicated PD kinase isozymes (PDK1, PDK2, PDK3 and PDK4). Via binding to the inner lipoyl domain (L2) of the dihydrolipoyl acetyltransferase (E2 60mer), PDK rapidly access their E2-bound PD substrate. The E2-enhanced activity of the widely distributed PDK2 is limited by dissociation of ADP from its C-terminal catalytic domain, and this is further slowed by pyruvate binding to the N-terminal regulatory (R) domain. Via the reverse of the PDC reaction, NADH and acetyl-CoA reductively acetylate lipoyl group of L2, which binds to the R domain and stimulates PDK2 activity by speeding up ADP dissociation. Activation of PDC by synthetic PDK inhibitors binding at the pyruvate or lipoyl binding sites decreased damage during heart ischemia and lowered blood glucose in insulin-resistant animals. PDC activation also triggers apoptosis in cancer cells that selectively convert glucose to lactate. Received 25 August 2006; received after revision 20 November 2006; accepted 20 December 2006     

Sur la caractérisation de dérivés guanidiques d'origine biologique par électrophorèse et chromatographie sur papier (chromatoélectrophorèse)

Summary Paper chromatography has been used in conjonction with electrophoresis in a perpendicular direction (chromatoelectrophoresis), in order to characterize various guanidoderivatives of biological interest and also citrulline. The isolation of definite spots can be obtained with a satisfactory selectivity by this procedure, at a higher speed than by bidimensional chromatography; and the use of a few coloured reactions (ninhydrine,Sakaguchi, diacetyle--naphtol andp-dimethylaminobenzaldehyde) on the same electrochromatogram has been successfully practised in this field.     

Selective inhibition of the anchorage-independent growth of myc-transfected fibroblasts by retinoic acid

Fischer rat 3T3 (FR3T3) fibroblasts transfected with a cellular myc gene can be induced to grow and form colonies in soft agar by treatment either with epidermal growth factor (EGF) alone or with the combination of platelet-derived growth factor (PDGF) and type-beta transforming growth factor (TGF-beta). We now show that induction of anchorage-independent growth by each of these sets of growth factors involves different cellular pathways which can be distinguished by their sensitivity to retinoic acid. Colony formation induced by the combined action of PDGF and TGF-beta is 100-fold more sensitive to inhibition by retinoic acid than is colony formation induced by treatment of the myc-transfected cells with EGF. Moreover, retinoic acid (10(-8) M) is inhibitory for colony growth whenever TGF-beta is present, regardless of whether the effects of TGF-beta are stimulatory, as occurs in the presence of PDGF, or inhibitory, as found in the presence of EGF.     

基于Runtime的iOS编程研究与实现

在iOS开发过程中,因为系统自带方法对应的功能不足,使部分业务需求不能有效地实现.为此,首先对Runtime库的主要API接口用途进行了研究,找到可利用的接口;然后对Runtime消息转发机制进行研究,证明函数调用的实质就是消息的传递;最后通过实际案例,证明了应用Runtime可以解决系统方法不足的问题.结果 表明,通过Runtime库给系统自带的类动态添加或修改成员变量和成员方法具有可行性,可为iOS开发者提供参考和借鉴.     

Invariant chain association with HLA-DR molecules inhibits immunogenic peptide binding

Class II major histocompatibility complex (MHC) molecules are heterodimeric cell surface glycoproteins which bind and present immunogenic peptides to T lymphocytes. Such peptides are normally derived from protein antigens internalized and proteolytically degraded by the antigen-presenting cell. Class I MHC molecules also bind immunogenic peptides, but these are derived from proteins synthesized within the target cell. Whereas class I molecules seem to bind peptides in the endoplasmic reticulum, class II molecules are thought to bind peptides late in transport. Intracellular class II molecules associate in the endoplasmic reticulum with a third glycoprotein, the invariant (I) chain, which is proteolytically removed before cell surface expression of the alpha beta class II heterodimer. It has been suggested that the I chain prevents peptides from associating with class II molecules early in transport. Preventing such binding until the class II molecules enter an endosomal compartment could maintain the functional dichotomy between class I and class II MHC molecules. We have examined the ability of I chain-associated HLA-DR5 molecules to bind a well characterized influenza haemagglutinin-derived peptide (HAp). The results show that whereas mature HLA-DR alpha beta dimers effectively bind this peptide, the I chain-associated form does not.     

La phosphatase des os et le mécanisme général de l'ossification

Summary A general survey of the actual knowledges on the bone phosphatase is given. The enzyme plays an important rôle in the calcification of bone and teeth, this process being unable to proceed at a physiological speed without the participation of a phosphatase. The biological function of the enzyme is thus to accelerate and not to promote the calcification.The knowledge of the mechanism of phosphatase activity in the skeletal organs and of the chemical composition of the bone salt cannot lead to a full understanding of the physiology of ossification. A prominent function in this field is devoted to the proteins of the ground substance of bone and to their evolution. The study of the protein matrix of bone is now the most important subject of work for the biochemistry of ossification.

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Conférence faite le 28 mai 1946 au Hallerianum de l'Université de Berne.     

Early hominid stone tool production and technical skill 2.34 Myr ago in West Turkana, Kenya.

Well-documented Pliocene archaeological sites are exceptional. At present they are known only in East Africa, in the Hadar and Shungura formations of Ethiopia and in the Nachukui formation of Kenya. Intensive archeological survey and a series of test excavations conducted in the Nachukui formation since 1987 have led to the discovery of more than 25 archaeological sites whose ages range from 2.34 to 0.7 million years before present (Myr), and to the extensive excavation of two 2.34-Myr sites, Lokalalei 1 in 1991 and Lokalalei 2C in 1997. Lokalalei 2C yielded nearly 3,000 archaeological finds from a context of such good preservation that it was possible to reconstitute more than 60 sets of complementary matching stone artefacts. These refits, predating the Koobi Fora refits by 500 Kyr, are the oldest ever studied. Here we describe a technological analysis of the core reduction sequences, based on these refits, which allows unprecedented accuracy in the understanding of flake production processes. We can thus demonstrate greater cognitive capacity and motor skill than previously assumed for early hominids, and highlight the diversity of Pliocene technical behaviour.     

Symbiotic host-specificity of Rhizobium meliloti is determined by a sulphated and acylated glucosamine oligosaccharide signal

Rhizobia are symbiotic bacteria that elicit the formation on leguminous plants of specialized organs, root nodules, in which they fix nitrogen. In various Rhizobium species, such as R. leguminosarum and R. meliloti, common and host-specific nodulation (nod) genes have been identified which determine infection and nodulation of specific hosts. Common nodABC genes as well as host-specific nodH and nodQ genes were shown recently, using bioassays, to be involved in the production of extracellular Nod signals. Using R. meliloti strains overproducing symbiotic Nod factors, we have purified the major alfalfa-specific signal, NodRm-1, by gel permeation, ion exchange and C18 reverse-phase high performance liquid chromatography. From mass spectrometry, nuclear magnetic resonance, (35)S-labelling and chemical modification studies, NodRm-1 was shown to be a sulphated beta-1,4-tetrasaccharide of D-glucosamine (Mr 1,102) in which three amino groups were acetylated and one was acylated with a C16 bis-unsaturated fatty acid. This purified Nod signal specifically elicited root hair deformation on the homologous host when added in nanomolar concentration.