Attenuation of FGF signalling in mouse beta-cells leads to diabetes

Fibroblast growth factor (FGF) signalling has been implicated in patterning, proliferation and cell differentiation in many organs, including the developing pancreas. Here we show that the FGF receptors (FGFRs) 1 and 2, together with the ligands FGF1, FGF2, FGF4, FGF5, FGF7 and FGF10, are expressed in adult mouse beta-cells, indicating that FGF signalling may have a role in differentiated beta-cells. When we perturbed signalling by expressing dominant-negative forms of the receptors, FGFR1c and FGFR2b, in the pancreas, we found that that mice with attenuated FGFR1c signalling, but not those with reduced FGFR2b signalling, develop diabetes with age and exhibit a decreased number of beta-cells, impaired expression of glucose transporter 2 and increased proinsulin content in beta-cells owing to impaired expression of prohormone convertases 1/3 and 2. These defects are all characteristic of patients with type-2 diabetes. Mutations in the homeobox gene Ipf1/Pdx1 are linked to diabetes in both mouse and human. We also show that Ipf1/Pdx1 is required for the expression of FGFR1 signalling components in beta-cells, indicating that Ipf1/Pdx1 acts upstream of FGFR1 signalling in beta-cells to maintain proper glucose sensing, insulin processing and glucose homeostasis.     

钢筋混凝土构件的断裂韧度

本文对带裂纹的钢筋混凝土构件进行了断裂力学分析,并通过试验和有限元计算得到了含裂纹钢筋混凝土构件中KIc的尺寸效应和s/w(跨高比)值对KIc值的影响等问题进行了研究.在测试中还成功地应用了声发射测试技术监测裂纹的临界扩展点.     

A structural change in the kinesin motor protein that drives motility

Kinesin motors power many motile processes by converting ATP energy into unidirectional motion along microtubules. The force-generating and enzymatic properties of conventional kinesin have been extensively studied; however, the structural basis of movement is unknown. Here we have detected and visualized a large conformational change of an approximately 15-amino-acid region (the neck linker) in kinesin using electron paramagnetic resonance, fluorescence resonance energy transfer, pre-steady state kinetics and cryo-electron microscopy. This region becomes immobilized and extended towards the microtubule 'plus' end when kinesin binds microtubules and ATP, and reverts to a more mobile conformation when gamma-phosphate is released after nucleotide hydrolysis. This conformational change explains both the direction of kinesin motion and processive movement by the kinesin dimer.     

Depressor effects of muscarinic and non-muscarinic mediation induced by lateral hypothalamic stimulation in the rat

Summary Transient sympathetically-mediated depressor effects were induced by stimulation of a small locus in the lateral hypothalamic peri-fornical region, medial to the fields of Forel. The ganglionic blocking agent, atropine methyl nitrate (ATMN), was used to show that muscarinic as well as non-muscarinic sympathetic ganglion receptor neurotransmission was involved. Evidence is presented that stimulation of this LH site co-activates a number of mechanisms and that depending on which of these are activated, the ganglionic blocking agent ATMN may either block, reverse or potentiate the depressor effect.     

Synaptic vesicle depletion and glutamate uptake in a nerve-muscle preparation of the locust,Locusta migratoria L

Summary Excitatory terminals, depleted of their synaptic vesicles by stimulation at high frequency, were incubated in the radiolabelled putative neurotransmitter, L-glutamate. Quantitative electron microscope autoradiography revealed that the axoplasm of these recovering terminals had accumulated the³H L-glutamate.Acknowledgment. The authors wish to thank Dr N. M. Blackett for running the computer analyses of the autoradiographical results. R. P. Botham gratefully acknowledges the SRC for financial assistance.