A calcium sensor in the sodium channel modulates cardiac excitability.

Sodium channels are principal molecular determinants responsible for myocardial conduction and maintenance of the cardiac rhythm. Calcium ions (Ca2+) have a fundamental role in the coupling of cardiac myocyte excitation and contraction, yet mechanisms whereby intracellular Ca2+ may directly modulate Na channel function have yet to be identified. Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. Mutations targeted to the IQ domain disrupted CaM binding and eliminated Ca2+/CaM-dependent slow inactivation, whereas the gating effects of Ca2+/CaM were restored by intracellular application of a peptide modelled after the IQ domain. A naturally occurring mutation (A1924T) in the IQ domain altered hH1 function in a manner characteristic of the Brugada arrhythmia syndrome, but at the same time inhibited slow inactivation induced by Ca2+/CaM, yielding a clinically benign (arrhythmia free) phenotype.     

五台山滹沱群SHRIMP锆石U-Pb年龄: 华北克拉通早元古代拼合新证据

采自五台山台怀镇南8 km处滹沱群变质火山-沉积岩层中的长英质凝灰岩样品含有两组锆石, 所记录的SHRIMP锆石方法²⁰⁷Pb/²⁰⁶Pb年龄分别为2180±5 Ma和2087±9 Ma. 在误差范围内, 较老的一组年龄与五台山大洼梁花岗岩年龄相当, 表明它们来自相似的地壳岩浆源; 而较年轻的一组锆石年龄与相邻地区阜平杂岩湾子表壳岩中变沉积岩和变火山岩及南营花岗片麻岩年龄相当, 因而被解释为滹沱群火山作用年龄. 这两组年龄的存在表明: (1) 滹沱群形成于早元古代而非太古宙; (2) 早元古代火山-沉积作用在五台和阜平地区同时间发生. 这样, 早元古代沉积作用在该区是广泛的, 它们代表了华北克拉通东部陆块西侧大陆边缘相沉积. 滹沱群火山作用年龄的确定也表明该群所经历的变质-变形事件发生在2087±9 Ma 之后, 这进一步佐证我们最近根据其他方面研究结果所得出的吕梁造山事件(约1.8 Ga)是该区主要构造事件的结论: 该事件导致华北克拉通东部陆块和西部陆块的最终拼合, 并成为全球早-中元古代超级大陆组成部分之一.     

PTC124 targets genetic disorders caused by nonsense mutations

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.     

早-中元古代Columbia超级大陆研究进展

地球在过去25亿年里曾发生过几次全球性大规模碰撞造山事件（如 Grenville事件,Pan-African事件等）;地质学家由此推测大陆块自早元古代以来曾发生过周期性拼合和分离,从而导致古超级大陆的形成和裂解[1].在过去10年里（1991～2001年）,被认为由约1.0 Ga Grenville造山事件所形成的超级大陆Rodinia已成为古大陆重建的一个热点[2,3].然而,地质学家们在重建Rodinia 过程中发现,并非全部Rodinia组成陆块都是由Grenville造山带所焊接,而     

Cholera toxin genes: nucleotide sequence, deletion analysis and vaccine development

Nucleotide sequence and deletion analysis have been used to identify the regulatory and coding sequences comprising the cholera toxin operon (ctx). Incorporation of defined in vitro-generated ctx deletion mutations into Vibrio cholerae by in vivo genetic recombination produced strains which have practical value in cholera vaccine development.     

Thermal radiation scanning tunnelling microscopy

In standard near-field scanning optical microscopy (NSOM), a subwavelength probe acts as an optical 'stethoscope' to map the near field produced at the sample surface by external illumination. This technique has been applied using visible, infrared, terahertz and gigahertz radiation to illuminate the sample, providing a resolution well beyond the diffraction limit. NSOM is well suited to study surface waves such as surface plasmons or surface-phonon polaritons. Using an aperture NSOM with visible laser illumination, a near-field interference pattern around a corral structure has been observed, whose features were similar to the scanning tunnelling microscope image of the electronic waves in a quantum corral. Here we describe an infrared NSOM that operates without any external illumination: it is a near-field analogue of a night-vision camera, making use of the thermal infrared evanescent fields emitted by the surface, and behaves as an optical scanning tunnelling microscope. We therefore term this instrument a 'thermal radiation scanning tunnelling microscope' (TRSTM). We show the first TRSTM images of thermally excited surface plasmons, and demonstrate spatial coherence effects in near-field thermal emission.     

Extrusion Freeforming of Millimeter-Wave Electromagnetic Bandgap (EBG) Photonic Crystals

Extrusion freeforming can be used for the rapid prototyping of millimeter-wave electromagnetic bandgap (EBG) structures. In this work, an alumina-polymer paste with a relatively high volatility solvent (propanol) was used and the characteristics of the ceramic paste, particularly the rheological features are described. The advantage of high volatility solvent is that the viscosity and elastic modulus of the paste are increased sharply as the solvent evaporates. Thus, the rigidity of the extruded filament is quickly increased as a small amount of solvent evaporates. Finally, by employing this procedure, different EBG structures such as 2-D, 3-D woodpile and aperiodic structures were fabricated and their bandgaps were measured. The experimental results show that extrusion freeforming is a relatively simple and easy method to fabricate these woodpile structures with a bandgap in the 90–110 GHz region.     

Solid Freeforming and Combinatorial Research

A view of manufacturing processes is presented in which five distinct categories are defined as casting, deformation, machining, joining, and solid freeforming. Solid freeforming is essentially biomimetic and shares problems of morphogenesis with natural processes. Our team in University of London has been exploring three mechanisms of solid freeforming. In dry powder deposition and direct ink-jet printing, the emphasis has turned to the problem of delivering a complex shape in which the three dimensional spatial arrangement of composition is delivered from the design file. In extrusion freeforming, the aim is to control microstructure at hierarchical levels also from the design file. The quest for 3-D functional gradients is satisfied by acoustic and ultrasonic dispensing and mixing of powders so that each layer can be patterned. These methods could be extended to deliver the complex patterns demanded by left-handed microwave metamaterials. Dry powder deposition and direct ink-jet printing are turning towards combinatorial methods in which multiple sample libraries are used to accelerate discovery. In turn, this paves the way for ‘autonomous research machines’ which steer their own search refinements in response to our requests for new materials. In this way, solid freeforming used for sample preparation can give an ‘arm’ to an intelligent machine so that it can conduct its own experimentation and learning; an idea that originated with Alan Turing in the late 1940s.     

Calmodulin-associated post-translational regulation of rat organic cation transporter 2 in the kidney is gender dependent

In this work, regulation of organic cation transporter type 2 from rat (rOCT2) stably transfected in HEK293 cells was investigated by microfluorimetry with 4-(4-(dimethylamino)styryl)-N-methylpyridinium as substrate. The transport mediated by rOCT2 was specifically stimulated by PKA, phosphatidylinositol-3-kinase, p56^lck tyrosine kinase, mitogen-extracellular-signal-regulated-kinase-1/2, calmodulin (CaM), and CaM-kinase-II. The regulatory pattern of rOCT2 differs markedly quantitatively and qualitatively from that of other OCT isoforms. Only CaM-dependent upregulation is conserved throughout the OCT family. For this reason, CaM regulation of rOCT2 was also investigated in isolated S3-segments (known to express only rOCT2) of male and female rat proximal tubules. Inhibition of CaM by calmidazolium significantly decreased rOCT2 activity (−49.0 ± 13.6%, n = 4) in male but not female (9.0 ± 13.0%, n = 4) rats. Real-time PCR and Western blot investigations of CaM expression in rat kidneys showed that male animals have significantly higher CaM expression. This is the first study describing post-translational gender-dependent rOCT2 regulation. Received 26 February 2009; accepted 16 March 2009