核仁组成区蛋白在软组织肿瘤及瘤样病变中的表达与意义

应用胶银技术,对软组织肿瘤特别是纤维源性肿瘤核仁组成区蛋白进行了定量研究。在软组织一些恶性肿瘤中,以血管肉瘤、横纹肌肉瘤核仁组成区蛋白均值最高,并以此排列了它们的恶性度顺序。在纤维源性肿瘤中,纤维瘤、瘤样纤维组织增生、纤维肉瘤及其亚类核仁组成区蛋白均值有显著与高度显著性差异(P<0.05、P<0.001),其中随访的34例纤维肉瘤患者,具有高核仁组成区蛋白均值(≥5)与低核仁组成区蛋白均值(<5)的5年生存率分别是20％和53％(P<0.05)。因此,作者认为核仁组成区蛋白定量在判定软组织肿瘤的恶性度、鉴别其良恶性及预测患者预后中均有一定实用价值。     

3-D ultrastructure of O. tauri: electron cryotomography of an entire eukaryotic cell

The hallmark of eukaryotic cells is their segregation of key biological functions into discrete, membrane-bound organelles. Creating accurate models of their ultrastructural complexity has been difficult in part because of the limited resolution of light microscopy and the artifact-prone nature of conventional electron microscopy. Here we explored the potential of the emerging technology electron cryotomography to produce three-dimensional images of an entire eukaryotic cell in a near-native state. Ostreococcus tauri was chosen as the specimen because as a unicellular picoplankton with just one copy of each organelle, it is the smallest known eukaryote and was therefore likely to yield the highest resolution images. Whole cells were imaged at various stages of the cell cycle, yielding 3-D reconstructions of complete chloroplasts, mitochondria, endoplasmic reticula, Golgi bodies, peroxisomes, microtubules, and putative ribosome distributions in-situ. Surprisingly, the nucleus was seen to open long before mitosis, and while one microtubule (or two in some predivisional cells) was consistently present, no mitotic spindle was ever observed, prompting speculation that a single microtubule might be sufficient to segregate multiple chromosomes.     

HIP1 functions in clathrin-mediated endocytosis through binding to clathrin and adaptor protein 2

Polyglutamine expansion in huntingtin is the underlying mutation leading to neurodegeneration in Huntington disease. This mutation influences the interaction of huntingtin with different proteins, including huntingtin-interacting protein 1 (HIP1), in which affinity to bind to mutant huntingtin is profoundly reduced. Here we demonstrate that HIP1 colocalizes with markers of clathrin-mediated endocytosis in neuronal cells and is highly enriched on clathrin-coated vesicles (CCVs) purified from brain homogenates. HIP1 binds to the clathrin adaptor protein 2 (AP2) and the terminal domain of the clathrin heavy chain, predominantly through a small fragment encompassing amino acids 276-335. This region, which contains consensus clathrin- and AP2-binding sites, functions in conjunction with the coiled-coil domain to target HIP1 to CCVs. Expression of various HIP1 fragments leads to a potent block of clathrin-mediated endocytosis. Our findings demonstrate that HIP1 is a novel component of the endocytic machinery.     

Lumped parametric model of the human ear for sound transmission

A lumped parametric model of the human auditoria peripherals consisting of six masses suspended with six springs and ten dashpots was proposed. This model will provide the quantitative basis for the construction of a physical model of the human middle ear. The lumped model parameters were first identified using published anatomical data, and then determined through a parameter optimization process. The transfer function of the middle ear obtained from human temporal bone experiments with laser Doppler interferometers was used for creating the target function during the optimization process. It was found that, among 14 spring and dashpot parameters, there were five parameters which had pronounced effects on the dynamic behaviors of the model. The detailed discussion on the sensitivity of those parameters was provided with appropriate applications for sound transmission in the ear. We expect that the methods for characterizing the lumped model of the human ear and the model parameters will be useful for theoretical modeling of the ear function and construction of the ear physical model.Supported by Oklahoma Center for the Advancement of Science and Technology.     

Hsp90 restrains ErbB-2/HER2 signalling by limiting heterodimer formation

ErbB-2/HER2 is an oncogenic tyrosine kinase that regulates a signalling network by forming ligand-induced heterodimers with several growth factor receptors of the ErbB family. Hsp90 and co-chaperones regulate degradation of ErbB-2 but not other ErbB members. Here, we report that the role of Hsp90 in modulating the ErbB network extends beyond regulation of protein stability. The capacity of ErbB-2 to recruit ligand-bound receptors into active heterodimers is limited by Hsp90, which is dissociated from ErbB-2 following ligand-induced heterodimerization. We show that Hsp90 binds a specific loop within the kinase domain of ErbB-2, thereby restraining heterodimer formation and catalytic function. These results define a role for Hsp90 as a molecular switch regulating the ErbB signalling network by limiting formation of ErbB-2-centred receptor complexes.     

电刺激右后背海马诱导双侧前背海马网络癫痫

目的 :急性强直电刺激右侧后背HPC诱导双侧HPC癫痫电网络形成的细胞机制。方法 :强直电刺激 (6 0Hz,2s,0 .4～ 0 .6mA)大鼠右后背HPCCA1基树突区 ,每隔 10min刺激一次 ,施加 10个刺激串。结果 :①分别抑制双侧CA1神经元单位放电频率 ,对侧的抑制效应更明显 (对侧 :6 2 .94 %± 3.6 8% ;同侧 :36 .6 1%± 3.14 % ,P <0 .0 1) ,出现抑制后爆发式放电。随着刺激串数的增加 ,抑制作用逐渐减弱。②同步原发性网络和单位后放电 ,以同侧CA1多见 (P<0 .0 1)。③ 90Hz或 12 0Hz原发性或继发性网络后放电仅仅累及同侧CA1。④对侧CA3基树突区网络与下托神经元单位放电出现同步继发性后放电 ,反复发作 ,持续约数小时。结论 :电刺激诱导的对侧HPC抑制后爆发式放电和长时程、反复发作的网络与单个神经元同步继发性后放电可能是跨半球癫痫网络形成的重要表现形式。     

Noncovalent inhibitors of human leukocyte elastase based on the 4-imidazolidinone scaffold

A central problem associated with the design of enzyme inhibitors in general, and serine protease inhibitors in particular, is the identification of templates capable of binding to the active site of an enzyme in a predictable and substrate-like fashion, orienting appended recognition elements in a correct spatial relationship so that favorable binding interactions with multiple sites are achieved. Described herein for the first time is the design of noncovalent inhibitors of human leukocyte elastase that employs a functionalized 4-imidazolidinone scaffold.     

The immunosuppressive agent mizoribine monophosphate forms a transition state analogue complex with inosine monophosphate dehydrogenase

Mizoribine monophosphate (MZP) is the active metabolite of the immunosuppressive agent mizoribine and a potent inhibitor of IMP dehydrogenase (IMPDH). This enzyme catalyzes the oxidation of IMP to XMP with the concomitant reduction of NAD via a covalent intermediate at Cys319 (E-XMP). Surprisingly, mutational analysis indicates that MZP is a transition state analogue although its structure does not resemble that of the expected transition state. Here we report the X-ray crystal structure of the E.MZP complex at 2.0 A resolution that reveals a transition state-like structure and solves the mechanistic puzzle of the IMPDH reaction. The protein assumes a new conformation where a flap folds into the NAD site and MZP, Cys319, and a water molecule are arranged in a geometry resembling the transition state. The water appears to be activated by interactions with a conserved Arg418-Tyr419 dyad. Mutagenesis experiments confirm that this new closed conformation is required for the hydrolysis of E-XMP, but not for the reduction of NAD. The closed conformation provides a structural explanation for the differences in drug selectivity and catalytic efficiency of IMPDH isozymes.