Concomitant activation of MEK-1 and Rac-1 increases the proliferative potential of thyroid epithelial cells, without affecting their differentiation

Activating point mutations in the Ras oncogene occur in a large number of human tumors, especially of epithelial origin. In thyroid follicular cells, ectopic expression of oncogenic H-Ras results in growth factor-independent proliferation, loss of differentiation and tumor formation in nude mice. In fibroblasts concomitant activation of the MAP kinase cascade and the small GTPase Rac-1 leads to full malignant transformation. We have tested the effects of these key downstream mediators of Ras in thyroid epithelial cells, by stably expressing either a constitutively active form of MEK-1 (MEK(deltaN3/S218E/S222D)), a constitutively active form of Rac-1 (Val12-Rac), or both. While the activation of one molecule or the other results in a weak phenotype, concomitant activation of both MEK-1 and Rac-1 in thyroid cells leads to growth factor-independent proliferation, morphological transformation and anchorage-independent growth. However, in contrast to Ras-transformed thyroid cells, the ones expressing the constitutively active forms of MEK-1 and Rac-1 maintain their differentiate phenotype and fail to form tumors when injected into nude mice. Thus, in thyroid epithelial cells, concomitant activation of MEK-1 and Rac-1 can reproduce only a subset of the Ras-induced effects and is not sufficient to cause full malignant transformation. Significantly, Ras-mediated increased proliferation and loss of differentiation can be dissociated in these cells.     

Thermodynamics of inositol hexakisphosphate interaction with human oxyhemoglobin

The interaction of inositol hexakisphosphate (IHP) with oxygenated human adult hemoglobin (Hb) was investigated at 25 degreesC. The affinity of IHP for oxygenated Hb is strongly pH-dependent, and potentiometric measurements of proton uptake and release upon IHP addition have shown that over the range between pH 8.0 and pH 6.0 in oxygenated Hb there are three groups of residues that change their pKa values after IHP addition, likely because of their interaction with negative charges of the heterotropic effector. On the basis of previous calculations on the electrostatic properties of human Hb (Matthew, J. B., Hanania, G. I. H., and Gurd, F. R. N. (1979) Biochemistry 18, 1919-1928; Lee, A. W.-m., Karplus, M., Poyart, C., and Bursaux, E. (1988) Biochemistry 27, 1285-1301), two of these groups might be Val1beta and His143beta, which are located in the beta1beta2 dyad axis, where they have been also proposed to interact with 2,3-diphosphoglycerate, whereas the third group does not appear easily identifiable. Calorimetric measurements of the heat associated with IHP binding at different pH values over the same range indicate that IHP binding is mostly enthalpy-driven at pH < 7 and mostly entropy-driven at pH > 7.     

A simplified dispersion limit formula for IM/DD systems and itscomparison with experimental results

A simplified formula for the dispersion limit of single-mode-fiber intensity modulation/direct detection (IM/DD) systems is derived for arbitrary given normalized pulse width U, eye opening penalty X and source linewidth enhancement factor α. From the comparison with published theoretical analyses, computer simulation and experimental data, its validity and the limits of existing formulae are shown. Using this simple and general formula, one can easily obtain the dispersion limit of various fiber types under different working conditions in IM/DD systems     

Necessary conditions for asymptotic tracking in nonlinear systems

In the literature, it has been shown that if a single-input single-output analytic nonlinear plant 1) has a well-defined relative degree and 2) is minimum-phase, it is possible to achieve asymptotic tracking for an open set of output trajectories containing the origin in C^N [0, ∞), the space of N-times continuously differentiable functions taking values in R. When either of these sufficient conditions is not met, various authors have investigated approximate analytic solutions, discontinuous solutions and solutions for restricted sets of trajectories. In this paper, it is shown that conditions 1) and 2) are necessary for the existence of an analytic compensator which yields asymptotic tracking for an open set of output trajectories. Analogous results are established for multi-input multi-output systems     

Macrophage-derived cytokines in the follicular fluids of women with infertility due to immunological causes. Elevated levels of interleukin 6 and low levels of granulocyte-macrophage colony-stimulating factor

Myoclonus of the middle ear is a rare condition characterized by abnormal repetitive muscle contractions of the tympanic cavity. In this paper we describe what we believe is the first reported case of continuous high-frequency objective tinnitus caused by middle ear myoclonus. During exploratory tympanomastoidectomy it was hypothesized that a small dural arteriovenous malformation not identified on previous tests was the cause of the tinnitus. However, complete disappearance of the tinnitus during administration of curare for anesthesia led us to believe that the tinnitus might have been caused by myoclonus of the middle ear. Sectioning of the stapedius and tensor tympani tendons rendered the patient asymptomatic and confirmed the diagnosis of middle ear myoclonus. At follow-up of one year, the patient's quality of life had improved substantially; the tinnitus did not recur and she no longer had vertigo.     

飞行器火工装置的冲击隔离结构方案实验研究

飞行器由于采用了××炸药索作为级间分离及壁板减重的火工装置，当火工品引炸时，对周围的仪器支架和脱拔插头产生高达３００００ｇ的冲击加速度。为保护仪器支架和脱拔插头，本文，总结了多种隔冲击结构方案的试验结果，选出了一种最佳方案，即二级硅橡胶缓冲器与阻尼复合结构的结合形式。该方案可使冲击加速度衰减至１６０ｇ以下。测的是周向过载。４结语粘弹阻尼复合结构用于高频响、高过载的冲击衰减系统尚是一种新的尝试。由于本课题所设计的缓冲支架采用了多级隔冲方式，冲击载荷传递的环节多，而且是三维冲击响应，载荷的波形复杂，不确定因素多，无法采用理论分析的方法进行研究。虽然如此，缓冲器的隔冲特性以及粘弹阻尼复合结构的减振性能还是可以估算的。这方面的理论问题有待于进一步研究。从试验角度而言，本次试验已解决了飞行器的仪器盒及脱拔插头的隔冲击振动问题，证明所设计的隔冲击支架满足使用要求。通过对不同支承界面联接方式的研究，选出了较佳的支承结构形式，即文中的标准状态。该结构形式隔冲击性能好，衰减倍数大，安装和更换方便，防热性能好。试验数据表明，仪器架的衰减倍数大于４００倍，脱拔插头支架大于２９０倍；在最大过载约３００００ｇ，最大响应频率约２２．４     

Synthesis and Properties of the Bi-Based Superconducting Powder Prepared by the Pechini Process

Bi-based superconductors are of great interest in high-temperature superconductors. We describe what is believed to be the first synthesis of these materials using the Pechini process, a low-temperature synthetic method that often yields inorganic oxide of excellent phase purity and well-controlled stoichiometry. Using this process, it has been possible to synthesize phase-pure Bi-2223 phase by calcining the appropriate polymeric precursors in air at 800°C for several hours. The superconductivity studies show that the Pechini-synthesized materials appear to offer high-quality performance.     

Synthesis and antitumor evaluation of 2,5-disubstituted-indazolo[4, 3-gh]isoquinolin-6(2H)-ones (9-aza-anthrapyrazoles)

The synthesis and antitumor evaluation of 2, 5-disubstituted-indazolo[4,3-gh]isoquinolin-6(2H)-ones (9-aza-APs) are described. The key intermediates in the synthesis are benz[g]isoquinoline-5,10-diones which are substituted at positions 6 and 9 with groups of different nucleofugacity for SNAr displacements. The initial displacement of fluoride by a substituted hydrazine leads to the pyrazole analogues. Substitution of the remaining leaving group by an amine or BOC-protected amines leads to the 9-aza-APs 12. These analogues were converted into their maleate or hydrochloride salts 13. In two cases, namely, 13x and 13z, sidearm buildup was also employed in the synthetic pathway. In vitro evaluation of 9-aza-APs against the human colon tumor cell line LoVo uncovered for most of the compounds a cytotoxic potency lower than that of DuP-941 or mitoxantrone and comparable to that of doxorubicin. Only analogues 13c, 13n, and 13ff were as cytotoxic as DuP-941. Interestingly, while DuP-941 was highly cross-resistant in the LoVo cell line resistant to doxorubicin (LoVo/Dx), the 9-aza-APs carrying a distal lipophilic tertiary amine moiety in both chains were capable of overcoming the MDR resistance induced in this cell line. The 9-aza-APs show outstanding in vivo antitumor activity against both systemic P388 murine leukemia and MX-1 human mammary carcinoma transplanted in nude mice. At their optimal dosages, congeners 13a-c, 13f, 13n, 13q, 13x, and 13dd were highly effective against P388 leukemia with T/C% of 200-381, while the T/C% value of DuP-941 was 147. In the MX-1 tumor model, 24 compounds elicited percentages of tumor weight inhibitions (TWI) ranging from 50% to 99%. Congeners 13d, 13k, 13l, 13x, 13z, and 13ee emerged as the most effective ones, with TWI% 96, simliar to that of DuP-941 (TWI% = 95). On the basis of their efficacy profile in additional experimental tumors and lack of cardiotoxicity in preclinical models, two congeners have surfaced as potential clinical candidates.     

Effects of long-term growth hormone therapy on adrenal steroidogenesis in Turner syndrome

Nature's most potent molecules are produced by enzyme-catalysed reactions, coupled with the natural selection of those products that possess optimal biological activity. Combinatorial biocatalysis harnesses the natural diversity of enzymatic reactions for the iterative synthesis of organic libraries. Iterative reactions can be performed using isolated enzymes or whole cells, in natural and unnatural environments, and on substrates in solution or on a solid phase. Combinatorial biocatalysis is a powerful addition to the expanding array of combinatorial methods for the generation and optimization of lead compounds in drug discovery and development.     

In vivo roles of receptor tyrosine kinases and cytokine receptors in early thymocyte development

The early phases of T-cell development require both cell-cell interactions and soluble factors provided by stromal cells within the thymic microenvironment. Still, the precise nature of the signals delivered in vivo by cytokines (resulting in survival, proliferation or differentiation) remains unclear. Recent studies using mice deficient in cytokines or in their receptors have helped to identify essential signaling pathways required for the development of intrathymic precursors to mature alpha beta and gamma delta T cells. In addition, cytokine requirements for the development of natural killer cells were revealed in such mutants. The results obtained demonstrate that the development of all classes of lymphocytes (natural killer, gamma delta T cells and alpha beta T cells) is cytokine dependent, but the specific requirements differ for each lineage.