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1.
目的:考察叶酸-聚乙二醇-阿霉素连接物(FA-PEG-hyd-DOX)及其制剂在不同实验条件下的稳定性,为其开发应用奠定基础。方法:参照2010版《中国药典》二部附录XIXC《原料药与药物制剂稳定性试验指导原则》,将DOX、FA-PEG-hyd-DOX连接物原料及其冻干粉制剂置于高温、高湿、强光照环境中,不同时间对样品的DOX质量百分含量、熔点、外观性状等指标进行考察分析。结果:DOX在高温、高湿、强光照环境中放置10天后,DOX质量百分含量分别为31.95%、66.36%和61.27%,熔点分别为195℃、194℃和194℃。FA-PEG-hyd-DOX连接物在高温、高湿、强光照环境中放置10天后,DOX质量百分含量分别为2.71%、3.85%和3.14%,熔点范围分别为169-175℃、170-175℃和170-175℃。FA-PEG-hyd-DOX冻干粉制剂在高温、高湿、强光照环境中放置10天后,DOX质量百分含量分别为3.80%、5.76%和4.80%。结论:FA-PEG-hyd-DOX连接物原料的稳定性高于DOX,FA-PEG-hyd-DOX甘露醇冻干粉制剂的稳定性高于其原料药。 相似文献
2.
Yoko Akazawa-Ogawa Mizuki Takashima Young-Ho Lee Takahisa Ikegami Yuji Goto Koichi Uegaki Yoshihisa Hagihara 《The Journal of biological chemistry》2014,289(22):15666-15679
The variable domain of camelid heavy chain antibody (VHH) is highly heat-resistant and is therefore ideal for many applications. Although understanding the process of heat-induced irreversible denaturation is essential to improve the efficacy of VHH, its inactivation mechanism remains unclear. Here, we showed that chemical modifications predominantly governed the irreversible denaturation of VHH at high temperatures. After heat treatment, the activity of VHH was dependent only on the incubation time at 90 °C and was insensitive to the number of heating (90 °C)-cooling (20 °C) cycles, indicating a negligible role for folding/unfolding intermediates on permanent denaturation. The residual activity was independent of concentration; therefore, VHH lost its activity in a unimolecular manner, not by aggregation. A VHH mutant lacking Asn, which is susceptible to chemical modifications, had significantly higher heat resistance than did the wild-type protein, indicating the importance of chemical modifications to VHH denaturation. 相似文献
3.
Shanti Swaroop Srivastava Amita Mishra Bal Krishnan Yogendra Sharma 《The Journal of biological chemistry》2014,289(16):10958-10966
βγ-Crystallin-type double clamp (N/D)(N/D)XX(S/T)S motif is an established but sparsely investigated motif for Ca2+ binding. A βγ-crystallin domain is formed of two Greek key motifs, accommodating two Ca2+-binding sites. βγ-Crystallins make a separate class of Ca2+-binding proteins (CaBP), apparently a major group of CaBP in bacteria. Paralleling the diversity in βγ-crystallin domains, these motifs also show great diversity, both in structure and in function. Although the expression of some of them has been associated with stress, virulence, and adhesion, the functional implications of Ca2+ binding to βγ-crystallins in mediating biological processes are yet to be elucidated. 相似文献
4.
Maintenance of spine stability is considered to be a critical component of spine health. Ross et al. (2015) used a topical capsaicin/heat pain sensitization model to experimentally induce lower back pain, and demonstrated that the experimental pain experience caused a decrease in the muscular contribution to lumbar spine rotational stiffness (related to mechanical stability) as well as lower back local dynamic stability (LDS). It has yet to be established if pain elsewhere in the body, specifically in other regions of the spine, can similarly affect the stability of the lower back. The purpose of this investigation was therefore to quantify thoracic and lumbar spine LDS as well as the muscular contribution to lumbar spine rotational stiffness after an experimental neck pain protocol. Results demonstrated that LDS of the thoracic spine decreased in response to the capsaicin/heat induced neck pain. Limited adaptation was required at the lumbar spine as demonstrated by the lack of statistically significant changes in lower back LDS or rotational stiffness. 相似文献
5.
Here, we seek to determine how compliantly suspended loads could affect the dynamic stability of legged locomotion. We theoretically model the dynamic stability of a human carrying a load using a coupled spring-mass-damper model and an actuated spring-loaded inverted pendulum model, as these models have demonstrated the ability to correctly predict other aspects of locomotion with a load in prior work, such as body forces and energetic cost. We report that minimizing the load suspension natural frequency and damping ratio significantly reduces the stability of the load mass but may slightly improve the body stability of locomotion when compared to a rigidly attached load. These results imply that a highly-compliant load suspension could help stabilize body motion during human, animal, or robot load carriage, but at the cost of a more awkward (less stable) load. 相似文献
6.
Understanding the regulation of natural populations has been a long-standing problem in ecology. Here we analyze the population dynamics of 17 species of saproxylic beetles in Shizuoka Prefecture, Japan collected over 11–12 years using autoregressive integrated moving average (ARIMA) models. We first examined the dynamics for indications of the order of the ARIMA models and evaluated the time series to determine that it was not simply a random, white noise sequence. All species dynamics were not mere random noise, and ARIMA models up to lag 3 were considered. The best model was selected from the possible ones using several criteria: model convergence, weak residual autocorrelation, the small sample AIC must be among the smallest that were not significantly different, and the lag indicated by the cutoff values in the detrended partial autocorrelation function. We found significant and nearly significant direct density-dependence for 14 of the 17 species, varying from −0.709 and stronger. The characteristic return rates were strong and only one species had a weak return rate (>0.9), implying that these species were strongly regulated by density-dependent factors. We found that populations with higher order ARIMA models (lag 2 and 3) had weaker return rates than populations with ARIMA models with only one lag, suggesting that species with more complex dynamics were more weakly regulated. These results contrast with previous suggestions that 20+ years are needed to detect density dependence from population time series and that most populations are weakly regulated. 相似文献
7.
A growing body of evidence suggests, that excessive body weight is inseparably connected with postural instability. In none of previous studies, body weight distribution has been considered as a factor, which may affect results of a static posturography. The purpose of the present study is to quantify some center of foot pressure (COP) characteristics in 40 obese women with android type of obesity (waist-to-hip ratio - WHR ≥ 0.85, BMI: 37.5 ± 5.4) and 40 obese women with gynoid type of obesity (WHR < 0.85, BMI: 36.9 ± 5.1). Variables of postural sway were acquired while subjects were standing quietly on a force plate with eyes open and closed. Both in the sagittal and frontal plane sway range, average velocity, and maximal velocity of COP were calculated. Moreover, the total average velocity and total maximal velocity of the COP displacement were computed.Women with abdominal obesity showed a larger sway range in the anterior-posterior plane with eyes open (p < 0.0282) and eyes closed conditions (p < 0.0115) and a greater maximal COP velocity to compare with subjects with gynoidal obese type (p < 0.0112) with eyes closed condition.The postural stability in obese women from the biomechanical point of view is strongly dependent on body distribution. Women with the abdominal obesity type may be exposed to a greater risk of postural instability as compare to women with gynoid fat distribution. 相似文献
8.
Jason E. Drury Rebekka Mindnich Trevor M. Penning 《The Journal of biological chemistry》2010,285(32):24529-24537
Bile acid deficiency is a serious syndrome in newborns that can result in death if untreated. 5β-Reductase deficiency is one form of bile acid deficiency and is characterized by dramatically decreased levels of physiologically active 5β-reduced bile acids. AKR1D1 (aldo-keto reductase 1D1) is the only known human enzyme that stereo-specifically reduces the Δ4 double bond in 3-keto steroids and sterols to yield the 5β-hydrogenated product. Analysis of the AKR1D1 gene in five patients with 5β-reductase deficiency revealed five different mutations resulting in an amino acid substitution in the protein. To investigate a causal role for these observed point mutations in AKR1D1 in 5β-reductase deficiency, we characterized their effect on enzymatic properties. Attempts to purify mutant enzymes by overexpression in Escherichia coli only yielded sufficient amounts of the P133R mutant for further characterization. This enzyme displayed a highly reduced Km and Vmax reminiscent of uncompetitive kinetics with 4-cholesten-7α-ol-3-one as substrate. In addition, this mutant displayed no change in cofactor affinity but was more thermolabile in the absence of NADPH as judged by CD spectroscopy. All mutants were compared following expression in HEK 293 cells. Although these enzymes were equally expressed based on mRNA levels, protein expression and functional activity were dramatically reduced. Cycloheximide treatment also revealed that several of the expressed mutants were less stable. Our findings show that the reported mutations in AKR1D1 in patients with 5β-reductase lead to significantly decreased levels of active enzyme and could be causal in the development of bile acid deficiency syndrome. 相似文献
9.
John Koren III Umesh K. Jinwal Ying Jin John O'Leary Jeff R. Jones Amelia G. Johnson Laura J. Blair Jose F. Abisambra Lyra Chang Yoshinari Miyata Anna M. Cheng Jianping Guo Jin Q. Cheng Jason E. Gestwicki Chad A. Dickey 《The Journal of biological chemistry》2010,285(4):2498-2505
Members of the 70-kDa heat shock family can control and manipulate a host of oncogenic client proteins. This role of Hsp70 in both the folding and degradation of these client proteins makes it a potential drug target for certain forms of cancer. The phenothiazine family of compounds, as well as the flavonoid myricetin, was recently shown to inhibit Hsp70-ATPase activity, whereas members of the dihydropyrimidine family stimulated ATPase function. Akt, a major survival kinase, was found to be under the regulation of Hsp70, and when the ATPase activity of Hsp70 was increased or decreased by these compounds, Akt levels were also increased or decreased. Also, increasing Hsp70 levels concurrent with inhibition of its ATPase function synergistically reduced Akt levels to a greater extent than either manipulation alone, providing new insights about client fate decisions. Akt reductions mediated by Hsp70 inhibitors were prevented when Hsp70 expression was silenced with small interfering RNA. Inhibiting Hsp70 ATPase function produced cytotoxic events only in breast cancer cell lines where Akt dysfunction was previously shown, suggesting therapeutic specificity depending on the Hsp70 client profile. Thus, increasing Hsp70 levels combined with inhibiting its ATPase function may serve to dramatically reduce Akt levels and facilitate cell death in certain types of cancer. 相似文献
10.
研究带有年龄结构的捕食者-食饵模型的渐近行为.本文所研究的模型假定捕食者从幼年阶段到成年阶段的转变率依赖于幼年种群的密度,还假定幼年捕食者捕食食饵.本文最终给出了有年龄结构的捕食者-食饵模型的捕食者持久和灭绝的若干条件. 相似文献