Replacing the Factor VIII C1 Domain with a Second C2 Domain Reduces Factor VIII Stability and Affinity for Factor IXa

Factor VIII (FVIII) consists of a heavy chain (A1(a1)A2(a2)B domains) and light chain ((a3)A3C1C2 domains). To gain insights into a role of the FVIII C domains, we eliminated the C1 domain by replacing it with the homologous C2 domain. FVIII stability of the mutant (FVIII_C2C2) as measured by thermal decay at 55 °C of FVIII activity was markedly reduced (∼11-fold), whereas the decay rate of FVIIIa due to A2 subunit dissociation was similar to WT FVIIIa. The binding affinity of FVIII_C2C2 for phospholipid membranes as measured by fluorescence resonance energy transfer was modestly lower (∼2.8-fold) than that for WT FVIII. Among several anti-FVIII antibodies tested (anti-C1 (GMA8011), anti-C2 (ESH4 and ESH8), and anti-A3 (2D2) antibody), only ESH4 inhibited membrane binding of both WT FVIII and FVIII_C2C2. FVIIIa cofactor activity measured in the presence of each of the above antibodies was examined by FXa generation assays. The activity of WT FVIIIa was inhibited by both GMA8011 and ESH4, whereas the activity of FVIII_C2C2 was inhibited by both the anti-C2 antibodies, ESH4 and ESH8. Interestingly, factor IXa (FIXa) binding affinity for WT FVIIIa was significantly reduced in the presence of GMA8011 (∼10-fold), whereas the anti-C2 antibodies reduced FIXa binding affinity of FVIII_C2C2 variant (∼4-fold). Together, the reduced stability plus impaired FIXa interaction of FVIII_C2C2 suggest that the C1 domain resides in close proximity to FIXa in the FXase complex and contributes a critical role to FVIII structure and function.     

Mathematical modeling of cascading migration in a tri-trophic food-chain system

Diel vertical migration is a behavioral antipredator defense that is shaped by a trade-off between higher predation risk in surface waters and reduced growth in deeper waters. The strength of migration of zooplankton increases with a rise in the abundance of predators and their exudates (kairomone). Recent studies span multiple trophic levels, which lead to the concept of coupled vertical migration. The migrations that occur at one trophic level can affect the vertical migration of the next lower trophic level, and so on, throughout the food chain. This is called cascading migration. In this paper, we introduce cascading migration in a well-known model (Hastings and Powell, Ecology 73:896–903, 1991). We represent the dynamics of the system as proposed by Hastings and Powell as a phytoplankton–zooplankton–fish (prey–middle predator–top predator) model where fish affect the migrations of zooplankton, which in turn affect the migrations of motile phytoplankton. The system under cascading migration enhances system stability and population coexistence. It is also observed that for a higher rate of cascading migration, the system shows chaotic behavior. We conclude that the observations of Hastings and Powell remain true if the cascading migration rate is high enough.     

3,5-Bis(benzylidene)-4-piperidones and related N-acyl analogs: A novel cluster of antimalarials targeting the liver stage of Plasmodium falciparum

Drug resistance is a major challenge in antimalarial chemotherapy. In addition, a complete cure of malaria requires intervention at various stages in the development of the parasite within the host. There are only a few antimalarials that target the liver stage of the Plasmodium species which is an essential part of the life cycle of the malarial parasite. We report a series of antimalarial 3,5-bis(benzylidene)-4-piperidones and related N-acyl analogs 1–5, a number of which exhibit potent in vitro growth-inhibiting properties towards drug-sensitive D6 and drug-resistant C235 strains of Plasmodium falciparum as well as inhibiting the liver stage development of the malarial life cycle. The compounds 2b (IC₅₀: 165 ng/mL), 3b (IC₅₀: 186 ng/mL), 5c (IC₅₀: 159 ng/mL) and 5d (IC₅₀: 93.5 ng/mL) emerged as lead molecules that inhibit liver stage Plasmodium berghei and are significantly more potent than chloroquine (IC₅₀: >2000 ng/mL) and mefloquine (IC₅₀: >2000 ng/mL) in this screen. All the compounds that showed potent inhibitory activity against the P. berghei liver stage were nontoxic to human HepG2 liver cells (IC₅₀: >2000 ng/mL). The compounds 5a and 5b exhibit comparable metabolic stability as chloroquine and mefloquine in human plasma and the most potent compound 5d demonstrated suitable permeability characteristics using the MDCK monolayer. These results emphasize the value of 3,5-bis(benzylidene)-4-piperidones as novel antimalarials for further drug development.     

一类人禽间传染病模型的动力学分析

讨论了一类人禽传染病模型,其中禽类被病毒感染后人们采取措施治疗病禽．治疗有助于禽类的存活,但人们可能通过接触病禽而被感染．禽间的疾病传播服从饱和接触率函数,人与禽的接触服从线性接触率．完成了稳定性和持久性研究,且进行了数值模拟以评估治疗的效果和风险．     

流感病毒裂解疫苗裂解剂去除工艺改进及稳定性研究

目的改进流感病毒裂解疫苗裂解剂去除工艺,降低残余卵清蛋白和裂解剂含量,提高疫苗质量,降低成本。方法分别将A1、A3和B型流感病毒纯化液用磷酸缓冲液（PB）沉淀法去除裂解剂,经超滤、除菌制备原液,配制6批半成品,其中3批不含硫柳汞,3批含硫柳汞,经全面检定,并观察放置37℃、25℃和2～8℃不同时间的稳定性。结果该疫苗各项指标均符合《中国药典》（2010年版）三部要求,其中卵清蛋白平均为3．83ng／mL,裂解剂平均为57μg／mL,比改进前分别降低97．9％和69％。37℃放置4周、25℃3个月及2-8℃12个月后检定全部合格。结论该工艺步骤简单,去除卵清蛋白和裂解剂效果明显,是进一步提高疫苗质量和降低成本的有效工艺。     

耐药结核分枝杆菌潜伏-复发感染动物模型的研究进展

潜伏结核感染(latent tuberculosis infection,LTBI)复发是新发结核病的主要来源,其中耐药结核病所占比例较大,使耐药LTBI复发的防控成为结核病研究的重点。耐药结核分枝杆菌潜伏-复发感染动物模型是开展耐药结核病防控相关机制研究、抗耐药结核分枝杆菌药物和疫苗研究的基础。目前耐药结核分枝杆菌感染动物模型缺乏,而已有的结核分枝杆菌标准株H37Rv潜伏-复发感染模型存在缺陷,如小鼠模型的潜伏期荷菌量偏高、复发期变异大,而猴模型的潜伏期和复发期不可预测。模型的可控性差使其应用困难,且缺乏可用的免疫学评价指标,导致远期复发无法预测。因此,基于现有H37Rv潜伏-复发感染动物模型的制备方法,展望耐药结核分枝杆菌潜伏-复发感染动物模型可能存在的缺陷,通过选用新的抑菌剂和诱导剂,制备有稳定潜伏期、潜伏时长适中、复发起点和复发水平变异小的动物模型,是未来耐药结核分枝杆菌潜伏-复发感染动物模型研究的方向。     

粒毛盘菌黄色素的稳定性研究

【目的】评价粒毛盘菌黄色素的稳定性。【方法】以色素吸光值为指标,研究温度、光照、pH、金属离子、氧化剂、还原剂及食品添加剂对黄色素稳定性的影响。【结果】该黄色素属黄酮类物质,易溶于水,在水溶液中紫外区及可见光区各呈现一个吸收峰,最大吸收波长分别为300 nm和410 nm;热稳定性较好,70°C处理4 h的色素保存率近90%;光照能降低黄色素水溶液的稳定性;随着pH的升高,色素溶液颜色逐渐加深,其A410增大;色素溶液在pH 9.0-10.0下较稳定,pH 10.0的色素溶液放置5 d后色素保存率近90%;Na_2SO_3对色素水溶液有增色作用,色素水溶液抗NaNO_2、H_2O_2能力较强,对抗坏血酸敏感。Fe~(3+)、Fe~(2+)与色素反应而改变色素颜色,Al~(3+)、Cu~(2+)、Zn~(2+)对色素水溶液具有一定的褪色作用,Ca~(2+)、K~+、Mg~(2+)对色素溶液无明显影响。蔗糖、葡萄糖和山梨酸钾对色素水溶液无明显影响,氯化钠对色素水溶液具有较弱的褪色作用。【结论】粒毛盘菌黄色素在稳定性上呈现出一定优势,具有开发潜力。     

Interannual variability,stability and resilience in UK plant communities

Plant communities are often assumed to be stable on a year-to-year basis. We present evidence that species composition in permanent quadrats changes considerably between years at a range of Environmental Change Network sites across the UK. The extent of this variability varies with habitat type. Communities associated with low disturbance levels and low agricultural inputs, particularly moorland (upland grass and heath) and bog communities, are most stable.Inter-annual variability should, therefore, be considered in designing monitoring schemes to ensure that frequency of recording is sufficient to avoid short-term fluctuations obscuring long-term trends.More diverse communities were more stable, with less species turnover between years. However, diverse communities also tended to be dominated by slow-growing, slow-reproducing plants, adapted to low nutrient conditions, identified as ‘stress tolerators’ in the Grime CSR scheme and low Ellenberg N values. Species compositional stability was more strongly correlated with these indices of plant functional types than species richness. Nevertheless, a significant effect of species richness could be identified, even after other causes of variation were accounted for.More stable communities in our study are likely to be resilient to low levels of environmental change, although they may still change, and possibly change dramatically if critical ‘tipping points’ are reached.     

Stability,sensitivity and uncertainty rates in the flow equations of ecological models

In previous work by the authors about dynamic system modeling, basic ecosystems concepts and their application to ecological modeling theory were formalized. Measuring how a variable effects certain processes leads to improvements in dynamic systems modelling and facilitates the author’s study of system diversity in which model sensitivity is a key theme. Initially, some variables and their numeric data are used for modeling. Predictions from the constructed models depend on these data. Generic study of sensitivity aims to show to what degree model behavior is altered by modification of some specific data. If small variations cause important modifications in the model’s global behavior then the model is very sensitive in relation to the variables used. If uncertain systems are considered, then it is important to submit the system to extreme situations and analyze its behavior. In this article, some indexes of uncertainty will be defined in order to determine the variables' influence in the case of extreme changes. This will permit analysis of the system’s sensitivity in relation to several simulations.