Hybrid physics-based and data-driven modeling for bioprocess online simulation and optimization

Model-based online optimization has not been widely applied to bioprocesses due to the challenges of modeling complex biological behaviors, low-quality industrial measurements, and lack of visualization techniques for ongoing processes. This study proposes an innovative hybrid modeling framework which takes advantages of both physics-based and data-driven modeling for bioprocess online monitoring, prediction, and optimization. The framework initially generates high-quality data by correcting raw process measurements via a physics-based noise filter (a generally available simple kinetic model with high fitting but low predictive performance); then constructs a predictive data-driven model to identify optimal control actions and predict discrete future bioprocess behaviors. Continuous future process trajectories are subsequently visualized by re-fitting the simple kinetic model (soft sensor) using the data-driven model predicted discrete future data points, enabling the accurate monitoring of ongoing processes at any operating time. This framework was tested to maximize fed-batch microalgal lutein production by combining with different online optimization schemes and compared against the conventional open-loop optimization technique. The optimal results using the proposed framework were found to be comparable to the theoretically best production, demonstrating its high predictive and flexible capabilities as well as its potential for industrial application.     

Anaerobic and aerobic continuous cultures of<Emphasis Type="Italic"> Saccharomyces cerevisiae</Emphasis>: comparison of plasmid stability and<Emphasis Type="Italic"> EXG1</Emphasis> gene expression

Two bioreactor continuous cultures, at anaerobic and aerobic conditions, were carried out using a recombinant Saccharomyces cerevisiae strain that over-expresses the homologous gene EXG1. This recombinant system was used to study the effect of dissolved oxygen concentration on plasmid stability and gene over-expression. Bioreactor cultures were operated at two dilution rates (0.14 and 0.03 h^–1) to investigate the effect of other process parameters on EXG1 expression. Both cultures suffered severe plasmid instability during the first 16 generations. Segregational plasmid loss rate for the aerobic culture was two-fold that of the anaerobic operation. In spite of this fact, exo--glucanase activity at aerobic conditions was 12-fold that of the anaerobic culture. This maximal activity (30 U ml^–1) was attained at the lowest dilution rate when biomass reached its greatest value and glucose concentration was zero.     

Influence of alterations in culture condition and changes in perfusion parameters on the retention performance of a 20 μm spinfilter during a perfusion cultivation of a recombinant CHO cell line in pilot scale

Since 1969 much attention has been devoted to the useof spinfilter systems for retention of mammalian cellsin continuous perfusion cultivations. Previousinvestigations dealt with hydrodynamic conditions,fouling processes and upscaling. But hydrodynamicconditions and fouling processes seem to have asecondary importance in spinfilter performance duringauthentic perfusion cultivations. Obviously,alterations in culture condition are more relevantespecially during long-term processes. Therefore, ourpratical approach focussed on the performance qualityof a commercially available 20 m spinfilterduring a perfusion cultivation of a recombinant CHOcell line in pilot scale regarding the followingissues: 1) retention of viable cells in thebioreactor; 2) removal of dead cells and cell debrisfrom the bioreactor; 3) alterations in culturecondition; and 4) changes in perfusion mode.Furthermore, we tested the performance of 20 mspinfilters in 2 and 100 l pilot scale using solidmodel particles instead of cells. Our investigationsshowed that retention of viable cells in pilot scalewas independent of spinfilter rotation velocity andperfusion rate; the retention increased from 75 to 95%corresponding to operation time, enlarging celldiameter and enhanced formation of aggregates in theculture during the perfusion cultivation. By means ofthe Cell Counter and Analyzer System (CASY) anoperation cut off of 13 m was determined forthis spinfilter. Using solid model particles in 2 lscale, optimal retention was achieved at a tip speedof 0.43 m s^-1 (141 rpm) – furtherenhancement of spinfilter rotation velocity up to0.56 m s^-1 (185 rpm) decreased the retentionrapidly. In pilot scale best retention performance wasobtained with tip speeds of 0.37 m s^-1(35 rpm) and 1.26 m s^-1 (120 rpm). Hence,significant retention in pilot scale could already beachieved with low agitation. Therefore, the additionof shear force protectives could be avoided so thatthe purification of the target protein from thesupernatant would be facilitated.     

Aquatic worms eating waste sludge in a continuous system

Aquatic worms are a biological approach to decrease the amount of biological waste sludge produced at waste water treatment plants. A new reactor concept was recently introduced in which the aquatic oligochaete Lumbriculus variegatus is immobilised in a carrier material. The current paper describes the experiments that were performed to test whether this concept could also be applied in continuous operation, for which worm growth is an important condition. This was tested for two mesh sizes of the carrier material. With an increase in mesh size from 300 to 350 μm, worm biomass growth was possible in the reactor at a rate of 0.013 d⁻¹ and with a yield of 0.13 g dw/g VSS digested by the worms. Mass balances over the worm reactors showed the importance of correcting for natural sludge breakdown, as the contribution of the worms to total VSS reduction was 41–71%.     

同期施行冠状动脉搭桥和心脏瓣膜手术的体外循环

目的总结和分析同期施行冠状动脉搭桥和心脏瓣膜手术的体外循环方法。方法125例患者分为3组:M组(冠脉病变及二尖瓣病变)75例,A组(冠脉病变及主动脉瓣病变)34例,D组(冠脉病变及二尖瓣和主动脉瓣病变)16例。心肌保护采用4:1冷含血停搏液,应用单纯顺灌、顺灌逆灌结合、顺灌桥灌结合、顺逆灌和桥灌结合技术。结果术中转流平稳,血流动力学稳定,监测指标均在正常范围,无手术死亡。结论同期施行冠状动脉搭桥和心脏瓣膜手术,术中良好的心肌保护方法和合理的体外循环灌注是保证手术顺利成功的重要因素。     

医疗设备维修标准化管理的探讨

本文主要阐述现代医院在医疗设备购置过程中,怎样来进一步增强售后服务意识,事先防范风险。在医疗设备维修过程中,怎样来规范维修合同,制定标准合同,加强售后服务管理。     

食管癌患者手术前后免疫功能改变对外周血细胞凋亡的影响

为探讨食管癌手术前后患者外周血细胞的凋亡情况。利用流式细胞仪对70例食管癌手术前及其手术后10天~14天患者外周血细胞的DNA和CD4,CD8和CD16/56含量进行了分析。结果显示:手术前后患者外周血细胞的凋亡有差异(P<0.05),但血细胞的DNA合成期细胞比率(S-phage fraction,SPE)、细胞增长指数无明显的差异(P>0.05)。两组的CD4/CD8比值或CD16/56比例有明显差异(P<0.001)。实验数据表明:手术前患者的细胞凋亡增加可能有利于平衡肿瘤细胞的恶性增殖;而外周血细胞的CD8、NK(自然杀伤细胞,natural killer cells)增高,可能有助于这种平衡作用。但手术后患者肿瘤负荷减轻,免疫功能恢复常态,细胞凋亡率相应降低。     

Pre-release monitoring of Alliaria petiolata (garlic mustard) invasions and the impacts of extant natural enemies in southern Michigan forests

Monitoring of populations of a target weed species prior to releasing natural enemies has the potential to improve the rigor and safety of biological control and to determine the invader’s impacts on native communities while creating a reference point for evaluating the efficacy of subsequent biocontrol agent releases. Eight populations of garlic mustard, Alliaria petiolata (M. Bieb) Cavara and Grande (Brassicaceae), an invasive weed in southern Michigan, were monitored in anticipation of releases of classical biological control agents. The A. petiolata populations were shown to be expanding with 44.4% of initially uninvaded sampling quadrats becoming invaded after four years. While 88.2% of quadrats with A. petiolata showed evidence of foliar damage from pathogens and browsing by mammals, insects and other invertebrates, levels of damage were low and had little impact on rosette or seedling survival. Contrary to expectations, damage was positively correlated with A. petiolata fecundity (P = 0.0465). Given the continued expansion of A. petiolata and the lack of significant herbivore damage by acquired natural enemies, a biological control program should be considered against this invasive plant. If biological control agents are released, the results of this study will provide a benchmark for evaluating their performance.     

三峡水库运行期间原生动物群落的时空异质性

于2010年10月—2011年6月三峡水库正常运行周期内对库区干流原生动物进行调查,研究其空间分布及水库周期排蓄期间的变化。共检测到原生动物99种,蓄水后纤毛虫有增多的趋势。水库运行的不同阶段优势种不同,大致演变为:砂壳纤毛虫(蓄水期)—非砂壳类纤毛虫(高位运行期间)—有壳肉足虫(低位运行期间)。不同水域优势种也存在差异,从上游到下游特征指示种变化为:有壳肉足虫(变动回水区)—纤毛虫(湖泊区)。结果表明,三峡水库原生动物的分布具有明显的时空异质性(P0.05),影响原生动物时空分布的主要因素有透明度、温度、电导率和叶绿素a。原生动物平均密度为952.19个/L,平均生物量为8.14μg/L。蓄水期上游现存量高于下游,低位运行期间则低于下游。原生动物Marglef和Shannonn-Weiver多样性指数平均值分别为3.78和2.18,1月份最低,6月份最高。蓄水175 m后上游变动回水区原生动物具有较高的丰度。水库冬蓄夏排的运行模式模糊了河流本身的季节变化,使原生动物的种类和现存量更多的受水库水动力学的影响,使水体理化因子和水文特征呈现明显的时空差异,最终形成原生动物种群的时空异质性分布。     

香港特区公营医院运行机制评估及对内地的启示

回顾香港医疗融资的发展历程并简述香港公营医院的运营状况与开支构成比,重点分析香港公营医院的管理机构——香港医院管理局,研究其宗旨任务与目标策略相结合的管理医院管理战略,跟踪其主要经费来源的变化趋势,对其财务状况进行深入探究并进行预测。在对香港公营医院运行机制进行评估的基础上,探讨香港公营医院存在的问题以及对内地的启示,为内地医院管理机构借鉴香港逐步建立以政府投入为主体的医疗融资体系提供参考。