Development of Escherichia coli asparaginase II for the Treatment of Acute Lymphocytic Leukemia: In Silico Reduction of asparaginase II Side Effects by a Novel Mutant (V27F)

Acute lymphoblastic leukemia (ALL) is a common blood disease in children that is accountable for many deaths. Due to major improvements in treatment procedures in the past 50 years, the survivability of this disease has risen dramatically to about 90 percent today. L-asparaginase (ASNase) has been used to treat ALL. The glutaminase (GLNase) activity of this enzyme causes some side effects and is unnecessary for anticancer activity. This study investigated mutagenesis in Escherichia coli ASNase II to find a mutant with lower GLNase activity via molecular dynamics (MD) simulation. Residues with low binding energy to asparagine (Asn) and high binding energy to glutamine (Gln) were chosen for mutagenesis. A mutant with low free binding energy to Gln was then selected for molecular docking and MD studies. The results showed that V27F is a good candidate for reducing GLNase activity and that it has little effect on enzyme ASNase activity. A simulation analysis showed that the V27F mutant was more stable than the WT ASNase and that mutagenesis was quite successful.     

人体系统变质量块体动力学研究

在人体系统变质量力学模型研究基础上,开展了人体系统变质量块体动力学研究.主要内容有人体系统变质量块体的概念、人体系统变质量块体坐标系与基本定义、人体系统变质量块体的质心运动定理、人体系统变质量体定点的运动定理,为人体系统变质量力学模型和人体系统在质量变化过程中的物质流、能量流、信息流的运动规律的数字化研究提供理论基础.     

Influence of Ethanol as a Co-Solvent in Cyclodextrin Inclusion Complexation: A Molecular Dynamics Study

Molecular dynamics (MD) simulations were used to investigate the dynamics and host-guest interactions of the inclusion complexes between a potent anti-HIV agent, UC781, and three different types of cyclodextrins (CDs) including βCD, 2,6-dimethyl-βCD (MβCD), and 2-hydroxypropyl-βCD (HPβCD) in aqueous solution with ethanol (EtOH) as a co-solvent. The MD simulation results revealed that EtOH as the co-solvent and the type of cyclodextrin affected the inclusion complex formation. From this study, UC781/MβCD provided the most stable inclusion complex. The competition for the cavity of βCD between UC781 and EtOH and the ensuing occupation of βCD cavities by EtOH resulted in a weaker interaction between βCD and UC781. In HPβCD, a supramolecular complex of UC781−HPβCD−EtOH was formed. The EtOH could easily fill the residual void space of the interior of unoccupied HPβCD due to the movement of UC781. In MβCD, the strong hydrogen bond interactions between the UC781 amide group and the secondary hydroxyl groups of MβCD significantly stabilized the inclusion complex in the presence of EtOH.     

Employment Hardships and Single Mothers’ Self-Rated Health: Evidence from the Panel Study of Income Dynamics

Using a national sample of single mothers from the 2007 and 2009 waves of the Panel Study of Income Dynamics, this study examined the effects of multiple employment statuses on the selfrated health of single mothers during the recent economic recession. Unlike other studies, the current study minimized selection bias by controlling for prior self-rated health, in addition to other predisposing factors, enabling factors, and need factors. We found that underemployment, but not unemployment, is associated with lower levels of self-rated health of single mothers. Results further indicate that the 25–39 age range (compared to the 18–24 age range), lower family income, prior lower self-rated health, more chronic diseases, and binge drinking place single mothers at an increased risk of lower levels of self-rated health. In contrast, strength-building physical activity is significantly associated with higher levels of self-rated health. Implications for health care policy and social work practice are drawn from the results.     

NONLINEAR INTERDEPENDENCE IN NEURAL SYSTEMS: MOTIVATION,THEORY, AND RELEVANCE

In this article, we motivate models of medium to large-scale neural activity that place an emphasis on the modular nature of neocortical organization and discuss the occurrence of nonlinear interdependence in such models. On the basis of their functional, anatomical, and physiological properties, it is argued that cortical columns may be treated as the basic dynamical modules of cortical systems. Coupling between these columns is introduced to represent sparse long-range cortical connectivity. Thus, neocortical activity can be modeled as an array of weakly coupled dynamical subsystems. The behavior of such systems is represented by dynamical attractors, which may be fixed point, limit cycle, or chaotic in nature. If all the subsystems are perfectly identical, then the state of identical chaotic synchronization is a possible attractor for the array. Following the introduction of parameter variation across the array, such a state is not possible, although two other important nonlinear interdependences--generalized and phase synchronized--are possible. We suggest that an understanding of nonlinear interdependence may assist advances in models of neural activity and neuroscience time series analysis.     

A New Multiparameter Approach to Computational Simulation for Fontan Assessment and Redesign

Introduction. Despite an abundance of prior Fontan simulation articles, there have been relatively few clinical advances that are a direct result of computational methods. We address a few key limitations of previous Fontan simulations as a step towards increasing clinical relevance. Previous simulations have been limited in scope because they have primarily focused on a single energy loss parameter. We present a multi-parameter approach to Fontan modeling that establishes a platform for clinical decision making and comprehensive evaluation of proposed interventions. Methods. Time-dependent, 3-D blood flow simulations were performed on six patient-specific Fontan models. Key modeling advances include detailed pulmonary anatomy, catheterization-derived pressures, and MRI-derived flow with respiration. The following performance parameters were used to rank patients at rest and simulated exercise from best to worst performing: energy efficiency, inferior and superior vena cava (IVC, SVC) pressures, wall shear stress, and IVC flow distribution. Results. Simulated pressures were well matched to catheterization data, but low Fontan pressure did not correlate with high efficiency. Efficiency varied from 74% to 96% at rest, and from 63% to 91% with exercise. Distribution of IVC flow ranged from 88%/12% (LPA/RPA) to 53%/47%. A “transcatheter” virtual intervention demonstrates the utility of computation in evaluating interventional strategies, and is shown to result in increased energy efficiency. Conclusions. A multiparameter approach demonstrates that each parameter results in a different ranking of Fontan performance. Ranking patients using energy efficiency does not correlate with the ranking using other parameters of presumed clinical importance. As such, current simulation methods that evaluate energy dissipation alone are not sufficient for a comprehensive evaluation of new Fontan designs.     

“统管统分药品毛利”方案的利弊、动力阻力和前提条件研究

该文论证了“统管统分药品毛利”方案的利弊得失、动力阻力以及实施的前提条件。     

Optimal vaccine stockpile design for an eradicated disease: Application to polio

Eradication of a disease promises significant health and financial benefits. Preserving those benefits, hopefully in perpetuity, requires preparing for the possibility that the causal agent could re-emerge (unintentionally or intentionally). In the case of a vaccine-preventable disease, creation and planning for the use of a vaccine stockpile becomes a primary concern. Doing so requires consideration of the dynamics at different levels, including the stockpile supply chain and transmission of the causal agent. This paper develops a mathematical framework for determining the optimal management of a vaccine stockpile over time. We apply the framework to the polio vaccine stockpile for the post-eradication era and present examples of solutions to one possible framing of the optimization problem. We use the framework to discuss issues relevant to the development and use of the polio vaccine stockpile, including capacity constraints, production and filling delays, risks associated with the stockpile, dynamics and uncertainty of vaccine needs, issues of funding, location, and serotype dependent behavior, and the implications of likely changes over time that might occur. This framework serves as a helpful context for discussions and analyses related to the process of designing and maintaining a stockpile for an eradicated disease.     

PD-ECGF及VEGF在急性脑梗死患者中的动态变化

目的探讨PD-ECGF及VEGF在急性脑梗死患者中的动态变化。方法对2011年2月~2013年4月来我院进行治疗的60例急性脑梗死患者的临床资料进行回顾性分析,根据梗死体积将脑梗死组患者分为L(n=18)、M(n=23)、S(n=19)三个亚组,根据病因将脑梗死组患者分为大动脉粥样硬化组A(n=26)、小血管病变组B(n=18)、心源性组C(n=16)三个亚组;对照组为同期来我院进行健康体检的50例健康研究对象。比较梗死组患者发病后1、3、7、14 d及对照组的PD-ECGF及VEGF浓度。结果脑梗死组患者在发病后1、3、7、14d的PD-ECGF浓度及VEGF浓度均明显高于对照组(P<0.05)。脑梗死发病后3d的PD-ECGF浓度高于其他的时间,发病后7d的VEGF浓度高于其他时间(P<0.05)。发病后3、7、14d,L组PD-ECGF浓度与S组比较明显增高,B组则明显低于A组、C组(P<0.05)。发病后7、14d,L组VEGF浓度明显高于S组,A组明显高于B组(P<0.05)。结论急性脑梗死患者PD-ECGF及VEGF浓度与正常人比较明显增高,不同的梗死灶体积及不同病因类型升高的程度不同,与VEGF浓度达峰时间比较,PD-ECGF达峰时间更为提前。