Emerging principles of de novo catalyst design

Considerable progress has been made in the understanding of how to exploit hydrophobic and charge-charge interactions in forming binding sites for peptides and small molecules in folded polypeptide catalysts. This knowledge has enabled the introduction of feedback and control functions into catalytic cycles and the construction of folded polypeptide catalysts that follow saturation kinetics. Major advances have also been made in the design of metalloproteins and metallopeptides, especially with regards to understanding redox potential control.     

自然保护区设计的主要原理和方法

本文回顾了自然保护区设计的主要原理和方法。建立自然保护区的目的是防止物种绝灭和生物多样性消失。岛屿生物地理学的“平衡理论”的设计原则未涉及到物种绝灭的中心问题———种群生存力,所以该理论对保护实践贡献较小。种群生存力分析和最小可存活种群的理论及模型用于物种绝灭问题的研究,同时关键种的生存力用于确定生态系统的生存力,因而该理论和模型成为自然保护区设计的理论基础。保护评估方法已应用于自然保护区的选择和检验中。走廊辩论取代了ＳＬＯＳＳ辩论,成为自然保护区设计争论的热点     

Application of bioreactor design principles to plant micropropagation

Principles of oxygen consumption, oxygen transport, suspension, and mixing are discussed in the context of propagating aggregates of plant tissue in liquid suspension bioreactors. Although micropropagated plants have a relatively low biological oxygen demand (BOD), the relatively large tissue size and localization of BOD in meristematic regions will typically result in oxygen mass transfer limitations in liquid culture. In contrast to the typical focus of bioreactor design on gas–liquid mass transfer, it is shown that media-solid mass transfer limitations limit oxygen available for aerobic plant tissue respiration. Approaches to improve oxygen availability through gas supplementation and bioreactor pressurization are discussed. The influence of media components on oxygen availability are also quantified for plant culture media. Experimental studies of polystyrene beads in suspension in a 30-l air-lift and stirred bioreactors are used to illustrate design principles for circulation and mixing. Potential limitations to the use of liquid suspension culture due to plant physiological requirements are acknowledged.     

On the design principles of metabolic flux sensing

Metabolism is precisely coordinated, with the goal of balancing fluxes to maintain robust growth. However, coordinating fluxes requires information about rates, which can only be inferred through concentrations. While flux-sensitive metabolites have been reported, the design principles underlying such sensing have not been clearly elucidated. Here we use kinetic modeling to show that substrate concentrations of thermodynamically constrained reactions reflect upstream flux and therefore carry information about rates. Then we use untargeted multi-omic data from Escherichia coli and Saccharomyces cerevisiae to show that the concentrations of some metabolites in central carbon metabolism reflect fluxes as a result of thermodynamic constraints. We then establish, using 37 real concentration-flux relationships across both organisms, that in vivo $\text{Δ}{G}^{°}\ge ?4$ kJ/mol is the threshold above which substrates are likely to be sensitive to upstream flux(es).     

Engineering design principles for organelle size control systems

Organelle size is an important determinant of organelle function, and for this reason cells have evolved mechanisms to control and adjust organelle size in the face of intrinsic biological fluctuations. Size control systems have been found that employ a variety of distinct mechanisms, which fall into a small number of classes. Each class represents a design principle by which artificial size controllers could be developed for synthetic biology applications.     

PAR polarity: From complexity to design principles

The par-titioning-defective or PAR proteins comprise the core of an essential cell polarity network that underlies polarization in a wide variety of cell types and developmental contexts. The output of this network in nearly every case is the establishment of opposing and complementary membrane domains that define a cell?s polarity axis. Yet, behind this simple pattern is a complex system of interactions, regulation and dynamic behaviors. How these various parts combine to generate polarized patterns of protein localization in cells is only beginning to become clear. This review, part of the Special Issue on Cell Polarity, aims to highlight several emerging themes and design principles that underlie the process of cell polarization by components of the PAR network.     

Exploiting structural principles to design cyclin-dependent kinase inhibitors

Although cyclin-dependent kinases (CDKs) have been extensively targeted in anti cancer drug design, no CDK inhibitor has yet been approved for use in cancer therapy. While this may in part be because inhibitors clinically evaluated to date have not demonstrated clean inhibition of a single CDK, another contributing factor is an apparent latent functional redundancy in the CDK cell-cycle regulatory system. This further complicates the already challenging goal of targeting CDKs, since it implies that a therapeutically useful inhibitor will have to selectively inhibit more than one CDK family member among the complement of cellular proteins. Despite these difficulties, achieving an appropriate profile of CDK inhibition may yet be possible using ATP-competitive inhibitors, thanks to advances in computational and experimental methods of drug design. However, as an alternative to ATP-competitive inhibitors, inhibitors that interfere with a CDK-specific protein:protein interaction, such as that which occurs at the recruitment site found on several cyclins, may offer a route to a therapeutically useful inhibitory profile.     

Building the cell: design principles of cellular architecture

The astounding structural complexity of a cell arises from the action of a relatively small number of genes, raising the question of how this complexity is achieved. Self-organizing processes combined with simple physical constraints seem to have key roles in controlling organelle size, number, shape and position, and these factors then combine to produce the overall cell architecture. By examining how these parameters are controlled in specific cell biological examples we can identify a handful of simple design principles that seem to underlie cellular architecture and assembly.     

Screening of bioagents against root rot of mung bean caused by Rhizoctonia solani

A laboratory and green house experiment was carried out on the comparative antagonistic performance of four different bioagents (Aspergillus sp., Gliocladium virens, Trichoderma harzianum and T. viride) isolated from soil against Rhizoctonia solani. Under laboratory conditions, T. harzianum exhibited maximum (75.55%) mycelial growth inhibition of R. solani This was followed by T. viride, which showed 65.93 per cent mycelial growth inhibition of the pathogen. Gliocladium virens was also found to be effective antagonists, which exhibited 57.77 per cent mycelial growth inhibition. While Aspergillus sp exhibited minimum growth inhibition (45.74%) in comparison to other bioagents. Under green house conditions, T. harzianum gave maximum protection of the disease (72.72%) followed by T. viride, which exhibited 54.54 per cent disease control. However, G. virens and Aspergillus sp were found least effective in controlling root rot of mungbean.     

Evolutionary imprint of activation: The design principles of VSDs

Voltage-sensor domains (VSDs) are modular biomolecular machines that transduce electrical signals in cells through a highly conserved activation mechanism. Here, we investigate sequence–function relationships in VSDs with approaches from information theory and probabilistic modeling. Specifically, we collect over 6,600 unique VSD sequences from diverse, long-diverged phylogenetic lineages and relate the statistical properties of this ensemble to functional constraints imposed by evolution. The VSD is a helical bundle with helices labeled S1–S4. Surrounding conserved VSD residues such as the countercharges and the S2 phenylalanine, we discover sparse networks of coevolving residues. Additional networks are found lining the VSD lumen, tuning the local hydrophilicity. Notably, state-dependent contacts and the absence of coevolution between S4 and the rest of the bundle are imprints of the activation mechanism on the VSD sequence ensemble. These design principles rationalize existing experimental results and generate testable hypotheses.     

Process optimization using combinatorial design principles: parallel synthesis and design of experiment methods

The use of parallel synthesis techniques with statistical design of experiment (DoE) methods is a powerful combination for the optimization of chemical processes. Advances in parallel synthesis equipment and easy to use software for statistical DoE have fueled a growing acceptance of these techniques in the pharmaceutical industry. As drug candidate structures become more complex at the same time that development timelines are compressed, these enabling technologies promise to become more important in the future.