抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Social Network Analysis

Dynamic crack growth is analysed numerically for a plane strain block with an initial central crack subject to tensile loading. The continuum is characterized by a material constitutive law that relates stress and strain, and by a relation between the tractions and displacement jumps across a specified set of cohesive surfaces. The material constitutive relation is that of an isotropic hyperelastic solid. The cohesive surface constitutive relation allows for the creation of new free surface and dimensional considerations introduce a characteristic length into the formulation. Full transient analyses are carried out. Crack branching emerges as a natural outcome of the initial-boundary value problem solution, without any ad hoc assumption regarding branching criteria. Coarse mesh calculations are used to explore various qualitative features such as the effect of impact velocity on crack branching, and the effect of an inhomogeneity in strength, as in crack growth along or up to an interface. The effect of cohesive surface orientation on crack path is also explored, and for a range of orientations zigzag crack growth precedes crack branching. Finer mesh calculations are carried out where crack growth is confined to the initial crack plane. The crack accelerates and then grows at a constant speed that, for high impact velocities, can exceed the Rayleigh wave speed. This is due to the finite strength of the cohesive surfaces. A fine mesh calculation is also carried out where the path of crack growth is not constrained. The crack speed reaches about 45% of the Rayleigh wave speed, then the crack speed begins to oscillate and crack branching at an angle of about 29° from the initial crack plane occurs. The numerical results are at least qualitatively in accord with a wide variety of experimental observations on fast crack growth in brittle solids.

Numerical simulations of fast crack growth in brittle solids

The emergence of tissue engineering raises new possibilities for the study of complex physiological and pathophysiological processes in vitro. Many tools are now available to create 3D tissue models in vitro, but the blueprints for what to make have been slower to arrive. We discuss here some of the 'design principles' for recreating the interwoven set of biochemical and mechanical cues in the cellular microenvironment, and the methods for implementing them. We emphasize applications that involve epithelial tissues for which 3D models could explain mechanisms of disease or aid in drug development.

Capturing complex 3D tissue physiology in vitro.

Single-molecule force spectroscopy has emerged as a powerful tool to investigate the forces and motions associated with biological molecules and enzymatic activity. The most common force spectroscopy techniques are optical tweezers, magnetic tweezers and atomic force microscopy. Here we describe these techniques and illustrate them with examples highlighting current capabilities and limitations.

Single-molecule force spectroscopy: optical tweezers, magnetic tweezers and atomic force microscopy

Cytoskeletal molecular motors belonging to the kinesin and dynein families transport cargos (for example, messenger RNA, endosomes, virus) on polymerized linear structures called microtubules in the cell1. These ‘nanomachines’ use energy obtained from ATP hydrolysis to generate force2, and move in a step-like manner on microtubules. Dynein3,4,5 has a complex and fundamentally different structure from other motor families. Thus, understanding dynein's force generation can yield new insight into the architecture and function of nanomachines. Here, we use an optical trap6 to quantify motion of polystyrene beads driven along microtubules by single cytoplasmic dynein motors. Under no load, dynein moves predominantly with a mixture of 24-nm and 32-nm steps. When moving against load applied by an optical trap, dynein can decrease step size to 8 nm and produce force up to 1.1 pN. This correlation between step size and force production is consistent with a molecular gear mechanism. The ability to take smaller but more powerful strokes under load—that is, to shift gears—depends on the availability of ATP. We propose a model whereby the gear is downshifted through load-induced binding of ATP at secondary sites in the dynein head.

Cytoplasmic dynein functions as a gear in response to load

We describe the design and construction of two different types of multiple-beam optical tweezers, each equipped with nanometer-resolution position detectors. Multiple optical traps can be created either by splitting a laser beam in two parts, based on its polarization, or time-sharing a single beam among several different locations. The advantages and disadvantages of optical tweezers based on either scheme are discussed, along with details of specific implementations. Various ways to detect microscopic movements of an optically trapped object are presented and compared, including designs that are relatively insensitive to absolute location of a trapped particle within the field of view. Two of many possible applications for such instruments are illustrated: the detection of molecular steps by kinesin motor molecules, and determinations of the stiffness of single microtubules.

/pdf/construction-of-multiple-beam-optical-traps-with-nanometer-1hopf6xjt1.pdf

Construction of multiple-beam optical traps with nanometer-resolution position sensing

The Lipid-Droplet Proteome Reveals that Droplets Are a Protein-Storage Depot

Motor-based intracellular transport and its regulation are crucial to the functioning of a cell. Disruption of transport is linked to Alzheimer's and other neurodegenerative diseases. However, many fundamental aspects of transport are poorly understood. An important issue is how cells achieve and regulate efficient long-distance transport. Mounting evidence suggests that many in vivo cargoes are transported along microtubules by more than one motor, but we do not know how multiple motors work together or can be regulated. Here we first show that multiple kinesin motors, working in conjunction, can achieve very long distance transport and apply significantly larger forces without the need of additional factors. We then demonstrate in vitro that the important microtubule-associated protein, tau, regulates the number of engaged kinesin motors per cargo via its local concentration on microtubules. This function of tau provides a previously unappreciated mechanism to regulate transport. By reducing motor reattachment rates, tau affects cargo travel distance, motive force, and cargo dispersal. We also show that different isoforms of tau, at concentrations similar to those in cells, have dramatically different potency. These results provide a well defined mechanism for how altered tau isoform levels could impair transport and thereby lead to neurodegeneration without the need of any other pathway.

https://www.pnas.org/content/pnas/104/1/87.full.pdf

Multiple-motor based transport and its regulation by Tau

https://www.cell.com/cell/pdf/S0092-8674(00)80947-2.pdf

Steven P. Gross

Papers

Cytoplasmic dynein functions as a gear in response to load

Construction of multiple-beam optical traps with nanometer-resolution position sensing

The Lipid-Droplet Proteome Reveals that Droplets Are a Protein-Storage Depot

Multiple-motor based transport and its regulation by Tau

Developmental regulation of vesicle transport in Drosophila embryos: forces and kinetics.