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

▪ Abstract Synaptic transmission is a dynamic process. Postsynaptic responses wax and wane as presynaptic activity evolves. This prominent characteristic of chemical synaptic transmission is a crucial determinant of the response properties of synapses and, in turn, of the stimulus properties selected by neural networks and of the patterns of activity generated by those networks. This review focuses on synaptic changes that result from prior activity in the synapse under study, and is restricted to short-term effects that last for at most a few minutes. Forms of synaptic enhancement, such as facilitation, augmentation, and post-tetanic potentiation, are usually attributed to effects of a residual elevation in presynaptic [Ca2+]i, acting on one or more molecular targets that appear to be distinct from the secretory trigger responsible for fast exocytosis and phasic release of transmitter to single action potentials. We discuss the evidence for this hypothesis, and the origins of the different kinetic phases...

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Short-Term Synaptic Plasticity

TRP channels are the vanguard of our sensory systems, responding to temperature, touch, pain, osmolarity, pheromones, taste and other stimuli. But their role is much broader than classical sensory transduction. They are an ancient sensory apparatus for the cell, not just the multicellular organism, and they have been adapted to respond to all manner of stimuli, from both within and outside the cell.

TRP channels as cellular sensors

The present invention relates to a structure comprising a biological membrane and a porous or perforated substrate, a biological membrane, a substrate, a high throughput screen, methods for production of the structure membrane and substrate, and a method for screening a large number of test compounds in a short period. More particularly it relates to a structure comprising a biological membrane adhered to a porous or perforated substrate, a biological membrane capable of adhering with high resistance seals to a substrate such as perforated glass and the ability to form sheets having predominantly an ion channel or transporter of interest, a high throughput screen for determining the effect of test compounds on ion channel or transporter activity, methods for manufacture of the structure, membrane and substrate, and a method for monitoring ion channel or transporter activity in a membrane.

High throughput screen

Recognition of an avirulent pathogen triggers the rapid production of the reactive oxygen intermediates superoxide (O2-) and hydrogen peroxide (H2O2) This oxidative burst drives crosslinking of the cell wall, induces several plant genes involved in cellular protection and defence, and is necessary for the initiation of host cell death in the hypersensitive disease-resistance response However, this burst is not enough to support a strong disease-resistance response Here we show that nitric oxide, which acts as a signal in the immune, nervous and vascular systems, potentiates the induction of hypersensitive cell death in soybean cells by reactive oxygen intermediates and functions independently of such intermediates to induce genes for the synthesis of protective natural products Moreover, inhibitors of nitric oxide synthesis compromise the hypersensitive disease-resistance response of Arabidopsis leaves to Pseudomonas syringae, promoting disease and bacterial growth We conclude that nitric oxide plays a key role in disease resistance in plants

Nitric oxide functions as a signal in plant disease resistance

Calcium ions serve as intracellular messengers in 2 activities of hair cells: in conjunction with Ca2(+)-activated K+ channels, they produce the electrical resonance that tunes each cell to a specific frequency of stimulation, and they trigger the release of a chemical synaptic transmitter. Our experiments indicate that both of these functions are conducted within a region that extends a few hundred nanometers around each presynaptic active zone. In focal electrical recordings from the plasma membranes of isolated anuran hair cells, we found nearly all of a cell's Ca2+ channels and Ca2(+)-activated K+ channels clumped at a fixed ratio in an average of 20 clusters on the basolateral membrane surface. Because serial-section electron microscopy indicated that each hair cell has approximately 19 afferent synaptic contacts with a similar distribution upon its basolateral surface, we conclude that the channel clusters coincide with synaptic active zones. Ensemble-variance analysis of current fluctuations indicated that each cell has a total of approximately 1800 Ca2+ channels and approximately 700 Ca2(+)- activated K+ channels; if these are uniformly divided, we estimate that each channel cluster contains approximately 90 Ca2+ and approximately 40 Ca2(+)-activated K+ channels. Freeze-fracture electron microscopy demonstrated an average of 133 large intramembrane particles in the presynaptic membrane at each active zone, an observation that suggests that the particles are the clustered channels. We used the K+ channel's sensitivity to intracellular Ca2+ to assay the concentration of free Ca2+ in the presynaptic cytoplasm, which we found to vary between 10 microM and 1 mM over the physiological range of membrane potentials. The inferred concentrations agreed with the values predicted for free diffusion of Ca2+ away from Ca2+ channels scattered randomly within a 300-nm-diameter synaptic active zone. The close association among Ca2+ channels, Ca2(+)-activated K+ channels, and synaptic active zones is necessary both for the rapid activation of K+ currents required in electrical resonance and for the transmission at afferent synapses of information about the phases of high-frequency stimuli.

https://www.jneurosci.org/content/jneuro/10/11/3664.full.pdf

Colocalization of ion channels involved in frequency selectivity and synaptic transmission at presynaptic active zones of hair cells

A recent study (Roberts, 1993) of saccular hair cells from grass frogs (Rana pipiens) has suggested a mechanism by which the unusually high concentrations of calcium-binding proteins found in certain sensory receptors and neurons, particularly in the auditory system, can influence short-range intracellular calcium signaling. In frog saccular hair cells, the mechanism operates within arrays of calcium channels and calcium-activated potassium channels that are involved in the cells' electrical resonance and synaptic transmission. The present study tests the hypothesis that calbindin-D28k, one of the most abundant proteins in these cells, can serve as a mobile calcium buffer that reduces and localizes changes in the intracellular free-calcium concentration ([Ca2+]i) by shuttling calcium away from the channel arrays. Based upon theoretical analysis and computer modeling, it is shown that [Ca2+]i near one or more open channels quickly reaches a steady-state level determined primarily by two properties of the buffer, the mean time (tau c) before it captures a free-calcium ion and a replenishment factor (R), which are related to the buffer's diffusional mobility (DBu), association rate constant (kon), and concentration (Bo) by tau c = (konB0)-1 and R = B0DBu. Simulation of calcium entry through a channel array showed that approximately 1.5 mM of a molecule with the diffusional and binding properties expected for calbindin-D28k (Bo approximately 8 mM calcium-binding sites) is needed to reproduce the previous experimental results. A lower concentration (B0 = 2 mM) was almost completely depleted within the channel array by a modest calcium current (8 pA = 12% of calcium channels open), but still had two important effects: it caused [Ca2+]i to fall steeply with distance outside the array (space constant < 50 nm), and returned [Ca2+]i quickly to the resting level after the channels closed. A high concentration of calbindin-D28k can thus influence the cell's electrical resonance and synaptic transmission. Its most important functions may be to localize regions of high [Ca2+]i and speed the return of [Ca2+]i toward the resting level.

https://www.jneurosci.org/content/jneuro/14/5/3246.full.pdf

Localization of calcium signals by a mobile calcium buffer in frog saccular hair cells

STRUCTURE AND STIMULATION OF THE HAIR BUNDLE 100 Structure of the Hair Bundle.... ......... .. . . . .... . . . . . . . . . . . . . . . . . . . . . .. . . . . . 100 Mechanical Properties of the Hair Bundle ....... ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 Electrical Response to Mechanical Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

Mechanoelectrical transduction by hair cells.

The potential importance of intracellular calcium-binding proteins in rapid and highly localized Ca2+ signalling is poorly understood. During fast synaptic transmission, which occurs at specialized active zones where Ca2+ diffuses only a few tens of nanometers from channels to neurotransmitter release sites, a cytoplasmic Ca2+ buffer would have to be extremely fast or present in millimolar concentrations to intercept a significant fraction of the calcium ions en route to their targets. Therefore, Ca2+ buffers have been presumed to be unimportant in fast exocytosis and another fast calcium-mediated process, electrical resonance in hair cells. Here I present evidence to the contrary by showing that hair cells in the frog sacculus contain millimolar concentrations of a mobile cytoplasmic calcium buffer that captures Ca2+ within a few microseconds after it enters through presynaptic Ca2+ channels and carries it away from the point of entry. This spatial buffering reduces the presynaptic free Ca2+ by up to 60 per cent and probably restricts the region in which the internal calcium ion concentration exceeds 1 microM to within < 250 nm of each synaptic site. The buffer can thus influence both electrical resonance and synaptic transmission. Calbindin-D28K or a related protein may serve as the mobile calcium buffer, an action similar to its function in transporting Ca2+ across intestinal epithelial cells.

William M. Roberts

Papers

Colocalization of ion channels involved in frequency selectivity and synaptic transmission at presynaptic active zones of hair cells

Localization of calcium signals by a mobile calcium buffer in frog saccular hair cells

Mechanoelectrical transduction by hair cells.

Spatial calcium buffering in saccular hair cells

Calcium-triggered exocytosis and endocytosis in an isolated presynaptic cell: capacitance measurements in saccular hair cells.