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

Derivation of auditory filter shapes from notched-noise data

Dendritic spines of pyramidal neurons in the cerebral cortex undergo activity-dependent structural remodelling that has been proposed to be a cellular basis of learning and memory. How structural remodelling supports synaptic plasticity, such as long-term potentiation, and whether such plasticity is input-specific at the level of the individual spine has remained unknown. We investigated the structural basis of long-term potentiation using two-photon photolysis of caged glutamate at single spines of hippocampal CA1 pyramidal neurons. Here we show that repetitive quantum-like photorelease (uncaging) of glutamate induces a rapid and selective enlargement of stimulated spines that is transient in large mushroom spines but persistent in small spines. Spine enlargement is associated with an increase in AMPA-receptor-mediated currents at the stimulated synapse and is dependent on NMDA receptors, calmodulin and actin polymerization. Long-lasting spine enlargement also requires Ca2+/calmodulin-dependent protein kinase II. Our results thus indicate that spines individually follow Hebb's postulate for learning. They further suggest that small spines are preferential sites for long-term potentiation induction, whereas large spines might represent physical traces of long-term memory.

Structural basis of long-term potentiation in single dendritic spines

In mammals, environmental sounds stimulate the auditory receptor, the cochlea, via vibrations of the stapes, the innermost of the middle ear ossicles. These vibrations produce displacement waves that travel on the elongated and spirally wound basilar membrane (BM). As they travel, waves grow in amplitude, reaching a maximum and then dying out. The location of maximum BM motion is a function of stimulus frequency, with high-frequency waves being localized to the “base” of the cochlea (near the stapes) and low-frequency waves approaching the “apex” of the cochlea. Thus each cochlear site has a characteristic frequency (CF), to which it responds maximally. BM vibrations produce motion of hair cell stereocilia, which gates stereociliar transduction channels leading to the generation of hair cell receptor potentials and the excitation of afferent auditory nerve fibers. At the base of the cochlea, BM motion exhibits a CF-specific and level-dependent compressive nonlinearity such that responses to low-level, near-CF stimuli are sensitive and sharply frequency-tuned and responses to intense stimuli are insensitive and poorly tuned. The high sensitivity and sharp-frequency tuning, as well as compression and other nonlinearities (two-tone suppression and intermodulation distortion), are highly labile, indicating the presence in normal cochleae of a positive feedback from the organ of Corti, the “cochlear amplifier.” This mechanism involves forces generated by the outer hair cells and controlled, directly or indirectly, by their transduction currents. At the apex of the cochlea, nonlinearities appear to be less prominent than at the base, perhaps implying that the cochlear amplifier plays a lesser role in determining apical mechanical responses to sound. Whether at the base or the apex, the properties of BM vibration adequately account for most frequency-specific properties of the responses to sound of auditory nerve fibers.

/pdf/mechanics-of-the-mammalian-cochlea-368l279klj.pdf

Mechanics of the Mammalian Cochlea

Phantom auditory perception (tinnitus): mechanisms of generation and perception

The outer and inner hair cells of the mammalian cochlea perform different functions. In response to changes in membrane potential, the cylindrical outer hair cell rapidly alters its length and stiffness. These mechanical changes, driven by putative molecular motors, are assumed to produce amplification of vibrations in the cochlea that are transduced by inner hair cells. Here we have identified an abundant complementary DNA from a gene, designated Prestin, which is specifically expressed in outer hair cells. Regions of the encoded protein show moderate sequence similarity to pendrin and related sulphate/anion transport proteins. Voltage-induced shape changes can be elicited in cultured human kidney cells that express prestin. The mechanical response of outer hair cells to voltage change is accompanied by a 'gating current', which is manifested as nonlinear capacitance. We also demonstrate this nonlinear capacitance in transfected kidney cells. We conclude that prestin is the motor protein of the cochlear outer hair cell.

Prestin is the motor protein of cochlear outer hair cells.

Peter Dallas Auditory Physiology Laboratory (The Hugh Knowles Center) and Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208 The cochlea is a hydromechanical frequency analyzer located in the inner ear (Fig. 1 a). Its principal role is to perform a real- time spectral decomposition of the acoustic signal in producing a spatial frequency map. The frequency analysis may be un- derstood with the aid of Figure 1 b, which shows a straightened cochlea with a snapshot of its basilar membrane displaced in response to a single-frequency sound (pure tone). Upon delivery of an acoustic signal into the fluid-filled cochlea, the basilar membrane undergoes an oscillatory motion at the frequency of the sound, resulting in a wave traveling toward its distal end. The drawing shows an instantaneous view ofthis traveling wave. The wave is spatially confined along the length of the basilar membrane, and the location of its maximum amplitude is re- lated to the frequency of the sound. The higher the frequency, the more restricted the disturbance to the proximal end. The vibrating membrane supports the sense organ of hearing, the spiral organ of Corti (Fig. 2) which is deformed maximally in the region of the peak of the traveling wave. In this location, the sensory receptor cells of the organ of Corti receive maximal mechanical stimulation, transduce it into maximal electrical signals, and thus produce maximal afferent sensory outflow from the cochlea. Thus, mechanical frequency analysis is performed by matching particular frequencies with particular groups of auditory receptor cells and their nerve fibers. Understanding of frequency analysis in the inner ear pro- gressed through three main epochs. The first was dominated by Helmholtz’s suggestions that lightly damped, spatially ordered, mechanically resonant elements in the cochlea perform the spec- tral analysis (this period was reviewed by Wever, 1949). The second epoch, lasting from the late 1940s to the early 1970s was dominated by von Bekesy’s description of the traveling wave (von BtkCsy, 1960). We are now in the third epoch (an overview of its evolution is given in Dallos, 1988) during which a fundamentally different paradigm has emerged. According to this paradigm, von Btktsy’s traveling wave is boosted by a local electromechanical amplification process in which one of the mammalian ear’s sensory cell groups, outer hair cells, function as both sensors and mechanical feedback elements. The ideas that the operation of a sense organ is dependent upon local mechanical feedback modification by what resembles a sensory receptor cell, that such mechanical feedback may operate at audio frequencies utilizing some novel cellular motor, and that

https://www.jneurosci.org/content/jneuro/12/12/4575.full.pdf

The active cochlea.

Outer hair cells (OHCs) of the mammalian cochlea actively change their cell length in response to changes in membrane potential. This electromotility, thought to be the basis of cochlear amplification, is mediated by a voltage-sensitive motor molecule recently identified as the membrane protein prestin. Here, we show that voltage sensitivity is conferred to prestin by the intracellular anions chloride and bicarbonate. Removal of these anions abolished fast voltage-dependent motility, as well as the characteristic nonlinear charge movement ("gating currents") driving the underlying structural rearrangements of the protein. The results support a model in which anions act as extrinsic voltage sensors, which bind to the prestin molecule and thus trigger the conformational changes required for motility of OHCs.

https://science.sciencemag.org/content/sci/292/5525/2340.full.pdf

Intracellular anions as the voltage sensor of prestin, the outer hair cell motor protein

1. Recordings were made from chinchilla auditory nerve fibers after portions of the cochlear outer hair cell (OHC) population were destroyed with the antibiotic kanamycin. In most cases the inner hair cell (IHC) population was completely preserved as determined by phase-contrast microscopy. We presume that the remaining IHCs are functionally normal, and thus that recordings obtained from fibers originating from the lesioned cochlear segment reflect IHC behavior. 2. Behavioral thresholds were measured for all animals both before and after the production of the cochlear lesion. The audiograms and the histological evaluation of the ears were the basis for assessing whether a particular fiber originated in a normal, pathological (shifted threshold; IHC only), or border region. These criteria also identified the animals that sustained IHC damage together with the destruction of part of the OHC population. Only the data obtained from those fibers which probably originated from the OHC-free segment of the cochlea are considered in detail. 3. Fibers whose characteristic frequency (CF) identified them as belonging to the normal (audiometrically and histologically) region, were found to be normal in all respects. 4. Fibers from the border region (where the audiogram has a steep slope between normal and hearing-loss regions probably corresponding to the segment where OHC loss progresses from less than 10% to more than 90%) had very complex response patterns. Their frequency threshold curves (FTC) showed great variability. In general, the closer the fiber was to the fully developed lesion, the more abnormal its FTC became. 5. Those units that were concluded to have originated from the OHC-free part of the cochlea could be divided into three categories on the basis of the shape of their FTCs. A small fraction had very broad tuning (9%). The majority (53%) had approximately normal tail segment, normal bandwidth of the tip segment, and highly elevated threshold at CF. A group of fibers (38%) could not be assigned a CF. Probably the FTC of most of these latter fibers are similar to those of the previous group, but the sharply tuned short tip segment was either missed or was not reachable on account of its extremely high threshold level. 6. Such indexes of fiber response as latency, spontaneous rate, and time pattern (PST histograms) were not affected by the loss of OHCs. 7. On the basis of the data and of the assumptions made it was suggested that outer hair cells provide a frequency-dependent sensitizing influence to the inner hair cells. The frequency dependence could best be expressed as a flat-topped band pass characteristic.

Properties of auditory nerve responses in absence of outer hair cells

1. Responses of single fibers were obtained from the auditory nerve of chinchillas. Tone-burst stimuli consisted of a masking stimulus followed by a probe stimulus. Forward masking of a fiber's response is defined as a reduction in the magnitude of the probe-evoked response caused by the addition of the masking stimulus. 2. The recovery of probe response magnitude as a function of the time interval between masker offset and probe onset (delta T) follows an exponential time course. A relationship between the time course or magnitude of poststimulus recovery and the characteristic frequency (CF) of a fiber was not detected. 3. The iso-forward masking contour near the threshold of the masking effect across masker frequencies approximates a fiber's frequency threshold curve (FTC). In other words, forward masking tuning curves are essentially the same as frequency threshold curves. 4. The frequency dependence of forward masking is compared to that of two-tone suppression. Tonal stimuli outside the boundaries of a fiber's FTC that produce two-tone suppression are ineffective forward maskers. Certain frequency/intensity combinations within the FTC may produce both suppression and forward masking and tones within the remaining area of the FTC produce no suppression but are effective forward maskers. 5. Both the time course and the magnitude of the forward masking effect are dependent on the discharge rate evoked by the masker regardless of the masker's absolute level or spectral content. An increase in masker-evoked excitation causes an increase in time constant and a greater reduction in probe response magnitude, rd. The function relating rd to masker level parallels the firing rate/masker level function up to 40 dB above response threshold. 6. A decrease in masker duration from 100 ms leads to a decrease in both rd and the time constant of recovery. There is no significant difference between the 100 and 200 ms duration conditions. 7. Forward masking in single fibers is related to the period of poststimulus recovery of spontaneous activity, a component of a fiber's response pattern to the masker, and this component is tentatively identified as a period of recovery from short-term adaptation.

Peter Dallos

Papers

Prestin is the motor protein of cochlear outer hair cells.

The active cochlea.

Intracellular anions as the voltage sensor of prestin, the outer hair cell motor protein

Properties of auditory nerve responses in absence of outer hair cells

Forward masking of auditory nerve fiber responses