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

Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.

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A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.

The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders

Review of recent research on hepatitis C therapy for 54th annual meeting of the American association for the study of liver diseases

Mammalian skeletal muscle comprises different fiber types, whose identity is first established during embryonic development by intrinsic myogenic control mechanisms and is later modulated by neural and hormonal factors. The relative proportion of the different fiber types varies strikingly between species, and in humans shows significant variability between individuals. Myosin heavy chain isoforms, whose complete inventory and expression pattern are now available, provide a useful marker for fiber types, both for the four major forms present in trunk and limb muscles and the minor forms present in head and neck muscles. However, muscle fiber diversity involves all functional muscle cell compartments, including membrane excitation, excitation-contraction coupling, contractile machinery, cytoskeleton scaffold, and energy supply systems. Variations within each compartment are limited by the need of matching fiber type properties between different compartments. Nerve activity is a major control mechanism of the fiber type profile, and multiple signaling pathways are implicated in activity-dependent changes of muscle fibers. The characterization of these pathways is raising increasing interest in clinical medicine, given the potentially beneficial effects of muscle fiber type switching in the prevention and treatment of metabolic diseases.

Fiber types in mammalian skeletal muscles.

Objective: Among the pleiotropic effects of statins, we have previously reported that fluvastatin increases the amount of plasma membrane-expressed AQP2 in renal collecting duct cells both in vitro and in vivo, independently of vasopressin. This effect may be of potential clinical significance for the treatment of patients affected by nephrogenic diabetes insipidus forms caused by inactivating mutations of the vasopressin type 2 receptor. Here we report the effect of fluvastatin on AQP2 plasma membrane abundance on an adult male XNDI patient treated with statins.
Methods: An adult male NDI patient, carrying an inactivating mutation of the V2R, under conventional treatment to reduce polyuria, was also treated with fluvastatin because of high levels of blood cholesterol. AQP2 plasma membrane expression in the kidney was monitored by measuring urinary excreted AQP2 (u-AQP2), before starting fluvastatin treatment and during a three months follow-up period. The effect of fluvastatin was also tested in vitro in mouse kidney cortical collecting duct MCD4 cells.
Results: u-AQP2 increased in a time- and dose-dependent manner after treatment with 40 and 80 mg/day of fluvastatin for 90 days. However, at this drug dosage, increased uAQP2 was not accompanied by reduction of diuresis and increase of urine osmolality. The effect of fluvastatin on AQP2 excretion was confirmed in vitro in cultured renal cells.
Conclusions: We first demonstrate that the use of fluvastatin increased AQP2 plasma membrane expression in an NDI dyslipidemic patient. This observation was confirmed by in vitro studies using mouse cultured renal cells treated with fluvastatin. Although a clinical relevant effect of fluvastatin on total diuresis and urine osmolality was not observed at the used dosages, these results suggest further investigation on the possible role of HMG CoA reductase inhibitors to improve the efficacy of the current NDI therapy.

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Fluvastatin Increases AQP2 Urine Excretion in a Dyslipidemic Patient with Nephrogenic Diabetes Insipidus: An In Vivo and In Vitro Study

Role of the H-bond between L53 and T56 for Aquaporin-4 epitope in Neuromyelitis Optica

It is now generally accepted that changes in water permeability in anti-diuretic hormone (ADH)-responsive target epithelial cells result from the insertion in the plasma apical membrane of new components that contain channels for water. The specificity of these channels suggests that they are formed by intrinsic proteins having access to both facies and spanning the whole membrane. We have previously shown that Triton X-100 apical extracts from ADH-stimulated frog urinary bladder contain some proteins inserted under hormonal stimulation. In the present study we have developed polyclonal antibodies using Triton X-100 extract as an immunogen. After considering the inhibitory effect exerted by the whole immune serum on the osmotic water flow, we used different adsorption steps to select, from the immune serum, antibodies to apical membrane proteins inserted in response to the hormone. Immunoblot analysis of these selected antibodies shows that they recognize seven to eight proteins, of which 55-, 35-, 26-, and 17-kDa proteins are always present. Antibodies to these four proteins, affinity purified on nitrocellulose sheets, inhibited ADH-induced osmotic water flow. Altogether these results strongly suggest that proteins of 55, 35, 26, and 17 kDa (or at least one of them) are likely to be involved in the mechanism of water transport.

Polyclonal antibodies in study of ADH-induced water channels in frog urinary bladder

Transport of some non-electrolytes through amphibian skins.

Aquaporin CHIP, a 28 kDa channel forming protein, has been proposed to function as water channel in both erythrocyte and kidney proximal tubule. Recently, we have reported that in frog urinary bladder, a model of the kidney collecting tubule, polyclonal antibodies against human erythrocyte CHIP recognize and immunoprecipitate a 30 kDa protein from the epithelial cell homogenate. In the present work confocal fluorescence microscopy was used to determine the cellular and subcellular localization of CHIP28-like proteins in the urinary epithelium. A clear labeling of the apical border was found after Triton X-100 permeabilization. The labeling was distributed throughout the apical domain and not restricted to specific domains of the membrane. The staining was also present in the deeper confocal sections where the fluorescence seems to be localized at the cellular contour. No difference in the labeling patterns was observed between resting and ADH-treated bladder. Specificity of the staining was confirmed by the absence of the labeling pattern when antiserum was preadsorbed on CHIP28 protein immobilized on Immobilon P stripes. Our results suggest that CHIP-like proteins are not proteins inserted in the apical membrane during the antidiuretic response. Moreover, we do not know whether the labeling was due to the presence of CHIP28 itself or an as-yet-unidentified protein sharing immunological analogies with aquaporin CHIP.

Maria Svelto

Papers

Fluvastatin Increases AQP2 Urine Excretion in a Dyslipidemic Patient with Nephrogenic Diabetes Insipidus: An In Vivo and In Vitro Study

Role of the H-bond between L53 and T56 for Aquaporin-4 epitope in Neuromyelitis Optica

Polyclonal antibodies in study of ADH-induced water channels in frog urinary bladder

Transport of some non-electrolytes through amphibian skins.

Aquaporin-CHIP-related protein in frog urinary bladder: Localization by confocal microscopy