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.

D184E mutation in aquaporin-4 gene impairs water permeability and links to deafness.

Water represents the major component of all living organisms. To make the cell to adapt to the surrounding environment and carry out its biological functions, water has to move into and out of the cell interior driven by osmotic forces. For over a century, scientists studying the movement of fluid into and out of the cell struggled with a difficult biophysical question: how does water pass through the cell? Movement of water across the membrane was indicated almost as soon as the lipid bilayer was recognized as being the plasma membrane of cells, back in the 1920s. Simple diffusion of water across the lipid bilayer occurs through all biological membranes. However, its low velocity and finite extent soon became apparent, suggesting the existence of additional pathways for water moving through the membrane. In spite of the enormous amount of work carried out in this area, the precise and complete answer only came relatively recently with the discovery of aquaporins, transmembrane channel proteins making the membrane tenfold to 100-fold more permeable to water than membranes lacking such pores. The water conductance featured by the aquaporins is astonishing: in fact, each single aquaporin pore can conduct billions of water molecules per second. A branch of the aquaporin family, the aquaglyceroporins, features conductance to small neutral solutes in addition to water. This review summarizes recent updates on the molecular structure, regulation, biophysics, and biological functions of aquaporins. Possible biotechnological applications of aquaporins are also described.

Aquaporin Membrane Channels: Biophysics, Classification, Functions, and Possible Biotechnological Applications

Water handling and aquaporins in bile formation: recent advances and research trends.

The Milan hypertensive strain of rats (MHS) develops hypertension as a consequence of the increased tubular Na+ reabsorption sustained by enhanced expression and activity of the renal tubular Na–K–ATPase. To verify whether the Na–K–2Cl cotransporter (NKCC2) is involved in the maintenance of hypertension in MHS rats, we have analysed the phosphorylation state and the activation of NKCC2 in Milan rats. Western blotting and immunofluorescence experiments were performed using specific antibodies against the regulatory phospho-threonines in the NKCC2 N terminus (R5 antibody). The phosphorylation levels of NKCC2 were significantly increased in the kidney of MHS rats. Moreover, the administration of furosemide in vivo decreased the blood pressure and increased the urine output and natriuresis in MHS rats demonstrating the actual involvement of NKCC2 activity in the pathogenesis of hypertension in this strain of rats. The up-regulation of NKCC2 activity is most probably mediated by a STE20/SPS1-related proline/alanine-rich kinase (SPAK) phosphorylation at serine-325 since it was significantly increased in MHS rats. Interestingly, aldosterone treatment caused an increase in NKCC2 phosphorylation in NKCC2-expressing MDCK cells. In conclusion, we demonstrated an increase in the activity of NKCC2 along the TAL that significantly contributes to the increase in systemic blood pressure in MHS rats. The elevated plasma levels of aldosterone, found in MHS rats, may influence Na+ balance through a SPAK-dependent regulation of NKCC2 accounting for the maintenance of the hypertensive state in MHS rats.

NKCC2 is activated in Milan hypertensive rats contributing to the maintenance of salt-sensitive hypertension

The two predominant isoforms of Aquaporin-4 (AQP4), AQP4-M23 and AQP4-M1, assemble in the plasma membrane to form supramolecular structures called Orthogonal Array of Particles (OAPs) whose dimension is tightly associated to the M1/M23 ratio. Here, we explore translational regulation contribution to M1/M23 expression in primary cultures of rat astrocytes, and analyze the role of M1 mRNA 5′untranslated region (5′UTR) in this mechanism. Using isoform-specific RNAi we found that in rat astrocytes primary cultures a large proportion of M23 protein derives from M1 mRNA translation. Furthermore, site-specific mutagenesis of the 5′UTR sequence of AQP4-M1 mRNA indicates that a multiple-site leaky scanning mechanism, an out-of-frame upstream ORF (uORF), and a reinitiation mechanism are able to modulate the M1/M23 ratio and consequently, OAPs formation. These mechanisms are likely to be shared by different species, including human, and they can also be assumed to play a role in those pathophysiological situations where the organization of AQP4 in supramolecular structures (OAPs) is involved. Finally, we report that, when transfected in Hela cells, the longer rat AQP4 isoform, called Mz, which is not present in human impairs OAPs formation. © 2011 Wiley-Liss, Inc.

Maria Svelto

Papers

D184E mutation in aquaporin-4 gene impairs water permeability and links to deafness.

Aquaporin Membrane Channels: Biophysics, Classification, Functions, and Possible Biotechnological Applications

Water handling and aquaporins in bile formation: recent advances and research trends.

NKCC2 is activated in Milan hypertensive rats contributing to the maintenance of salt-sensitive hypertension

Translational regulation mechanisms of aquaporin-4 supramolecular organization in astrocytes.