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

Cells release into the extracellular environment diverse types of membrane vesicles of endosomal and plasma membrane origin called exosomes and microvesicles, respectively. These extracellular vesicles (EVs) represent an important mode of intercellular communication by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and RNA. Deficiencies in our knowledge of the molecular mechanisms for EV formation and lack of methods to interfere with the packaging of cargo or with vesicle release, however, still hamper identification of their physiological relevance in vivo. In this review, we focus on the characterization of EVs and on currently proposed mechanisms for their formation, targeting, and function.

https://rupress.org/jcb/article-pdf/200/4/373/1262520/jcb_201211138.pdf

Extracellular vesicles: exosomes, microvesicles, and friends.

▪ 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...

/pdf/short-term-synaptic-plasticity-5d4dx79319.pdf

Short-Term Synaptic Plasticity

Neurotrophins regulate development, maintenance, and function of vertebrate nervous systems. Neurotrophins activate two different classes of receptors, the Trk family of receptor tyrosine kinases and p75NTR, a member of the TNF receptor superfamily. Through these, neurotrophins activate many signaling pathways, including those mediated by ras and members of the cdc-42/ras/rho G protein families, and the MAP kinase, PI-3 kinase, and Jun kinase cascades. During development, limiting amounts of neurotrophins function as survival factors to ensure a match between the number of surviving neurons and the requirement for appropriate target innervation. They also regulate cell fate decisions, axon growth, dendrite pruning, the patterning of innervation and the expression of proteins crucial for normal neuronal function, such as neurotransmitters and ion channels. These proteins also regulate many aspects of neural function. In the mature nervous system, they control synaptic function and synaptic plasticity, while continuing to modulate neuronal survival.

Neurotrophins: roles in neuronal development and function.

http://experimentationlab.berkeley.edu/sites/default/files/AFMImages/butt_AFM.pdf

Force measurements with the atomic force microscope: Technique, interpretation and applications

We read with interest the letter recently published in the European Journal of Neurology by Yang et al. [1]. In this case report, a novel heterozygous frameshift mutation in the KIDINS220 gene was identified as a possible genetic determinant of severe spastic paraplegia associated with obesity in a 3-year-old Chinese girl. This is a very interesting finding, as similar heterozygous mutations have been recently reported to cause spastic paraplegia, intellectual disability, nystagmus and obesity (‘SINO’ syndrome) in three unrelated children [2]. Moreover, when in homozygosis, loss-of-function KIDINS220 variants cause extremely severe neurodevelopmental defects that are embryonically lethal [3]. Thus, evidence is accumulating in support of the notion that this protein plays a fundamental role during nervous system development as well as in the maintenance of neuronal homeostasis during adolescence and adulthood. The kinase D interacting substrate of 220 kDa (Kidins220)/ankyrin repeat-rich membrane spanning (ARMS) protein was originally identified in 2000 as the first neuronal substrate for protein kinase D phosphorylation [4], as well as a downstream target of neurotrophin and ephrin receptors [5]. Early work on this protein was conducted in the laboratories of Dr Schiavo (UCL Institute of Neurology, London, UK) and Dr Chao (Skirball Institute of Biomolecular Medicine, New York, NY, USA), and contributed to establish Kidins220 as a crucial mediator of neurotrophin signaling in neurons (reviewed in [6]). In the case report of Yang et al., the authors wrongly state that ‘no mammalian model has yet been established’ [1]. On the contrary, at least two Kidins220 genetically modified mouse lines are presently available that, in view of the most recent literature, represent valuable preclinical models for spastic paraplegia and related pathologies. The first mouse strain generated by Dr Chao’s group at New York University is a heterozygous line expressing about 60–70% of the levels of the wild-type protein, which causes reduced dendritic complexity and spine instability [7]. The other independent mouse strain, generated in Dr Schiavo’s laboratory, carries a floxed Kidins220 gene, which was initially used to drive the full Kidins220 knockout. The complete ablation of Kidins220 is lethal at late embryonic stages. Knockout embryos present extensive apoptosis in the central and peripheral nervous systems, coupled to hydrocephalus as well as to defects of cardiovascular development [8,9]. Importantly, some of the phenotypes characterizing the Kidins220 knockout embryos resemble the defects observed in the human embryos carrying homozygous Kidins220 loss-of-function mutations [3]. Moreover, the immune system-specific deletion of Kidins220 leads to severe alterations of B cell development and activation [10]. We are currently analyzing animals bearing the brain-specific deletion of the protein, which present specific phenotypes in terms of brain development and behavior (F. Cesca, unpublished observations). We thus believe that the knowledge acquired through the analysis of Kidins220 mutant lines could help to elucidate the molecular and cellular mechanisms leading to the human pathologies, and possibly open the way to new avenues for therapeutic interventions.

Kidins220/ARMS transgenic lines could be instrumental in the understanding of the molecular mechanisms leading to spastic paraplegia and obesity.

Organic Optoelectronic Interfaces for Vision Restoration

Mutations in the PRRT2 gene are the main cause for a group of paroxysmal neurological diseases including paroxysmal kinesigenic dyskinesia, episodic ataxia, benign familial infantile seizures, and hemiplegic migraine. In the mature central nervous system, the protein has both a functional and a structural role at the synapse. Indeed, PRRT2 participates in the regulation of neurotransmitter release, as well as of actin cytoskeleton dynamics during synaptogenesis. Here, we show a role of the protein also during early stages of neuronal development. We found that PRRT2 accumulates at the growth cone in cultured hippocampal neurons. Overexpression of the protein causes an increase in the size and the morphological complexity of growth cones. In contrast, the growth cones of neurons derived from PRRT2 KO mice are smaller and less elaborated. Finally, we demonstrated that the aberrant shape of PRRT2 KO growth cones is associated with a selective alteration of the growth cone actin cytoskeleton. Our data support a key role of PRRT2 in the regulation of growth cone morphology during neuronal development.

An Emerging Role of PRRT2 in Regulating Growth Cone Morphology.

Conjugated polymers are increasingly exploited for biomedical applications. In this work, we explored the optical characteristics of conjugated polymers of variable chemical structures at multiple levels relevant to biological interfacing, from fluorescence yield to their influence on cellular membrane potential. We systematically compared the performance of conjugated polymer as cast thin films and as nanoparticles stabilized with amphiphilic polyethylene glycol-poly lactic acid-co-glycolic acid (PEG-PLGA). We assessed in both the dark and under illumination the stability of key optoelectronic properties in various environments, including air and biologically relevant physiological saline solutions. We found that photoreduction of oxygen correlates with nanoparticle and film degradation in physiologically relevant media. Using patch-clamp recordings in cell lines and primary neurons, we identified two broad classes of membrane potential response, which correspond to photosensitizer- and photothermal-mediated effects. Last, we introduced a metric named OED50 (optical energy for 50% depolarization), which conveys the phototoxic potency of a given agent and thereby its operational photo-safety profile.

Photosensitized and Photothermal Stimulation of Cellular Membranes by Organic Thin Films and Nanoparticles

The capability to selectively affect vital functions in cell networks and sub-cell compartments in vitro or in vivo is a mission critical tool in neuroscience and medicine. Optical excitation is one of the main strategies used to achieve high spatial and temporal resolution. In the following we describe recent results and future approaches of cell photostimulation mediated by organic semiconducting polymers.

/pdf/controlling-cell-functions-by-light-p64271hftp.pdf

Fabio Benfenati

Papers

Kidins220/ARMS transgenic lines could be instrumental in the understanding of the molecular mechanisms leading to spastic paraplegia and obesity.

Organic Optoelectronic Interfaces for Vision Restoration

An Emerging Role of PRRT2 in Regulating Growth Cone Morphology.

Photosensitized and Photothermal Stimulation of Cellular Membranes by Organic Thin Films and Nanoparticles

Controlling cell functions by light