What genetics tells us about the causes and mechanisms of Parkinson's disease

Parkinson's disease (PD) is a common motor disorder of mysterious etiology. It is due to the progressive degeneration of the dopaminergic neurons of the substantia nigra and is accompanied by the appearance of intraneuronal inclusions enriched in α-synuclein, the Lewy bodies. It is becoming increasingly clear that genetic factors contribute to its complex pathogenesis. Over the past decade, the genetic basis of rare PD forms with Mendelian inheritance, representing no more than 10% of the cases, has been investigated. More than 16 loci and 11 associated genes have been identified so far; genome-wide association studies have provided convincing evidence that polymorphic variants in these genes contribute to sporadic PD. The knowledge acquired of the functions of their protein products has revealed pathways of neurodegeneration that may be shared between inherited and sporadic PD. An impressive set of data in different model systems strongly suggest that mitochondrial dysfunction plays a central role in clinically similar, early-onset autosomal recessive PD forms caused by parkin and PINK1, and possibly DJ-1 gene mutations. In contrast, α-synuclein accumulation in Lewy bodies defines a spectrum of disorders ranging from typical late-onset PD to PD dementia and including sporadic and autosomal dominant PD forms due to mutations in SCNA and LRRK2. However, the pathological role of Lewy bodies remains uncertain, as they may or may not be present in PD forms with one and the same LRRK2 mutation. Impairment of autophagy-based protein/organelle degradation pathways is emerging as a possible unifying but still fragile pathogenic scenario in PD. Strengthening these discoveries and finding other convergence points by identifying new genes responsible for Mendelian forms of PD and exploring their functions and relationships are the main challenges of the next decade. It is also the way to follow to open new promising avenues of neuroprotective treatment for this devastating disorder.     

What fungal CNS infections can teach us about neuroimmunology and CNS-specific immunity

Immunity to fungal infections of the central nervous system (CNS) is one of the most poorly understood subjects within the field of medical mycology. Yet, the majority of deaths from invasive fungal infections are caused by brain-tropic fungi. In recent years, there have been several significant discoveries in the regulation of neuroinflammation and the role of the immune system in tissue homeostasis within the CNS. In this review, I highlight five important advances in the neuroimmunology field over the last decade and discuss how we should capitalise on these discoveries to better understand the pathogenesis of fungal CNS infections. In addition, the latest insights into fungal invasion tactics, microglia-astrocyte crosstalk and regulation of antifungal adaptive immune responses are summarised in the context of our contemporary understanding of CNS-specific immunity.     

What percolation theory can tell us about COPD

Damage to the lung elastic fiber network is largely responsible for the distention and rupture of alveolar walls in chronic obstructive pulmonary disease (COPD). It has therefore been suggested that blood or urine levels of the unique elastic fiber crosslinks, desmosine and isodesmosine (DID), may serve as a biomarker for the progression of the disease. The prognostic value of DID may be limited, however, by the large degree of variance associated with their measurement in patients with COPD. To overcome this problem, we propose that specific patterns of DID release from damaged elastic fibers, rather than their absolute quantity, may provide a better indication of morphological changes in the lungs of patients with COPD. Using percolation theory to model the elastic fiber network in the lung, it will be shown that the relative amounts of damaged and intact elastic fibers may be reflected at the molecular level by urinary levels of free and peptide-bound DID, respectively. The self-similar nature of percolation networks further suggests that detachment of crosslinks from elastic fibers may be analogous to the rupture of alveolar walls in COPD. Consequently, the ratio of free to bound DID may be a measure of emphysematous changes in this disease.     

What eye fixation patterns tell us about subitizing

Differences between the enumeration of very small (1-3) versus larger (4-6) numerosities were examined by investigating where people fixate when they are enumerating different numbers of items. Overall, fixations were more likely to be located in regions of the array that contained target items when the array contained 4 or more targets than when it contained 3 or fewer, a result that is consistent with previous research indicating that the enumeration of very small sets is less dependent on attentional processing than is the enumeration of larger sets. However, both the pattern of fixations across different distractor conditions and an analysis of the temporal course of fixations in the absence of distractors were inconsistent with a dichotomous distinction between pre-attentive and attentional forms of enumeration. Rather, our results suggest that, irrespective of numerosity, enumeration entails some attentional processing of target items, but attentional processing plays a markedly greater role in the enumeration of 4 or more items than in the enumeration of 3 or fewer.     

What delay fields tell us about striate cortex

It is well known that electrical activation of striate cortex (area V1) can disrupt visual behavior. Based on this knowledge, we discovered that electrical microstimulation of V1 in macaque monkeys delays saccadic eye movements when made to visual targets located in the receptive field of the stimulated neurons. This review discusses the following issues. First, the parameters that affect the delay of saccades by microstimulation of V1 are reviewed. Second, the excitability properties of the V1 elements mediating the delay are discussed. Third, the properties that determine the size and shape of the region of visual space affected by stimulation of V1 are described. This region is called a delay field. Fourth, whether the delay effect is mainly due to a disruption of the visual signal transmitted through V1 or whether it is a disturbance of the motor signal transmitted between V1 and the brain stem saccade generator is investigated. Fifth, the properties of delay fields are used to estimate the number of elements activated directly by electrical microstimulation of macaque V1. Sixth, these properties are used to make inferences about the characteristics of visual percepts induced by such stimulation. Seventh, the disruptive effects of V1 stimulation in monkeys and humans are compared. Eighth, a cortical mechanism to account for the disruptive effects of V1 stimulation is proposed. Finally, these effects are related to normal vision.     

What single-channel analysis tells us of the activation mechanism of ligand-gated channels: the case of the glycine receptor

Glycine receptors are, in several ways, the member of the nicotinic superfamily that is best-suited for single-channel recording. That means that they are ideal for testing ideas about how activation proceeds in a ligand-gated ion channel from the binding of the agonist to the opening of the channel. This review describes the quantitative characterization by single-channel analysis of a novel activation mechanism for the glycine receptor. The favourable properties of the glycine receptor allowed the first detection of a conformation change that follows the binding of the agonist but precedes the opening of the channel. We used the term 'flipping' to describe this pre-opening conformational change. The 'flipped' state has a binding affinity higher than the resting state, but lower than the open state. This increased affinity presumably reflects a structural change near the agonist binding site, possibly the 'capping' of the C-loop. The significance of the 'flip' activation mechanism goes beyond understanding the behaviour and the structure–function relation of glycine channels, as this mechanism can be applied also to other members of the superfamily, such as the muscle nicotinic receptor. The 'flip' mechanism has thrown light on the question of why partial agonists are not efficacious at keeping the channel open, a question that is fundamental to rational drug design. In both muscle nicotinic and glycine receptors, partial agonists are as good as full agonists at opening the channel once flipping has occurred, but are not as effective as full agonists in eliciting this early conformational change.     

What birdsong can teach us about the central noradrenergic system

Increasing evidence indicates that the noradrenergic system plays a key role in biasing the nervous system towards producing behaviors that help animals adapt to constantly changing environments. Most of the studies investigating noradrenergic function are performed in animals that have a limited repertoire of tractable natural behaviors. Songbirds, in contrast, with their rich set of precisely quantifiable vocal behaviors, provide a unique model system to study the noradrenergic system. An additional advantage of this system is the existence of a well-defined neural circuit, known as the song system, that is necessary for the production, learning and perception of song and can be studied at many different levels. These include the ability to investigate the effect of norepinephrine on synaptic function using brain slices, identifying its influence on singing-related gene expression and monitoring its impact on the activity of single neurons recorded in awake behaving birds. In this review article, we describe the similarities and differences, both anatomical and functional, between the avian and mammalian noradrenergic system and its role in sensory processing, learning, attention and synaptic modulation. We also describe how the noradrenergic system influences motor production, an under-explored aspect of norepinephrine function in mammalian studies. We argue that the richness of behaviors observed in songbirds provides a unique opportunity to study the noradrenergic system in a highly integrative manner that will ultimately provide important insights into the role of this system in normal behavior and disease.     

What sharks can tell us about the evolution of MHC genes

Summary: Similarity in structural features would argue that sharks possess class I. class IIA and class IIB genes, coding for classical peptide-presenting molecules, as well as non-classical class I genes. Some aspects of shark major histocompatibility complex genes are similar to teleost genes and others are similar to tetrapod genes. Shark class I genes form a monophyletic group, as also seen for tetrapods, but the classical and nonclassical genes form two orthologous clades, as seen for teleosts. Teleost class I genes arose independently at least four different times with the nonclassical genes of ray-finned fishes and all the shark and lobe-finned fish class I genes forming 1 clade. The ray-finned fish classical class I genes arose separately. In phylogenetic trees of class II α2 and β2 domains, the shark and tetrapod genes cluster more closely than the teleost genes and, unlike the teleost sequences, the class II α1 domains of sharks and tetrapods lack cysteines. On the other hand, both shark and teleost genes display sequence motifs in che antigen-binding cleft that have persisted over very long time periods. The similarities may reflect common selective pressures on species in aqueous environments while differences may be due to different evolutionary rates.     

白细胞介素-17参与固有免疫应答的研究进展

白细胞介素(IL)-17是一类重要的细胞因子,通常认为IL-17主要由Th17细胞分泌,参与机体的适应性免疫应答.近年来大量研究表明,在肺、胃肠黏膜及皮肤等屏障组织中存在多种固有免疫细胞可以分泌IL-17,作为的机体免疫系统第一道防线的重要成员,一方面通过模式识别受体迅速感知外来抗原的刺激,趋化募集到损伤部位,不经克隆扩增即可发挥清除病原,参与炎症、应激或者超敏反应的作用.另一方面,分泌IL-17的固有免疫细胞能够与慢性炎症的记忆细胞相互作用,启动适应性免疫应答,发挥调节机体免疫稳态的功能.     

What violence prevention research can tell us about developmental psychopathology

This article reviews major issues of a developmental psychopathology understanding of youth violence and related insights gained from violence prevention efforts to date. Based in a perspective that emphasizes three areas of knowledge, epidemiology, risk factors and models, and developmental trajectories, findings are reviewed that help clarify theoretical propositions about the developmental patterns, influences, and pathways related to youth violence. Extant research is able to support several major contentions of basic developmental psychopathology theories of youth violence. Support is most robust for risk factors central to prevailing models of the development of youth violence. In addition to noting current knowledge contributions, the review suggests areas of needed additional analytic progress and theoretical extension to refine knowledge and expand understanding of the development of violence risk and its prevention.     

What developmental disorders can tell us about the nature and origins of language

Few areas in the cognitive sciences evoke more controversy than language evolution, due in part to the difficulty in gathering relevant empirical data. The study of developmental disorders is well placed to provide important new clues, but has been hampered by a lack of consensus on the aims and interpretation of the research project. We suggest that the application of the Darwinian principle of 'descent with modification' can help to reconcile much apparently inconsistent data. We close by illustrating how systematic analyses within and between disorders, suitably informed by evolutionary theory-and ideally facilitated by the creation of an open-access database-could provide new insights into language evolution.     

What transgenic and knockout mouse models teach us about experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is a disease of the central nervous system with presumed autoimmune etiology. Experimental autoimmune encephalomyelitis (EAE), an inducible autoimmune disease in laboratory animals, is a widely accepted animal model of MS. Although it is well known that EAE is induced by autoreactive CD4+ T cells specific for myelin antigens, the demyelination process is manifested as a result of complex interactions among encephalitogenic, regulatory and accessory cell populations and factors produced by these cells. The outcome of the disease depends on which components become dominant. Examination of these components using genetically manipulated transgenic or gene-disrupted animal models has proved to be very useful. Here we examine the main processes leading to the development of EAE. The participation of different lymphocyte populations such as T, B cells or NK cells, as well as regulatory molecules and cytokines in the induction and regulation of EAE is discussed in the light of transgenic and knockout animal experiments. These animal models clearly show that autoimmune processes are regulated in a complex way, and that a given factor in this regulation can have very different effects according to the given microenvironment in which it acts.     

Tissue-resident innate immunity in the lung

The lung is a unique organ that must protect against inhaled pathogens and toxins, without mounting a disproportionate response against harmless particulate matter and without compromising its vital function. Tissue-resident immune cells within the lung provide local immunity and protection from infection but are also responsible for causing disease when dysregulated. There is a growing appreciation of the importance of tissue-resident memory T cells to lung immunity, but non-recirculating, tissue-resident, innate immune cells also exist. These cells provide the first line of defence against pulmonary infection and are essential for co-ordinating the subsequent adaptive response. In this review, we discuss the main lung-resident innate immune subsets and their functions in common pulmonary diseases, such as influenza, bacterial pneumonia, asthma and inflammatory disorders.     

Molecular mechanisms of innate immunity

All species require a rapid, systemic reply to pathogens in their environment. This response is known as the innate immune response and is characterized by de novo synthesis of mediators that directly or indirectly through phagocytosis remove and kill the pathogen. Innate immune responses have been preserved throughout evolution and have been studied in detail in organisms from the fruit fly Drosophila melanogaster to humans. In my laboratory, studies performed during the past 25 yr have focused on defining the molecular basis of innate immune responses to microbial pathogens. Specifically, we have used bacterial endotoxin (lipopolysaccharide) as a model stimulus to define how the innate immune system recognizes products of microbial pathogens and initiates responses to remove and/or kill such organisms. Such studies also serve as models to understand more fully the mechanisms underlying a serious human disease known as septic shock. This article discusses septic shock and its relationship to innate immunity.     

What does the Edinburgh high‐risk study tell us about schizophrenia?

The Edinburgh High Risk Study concerns 162 young people aged 16 to 25 at ascertainment who have at least two close relatives with schizophrenia. They are compared with two control groups (1) of age‐matched well subjects and (2) of age‐matched subjects with first schizophrenic episodes. The interim results show that schizophrenia has developed in 10 high‐risk subjects and no controls and that all categories of psychopathology are more marked in the high‐risk subjects. Psychopathology shows no relationships with measures of genetic liability. Neuropsychological measures are most impaired in the individuals with first‐episode schizophrenia, with high‐risk subjects performing better and well controls better still. The greater the genetic liability of the high‐risk subjects, the poorer the neuropsychological performance. Neuropsychological impairments occurred in more high‐risk subjects than are expected to develop schizophrenia. Structural brain scans show significant differences between those with first‐episode schizophrenia, high‐risk subjects, and well controls. Brain structure is related to genetic liability in that high‐risk subjects with higher genetic liability have smaller right and left prefrontal lobes and smaller right and left thalami. In those high‐risk subjects with two scans, there was a significantly greater reduction in temporal lobe size in those with psychotic symptoms than in those without. It is suggested that in high‐risk subjects, the change from vulnerability to psychosis may be preceded by reduction in size and deteriorating function of the temporal lobe. © 2002 Wiley‐Liss, Inc.     

Systems biology of innate immunity

Summary:  Systems biology is the comprehensive and quantitative analysis of the interactions between all of the components of biological systems over time. Systems biology involves an iterative cycle, in which emerging biological problems drive the development of new technologies and computational tools. These technologies and tools then open new frontiers that revolutionize biology. Innate immunity is well suited for systems analysis, because the relevant cells can be isolated in various functional states and their interactions can be reconstituted in a biologically meaningful manner. Application of the tools of systems biology to the innate immune system will enable comprehensive analysis of the complex interactions that maintain the difficult balance between host defense and inflammatory disease. In this review, we discuss innate immunity in the context of the systems biology concepts, emergence, robustness, and modularity, and we describe emerging technologies we are applying in our systems-level analyses. These technologies include genomics, proteomics, computational analysis, forward genetics screens, and analyses that link human genetic polymorphisms to disease resistance.