肠道菌群紊乱所致炎症反应与抑郁症

抑郁症是一种与炎症反应、神经免疫关系密切的神经精神疾病。微生物,尤其是肠道菌群,则与人类免疫调节机制形成、感染和炎症反应息息相关。研究已证实,肠道菌群在炎症性肠病、哮喘等自身免疫性疾病的发生发展过程中起了相当大的作用。这些探讨非感染性疾病与微生物的关系的研究和理论形成了卫生学假说,亦即"老朋友"假说。目前,很多研究正在运用卫生学假说的观念,探索肠道菌群与抑郁症发生、发展、预防和治疗之间的联系,并取得了一些进展。本文重点就肠道菌群失调是否能够促进抑郁症发生及其可能机制做一综述。     

A unified hypothesis of coeliac disease with implications for management of patients

Summary. This mini-review presents the research carried out within the context of two of the main hypotheses of the aetiology of coeliac disease. The enzymopathic hypothesis of the disease has been placed clearly as the underlying deficiency causing increased levels of toxic peptides, while the immunological hypothesis has been implicated in the pathogenesis of the disorder as the result of the action of undigested peptides in the small intestine. As a consequence, we are proposing a unified hypothesis of coeliac disease, which takes into account the actions of these undigested peptides through their direct cytotoxicity and their immunoactivity. At the same time, work aimed at defining some of these biologically active peptides, which could be said to be involved in the aetiopathogenesis of coeliac disease, will be reported. The review also focusses on the use of enzyme therapy for management of the disease, which when used in conjunction with the gluten-free diet, offers a safeguard against damage to the small intestine caused by small amounts of gluten.     

Molecular mechanisms of schizophrenia.

Schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders.     

Circulating nucleic acids in plasma and serum (CNAPS) and its relation to stem cells and cancer metastasis: state of the issue

The presence of circulating cell-free nucleic acids has been demonstrated both in disease and health. In the last decade, a burst of papers about Circulating Nucleic Acids in Plasma and Serum (CNAPS) have been found in the literature, showing the scientific interest raised by this phenomenon and their putative clinical interest, especially in the field of cancer. Today, the detection of extracellular tumor-derived DNA and/or RNA is considered by many authors as a new molecular marker for situations such as cancer diagnosis, monitoring the outcome of a disease and, even, as a treatment response indicator. Furthermore, in some studies it has been suggested a possible role of tumor CNAPS in the development of metastasis. Specifically, the hypothesis known as the "genometastasis hypothesis" proposes that stem cells might be naturally transfected with dominant oncogenes as a result of dissemination of such genes in the plasma. On the other hand, current studies concerned with the biology of metastatic cells are increasingly being focused on the striking similarities found between these cells and stem cells. In this review we intend to expound and integrate two theories about metastatization: the "genometastasis hypothesis" and the idea of stem cells as cancer stem cells.     

Density-dependent prophylaxis in the coral-eating crown-of-thorns sea star, Acanthaster planci

The density-dependent prophylaxis hypothesis predicts that individuals at high density will invest more resources into immune defence than individuals at lower densities as a counter-measure to density-dependent pathogen transmission rates. Evidence has been found for this hypothesis in insects, but not in a non-arthropod taxon. To investigate this hypothesis in the coral-eating crown-of-thorns sea star, Acanthaster planci, density treatments were set up over 21 days, and pathogen infection was simulated with bacterial injection. Five immune responses: amoebocyte count, amoebocyte viability, lysosomal membrane integrity, respiratory burst and peroxidase activity were all upregulated at high density. These results demonstrate that immune investment shows phenotypic plasticity with adult population density in agreement with the density-dependent prophylaxis hypothesis. Here I show that the density-dependent prophylaxis hypothesis is neither dependent on larval density nor restricted to insects, and hence may potentially have important consequences on disease dynamics in any species with widely fluctuating population densities. This is the first demonstration of the density-dependent prophylaxis hypothesis outside arthropods.     

Taxonomic map of the schizophrenias,with special reference to puerperal psychosis.

Data collected by a single observer on 147 schizophrenic patients were subjected to clustering analysis. The results produced the hypothesis that schizophrenic illnesses directly after childbirth are a separate disease entity. This hypothesis was not disproved by experimental testing. Several disease entities may be included in the term schizophrenia. If this is so, the methods used in generating and testing the hypothesis that puerperal schizophrenia is a separate disease may provide a systematic method of classifying the various illnesses.     

Metallostasis in Alzheimer's disease

2012 has been another year in which multiple large-scale clinical trials for Alzheimer's disease (AD) have failed to meet their clinical endpoints. With the social and financial burden of this disease increasing every year, the onus is now on the field of AD researchers to investigate alternative ideas to deliver outcomes for patients. Although several major clinical trials targeting Aβ have failed, three smaller clinical trials targeting metal interactions with Aβ have all shown benefit for patients. Here we review the genetic, pathological, biochemical, and pharmacological evidence that underlies the metal hypothesis of AD. The AD-affected brain suffers from metallostasis, or fatigue of metal trafficking, resulting in redistribution of metals into inappropriate compartments. The metal hypothesis is built upon a triad of transition elements: iron, copper, and zinc. The hypothesis has matured from early investigations showing amyloidogenic and oxidative stress consequences of these metals; recently, disease-related proteins, APP, tau, and presenilin, have been shown to have major roles in metal regulation, which provides insight into the pathway of neurodegeneration in AD and illuminates potential new therapeutic avenues.     

Abeta,oxidative stress in Alzheimer disease: Evidence based on proteomics studies

The initiation and progression of Alzheimer disease (AD) is a complex process not yet fully understood. While many hypotheses have been provided as to the cause of the disease, the exact mechanisms remain elusive and difficult to verify. Proteomic applications in disease models of AD have provided valuable insights into the molecular basis of this disorder, demonstrating that on a protein level, disease progression impacts numerous cellular processes such as energy production, cellular structure, signal transduction, synaptic function, mitochondrial function, cell cycle progression, and proteasome function. Each of these cellular functions contributes to the overall health of the cell, and the dysregulation of one or more could contribute to the pathology and clinical presentation in AD. In this review, foci reside primarily on the amyloid β-peptide (Aβ) induced oxidative stress hypothesis and the proteomic studies that have been conducted by our laboratory and others that contribute to the overall understanding of this devastating neurodegenerative disease. This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial Dysfunction, and Neurodegenerative Diseases.     

The lipid translocase, ABCA4: seeing is believing

Mutations to members of the A subfamily of ATP binding cassette (ABC) proteins are responsible for a number of diseases; typically they are associated with aberrant cellular lipid transport processes. Mutations to the ABCA4 protein are linked to a number of visual disorders including Stargardt's disease and retinitis pigmentosa. Over 500 disease-associated mutations in ABCA4 have been demonstrated; however, the genotype-phenotype link has not been firmly established. This shortfall is primarily because the function of ABCA4 in the visual cycle is not yet fully understood. One hypothesis suggests that ABCA4 mediates the trans-bilayer translocation of retinal-phosphatidylethanolamine conjugates to facilitate the retinal regeneration process in the visual cycle. This review examines the evidence to support, or refute, this working hypothesis on the function of this clinically important protein.     

A discussion on disease severity index values. Part II: using the disease severity index for null hypothesis testing

A disease severity index (DSI) is a single number for summarising a large amount of information on disease severity. The DSI has most often been used with data based on a special type of ordinal scale comprising a series of consecutive ranges of defined numeric intervals, generally based on the percent area of symptoms presenting on the specimen(s). Plant pathologists and other professionals use such ordinal scale data in conjunction with a DSI (%) for treatment comparisons. The objective of this work is to explore the effects on both of different scales (i.e. those having equal or unequal classes, or different widths of intervals) and of the selection of values for scale intervals (i.e. the ordinal grade for the category or the midpoint value of the interval) on the null hypothesis test for the treatment comparison. A two‐stage simulation approach was employed to approximate the real mechanisms governing the disease‐severity sampling design. Subsequently, a meta‐analysis was performed to compare the effects of two treatments, which demonstrated that using quantitative ordinal rating grades or the midpoint conversion for the ranges of disease severity yielded very comparable results with respect to the power of hypothesis testing. However, the principal factor determining the power of the hypothesis test is the nature of the intervals, not the selection of values for ordinal scale intervals (i.e. not the mid‐point or ordinal grade). Although using the percent scale is always preferable, the results of this study provide a framework for developing improved research methods where the use of ordinal scales in conjunction with a DSI is either preferred or a necessity for comparing disease severities.     

Optogenetic stimulation of serotonin nuclei retrieve the lost memory in Alzheimer's disease

How are memories stored and retrieved? It was one of the most discussed questions in the past century by neuroscientists. Leading studies of the period brought two different explanations to this question: The first statement considers memory as a physiological change in the brain and suggest that the retrieval of memory is only occurred by the same physiologic changes observed during the memory formation, while the second suggests that memory is a psychic mood stored in mind and the retrieval of memory is occurred by mystical energy fluctuations. Although the exact reason and the pathogenesis of Alzheimer's disease have not yet been fully understood, the approaches that centered the retrieval strategy of lost memory constitutes the basis of the treatment strategies in Alzheimer's disease today. The majority of treatment studies has based on the manipulation of the cholinergic system; however, although serotonin has mnemonic effects, its role in the pathogenesis of Alzheimer's disease has not been investigated as much as the cholinergic system. Here we show how serotonin affects the pathogenesis of Alzheimer's disease in a comprehensive perspective and we suggest that the optogenetics manipulation of serotonin nuclei retrieve the lost memory by closing the inward-rectifier potassium channel Kir2 on the memory engram cells. Also, we raise the possible effects of serotonin on the memory engram cells and the interactions between the amyloid-centric hypothesis of Alzheimer's disease and the memory engram hypothesis to explain the pathophysiology of memory loss in Alzheimer's disease.     

The reconstitution of mammalian prion infectivity de novo

The discovery of prion disease transmission in mammals, as well as a non-Mendelian type of inheritance in yeast, has led to the establishment of a new concept in biology, the prion hypothesis. The prion hypothesis postulates that an abnormal protein conformation propagates itself in an autocatalytic manner using the normal isoform of the same protein as a substrate and thereby acts either as a transmissible agent of disease (in mammals), or as a heritable determinant of phenotype (in yeast and fungus). While the prion biology of yeast and fungus supports this idea strongly, the direct proof of the prion hypothesis in mammals, specifically the reconstitution of the disease-associated isoform of the prion protein (PrP(Sc)) in vitro de novo from noninfectious prion protein, has been difficult to achieve despite many years of effort. The present review summarizes our current knowledge about the biochemical nature of the prion infectious agent and structure of PrP(Sc), describes potential strategies for generating prion infectivity de novo and provides some insight on why the reconstitution of infectivity has been difficult to achieve in vitro. Several hypotheses are proposed to explain the apparently low infectivity of the first generation of recently reported synthetic mammalian prions.     

Normal and abnormal fetal growth

The fetal origins of adult disease hypothesis suggests that poor intrauterine growth is associated with an increased risk of cardiovascular disease. The hypothesis goes on to implicate different growth 'phenotypes', particularly disproportionate growth, in the determination of the type of cardiovascular disease that develops. Analysis of the antenatal growth of a low-risk pregnancy population does not identify such growth phenotypes within the general population. Rather, intrauterine growth is characterized by poor predictability of subsequent size, suggesting that centile crossing is a common feature of intrauterine growth. Furthermore, there is a sexually dimorphic pattern to this growth that needs to be considered in further work to test the fetal origins hypothesis.     

Microorganisms and autoimmunity: making the barren field fertile?

Microorganisms induce strong immune responses, most of which are specific for their encoded antigens. However, microbial infections can also trigger responses against self antigens (autoimmunity), and it has been proposed that this phenomenon could underlie several chronic human diseases, such as type 1 diabetes and multiple sclerosis. Nevertheless, despite intensive efforts, it has proven difficult to identify any single microorganism as the cause of a human autoimmune disease, indicating that the 'one organism-one disease' paradigm that is central to Koch's postulates might not invariably apply to microbially induced autoimmune disease. Here, we review the mechanisms by which microorganisms might induce autoimmunity, and we outline a hypothesis that we call the fertile-field hypothesis to explain how a single autoimmune disease could be induced and exacerbated by many different microbial infections.     

Decreased DNA repair in familial Alzheimer's disease

Alterations in the capacity of a cell to repair DNA lesions play an important role in a number of human diseases. We and others have demonstrated defective DNA repair of alkylation damage in cells from patients with Alzheimer's disease. It has been hypothesized that this defect is related to the cause of Alzheimer's disease and results in the accumulation of lesions in the central nervous system neurons. One prediction of this hypothesis is that in dominantly inherited Alzheimer's disease, the repair defect will be present in half of the offspring of affected patients long before they develop symptoms of the disease. In order to test the hypothesis that decreased DNA repair is responsible for familial Alzheimer's disease and their at-risk offspring we have studied DNA repair in these individuals after exposure of lymphoblasts to alkylating agents. Our results indicate that cell lines from affected patients repair significantly less damage in 3 h than cell lines from healthy controls. A small number of at-risk individuals were also studied and some of these had lower levels of repair, although more cell lines from individuals in this group must be studied. These findings provide further support for defective DNA repair playing a role in the pathogenesis of Alzheimer's disease.     

Comparing the likelihood ratios of two binary diagnostic tests in the presence of partial verification

The comparison of the efficiency of two binary diagnostic tests requires one to know the disease status for all patients in the sample, by applying a gold standard. In two-phase studies the gold standard is not applied to all patients in a sample, and the problem of partial verification of the disease arises. At present, one of the approaches most used for comparing two binary diagnostic tests are the likelihood ratios. In this study, the maximum likelihood estimators of likelihood ratios are obtained. The tests of hypothesis to compare the likelihood ratios of two binary diagnostic tests when both are applied to the same random sample in the presence of verification bias are deduced, and simulation experiments are performed in order to investigate the asymptotic behaviour of the tests of hypothesis. The results obtained have been applied to the study of Alzheimer's disease.     

老年性痴呆抗体药物研究进展

老年性痴呆(Alzhimer's disease,AD)是一种渐进性神经退化性疾病,其主要表现为记忆功能衰减及识别能力障碍,同时伴有各种神经症状和行为障碍,具有非常高的发病率,目前还没有特异性治疗药物。随着世界人口老龄化,AD发病率逐年增高,成为本世纪威胁人类健康最严重的疾病之一。近年来AD的发病机理和药物研究方面都有突破性进展,尤其是制备针对β淀粉样蛋白（amyloid beta protein,Aβ）特异性抗体药物成为AD治疗极具价值的途径。本文主要对以Aβ为主的AD发病机理和针对Aβ的抗体药物的治疗机制、研究现状及进展进行综述,为进一步研发AD治疗药物提供参考。     

Molecular analysis of Fanconi anaemia

The autosomal recessive genetic disease, Fanconi anaemia, is perceived as another manifestation of defective cellular DNA repair, just as in the autosomal recessive disease Xeroderma pigmentosum. The biochemistry and cellular biology of Xeroderma pigmentosum have been convincingly elucidated, but the same has not been true for Fanconi anaemia. In this review we consider the pleiotropic nature of Fanconi anaemia, its clinical and cellular variability and its genetic heterogeneity. We take into account the wealth of experimental findings available and offer a novel hypothesis involving feedback control of DNA replication during S phase of the cell cycle to explain the basic defect in the disease.