The human genome project--some implications of extensive "reverse genetic" medicine

Impressive progress has been made during the past several decades in understanding the pathogenesis of human genetic disease. The tools of molecular biology have allowed the isolation of many disease-related genes by forward and a few by reverse genetics, and the imminent completion of a complete human genetic linkage map will accelerate the genetic characterization of many more genetic diseases. The major impacts of the molecular characterization of human genetic diseases will be 1. To increase markedly the number of human diseases that we recognize to have major genetic components. We already understand that genetic diseases are not rare medical curiosities with negligible societal impact, but rather constitute a wide spectrum of both rare and extremely common diseases responsible for an immense amount of suffering in all human societies. The characterization of the human genome will lead to the identification of genetic factors in many more human diseases, even those that now seem too multifactorial or polygenic for ready understanding. 2. To allow the development of powerful new approaches to diagnosis, detection, screening and even therapy of these disorders aimed directly at the mutant genes rather than at the gene products. This should eventually allow much more accurate and specific management of human genetic disease and the genetic factors in many human maladies. The preparation of a fine-structure physical map of the entire human genome together with an overlapping contiguous set of clones spanning entire chromosomes or large portions of chromosomes is rapidly becoming feasible, and the information that will flow from this effort promises eventually to affect the management of many important genetic diseases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Computer-assisted measurement of vessel shape from 3T magnetic resonance angiography of mouse brain

Blood vessel morphology (vessel radius, branching pattern, and tortuosity) is altered by a multitude of diseases. Although murine models of human pathology are important to the investigation of many diseases, there are few publications that address quantitative measurements of murine vascular morphology. This report outlines methods of imaging mice in vivo using magnetic resonance angiograms obtained on a clinical 3T unit, of defining mouse vasculature from these images, and of quantifying measures of vessel shape. We provide examples of both healthy and diseased vasculature and illustrate how the approach can be used to assess pathology both visually and quantitatively. The method is amenable to the assessment of many diseases in both human beings and mice.     

The potential of using blood circular RNA as liquid biopsy biomarker for human diseases

Circular RNA (circRNA) is a novel class of single-stranded RNAs with a closed loop structure. The majority of circRNAs are formed by a back-splicing process in pre-mRNA splicing. Their expression is dynamically regulated and shows spatiotemporal patterns among cell types, tissues and developmental stages. CircRNAs have important biological functions in many physiological processes, and their aberrant expression is implicated in many human diseases. Due to their high stability, circRNAs are becoming promising biomarkers in many human diseases, such as cardiovascular diseases, autoimmune diseases and human cancers. In this review, we focus on the translational potential of using human blood circRNAs as liquid biopsy biomarkers for human diseases. We highlight their abundant expression, essential biological functions and significant correlations to human diseases in various components of peripheral blood, including whole blood, blood cells and extracellular vesicles. In addition, we summarize the current knowledge of blood circRNA biomarkers for disease diagnosis or prognosis.     

Mitochondrial dysfunction, oxidative stress, regulation of exocytosis and their relevance to neurodegenerative diseases

A common feature in the early stages of many neurodegenerative diseases lies in mitochondrial dysfunction, oxidative stress, and reduced levels of synaptic transmission. Many genes associated with neurodegenerative diseases are now known to regulate either mitochondrial function, redox state, or the exocytosis of neurotransmitters. Mitochondria are the primary source of reactive oxygen species and ATP and control apoptosis. Mitochondria are concentrated in synapses and significant alterations to synaptic mitochondrial localization, number, morphology, or function can be detrimental to synaptic transmission. Mitochondrial by-products are capable of regulating various steps of neurotransmission and mitochondrial dysfunction and oxidative stress occur in the early stages of many neurodegenerative diseases. This mini-review will highlight the prospect that mitochondria regulates synaptic exocytosis by controlling synaptic ATP and reactive oxygen species levels and that dysfunctional exocytosis caused by mitochondrial abnormalities may be a common underlying phenomenon in the initial stages of some human neurodegenerative diseases.     

Animal models of focal and global cerebral ischemia

The use of appropriate animal models is essential to predict the value and effect of therapeutic approaches in human subjects. Focal (stroke) and global (cardiac arrest) cerebral ischemia represents diseases that are common in the human population. Stroke and cardiac arrest, which are major causes of death and disability, affect millions of individuals around the world and are responsible for the leading health care costs of all diseases. Understanding the mechanisms of injury and neuroprotection in these diseases is critical if we are ever to learn new target sites to treat ischemia. There are many animal models available to investigate injury mechanisms and neuroprotective strategies. This review summarizes many (but not all) small and large animal models of focal and global cerebral ischemia and discusses their advantages and disadvantages.     

HDAC inhibitors in parasitic diseases

Parasitic diseases cause significant global morbidity and mortality, particularly in underdeveloped regions of the world. Malaria alone causes ~800000 deaths each year, with children and pregnant women being at highest risk. There is no licensed vaccine available for any human parasitic disease and drug resistance is compromising the efficacy of many available anti-parasitic drugs. This is driving drug discovery research on new agents with novel modes of action. Histone deacetylase (HDAC) inhibitors are being investigated as drugs for a range of diseases, including cancers and infectious diseases such as HIV/AIDS, and several parasitic diseases. This review focuses on the current state of knowledge of HDAC inhibitors targeted to the major human parasitic diseases malaria, schistosomiasis, trypanosomiasis, toxoplasmosis and leishmaniasis. Insights are provided into the unique challenges that will need to be considered if HDAC inhibitors are to be progressed towards clinical development as potential new anti-parasitic drugs.     

Yeast as a model for studying human neurodegenerative disorders

Protein misfolding and aggregation are central events in many disorders including several neurodegenerative diseases. This suggests that alterations in normal protein homeostasis may contribute to pathogenesis, but the exact molecular mechanisms involved are still poorly understood. The budding yeast Saccharomyces cerevisiae is one of the model systems of choice for studies in molecular medicine. Modeling human neurodegenerative diseases in this simple organism has already shown the incredible power of yeast to unravel the complex mechanisms and pathways underlying these pathologies. Indeed, this work has led to the identification of several potential therapeutic targets and drugs for many diseases, including the neurodegenerative diseases. Several features associated with these diseases, such as formation of protein aggregates, cellular toxicity mediated by misfolded proteins, oxidative stress and hallmarks of apoptosis have been faithfully recapitulated in yeast, enabling researchers to take advantage of this powerful model to rapidly perform genetic and compound screens with the aim of identifying novel candidate therapeutic targets and drugs. Here we review the work undertaken to model human brain disorders in yeast, and how these models provide insight into novel therapeutic approaches for these diseases.     

新型人类逆转录病毒XMRV研究进展

异嗜性鼠白血病病毒相关病毒(xenotropic murine leukemia virus-related virus,XMRV)是迄今发现的第一种可以感染人类的r逆转录病毒。XMRV最初于2006年在RNase L基因缺陷型的前列腺癌组织中首次被鉴定,其序列与鼠科白血病病毒(murine leukemia virus,MLV)十分相似。目前,北美、欧洲和亚洲的多个研究机构在人类前列腺癌和慢性疲劳综合征(chronic fatigue syndrome,CFS)患者中检测到XMRV。但不同研究间结果差异很大,XMRV感染与人类疾病之间的相关性尚不明确。该文综述了目前XMRV的相关研究进展,包括与人类疾病的关系、XMRV的基本特征、病理生理学可能的机制等方面,并就今后研究趋势和注意问题进行了讨论。     

Target discovery and validation in the post-genomic era

The recent publication of the human genome sequence provides an opportunity both to combat diseases that are presently considered as pharmaceutically intractable and also to improve current therapies for many common human diseases. The identification of every human gene by ongoing bioinformatic efforts has the potential, when combined with functional genomic approaches, to pinpoint the molecular basis of every human disease, and to discover appropriate intervention points. This exciting prospect is directly relevant to the successful development of effective therapeutics because the past record of drug discovery suggests that 30%–40% of experimental drugs fail because an inappropriate biological target was pursued. The major impact of genomic information may therefore be to reduce this biological failure rate by earlier definition of drug targets related to disease susceptibility or progression. This paper briefly reviews some of the approaches that can be used to identify biologically relevant drug targets.     

Understanding hereditary diseases using the dog and human as companion model systems

Animal models are requisite for genetic dissection of, and improved treatment regimens for, human hereditary diseases. While several animals have been used in academic and industrial research, the primary model for dissection of hereditary diseases has been the many strains of the laboratory mouse. However, given its greater (than the mouse) genetic similarity to the human, high number of naturally occurring hereditary diseases, unique population structure, and the availability of the complete genome sequence, the purebred dog has emerged as a powerful model for study of diseases. The major advantage the dog provides is that it is afflicted with approximately 450 hereditary diseases, about half of which have remarkable clinical similarities to corresponding diseases of the human. In addition, humankind has a strong desire to cure diseases of the dog so these two facts make the dog an ideal clinical and genetic model. This review highlights several of these shared hereditary diseases. Specifically, the canine models discussed herein have played important roles in identification of causative genes and/or have been utilized in novel therapeutic approaches of interest to the dog and human.     

Integrating cell-signalling pathways with NF-kappaB and IKK function

Nuclear factor (NF)-kappaB and inhibitor of NF-kappaB kinase (IKK) proteins regulate many physiological processes, including the innate- and adaptive-immune responses, cell death and inflammation. Disruption of NF-kappaB or IKK function contributes to many human diseases, including cancer. However, the NF-kappaB and IKK pathways do not exist in isolation and there are many mechanisms that integrate their activity with other cell-signalling networks. This crosstalk constitutes a decision-making process that determines the consequences of NF-kappaB and IKK activation and, ultimately, cell fate.     

Activity of selected aromatic amino acids in biological systems

Besides the structural function in proteins, aromatic amino acids are precursors of many important biological compounds essential for normal functioning of the human organism. Many of these compounds may be used as markers for identification of specific pathological states. Comprehensive knowledge about the metabolism of aromatic amino acids and mechanisms of action of their metabolites made it possible to develop effective treatments for many disorders. However, it should not be forgotten that in some pathological conditions, these compounds could not only be involved in the pathogenesis of many disease entities but could also be used as an important tool in prediction of many diseases. This paper contains a review of published literature on aromatic amino acids in the context of physiological processes of the human body and chosen social disorders, such as cancers; psychiatric disorders: depression, anxiety states, schizophrenia, bipolar affective disorders; neurodegenerative, and cardiovascular diseases; chronic kidney insufficiency or diabetes.     

端粒与衰老及心脑血管疾病的研究进展

端粒是真核细胞染色体末端的一种保护性结构,在维持染色体末端稳定性等方面起重要作用。端粒被认为是细胞衰老的生物钟。研究证明端粒的长度随着人体的衰老呈进行性缩短。近年来,分子流行病学研究表明端粒的长度与人的寿命呈负相关。越来越多的相关研究发现,端粒的长度与许多衰老相关的疾病密切相关。原发性高血压（esential hypertension,EH）、冠状动脉粥样硬化（coronary atherosclerosis,CA）、心力衰竭（heart failure,HF）和脑卒中（stroke）等心脑血管疾病的发生发展过程中都伴有端粒长度的改变。影响端粒长度的因素有很多,包括遗传因素和非遗传因素,其中有关端粒长度和非遗传因素的关系还不确定。另外,端粒是否可以作为衰老及其相关疾病的预测因子还没有定论。本文现就端粒在人类疾病中的相关研究进展作一简要综述。     

宠物与外来动物病

宠物伴随人类文明已有数千年的历史。当今宠物日益受到大众青睐,给人们带来精神上享受,但宠物是外来动物疾病一个潜在载体,对人们身体健康和畜牧生产造成影响。本文概括了我国宠物外来动物疾病的现状及潜在的威胁,简要分析了几种外来动物疾病的特点,对防止宠物引入外来动物疾病给出了意见和建议。     

结核病动物模型研究进展

结核病是由结核分枝杆菌感染引起的传染病,是危害人类健康的主要传染病之一。动物模型已经成为研究人类传染病的标准化工具。虽然对于结核分枝杆菌而言并没有真正意义的动物资源,但由于不同种类的动物,对分枝杆菌的敏感性不一样,因此可以成为结核病研究的有利工具。结核病最常用的实验动物模型包括小鼠、兔和豚鼠。每种动物有其自身特点,但并不能完全模拟人类疾病。通过建立结核病的动物模型,可以大大增加我们对疾病的病因、毒力和发病机制的理解。除了这三种模型外,非人灵长类也常被用于结核病的研究。本文总结了这几种结核病模型的研究状况。     

Amplification of autoimmune disease by infection

Reports of infection with certain chronic persistent microbes (herpesviruses or Chlamydiae) in human autoimmune diseases are consistent with the hypothesis that these microbes are reactivated in the setting of immunodeficiency and often target the site of autoimmune inflammation. New experimental animal models demonstrate the principle. A herpesvirus or Chlamydia species can be used to infect mice with induced transient autoimmune diseases. This results in increased disease severity and even relapse. The evidence suggests that the organisms are specifically imported to the inflammatory sites and cause further tissue destruction, especially when the host is immunosuppressed. We review the evidence for the amplification of autoimmune inflammatory disease by microbial infection, which may be a general mechanism applicable to many human diseases. We suggest that patients with autoimmune disorders receiving immunosuppressing drugs should benefit from preventive antiviral therapy.     

Negative regulation of Toll-like receptor signaling pathway

TLRs are primary sensors of invading pathogens, recognizing conserved microbial molecules and activating signaling pathways that are pivotal to innate and adaptive immune responses. However, a TLR signaling pathway must be tightly controlled because its excessive activation can contribute to the pathogenesis of many human diseases. This review provides a summary of the different mechanisms that are involved in the negative regulation of TLR signaling pathways.     

Aquatic models of human ciliary diseases

Cilia are microtubule‐based structures that either transmit information into the cell or move fluid outside of the cell. There are many human diseases that arise from malfunctioning cilia. Although mammalian models provide vital insights into the underlying pathology of these diseases, aquatic organisms such as Xenopus and zebrafish provide valuable tools to help screen and dissect out the underlying causes of these diseases. In this review we focus on recent studies that identify or describe different types of human ciliopathies and outline how aquatic organisms have aided our understanding of these diseases.     

Searching for biomarkers: humoral response profiling with luciferase immunoprecipitation systems

B-cell-mediated humoral responses are triggered in many human diseases, including autoimmune diseases, cancer, and neurologic and infectious diseases. However, the full exploitation of the information contained within a patient’s antibody repertoire for diagnosis, monitoring and even disease prediction has been limited due to the poor diagnostic performance of many immunoassay formats. We have developed luciferase immunoprecipitation systems (LIPS) that harnesses light-emitting proteins to generate high-definition antibody profiles that are optimal for both diagnostics and biomarker discovery. Here, we describe the results and implications from a range of LIPS-antibody profiling studies performed in our laboratory. These include highly sensitive diagnostics for domestic and global pathogens, insights into infection-related diseases, discovery of new biomarkers for human diseases, subcategorization of symptoms and identification of pathogenic autoantibodies against self-proteins. These investigations highlight the types of humoral response profiles associated with different diseases, provide new information related to disease pathogenesis and offer a framework for incorporating LIPS antibody profiling into global health initiatives and disease monitoring.