New strategy for virus discovery: viruses identified in human feces in the last decade

Emerging and re-emerging viruses continue to surface all over the world.Some of these viruses have the potential for rapid and global spread with high morbidity and mortality,such as the SARS coronavirus outbreak.It is extremely urgent and important to identify a novel virus near-instantaneously to develop an active preventive and/or control strategy.As a cultureindependent approach,viral metagenomics has been widely used to investigate highly divergent and completely new viruses in humans,animals,and even environmental samples in the past decade.A new model of Koch’s postulates,named the metagenomic Koch’s postulates,has provided guidance for the study of the pathogenicity of novel viruses.This review explains the viral metagenomics strategy for virus discovery and describes viruses discovered in human feces in the past 10 years using this approach.This review also addresses issues related to the metagenomic Koch’s postulates and the challenges for virus discovery in the future.     

History of genetic disease: the molecular genetics of Huntington disease - a history

The Huntington disease gene was mapped to human chromosome 4p in 1983 and 10 years later the pathogenic mutation was identified as a CAG-repeat expansion. Our current understanding of the molecular pathogenesis of Huntington disease could never have been achieved without the recent progress in the field of molecular genetics. We are now equipped with powerful genetic models that continue to uncover new aspects of the pathogenesis of Huntington disease and will be instrumental for the development of therapeutic approaches for this disease.     

Understanding emerging treatment paradigms in rheumatoid arthritis

Treatment strategies for rheumatoid arthritis (RA) will continue to evolve as new drugs are developed, as new data become available, and as our potential to achieve greater and more consistent outcomes becomes more routine. Many patients will find both symptom relief and modest control of their disease with disease-modifying antirheumatic drugs (DMARDs), yet this course of therapy is clearly not effective in all patients. In fact, despite strong evidence that intensive treatment in the early stages of RA can slow or stop disease progression and may prevent disability, many patients continue to be managed in a stepwise manner and are treated with an ongoing monotherapy regimen with DMARDs. There is now a large body of evidence demonstrating the success of treating RA patients with anti-TNF therapy, usually in combination with methotrexate. As a result of the increased use of anti-TNF therapy, treatment paradigms have changed - and our practice is beginning to reflect this change. In the present review, we summarize the salient points of several recently proposed and emerging treatment paradigms with an emphasis on how these strategies may impact future practice.     

Peptide-mediated interactions in biological systems: new discoveries and applications

Peptide-mediated interactions play very important roles in cellular processes. Recent years have seen much activity in the discovery of new bioactive peptides, and interactions mediated by protein-peptide binding events. At the same time, computational approaches continue to be developed that allow protein-peptide interactions to be discovered with great accuracy. There are also a growing number of chemicals that can target these interactions with various applications in disease. Both new discoveries and predictions suggest that these protein-peptide interactions play greater roles in cellular processes than previously thought. We propose that projects to uncover the protein-peptide repertoire used in Nature in a systematic way will have numerous applications in molecular biology and medicine.     

Ticks (Acari: Ixodidae) spread by the international trade in reptiles and their potential roles in dissemination of diseases

The international trade in live reptiles has grown dramatically in the last decade. Since many of these reptiles are infested with ticks, the number of ticks introduced to new exotic locations has also increased. This is causing concern in importing countries such as the United States because some of the reptilian ticks are known to be vectors of diseases of veterinary and economic importance, such as heartwater. Rational measures to control these tick species and to eradicate new introductions have been slow to develop due in part to the scattered and often obscure sources of available data on the exotic ticks. This review is an attempt to collate information on the geographical distribution, host range, life cycle and associations with diseases for four Amblyomma species, A. marmoreum Koch, A. nuttalli D?nitz, A. sparsum Newmann, and for four Aponomma species, A. exornatum (Koch), A. flavomaculatum (Lucas), A. latum (Koch)( and A. varanensis (Supino), that have recently been introduced into Florida, USA on imported reptiles.     

A possible emerging role of phytochemicals in improving age-related neurological dysfunctions: a multiplicity of effects

It is rare to see a day pass in which we are not told through some popular medium that the population is becoming older. Along with this information comes the "new" revelation that as we enter the next millennium there will be increases in age-associated diseases (e.g., cancer, cardiovascular disease) including the most devastating of these, which involve the nervous system (e.g., Alzheimer's disease [AD] and Parkinson's disease [PD]). It is estimated that within the next 50 years approximately 30% of the population will be aged 65 years or older. Of those between 75 and 84 years of age, 6 million will exhibit some form of AD symptoms, and of those older than 85 years, over 12 million will have some form of dementia associated with AD. What appears more ominous is that many cognitive changes occur even in the absence of specific age-related neurodegenerative diseases. Common components thought to contribute to the manifestation of these disorders and normal age-related declines in brain performance are increased susceptibility to long-term effects of oxidative stress (OS) and inflammatory insults. Unless some means is found to reduce these age-related decrements in neuronal function, health care costs will continue to rise exponentially. Thus, it is extremely important to explore methods to retard or reverse age-related neuronal deficits as well as their subsequent, behavioral manifestations. Fortunately, the growth of knowledge in the biochemistry of cell viability has opened new avenues of research focused at identifying new therapeutic agents that could potentially disrupt the perpetual cycle of events involved in the decrements associated with these detrimental processes. In this regard, a new role in which certain dietary components may play important roles in alleviating certain disorders are beginning to receive increased attention, in particular those involving phytochemicals found in fruits and vegetables.     

Microtubule-targeting agents are clinically successful due to both mitotic and interphase impairment of microtubule function

Microtubules undergo continual dynamic changes in mitotic cells as the mitotic spindle forms and is broken down and in interphase cells where they play a central role in intracellular trafficking, cell signaling, cell migration, and angiogenesis. Compounds that target the microtubule have been hugely successful in the clinic as chemotherapeutics, and this success is likely due to their ability to target cells regardless of their cell cycle stage. Additionally, new generation antibody-conjugated microtubule-targeting agents are improving the targeting of these drugs to tumors. Microtubule-targeting agents have been shown to have anti-angiogenic and vascular-disrupting properties as well as effects on cellular migration, intracellular trafficking, and cell secretion. There are a number of these compounds in development that target the vasculature, and different formulations of clinically used drugs are being developed to take advantage of these anti-angiogenic properties. Microtubule-targeting agents have also been shown to have the potential to treat neurodegenerative diseases, such as Alzheimer’s disease. Thus, drugs that target the microtubule will continue to have a major impact in oncology not only as anti-mitotics but also as potent inhibitors of interphase functions, and in future may also prove to be effective in reducing the consequences of neurodegenerative disease.     

Evolving disease resistance genes

Defenses against most specialized plant pathogens are often initiated by a plant disease resistance gene. Plant genomes encode several classes of genes that can function as resistance genes. Many of the mechanisms that drive the molecular evolution of these genes are now becoming clear. The processes that contribute to the diversity of R genes include tandem and segmental gene duplications, recombination, unequal crossing-over, point mutations, and diversifying selection. Diversity within populations is maintained by balancing selection. Analyses of whole-genome sequences have and will continue to provide new insight into the dynamics of resistance gene evolution.     

Richard Pfeiffer and Alexandre Besredka: creators of the concept of endotoxin and anti-endotoxin

Richard Pfeiffer, working with Robert Koch in Berlin, intellectually and experimentally conceived the concept of endotoxin as a heat-stable bacterial poison responsible for the pathophysiological consequences of certain infectious diseases. Pfeiffer's definition of endotoxin included the inability to evoke neutralizing antibodies against this bacterial toxin. Alexandre Besredka, Ilya (Elie) Metchnikoff's successor at the Institut Pasteur in Paris, was the first to demonstrate that, in fact, antibodies could be engendered which were capable of suppressing the poisonous effects of endotoxin. Endotoxin and anti-endotoxin antibodies have since then fascinated researchers of many disciplines and continue to do so, particularly in the fields of diagnosis, prevention, and therapy of severe Gram-negative infections.     

Cause and effect considerations in diagnostic pathology and pathology phenotyping of genetically engineered mice (GEM)

Over the next several decades, biology is embarking on its most ambitious project yet: to annotate the human genome functionally, prioritizing and focusing on those genes relevant to development and disease. Model systems are fundamental prerequisites for this task, and genetically engineered mice (GEM) are by far the most accessible mammalian system because of their anatomical, physiological, and genetic similarity to humans. The scientific utility of GEM has become commonplace since the technology to produce them was established in the early 1980s. Conceptually, however, an efficiently coordinated high-throughput approach that permits correlation between newly discovered genes, functional properties of their protein products, and biological relevance of these products as drug targets has yet to be established. The discipline of veterinary anatomical pathology (hereafter referred to as pathology) is not immune to this requirement for evolution and adaptation, and to address relationships and tissue consequences between tens of thousands of genes and their cognate proteins, novel interdisciplinary technologies and approaches must emerge. Although many of the techniques of pathology are well established, in the context of pathology's contribution to functional annotation of the genome, several conceptually important and unresolved issues remain to be addressed. While an ever-increasing arsenal of genetic and molecular tool-sets are available to evaluate and understand the function of genes and their pathophysiological mechanisms, pathology will continue to play an essential role in confirming cause and effect relationships of gene function in development and disease. This role will continue to be dependent on keen observation, a systematic but disciplined approach, expert knowledge of strain-dependent anatomical differences and incidental lesions, and relevant tissue-based evidence. Miniaturization and high-throughput adaptation of these methods must also continue so that they can complement parallel phenotyping efforts, provide pathology-based data in pace with concurrent phenotyping efforts, and continue to find new utility in the collective effort of functional annotation.     

Drug discovery in the new millennium: the pivotal role of biotechnology

Biotechnology has made, and will continue to make, a major contribution to the health of mankind by providing new insights into disease and acting as a pivotal enabler for the drug-discovery process. The available techniques are diverse and changing rapidly: selecting and integrating the best approach is the key to success.     

Linking cause and disease in the laboratory: Robert Koch's method of superimposing visual and 'functional' representations of bacteria

Robert Koch based his claim that specific microorganisms cause particular diseases on laboratory studies. This paper examines how Koch set up a plausible line of argument by using special methods of representing bacteria. One kind of representation consisted in making the bacteria visible; the other mode of representation was based on disease phenomena. Using a range of techniques of isolating and controlling microorganisms, Koch combined these different modes of representation in a way that made his claims convincing. Thus, the microorganism as a specific cause of disease emerged through a chain of repeated processes of selection and representation in the laboratory.     

Conditional gene targeting in the kidney

Complete mapping of the genome in a number of organisms provides a challenge for experimental nephrologists to identify potential functions of a vast number of new genes in the kidney. Since knockout technologies have evolved in the early eighties the mouse has become a valuable model organism. Researchers can now artificially eliminate the expression of specific genes in a mammalian organism and examine the phenotype. New developments have emerged that allow investigators to knock out a gene specifically in the kidney. Several kidney-specific promoters provide valuable tools and bacterial artificial chromosome (BAC) based techniques like recombineering will enhance both number and accuracy of new mouse lines with spatially controlled gene expression. In addition to spatial control, tetracycline- or tamoxifen-inducible systems, provide the possibility of influencing the temporal expression pattern of a gene enabling researchers to dissect its functions in adult organisms. Knocking out a gene will continue to be the gold standard for defining the role of a specific gene whereas tissue-specific gene knockdown using RNA interference represents an alternative approach for generating lower-priced and fast loss of function models. In addition to reverse genetic approaches, forward genetic techniques like random mutagenesis in mice continue to evolve and will enhance our understanding of disease mechanisms in the kidney.     

Robert Koch and the white death: from tuberculosis to tuberculin

The German medical bacteriologist Robert Koch is commonly considered one of the founding fathers of medical bacteriology. His investigations into the aetiology of tuberculosis uncovered the pathogen of this condition, the tubercle bacillus today known as Mycobacterium tuberculosis, in 1882. This work can be seen as a cornerstone of contemporary medical bacteriology, its technologies and methods. It has often been asked how such successful research connected to the tuberculin episode of 1890/91, when Koch produced a medicine for that disease, which spectacularly failed when applied in practice. The analysis concentrates on the path of mostly experimental investigations which Koch followed between 1882 and 1890. From Koch's laboratory notes it becomes clear that tuberculin therapy did in fact work in Koch's laboratory, even though it failed to do so almost anywhere else. The clue to this contradictory picture lies in the peculiar nature of Koch's understanding of tuberculosis as a disease e.g. his reliance an animal experiments, which essentially differed from what many of his contemporaries held as essentials of that condition.     

Gene therapy and tissue engineering in repair of the musculoskeletal system

Historically, surgeons have sought and used different procedures in order to augment the repair of various skeletal tissues. Now, with the completion of the Human Genome Project, many researchers have turned to gene therapy as a means to aid various ailments. In the orthopedic field, many strides have been made toward using gene therapy and tissue engineering in a clinical setting. In this review, several studies are outlined in different areas that gene therapy has or will influence orthopedic surgery. Gene therapy and tissue engineering can aid in fracture healing and spinal fusions by inducing bone formation, ligamentous repairs by increasing the production of connective tissue fibers, intervertebral disc disease by creating potential replacements, and articular cartilage repairs by providing means to improve cartilage. As we continue to see great contributions, such as the few mentioned here, this field will continue to mature and develop.     

Recent progress in the study of G protein-coupled receptors with molecular dynamics computer simulations

G protein-coupled receptors (GPCRs) are a large, biomedically important family of proteins, and the recent explosion of new high-resolution structural information about them has provided an enormous opportunity for computational modeling to make major contributions. In particular, molecular dynamics simulations have become a driving factor in many areas of GPCR biophysics, improving our understanding of lipid-protein interaction, activation mechanisms, and internal hydration. Given that computers will continue to get faster and more structures will be solved, the importance of computational methods will only continue to grow, particularly as simulation research is more closely coupled to experiment.     

The era of microbiology: a golden phoenix.

The discoveries over the last decade have demonstrated that microbiology is a central scientific discipline with practical applications in agriculture, medicine, bioremediation, biotechnology, engineering, and other fields. It is clear that the roles of microbes in nature are so diverse that the process of mining this genetic variation for new applications will continue long into the future. Moreover, the rapid rate of microbial evolution ensures that there will be no permanent solution to agricultural, medical, or environmental problems caused by microbes. These problems will demand a continual stream of creative new approaches that evolve along with the microbes. Thus, the excitement of this field will continue long into the future. However, these opportunities and imperatives demand a deep understanding of basic microbial physiology, genetics, and ecology. Major challenges that lay ahead are to impart the broad training needed to entice and enable the next generation of microbiologists, and to educate the public and government representatives about the continued and critical importance of this field for health and the economy.     

High Rates of Obesity and Non-Communicable Diseases Predicted across Latin America

Non-communicable diseases (NCDs) such as cardiovascular disease and stroke are a major public health concern across Latin America. A key modifiable risk factor for NCDs is overweight and obesity highlighting the need for policy to reduce prevalence rates and ameliorate rising levels of NCDs. A cross-sectional regression analysis was used to project BMI and related disease trends to 2050. We tested the extent to which interventions that decrease body mass index (BMI) have an effect upon the number of incidence cases avoided for each disease. Without intervention obesity trends will continue to rise across much of Latin America. Effective interventions are necessary if rates of obesity and related diseases are to be reduced.     

The future of Chagas disease control

In the past 15 years, there have been major advances in the control of Chagas disease in most of the countries endemic for this infection. Attention now turns to the future continuity of surveillance and control interventions - especially in regions where control has been so successful that the epidemiological significance of Chagas disease is in steep decline. The effort and expenditure of the recent past cannot continue indefinitely, but a degree of surveillance and selective intervention will be required because of the risk of new infestations and infections resulting from adventitious silvatic vectors accidentally entering houses. In this review, we summarize the progress of multinational control initiatives against Chagas disease. In addition, we suggest that the most sustainable approach to future surveillance involves both the primary healthcare system and university-based teams, with progressively greater attention given to case detection and treatment. Such an idea is not new, but we believe that it merits extensive discussion because of the different ways that research and health interventions are financed and because of the need to establish clearer reporting links between the research communities and the national health authorities.     

生命科学与人类疾病研究的重要模型——果蝇

黑腹果蝇(Drosophilamelanogaster)是生物学研究中最重要的模式生物之一,它在遗传的染色体理论建立中起到非常重要的作用。由于果蝇自身独特的优势,20世纪70年代以来,它又在发育生物学、神经科学、人类疾病研究等领域得到广泛应用,作出许多新的重要贡献。果蝇在神经退行性疾病研究中是非常有用的模型。可以预期,随着研究手段的丰富及科学的发展,果蝇将作为一种理想的模式生物在生物医学中发挥更大的作用。