Ivermectin 20 years on: maturation of a wonder drug

Ivermectin has been on the veterinary market for almost a quarter of a century and has been approved for human use for 18 years. Its use has revolutionized the treatment of nematode and arthropod parasites in animals and has provided hope for the control or even eradication of filariases in humans. Although much remains to be learned about how the drug works and how resistance to it will develop, it has earned the title of "wonder drug".     

Bacteriophage applications: where are we now?

Bacteriophages are bacterial viruses and have been used for almost a century as antimicrobial agents. In the West, their use diminished when chemical antibiotics were introduced, but they remain a common therapeutic approach in parts of eastern Europe. Increasing antibiotic resistance in bacteria has driven the demand for novel therapies to control infections and led to the replacement of antibiotics in animal husbandry. Alongside this, increased pressure to improve food safety has created a need for faster detection of pathogenic bacteria. Hence, there has been a resurgence of interest in bacteriophage applications, and this has encouraged the emergence of a large number of biotech companies hoping to commercialize their use. Research in Europe and the United States has increased steadily, leading to the development of a range of applications for bacteriophage agents for the healthcare, veterinary and agricultural sectors. This article will attempt to answer the question of whether bacteriophages are now delivering on their potential.     

What's hot in animal biosafety?

In recent years, the emergence or re-emergence of critical issues in infectious disease and public health has presented new challenges and opportunities for laboratory animal care professionals. The re-emergence of bioterrorism as a threat activity of individuals or small groups has caused a heightened awareness of biosecurity and improved biosafety. The need for animal work involving high-risk or high-consequence pathogens and for arthropod-borne diseases has stimulated renewed interest in animal biosafety matters, particularly for work in containment. Application of these principles to animals retained in outdoor environments has been a consequence of disease eradication programs. The anticipated global eradication of wild poliovirus has prompted the promulgation of new biosafety guidelines for future laboratory and animal work. Increased concern regarding the use of biologically derived toxins and hazardous chemicals has stimulated a new categorization of facility containment based on risk assessment. Recognition that prion disease agents and other high-consequence pathogens require safe handling and thorough destruction during terminal decontamination treatment has led to the development of new biosafety guidelines and technologies. The implementation of these guidelines and technologies will promote state-of-the-art research while minimizing risk to laboratory animals, researchers, and the environment.     

Coding and traceability for cells,tissues and organs for transplantation

Modern transplantation of cells, tissues and organs has been practiced within the last century achieving both life saving and enhancing results. Associated risks have been recognized including infectious disease transmission, malignancy, immune mediated disease and graft failure. This has resulted in establishment of government regulation, professional standard setting and establishment of vigilance and surveillance systems for early detection and prevention and to improve patient safety. The increased transportation of grafts across national boundaries has made traceability difficult and sometimes impossible. Experience during the first Gulf War with miss-identification of blood units coming from multiple countries without standardized coding and labeling has led international organizations to develop standardized nomenclature and coding for blood. Following this example, cell therapy and tissue transplant practitioners have also moved to standardization of coding systems. Establishment of an international coding system has progressed rapidly and implementation for blood has demonstrated multiple advantages. WHO has held two global consultations on human cells and tissues for transplantation, which recognized the global circulation of cells and tissues and growing commercialization and the need for means of coding to identify tissues and cells used in transplantation, are essential for full traceability. There is currently a wide diversity in the identification and coding of tissue and cell products. For tissues, with a few exceptions, product terminology has not been standardized even at the national level. Progress has been made in blood and cell therapies with a slow and steady trend towards implementation of the international code ISBT 128. Across all fields, there are now 3,700 licensed facilities in 66 countries. Efforts are necessary to encourage the introduction of a standardized international coding system for donation identification numbers, such as ISBT 128, for all donated biologic products.     

Bacteriophage defence systems in lactic acid bacteria

The study of the interactions between lactic acid bacteria and their bacteriophages has been a vibrant and rewarding research activity for a considerable number of years. In the more recent past, the application of molecular genetics for the analysis of phage-host relationships has contributed enormously to the unravelling of specific events which dictate insensitivity to bacteriophage infection and has revealed that while they are complex and intricate in nature, they are also extremely effective. In addition, the strategy has laid solid foundations for the construction of phage resistant strains for use in commercial applications and has provided a sound basis for continued investigations into existing, naturally-derived and novel, genetically-engineered defence systems. Of course, it has also become clear that phage particles are highly dynamic in their response to those defence systems which they do encounter and that they can readily adapt to them as a consequence of their genetic flexibility and plasticity. This paper reviews the exciting developments that have been described in the literature regarding the study of phage-host interactions in lactic acid bacteria and the innovative approaches that can be taken to exploit this basic information for curtailing phage infection.     

A Point-Wise Model of Adhesion Suitable for Real-Time Applications of Bio-Inspired Climbing Robots

Bio-inspired climbing robots relying on adhesion systems are believed to become essential tools for several industrial applications in the near future. In recent years, research has mainly focused on modeling micro-scale adhesion phenomena; a macro-scale adhesion model has however to be developed for the design of macro-scale systems. In this paper a macro-model of adhesion suitable for real-time applications is presented; it relies on a continuous representation of adhesion. An extension of the von Mises criterion is proposed as failure adhesion criterion in order to estimate the occurrence of detachment at any point of the contacting surface. An experimental set up has been designed in order to define the parameters of the model. A semi-automatic process has been developed to ensure repeatability and accuracy of the results. Polydimethylsiloxane (PDMS), which has revealed promising adhesive features for robotic use, has been used during the experimental phase. The macro-model of adhesion has been implemented in a multi-body dynamics environment based on Open Dynamics Engine (ODE) to simulate a spider-inspired robot. Simulations based on this model are suitable to represent the behaviour of climbing robots and also to optimize their design.     

Tetrathiomolybdate anticopper therapy for Wilson's disease inhibits angiogenesis,fibrosis and inflammation

The need for agents to lower body copper in Wilson's disease, a disease which results from copper toxicity has been the driving force for the development of the effective anticopper drugs penicillamine, trientine, zinc, and now tetrathiomolybdate (TM). Because of its rapid action, potency, and safety, TM is proving to be a very effective drug for initial treatment of acutely ill Wilson's disease patients. Beyond this, TM has antiangiogenic effects, because many proangiogenic cytokines require normal levels of copper. This has led to use of TM in cancer, where it is generally effective in animal tumor models, and has shown efficacy in preliminary clinical studies. Most recently, it has been found that TM has antifibrotic and antiinflammatory effects through inhibition of profibrotic and proinflammatory cytokines.     

The Na,K-ATPase of nervous tissue

The Na,K-ATPase has been only partially purified from nervous tissue, yet it is clear that two forms (and +) of the catalytic subunit are present. is a component subunit of the glial Na,K-ATPase, which has a relatively low affinity for binding cardiac glycosides and + has been identified as a subunit of the Na,K-ATPase which has relatively high affinity for cardiac glycosides. The + form may also be sensitive to indirect modulation by neurotransmitters or hormones. The ratio of + / changes in the nervous system during development, and + appears to be the predominant species in adult neurones. Changes in Na,K-ATPase activity have been associated with several abnormalities in the nervous system, including epilepsy and altered nerve conduction velocity, but a causal relationship has not been definitively established. Although the Na,K-ATPase has a pivotal role in Na⁺ and K⁺ transport in the nervous system, a special role for the glial Na,K-ATPase in clearing extracellular K⁺ remains controversial.     

A scaleable and integrated crystallization pipeline applied to mining the Thermotoga maritima proteome

The wealth of genomic data available for many organisms has set the stage for the next phase of structure-function analysis. High-throughput structural genomics is currently the method of choice for rapid analysis of protein structure-function relationships on a proteome-wide basis. The Joint Center for Structural Genomics (JCSG), established in 2000 under the NIH/NIGMS Protein Structure Initiative, has developed and implemented an integrated high-throughput structure pipeline and applied it in a 2-tiered approach to mining the proteome of the thermophilic bacterium Thermotoga maritima. In the first tier, the successful application of this integrated pipeline has resulted in the cloning and expression of 73% of the T. maritima proteome (1376 out of 1877 predicted genes), and has identified 465 proteins which produced crystal hits. These 465 proteins were compared with existing structural information and a subset of 269 targets were selected to process towards structure determination in a second tier effort. To date, the JCSG pipeline applied to the Thermotoga maritima proteome has resulted in 55 new structures and has identified 6 novel folds and continues to identify structures with novel features.     

Fertility and the aging male

In the United States since 1980, the birth rate in women aged > 35 years has increased by nearly 60%, whereas the birth rate for women aged 20 to 34 years has increased by only 10%. The trend in parenthood at an older age has also been seen in men. Since 1980, the fertility rate for men in their 30s has increased by 21% and for men aged 40 years and older, the rate has increased nearly 30%. In contrast, the fertility rate in men younger than age 30 years has decreased by 15%. Age-related infertility will continue to be a problem. A basic understanding of the issues is critical for health care professionals so that they can effectively counsel patients who are considering a delay in childbearing for social reasons or for those seeking fertility treatments. This review details the changes in fertility seen in the aging male.     

Persistence of bacterial pathogens as a physiological phenomenon

The complex ecosystem of humans and microbes has been presented as an associative symbiosis based on a mutual support of symbionts with different consequences for them. Conditions for the persistence of bacteria have been defined: their resistance to environmental factors, antagonism in biocenosis, and stability to withstand host defense mechanisms. The key role of bacterial peptidoglycan has been defined for their survival in an infected organism, and the classification for persistent mechanisms of pathogens has been given. The group of bacterial secreted protease providing microbial resistance to defense factors of the organism has been described. Host colonizing resistance has been presented as a physiological regulatory system controlling bacterial penetration into an organism. Regulatory mechanisms for bacterial persistence have been discussed.     

Use of Ranks in Comparisons of Variability in the Non-Normal Populations

A method of analysis for comparing the variability of two samples drawn from two populations has been developed. The method is also suitable for the nonnumeric form of data. A test based on ordered observations for testing the null hypothesis of equality of two variances has been given. The test statistic is a function of the sum of ranks assigned to smaller size sample. Ranking procedure has been modified to depict the variability in the data by the sum of ranks. The null distribution of the test-statistic has been worked out for small samples and it turns out to be chi-square distribution for large samples. The analytical procedure has been explained by a numerical example on the productivity and production of rice and wheat in India from 1950–51 to 1983–84.     

RNA interference for analysis of gene function in trypanosomatids

Gene-specific silencing by RNA interference is a valuable tool for analysis of gene function in the protozoan parasite Trypanosoma brucei. The development of tetracycline-regulated vectors for production of double-stranded RNA has facilitated its widespread use. RNA interference provides a fast and efficient method for determining whether a gene is essential for growth and viability, reveals mechanistic information on gene function, and has greatly enhanced our understanding of complex biological processes. Finally, the creation of an RNA interference-based library has allowed, for the first time, an approach for conducting forward genetic experiments in this organism.     

Chemical modification of enzymes for enhanced functionality.

The explosion in commercial and synthetic applications of enzymes has stimulated much of the interest in enhancing enzyme functionality and stability. Covalent chemical modification, the original method available for altering protein properties, has now re-emerged as a powerful complementary approach to site-directed mutagenesis and directed evolution for tailoring proteins and enzymes. Glutaraldehyde crosslinking of enzyme crystals and polyethylene glycol (PEG) modification of enzyme surface amino groups are practical methods to enhance biocatalyst stability. Whereas crosslinking of enzyme crystals generates easily recoverable insoluble biocatalysts, PEGylation increases solubility in organic solvents. Chemical modification has been exploited for the incorporation of cofactors onto protein templates and for atom replacement in order to generate new functionality, such as the conversion of a hydrolase into a peroxidase. Despite the breadth of applicability of chemically modified enzymes, a difficulty that has previously impeded their implementation is the lack of chemo- or regio-specificity of chemical modifications, which can yield heterogeneous and irreproducible product mixtures. This challenge has recently been addressed by the introduction of a unique position for modification by a site-directed mutation that can subsequently be chemically modified to introduce an unnatural amino acid sidechain in a highly chemo- and regio-specific manner.     

Titanocene anticancer complexes and their binding mode of action to human serum albumin: a computational study

Due to the pivotal role played by human serum albumin (HSA) in the transport and cytotoxicity of titanocene complexes, a docking study has been performed on a selected set of titanocene complexes to aid in the current understanding of the potential mode of action of these titanocenes upon binding HSA. Analysis of the docking results has revealed potential binding at the known drug binding sites in HSA and has provided some explanation for the specificity and subsequent cytotoxicity of these titanocenes. Additionally, a new alternative binding site for these titanocenes has been postulated.     

Dynein: An ancient motor protein involved in multiple modes of transport

Cytoplasmic dynein has long been thought to be responsible for retrograde axonal transport. As the number of cellular roles for this multifunctional protein has expanded, the complexity of its contribution to axonal transport has increased. In this article the increasing evidence for a role for cytoplasmic dynein in anterograde as well as retrograde transport is discussed. The current status of the complex dynein cargo-binding mechanism is evaluated. Finally, recent genetic evidence supporting a role in axonal transport and revealing a role in neurodegenerative conditions is reviewed.     

WNT Signaling: an Emerging Mediator of Cancer Cell Metabolism?

WNT signaling was discovered in tumor models and has been recognized as a regulator of cancer development and progression for over 3 decades. Recent work has highlighted a critical role for WNT signaling in the metabolic homeostasis of mammals, where its misregulation has been heavily implicated in diabetes. While the majority of WNT metabolism research has focused on nontransformed tissues, the role of WNT in cancer metabolism remains underinvestigated. Cancer is also a metabolic disease where oncogenic signaling pathways regulate energy production and macromolecular synthesis to fuel rapidly proliferating tumors. This review highlights the emerging evidence for WNT signaling in the reprogramming of cancer cell metabolism and examines the role of these signaling pathways as mediators of tumor bioenergetics.     

线粒体控制区在鱼类种内遗传分化中的意义

线粒体DNA（mtDNA）作为分子标记已被广泛应用于各物种系统发生的研究。mtDNA控制区序列（D-Loop）以其较高的突变积累对于研究物种种内的遗传分化具有重要价值。鱼类是脊椎动物中最原始但在种属数量上又最占优势的类群,其物种繁多,分布广泛,起源复杂,研究其系统发生历来是令人饶有兴趣的课题。D-Loop在研究鱼类种内遗传分化中具有多方面的重要意义。近年来,已有越来越多的研究工作将D-Loop作为分子标记来探讨各种鱼类的种内遗传分化,并且获得了许多有启发性的结果。青海湖是我国内陆最大的咸水湖,湖中主要鱼类为青海湖裸鲤（Gymnocypris przewalskii）,D-Loop分析初步结果显示青海湖及其周围河流中的裸鲤似乎没有新的种内遗传分化现象。      

Diffuse alveolar damage syndrome associated with amiodarone therapy.

Amiodarone is an effective antiarrhythmic that has been used in Europe for over a decade and has been available for investigational use in North America for a shorter time. It has several well recognized side effects. Recent reports have related pulmonary disorders to the use of this drug; fibrosing alveolitis has been found by lung biopsy. Amiodarone''s toxicity to the lung does not appear to be dose-related. Besides cessation of amiodarone administration, management of this complication includes steroid therapy. A case is described of nonspecific diffuse alveolar damage syndrome in a patient who had received amiodarone.