Understanding circadian rhythmicity in Neurospora crassa: from behavior to genes and back again

Circadian clocks have been described in organisms ranging in complexity from unicells to mammals, in which they function to control daily rhythms in cellular activities and behavior. The significance of a detailed understanding of the clock can be appreciated by its ubiquity and its established involvement in human physiology, including endocrine function, sleep/wake cycles, psychiatric illness, and drug tolerances and effectiveness. Because the clock in all organisms is assembled within the cell and clock mechanisms are evolutionarily conserved, simple eukaryotes provide appropriate experimental systems for dissecting the clock. Significant progress has been made in deciphering the circadian system in Neurospora crassa using both genetic and molecular approaches, and Neurospora has contributed greatly to our understanding of (1) the feedback cycle that comprises a circadian oscillator, (2) the mechanisms by which the clock is kept in synchrony with the environment, and (3) the genes that reside in rhythmic output pathways. Importantly, the lessons learned in Neurospora are relevant to our understanding of clocks in higher eukaryotes.     

The olfactory circuit of the fruit fly Drosophila melanogaster

The olfactory circuit of the fruit fly Drosophila melanogaster has emerged in recent years as an excellent paradigm for studying the principles and mechanisms of information processing in neuronal circuits. We discuss here the organizational principles of the olfactory circuit that make it an attractive model for experimental manipulations, the lessons that have been learned, and future challenges.     

Lessons learned from Art Pardee in cell cycle, science, and life

This essay is written to honor Dr Art Pardee's 85th birthday (July 13, 2006). In this essay, I have summarized the lessons I learned from Art and the cell-cycle research I performed in Art's laboratory during my postdoctoral training period. I have also summarized some research from my own laboratory that has been inspired by the lessons I learned from Art, including the interactions between cell cycle and cell death regulators and discovery of novel polyphenol- and copper-based proteasome inhibitors. Finally, I have discussed the potential use of these proteasome inhibitors in cancer prevention and treatment.     

New approaches to the therapy of demyelinating disease.

The pace of research on the pathogenesis and treatment of multiple sclerosis, the principal human demyelinating disease of the central nervous system, has intensified in the past 3 years, due in part, to the application of advances in molecular and cellular immunology. Many lessons that have been learned in an animal model of central nervous system demyelinating disease, experimental allergic encephalomyelitis, also apply to multiple sclerosis and certain successful approaches for the treatment of this disease are now being attempted in humans.     

Towards a molecular therapy for glycogen storage disease type II (Pompe disease)

Glycogen storage disease type II (GSD-II), also known as Pompe disease, is a fatal genetic muscle disorder caused by a deficiency of acid alpha-glucosidase, a glycogen-degrading lysosomal enzyme. Currently, there is no treatment for this fatal disorder. However, several lines of research suggest the possibility of future treatment. Enzyme replacement strategies hold the greatest hope for patients currently affected by GSD-II, but future strategies could include in vivo or ex vivo gene therapy approaches and/or mesenchymal stem cell or bone-marrow transplantation approaches. Each of the approaches might eventually be combined to further improve the overall clinical efficacy of any one treatment regimen. The lessons learned from GSD-II research will also benefit a great number of individuals affected by other genetic disorders.     

A review of malaria vaccine clinical projects based on the WHO rainbow table

Development and Phase 3 testing of the most advanced malaria vaccine, RTS,S/AS01, indicates that malaria vaccine R&D is moving into a new phase. Field trials of several research malaria vaccines have also confirmed that it is possible to impact the host-parasite relationship through vaccine-induced immune responses to multiple antigenic targets using different platforms. Other approaches have been appropriately tested but turned out to be disappointing after clinical evaluation. As the malaria community considers the potential role of a first-generation malaria vaccine in malaria control efforts, it is an apposite time to carefully document terminated and ongoing malaria vaccine research projects so that lessons learned can be applied to increase the chances of success for second-generation malaria vaccines over the next 10 years. The most comprehensive resource of malaria vaccine projects is a spreadsheet compiled by WHO thanks to the input from funding agencies, sponsors and investigators worldwide. This spreadsheet, available from WHO's website, is known as "the rainbow table". By summarizing the published and some unpublished information available for each project on the rainbow table, the most comprehensive review of malaria vaccine projects to be published in the last several years is provided below.     

Lessons from microRNA mutants in worms,flies and mice

It is apparent that microRNAs (miRNAs) are important components in the regulation of genetic networks in many biological contexts. Based on computational analysis, typical miRNAs are inferred to have tens to hundreds of conserved targets. Many miRNA-target interactions have been validated by various means, including heterologous tests in cultured cells and gain-of-function approaches that can yield striking phenotypes in whole animals. However, these strategies do not report on the endogenous importance of such miRNA activities. Likewise, studies of miRNA pathway mutants can suggest an endogenous role for miRNAs in a given setting, but do not identify roles for specific miRNAs. Therefore, these approaches must be complemented with the analysis of miRNA mutant alleles. In this review, we describe some of the lessons learned from studying miRNA gene deletions in worms, flies and mice, and discuss their implications for the control of endogenous regulatory networks.     

Proteome analysis of host-pathogen interactions: Investigation of pathogen responses to the host cell environment

Infectious diseases are still a major health risk, and thus a better understanding of the interaction between human host cells and pathogenic microbes is urgently required. Since the interplay between both partners is highly complex, genome-wide analysis by OMICs approaches will likely make a major contribution to the elucidation of the pathophysiology of infection processes. In the concert of OMICs technologies, proteomics is particularly important because it reveals changes in the active players of the cell and has thus a close relationship to the phenotypic changes observed. While proteomic studies of in vitro-grown microbial pathogens are routinely established in many labs, in vivo proteomic approaches are still rare. Here, we will review the challenges and recent developments of proteomic analysis of microbial pathogens derived from cell culture or in vivo infection settings and summarize some lessons that have been learned from these studies.     

Taking account of fish welfare: lessons from aquaculture

This paper explores the possibility that lessons learned from aquaculture might contribute to current debate on welfare and fisheries. After looking briefly at the history of research interest in the welfare of farmed fishes, some implications of using different definitions of and approaches to the concept of welfare are discussed. Consideration is given to the way in which the aquaculture industry has responded to public concern about fish welfare and, for cases where these responses have been effective, why this might be the case. Finally, possible cross‐over points between aquaculture and fisheries in the context of fish welfare, as well as experience and expertise that might be shared between these two areas, are identified.     

VEGF inhibition: insights from preclinical and clinical studies

Angiogenesis, the growth of new blood vessels, is required for a variety of normal proliferative processes. Furthermore, angiogenesis is well established as also playing an important role in neoplastic growth and metastasis. Numerous regulators of angiogenesis have been identified and characterized over the last few decades. Among these, vascular endothelial growth factor (VEGF)-A appears especially important in several pathophysiological processes. Several VEGF inhibitors have been approved, by the US Food and Drug Administration, for the treatment of tumors or age-releted macular degeneration. This review examines the various mouse tumor models in which VEGF inhibitors have been tested and the lessons learned from these studies.     

Molecular insights into the evolution of crop plants

The domestication and improvement of crop plants have long fascinated evolutionary biologists, geneticists, and anthropologists. In recent years, the development of increasingly powerful molecular and statistical tools has reinvigorated this now fast-paced field of research. In this paper, we provide an overview of how such tools have been applied to the study of crop evolution. We also highlight lessons that have been learned in light of a few long-standing and interrelated hypotheses concerning the origins of crop plants and the nature of the genetic changes underlying their evolution. We conclude by discussing compelling evolutionary genomic approaches that make possible the efficient and unbiased identification of genes controlling crop-related traits and provide further insight into the actual timing of selection on particular genomic regions.     

Injury biomechanics research: an essential element in the prevention of trauma

The central aspects of injury biomechanics research are defined and research approaches described. These aspects include the identification and definition of impact injury mechanisms, the quantification of biomechanical response to impact, the determination of impact tolerance levels, and the development and use of injury assessment devices and techniques for evaluating injury prevention systems. The current status of knowledge and technology is then reviewed for the head, cervical spine, thorax, abdomen, and lower extremity. Important gaps are identified, and research priorities emphasizing functional impairment are proposed.     

Cervical spine vertebral and facet joint kinematics under whiplash.

Whiplash injuries sustained during a rear-end automobile collision have significant societal impact. The scientific literature on whiplash loading is both diverse and confusing. Definitive studies are lacking to describe the local mechanisms of injury that induce either acute or chronic pain symptoms. A methodology has been presented to quantify the kinematics of the cervical spine components by inducing controlled whiplash-type forces to intact human head-neck complexes. The localized facet joint kinematics and the overall segmental motions of the cervical spine are presented. It is anticipated that the use of this methodology will assist in a better delineation of the localized mechanisms of injury leading to whiplash pain.     

Ribonucleotide reductases: radical chemistry and inhibition at the active site

Ribonucleoside 5'-diphosphate reductases (RDPRs) have been studied for several decades. Increasingly sophisticated mechanisms have been proposed for the reduction of natural substrate ribonucleotides to their 2'-deoxy counterparts and for mechanism-based inactivation of RDPRs with 2'-substituted-ribonucleotides. We now discuss biomimetic reactions of model substrate and inhibitor analogues, which clarify three aspects of previously proposed mechanisms postulated to occur at the active site of RDPRs.     

The pathogenesis of radiation injury in complex tissues: an overview of problems and probes

The evaluation of radiation injury in complex organs has tended to lag behind comparable areas of investigative interest. This observation is somewhat surprising in view of the increased use of radiotherapy as a primary or adjuvant mode of therapy for malignant disease. In part, this problem appears to relate to the difficulty of identifying and quantifying the morphologic consequences of radiation injury in complex organs, in which the various component tissues exhibit a broad spectrum of radiosensitivities. Two approaches have been employed to address this problem: (1) utilization of sophisticated probes to evaluate the functional and morphologic sequelae of radiation injury and (2) segmentation of complex tissues into their component parts, which are then evaluated individually. Both approaches are illustrated in the papers presented in this issue. The purpose of this overview is to call attention to some of the attendant difficulties of the former approach, as seen in an ongoing investigative program concerned with radiation injury of the kidney.     

Trials and tribulations of immunotherapy as a treatment option for patients with squamous cell carcinoma of the head and neck

Head and neck squamous cell carcinoma (HNSCC) is an aggressive epithelial malignancy that is the sixth most common neoplasm in the world. Despite numerous advances in treatments involving surgery, radiation, and chemotherapy, the 5-year survival has remained at less than 50% for the last 30 years primarily due to local recurrences [66]. Consequently, the possibility of developing immunotherapeutic approaches as a treatment for HNSCC has gained interest. The present review has 3 objectives pertaining to immunotherapeutic means to treat HNSCC patients: (1) to summarize the feasibility of such approaches, (2) to provide an overview of the obstacles to attaining protective immune reactivity, and (3) to consider how these obstacles can be overcome to stimulate immune reactivity to HNSCC. These objectives will also be considered in the context of what lessons have been learned from immunotherapeutic trials for other solid malignancies and the applicability of this information to HNSCC.     

Inhibition mechanisms of hematophagous invertebrate compounds acting on the host blood coagulation and platelet aggregation pathways

To facilitate blood feeding, hematophagous invertebrates have evolved a sophisticated array of physiological compounds that counteract homeostatic systems and inflammatory reactions of the vertebrate host. For this reason, hematophagous invertebrates possess a variety of anticoagulation components that are inhibitors of coagulant factors or antagonists of the platelet receptor. The examination of kinetic data and the crystal structure analysis have exposed the inhibition mechanisms for many of these anticoagulant reagents. Here, we attempt to classify the antihemostatic molecules and to focus on the kinetic approaches that have been instrumental in defining these mechanisms.     

National survey of spinal injuries in hockey players.

There has been an alarming increase in the number of spinal injuries in hockey players. Between 1976 and 1983, 42 were reported to the Committee on Prevention of Spinal Injuries due to Hockey. The median age of the injured players was 17 years. Of the 42 players 28 had spinal cord injuries, and 17 of them had complete paralysis below the vertebral level of the injury. Strikes from behind and collisions with the boards were common mechanisms of injury. Many of the players had suffered a burst fracture of the cervical spine following a blow to the top of the helmet when the neck was slightly flexed. The committee studied a number of possible etiologic factors and made several recommendations regarding prevention. League officials, coaches, players and equipment manufacturers can all play a role in prevention.