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PubMed2001

Structure of CD40 ligand in complex with the Fab fragment of a neutralizing humanized antibody.

BACKGROUND: CD40 ligand (CD40L or CD154), a member of the tumor necrosis factor (TNF) family, plays a critical role in both humoral and cellular immune responses and has been implicated in biological pathways involving epithelial cells, fibroblasts, and platelets. Such a pathway is T cell-mediated B cell activation, a process that occurs through the interaction of CD40L with CD40 receptor expressed on B cells. It results in various B cell responses, including immunoglobulin isotype switching and B cell differentiation and proliferation. These responses can be inhibited by the monoclonal antibody 5c8, which binds with high affinity to CD40L. RESULTS: To understand the structural basis of the inhibition, we determined the crystal structure of the complex of the extracellular domain of CD40L and the Fab fragment of humanized 5c8 antibody. The structure shows that the complex has the shape of a three-bladed propeller with three Fab fragments bound symmetrically to a CD40L homotrimer. To further study the nature of the antibody-antigen interface, we assessed the ability of 23 site-directed mutants of CD40L to bind to 5c8 and CD40 and analyzed the results in the context of the crystal structure. Finally, we observed via confocal microscopy that 5c8 binding to CD40L on the cell surface results in the formation of patches of clustered complexes. CONCLUSIONS: The structure reveals that 5c8 neutralizes CD40L function by sterically blocking CD40 binding. The antigenic epitope is localized in a region of the surface that is likely to be structurally perturbed as a result of genetic mutations that cause hyper-IgM syndrome. The symmetric trimeric arrangement of the Fab fragments in the complex results in a geometry that facilitates the formation of large clusters of complexes on the cell surface.

Amino Acid Sequence↗

PubMed1998

Small-molecule-based strategies for controlling gene expression.

A central goal in chemical biology is to gain control over biological pathways using small molecules, and the mRNA-synthesizing machinery is a particular important target. New advances in our understanding of transcriptional regulation suggests strategies to manipulate these pathways using small molecules.

Animals↗

PubMed2003

Mouse models as tools for dissecting disorders of lipoprotein metabolism.

The overexpression of proteins as transgenes or by adenovirus-mediated gene transfer as well as the disruption of genes by homologous DNA recombination in the mouse provide powerful tools to dissect the role of individual proteins in complex biological pathways. These and similar techniques have been widely used to characterize the function of most of the players involved in lipoprotein metabolism. These models are expected to greatly advance the finding of new therapeutic strategies for the treatment of disorders of lipoprotein metabolism.

Animals↗

PubMedDate not supplied

Genetics of primary generalized osteoarthritis.

Osteoarthritis (OA) is a common joint disease with complex etiology, including biomechanical, biochemical, and genetic components. The genetics of primary idiopathic OA is likely complex as multiple susceptibility loci have been identified from genome-wide scans. The future lies in finer mapping of these chromosomal regions, association studies, and candidate gene analysis and identification, which should collectively give rise to an improved understanding of the genetic mutations and biological pathways which increase the risk of developing this common joint disorder.

Chromosome Mapping↗

PubMed2002

[Target-volume selection and delineation in the cervico-maxillo-facial region: beyond the concepts of the ICRU].

Improvement in irradiation techniques, which allows dose distributions sculpting around volumes of very complex shapes, has revealed the limitations in selection and delineation of target volumes. The use of functional imaging (PET, fMRI) in addition to anatomic imaging, will probably bring an extra level of complexity to this issue. In particular, the use of specific markers to visualize biological pathways known to influence response to ionizing radiation (e.g. hypoxia, proliferation) could lead to the delineation of sub-target volumes for delivering an extra boost dose. Such concept of Image-Guided Radiation Therapy still need to be tested in experimental models and in well defined clinical situations before its use in a routine clinical set-up.

Head and Neck Neoplasms↗

PubMed2001

Recent developments in computational proteomics.

The mapping of the human genome was completed earlier this year and efforts are underway to understand the role of gene products (i.e. proteins) in biological pathways and human disease and to exploit their functional roles to derive protein therapeutics and protein-based drugs. A key component to the next revolution in the 'post-genomic' era will be the increasingly widespread use of protein structure in rational experimental design. Improvements in quality, availability and utility of large-scale three- and four-dimensional protein structural information are enabling a revolution in rational design, having particular impact on drug discovery and optimization. New computational methodologies now yield modeled structures that are, in many cases, quantitatively comparable with crystal structures, at a fraction of the cost.

Journal Article↗

PubMed2005

Foundation Review: Transgenic animals and their impact on the drug discovery industry.

The ability to direct genetic changes at the molecular level has resulted in a revolution in biology. Nowhere has this been more apparent than in the production of transgenic animals. Transgenic technology lies at the junction of several enabling techniques in such diverse fields as embryology, cell biology and molecular genetics. A host of techniques have been used to effect change in gene expression and develop new pharmaceutical and nutraceutical compounds cost-effectively. Scientific advances gained by transgenic capabilities enable further understanding of basic biological pathways and yield insights into how changes in fundamental processes can perturb programmed development or culminate in disease pathogenesis.

Animals↗

PubMed2003

Genetics of osteoarthritis and potential for drug development.

Genome-wide linkage scans for the mapping of osteoarthritis susceptibility loci have come to the fore in recent years, driven by the failure of candidate gene association studies. Four scans have been published, with several strong linkages reported. These do not encompass the major cartilage structural genes that many consider the most likely susceptibility loci. This has increased the probability that the biological pathways responsible for susceptibility are modifiable by drug treatment, which one would not reasonably expect for a structural protein. This in itself has stimulated the interest of several pharmaceutical companies. Such interest will be to the benefit of patients, but will require candid co-operation between academics and industry if the delay in transferring research findings from the laboratory to the clinic is to be minimised.

Drug Delivery Systems↗

PubMed2005

The age-dependent relation of blood pressure to cognitive function and dementia.

The relation of blood pressure with cognitive function and dementia has, in recent years, received much attention from epidemiological research. Some cross-sectional studies have shown an inverse association between blood pressure and the prevalence of dementia and Alzheimer's disease, whereas longitudinal studies yield mixed results that largely depend on the age at which blood pressure is measured and the time interval between blood pressure and outcome assessments. Some studies suggest that midlife high blood pressure is a risk factor for late-life cognitive impairment and dementia, and that low diastolic pressure and very high systolic pressure in older adults may be associated with subsequent development of dementia and Alzheimer's disease. Observational studies and randomised clinical trials provide limited evidence for a protective effect of antihypertensive therapy against dementia and stroke-related cognitive decline. Atherosclerosis resulting from long-standing hypertension, and cerebral hypoperfusion secondary to severe atherosclerosis and to low blood pressure may be major biological pathways linking both high blood pressure in midlife and low blood pressure in late-life to cognitive decline and dementia.

Aged↗

PubMedDate not supplied

A life course perspective: understanding food choices in time, social location, and history.

A life course perspective provides a framework for understanding how food choices develop in changing temporal, social, and historical contexts. This article describes the application of life course concepts to food choices, including trajectories, transitions, turning points, lives in place and time, and timing of events in lives. A life course approach to food choice can contribute to understanding the social and biological pathways of health risk and resilience over the life span. Life course analysis is a useful research and practice tool because of the many ways in which foods, the individuals choosing them, and food choice environments are changing.

Choice Behavior↗

PubMed2003

Effects of gender, anthropometric variables, and aging on the evolution of hip strength in men and women aged over 65.

Although gender differences in fall rates may partly explain the higher prevalence of fractures in elderly women than men, male bones may also be intrinsically stronger or suffer less structural degradation with age than those of women. We used hip structural analysis (HSA) to study gender differences in hip geometry and bone mineral density (BMD) as they evolved over time in elderly white men and women with the aim of identifying candidate biological pathways leading to heightened risk of hip fracture. We recruited 443 women and 439 men aged 67-79 years from a diet and cancer prospective population-based cohort study to a study of hip bone loss. Hip BMD was measured on two occasions 2-5 years apart by dual-energy X-ray absorptiometry and HSA software used to derive BMD and structural parameters at the narrow neck (NN), the intertrochanter (IT), and the shaft (S) regions. Structural indices calculated in each region were cross-sectional area (CSA)-amount of bone surface area in the cross section after excluding soft tissue space; section modulus (Z)-an index of bending resistance, subperiosteal width, endocortical width, cortical thickness; and cortical buckling ratio (CBR)-a measure of cortical instability. Compared to men, women had lower values of BMD, CSA, Z, subperiosteal width, endocortical width, and cortical thickness in all regions, except S endocortical width, after adjusting for weight, height, and age (P < 0.0001). CBR was higher in women than in men (P < 0.0001) in all regions. Longitudinal analysis of rates of change revealed faster rates of BMD decline in women than in men at the Hologic total hip, Hologic femoral neck, and IT regions (P < 0.029). Women had faster rates of subperiosteal and endosteal expansion than men at the NN (P < 0.011) and IT (P < 0.049) and faster increase in Z at the NN (P = 0.029). At the IT region, cortical thinning was faster in women than in men (P = 0.037) and CBR increased at a faster rate in women (P = 0.011). In conclusion, Z is lower in women than in men and expansion of the proximal femur occurs in both sexes, being faster in women than in men. Z does not decline at the same rate as BMD, implying that part of the effect of aging on BMD is due to expansion of the bony envelope without loss of bone mineral content. Faster expansion in the female femoral neck may in turn lead to greater fragility if wider diameter and thinner cortices become locally unstable.

Age Distribution↗

PubMed2006

Social networks and inflammatory markers in the Framingham Heart Study.

Lack of social integration predicts coronary heart disease mortality in prospective studies; however, the biological pathways that may be responsible are poorly understood. The specific aims of this study were to examine whether social networks are associated with serum concentrations of the inflammatory markers interleukin-6 (IL-6), C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1) and monocyte chemoattractant protein-1 (MCP-1). Participants in the Framingham Study attending examinations from 1998 to 2001 (n=3267) were eligible for inclusion in the study. Social networks were assessed using the Berkman-Syme Social Network Index (SNI). Concentrations of IL-6, CRP, sICAM-1 and MCP-1 were measured in fasting serum samples. Multivariable linear regression analyses were used to assess the association of social networks with inflammatory markers adjusting for potential confounders including age, smoking, blood pressure, total:HDL cholesterol ratio, body mass index, lipid-lowering and antihypertensive medication, diabetes, cardiovascular disease, depression and socioeconomic status. Results found that the SNI was significantly inversely associated with IL-6 in men (p=0.03) after adjusting for potential confounders. In age-adjusted analyses, social networks also were significantly inversely associated with IL-6 for women (p=0.03) and were marginally to modestly associated with CRP and sICAM-1 for men (p=0.08 and 0.02, respectively), but these associations were not significant in the multivariate analyses. In conclusion, social networks were found to be inversely associated with interleukin-6 levels in men. The possibility that inflammatory markers may be potential mediators between social integration and coronary heart disease merits further investigation.

Biomarkers↗

PubMed1997

Social network in relation to plasma fibrinogen.

Consistent findings about the inverse association of social network level with coronary heart disease mortality and morbidity suggest the importance of investigating biological pathways of association. Differences in plasma fibrinogen level were investigated among middle-aged men with weak and strong structural and functional social network ties. Men with low scores in the adequacy of social participation variable (structural) had higher mean values of plasma fibrinogen than those with high scores. The difference remained after adjustment for age, smoking and cardiovascular health status and after possible modifying factors were taken into account, but did not remain significant after allowing for physical fitness. Men with high scores in overall support (functional) had higher plasma fibrinogen levels compared to the men with low scores. This difference persisted after age and cardiovascular health status were taken into account but was explained by smoking. The data suggest that smoking and cardiorespiratory fitness are important mediating or modifying factors between structural and functional aspects of social network ties and plasma fibrinogen.

Cardiovascular Diseases↗

PubMed2006

Developmental imaging genetics: challenges and promises for translational research.

Advances in molecular biology, neuroimaging, genetic epidemiology, and developmental psychopathology have provided a unique opportunity to explore the interplay of genes, brain, and behavior within a translational research framework. Herein, we begin by outlining an experimental strategy by which genetic effects on brain function can be explored using neuroimaging, namely, imaging genetics. We next describe some major findings in imaging genetics to highlight the effectiveness of this strategy for delineating biological pathways and mechanisms by which individual differences in brain function emerge and potentially bias behavior and risk for psychiatric illness. We then discuss the importance of applying imaging genetics to the study of psychopathology within a developmental framework. By beginning to move toward a systems-level approach to understanding pathways to behavioral outcomes as they are expressed across development, it is anticipated that we will move closer to understanding the complexities of the specific mechanisms involved in the etiology of psychiatric disease. Despite the numerous challenges that lie ahead, we believe that developmental imaging genetics has potential to yield highly informative results that will ultimately translate into public health benefits. We attempt to set out guidelines and provide exemplars that may help in designing fruitful translational research applications that incorporate a developmental imaging genetics strategy.

Antisocial Personality Disorder↗

PubMedDate not supplied

How does stress affect you? An overview of stress, immunity, depression and disease.

OBJECTIVE: Stress is a term that has become synonymous with modern life. This review aims to appraise the evidence linking stress with disease with particular reference to the major causes of morbidity and mortality in the Western World, cardiovascular disease, cancer, and depression. Changes in immune parameters in stressful situations were reviewed as a possible pathophysiological mechanism for such effects. METHOD: A Medline search was carried out for the period 1996-2000 to identify recent findings in this field using the terms "stress", "disease", "immune system". Relevant references that were found in all identified publications were also followed up. RESULTS: There is evidence to link stress with the onset of major depression and with a poorer prognosis in cardiovascular disease and cancer. Few small studies suggest that stress management strategies may help to improve survival. Chronic stress appears to result in suppression of the immune response, whereas immune activation and suppression have been associated with acute stress. Inflammatory cytokines, soluble mediators of the immune response, can result in symptoms of depression. CONCLUSION: Further prospective epidemiologically based studies are needed to clarify the role of stress on disease onset, course, and prognosis. Stress management strategies, aimed at prolonging survival in patients with cardiovascular disease, cancer, and possibly other chronic illnesses, are an exciting area of further research. Immune system changes may account for the relationship between stress and disease. We propose the "stress, cytokine, depression" model as a biological pathway to explain the link between stressful life events and depression.

Coronary Disease↗

PubMed2000

Vitamin A and causes of maternal mortality: association and biological plausibility.

OBJECTIVE: To review the association between major causes of maternal mortality and vitamin A, trying to determine if these associations are causal in nature, and to highlight possible biological pathways that may explain vitamin A effects. DESIGN: Literature review, observational studies and clinical trials. The strength of association was determined by applying Bradford Hill criteria of causality. RESULTS: In a vitamin A deficient population, vitamin A is essential for adequate treatment of anaemia. While vitamin A does not seem to be capable of preventing uterine atony, obstetric or surgical trauma, which are important causes of haemorrhage, it might be capable of preventing or decreasing coagulopathy. Possible effects on the placenta as regards implantation, site and size are not clear. As regards pregnancy-related infections, vitamin A supplementation can improve wound healing by decreasing fibrosis and increasing transforming growth factor-beta (TFG-beta). It can increase resistance to infection by increasing mucosal integrity, increasing surface immunoglobulin A (sIgA) and enhancing adequate neutrophil function. If infection occurs, vitamin A can act as an immune enhancer, increasing the adequacy of natural killer (NK) cells and increasing antibody production. beta-carotene in its provitamin form can act as an antioxidant by decreasing endothelial cell damage (the pathognomonic feature of pre-eclampsia) and promote the vasodilator effect of nitric oxide that might bring about a better outcome of toxaemia in pregnancy. It is unlikely that vitamin A or beta-carotene has an effect on obstructed labour. CONCLUSIONS: Plausible biomedical pathways can only be constructed for obstetric haemorrhage, anaemia in pregnancy, hypertension in pregnancy and pregnancy-related infections. A 40% reduction in the maternal mortality ratio, as observed in Nepal, is unlikely to be solely explained through the aforementioned pathways.

Anemia↗

PubMed2005

Apparatus for preparing mimics of suspended particles in the troposphere and their controlled deposition onto individual lung cells in culture with measurement of downstream biological response.

Inhalation exposure to particles <10 microm in size that are suspended in the troposphere (PM10) is a factor in respiratory and cardiovascular diseases. The extent of the injury, local to systemic inflammation, is dependent on the number, size, and composition of the particles to which an individual is exposed. The physical properties of and compounds on PM10 that are responsible for these adverse effects on human health are the subject of intense investigation. Here, we report a laboratory method that involved the creation of 1-120 particles per trial that were of known size and composition, followed by deposition of them directly onto individual human lung cells within a cell culture, and after an incubation period, a downstream biological response was measured. To illustrate this methodology, particles that each contained 50 pg of lipopolysaccharide were created and deposited onto individual cells over a region <0.36 mm2 within a genetically modified A549 cell culture. The biological readout was the relative expression of intercellular cell adhesion molecule 1 after 24 h of incubation using an immunocytochemistry assay. The apparatus and methodology introduced here enables studies at the interface between the relevant but diverse areas of atmospheric particle chemistry and lung cell biology to identify the chemical and physical factors of PM10 that cause/exacerbate respiratory and cardiovascular diseases by triggering various biological pathways.

Atmosphere↗

PubMed2007

The alpha helix of ubiquitin interacts with yeast cyclin-dependent kinase subunit CKS1.

Ubiquitin serves as a molecular zipcode to direct and sort ubiquitinylated proteins into distinct biological pathways. Although novel modes of ubiquitin interaction have recently been characterized, conventional ubiquitin-binding domains (UBDs) recognize ubiquitin through a hydrophobic pocket centered around isoleucine 44 and lined by residues in beta sheets 3 and 4. In this study, we report a novel mode of interaction between ubiquitin and the cyclin-dependent kinase subunit of Saccharomyces cerevisiae, Cks1p, an adaptor protein involved in transcriptional regulation through recruitment of proteasomal subunits to gene promoters. Cks1p interacts specifically with monoubiquitin and tetraubiquitin with an affinity several orders of magnitude greater than that of other ubiquitin-binding domains and in an unconventional fashion, which differs from interactions documented so far between ubiquitin and conventional UBDs. The loop between helices alpha 1 and alpha 2, and to a minor extent the N-terminal alpha-helix of Cks1p, are involved in the interaction with the alpha-helix of ubiquitin, instead of its I44-centered hydrophobic pocket. Not only is this the first time the alpha-helix of ubiquitin is implicated in a protein/protein interaction, thereby shedding new light on the mechanisms of ubiquitin recognition, but also the first report of a direct physical interaction between ubiquitin and Cks1p, inferring a role for ubiquitin binding in the transcriptional function of Cks1p.

Adaptor Proteins, Signal Transducing↗