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PubMed2003

A need for a 'whole-istic functional genomics' approach in complex human diseases: arthritis.

'Genomic tools', such as gene/protein chips, single nucleotide polymorphism and haplotype analyses, are empowering us to generate staggering amounts of correlative data, from human/animal genetics and from normal and disease-affected tissues obtained from complex diseases such as arthritis. These tools are transforming molecular biology into a 'data rich' science, with subjects with an '-omic' suffix. These disciplines have to converge and integrate at a systemic level to examine the structure and dynamics of cellular and organismal function ('functionomics') simultaneously, using a multidimensional approach for cells, tissues, organs, rodents and Zebra fish models, which intertwines various approaches and readouts to study the development and homeostasis of a system. In summary, the postgenomic era of functionomics will facilitate narrowing the bridge between correlative data and causative data, thus integrating 'intercoms' of interacting and interdependent disciplines and forming a unified whole.

Arthritis↗

PubMed2001

Lamins in disease: why do ubiquitously expressed nuclear envelope proteins give rise to tissue-specific disease phenotypes?

The nuclear lamina is a filamentous structure composed of lamins that supports the inner nuclear membrane. Several integral membrane proteins including emerin, LBR, LAP1 and LAP2 bind to nuclear lamins in vitro and can influence lamin function and dynamics in vivo. Results from various studies suggest that lamins function in DNA replication and nuclear envelope assembly and determine the size and shape of the nuclear envelope. In addition, lamins also bind chromatin and certain DNA sequences, and might influence chromosome position. Recent evidence has revealed that mutations in A-type lamins give rise to a range of rare, but dominant, genetic disorders, including Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy with conduction-system disease and Dunnigan-type familial partial lipodystrophy. An examination of how lamins A/C, emerin and other integral membrane proteins interact at the INM provides the basis for a novel model for how mutations that promote disease phenotypes are likely to influence these interactions and therefore cause cellular pathology through a combination of weakness of the lamina or altered gene expression.

Animals↗

PubMed2000

Altered body image: managing social encounters.

For terminally ill people who are still active within the community, altered body image can pose significant problems. Patients may have an obvious change in appearance or function, but be unsure how to present a positive image to others. Moreover, lay supporters are often equally unsure how to react to the changed appearance of the dying person. Changes in physical appearance and function associated with disease processes (and sometimes treatment) need to be integrated into the interaction that occurs between patients and lay carers. This is likely to be a difficult matter to facilitate, taxing the ingenuity of the palliative care nurse who hopes to assist the patient in this regard. This article uses a case study from the community-based palliative care setting to introduce steps that nurses and patients might consider as the patient sets out to manage such social encounters.

Body Image↗

PubMed1993

Regulation of the acute phase response by cytokines.

Cytokines appear to function as part of a complex regulatory network, a signaling language in which informational content resides in the combinations, and perhaps sequence, of cytokines and other extracellular messenger molecules received by a cell. The effects of combinations of cytokines are complex and often differ from their in vitro effects or when administered by themselves. (From this perspective, to use a somewhat crude simile, individual cytokines can be thought of as words which bear informational content. Although individual cytokines may, on occasion, communicate a complete message, more commonly the actual messages received by cells probably resemble sentences, in which it is the combination and sequence of words which convey information.) Currently available data suggest an in vivo scenario in the acute phase response in which the hepatocyte receives a complex mixture of humoral or paracrine signals which are integrated by multiple interacting post-receptor and gene regulatory mechanisms to cause finely regulated changes in plasma protein synthesis. Regulation often occurs by transcriptional control, but post-transcriptional mechanisms, including translational regulation, may participate. Both the extracellular and intracellular mechanisms that mediate the response of the hepatocyte to inflammatory stimuli appear to be highly complex and involve multiple overlapping, concurrent, and parallel pathways. Enough is known at present to conclude that IL-6 is a major participant in these changes in man. Regulation of non-hepatocyte acute phase phenomena has not been delineated as thoroughly, but clearly involves a number of cytokines.

Acute-Phase Reaction↗

PubMed2002

Rab3D: a regulator of exocytosis in non-neuronal cells.

Rab3D, a small Ras-like GTPase, is a key regulator of intracellular vesicle transport during exocytosis. It has been shown that Rab3 GTPases are abundant in cells with regulated secretory pathways and are thought to confer the specificity of docking and fusion during regulated exocytosis. Unlike other Rab3 isoforms, Rab3D is enriched in a number of non-neuronal tissues and is localised to secretory granules in the cytoplasm of these cells. The structure of Rab3D exhibits all of the conserved domains from the Rab family and also contains hypervariable N- and C-terminal regions. Rab3D undergoes post-translational isoprenylation and cycles between GDP- and GTP-bound forms. Apart from the factors involved in the Rab activation cycle, few Rab3D effector proteins have been identified to date. Nevertheless, it has long been suggested that Rab3D plays a role in regulated exocytotic processes as well as apically directed transcytosis. This review summarises the recent work on the biological function, structural integrity and molecular interactions of Rab3D in non-neuronal cells.

Amino Acid Sequence↗

PubMed2004

Linguistic styles and complementarities in analyzing character.

This paper discusses and illustrates some technical implications of D. Liberman's contributions to character analysis. Psychoanalysis is an extended conversation, and character structure is expressed linguistically as part of an interactive linguistic field. Liberman's notions of linguistic styles and communicative interaction define a unique analytic surface from which to examine the syntactic, semantic and pragmatic aspects of character. The presence of a rigid and defensive linguistic style reflects resistance and communicative impasse within the transference and countertransference matrix. A fully interactive communicative experience integrates all aspects of the conversation and allows both participants to take part in a shared semantic field, the precondition to the generation of new meanings. Liberman suggests responding to miscommunication by means of a methodical linguistic attitude. Various such complementary responses are explored through several vignettes, with a particular focus on the interplay of the epic and narrative modes.

Character↗

PubMed2003

Evaluation of risks related to the use of adeno-associated virus-based vectors.

Recombinant AAV efficacy has been demonstrated in numerous gene therapy preclinical studies. As this vector is increasingly applied to human clinical trials, it is a priority to evaluate the risks of its use for workers involved in research and clinical trials as well as for the patients and their descendants. At high multiplicity of infection, wild-type AAV integrates into human chromosome 19 in approximately 60% of latently infected cell lines. However, it has been recently demonstrated that only approximately 1 out of 1000 infectious units can integrate. The mechanism of this site-specific integration involves AAV Rep proteins which are absent in vectors. Accordingly, recombinant AAV (rAAV) do not integrate site-specifically. Random integration of vector sequences has been demonstrated in established cell lines but only in some cases and at low frequency in primary cultures and in vivo. In contrast, episomal concatemers predominate.Therefore, the risks of insertional mutagenesis and activation of oncogenes are considered low. Biodistribution studies in non-human primates after intramuscular, intrabronchial, hepatic artery and subretinal administration showed low and transient levels of vector DNA in body fluids and distal organs. Analysis of patients body fluids revealed rAAV sequences in urine, saliva and serum at short-term. Transient shedding into the semen has been observed after delivery to the hepatic artery. However, motile germ cells seemed refractory to rAAV infection even when directly exposed to the viral particles, suggesting that the risk of insertion of new genetic material into the germ line is absent or extremely low. Risks related to viral capsid-induced inflammation also seem to be absent since immune response is restricted to generation of antibodies. In contrast, transgene products can elicit both cellular and humoral immune responses, depending on the nature of the expressed protein and of the route of vector administration. Finally, a correlation between early abortion as well as male infertility and the presence of wt AAV DNA in the genital tract has been suggested. Although no causal relationship has been established, this issue stresses the importance of using rAAV stocks devoid of contaminating replication-competent AAV. This review comprehensively examines virus integration, biodistribution, immune interactions, and other safety concerns regarding the wild-type AAV and recombinant AAV vectors.

Animals↗

PubMed1993

Aminoacylation of RNA minihelices: implications for tRNA synthetase structural design and evolution.

The genetic code is based on the aminoacylation of tRNA with amino acids catalyzed by the aminoacyl-tRNA synthetases. The synthetases are constructed from discrete domains and all synthetases possess a core catalytic domain that catalyzes amino acid activation, binds the acceptor stem of tRNA, and transfers the amino acid to tRNA. Fused to the core domain are additional domains that mediate RNA interactions distal to the acceptor stem. Several synthetases catalyze the aminoacylation of RNA oligonucleotide substrates that recreate only the tRNA acceptor stems. In one case, a relatively small catalytic domain catalyzes the aminoacylation of these substrates independent of the rest of the protein. Thus, the active site domain may represent a primordial synthetase in which polypeptide insertions that mediate RNA acceptor stem interactions are tightly integrated with determinants for aminoacyl adenylate synthesis. The relationship between nucleotide sequences in small RNA oligonucleotides and the specific amino acids that are attached to these oligonucleotides could constitute a second genetic code.

Amino Acid Sequence↗

PubMedDate not supplied

Biochemical approaches to examine the specificity of interactions between receptors and guanine nuclotide binding proteins.

It is now appreciated both that G-protein-linked receptors and signal transducing heterotrimeric G-proteins consist of large multi-member superfamilies and that regulation of a signal transduction cascade can be produced by a variety of means following activation of a G-protein by a receptor. To begin to unravel the complexities of this regulation it is clearly important to be able to define the molecular identity of the G-protein or G-proteins activated by a receptor and to assess the quantitative importance of such interactions for the integration of signals produced by a receptor agonist. Substantial progress has been made towards these goals in recent years and the purpose of this short review will be to discuss the use and potential limitations of some of the currently most widely used approaches.

Animals↗

PubMed2026

Systematic common and rare variant association testing in 392,030 whole genomes in All of Us.

Large-scale genome-wide association studies (GWAS) and rare variant association studies (RVAS) from population biobanks provide valuable resources for gene discovery in complex human traits. We present an analysis of the All of Us Research Program v8 release, which includes whole genome sequencing data and harmonized phenotypic information of 392,030 participants after quality control, enabling a unified investigation of rare and common variants across a spectrum of human traits and diseases. We build an extensive phenome- and genome-wide ("All by All") computational framework to perform GWAS and RVAS on 3,602 phenotypes and identify 49,863 approximately independent, high-quality single-variant and gene-level associations. Meta-analyses of All of Us and UK Biobank, with sample sizes as large as 786,871 participants, further enhance statistical power and find 193 pLoF gene-phenotype associations that are not significant in either cohort alone, including 22 associations not highlighted by previous studies. We also present a public interactive browser that integrates association results for common and rare variants to facilitate interpretation and rapid querying of summary statistics, along with supporting documentation, and a Featured Workspace in the All of Us Researcher Workbench. Our framework will apply to iterative data releases as All of Us grows, empowering researchers worldwide to uncover insights into the functional effects of genetic components on complex traits and diseases.

Journal Article↗

PubMed2000

HIV-1 gp120- and gp160-induced apoptosis in cultured endothelial cells is mediated by caspases.

The immune dysfunction and cell destruction that occur in the human immunodeficiency virus (HIV)-infected host appear to result from the direct cytopathic effects of viral infection and the effects of viral proteins on uninfected bystander cells. Recently, the alpha-chemokine receptor CXCR4 has been reported to mediate apoptosis in neuronal cells and in CD4(+) and CD8(+) T cells after its binding to HIV-1 envelope proteins. In the current study, it was observed that human umbilical vein endothelial cells (HUVEC) undergo apoptosis after their treatment with the HIV-1 envelope proteins gp120/160. Anti-CXCR4 monoclonal antibody decreased HIV-1 gp120/160-induced apoptosis, suggesting that the CXCR4 chemokine receptor mediates the apoptotic effects of these HIV envelope glycoproteins. Further studies revealed that caspases play an important role in this process because the pretreatment of cells with a general caspase enzyme inhibitor decreased the extent of HUVEC apoptosis induced by gp120/160. In addition, it was found that caspase-3 was activated on HIV-1 gp120/160 treatment of these cells. It was also observed that gp120/160 treatment slightly increased the expression of the pro-apoptotic molecule Bax. These results suggest that HIV-1 envelope glycoproteins can disrupt endothelial integrity through the interaction with CXCR4, thereby facilitating virus transit out of the bloodstream and contributing to the vascular injury syndromes seen in acquired immunodeficiency syndrome. (Blood. 2000;96:1438-1442)

Apoptosis↗

PubMed2000

The French Virtual Medical University.

This paper is the description of a French Virtual Medical University based on the federation of existing or currently being developed resources in several Medical Schools in France. The objectives of the project is not only to share experiences across the country but also to integrate several resources using the New Information and Communication Technologies to support new pedagogical approaches for medical students and also for continuing medical education. The project includes: A virtual Medical Campus using secure access from several sites, The Integration of new interactive resources based on pedagogical methods, Implementation of new indexing and search engines based on medical vocabularies and ontologies, The definition of general and specific portals, the evaluation of the system for ergonomics and contents.

Computer-Assisted Instruction↗

PubMed2001

Do patient assessments of primary care differ by patient ethnicity?

OBJECTIVE: To determine if patient assessments (reports and ratings) of primary care differ by patient ethnicity. DATA SOURCES/STUDY DESIGN: A self-administered patient survey of 6,092 Massachusetts employees measured seven defining characteristics of primary care: (1) access (financial, organizational); (2) continuity (longitudinal, visit based); (3) comprehensiveness (knowledge of patient, preventive counseling); (4) integration; (5) clinical interaction (communication, thoroughness of physical examinations); (6) interpersonal treatment; and (7) trust. The study employed a cross-sectional observational design. PRINCIPAL FINDINGS: Asians had the lowest primary care performance assessments of any ethnic group after adjustment for socioeconomic and other factors. For example, compared to whites, Asians had lower scores for communication (69 vs. 79, p = .001) and comprehensive knowledge of patient (56 vs. 48, p = .002), African Americans and Latinos had less access to care, and African Americans had less longitudinal continuity than whites. CONCLUSIONS: We do not know what accounts for the observed differences in patient assessments of primary care. The fact that patient reports as well as the more subjective ratings of care differed by ethnicity suggests that quality differences might exist that need to be addressed.

Adult↗

PubMed2002

"A system biology" approach to bioinformatics and functional genomics in complex human diseases: arthritis.

Human and other annotated genome sequences have facilitated generation of vast amounts of correlative data, from human/animal genetics, normal and disease-affected tissues from complex diseases such as arthritis using gene/protein chips and SNP analysis. These data sets include genes/proteins whose functions are partially known at the cellular level or may be completely unknown (e.g. ESTs). Thus, genomic research has transformed molecular biology from "data poor" to "data rich" science, allowing further division into subpopulations of subcellular fractions, which are often given an "-omic" suffix. These disciplines have to converge at a systemic level to examine the structure and dynamics of cellular and organismal function. The challenge of characterizing ESTs linked to complex diseases is like interpreting sharp images on a blurred background and therefore requires a multidimensional screen for functional genomics ("functionomics") in tissues, mice and zebra fish model, which intertwines various approaches and readouts to study development and homeostasis of a system. In summary, the post-genomic era of functionomics will facilitate to narrow the bridge between correlative data and causative data by quaint hypothesis-driven research using a system approach integrating "intercoms" of interacting and interdependent disciplines forming a unified whole as described in this review for Arthritis.

Animals↗

PubMed2002

[The medico-surgical department of vascular disease].

The Department of Vascular Diseases can be defined as a multidisciplinary integrated clinical entity involving internists and surgeons interested in patient care, education and research in the field of arterial, venous and lymphatic diseases. Because of the increasing medical complexity with the proliferation of treatment options available, the combined expertise of specialists from different training background is required to provide the optimal patient management. The truly integrated entity with interactions on daily basis between internists and surgeons also provides opportunities for improvement in the training of fellows in vascular medicine. Basic and clinical research is focused on thrombosis and atherosclerosis. The main topics that have been developed include: the pathophysiology of thrombosis, atherogenesis and the diagnosis and treatment of venous thromboembolic disease. The successful development of our Department demonstrates that the combined expertise of internists and surgeons has resulted in marked improvement in the efficiency of patient management.

Belgium↗

PubMed2003

Stressful neighborhoods and depression: a prospective study of the impact of neighborhood disorder.

Quantitative and qualitative research suggests that urban disadvantaged environments may be highly stressful to their inhabitants. Social disorganization may be deleterious to both physical and mental health. The relationships among perceptions of one's neighborhood, measures of social support and social integration, and level of subsequent depressive symptoms was examined with a community sample of 818 individuals screened for an HIV prevention intervention, most of whom were current or former drug users. After adjusting for baseline levels of depressive symptoms, perceptions of neighborhood characteristics (vandalism, litter or trash, vacant housing, teenagers hanging out, burglary, drug selling, and robbery) predicted depressive symptoms at a 9-month follow-up interview. Measures of social support and social integration, entered as interactions with neighborhood perceptions, did not buffer the effect of neighborhood perceptions. However, CES-D scores at follow-up for frequent church attendees were lower. The data support theories of social disorganization and social stress and suggest the need for structural intervention.

Adult↗

PubMed1992

Receptor-mediated internalization of bradykinin. DDT1 MF-2 smooth muscle cells process internalized bradykinin via multiple degradative pathways.

This study was undertaken to evaluate the role of internalization in the action of the peptide autacoid bradykinin (BK). At 4 degrees C [3H]BK binds to an apparently single class of B2 kinin receptors on DDT1 MF-2 smooth muscle cells (C. M. Munoz, S. Cotecchia, and L. M. F. Leeb-Lundberg, manuscript submitted). At this temperature the [3H]BK binding was confined exclusively to the cell surface. On the other hand, at 37 degrees C the B2 receptor-specific cell surface [3H]BK binding was rapidly followed by a receptor-specific internalization of [3H]BK (t1/2 approximately 9 min). The internalization reached a steady-state level after 30-40 min that was 80-100% of the level of specifically bound [3H]BK on the cell surface at 4 degrees C, and this level was maintained for greater than or equal to 2 h. Internalized [3H]BK was routed via at least two intracellular degradative pathways which were distinguished primarily based on subcellular localization but also on a small but significant difference in the rate of [3H]BK degradation. One pathway was localized in a plasma membrane-enriched fraction and had a relatively high degradative capacity. Another pathway was localized in a microsomal fraction and had a relatively low degradative capacity. The internalized [3H]BK activity was rapidly released into the media (t1/2 approximately 24 min). Following a single round of internalization, the released activity consisted almost exclusively of small [3H]BK fragments (less than [3H]BK(1-5)). In contrast, at steady-state [3H]BK represented 30-40% of the released activity. While chloroquine (100 microM) did not alter the rate of [3H]BK internalization or release or the intracellular distribution of [3H]BK, this agent significantly decreased the rate of [3H]BK degradation in both pathways. In all, these results show that B2 kinin receptor-mediated internalization of BK is a process integral to the interaction of BK with DDT1 MF-2 smooth muscle cells and may be a mechanism for terminating BK actions by rapidly removing extracellular free and receptor-bound BK and accessing various intracellular BK degradative pathways.

Amino Acid Sequence↗

PubMed2004

Intermittent exposure to bright light in field conditions.

The Interactive Neurobehavioral Model integrates Kronauer's and Jewett's latest mathematical model of the resetting effect of light on the human circadian pacemaker. This model is based on several lines of experimental evidence and considers the endogenous circadian pacemaker as a complex oscillatory system that responds dynamically to the resetting effect of light. This model can help us understand the results of an experiment using intermittent bright light exposure in the workplace environment. Intermittent exposure to bright light was effectively used as part of an intervention to promote circadian re-entrainment of a group of nurses to their permanent night work schedule. Regular exposure to lower light levels and darkness also provided a significant phase delay of endogenous circadian rhythms, although the adaptation was incomplete in this group of workers. These last results are consistent with the intensity-dependent component of the model. The development of better tools to measure retinal exposure to light throughout the 24-h day is required to adequately test modeling predictions under field conditions.

Acclimatization↗