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PubMed2003

Neuroendocrine differentiation in prostatic carcinoma.

Knowledge and understanding of the pathophysiology of prostate cancer remain rudimentary. However, insight into epigenetic events and cellular interactions between cancer cells and the surrounding milieu has recently opened up a broader concept of cancer development. Throughout the entire process of prostate cancer aetiology, progression and metastasis, the microenvironment of the local host tissue is an active participant, and the selective pressure exercised on the malignant cells changes with the tumour-host setting. Thus primary cancers and metastases may respond differently to biomolecules and treatment modalities. Indeed, treatment itself changes the selective pressure, and new cellular capabilities may evolve. In prostate cancer, neuroendocrine differentiation is believed to occur in response to androgen ablation, and neuroendocrine paracrine factors have been shown to stimulate growth of androgen-independent cancer cells. Review of the accumulated knowledge in this field suggests that we need to improve our understanding of neuroendocrine cells and their regulatory products and their influence in the prostate gland. Recent research shows promise however, and no doubt new protocols will soon emerge in the treatment of prostate cancer, based on neuroendocrine hormones and their intracellular pathways.

Androgens↗
PubMed2002

[Qualitative methods in medical research--an ethnographic perspective].

In the social sciences, "method" refers not only to practical techniques of investigation but also to the underlying assumptions regarding how knowledge is generated (epistemology) and to the strategies derived for knowledge accumulation. In order to consider fruitfully the role of qualitative methods in health research, this three-dimensional understanding of method must be kept in mind. Specifically, in order to understand the contribution of ethnography to health research, the foundational epistemological and research strategic assumptions must be clarified. With examples from Norway and other Western countries and from more traditional regions of ethnographic research, the authors discuss how ethnographic research can be carried out and how ethnography might complement other qualitative methodologies as well as epidemiological research.

Anthropology, Cultural↗
PubMed1999

Structural basis of T cell recognition.

Exciting breakthroughs in the last two years have begun to elucidate the structural basis of cellular immune recognition. Crystal structures have been determined for full-length and truncated forms of alpha beta T cell receptor (TCR) heterodimers, both alone and in complex with their peptide-MHC (pMHC) ligands or with anti-TCR antibodies. In addition, a truncated CD8 coreceptor has been visualized with a pMHC. Aided in large part by the substantial body of knowledge accumulated over the last 25 years on antibody structure, a number of general conclusions about TCR structure and its recognition of antigen can already be derived from the relatively few TCR structures that have been determined. Small, but important, variations between TCR and antibody structures bear on their functional differences as well as on their specific antigen recognition requirements. As observed in antibodies, canonical CDR loop structures are already emerging for some of the TCR CDR loops. Highly similar docking orientations of the TCR V alpha domains in the TCR/pMHC complex appear to play a primary role in dictating orientation, but the V beta positions diverge widely. Similar TCR contact positions, but whose exact amino acid content can vary, coupled with relatively poor interface shape complementarity, may explain the flexibility and short half-lives of many TCR interactions with pMHC. Here we summarize the current state of this field, and suggest that the knowledge gap between the three-dimensional structure and the signaling function of the TCR can be bridged through a synthesis of molecular biological and biophysical techniques.

Animals↗
PubMed2005

Design and evaluation of traps for Idiarthron subquadratum (Orthoptera: Tettigoniidae) with farmer participation in coffee plantations in Chiapas, Mexico.

Three new types of traps designed and made by farmers were evaluated for capture of Idiarthron subquadratum Saussure & Pictet. Bag, sack, and fabric traps were compared with previously used bamboo internode traps. A participatory methodology was used involving farmer interviews and workshops to design and make the traps. Farmer participation was useful for obtaining information on perceptions, knowledge, and control activities of I. subquadratum. The bag trap captured a greater number of individuals than the bamboo and fabric traps, but its captures were similar to those of sack trap; captures were similar in bamboo, sack, and fabric traps. When captured individuals were analyzed by stage of development, no significant differences between types of traps were detected for captured adults. The number of individuals captured in the traps showed a similar trend to that counted in nocturnal sampling. A significant positive relationship was detected between numbers of adults captured and the damage of leaves and fruits. Taylor's Power Law indicates that I. subquadratum individuals were more abundant in some traps than in others. With densities greater than five individuals per trap, a smaller number of bag traps was required to estimate the same population compared with the other types of traps. Sampling procedure that used the bag traps had the lowest cost. This study shows that resource-poor coffee, Coffea arabica L., farmers had accumulated knowledge of I. subquadratum based on unpublished data and experience and that they were capable of applying this knowledge to develop an economical and more suitable technology for their conditions.

Agriculture↗
PubMed2004

Thrombopoiesis: new concepts.

Although platelets were already discovered light-microscopically in the 19th century, it became only clear in 1906 that they originate from megakaryocytes. The discovery of thrombopoietin in 1994 facilitated research on the origin of platelets, because this growth factor enabled expansion of megakaryocytes in culture. Thus, cell biological and molecular studies could be undertaken. Knowledge accumulated further by studying mouse models and by unravelling the defect in patients with hereditary thrombocytopenia. How a megakaryocyte originates from a hematopoietic stem cell and how this cell undergoes further maturation and differentiation is a complex process, controlled at different stages by several transcription factor. These transcription factors influence the expression of their own target genes, leading to megakaryocyte maturation and platelet release. One of the transcription factors that is most studied in this regard is GATA1, that forms a transcriptional complex with its cofactor FOG1. Families with hereditary thrombocytopenia have been described due to mutations in the GATA1 gene, and target genes were studied. This broadens our insight in normal megakaryocyte differentiation. The final release of platelets from the megakaryocyte is strongly dependent on the formation of so-called proplatelets. The formation of pseudopodia requires the presence of microtubuli. Beta 1-tubulin is a major part of these microtubuli and plays an important role not only in the genesis of platelets but also in the final discoid form of the platelet. Despite a renewed interest and expanding knowledge in this area, there are more questions than answers at this day.

Blood Platelets↗
PubMed1999

Human longevity: an evolutionary approach.

Humans are unique in having a considerably longer life span post female reproductive age as compared to other primates. It is proposed that transmission of knowledge from grandparents to progeny served as a driving force for extending human longevity. It is suggested that grandparents and grandchildren have evolved adaptive complementary behaviors that fit the educator/pupil roles. Older individuals specifically retain the ability to preserve their knowledge base that allows them to focus on transmitting to children knowledge accumulated over generations. A repair management model of aging is proposed, according to which inhibition of repair in older individuals at times of stress allows to focus resources on the task at hand. Such an adaptation will inevitably accelerate the rate of aging in animals and in humans and will appear as 'programmed aging'. It is further suggested that in humans, older individuals in early societies who are no longer useful could increase their reproductive success by activating this programmed aging mechanism, which would result in channeling resources to progeny. Decreased emotional support and mastery are mortality risk factors in the elderly, supporting this hypothesis of programmed death in humans, and providing a rationale for increasing longevity.

Aged↗
PubMed1999

Novel RNA-binding motif: the KH module.

The KH motif has recently been identified in single or multiple copies in a number of RNA associated proteins. Here we review the current knowledge accumulated about the sequence, structure, and functions of the KH. The multidomain architecture of most of the KH-containing proteins inspired an approach based on the production of peptides spanning the sequence of an isolated KH motif. Correct identification of the minimal length necessary for producing a folded peptide has had a number of important consequences for interpreting functional data. The presence of the KH motifs in fmr1, the protein responsible for the fragile X syndrome, and their possible role in the fmr1 functions are also discussed.

Amino Acid Sequence↗
PubMed1996

Estimating disease risks for individuals with a given family history in different populations with an application to breast cancer.

For many chronic diseases, including most of the common cancers, a family history is known to be a strong independent risk factor. For breast cancer, estimation of risk as a function of family history is considered to provide useful risk assessment for women with a family history of breast cancer. Detailed tables that predict the cumulative risk of breast cancer at specific ages based on various combinations of family history have been constructed for the American white population. Most chronic diseases, however, have a multiple etiology, with multiple genetic and environmental factors. Family history can thus be a result of different susceptibility loci and the aggregation of sporadic cases by chance. Since the relative contribution of the genetic factor may differ in different populations, these tables may not be directly applicable to other populations. We present a method to decompose available estimates of risk based on family history for an arbitrary disease into probabilities for genotype frequency given a particular family history and for disease probabilities by genotype carrier status. These can be reconstructed to obtain risk estimates for different populations. Implicit assumptions are made in the estimation process. These are based on the current state of knowledge and can be updated as further knowledge accumulates.

Adult↗
PubMed2000

Wherefore Art Thou Copper? Structures and Reaction Mechanisms of Organocuprate Clusters in Organic Chemistry.

Organocopper reagents provide the most general synthetic tools in organic chemistry for nucleophilic delivery of hard carbanions to electrophilic carbon centers. A number of structural and mechanistic studies have been reported and have led to a wide variety of mechanistic proposals, some of which might even be contradictory to others. With the recent advent of physical and theoretical methodologies, the accumulated knowledge on organocopper chemistry is being put together into a few major mechanistic principles. This review will summarize first the general structural features of organocopper compounds and the previous mechanistic arguments, and then describe the most recent mechanistic pictures obtained through high-level quantum mechanical calculations for three typical organocuprate reactions, carbocupration, conjugate addition, and S(N)2 alkylation. The unified view on the nucleophilic reactivities of metal organocuprate clusters thus obtained has indicated that organocuprate chemistry represents an intricate example of molecular recognition and supramolecular chemistry, which chemists have long exploited without knowing it. Reasoning about the uniqueness of the copper atom among neighboring metal elements in the periodic table will be presented.

Journal Article↗
PubMed1978

Guidelines for protocol studies in chronic lymphocytic leukemia.

The treatment of any malignant disease requires appropriate criteria for diagnosis of the disease, appropriate methods for study, and techniques for evaluating response to treatment. In the past five years, there have been a number of proposed guidelines for studies in chronic lymphocytic leukemia (CLL). These submitted guidelines represent a further re-evaluation of concepts in CLL, and are currently in use by Cancer and Leukemia Group B for protocol studies. It is clear that revisions will continue to be make as new knowledge accumulates. In the meantime, these are submitted for publication for use by other investigators.

Drug Therapy↗
PubMed2004

Cardiovascular potential of embryonic stem cells.

Initial events involved in the process of heart formation consist of myocardial differentiation as well as development of endothelial and endocardial tissues. As only limited means are allocated to the studying of cardiovascular system development, embryonic stem cells (ESCs) isolated from the inner cell mass (ICM) of developing mice or human blastocysts offer the first step toward the understanding of these complex and intriguing events. ESCs are able to differentiate into a wide range of cell types, including various vascular cells and cardiomyocytes, and their self-renewal capability renders them a unique, homogeneous, and unlimited preliminary population of cells for the investigation of early developmental events of cardiovascular system and lineage commitment. This review summarizes the accumulated knowledge of the cellular and molecular mechanisms involved in the development of the cardiovascular system.

Animals↗
PubMed2006

Highly potent vitamin D receptor antagonists: design, synthesis, and biological evaluation.

Vitamin D receptor (VDR) antagonists have attracted significant levels of interest because of their potential utility in the treatment of Paget's disease, which is known as the most flagrant example of disordered bone remodeling and the second most common bone disease after osteoporosis in Anglo-Saxons. Recent studies on Paget's disease suggested a specific increase in osteoclasts' sensitivity to the differentiation activity of active vitamin D(3) as the principal mechanism for abnormal bone formation. We set out to conduct a structure-activity relationship study on the first VDR antagonists, TEI-9647 and TEI-9648 (25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone), with the goal of improved VDR antagonistic activity. Given that both potent agonists and antagonists must have high affinity for the VDR, we hoped that our accumulated knowledge in the field of VDR agonists would help us identify potent antagonists. First 2alpha-modified TEI-9647 analogues were synthesized, and then 24-substitution to stabilize the lactone structure under physiological conditions was investigated. Finally, 2alpha-modified 24-methyl-, 24,24-dimethyl-, and 24,24-ethano-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone analogues were synthesized. The synthesis of the 24,24-ethano-TEI lactone was accomplished through Ru-catalyzed intermolecular enyne metathesis of the alkynone CD-ring side chain with ethylene to give a dienone, followed by regioselective cyclopropanation. It was found that 2alpha,24,24-trimethyl-TEI-9647 (39) possessed an antagonistic activity (IC(50)=0.093 nM) approximately 90 times that of the original TEI-9647 (IC(50)=8.3 nM).

Binding Sites↗
PubMed2005

Consistent organization of glomeruli in the antennal lobes of related species of heliothine moths.

The glomeruli of the antennal lobes in insects reflect the organization of the olfactory system, which is important for species-specific behaviors in response to insect- and plant-produced odorants. We studied the antennal lobes of the polyphagous moth Helicoverpa armigera and the oligophagous H. assulta (Heliothinae; Lepidoptera; Noctuidae) in order to see whether there are any anatomical differences that might elucidate how information about odorants is analyzed. Three-dimensional models of the antennal lobes were made, based on synaptic antibody staining combined with confocal laser scanning microscopy. These showed 65 glomeruli in each sex of H. armigera and 66 glomeruli in females of H. assulta. Sixty-two of the glomeruli were identified in both sexes and species and were given the same numbers. The sex-specific glomeruli included three macroglomerular units in H. armigera males, as well as three and four female-specific glomeruli in H. armigera and H. assulta, respectively. The species specificity of H. assulta females also appeared by the particular large size of two ordinary glomeruli. The accumulating knowledge on how biologically relevant information is encoded in receptor and antennal lobe neurons in heliothines makes these moths particularly interesting for studying the functional organization of the glomeruli. The anatomical atlases of the antennal lobes, as presented here, are prerequisites for identifying glomeruli ascribed to particular functions across sexes and species.

Anatomy, Artistic↗
PubMed2007

Huddling by rat pups: ontogeny of individual and group behavior.

A full account of behavioral development in rats must include the ontogeny of both individual and group behavior. Most of our accumulated knowledge, however, pertains to individual ontogenesis. Group behavior and its development are readily seen in the huddling behavior of rat pups. A rat huddle is an entity with characteristics and capabilities distinct from those of the individuals that comprise it. The huddle is a natural context for acquiring olfactory preferences for species odors. Olfactory learning in a huddle involves thermal and tactile stimulation from the mother's body but, surprisingly, not the rewards of suckling or of milk transfer. Although there is complete developmental continuity of huddling behavior, the sensory controls of huddling change dramatically during the first 2 weeks of postnatal life. Huddling behavior is initially controlled by thermal cues ("physiological huddling") and then becomes dominated by olfactory stimuli ("filial huddling"). The complex group behavior of huddling was modeled successfully with computational methods. Group behavior emerges from individual interactions, guided entirely by rules of individual behavior (no rules for group behavior). Three simple rules of autonomous activity/inactivity can spawn the patterns of aggregon formation displayed by groups of 7-day-old pups, but not by 10-day-olds. The developmental change evident by Day 10 requires adding a rule by which each individual is affected by the activity state of adjacent pups. Group behavior responded to manipulations of central oxytocin on Day 10, but not on Day 7.

Animals↗
PubMed2003

Miniaturization in carbohydrate analysis.

Recent progress of microchip electrophoresis (ME) of carbohydrates is overviewed. Carbohydrate analysis by ME encounters difficulties such as lack of electric charge and deficiency of a chromophore/fluorophore in analyte molecules, however, it benefits from the accumulated knowledge of capillary electrophoresis (CE) and rapid separation of simple sugars also by ME, with high column efficiency comparable to CE, has become possible. Analysis at high pH, with electrochemical detection, is a promising approach because carbohydrates can be ionized by weak dissociation of the hydroxyl groups and the in situ formed ionic species can be effectively separated by the zone electrophoresis mode. The separated species can be sensitively monitored by electrochemical detection on a gold or copper electrode. Ionization as borate complexes and refractometric detection is also possible, though sensitivity is lower. Introduction of UV-absorbing or fluorescent tags is potentially useful but the time-consuming derivatization processes sacrifice the rapidity of ME. Examples of ME of carbohydrates as 1-phenyl-3-methyl-5-pyrazolone (PMP; for simple mono- and oligosaccharides with UV detection), 8-aminopyrene-1,3,6-trisulfonate (APTS; for oligosaccharides ladders with LIF detection), and 4-nitro-2,1,3-benzoxadiazole (NBD-F; for amino sugars and aminoalditols with LIF detection) derivatives are presented, with details of the analytical conditions. Since ME in a short separation channel enables rapid analysis within 1 min, it presents an ideal tool for clinical analysis, as shown in a few papers reporting protocols for specific blood glucose assay. Finally, the usefulness of microfluidic reactors and microarrays for enzyme-assisted carbohydrate analysis as well as glycan profiling is pointed out.

Carbohydrates↗
PubMed2001

A comparison of normal and leukemic stem cell biology in Chronic Myeloid Leukemia.

Chronic Myeloid Leukemia (CML), a myeloproliferative disease of stem cell origin, is characterized by the presence of the Philadelphia (Ph) chromosome and the bcr-abl oncogene. The BCR-ABL fusion gene product, thought to be causative in CML, has multiple effects on diverse cell functions such as growth, differentiation and turnover as well as adhesion and apoptosis. Persistent Ph-negative progenitors co-exist with leukemic cells, both in the marrow and blood of patients, in the early chronic phase of the disease. Despite accumulating knowledge of hemopoiesis and the disease process, CML remains incurable with conventional chemotherapy. Nonetheless, with the efficacy of the ABL tyrosine kinase inhibitor STI-571 (signal transduction inhibitor 571) as a novel therapy in CML recently being realized in clinical trials, it is therefore timely to review our current understanding of the cell biology of this fascinating disease.

Animals↗
PubMed1994

Sleep and circadian rhythms in space.

This paper presents a detailed critical review of the knowledge accumulated in the last three decades concerning research on sleep, work-rest schedules, and circadian rhythms in space. The focus of the paper is preceded by a brief review of the basic principles of the human circadian system and the physiology of the sleep-wake cycle, relevant to understanding the problem of astronaut work-rest scheduling. Much of what is known is based on anecdotal reports, mission log books, and debriefing of astronauts after flights. The broad literature reviewed, which includes studies from American and Soviet space missions, as well as some studies conducted under simulated weightlessness, offers just a handful of objective studies on the physiology of sleep and circadian rhythms in space. Nevertheless, the data are remarkably consistent, and indicate that sleep can be of reasonably good quality in space. The risk of sleep loss and associated performance degradation appears to be a manageable one. However, one clear conclusion arises from this review: whatever the type of mission of flight plan, its success will depend on whether the principles of circadian and sleep-wake regulation have been taken into account during the planning phase of work-rest schedules. That is, satisfactory sleep and alertness is more likely to occur if crews maintain a reasonable (i.e., constant) relation with their normal terrestrial rhythm. This is not as easy a task as it may appear; indeed, unexpected, high-intensity operational demands have been the major cause of acute problems of sleep loss and performance degradation in space. Moreover, the growing complexity of space missions indicate that emergencies will never disappear. Therefore, one of the most important research challenges for future space missions is the development of strategies that could permit astronauts to function closest to maximal efficiency during intensive and prolonged work. Countermeasures for optimizing astronaut performance, as well as other factors affecting sleep and performance in space, are reviewed and discussed in detail in this paper.

Circadian Rhythm↗
PubMed2003

Endothelial cell functions.

Endothelial cells play a wide variety of critical roles in the control of vascular function. Indeed, since the early 1980s, the accumulating knowledge of the endothelial cell structure as well as of the functional properties of the endothelial cells shifted their role from a passive membrane or barrier to a complex tissue with complex functions adaptable to needs specific in time and location. Hence, it participates to all aspects of the vascular homeostasis but also to physiological or pathological processes like thrombosis, inflammation, or vascular wall remodeling. Some of the most important endothelial functions will be described in the following review and more specifically, their role in blood vessel formation, in coagulation and fibribolysis, in the regulation of vascular tone as well as their participation in inflammatory reactions and in tumor neoangiogenesis.

Animals↗