Mechanism of crystal growth for the enzyme chymotrypsinogen.
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Birefringence↗
Biomedical subjects
J A Hamilton
Publications and source records attributed to J A Hamilton.
Effect of the age of the rat at the time of hemicastration on the weight, estimated secretory activity and delta-5-3-beta-hydroxysteroid dehydrogenase activity of the remaining ovary.
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Aging↗
The ionization behavior of fatty acids and bile acids in micelles and membranes.
The ionization behavior of carboxylic acids including aliphatic chain fatty acids and bile acids in solutions, micelles, membranes and proteins is of considerable biological interest. The 13C nuclear magnetic resonance chemical shift of carboxyl carbon of a variety of acids has been shown to be a linear function of the state of ionization of the carboxyl group. Thus, by measuring the chemical shift as a function of the amount of acid or base added to a solution, the state of ionization and the apparent pKa of the carboxyl group may be determined. The method is illustrated in this paper using butyric acid, and results (given as apparent pKa values) are tabulated for a variety of fatty acids and cholic acid in different environments such as monomeric solutions, micelles, membranes and bound to albumin. The apparent pKa varies greatly depending upon the environment. For instance, the apparent pKa of oleic acid is about 4.2 when bound to albumin whereas it is about 7.5 when incorporated in the bilayer of a phospholipid vesicle. Cholic acid shows similar changes in the apparent pKa, being approximately 5.2 in sodium taurocholate micelles and at least 6.8 in phospholipid vesicles. The use of 13C nuclear magnetic resonance (NMR) and, in particular, 13C NMR of 13C-enriched carboxyl groups provides a method for direct observation of the state of ionization of the carboxyl group in biologically interesting acids. Such techniques may be adapted for use in biological systems, such as cells or tissues.
Albumins↗
Direct effects of fatty acids and other charged lipids on ion channel activity in smooth muscle cells.
A variety of fatty acids increase the activity of certain types of K+ channels. This effect is not dependent on the three enzymatic pathways that convert arachidonic acid to various bioactive oxygenated metabolites. One type of K+ channel in toad stomach smooth muscle cell membranes in activated by fatty acids and other single chain lipids which possess both a negatively charged head group and a sufficiently hydrophobic acyl chain. Neutral lipids have no effect on K+ channel activity, while positively charged lipids with a sufficiently hydrophobic acyl chain suppress channel activity. Acyl Coenzyme A's, which do not flip across the bilayer, act only from the cytosolic surface of the membrane, suggesting that the binding site for channel activation is also located there. This fatty acid-activated channel is also activated by membrane stretch. Moreover, this mechanical response is either mediated or modulated by fatty acids. Thus, fatty acids and other charged single chain lipids may comprise another class of first or second messenger molecules that target ion channels.
Acyl Coenzyme A↗
Transport of fatty acids across membranes by the diffusion mechanism.
In early research on fatty acid transport, passive diffusion seemed to provide an adequate explanation for movement of fatty acids through the membrane bilayer. This simple hypothesis was later challenged by the discovery of several proteins that appeared to be membrane-related fatty acid transporters. In addition, some biophysical studies suggested that fatty acids moved slowly through the simple model membranes (phospholipid bilayers), which would provide a rationale for protein-assisted transport. Furthermore, it was difficult to rationalize how fatty acids could diffuse passively across the bilayer as anions. Newer studies have shown that fatty acids are present in membranes in the un-ionized as well as the ionized form, and that the un-ionized form can cross a protein-free phospholipid bilayer quickly. This flip-flop mechanism has been validated in cells by intracellular pH measurements. The role of putative fatty acid transport proteins remains to be clarified.
Animals↗
How fatty acids bind to proteins: the inside story from protein structures.
The interactions of fatty acids with proteins have been probed with a great variety of techniques and strategies. Many approaches have substituted covalently labeled fatty acids or structurally related molecules. Information from such studies ultimately requires validation by studies with natural fatty acids. However, even the best conventional approaches with natural fatty acids generally have revealed only limited aspects of fatty acid-protein interactions. In contrast, recent crystallographic and NMR studies of several proteins with bound fatty acids provide complete three-dimensional structures with molecular details of these interactions. This presentation reviews three examples of proteins that are indirectly or directly involved in cell signaling: a protein in the plasma compartment (human serum albumin); a protein family in the cytosolic compartment of mammalian cells (fatty-acid-binding proteins), and a nuclear protein (peroxisome proliferator-activated receptor): it also discusses the structures of these proteins and their binding pocket(s), compares their specific modes of interactions with fatty acids, and discusses established and potential roles of fatty acid-protein interactions in cell signaling.
Animals↗
Measurement of blood flow and vascular permeability changes in response to 12-O-tetradecanoyl-phorbol-13-acetate and to asbestos fibers.
The hyperemia (increased blood flow) and vascular permeability changes induced in rabbit skin by the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate and by asbestos fibers have been quantitated. The resultant hyperemia, measured with radiolabeled microspheres, was inhibited in both cases by steroidal and nonsteroidal anti-inflammatory drugs. Since the inflammatory responses resulting from exposure to these agents might be important for the subsequent development of neoplasms, it is proposed that such a specific and quantitative technique be used to analyze the components of these inflammatory responses in more detail.
Administration, Topical↗
Using daily ratings to confirm premenstrual syndrome/late luteal phase dysphoric disorder. Part I. Effects of demand characteristics and expectations.
Daily symptom ratings were evaluated in 31 women who met DSM III-R criteria for a diagnosis of Late Luteal Phase Dysphoric Disorder (LLPDD), and 34 women who reported no premenstrual symptomatology. Women in both groups were randomly assigned to be aware or unaware of the menstrual cycle focus of the study. Results revealed a consistent pattern of cyclic effects, with higher ratings in the mid-luteal, premenstrual and menstrual phases for many symptoms. Ratings of women reporting severe symptoms were not affected by knowing the purpose of the study and were higher than ratings in the asymptomatic group for many symptoms relevant to the LLPDD diagnosis. Awareness of the study focus did increase cyclicity in the ratings of asymptomatic women aware of the study focus compared with those who were unaware, but these differences were small and most were not significant. The implications of these findings for research and clinical diagnosis of PMS/LLPDD are discussed.
Adaptation, Psychological↗
Using daily ratings to confirm premenstrual syndrome/late luteal phase dysphoric disorder. Part II. What makes a "real" difference?
Five degree of change criteria used in previous research to confirm premenstrual syndrome/late luteal phase dysphoric disorder (PMS/LLPDD) based on daily ratings were examined to determine how well each differentiated between women claiming to experience severe symptoms and women with normal menstrual experience. Frequency and nature of stressful events and subjective perceptions of impairment were also examined. Ratings were evaluated in 31 women who met DSM III-R criteria for a provisional diagnosis of LLPDD, and 34 women who reported no premenstrual symptomatology. Ratings for a sample of women taking oral contraceptives and a sample of men were also included for comparison purposes. Results indicated no differences between the groups in the frequency of stressful events. However, the PMS/LLPDD group rated their problems as more disturbing and evidenced a cyclical pattern in the occurrence of negative interpersonal interactions at work that was suggestive of some impaired functioning. None of the five change criteria differentiated the PMS/LLPDD group from the normally cycling No PMS group, and only one differentiated this group from the oral contraceptive No PMS group. This was true whether a liberal or conservative standard of confirmation was applied. The implications of these findings for using daily ratings to confirm PMS/LLPDD are discussed.
Circadian Rhythm↗
Brain uptake and utilization of fatty acids: recommendations for future research.
A primary goal of the international workshop "Brain Uptake and Utilization of Fatty Acids" was to identify research areas that would benefit from further investigation. The major themes for future research are presented below: (1) Elucidating the role of the developing and mature cerebrovascular endothelium (CVE) in the uptake of fatty acids (FA) into the brain. (2) Clarifying the role of diffusion and receptor-mediated uptake of FAs by various brain cell membranes and protein-mediated shuttling of FAs between the CVE and various brain cells and tissues. (3) Illuminating the mechanisms of intermediate metabolism and the roles of polyunsaturated fatty acids (PUFA) in astrocytes, neurons and oligodendrocytes. Of special interest are the long-chain omega-3 PUFA and their derivatives, such as lipoproteins, phospholipids and plasmalogens, that have been associated with various disease states (such as those listed in [5], below). (4) Elucidating the role of gene expression on long-chain omega-3 PUFA incorporation in membranes and the regulatory role these and other PUFA have on gene expression in the brain. (5) Elucidating the recently identified roles of long-chain omega-3 PUFA in mood disorders, schizophrenia, stroke, peroxisomal biogenesis disorders, Huntington's disease, other neurodegenerative disorders and disorders of oxidative stress. (6) Undertaking placebo-controlled clinical trials to assess the therapeutic potential of omega-3 PUFA in the above disorders. (7) Developing new, and utilizing existing animal models in the above studies. (8) Developing noninvasive imaging and tagging methods for quantifying the migration and distribution of PUFA and their derivatives in the brain. (9) Applying multi-disciplinary collaborations among biophysicists, physiologists and molecular biologists to the resolution of the above.
Animals↗
Brain uptake and utilization of fatty acids: applications to peroxisomal biogenesis diseases.
The brain is rich in diverse fatty acids saturated, monounsaturated and polyunsaturated fatty acids with chain lengths ranging from less than 16 to more than 24 carbons that make up the complex lipids present in this organ. While some fatty acids are derived from endogenous synthesis, others must come from exogenous sources. The mechanism(s) by which fatty acids enter cells has been the subject of much debate. While some investigators argue for a protein-mediated process, others suggest that simple diffusion is sufficient. In the brain, uptake is further complicated by the presence of the blood-brain barrier. Brain fatty acid homeostasis is disturbed in many human disorders, as typified by the peroxisomal biogenesis diseases. A workshop designed to bring together researchers from varied backgrounds to discuss these issues in an open forum was held in March, 2000. In addition to assessing the current state of knowledge, areas requiring additional investigation were identified and recommendations for future research were made. A brief overview of the invited talks is presented here.
Animals↗
Fatty acid transport: the diffusion mechanism in model and biological membranes.
The transport of fatty acids (FA) across membranes can be described by three fundamental steps: adsorption, transmembrane movement, and desorption. In model membranes, these steps are all rapid and spontaneous for most fatty acids, suggesting that FA can enter cells by free diffusion rather than by protein-mediated mechanisms. Here we present new fluorescence approaches that measure adsorption and transmembrane movement of FA independently. We show that FA adsorb to the plasma membrane of adipocytes and diffuse through the membrane by the flip-flop mechanism within the time resolution of our measurements (approximately 5 s). Thus we show that passive diffusion is a viable mechanism, although we did not evaluate its exclusivity. Important implications of the diffusion mechanism for neural cells are that all types of FA could be available and that selectivity is controlled by metabolism. Studies of FA uptake into brain endothelial cells and other brain cell types need to be performed to determine mechanisms of uptake, and metabolism of FA must be separated in order to understand the role of membrane transport in the overall uptake process.
Adipocytes↗
Plasminogen activator activity of rheumatoid and nonrheumatoid synovial fibroblasts.
Extracellular and cell associated plasminogen activator (PA) activities were measured in a series of synovial fibroblast cell lines, derived by outgrowth and passage from both rheumatoid and nonrheumatoid tissue. In early passages of these cell lines under standardized culture conditions, the enzyme activity was low for most lines but relatively high in a few. There was no significant difference in the PA levels of the cell lines from either source. In addition, cells from both groups increased their PA activity in response to conditioned medium from peripheral blood mononuclear cells. It is concluded that the presence of fibrin-like material in rheumatoid joints cannot be simply explained by a relative defect in PA production by cells obtained after outgrowth and passage from rheumatoid explant material.
Adult↗
Including women in clinical trials: how about the women scientists?
What happens when women scientists are excluded from designing and conducting research? This paper discusses the importance of recruiting and retaining women as scientists. It explores the impact on science of discrimination, harassment, and retaliation against women scientists. The paper presents case examples suggesting that when women scientists' careers are stymied, research that could be beneficial to women may be devalued, delayed, or derailed.
Humans↗