Nobel laureates' letter to President Bush.
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Embryo Disposition↗
Biomedical subjects
E H Fischer
Publications and source records attributed to E H Fischer.
Characteristics of people lost to attrition in psychiatric follow-up studies.
In a large (N = 1,744) study of previously hospitalized psychiatric patients, multiple follow-up attempts were made to contact the ex-patients over a 1-year period after their discharges. When contacted they were asked to provide information about their posthospital adjustment; 59.5% of the sample was reached at least once and usable data obtained either in a telephone interview or from a mailed survey form. The contacted and noncontacted people represented very different subpopulations, both demographically and in terms of typical psychiatric descriptors. Those who were of lower socioeconomic status, male, unmarried, racial minorities, and those with records of substance abuse or assaultiveness, and who were generally more severely impaired during the baseline hospitalization were underrepresented in the contacted group. Possible reasons for these sample biases, the implications for hospitals conducting outcome assessments (i.e., for research and program evaluation purposes), and strategies for dealing with this kind of methodological problem are discussed.
Adolescent↗
Tyrosine phosphatase SHP-1 immunoreactivity increases in a subset of astrocytes following deafferentation of the chicken auditory brainstem.
Proliferation of astrocytes is a dramatic response of the central nervous system (CNS) to injury and disease. Such proliferation results in the formation of the neural/glial scar and the reconstitution of the glial limitans. However, not all astrocytes enter the proliferative cycle following injury, and for those that do, the period of cell division is limited. Little attention has focused on the events that regulate the duration and extent of astrocyte proliferation following damage, but clearly control mechanisms are in place as CNS injury does not result in the continuous astrocyte proliferation seen in glial tumorigenesis. Protein tyrosine phosphorylation has been implicated in both astrocyte proliferation and differentiation and plays an important role in the regulation of the cell cycle in a number of different systems. We have found a small subset of astrocytes in the chick auditory brainstem that are immunopositive for the protein tyrosine phosphatase SHP-1. SHP-1 appears to negatively regulate cellular division in the hematopoietic system and is involved in the mitogenic response to various growth factors. Following cochlea removal, there is a marked increase within the auditory brainstem nucleus, nucleus magnocellularis (NM), in both in the number of SHP-1-positive astrocytes and the length of their immunopositive fibers. Significantly, those animals showing the greatest increases in SHP-1 immunoreactivity do not exhibit large amounts of astrocyte proliferation. We hypothesize that the expression of SHP-1 plays a role in negatively regulating the mitotic behavior of astrocytes following deafferentation.
Animals↗
Inhibitory sites in enzymes: zinc removal and reactivation by thionein.
Thionein (T) has not been isolated previously from biological material. However, it is generated transiently in situ by removal of zinc from metallothionein under oxidoreductive conditions, particularly in the presence of selenium compounds. T very rapidly activates a group of enzymes in which zinc is bound at an inhibitory site. The reaction is selective, as is apparent from the fact that T does not remove zinc from the catalytic sites of zinc metalloenzymes. T instantaneously reverses the zinc inhibition with a stoichiometry commensurate with its known capacity to bind seven zinc atoms in the form of clusters in metallothionein. The zinc inhibition is much more pronounced than was previously reported, with dissociation constants in the low nanomolar range. Thus, T is an effective, endogenous chelating agent, suggesting the existence of a hitherto unknown and unrecognized biological regulatory system. T removes the metal from an inhibitory zinc-specific enzymatic site with a resultant marked increase of activity. The potential significance of this system is supported by the demonstration of its operations in enzymes involved in glycolysis and signal transduction.
Aldehyde Dehydrogenase↗
Cell signaling by protein tyrosine phosphorylation.
The above data, and others not described herein, indicate the following: First, that phosphatases are not scavenger enzymes, simply there to remove the phosphate groups introduced by the kinases. They cannot be viewed simply as providing an 'off' switch in an 'on/off' kinase/phosphatase system. Kinases and phosphatases do not carry out one-way and opposing reactions. The same enzyme, depending on where it localizes within the cell, or the molecule with which it might interact, can serve either as a positive or negative determinant in defining cell behavior. In many instances, it can act synergistically with the kinases to enhance the phosphorylation reaction. Second, the factors that determine whether a phosphatase would enhance or oppose a kinase reaction would seem to depend less on its state of activity than on its subcellular localization. This would suggest that if one wanted to call upon it to control transformation, one should try to tamper with its localization segments or whatever binding proteins it might be attached to--rather than with its catalytic domains. Displacement of these enzymes from where they are meant to bind would seem a more promising approach than trying to modulate their catalytic activity. Finally, their architectural features are so basically different from those of the kinases, with receptor tyrosine phosphatases displaying all the structural characteristics of cell adhesion molecules, that they must also have a mission of their own in cell development, survival and death, quite apart from that of the kinases.
Animals↗
Recent excitement regarding metallothionein.
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Animals↗
Anxiety and alcohol abuse in patients in treatment for depression.
Anxiety may be an important factor in explaining the prevalence of alcohol abuse among depressive patients. However, it is unclear whether anxiety has effects that are independent of other core symptoms in depression, and whether it is linked to alcoholic problems in both sexes. The present study of hospitalized depressive patients found a strong association between anxiety and alcohol abuse for women, and a weaker association for men. These effects were independent of severity of depression and global pathology. Whereas the correlation appeared to be linear for men, with each higher level of anxiety being associated with more alcohol problems, for women depressives those in a moderate-anxiety subgroup had the most difficulty with alcohol.
Adult↗
Cellular regulation by protein phosphorylation: a historical overview.
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Animals↗
Mitogen-activated protein kinase/extracellular signal-regulated kinase 2 regulates cytoskeletal organization and chemotaxis via catalytic and microtubule-specific interactions.
The extracellular signal-regulated kinases (ERKs) 1 and 2 are mitogen-activated protein kinases that act as key components in a signaling cascade linking growth factor receptors to the cytoskeleton and the nucleus. ERK2 mutants have been used to alter cytoskeletal regulation in Chinese hamster ovary cells without affecting cell growth or feedback signaling. Mutation of the unique loop L6 (residues 91-95), which is in a portion of the molecule that is cryptic upon the binding of ERK2 to the microtubules (MTs), generated significant morphological alterations. Most notable phenotypes were observed after expression of a combined mutant incorporating changes to both L6 and the TEY phosphorylation lip, including a 70% increase in cell spreading. Actin stress fibers in these cells, which normally formed a single broad parallel array, were arranged in three or more orientations or in fan-like arrays. MTs, which ordinarily extend longitudinally from the centrosome, spread radially, covering a larger surface area. Single, but not the double, mutations of the Thr and Tyr residues of the TEY phosphorylation lip caused a ca. 25% increase in cell spreading, accompanied by a threefold increase in chemotactic cell migration. Mutation of Lys-52 triggered a 48% increase in cell spreading but no alteration to chemotaxis. These findings suggest that wild-type ERK2 inhibits the organization of the cytoskeleton, the spreading of the cell, and chemotactic migration. This involves control of the orientation of actin and MTs and the positioning of focal adhesions via regulatory interactions that may occur on the MTs.
Adaptor Proteins, Signal Transducing↗
Measurement of depression and anxiety for hospitalized depressed patients.
Standard scales for measuring anxiety and depression did not distinguish between these two psychological constructs in a sample of 295 inpatients with major depressive disorder. Items from these scales were used to form new measures, based on the results of a factor analysis. The new depression and anxiety subscales were internally consistent and only moderately correlated with one another, compared with the standard measures, which were highly correlated. When the factorial procedure was repeated with a subsample of patients with only mild to moderate symptoms, there was no discrimination between depression and anxiety. This finding suggests that when measured in a sample with a restricted range of symptom severity, anxiety and depression have poor discriminant validity.
Adolescent↗
Assessing outcomes: identifying psychiatric patients with severe and persistent illness.
BACKGROUND: Identification of psychiatric patients with severe and persisting impairments can facilitate treatment, aid in program planning, and provide data for cost-of-care projections. METHODS: In this prospective study of patient outcomes, 1,679 inpatients were classified on admission using a functional status measure developed by the authors. Consenting subjects were reassessed at discharge and at 3, 6, and 12 months postdischarge to determine what proportion of patients classified as low functioning on admission remained so at follow-up. RESULTS: Patients classified as low functioning on admission represented 23.4% of the sample; the proportion that remained low functioning at the follow-ups ranged from 56.1% to 65.2%. Compared to the high functioning group, three times more low functioning patients were rehospitalized within 12 months of discharge (9.4% vs 32%). CONCLUSIONS: Patients with increased risk of persisting disability can be identified on admission using commonly available clinical measures. Of patients with low functioning on admission, more than half will have long-term impairment.
Adolescent↗
Expression and characterization of glycogen synthase kinase-3 mutants and their effect on glycogen synthase activity in intact cells.
In these studies we expressed and characterized wild-type (WT) GSK-3 (glycogen synthase kinase-3) and its mutants, and examined their physiological effect on glycogen synthase activity. The GSK-3 mutants included mutation at serine-9 either to alanine (S9A) or glutamic acid (S9E) and an inactive mutant, K85,86MA. Expression of WT and the various mutants in a cell-free system indicated that S9A and S9E exhibit increased kinase activity as compared with WT. Subsequently, 293 cells were transiently transfected with WT GSK-3 and mutants. Cells expressing the S9A mutant exhibited higher kinase activity (2.6-fold of control cells) as compared with cells expressing WT and S9E (1.8- and 2.0-fold, respectively, of control cells). Combined, these results suggest serine-9 as a key regulatory site of GSK-3 inactivation, and indicate that glutamic acid cannot mimic the function of the phosphorylated residue. The GSK-3-expressing cell system enabled us to examine whether GSK-3 can induce changes in the endogenous glycogen synthase activity. A decrease in glycogen synthase activity (50%) was observed in cells expressing the S9A mutant. Similarly, glycogen synthase activity was suppressed in cells expressing WT and the S9E mutant (20-30%, respectively). These studies indicate that activation of GSK-3 is sufficient to inhibit glycogen synthase in intact cells, and provide evidence supporting a physiological role for GSK-3 in regulating glycogen synthase and glycogen metabolism.
Alanine↗
Activation of mitogen-activated protein (MAP) kinase pathway by pervanadate, a potent inhibitor of tyrosine phosphatases.
Rapid tyrosine phosphorylation of key cellular proteins is a crucial event in signal transduction. The regulatory role of protein-tyrosine phosphatases (PTPs) in this process was explored by studying the effects of a powerful PTP inhibitor, pervanadate, on the activation of the mitogen-activated protein (MAP) kinase cascade. Treatment of HeLa cells with pervanadate resulted in a marked inhibition of PTP activity, accompanied by a drastic increase in tyrosine phosphorylation of cellular proteins. The increased tyrosine phosphorylation coincided with the activation of the MAP kinase cascade as indicated by enzymatic activity assays of MEK (MAP kinase/ERK-kinase) and MAP kinase and gel mobility shift analyses of Raf-1 and MAP kinase. The activation was sustained but reversible. Upon removal of pervanadate, both tyrosine phosphorylation and MAP kinase activation declined to basal levels. Therefore, inhibition of PTP activity is sufficient per se to initiate a complete MAP kinase activation program.
Calcium-Calmodulin-Dependent Protein Kinases↗
Positive effect of overexpressed protein-tyrosine phosphatase PTP1C on mitogen-activated signaling in 293 cells.
PTP1C, an SH2 domain-containing protein-tyrosine phosphatase, is predominantly expressed in hematopoietic cells, in which it negatively regulates cellular signaling. However, this enzyme is also expressed in many non-hematopoietic cells. We demonstrate here that in non-hematopoietic 293 cells, overexpression of a catalytically inactive mutant of PTP1C strongly suppressed the stimulatory effects of the epidermal growth factor or serum on cell proliferation, early gene transcription, and DNA synthesis. Similarly, the phosphorylation of the mitogen-activated protein kinase and mitogen-activated protein kinase kinase activity was markedly inhibited by overexpression of mutant PTP1C. The inhibitory effect of mutant PTP1C was overcome by cotransfection with wild-type PTP1C, but not with the structurally related PTP2C. Furthermore, expression of the mutant phosphatase resulted in hyperphosphorylation on tyrosine of a 95-kDa protein that was co-immunoprecipitated with the mutant, but not with the wild-type protein. These results suggest that, unlike in hematopoietic cells, PTP1C in 293 cells plays a positive role in epidermal growth factor- or serum-activated mitogenesis. Thus, PTP1C participates in multiple signaling pathways, where the enzyme, depending on its target molecules, may function as either a positive or negative mediator.
Cell Division↗
Mammalian SH2-containing protein tyrosine phosphatases.
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Animals↗
CD22 associates with protein tyrosine phosphatase 1C, Syk, and phospholipase C-gamma(1) upon B cell activation.
Cross-linking B cell antigen receptor (BCR) elicits early signal transduction events, including activation of protein tyrosine kinases, phosphorylation of receptor components, activation of phospholipase C-gamma (PLC-gamma), and increases in intracellular free Ca2+. In this article, we report that cross-linking the BCR led to a rapid translocation of cytosolic protein tyrosine phosphatase (PTP) 1C to the particulate fraction, where it became associated with a 140-150-kD tyrosyl-phosphorylated protein. Western blotting analysis identified this 140-150-kD protein to be CD22. The association of PTP-1C with CD22 was mediated by the NH2-terminal Src homology 2 (SH2) domain of PTP-1C. Complexes of either CD22/PTP-1C/Syk/PLC-gamma(1) could be isolated from B cells stimulated by BCR engagement or a mixture of hydrogen peroxidase and sodium orthovanadate, respectively. The binding of PLC-gamma(1) and Syk to tyrosyl-phosphorylated CD22 was mediated by the NH2-terminal SH2 domain of PLC-gamma(1) and the COOH-terminal SH2 domain of Syk, respectively. These observations suggest that tyrosyl-phosphorylated CD22 may downmodulate the activity of this complex by dephosphorylation of CD22, Syk, and/or PLC-gamma(1). Transient expression of CD22 and a null mutant of PTP-1C (PTP-1CM) in COS cells resulted in an increase in tyrosyl phosphorylation of CD22 and its interaction with PTP-1CM. By contrast, CD22 was not tyrosyl phosphorylated or associated with PTP-1CM in the presence of wild-type PTP-1C. These results suggest that tyrosyl-phosphorylated CD22 may be a substrate for PTP-1C regulates tyrosyl phosphorylation of CD22.
Antigens, CD↗
Ambulatory care heads for the 21st century.
There is increasing market pressure to deliver ambulatory care in a most traditional manner, that is, with a high level of service and personal touch. The ambulatory care providers of the future will meet this demand. However, they will do so with approaches and support systems that are anything but traditional. Care is increasingly being delivered in large, integrated systems. Extraordinary service levels are being made feasible again--this time through a combination of new support systems, including total quality management task forces, patterns of care software, consolidated phone centers that can provide access from anywhere anytime, electronic data interfaces, and the Internet.
Ambulatory Care↗