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Showing papers by "Case Western Reserve University published in 1994"


Journal ArticleDOI
03 Jun 1994-Science
TL;DR: A previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that phosphorylate substrate proteins called STATs (signal transducers and activators of transcription).
Abstract: Through the study of transcriptional activation in response to interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma), a previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that then phosphorylate substrate proteins called STATs (signal transducers and activators of transcription). The phosphorylated STAT proteins move to the nucleus, bind specific DNA elements, and direct transcription. Recognition of the molecules involved in the IFN-alpha and IFN-gamma pathway has led to discoveries that a number of STAT family members exist and that other polypeptide ligands also use the Jak-STAT molecules in signal transduction.

5,746 citations


Journal ArticleDOI
30 Sep 1994-Science
TL;DR: This article synthesizes the current state of the genetic dissection of complex traits--describing the methods, limitations, and recent applications to biological problems.
Abstract: Medical genetics was revolutionized during the 1980s by the application of genetic mapping to locate the genes responsible for simple Mendelian diseases. Most diseases and traits, however, do not follow simple inheritance patterns. Genetics have thus begun taking up the even greater challenge of the genetic dissection of complex traits. Four major approaches have been developed: linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses. This article synthesizes the current state of the genetic dissection of complex traits--describing the methods, limitations, and recent applications to biological problems.

3,216 citations


Journal ArticleDOI
TL;DR: A growing body of conceptual and empirical literature addresses different aspects of in-channel relationship management in marketing channels literature as mentioned in this paper, which is becoming a central research paradigm in the marketing channel literature.
Abstract: Relationship management rapidly is becoming a central research paradigm in the marketing channels literature. A growing body of conceptual and empirical literature addresses different aspects of in...

2,204 citations


Book
21 Nov 1994
TL;DR: In this article, the authors present a survey of self-regulation failure in social and theoretical contexts, focusing on the following: Self-Regulation Failure: Blowing It. Failure to Control Emotions and Moods.
Abstract: Basic Issues: Introduction: Self-Regulation Failure in Social and Theoretical Context. General Patterns and Mechanisms of Self-Regulation Failure. Controlling Thoughts, Feelings, and Actions: Task Performance and Self-Regulation Failure: Blowing It. Self-Management: Taking Care of Yourself. Thoughts Out of Control. Failure to Control Emotions and Moods. Controlling Impulses and Appetities: Impulses and Appetites. Alcohol Consumption and Abuse. Eating Too Much. Smoking. A Sampler of Other Behavioral Control Problems: Gambling, Shopping, and Aggression. Conclusion: Self Regulation: Propects, Problems, and Promises. References. Subject Index.

1,949 citations


Journal ArticleDOI
TL;DR: The International Standards Booklet for Neurological and Functional Classification of Spinal Cord Injury (ISBWC) as mentioned in this paper is a standard for the classification of spinal cord injury. But it is not a classification of neurological disorders.
Abstract: The International Standards Booklet for Neurological and Functional Classification of Spinal Cord Injury

1,709 citations


Journal ArticleDOI
TL;DR: The model provides the basis for the study of arrhythmogenic activity of the single myocyte including afterdepolarizations and triggered activity and can simulate cellular responses under different degrees of Ca2+ overload.
Abstract: A mathematical model of the cardiac ventricular action potential is presented. In our previous work, the membrane Na+ current and K+ currents were formulated. The present article focuses on processes that regulate intracellular Ca2+ and depend on its concentration. The model presented here for the mammalian ventricular action potential is based mostly on the guinea pig ventricular cell. However, it provides the framework for modeling other types of ventricular cells with appropriate modifications made to account for species differences. The following processes are formulated: Ca2+ current through the L-type channel (ICa), the Na(+)-Ca2+ exchanger, Ca2+ release and uptake by the sarcoplasmic reticulum (SR), buffering of Ca2+ in the SR and in the myoplasm, a Ca2+ pump in the sarcolemma, the Na(+)-K+ pump, and a nonspecific Ca(2+)-activated membrane current. Activation of ICa is an order of magnitude faster than in previous models. Inactivation of ICa depends on both the membrane voltage and [Ca2+]i. SR is divided into two subcompartments, a network SR (NSR) and a junctional SR (JSR). Functionally, Ca2+ enters the NSR and translocates to the JSR following a monoexponential function. Release of Ca2+ occurs at JSR and can be triggered by two different mechanisms, Ca(2+)-induced Ca2+ release and spontaneous release. The model provides the basis for the study of arrhythmogenic activity of the single myocyte including afterdepolarizations and triggered activity. It can simulate cellular responses under different degrees of Ca2+ overload. Such simulations are presented in our accompanying article in this issue of Circulation Research.

1,612 citations


Journal ArticleDOI
27 May 1994-Science
TL;DR: Human neuroblastoma cells transfected with constructs expressing wild-type beta APP or the beta APP717 mutants linked to familial Alzheimer's disease were compared and it was demonstrated that the 4-kilodalton A beta released from wild- type beta APP is primarily but not exclusively A beta 1-40.
Abstract: Normal processing of the amyloid beta protein precursor (beta APP) results in secretion of a soluble 4-kilodalton protein essentially identical to the amyloid beta protein (A beta) that forms insoluble fibrillar deposits in Alzheimer's disease. Human neuroblastoma (M17) cells transfected with constructs expressing wild-type beta APP or the beta APP717 mutants linked to familial Alzheimer's disease were compared by (i) isolation of metabolically labeled 4-kilodalton A beta from conditioned medium, digestion with cyanogen bromide, and analysis of the carboxyl-terminal peptides released, or (ii) analysis of the A beta in conditioned medium with sandwich enzyme-linked immunosorbent assays that discriminate A beta 1-40 from the longer A beta 1-42. Both methods demonstrated that the 4-kilodalton A beta released from wild-type beta APP is primarily but not exclusively A beta 1-40. The beta APP717 mutations, which are located three residues carboxyl to A beta 43, consistently caused a 1.5- to 1.9-fold increase in the percentage of longer A beta generated. Long A beta (for example, A beta 1-42) forms insoluble amyloid fibrils more rapidly than A beta 1-40. Thus, the beta APP717 mutants may cause Alzheimer's disease because they secrete increased amounts of long A beta, thereby fostering amyloid deposition.

1,543 citations


Journal ArticleDOI
TL;DR: Osteochondral progenitor cells were used to repair large, full-thickness defects of the articular cartilage that had been created in the knees of rabbits.
Abstract: Osteochondral progenitor cells were used to repair large, full-thickness defects of the articular cartilage that had been created in the knees of rabbits. Adherent cells from bone marrow, or cells from the periosteum that had been liberated from connective tissue by collagenase digestion, were grown in culture, dispersed in a type-I collagen gel, and transplanted into a large (three-by-six-millimeter), full-thickness (three-millimeter) defect in the weight-bearing surface of the medial femoral condyle. The contralateral knee served as a control: either the defect in that knee was left empty or a cell-free collagen gel was implanted. The periosteal and the bone-marrow-derived cells showed similar patterns of differentiation into articular cartilage and subchondral bone. Specimens of reparative tissue were analyzed with use of a semiquantitative histological grading system and by mechanical testing with employment of a porous indenter to measure the compliance of the tissue at intervals until twenty-four weeks after the operation. There was no apparent difference between the results obtained with the cells from the bone marrow and those from the periosteum. As early as two weeks after transplantation, the autologous osteochondral progenitor cells had uniformly differentiated into chondrocytes throughout the defects. This repair cartilage was subsequently replaced with bone in a proximal-to-distal direction, until, at twenty-four weeks after transplantation, the subchondral bone was completely repaired, without loss of overlying articular cartilage. The mechanical testing data were a useful index of the quality of the long-term repair. Twenty-four weeks after transplantation, the reparative tissue of both the bone-marrow and the periosteal cells was stiffer and less compliant than the tissue derived from the empty defects but less stiff and more compliant than normal cartilage. Clinical Relevance: The current modalities for the repair of defects of the articular cartilage have many disadvantages. The transplantation of progenitor cells that will form cartilage and bone offers a possible alternative to these methods. As demonstrated in this report, autologous, bone-marrow-derived, osteochondral progenitor cells can be isolated and grown in vitro without the loss of their capacity to differentiate into cartilage or bone. Sufficient autologous cells can be generated to initiate the repair of articular cartilage and the reformation of subchondral bone. The repair tissues appear to undergo the same developmental transitions that originally led to the formation of articular tissue in the embryo.(ABSTRACT TRUNCATED AT 400 WORDS)

1,522 citations


Journal ArticleDOI
06 Jul 1994-JAMA
TL;DR: It is concluded that ulcer patients with H. pylori infection require treatment with antimicrobial agents in addition to antisecretory drugs whether on first presentation with the illness or on recurrence.
Abstract: The National Institutes of Health Consensus Development Conference onHelicobacter pyloriin Peptic Ulcer Disease brought together specialists in gastroenterology, surgery, infectious diseases, epidemiology, and pathology, as well as the public to address the following questions: (1) What is the causal relationship ofH pylorito upper gastrointestinal disease? (2) How does one diagnose and eradicateH pyloriinfection? (3) Does eradication ofH pyloriinfection benefit the patient with peptic ulcer disease? (4) What is the relationship betweenH pyloriinfection and gastric malignancy? (5) WhichH pylori—infected patients should be treated? (6) What are the most important questions that must be addressed by future research inH pyloriinfections? Following 1½ days of presentations by experts and discussion by the audience, a consensus panel weighed the evidence and prepared their consensus statement. Among their findings, the consensus panel concluded that (1) ulcer patients withH pyloriinfection require treatment with antimicrobial agents in addition to antisecretory drugs whether on first presentation with the illness or on recurrence; (2) the value of treating of nonulcerative dyspepsia patients withH pyloriinfection remains to be determined; and (3) the interesting relationship betweenH pyloriinfection and gastric cancers requires further exploration. (JAMA. 1994;272:65-69)

1,436 citations


Journal ArticleDOI
TL;DR: The isolation and in vitro mitotic expansion of autologous human MSCs will support the development of novel protocols for the treatment of many clinically challenging conditions, and can begin to explore therapeutic options that have never before been available.
Abstract: Bone formation in the embryo, and during adult fracture repair and remodeling, involves the progeny of a small number of cells called mesenchymal stem cells (MSCs). These cells continuously replicate themselves, while a portion become committed to mesenchymal cell lineages such as bone, cartilage, tendon, ligament, and muscle. The differentiation of these cells, within each lineage, is a complex multistep pathway involving discrete cellular transitions much like that which occurs during hematopoiesis. Progression from one stage to the next depends on the presence of specific bioactive factors, nutrients, and other environmental cues whose exquisitely controlled contributions orchestrate the entire differentiation phenomenon. An understanding of the cellular and molecular events of osteogenic differentiation of MSCs provides the foundation for the emergence of a new therapeutic technology for cell therapy. The isolation and in vitro mitotic expansion of autologous human MSCs will support the development of novel protocols for the treatment of many clinically challenging conditions. For example, local bone defects can be repaired through site-directed delivery of MSCs in an appropriate carrier vehicle. Generalized conditions, such as osteoporosis, may be treatable by systemic administration of culture-expanded autologous MSCs or through biopharmaceutical regimens based on the discovery of critical regulatory molecules in the differentiation process. With this in mind, we can begin to explore therapeutic options that have never before been available.

934 citations


Journal ArticleDOI
21 Oct 1994-Cell
TL;DR: It is concluded that mGLUR1 is required for the induction of LTD and that the ataxic behavior and impaired eyeblink conditioning of the mGluR1 mutant mice are primarily due to deficient LTD.

Journal ArticleDOI
TL;DR: The learning and generalization characteristics of the random vector version of the Functional-link net are explored and compared with those attainable with the GDR algorithm and it seems that ‘ overtraining ’ occurs for stochastic mappings.

Journal ArticleDOI
TL;DR: In this paper, the synthesis, composition, and structural analysis of precursors based on bisphenol-A are discussed, and the materials thus obtained exhibit excellent mechanical integrity with glass transition temperatures over 200°C.
Abstract: SYNOPSIS Compounds with bifunctional benzoxazine groups in their molecular structures form crosslinked structures characteristic of phenolic materials through a ring-opening reaction mechanism. This family of compounds offers greater flexibility than conventional novolac or resole resins in terms of molecular design. It is also superior to conventional phenolic resin in process control since it releases no by-product during curing reactions. The materials thus obtained exhibit excellent mechanical integrity with glass transition temperatures over 200°C. The synthesis, composition, and structural analysis of precursors based on bisphenol-A are discussed herein. 0 1994 John Wiley & Sons, Inc.

Journal ArticleDOI
30 Dec 1994-Cell
TL;DR: This work has identified in HSCR patients a G-->T missense mutation in EDNRB exon 4 that substitutes the highly conserved Trp-276 residue in the fifth transmembrane helix of the G protein-coupled receptor with a Cys residue (W276C).

Journal ArticleDOI
23 Mar 1994-JAMA
TL;DR: Divalproex was as effective in rapid-cycling manic patients as in other patients and appears to be independent of prior responsiveness to lithium, while lithium was significantly more effective than placebo in reducing the symptoms of acute mania.
Abstract: Objective. —To compare the effectiveness of divalproex sodium with that of lithium and placebo in patients with acute mania. Design. —Randomized, double-blind, parallel-group study of treatment outcomes in patients with manic-depressive illness. Patients. —A total of 179 hospitalized, acutely manic patients meeting the Research Diagnostic Criteria for manic disorder, approximately half of whom had been nonresponsive to lithium previously, were studied at nine university-affiliated hospitals. Interventions. —After a minimum 3-day washout period, random assignment for 21 days to divalproex, lithium, or placebo in a 2:1:2 ratio. Dosage of divalproex and lithium was increased if tolerated to a target concentration of 1041 μmol/L (150 μg/ mL) or 1.5 mmol/L (conventionally expressed as milliequivalents per liter), respectively. Main Outcome Measures. —Primary outcome measures were changes in the Mania Rating scale derived from the Schedule for Affective Disorders and Schizophrenia. Results. —Intent-to-treat analysis for efficacy was based on data from 68, 35, and 73 patients in the divalproex, lithium, and placebo groups, respectively. Groups were initially comparable except that all eight patients with four or more manic episodes in the previous year were in the divalproex group. In 30%, 33%, and 51% of the above groups, treatment was prematurely terminated due to lack of efficacy, with fewer premature terminations from divalproex than placebo (P=.017). The proportions of patients improving at least 50% were higher for divalproex and lithium groups than for the placebo group: 48% for divalproex (P=.004) and 49% for lithium (P=.025) vs 25% for placebo. Divalproex was as effective in rapid-cycling manic patients as in other patients. Conclusions. —Both divalproex and lithium were significantly more effective than placebo in reducing the symptoms of acute mania. The efficacy of divalproex appears to be independent of prior responsiveness to lithium. (JAMA. 1994;271:918-924)

Journal ArticleDOI
TL;DR: The early use of deferoxamine in an amount proportional to the transfusional iron load reduces the body iron burden and helps protect against diabetes mellitus, cardiac disease, and early death in patients with thalassemia major.
Abstract: Background To determine whether deferoxamine prevents the complications of transfusional iron overload in thalassemia major, we evaluated 59 patients (30 were female and 29 male; age range, 7 to 31 years) periodically for 4 to 10 years or until death. Methods At each follow-up visit, we performed a detailed clinical and laboratory evaluation and measured hepatic iron stores with a noninvasive magnetic device. Results The body iron burden as assessed by magnetic measurement of hepatic iron stores was closely correlated (R = 0.89, P<0.001) with the ratio of cumulative transfusional iron load to cumulative deferoxamine use (expressed in millimoles of iron per kilogram of body weight, in relation to grams of deferoxamine per kilogram, transformed into the natural logarithm). Each increase of one unit in the natural logarithm of the ratio (transfusional iron load to deferoxamine use) was associated with an increased risk of impaired glucose tolerance (relative risk, 19.3; 95 percent confidence interval, 4.8 to...

Journal ArticleDOI
TL;DR: The preliminary neuropathologic criteria for progressive supranuclear palsy (PSP) are presented as proposed at a workshop held at the National Institutes of Health, Bethesda, MD, April 24 and 25, 1993.
Abstract: We present the preliminary neuropathologic criteria for progressive supranuclear palsy (PSP) as proposed at a workshop held at the National Institutes of Health, Bethesda, MD, April 24 and 25, 1993. The criteria distinguish typical, atypical, and combined PSP. A semiquantitative distribution of neurofibrillary tangles is the basis for the diagnosis of PSP. A high density of neurofibrillary tangles and neuropil threads in the basal ganglia and brain-stem is crucial for the diagnosis of typical PSP. Tau-positive astrocytes or their processes in areas of involvement help to confirm the diagnosis. Atypical cases of PSP are variants in which the severity or distribution of abnormalities deviates from the typical pattern. Criteria excluding the diagnosis of typical and atypical PSP are large or numerous infarcts, marked diffuse or focal atrophy, Lewy bodies, changes diagnostic of Alzheimer's disease, oligodendroglial argyrophilic inclusions, Pick bodies, diffuse spongiosis, and prion protein-positive amyloid plaques. The diagnosis of combined PSP is proposed when other neurologic disorders exist concomitantly with PSP.

Journal ArticleDOI
01 Dec 1994-Nature
TL;DR: Induction of MEKK does not result in the activation of MAPK, but instead stimulates the stress-activated protein kinases (SAPKs)6–8 which are identical to a Jun amino-terminal kinase9,10 which in turn phosphorylates and activates SAPK.
Abstract: A kinase distinct from the MEK activator Raf, termed MEK kinase-1 (MEKK), was originally identified by virtue of its homology to kinases involved in yeast mating signal cascades. Like Raf, MEKK is capable of activating MEK in vitro. High-level expression of MEKK in COS-7 cells or using vaccinia virus vectors also activates MEK and MAPK, indicating that MEKK and Raf provide alternative means of activating the MAPK signalling pathway. We have derived NIH3T3 cell sublines that can be induced to express active MEKK. Here we show that induction of MEKK does not result in the activation of MAPK, but instead stimulates the stress-activated protein kinases (SAPKs) which are identical to a Jun amino-terminal kinase. We find that MEKK regulates a new signalling cascade by phosphorylating an SAPK activator, SEK1 which in turn phosphorylates and activates SAPK.

Journal ArticleDOI
TL;DR: In this article, the authors present evidence that the characteristic pathological structures associated with Alzheimer disease contain modifications typical of advanced Maillard reaction end products, which are initiated by the condensation between amino groups of proteins and reducing sugars.
Abstract: During aging long-lived proteins accumulate specific post-translational modifications. One family of modifications, termed Maillard reaction products, are initiated by the condensation between amino groups of proteins and reducing sugars. Protein modification by the Maillard reaction is associated with crosslink formation, decreased protein solubility, and increased protease resistance. Here, we present evidence that the characteristic pathological structures associated with Alzheimer disease contain modifications typical of advanced Maillard reaction end products. Specifically, antibodies against two Maillard end products, pyrraline and pentosidine, immunocytochemically label neurofibrillary tangles and senile plaques in brain tissue from patients with Alzheimer disease. In contrast, little or no staining is observed in apparently healthy neurons of the same brain. The Maillard-reaction-related modifications described herein could account for the biochemical and insolubility properties of the lesions of Alzheimer disease through the formation of protein crosslinks.

Journal ArticleDOI
TL;DR: The genesis of mesodermal tissues, such as bone, cartilage, muscle, marrow stoma, tendon, fat, dermis, and connective tissues, in either embryos or adult organisms is referred to as the mesengenic process and provides a logic for understanding the rapid repair of tissue injuries.

Journal ArticleDOI
TL;DR: Children with birth weights under 750 g were inferior to both comparison groups in cognitive ability, psychomotor skills, and academic achievement and had poorer social skills and adaptive behavior and more behavioral and attention problems.
Abstract: Background Since the mid-1980s, increasing numbers of children with birth weights under 750 g have survived to school age. Methods We matched a regional cohort of 68 surviving children born from 1982 through 1986 with birth weights under 750 g (mean, 670 g; gestational age, 25.7 weeks) with 65 children weighing 750 to 1499 g at birth and 61 children born at term. Growth, neurosensory status, and functioning at school age in the three groups were compared. Associations of biologic and social risk factors with major developmental outcomes were examined by means of logistic-regression analyses. Results Children with birth weights under 750 g were inferior to both comparison groups in cognitive ability, psychomotor skills, and academic achievement. They had poorer social skills and adaptive behavior and more behavioral and attention problems. The mean (±SD) Mental Processing Composite score for the cohort was 87 ±15, as compared with 93 ±14 for children with birth weights of 750 to 1499 g and 100 ±13 for chil...

Journal ArticleDOI
TL;DR: It is suggested that BCL-2 either directly or indirectly regulates the flux of Ca2+ across the ER membrane, thereby abrogating Ca2- signaling of apoptosis.
Abstract: BCL-2 is a 26-kDa integral membrane protein that represses apoptosis by an unknown mechanism. Recent findings indicate that Ca2+ release from the endoplasmic reticulum (ER) mediates apoptosis in mouse lymphoma cells. In view of growing evidence that BCL-2 localizes to the ER, as well as mitochondria and the perinuclear membrane, we investigated the possibility that BCL-2 represses apoptosis by regulating Ca2+ fluxes through the ER membrane. A cDNA encoding BCL-2 was introduced into WEHI7.2 cells and two subclones, W.Hb12 and W.Hb13, which express high and low levels of BCL-2 mRNA and protein, respectively, were isolated. WEHI7.2 cells underwent apoptosis in response to treatment with the glucocorticoid hormone dexamethasone, whereas W.Hb12 and W.Hb13 cells were protected from apoptosis, revealing a direct relationship between the level of BCL-2 expression and the degree of protection. Significantly, BCL-2 also blocked induction of apoptosis by thapsigargin (TG), a highly specific inhibitor of the ER-associated Ca2+ pump. TG completely inhibited ER Ca2+ pumping in both WEHI7.2 and W.Hb12 cells, but the release of Ca2+ into the cytosol after inhibition of ER Ca2+ pumping was significantly less in W.Hb12 cells than in WEHI7.2 cells, indicating that BCL-2 reduces Ca2+ efflux through the ER membrane. By reducing ER Ca2+ efflux, BCL-2 interfered with a signal for "capacitative" entry of extracellular Ca2+, preventing a sustained increase of cytosolic Ca2+ in TG-treated cells. These findings suggest that BCL-2 either directly or indirectly regulates the flux of Ca2+ across the ER membrane, thereby abrogating Ca2+ signaling of apoptosis.

Journal ArticleDOI
TL;DR: In this article, the authors define the burnout construct and develop hypotheses to examine if burnout act as a predictor of customer service representatives' job performance degradation and burnout in marketing boundary spanners.
Abstract: Marketing boundary spanners—especially customer service representatives—are notably susceptible to burnout. The authors define the burnout construct and develop hypotheses to examine if burnout act...

Journal ArticleDOI
TL;DR: The action potential model presented in this journal is used to investigate phenomena that involve dynamic changes of [Ca2+]i, as described below, and reflects the time delay associated with translocation of Ca2+ from network SR to junctional SR.
Abstract: The action potential model presented in our accompanying article in this journal is used to investigate phenomena that involve dynamic changes of [Ca2+]i, as described below Delayed afterdepolarizations (DADs) are induced by spontaneous Ca2+ release from the sarcoplasmic reticulum (SR), which, in turn, activates both the Na(+)-Ca2+ exchanger (INaCa) and a nonspecific Ca(2+)-activated current (Ins(Ca)) The relative contributions of INaCa and of Ins(Ca) to the generation of DADs are different under different degrees of Ca2+ overload Early afterdepolarizations (EADs) can be categorized into two types: (1) plateau EADs, resulting from a secondary activation of the L-type Ca2+ current during the plateau of an action potential, and (2) phase-3 EADs, resulting from activation of INaCa and Ins(Ca) by increased [Ca2+]i due to spontaneous Ca2+ release from the SR during the late repolarization phase Spontaneous rhythmic activity and triggered activity are caused by spontaneous Ca2+ release from the SR under conditions of Ca2+ overload Postextrasystolic potentiation reflects the time delay associated with translocation of Ca2+ from network SR to junctional SR The cell is paced at high frequencies to investigate the long-term effects on the intracellular ionic concentrations

Journal ArticleDOI
21 Oct 1994-Cell
TL;DR: It is proposed that mGluR1 is not "in line" in LTP production, but rather modulates the plasticity process, and hence affects context-specific associative learning.

Journal ArticleDOI
TL;DR: Novel roles are established in reproductive function of Steroidogenic factor 1 at other levels of the hypothalamic/pituitary/gonadal axis and a possible mechanism for the impaired gonadotropin expression in Ftz-F1-disrupted mice is established.
Abstract: Steroidogenic factor 1 (SF-1), an orphan nuclear receptor, regulates the enzymes that produce sex steroids, and disruption of the Ftz-F1 gene encoding SF-1 precludes adrenal and gonadal development. We now study the role of SF-1 at other levels of the hypothalamic/pituitary/gonadal axis. In Ftz-F1-disrupted mice, immunohistochemical analyses with antibodies against pituitary trophic hormones showed a selective loss of gonadotrope-specific markers, supporting the role of SF-1 in gonadotrope function. In situ hybridization analyses confirmed these results; pituitaries from Ftz-F1-disrupted mice lacked transcripts for three gonadotrope-specific markers (LH beta, FSH beta, and the receptor for gonadotropin-releasing hormone), whereas they exhibited decreased but detectable expression of the alpha-subunit of glycoprotein hormones. SF-1 transcripts in the developing mouse pituitary, which first became detectable at embryonic day 13.5-14.5, preceded the appearance of FSH beta and LH beta transcripts. In adult rat pituitary cells, SF-1 transcripts colocalized with immunoreactivity for the gonadotrope-specific LH. Finally, SF-1 interacted with a previously defined promoter element in the glycoprotein hormone alpha-subunit gene, providing a possible mechanism for the impaired gonadotropin expression in Ftz-F1-disrupted mice. These studies establish novel roles of this orphan nuclear receptor in reproductive function.

Journal ArticleDOI
TL;DR: It is proposed that in Alzheimer disease, AGEs in paired helical filament tau can induce oxidant stress, thereby promoting neuronal dysfunction, and being ideal substrates for nonenzymatic glycation.
Abstract: The stability of proteins that constitute the neurofibrillary tangles and senile plaques of Alzheimer disease suggests that they would be ideal substrates for nonenzymatic glycation, a process that occurs over long times, even at normal levels of glucose, ultimately resulting in the formation of advanced glycation end products (AGEs). AGE-modified proteins aggregate, and they generate reactive oxygen intermediates. Using monospecific antibody to AGEs, we have colocalized these AGEs with paired helical filament tau in neurofibrillary tangles in sporadic Alzheimer disease. Such neurons also exhibited evidence of oxidant stress: induction of malondialdehyde epitopes and heme oxygenase 1 antigen. AGE-recombinant tau generated reactive oxygen intermediates and, when introduced into the cytoplasm of SH-SY5Y neuroblastoma cells, induced oxidant stress. We propose that in Alzheimer disease, AGEs in paired helical filament tau can induce oxidant stress, thereby promoting neuronal dysfunction.

Journal ArticleDOI
11 Nov 1994-Science
TL;DR: "Intrinsic" gating can be restored in excised patches by nanomolar concentrations of two naturally occurring polyamines, spermine and spermidine, and may reflect voltage-dependent block by these cations.
Abstract: Inward rectifier K+ channels pass prominent inward currents, while outward currents are largely blocked. The inward rectification is due to block by intracellular Mg2+ and a Mg(2+)-independent process described as intrinsic gating. The rapid loss of gating upon patch excision suggests that cytoplasmic factors participate in gating. "Intrinsic" gating can be restored in excised patches by nanomolar concentrations of two naturally occurring polyamines, spermine and spermidine. Spermine and spermidine may function as physiological blockers of inward rectifier K+ channels and "intrinsic" gating may largely reflect voltage-dependent block by these cations.

Journal ArticleDOI
TL;DR: The authors argue that much of the effort to design information technology to support cognition in organizations has not addressed its distributed quality, and that such systems have tended to focus either on the individual as an isolated decision maker, or on the group as a producer of a decision or policy statement in common.
Abstract: Cognition in organizations is a distributed phenomenon, in which individual members of an organization reflect upon their experience, make plans, or take action. Organizational learning or organizational cognition are familiar terms, but it is only the individual persons in an organization who create interpretations and test understandings, as they think and learn in their organizational setting. Coordinated outcomes emerge in organizations when individuals think and act in ways that take others in the organization and their interdependencies into account. We argue that much of the effort to design information technology to support cognition in organizations has not addressed its distributed quality. Such systems have tended to focus either on the individual as an isolated decision maker, or on the group as a producer of a decision or policy statement in common. In distributed cognition, by contrast, the group is a set of autonomous agents who act independently yet recognize that they have interdependenci...

Journal ArticleDOI
TL;DR: To determine the extent of airway infection and inflammation in adolescents and adults with cystic fibrosis who have mild lung disease and are without symptoms of active infection, bronchoalveolar lavage was performed on 18 CF patients > or = 12 yr of age who were stable, appeared clinically well, and had mean (+/- SEM) FEV1 of 79 +/- 4% of predicted.
Abstract: To determine the extent of airway infection and inflammation in adolescents and adults with cystic fibrosis (CF) who have mild lung disease and are without symptoms of active infection, we performed bronchoalveolar lavage (BAL) on 18 CF patients > or = 12 yr of age who were stable, appeared clinically well, and had mean (+/- SEM) FEV1 of 79 +/- 4% of predicted. We quantitated the bacteria, inflammatory cells, immunoglobulins, and mediators of inflammatory tissue damage in the epithelial lining fluid (ELF) of these patients and in 23 healthy control subjects. All CF patients were found to be infected with Pseudomonas aeruginosa, Staphylococcus aureus, and/or Haemophilus influenzae; no organisms were isolated from the control subjects. The mean number of cells in the ELF was 14 times greater in the CF patients than in the control subjects. Neutrophils constituted 57% of the recovered cells in the CF patients versus 3% in the control subjects, and their concentration was 380 times greater in the CF patients versus the control subjects. IgG, IgA, and IgM were 2.5 to 6 times greater in CF ELF versus that of control subjects. Abundant active elastase was present in the ELF of the CF patients (2.3 +/- 0.9 microM) despite threefold elevated levels of alpha 1-protease inhibitor (alpha 1-PI). No active elastase was detectable in the control subjects. alpha 1-PI was functional in CF as demonstrated by elevated elastase:alpha 1-PI complex (0.045 microM in CF versus 0.002 microM in control subjects). This active elastase caused proteolytic destruction of surface complement receptors on airway neutrophils in situ.(ABSTRACT TRUNCATED AT 250 WORDS)