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PubMed1995

A signaling pathway coupled to T cell receptor ligation by MMTV superantigen leading to transient activation and programmed cell death.

Stimulation of T cells by retroviral and bacterial super-antigens is followed by specific T cell elimination, in contrast with stimulation of T cells by peptide, which is usually associated with clonal expansion. We show here that this differential response phenotype is apparent at the level of individual T cell clones following TCR ligation with peptide or MTV antigen. We exploited selective coupling of apoptosis to TCR ligation by MTV7 to examine some of the intracellular biochemical events that underlie this response. MTV-dependent activation resulting in apoptosis was associated with activation of phospholipase A2 and the generation of reactive oxygen intermediates. Inhibition of these biochemical events prevented both MTV-dependent activation and apoptosis without affecting the peptide-dependent response of the same T cell clones. These results indicate that clonal expansion or programmed cell death following TCR ligation may be consequences of distinct TCR-coupled signaling pathways.

Animals↗
PubMed2025

Boolean matrix logic programming for active learning of gene functions in genome-scale metabolic network models.

Reasoning about hypotheses and updating knowledge through empirical observations are central to scientific discovery. In this work, we applied logic-based machine learning methods to drive biological discovery by guiding experimentation. Genome-scale metabolic network models (GEMs) - comprehensive representations of metabolic genes and reactions - are widely used to evaluate genetic engineering of biological systems. However, GEMs often fail to accurately predict the behaviour of genetically engineered cells, primarily due to incomplete annotations of gene interactions. The task of learning the intricate genetic interactions within GEMs presents computational and empirical challenges. To efficiently predict using GEM, we describe a novel approach called Boolean Matrix Logic Programming (BMLP) by leveraging Boolean matrices to evaluate large logic programs. We developed a new system, [Formula: see text], which guides cost-effective experimentation and uses interpretable logic programs to encode a state-of-the-art GEM of a model bacterial organism. Notably, [Formula: see text] successfully learned the interaction between a gene pair with fewer training examples than random experimentation, overcoming the increase in experimental design space. [Formula: see text] enables rapid optimisation of metabolic models to reliably engineer biological systems for producing useful compounds. It offers a realistic approach to creating a self-driving lab for biological discovery, which would then facilitate microbial engineering for practical applications.

Active learning↗
PubMed1983

Physical activity and the healthy mind.

Physicians should seek to enhance the quality rather than the quantity of human life. Physical activity programs can increase life satisfaction through an immediate increase of arousal and a long-term enhancement of self-esteem and body image. In the young child competition can cause excessive arousal, but long-term adverse effects are rare. In the adult a reduction of anxiety and stress and a general feeling of well-being reduce the frequency of minor medical complaints, generating important economic benefits. Physical activity programs also help to correct the reactive depression that accompanies conditions such as myocardial infarction. Interest in physical activity should be stimulated from the earliest years of primary school. The allocation of curricular time to physical education does not hamper academic achievement. Rather, through its impact on psychomotor learning, it enhances the total process of intellectual and psychomotor development.

Aged↗
PubMed1995

The association between alcohol use and health behaviors related to the risk of cardiovascular disease: the South Carolina Cardiovascular Disease Prevention Project.

OBJECTIVE: This study examines the relationship between alcohol use and health behaviors related to the risk of cardiovascular disease (CVD). In particular, we examined the relationship between alcohol use and leisure time physical activity, participation in community physical activity programs and behaviors used for weight loss. Numerous studies have found a "protective" effect of moderate alcohol consumption on the risk of CVD. However, most of these studies have not adequately controlled for potential confounding by health behaviors associated with alcohol use. METHOD: We used descriptive and logistic regression analyses to examine cross-sectional survey data from 2,072 participants in the South Carolina Cardiovascular Disease Prevention Project. RESULTS: After controlling for age, race, education and preexisting CVD, moderate and heavy drinkers who do not smoke were more likely than nondrinkers to report engaging in regular leisure time physical activity. The relationship between other health behaviors and alcohol consumption was less clear. Among men, moderate and heavy drinkers were no more likely than nondrinkers to participate in community physical activity programs; among women, moderate and heavy drinkers were more likely than nondrinkers to report this activity. Moderate drinkers were more likely than nondrinkers to report that they were attempting to lose weight, however this difference was not statistically significant. CONCLUSIONS: These data suggest that at least some of the apparent protective effect of moderate alcohol consumption found in other studies may be due to differences between nondrinkers and drinkers with respect to physical activity and other health practices.

Adolescent↗
PubMed1981

[Central program for activation of hindlimb muscles during scratching in cats].

Electrical activity in nerves of different hindlimb muscles was investigated during fictitious scratching in decerebrated and decapitated cats. Phases of motor discharges could be distinguished corresponding to the phases of real scratching: aiming (flexion in the thigh and ankle joints and extension in the knee joint) and scratching (opposite movements in the same joints). According to the pattern of the discharges the hindlimb muscles were divided into three groups. In the nerves to the muscles of the 1st group the activity was observed during "initial aiming" period and during rhythmic "aiming phases". It was reciprocal to the activity in the nerves to the muscles of the 2nd group appearing during "scratching phases". In the nerves to the muscles of the 3d group the activity was observed both in "initial aiming" period and in rhythmic "aiming and scratching phases". Passive forward deflexion of the limb intensified the "scratching phases" and decreased the intensity of the discharges during "initial aiming" and "aiming phases". Physiological significance of such an organization of central program and structure of spinal scratching generator are discussed.

Animals↗
PubMed1992

Correlation of calcineurin phosphatase activity and programmed cell death in murine T cell hybridomas.

Ligation of T cell receptor/CD3 complexes induces programmed cell death, or apoptosis, in immature thymocytes and many T cell hybridomas. While it has been demonstrated that T cell receptor-mediated apoptosis requires an increase in intracellular calcium concentration, the specific calcium-dependent signalling events leading to cell death are poorly defined. We have previously shown that T cell receptor/CD3-mediated induction of apoptosis in a murine T cell hybridoma is inhibited by the immunosuppressive drugs cyclosporin A (CsA) and FK506. Recently, it has been determined that these agents inhibit the activity of calcineurin, a calcium- and calmodulin-dependent serine/threonine phosphatase. Using an assay which measures calcineurin activity in cell lysates, we find that calcineurin-dependent dephosphorylation of a phosphopeptide substrate is potently inhibited in hybridomas treated with CsA or FK506. Drug dose-response analyses indicate that the level of cellular calcineurin activity correlates closely with the ability of these cells to undergo apoptosis. Thus, calcineurin appears to be a critical mediator of T cell receptor/CD3 signalling leading to programmed cell death in T cell hybridomas.

Amino Acid Sequence↗
PubMed1992

The effect of graded activity on patients with subacute low back pain: a randomized prospective clinical study with an operant-conditioning behavioral approach.

The aim of this study was to determine whether graded activity restored occupational function in industrial blue-collar workers who were sick-listed for 8 weeks because of subacute, nonspecific, mechanical low back pain (LBP). Patients with LBP, who had been examined by an orthopedic surgeon and a social worker, were randomly assigned to either an activity group (n = 51) or a control group (n = 52). Patients with defined orthopedic, medical, or psychiatric diagnoses were excluded before randomization. The graded activity program consisted of four parts: (1) measurements of functional capacity; (2) a work-place visit; (3) back school education; and (4) an individual, submaximal, gradually increased exercise program, with an operant-conditioning behavioral approach, based on the results of the tests and the demands of the patient's work. Records of the amount of sick leave taken over a 3-year period (ie, the 1-year periods before, during, and after intervention) were obtained from each patient's Social Insurance Office. The patients in the activity group returned to work significantly earlier than did the patients in the control group. The median number of physical therapist appointments before return to work was 5, and the average number of appointments was 10.7 (SD = 12.3). The average duration of sick leave attributable to LBP during the second follow-up year was 12.1 weeks (SD = 18.4) in the activity group and 19.6 weeks (SD = 20.7) in the control group. Four patients in the control group and 1 patient in the activity group received permanent disability pensions. The graded activity program made the patients occupationally functional again, as measured by return to work and significantly reduced long-term sick leave.

Absenteeism↗
PubMed1993

Surveillance for primary and secondary syphilis--United States, 1991.

PROBLEM/CONDITION: From 1986 through 1990, an epidemic of syphilis occurred throughout the United States. In 1991, the number of reported cases of primary and secondary (P&S) syphilis in the United States declined for the first time since 1985. REPORTING PERIOD COVERED: To examine how this decline reflected sex-specific, race/ethnicity-specific, and regional patterns of syphilis morbidity, we analyzed data for syphilis cases reported to CDC from 1984 through 1991. DESCRIPTION OF SYSTEM: Summary data for cases of syphilis reported to state health departments were sent quarterly and annually to CDC. The quarterly data from each state included total number of syphilis cases by sex, stage of disease (primary, secondary, early latent, and late latent), and source of report (public or private). The annual data from each state included total number of P&S syphilis cases by sex, racial/ethnic group (white, not of Hispanic origin; black, not of Hispanic origin; Hispanic; Asian/Pacific Islander; or American Indian/Alaskan Native), 5-year age group, and source of report. RESULTS: The decline in both the number and rate of reported syphilis cases in 1991 occurred in every racial group in the United States and in both sexes. This decline also occurred in every region of the United States except the Midwest, where the total P&S syphilis rate increased 37.3% from 1990 through 1991. Despite the increase in syphilis rates in the Midwest, the highest rates of P&S syphilis in 1991 were reported from the South. INTERPRETATION: The reasons for the decline in syphilis are unclear. No data exist to conclusively identify which STD control program activities affected the level of syphilis morbidity or to what extent those activities may have contributed to the decline. Changes in drug use and limited immunity to Treponema pallidum may have accounted for some of the decrease in syphilis incidence. Higher levels of poverty in the South and poor access to health-care services associated with poverty probably contributed to continued high levels of disease transmission in the South. ACTIONS TAKEN: Better evaluation of STD control program activities will be necessary to help determine the most effective strategies for preventing and controlling syphilis in different high-risk populations.

Female↗
PubMed1975

Evaluation by objectives: A systematic approach to the evaluation of educational programs and activities in dental education.

In response to the need for more effective utilization of resources, many institutions of higher learning are beginning to use corporate management methods. These methods, MBO being the most familiar example, center on the common comprehension at all levels of the goals of the corporation. However, institutions of higher learning uniformly lack a cohesiveness of purpose that extends from the level of president to that of teaching faculty. It is a mistake to assume that institutional educational goals are understood and supported by appropriate educational objectives at the department and program level. The evaluation-by-objective format is a concise graphical way to identify areas of support and confusion. It can be applied at each level of the institution and transmitted upward so that personnel at each administrative level can see the way in which its goals and objectives are perceived at lower levels. The proposed format facilitates grouping of educational objectives into programs, providing a framework for the estimation of effort and of needed resources. Since perceptions of effort and required resources will differ depending upon perspective, important issues will be identified, a most significant benefit of the system. The format leads to the formulation of an action plan, which should be reviewed periodically. The first step toward scientific management in institutions of higher learning must be a clear understanding of institutional and subunit goals, along with a set of education objectives that will accomplish these goals. The evaluation-by-objective format directs itself to exactly that concern.

Education, Dental↗
PubMed2025

Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing.

Transition between activation and quiescence states in hematopoietic stem and progenitor cells (HSPCs) is tightly governed by cell-intrinsic means and microenvironmental co-adaptation. Although this balance is fundamental for lifelong hematopoiesis and immunity, the underlying molecular mechanisms remain poorly defined. Multimodal analysis divulging differential transcriptional activity between distinct HSPC states indicates the presence of Fli-1 transcription factor binding motif in activated hematopoietic stem cells. We reveal that Fli-1 activity is essential during regenerative hematopoiesis in mice. Fli-1 directs activation programs while priming cellular sensory and output machineries, enabling HSPCs co-adoptability with a stimulated vascular niche through propagation of niche-derived angiocrine Notch1 signaling. Constitutively induced Notch1 signaling is sufficient to recuperate functional hematopoietic stem cells impairments in the absence of Fli-1, without leukemic transformation. Applying FLI-1 transient modified-mRNA transduction into latent adult human mobilized HSPCs, enables their niche-mediated expansion and superior engraftment capacities. Thus, decryption of stem cell activation programs offers valuable insights for immunological regenerative medicine.

Animals↗
PubMed1998

GATA-1 dominantly activates a program of erythroid gene expression in factor-dependent myeloid FDCW2 cells.

Erythrocyte development has previously been shown to depend upon the expression of the lineage-restricted trans-acting factor GATA-1. Despite predicted roles for this factor during early development, GATA-1-deficient cells in chimeric mice and embryonic stem cell cultures mature to a late proerythroblast stage and express at least certain genes that normally are thought to be regulated by GATA-1 (including erythroid Krüppel-like factor [EKLF] and the erythropoietin [Epo] receptor). Opportunities to test roles for GATA-1 in erythroid gene activation in these systems therefore are limited. In the present study, in an alternate approach to test the function of GATA-1, GATA-1 has been expressed together with the Epo receptor in myeloid FDCW2 cells and the resulting effects on cytokine-dependent proliferation and erythroid gene expression have been assessed. GATA-1 expression at low levels delayed FDCW2ER cell cycle progression at the G1 phase specifically during Epo-induced mitogenesis. Upon expression of GATA-1 at increased levels, proliferation in response to Epo, interleukin-3 (IL-3), and stem cell factor was attenuated and endogenous GATA-1, EKLF and betamaj-globin gene expression was activated. Friend of GATA-1 (FOG) transcript levels also were enhanced, and ets-1 and c-mpl but not Epo receptor gene expression was induced. Finally, in FDCW2 cells expressing increased levels of GATA-1 and a carboxyl-terminally truncated Epo receptor, Epo (with respect to IL-3 as a control) was shown to markedly promote globin transcript expression. Thus, novel evidence for select hierarchical roles for GATA-1 and Epo in erythroid lineage specification is provided.

Animals↗
PubMed1996

Function of killer cell inhibitory receptors for MHC class I molecules.

NK- and T-cells express at their surface, members of a multigenic family of killer-cell inhibitory receptors (KIR) for MHC Class I molecules. KIR engagement leads to the inhibition of NK- and T-cell activation programs. These receptors recruit the protein tyrosine phosphatases (PTPase), SHP-1 and SHP-2, upon tyrosine phosphorylation of immunoreceptor tyrosine-based inhibition motif (ITIM) expressed in both human and mouse KIR. We further define the ITIM amino acids sequence required in that recognition and demonstrate the critical role of the phosphoY-2 amino acid residue in this V/IxYxxL/V motif. In addition, using RBL-2H3 cells expressing endogenous Fc epsilonRI receptors as well as transfected CD25/CD3zeta chimera and p58.183 human KIR, we show that KIR inhibitory function requires co-engagement of KIR and ITAM-containing receptors. These results document the pathway used by KIR to down-regulate NK- and T-cell activation programs.

Amino Acid Sequence↗
PubMed1984

Programmed electromyographic activity and negative incremental muscle stiffness in monkeys jumping downward.

We trained monkeys to jump down from different heights, and recorded electromyograms (e.m.g.s) in arm muscles, and ground reaction forces. The landing movements were also recorded by high-speed cinematography. The e.m.g. of the triceps began about 80 ms before landing. The initial burst lasted until about 20 ms after ground contact and was succeeded by bursts of gradually declining amplitude. These discharges were not of reflex origin, because when the monkey was deceived by a collapsible platform, they were time-locked to the expected, not to the true landing. The amplitude of the e.m.g. in the triceps increased with the height of the jump, indicating adaptive control. The timing of the e.m.g. pattern was assumed to be programmed before take off, because it was unaffected by extinction of the light during the fall. The vertical ground reaction force produced by the arms had an inflexion on its rising phase which arose from the very rapid stretch of the muscles which control the wrist. Then came a sharp peak produced mainly by stretch of the triceps. The inflexion and the sharp peak were probably produced by short-range stiffness of the muscles of the upper arm. The torque acting on the elbow joint, and the elbow joint stiffness were calculated from the ground reaction forces and the movement of the arm. The torque was high at impact and gradually declined during the landing. The force produced by the triceps increased sharply, then decreased while it continued to lengthen. Thus, the elbow joint showed high initial stiffness, which then decreased, and finally became negative. This dynamic relation between length and tension was very different from the static length-tension characteristic of skeletal muscles. The observed behaviour of the muscles presumably takes advantage of the resistance of the musculo-skeletal system to transient forces. The observed negative stiffness occurs only during submaximal contractions. We propose that the segmented pattern in the e.m.g. produces submaximal contractions in both slow and fast fibres in spite of a high excitatory drive.

Animals↗
PubMed1995

Daily physical activity of schoolchildren with spastic diplegia and of healthy control subjects.

OBJECTIVE: To assess the differences in daily physical activity between children with spastic diplegia and healthy schoolchildren, to determine whether special physical activity programs are needed in the population with cerebral palsy. DESIGN: Cross-sectional design. SETTING: Children's rehabilitation center Franciscusoord (day care center) and elementary schools. SUBJECTS: Children with spastic diplegia (5 boys; mean (+/- SD) age 8.0 +/- 1.4 years; 9 ambulant, 1 wheelchair use) and healthy children (5 boys; mean (+/- SD) age 8.4 +/- 1.0 years). MEASUREMENTS: Total daily energy expenditure (TEE) and sleeping metabolic rate (SMR) were measured by the doubly labeled water technique and a respiration chamber. The TEE/SMR ratio was used as an index for the level of daily physical activity. RESULTS: The TEE/SMR ratio under normal daily conditions in the children with cerebral palsy (mean +/- SD): 1.56 +/- 0.19) was significantly lower (p < 0.05) than in their healthy peers (mean +/- SD: 1.83 +/- 0.23) and was similar to the TEE/SMR ratio in a room-sized chamber. CONCLUSION: Children with spastic diplegia are considerably less active than their healthy peers. We recommend special physical activity programs for these children.

Body Height↗
PubMed1993

Murine T helper cell-2 lymphocytes express type I and type II IL-1 receptors, but only the type I receptor mediates costimulatory activity.

The role of IL-1 in augmenting the Ag receptor-initiated activation program was evaluated in IL-4-producing (Th2) CD4+ murine T lymphocytes. Northern blot and 125I-labeled IL-1 alpha cross-linking analyses demonstrated that Th2 lymphocytes express both type I and type II IL-1R. The expression of both IL-1R isoforms on the surface of the Th2 cells is coordinately up-regulated in response to anti-CD3 cross-linking in the absence of detectable accessory cells. Analyses of the kinetics of IL-1R acquisition demonstrated that the peak level of type I and type II IL-1R mRNA expression occurs after the peak expression of mRNA encoding IL-2R alpha and IL-4, which are two IL-1-responsive events in the Th2 activation program. Type I IL-1R ligand-binding antagonists, IL-1R antagonist and anti-type I mAb, were used to evaluate the functional significance of Th2 cell expression of two IL-1R isoforms. The addition of either IL-1R antagonist or anti-type I mAb completely inhibited the IL-1 alpha-augmented component of the proliferative response stimulated by anti-CD3 plus exogenous IL-1 alpha. Together, these studies indicate that, although Th2 clones express inducible levels of both type I and type II IL-1R isoforms, the IL-1-induced intracellular signals involved in augmenting an anti-CD3-stimulated proliferative response are mediated solely through the type I IL-1R.

Animals↗
PubMed1990

Activation of programmed cell death (apoptosis) by cisplatin, other anticancer drugs, toxins and hyperthermia.

Cell death induced by cisplatin was studied in Chinese hamster ovary cell lines, one proficient and the other deficient (100-fold sensitive) in DNA excision repair. Previous experiments demonstrated that cells progressed to and arrested in the G2 phase of the cell cycle before dying. DNA double-strand breaks were detected following G2 arrest and prior to loss of membrane integrity. These DNA breaks have been studied in more detail. DNA fragments were observed consisting of multimers of approximately 180 base pairs. These fragments are consistent with internucleosomal cleavage of chromatin by an endonuclease. At LC90 concentrations, DNA digestion began 48 hr cisplatin treatment followed by loss of membrane integrity and cell shrinkage 24 hr later. High concentrations of cisplatin (170 logs of kill) induced DNA digestion 12 hr after drug treatment but loss of membrane integrity occurred 12 hr later. Both cell death and DNA fragmentation were inhibited by cycloheximide, suggesting the requirement for new protein synthesis. Cells incubated with many other agents demonstrated the same characteristic pattern of DNA degradation. At 90% lethal conditions, DNA digestion was induced within 30 min by hyperthermia, 18 hr by methotrexate, and 48-72 hr by all other agents tested. DNA digestion always preceded loss of membrane integrity and cell shrinkage. These observations are consistent with cell death occurring by the process of apoptosis, or prorammed cell death, and demonstrate the importance of DNA digestion as an early and presumably essential step in cell death. The results suggest that, irrespective of the primary site of action of a drug, cell death by most pharmacologic agents is mediated by activation of the signal transduction pathway for apoptosis. The results also suggest two signal pathways for apoptosis, one directly associated with drug action and a second that requires cell cycle-related events.

Animals↗
PubMed1997

Class I- and class II-reactive TCRs coexpressed on CD4+ T cells both trigger CD4/CD8-shared and CD4-unique functions.

CD4+ and CD8+ T cells emerge from thymic selection expressing a TCR restricted by MHC class II (TCRII) and MHC class I (TCRI), and upon Ag stimulation develop respectively into Th and CTL effector cells. The influence of thymic differentiation and antigenic stimulation on the determination of T cell functions was studied, with CD4+ T cells expressing a transgenic TCRI that reacts with the class I alloantigen H-2K(b) in a CD8-independent fashion. Such T cells additionally express a TCR, probably TCRII, in which the transgenic TCR beta-chain is associated with endogenously rearranged TCR alpha-chains. Upon in vitro stimulation with H-2K(b)-expressing cells, both CD8+ and CD4+ transgenic TCR+ T cells developed into CTL capable of killing Ag-expressing target cells through a perforin-dependent mechanism, and secreted IL-2 and IFN-gamma. Fas ligand-dependent killing could also be induced in both CD8+ and CD4+ in vitro stimulated T cells. The capacity to secrete IL-4 was restricted to the CD4+ T cells, however, suggesting that both CD8/CD4-shared and CD4-unique programs can be elicited by stimulation of CD4 T cells through a TCRI. Acquisition of CTL function was also induced upon class II alloantigen stimulation through the endogenously rearranged TCRII, which represents a polyclonal set of TCRs. IL-2, IFN-gamma, and after restimulation, IL-4, were also produced. Thus: 1) events associated with intrathymic selection influence the gene program activated in response to the same TCRI/APC interaction; and 2) CD4+ T cells expressing a TCRI and a TCRII can activate the same gene program after engagement of either one of these TCRs.

Animals↗