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Results for “Step selection function”

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PubMed1985

Differential modulation of the expression of axonal proteins by non-neuronal cells of the peripheral and central nervous system.

Axonal behavior during the formation of the neuronal network of the nervous system has been shown to be under environmental control. Hence, as a first step in a project aiming to elucidate the molecular basis of axonal functions, we have identified axonal proteins whose synthesis is subject to environmentally induced changes. Neurons from chicken embryonic dorsal root ganglia (DRG) were grown in a compartmental cell culture system that allows selective examination of axonal proteins. Non-neuronal cells of the peripheral or central nervous system were co-cultured with the DRG axons. The axonal proteins expressed under these different environmental conditions were examined by metabolic labeling and two-dimensional SDS-polyacrylamide gel electrophoresis. Computerized quantification revealed that 12 out of 400 axonal proteins responded to changes in the local axonal environment by a change in their relative abundance. Some proteins changed in response to both types of co-cultures whereas some changed specifically under the influence of either peripheral or central non-neuronal cells.

Animals↗

PubMed1986

A cloned T cell line that selectively augments antibody responses of phosphorylcholine-specific B cells bearing the T15 idiotype.

Helper T (Th) cells have shown to be heterogeneous both in their function and in their specificity. Several studies have demonstrated that there exist Th cells which do not appear to be specific for antigen:Ia complexes (not H-2 restricted) but interact with the target B cell via recognition of immunoglobulin idiotypic determinants. In analyzing anti-phosphorylcholine (PC) responses, such idiotype-specific Th cells are characterized by 1) their ability to increase responses to phosphorylcholine by augmenting selectively the activation of T15-idiotype-bearing PC-specific B cells, 2) their ability to bind specifically to T15-bearing immunoglobulin and 3) the dependence of their maturation on circulating T15 idiotype rather than Ia. Our aim is to explore further the relationship between Ia-specific and T15-specific Th cells. These studies describe the first step in comparing specificity and function of idiotype-specific Th cells to other known Th cells by the cloning of a T15-specific Lyl T cell (ThId) with properties consistent with those described for uncloned populations. The cloned ThId cells generated do not activate B cells to secrete antibody but augment anti-PC plaque forming cell (PFC) responses induced by Ia-restricted Th cells. This augmentation is seen only in the T15-bearing PFC responses even though non-T15-bearing B cells are equally accessible, and it is seen only in PC responses and not responses to TNP under identical culture conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Isolation of highly purified lymphocyte subsets for functional studies by means of an indirect rosette technique.

An indirect rosette assay, utilizing ox erythrocytes (RBC) coupled with rabbit anti-mouse IgG and lymphocytes sensitized with monoclonal mouse antibodies against membrane markers, was used for purification of lymphocyte subsets that were functionally intact. Either peripheral blood mononuclear cells (PBMC) or T lymphocytes isolated by sheep RBC rosetting could be used as starting material for obtaining pure T-cell subsets (T4 or T8). The following steps of the method were evaluated: the procedure of coupling rabbit anti-mouse IgG to ox RBC via the CrCl3 method, the experimental conditions for specific rosetting, and the use of Percoll for the separation of rosettes from the non-rosetting cells. Under optimal experimental conditions the recovery of positively selected cells was 45-55% of the cells originally present in the PBMC. The purity of these cells reached a value of more than 95%, whereas the contamination of the depleted fraction was less than 3%. The functional integrity, manifesting itself as proliferation after mitogen stimulation and as regulatory influences on in vitro Ig synthesis, appeared to be unimpaired. The described technique may be applied to the purification of various cell subpopulations for functional studies, provided monoclonal antibodies against membrane antigens are available.

Animals↗

PubMed1992

Involvement of the N-methyl D-aspartate (NMDA) receptor in synapse elimination during cerebellar development.

In many instances, the establishment of highly specific neuronal connections during development results from the rearrangement of axonal projections through the trimming of exuberant collaterals or the elimination of functional synapses or both. Although the involvement of the N-methyl D-aspartate (NMDA) subtype of the glutamate receptor has been demonstrated in the shaping of axonal arbors, its participation in the process of selective stabilization of synapses remains an open issue. In this study, the effects of chronic in vivo application of D,L-2-amino-5-phosphonovaleric acid (D,L-APV), a selective antagonist of the NMDA receptor, on the synapse elimination process that takes place in the developing cerebellum of the rat have been analyzed. D,L-APV treatment prevented the regression of supernumerary climbing fiber synapses in 49 percent of the recorded Purkinje cells, while the inactive isomer L-APV was ineffective. Thus, activation of the NMDA receptor is a critical step in the regression of functional synapses during development.

2-Amino-5-phosphonovalerate↗

PubMed1989

Bioassay for trans-activation using purified human immunodeficiency virus tat-encoded protein: trans-activation requires mRNA synthesis.

Expression of the human immunodeficiency virus tat-encoded protein (Tat) is required for virus replication. A genetic approach was used to facilitate the purification of biologically active Tat. A recombinant Tat protein containing a stretch of six histidine residues and a protease cleavage site was engineered and purified to greater than 95% homogeneity in a single step by immobilized metal-ion chromatography with a special affinity resin that has selectivity for proteins with neighboring histidine residues. A modified scrape loading method for introduction of protein into cell monolayers was used to demonstrate that the purified Tat retained biological activity. Tat function was completely blocked in the presence of transcription inhibitors, which demonstrates the requirement of ongoing mRNA synthesis for trans-activation. These studies indicate that the mechanism of trans-activation is unlikely to involve a direct action of Tat on mRNA stability, transport, or translation and provides the basis for a rapid assay that can be used to identify inhibitors of trans-activation. The methods described herein should be useful for the functional analysis of other proteins that do not confer activity through a receptor-mediated pathway.

Amino Acid Sequence↗

PubMed1978

A new anesthesia delivery system.

A prototype anesthesia delivery system has been developed to test the appropriateness of new technological design approaches. The objectives were to eliminate human-factors problems associated with present anesthesia apparatus and to lay a suitable technical foundation for the development of new techniques in anesthesia management. This prototype performs all the functions of a conventional anesthesia machine, as well as many monitoring and surveillance tasks. Eventual incorporation of new teaching functions, and additional monitoring and record-keeping activities, are intended. The system is fundamentally electronic with few moving parts. Reliability, safety, and clarity of operation were the primary criteria in selection and application of the specific technologies employed. The result is a promising first step in the development of a system oriented toward supporting rather than preoccupying the anesthestist.

Anesthesia↗

PubMed1979

Mode of uptake and degradation of 125I-labelled insulin by isolated hepatocytes and H4 hepatoma cells.

The effects of various agents on the binding and degradation of 125I-labelled insulin by isolated rat hepatocytes and cultured H4 hepatoma cells were studied. Various lysosomotropic agents, including chloroquine, ammonium chloride, and the topical anesthetics, lidocaine and procaine inhibited insulin degradation by H4 hepatoma cells but had little effect on the binding of the hormone. Similarly, tosyl-L-lysyl chloromethyl ketone selectively inhibited the degradation of 125I-labelled insulin by isolated hepatocytes, as did the sulfhydryl reagents, p-hydroxy- and p-chloromercuriphenyl sulfonic acid. Inhibitors of energy production, including sodium fluoride, sodium azide, and dinitrophenol, also selectively inhibited the degradation of insulin by hepatocytes, although cyanide had no effect under the conditions used. Lectins and antimicrotubular agents, which are known to affect the mobility of plasma membrane proteins or of intracytoplasmic vesicles, selectively inhibited insulin degradation by hepatocytes to varying degrees, whereas agents which inhibit the function of microfilaments had no effect. At temperatures below 20 degrees C, insulin degradation was negligible but rose rapidly between 20 and 37 degrees C, suggesting that a membrane-related step is rate limiting in the overall degradative process. These results are all consistent with a model of insulin uptake by target tissue involving pinocytosis of receptor-bound hormone followed by intralysosomal degradation.

Animals↗

PubMed2026

Graph neural network-based risk stratification of prostate cancer using gene expression and SHAP interpretability.

Accurate risk stratification is essential for guiding treatment decisions and preventing over treatment of prostate cancer, which remains one of the most prevalent cancers among adult men. While the Gleason score, obtained from prostate biopsies, is routinely used to assess tumor aggressiveness, the biopsy procedure carries risks such as pain, infection, and, in some cases, serious complications such as sepsis. In this study, we proposed an artificial intelligence-based framework that integrates mRNA expression profiles with functional interaction networks to classify prostate cancer patients into low-, medium-, and high-risk groups defined by Gleason scores. The pipeline comprised five steps: (1) data collection from The Cancer Genome Atlas (TCGA), (2) preprocessing of gene expression data, (3) two-stage feature selection to identify informative biomarkers, (4) risk classification using a dual-branch graph neural network (GNN) that combines gene-gene interaction graphs with sample-level expression features, and (5) model interpretation using SHAP to quantify feature contributions. Differentially expressed genes were identified in the High (ASPN, GMNN, PEBP4, C2, KNCK17), Medium (C2, IGSF1, ASPN, CDKN3, AMH), and Low (TNMD, VWA5B2, ST6GALNAC5, CYP3A5, PHGR1) risk groups, underscoring the molecular heterogeneity of disease progression. On an independent held-out test set, the model achieved AUCs of 0.86, 0.88, and 0.95 for the low-, medium-, and high-risk groups, respectively, with an overall accuracy of 80%. These results suggest that combining GNN-based modeling with explainable AI can capture both global and local molecular patterns relevant to tumor aggressiveness. However, as the model was developed and evaluated solely on the TCGA cohort, the findings should be regarded as exploratory, and external validation will be required to establish generalizability. Within these limitations, the proposed framework highlights the potential of molecular profiling and graph-based deep learning to support more precise, potentially less invasive, risk assessment and individualized treatment planning in prostate cancer.

Prostatic Neoplasms↗

PubMed1988

Protection of phosphoglycerate kinase against in vitro aging by selective cysteine methylation.

Recent studies have demonstrated that the aging effects in phosphoglycerate kinase (PGK) may be simulated in vitro by prolonged incubation of the enzyme under nonreducing conditions followed by reduction with excess 2-mercaptoethanol. The simulated-old enzyme thus produced appears to be identical to native old PGK and, like the latter enzyme, may be successfully rejuvenated by an unfolding-refolding procedure. A model for PGK aging was proposed in which initial and reversible oxidation of the enzyme is followed by conformational modifications that persist after the enzyme is re-reduced. The role of specific cysteine oxidation in the initial step of PGK aging was tested in the present study by selectively methylating the fast-reacting cysteine residues in this enzyme, thus blocking the putative oxidation sites, and producing in vitro a young form of PGK that is immune to aging. The methylation was performed by treating the enzyme with excess iodomethane and monitoring the reaction by determining the concentration of unreacted cysteines in the enzyme as a function of time. Unmethylated controls were incubated similarly but in the absence of iodomethane. The methylated as well as control samples of PGK were subsequently incubated under conditions which caused native young PGK to develop the age-related effects and become identical to native old PGK. In contrast, the methylated enzyme remained identical to young PGK. These findings strongly support the hypothesis that cysteine oxidation is an essential step in the aging of rat muscle phosphoglycerate kinase.

Aging↗

PubMed1989

Anaerobic threshold: reproducibility out from ventilatory parameter estimation.

Anaerobic threshold (AT) during exercise is usually noninvasively determined by assuming a two-segment mathematical relationship between two ventilatory parameters. In the literature, all the possible pairs of segments are first considered, and the most appropriate pair is then selected according to at least-squares method. In such a model, the AT is considered to be related to the joining point of the two segments. In order to test the reliability of the model, we compare the results of the least-squares method to those based on maximum probability method in discriminating the two regression coefficients. In order to test the reproducibility of the two different criteria, comparisons have been repeated after data have been filtered. A paired t test was used to carry out comparisons. Ventilatory parameters were collected in 10 healthy subjects during the use of a bicycle ergometer. The required power was increased every 15 s by steps of 30 W, starting from 50 W. Ve, VO2 and VCO2 have been sampled every 15 s, then the three functions--Ve versus VO2, Ve versus VCO2 and VCO2 versus VO2--were considered. Each function was stylized with two linear segments. Each segment was estimated by using a second-kind linear fitting. We verified that: (i) the AT may be reliably appreciated depending on the pair of selected parameters; (ii) only when data are smoothed is no difference between the two criteria documented (Ve vs. VO2, p = 0.99; Ve vs. VCO2, p = 0.54); (iii) no significant difference, related to smoothing, is documented both in using the least-squares method (Ve vs. VO2, p = 0.61; Ve vs. VCO2, p = 0.15) and the maximum p level criterion (Ve vs. VO2, p = 0.59; Ve vs. VCO2, p = 0.19).

Adolescent↗

PubMedDate not supplied

Use of a symmetry condition to compute the conformation of gramicidin S1.

Using an improved method for computing conformations of closed rings with symmetry, in conjunction with an improved empirical energy function, the conformational space of Gramicidin S is reexamined. The search for minimum energy conformations is confined to the subspace containing closed symmetric rings. A large number of initial conformations selected from that subspace is subjected to energy minimization or is eliminated in a sequence of steps designed to locate the global minimum-energy conformation. One conformation having distinctly low energy is found and is judged to be the global minimum-energy conformation. This conformation is of the beta-pleated sheet type and is in complete agreement with experimental data. Similar structures with beta-pleated sheet-type conformations have been proposed previously on the basis of less extensive examiniations of the conformational space; the condition of exact ring closure, and the extensive examination of conformational space, used here, establish this structure on a firm basis.

Computers↗

PubMed1990

Pathogenicity of 5-fluorocytosine resistant strains of Candida albicans.

Mutants of Candida albicans blocked in pyrimidine transport and salvage metabolism were produced by a two step mutagenic procedure and selected by their resistance to 5-fluorocytosine (flucytosine). The growth rates and growth yields of these mutants did not differ significantly from the parental strain of C. albicans. Examination of their pathogenicity to mice demonstrated that a defect in the uridine transport function decreased the pathogenicity of C. albicans.

Animals↗

PubMed1985

Calmodulin: calcium, potassium, and magnesium ion multiple equilibria and kinetics for interconversion, including the effect of repeated stimulation.

Using computer simulations, with realistic values for the intrinsic thermodynamic binding constants and kinetic on and off rate constants at the four metal-binding sites, the calmodulin molecule is shown to have been optimally adjusted by evolution for biological function. Despite a very large number of potential molecular states, depending upon occupation by potassium, calcium, or magnesium ions, the system restricts itself to a small number of physiologically-significant equilibrium species. It appears to possess built-in triggers for biological processes, with rapid (approximately 20 ms time-scale), step-function shaped, changes of the populations of the CMKK, CMMK, CKKK, CMMM (and CCKK) states. The time-response of calmodulin to periodic changes in ionic levels (2 and 5 s-1) makes it quite adequate for repeated stimulations. In short, calmodulin appears as a very selective information transmitter at the molecular level.

Binding Sites↗

PubMed1991

Identification of T-cell epitopes without B-cell activity in the first and second conserved regions of the HIV Env protein.

We have previously hypothesized that an effective vaccine against HIV should elicit cell-mediated immunity without antiviral antibody production. As a first step towards this goal we have identified potential T-cell epitopes, without B-cell activity against the native protein, from the first and second conserved sequences, and from three functionally important regions of the HIV-1 envelope protein gp160. For this approach, short peptide sequences selected by established computer programs were synthesized and chemically modified to generate either polymers with disulfide bonds, or micelles with two palmitic acid residues attached to the amino-terminal lysine. In both configurations several peptides were immunogenic without the need for coupling to carrier molecules. Of the 19 peptides we tested in our present studies, seven induced good T-cell proliferative response in mice representing four major histocompatibility complex haplotypes. None of these seven peptides produced antibodies that could recognize the envelope protein gp160.

Amino Acid Sequence↗

PubMed1992

von Willebrand factor as a target for antithrombotic intervention.

The adhesive protein von Willebrand factor is essential for the formation of platelet thrombi under flow conditions characterized by high shear stress. This function requires the interaction with two distinct platelet receptors, the glycoprotein complexes Ib-IX-V and IIb-IIIa. Interaction with the former results in platelet activation, a necessary step for binding to the latter and supporting stable aggregation. The inhibition of von Willebrand factor binding to glycoprotein Ib can be achieved with small recombinant fragments containing the specific functional domain of the molecule that interacts with this platelet receptor. Such fragments may provide a new selective approach to antithrombotic therapy.

Amino Acid Sequence↗

PubMed1989

The visual superior colliculus and pulvinar.

The data reviewed here suggest several relationships between the superior colliculus, pulvinar and saccadic eye movements. These will be summarized in a series of steps in the visual initiation of saccadic eye movements. Area Pdm of the pulvinar appears to be involved in visual spatial attention. As such it may participate in the earliest decisions to make an eye movement: the shift of attention. This function is suggested by the spatially selective enhancement seen in the activity of individual neurons and the effects of drug injections on attentional performance. The attentional function of area Pdm is probably accomplished in coordination with cortical area 7 and possibly other areas. The spatially non-selective enhancement found in PI and PL may precede or follow the enhancement in Pdm. The next oculomotor function may be played by the visual cells in the superficial layers of the colliculus. Here the enhancement effect appears to be related to target selection which is specifically used with saccadic eye movements. Lesions here lead to animals who are not easily distracted by peripheral events; they do not select saccade targets. Thus the visual regions of the superior colliculus and Pdm may provide separate initiatives to the saccadic system. Once the eye begins to move, there are many relations manifested in both brain areas. Many of the visual collicular cells and those in parts of the pulvinar are unresponsive to visual stimuli during eye movements. In the colliculus, this particular effect may function to minimize erroneous visual targets whereas in the pulvinar the process may be more important perceptually. Finally there is a population of cells in the pulvinar which discharge during and after saccadic eye movements. These cells may have a role in the termination of one attentional scan and the beginning of the next. The pathways through which these effects may be mediated are totally unclear. The visual signal from the superficial layers related to saccade initiation may impinge directly on the cells in the intermediate layers or may reach the oculomotor system through other pathways. The parts of the pulvinar which relate to visual spatial attention are interconnected with posterior parietal cortex and probably function in concert with that area. How those data get to the oculomotor system has yet to be determined. Since the pulvinar is extensively interconnected with the cortex, it is most likely through this route that eye movement information coming from the superior colliculus is brought to higher perceptual areas.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1986

Macrophage antigens and the effect of a macrophage activating factor, interferon-gamma.

Molecules characteristic of mononuclear phagocytes have been identified using monoclonal antibodies (MAb). MAb 3.9 reacts with a 150/95 000 dalton heterodimer which is found exclusively on monocytes and macrophages and appears to be the third member of the lymphocyte function-associated (LFA) family of molecules. In contrast, the reactivity of MAb 24, which bonds to a 175 000 dalton protein, is most highly expressed on the macrophages in lymphoid tissue. Both 3.9 and 24 detect the interdigitating cells in the T cell areas of these tissues, which strongly suggests that this cell type belongs to the macrophage family. A third MAb, 10.1, reacts selectively with a set of macrophages outside lymphoid tissue, particularly on Kupffer cells, alveolar macrophages and microglia. Thus subsets of tissue macrophages are proving easy to identify whereas it appears that circulating monocytes are not easily subdivided. None of the MAbs detected either Langerhans' cells, dendritic reticulum cells of B cell areas, or osteoclasts, indicating that these cells are not mononuclear phagocytes. As a first step towards identifying macrophage molecules which have a biological function, we have investigated the effect of macrophage-activating factor, interferon-gamma, on the expression of macrophage membrane molecules. There was greatly increased expression of only two out of ten molecules detected with anti-myeloid antibodies.

Antibodies, Monoclonal↗

PubMed1991

Modular organization of genes required for complex polyketide biosynthesis.

In Saccharopolyspora erythraea, the genes that govern synthesis of the polyketide portion of the macrolide antibiotic erythromycin are organized in six repeated units that encode fatty acid synthase (FAS)-like activities. Each repeated unit is designated a module, and two modules are contained in a single open reading frame. A model for the synthesis of this complex polyketide is proposed, where each module encodes a functional synthase unit and each synthase unit participates specifically in one of the six FAS-like elongation steps required for formation of the polyketide. In addition, genetic organization and biochemical order of events appear to be colinear. Evidence for the model is provided by construction of a selected mutant and by isolation of a polyketide of predicted structure.

Amino Acid Sequence↗