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Results for “Step selection function”

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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↗

PubMed1989

[Immunologic examination of the blood in the differential diagnosis of acute gouty arthritis and rheumatoid arthritis].

In 16 patients with acute gouty arthritis, 30 IgM RF seropositive cases of rheumatoid arthritis (RA) and 20 IgM RF seronegative cases of RA the values of 14 indicators of antibody and natural immunity were assessed in serum. The assembled data were evaluated by step-wise discrimination analysis. This made it possible to select consecutively signs important for the differentiation of acute gouty arthritis from IgM RF seropositive RA (immunocomplexes, beta-2 microglobulin, C3) and for its differentiation from IgM RF seronegative RA (IgE, C3, transferrin, free SH groups). Thus obtained classification functions make it possible to classify correctly, random subjects with a probability of 76.7-93.7%.

Acute Disease↗

PubMed1985

[Prediction of pulmonary hypertension from simple, noninvasive parameters using discriminant analysis].

Based on a large number of males with chronic obstructive bronchitis, the usefulness of discriminant analysis for prediction of pulmonary hypertension has been investigated. Two groups were formed: 227 men with overt pulmonary hypertension; 145 patients without pulmonary hypertension Applying the discriminant analysis, 9 variables were selected step by step; 6 out of them were measurably contributing to the discrimination of both groups. As relevant turned out diameter of the right descending pulmonary artery, FVC% predicted, FEV1% FVC, pa2, systolic blood pressure, and RV% TLC. In a procedure of reclassification, based upon the calculated discriminant functions, 82,6% of the cases were correctly classified (sensitivity 80,6%, specificity 86,2%). A pocket calculator programme following the method by Läuter gave identical results. The application of the discriminant function to a new group of 147 unselected men with chronic obstructive bronchitis corroborated the foregoing results. 79,1% of all patients with overt or latent pulmonary hyper-tension were detected. For overt hypertension the sensitivity was 88,4%, for latent hypertension 62,5%. Using this method, decision-making regarding heart catheterism can be improved. It must be stressed, however, that this discriminant function is not valid for women and for other diagnosis groups in males.

Bronchitis↗

PubMed1983

Structural and functional evidence for multiple channel complexes in the outer membrane of Neurospora crassa mitochondria.

The outer membrane of mitochondria contains proteins that form channels called VDAC (voltage-dependent anion-selective channels). Two independent lines of evidence suggest that these channels occur in specific complexes in the outer membrane of Neurospora mitochondria. Electron microscopic images of these outer membranes reveal polymorphic crystalline arrays of putative pores. These arrays can be shown to be interrelated by movement in the membrane plane of a particular rigid channel triplet or of regular aggregates of this triplet. Detergent extracts of the same outer membranes induce single- and multiple-step conductances in planar phospholipid membranes, with a marked preference for the insertion of triplets and multiples of triplets. The tendency of the mitochondrial channels to occur as extended arrays, apparently built up from triplets, may have important functional and evolutionary implications.

Biological Transport↗

PubMed1992

Motor activity and the mesotelencephalic dopamine function. I. High-resolution temporal and genetic analysis of open-field behavior.

In a genetic selection experiment whose goal was to construct congenic neurological animal model lines with different mesotelencephalic dopamine systems, we produced foundation F2 generations derived from crosses (C57BL/6ByJXBALB/cJ and C57BL/6ByJXCXBI/ByJ) between highly inbred mouse lines with different dopamine systems. In this report, temporal distribution, latency, and genetic variability of open-field (OF) behavioral variables were investigated in order to establish a behavioral profile for the various generations and to provide behavioral data as a first step towards multivariate studies on correlations between OF behaviors and mesencephalic and striatal tyrosine hydroxylase activity. Analysis of the behavioral data provided evidence that measures of the open-field behaviors varied significantly across time segments of the test and that the temporal profiles of several behavioral variables were genotype-dependent. It is suggested that (1) OF behaviors have dynamic temporal profiles, and (2) temporal-genetic analysis can be a useful auxiliary method in the functional interpretation of behavior.

Animals↗

PubMed1991

CD-13 ('gp150'; aminopeptidase-N): co-expression on endothelial and haemopoietic cells with conservation of functional activity.

This report details experimental results which show the presence of enzymic aminopeptidase-N-like activity on endothelial cells, concomitant with cell surface expression previously detected by both ELISA and indirect immunofluorescence. This activity, detected using selected chromogenic substrates in 'functional' assays, is shown to be due (at least in part) to a molecule previously termed 'gp 150' and recognized by MoAb belonging to CD-13, since such antibodies can be shown to inhibit this activity. Activity, as detected on endothelial cells, is similar to that observed on various haemopoietic cells. These assays not only provide a functional basis to cell surface gp150 (CD-13) co-expression on haemopoietic and endothelial cells but have also been used to help define structural epitopes present on aminopeptidase-N/gp150, previously analysed using radiolabelled antibodies in competitive binding assays. Appraisal of these new data suggests that the number of distinct antibody binding sites on this molecule is greater than that previously demonstrated. This study is therefore an important first step in investigating the potential involvement of this selective peptidase molecule in the control of haemopoietic cell growth and differentiation and in haemostatic mechanisms.

Aminopeptidases↗

PubMed1990

Tumor suppressor genes.

The retinoblastoma sensitivity protein (Rb) and the p53 gene product both appear to function as negative regulators of cell division or abnormal cellular growth in some differentiated cell types. Several types of cancers have been shown to be derived from cells that have extensively mutated both alleles of one or both of these genes, resulting in a loss-of-function mutation. In the case of the p53 gene, this mutational process appears to occur in two steps, with the first mutation at the p53 locus resulting in a trans-dominant phenotype. The mutant p53 gene product enters into an oligomeric protein complex with the wild-type p53 protein derived from the other normal allele and such a complex is inactive or less efficient in its negative regulation of growth control. This intermediate stage of carcinogenesis selects for the proliferation of cells with one mutant allele, enhancing the probability of obtaining a cancer cell with both alleles damaged. The DNA tumor viruses have evolved mechanisms to interact with the Rb and p53 negative regulators of cellular growth in order to enhance their own replication in growing cells. SV40 and adenovirus type 5 produce viral encoded proteins that also form oligomeric protein complexes with p53 and Rb, presumably inactivating their functions. These viral proteins are also the oncogene products of these viruses. Thus, the mechanisms by which cancer may arise in a host, via mutations or virus infections, have fundamental common pathways effecting the same cellular genes and gene products; Rb and p53.

Amino Acid Sequence↗

PubMed2026

Alternatively spliced killer-protector system confers S19-mediated hybrid male sterility in rice.

Hybrid sterility limits the use of strong interspecific heterosis and S19 is a major locus that confers hybrid sterility between Oryza sativa (Asian cultivated rice) and Oryza glaberrima (African cultivated rice). However, the S19 is not yet cloned and its underlying mechanism remains elusive. In this study, we identify two closely linked genes (S19A1 and S19A7) specific to African rice allele that encode a killer-protector module at the S19 locus. Two alternatively spliced transcripts expressed from the killer gene S19A1 (S19A1.1 and S19A1.2) encode mitochondria-targeted cytotoxic proteins that cause toxicity diversity for somatic and/or gametic cell death, respectively. However, S19A7 interacts with S19A1.1 and S19A1.2, blocking their cytotoxic effect. Because the Asian rice S19 allele lacks S19A1 and S19A7, male gametes that carry this allele are selectively aborted in Asian-African F1 hybrids. Knockout of S19A1 can overcome S19-mediated hybrid sterility. Haplotype analysis reveals that the functional S19 allele is absent in non-AA-genome Oryza species and likely emerged in the O. barthii-O. glaberrima lineage through a multi-step evolutionary process. Our findings provide insight into the genetic mechanisms responsible for hybrid sterility between Asian and African rice and suggest genetic and biotechnological strategies for the use of interspecific heterosis in rice.

Oryza↗

PubMed1987

TUF, the yeast DNA-binding factor specific for UASrpg upstream activating sequences: identification of the protein and its DNA-binding domain.

The factor TUF interacts specifically with RPG or HOMOL1 sequences, which are present upstream of many genes coding for the yeast translational apparatus. Here we present evidence that the RPG and HOMOL1 motifs are variants of a consensus UASrpg (upstream activating sequence) recognized by the same factor. Factor TUF was identified by using two highly selective methods. The DNA-protein complex was isolated by pore-limit electrophoresis in polyacrylamide gradient gels and found to contain a single polypeptide of 150 kDa. In a two-step protein-blotting/nuclease-protection ("footprinting") procedure, the same 150-kDa polypeptide blotted on nitrocellulose exhibited the same specific DNA-binding properties as TUF factor. A 50-kDa DNA-binding domain of TUF was isolated by selective proteolysis. This suggests a bipolarization of the TUF protein, with distinct functional domains.

Base Sequence↗

PubMed1992

Isolation and functional analysis of histidine-tagged elongation factor Tu.

The study of the structure/function relationships of the Escherichia coli elongation factor Tu (EF-Tu) via mutagenesis has been hampered by difficulties encountered in separating the mutated factor from other proteins, in particular native EF-Tu. Here we describe a novel system for the purification of EF-Tu mutant species, based on metal-ion affinity chromatography. To facilitate rapid and efficient purification we designed a recombinant EF-Tu with an additional C-terminal sequence of one serine and six histidine residues. A cell extract containing the His-tagged EF-Tu (EF-TuHis) is applied to a Ni(2+)-nitrilotriacetic acid column. EF-TuHis can be selectively eluted with an imidazole containing buffer, yielding a preparation of more than 95% purity, free of wild-type EF-Tu. In-vitro and in-vivo functional analyses show that EF-TuHis resembles the wild-type EF-Tu, which makes this one-step isolation procedure a promising tool for the study of the interactions of mutant EF-Tu with the various components of the elongation cycle. The new isolation procedure was successfully applied for the purification of a mutant EF-TuHis with a Glu substitution for Lys237, a residue possibly involved in the binding of aminoacyl-tRNA.

Amino Acid Sequence↗

PubMed1990

In-series compliance of gastrocnemius muscle in cat step cycle: do spindles signal origin-to-insertion length?

1. It has been claimed that stretch in the non-contractile (extramysial) portion of muscles is substantial, and may produce large discrepancies between the origin-to-insertion muscle length and the internal length variations 'seen' by muscle spindle endings. 2. In eight pentobarbitone-anaesthetized cats, we estimated stretch in the extramysial portion of medial gastrocnemius (MG) muscle with a method similar to the spindle null technique. 3. Length variations of MG previously monitored in a normal step cycle were reproduced with a computer-controlled length servo. The responses of test MG spindle endings were monitored in dorsal root filaments. Distributed stimulation of ventral root filaments, rate-modulated by the step-cycle EMG envelope, served to reproduce step-cycle forces. The filaments were selected so as to have no fusimotor action on the test spindle. 4. Spindle responses in active cycles were compared with those in passive cycles (stretch, but no distributed stimulation). In some cases concomitant tonic fusimotor stimulation was used to maintain spindle responsiveness throughout the cycle, both in active and passive trials. Generally, small discrepancies in spindle firing were seen. The passive trials were now repeated, with iterative adjustments of the length function, until the response matched the spindle firing profile in the active trial. The spindle 'saw' the same internal length change in the final passive trial as in the active trial. Any difference between the corresponding length profiles was attributed to extramysial displacement. 5. Extramysial displacement estimated in this was was maximal at short mean muscle lengths, reaching about 0.5 mm in a typical step cycle (force rising from 0 to 10 N). At longer mean muscle lengths where muscle force rose from say 2 to 12 N in the cycle, extramysial displacement was in the range 0.2-0.4 mm. 6. Except at very short lengths, the displacement was probably mainly tendinous. On this assumption, our results suggested that the stiffness of the MG tendinous compartment was force related, and about double that of cat soleus muscle at any given force. Calculations indicated that though the stretch was small, the MG tendon would store and release enough strain energy per cycle to contribute significantly to the E3 phase of the step cycle. The discrepancies in spindle firing were generally quite subtle, so we reject the claim that extramysial stretch poses a serious difficulty for inferences about fusimotion from chronic spindle afferent recordings.

Action Potentials↗

PubMed1990

How Escherichia coli RNA polymerase can negatively regulate transcription from a constitutive promoter.

We previously described the structures and functions of specific complexes between the bla promoter from Tn3 (present in pBR322) and RNA polymerase (RNAP), showing that, at excess RNAP, complexes can form in which one or two RNAPs bind to the same promoter (1:1 and 2:1 complexes) (Duval-Valentin and Ehrlich, 1988). We report here that the 2:1 complex cannot be detected below 25 degrees C; above that temperature, a 1:1 complex forms at a rate one order of magnitude faster than that of the 2:1 complex, and above 30 degrees C, the amounts of both species become equal for RNAP/promoter ratio r30 less than or equal to r less than or equal to 70. The 2:1 complex decays back to a 1:1 complex losing the last RNAP at a rate about three times that of the 1:1 complex decay. Functional assays of the complexes formed at excess RNAP show that both 1:1 and 2:1 complexes are immediately and permanently inhibited, even when the promoters are pre-incubated with ribonucleotide selections potentially enabling entrance into abortive cycling or formation of a stressed complex. We conclude that the inhibition step probably takes place in the complex formation pathway between RPi and RPo, at a novel stable intermediate isomer, RPj, formed above 25 degrees C. A possible mechanism of formation of the 2:1 complex is outlined. In vivo studies, in which r was modified by varying the bacterial growth rate, show a reduction of bla expression as r values are upshifted, specific to the bla promoter from Tn3.

DNA-Directed RNA Polymerases↗

PubMed1988

Evaluation of the infertile couple.

The evaluation of the infertile couple is usually a lengthy investigation in which all possible etiologic factors in both partners have to be considered. Optimal and cost-effective investigation requires adequate recognition of significant historical data and physical findings. Males without stigmata of endocrinopathies or general medical illnesses require an analysis of their semen as the minimum initial step of evaluation. Those suspected of deficient androgen production and/or action and those with abnormal sperm counts, motility, and/or morphology need assessment of their serum concentrations of selected reproductive hormones. When these initial investigations are negative and there are no demonstrable etiologic female factors underlying the state of infertility, specialized sperm function and sperm allergy testing needs to be performed. The initial investigation of the female partner is best served by assessing the frequency of ovulation and adequacy of corpus luteum function. Women without ovulatory defects should be assessed for the presence of the hostile cervical mucus and structural anomalies of the reproductive tract. Investigations of patients with menstrual dysfunctions should be based upon the presence or absence of hirsutism, changes in body weight, and evidence of other endocrinopathies or medical illnesses. Following the identification and normalization of causes of anovulation, further work-up of patients who remain infertile is similar to those with regular menstrual cycles. The diagnosis of idiopathic infertility is essentially by exclusion of all other causes. Algorithms for the diagnostic evaluation of most infertile couples are provided.

Female↗

PubMed1976

Percent satellite DNA as a function of tissue and age of mice.

A selective loss of satellite DNA was found to occur to different extents as a function of tissue and age of mice using several common DNA extraction and purification procedures. This result emphasizes a serious problem that may be encountered in comparative studies of DNA structure and composition if selective loss of specific DNA sequences occurs. We have developed a DNA extraction and purification procedure that is simple and reliable and gives a high percent DNA yield, which substantially reduces the selective loss of heterochromatin DNA sequences. The method features a centrifugation step of a proteolytic digest of chromatin in 2.4 M CsCl. Percent DNA yield of 82-98% are routinely obtained with no apparent loss of satellite DNA sequences from different tissues or ages of mice. Utilizing this method, percent satellite DNA was found to remain essentially constant at 11 +/- 1% for spleen, kidney, and brain tissues obtained from mice of 10-780 days of age. However, for liver, percent satellite DNA remained at about 7-8% from 10 to 300 days of age and then increased to about 12-13% from 300 to 600 days of age. During this latter time interval (300-600 days), an increase of DNA per nucleus of about 3-fold occurred, due to the formation of tetra- and octaploid cell types. A steady loss in the total number of nuclei per gram of liver as a function of age was also found. These two opposing effects resulted in a nearly constant amount of DNA per gram and per organ for liver throughout the lifespan of the mouse.

Aging↗