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PubMed1980

Genetic control of T-cell proliferative responses to poly(glu40ala60) and poly(glu51lys34tyr15): subregion-specific inhibition of the responses with monoclonal Ia antibodies.

The relationship between Ir genes and Ia antigens was studied in the T-cell proliferative responses to two synthetic polypeptides poly(glu40ala60) (GA) and poly(glu51lys34tyr15) (GLT15). The response to GA was found to be controlled by an Ir gene in the I-A subregion, whereas the anti-GLT15 response was shown to be under dual control, one Ir gene mapping probably in the I-A subregion, and the other in the I-E subregion. We obtained two different lines of evidence suggesting identity of Ir and Ia genes. First, the presence of certain serologically identified allelic forms of the I-A-encoded A molecule correlated with the responder status to GA both in inbred strains and in B10.W lines, the latter carrying wild-derived H-2 haplotypes. Thus the Ir and Ia phenotypes were not separable in strains of independent origin. Second, the anti-GA response was completely inhibited by monoclonal antibodies against determinants on the A molecule (Ia.8, 15, and 19), but not by a monoclonal antibody against a determinant on the E molecule (Ia.7). In contrast, the anti-GLT15 response was only inhibited by a monoclonal antibody against the E molecule, but not by antibodies against the A molecule. Our data support the hypothesis that Ia antigens, as restriction elements for T-cell recognition, may in fact be the phenotypic manifestation of Ir genes.

Alanine↗

PubMedDate not supplied

Adrenergic versus VIPergic control of cyclic AMP in human colonic crypts.

The actions of catecholamines on VIP-induced cyclic AMP is studied in human colon. We show that: (1) Epinephrine in the 10(-7)-10(-3) M concentration range (ED50 = 11.10(-6) M) inhibits VIP-induced cyclic AMP rise in isolated colonic epithelial cells; the maximal inhibition reaches 30% of VIP effect; epinephrine alters the efficacy of the peptide and does not modify its potency; epinephrine also reduces the basal cyclic AMP level. (2) The inhibition is found with other alpha adrenergic agonists with the order of potencies epinephrine greater than norepinephrine greater than phenylephrine. Clonidine has a poor intrinsic activity but antagonizes the action of epinephrine. (3) The inhibition of VIP action by epinephrine is reversed by the alpha antagonists dihydroergotamine, phentolamine and the alpha 2 antagonist yohimbine, while unaffected by the beta antagonist propranolol and the alpha 1 antagonist prazosin, (4) Epinephrine inhibits VIP-stimulated adenylate cyclase activity in preparations of colonic plasma membranes. Thus catecholamines exert through an alpha 2 adrenoreceptor a negative control on basal and VIP-stimulated cyclic AMP formation in human colon. We suggest that colonic cyclic AMP metabolism undergoes a dual control: VIPergic, activator and adrenergic, inhibitor.

Adenylyl Cyclases↗

PubMed2004

Sexual addiction, sexual compulsivity, sexual impulsivity, or what? Toward a theoretical model.

We critically review the concepts of sexual addiction, sexual compulsivity, and sexual impulsivity and discuss their theoretical bases. A sample of 31 self-defined sex addicts were assessed by means of interview and questionnaires and compared with a large age-matched control group. A tendency to experience increased sexual interest in states of depression or anxiety was strongly characteristic of the sex addict group. Dissociative experiences were described by 45% of sex addicts and may have some explanatory relevance. Obsessive-compulsive mechanisms may be relevant in some cases, and the addiction concept may prove to be relevant with further research. Overall, results suggested that out of control sexual behavior results from a variety of mechanisms. We propose an alternative theoretical approach to investigating these mechanisms based on the dual control model and recent research on the relation between mood and sexuality.

Adult↗

PubMed1995

Analysis of 14q+ derivative chromosomes in non-Hodgkin's lymphomas by fluorescence in-situ hybridization.

The most common chromosomal abnormality observed in non-Hodgkin's lymphomas (NHL) involves the structural alteration of the q arm of chromosome 14. It is not always possible, however, to fully analyse such derivative chromosomes by Giemsa-banding. Therefore, we have applied the fluorescence in-situ hybridization (FISH) technique of chromosome painting to elucidate the origins of the der(14) chromosomes in 8 cases of NHL. In 2 NHL the der(14) appeared to be the product of the t(14;18)(q32;q21) translocation, but were not accompanied by the reciprocal der(18) chromosome. In 3 cases the breakpoint was at 14q32 but the translocated material appeared not to be from chromosome 18 and in 2 cases the breakpoint was centromeric to 14q32. One case with a t(14;18)(q32;q21) was also analysed as a control. Dual painting was carried out with paints for chromosome 14 and either chromosome 3, 8, 10, 11, 18 or 19. In the control and 2 other cases the translocated material was demonstrated to be from chromosome 18, in two cases it was from chromosome 3 and in 1 case there was an unusual insertion of chromosome 11 material. We were unable to identify the origins of the translocated material in 1 NHL and in the final case the apparent der(14) was demonstrated not to contain chromosome 14 material. These data demonstrated the utility of the FISH technique for analysing malignant cell karyotypes, and in particular indicated the potential of this approach for identifying cases containing putative NHL associated oncogenes that may have been translocated adjacent to the immunoglobulin locus at 14q32.

Chromosome Aberrations↗

PubMed1992

The role of inhibin and oestradiol in the control of FSH secretion in the sheep.

The relative importance of inhibin and oestradiol in the control of FSH and LH secretion in the ewe was investigated by passive immunization in intact animals and by hormone replacement therapy following acute ovariectomy, in the same experiment. Mature Scottish Blackface ewes on day 10 of the luteal phase were allocated to nine groups of four to five animals. Four groups were ovariectomized and immediately treated with either progesterone alone or in combination with steroid-stripped ovine follicular fluid ('inhibin') and/or oestradiol. Three further groups of ewes were left intact and injected with antibodies to the 1-26 alpha peptide fragment of porcine inhibin and/or oestradiol-17 beta. Two groups of animals were either ovariectomized alone with no further treatment, or were left intact and treated with normal sheep plasma to act as controls. Blood samples were collected at 2 h intervals from 12 h before until 48 h after ovariectomy/immunization, and from 12 to 24 h after treatment, blood samples were collected at 10-min intervals. After ovariectomy there was a large rise in the peripheral concentration of LH (P less than 0.001) which was not affected by treatment with progesterone alone but was completely prevented by treatment with progesterone and oestradiol. Treatment with inhibin had no effect on this post-castrational rise in LH. In intact ewes, immunization against oestradiol, alone or in combination with inhibin, resulted in a rise in the concentration of LH, while immunization against inhibin had no effect on LH concentration. The peripheral concentration of FSH showed a significant (P less than 0.001) increase after ovariectomy which was not affected by treatment with progesterone alone. Treatment with inhibin or oestradiol alone caused a significant (P less than 0.01) reduction in this rise, while treatment with inhibin and oestradiol together completely prevented this post-castrational rise in FSH concentration. Passive immunization against inhibin or oestradiol alone resulted in a transitory (P less than 0.01) rise in the peripheral concentration of FSH, while immunization against the two hormones in combination resulted in a significantly (P less than 0.01) larger rise. During the 14-h period after treatment, the rise in the concentration of FSH in this combined immunization group was not significantly different from that seen in the control ovariectomized group. These results provide evidence that FSH secretion is under the control of both oestradiol and inhibin, while reinforcing the hypothesis that inhibin is not involved in the regulation of LH production, which is under the dual control of oestradiol and progesterone.

Animals↗

PubMed2005

The sensitivity and specificity of electrodiagnostic testing for the clinical syndrome of lumbar spinal stenosis.

STUDY DESIGN: Prospective, masked, double controlled diagnostic trial. OBJECTIVES: To determine the sensitivity and specificity of electrodiagnostic consultation (EDX) for the clinical syndrome of lumbar spinal stenosis. SUMMARY OF BACKGROUND DATA: EDX has been used for more than 50 years to diagnose spinal disorders but has not met the new standards of evidence-based medicine. METHODS: A total of 150 subjects (asymptomatic volunteers and patients with MRIs suggesting back pain or spinal stenosis; 55-80 years of age) underwent physiatrist history and physical examination, MRI, and review of this data by a neurosurgeon, with each clinician masked to any outside information, leading to a unanimous consensus on diagnosis in 55. After masked EDX testing, 7 subjects with undiagnosed neuromuscular disease were discovered. EDX findings were related to "clinical gold standard" diagnoses in 48 persons. RESULTS: Paraspinal mapping EMG score of >4 had 100% specificity and 30% sensitivity for stenosis compared with either the back pain or asymptomatic groups (each, P < 0.04). A composite limb and paraspinal fibrillation score had a sensitivity of 47.8% and specificity of 87.5% (P = 0.008), and H-wave sensitivity was 36.4, specificity 91.3 (P = 0.026) for stenosis versus all controls. CONCLUSIONS: This first masked study in the 60-year history of needle electromyography also introduces anatomically validated needle placement, quantified and reproducible examination of the paraspinal muscles, and dual control populations to EDX research in spinal disorders. EDX has statistically significant, clinically meaningful specificity for spinal stenosis and detects neuromuscular diseases that may masquerade as stenosis.

Aged↗

PubMed1983

The legacy from the oocyte and its role in controlling early development of the mouse embryo.

Mouse embryogenesis from ovulation to the early two-cell stage is controlled at a post-transcriptional level by components of the egg assembled during oogenesis and, in some cases, sequestered in an inactive form. These molecular changes appear to be under dual control. The terminal stages of oogenesis initiate a programme of sequential activation of previously untranslated mRNAs and post-translational modifications of pre-existing and newly synthesized polypeptides. Superimposed upon this programme is a sequence of events set in train by fertilization. The earliest of these events that we have detected is a post-translational modification(s). This is followed closely by the activation and translation of new species of mRNA(s). We suggest that the oocyte programme controls the general 'housekeeping' functions of the cell and that the transition to the fertilized state may be initiated at the post-translational level and lead to other 'fertilization-specific' changes that influence processes later in development. The transition from maternal (post-transcriptional) to embryonic (transcriptional) control of development occurs at the early two-cell stage and involves two periods of transcriptional activity closely coupled to translation. In contrast, the maternal mRNAs show an abrupt decline in stability during the two-cell stage. However, many of their polypeptide products appear to persist undegraded until at least the morula stage.

Animals↗

PubMed1992

Activation of the Na+/H+ antiporter during cell volume regulation. Evidence for a phosphorylation-independent mechanism.

A variety of cell types regulate their volume in anisotonic media by stimulating Na+/H+ exchange. Like growth factors, osmotic challenge activates the Na+/H+ antiport by increasing its sensitivity to intracellular [H+]. To investigate the molecular mechanism underlying this shift in pH sensitivity, the antiporter of 32P-labeled human bladder carcinoma cells and of Chinese hamster ovary cells was immunoprecipitated using antibodies raised against the cytosolic domain of the NHE-1 isoform of the Na+/H+ exchanger. Unlike the effects of growth promoters, activation of the antiport during volume regulation was not associated with increased phosphorylation. The possible coexistence of multiple antiporter isoforms was considered. The cytosolic alkalosis normally elicited by hypertonic media was found to be absent in Na+/H+ exchange-deficient fibroblasts. Responsiveness to osmotic challenge was restored by stable transfection of these cells with the cDNA encoding NHE-1. In these transfectants, phosphorylation of the antiporter was also unaffected during osmotic activation. The unchanged phosphate content of the antiporter might be explained by dephosphorylation of one site with concomitant phosphorylation at a different site. However, this possibility appears unlikely since phosphoamino acid analysis revealed that serine was the only residue phosphorylated in immunoprecipitated antiports of both control and osmotically stimulated cells. Moreover, phosphopeptide maps of control and hypertonically activated antiports were identical. These findings reveal a novel mode of activation of Na+/H+ exchange not requiring direct phosphorylation of the antiporter. We propose the existence of dual control of Na+/H+ exchange by phosphorylation-dependent and -independent mechanisms.

Animals↗

PubMed1993

Language matches: illuminating or confounding? Research note.

The practice of matching younger, language-matched controls, in addition to age-matched controls, is often used in studies of language-disordered children to examine the role of "language level" on performance. However, the interpretation of the relative performance of subjects in studies using such dual control groups is problematic. Conceptual concerns arise with the use of language matches because language is a multidimensional skill that is not reflected equivalently for the language-disordered children and their language-matched controls. Furthermore, matching by language level inevitably introduces an extraneous age effect that confounds interpretation. In addition, erroneous interpretations of null findings can occur when no differences are found between language-disordered and language-matched groups.

Age Factors↗

PubMedDate not supplied

Patterns of adrenoceptor change during liver regeneration of the Wistar Kyoto rat: a binding study.

BACKGROUND: Adrenoceptors have been involved in the regulation of hepatocyte proliferation after partial hepatectomy, as well as in primary culture. This report characterizes alpha 1- and beta-adrenoceptor change during the time-course of liver regeneration in adult Wistar Kyoto rats. METHODS: Saturation binding assays with [3H]prazosin or [3H]dihydroalprenolol (for alpha 1- and beta-adrenoceptors, respectively) were done in liver plasma membranes from 6-month-old rats subjected to 70% hepatectomy followed by hepatic regeneration. RESULTS: [3H]Prazosin and [3H]dihydroalprenolol binding gave control Bmax values of 101 +/- 10 and 12 +/- 1 fmol/mg protein and Kd of 0.50 +/- 0.10 and 4.1 +/- 0.4 nM for alpha 1- and beta-adrenoceptors, respectively. alpha 1-Adrenoceptor number and Kd increased at 24 and 48 h and returned to control values at 72 and 96 h after surgery, whereas beta-adrenoceptors augmented at 48 and 72 h, with a Kd change at 24 and 48 h posthepatectomy. CONCLUSIONS: These results suggest that dual control of alpha 1- and beta-adrenoceptor membrane expression could be involved in different steps during hepatocyte proliferation, and that Wistar Kyoto rats have a different adrenoceptor pattern expression from other rat strains.

Adrenergic alpha-Antagonists↗

PubMed2001

Pattern- and growth-linked cell cycles in Drosophila development.

During Drosophila development the cell cycle is subject to diverse regulatory inputs. In embryos, cells divide in stereotypic patterns that correspond to the cell fate map. There is little cell growth during this period, and cell proliferation is regulated at G2/M transitions by patterned transcription of the Cdk1-activator, Cdc25/String. The string locus senses pattern information via a > 40 kb cis-regulatory region composed of many cell-type specific transcriptional enhancers. Later, in differentiated larval tissues, the cell cycle responds to nutrition via mechanisms that sense cellular growth. These larval cell cycles lack mitoses altogether, and are regulated at G/S transitions. Cells in developing imaginal discs exhibit a cycle that is regulated at both G1/S and G2/M transitions. G2/M progression in disc cells is regulated, as in the embryo, by string transcription and is thus influenced by the many transcription factors that interact with string's 'pattern-sensing' control region. G1/S progression in disc cells is controlled, at least in part, by factors that regulate cell growth such as Myc, Ras and phosphatidylinositol-3-kinase. Thus G1/S progression appears to be growth-coupled, much as in the larval endocycles. The dual control mechanism used by imaginal disc cells allows integration of diverse inputs which operate in both cell specification and cell metabolism.

Animals↗

PubMed1993

Osteoporosis and normal weight bulimia nervosa--which patients are at risk?

This study assesses the degree of bone mineral loss in women with active DSM IIIR bulimia nervosa. The subjects in this study were 20 GP-referred female patients of normal weight who met criteria for bulimia nervosa and 16 healthy age, sex and weight matched controls. Dual energy X-ray densitometry of lumbar L1-L4 vertebrae was performed on all subjects. The patients with bulimia nervosa had a significantly lower mean lumbar bone mineral density (0.964 g/cm2) than the control group (1.043 g/cm2, p < 0.01). Within the patient group only subjects with a past history of anorexia nervosa had a significantly lower mean bone mineral density (BMD) than the controls. Small sample sizes limit the power of the study, however significant correlations were found between duration of amenorrhoea, low BMI and lumbar BMD. Bulimic patients do suffer from osteoporosis. Risk factors for this may be; a past history of anorexia nervosa, prolonged secondary amenorrhoea, and a persistently low body mass index.

Adolescent↗

PubMed2005

Novel gene switches for targeted and timed expression of proteins of interest.

This article reports on the construction and analysis in vitro and in vivo of novel gene switches that can be used to achieve spatial as well as temporal control over the expression of a transgene of interest. The switches are expected to be functional in virtually any tissue and cell type. They consist of (a) a foreign or modified transactivator expressed under the dual control of a promoter or promoter cassette that is responsive to heat and the transactivator and (b) a promoter responsive to the transactivator for controlling the transgene of interest. A preferred gene switch of this type incorporated a mifepristone-dependent transactivator. This gene switch could be activated by a transient heat treatment in the presence of mifepristone. Activity increased with the intensity of the activating heat treatment and was found to persist for more than 6 days. The gene switch was essentially inactive prior to an activating heat treatment, in the absence or presence of mifepristone. Activated gene switch could be silenced by removal/withdrawal of mifepristone.

Gene Expression Regulation↗

PubMed1996

Promoters controlling expression of the alternative nitrogenase and the molybdenum uptake system in Rhodobacter capsulatus are activated by NtrC, independent of sigma54, and repressed by molybdenum.

The alternative nitrogenase of Rhodobacter capsulatus is expressed only under conditions of nitrogen and molybdenum depletion. The analysis of anfA-lacZ fusions demonstrated that this dual control occurred at the level of transcription of anfA, which encodes a transcriptional activator specific for the alternative nitrogenase. The anfA promoter was found to be activated under nitrogen-limiting conditions by NtrC in a sigma54-independent manner. In addition, anfA transcription was repressed by traces of molybdenum. This molybdenum-dependent repression of anfA was released in R. capsulatus mutants carrying either lesions in the high-affinity molybdenum uptake system (modABCD) or a double deletion of mopA and mopB, two genes encoding molybdenum-pterin-binding proteins. The expression of the molybdenum transport system itself was shown to be negatively regulated by molybdenum and, unexpectedly, to be also regulated by NtrC. This finding is in line with the presence of two tandemly arranged DNA motifs located in front of the R. capsulatus mopA-modABCD operon, which are homologous to R. capsulatus NtrC binding sites. Mapping of the transcriptional initiation sites of mopA and anfA revealed promoter sequences exhibiting significant homology to each other but no homology to known prokaryotic promoters. In addition, a conserved DNA sequence of dyad symmetry overlapping the transcriptional initiation sites of mopA and anfA was found. Deletions within this element resulted in molybdenum-independent expression of anfA, indicating that this DNA sequence may be the target of MopA/MopB-mediated repression.

Bacterial Proteins↗

PubMed1987

The effects of anterior hypothalamic deafferentation on FSH-releasing activity in the intact female hamster.

To study the role of the anterior hypothalamic area (AHA) in the control of the estrous (E) rise of follicle stimulating hormone (FSH), female hamsters were subjected to anterior hypothalamic deafferentation (D) or sham deafferentation (S) on 1500 h of proestrus (P). Serum levels of FSH and luteinizing hormone (LH) were measured by radioimmunoassay and FSH and LH releasing activities measured by bioassay in the anterior (AH) and medial basal hypothalamus (MBH) at several time periods during P and E. D did not affect serum levels of LH, whereas there was an attenuation of FSH levels during P and E. D caused an increase in FSH releasing activity in the AH within 1 h, while LH releasing activity was elevated 8 h after D. In animals with D, LH releasing activity in the MBH was elevated during P and was similar to controls during E. FSH releasing activity in the MBH increased during early E and dropped precipitously by 1400 h of E. Collectively, these data demonstrate dichotomous changes in FSH and LH releasing activities and provide further evidence for dual control mechanisms for these two gonadotropins.

Animals↗

PubMed2006

Both prothoracicotropic hormone and an autocrine factor are involved in control of prothoracic gland ecdysteroidogenesis in Locusta migratoria and Schistocerca gregaria.

In Bombyx mori, ecdysteroidogenesis by the prothoracic glands (PGs) is controlled by both prothoracicotropic hormone (PTTH) and a factor secreted by the glands themselves. This factor, which is active both in vitro and in vivo, has been named 'autocrine factor' (AF). To find out whether or not this dual control also exists in other species, in particular in hemimetabolous ones, we applied similar methods as were used to discover AF in Bombyx to the locusts Locusta migratoria and Schistocerca gregaria. Our results unequivocally show that locust PGs also secrete an as yet unidentified autocrine factor. Possible roles of AF are discussed.

Animals↗

PubMed1996

The erythrocyte Na+/H+ exchangers of eel (Anguilla anguilla) and rainbow trout (Oncorhynchus mykiss): a comparative study

Trout and eel red blood cell Na+/H+ exchangers show widely different regulatory properties. Catecholamines, cyclic AMP and phorbol esters, which activate the trout red cell antiporter, do not affect the eel exchanger. Unlike the trout red cell exchanger, the eel red cell exchanger is strongly activated by cell shrinkage, allowing a remarkable cell volume recovery. These different regulatory properties probably indicate the existence of different isoforms of the exchangers in nucleated erythrocytes, since sensitivity to catecholamines is known to be dependent upon the presence of protein kinase A consensus sites on the cytoplasmic domain of the antiporter. After shrinkage of eel erythrocytes, the Na+/H+ exchange rate gradually increases to reach a maximum value after about 10 min. The magnitude of activation is a graded function of cell shrinkage. Deactivation, like activation, is induced by a volume change and occurs after some delay (lag time). The response of the trout antiporter (betaNHE) to cell shrinkage is much reduced compared with that of the eel antiporter. In addition, the antiporter is deactivated prior to restoration of the normal control volume, leaving cell volume regulation notably defective. The trout red cell antiporter, which is desensitized and enters a refractory state following hormonal activation, is only deactivated (it can be reversibly reactivated) after shrinkage-induced activation. This dual control may occur by both phosphorylation-dependent and phosphorylation-independent mechanisms. In view of the similarities in the regulatory properties of eel and salamander (Amphiuma sp.) Na+/H+ exchangers, the expression of a putative K+/H+ exchange mediated by the N+/H+ exchanger was sought in eel erythrocytes. However, neither osmotic swelling nor calyculin-A-dependent phosphorylation revealed such a K+/H+ exchange.

Journal Article↗

PubMed2000

Targeting gene expression to tumor cells with loss of wild-type p53 function.

The tumor suppressor protein p53 is a transcription factor that can positively regulate the expression of critical target genes involved in negative control of cell growth or induction of apoptosis; p53 is also able to suppress the transcription of other genes by virtue of its ability to bind components of the basal transcription machinery. Over 50% of human tumors are characterized by p53 mutations that result in a loss of wild-type p53 (wtp53) function in the transcriptional control of these target genes. We have exploited this loss of p53 function in the regulation of gene transcription to develop a novel gene therapy strategy that maximizes expression of the potential therapeutic gene in tumors while simultaneously down-regulating the same gene in normal cells. In one construct (unit I), the potential therapeutic gene (in this case represented by a luciferase reporter) is placed under the control of a promoter such as the heat shock protein 70 gene promoter, which is repressed by wtp53 but overexpressed in many tumor cells with defective p53 function. Residual expression of the reporter in normal cells is repressed by cotransfection of another construct (unit II) consisting of a repressor of unit I under the control of a promoter that is activated by wtp53 expression. Unit II contains a promoter with a consensus wtp53 binding site driving a transcriptional repressor or an antisense construct for the gene in unit I. Our results suggest that this dual control approach may represent a strategy with wide applications in the field of cancer gene therapy.

Feasibility Studies↗