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Results for “augmented feedback”

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PubMed2006

Human voluntary activity integration in the control of a standing-up rehabilitation robot: a simulation study.

The paper presents a novel control approach for the robot-assisted motion augmentation of disabled subjects during the standing-up manoeuvre. The main goal of the proposal is to integrate the voluntary activity of a person in the control scheme of the rehabilitation robot. The algorithm determines the supportive force to be tracked by a robot force controller. The basic idea behind the calculation of supportive force is to quantify the deficit in the dynamic equilibrium of the trunk. The proposed algorithm was implemented as a Kalman filter procedure and evaluated in a simulation environment. The simulation results proved the adequate and robust performance of "patient-driven" robot-assisted standing-up training. In addition, the possibility of varying the training conditions with different degrees of the subject's initiative is demonstrated.

Adult↗

PubMed2001

Interleukin-1beta and rhinovirus sensitize adenylyl cyclase in human airway smooth-muscle cells.

Rhinovirus (RV) is a major cause of wheezing in asthmatics and has been reported to cause beta2 adrenergic receptor hyporesponsiveness in human airway smooth muscle (HASM) via cellular secretion of interleukin (IL)-1beta. We studied the effects of IL-1beta and RV on cyclic adenosine monophosphate (cAMP) production in HASM cells. Chronic incubation with IL-1beta or RV caused a significant increase (approximately 3- and approximately 2-fold, respectively) in forskolin (FSK)-stimulated cAMP production, suggesting a sensitization of adenylyl cyclase (AC). The observed augmentation of FSK-stimulated cAMP formation by IL-1beta was completely abrogated by pretreatment with an IL-1 receptor antagonist or cycloheximide, demonstrating that the effect is mediated via the IL-1 receptor 1 (IL-1R1) and that de novo protein synthesis is required. In contrast, RV-induced AC sensitization was not mediated via the IL-1R1 but was observed to be protein kinase C-dependent. We suggest that the sensitization of AC observed after exposure to IL-1beta or RV infection is a cellular defense mechanism to promote pathways that induce relaxation in the inflamed airway.

Adenylate Cyclase Toxin↗

PubMed2003

Circulating ghrelin levels of visceral obese men are not modified by a short-term treatment with very low doses of GH replacement.

Ghrelin, the endogenous ligand for the GH secretagogue-receptor (GHS-R), in addition to its GH-releasing action, has orexigenic and adipogenic properties. These characteristics make ghrelin a potential hormone involved in the pathogenesis of obesity. Ghrelin levels are decreased in obese humans and it is unknown whether this decrease is responsible for the blunted GH secretion reported in visceral obesity. Since only few data are available on the potential feedback regulation by GH on systemic ghrelin concentrations, it remains to be established whether the correction of circulating GH concentrations in obese individuals affects ghrelin concentrations. To answer this question, we measured plasma ghrelin levels after a week of administration of low doses of recombinant human GH (rhGH) in a randomized, double-blind, placebo (PL)-controlled trial. This study was originally designed to evaluate the effects of GH replacement on lipid kinetics in visceral obese men. Six adult men with abdominal/visceral obesity (age 42+/-3 yr, body weight 107 +/- 10 kg, BMI 33 +/- 1 kg/m2, waist circumference 111 +/- 3 cm, mean +/- SE) were evaluated in the basal state (BS) and after one week of treatment with subcutaneous bedtime injections of either PL, 2.5 (GH2.5) or 3.3 (GH3.3) pg/kg/die of rhGH. In comparison to BS either PL, GH2.5 or GH3.3 did not significantly modify circulating ghrelin concentrations (p = 0.77). In contrast, a significant increase of serum GH (p = 0.0028), IGF-I (p = 0.0033) and whole body rate of lipolysis (p = 0.038, GH2.5; p = 0.009, GH3.3) occurred, in comparison to BS or PL, after GH2.5 and GH3.3, without differences between the two treatments. These data demonstrate that in abdominal/visceral obese men a short-term treatment with very low doses of rhGH replacement, sufficient to augment the rate of lipolysis, do not modify circulating ghrelin levels.

Adult↗

PubMed1998

Lung cancer--management and outcome in Glasgow, 1991-92.

Current practice and outcome for patients with lung cancer were determined by retrospective case note review of a random sample of all lung cancer cases registered for a calendar year and augmented by review of all surgical and radical radiotherapy cases. A total of 262 patients - 231 patients less than 75 years of age and 31 patients more than 75 years of age - represented 83% of the random sample. Eighty-three per cent of patients were seen within 2 weeks of referral. One-third reported symptoms occurring for less than 1 month and one-third had experienced symptoms for more than 3 months. The median time interval from first hospital contact until the making of a management decision was 18 days. The median interval from first contact to surgery was 63 days, and to starting radical radiotherapy 70 days. Histological confirmation was obtained in 69% of patients. Ten per cent of all lung cancer patients were calculated to have received chemotherapy. Five per cent of the whole cohort had definitive surgery and 64% of these were judged to be free of the disease at 3 years. Overall survival was 9% at 3 years, with no differences relating to cell type or area of residence. Many areas of good practice have been identified, but the lack of tumour staging or performance status data, the low proportion receiving chemotherapy or definitive surgery and the poor outcome after radical radiotherapy indicate the need for prospective audit and feedback of results. The long time interval from management decision to surgery and radiotherapy suggests organizational issues which need attention.

Adult↗

PubMed1976

Assessments of the functional capacity of the gonadotrophs in men: effects of estrogen and clomiphene.

Serum LH and FSH responses to serial injections of LRF with small (10 mug x 5), large (150 mug x 5), decremental (300 to 10 mug), and incremental (10 to 300 mug) doses at 2-hour intervals were assessed in eugonadal men. At constant doses, pulses of LRF induced pulsatile LH release which was qualitatively similar but quantitatively greater for the large than for the small dose of LRF. There were no periods of refractoriness or augmentation of subsequent responses from prior exposure to LRF when administered at 2-hour intervals. LH responses to incremental and decremental doses of LRF resulted in corresponding measurable changes in the magnitude of pituitary LH release. The FSH responses to pulses of LRF at all doses tested were uniformly small. These data suggest that analyses of the initial and integrated release (10 h experiment) to pulses of LRF may disclose the functional capacity of the gonadotrophs and that small variations in the endogenous LRF delivered may represent a significant factor in the control of LH release. The small dose (10 mug x 5) of pulses of LRF was utilized in the assessment of estrogen and clomiphene treatments on the functional capacity of the gonadotrophs in normal men. Compared with the pretreatment results, both constant doses of ethinyl estradiol (50 mug/day x 7 days) and incremental doses of estradiol benzoate (100 to 400 mug, twice daily injections x 4 d) induced an attenuation of the initial release as well as of the integrated response 10 h) to pulses of LRF. Clomiphene treatment (100 mg/day x 5 d), likewise, resulted in a reduction of gonadotropin release to all pulses of LRF. These data suggest that circulating estrogen in intact men may have both a negative and a positive feedback effect on the gonadotrophs and that the testicular estrogen secretion as well as the extraglandular sources of estrogen, may play a critical role in the regulations of gonadotropin secretion in man.

Adult↗

PubMed1995

In vivo regulation of macrophage IL-12 production during type 1 and type 2 cytokine-mediated granuloma formation.

IL-12 is a pivitol cytokine that promotes NK cell activity and Th1 (type 1)-mediated immune responses. This study analyzed the cytokines that regulate macrophage (M phi) IL-12 production in vitro and in vivo. IL-12 was produced by elicited but not resident peritoneal M phi stimulated with endotoxin. Addition of graded doses of cytokines (0.1 to 10 ng/ml) indicated that the Th1-related (type 1) cytokine, IFN-gamma, augmented endotoxin-stimulated IL-12 production by nearly sixfold in oil-elicited M phi. TNF-alpha also increased production but only at the 10 ng/ml concentration. In contrast, the Th2-related (type 2) cytokines, IL-4 and especially IL-10, were profoundly inhibitory. IL-1 beta and IL-2 had no effect. For in vivo analysis, type 1 and type 2 cytokine-mediated lung granulomas (GR) were induced in presensitized mice by embolization of beads coupled to purified protein derivative of Mycobacteria tuberculosis or soluble Ags derived from Schistosoma mansoni eggs. Analysis of M phi isolated from type 1, type 2, or control pulmonary GR revealed that M phi of type 2 GR develop impaired IL-12-producing capacity. Depletion studies using anti-IFN, anti-IL-12, anti-IL-10, and anti-IL-4 neutralizing polyclonal Abs corroborated the in vitro studies. Anti-IFN or anti-IL-12 reduced IL-12 production by M phi from type 1 GR (70 to 80%) as well as IFN and IL-12 production by draining lymph nodes (75 to 90%). Conversely, anti-IL-10 and anti-IL-4 reversed the impaired IL-12 production observed in type 2 GR M phi. These data indicate a positive feedback stimulation of IL-12 production by IFN that is regulated by IL-10 and IL-4 in vivo.

Animals↗

PubMed1980

Pre- and post-junctional adrenergic mechanisms and hypertension.

1. The ability of the blood vessel wall to synthesize noradrenaline is augmented at the early stages of genetic hypertension in animals. It usually is normal, or reduced in chronic hypertension. 2. The exocytotic release of noradrenaline is greater than normal, in the early stages of a number of experimental models of hypertension. 3. Postjunctional receptors for noradrenaline are not uniform throughout the vascular tree. Their sensitivity changes during the development of high blood pressure. 4. In chronic hypertension neuronal uptake and the extraneuronal disposition of released noradrenaline is depressed in the heart, but accelerated in the blood vessel wall. 5. The adrenergic neuro-effector interaction undergoes a diverging long-term adaptation in the heart and the blood vessels of hypertensive animals. In the former this tends to increase, but in the latter to reduce, the efficiency of sympathetic nervous control.

Angiotensin II↗

PubMed1985

Evidence for the involvement of the thromboxane synthase pathway in human natural cytotoxic cell activity.

We and other investigators have recently shown that inhibitors of lipoxygenase reversibly inhibit natural cytotoxic (NC) or natural killer (NK) cell activity, whereas some inhibitors of cyclooxygenase enhance these functions. In addition, exogenous LTB4 augments NC and NK activity, whereas PGE2 depresses it. In the present studies, we sought to investigate the possible role of the TxA2 synthase pathway in NC function. Inhibition of this pathway by OKY-1581 or dazoxiben significantly inhibited NC activity against HSV-infected cells as well as NK function against K562 target cells. The inhibition was dose dependent, reversible, and not due to direct toxicity. NC activity was also significantly inhibited by the addition of PGE2 or PGI2 to the 4-hr assay, whereas addition of 6-keto-PGF1 alpha had no effect. Addition of PGH2, which could be converted to TxA2 or other PG, had no significant effect, but concomitant use of OKY-1581 produced a greater inhibition of NC function than by using OKY-1581 alone. U44069, a TxA2 analog, was inhibitory by itself and could not alter the inhibition caused by OKY-1581 or dazoxiben. In contrast, the TxA2 receptor blocker 13-APA significantly enhanced NC activity and even reversed the inhibitory effect of U44069 at equimolar (10(-7)M) concentrations. Taken together, these data suggest that most of the inhibitory effect of the TxA2 synthase inhibitors on NC and NK cell function derives from their ability to reorient cyclic endoperoxide metabolism toward more inhibitory compounds. In addition, TxA2 itself could exert a negative feedback on NC function through its receptor, as evidenced by the use of a TxA2 analog and a TxA2 blocker.

Cytotoxicity Tests, Immunologic↗

PubMed2006

Refractoriness to short day lengths augments tonic and gonadotrophin-releasing hormone-stimulated lutenising hormone secretion.

Siberian hamsters (Phodopus sungorus) undergo reproductive involution following exposure to short winter day lengths. Following approximately 20 weeks of exposure to short day (SD) lengths, hamsters become refractory to the inhibitory effects of SD, and reproductive competence is restored in anticipation of spring. The extent to which changes in gonadal steroid-dependent and -independent regulation of gonadotrophin secretion participate in this vernal reactivation of the gonads is not known. This experiment tested whether tonic and gonadotrophin-releasing hormone (GnRH)-stimulated regulation of lutenising hormone (LH) secretion differs between photoresponsive and photorefractory Siberian hamsters. Male hamsters born into long day (LD) lengths were castrated or subjected to a sham-castration surgery at 17 days of age, implanted s.c. with blank or testosterone-filled capsules, and housed in LD or SD thereafter. Baseline LH and LH responses to GnRH (200 ng/kg, s.c) were measured at 14 (photoresponsive) and 40 (photorefractory) weeks of age. Despite lower circulating testosterone concentrations in gonadally regressed SD hamsters on week 14, tonic LH concentrations were comparable among all groups of gonad-intact hamsters on weeks 14 and 40; however, week 14 SD hamsters exhibited significantly higher GnRH-stimulated LH responses. Tonic LH concentrations were indistinguishable among all groups of castrated hamsters bearing empty implants on week 14, but prolonged exposure to LD led to a decrease in resting LH, whereas prolonged exposure to SD resulted in an increase in LH. In castrated hamsters bearing testosterone implants, baseline LH concentrations were comparable in all groups, but GnRH treatment resulted in significantly higher LH concentrations in photorefractory (week 40, SD) hamsters relative to all other groups. The data suggest that the development of photorefractoriness in Siberian hamsters is characterised by enhanced gonadal hormone-independent stimulation of LH secretion, and diminished sensitivity to inhibitory negative-feedback effects of testosterone on LH secretion. Decreases in responsiveness of gonadotrophin secretion to gonadal hormone negative feedback may contribute to the process of photorefractoriness and assist in maintaining the growth of reproductive organs during the process of gonadal recrudescence.

Adaptation, Physiological↗

PubMed1998

MEK inhibition augments Raf activity, but has variable effects on mitogenesis, in vascular smooth muscle cells.

Proteins comprising the mitogen-activated protein (MAP) kinase signaling cascade are activated by a variety of growth factors, but the precise role of this series of kinase reactions, especially Raf kinase and MAP kinase kinase (MEK), in vascular smooth muscle (VSM) cell mitogenesis is not known. In this study, a specific and selective inhibitor of MEK, PD-98059, was used to examine the role of MEK in DNA synthesis and Raf-1 activity in VSM cells stimulated with serum as well as with growth factors encompassing both tyrosine kinase and G protein-coupled receptor classes. Although significant increases in DNA synthesis are seen after stimulation of VSM cells with either 10% serum,platelet-derived growth factor (PDGF)-BB, or alpha-thrombin, preincubation of the cells with 50 microM PD-98059 for 1 h inhibits stimulation by PDGF and thrombin, but not by serum. There is a dose-dependent inhibition of the mitogenic effect by PD-98059 in all cases; these results are not affected when PD-98059 is added at times ranging from 4 h before to 2 h after growth factor addition (times at which PD-98059 exerts its inhibitory effect). In the presence of PD-98059, stimulated MAP kinase activity is attenuated when growth factors are added between 10 min and 4 h, times which correspond to both early and sustained phases of MAP kinase activity. In addition, Raf-1 activity is markedly increased by incubation of the cells with PD-98059,despite attenuation of hyperphosphorylation of this kinase. Thus growth factors coupled to both tyrosine kinase and G protein receptors require components of the MAP kinase cascade (MEK and/or MAP kinase) for VSM cell mitogenesis, whereas serum is capable of stimulatory effects in the absence of active MEK and MAP kinase. Furthermore, there exists a functional feedback stimulatory effect of inhibited MEK on its upstream activator Raf-1 in the case of serum as well as growth factors coupled to tyrosine kinase and G protein receptors.

Animals↗

PubMed2000

Physical interaction between CDK9 and B-Myb results in suppression of B-Myb gene autoregulation.

B-Myb is a transcription factor belonging to the myb family, whose activity has been associated with augmented DNA synthesis and cell cycle progression. We showed recently that B-Myb autoregulates its own expression through promoter transactivation. We report in this study that CDK9, the cyclin T associated kinase, which phosphorylates and activates RNA-Polymerase II, suppresses B-Myb autoregulation through direct interaction with the carboxyl-terminus of the B-Myb protein. Down-regulation of the transactivating ability of B-Myb is independent of the kinase activity of CDK9, because a kinase deficient mutant (dn-CDK9) also represses B-myb gene autoregulation. Overexpression of CDK9 did not result in suppression of p53-dependent transactivation or inhibition of the basal activity of the promoters tested so far, demonstrating that CDK9 is a B-Myb-specific repressor. Rather, transfection of the dominant negative dn-CDK9 construct inhibited the basal activity of the reporter genes, confirming an essential role for CDK9 in gene transcription. In addition, Cyclin T1 restores B-Myb transactivating activity when co-transfected along with CDK9, suggesting that the down-regulatory effect observed on B-Myb is specifically due to CDK9 alone. Thus, our data suggest that CDK9 is involved in the negative regulation of activated transcription mediated by certain transcription factors, such as B-Myb. This may indicate the existence of a feedback loop, mediated by the different activities of CDK9, which links basal with activated transcription.

Cell Cycle Proteins↗

PubMed1998

Role of acetylcholine receptors and dopamine transporter in regulation of extracellular dopamine in rat carotid body cultures grown in chronic hypoxia or nicotine.

Using dissociated rat carotid body (CB) cultures, we compared levels of extracellular dopamine (DA) around oxygen-sensitive glomus cells grown for approximately 12 days in normoxia (Nox; 20% O2), chronic hypoxia (CHox; 6% O2), or chronic nicotine (CNic; 10 microM nicotine, 20% O2), with or without acetylcholine (ACh) receptor (AChR) agonists/antagonists and blockers of DA uptake. In Nox cultures, extracellular DA, determined by HPLC and normalized to the number of tyrosine hydroxylase-positive glomus cells present, was augmented by acute (approximately 15-min) exposure to hypoxia (5% O2; approximately 6x basal), high extracellular K+ (30 mM; approximately 10x basal), nomifensine (1 microM; a selective DA uptake inhibitor; approximately 3x basal), and nicotine (100 microM; approximately 5x basal), but not methylcholine (300 microM; a specific muscarinic agonist). In contrast, in CHox cultures where basal DA release is markedly elevated (approximately 9x control), the stimulatory effect of high K+ (3-4x basal) and acute hypoxia (approximately 2x basal) on DA release persisted, but nicotine and nomifensine were no longer effective and methylcholine had a partial inhibitory effect. In CNic cultures, basal DA levels were also elevated (approximately 9x control), similar to that in CHox cultures; however, although acute hypoxia had a stimulatory effect on DA release (approximately 2x basal), nicotine, nomifensine, and high K+ were ineffective. The elevated basal DA in both CHox and CNic cultures was attenuated by acute or chronic treatment with mecamylamine (100 microM), a nicotinic AChR (nAChR) antagonist. In addition, long-term (16-h), but not acute (15-min), treatment with the muscarinic antagonist atropine (1 microM) produced an additional enhancement of basal DA levels in CHox cultures. Thus, after chronic hypoxia or nicotine in vitro, extracellular DA levels around CB chemoreceptor cell clusters appear to be set by a variety of factors including released ACh, positive and negative feedback regulation via nAChRs and muscarinic AChRs, respectively, and modulation of DA transporters. These results provide insight into roles of endogenous transmitters in the adaptation of CB chemoreceptors to chronic hypoxia and suggest pathways by which neuroactive drugs, e.g., nicotine, can interfere with the protective chemoreflex response against hypoxia.

Animals↗

PubMed1999

Pindolol, a putative 5-hydroxytryptamine(1A) antagonist, does not reverse the inhibition of serotonergic neuronal activity induced by fluoxetine in awake cats: comparison to WAY-100635.

The ability of pindolol to enhance the clinical antidepressant response to selective serotonin reuptake inhibitors (SSRIs) is generally attributed to a blockade of the feedback inhibition of serotonergic neuronal activity mediated by somatodendritic 5-hydroxytryptamine (5-HT)(1A) autoreceptors. The current study examined the ability of pindolol to restore the single-unit activity of serotonergic dorsal raphe nucleus neurons in awake cats after acute treatment with the SSRI fluoxetine. The effects of pindolol were compared with those of N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide (WAY-100635), a selective 5-HT(1A) receptor antagonist. Systemic administration of fluoxetine (0.5 and 5 mg/kg i. v.) decreased neuronal firing rates to approximately 50 and 1%, respectively, of baseline levels. The subsequent administration of cumulative doses of (+/-)-pindolol (0.1-5 mg/kg i.v.) failed to reverse the neuronal inhibition produced by either dose of fluoxetine. In addition to lacking efficacy as an antagonist in these experiments, (+/-)-pindolol produced an additional decrease in neuronal activity in animals pretreated with the low dose of fluoxetine. The active enantiomer, (-)-pindolol (1 mg/kg i.v.), also was ineffective in restoring neuronal activity after fluoxetine. In contrast, systemic administration of WAY-100635 completely reversed the effect of fluoxetine (5 mg/kg) at low doses (0.025 mg/kg i.v.), and further elevated the firing rate of these neurons above prefluoxetine baseline levels. Overall, these results indicate that pindolol, unlike WAY-100635, lacks appreciable antagonist activity at 5-HT(1A) autoreceptors. Thus, the clinical efficacy of pindolol in augmenting the antidepressant response to SSRIs, such as fluoxetine, may be unrelated to a restoration of serotonergic neuronal activity.

Animals↗

PubMed2006

Continuous shared control for stabilizing reaching and grasping with brain-machine interfaces.

Research on brain-machine interfaces (BMI's) is directed toward enabling paralyzed individuals to manipulate their environment through slave robots. Even for able-bodied individuals, using a robot to reach and grasp objects in unstructured environments can be a difficult telemanipulation task. Controlling the slave directly with neural signals instead of a hand-master adds further challenges, such as uncertainty about the intended trajectory coupled with a low update rate for the command signal. To address these challenges, a continuous shared control (CSC) paradigm is introduced for BMI where robot sensors produce reflex-like reactions to augment brain-controlled trajectories. To test the merits of this approach, CSC was implemented on a 3-degree-of-freedom robot with a gripper bearing three co-located range sensors. The robot was commanded to follow eighty-three reach-and-grasp trajectories estimated previously from the outputs of a population of neurons recorded from the brain of a monkey. Five different levels of sensor-based reflexes were tested. Weighting brain commands 70% and sensor commands 30% produced the best task performance, better than brain signals alone by more than seven-fold. Such a marked performance improvement in this test case suggests that some level of machine autonomy will be an important component of successful BMI systems in general.

Arm↗

PubMed2002

Insight into the physiological actions of thyroid hormone receptors from genetically modified mice.

Thyroid hormones exert a range of developmental and physiological actions in all vertebrates. Serum concentrations of L-thyroxine (T4) and 3,5,3 -L-triiodothyronine (T3) are maintained by a negative feedback loop involving T3-inhibition of hypothalamic thyrotrophin releasing hormone (TRH) and pituitary thyroid stimulating hormone (TSH) secretion, and by tissue specific and hormone-regulated expression of the three iodothyronine deiodinase enzymes that activate or metabolise thyroid hormones. T3 actions are mediated by two T3-receptors, TRalpha and TRbeta, which act as hormone-inducible transcription factors. The TRalpha (NR1A1) and TRbeta (NR1A2) genes encode mRNAs that are alternatively spliced to generate 9 mRNA isoforms (TRalpha1, alpha2, alpha3, Deltaalpha1, Deltaalpha2, beta1, beta2, beta3 and Deltabeta3), of which four (TRalpha1, alpha2, beta1 and beta2) are known to be expressed at the protein level in vivo. The numerous TR mRNAs are expressed widely in tissue- and developmental stage-specific patterns, although it is important to note that levels of mRNA expression may not correlate with receptor protein concentrations in individual tissues. The TRalpha2, alpha3, Deltaalpha1 and Deltaalpha2 transcripts encode proteins that fail to bind T3 in vitro. These non-binding isoforms, in addition to TRDeltabeta3 which does bind hormone, may act as dominant negative antagonists of the true T3-binding receptors in vitro, but their physiological functions and those of the TRbeta3 isoform have not been determined. In order to obtain a new understanding of the complexities of T3 action in vivo and the role of TRs during development, many mouse models of disrupted or augmented thyroid hormone signalling have been generated. The aim of this review is to provide a picture of the physiological actions of thyroid hormones by considering the phenotypes of these genetically modified mice.

Animals↗

PubMed2006

Role of endosomal trafficking dynamics on the regulation of hepatic insulin receptor activity: models for Fao cells.

Evidence indicates that endosomal insulin receptor (IR) trafficking plays a role in regulating insulin signal transduction. To evaluate its importance, we developed a series of biokinetic models for quantifying activated surface and endosomal IR dynamics from published experimental data. Starting with a published two-compartment Fao hepatoma model, a four-pool model was formulated that depicts IR autophosphorylation after receptor binding, IR endosomal internalization/trafficking, insulin dissociation from and dephosphorylation of internalized IR, and recycling of unliganded, dephosphorylated IR to the plasma membrane. Quantification required three additional data sets, two measured, but unmodeled by the same group. A five-pool model created to include endosomal trafficking of the nonphosphorylated insulin-IR complex was fitted using the same data sets, augmented with another published data set. Creation of a six-pool model added the physiologically relevant dissociation of insulin ligand from the activated endosomal IR. More importantly, all three models, validated against additional data not used in model fitting, predict that, mechanistically, internalization of activated IR is a rate-limiting step, at least under the receptor saturating conditions of the fitting data. This rate includes the transit time to a site where insulin dissociation from and/or dephosphorylation of the IR occurs by docking with protein-tyrosine phosphatases (PTPases), or where a sufficient conformational change occurs in the IR, perhaps due to insulin-IR dissociation, where associated PTPases may complete IR dephosphorylation. Our new models indicate that key events in endosomal IR trafficking have significance in mediating IR activity, possibly serving to regulate insulin signal transduction.

Animals↗

PubMed1986

Paracrine mechanisms involved in granulosa cell differentiation.

Since the heterogeneous development of individual follicles in a given ovary cannot be accounted for by changes in circulating gonadotropin levels, local modulatory factors play an important role in the paracrine control of follicular development. The important paracrine role of ovarian steroids has been well established. Oestrogen is important in the augmentation of gonadotropin action. High local concentration of oestrogens enhances the gonadotropin stimulation of aromatase activity, resulting in further increases in oestrogen production. The elevated local oestrogens in the follicular fluid are also capable of enhancing the FSH induction of LH receptors. Similar to oestrogens, local high concentrations of progesterone may enhance the gonadotropin stimulation of progesterone biosynthesis in granulosa and luteal cells. This positive autofeedback mechanism is believed to be important for the autonomy of luteal cell steroidogenesis. Ovarian actions of androgens are diverse. In the absence of FSH, androgens exert mainly negative effects at the follicular level by causing atresia and granulosa cell death, whereas in the presence of FSH, androgens augment FSH stimulation of progesterone and oestrogen biosynthesis. Since androgen and oestrogen appear to antagonize each other's actions, the ratio of these two steroids is important in determining the fate of an individual follicle. In contrast to ovarian steroids, the role of ovarian peptides as paracrine signals is less clear. In vitro studies clearly demonstrated that GnRH exerts both stimulatory and inhibitory actions on follicular functions, while IGF-I and VIP stimulate ovarian steroidogenesis. The actions of these peptides are presumably mediated through specific granulosa cell receptors that have been tentatively identified. It is presumed that GnRH and IGF-I may be produced by ovarian cells, while VIP may be derived from ovarian nerves. It is anticipated that new methodologies will be developed to study individual follicles as independent units, capable of synthesizing hormones, releasing them, and exerting local paracrine functions.

Androgens↗

PubMed1997

Acute effects of estradiol infusion and naloxone on luteinizing hormone secretion in pubertal boys.

We have shown previously in pubertal boys that testosterone (T) suppresses the nocturnal augmentation of luteinizing hormone (LH) secretion principally by decreasing LH pulse frequency. As T can be aromatised to estradiol (E2), and E2 effects on LH secretory dynamics may be separate from those of T, we examined the effects of acute E2 infusion on LH secretion in pubertal boys. Opioid receptor blockade has been reported to increase LH secretion after estradiol suppression in adult men, so we also examined whether naloxone might augment LH secretion during E2 treatment in pubertal boys. Starting at 1000 h, eight pubertal boys were given a 33 h saline infusion, followed 1 week later by an E2 infusion at 4.6 nmol/m2/h. During both infusions, four iv boluses of saline were given hourly beginning at 1200 h on the first day, and four naloxone iv boluses, 0.1 mg/kg each, were given hourly beginning at 1200 h on the second day. Blood was obtained every 15 min for LH, and every 60 min for T and E2, from 1200 h until the end of the infusion. Pituitary responsiveness to gonadotropin-releasing hormone (GnRH) was assessed after both infusions by iv administration of 250 ng/kg synthetic GnRH. Estradiol infusion increased the mean plasma E2 concentration from 23 +/- 4 to 46 +/- 6 pmol/L (P < 0.01) and suppressed mean plasma T from 4.9 +/- 1.4 to 3.0 +/- 3.5 nmol/L (saline vs. E2 infusion, P < 0.05). The overall mean LH was suppressed by E2 infusion from 3.7 +/- 0.5 to 2.2 +/- 0.4 IU/L (saline vs. E2 infusion, P < 0.01). LH pulse frequency was suppressed by 50%, whereas mean LH pulse amplitude was not different between saline and E2 infusions. Administration of naloxone did not alter the mean LH, LH pulse frequency, or amplitude during either saline or E2 infusions. Pituitary responsiveness to exogenous GnRH was similar during both infusions. These studies indicate that E2 produces its negative feedback in pubertal boys principally by suppression of LH pulse frequency, and naloxone does not reverse these suppressive effects. Thus E2 suppression of LH secretion is mediated by a decrease of hypothalamic GnRH secretion that is independent of endogenous opioid pathways.

Adolescent↗