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Sample records for 4d regulates gonadotropin

  1. Semaphorin 4D regulates gonadotropin hormone-releasing hormone-1 neuronal migration through PlexinB1-Met complex.

    PubMed

    Giacobini, Paolo; Messina, Andrea; Morello, Francesca; Ferraris, Nicoletta; Corso, Simona; Penachioni, Junia; Giordano, Silvia; Tamagnone, Luca; Fasolo, Aldo

    2008-11-01

    In mammals, reproduction is dependent on specific neurons secreting the neuropeptide gonadotropin hormone-releasing hormone-1 (GnRH-1). These cells originate during embryonic development in the olfactory placode and migrate into the forebrain, where they become integral members of the hypothalamic-pituitary-gonadal axis. This migratory process is regulated by a wide range of guidance cues, which allow GnRH-1 cells to travel over long distances to reach their appropriate destinations. The Semaphorin4D (Sema4D) receptor, PlexinB1, is highly expressed in the developing olfactory placode, but its function in this context is still unknown. Here, we demonstrate that PlexinB1-deficient mice exhibit a migratory defect of GnRH-1 neurons, resulting in reduction of this cell population in the adult brain. Moreover, Sema4D promotes directional migration in GnRH-1 cells by coupling PlexinB1 with activation of the Met tyrosine kinase (hepatocyte growth factor receptor). This work identifies a function for PlexinB1 during brain development and provides evidence that Sema4D controls migration of GnRH-1 neurons.

  2. Neuroendocrine regulation of gonadotropin secretion in seasonally breeding birds

    PubMed Central

    Ubuka, Takayoshi; Bentley, George E.; Tsutsui, Kazuyoshi

    2013-01-01

    Seasonally breeding birds detect environmental signals, such as light, temperature, food availability, and presence of mates to time reproduction. Hypothalamic neurons integrate external and internal signals, and regulate reproduction by releasing neurohormones to the pituitary gland. The pituitary gland synthesizes and releases gonadotropins which in turn act on the gonads to stimulate gametogenesis and sex steroid secretion. Accordingly, how gonadotropin secretion is controlled by the hypothalamus is key to our understanding of the mechanisms of seasonal reproduction. A hypothalamic neuropeptide, gonadotropin-releasing hormone (GnRH), activates reproduction by stimulating gonadotropin synthesis and release. Another hypothalamic neuropeptide, gonadotropin-inhibitory hormone (GnIH), inhibits gonadotropin synthesis and release directly by acting on the pituitary gland or indirectly by decreasing the activity of GnRH neurons. Therefore, the next step to understand seasonal reproduction is to investigate how the activities of GnRH and GnIH neurons in the hypothalamus and their receptors in the pituitary gland are regulated by external and internal signals. It is possible that locally-produced triiodothyronine resulting from the action of type 2 iodothyronine deiodinase on thyroxine stimulates the release of gonadotropins, perhaps by action on GnRH neurons. The function of GnRH neurons is also regulated by transcription of the GnRH gene. Melatonin, a nocturnal hormone, stimulates the synthesis and release of GnIH and GnIH may therefore regulate a daily rhythm of gonadotropin secretion. GnIH may also temporally suppress gonadotropin secretion when environmental conditions are unfavorable. Environmental and social milieus fluctuate seasonally in the wild. Accordingly, complex interactions of various neuronal and hormonal systems need to be considered if we are to understand the mechanisms underlying seasonal reproduction. PMID:23531789

  3. Regulation of gonadotropins by corticotropin-releasing factor and urocortin.

    PubMed

    Kageyama, Kazunori

    2013-01-01

    While stress activates the hypothalamic-pituitary-adrenal (HPA) axis, it suppresses the hypothalamic-pituitary-gonadal (HPG) axis. Corticotropin-releasing factor (CRF) is a major regulatory peptide in the HPA axis during stress. Urocortin 1 (Ucn1), a member of the CRF family of peptides, has a variety of physiological functions and both CRF and Ucn1 contribute to the stress response via G protein-coupled seven transmembrane receptors. Ucn2 and Ucn3, which belong to a separate paralogous lineage from CRF, are highly selective for the CRF type 2 receptor (CRF(2) receptor). The HPA and HPG axes interact with each other, and gonadal function and reproduction are suppressed in response to various stressors. In this review, we focus on the regulation of gonadotropins by CRF and Ucn2 in pituitary gonadotrophs and of gonadotropin-releasing hormone (GnRH) via CRF receptors in the hypothalamus. In corticotrophs, stress-induced increases in CRF stimulate Ucn2 production, which leads to the inhibition of gonadotropin secretion via the CRF(2) receptor in the pituitary. GnRH in the hypothalamus is regulated by a variety of stress conditions. CRF is also involved in the suppression of the HPG axis, especially the GnRH pulse generator, via CRF receptors in the hypothalamus. Thus, complicated regulation of GnRH in the hypothalamus and gonadotropins in the pituitary via CRF receptors contributes to stress responses and adaptation of gonadal functions.

  4. Behavioral regulation of gonadotropin-releasing hormone.

    PubMed

    Rissman, E F

    1996-02-01

    GnRH controls the hypothalamic-pituitary-gonadal axis in all vertebrate species. Yet despite intense efforts, limited progress has been made toward determining how production of this neuropeptide is regulated. An alternative approach to this problem is to study species whose reproductive status is sensitive to behavioral influences and then to use behavioral interactions to probe the GnRH neuronal system. In this review, data on behaviorally induced alterations in the GnRH system will be presented. In several species of fishes, reproductive status and sex can be altered in adults by changes in the social environment. In these fishes, the numbers and size of GnRH-immunoreactive (GnRH-ir) neurons are modified by an individual's social and sexual status. In the ring dove, courtship activates ovarian follicular development and stimulates androgen production in males. During courtship, mast cells containing GnRH-like immunoreactivity enter the brain. This finding presents a new avenue for examining behavioral endocrine and immune interactions. In the musk shrew, most aspects of female reproduction are activated by contact with a male. Interactions with males trigger changes in the numbers of GnRH-ir cells and rapid production of GnRH peptide. The use of comparative animal models provides us with new insights into neuronal plasticity, neuroendoimmunology, and reproductive biology.

  5. Leptin regulates gonadotropins and steroid receptors in the rats ovary.

    PubMed

    Silveira Cavalcante, Fernanda; Aiceles, Verónica; da Fonte Ramos, Cristiane

    2013-01-01

    The leptin hormone is important to satiety and an important link between the nutritional status and reproductive processes. Owing to the contradictory effects of leptin on the ovary and the failure to clarify the precise mechanism by which leptin affects the ovary, our aim was to contribute to evaluation if leptin can directly regulate the gene expression of leptin itself and its receptors, and the expression of several genes related to the ovary function by a model of tissue culture. Ovaries from Wistar dams were used at 90 days of age and were submitted to medium with presence and absence of leptin. The results can demonstrate that leptin regulates gonadotropins and steroid receptors, which could suggest that the ovarian leptin role could be secondary to the changes in these receptors expression in rats.

  6. Molecular mechanisms of gonadotropin-releasing hormone receptor gene regulation.

    PubMed

    Norwitz, E R; Jeong, K H; Chin, W W

    1999-01-01

    GnRH plays a critical role in regulating mammalian reproductive development and function. At the level of the anterior pituitary, GnRH binds to the GnRH receptor (GnRHR) on the cell surface of pituitary gonadotropes. Here, it activates intracellular signal transduction pathways to effect both the synthesis and intermittent release of the gonadotropins LH and FSH. These hormones then enter the systemic circulation to regulate gonadal function, including steroid hormone synthesis and gametogenesis. The response of pituitary gonadotropes to GnRH correlates directly with the concentration of GnRHR on the cell surface, which is mediated, at least in part, at the level of gene expression. A number of endocrine, paracrine, and autocrine factors are known to regulate GnRHR gene expression. This article reviews in detail the role of the GnRHR in the hypothalamic-pituitary-gonadal axis and the factors mediating expression of this gene. A better understanding of the molecular mechanisms that regulate transcription of the GnRHR gene will further our knowledge about the role of this receptor in mammalian reproductive physiology in health and disease.

  7. Regulation of gonadotropin gene expression by Mullerian inhibiting substance.

    PubMed

    Bédécarrats, Grégoy Y; O'Neill, Francis H; Norwitz, Errol R; Kaiser, Ursula B; Teixeira, Jose

    2003-08-01

    In addition to its role in causing Müllerian duct regression, Müllerian inhibiting substance (MIS) is implicated in the regulation of steroidogenesis, breast and prostate growth, and ovarian follicle recruitment, all of which are processes controlled or influenced by the hypothalamic-pituitary-gonadal axis. Whereas the direct effect of MIS on gonadal, prostate, and breast cells is under investigation, the ability of MIS to modulate pituitary function, thereby affecting those tissues indirectly, has not yet been studied. Using LbetaT2 cells, a murine gonadotrope-derived cell line, we have evaluated the effects of MIS on the expression of the gonadotropin genes. We show that both LbetaT2 cells and adult rat pituitaries express MIS type II receptor (MISRII) mRNA. Within 2 h, follicle-stimulating hormone beta subunit (FSHbeta) mRNA levels are significantly induced by addition of MIS to LbetaT2 cells and remain elevated through 8 h of treatment. Transcriptional activation of both the FSHbeta and luteinizing hormone beta subunit (LHbeta) gene promoters was observed by MIS, which enhances the effect of gonadotropin-releasing hormone (GnRH) agonist on the FSHbeta gene promoter and synergizes with the GnRH agonist to stimulate LHbeta gene promoter activity. Addition of MIS to LbetaT2 cells stimulates the activity of the rat LHbeta gene promoter with as little as 1 microg/ml and in a dose-dependent manner. These studies report both MISRII expression in rat pituitary cells and a gonadotrope-derived cell line and MIS-mediated activation of LHbeta and FSHbeta gene expression, and suggest that MIS may modulate the hypothalamic-pituitary-gonadal axis at more than one level.

  8. Gonadotropin-releasing hormone: gene evolution, expression, and regulation.

    PubMed

    Belsham, Denise D; Lovejoy, David A

    2005-01-01

    The gonadotropin-releasing hormone (GnRH) gene is a superb example of the diverse regulation that is required to maintain the function of an evolutionarily conserved and fundamental gene. Because reproductive capacity is critical to the survival of the species, physiological homeostasis dictates optimal conditions for reproductive success, and any perturbation from this balance may affect GnRH expression. These disturbances may include alterations in signals dictated by stress, nutritional imbalance, body weight, and neurological problems; therefore, changes in other neuroendocrine systems may directly influence the hypothalamic-pituitary-gonadal axis through direct regulation of GnRH. Thus, to maintain optimal reproductive capacity, the regulation of the GnRH gene is tightly constrained by a number of diverse signaling pathways and neuromodulators. In this review, we summarize what is currently known of GnRH gene structure, the location and function of the two isoforms of the GnRH gene, some of the many hormones and neuromodulators found to affect GnRH expression, and the molecular mechanisms responsible for the regulation of the GnRH gene. We also discuss the latest models used to study the transcriptional regulation of the GnRH gene, from cell models to evolving in vivo technologies. Although we have come a long way in the last two decades toward uncovering the intricacies behind the control of the GnRH neuron, there remain vast distances to cover before direct therapeutic manipulation of the GnRH gene to control reproductive competence is possible.

  9. Gonadotropin-regulated Testicular RNA Helicase (GRTH/DDX25), a Negative Regulator of Luteinizing/Chorionic Gonadotropin Hormone-induced Steroidogenesis in Leydig Cells

    PubMed Central

    Fukushima, Masato; Villar, Joaquin; Tsai-Morris, Chon-Hwa; Dufau, Maria L.

    2011-01-01

    Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25) is a testis-specific gonadotropin-regulated RNA helicase that is present in Leydig cells (LCs) and germ cells and is essential for spermatid development and completion of spermatogenesis. Normal basal levels of testosterone in serum and LCs were observed in GRTH null (GRTH−/−) mice. However, testosterone production was enhanced in LCs of GRTH−/− mice compared with WT mice by both in vivo and in vitro human chorionic gonadotropin stimulation. LCs of GRTH−/− mice had swollen mitochondria with a significantly increased cholesterol content in the inner mitochondrial membrane. Basal protein levels of SREBP2, HMG-CoA reductase, and steroidogenic acute regulatory protein (StAR; a protein that transports cholesterol to the inner mitochondrial membrane) were markedly increased in LCs of GRTH−/− mice compared with WT mice. Gonadotropin stimulation caused an increase in StAR mRNA levels and protein expression in GRTH−/− mice versus WT mice, with no further increase in SREBP2 and down-regulation of HMG-CoA reductase protein. The half-life of StAR mRNA was significantly increased in GRTH−/− mice. Moreover, association of StAR mRNA with GRTH protein was observed in WT mice. Human chorionic gonadotropin increased GRTH gene expression and its associated StAR protein at cytoplasmic sites. Taken together, these findings indicate that, through its negative role in StAR message stability, GRTH regulates cholesterol availability at the mitochondrial level. The finding of an inhibitory action of GRTH associated with gonadotropin-mediated steroidogenesis has provided insights into a novel negative autocrine molecular control mechanism of this helicase in the regulation of steroid production in the male. PMID:21719703

  10. The Rab GTPase RabA4d regulates pollen tube tip growth in Arabidopsis thaliana.

    PubMed

    Szumlanski, Amy L; Nielsen, Erik

    2009-02-01

    During reproduction in flowering plants, pollen grains form a tube that grows in a polarized fashion through the female tissues to eventually fertilize the egg cell. These highly polarized pollen tubes have a rapid rate of growth that is supported by a tip-focused delivery of membrane and cell wall components. To gain a better understanding of how this growth is regulated, we investigated the function RABA4D, a member of the Arabidopsis thaliana RabA4 subfamily of Rab GTPase proteins. Here, we show that RABA4D was expressed in a pollen-specific manner and that enhanced yellow fluorescent protein (EYFP)-RabA4d-labeled membrane compartments localized to the tips of growing pollen tubes. Mutant pollen in which the RABA4D gene was disrupted displayed bulged pollen tubes with a reduced rate of growth in vitro and displayed altered deposition of some cell wall components. Expression of EYFP-RabA4d restored wild-type phenotypes to the raba4d mutant pollen tubes, while expression of EYFP-RabA4b did not rescue the raba4d phenotype. In vivo, disruption of RABA4D resulted in a male-specific transmission defect with mutant raba4d pollen tubes displaying aberrant growth in the ovary and reduced guidance at the micropyle. We propose that RabA4d plays an important role in the regulation of pollen tube tip growth.

  11. Regulation of tonic gonadotropin release in prepubertal female hamsters

    SciTech Connect

    Smith, S.G.; Matt, K.S.; Prestowitz, W.F.; Stetson, M.H.

    1982-04-01

    Basal serum gonadotropin levels were monitored weekly in female hamsters from birth to 10 weeks of age. Hamsters raised on three different photoperiods presented uniform pre- and postpubertal patterns of serum LH and FSH, suggesting that gonadotropin release in the young hamster occurs independently of ambient photoperiod. In all groups, serum LH levels increased gradually in animals up to 4 weeks of age, after which levels plateaued at 50--100 ng/ml. Serum FSH was markedly elevated in 2- and 3-week-old hamsters (800--1200 ng/ml), but remained at 200--400 ng/ml in all other groups. We next examined the change in the responsiveness of the pituitary to exogenous gonadotropin-releasing hormone (GnRH) challenge. Female hamsters 2 days of age failed to respond to any dose (0.025--1000 ng) of GnRH, while 10-day old females responded in typical dose-dependent fashion. GnRH-stimulated LH release first occurred in 6-day-old hamsters and was maximal by day 9, whereas FSH release first occurred on day 8 and was maximal by day 9. The prepubertal pattern of gonadotropin release can, in part, be explained on the basis of the development of pituitary GnRH sensitivity, which occurs independently of photoperiod.

  12. Do androgens directly regulate gonadotropin secretion in the polycystic ovary syndrome?

    PubMed

    Dunaif, A

    1986-07-01

    This study was designed to investigate whether androgens directly, independent of their aromatization to estrogens, disrupt gonadotropin secretion in hyperandrogenic women with the polycystic ovary syndrome (PCO). Pulsatile gonadotropin release and gonadotroph sensitivity to GnRH were determined on consecutive study days basally and during a primed continuous infusion of testosterone (T; n = 4; 100 micrograms/h; twice the mean production rate of T in PCO) or dihydrotestosterone (DHT; n = 5; 50 micrograms/h). To determine if the gonadotropin secretory changes during T infusion were secondary to spontaneous variation, four patients had two consecutive basal studies, and all patients received DHT on the third study day. T infusion that increased mean plasma T levels from 76 +/- 12 (+/- SE) to 315 +/- 28 ng/dl produced no significant changes in the amount or pattern of LH release or in LH sensitivity to GnRH. Mean plasma FSH levels decreased slightly but significantly during T infusion (basal, 242 +/- 29 vs. T 226 +/- 30 ng/ml LER-907; P less than 0.05 by two-tailed paired t test), but the pulsatile pattern of FSH release and FSH sensitivity to GnRH did not change. DHT infusion increased plasma DHT levels from 17 +/- 3 to 244 +/- 31 ng/dl, but did not alter the mean levels, pulsatile patterns, or sensitivity to GnRH of LH or FSH. These data suggest that androgens do not directly alter gonadotropin release in PCO. Thus, regulation of the hypothalamic-pituitary axis in women with PCO is different from that in men despite chronic exposure to hyperandrogenemia.

  13. Central and direct regulation of testicular activity by gonadotropin-inhibitory hormone and its receptor.

    PubMed

    Ubuka, Takayoshi; Son, You Lee; Tobari, Yasuko; Narihiro, Misato; Bentley, George E; Kriegsfeld, Lance J; Tsutsui, Kazuyoshi

    2014-01-01

    Gonadotropin-inhibitory hormone (GnIH) was first identified in Japanese quail to be an inhibitor of gonadotropin synthesis and release. GnIH peptides have since been identified in all vertebrates, and all share an LPXRFamide (X = L or Q) motif at their C-termini. The receptor for GnIH is the G protein-coupled receptor 147 (GPR147), which inhibits cAMP signaling. Cell bodies of GnIH neurons are located in the paraventricular nucleus (PVN) in birds and the dorsomedial hypothalamic area (DMH) in most mammals. GnIH neurons in the PVN or DMH project to the median eminence to control anterior pituitary function via GPR147 expressed in gonadotropes. Further, GnIH inhibits gonadotropin-releasing hormone (GnRH)-induced gonadotropin subunit gene transcription by inhibiting the adenylate cyclase/cAMP/PKA-dependent ERK pathway in an immortalized mouse gonadotrope cell line (LβT2 cells). GnIH neurons also project to GnRH neurons that express GPR147 in the preoptic area (POA) in birds and mammals. Accordingly, GnIH can inhibit gonadotropin synthesis and release by decreasing the activity of GnRH neurons as well as by directly inhibiting pituitary gonadotrope activity. GnIH and GPR147 can thus centrally suppress testosterone secretion and spermatogenesis by acting in the hypothalamic-pituitary-gonadal axis. GnIH and GPR147 are also expressed in the testis of birds and mammals, possibly acting in an autocrine/paracrine manner to suppress testosterone secretion and spermatogenesis. GnIH expression is also regulated by melatonin, stress, and social environment in birds and mammals. Accordingly, the GnIH-GPR147 system may play a role in transducing physical and social environmental information to regulate optimal testicular activity in birds and mammals. This review discusses central and direct inhibitory effects of GnIH and GPR147 on testosterone secretion and spermatogenesis in birds and mammals.

  14. Identification of a calmodulin-binding domain in Sema4D that regulates its exodomain shedding in platelets

    PubMed Central

    Mou, Peipei; Zeng, Zhao; Li, Qiang; Liu, Xiaohui; Xin, Xiaoran; Wannemacher, Kenneth M.; Ruan, Changgeng; Li, Renhao; Brass, Lawrence F.

    2013-01-01

    Semaphorin 4D (Sema4D) is a transmembrane protein that supports contact-dependent amplification of platelet activation by collagen before being gradually cleaved by the metalloprotease ADAM17, as we have previously shown. Cleavage releases a soluble 120-kDa exodomain fragment for which receptors exist on platelets and endothelial cells. Here we have examined the mechanism that regulates Sema4D exodomain cleavage. The results show that the membrane-proximal cytoplasmic domain of Sema4D contains a binding site for calmodulin within the polybasic region Arg762-Lys779. Coprecipitation studies show that Sema4D and calmodulin are associated in resting platelets, forming a complex that dissociates upon platelet activation by the agonists that trigger Sema4D cleavage. Inhibiting calmodulin with W7 or introducing a membrane-permeable peptide corresponding to the calmodulin-binding site is sufficient to trigger the dissociation of Sema4D from calmodulin and initiate cleavage. Conversely, deletion of the calmodulin-binding site causes constitutive shedding of Sema4D. These results show that (1) Sema4D is a calmodulin-binding protein with a site of interaction in its membrane-proximal cytoplasmic domain, (2) platelet agonists cause dissociation of the calmodulin–Sema4D complex, and (3) dissociation of the complex is sufficient to trigger ADAM17-dependent cleavage of Sema4D, releasing a bioactive fragment. PMID:23564909

  15. Regulation of Gonadotropin-Releasing Hormone Secretion by Cannabinoids

    PubMed Central

    GAMMON, C. MICHAEL; FREEMAN, G. MARK; XIE, WEIHUA; PETERSEN, SANDRA L.; WETSEL, WILLIAM C.

    2005-01-01

    Cannabinoids (CBs) exert untoward effects on reproduction by reducing LH secretion and suppressing gonadal function. Recent evidence suggests these effects are due primarily to hypothalamic dysfunction; however, the mechanism is obscure. Using immortalized hypothalamic GnRH neurons, we find these cells produce and secrete at least two different endocannabinoids. Following release, 2-arachidonyl monoacylglycerol and anandamide are rapidly transported into GnRH neurons and are degraded to other lipids by fatty-acid amide hydrolase. The immortalized GnRH neurons also possess CB1 and CB2 receptors that are coupled to Gi/Go proteins whose activation leads to inhibition of GnRH secretion. In perifusion experiments, CBs block pulsatile release of GnRH. When a CB receptor agonist is delivered into the third ventricle of adult female mice, estrous cycles are prolonged by at least 2 days. Although in situ hybridization experiments suggest either that GnRH neurons in vivo do not possess CB1 receptors or that they are very low, transcripts are localized in close proximity to these neurons. Inasmuch as GnRH neurons in vivo possess G protein receptors that are coupled to phospholipase C and increased intracellular Ca2+, these same neurons should also be able to synthesize endocannabinoids. These lipids, in turn, could bind to CB receptors on neighboring cells and perhaps, GnRH neurons, to exert feedback control over GnRH function. This network could serve as a novel mechanism for regulating GnRH secretion where reproductive functions as diverse as the onset of puberty, timing of ovulation, duration of lactational infertility, and initiation/persistence of menopause may be affected. PMID:16020480

  16. [Mechanism of regulation of synthesis and secretion of human chorionic gonadotropin (hCG) during pregnancy].

    PubMed

    Barrera, David; Chirinos, Mayel; García-Becerra, Rocío

    2008-01-01

    Human chorionic gonadotropin (hCG) is an essential hormone for development and sustaining of gestation. Adequate hCG production is fundamental for pregnancy success since abnormal hCG serum concentrations have been correlated with pregnancy anomalies such as recurrent abortions and preeclampsia. Regulation of hCG production involves diverse molecules associated with different signaling pathways, which have complicated the establishment of the mechanisms involved in its production. The present study provides a critical review of the most relevant findings related to hCG production and functions during pregnancy, in order to help to understand some related pathologies and to treat them more adequately.

  17. A CaMKII/PDE4D negative feedback regulates cAMP signaling

    PubMed Central

    Mika, Delphine; Richter, Wito; Conti, Marco

    2015-01-01

    cAMP production and protein kinase A (PKA) are the most widely studied steps in β-adrenergic receptor (βAR) signaling in the heart; however, the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is also activated in response to βAR stimulation and is involved in the regulation of cardiac excitation-contraction coupling. Its activity and expression are increased during cardiac hypertrophy, in heart failure, and under conditions that promote arrhythmias both in animal models and in the human heart, underscoring the clinical relevance of CaMKII in cardiac pathophysiology. Both CaMKII and PKA phosphorylate a number of protein targets critical for Ca2+ handling and contraction with similar, but not always identical, functional consequences. How these two pathways communicate with each other remains incompletely understood, however. To maintain homeostasis, cyclic nucleotide levels are regulated by phosphodiesterases (PDEs), with PDE4s predominantly responsible for cAMP degradation in the rodent heart. Here we have reassessed the interaction between cAMP/PKA and Ca2+/CaMKII signaling. We demonstrate that CaMKII activity constrains basal and βAR-activated cAMP levels. Moreover, we show that these effects are mediated, at least in part, by CaMKII regulation of PDE4D. This regulation establishes a negative feedback loop necessary to maintain cAMP/CaMKII homeostasis, revealing a previously unidentified function for PDE4D as a critical integrator of cAMP/PKA and Ca2+/CaMKII signaling. PMID:25646485

  18. Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25), a negative regulator of luteinizing/chorionic gonadotropin hormone-induced steroidogenesis in Leydig cells: central role of steroidogenic acute regulatory protein (StAR).

    PubMed

    Fukushima, Masato; Villar, Joaquin; Tsai-Morris, Chon-Hwa; Dufau, Maria L

    2011-08-26

    Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25) is a testis-specific gonadotropin-regulated RNA helicase that is present in Leydig cells (LCs) and germ cells and is essential for spermatid development and completion of spermatogenesis. Normal basal levels of testosterone in serum and LCs were observed in GRTH null (GRTH(-/-)) mice. However, testosterone production was enhanced in LCs of GRTH(-/-) mice compared with WT mice by both in vivo and in vitro human chorionic gonadotropin stimulation. LCs of GRTH(-/-) mice had swollen mitochondria with a significantly increased cholesterol content in the inner mitochondrial membrane. Basal protein levels of SREBP2, HMG-CoA reductase, and steroidogenic acute regulatory protein (StAR; a protein that transports cholesterol to the inner mitochondrial membrane) were markedly increased in LCs of GRTH(-/-) mice compared with WT mice. Gonadotropin stimulation caused an increase in StAR mRNA levels and protein expression in GRTH(-/-) mice versus WT mice, with no further increase in SREBP2 and down-regulation of HMG-CoA reductase protein. The half-life of StAR mRNA was significantly increased in GRTH(-/-) mice. Moreover, association of StAR mRNA with GRTH protein was observed in WT mice. Human chorionic gonadotropin increased GRTH gene expression and its associated StAR protein at cytoplasmic sites. Taken together, these findings indicate that, through its negative role in StAR message stability, GRTH regulates cholesterol availability at the mitochondrial level. The finding of an inhibitory action of GRTH associated with gonadotropin-mediated steroidogenesis has provided insights into a novel negative autocrine molecular control mechanism of this helicase in the regulation of steroid production in the male.

  19. Leptin and the hypothalamic-pituitary regulation of the gonadotropin-gonadal axis.

    PubMed

    Chan, J L; Mantzoros, C S

    2001-01-01

    Leptin is an adipocyte-derived protein hormone which not only conveys a signal of the amount of energy stores to the central nervous system but also plays an important role in regulating neuroendocrine function. The importance of leptin in the reproductive system has been suggested by the reproductive dysfunction associated with leptin deficiency and resistance in both animal models and humans as well as the ability of leptin to accelerate the onset of reproductive function in normal mice. Transgenic mice overexpressing leptin also have accelerated puberty, and leptin administration reverses the fasting-induced suppression of sexual maturation in rodents, indicating that leptin may serve as the critical link between sufficient energy stores and proper functioning of the reproductive system. Normal women have a pulsatile release pattern of leptin that is significantly associated with the variations in luteinizing hormone (LH) and estradiol levels. In various animal models, leptin administration restores the LH pulsatility pattern which is suppressed during fasting, indicating a hypothalamic site of action since LH pulsatility is under the control of gonadotropin-releasing hormone (GnRH). In humans, leptin has been administered to a 9-year-old leptin-deficient girl, resulting in a gonadotropin secretory pattern consistent with early puberty. While in vitro experiments with hypothalamic explants and a GnRH-secreting neuronal cell line have shown that leptin can directly stimulate GnRH secretion, the lack of leptin receptors on GnRH neurons suggests that leptin may act through other hypothalamic neuropeptides. Several neuropeptides which act as downstream effectors of leptin have been investigated, and recent studies indicate that cocaine and amphetamine-regulated transcript may be such a mediator of leptin's effect on GnRH. Leptin receptors have also been identified in human pituitaries, and leptin may influence LH release from the pituitary. However, the current

  20. The role of kisspeptin and gonadotropin inhibitory hormone in the seasonal regulation of reproduction in sheep.

    PubMed

    Smith, J T

    2012-08-01

    Sheep are seasonal breeders, experiencing an annual period of reproductive quiescence in response to increased photoperiod during the late-winter into spring and renaissance during the late summer. The nonbreeding (anestrous) season is characterized by a reduction in the pulsatile secretion of GnRH from the brain, in part because of an increase in negative feedback activity of estrogen. Neuronal populations in the hypothalamus that produce kisspeptin and gonadotropin-inhibitory hormone (GnIH) appear to be important for the seasonal shift in reproductive activity, and the former are also mandatory for puberty onset. Kisspeptin cells in the arcuate nucleus (ARC) and preoptic area appear to regulate GnRH neurons and transmit sex-steroid feedback signals to these neurons. Moreover, kisspeptin expression in the ARC is markedly up-regulated at the onset of the breeding season, as too are the number of kisspeptin fibers in close apposition to GnRH neurons. The lower levels of kisspeptin seen during the nonbreeding season can be "corrected" by infusion of kisspeptin, which causes ovulation in seasonally acyclic females. The role of GnIH is less clear, but mounting evidence supports a role for this neuropeptide in the inhibitory regulation of both GnRH secretion and gonadotropin release from the pituitary gland. Contrary to kisspeptin, GnIH expression is markedly reduced at the onset of the breeding season. In addition, the number of GnIH fibers in close apposition to GnRH neurons also decreases during this time. Importantly, exogenous GnIH treatment can block both the pulsatile release of LH and the preovulatory LH surge during the breeding season. In summary, it is most likely the integrated function of both these neuropeptide systems that modulate the annual shift in photoperiod to a physiological change in fertility.

  1. The involvement of gonadotropin inhibitory hormone and kisspeptin in the metabolic regulation of reproduction.

    PubMed

    Wahab, F; Shahab, M; Behr, R

    2015-05-01

    Recently, kisspeptin (KP) and gonadotropin inhibitory hormone (GnIH), two counteracting neuropeptides, have been acknowledged as significant regulators of reproductive function. KP stimulates reproduction while GnIH inhibits it. These two neuropeptides seem to be pivotal for the modulation of reproductive activity in response to internal and external cues. It is well-documented that the current metabolic status of the body is closely linked to its reproductive output. However, how reproductive function is regulated by the body's energy status is less clear. Recent studies have suggested an active participation of hypothalamic KP and GnIH in the modulation of reproductive function according to available metabolic cues. Expression of KISS1, the KP encoding gene, is decreased while expression of RFRP (NPVF), the gene encoding GnIH, is increased in metabolic deficiency conditions. The lower levels of KP, as suggested by a decrease in KISS1 gene mRNA expression, during metabolic deficiency can be corrected by administration of exogenous KP, which leads to an increase in reproductive hormone levels. Likewise, administration of RF9, a GnIH receptor antagonist, can reverse the inhibitory effect of fasting on testosterone in monkeys. Together, it is likely that the integrated function of both these hypothalamic neuropeptides works as a reproductive output regulator in response to a change in metabolic status. In this review, we have summarized literature from nonprimate and primate studies that demonstrate the involvement of KP and GnIH in the metabolic regulation of reproduction.

  2. Regulation of gonadotropin gene expression by Müllerian inhibiting substance

    PubMed Central

    Bédécarrats, Grégoy Y.; O'Neill, Francis H.; Norwitz, Errol R.; Kaiser, Ursula B.; Teixeira, Jose

    2003-01-01

    In addition to its role in causing Müllerian duct regression, Müllerian inhibiting substance (MIS) is implicated in the regulation of steroidogenesis, breast and prostate growth, and ovarian follicle recruitment, all of which are processes controlled or influenced by the hypothalamic–pituitary–gonadal axis. Whereas the direct effect of MIS on gonadal, prostate, and breast cells is under investigation, the ability of MIS to modulate pituitary function, thereby affecting those tissues indirectly, has not yet been studied. Using LβT2 cells, a murine gonadotrope-derived cell line, we have evaluated the effects of MIS on the expression of the gonadotropin genes. We show that both LβT2 cells and adult rat pituitaries express MIS type II receptor (MISRII) mRNA. Within 2 h, follicle-stimulating hormone β subunit (FSHβ) mRNA levels are significantly induced by addition of MIS to LβT2 cells and remain elevated through 8 h of treatment. Transcriptional activation of both the FSHβ and luteinizing hormone β subunit (LHβ) gene promoters was observed by MIS, which enhances the effect of gonadotropin-releasing hormone (GnRH) agonist on the FSHβ gene promoter and synergizes with the GnRH agonist to stimulate LHβ gene promoter activity. Addition of MIS to LβT2 cells stimulates the activity of the rat LHβ gene promoter with as little as 1 μg/ml and in a dose-dependent manner. These studies report both MISRII expression in rat pituitary cells and a gonadotrope-derived cell line and MIS-mediated activation of LHβ and FSHβ gene expression, and suggest that MIS may modulate the hypothalamic–pituitary–gonadal axis at more than one level. PMID:12878721

  3. Differential social regulation of two pituitary gonadotropin-releasing hormone receptors.

    PubMed

    Au, Teresa M; Greenwood, Anna K; Fernald, Russell D

    2006-06-30

    In many vertebrates, social interactions regulate reproductive capacity by altering the activity of the hypothalamic-pituitary-gonadal (HPG) axis. To better understand the mechanisms underlying social regulation of reproduction, we investigated the relationship between social status and one main component of the HPG axis: expression levels of gonadotropin-releasing hormone receptor (GnRH-R). Social interactions dictate reproductive capacity in the cichlid fish Astatotilapia burtoni. Reproductively active territory holders suppress the HPG axis of non-territorial males through repeated aggressive encounters. To determine whether the expression of GnRH-R is socially regulated, we quantified mRNA levels of two GnRH-R variants in the pituitaries and brains of territorial (T) and non-territorial (NT) A. burtoni males. We found that T males had significantly higher levels of pituitary GnRH-R1 mRNA than NT males. In contrast, GnRH-R2 mRNA levels in the pituitary did not vary with social status. Pituitaries from both T and NT males expressed significantly higher mRNA levels of GnRH-R1 than GnRH-R2. GnRH mRNA levels in the brain correlated positively with GnRH-R1 mRNA levels in the pituitary but did not correlate with pituitary GnRH-R2. Measurements of GnRH-R1 and GnRH-R2 mRNA levels across the whole brain revealed no social status differences. These results show that, in addition to the known effects of social status on other levels of the HPG axis, GnRH receptor in the pituitary is also a target of social regulation.

  4. Human chorionic gonadotropin β subunit affects the expression of apoptosis-regulating factors in ovarian cancer.

    PubMed

    Szczerba, Anna; Śliwa, Aleksandra; Kubiczak, Marta; Nowak-Markwitz, Ewa; Jankowska, Anna

    2016-01-01

    Expression of human chorionic gonadotropin, especially its free β subunit (hCGβ) were shown to play an important role in cancer growth, invasion and metastasis. It is postulated that hCGβ is one of the factors determining cancer cell survival. To test this hypothesis, we applied two models: an in vitro model of ovarian cancer using OVCAR-3 and SKOV-3 cell lines transfected with the CGB5 gene and an in vivo model of ovarian cancer tissues. The material was tested against changes in expression level of genes encoding factors involved in apoptosis: BCL2, BAX and BIRC5. Overexpression of hCGβ was found to cause a decrease in expression of the analyzed genes in the transfected cells compared with the control cells. In ovarian cancer tissues, high expression of CGB was related to significantly lower BCL2 but higher BAX and BIRC5 transcript levels. Moreover, a low BCL2/BAX ratio, characteristic of advanced stages of ovarian cancer, was revealed. Since tumors were discriminated by a significantly lower LHCGR level than the level noted in healthy fallopian tubes and ovaries, it may be stated that the effect of hCGβ on changes in the expression of apoptosis-regulating agents observed in ovarian cancer is LHCGR-independent. The results of the study suggest that the biological effects evoked by hCGβ are related to apoptosis suppression.

  5. Distribution and regulation by oestrogen of fully processed and variant transcripts of gonadotropin releasing hormone I and gonadotropin releasing hormone receptor mRNAs in the male chicken.

    PubMed

    Sun, Y M; Dunn, I C; Baines, E; Talbot, R T; Illing, N; Millar, R P; Sharp, P J

    2001-01-01

    The aim of this study was to increase understanding of the occurrence and regulation of chicken gonadotropin releasing hormone I (cGnRH I) and chicken gonadotropin releasing hormone receptor (cGnRH-R) mRNA variants in the hypothalamic-pituitary-testicular axis (HPTA). The study was carried out in the cockerel. Fully processed cGnRH I mRNA (cGnRH Ia) and a variant transcript (cGnRH Ib) with a retained intron 1 were observed in the preoptic/anterior hypothalamus (POA), the basal hypothalamus, anterior pituitary gland, and testes. Fully processed cGnRH-R mRNA (cGnRH-Ra) and a variant transcript (cGnRH-Rb) with a deletion were detected in the same tissues. In juvenile cockerels, concentrations of cGnRH Ia and b in the POA increased after castration, and this was prevented by oestrogen treatment. In the anterior pituitary gland, the concentration of cGnRH-Ra increased after castration and this was reversed by oestrogen treatment. In intact adult cockerels, oestrogen treatment depressed plasma luteinizing hormone but did not affect concentrations of cGnRH I and cGnRH-R mRNAs in the POA, basal hypothalamus, and anterior pituitary gland, suggesting that locally produced oestrogen, by aromatization, may exert maximal suppression on cGnRH I and GnRH-R mRNAs. In intact adult cockerels, the concentrations of cGnRH Ia and b in the testis, but not cGnRH-Ra and b, were depressed by oestrogen treatment. It was concluded that fully processed and variant cGnRH I and cGnRH-R mRNAs occur in all components of the HPTA. Oestrogen appears to play a role in the regulation of cGnRH Ia and b in the POA and testes, and of cGnRH-Ra in the POA and anterior pituitary gland.

  6. Regulation of serum testosterone in men with steroid sulfatase deficiency: response to human chorionic gonadotropin.

    PubMed

    Ruokonen, A; Oikarinen, A; Vihko, R

    1986-07-01

    Human chorionic gonadotropin (hCG; 5000 IU) was administered to 6 control men and 6 patients with recessive x-linked ichthyosis (RXLI) with verified 3 beta-hydroxysteroid sulfate sulfatase (3 beta-HSS) deficiency in their skin biopsy samples. Concentrations of steroids and their sulfate conjugates were determined in peripheral serum specimens collected a day before and 4 days after hCG administration. Testosterone concentrations were identical in patients and controls. Baseline serum LH concentrations were also identical in the 2 groups showing that there were no major differences in the regulation of the hypothalamic-pituitary-gonadal axis. The significantly increased (31-82%) serum concentrations of sulfated pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone and 5-androstene-3 beta,17 beta-diol in patients compared with controls indicated that their circulating concentrations were regulated by 3 beta-HSS. This is in line with the fact that the baseline concentrations of the same unconjugated steroids were significantly lower (32-90%) in patients with RXLI, suggesting that a proportion of these circulating steroids were derived from the corresponding sulfated precursors. The response patterns and actual concentrations of testosterone, 17-hydroxyprogesterone and estradiol were similar in the patients and the controls after hCG. The decreased concentrations of testosterone sulfated at carbon 17 under baseline conditions and after hCG in patients with RXLI remains enigmatic. In conclusion, testosterone production and the response to hCG seem to be identical in patients with RXLI and controls despite the fact that significant differences were observed in the circulating concentrations of several unconjugated and sulfated testosterone precursors.

  7. Evidence that estrogen regulation of testosterone secretion in adult rams is mediated by both indirect (gonadotropin dependent) and direct (gonadotropin independent) means.

    PubMed

    Sanford, L M

    1985-01-01

    Involvement of endogenous estrogen in the regulation of gonadotropin and testosterone secretion was investigated in adult rams. Groups of four rams were either passively immunized against estradiol or treated with the antiestrogen tamoxifen for 2 weeks during the breeding season (October). Circulating testosterone levels in immunized rams increased eight-fold to supraphysiologic values as episodic elevations and baseline levels increased in magnitude; only moderate increases in LH peak frequency and magnitude occurred, and prolactin fell to undetectable levels. Tamoxifen treatment was not associated with changes in mean hormone levels, although there was a tendency toward reductions in the magnitude of episodic LH and testosterone secretion. When rams were challenged with exogenous GnRH and LH, a greater testicular endocrine response was observed in the immunized rams and the pituitary endocrine response was delayed in the tamoxifen-treated rams. Results indicate that in the ram 1) circulating levels of estradiol provide negative feedback signals of different intensities to the testis and the hypothalamic-pituitary axis and 2) tamoxifen exerts a mild estrogenic effect when administered at the dose of 25 mg/day.

  8. Dexamethasone suppresses gonadotropin-releasing hormone (GnRH) secretion and has direct pituitary effects in male rats: differential regulation of GnRH receptor and gonadotropin responses to GnRH.

    PubMed

    Rosen, H; Jameel, M L; Barkan, A L

    1988-06-01

    Endogenous or exogenous glucocorticoid excess leads to the development of hypogonadotropic hypogonadism, but the site(s) and mechanisms of glucocorticoid action are uncertain. We studied the effects of various doses of dexamethasone (Dex) on the hypothalamic-pituitary-gonadal axis in intact and castrate testosterone-replaced (cast + T) male rats and attempted to determine possible sites of Dex effects. A dose-dependent suppression of basal gonadotropin secretion was induced by 5 days of Dex treatment (20, 100, 500, or 2,500 micrograms/kg.day), and the highest dose completely abolished the postcastration rise in pituitary GnRH receptor number (GnRH-R) and serum gonadotropin levels. Administration of exogenous GnRH (0.02-200 micrograms/day over 2 days) resulted in a dose-dependent induction in GnRH-R in both intact and cast + T rats, but the effect was significantly (P less than 0.01) augmented in Dex-treated animals. In contrast, acute LH and FSH responses to GnRH (10, 25, 50, 100, or 250 ng, iv) were significantly blunted in Dex-treated rats. The data suggest that 1) Dex suppresses hypothalamic GnRH secretion, thereby preventing the postcastration rises in GnRH-R and gonadotropins; 2) at the pituitary level, Dex dissociates GnRH-R and gonadotropin responses to GnRH, augmenting GnRH-R induction by GnRH and suppressing gonadotropin responses to GnRH at a postreceptor site; and 3) the model of Dex-treated rats may be useful to study differential GnRH regulation of GnRH-R and gonadotropin secretion.

  9. Regulation of genes encoding steroidogenic factor-1 (SF-1) and gonadotropin subunits in the ovine pituitary gland.

    PubMed

    Baratta, M; Turzillo, A M; Arreguin-Arevalo, A; Clay, C M; Nett, T M

    2003-07-01

    Steroidogenic factor-1 (SF-1) is a transcription factor originally characterized as a mediator of gene expression in steroidogenic tissues. Studies in SF-1 knockout mice revealed that SF-1 has additional roles at multiple levels of the hypothalamic-pituitary-gonadal axis, including regulation of gene expression in pituitary gonadotropes. Specific binding sites for SF-1 have been demonstrated in several pituitary genes with essential roles in gonadotropin synthesis, including alpha subunit, LHbeta subunit, and GnRH receptor. In studies aimed at identifying physiological factors controlling pituitary expression of SF-1, GnRH has been implicated as a co-regulator of SF-1 and gonadotropin subunit genes. In both rats and ewes, elevated endogenous secretion of GnRH following ovariectomy was associated with increased amounts of SF-1 mRNA in the anterior pituitary gland. Conversely, removal of GnRH input to the pituitary gland by hypothalamic-pituitary disconnection (HPD) in ovariectomized (OVX) ewes reduced SF-1 expression. Despite these changes, however, treatment of OVX ewes with GnRH following HPD only partially restored levels of SF-1 mRNA in the pituitary gland. Therefore, it is possible that regulation of SF-1 gene expression by GnRH during the estrous cycle may involve ovarian hormones or other hypothalamic factors. Additional studies are required to further define the physiological roles of SF-1 in regulation of the hypothalamic-pituitary-gonadal axis in domestic ruminants.

  10. The Regulation and Function of Fibroblast Growth Factor 8 and Its Function during Gonadotropin-Releasing Hormone Neuron Development

    PubMed Central

    Chung, Wilson C. J.; Linscott, Megan L.; Rodriguez, Karla M.; Stewart, Courtney E.

    2016-01-01

    Over the last few years, numerous studies solidified the hypothesis that fibroblast growth factor (FGF) signaling regulates neuroendocrine progenitor cell proliferation, fate specification, and cell survival and, therefore, is critical for the regulation and maintenance of homeostasis of the body. One important example that underscores the involvement of FGF signaling during neuroendocrine cell development is gonadotropin-releasing hormone (GnRH) neuron ontogenesis. Indeed, transgenic mice with reduced olfactory placode (OP) Fgf8 expression do not have GnRH neurons. This observation indicates the requirement of FGF8 signaling for the emergence of the GnRH neuronal system in the embryonic OP, the putative birth place of GnRH neurons. Mammalian reproductive success depends on the presence of GnRH neurons to stimulate gonadotropin secretion from the anterior pituitary, which activates gonadal steroidogenesis and gametogenesis. Together, these observations are critical for understanding the function of GnRH neurons and their control of the hypothalamus–pituitary–gonadal (HPG) axis to maintain fertility. Taken together, these studies illustrate that GnRH neuron emergence and hence HPG function is vulnerable to genomic and molecular signals that abnormally modify Fgf8 expression in the developing mouse OP. In this short review, we focus on research that is aimed at unraveling how androgen, all-trans retinoic acid, and how epigenetic factors modify control mouse OP Fgf8 transcription in the context of GnRH neuronal development and mammalian reproductive success. PMID:27656162

  11. The Regulation and Function of Fibroblast Growth Factor 8 and Its Function during Gonadotropin-Releasing Hormone Neuron Development

    PubMed Central

    Chung, Wilson C. J.; Linscott, Megan L.; Rodriguez, Karla M.; Stewart, Courtney E.

    2016-01-01

    Over the last few years, numerous studies solidified the hypothesis that fibroblast growth factor (FGF) signaling regulates neuroendocrine progenitor cell proliferation, fate specification, and cell survival and, therefore, is critical for the regulation and maintenance of homeostasis of the body. One important example that underscores the involvement of FGF signaling during neuroendocrine cell development is gonadotropin-releasing hormone (GnRH) neuron ontogenesis. Indeed, transgenic mice with reduced olfactory placode (OP) Fgf8 expression do not have GnRH neurons. This observation indicates the requirement of FGF8 signaling for the emergence of the GnRH neuronal system in the embryonic OP, the putative birth place of GnRH neurons. Mammalian reproductive success depends on the presence of GnRH neurons to stimulate gonadotropin secretion from the anterior pituitary, which activates gonadal steroidogenesis and gametogenesis. Together, these observations are critical for understanding the function of GnRH neurons and their control of the hypothalamus–pituitary–gonadal (HPG) axis to maintain fertility. Taken together, these studies illustrate that GnRH neuron emergence and hence HPG function is vulnerable to genomic and molecular signals that abnormally modify Fgf8 expression in the developing mouse OP. In this short review, we focus on research that is aimed at unraveling how androgen, all-trans retinoic acid, and how epigenetic factors modify control mouse OP Fgf8 transcription in the context of GnRH neuronal development and mammalian reproductive success.

  12. The Regulation and Function of Fibroblast Growth Factor 8 and Its Function during Gonadotropin-Releasing Hormone Neuron Development.

    PubMed

    Chung, Wilson C J; Linscott, Megan L; Rodriguez, Karla M; Stewart, Courtney E

    2016-01-01

    Over the last few years, numerous studies solidified the hypothesis that fibroblast growth factor (FGF) signaling regulates neuroendocrine progenitor cell proliferation, fate specification, and cell survival and, therefore, is critical for the regulation and maintenance of homeostasis of the body. One important example that underscores the involvement of FGF signaling during neuroendocrine cell development is gonadotropin-releasing hormone (GnRH) neuron ontogenesis. Indeed, transgenic mice with reduced olfactory placode (OP) Fgf8 expression do not have GnRH neurons. This observation indicates the requirement of FGF8 signaling for the emergence of the GnRH neuronal system in the embryonic OP, the putative birth place of GnRH neurons. Mammalian reproductive success depends on the presence of GnRH neurons to stimulate gonadotropin secretion from the anterior pituitary, which activates gonadal steroidogenesis and gametogenesis. Together, these observations are critical for understanding the function of GnRH neurons and their control of the hypothalamus-pituitary-gonadal (HPG) axis to maintain fertility. Taken together, these studies illustrate that GnRH neuron emergence and hence HPG function is vulnerable to genomic and molecular signals that abnormally modify Fgf8 expression in the developing mouse OP. In this short review, we focus on research that is aimed at unraveling how androgen, all-trans retinoic acid, and how epigenetic factors modify control mouse OP Fgf8 transcription in the context of GnRH neuronal development and mammalian reproductive success. PMID:27656162

  13. Notch1 Is Regulated by Chorionic Gonadotropin and Progesterone in Endometrial Stromal Cells and Modulates Decidualization in Primates

    PubMed Central

    Afshar, Yalda; Miele, Lucio

    2012-01-01

    No other tissue in the body undergoes such a vast and extensive growth and remodeling in a relatively short period of time as the primate endometrium. Endometrial integrity is coordinated by ovarian hormones, namely, estrogens, progesterone, and the embryonic hormone chorionic gonadotropin (CG). These regulated events modulate the menstrual cycle and decidualization. The Notch family of transmembrane receptors regulate cellular proliferation, differentiation, and apoptosis, cellular processes required to maintain endometrial integrity. In two primate models, the human and the simulated pregnant baboon model, we demonstrated that Notch1 is increased during the window of uterine receptivity, concomitant with CG. Furthermore, CG combined with estrogens and progesterone up-regulate the level of Notch1, whereas progesterone increases the intracellular transcriptionally competent Notch1, which binds in a complex with progesterone receptor. Inhibition of Notch1 prevented decidualization, and alternatively, when decidualization is biochemically recapitulated in vitro, Notch1 is down-regulated. A focused microarray demonstrated that the Notch inhibitor, Numb, dramatically increased when Notch1 decreased during decidualization. We propose that in the endometrium, Notch has a dual role during the window of uterine receptivity. Initially, Notch1 mediates a survival signal in the uterine endometrium in response to CG from the implanting blastocyst and progesterone, so that menstrual sloughing is averted. Subsequently, Notch1 down-regulation may be critical for the transition of stromal fibroblast to decidual cells, which is essential for the establishment of a successful pregnancy. PMID:22535768

  14. Developmental regulation of gonadotropin-releasing hormone gene expression by the MSX and DLX homeodomain protein families.

    PubMed

    Givens, Marjory L; Rave-Harel, Naama; Goonewardena, Vinodha D; Kurotani, Reiko; Berdy, Sara E; Swan, Christo H; Rubenstein, John L R; Robert, Benoit; Mellon, Pamela L

    2005-05-13

    Gonadotropin-releasing hormone (GnRH) is the central regulator of the hypothalamic-pituitary-gonadal axis, controlling sexual maturation and fertility in diverse species from fish to humans. GnRH gene expression is limited to a discrete population of neurons that migrate through the nasal region into the hypothalamus during embryonic development. The GnRH regulatory region contains four conserved homeodomain binding sites (ATTA) that are essential for basal promoter activity and cell-specific expression of the GnRH gene. MSX and DLX are members of the Antennapedia class of non-Hox homeodomain transcription factors that regulate gene expression and influence development of the craniofacial structures and anterior forebrain. Here, we report that expression patterns of the Msx and Dlx families of homeodomain transcription factors largely coincide with the migratory route of GnRH neurons and co-express with GnRH in neurons during embryonic development. In addition, MSX and DLX family members bind directly to the ATTA consensus sequences and regulate transcriptional activity of the GnRH promoter. Finally, mice lacking MSX1 or DLX1 and 2 show altered numbers of GnRH-expressing cells in regions where these factors likely function. These findings strongly support a role for MSX and DLX in contributing to spatiotemporal regulation of GnRH transcription during development.

  15. Seasonal variation in the gonadotropin-releasing hormone response to kisspeptin in sheep: possible kisspeptin regulation of the kisspeptin receptor.

    PubMed

    Li, Qun; Roa, Alexandra; Clarke, Iain J; Smith, Jeremy T

    2012-01-01

    Kisspeptin signaling in the hypothalamus appears critical for the onset of puberty and driving the reproductive axis. In sheep, reproduction is seasonal, being activated by short days and inhibited by long days. During the non-breeding (anestrous) season, gonadotropin-releasing hormone (GnRH) and gonadotropin secretion is reduced, as is the expression of Kiss1 mRNA in the brain. Conversely, the luteinizing hormone response to kisspeptin during this time is greater. To determine whether the GnRH response to kisspeptin is increased during anestrus, we utilized hypophysial portal blood sampling. In anestrus ewes, the GnRH and LH responses to kisspeptin were greater compared to the breeding season (luteal phase). To ascertain whether this difference reflects a change in Kiss1r, we measured its expression on GnRH neurons using in situ hybridization. The level of Kiss1r was greater during the non-breeding season compared to the breeding season. To further examine the mechanism underlying this change in Kiss1r, we examined Kiss1r/GnRH expression in ovariectomized ewes (controlling for sex steroids) during the breeding and non-breeding seasons, and also ovariectomized non-breeding season ewes with or without estradiol replacement. In both experiments, Kiss1r expression on GnRH neurons was unchanged. Finally, we examined the effect of kisspeptin treatment on Kiss1r. Kiss1r expression on GnRH neurons was reduced by kisspeptin infusion. These studies indicate the kisspeptin response is indeed greater during the non-breeding season and this may be due in part to increased Kiss1r expression on GnRH neurons. We also show that kisspeptin may regulate the expression of its own receptor.

  16. The Dynamics of Connexin Expression, Degradation and Localisation Are Regulated by Gonadotropins during the Early Stages of In Vitro Maturation of Swine Oocytes

    PubMed Central

    Santiquet, Nicolas; Robert, Claude; Richard, François J.

    2013-01-01

    Gap junctional communication (GJC) plays a primordial role in oocyte maturation and meiotic resumption in mammals by directing the transfer of numerous molecules between cumulus cells and the oocyte. Gap junctions are made of connexins (Cx), proteins that regulate GJC in numerous ways. Understanding the dynamic regulation of connexin arrangements during in vitro maturation (IVM) could provide a powerful tool for controlling meiotic resumption and consequently in vitro development of fully competent oocytes. However, physiological events happening during the early hours of IVM may still be elucidated. The present study reports the dynamic regulation of connexin expression, degradation and localization during this stage. Cx43, Cx45 and Cx60 were identified as the main connexins expressed in swine COC. Cx43 and Cx45 transcripts were judged too static to be a regulator of GJC, while Cx43 protein expression was highly responsive to gonadotropins, suggesting that it might be the principal regulator of GJC. In addition, the degradation of Cx43 expressed after 4.5 h of IVM in response to equine chorionic gonadotropin appeared to involve the proteasomal complex. Cx43 localisation appeared to be associated with GJC. Taken together, these results show for the first time that gonadotropins regulate Cx43 protein expression, degradation and localisation in porcine COC during the first several hours of IVM. Regulation of Cx43 may in turn, via GJC, participate in the development of fully competent oocytes. PMID:23861906

  17. Development of gonadotropin-releasing hormone (GnRH) neuron regulation in the female rat.

    PubMed

    Becú-Villalobos, D; Libertun, C

    1995-02-01

    1. After reaching its final destination the GnRH neuronal network develops under the influence of both excitatory and inhibitory inputs. 2. In the first 2 weeks of life, the immaturity of the GnRH neuronal system is reflected in sporadic unsynchronized bursts of the decapeptide, which determine the pattern of serum gonadotropin levels observed in female rats: high FSH levels and transient bursts of LH. The main inhibitory neuronal systems that operate in this period are the opioid and dopaminergic systems. A decrease in their inhibitory effectiveness may not be sufficient correctly to activate and synchronize the GnRH neuronal system. 3. There is a concomitant increase in excitatory inputs, mainly noradrenaline, excitatory amino acids, and NPY, which increase the synthesis and release of GnRH at the beginning of the juvenile period and participate in the coupling of GnRH neural activity to the ongoing rhythmic activity of a hypothalamic circadian oscillator. 4. The morphological changes of GnRH neurons which take place during the third and fourth weeks of life, and which are probably related to increasing estradiol levels, reflects the increasing complexity of the GnRH neuronal network, which establishes synaptic contacts to enable the expression of pulsatility and of the positive feedback of estradiol, both necessary components for the occurrence of puberty.

  18. Negative feedback regulation of gonadotropin secretion by androgens in fetal rhesus macaques.

    PubMed

    Resko, J A; Ellinwood, W E

    1985-09-01

    Previously we described sex differences in circulating gonadotropin concentrations (greater in females) in fetal rhesus macaques, and demonstrated that these sex differences relate, at least in part, to the negative feedback actions of testicular secretions. A fully functional gonadal-hypothalamic-pituitary feedback relationship is present as early as Day 100 of gestation in fetal males because castration at this time results in a dramatic increase (greater than 10-fold) in fetal luteinizing hormone (LH) concentrations. Although short-term (6-h) treatment of fetuses with testosterone (T) 3 wk after gonadectomy (GX) does not lower LH levels in males, it is completely effective in females. These data suggest that either T is not the primary testicular factor responsible for feedback suppression of LH in fetal males, or the hypothalamic-pituitary axis becomes insensitive to T after GX. To determine if immediate treatment with T after GX is effective in maintaining LH levels, we gonadectomized five fetal rhesus males on Days 98-104 of gestation and immediately implanted crystalline-T-containing intraabdominal Silastic capsules. An additional five fetuses were treated with the nonaromatizable androgen dihydrotestosterone (DHT). Umbilical arterial samples for hormone analysis were obtained prior to GX and again approximately 3 wk later. Serum from control males (n = 11) castrated in utero on Day 100 of gestation contained significantly greater concentrations of LH and follicle-stimulating hormone (FSH) 3 wk after the operation than before GX. Five sham-operated male fetuses did not have elevated levels of either LH or FSH in their serum on Day 120 of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Mollusc gonadotropin-releasing hormone directly regulates gonadal functions: a primitive endocrine system controlling reproduction.

    PubMed

    Treen, Nicholas; Itoh, Naoki; Miura, Hanae; Kikuchi, Ippei; Ueda, Takenori; Takahashi, Keisuke G; Ubuka, Takayoshi; Yamamoto, Kazutoshi; Sharp, Peter J; Tsutsui, Kazuyoshi; Osada, Makoto

    2012-04-01

    Gonadotropin-releasing hormone (GnRH) is central to the control of vertebrate reproductive cycles and since GnRH orthologs are also present in invertebrates, it is likely that the common ancestor of bilateral animals possessed a GnRH-like peptide. In order to understand the evolutionary and comparative biology of GnRH peptides we cloned the cDNA transcripts of prepro GnRH-like peptides from two species of bivalve molluscs, the Yesso scallop Patinopecten yessoensis and the Pacific oyster Crassostrea gigas. We compared their deduced uncleaved and mature amino acid sequences with those from other invertebrates and vertebrates, and determined their sites of expression and biological activity. The two molluscan GnRH sequences increased the number of known protostome GnRHs to six different forms, indicating the current classification of protostome GnRHs requires further revision. In both molluscs, RT-PCR analysis showed that the genes were highly expressed in nervous tissue with lower levels present in peripheral tissues including the gonads, while immunocytochemistry, using anti-octopus GnRH-like peptide, demonstrated the presence of GnRH-like peptide in neural tissue. Putative scallop GnRH-like peptide stimulated spermatogonial cell division in cultured scallop testis, but the scallop GnRH-like peptide did not stimulate LH release from cultured quail pituitary cells. This is the first report of the cloning of bivalve GnRH-like peptide genes and of molluscan GnRH-like peptides that are biologically active in molluscs, but not in a vertebrate.

  20. Regulation of sex steroid production and mRNAs encoding gonadotropin receptors and steroidogenic proteins by gonadotropins, cyclic AMP and insulin-like growth factor-I in ovarian follicles of rainbow trout (Oncorhynchus mykiss) at two stages of vitellogenesis.

    PubMed

    Nakamura, Ikumi; Kusakabe, Makoto; Swanson, Penny; Young, Graham

    2016-11-01

    At the completion of vitellogenesis, the steroid biosynthetic pathway in teleost ovarian follicles switches from estradiol-17β (E2) to maturational progestin production, associated with decreased follicle stimulating hormone (Fsh) and increased luteinizing hormone (Lh) signaling. This study compared effects of gonadotropins, human insulin-like growth factor-I (IGF1), and cAMP/protein kinase A signaling (forskolin) on E2 production and levels of mRNAs encoding steroidogenic proteins and gonadotropin receptors using midvitellogenic (MV) and late/postvitellogenic (L/PV) ovarian follicles of rainbow trout. Fsh, Lh and forskolin, but not IGF1, increased testosterone and E2 production in MV and L/PV follicles. Fsh increased steroidogenic acute regulatory protein (star; MV), 3β-hydroxysteroid dehydrogenase/Δ(5-4) isomerase (hsd3b; MV) and P450 aromatase (cyp19a1a; MV) transcript levels. Lh increased star mRNA levels (MV, L/PV) but reduced cyp19a1a transcripts in L/PV follicles. At both follicle stages, IGF1 reduced levels of hsd3b transcripts. In MV follicles, IGF1 decreased P450 side-chain cleavage enzyme (cyp11a1) transcripts but increased cyp19a1a transcripts. In MV follicles only, forskolin increased star and hsd3b transcripts. Forskolin reduced MV follicle cyp11a1 transcripts and reduced cyp19a1a transcripts in follicles at both stages. Fsh and Lh reduced fshr transcripts in L/PV follicles. Lh also reduced lhcgr transcripts (L/PV). IGF1 had no effect on gonadotropin receptor transcripts. Forskolin reduced MV follicle fshr transcript levels and reduced lhcgr transcripts in L/PV follicles. These results reveal hormone- and stage-specific transcriptional regulation of steroidogenic protein and gonadotropin receptor genes and suggest that the steroidogenic shift at the completion of vitellogenesis involves loss of stimulatory effects of Fsh and Igfs on cyp19a1a expression and inhibition of cyp19a1a transcription by Lh.

  1. LPXRFa, the piscine ortholog of GnIH, and LPXRF receptor positively regulate gonadotropin secretion in Tilapia (Oreochromis niloticus).

    PubMed

    Biran, Jakob; Golan, Matan; Mizrahi, Naama; Ogawa, Satoshi; Parhar, Ishwar S; Levavi-Sivan, Berta

    2014-11-01

    LPXRFamide (LPXRFa) peptides have been characterized for their ability to inhibit gonadotropin (GTH) release in birds and stimulate growth hormone (GH) release in frogs. However, their involvement in regulating the reproductive hypothalamo-pituitary-gonadal axis in mammals and fish is inconclusive. To study the role of LPXRFa peptides in the regulation of GTH secretion, we cloned tilapia LPXRFa and LPXRF receptor (LPXRF-R). Processing of the tilapia preproLPXRFa liberated three mature LPXRFa peptides that varied in size and post-translational modifications. Phylogenetic analysis of LPXRFa and the closely related RFamide peptide PQRFa showed clear clustering of each peptide sequence with its orthologs from various vertebrates. Signal-transduction analysis of the tilapia LPXRF-R in COS-7 cells showed clear stimulation of CRE-dependent luciferase activity, whereas the human NPFFR1 showed suppression of forskolin-induced CRE-dependent activity in this system. Administration of the tilapia pyroglutaminated LPXRFa-2 peptide to primary cell culture of tilapia pituitaries, or to reproductive female tilapia by ip injection, positively regulated both LH and FSH release in vivo and in vitro. Using double-labeled fluorescent in-situ hybridization and immunofluorescence, βLH cells were found to co-express both tilapia lpxrf and tilapia lpxrf-r mRNA, whereas some of the βFSH cells coexpressed only lpxrf-r mRNA. No coexpression of tilapia lpxrf-r was identified in GH-positive cells. These findings suggest that the LPXRFa system is a potent positive regulator of the reproductive neuroendocrine axis of tilapia. PMID:25144920

  2. Testicular Steroidogenesis and Locomotor Activity Are Regulated by Gonadotropin-Inhibitory Hormone in Male European Sea Bass

    PubMed Central

    Paullada-Salmerón, José A.; Cowan, Mairi; Aliaga-Guerrero, María; López-Olmeda, José F.; Mañanós, Evaristo L.; Zanuy, Silvia

    2016-01-01

    Gonadotropin-inhibitory hormone (GnIH) is a neurohormone that suppresses reproduction by acting at both the brain and pituitary levels. In addition to the brain, GnIH may also be produced in gonads and can regulate steroidogenesis and gametogenesis. However, the function of GnIH in gonadal physiology has received little attention in fish. The main objective of this study was to evaluate the effects of peripheral sbGnih-1 and sbGnih-2 implants on gonadal development and steroidogenesis during the reproductive cycle of male sea bass (Dicentrarchus labrax). Both Gnihs decreased testosterone (T) and 11-ketotestosterone (11-KT) plasma levels in November and December (early- and mid-spermatogenesis) but did not affect plasma levels of the progestin 17,20β-dihydroxy-4-pregnen-3-one (DHP). In February (spermiation), fish treated with sbGnih-1 and sbGnih-2 exhibited testicles with abundant type A spermatogonia and partial spermatogenesis. In addition, we determined the effects of peripheral Gnih implants on plasma follicle-stimulating hormone (Fsh) and luteinizing hormone (Lh) levels, as well as on brain and pituitary expression of the main reproductive hormone genes and their receptors during the spermiation period (February). Treatment with sbGnih-2 increased brain gnrh2, gnih, kiss1r and gnihr transcript levels. Whereas, both Gnihs decreased lhbeta expression and plasma Lh levels, and sbGnih-1 reduced plasmatic Fsh. Finally, through behavioral recording we showed that Gnih implanted animals exhibited a significant increase in diurnal activity from late spermatogenic to early spermiogenic stages. Our results indicate that Gnih may regulate the reproductive axis of sea bass acting not only on brain and pituitary hormones but also on gonadal physiology and behavior. PMID:27788270

  3. Activin A regulation of gonadotropin-releasing hormone synthesis and release in vitro.

    PubMed

    MacConell, L A; Lawson, M A; Mellon, P L; Roberts, V J

    1999-10-01

    Activin is essential for the regulation of normal mammalian reproductive function at both the pituitary and gonadal levels. However, its central actions in the control of the hypothalamic-pituitary-gonadal axis remain largely unexplored. The present study aims to determine whether activin could regulate the reproductive axis at the level of the hypothalamus, through control of the GnRH neuroendocrine system. Using the GnRH-secreting GT1-7 neuronal cell line as a model system, we demonstrate expression of mRNAs encoding activin receptor types I, IB, and II. We examined the effects of activin A on GnRH protein secretion and mRNA levels in GT1-7 cells. Treatment with rh-activin A regulated both GnRH protein secretion and GnRH mRNA expression in the GT1-7 cells in a time-dependent fashion. Using transient transfection assays, we explored a potential transcriptional basis for these changes. Activin A increased reporter gene activity driven by minimal GnRH enhancer and promoter elements, suggesting that activin may regulate GnRH gene expression at the level of transcription. Lastly, activin A treatment of male rat hypothalami, in vitro, increased GnRH protein secretion. Collectively, molecular and physiological evidence support the presence of an activin system which might act at a hypothalamic site to regulate mammalian reproduction via activation of GnRH synthesis and release.

  4. Characterization of bmp15 and its regulation by human chorionic gonadotropin in the follicle of gibel carp (Carassius auratus gibelio).

    PubMed

    Chen, A-Qin; Liu, Zhi-Wei; Yang, Zhi-Gang; Leng, Xiang-Jun

    2012-09-01

    Bone morphogenetic protein (BMP15) is a member of the transforming growth factor β (TGF-β) superfamily with a key role in regulating follicle development in mammals and birds. However, potential ovarian roles of BMPs remain unexplored in teleosts. In this study, the full-length sequences of bmp15 were obtained using rapid-amplification of cDNA ends (RACE). The full-length cDNA sequence of bmp15 is 2217 bp which contained 214 bp 5'-UTR and 845 bp 3'-UTR. The open reading frame (ORF) sequence of bmp15 is 1158 bp, encoding a predicted protein of 385 amino acid residues. BMP15 has a specific RXXR protease cleavage site of TGF-β superfamily (is RIRR) and six conserved cysteine residues. Using real-time quantitative PCR revealed that bmp15 mRNA was largely expressed in the ovary and testis and mostly in oocytes within the follicle, slightly expressed in muscle, liver and pituitary. BMP15 is mainly present at stage I follicles by real-time quantitative PCR and immunohistochemistry. Phylogenetic analysis showed that gibel carp bmp15 was similar to bmp15 of zebrafish and other fish species. Treatment with human chorionic gonadotropin (hCG) in isolated follicles of gibel carp in vitro showed altered bmp15 mRNA expression: when treated with 10 ng/mL hCG for 10h, the expression level of bmp15 was significantly increased. However, with proceeding cultivation, the expression level of BMP15 mRNA decreased. The results of this study indicate that bmp15 may play a key role during development of follicles in gibel carp, especially in early stage follicles.

  5. Cranial neural crest-derived mesenchymal proliferation is regulated by Msx1-mediated p19(INK4d) expression during odontogenesis.

    PubMed

    Han, Jun; Ito, Yoshihiro; Yeo, Jae Yong; Sucov, Henry M; Maas, Richard; Chai, Yang

    2003-09-01

    Neural crest cells are multipotential progenitors that contribute to various cell and tissue types during embryogenesis. Here, we have investigated the molecular and cellular mechanism by which the fate of neural crest cell is regulated during tooth development. Using a two- component genetic system for indelibly marking the progeny of neural crest cells, we provide in vivo evidence of a deficiency of CNC-derived dental mesenchyme in Msx1 null mutant mouse embryos. The deficiency of the CNC results from an elevated CDK inhibitor p19(INK4d) activity and the disruption of cell proliferation. Interestingly, in the absence of Msx1, the CNC-derived dental mesenchyme misdifferentiates and possesses properties consistent with a neuronal fate, possibly through a default mechanism. Attenuation of p19(INK4d) in Msx1 null mutant mandibular explants restores mitotic activity in the dental mesenchyme, demonstrating the functional significance of Msx1-mediated p19(INK4d) expression in regulating CNC cell proliferation during odontogenesis. Collectively, our results demonstrate that homeobox gene Msx1 regulates the fate of CNC cells by controlling the progression of the cell cycle. Genetic mutation of Msx1 may alternatively instruct the fate of these progenitor cells during craniofacial development.

  6. Regulation and distribution of squirrel monkey chorionic gonadotropin and secretogranin II in the pituitary

    PubMed Central

    Vasauskas, Audrey A.; Hubler, Tina R.; Mahanic, Christina; Gibson, Susan; Kahn, Andrea G.; Scammell, Jonathan G.

    2011-01-01

    Secretogranin II (SgII) is a member of the granin family of proteins found in neuroendocrine and endocrine cells. The expression and storage of SgII in the pituitary gland of Old World primates and rodents have been linked with those of luteinizing hormone (LH). However, New World primates including squirrel monkeys do not express LH in the pituitary gland, but rather CG is expressed. If CG takes on the luteotropic role of LH in New World primates, SgII may be associated with the expression and storage of CG in the pituitary gland. The goal of this study was to evaluate the regulation and distribution of CG and SgII in the squirrel monkey. A DNA fragment containing approximately 750 bp of squirrel monkey SgII promoter was isolated from genomic DNA and found to contain a cyclic AMP response element that is also present in the human SgII promoter and important for GnRH responsiveness. The squirrel monkey and human SgII promoters were similarly activated by GnRH in luciferase reporter gene assays in LβT2 cells. Double immunofluorescence microscopy demonstrated close association of SgII and CG in gonadotrophs of squirrel monkey pituitary gland. These results suggest that CG and SgII have a similar intercellular distribution and are coregulated in squirrel monkey pituitary gland. PMID:21095191

  7. Regulation of gonadotropin-releasing hormone secretion: insights from GT1 immortal GnRH neurons.

    PubMed

    Martínez de la Escalera, G; Clapp, C

    2001-01-01

    The study of the mammalian GnRH system has been greatly advanced by the development of immortalized cell lines. Of particular relevance are the so-called GT1 cells. Not only do they exhibit many of the known physiologic characteristics of GnRH neurons in situ, but in approximately one decade have yielded new insights regarding the intrinsic physiology of individual cells and networks of GnRH neurons, as well as the nature of central and peripheral signals that directly modulate their function. For instance, valuable information has been generated concerning intrinsic properties of the system such as the inherent pulsatile pattern of secretion displayed by networks of GT1 cells. Concepts regarding feedback regulation and autocrine feedback of GnRH neurons have been dramatically expanded. Likewise, the nature of the receptors and of the proximal and distal signal transduction mechanisms involved in the actions of multiple afferent signals has been identified. Understanding this neuronal system allows a better comprehension of the hypothalamic-pituitary-gonadal axis and of the regulatory influences that ultimately control reproductive competence.

  8. Germ Cell Nuclear Factor (GCNF/RTR) Regulates Transcription of Gonadotropin-Regulated Testicular RNA Helicase (GRTH/DDX25) in Testicular Germ Cells--The Androgen Connection.

    PubMed

    Kavarthapu, Raghuveer; Dufau, Maria L

    2015-12-01

    Gonadotropin-regulated testicular RNA helicase (GRTH) (GRTH/DDX25), is a testis-specific protein essential for completion of spermatogenesis. Transgenic mice carrying 5'-flanking regions of the GRTH gene/green fluorescence protein (GFP) reporter revealed a region (-6.4/-3.6 kb) which directs its expression in germ cells (GCs) via androgen action. This study identifies a functional cis-binding element on the GRTH gene for GC nuclear factor (GCNF) (GCNF/RTR) required to regulate GRTH gene expression in postmeiotic testis GCs and explore the action of androgen on GCNF and GRTH transcription/expression. GCNF expression decreased in mice testis upon flutamide (androgen receptor antagonist) treatment, indicating the presence of an androgen/GCNF network to direct GRTH expression in GC. Binding studies and chromatin immunoprecipitation demonstrated specific association of GCNF to a consensus half-site (-5270/-5252) of the GRTH gene in both round spermatids and spermatocytes, which was abolished by flutamide treatment in round spermatids. Moreover, flutamide treatment of wild-type mice caused selective reduction of GCNF and GRTH in round spermatids. GCNF knock-down in seminiferous tubules from GRTH-transgenic mice (dark zone, round spermatid rich) caused decreased GFP expression. Exposure of tubules to flutamide caused decrease in GCNF and GFP expression, whereas androgen exposure induced significant increase. Our studies provide evidence for actions of androgen on GCNF cell-specific regulation of GRTH expression in GC. GRTH associates with GCNF mRNA, its absence caused increase on GCNF expression and mRNA stability indicative of a negative autocrine regulation of GCNF by GRTH. These in vivo/in vitro models link androgen actions to GC through GCNF, as regulated transfactor that controls transcription/expression of GRTH. PMID:26484580

  9. Gonadotropin-Activated Androgen-Dependent and Independent Pathways Regulate Aquaporin Expression during Teleost (Sparus aurata) Spermatogenesis

    PubMed Central

    Zapater, Cinta; Cerdà, Joan

    2015-01-01

    The mediation of fluid homeostasis by multiple classes of aquaporins has been suggested to be essential during spermatogenesis and spermiation. In the marine teleost gilthead seabream (Sparus aurata), seven distinct aquaporins, Aqp0a, -1aa, -1ab, -7, -8b, -9b and -10b, are differentially expressed in the somatic and germ cell lineages of the spermiating testis, but the endocrine regulation of these channels during germ cell development is unknown. In this study, we investigated the in vivo developmental expression of aquaporins in the seabream testis together with plasma androgen concentrations. We then examined the in vitro regulatory effects of recombinant piscine gonadotropins, follicle-stimulating (rFsh) and luteinizing (rLh) hormones, and sex steroids on aquaporin mRNA levels during the spermatogenic cycle. During the resting phase, when plasma levels of androgens were low, the testis exclusively contained proliferating spermatogonia expressing Aqp1ab, whereas Aqp10b and -9b were localized in Sertoli and Leydig cells, respectively. At the onset of spermatogenesis and during spermiation, the increase of androgen plasma levels correlated with the additional appearance of Aqp0a and -7 in Sertoli cells, Aqp0a in spermatogonia and spermatocytes, Aqp1ab, -7 and -10b from spermatogonia to spermatozoa, and Aqp1aa and -8b in spermatids and spermatozoa. Short-term in vitro incubation of testis explants indicated that most aquaporins in Sertoli cells and early germ cells were upregulated by rFsh and/or rLh through androgen-dependent pathways, although Aqp1ab in proliferating spermatogonia was also activated by estrogens. However, expression of Aqp9b in Leydig cells, and of Aqp1aa and -7 in spermatocytes and spermatids, was also directly stimulated by rLh. These results reveal a complex gonadotropic control of aquaporin expression during seabream germ cell development, apparently involving both androgen-dependent and independent pathways, which may assure the fine tuning

  10. Frequency-Dependent Regulation of Follicle-Stimulating Hormone β by Pulsatile Gonadotropin-Releasing Hormone Is Mediated by Functional Antagonism of bZIP Transcription Factors ▿

    PubMed Central

    Ciccone, Nick A.; Xu, Shuyun; Lacza, Charlemagne T.; Carroll, Rona S.; Kaiser, Ursula B.

    2010-01-01

    Oscillatory synthesis and secretion of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), under the control of pulsatile hypothalamic gonadotropin-releasing hormone (GnRH), is essential for normal reproductive development and fertility. The molecular mechanisms by which various patterns of pulsatile GnRH regulate gonadotrope responsiveness remain poorly understood. In contrast to the α and LHβ subunit genes, FSHβ subunit transcription is preferentially stimulated at low rather than high frequencies of pulsatile GnRH. In this study, mutation of a cyclic AMP response element (CRE) within the FSHβ promoter resulted in the loss of preferential GnRH stimulation at low pulse frequencies. We hypothesized that high GnRH pulse frequencies might stimulate a transcriptional repressor(s) to attenuate the action of CRE binding protein (CREB) and show that inducible cAMP early repressor (ICER) fulfills such a role. ICER was not detected under basal conditions, but pulsatile GnRH stimulated ICER to a greater extent at high than at low pulse frequencies. ICER binds to the FSHβ CRE site to reduce CREB occupation and abrogates both maximal GnRH stimulation and GnRH pulse frequency-dependent effects on FSHβ transcription. These data suggest that ICER production antagonizes the stimulatory action of CREB to attenuate FSHβ transcription at high GnRH pulse frequencies, thereby playing a critical role in regulating cyclic reproductive function. PMID:20008557

  11. The activity of cAMP-phosphodiesterase 4D7 (PDE4D7) is regulated by protein kinase A-dependent phosphorylation within its unique N-terminus

    PubMed Central

    Byrne, Ashleigh M.; Elliott, Christina; Hoffmann, Ralf; Baillie, George S.

    2015-01-01

    The cyclic AMP phosphodiesterases type 4 (PDE4s) are expressed in a cell specific manner, with intracellular targeting directed by unique N-terminal anchor domains. All long form PDE4s are phosphorylated and activated by PKA phosphorylation within their upstream conserved region 1 (UCR1). Here, we identify and characterise a novel PKA site (serine 42) within the N-terminal region of PDE4D7, an isoform whose activity is known to be important in prostate cancer progression and ischemic stroke. In contrast to the UCR1 site, PKA phosphorylation of the PDE4D7 N-terminus appears to occur constitutively and inhibits PDE4 activity to allow cAMP signalling under basal conditions. PMID:25680530

  12. The interaction of castration and photoperiod in the regulation of hypophyseal and serum gonadotropin levels in male golden hamsters.

    PubMed

    Turek, F W; Elliott, J A; Alvis, J D; Menaker, M

    1975-04-01

    Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured in intact and castrate adult male hamsters maintained on photostimulatory (LD 14:10) and non-photostimulatory (LD 6:18) light:dark cycles to assess the interaction of photic stimuli and gonadal hormones on pituitary gonadotropin release. Immunoreactive serum LH and FSH levels increased 1.6- and 8-fold respectively, within 3 days after photostimulated hamsters were castrated. In contrast, castration failed to alter serum LH concentration and had only a slight, if any, effect on FSH concentration in hamsters exposed to nonstimulatory photoperiods that induced testicular atrophy. In a second experiment, male hamsters previously maintained on LD 14:10 were castrated, transferred with intact animals to LD 6:18, and killed periodically over 60 days. In intact animals, pituitary content and serum levels of LH and FSH declined substantially during exposure to the non-stimulatory LD 6:18 cycle. In castrated animals, serum LH and FSH levels which had increased 2- and 8-fold in response to the castration eventually declined to about the levels found in the intact initial control animals. In contrast to serum gonadotropins, the increased hypophyseal content of LH and FSH following castration was not reduced during exposure to LD 6:18. Exposure to nonstimulatory photoperiods does not alter the increased hypophyseal LH and FSH content observed after castration. However, our results indicate that exposure to short days renders the hypothalamic-hypophyseal neuroendocrine system governing gonadotropin release relatively insensitive to gonadal steroid hormone feedback. PMID:1120474

  13. PPARG regulates gonadotropin-releasing hormone signaling in LbetaT2 cells in vitro and pituitary gonadotroph function in vivo in mice.

    PubMed

    Sharma, Shweta; Sharma, Prem M; Mistry, Devendra S; Chang, R Jeffery; Olefsky, Jerrold M; Mellon, Pamela L; Webster, Nicholas J G

    2011-03-01

    Peroxisome proliferators-activated receptor gamma (PPARG) ligands improve insulin sensitivity in type 2 diabetes and polycystic ovarian syndrome (PCOS). Despite clinical studies showing normalization of pituitary responsiveness to gonadotropin-releasing hormone (GnRH) in patients with PCOS, the precise role of PPARG in regulating the hypothalamic-pituitary-gonadal axis remains unclear. In the present study, we tested the hypothesis that the PPARG agonist rosiglitazone has a direct effect on the pituitary. In mouse LbetaT2 immortalized gonadotrophs, rosiglitazone treatment inhibited GnRH stimulation of the stress kinases p38MAPK and MAPKs/JNKs, but did not alter activation of ERKs, both in the presence and absence of activin. Furthermore, p38MAPK signaling was critical for both Lhb and Fshb promoter activity, and rosiglitazone suppressed the GnRH-mediated induction of Lhb and Fshb mRNA. Depletion of PPARG using a lentivirally encoded short hairpin RNA abolishes the effect of rosiglitazone to suppress activation of JNKs and induction of the transcription factors EGR1 and FOS as well as the gonadotropin genes Lhb and Fshb. Lastly, we show conditional knockout of Pparg in pituitary gonadotrophs caused an increase in luteinizing hormone levels in female mice, a decrease in follicle-stimulating hormone in male mice, and a fertility defect characterized by reduced litter size. Taken together, our data support a direct role for PPARG in modulating pituitary function in vitro and in vivo.

  14. Gonadotropin response to gonadotropin releasing hormone in acute schizophrenia.

    PubMed

    Cantalamessa, L; Catania, A; Silva, A; Orsatti, A; Baldini, M; Mosca, G; Zanussi, C; Cazzullo, C L

    1984-01-01

    To evaluate hypothalamic-pituitary-gonadal axis in acute schizophrenia, plasma FSH and LH concentrations were estimated both in basal conditions and after stimulation with gonadotropin releasing hormone (GnRH, 200 micrograms i.v.) in 14 young male patients with acute schizophrenia and in a age-matched group of 14 healthy male controls. Basal plasma PRL and testosterone levels were also measured. The mean basal levels of LH and FSH were slightly lower in schizophrenics, while the mean testosterone and prolactin levels were similar in the two groups. The FSH response to GnRH was significantly reduced in patients with acute schizophrenia, while the response of LH was similar in schizophrenics and in the controls. The possible significance of these findings is discussed in the contest of the complex neuroendocrine regulation of gonadotropin secretion and the overactivity of dopaminergic systems in acute schizophrenia.

  15. Challenge of human Jurkat T-cells with the adenylate cyclase activator forskolin elicits major changes in cAMP phosphodiesterase (PDE) expression by up-regulating PDE3 and inducing PDE4D1 and PDE4D2 splice variants as well as down-regulating a novel PDE4A splice variant.

    PubMed Central

    Erdogan, S; Houslay, M D

    1997-01-01

    cells. Forskolin treatment led to a marked decrease of this novel PDE4A species and allowed the detection of a strong signal for an approximately 67 kDa PDE4D species, suggested to be PDE4D1, but did not induce PDE4B and PDE4C isoforms. Elevation of intracellular cAMP concentrations in Jurkat T-cells thus exerts a highly selective effect on the transcriptional activity of the genes encoding the various PDE4 isoforms. This leads to the down-regulation of a novel PDE4A splice variant and the induction of PDE4D1 and PDE4D2 splice variants, leading to a net increase in the total PDE4 activity of Jurkat T-cells. PMID:9003416

  16. Lessons from the gonadotropin-regulated long chain acyl-CoA synthetase (GR-LACS) null mouse model: a role in steroidogenesis, but not result in X-ALD phenotype.

    PubMed

    Sheng, Yi; Tsai-Morris, Chon-Hwa; Li, Jie; Dufau, Maria L

    2009-03-01

    Gonadotropin-regulated long chain fatty acid Acyl-CoA synthetase (GR-LACS), is a member of the LACS family that is regulated by gonadotropin in the rat Leydig cell (LC). Its mouse/human homologs, lipidosin/bubblegum, have been suggested to participate in X-linked adrenoleukodystrophy (X-ALD), an adreno/neurodegenerative disorder with accumulation of very long chain fatty acids (VLCFA) in tissues and plasma. To further gain insights into its regulatory function, a GR-LACS/lipidosin null mouse was generated. No apparent phenotypic abnormalities were observed in the X-ALD target tissues (brain, testis, adrenal). Nuclear inclusions seen in mice >15 month-old, were present in LC of 9 month-old GR-LACS(-/-) mice. LC of the null mice showed refractoriness to the gonadotropin-induced desensitization of testosterone production that is observed in adult animals. LCFAs were moderately increased in the testis, ovary and brain, but not in the adrenal gland of GR-LACS(-/-) mice, with no major changes in VLCFA. No change in LACS activity was observed in these tissues, suggesting a compensatory mechanism exhibited by other LACS members. The GR-LACS(-/-) model did not support its association with X-ALD. These studies revealed a role of GR-LACS in reducing the aging process of the LC, and its participation in gonadotropin-induced testicular desensitization of testosterone production.

  17. 4-D Photoacoustic Tomography

    NASA Astrophysics Data System (ADS)

    Xiang, Liangzhong; Wang, Bo; Ji, Lijun; Jiang, Huabei

    2013-01-01

    Photoacoustic tomography (PAT) offers three-dimensional (3D) structural and functional imaging of living biological tissue with label-free, optical absorption contrast. These attributes lend PAT imaging to a wide variety of applications in clinical medicine and preclinical research. Despite advances in live animal imaging with PAT, there is still a need for 3D imaging at centimeter depths in real-time. We report the development of four dimensional (4D) PAT, which integrates time resolutions with 3D spatial resolution, obtained using spherical arrays of ultrasonic detectors. The 4D PAT technique generates motion pictures of imaged tissue, enabling real time tracking of dynamic physiological and pathological processes at hundred micrometer-millisecond resolutions. The 4D PAT technique is used here to image needle-based drug delivery and pharmacokinetics. We also use this technique to monitor 1) fast hemodynamic changes during inter-ictal epileptic seizures and 2) temperature variations during tumor thermal therapy.

  18. 4D Electron Tomography

    NASA Astrophysics Data System (ADS)

    Kwon, Oh-Hoon; Zewail, Ahmed H.

    2010-06-01

    Electron tomography provides three-dimensional (3D) imaging of noncrystalline and crystalline equilibrium structures, as well as elemental volume composition, of materials and biological specimens, including those of viruses and cells. We report the development of 4D electron tomography by integrating the fourth dimension (time resolution) with the 3D spatial resolution obtained from a complete tilt series of 2D projections of an object. The different time frames of tomograms constitute a movie of the object in motion, thus enabling studies of nonequilibrium structures and transient processes. The method was demonstrated using carbon nanotubes of a bracelet-like ring structure for which 4D tomograms display different modes of motion, such as breathing and wiggling, with resonance frequencies up to 30 megahertz. Applications can now make use of the full space-time range with the nanometer-femtosecond resolution of ultrafast electron tomography.

  19. Redefining gonadotropin-releasing hormone (GnRH) cell groups in the male Syrian hamster: testosterone regulates GnRH mRNA in the tenia tecta.

    PubMed

    Richardson, Heather N; Parfitt, David B; Thompson, Robert C; Sisk, Cheryl L

    2002-05-01

    Gonadotropin-releasing hormone (GnRH) regulates the production of testosterone via the hypothalamic-pituitary-gonadal axis and testosterone, in turn, regulates the GnRH system via negative feedback. We compared testosterone regulation of GnRH mRNA expression in four anatomically defined GnRH cell groups in juvenile and adult male Syrian hamsters, including a rostral population of GnRH cells in the tenia tecta. In situ hybridization histochemistry (ISHH) was used to measure GnRH mRNA in brains from castrated juveniles and adults treated with 0 mg or 2.5 mg testosterone pellets for one week. ISHH was performed on coronal sections using a 35S-cRNA probe generated from Syrian hamster GnRH cDNA. Testosterone treatment resulted in a significant reduction in mean area of GnRH neurones covered by silver grains within the tenia tecta, but only a trend toward decreased GnRH mRNA in the diagonal band of Broca/organum vasculosum of the lamina terminalis (DBB/OVLT), medial septum (MS), and caudal preoptic area (cPOA). The effects of testosterone were independent of age. Frequency distribution analyses unveiled a significant reduction in the number of heavily labelled cells following testosterone treatment within the tenia tecta and MS. Simple regression analyses revealed a significant positive correlation between plasma luteinizing hormone concentrations and GnRH mRNA only in the tenia tecta. These data indicate that, overall, GnRH mRNA is modestly reduced by testosterone, and the most robust attenuation of GnRH mRNA occurs within the tenia tecta. This is the first report to link mechanisms of steroid negative feedback with tenia tecta GnRH neurones, providing a new focus for investigating brain region-specific steroidal regulation of GnRH synthesis.

  20. From gonadotropin-inhibitory hormone to SIFamides: are echinoderm SALMFamides the "missing link" in a bilaterian family of neuropeptides that regulate reproductive processes?

    PubMed

    Elphick, Maurice R

    2013-11-01

    Gonadotropin-inhibitory hormone (GnIH) belongs to a family of vertebrate neuropeptides with a C-terminal PxRFamide motif, which exert effects by activating the G-protein coupled receptors NPFF1 and/or NPFF2. Comparative analysis of genome sequence data has revealed that orthologs of NPFF1/NPFF2-type receptors occur throughout the Bilateria and the neuropeptide ligand that activates the Drosophila NPFF1/NPFF2-type receptor has been identified as AYRKPPFNGSIFamide ("SIFamide"). Therefore, SIFamide-type neuropeptides, which occur throughout protostomian invertebrates, probably share a common evolutionary origin with vertebrate PxRFamide-type neuropeptides. Based on structural similarities, here SALMFamide neuropeptides are identified as candidate ligand components of this ancient bilaterian peptide-receptor signaling system in a deuterostomian invertebrate phylum, the echinoderms (e.g., starfish, sea urchins). Furthermore, functional studies provide evidence that PxRFamide/SALMFamide/SIFamide-type neuropeptides have evolutionarily conserved roles in regulation (typically inhibitory) of reproductive processes.

  1. Human chorionic gonadotropin-dependent up-regulation of genes responsible for estrogen sulfoconjugation and export in granulosa cells of luteinizing preovulatory follicles.

    PubMed

    Brown, Kristy A; Doré, Monique; Lussier, Jacques G; Sirois, Jean

    2006-09-01

    Estrogen sulfotransferase (EST) is responsible for the sulfoconjugation of estrogens, thereby changing their physical properties and preventing their action via the estrogen receptors. These sulfoconjugated steroids no longer diffuse freely across the lipid bilayer; instead, they are exported by members of the ATP-binding cassette family, such as ABCC1. The objective of this study was to investigate the regulation of EST and ABCC1 during human chorionic gonadotropin (hCG)-induced ovulation/luteinization. The transcripts for EST and ABCC1 were cloned by RT-PCR, and the regulation of their mRNAs was studied in preovulatory follicles obtained during estrus at 0, 12, 24, 30, 33, 36, and 39 h after hCG. Results obtained from RT-PCR/Southern blot analyses showed significant changes in steady-state levels of both EST and ABCC1 mRNA after hCG treatment (P < 0.05). In granulosa cells, a significant increase in EST transcript was observed 30-39 h after hCG. Similarly, ABCC1 transcript levels were induced in granulosa cells 12-39 h after hCG. In contrast, no significant changes in either EST or ABCC1 were detected in theca interna samples after hCG. The increase in EST and ABCC1 transcripts observed in granulosa cells was reflected in preparations of intact follicle walls, suggesting that the granulosa cell layer contributes the majority of EST and ABCC1 expression in preovulatory follicles. The present study demonstrates that follicular luteinization is accompanied not only by a decrease in 17 beta-estradiol biosynthesis but also by an increase in expression of genes responsible for estrogen inactivation and elimination from granulosa cells, such as EST and ABCC1, respectively.

  2. Down-regulation of messenger ribonucleic acid encoding an importer of sulfoconjugated steroids during human chorionic gonadotropin-induced follicular luteinization in vivo.

    PubMed

    Brown, Kristy A; Bouchard, Nadine; Lussier, Jacques G; Sirois, Jean

    2007-01-01

    Members of the organic anion transporting polypeptide (SLCO/OATP) superfamily are capable of importing anionic compounds across the lipid bilayer in a sodium-independent manner. Member 2B1 has been shown to transport few substrates, two of which are dihydroepiandrosterone-3-sulfate (DHEA-S) and estrone-3-sulfate. Steroid sulfatase (STS) catalyses the hydrolysis of these steroids into their unconjugated counterparts. The objective of this study was to investigate the regulation of SLCO2B1 and STS mRNAs during human chorionic gonadotropin (hCG)-induced ovulation/luteinization. The equine SLCO2B1 cDNA was cloned and shown to encode a 709-amino acid protein (OATP2B1) that is highly conserved when compared to mammalian orthologs. RT-PCR/Southern blot analyses were performed to study the regulation of SLCO2B1 and STS transcripts in equine preovulatory follicles isolated between 0 and 39h after hCG treatment. Results showed high levels of SLCO2B1 mRNA expression before hCG, with a marked decrease observed in follicles obtained 24-39h post-hCG (P<0.05). Analyses of isolated granulosa and theca interna cells identified high mRNA expression in both cell types prior to hCG treatment, with granulosa cells showing a more rapid SLCO2B1 mRNA down-regulation. No significant change in STS mRNA was observed in intact follicle walls. However, when both cell types were isolated, a significant decrease in STS mRNA was observed in granulosa cells 24-39h post-hCG. Collectively, these results demonstrate that the hCG-dependent induction of follicular luteinization is accompanied by the down-regulation of SLCO2B1 and STS transcripts. Considering that OATP2B1 can import sulfoconjugated DHEA and estrogens, and that STS can remove the sulfonate moiety from these steroids, their down-regulation in luteinizing preovulatory follicles may provide an additional biochemical basis for the decrease in ovarian 17beta-estradiol biosynthesis after the LH surge.

  3. Gonadotropin-releasing hormone type II (GnRH-II) agonist regulates the motility of human decidual endometrial stromal cells: possible effect on embryo implantation and pregnancy.

    PubMed

    Wu, Hsien-Ming; Huang, Hong-Yuan; Lee, Chyi-Long; Soong, Yung-Kuei; Leung, Peter C K; Wang, Hsin-Shih

    2015-04-01

    Invasion of the maternal decidua by extravillous trophoblast is an important process for embryo implantation and placentation in humans. Motile behavior of decidual endometrial stromal cells has been considered of critical importance for embryo implantation and programming of human pregnancy. The gonadotropin-releasing hormone (GnRH) effects in endometrium have raised concerns in reproduction. In the present study, we examined the action of GnRH-II agonist-promoted motility of human decidual endometrial stromal cells and the mechanisms of the action, indicating the role of GnRH-II agonist in embryo implantation and early pregnancy. Human decidual endometrial stromal cells were isolated from the decidual tissue from healthy women undergoing elective pregnancy termination of a normal pregnancy at 6- to 12-wk gestation, after informed consent. Cell motility was estimated by invasion and migration assay. Zymography and immunoblot analysis were performed to investigate the mechanisms of the GnRH-II action. The GnRH-I receptor (GnRH-IR) was expressed in human decidual tissue and endometrial stromal cells. The GnRH-II agonist promoted cell motility. Mitogen-activated protein kinase inhibitors abolished GnRH-II agonist-induced cell motility and activation of MMP-2 and MMP-9. GnRH-II agonist-mediated cell motility was suppressed by knockdown of endogenous GnRH-IR, MMP (matrix metalloproteinase)-2, and MMP-9 with small interfering RNA and MMP inhibitors. Our study demonstrates that the GnRH-II agonist promoted the cell motility of human decidual endometrial stromal cells through the GnRH-IR and the phosphorylation of extracellular signal-regulated protein kinase 1/2 and JNK-dependent activation of MMP-2 and MMP-9. Our findings represent a new concept regarding the mechanisms of GnRH-II-promoted cell motility, suggesting that GnRH-II agonist has strong effects on embryo implantation and decidual programming of human pregnancy. PMID:25761596

  4. Phosphodiesterase4D (PDE4D)--A risk factor for atrial fibrillation and stroke?

    PubMed

    Jørgensen, Carina; Yasmeen, Saiqa; Iversen, Helle K; Kruuse, Christina

    2015-12-15

    Mutations in the gene encoding phosphodiesterase 4D (PDE4D) enzyme are associated with ischemic stroke; however the functional implications of such mutations are not well understood. PDE4D is part of a complex protein family modulating intracellular signalling by cyclic nucleotides. The PDE4 family includes subtypes A-D, all of which show unique intracellular, cellular and tissue distribution. PDE4D is the major subtype expressed in human atrial myocytes and involved in the pathophysiology of arrhythmias, such as atrial fibrillation. The PDE4D enzyme hydrolyses cyclic adenosine monophosphate (cAMP). Though diverging results are reported, several population based studies describe association of various PDE4D single nucleotide polymorphisms (SNP) with cardio-embolic stroke in particular. Functionally, a down regulation of PDE4D variants has been reported in stroke patients. The anti-inflammatory and vasodilator properties of PDE4 inhibitors make them suitable for treatment of stroke and cardiovascular disease. PDE4D has recently been suggested as factor in atrial fibrillation. This review summarizes the possible function of PDE4D in the brain, heart, and vasculature. Further, association of the described SNPs, in particular, with cardioembolic stroke, is reviewed. Current findings on the PDE4D mutations suggest functionality involves an increased cardiac risk factor as well as augmented risk of atrial fibrillation. PMID:26671126

  5. 17 CFR 260.4d-8 - Content.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Content. 260.4d-8 Section 260.4d-8 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 304 § 260.4d-8 Content. (a)...

  6. 17 CFR 260.4d-8 - Content.

    Code of Federal Regulations, 2012 CFR

    2005-04-01

    ... 17 Commodity and Securities Exchanges 3 2005-04-01 2005-04-01 false Content. 260.4d-8 Section 260.4d-8 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 304 § 260.4d-8 Content. (a)...

  7. 17 CFR 260.4d-8 - Content.

    Code of Federal Regulations, 2013 CFR

    2000-04-01

    ... 17 Commodity and Securities Exchanges 3 2000-04-01 2000-04-01 false Content. 260.4d-8 Section 260.4d-8 Commodity and Securities Exchanges GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 304 § 260.4d-8 Content. (a) Each application for an order under section 304(d)...

  8. 17 CFR 260.4d-8 - Content.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Content. 260.4d-8 Section 260.4d-8 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 304 § 260.4d-8 Content. (a)...

  9. 17 CFR 260.4d-8 - Content.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Content. 260.4d-8 Section 260.4d-8 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 304 § 260.4d-8 Content. (a)...

  10. 17 CFR 260.4d-8 - Content.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Content. 260.4d-8 Section 260.4d-8 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 304 § 260.4d-8 Content. (a)...

  11. 76 FR 55814 - 2,4-D; Pesticide Tolerances

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-09

    ... AGENCY 40 CFR Part 180 2,4-D; Pesticide Tolerances AGENCY: Environmental Protection Agency (EPA). ACTION: Final rule. SUMMARY: This regulation establishes tolerances for residues of 2,4-D in or on teff, bran... 180.142 be amended by establishing a tolerance for residues of the herbicide 2,4-D...

  12. 17 CFR 260.4d-8 - Content.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Content. 260.4d-8 Section 260.4d-8 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 304 § 260.4d-8 Content. (a)...

  13. 21 CFR 522.1079 - Serum gonadotropin and chorionic gonadotropin.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Serum gonadotropin and chorionic gonadotropin. 522.1079 Section 522.1079 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN.... (i) Gilts. For induction of fertile estrus (heat) in healthy prepuberal (noncycling) gilts. (ii)...

  14. Genetically modified mouse models addressing gonadotropin function.

    PubMed

    Ratner, Laura D; Rulli, Susana B; Huhtaniemi, Ilpo T

    2014-03-01

    The development of genetically modified animals has been useful to understand the mechanisms involved in the regulation of the gonadotropin function. It is well known that alterations in the secretion of a single hormone is capable of producing profound reproductive abnormalities. Human chorionic gonadotropin (hCG) is a glycoprotein hormone normally secreted by the human placenta, and structurally and functionally it is related to pituitary LH. LH and hCG bind to the same LH/hCG receptor, and hCG is often used as an analog of LH to boost gonadotropin action. There are many physiological and pathological conditions where LH/hCG levels and actions are elevated. In order to understand how elevated LH/hCG levels may impact on the hypothalamic-pituitary-gonadal axis we have developed a transgenic mouse model with chronic hCG hypersecretion. Female mice develop many gonadal and extragonadal phenotypes including obesity, infertility, hyperprolactinemia, and pituitary and mammary gland tumors. This article summarizes recent findings on the mechanisms involved in pituitary gland tumorigenesis and hyperprolactinemia in the female mice hypersecreting hCG, in particular the relationship of progesterone with the hyperprolactinemic condition of the model. In addition, we describe the role of hyperprolactinemia as the main cause of infertility and the phenotypic abnormalities in these mice, and the use of dopamine agonists bromocriptine and cabergoline to normalize these conditions.

  15. Testosterone selectively increases serum follicle-stimulating hormonal (FSH) but not luteinizing hormone (LH) in gonadotropin-releasing hormone antagonist-treated male rats: evidence for differential regulation of LH and FSH secretion.

    PubMed

    Bhasin, S; Fielder, T J; Swerdloff, R S

    1987-08-01

    Both testosterone (T) and gonadotropin-releasing hormone (GnRH)-antagonist (GnRH-A) when given alone lower serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in intact and castrated rats. However, when graded doses of testosterone enanthate (T.E.) were given to GnRH-A-treated intact male rats, a paradoxical dose-dependent increase in serum FSH occurred; whereas serum LH remained suppressed. This surprising finding led us to ask whether the paradoxical increase in serum FSH in GnRH-A-suppressed animals was a direct stimulatory effect of T on the hypothalamic-pituitary axis or the result of a T effect on a testicular regulator of FSH. To test these hypotheses, we treated adult male castrated rats with GnRH-A and graded doses of T.E. In both intact and castrated rats, serum LH remained undetectable in GnRH-A-treated rats with or without T.E. However, addition of T.E. to GnRH-A led to a dose-dependent increase in serum FSH in castrated animals as well, thus pointing against mediation by a selective testicular regulator of FSH. These data provide evidence that pituitary LH and FSH responses may be differentially regulated under certain conditions. When the action of GnRH is blocked (such as in GnRH-A-treated animals), T directly and selectively increases pituitary FSH secretion.

  16. Side Effects of Injectable Fertility Drugs (Gonadotropins)

    MedlinePlus

    ... usually are used during fertility treatments such as intrauterine insemination (IUI) or in vitro fertilization (IVF). Injections of gonadotropins ... Gestation. When using injectable gonadotropins alone or with IUI, up to 30% of pregnancies are associated with ...

  17. Distribution and regulation of gonadotropin-releasing hormone, kisspeptin, RF-amide related peptide-3, and dynorphin in the bovine hypothalamus

    PubMed Central

    Tanco, Valeria M.; Whitlock, Brian K.; Jones, Melaney A.; Wilborn, Robyn R.; Brandebourg, Terry D.

    2016-01-01

    Recent work has led to the hypothesis that kisspeptin/neurokinin B/dynorphin (KNDy) neurons in the arcuate nucleus (ARC) play a key role in gonadotropin-releasing hormone (GnRH) pulse generation and gonadal steroid feedback, with kisspeptin driving GnRH release and neurokinin B and dynorphin acting as pulse start and stop signals, respectively. A separate cell group, expressing RFamide-related peptide-3 (RFRP-3) has been shown to be a primary inhibitor of GnRH release. Very little is known regarding these cell groups in the bovine. In this study, we examined the relative immunoreactivity of kisspeptin, dynorphin, and RFRP-3 and their possible connectivity to GnRH neurons in the hypothalami of periestrus and diestrus bovine. While GnRH and RFRP-3 immunoreactivity were unchanged, kisspeptin and dynorphin immunoreactivity levels varied in relation to plasma progesterone concentrations and estrous status. Animals with higher plasma progesterone concentrations in diestrus had lower kisspeptin and increased dynorphin immunoreactivity in the ARC. The percentage of GnRH cells with kisspeptin or RFRP-3 fibers in close apposition did not differ between estrous stages. However, the proportions of GnRH cells with kisspeptin or RFRP-3 contacts (∼49.8% and ∼31.3%, respectively) suggest direct communication between kisspeptin and RFRP-3 cells to GnRH cells in the bovine. The data produced in this work support roles for kisspeptin and dynorphin, within the KNDy neural network, in controlling GnRH release over the ovarian cycle and conveying progesterone-negative feedback onto GnRH neurons in the bovine. PMID:27014517

  18. Distribution and regulation of gonadotropin-releasing hormone, kisspeptin, RF-amide related peptide-3, and dynorphin in the bovine hypothalamus.

    PubMed

    Tanco, Valeria M; Whitlock, Brian K; Jones, Melaney A; Wilborn, Robyn R; Brandebourg, Terry D; Foradori, Chad D

    2016-01-01

    Recent work has led to the hypothesis that kisspeptin/neurokinin B/dynorphin (KNDy) neurons in the arcuate nucleus (ARC) play a key role in gonadotropin-releasing hormone (GnRH) pulse generation and gonadal steroid feedback, with kisspeptin driving GnRH release and neurokinin B and dynorphin acting as pulse start and stop signals, respectively. A separate cell group, expressing RFamide-related peptide-3 (RFRP-3) has been shown to be a primary inhibitor of GnRH release. Very little is known regarding these cell groups in the bovine. In this study, we examined the relative immunoreactivity of kisspeptin, dynorphin, and RFRP-3 and their possible connectivity to GnRH neurons in the hypothalami of periestrus and diestrus bovine. While GnRH and RFRP-3 immunoreactivity were unchanged, kisspeptin and dynorphin immunoreactivity levels varied in relation to plasma progesterone concentrations and estrous status. Animals with higher plasma progesterone concentrations in diestrus had lower kisspeptin and increased dynorphin immunoreactivity in the ARC. The percentage of GnRH cells with kisspeptin or RFRP-3 fibers in close apposition did not differ between estrous stages. However, the proportions of GnRH cells with kisspeptin or RFRP-3 contacts (∼49.8% and ∼31.3%, respectively) suggest direct communication between kisspeptin and RFRP-3 cells to GnRH cells in the bovine. The data produced in this work support roles for kisspeptin and dynorphin, within the KNDy neural network, in controlling GnRH release over the ovarian cycle and conveying progesterone-negative feedback onto GnRH neurons in the bovine. PMID:27014517

  19. A Novel Gonadotropin-Releasing Hormone 1 (Gnrh1) Enhancer-Derived Noncoding RNA Regulates Gnrh1 Gene Expression in GnRH Neuronal Cell Models.

    PubMed

    Huang, Polly P; Brusman, Liza E; Iyer, Anita K; Webster, Nicholas J G; Mellon, Pamela L

    2016-01-01

    Gonadotropin-releasing hormone (GnRH), a neuropeptide released from a small population of neurons in the hypothalamus, is the central mediator of the hypothalamic-pituitary-gonadal axis, and is required for normal reproductive development and function. Evolutionarily conserved regulatory elements in the mouse, rat, and human Gnrh1 gene include three enhancers and the proximal promoter, which confer Gnrh1 gene expression specifically in GnRH neurons. In immortalized mouse hypothalamic GnRH (GT1-7) neurons, which show pulsatile GnRH release in culture, RNA sequencing and RT-qPCR revealed that expression of a novel long noncoding RNA at Gnrh1 enhancer 1 correlates with high levels of GnRH mRNA expression. In GT1-7 neurons, which contain a transgene carrying 3 kb of the rat Gnrh1 regulatory region, both the mouse and rat Gnrh1 enhancer-derived noncoding RNAs (GnRH-E1 RNAs) are expressed. We investigated the characteristics and function of the endogenous mouse GnRH-E1 RNA. Strand-specific RT-PCR analysis of GnRH-E1 RNA in GT1-7 cells revealed GnRH-E1 RNAs that are transcribed in the sense and antisense directions from distinct 5' start sites, are 3' polyadenylated, and are over 2 kb in length. These RNAs are localized in the nucleus and have a half-life of over 8 hours. In GT1-7 neurons, siRNA knockdown of mouse GnRH-E1 RNA resulted in a significant decrease in the expression of the Gnrh1 primary transcript and Gnrh1 mRNA. Over-expression of either the sense or antisense mouse GnRH-E1 RNA in immature, migratory GnRH (GN11) neurons, which do not express either GnRH-E1 RNA or GnRH mRNA, induced the transcriptional activity of co-transfected rat Gnrh1 gene regulatory elements, where the induction requires the presence of the rat Gnrh1 promoter. Together, these data indicate that GnRH-E1 RNA is an inducer of Gnrh1 gene expression. GnRH-E1 RNA may play an important role in the development and maturation of GnRH neurons.

  20. A Novel Gonadotropin-Releasing Hormone 1 (Gnrh1) Enhancer-Derived Noncoding RNA Regulates Gnrh1 Gene Expression in GnRH Neuronal Cell Models

    PubMed Central

    Huang, Polly P.; Brusman, Liza E.; Iyer, Anita K.; Webster, Nicholas J. G.

    2016-01-01

    Gonadotropin-releasing hormone (GnRH), a neuropeptide released from a small population of neurons in the hypothalamus, is the central mediator of the hypothalamic-pituitary-gonadal axis, and is required for normal reproductive development and function. Evolutionarily conserved regulatory elements in the mouse, rat, and human Gnrh1 gene include three enhancers and the proximal promoter, which confer Gnrh1 gene expression specifically in GnRH neurons. In immortalized mouse hypothalamic GnRH (GT1-7) neurons, which show pulsatile GnRH release in culture, RNA sequencing and RT-qPCR revealed that expression of a novel long noncoding RNA at Gnrh1 enhancer 1 correlates with high levels of GnRH mRNA expression. In GT1-7 neurons, which contain a transgene carrying 3 kb of the rat Gnrh1 regulatory region, both the mouse and rat Gnrh1 enhancer-derived noncoding RNAs (GnRH-E1 RNAs) are expressed. We investigated the characteristics and function of the endogenous mouse GnRH-E1 RNA. Strand-specific RT-PCR analysis of GnRH-E1 RNA in GT1-7 cells revealed GnRH-E1 RNAs that are transcribed in the sense and antisense directions from distinct 5’ start sites, are 3’ polyadenylated, and are over 2 kb in length. These RNAs are localized in the nucleus and have a half-life of over 8 hours. In GT1-7 neurons, siRNA knockdown of mouse GnRH-E1 RNA resulted in a significant decrease in the expression of the Gnrh1 primary transcript and Gnrh1 mRNA. Over-expression of either the sense or antisense mouse GnRH-E1 RNA in immature, migratory GnRH (GN11) neurons, which do not express either GnRH-E1 RNA or GnRH mRNA, induced the transcriptional activity of co-transfected rat Gnrh1 gene regulatory elements, where the induction requires the presence of the rat Gnrh1 promoter. Together, these data indicate that GnRH-E1 RNA is an inducer of Gnrh1 gene expression. GnRH-E1 RNA may play an important role in the development and maturation of GnRH neurons. PMID:27389022

  1. A Novel Gonadotropin-Releasing Hormone 1 (Gnrh1) Enhancer-Derived Noncoding RNA Regulates Gnrh1 Gene Expression in GnRH Neuronal Cell Models.

    PubMed

    Huang, Polly P; Brusman, Liza E; Iyer, Anita K; Webster, Nicholas J G; Mellon, Pamela L

    2016-01-01

    Gonadotropin-releasing hormone (GnRH), a neuropeptide released from a small population of neurons in the hypothalamus, is the central mediator of the hypothalamic-pituitary-gonadal axis, and is required for normal reproductive development and function. Evolutionarily conserved regulatory elements in the mouse, rat, and human Gnrh1 gene include three enhancers and the proximal promoter, which confer Gnrh1 gene expression specifically in GnRH neurons. In immortalized mouse hypothalamic GnRH (GT1-7) neurons, which show pulsatile GnRH release in culture, RNA sequencing and RT-qPCR revealed that expression of a novel long noncoding RNA at Gnrh1 enhancer 1 correlates with high levels of GnRH mRNA expression. In GT1-7 neurons, which contain a transgene carrying 3 kb of the rat Gnrh1 regulatory region, both the mouse and rat Gnrh1 enhancer-derived noncoding RNAs (GnRH-E1 RNAs) are expressed. We investigated the characteristics and function of the endogenous mouse GnRH-E1 RNA. Strand-specific RT-PCR analysis of GnRH-E1 RNA in GT1-7 cells revealed GnRH-E1 RNAs that are transcribed in the sense and antisense directions from distinct 5' start sites, are 3' polyadenylated, and are over 2 kb in length. These RNAs are localized in the nucleus and have a half-life of over 8 hours. In GT1-7 neurons, siRNA knockdown of mouse GnRH-E1 RNA resulted in a significant decrease in the expression of the Gnrh1 primary transcript and Gnrh1 mRNA. Over-expression of either the sense or antisense mouse GnRH-E1 RNA in immature, migratory GnRH (GN11) neurons, which do not express either GnRH-E1 RNA or GnRH mRNA, induced the transcriptional activity of co-transfected rat Gnrh1 gene regulatory elements, where the induction requires the presence of the rat Gnrh1 promoter. Together, these data indicate that GnRH-E1 RNA is an inducer of Gnrh1 gene expression. GnRH-E1 RNA may play an important role in the development and maturation of GnRH neurons. PMID:27389022

  2. Gonadotropin excretion and body composition.

    PubMed

    Penny, R; Goldstein, I P; Frasier, S D

    1978-02-01

    Urinary follicle stimulating hormone (FSH) and luteinizing hormone (LH) excretion was correlated with calculated total body water (TBW) and body fat (BF) in 140 normal girls and 142 normal boys, ages 3 to 16 years. In girls, there was a significant increase in gonadotropin excretion at the time of a significant increase in BF as a percent of body weight and decrease in TBW as a percent of body weight. Pubertal changes in body composition were seen in girls at the same chronological age and stage of puberty as increased gonadotropin excretion. Similar findings were observed in boys. Pubertal changes in body composition (an increase in TBW as a percent of body weight and decrease of BF as a percent of body weight) accompanied significantly increased gonadotropin excretion. Both developmental changes were seen at the same chronological age and stage of puberty. Our findings are consistent with the hypothesis that characteristic changes in body composition as well as the other hallmarks of puberty, including menarche in girls, result from increased gonadotropin and gonadal steroid secretion. They do not support the hypothesis that changes of body composition trigger increased hypothalamic function and hormone secretion leading to the subsequent events of puberty. PMID:634687

  3. Aberrant gonadotropin-releasing hormone receptor (GnRHR) expression and its regulation of CYP11B2 expression and aldosterone production in adrenal aldosterone-producing adenoma (APA).

    PubMed

    Nakamura, Yasuhiro; Hattangady, Namita G; Ye, Ping; Satoh, Fumitoshi; Morimoto, Ryo; Ito-Saito, Takako; Sugawara, Akira; Ohba, Koji; Takahashi, Kazuhiro; Rainey, William E; Sasano, Hironobu

    2014-03-25

    Aberrant expression of gonadotropin-releasing hormone receptor (GnRHR) has been reported in human adrenal tissues including aldosterone-producing adenoma (APA). However, the details of its expression and functional role in adrenals are still not clear. In this study, quantitative RT-PCR analysis revealed the mean level of GnRHR mRNA was significantly higher in APAs than in human normal adrenal (NA) (P=0.004). GnRHR protein expression was detected in human NA and neoplastic adrenal tissues. In H295R cells transfected with GnRHR, treatment with GnRH resulted in a concentration-dependent increase in CYP11B2 reporter activity. Chronic activation of GnRHR with GnRH (100nM), in a cell line with doxycycline-inducible GnRHR (H295R-TR/GnRHR), increased CYP11B2 expression and aldosterone production. These agonistic effects were inhibited by blockers for the calcium signaling pathway, KN93 and calmidazolium. These results suggest GnRH, through heterotopic expression of its receptor, may be a potential regulator of CYP11B2 expression levels in some cases of APA.

  4. Proline-Rich Tyrosine Kinase 2 Mediates Gonadotropin-Releasing Hormone Signaling to a Specific Extracellularly Regulated Kinase-Sensitive Transcriptional Locus in the Luteinizing Hormone β-Subunit Gene

    PubMed Central

    Maudsley, Stuart; Naor, Zvi; Bonfil, David; Davidson, Lindsay; Karali, Dimitra; Pawson, Adam J.; Larder, Rachel; Pope, Caroline; Nelson, Nancy; Millar, Robert P.; Brown, Pamela

    2007-01-01

    G protein-coupled receptor regulation of gene transcription primarily occurs through the phosphorylation of transcription factors by MAPKs. This requires transduction of an activating signal via scaffold proteins that can ultimately determine the outcome by binding signaling kinases and adapter proteins with effects on the target transcription factor and locus of activation. By investigating these mechanisms, we have elucidated how pituitary gonadotrope cells decode an input GnRH signal into coherent transcriptional output from the LH β-subunit gene promoter. We show that GnRH activates c-Src and multiple members of the MAPK family, c-Jun NH2-terminal kinase 1/2, p38MAPK, and ERK1/2. Using dominant-negative point mutations and chemical inhibitors, we identified that calcium-dependent proline-rich tyrosine kinase 2 specifically acts as a scaffold for a focal adhesion/cytoskeleton-dependent complex comprised of c-Src, Grb2, and mSos that translocates an ERK-activating signal to the nucleus. The locus of action of ERK was specifically mapped to early growth response-1 (Egr-1) DNA binding sites within the LH β-subunit gene proximal promoter, which was also activated by p38MAPK, but not c-Jun NH2-terminal kinase 1/2. Egr-1 was confirmed as the transcription factor target of ERK and p38MAPK by blockade of protein expression, transcriptional activity, and DNA binding. We have identified a novel GnRH-activated proline-rich tyrosine kinase 2-dependent ERK-mediated signal transduction pathway that specifically regulates Egr-1 activation of the LH β-subunit proximal gene promoter, and thus provide insight into the molecular mechanisms required for differential regulation of gonadotropin gene expression. PMID:17327421

  5. The gonadotropin connection in Alzheimer's disease.

    PubMed

    Meethal, Sivan Vadakkadath; Smith, Mark A; Bowen, Richard L; Atwood, Craig S

    2005-04-01

    Although not traditionally thought of as regulators of neuronal function, the hypothalamic-pituitary-gonadal (HPG) hormones luteinizing hormone (LH), gonadotropin-releasing hormone (GnRH), and activins possess neuronal receptors. These receptors are found throughout the limbic system on a number of different cell types, and, like reproductive tissues, the expression of these receptors is regulated by hormonal feedback loops. These hormones and their receptors regulate structure and a diverse range of functions in the brain. Therefore, it is not surprising that the dysregulation of the HPG axis with menopause and andropause (leading to elevated LH, GnRH, and activin signaling but decreased sex steroid signaling) might promote alterations in both the structure and function of neuronal cells. To date, most evidence has accumulated for a role of LH in promoting neurodegenerative changes. LH is known to cross the blood-brain barrier, receptors for LH are most concentrated in the hippocampus, that region of the brain most vulnerable to Alzheimer's disease (AD) and LH is significantly elevated in both the serum and the pyramidal neurons of AD subjects. LH promotes the amyloidogenic processing of the amyloid-beta precursor protein in vitro, and the antigonadotropin leuprolide acetate decreases amyloid generation in mice. Moreover, leuprolide acetate improves the cognitive performance and decreases amyloid-beta deposition in aged transgenic mice carrying the Swedish AbetaPP mutation. Therefore, the elevation of LH with the dysregulation of the HPG axis at menopause and andropause is a physiologically relevant signal that could promote neurodegeneration. Epidemiological support for a role of LH/GnRH in AD is evidenced by a reduction in neurodegenerative disease among prostate cancer patients a group known to GnRH agonists. Clinical trials are underway for the treatment of AD using GnRH analogs and should provide further insights into the gonadotropin connection in AD.

  6. Polymorphisms in gonadotropin and gonadotropin receptor genes as markers of ovarian reserve and response in in vitro fertilization.

    PubMed

    La Marca, Antonio; Sighinolfi, Giovanna; Argento, Cindy; Grisendi, Valentina; Casarini, Livio; Volpe, Annibale; Simoni, Manuela

    2013-03-15

    Since gonadotropins are the fundamental hormones that control ovarian activity, genetic polymorphisms may alter gonadal responsiveness to glycoproteins; hence they are important regulators of hormone activity at the target level. The establishment of the pool of primordial follicles takes place during fetal life and is mainly under genetic control. Consequently, single nucleotide polymorphisms (SNPs) in gonadotropins and their receptors do not seem to be associated with any significant modification in the endowment of nongrowing follicles in the ovary. Indeed, the age at menopause, a biological characteristic strongly related to ovarian reserve, as well as markers of functional ovarian reserve such as anti-Müllerian hormone and antral follicle count, are not different in women with different genetic variants. Conversely, some polymorphisms in FSH receptor (FSHR) seem to be associated with modifications in ovarian activity. In particular, studies suggest that the Ser680 genotype for FSHR is a factor of relative resistance to FSH stimulation resulting in slightly higher FSH serum levels, thus leading to a prolonged duration of the menstrual cycle. Moreover, some FSHR gene polymorphisms show a positive association with ovarian response to exogenous gonadotropin administration, hence exhibiting some potential for a pharmacogenetic estimation of the FSH dosage in controlled ovarian stimulation. The study of SNPs of the FSHR gene is an interesting field of research that could provide us with new information about the way each woman responds to exogenous gonadotropin administration during ovulation induction.

  7. Gonadotropin-releasing hormone-stimulated gonadotropin levels in women with premenstrual dysphoria.

    PubMed

    Smith, M J; Schmidt, P J; Su, T P; Rubinow, D R

    2004-12-01

    Despite consistent evidence that premenstrual dysphoria (PMD) is not characterized by abnormalities in basal ovarian hormone secretion, the possibility remains that PMD is associated with an abnormality in the regulation of the hypothalamic-pituitary-ovarian (HPO) axis. We studied HPO axis regulation in 11 women with prospectively confirmed PMD and 20 asymptomatic controls, during both the follicular and luteal phases of the menstrual cycle. Plasma levels of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), were obtained before and after stimulation with gonadotropin-releasing hormone (GnRH) (100 microg intravenously). Potential diagnostic- and menstrual cycle phase-related diferences in basal and plasma hormone levels were analyzed by repeated-measures analysis of variance. No significant differences were observed between women with PMD and controls in either basal or stimulated levels of FSH and LH. Stimulated FSH was significantly increased and stimulated LH was significantly decreased during the follicular compared with the luteal phase in both women with PMD and controls. These data are consistent with prior findings of normal basal reproductive hormone levels in women with PMD. Our data suggest the absence in women with PMD of an abnormality of dynamic ovarian function as measured by GnRH stimulation.

  8. Further evidence for the role of glucose as a metabolic regulator of hypothalamic gonadotropin-releasing hormone pulse generator activity in goats.

    PubMed

    Ohkura, Satoshi; Ichimaru, Toru; Itoh, Fumiaki; Matsuyama, Shuichi; Okamura, Hiroaki

    2004-07-01

    The present study examined the relative importance of blood glucose vs. free fatty acids as a metabolic signal regulating GnRH release as measured electrophysiologically by multiple-unit activity (MUA) in the arcuate nucleus/median eminence region in ovariectomized, estradiol-treated goats. MUA was recorded before, during, and after: 1) cellular glucoprivation by peripheral infusion of 2-deoxy-d-glucose (2DG; 25, 50, and 75 mg/kg.h, iv); 2) peripheral hypoglycemia in response to various doses (15-195 mU/kg.h, iv) of insulin infusion; and 3) cellular lipoprivation induced by peripheral infusion of sodium mercaptoacetate (MA; 2.4 mg/kg.h alone or combined with 25 mg/kg.h of 2DG, iv), and effects on the interval of characteristic increases in MUA (MUA volleys) were examined. Infusion of the highest dose of 2DG increased the mean interval between MUA volleys, whereas the lower doses of 2DG had no effect on volley interval. The MUA volley intervals lengthened as insulin-induced hypoglycemia became profound. There was a negative correlation between MUA volley intervals and blood glucose concentrations during insulin infusion, and coinfusion of glucose with insulin returned the MUA volley interval to a normal frequency. Infusion of MA alone or MA with 2DG did not increase MUA volley intervals. These findings demonstrate that glucose availability, but not fatty acids, regulates the GnRH pulse generator activity in the ruminant. Glucose is considered a key metabolic regulator that fine-tunes pulsatile GnRH release. PMID:15044379

  9. 40 CFR 180.142 - 2,4-D; tolerances for residues.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 24 2014-07-01 2014-07-01 false 2,4-D; tolerances for residues. 180..., plant regulator, and fungicide 2,4-D, including its metabolites and degradates, in or on the commodities... 2,4-D (2,4-dichlorophenoxyacetic acid), both free and conjugated, determined as the acid, in or...

  10. 4-D OCT in Developmental Cardiology

    NASA Astrophysics Data System (ADS)

    Jenkins, Michael W.; Rollins, Andrew M.

    Although strong evidence exists to suggest that altered cardiac function can lead to CHDs, few studies have investigated the influential role of cardiac function and biophysical forces on the development of the cardiovascular system due to a lack of proper in vivo imaging tools. 4-D imaging is needed to decipher the complex spatial and temporal patterns of biomechanical forces acting upon the heart. Numerous solutions over the past several years have demonstrated 4-D OCT imaging of the developing cardiovascular system. This chapter will focus on these solutions and explain their context in the evolution of 4-D OCT imaging. The first sections describe the relevant techniques (prospective gating, direct 4-D imaging, retrospective gating), while later sections focus on 4-D Doppler imaging and measurements of force implementing 4-D OCT Doppler. Finally, the techniques are summarized, and some possible future directions are discussed.

  11. Gonadotropin therapy: a 20th century relic.

    PubMed

    Reindollar, Richard H; Goldman, Marlene B

    2012-04-01

    Gonadotropin therapy has been a cornerstone of infertility therapy for half a century. From the very beginning, its use has been associated with a high rate of multiple births, particularly high order multiples, and ovarian hyperstimulation syndrome. Initially, success rates seemed acceptable when used for superovulation (SO)/IUI therapy. However, as data from RCTs have emerged, reported outcomes suggest that we question the use of injectible gonadotropins. This manuscript examines the studies that have challenged gonadotropin use for SO/IUI and other research that supports reduced doses of gonadotropins for IVF. We examine the challenges for its continued use for SO/IUI and for moving to lower doses worldwide for IVF. We propose a future that views gonadotropins as a relic of the twentieth century. PMID:22463775

  12. Advances in 4D radiation therapy for managing respiration: part I - 4D imaging.

    PubMed

    Hugo, Geoffrey D; Rosu, Mihaela

    2012-12-01

    Techniques for managing respiration during imaging and planning of radiation therapy are reviewed, concentrating on free-breathing (4D) approaches. First, we focus on detailing the historical development and basic operational principles of currently-available "first generation" 4D imaging modalities: 4D computed tomography, 4D cone beam computed tomography, 4D magnetic resonance imaging, and 4D positron emission tomography. Features and limitations of these first generation systems are described, including necessity of breathing surrogates for 4D image reconstruction, assumptions made in acquisition and reconstruction about the breathing pattern, and commonly-observed artifacts. Both established and developmental methods to deal with these limitations are detailed. Finally, strategies to construct 4D targets and images and, alternatively, to compress 4D information into static targets and images for radiation therapy planning are described.

  13. Advances in 4D Radiation Therapy for Managing Respiration: Part I – 4D Imaging

    PubMed Central

    Hugo, Geoffrey D.; Rosu, Mihaela

    2014-01-01

    Techniques for managing respiration during imaging and planning of radiation therapy are reviewed, concentrating on free-breathing (4D) approaches. First, we focus on detailing the historical development and basic operational principles of currently-available “first generation” 4D imaging modalities: 4D computed tomography, 4D cone beam computed tomography, 4D magnetic resonance imaging, and 4D positron emission tomography. Features and limitations of these first generation systems are described, including necessity of breathing surrogates for 4D image reconstruction, assumptions made in acquisition and reconstruction about the breathing pattern, and commonly-observed artifacts. Both established and developmental methods to deal with these limitations are detailed. Finally, strategies to construct 4D targets and images and, alternatively, to compress 4D information into static targets and images for radiation therapy planning are described. PMID:22784929

  14. Effects of echinomycin on endothelin-2 expression and ovulation in immature rats primed with gonadotropins

    PubMed Central

    Zhang, Zhenghong; Wu, Yanqing; Chen, Liyun; Luo, Qianping; Zhang, Jisen; Chen, Jiajie; Luo, Zimiao; Huang, Xiaohong; Cheng, Yong

    2012-01-01

    Echinomycin is a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity, which plays a crucial role in ovarian ovulation in mammalians. The present study was designed to test the hypothesis that hypoxia-inducible factor (HIF)-1α-mediated endothelin (ET)-2 expressions contributed to ovarian ovulation in response to human chorionic gonadotropin (hCG) during gonadotropin-induced superuvulation. By real-time RT-PCR analysis, ET-2 mRNA level was found to significantly decrease in the ovaries after echinomycin treatment, while HIF-1α mRNA and protein expression was not obviously changed. Further analysis also showed that these changes of ET-2 mRNA were consistent with HIF-1 activity in the ovaires, which is similar with HIF-1α and ET-2 expression in the granulosa cells with gonadotropin and echinomycin treatments. The results of HIF-1α and ET-2 expression in the granulosa cells transfected with cis-element oligodeoxynucleotide (dsODN) under gonadotropin treatment further indicated HIF-1α directly mediated the transcriptional activation of ET-2 during gonadotropin-induced superuvulation. Taken together, these results demonstrated that HIF-1α-mediated ET-2 transcriptional activation is one of the important mechanisms regulating gonadotropin-induced mammalian ovulatory precess in vivo. PMID:22874467

  15. Los Alamos National Laboratory 4D Database

    SciTech Connect

    Atencio, Julian J.

    2014-05-02

    4D is an integrated development platform - a single product comprised of the components you need to create and distribute professional applications. You get a graphical design environment, SQL database, a programming language, integrated PHP execution, HTTP server, application server, executable generator, and much more. 4D offers multi-platform development and deployment, meaning whatever you create on a Mac can be used on Windows, and vice-versa. Beyond productive development, 4D is renowned for its great flexibility in maintenance and modification of existing applications, and its extreme ease of implementation in its numerous deployment options. Your professional application can be put into production more quickly, at a lower cost, and will always be instantly scalable. 4D makes it easy, whether you're looking to create a classic desktop application, a client-server system, a distributed solution for Web or mobile clients - or all of the above!

  16. Helical 4D CT and Comparison with Cine 4D CT

    NASA Astrophysics Data System (ADS)

    Pan, Tinsu

    4D CT was one of the most important developments in radiation oncology in the last decade. Its early development in single slice CT and commercialization in multi-slice CT has radically changed our practice in radiation treatment of lung cancer, and has enabled the stereotactic radiosurgery of early stage lung cancer. In this chapter, we will document the history of 4D CT development, detail the data sufficiency condition governing the 4D CT data collection; present the design of the commercial helical 4D CTs from Philips and Siemens; compare the differences between the helical 4D CT and the GE cine 4D CT in data acquisition, slice thickness, acquisition time and work flow; review the respiratory monitoring devices; and understand the causes of image artifacts in 4D CT.

  17. 4D flow imaging with MRI

    PubMed Central

    Stankovic, Zoran; Allen, Bradley D.; Garcia, Julio; Jarvis, Kelly B.

    2014-01-01

    Magnetic resonance imaging (MRI) has become an important tool for the clinical evaluation of patients with cardiovascular disease. Since its introduction in the late 1980s, 2-dimensional phase contrast MRI (2D PC-MRI) has become a routine part of standard-of-care cardiac MRI for the assessment of regional blood flow in the heart and great vessels. More recently, time-resolved PC-MRI with velocity encoding along all three flow directions and three-dimensional (3D) anatomic coverage (also termed ‘4D flow MRI’) has been developed and applied for the evaluation of cardiovascular hemodynamics in multiple regions of the human body. 4D flow MRI allows for the comprehensive evaluation of complex blood flow patterns by 3D blood flow visualization and flexible retrospective quantification of flow parameters. Recent technical developments, including the utilization of advanced parallel imaging techniques such as k-t GRAPPA, have resulted in reasonable overall scan times, e.g., 8-12 minutes for 4D flow MRI of the aorta and 10-20 minutes for whole heart coverage. As a result, the application of 4D flow MRI in a clinical setting has become more feasible, as documented by an increased number of recent reports on the utility of the technique for the assessment of cardiac and vascular hemodynamics in patient studies. A number of studies have demonstrated the potential of 4D flow MRI to provide an improved assessment of hemodynamics which might aid in the diagnosis and therapeutic management of cardiovascular diseases. The purpose of this review is to describe the methods used for 4D flow MRI acquisition, post-processing and data analysis. In addition, the article provides an overview of the clinical applications of 4D flow MRI and includes a review of applications in the heart, thoracic aorta and hepatic system. PMID:24834414

  18. Endocrine disrupting effects of dichlorodiphenyltrichloroethane analogues on gonadotropin hormones in pituitary gonadotrope cells.

    PubMed

    Zhou, Jinghua; Yang, Ye; Xiong, Kang; Liu, Jing

    2014-05-01

    It has been shown that exposure to dichlorodiphenyltrichloroethane (DDT) analogues leads to disharmony of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). However, the effects and mechanisms of DDT analogues on the expression of gonadotropin genes (FSHβ, LHβ and Cgα), which is the rate-limiting step of FSH and LH biosynthesis, remain unknown. In this study, we assessed the effects of p,p'-DDT, o,p'-DDT, p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) and methoxychlor (MXC) on gonadotropin genes expression and hormones synthesis in gonadotrope cells. p,p'-DDT and MXC at test concentrations ranging from 10(-9) to 10(-7)mol/L, stimulated gonadotropin genes expression and hormones synthesis in a dose-dependent manner. The activation of extracellular signal-regulated kinase (ERK) was required for the induction of gonadotropin genes expression and hormones synthesis by p,p'-DDT or MXC exposure. This study showed for the first time that p,p'-DDT and MXC regulated gonadotropin genes expression and hormones synthesis through ERK pathway in gonadotrope cells.

  19. Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function.

    PubMed

    Themmen APN; Huhtaniemi, I T

    2000-10-01

    The recent unraveling of structures of genes for the gonadotropin subunits and gonadotropin receptors has provided reproductive endocrinologists with new tools to study normal and pathological functions of the hypothalamic-pituitary-gonadal axis. Rare inactivating mutations that produce distinctive phenotypes of isolated LH or FSH deficiency have been discovered in gonadotropin subunit genes. In addition, there is a common polymorphism in the LHbeta subunit gene with possible clinical significance as a contributing factor to pathologies of LH-dependent gonadal functions. Both activating and inactivating mutations have been detected in the gonadotropin receptor genes, a larger number in the LH receptor gene, but so far only a few in the gene for the FSH receptor. These mutations corroborate and extend our knowledge of clinical consequences of gonadotropin resistance and inappropriate gonadotropin action. The information obtained from human mutations has been complemented by animal models with disrupted or inappropriately activated gonadotropin ligand or receptor genes. These clinical and experimental genetic disease models form a powerful tool for exploring the physiology and pathophysiology of gonadotropin function and provide an excellent example of the power of molecular biological approaches in the study of pathogenesis of diseases.

  20. Shadow-driven 4D haptic visualization.

    PubMed

    Zhang, Hui; Hanson, Andrew

    2007-01-01

    Just as we can work with two-dimensional floor plans to communicate 3D architectural design, we can exploit reduced-dimension shadows to manipulate the higher-dimensional objects generating the shadows. In particular, by taking advantage of physically reactive 3D shadow-space controllers, we can transform the task of interacting with 4D objects to a new level of physical reality. We begin with a teaching tool that uses 2D knot diagrams to manipulate the geometry of 3D mathematical knots via their projections; our unique 2D haptic interface allows the user to become familiar with sketching, editing, exploration, and manipulation of 3D knots rendered as projected imageson a 2D shadow space. By combining graphics and collision-sensing haptics, we can enhance the 2D shadow-driven editing protocol to successfully leverage 2D pen-and-paper or blackboard skills. Building on the reduced-dimension 2D editing tool for manipulating 3D shapes, we develop the natural analogy to produce a reduced-dimension 3D tool for manipulating 4D shapes. By physically modeling the correct properties of 4D surfaces, their bending forces, and their collisions in the 3D haptic controller interface, we can support full-featured physical exploration of 4D mathematical objects in a manner that is otherwise far beyond the experience accessible to human beings. As far as we are aware, this paper reports the first interactive system with force-feedback that provides "4D haptic visualization" permitting the user to model and interact with 4D cloth-like objects.

  1. Enterococcus faecalis promotes osteoclastogenesis and semaphorin 4D expression.

    PubMed

    Wang, Shuai; Deng, Zuhui; Seneviratne, Chaminda J; Cheung, Gary S P; Jin, Lijian; Zhao, Baohong; Zhang, Chengfei

    2015-10-01

    Enterococcus faecalis is considered a major bacterial pathogen implicated in endodontic infections and contributes considerably to periapical periodontitis. This study aimed to investigate the potential mechanisms by which E. faecalis accounts for the bone destruction in periapical periodontitis in vitro. Osteoclast precursor RAW264.7 cells were treated with E. faecalis ATCC 29212 and a wild strain of E. faecalis derived clinically from an infected root canal. The results showed that, to some extent, E. faecalis induced the RAW264.7 cells to form tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclast-like cells. This pathogen markedly stimulated RAW264.7 cells to express semaphorin 4D (Sema4D), which inhibits bone formation. Once RAW264.7 cells were primed by low-dose receptor activator of nuclear factor-kappa B ligand (RANKL), E. faecalis could significantly increase the production of TRAP-positive multinucleated cells and up-regulate the expression of osteoclast-specific markers, including NFATc1, TRAP and cathepsin K. Both p38 and ERK1/2 MAPK signaling pathways were activated by E. faecalis in RANKL-primed RAW264.7 cells, and meanwhile the expression of Sema4D was highly increased. In conclusion, E. faecalis may greatly contribute to the bone resorption in periapical periodontitis by promoting RANKL-dependent osteoclastogenesis and expression of Sema4D through activation of p38 and ERK1/2 MAPK signaling pathways.

  2. 4D Confocal Imaging of Yeast Organelles.

    PubMed

    Day, Kasey J; Papanikou, Effrosyni; Glick, Benjamin S

    2016-01-01

    Yeast cells are well suited to visualizing organelles by 4D confocal microscopy. Typically, one or more cellular compartments are labeled with a fluorescent protein or dye, and a stack of confocal sections spanning the entire cell volume is captured every few seconds. Under appropriate conditions, organelle dynamics can be observed for many minutes with only limited photobleaching. Images are captured at a relatively low signal-to-noise ratio and are subsequently processed to generate movies that can be analyzed and quantified. Here, we describe methods for acquiring and processing 4D data using conventional scanning confocal microscopy. PMID:27631997

  3. The scientific value of 4D visualizations

    NASA Astrophysics Data System (ADS)

    Minster, J.; Olsen, K.; Day, S.; Moore, R.; Jordan, T. H.; Maechling, P.; Chourasia, A.

    2006-12-01

    Significant scientific insights derive from viewing measured, or calculated three-dimensional, time-dependent -- that is four-dimensional-- fields. This issue cuts across all disciplines of Earth Sciences. Addressing it calls for close collaborations between "domain" scientists and "IT" visualization specialists. Techniques to display such 4D fields in a intuitive way are a major challenge, especially when the relevant variables to be displayed are not scalars but tensors. This talk will illustrate some attempts to deal with this challenge, using seismic wave fields as specific objects to display. We will highlight how 4D displays can help address very difficult issues of significant scientific import.

  4. Constrained reconstructions for 4D intervention guidance.

    PubMed

    Kuntz, J; Flach, B; Kueres, R; Semmler, W; Kachelriess, M; Bartling, S

    2013-05-21

    Image-guided interventions are an increasingly important part of clinical minimally invasive procedures. However, up to now they cannot be performed under 4D (3D + time) guidance due to the exceedingly high x-ray dose. In this work we investigate the applicability of compressed sensing reconstructions for highly undersampled CT datasets combined with the incorporation of prior images in order to yield low dose 4D intervention guidance. We present a new reconstruction scheme prior image dynamic interventional CT (PrIDICT) that accounts for specific image features in intervention guidance and compare it to PICCS and ASD-POCS. The optimal parameters for the dose per projection and the numbers of projections per reconstruction are determined in phantom simulations and measurements. In vivo experiments in six pigs are performed in a cone-beam CT; measured doses are compared to current gold-standard intervention guidance represented by a clinical fluoroscopy system. Phantom studies show maximum image quality for identical overall doses in the range of 14 to 21 projections per reconstruction. In vivo studies reveal that interventional materials can be followed in 4D visualization and that PrIDICT, compared to PICCS and ASD-POCS, shows superior reconstruction results and fewer artifacts in the periphery with dose in the order of biplane fluoroscopy. These results suggest that 4D intervention guidance can be realized with today's flat detector and gantry systems using the herein presented reconstruction scheme.

  5. 4D-Var Developement at GMAO

    NASA Technical Reports Server (NTRS)

    Pelc, Joanna S.; Todling, Ricardo; Akkraoui, Amal El

    2014-01-01

    The Global Modeling and Assimilation Offce (GMAO) is currently using an IAU-based 3D-Var data assimilation system. GMAO has been experimenting with a 3D-Var-hybrid version of its data assimilation system (DAS) for over a year now, which will soon become operational and it will rapidly progress toward a 4D-EnVar. Concurrently, the machinery to exercise traditional 4DVar is in place and it is desirable to have a comparison of the traditional 4D approach with the other available options, and evaluate their performance in the Goddard Earth Observing System (GEOS) DAS. This work will also explore the possibility for constructing a reduced order model (ROM) to make traditional 4D-Var computationally attractive for increasing model resolutions. Part of the research on ROM will be to search for a suitably acceptable space to carry on the corresponding reduction. This poster illustrates how the IAU-based 4D-Var assimilation compares with our currently used IAU-based 3D-Var.

  6. Constrained reconstructions for 4D intervention guidance

    NASA Astrophysics Data System (ADS)

    Kuntz, J.; Flach, B.; Kueres, R.; Semmler, W.; Kachelrieß, M.; Bartling, S.

    2013-05-01

    Image-guided interventions are an increasingly important part of clinical minimally invasive procedures. However, up to now they cannot be performed under 4D (3D + time) guidance due to the exceedingly high x-ray dose. In this work we investigate the applicability of compressed sensing reconstructions for highly undersampled CT datasets combined with the incorporation of prior images in order to yield low dose 4D intervention guidance. We present a new reconstruction scheme prior image dynamic interventional CT (PrIDICT) that accounts for specific image features in intervention guidance and compare it to PICCS and ASD-POCS. The optimal parameters for the dose per projection and the numbers of projections per reconstruction are determined in phantom simulations and measurements. In vivo experiments in six pigs are performed in a cone-beam CT; measured doses are compared to current gold-standard intervention guidance represented by a clinical fluoroscopy system. Phantom studies show maximum image quality for identical overall doses in the range of 14 to 21 projections per reconstruction. In vivo studies reveal that interventional materials can be followed in 4D visualization and that PrIDICT, compared to PICCS and ASD-POCS, shows superior reconstruction results and fewer artifacts in the periphery with dose in the order of biplane fluoroscopy. These results suggest that 4D intervention guidance can be realized with today’s flat detector and gantry systems using the herein presented reconstruction scheme.

  7. Gonadotropins and Alzheimer's disease: the link between estrogen replacement therapy and neuroprotection.

    PubMed

    Webber, Kate M; Bowen, Richard; Casadesus, Gemma; Perry, George; Atwood, Craig S; Smith, Mark A

    2004-01-01

    The search for a definitive gender bias in Alzheimer's disease has resulted in a multitude of epidemiological findings that point to a higher prevalence and incidence of Alzheimer's disease in women. Due to this reported predisposition of women to Alzheimer's disease, the sex steroid estrogen has become the primary focus of research in this field, however, inconclusive data regarding estrogen replacement therapy has lead some researchers to further investigate the role of the other hormones of the hypothalamic-pituitary-gonadal (HPG) axis that have been, for the most, part overlooked. The hormones of the HPG axis, such as the gonadotropin, (luteinizing hormone and follicle-stimulating hormone), are involved in regulating reproductive function via a complex feedback loop. We propose that it is in fact the increase in gonadotropin concentrations and not the decrease in steroid hormone (e.g., estrogen) production following menopause/andropause that results in an increased risk of Alzheimer's disease. Furthermore, when the role of gonadotropins is taken into account, the data obtained from recent epidemiological studies and randomized trials suggesting the ineffectiveness estrogen may indeed be misinterpreted. In this review, we examine how hormones of the hypothalamic-pituitary-gonadal axis, in particular the gonadotropins, play a central and determining role in modulating the susceptibility to and progression of Alzheimer's disease. Based on this, we suggest that therapeutic interventions targeted at gonadotropins could both prevent disease in those patients currently asymptomatic or halt, and even reverse, disease in those currently afflicted.

  8. Ig-like transcript 4 as a cellular receptor for soluble complement fragment C4d.

    PubMed

    Hofer, Johannes; Forster, Florian; Isenman, David E; Wahrmann, Markus; Leitner, Judith; Hölzl, Markus A; Kovarik, Johannes J; Stockinger, Hannes; Böhmig, Georg A; Steinberger, Peter; Zlabinger, Gerhard J

    2016-04-01

    Complement regulation leads to the generation of complement split products (CSPs) such as complement component (C)4d, a marker for disease activity in autoimmune syndromes or antibody-mediated allograft rejection. However, the physiologic role of C4d has been unknown. By screening murine thymoma BW5147 cells expressing a cDNA library generated from human monocyte-derived dendritic cells with recombinant human C4d, we identified Ig-like transcript (ILT)4 and ILT5v2 as cellular receptors for C4d. Both receptors, expressed on monocytes, macrophages, and dendritic cells, also interacted with the CSPs C3d, C4b, C3b, and iC3b. However, C4d did not bind to classic complement receptors (CRs). Interaction between cell surface-resident ILT4 and soluble monomeric C4d resulted in endocytosis of C4d. Surprisingly, binding of soluble ILT4 to C4d covalently immobilized to a cellular surface following classic complement activation could not be detected. Remarkably, C4d immobilized to a solid phaseviaits intrinsic thioester conferred a dose-dependent inhibition of TNF-α and IL-6 secretion in monocytes activatedviaFc-cross-linking of up to 50% as compared to baseline. Similarly, C4d conferred an attenuation of intracellular Ca(2+)flux in monocytes activatedviaFc-cross-linking. In conclusion, ILT4 represents a scavenger-type endocytotic CR for soluble monomeric C4d, whereas attenuation of monocyte activation by physiologically oriented C4d on a surface appears to be dependent on a yet to be identified C4d receptor.-Hofer, J., Forster, F., Isenman, D. E., Wahrmann, M., Leitner, J., Hölzl, M. A., Kovarik, J. K., Stockinger, H., Böhmig, G. A., Steinberger, P., Zlabinger, G. J. Ig-like transcript 4 as a cellular receptor for soluble complement fragment C4d.

  9. 77 FR 4227 - Implantation or Injectable Dosage Form New Animal Drugs; Gonadotropin Releasing Factor Analog...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-27

    ... regulations in 21 CFR 522.1083 are amended to reflect the approval. In accordance with the freedom of... CFR part 522 continues to read as follows: Authority: 21 U.S.C. 360b. 0 2. In Sec. 522.1083, revise paragraphs (c)(1) and (c)(3) to read as follows: Sec. 522.1083 Gonadotropin releasing factor...

  10. 76 FR 27888 - Implantation or Injectable Dosage Form New Animal Drugs; Gonadotropin Releasing Factor-Diphtheria...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-13

    ... drug regulations to reflect approval of a new animal drug application (NADA) filed by Pfizer, Inc. The NADA provides for the veterinary prescription use of gonadotropin releasing factor-diphtheria toxoid...-5755, filed NADA 141-322 that provides for the veterinary prescription use of IMPROVEST...

  11. Mutations affecting gonadotropin secretion and action.

    PubMed

    Huhtaniemi, Ilpo

    2003-01-01

    A number of mutations are known to disturb the development and function of the hypothalamic-pituitary-gonadal axis. They affect hypothalamic-pituitary-gonadal function at multiple levels, from the migration of gonadotropin releasing hormone neurons to the hypothalamus right through to gonadotropin action in the ovary and testis. Most of the mutations are inactivating, causing various forms of hypogonadism. Exceptions are the activating mutations of the luteinizing hormone receptor, causing male-limited gonadotropin-independent precocious puberty. The human mutations and genetically modified animal models have clarified the molecular pathogenesis of hypogonadism and such disorders can now be diagnosed using molecular biological techniques, enabling selection of specific treatments and appropriate counselling of patients and their families.

  12. Interactive animation of 4D performance capture.

    PubMed

    Casas, Dan; Tejera, Margara; Guillemaut, Jean-Yves; Hilton, Adrian

    2013-05-01

    A 4D parametric motion graph representation is presented for interactive animation from actor performance capture in a multiple camera studio. The representation is based on a 4D model database of temporally aligned mesh sequence reconstructions for multiple motions. High-level movement controls such as speed and direction are achieved by blending multiple mesh sequences of related motions. A real-time mesh sequence blending approach is introduced, which combines the realistic deformation of previous nonlinear solutions with efficient online computation. Transitions between different parametric motion spaces are evaluated in real time based on surface shape and motion similarity. Four-dimensional parametric motion graphs allow real-time interactive character animation while preserving the natural dynamics of the captured performance.

  13. Nondipole Effects in Xe 4d Photoemission

    SciTech Connect

    Hemmers, O; Guillemin, R; Wolska, A; Lindle, D W; Rolles, D; Cheng, K T; Johnson, W R; Zhou, H L; Manson, S T

    2004-07-14

    We measured the nondipole parameters for the spin-orbit doublets Xe 4d{sub 5/2} and Xe 4d{sub 3/2} over a photon-energy range from 100 eV to 250 eV at beamline 8.0.1.3 of the Advanced Light Source at the Lawrence Berkeley National Laboratory. Significant nondipole effects are found at relatively low energies as a result of Cooper minima in dipole channels and interchannel coupling in quadrupole channels. Most importantly, sharp disagreement between experiment and theory, when otherwise excellent agreement was expected, has provided the first evidence of satellite two-electron quadrupole photoionization transitions, along with their crucial importance for a quantitatively accurate theory.

  14. Interactive animation of 4D performance capture.

    PubMed

    Casas, Dan; Tejera, Margara; Guillemaut, Jean-Yves; Hilton, Adrian

    2013-05-01

    A 4D parametric motion graph representation is presented for interactive animation from actor performance capture in a multiple camera studio. The representation is based on a 4D model database of temporally aligned mesh sequence reconstructions for multiple motions. High-level movement controls such as speed and direction are achieved by blending multiple mesh sequences of related motions. A real-time mesh sequence blending approach is introduced, which combines the realistic deformation of previous nonlinear solutions with efficient online computation. Transitions between different parametric motion spaces are evaluated in real time based on surface shape and motion similarity. Four-dimensional parametric motion graphs allow real-time interactive character animation while preserving the natural dynamics of the captured performance. PMID:23492379

  15. Aspirin inhibits androgen response to chorionic gonadotropin in humans.

    PubMed

    Conte, D; Romanelli, F; Fillo, S; Guidetti, L; Isidori, A; Franceschi, F; Latini, M; di Luigi, L

    1999-12-01

    Eicosanoids play an important role in the regulation of the hypothalamic-pituitary axis; less clear is their role in testicular steroidogenesis. To evaluate the involvement of cyclooxygenase metabolites, such as prostaglandins, in the regulation of human testicular steroidogenesis, we examined the effects of a prostaglandin-blocker, aspirin, on plasma testosterone, pregnenolone, progesterone, 17OH-progesterone, androstenedione, dehydroepiandrosterone, and 17beta-estradiol response to human chorionic gonadotropin (hCG) in normal male volunteers in a placebo-controlled, single-blinded study. To test the efficacy of aspirin, seminal prostaglandin E(2) levels were also determined. hCG stimulation increased peripheral levels of testosterone, 17OH-progesterone, androstenedione, dehydroepiandrosterone, and 17beta-estradiol, without affecting circulating pregnenolone and progesterone values. Aspirin significantly lowered seminal prostaglandin E(2) levels, whereas it did not modify steroid concentrations not exposed to exogenous hCG. Moreover, the drug significantly reduced the response of testosterone, 17OH-progesterone, androstenedione, and dehydroepiandrosterone to hCG, as assessed by the mean integrated area under the curve, whereas it did not influence 17beta-estradiol response. In conclusion, aspirin treatment inhibits androgen response to chorionic gonadotropin stimulation in normal humans. The action of aspirin is probably mediated via an effective arachidonate cyclooxygenase block.

  16. Luteinizing hormone and human chorionic gonadotropin: distinguishing unique physiologic roles.

    PubMed

    Choi, Janet; Smitz, Johan

    2014-03-01

    Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) are integral components of the hypothalamic-pituitary-gonadal axis, which controls sexual maturation and functionality. In the absence of signaling through their shared receptor, fetal sexual differentiation and post-natal development cannot proceed normally. Although they share a high degree of homology, the physiologic roles of these hormones are unique, governed by differences in expression pattern, biopotency and regulation. Whereas LH is a key regulator of gonadal steroidogenesis and ovulation, hCG is predominantly active in pregnancy and fetal development. Emerging evidence has revealed endogenous functions not previously ascribed to hCG, including participation in ovulation and fertilization, implantation, placentation and other activities in support of successful pregnancy. Spontaneous and induced mutations in LH, hCG and their mutual receptor have contributed substantially to our understanding of reproductive development and function. The lack of naturally occurring, functionally significant mutations in the β-subunit of hCG reinforce its putative role in establishment of pregnancy. Rescue of reproductive abnormalities resulting from aberrant gonadotropin signaling is possible in certain clinical contexts, depending on the nature of the underlying defect. By understanding the physiologic roles of LH and hCG in normal and pathologic states, we may better harness their diagnostic, prognostic and therapeutic potential.

  17. Gonadotropin secretion in bulimia nervosa.

    PubMed

    Schweiger, U; Pirke, K M; Laessle, R G; Fichter, M M

    1992-05-01

    Twenty-two normal weight women with bulimia nervosa (BN) were studied (mean age, 25 +/- 5 yr; body mass index, 20.2 +/- 2.6 kg/m2). Sixteen of them reported menstrual cycles in the range of 21-42 days, and 6 had experienced absence of menstruation for at least 3 months. Twenty-one healthy women with regular menstrual cycles (mean age, 23 +/- 2 yr; body mass index, 20.7 +/- 1.4) served as the control subjects. Frequent morning blood samples for estradiol (E2) and progesterone (P4) determinations were obtained for the duration of 1 menstrual cycle or for 6 weeks in the case of amenorrhea. LH, FSH, cortisol, and insulin secretion were studied on day 3, 4, or 5 after the onset of a menstrual cycle or on a random day in the 6 BN women with amenorrhea. Blood samples were collected at 15-min intervals from 1800-0600 h for LH and FSH and at 30-min intervals from 2400-0600 h for cortisol and insulin. Nineteen of the 21 controls, but only 10 of the 22 BN women, fulfilled the following standard criteria: maximum E2 above 440 pmol/L, maximum P4 above 19 nmol/L, and luteal phase length of 9 days or more. The 10 BN women with normal menstrual cycles had lower mean insulin concentrations than the controls (70 +/- 20 vs. 120 +/- 30 pmol/L; P less than 0.01), but gonadotropin secretion, cortisol, and T3 concentrations were similar. The 8 BN women with amenorrhea or ovulatory dysfunction (maximum E2, less than 440 pmol/L; maximum P4, less than 6 nmol/L) displayed decreased mean LH pulse frequency (2.6 +/- 2.4 vs. 5.7 +/- 2.0 pulses/12 h; P less than 0.01), increased mean cortisol (120 +/- 40 vs. 80 +/- 20 nmol/L; P less than 0.01), decreased mean insulin (90 +/- 40 vs. 120 +/- 30 pmol/L; P less than 0.05), and decreased mean T3 concentrations (1.5 +/- 0.3 vs. 1.8 +/- 0.2 nmol/L; P less than 0.01). The data suggest that BN in normal weight women is associated with an increased rate of ovarian dysfunction; decreased pulsatile LH secretion seems to be an important mechanism. Increased

  18. Abdominal and pancreatic motion correlation using 4D CT, 4D transponders, and a gating belt.

    PubMed

    Betancourt, Ricardo; Zou, Wei; Plastaras, John P; Metz, James M; Teo, Boon-Keng; Kassaee, Alireza

    2013-01-01

    The correlation between the pancreatic and external abdominal motion due to respiration was investigated on two patients. These studies utilized four dimensional computer tomography (4D CT), a four dimensional (4D) electromagnetic transponder system, and a gating belt system. One 4D CT study was performed during simulation to quantify the pancreatic motion using computer tomography images at eight breathing phases. The motion under free breathing and breath-hold were analyzed for the 4D electromagnetic transponder system and the gating belt system during treatment. A linear curve was fitted for all data sets and correlation factors were evaluated between the 4D electromagnetic transponder system and the gating belt system data. The 4D CT study demonstrated a modest correlation between the external marker and the pancreatic motion with R-square values larger than 0.8 for the inferior-superior (inf-sup). Then, the relative pressure from the belt gating system correlated well with the 4D electromagnetic transponder system's motion in the anterior-posterior (ant-post) and the inf-post directions. These directions have a correlation value of -0.93 and 0.76, while the lateral only had a 0.03 correlation coefficient. Based on our limited study, external surrogates can be used as predictors of the pancreatic motion in the inf-sup and the ant-post directions. Although there is a low correlation on the lateral direction, its motion is significantly shorter. In conclusion, an appropriate treatment delivery can be used for pancreatic cancer when an internal tracking system, such as the 4D electromagnetic transponder system, is unavailable. PMID:23652242

  19. Abdominal and pancreatic motion correlation using 4D CT, 4D transponders, and a gating belt.

    PubMed

    Betancourt, Ricardo; Zou, Wei; Plastaras, John P; Metz, James M; Teo, Boon-Keng; Kassaee, Alireza

    2013-05-06

    The correlation between the pancreatic and external abdominal motion due to respiration was investigated on two patients. These studies utilized four dimensional computer tomography (4D CT), a four dimensional (4D) electromagnetic transponder system, and a gating belt system. One 4D CT study was performed during simulation to quantify the pancreatic motion using computer tomography images at eight breathing phases. The motion under free breathing and breath-hold were analyzed for the 4D electromagnetic transponder system and the gating belt system during treatment. A linear curve was fitted for all data sets and correlation factors were evaluated between the 4D electromagnetic transponder system and the gating belt system data. The 4D CT study demonstrated a modest correlation between the external marker and the pancreatic motion with R-square values larger than 0.8 for the inferior-superior (inf-sup). Then, the relative pressure from the belt gating system correlated well with the 4D electromagnetic transponder system's motion in the anterior-posterior (ant-post) and the inf-post directions. These directions have a correlation value of -0.93 and 0.76, while the lateral only had a 0.03 correlation coefficient. Based on our limited study, external surrogates can be used as predictors of the pancreatic motion in the inf-sup and the ant-post directions. Although there is a low correlation on the lateral direction, its motion is significantly shorter. In conclusion, an appropriate treatment delivery can be used for pancreatic cancer when an internal tracking system, such as the 4D electromagnetic transponder system, is unavailable.

  20. 21 CFR 556.304 - Gonadotropin.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS TOLERANCES FOR RESIDUES OF NEW ANIMAL DRUGS IN FOOD Specific Tolerances for Residues of New Animal Drugs § 556.304 Gonadotropin. (a) Acceptable daily intake (ADI). The ADI...

  1. 21 CFR 556.304 - Gonadotropin.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS TOLERANCES FOR RESIDUES OF NEW ANIMAL DRUGS IN FOOD Specific Tolerances for Residues of New Animal Drugs § 556.304 Gonadotropin. (a) Acceptable daily intake (ADI). The ADI...

  2. The role of semaphorin 4D in tumor development and angiogenesis in human breast cancer

    PubMed Central

    Jiang, Hongchao; Chen, Ceshi; Sun, Qiangming; Wu, Jing; Qiu, Lijuan; Gao, Change; Liu, Weiqing; Yang, Jun; Jun, Nie; Dong, Jian

    2016-01-01

    Background Semaphorin 4D (Sema4D) is highly expressed in certain types of tumors and functions in the regulation of tumor angiogenesis and growth. However, it is still not clear regarding the roles of Sema4D in breast cancer. This study was designed to explore the effects of Sema4D on proliferation, cell cycle progression, apoptosis, invasion, migration, tumor growth, and angiogenesis in breast cancer. Materials and methods The expression level of Sema4D was investigated in MCF10A, 184A1, HCC1937, MDA-MB-468, MDA-MB-231, Hs578T, BT474, MCF-7, and T47D breast cancer cell lines by Western blotting analysis. Sema4D downregulation or overexpression was established by infection with lentiviruses-encoding Sema4D short hairpin RNA (shRNA) or Sema4D. To evaluate the effects of Sema4D on cell proliferation, cell cycle progression, apoptosis, invasion, and migration of MDA-MB-231 and MDA-MB-468 cells, methods including MTT assay, flow cytometry, wound healing assay, and transwell experiments were applied. BALB/c nude mice were injected with MDA-MB-231 cells, which were respectively infected with lentiviruses-encoding Sema4D, Sema4D shRNA, and GFP, followed by tumor angiogenesis assay. Results Sema4D was expressed at higher levels in breast cancer cell lines compared with the normal human breast epithelial cell lines, especially in MDA-MB-231 and MDA-MB-468 cells. Cell proliferation ability was remarkably inhibited in Sema4D downregulated condition, whereas the proportions of cells in the G0/G1 phase and apoptosis increased in MDA-MB-231 and MDA-MB-468 cells. In addition, the invasion and migration abilities of these cells were obviously reduced. Xenograft growth as well as angiogenesis was inhibited when infected with lentiviruses-encoding Sema4D shRNA in vivo. Conclusion Downregulation of Sema4D had notable influence on cell proliferation ability, invasion, migration, and apoptosis of both MDA-MB-231 and MDA-MB-468 cells. Furthermore, infection with lentiviruses

  3. CMT4D (NDRG1 mutation): genotype-phenotype correlations.

    PubMed

    Ricard, Emilie; Mathis, Stéphane; Magdelaine, Corinne; Delisle, Marie-Bernadette; Magy, Laurent; Funalot, Benoît; Vallat, Jean-Michel

    2013-09-01

    Charcot-Marie-Tooth (CMT) disease is a heterogeneous condition with a large number of clinical, electrophysiological and pathological phenotypes. More than 40 genes are involved. We report a child of gypsy origin with an autosomal recessive demyelinating phenotype. Clinical data, familial history, and electrophysiological studies were in favor of a CMT4 sub-type. The characteristic N-Myc downstream-regulated gene 1 (NDRG1) mutation responsible for this CMT4D phenotype was confirmed: p.R148X. The exact molecular function of the NDRG1 protein has yet to be elucidated.

  4. Insulin Augments Gonadotropin-Releasing Hormone Induction of Translation in LβT2 Cells

    PubMed Central

    Navratil, Amy M.; Song, Hyunjin; Hernandez, Jeniffer B.; Cherrington, Brian D.; Santos, Sharon J.; Low, Janine M.; Do, Minh-Ha T.; Lawson, Mark A.

    2009-01-01

    Summary The integrated signaling of insulin and gonadotropin-releasing hormone in the pituitary gonadotropes may have a profound bearing on reproductive function, although the cross-receptor signaling mechanisms are unclear. We demonstrate that the insulin receptor is constitutively localized to non-caveolar lipid raft microdomains in the pituitary gonadotrope cell line LβT2. The localization to rafts is consistent with similar localization of the GnRH receptor. Insulin receptor phosphorylation occurs in raft domains and activates the downstream signaling targets Insulin Receptor Substrate1 and Akt/Protein Kinase B. Although insulin alone does not strongly activate the extracellular signal-regulated kinase second messenger cascade, co-stimulation potentiates the phosphorylation of the extracellular signal-regulated kinase by gonadotropin-releasing hormone. The co-stimulatory effect of insulin and gonadotropin-releasing hormone is also evident in increased activation of cap-dependent translation. In contrast, co-stimulation attenuates Akt/Protein Kinase B activation. Our results show that both gonadotropin-releasing hormone and insulin are capable of mutually altering their respective regulatory signaling cascades. We suggest that this provides a mechanism to integrate neuropeptide and energy homeostatic signals to modulate reproductive function. PMID:19632296

  5. Tissue-specific expression of squirrel monkey chorionic gonadotropin

    PubMed Central

    Vasauskas, Audrey A.; Hubler, Tina R.; Boston, Lori; Scammell, Jonathan G.

    2010-01-01

    Pituitary gonadotropins LH and FSH play central roles in reproductive function. In Old World primates, LH stimulates ovulation in females and testosterone production in males. Recent studies have found that squirrel monkeys and other New World primates lack expression of LH in the pituitary. Instead, chorionic gonadotropin (CG), which is normally only expressed in the placenta of Old World primates, is the active luteotropic pituitary hormone in these animals. The goal of this study was to investigate the tissue-specific regulation of squirrel monkey CG. We isolated the squirrel monkey CGβ gene and promoter from genomic DNA from squirrel monkey B-lymphoblasts and compared the promoter sequence to that of the common marmoset, another New World primate, and human CGβ and LHβ. Using reporter gene assays, we found that a squirrel monkey CGβ promoter fragment (−1898/+9) is active in both mouse pituitary LβT2 and human placenta JEG3 cells, but not in rat adrenal PC12 cells. Furthermore, within this construct separate cis-elements are responsible for pituitary- and placenta-specific expression. Pituitary-specific expression is governed by Egr-1 binding sites in the proximal 250 bp of the promoter, whereas placenta-specific expression is controlled by AP-2 sites further upstream. Thus, selective expression of the squirrel monkey CGβ promoter in pituitary and placental cells is governed by distinct cis-elements that exhibit homology with human LHβ and marmoset CGβ promoters, respectively. PMID:21130091

  6. Active origami by 4D printing

    NASA Astrophysics Data System (ADS)

    Ge, Qi; Dunn, Conner K.; Qi, H. Jerry; Dunn, Martin L.

    2014-09-01

    Recent advances in three dimensional (3D) printing technology that allow multiple materials to be printed within each layer enable the creation of materials and components with precisely controlled heterogeneous microstructures. In addition, active materials, such as shape memory polymers, can be printed to create an active microstructure within a solid. These active materials can subsequently be activated in a controlled manner to change the shape or configuration of the solid in response to an environmental stimulus. This has been termed 4D printing, with the 4th dimension being the time-dependent shape change after the printing. In this paper, we advance the 4D printing concept to the design and fabrication of active origami, where a flat sheet automatically folds into a complicated 3D component. Here we print active composites with shape memory polymer fibers precisely printed in an elastomeric matrix and use them as intelligent active hinges to enable origami folding patterns. We develop a theoretical model to provide guidance in selecting design parameters such as fiber dimensions, hinge length, and programming strains and temperature. Using the model, we design and fabricate several active origami components that assemble from flat polymer sheets, including a box, a pyramid, and two origami airplanes. In addition, we directly print a 3D box with active composite hinges and program it to assume a temporary flat shape that subsequently recovers to the 3D box shape on demand.

  7. Advances in 4D radiation therapy for managing respiration: part II - 4D treatment planning.

    PubMed

    Rosu, Mihaela; Hugo, Geoffrey D

    2012-12-01

    The development of 4D CT imaging technology made possible the creation of patient models that are reflective of respiration-induced anatomical changes by adding a temporal dimension to the conventional 3D, spatial-only, patient description. This had opened a new venue for treatment planning and radiation delivery, aimed at creating a comprehensive 4D radiation therapy process for moving targets. Unlike other breathing motion compensation strategies (e.g. breath-hold and gating techniques), 4D radiotherapy assumes treatment delivery over the entire respiratory cycle - an added bonus for both patient comfort and treatment time efficiency. The time-dependent positional and volumetric information holds the promise for optimal, highly conformal, radiotherapy for targets experiencing movements caused by respiration, with potentially elevated dose prescriptions and therefore higher cure rates, while avoiding the uninvolved nearby structures. In this paper, the current state of the 4D treatment planning is reviewed, from theory to the established practical routine. While the fundamental principles of 4D radiotherapy are well defined, the development of a complete, robust and clinically feasible process still remains a challenge, imposed by limitations in the available treatment planning and radiation delivery systems.

  8. Advances in 4D Radiation Therapy for Managing Respiration: Part II – 4D Treatment Planning

    PubMed Central

    Rosu, Mihaela; Hugo, Geoffrey D.

    2014-01-01

    The development of 4D CT imaging technology made possible the creation of patient models that are reflective of respiration-induced anatomical changes by adding a temporal dimension to the conventional 3D, spatial-only, patient description. This had opened a new venue for treatment planning and radiation delivery, aimed at creating a comprehensive 4D radiation therapy process for moving targets. Unlike other breathing motion compensation strategies (e.g. breath-hold and gating techniques), 4D radiotherapy assumes treatment delivery over the entire respiratory cycle – an added bonus for both patient comfort and treatment time efficiency. The time-dependent positional and volumetric information holds the promise for optimal, highly conformal, radiotherapy for targets experiencing movements caused by respiration, with potentially elevated dose prescriptions and therefore higher cure rates, while avoiding the uninvolved nearby structures. In this paper, the current state of the 4D treatment planning is reviewed, from theory to the established practical routine. While the fundamental principles of 4D radiotherapy are well defined, the development of a complete, robust and clinically feasible process still remains a challenge, imposed by limitations in the available treatment planning and radiation delivery systems. PMID:22796324

  9. ICT4D: A Computer Science Perspective

    NASA Astrophysics Data System (ADS)

    Sutinen, Erkki; Tedre, Matti

    The term ICT4D refers to the opportunities of Information and Communication Technology (ICT) as an agent of development. Research in that field is often focused on evaluating the feasibility of existing technologies, mostly of Western or Far East Asian origin, in the context of developing regions. A computer science perspective is complementary to that agenda. The computer science perspective focuses on exploring the resources, or inputs, of a particular context and on basing the design of a technical intervention on the available resources, so that the output makes a difference in the development context. The modus operandi of computer science, construction, interacts with evaluation and exploration practices. An analysis of a contextualized information technology curriculum of Tumaini University in southern Tanzania shows the potential of the computer science perspective for designing meaningful information and communication technology for a developing region.

  10. 4D Clinical Imaging for Dynamic CAD

    PubMed Central

    McIntyre, Frederick

    2013-01-01

    A basic 4D imaging system to capture the jaw motion has been developed that produces high resolution 3D surface data. Fluorescent microspheres are brushed onto the areas of the upper and the lower arches to be imaged, producing a high-contrast random optical pattern. A hand-held imaging device operated at about 10 cm from the mouth captures time-based perspective images of the fluorescent areas. Each set of images, containing both upper and the lower arch data, is converted to a 3d point mesh using photogrammetry, thereby providing an instantaneous relative jaw position. Eight 3d positions per second are captured. Using one of the 3d frames as a reference, incremental transforms are derived to express the free body motion of the mandible. Conventional 3d models of the dentition are directly registered to the reference frame, allowing them to be animated using the derived transforms. PMID:24082882

  11. Soft Route to 4D Tomography.

    PubMed

    Taillandier-Thomas, Thibault; Roux, Stéphane; Hild, François

    2016-07-01

    Based on the assumption that the time evolution of a sample observed by computed tomography requires many less parameters than the definition of the microstructure itself, it is proposed to reconstruct these changes based on the initial state (using computed tomography) and very few radiographs acquired at fixed intervals of time. This Letter presents a proof of concept that for a fatigue cracked sample its kinematics can be tracked from no more than two radiographs in situations where a complete 3D view would require several hundreds of radiographs. This 2 order of magnitude gain opens the way to a "computed" 4D tomography, which complements the recent progress achieved in fast or ultrafast computed tomography, which is based on beam brightness, detector sensitivity, and signal acquisition technologies.

  12. Soft Route to 4D Tomography

    NASA Astrophysics Data System (ADS)

    Taillandier-Thomas, Thibault; Roux, Stéphane; Hild, François

    2016-07-01

    Based on the assumption that the time evolution of a sample observed by computed tomography requires many less parameters than the definition of the microstructure itself, it is proposed to reconstruct these changes based on the initial state (using computed tomography) and very few radiographs acquired at fixed intervals of time. This Letter presents a proof of concept that for a fatigue cracked sample its kinematics can be tracked from no more than two radiographs in situations where a complete 3D view would require several hundreds of radiographs. This 2 order of magnitude gain opens the way to a "computed" 4D tomography, which complements the recent progress achieved in fast or ultrafast computed tomography, which is based on beam brightness, detector sensitivity, and signal acquisition technologies.

  13. Estrogen bows to a new master: the role of gonadotropins in Alzheimer pathogenesis.

    PubMed

    Webber, Kate M; Casadesus, Gemma; Marlatt, Michael W; Perry, George; Hamlin, Clive R; Atwood, Craig S; Bowen, Richard L; Smith, Mark A

    2005-06-01

    Epidemiological data showing a predisposition of women to develop Alzheimer disease (AD) led many researchers to investigate the role of sex steroids, namely estrogen, in disease pathogenesis. Although there is circumstantial support for the role of estrogen, the unexpected results of the Women's Health Initiative (WHI) Memory Study, which reported an increase in the risk for probable dementia and impaired cognitive performance in postmenopausal women treated with a combination of estrogen and progestin, have raised serious questions regarding the protective effects of estrogen. Although explanations for these surprising results vary greatly, the WHI Memory Study cannot be correctly interpreted without a complete investigation of the effects of the other hormones of the hypothalamic-pituitary-gonadal (HPG) axis on the aging brain. Certain hormones of the HPG axis, namely, the gonadotropins (luteinizing hormone and follicle-stimulating hormone), are not only involved in regulating reproductive function via a complex feedback loop but are also known to cross the blood-brain barrier. We propose that the increase in gonadotropin concentrations, and not the decrease in steroid hormone (e.g., estrogen) production following menopause/andropause, is a potentially primary causative factor for the development of AD. In this review, we examine how the gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, AD. On this basis, we suggest that the results of the WHI Memory Study are not only predictable but also avoidable by therapeutically targeting the gonadotropins instead of the sex steroids.

  14. Structural and Functional Divergence of Gonadotropin-Inhibitory Hormone from Jawless Fish to Mammals

    PubMed Central

    Ogawa, Satoshi; Parhar, Ishwar S.

    2014-01-01

    Gonadotropin-inhibitory hormone (GnIH) was discovered as a novel hypothalamic peptide that inhibits gonadotropin release in the quail. The presence of GnIH-homologous peptides and its receptors (GnIHRs) have been demonstrated in various vertebrate species including teleosts, suggesting that the GnIH-GnIHR family is evolutionarily conserved. In avian and mammalian brain, GnIH neurons are localized in the hypothalamic nuclei and their neural projections are widely distributed. GnIH acts on the pituitary and gonadotropin-releasing hormone neurons to inhibit reproductive functions by decreasing gonadotropin release and synthesis. In addition, GnIH-GnIHR signaling is regulated by various factors, such as environmental cues and stress. However, the function of fish GnIH orthologs remains inconclusive because the physiological properties of fish GnIH peptides are debatable. This review summarizes the current research progress in GnIH-GnIHR signaling and their physiological functions in vertebrates with special emphasis on non-mammalian vertebrate species. PMID:25386165

  15. Genetic insights into human isolated gonadotropin deficiency.

    PubMed

    Trarbach, Ericka Barbosa; Silveira, Leticia Gontijo; Latronico, Ana Claudia

    2007-01-01

    The identification of naturally occurring genetic mutations has provided unique insight into the current knowledge of the human hypothalamic-pituitary-gonadal axis. In the past decade, several monogenic causes have been reported in patients with isolated gonadotropin deficiency. Kallmann Syndrome is a clinically and genetically heterogeneous disorder, characterized by isolated hypogonadotropic hypogonadism and anosmia or hyposmia. To date, loss-of-function mutations in the genes encoding anosmin-1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1) have been described in the X-linked and autosomal dominant forms of this syndrome, respectively. More recently, several heterozygous, homozygous or compound heterozygous mutations in the G protein-coupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2) were described in Kallmann syndrome. In addition, complex genetic transmission (digenic inheritance) was recently demonstrated in this condition. Regarding isolated hypogonadotropic hypogonadism without olfactory abnormalities, loss-of-function mutations in the Gonadotropin-releasing hormone (GnRH) receptor (GnRH-R) or the G-protein coupled receptor 54 (GPR54) genes, both encoding transmembrane receptors, have been described, as well as FGFR1 mutations. Finally, mutations of the beta sub-units of LH and FSH have been described in patients with selective gonadotropin deficiency. We review the role of these distinct genetic factors in human isolated hypogonadotropic hypogonadism.

  16. Opening the Black Box of ICT4D: Advancing Our Understanding of ICT4D Partnerships

    ERIC Educational Resources Information Center

    Park, Sung Jin

    2013-01-01

    The term, Information and Communication Technologies for Development (ICT4D), pertains to programs or projects that strategically use ICTs (e.g. mobile phones, computers, and the internet) as a means toward the socio-economic betterment for the poor in developing contexts. Gaining the political and financial support of the international community…

  17. Dynamics of circulating concentrations of gonadotropins and ovarian hormones throughout the menstrual cycle in the bonnet monkey: role of inhibin A in the regulation of follicle-stimulating hormone secretion.

    PubMed

    Suresh, P S; Medhamurthy, R

    2009-10-01

    In higher primates, increased circulating follicle-stimulating hormone (FSH) levels seen during late menstrual cycle and during menstruation has been suggested to be necessary for initiation of follicular growth, recruitment of follicles and eventually culminating in ovulation of a single follicle. With a view to establish the dynamics of circulating FSH secretion with that of inhibin A (INH A) and progesterone (P(4)) secretions during the menstrual cycle, blood was collected daily from bonnet monkeys beginning day 1 of the menstrual cycle up to 35 days. Serum INH A levels were low during early follicular phase, increased significantly coinciding with the mid cycle luteinizing hormone (LH) surge to reach maximal levels during the mid luteal phase before declining at the late luteal phase, essentially paralleling the pattern of P(4) secretion seen throughout the luteal phase. Circulating FSH levels were low during early and mid luteal phases, but progressively increased during the late luteal phase and remained high for few days after the onset of menses. In another experiment, lutectomy performed during the mid luteal phase resulted in significant decrease in INH A concentration within 2 hr (58.3+/-2 vs. 27.3+/-3 pg/mL), and a 2- to 3-fold rise in circulating FSH levels by 24 hr (0.20+/-0.02 vs. 0.53+/-0.14 ng/mL) that remained high until 48 hr postlutectomy. Systemic administration of Cetrorelix (150 microg/kg body weight), a gonadotropin releasing hormone receptor antagonist, at mid luteal phase in monkeys led to suppression of serum INH A and P(4) concentrations 24 hr post treatment, but circulating FSH levels did not change. Administration of exogenous LH, but not FSH, significantly increased INH A concentration. The results taken together suggest a tight coupling between LH and INH A secretion and that INH A is largely responsible for maintenance of low FSH concentration seen during the luteal phase.

  18. Bacterial degradation of phenoxy herbicide mixtures 2,4-D and MCPP

    SciTech Connect

    Kyeheon Oh; Tuovinen, O.H. )

    1991-08-01

    The phenoxy herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and 2-(2-methyl-4-chlorophenoxy)propionic acid (MCPP) have auxin-like growth regulating properties and are extensively used for the control of broad-leaf angiosperm weeds. The microbiological degradation of 2,4-D by pure and mixed cultures has been examined in a number of studies. The authors have previously evaluated the concurrent microbiological degradation of 2,4-D and MCPP in stirred tank reactors. For the present paper, they examined the utilization of the two substrates by three mixed cultures that had a previous history of growth with the respective single phenoxy herbicide.

  19. The biology of gonadotropin-releasing hormone and its analogs.

    PubMed

    Glode, L M

    1986-01-01

    Gonadotropin-releasing hormone (GnRH) is one of the hormones involved in the complex hypothalamic-pituitary-gonadal axis which regulates the release of testosterone from the testes or estrogen from the ovaries. The development of GnRH analogs has helped elucidate the mechanism of action of the natural hormone, and provided possible new ways to treat hormonally related conditions including hormone-dependent cancers, precocious puberty, and endometriosis. The effectiveness of GnRH agonists in clinical use lies in their ability, with long-term administration, to suppress sex-hormone production. GnRH antagonists may eventually replace agonists because they are able to reduce hormone levels without the initial, temporary rise caused by agonists.

  20. Evaluation of gonadotropin responses to synthetic gonadotropin-releasing hormone in girls with idiopathic hypopituitarism.

    PubMed

    Foster, C M; Hopwood, N J; Beitins, I Z; Mendes, T M; Kletter, G B; Kelch, R P

    1992-10-01

    We hypothesized that prepubertal girls with gonadotropin deficiency would produce less follicle-stimulating hormone (FSH) in response to synthetic gonadotropin-releasing hormone (GnRH) than would gonadotropin-sufficient children. To test this hypothesis, we performed 103 GnRH tests serially in 21 children who had idiopathic hypopituitarism with growth hormone deficiency. We tried to predict whether puberty would occur in the 17 girls with bone ages of 8 years or less. Of these 17 girls, 4 failed to have spontaneous secondary sexual characteristics by age 16 1/2 years, and 12 had spontaneous complete pubertal development. One girl had incomplete pubertal maturation with partial gonadotropin deficiency; her results were combined with those of the girls who had no spontaneous pubertal development. With increasing bone age, the girls with complete pubertal development had a decrease in the increment of FSH released in response to GnRH, although basal gonadotropin concentrations did not change. For GnRH tests performed at bone ages of 8 years or less, basal luteinizing hormone (LH) values did not differ between girls with complete puberty and those with absent or incomplete puberty. However, basal FSH and the incremental response of LH and FSH to GnRH were greater in those with complete puberty. Only two girls with prepubertal bone ages at the time of testing, who subsequently had complete puberty, had incremental FSH responses to GnRH that were less than 5 IU/L. Individual incremental LH responses to GnRH did not discriminate well between groups. None of the girls with adrenocorticotropic hormone deficiency, either originally or subsequently, had spontaneous puberty, but 4 of 12 girls with thyrotropin deficiency, either originally or subsequently, had complete puberty. We conclude that a significant increase in GnRH-stimulated FSH suggests that spontaneous pubertal development will occur in girls with idiopathic hypopituitarism. However, a low FSH response to GnRH may

  1. Functional organization of the human 4D Nucleome

    PubMed Central

    Chen, Haiming; Chen, Jie; Muir, Lindsey A.; Ronquist, Scott; Meixner, Walter; Ljungman, Mats; Ried, Thomas; Smale, Stephen; Rajapakse, Indika

    2015-01-01

    The 4D organization of the interphase nucleus, or the 4D Nucleome (4DN), reflects a dynamical interaction between 3D genome structure and function and its relationship to phenotype. We present initial analyses of the human 4DN, capturing genome-wide structure using chromosome conformation capture and 3D imaging, and function using RNA-sequencing. We introduce a quantitative index that measures underlying topological stability of a genomic region. Our results show that structural features of genomic regions correlate with function with surprising persistence over time. Furthermore, constructing genome-wide gene-level contact maps aided in identifying gene pairs with high potential for coregulation and colocalization in a manner consistent with expression via transcription factories. We additionally use 2D phase planes to visualize patterns in 4DN data. Finally, we evaluated gene pairs within a circadian gene module using 3D imaging, and found periodicity in the movement of clock circadian regulator and period circadian clock 2 relative to each other that followed a circadian rhythm and entrained with their expression. PMID:26080430

  2. 4-D ultrafast shear-wave imaging.

    PubMed

    Gennisson, Jean-Luc; Provost, Jean; Deffieux, Thomas; Papadacci, Clément; Imbault, Marion; Pernot, Mathieu; Tanter, Mickael

    2015-06-01

    Over the last ten years, shear wave elastography (SWE) has seen considerable development and is now routinely used in clinics to provide mechanical characterization of tissues to improve diagnosis. The most advanced technique relies on the use of an ultrafast scanner to generate and image shear waves in real time in a 2-D plane at several thousands of frames per second. We have recently introduced 3-D ultrafast ultrasound imaging to acquire with matrix probes the 3-D propagation of shear waves generated by a dedicated radiation pressure transducer in a single acquisition. In this study, we demonstrate 3-D SWE based on ultrafast volumetric imaging in a clinically applicable configuration. A 32 × 32 matrix phased array driven by a customized, programmable, 1024-channel ultrasound system was designed to perform 4-D shear-wave imaging. A matrix phased array was used to generate and control in 3-D the shear waves inside the medium using the acoustic radiation force. The same matrix array was used with 3-D coherent plane wave compounding to perform high-quality ultrafast imaging of the shear wave propagation. Volumetric ultrafast acquisitions were then beamformed in 3-D using a delay-and-sum algorithm. 3-D volumetric maps of the shear modulus were reconstructed using a time-of-flight algorithm based on local multiscale cross-correlation of shear wave profiles in the three main directions using directional filters. Results are first presented in an isotropic homogeneous and elastic breast phantom. Then, a full 3-D stiffness reconstruction of the breast was performed in vivo on healthy volunteers. This new full 3-D ultrafast ultrasound system paves the way toward real-time 3-D SWE. PMID:26067040

  3. The effect of ovariectomy on gonadotropin release

    PubMed Central

    Yen, S. S. C.; Tsai, C. C.

    1971-01-01

    The sequential changes in the concentration and pattern of circulating luteinizing hormone (LH) and follicle-stimulating hormone (FSH)1 following bilateral ovariectomy were determined in 10 premenopausal women. The initial (1st wk) and delayed (3 wk) secretory responses of serum LH and FSH as related to the phases of the menstrual cycle were examined. Ovariectomy during follicular phase was accompanied by a prompt and much greater rise in both LH and FSH during the 1st wk. This rapid rise was followed by a transient decline between the 7th and 10th day which resulted in a biphasic pattern. In contrast, a slower and progressive rise in serum LH and FSH was observed in subjects ovariectomized during luteal phase of the cycle. The quantitative secretion (area under the curve) during the 1st wk after ovariectomy was significantly greater in patients operated on during the follicular phase than during the luteal phase for both LH (P < 0.05) and FSH (P < 0.01). Thereafter, a similar pattern of gonadotropin rise was observed for patients ovariectonized during either phase of the cycle and reached a plateau by the end of the 3rd wk. At this time, the mean LH concentration increased 6-fold for follicular phase surgery and 8-fold for luteal phase surgery. The mean serum FSH concentration increased 8-fold for follicular phase surgery and 12-fold for luteal phase surgery. The net increase in serum FSH level was higher than that in the serum LH level after surgery in both phases of the cycle and thus a reversal of FSH/LH ratio occurred. These data provide indirect evidence that the phase of ovarian steroid secretion may exert a quantitative influence on the gonadotropin turnover rate within the hypothalamic-pituitary system. The augmented gonadotropin release and the reversal of FSH/LH ratio following ovariectomy presumably could be due to an increased gonadotropin net synthesis which is more pronounced for FSH than for LH. Images PMID:5552412

  4. Heterozygous mutations in cyclic AMP phosphodiesterase-4D (PDE4D) and protein kinase A (PKA) provide new insights into the molecular pathology of acrodysostosis.

    PubMed

    Kaname, Tadashi; Ki, Chang-Seok; Niikawa, Norio; Baillie, George S; Day, Jonathan P; Yamamura, Ken-Ichi; Ohta, Tohru; Nishimura, Gen; Mastuura, Nobuo; Kim, Ok-Hwa; Sohn, Young Bae; Kim, Hyun Woo; Cho, Sung Yoon; Ko, Ah-Ra; Lee, Jin Young; Kim, Hyun Wook; Ryu, Sung Ho; Rhee, Hwanseok; Yang, Kap-Seok; Joo, Keehyoung; Lee, Jooyoung; Kim, Chi Hwa; Cho, Kwang-Hyun; Kim, Dongsan; Yanagi, Kumiko; Naritomi, Kenji; Yoshiura, Ko-Ichiro; Kondoh, Tatsuro; Nii, Eiji; Tonoki, Hidefumi; Houslay, Miles D; Jin, Dong-Kyu

    2014-11-01

    Acrodysostosis without hormone resistance is a rare skeletal disorder characterized by brachydactyly, nasal hypoplasia, mental retardation and occasionally developmental delay. Recently, loss-of-function mutations in the gene encoding cAMP-hydrolyzing phosphodiesterase-4D (PDE4D) have been reported to cause this rare condition but the pathomechanism has not been fully elucidated. To understand the pathogenetic mechanism of PDE4D mutations, we conducted 3D modeling studies to predict changes in the binding efficacy of cAMP to the catalytic pocket in PDE4D mutants. Our results indicated diminished enzyme activity in the two mutants we analyzed (Gly673Asp and Ile678Thr; based on PDE4D4 residue numbering). Ectopic expression of PDE4D mutants in HEK293 cells demonstrated this reduction in activity, which was identified by increased cAMP levels. However, the cells from an acrodysostosis patient showed low cAMP accumulation, which resulted in a decrease in the phosphorylated cAMP Response Element-Binding Protein (pCREB)/CREB ratio. The reason for this discrepancy was due to a compensatory increase in expression levels of PDE4A and PDE4B isoforms, which accounted for the paradoxical decrease in cAMP levels in the patient cells expressing mutant isoforms with a lowered PDE4D activity. Skeletal radiographs of 10-week-old knockout (KO) rats showed that the distal part of the forelimb was shorter than in wild-type (WT) rats and that all the metacarpals and phalanges were also shorter in KO, as the name acrodysostosis implies. Like the G-protein α-stimulatory subunit and PRKAR1A, PDE4D critically regulates the cAMP signal transduction pathway and influences bone formation in a way that activity-compromising PDE4D mutations can result in skeletal dysplasia. We propose that specific inhibitory PDE4D mutations can lead to the molecular pathology of acrodysostosis without hormone resistance but that the pathological phenotype may well be dependent on an over-compensatory induction

  5. Low 2D:4D Values Are Associated with Video Game Addiction

    PubMed Central

    Kornhuber, Johannes; Zenses, Eva-Maria; Lenz, Bernd; Stoessel, Christina; Bouna-Pyrrou, Polyxeni; Rehbein, Florian; Kliem, Sören; Mößle, Thomas

    2013-01-01

    Androgen-dependent signaling regulates the growth of the fingers on the human hand during embryogenesis. A higher androgen load results in lower 2D:4D (second digit to fourth digit) ratio values. Prenatal androgen exposure also impacts brain development. 2D:4D values are usually lower in males and are viewed as a proxy of male brain organization. Here, we quantified video gaming behavior in young males. We found lower mean 2D:4D values in subjects who were classified according to the CSAS-II as having at-risk/addicted behavior (n = 27) compared with individuals with unproblematic video gaming behavior (n = 27). Thus, prenatal androgen exposure and a hyper-male brain organization, as represented by low 2D:4D values, are associated with problematic video gaming behavior. These results may be used to improve the diagnosis, prediction, and prevention of video game addiction. PMID:24236143

  6. Low 2D:4D values are associated with video game addiction.

    PubMed

    Kornhuber, Johannes; Zenses, Eva-Maria; Lenz, Bernd; Stoessel, Christina; Bouna-Pyrrou, Polyxeni; Rehbein, Florian; Kliem, Sören; Mößle, Thomas

    2013-01-01

    Androgen-dependent signaling regulates the growth of the fingers on the human hand during embryogenesis. A higher androgen load results in lower 2D:4D (second digit to fourth digit) ratio values. Prenatal androgen exposure also impacts brain development. 2D:4D values are usually lower in males and are viewed as a proxy of male brain organization. Here, we quantified video gaming behavior in young males. We found lower mean 2D:4D values in subjects who were classified according to the CSAS-II as having at-risk/addicted behavior (n = 27) compared with individuals with unproblematic video gaming behavior (n = 27). Thus, prenatal androgen exposure and a hyper-male brain organization, as represented by low 2D:4D values, are associated with problematic video gaming behavior. These results may be used to improve the diagnosis, prediction, and prevention of video game addiction.

  7. Gonadotropin-dependent precocious puberty: neoplastic causes and endocrine considerations.

    PubMed

    Stephen, Matthew D; Zage, Peter E; Waguespack, Steven G

    2011-01-01

    Premature activation of the hypothalamic-pituitary-gonadal (HPG) axis manifests as gonadotropin-dependent precocious puberty. The mechanisms behind HPG activation are complex and a clear etiology for early activation is often not elucidated. Though collectively uncommon, the neoplastic and developmental causes of gonadotropin-dependent precocious puberty are very important to consider, as a delay in diagnosis may lead to adverse patient outcomes. The intent of the current paper is to review the neoplastic and developmental causes of gonadotropin-dependent precocious puberty. We discuss the common CNS lesions and human chorionic gonadotropin-secreting tumors that cause sexual precocity, review the relationship between therapeutic radiation and gonadotropin-dependent precocious puberty, and finally, provide an overview of the therapies available for height preservation in this unique patient population.

  8. Gonadotropin-associated psychosis in perimenstrual behavior disorder.

    PubMed

    Constant, M; Abrams, C A; Chasalow, F I

    1993-01-01

    Sexually provocative and violent behavior have been reported as a result of excess androgens. We now report a temporal relationship between increased gonadotropin levels and behavioral changes in two adolescent girls who presented with a history of aggressive and bizarre sexual behavior coincident with the onset of menarche. We evaluated the possibility of a cyclical hormonal cause with daily measurements of gonadotropins, androgens and estradiol levels and correlated the results with periodic reports on the girls' behavior. We concluded that a correlation exists between periods of extremely violent and sexually provocative behavior and peaks of gonadotropin hormone secretion, even though androgen levels were normal. Treatment with medroxyprogesterone acetate (Depo-Provera) in one case and with leuprolide acetate (Lupron-Depot) in the other suppressed gonadotropin levels, and behavior improved markedly. Thus, the behavioral changes (or psychosis) seen in these girls might have been induced by increased levels of gonadotropins.

  9. 4D electron microscopy: principles and applications.

    PubMed

    Flannigan, David J; Zewail, Ahmed H

    2012-10-16

    achievable with short intense pulses containing a large number of electrons, however, are limited to tens of nanometers and nanoseconds, respectively. This is because Coulomb repulsion is significant in such a pulse, and the electrons spread in space and time, thus limiting the beam coherence. It is therefore not possible to image the ultrafast elementary dynamics of complex transformations. The challenge was to retain the high spatial resolution of a conventional TEM while simultaneously enabling the temporal resolution required to visualize atomic-scale motions. In this Account, we discuss the development of four-dimensional ultrafast electron microscopy (4D UEM) and summarize techniques and applications that illustrate the power of the approach. In UEM, images are obtained either stroboscopically with coherent single-electron packets or with a single electron bunch. Coulomb repulsion is absent under the single-electron condition, thus permitting imaging, diffraction, and spectroscopy, all with high spatiotemporal resolution, the atomic scale (sub-nanometer and femtosecond). The time resolution is limited only by the laser pulse duration and energy carried by the electron packets; the CCD camera has no bearing on the temporal resolution. In the regime of single pulses of electrons, the temporal resolution of picoseconds can be attained when hundreds of electrons are in the bunch. The applications given here are selected to highlight phenomena of different length and time scales, from atomic motions during structural dynamics to phase transitions and nanomechanical oscillations. We conclude with a brief discussion of emerging methods, which include scanning ultrafast electron microscopy (S-UEM), scanning transmission ultrafast electron microscopy (ST-UEM) with convergent beams, and time-resolved imaging of biological structures at ambient conditions with environmental cells.

  10. Electrical synapses connect a network of gonadotropin releasing hormone neurons in a cichlid fish

    PubMed Central

    Ma, Yunyong; Hu, Caroline K.; Huguenard, John R.; Fernald, Russell D.

    2015-01-01

    Initiating and regulating vertebrate reproduction requires pulsatile release of gonadotropin-releasing hormone (GnRH1) from the hypothalamus. Coordinated GnRH1 release, not simply elevated absolute levels, effects the release of pituitary gonadotropins that drive steroid production in the gonads. However, the mechanisms underlying synchronization of GnRH1 neurons are unknown. Control of synchronicity by gap junctions between GnRH1 neurons has been proposed but not previously found. We recorded simultaneously from pairs of transgenically labeled GnRH1 neurons in adult male Astatotilapia burtoni cichlid fish. We report that GnRH1 neurons are strongly and uniformly interconnected by electrical synapses that can drive spiking in connected cells and can be reversibly blocked by meclofenamic acid. Our results suggest that electrical synapses could promote coordinated spike firing in a cellular assemblage of GnRH1 neurons to produce the pulsatile output necessary for activation of the pituitary and reproduction. PMID:25775522

  11. Motion4D-library extended

    NASA Astrophysics Data System (ADS)

    Müller, Thomas

    2011-06-01

    The new version of the Motion4D-library now also includes the integration of a Sachs basis and the Jacobi equation to determine gravitational lensing of pointlike sources for arbitrary spacetimes.New version program summaryProgram title: Motion4D-libraryCatalogue identifier: AEEX_v3_0Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEEX_v3_0.htmlProgram obtainable from: CPC Program Library, Queen's University, Belfast, N. IrelandLicensing provisions: Standard CPC licence, http://cpc.cs.qub.ac.uk/licence/licence.htmlNo. of lines in distributed program, including test data, etc.: 219 441No. of bytes in distributed program, including test data, etc.: 6 968 223Distribution format: tar.gzProgramming language: C++Computer: All platforms with a C++ compilerOperating system: Linux, WindowsRAM: 61 MbytesClassification: 1.5External routines: Gnu Scientic Library (GSL) (http://www.gnu.org/software/gsl/)Catalogue identifier of previous version: AEEX_v2_0Journal reference of previous version: Comput. Phys. Comm. 181 (2010) 703Does the new version supersede the previous version?: YesNature of problem: Solve geodesic equation, parallel and Fermi-Walker transport in four-dimensional Lorentzian spacetimes. Determine gravitational lensing by integration of Jacobi equation and parallel transport of Sachs basis.Solution method: Integration of ordinary differential equations.Reasons for new version: The main novelty of the current version is the extension to integrate the Jacobi equation and the parallel transport of the Sachs basis along null geodesics. In combination, the change of the cross section of a light bundle and thus the gravitational lensing effect of a spacetime can be determined. Furthermore, we have implemented several new metrics.Summary of revisions: The main novelty of the current version is the integration of the Jacobi equation and the parallel transport of the Sachs basis along null geodesics. The corresponding set of equations readd2xμdλ2=-Γρ

  12. The aryl hydrocarbon receptor is required for normal gonadotropin responsiveness in the mouse ovary

    SciTech Connect

    Barnett, Kimberly R.; Tomic, Dragana; Gupta, Rupesh K.; Babus, Janice K.; Roby, Katherine F.; Terranova, Paul F.; Flaws, Jodi A.

    2007-08-15

    The aryl hydrocarbon receptor (AHR) mediates the toxicity of a variety of environmental chemicals. Although little is known about the physiological role of the AHR, studies suggest that it plays an important role in regulating ovulation because Ahr deficient (AhRKO) mice have a reduced number of ovulations compared to wild-type (WT) mice. The reasons for the reduced ability of AhRKO mice to ovulate are unknown. Normal ovulation, however, requires estrous cyclicity, appropriate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and LH and FSH responsiveness. Thus, the purpose of this study was to test the hypothesis that Ahr deletion regulates ovulation by altering cyclicity, FSH and LH levels, follicle-stimulating hormone receptor (Fshr) and luteinizing hormone receptor (Lhcgr) levels and/or gonadotropin responsiveness. The data indicate that AhRKO and WT mice have similar levels of FSH and LH, but AhRKO mice have reduced Fshr and Lhcgr mRNA levels compared to WT mice. Furthermore, AhRKO ovaries contain fewer corpora lutea compared to WT ovaries after 5 IU equine chorionic gonadotropin (eCG) treatment. Lastly, both AhRKO and WT mice ovulate a similar number of eggs in response to 5 IU human chorionic gonadotropin (hCG), but AhRKO mice ovulate fewer eggs than WT mice in response to 2.5 IU and 1.25 IU hCG. Collectively, these data indicate that AhRKO follicles have a reduced capacity to ovulate compared to WT follicles and that this is due to reduced responsiveness to gonadotropins. Thus, in addition to mediating toxicity of environmental chemicals, the Ahr is required for normal ovulation.

  13. The 4D-TECS integration for NASA TSRV airplane

    NASA Technical Reports Server (NTRS)

    Kaminer, I.; Oshaughnessy, P. R.

    1989-01-01

    The integration of the Total Energy Control System (TECS) concept with 4D navigation is described. This integration was made to increase the operational capacity of modern aircraft and encourage incorporation of this increased capability with the evolving National Airspace System (NAS). Described herein is: 4D smoothing, the basic concepts of TECS, the spoiler integration concept, an algorithm for nulling out time error, speed and altitude profile modes, manual spoiler implementation, 4D logic, and the results of linear and nonlinear analysis.

  14. Killing Weeds with 2,4-D. Extension Bulletin 389.

    ERIC Educational Resources Information Center

    Lee, Oliver C.

    Discussed is the use of the herbicide 2,4-D. Though written for farmers and agricultural workers, the pamphlet considers turf weed control and use of 2,4-D near ornamental plants. Aspects of the use of this herbicide covered are: (1) the common forms of 2,4-D; (2) plant responses and tolerances to the herbicide; (3) dilution and concentration of…

  15. Pros and cons for C4d as a biomarker.

    PubMed

    Cohen, Danielle; Colvin, Robert B; Daha, Mohamed R; Drachenberg, Cinthia B; Haas, Mark; Nickeleit, Volker; Salmon, Jane E; Sis, Banu; Zhao, Ming-Hui; Bruijn, Jan A; Bajema, Ingeborg M

    2012-04-01

    The introduction of C4d in daily clinical practice in the late nineties aroused an ever-increasing interest in the role of antibody-mediated mechanisms in allograft rejection. As a marker of classical complement activation, C4d made it possible to visualize the direct link between anti-donor antibodies and tissue injury at sites of antibody binding in a graft. With the expanding use of C4d worldwide several limitations of C4d were identified. For instance, in ABO-incompatible transplantations C4d is present in the majority of grafts but this seems to point at 'graft accommodation' rather than antibody-mediated rejection. C4d is now increasingly recognized as a potential biomarker in other fields where antibodies can cause tissue damage, such as systemic autoimmune diseases and pregnancy. In all these fields, C4d holds promise to detect patients at risk for the consequences of antibody-mediated disease. Moreover, the emergence of new therapeutics that block complement activation makes C4d a marker with potential to identify patients who may possibly benefit from these drugs. This review provides an overview of the past, present, and future perspectives of C4d as a biomarker, focusing on its use in solid organ transplantation and discussing its possible new roles in autoimmunity and pregnancy. PMID:22297669

  16. Emerging functions of gonadotropin-releasing hormone II in mammalian physiology and behaviour.

    PubMed

    Kauffman, A S

    2004-09-01

    Gonadotropin-releasing hormone (GnRH) is the central neuroendocrine regulator of the hypothalamic-pituitary-gonadal axis. Multiple structural variants of GnRH are present in vertebrates. The first isoform isolated in the mammalian brain (GnRH I) was shown to regulate the release of pituitary gonadotropins. Recently, a second form has been discovered in mammals (GnRH II), both in the brain and periphery. Although it is unlikely to be a primary regulator of gonadotropin release, the highly conserved GnRH II variant appears to have a wide array of physiological functions. In the periphery, GnRH I and II have similar roles in regulating cell proliferation and mediating hormonal secretion from the ovary and placenta in an autocrine/paracrine manner. In the brain, GnRH I and II apparently modulate mammalian reproductive behaviours in different but complementary ways: GnRH I stimulates luteinizing hormone/follicle-stimulating hormone secretion (and thus gonadal steroids) and promotes sexual behaviour in ad libitum fed animals. By contrast, GnRH II acts as a permissive regulator of female reproductive behaviour based on energy status, as well as a modifier of short-term food intake. GnRH II has also been implicated in the regulation of calcium and potassium channels in nervous systems of amphibians, functions which may also be present in mammals. Increasing evidence suggests that the effects of GnRH II in both the periphery and brain may be mediated by GnRH receptor subtypes distinct from the type-1 GnRH receptor. It is likely that this evolutionarily conserved peptide has been co-opted over evolutionary time to possess multiple regulatory functions in a broad range of biological aspects, including, but not limited to, reproduction. Here, the proposed actions of both neural and peripheral GnRH II in affecting physiology and behaviour are summarized, and an outline of critical directions for future research is proposed.

  17. Phosphodiesterase 4D Inhibitors Limit Prostate Cancer Growth Potential

    PubMed Central

    Powers, Ginny L.; Hammer, Kimberly D.P.; Domenech, Maribella; Frantskevich, Katsiaryna; Malinowski, Rita L.; Bushman, Wade; Beebe, David J.; Marker, Paul C.

    2014-01-01

    Phosphodiesterase 4D (PDE4D) has recently been implicated as a proliferation-promoting factor in prostate cancer and is over-expressed in human prostate carcinoma. However, the effects of PDE4D inhibition using pharmacological inhibitors have not been examined in prostate cancer. These studies examined the effects of selective PDE4D inhibitors, NVP-ABE171 and cilomilast, as anti-prostate cancer therapies in both in vitro and in vivo models. The effects of PDE4D inhibitors on pathways that are critical in prostate cancer and/or downstream of cyclic AMP (cAMP) were examined. Both NVP-ABE171 and cilomilast decreased cell growth. In vitro, PDE4D inhibitors lead to decreased signaling of the sonic hedgehog (SHH), Androgen Receptor (AR), and MAPK pathways, but growth inhibition was best correlated to the sonic hedgehog pathway. PDE4D inhibition also reduced proliferation of epithelial cells induced by paracrine signaling from co-cultured stromal cells that had activated hedgehog signaling. In addition, PDE4D inhibitors decreased the weight of the prostate in wild-type mice. Prostate cancer xenografts grown in nude mice that were treated with cilomilast or NVP-ABE171 had decreased wet weight and increased apoptosis compared to vehicle treated controls. These studies suggest the pharmacological inhibition of PDE4D using small molecule inhibitors is an effective option for prostate cancer therapy. Implications PDE4D inhibitors decrease the growth of prostate cancer cells in vivo and in vitro, and PDE4D inhibition has therapeutic potential in prostate cancer. PMID:25149359

  18. Human chorionic gonadotropin (HCG) treatment of obesity.

    PubMed

    Shetty, K R; Kalkhoff, R K

    1977-02-01

    After a nine-day control period, six hospitalized obese women were placed on 500 calorie diets and were given 125 IU of human chorionic gonadotropin (HCG) intramuscularly daily for 30 days. Another five obese women received injections of diluent only and consumed identical diets for the same period. Mean weight loss in the HCG-treated group was nearly identical to that achieved by women given the placebo. Reduction of triceps skinfold thickness or circumferential body measurements of the chest, waist, hips, and thighs were not different. Patters of change of a variety of plasma and urine substrates, electrolytes, and hormones were similar in the two groups and consistent with semistarvation and weight loss. These results indicate that HCG has no effects on chemical and hormonal parameters measured and offers no advantage over calorie restriction in promoting weight loss. PMID:836112

  19. Gonadotropin binding sites in human ovarian follicles and corpora lutea during the menstrual cycle

    SciTech Connect

    Shima, K.; Kitayama, S.; Nakano, R.

    1987-05-01

    Gonadotropin binding sites were localized by autoradiography after incubation of human ovarian sections with /sup 125/I-labeled gonadotropins. The binding sites for /sup 125/I-labeled human follicle-stimulating hormone (/sup 125/I-hFSH) were identified in the granulosa cells and in the newly formed corpora lutea. The /sup 125/I-labeled human luteinizing hormone (/sup 125/I-hLH) binding to the thecal cells increased during follicular maturation, and a dramatic increase was preferentially observed in the granulosa cells of the large preovulatory follicle. In the corpora lutea, the binding of /sup 125/I-hLH increased from the early luteal phase and decreased toward the late luteal phase. The changes in 3 beta-hydroxysteroid dehydrogenase activity in the corpora lutea corresponded to the /sup 125/I-hLH binding. Thus, the changes in gonadotropin binding sites in the follicles and corpora lutea during the menstrual cycle may help in some important way to regulate human ovarian function.

  20. Beyond estrogen: targeting gonadotropin hormones in the treatment of Alzheimer's disease.

    PubMed

    Casadesus, Gemma; Zhu, Xiongwei; Atwood, Craig S; Webber, Kate M; Perry, George; Bowen, Richard L; Smith, Mark A

    2004-08-01

    Based on epidemiological and observational studies, estrogen and hormone-replacement therapy were until recently viewed as major factors in the prevention of Alzheimer's disease (AD). However, a recent randomized clinical trial revealed that hormone replacement therapy using estrogen plus progestin may actually exacerbate the incidence of dementia when administered to elderly women. These contradictory reports have cast grave doubt on the role of estrogen in disease pathogenesis and led us to consider an alternate hypothesis that would be consistent with both observations. Specifically, we suspect that hormones of the hypothalamic pituitary gonadal axis such as gonadotropins, that are regulated by estrogen (or in males by testosterone), are involved in the pathogenesis of Alzheimer's disease. One such gonadotropin, luteinizing hormone (LH), is significantly elevated in both the sera and brain tissue of patients with AD and leads to an increased production of amyloid-beta. Importantly, a key role in disease pathogenesis is further supported by the fact that the distribution of neuronal receptors for LH parallels those populations of neurons that degenerate during the course of the disease. That gonadotropins, not estrogen nor testosterone, mediate disease pathogenesis has led to a paradigm shift, not only for the treatment of AD but a wide variety of other age-related diseases. Therefore, the effects of agents that abolish LH, such as leuprolide acetate, which are currently being evaluated in Phase II clinical trials for the treatment of AD, are eagerly anticipated.

  1. Serum sex hormone and gonadotropin concentrations in premenopausal women with multiple sclerosis.

    PubMed

    Grinsted, L; Heltberg, A; Hagen, C; Djursing, H

    1989-10-01

    Dysfunctions within the hypothalamic-pituitary-gonadal axis occur frequently among women with multiple sclerosis (MS) and may induce menstrual disturbances and subsequent infertility. We have measured serum concentrations of prolactin. gonadotropins and sex hormone binding globulin (SHBG) as well as free and bound oestrogen and androgen levels in 14 women of fertile age with MS. These women all displayed regular cycles without having experienced fertility problems. As controls 14 normal women with regular periods and ideal body weight of 91% (range 80-101) were included. Serum from both groups was sampled during the early follicular phase. The MS-patients had significantly (P less than 0.05) higher concentrations of prolactin, LH, FSH, total and free testosterone (P less than 0.01) and a significantly lower serum concentration of oestrone sulphate (P less than 0.01). The abnormal hormone concentrations were not related to clinical status of the disease. We propose that the increased androgen levels are of ovarian origin as adrenal androgens were normal. The reason for the slight increase of prolactin and the marked increase of gonadotropins in women with MS is speculative. As oestradiol levels, however, were within normal range, we assume that a peripheral resistance to gonadotropins combined with an abnormal central regulation causes the increased pituitary secretion.

  2. Gonadotropin-releasing hormone and its receptor in normal and malignant cells.

    PubMed

    Harrison, G S; Wierman, M E; Nett, T M; Glode, L M

    2004-12-01

    Gonadotropin-releasing hormone (GnRH) is the hypothalamic factor that mediates reproductive competence. Intermittent GnRH secretion from the hypothalamus acts upon its receptor in the anterior pituitary to regulate the production and release of the gonadotropins, LH and FSH. LH and FSH then stimulate sex steroid hormone synthesis and gametogenesis in the gonads to ensure reproductive competence. The pituitary requires pulsatile stimulation by GnRH to synthesize and release the gonadotropins LH and FSH. Clinically, native GnRH is used in a pump delivery system to create an episodic delivery pattern to restore hormonal defects in patients with hypogonadotropic hypogonadism. Agonists of GnRH are delivered in a continuous mode to turn off reproductive function by inhibiting gonadotropin production, thus lowering sex steroid production, resulting in medical castration. They have been used in endocrine disorders such as precocious puberty, endometriosis and leiomyomata, but are also studied extensively in hormone-dependent malignancies. The detection of GnRH and its receptor in other tissues, including the breast, ovary, endometrium, placenta and prostate suggested that GnRH agonists and antagonists may also have direct actions at peripheral targets. This paper reviews the current data concerning differential control of GnRH and GnRH receptor expression and signaling in the hypothalamic-pituitary axis and extrapituitary tissues. Using these data as a backdrop, we then review the literature about the action of GnRH in cancer cells, the utility of GnRH analogs in various malignancies and then update the research in novel therapies targeted to the GnRH receptor in cancer cells to promote anti-proliferative effects and control of tumor burden.

  3. Impact of gene polymorphisms of gonadotropins and their receptors on human reproductive success.

    PubMed

    Casarini, Livio; Santi, Daniele; Marino, Marco

    2015-12-01

    Gonadotropins and their receptors' genes carry several single-nucleotide polymorphisms resulting in endocrine genotypes modulating reproductive parameters, diseases, and lifespan leading to important implications for reproductive success and potential relevance during human evolution. Here we illustrate common genotypes of the gonadotropins and gonadotropin receptors' genes and their clinical implications in phenotypes relevant for reproduction such as ovarian cycle length, age of menopause, testosterone levels, polycystic ovary syndrome, and cancer. We then discuss their possible role in human reproduction and adaptation to the environment. Gonadotropins and their receptors' variants are differently distributed among human populations. Some hints suggest that they may be the result of natural selection that occurred in ancient times, increasing the individual chance of successful mating, pregnancy, and effective post-natal parental cares. The gender-related differences in the regulation of the reproductive endocrine systems imply that many of these genotypes may lead to sex-dependent effects, increasing the chance of mating and reproductive success in one sex at the expenses of the other sex. Also, we suggest that sexual conflicts within the FSH and LH-choriogonadotropin receptor genes contributed to maintain genotypes linked to subfertility among humans. Because the distribution of polymorphic markers results in a defined geographical pattern due to human migrations rather than natural selection, these polymorphisms may have had only a weak impact on reproductive success. On the contrary, such genotypes could acquire relevant consequences in the modern, developed societies in which parenthood attempts often occur at a later age, during a short, suboptimal reproductive window, making clinical fertility treatments necessary.

  4. 4D Printing with Mechanically Robust, Thermally Actuating Hydrogels.

    PubMed

    Bakarich, Shannon E; Gorkin, Robert; in het Panhuis, Marc; Spinks, Geoffrey M

    2015-06-01

    A smart valve is created by 4D printing of hydrogels that are both mechanically robust and thermally actuating. The printed hydrogels are made up of an interpenetrating network of alginate and poly(N-isopropylacrylamide). 4D structures are created by printing the "dynamic" hydrogel ink alongside other static materials. PMID:25864515

  5. 32 CFR 1645.4 - Exclusion from Class 4-D.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... MINISTERS OF RELIGION § 1645.4 Exclusion from Class 4-D. A registrant is excluded from Class 4-D when his... duly ordained minister of religion in accordance with the ceremonial rite or discipline of a church... principles of religion and administer the ordinances of public worship, as embodied in the creed...

  6. 4D Printing with Mechanically Robust, Thermally Actuating Hydrogels.

    PubMed

    Bakarich, Shannon E; Gorkin, Robert; in het Panhuis, Marc; Spinks, Geoffrey M

    2015-06-01

    A smart valve is created by 4D printing of hydrogels that are both mechanically robust and thermally actuating. The printed hydrogels are made up of an interpenetrating network of alginate and poly(N-isopropylacrylamide). 4D structures are created by printing the "dynamic" hydrogel ink alongside other static materials.

  7. 32 CFR 1645.4 - Exclusion from Class 4-D.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... MINISTERS OF RELIGION § 1645.4 Exclusion from Class 4-D. A registrant is excluded from Class 4-D when his... duly ordained minister of religion in accordance with the ceremonial rite or discipline of a church... principles of religion and administer the ordinances of public worship, as embodied in the creed...

  8. 32 CFR 1645.4 - Exclusion from Class 4-D.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... MINISTERS OF RELIGION § 1645.4 Exclusion from Class 4-D. A registrant is excluded from Class 4-D when his... duly ordained minister of religion in accordance with the ceremonial rite or discipline of a church... principles of religion and administer the ordinances of public worship, as embodied in the creed...

  9. 32 CFR 1645.4 - Exclusion from Class 4-D.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... MINISTERS OF RELIGION § 1645.4 Exclusion from Class 4-D. A registrant is excluded from Class 4-D when his... duly ordained minister of religion in accordance with the ceremonial rite or discipline of a church... principles of religion and administer the ordinances of public worship, as embodied in the creed...

  10. 32 CFR 1645.4 - Exclusion from Class 4-D.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... MINISTERS OF RELIGION § 1645.4 Exclusion from Class 4-D. A registrant is excluded from Class 4-D when his... duly ordained minister of religion in accordance with the ceremonial rite or discipline of a church... principles of religion and administer the ordinances of public worship, as embodied in the creed...

  11. 4D-fingerprints, universal QSAR and QSPR descriptors.

    PubMed

    Senese, Craig L; Duca, J; Pan, D; Hopfinger, A J; Tseng, Y J

    2004-01-01

    An elusive goal in the field of chemoinformatics and molecular modeling has been the generation of a set of descriptors that, once calculated for a molecule, may be used in a wide variety of applications. Since such universal descriptors are generated free from external constraints, they are inherently independent of the data set in which they are employed. The realization of a set of universal descriptors would significantly streamline such chemoinformatics tasks as virtual high-throughout screening (VHTS) and toxicity profiling. The current study reports the derivation and validation of a potential set of universal descriptors, referred to as the 4D-fingerprints. The 4D-fingerprints are derived from the 4D-molecular similarity analysis. To evaluate the applicability of the 4D-fingerprints as universal descriptors, they are used to generate descriptive QSAR models for 5 independent training sets. Each of the training sets has been analyzed previously by several varying QSAR methods, and the results of the models generated using the 4D-fingerprints are compared to the results of the previous QSAR analyses. It was found that the models generated using the 4D-fingerprints are comparable in quality, based on statistical measures of fit and test set prediction, to the previously reported models for the other QSAR methods. This finding is particularly significant considering the 4D-fingerprints are generated independent of external constraints such as alignment, while the QSAR methods used for comparison all require an alignment analysis.

  12. Luteinizing hormone/human chorionic gonadotropin receptors in breast cancer.

    PubMed

    Meduri, G; Charnaux, N; Loosfelt, H; Jolivet, A; Spyratos, F; Brailly, S; Milgrom, E

    1997-03-01

    Recent studies have suggested that human choriogonadotropin (hCG), in addition to its function in regulating steroidogenesis, may also play a role as a growth factor. Immunocytochemistry using two different monoclonal antibodies (LHR29 and LHR1055) raised against the human luteinizing hormone/human chorionic gonadotropin (LH/hCG) receptor allowed us to detect this receptor in breast cancer cell lines (T47D, MCF7, and ZR75) in individual cancer biopsies and in benign breast lesions. The receptor was also present in epithelial cells of normal human and sow breast. In the latter, its concentration increased after ovulation. The presence of LH/hCG receptor mRNA was confirmed by reverse transcription-PCR using primers extending over exons 2-4, 5-11, and 9-11. The proportion of LH/hCG-receptor positive cells and the intensity of the immunolabeling varied in individual biopsies, but there was no obvious correlation with the histological type of the cancer. These results are compatible with previous studies suggesting that during pregnancy, hCG is involved in the differentiation of breast glandular epithelium and that this hormone may play an inhibitory role in mammary carcinogenesis and in the growth of breast tumors. PMID:9041186

  13. Identification of novel mutations confirms PDE4D as a major gene causing acrodysostosis.

    PubMed

    Lynch, Danielle C; Dyment, David A; Huang, Lijia; Nikkel, Sarah M; Lacombe, Didier; Campeau, Philippe M; Lee, Brendan; Bacino, Carlos A; Michaud, Jacques L; Bernier, Francois P; Parboosingh, Jillian S; Innes, A Micheil

    2013-01-01

    Acrodysostosis is characterized by nasal hypoplasia, peripheral dysostosis, variable short stature, and intellectual impairment. Recently, mutations in PRKAR1A were reported in patients with acrodysostosis and hormone resistance. Subsequently, mutations in a phosphodiesterase gene (PDE4D) were identified in seven sporadic cases. We sequenced PDE4D in seven acrodysostosis patients from five families. Missense mutations were identified in all cases. Families showed de novo inheritance except one family with three affected children whose father was subsequently found to have subtle features of acrodysostosis. There were no recurrent mutations. Short stature and endocrine resistance are rare in this series; however, cognitive involvement and obesity were frequent. This last finding is relevant given PDE4D is insulin responsive and potentially involved in lipolysis. PDE4D encodes a cyclic AMP regulator and places PDE4D-related acrodysostosis within the same family of diseases as pseudohypoparathyroidism, pseudopseudohypoparathyroidism, PRKAR1A-related acrodysostosis and brachydactyly-mental retardation syndrome; all characterized by cognitive impairment and short distal extremities. PMID:23033274

  14. Identification of novel mutations confirms PDE4D as a major gene causing acrodysostosis.

    PubMed

    Lynch, Danielle C; Dyment, David A; Huang, Lijia; Nikkel, Sarah M; Lacombe, Didier; Campeau, Philippe M; Lee, Brendan; Bacino, Carlos A; Michaud, Jacques L; Bernier, Francois P; Parboosingh, Jillian S; Innes, A Micheil

    2013-01-01

    Acrodysostosis is characterized by nasal hypoplasia, peripheral dysostosis, variable short stature, and intellectual impairment. Recently, mutations in PRKAR1A were reported in patients with acrodysostosis and hormone resistance. Subsequently, mutations in a phosphodiesterase gene (PDE4D) were identified in seven sporadic cases. We sequenced PDE4D in seven acrodysostosis patients from five families. Missense mutations were identified in all cases. Families showed de novo inheritance except one family with three affected children whose father was subsequently found to have subtle features of acrodysostosis. There were no recurrent mutations. Short stature and endocrine resistance are rare in this series; however, cognitive involvement and obesity were frequent. This last finding is relevant given PDE4D is insulin responsive and potentially involved in lipolysis. PDE4D encodes a cyclic AMP regulator and places PDE4D-related acrodysostosis within the same family of diseases as pseudohypoparathyroidism, pseudopseudohypoparathyroidism, PRKAR1A-related acrodysostosis and brachydactyly-mental retardation syndrome; all characterized by cognitive impairment and short distal extremities.

  15. Gonadotropin-releasing hormone modulates cholesterol synthesis and steroidogenesis in SH-SY5Y cells.

    PubMed

    Rosati, Fabiana; Sturli, Niccolò; Cungi, Maria Chiara; Morello, Matteo; Villanelli, Fabio; Bartolucci, Gianluca; Finocchi, Claudia; Peri, Alessandro; Serio, Mario; Danza, Giovanna

    2011-04-01

    Neurosteroids are involved in Central Nervous System development, brain functionality and neuroprotection but little is known about regulators of their biosynthesis. Recently gonadotropins, Gonadotropin-releasing Hormone (GnRH) and their receptors have been localized in different brain regions, such as hippocampus and cortex. Using human neuronal-like cells we found that GnRH up-regulates the expression of key genes of cholesterol and steroid synthesis when used in a narrow range around 1.0 nM. The expression of Hydroxysterol D24-reductase (seladin-1/DHCR24), that catalyzes the last step of cholesterol biosynthesis, is increased by 50% after 90 min of incubation with GnRH. StAR protein and P450 side chain cleavage (P450scc) are up-regulated by 3.3 times after 90 min and by 3.5 times after 3 h, respectively. GnRH action is mediated by LH and 1.0 nM GnRH enhances the expression of LHβ as well. A two fold increase of cell cholesterol is induced after 90 min of GnRH incubation and 17β-estradiol (E2) production is increased after 24, 48 and 72 h. These data indicate for the first time that GnRH regulates both cholesterol and steroid biosynthesis in human neuronal-like cells and suggest a new physiological role for GnRH in the brain. PMID:21296663

  16. C4d staining as immunohistochemical marker in inflammatory myopathies.

    PubMed

    Pytel, Peter

    2014-10-01

    The diagnosis of an inflammatory myopathy is often established based on basic histologic studies. Additional immunohistochemical studies are sometimes required to support the diagnosis and the classification of inflammatory myopathies. Staining for major histocompatibility complex 1 (MHC1) often shows increased sarcolemmal labeling in inflammatory myopathies. Endomysial capillary staining C5b-9 (membrane attack complex) is a feature that is reported as frequently associated with dermatomyositis. Immunohistochemical staining for C4d is widely used for various applications including the assessment of antibody-mediated rejection after solid organ transplantation. In the context of dermatomyositis, C4d staining has been described in skin biopsies but not in muscle biopsies. A total of 32 muscle biopsy specimens were examined. The hematoxylin and eosin-stained slides were reviewed, and immunohistochemical studies for MHC1, C5b-9, and C4d were conducted. The staining observed for C5b-9 and C4d was compared. Overall, the staining pattern for C4d mirrored the one observed for C5b-9 in the examined muscle biopsy specimens. There was high and statistically significant (P<0.0001) correlation between the staining seen with these 2 antibodies. Both antibodies labeled the cytoplasm of degenerating necrotic myofibers. In addition, both antibodies showed distinct endomysial capillary labeling in a subset of dermatomyositis. Areas with perifascicular atrophy often exhibited the most prominent vascular labeling for C4d and C5b-9. In conclusion, C4d and C5b-9 show similar expression patterns in muscle biopsies of patients with inflammatory myopathies and both highlight the presence of vascular labeling associated with dermatomyositis. C4d antibodies are widely used and may offer an alternative for C5b-9 staining.

  17. Substitutional 4d and 5d impurities in graphene.

    PubMed

    Alonso-Lanza, Tomás; Ayuela, Andrés; Aguilera-Granja, Faustino

    2016-08-21

    We describe the structural and electronic properties of graphene doped with substitutional impurities of 4d and 5d transition metals. The adsorption energies and distances for 4d and 5d metals in graphene show similar trends for the later groups in the periodic table, which are also well-known characteristics of 3d elements. However, along earlier groups the 4d impurities in graphene show very similar adsorption energies, distances and magnetic moments to the 5d ones, which can be related to the influence of the 4d and 5d lanthanide contraction. Surprisingly, within the manganese group, the total magnetic moment of 3 μB for manganese is reduced to 1 μB for technetium and rhenium. We find that compared with 3d elements, the larger size of the 4d and 5d elements causes a high degree of hybridization with the neighbouring carbon atoms, reducing spin splitting in the d levels. It seems that the magnetic adjustment of graphene could be significantly different if 4d or 5d impurities are used instead of 3d impurities.

  18. Substitutional 4d and 5d impurities in graphene.

    PubMed

    Alonso-Lanza, Tomás; Ayuela, Andrés; Aguilera-Granja, Faustino

    2016-08-21

    We describe the structural and electronic properties of graphene doped with substitutional impurities of 4d and 5d transition metals. The adsorption energies and distances for 4d and 5d metals in graphene show similar trends for the later groups in the periodic table, which are also well-known characteristics of 3d elements. However, along earlier groups the 4d impurities in graphene show very similar adsorption energies, distances and magnetic moments to the 5d ones, which can be related to the influence of the 4d and 5d lanthanide contraction. Surprisingly, within the manganese group, the total magnetic moment of 3 μB for manganese is reduced to 1 μB for technetium and rhenium. We find that compared with 3d elements, the larger size of the 4d and 5d elements causes a high degree of hybridization with the neighbouring carbon atoms, reducing spin splitting in the d levels. It seems that the magnetic adjustment of graphene could be significantly different if 4d or 5d impurities are used instead of 3d impurities. PMID:27439363

  19. PDE4D phosphorylation: A coincidence detector integrating multiple signaling pathways.

    PubMed

    Mika, Delphine; Conti, Marco

    2016-07-01

    In Eukaryotes, more than 100 different phosphodiesterase (PDE) proteins serve to fine-tune cyclic nucleotide (cAMP and cGMP) signals and contribute to specificity of signaling. In mammals, PDEs are divided into 11 families, of which PDE4 represents the largest family. Four genes (pde4a, pde4b, pde4c and pde4d) encode for this class of enzymes in mammals and give rise to more than 20 variants. Within this family of genes, PDE4D was discovered on the basis of its regulatory properties and its induction by hormones and cAMP. PDE4D has often been used as the prototype PDE4 and large body of work has been generated on the biochemical, pharmacological, and physiological properties of this enzyme. This review covers the regulation of PDE4D by phosphorylation, the impact of this regulation in the context of the structure of this protein, and the functional consequences of this complex pattern of posttranslational modifications. PMID:26562185

  20. Review: regulatory mechanisms of gonadotropin-inhibitory hormone (GnIH) synthesis and release in photoperiodic animals

    PubMed Central

    Tsutsui, Kazuyoshi; Ubuka, Takayoshi; Bentley, George E.; Kriegsfeld, Lance J.

    2013-01-01

    Gonadotropin-inhibitory hormone (GnIH) is a novel hypothalamic neuropeptide that was discovered in quail as an inhibitory factor for gonadotropin release. GnIH inhibits gonadotropin synthesis and release in birds through actions on gonadotropin-releasing hormone (GnRH) neurons and gonadotropes, mediated via the GnIH receptor (GnIH-R), GPR147. Subsequently, GnIH was identified in mammals and other vertebrates. As in birds, mammalian GnIH inhibits gonadotropin secretion, indicating a conserved role for this neuropeptide in the control of the hypothalamic-pituitary-gonadal (HPG) axis across species. Identification of the regulatory mechanisms governing GnIH expression and release is important in understanding the physiological role of the GnIH system. A nocturnal hormone, melatonin, appears to act directly on GnIH neurons through its receptor to induce expression and release of GnIH in quail, a photoperiodic bird. Recently, a similar, but opposite, action of melatonin on the inhibition of expression of mammalian GnIH was shown in hamsters and sheep, photoperiodic mammals. These results in photoperiodic animals demonstrate that GnIH expression is photoperiodically modulated via a melatonin-dependent process. Recent findings indicate that GnIH may be a mediator of stress-induced reproductive disruption in birds and mammals, pointing to a broad role for this neuropeptide in assessing physiological state and modifying reproductive effort accordingly. This paper summarizes the advances made in our knowledge regarding the regulation of GnIH synthesis and release in photoperiodic birds and mammals. This paper also discusses the neuroendocrine integration of environmental signals, such as photoperiods and stress, and internal signals, such as GnIH, melatonin, and glucocorticoids, to control avian and mammalian reproduction. PMID:23596387

  1. Review: regulatory mechanisms of gonadotropin-inhibitory hormone (GnIH) synthesis and release in photoperiodic animals.

    PubMed

    Tsutsui, Kazuyoshi; Ubuka, Takayoshi; Bentley, George E; Kriegsfeld, Lance J

    2013-01-01

    Gonadotropin-inhibitory hormone (GnIH) is a novel hypothalamic neuropeptide that was discovered in quail as an inhibitory factor for gonadotropin release. GnIH inhibits gonadotropin synthesis and release in birds through actions on gonadotropin-releasing hormone (GnRH) neurons and gonadotropes, mediated via the GnIH receptor (GnIH-R), GPR147. Subsequently, GnIH was identified in mammals and other vertebrates. As in birds, mammalian GnIH inhibits gonadotropin secretion, indicating a conserved role for this neuropeptide in the control of the hypothalamic-pituitary-gonadal (HPG) axis across species. Identification of the regulatory mechanisms governing GnIH expression and release is important in understanding the physiological role of the GnIH system. A nocturnal hormone, melatonin, appears to act directly on GnIH neurons through its receptor to induce expression and release of GnIH in quail, a photoperiodic bird. Recently, a similar, but opposite, action of melatonin on the inhibition of expression of mammalian GnIH was shown in hamsters and sheep, photoperiodic mammals. These results in photoperiodic animals demonstrate that GnIH expression is photoperiodically modulated via a melatonin-dependent process. Recent findings indicate that GnIH may be a mediator of stress-induced reproductive disruption in birds and mammals, pointing to a broad role for this neuropeptide in assessing physiological state and modifying reproductive effort accordingly. This paper summarizes the advances made in our knowledge regarding the regulation of GnIH synthesis and release in photoperiodic birds and mammals. This paper also discusses the neuroendocrine integration of environmental signals, such as photoperiods and stress, and internal signals, such as GnIH, melatonin, and glucocorticoids, to control avian and mammalian reproduction.

  2. Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis.

    PubMed

    Michot, Caroline; Le Goff, Carine; Goldenberg, Alice; Abhyankar, Avinash; Klein, Céline; Kinning, Esther; Guerrot, Anne-Marie; Flahaut, Philippe; Duncombe, Alice; Baujat, Genevieve; Lyonnet, Stanislas; Thalassinos, Caroline; Nitschke, Patrick; Casanova, Jean-Laurent; Le Merrer, Martine; Munnich, Arnold; Cormier-Daire, Valérie

    2012-04-01

    Acrodysostosis is a rare autosomal-dominant condition characterized by facial dysostosis, severe brachydactyly with cone-shaped epiphyses, and short stature. Moderate intellectual disability and resistance to multiple hormones might also be present. Recently, a recurrent mutation (c.1102C>T [p.Arg368*]) in PRKAR1A has been identified in three individuals with acrodysostosis and resistance to multiple hormones. After studying ten unrelated acrodysostosis cases, we report here de novo PRKAR1A mutations in five out of the ten individuals (we found c.1102C>T [p.Arg368(∗)] in four of the ten and c.1117T>C [p.Tyr373His] in one of the ten). We performed exome sequencing in two of the five remaining individuals and selected phosphodiesterase 4D (PDE4D) as a candidate gene. PDE4D encodes a class IV cyclic AMP (cAMP)-specific phosphodiesterase that regulates cAMP concentration. Exome analysis detected heterozygous PDE4D mutations (c.673C>A [p.Pro225Thr] and c.677T>C [p.Phe226Ser]) in these two individuals. Screening of PDE4D identified heterozygous mutations (c.568T>G [p.Ser190Ala] and c.1759A>C [p.Thr587Pro]) in two additional acrodysostosis cases. These mutations occurred de novo in all four cases. The four individuals with PDE4D mutations shared common clinical features, namely characteristic midface and nasal hypoplasia and moderate intellectual disability. Metabolic screening was normal in three of these four individuals. However, resistance to parathyroid hormone and thyrotropin was consistently observed in the five cases with PRKAR1A mutations. Finally, our study further supports the key role of the cAMP signaling pathway in skeletogenesis. PMID:22464250

  3. Semaphorin 4D Promotes Skeletal Metastasis in Breast Cancer.

    PubMed

    Yang, Ying-Hua; Buhamrah, Asma; Schneider, Abraham; Lin, Yi-Ling; Zhou, Hua; Bugshan, Amr; Basile, John R

    2016-01-01

    Bone density is controlled by interactions between osteoclasts, which resorb bone, and osteoblasts, which deposit it. The semaphorins and their receptors, the plexins, originally shown to function in the immune system and to provide chemotactic cues for axon guidance, are now known to play a role in this process as well. Emerging data have identified Semaphorin 4D (Sema4D) as a product of osteoclasts acting through its receptor Plexin-B1 on osteoblasts to inhibit their function, tipping the balance of bone homeostasis in favor of resorption. Breast cancers and other epithelial malignancies overexpress Sema4D, so we theorized that tumor cells could be exploiting this pathway to establish lytic skeletal metastases. Here, we use measurements of osteoblast and osteoclast differentiation and function in vitro and a mouse model of skeletal metastasis to demonstrate that both soluble Sema4D and protein produced by the breast cancer cell line MDA-MB-231 inhibits differentiation of MC3T3 cells, an osteoblast cell line, and their ability to form mineralized tissues, while Sema4D-mediated induction of IL-8 and LIX/CXCL5, the murine homologue of IL-8, increases osteoclast numbers and activity. We also observe a decrease in the number of bone metastases in mice injected with MDA-MB-231 cells when Sema4D is silenced by RNA interference. These results are significant because treatments directed at suppression of skeletal metastases in bone-homing malignancies usually work by arresting bone remodeling, potentially leading to skeletal fragility, a significant problem in patient management. Targeting Sema4D in these cancers would not affect bone remodeling and therefore could elicit an improved therapeutic result without the debilitating side effects.

  4. Soil matrix and macropore biodegradation of 2,4-D

    SciTech Connect

    Pivetz, B.E.; Steenhuis, T.S.

    1995-07-01

    Preferential flow of pesticides in macropores can lead to decreased travel times through the vadose zone and increased groundwater contamination. Macropores, however, may present a favorable environment for biodegradation because of greater oxygen, nutrient, and substrate supply, and higher microbial populations in earthworm burrows, compared to the soil matrix. The biodegradation of 2,4-dichlorophenoxyacetic acid (2,4-D) was measured in macropores and soil matrix of packed soil columns (7.0-cm diam., 10-cm length) and undisturbed cores contained as well-defined artificial macropore and the undisturbed cores contained earthworm-burrow macropores. A 50 {mu}g/L 2,4-D solution was continuously applied to the unsaturated soil surface and breakthrough curves (BTCs) indicating pesticide loss in the effluent were obtained from the soil matrix and macropore flow paths. Biodegradation rates were calculated separately for each flow path by comparing the BTCs to BTCs representing abiotic conditions, and dividing the 2,4-D loss by the travel time through each flow path. The biodegradation rates increased with time in both flow paths, and the final biodegradation rate in the macropore region surpassed that of the matrix, presumably because of increased microbial populations in the macropore. Complete loss of the 2,4-D in both flow paths was observed after continuous application of 2,4-D for 400 h, with maximum column-averaged 2,4-D loss rates of 0.879 {mu}g/(L h) in the matrix and 1.073 {mu}g/(L h) in the macropore. Biodegradation of 2,4-D was also observed in the macropore and matrix regions of the undisturbed soil cores. 19 refs., 7 figs., 2 tabs.

  5. Semaphorin 4D Promotes Skeletal Metastasis in Breast Cancer

    PubMed Central

    Yang, Ying-Hua; Buhamrah, Asma; Schneider, Abraham; Lin, Yi-Ling; Zhou, Hua; Bugshan, Amr; Basile, John R.

    2016-01-01

    Bone density is controlled by interactions between osteoclasts, which resorb bone, and osteoblasts, which deposit it. The semaphorins and their receptors, the plexins, originally shown to function in the immune system and to provide chemotactic cues for axon guidance, are now known to play a role in this process as well. Emerging data have identified Semaphorin 4D (Sema4D) as a product of osteoclasts acting through its receptor Plexin-B1 on osteoblasts to inhibit their function, tipping the balance of bone homeostasis in favor of resorption. Breast cancers and other epithelial malignancies overexpress Sema4D, so we theorized that tumor cells could be exploiting this pathway to establish lytic skeletal metastases. Here, we use measurements of osteoblast and osteoclast differentiation and function in vitro and a mouse model of skeletal metastasis to demonstrate that both soluble Sema4D and protein produced by the breast cancer cell line MDA-MB-231 inhibits differentiation of MC3T3 cells, an osteoblast cell line, and their ability to form mineralized tissues, while Sema4D-mediated induction of IL-8 and LIX/CXCL5, the murine homologue of IL-8, increases osteoclast numbers and activity. We also observe a decrease in the number of bone metastases in mice injected with MDA-MB-231 cells when Sema4D is silenced by RNA interference. These results are significant because treatments directed at suppression of skeletal metastases in bone-homing malignancies usually work by arresting bone remodeling, potentially leading to skeletal fragility, a significant problem in patient management. Targeting Sema4D in these cancers would not affect bone remodeling and therefore could elicit an improved therapeutic result without the debilitating side effects. PMID:26910109

  6. Estrogen receptor-β in the gonadotropin-releasing hormone neuron.

    PubMed

    Wolfe, Andrew; Wu, Sheng

    2012-01-01

    Estrogen regulation of gonadotropin-releasing hormone (GnRH) neuronal activity plays a crucial role in homeostatic regulation of the hypothalamic-pituitary-gonadal axis. Estrogen also coordinates a complex series of physiological changes culminating with a surge of gonadotropin secretion that triggers ovulation of a developed follicle from the ovary. The coordinated functions of estrogen ensure that the female will elaborate appropriate reproductive behaviors ultimately designed to deliver sperm to the oocyte and to provide a receptive uterine environment for the fertilized embryo. Although the effects of estrogen on GnRH neuronal function have long been proposed to be indirect due to the presumed lack of estrogen receptors in GnRH neurons, the identification of alternative estrogen signaling pathways, including estrogen receptor (ER)β and membrane ERs such as GPR30, has put the focus back on estrogen's effect at the level of the GnRH neuron itself. One candidate to mediate the effects of estrogen is the β isoform of the estrogen receptor. We review the evidence for a role for ERβ-mediated regulation of GnRH neuronal function.

  7. RNA Interference of Gonadotropin-Inhibitory Hormone Gene Induces Arousal in Songbirds

    PubMed Central

    Ubuka, Takayoshi; Mukai, Motoko; Wolfe, Jordan; Beverly, Ryan; Clegg, Sarah; Wang, Ariel; Hsia, Serena; Li, Molly; Krause, Jesse S.; Mizuno, Takanobu; Fukuda, Yujiro; Tsutsui, Kazuyoshi; Bentley, George E.; Wingfield, John C.

    2012-01-01

    Gonadotropin-inhibitory hormone (GnIH) was originally identified in quail as a hypothalamic neuropeptide inhibitor of pituitary gonadotropin synthesis and release. However, GnIH neuronal fibers do not only terminate in the median eminence to control anterior pituitary function but also extend widely in the brain, suggesting it has multiple roles in the regulation of behavior. To identify the role of GnIH neurons in the regulation of behavior, we investigated the effect of RNA interference (RNAi) of the GnIH gene on the behavior of white-crowned sparrows, a highly social songbird species. Administration of small interfering RNA against GnIH precursor mRNA into the third ventricle of male and female birds reduced resting time, spontaneous production of complex vocalizations, and stimulated brief agonistic vocalizations. GnIH RNAi further enhanced song production of short duration in male birds when they were challenged by playbacks of novel male songs. These behaviors resembled those of breeding birds during territorial defense. The overall results suggest that GnIH gene silencing induces arousal. In addition, the activities of male and female birds were negatively correlated with GnIH mRNA expression in the paraventricular nucleus. Density of GnIH neuronal fibers in the ventral tegmental area was decreased by GnIH RNAi treatment in female birds, and the number of gonadotropin-releasing hormone neurons that received close appositions of GnIH neuronal fiber terminals was negatively correlated with the activity of male birds. In summary, GnIH may decrease arousal level resulting in the inhibition of specific motivated behavior such as in reproductive contexts. PMID:22279571

  8. Gonadotropin hormone and receptor sequences from model teleost species.

    PubMed

    Wong, Andrew C; Van Eenennaam, Alison L

    2004-01-01

    Fish offer some advantages for the study of vertebrate reproductive physiology. Only a few of the genes encoding the components of the hypothalamic-pituitary-gonadal axis have been identified from model teleosts. This study describes a combination of database searching and molecular approaches to identify the FSH and LH gonadotropin beta-subunits (fshb and lhb, respectively), and the LH receptor (lhr) from two model teleost species: zebrafish (Danio rerio) and Fugu (Takifugu rubripes). Sequence and phylogenetic analyses were used to examine the relationships that exist between gonadotropins and their receptors from species representing several piscine orders. The gonadotropin alpha-subunit (Cga) is highly conserved among teleosts and tetrapods. The presence of a genomic pseudogene (cgap) was also noted in zebrafish. Generally, teleostean FSHbeta protein sequences share less identity with each other than do LHbeta protein sequences, supporting the hypothesis that FSHbeta diverged more rapidly during teleost evolution. Interestingly, and uniquely, zebrafish Fshb lacked two highly conserved cysteine residues in the "determinant loop" which is thought to contribute towards receptor binding and specificity. Teleost gonadotropin receptor sequences clearly diverged into two distinct groups, FSHR and LHR. As has been seen with mammalian gonadotropin receptor transcripts, splice variants of zebrafish lhr were also observed.

  9. Antibody Blockade of Semaphorin 4D Promotes Immune Infiltration into Tumor and Enhances Response to Other Immunomodulatory Therapies.

    PubMed

    Evans, Elizabeth E; Jonason, Alan S; Bussler, Holm; Torno, Sebold; Veeraraghavan, Janaki; Reilly, Christine; Doherty, Michael A; Seils, Jennifer; Winter, Laurie A; Mallow, Crystal; Kirk, Renee; Howell, Alan; Giralico, Susan; Scrivens, Maria; Klimatcheva, Katya; Fisher, Terrence L; Bowers, William J; Paris, Mark; Smith, Ernest S; Zauderer, Maurice

    2015-06-01

    Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 (PLXNB1) are broadly expressed in murine and human tumors, and their expression has been shown to correlate with invasive disease in several human tumors. SEMA4D normally functions to regulate the motility and differentiation of multiple cell types, including those of the immune, vascular, and nervous systems. In the setting of cancer, SEMA4D-PLXNB1 interactions have been reported to affect vascular stabilization and transactivation of ERBB2, but effects on immune-cell trafficking in the tumor microenvironment (TME) have not been investigated. We describe a novel immunomodulatory function of SEMA4D, whereby strong expression of SEMA4D at the invasive margins of actively growing tumors influences the infiltration and distribution of leukocytes in the TME. Antibody neutralization of SEMA4D disrupts this gradient of expression, enhances recruitment of activated monocytes and lymphocytes into the tumor, and shifts the balance of cells and cytokines toward a proinflammatory and antitumor milieu within the TME. This orchestrated change in the tumor architecture was associated with durable tumor rejection in murine Colon26 and ERBB2(+) mammary carcinoma models. The immunomodulatory activity of anti-SEMA4D antibody can be enhanced by combination with other immunotherapies, including immune checkpoint inhibition and chemotherapy. Strikingly, the combination of anti-SEMA4D antibody with antibody to CTLA-4 acts synergistically to promote complete tumor rejection and survival. Inhibition of SEMA4D represents a novel mechanism and therapeutic strategy to promote functional immune infiltration into the TME and inhibit tumor progression. PMID:25614511

  10. Antibody Blockade of Semaphorin 4D Promotes Immune Infiltration into Tumor and Enhances Response to Other Immunomodulatory Therapies.

    PubMed

    Evans, Elizabeth E; Jonason, Alan S; Bussler, Holm; Torno, Sebold; Veeraraghavan, Janaki; Reilly, Christine; Doherty, Michael A; Seils, Jennifer; Winter, Laurie A; Mallow, Crystal; Kirk, Renee; Howell, Alan; Giralico, Susan; Scrivens, Maria; Klimatcheva, Katya; Fisher, Terrence L; Bowers, William J; Paris, Mark; Smith, Ernest S; Zauderer, Maurice

    2015-06-01

    Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 (PLXNB1) are broadly expressed in murine and human tumors, and their expression has been shown to correlate with invasive disease in several human tumors. SEMA4D normally functions to regulate the motility and differentiation of multiple cell types, including those of the immune, vascular, and nervous systems. In the setting of cancer, SEMA4D-PLXNB1 interactions have been reported to affect vascular stabilization and transactivation of ERBB2, but effects on immune-cell trafficking in the tumor microenvironment (TME) have not been investigated. We describe a novel immunomodulatory function of SEMA4D, whereby strong expression of SEMA4D at the invasive margins of actively growing tumors influences the infiltration and distribution of leukocytes in the TME. Antibody neutralization of SEMA4D disrupts this gradient of expression, enhances recruitment of activated monocytes and lymphocytes into the tumor, and shifts the balance of cells and cytokines toward a proinflammatory and antitumor milieu within the TME. This orchestrated change in the tumor architecture was associated with durable tumor rejection in murine Colon26 and ERBB2(+) mammary carcinoma models. The immunomodulatory activity of anti-SEMA4D antibody can be enhanced by combination with other immunotherapies, including immune checkpoint inhibition and chemotherapy. Strikingly, the combination of anti-SEMA4D antibody with antibody to CTLA-4 acts synergistically to promote complete tumor rejection and survival. Inhibition of SEMA4D represents a novel mechanism and therapeutic strategy to promote functional immune infiltration into the TME and inhibit tumor progression.

  11. Motion artifacts occurring at the lung/diaphragm interface using 4D CT attenuation correction of 4D PET scans.

    PubMed

    Killoran, Joseph H; Gerbaudo, Victor H; Mamede, Marcelo; Ionascu, Dan; Park, Sang-June; Berbeco, Ross

    2011-11-15

    For PET/CT, fast CT acquisition time can lead to errors in attenuation correction, particularly at the lung/diaphragm interface. Gated 4D PET can reduce motion artifacts, though residual artifacts may persist depending on the CT dataset used for attenuation correction. We performed phantom studies to evaluate 4D PET images of targets near a density interface using three different methods for attenuation correction: a single 3D CT (3D CTAC), an averaged 4D CT (CINE CTAC), and a fully phase matched 4D CT (4D CTAC). A phantom was designed with two density regions corresponding to diaphragm and lung. An 8 mL sphere phantom loaded with 18F-FDG was used to represent a lung tumor and background FDG included at an 8:1 ratio. Motion patterns of sin(x) and sin4(x) were used for dynamic studies. Image data was acquired using a GE Discovery DVCT-PET/CT scanner. Attenuation correction methods were compared based on normalized recovery coefficient (NRC), as well as a novel quantity "fixed activity volume" (FAV) introduced in our report. Image metrics were compared to those determined from a 3D PET scan with no motion present (3D STATIC). Values of FAV and NRC showed significant variation over the motion cycle when corrected by 3D CTAC images. 4D CTAC- and CINE CTAC-corrected PET images reduced these motion artifacts. The amount of artifact reduction is greater when the target is surrounded by lower density material and when motion was based on sin4(x). 4D CTAC reduced artifacts more than CINE CTAC for most scenarios. For a target surrounded by water equivalent material, there was no advantage to 4D CTAC over CINE CTAC when using the sin(x) motion pattern. Attenuation correction using both 4D CTAC or CINE CTAC can reduce motion artifacts in regions that include a tissue interface such as the lung/diaphragm border. 4D CTAC is more effective than CINE CTAC at reducing artifacts in some, but not all, scenarios.

  12. A cryptic mitochondrial targeting motif in Atg4D links caspase cleavage with mitochondrial import and oxidative stress

    PubMed Central

    Betin, Virginie M.S.; MacVicar, Thomas D.B.; Parsons, Stephen F.; Anstee, David J.; Lane, Jon D.

    2012-01-01

    The Atg4 cysteine proteases play crucial roles in the processing of Atg8 proteins during autophagy, but their regulation during cellular stress and differentiation remains poorly understood. We have found that two Atg4 family members—Atg4C and Atg4D—contain cryptic mitochondrial targeting sequences immediately downstream of their canonical (DEVD) caspase cleavage sites. Consequently, caspase-cleaved Atg4D (ΔN63 Atg4D) localizes to the mitochondrial matrix when expressed in mammalian cells, where it undergoes further processing to a ~42 kDa mitochondrial form. Interestingly, caspase cleavage is not needed for Atg4D mitochondrial import, because ~42 kDa mitochondrial Atg4D is observed in cells treated with caspase inhibitors and in cells expressing caspase-resistant Atg4D (DEVA63). Using HeLa cell lines stably expressing ΔN63 Atg4D, we showed that mitochondrial Atg4D sensitizes cells to cell death in the presence of the mitochondrial uncoupler, CCCP, and that mitochondrial cristae are less extensive in these cells. We further showed that the organization of mitochondrial cristae is altered during the mitochondrial clearance phase in differentiating primary human erythroblasts stably expressing ΔN63 Atg4D, and that these cells have elevated levels of mitochondrial reactive oxygen species (ROS) during late stages of erythropoiesis. Together these data suggest that the import of Atg4D during cellular stress and differentiation may play important roles in the regulation of mitochondrial physiology, ROS, mitophagy and cell viability. PMID:22441018

  13. 4-D reconstruction for dynamic fluorescence diffuse optical tomography.

    PubMed

    Liu, Xin; Zhang, Bin; Luo, Jianwen; Bai, Jing

    2012-11-01

    Dynamic fluorescence diffuse optical tomography (FDOT) is important for the research of drug delivery, medical diagnosis and treatment. Conventionally, dynamic tomographic images are reconstructed frame by frame, independently. This approach fails to account for the temporal correlations in measurement data. Ideally, the entire image sequence should be considered as a whole and a four-dimensional (4-D) reconstruction should be performed. However, the fully 4-D reconstruction is computationally intensive. In this paper, we propose a new 4-D reconstruction approach for dynamic FDOT, which is achieved by applying a temporal Karhunen-Loève (KL) transformation to the imaging equation. By taking advantage of the decorrelation and compression properties of the KL transformation, the complex 4-D optical reconstruction problem is greatly simplified. To evaluate the performance of the method, simulation, phantom, and in vivo experiments (N=7) are performed on a hybrid FDOT/x-ray computed tomography imaging system. The experimental results indicate that the reconstruction images obtained by the KL method provide good reconstruction quality. Additionally, by discarding high-order KL components, the computation time involved with fully 4-D reconstruction can be greatly reduced in contrast to the conventional frame-by-frame reconstruction.

  14. New C4D Sensor with a Simulated Inductor

    PubMed Central

    Lyu, Yingchao; Ji, Haifeng; Yang, Shijie; Huang, Zhiyao; Wang, Baoliang; Li, Haiqing

    2016-01-01

    A new capacitively coupled contactless conductivity detection (C4D) sensor with an improved simulated inductor is developed in this work. The improved simulated inductor is designed on the basis of the Riordan-type floating simulated inductor. With the improved simulated inductor, the negative influence of the coupling capacitances is overcome and the conductivity measurement is implemented by the series resonance principle. The conductivity measurement experiments are carried out in three pipes with different inner diameters of 3.0 mm, 4.6 mm and 6.4 mm, respectively. The experimental results show that the designs of the new C4D sensor and the improved simulated inductor are successful. The maximum relative error of the conductivity measurement is less than 5%. Compared with the C4D sensors using practical inductors, the measurement accuracy of the new C4D sensor is comparable. The research results also indicate that the adjustability of a simulated inductor can reduce the requirement for the AC source and guarantee the interchangeableness. Meanwhile, it is recommended that making the potential of one terminal of a simulated inductor stable is beneficial to the running stability. Furthermore, this work indirectly verifies the possibility and feasibility of the miniaturization of the C4D sensor by using the simulated inductor technique and lays a good foundation for future research work. PMID:26828493

  15. Gonadotropin-releasing hormone and its analogs.

    PubMed

    Conn, P M; Crowley, W F

    1994-01-01

    GnRH and its analogues have led to exciting new avenues of therapy in virtually every subspecialty of internal medicine as well as in gynecology, pediatrics, and urology. Since their discovery in 1971, it has been demonstrated that GnRH and its analogues enable medical professionals to influence the hypothalamic-pituitary-gonadal axis in two distinct classes of therapeutic applications. The first provides natural sequence GnRH in a pulsatile fashion via portable infusion pumps to mimic the normal physiology of hypothalamic GnRH secretion and restores reproductive potential to infertile men and women with disorders of endogenous GnRH secretion. The second mode uses long-acting GnRH agonists administered in a depot delivery to produce a paradoxical desensitization of pituitary gonadotropin secretion which, in turn, results in a complete ablation of the reproductive axis. This biochemical castration induced by GnRH agonist administration is a safe, effective, complete, and reversible method of removing the overlay of gonadal steroids from a variety of diseases which they are known to exacerbate. These diseases include endometriosis and uterine fibroids in women, prostate cancer in men, and precocious puberty in both sexes. This review examines the physiologic and pharmacologic principles underlying the advances produced by these agents, the mechanism of action of GnRH and its analogues at the cellular level, and the individual therapeutic applications to which these analogues have been applied. Because virtually every subspecialty of medicine will be touched by the GnRH analogues, this review provides an overview and background of their use.

  16. Human chorionic gonadotropin measurements in parathyroid carcinoma

    PubMed Central

    Rubin, Mishaela R; Bilezikian, John P; Birken, Steven; Silverberg, Shonni J

    2010-01-01

    Objective Preoperatively, it is difficult to differentiate between parathyroid cancer (PtCa) and severe primary hyperparathyroidism (PHPT) due to a benign tumor. Human chorionic gonadotropin (hCG) is a tumor marker in trophoblastic and nontrophoblastic cancers and hyperglycosylated hCG is increased in hCG-secreting malignancies. We investigated whether hCG can distinguish PtCa cancer from benign disease and add prognostic information. Design Observational study. Methods Measurement of urinary hCG (total and malignant isoforms) and serum malignant hCG in 8 subjects with PtCa and in 18 subjects with PHPT (measurement of urine in ten and serum in eight). Results Total urinary hCG was normal in the benign PHPT control subjects (range: 0–17 fmol/mg Cr; nl < 50). In the PtCa subjects, three had normal total urinary hCG levels and survived complication free for at least 2 years; three had persistently elevated total urinary hCG levels (range: 217–1986 fmol/mg Cr) and sustained hip fracture (n = 3) and died (n = 2) within 3 and 6 months respectively; two had a rise in total urinary hCG and had hip fracture (n = 1) and died (n = 2) within 4 and 10 months respectively. Elevated urinary hCG was of the malignant hyperglycosylated isoform. Serum malignant hyperglycosylated hCG values in all of the cancer patients exceeded the maximal serum malignant hCG level of the PHPT subjects with benign disease (3.77 pmol/l). Conclusion hCG, especially itshyperglycosylated isoform, might add diagnostic and prognostic information in PtCa. Further studies would help to elucidate the role of hCG as a potential tumor marker in this disease. PMID:18625691

  17. Reduced gonadotropins in athymic mice: prevention by thymic transplantation.

    PubMed

    Rebar, R W; Morandini, I C; Benirschke, K; Petze, J E

    1980-12-01

    The reduction in pituitary concentrations of gonadotropins observed in 20-day old congenitally athymic nude mice in comparison to their normal heterozygous littermates was completely prevented in females and partially prevented in males by thymic transplantation on the first day of life. Those athymic mice receiving transplants but in which no thymic tissue could be found at sacrifice had reduced pituitary gonadotropin concentrations equivalent to sham-operated athymic animals. From these data we infer that the reduced concentrations of gonadotropins seen in the athymic animals are causally related to the absence of the thymus and suggest that the thymus, directly or indirectly, is necessary for development of normal function of the hypothalamic-pituitary-gonadal axis in mice.

  18. Response of micropenis to topical testosterone and gonadotropin.

    PubMed

    Klugo, R C; Cerny, J C

    1978-05-01

    Five patients were treated with gonadotropin and topical testosterone for micropenis associated with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonadotropin weekly for 3 weeks, with a 6-week interval followed by 10% topical testosterone cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent for both modes of therapy. Average penile growth response with gonadotropin was 14.3% increase in length and 5.0% increase of girth. Topical testosterone produced an average increase of 60% in penile length and 52.9% in girth. The greatest growth response occurred in prepubertal male subjects with a minimal response in postpubertal male subjects. This study suggests that 10% topical testosterone cream twice daily will produce effective penile growth. The response appears to be greater in younger children, which is consistent with previously published studies of age-related 5 reductase activity.

  19. A 4D Hyperspherical Interpretation of q-Space

    PubMed Central

    Hosseinbor, A. Pasha; Chung, Moo K.; Wu, Yu-Chien; Alexander, Andrew L.; Bendlin, Barbara B.

    2014-01-01

    3D q-space can be viewed as the surface of a 4D hypersphere. In this paper, we seek to develop a 4D hyperspherical interpretation of q-space by projecting it onto a hypersphere and subsequently modeling the q-space signal via 4D hyperspherical harmonics (HSH). Using this orthonormal basis, we analytically derive several quantitative indices and numerically estimate the diffusion ODF. Importantly, we derive the integral transform describing the relationship between the diffusion signal and propagator on a hypersphere. We also show that the HSH basis expends less fitting parameters than other well-established methods to achieve comparable signal and better ODF reconstructions. All in all, this work provides a new way of looking at q-space. PMID:24505799

  20. Relative charge transfer cross section from Rb (4d)

    NASA Astrophysics Data System (ADS)

    Shah, M. H.; Camp, H. A.; Trachy, M. L.; Fléchard, X.; Gearba, M. A.; Nguyen, H.; Brédy, R.; Lundeen, S. R.; Depaola, B. D.

    2005-08-01

    Relative charge transfer cross section measurements for the excited state Rb(4d) with 7keV Na+ is reported. The specific channels reported are Na++Rb(4d5/2)→Na(nl)+Rb+ , where the dominant transfer cross sections channels were nl=3d and 4s . Using a combination of a magneto-optical trap and recoil ion momentum spectroscopy (MOTRIMS methodology), the cross sections were measured relative to the previously studied Na++Rb(5s,5p) systems at the same collision energy.

  1. Relative charge transfer cross section from Rb(4d)

    SciTech Connect

    Shah, M.H.; Camp, H.A.; Trachy, M.L.; De Paola, B.D.; Flechard, X.; Gearba, M.A.; Nguyen, H.; Bredy, R.; Lundeen, S.R.

    2005-08-15

    Relative charge transfer cross section measurements for the excited state Rb(4d) with 7 keV Na{sup +} is reported. The specific channels reported are Na{sup +}+Rb(4d{sub 5/2}){yields}Na(nl)+Rb{sup +}, where the dominant transfer cross sections channels were nl=3d and 4s. Using a combination of a magneto-optical trap and recoil ion momentum spectroscopy (MOTRIMS methodology), the cross sections were measured relative to the previously studied Na{sup +}+Rb(5s,5p) systems at the same collision energy.

  2. The 4-D approach to visual control of autonomous systems

    NASA Technical Reports Server (NTRS)

    Dickmanns, Ernst D.

    1994-01-01

    Development of a 4-D approach to dynamic machine vision is described. Core elements of this method are spatio-temporal models oriented towards objects and laws of perspective projection in a foward mode. Integration of multi-sensory measurement data was achieved through spatio-temporal models as invariants for object recognition. Situation assessment and long term predictions were allowed through maintenance of a symbolic 4-D image of processes involving objects. Behavioral capabilities were easily realized by state feedback and feed-foward control.

  3. Emerging Applications of Abdominal 4D Flow MRI

    PubMed Central

    Roldán-Alzate, Alejandro; Francois, Christopher J.; Wieben, Oliver; Reeder, Scott B.

    2016-01-01

    OBJECTIVE Comprehensive assessment of abdominal hemodynamics is crucial for many clinical diagnoses but is challenged by a tremendous complexity of anatomy, normal physiology, and a wide variety of pathologic abnormalities. This article introduces 4D flow MRI as a powerful technique for noninvasive assessment of the hemodynamics of abdominal vascular territories. CONCLUSION Four-dimensional flow MRI provides clinicians with a more extensive and straightforward approach to evaluate disorders that affect blood flow in the abdomen. This review presents a series of clinical cases to illustrate the utility of 4D flow MRI in the comprehensive assessment of the abdominal circulation. PMID:27187681

  4. Biologically Active Chorionic Gonadotropin: Synthesis by the Human Fetus

    NASA Astrophysics Data System (ADS)

    McGregor, W. G.; Kuhn, R. W.; Jaffe, R. B.

    1983-04-01

    The kidney, and to a slight extent the liver, of human fetuses were found to synthesize and secrete the α subunit common to glycoprotein hormones. Fetal lung and muscle did not synthesize this protein. Since fetal kidney and liver were previously found to synthesize β chorionic gonadotropin, their ability to synthesize bioactive chorionic gonadotropin was also determined. The newly synthesized hormone bound to mouse Leydig cells and elicited a biological response: namely, the synthesis of testosterone. These results suggest that the human fetus may participate in metabolic homeostasis during its development.

  5. Gonadotropin-releasing hormone/human chorionic gonadotropin beta based recombinant antibodies and vaccines.

    PubMed

    Talwar, G P; Vyas, Hemant K; Purswani, Shilpi; Gupta, Jagdish C

    2009-12-01

    Gonadotropin-releasing hormone (GnRH) and human chorionic gonadotropin (hCG) are unique targets for the control of fertility. Immunological approaches to neutralizing these hormones have additional utility in cancer treatment. Vaccines have been developed against both GnRH and hCG and these have undergone Phase I/II clinical trials documenting their safety, reversibility and efficacy. The heterospecies dimer hCG vaccine prevented pregnancy in women of proven fertility without impairment of ovulation or derangement of menstrual regularity and bleeding profiles. The protective threshold of antibody titers to achieve efficacy was determined in these first-ever trials. Recently, a recombinant vaccine against the beta subunit of hCG linked to the B subunit of heat labile enterotoxin has been made and expressed as a glycosylated conjugate in Pichia pastoris. Experiments indicate its ability to generate antibodies above the protective threshold in all immunized Balb/c mice. Ectopic expression of hCG/hCGbeta is observed in many advanced stage cancers of various origins. A chimeric high affinity and specific recombinant antibody against hCGbeta linked to curcumin kills hCGbeta expressing T lymphoblastic leukemia cells without any deleterious effect. Several synthetic and recombinant vaccines have been developed against GnRH. These reduce serum testosterone to castration levels causing atrophy of the prostate. Three Phase I/II clinical trials conducted in India and Austria have shown that these vaccines elicit non-surgical reduction of testosterone, a fall in prostate specific antigen and clinical improvement of prostate carcinoma patients. A multimer recombinant vaccine against GnRH has high efficacy for sterilization of pigs and other animals. PMID:19854518

  6. Circulating kisspeptin and pituitary adenylate cyclase-activating polypeptide (PACAP) do not correlate with gonadotropin serum levels.

    PubMed

    Kanasaki, Haruhiko; Purwana, Indri N; Oride, Aki; Mijiddorj, Tselmeg; Sukhbaatar, Unurjargal; Miyazaki, Kohji

    2013-06-01

    Kisspeptins are known to be the principle regulators of the hypothalamic-pituitary gonadal (HPG) axis. In addition, the role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the regulation of pituitary gonadotropins has been elucidated. We measured plasma concentrations of kisspeptin and PACAP and determined whether the levels of these peptides varied in proportion to circulating gonadotropin levels. Plasma luteinizing hormone (LH) levels were higher in postmenopausal women and in patients with premature ovarian failure (POF) and lower in patients with idiopathic hypogonadotropic hypogonadism (IHH) compared with the LH level in normally menstruating women. Similarly, serum follicle-stimulating hormone levels were higher in postmenopausal women and in patients with POF but lower in pregnant women and patients with IHH compared with normally menstruating women. Plasma levels of kisspeptins were significantly higher in pregnant women compared with normally menstruating women. However, no significant differences were observed in postmenopausal women, patients with POF, and patients with IHH. On the other hand, plasma levels of PACAP were significantly lower in pregnant women, patients with POF, and in IHH patients when compared with normally menstruating women. No significant differences were observed in PACAP concentration between postmenopausal women and in normally menstruating women. Our observations suggest that the serum levels of kisspeptins and PACAP did not correlate with variations in serum gonadotropin levels.

  7. 2,4-Dichlorophenoxyacetic acid (2,4-D)

    Integrated Risk Information System (IRIS)

    2,4 - Dichlorophenoxyacetic acid ( 2,4 - D ) ; CASRN 94 - 75 - 7 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Asses

  8. 4D flow mri post-processing strategies for neuropathologies

    NASA Astrophysics Data System (ADS)

    Schrauben, Eric Mathew

    4D flow MRI allows for the measurement of a dynamic 3D velocity vector field. Blood flow velocities in large vascular territories can be qualitatively visualized with the added benefit of quantitative probing. Within cranial pathologies theorized to have vascular-based contributions or effects, 4D flow MRI provides a unique platform for comprehensive assessment of hemodynamic parameters. Targeted blood flow derived measurements, such as flow rate, pulsatility, retrograde flow, or wall shear stress may provide insight into the onset or characterization of more complex neuropathologies. Therefore, the thorough assessment of each parameter within the context of a given disease has important medical implications. Not surprisingly, the last decade has seen rapid growth in the use of 4D flow MRI. Data acquisition sequences are available to researchers on all major scanner platforms. However, the use has been limited mostly to small research trials. One major reason that has hindered the more widespread use and application in larger clinical trials is the complexity of the post-processing tasks and the lack of adequate tools for these tasks. Post-processing of 4D flow MRI must be semi-automated, fast, user-independent, robust, and reliably consistent for use in a clinical setting, within large patient studies, or across a multicenter trial. Development of proper post-processing methods coupled with systematic investigation in normal and patient populations pushes 4D flow MRI closer to clinical realization while elucidating potential underlying neuropathological origins. Within this framework, the work in this thesis assesses venous flow reproducibility and internal consistency in a healthy population. A preliminary analysis of venous flow parameters in healthy controls and multiple sclerosis patients is performed in a large study employing 4D flow MRI. These studies are performed in the context of the chronic cerebrospinal venous insufficiency hypothesis. Additionally, a

  9. Human Head and Neck Squamous Cell Carcinoma–Associated Semaphorin 4D Induces Expansion of Myeloid-Derived Suppressor Cells

    PubMed Central

    Han, Kyu Lee; Webb, Tonya J.

    2016-01-01

    One of the mechanisms by which malignancies can induce immune suppression is through the production of cytokines that affect the maturation and differentiation of inflammatory cells in the tumor microenvironment. Semaphorin 4D (Sema4D) is a proangiogenic cytokine produced by several malignancies, which has been described in the regulation of the immune system. In the present study, we examined the role of human head and neck squamous cell carcinoma (HNSCC)–secreted Sema4D on myeloid cell differentiation. CD33+ cells cultured in HNSCC cell line–derived conditioned medium differentiated into myeloid derived suppressor cells (MDSC) (CD33+CD11b+HLA-DR−/low). The addition of anti-Sema4D Ab to HNSCC conditioned medium significantly reduced the expansion of the MDSC population. Similarly, knockdown of Sema4D in an HNSCC cell line resulted in a loss of MDSC function as shown by a decrease in the production of the immune-suppressive cytokines arginase-1, TGF-β, and IL-10 by MDSC, concomitant with recovery of T cell proliferation and IFN-γ production following stimulation of CD3/CD28. Importantly, CD33+ myeloid and T cells cultured in conditioned medium of HNSCC cells in which Sema4D was knocked down promoted antitumor inflammatory profile, through recovery of the effector T cells (CD4+T-bet+ and CD8+T-bet+), as well as a decrease in regulatory T cells (CD4+CD25+FOXP3+). We also showed that Sema4D was comparable to GM-CSF in its induction of MDSC. Collectively, this study describes a novel immunosuppressive role for Sema4D in HNSCC through induction of MDSC, and it highlights Sema4D as a therapeutic target for future studies to enhance the antitumorigenic inflammatory response in HNSCC and other epithelial malignancies. PMID:26740106

  10. 4D MR imaging using robust internal respiratory signal

    NASA Astrophysics Data System (ADS)

    Hui, CheukKai; Wen, Zhifei; Stemkens, Bjorn; Tijssen, R. H. N.; van den Berg, C. A. T.; Hwang, Ken-Pin; Beddar, Sam

    2016-05-01

    The purpose of this study is to investigate the feasibility of using internal respiratory (IR) surrogates to sort four-dimensional (4D) magnetic resonance (MR) images. The 4D MR images were constructed by acquiring fast 2D cine MR images sequentially, with each slice scanned for more than one breathing cycle. The 4D volume was then sorted retrospectively using the IR signal. In this study, we propose to use multiple low-frequency components in the Fourier space as well as the anterior body boundary as potential IR surrogates. From these potential IR surrogates, we used a clustering algorithm to identify those that best represented the respiratory pattern to derive the IR signal. A study with healthy volunteers was performed to assess the feasibility of the proposed IR signal. We compared this proposed IR signal with the respiratory signal obtained using respiratory bellows. Overall, 99% of the IR signals matched the bellows signals. The average difference between the end inspiration times in the IR signal and bellows signal was 0.18 s in this cohort of matching signals. For the acquired images corresponding to the other 1% of non-matching signal pairs, the respiratory motion shown in the images was coherent with the respiratory phases determined by the IR signal, but not the bellows signal. This suggested that the IR signal determined by the proposed method could potentially correct the faulty bellows signal. The sorted 4D images showed minimal mismatched artefacts and potential clinical applicability. The proposed IR signal therefore provides a feasible alternative to effectively sort MR images in 4D.

  11. Inhibition of cyclic gonadotropin secretion by endogenous human prolactin.

    PubMed

    Tyson, J E; Khojandi, M; Huth, J; Smith, B; Thomas, P

    1975-02-01

    The resumption of cyclic uterine bleeding reportedly accompanies the use of human prolactin (HPRL)-suppressing agents in postpill galactorrhea-amenorrhea. In this laboratory, HPRL suppression with L-dopa was variable and short lived. Basal plasma HPRL levels were elevated before and after as much as five months of therapy. Galactorrhea persisted and mean gonadotropin concentrations were subnormal. An immediate and sustained attenuation of HPRL secretion ( less than 200 per cent) followed the use of 2-Br-alpha-ergocryptine (CB-154). Cyclic gonadotropin secretion resumed and was accompanied by ovulation and, in one instance, pregnancy. The cessation of galactorrhea was positively correlated with the rise in the daily concentration of 17 beta-estradiol. Cyclic postovulatory menstruation continued after the cessation of CB-154 treatment. HPRL levels remained normal. The daily patterns of human follicle-stimulating hormone (HFSH) and human tuteinizing hormone (HLH) secretion created by the suppression of HPRL displayed an inherent rhythmicity identical to that observed at the time of menarche. The inhibitory effects of HPRL appeared directed at cyclic rather than tonic gonadotropin secretion. At the same time, diminished ovarian estrogen production seemed to increase mammary gland sensitivity to HPRL, leading to lactation. One may postulate, therefore, that the ingestion of sex steroids is associated with an over-all suppression of endogenous cyclic and, to a lesser extent, tonic gonadotropin secretion secondary to which ovarian function is attenuated. Without physiologic concentration of circulating estrogen, HPRL induces mammary alveolar function with the production of a milklike secretion.

  12. Impact of incorporating visual biofeedback in 4D MRI.

    PubMed

    To, David T; Kim, Joshua P; Price, Ryan G; Chetty, Indrin J; Glide-Hurst, Carri K

    2016-05-08

    Precise radiation therapy (RT) for abdominal lesions is complicated by respiratory motion and suboptimal soft tissue contrast in 4D CT. 4D MRI offers improved con-trast although long scan times and irregular breathing patterns can be limiting. To address this, visual biofeedback (VBF) was introduced into 4D MRI. Ten volunteers were consented to an IRB-approved protocol. Prospective respiratory-triggered, T2-weighted, coronal 4D MRIs were acquired on an open 1.0T MR-SIM. VBF was integrated using an MR-compatible interactive breath-hold control system. Subjects visually monitored their breathing patterns to stay within predetermined tolerances. 4D MRIs were acquired with and without VBF for 2- and 8-phase acquisitions. Normalized respiratory waveforms were evaluated for scan time, duty cycle (programmed/acquisition time), breathing period, and breathing regularity (end-inhale coefficient of variation, EI-COV). Three reviewers performed image quality assessment to compare artifacts with and without VBF. Respiration-induced liver motion was calculated via centroid difference analysis of end-exhale (EE) and EI liver contours. Incorporating VBF reduced 2-phase acquisition time (4.7 ± 1.0 and 5.4 ± 1.5 min with and without VBF, respectively) while reducing EI-COV by 43.8% ± 16.6%. For 8-phase acquisitions, VBF reduced acquisition time by 1.9 ± 1.6 min and EI-COVs by 38.8% ± 25.7% despite breathing rate remaining similar (11.1 ± 3.8 breaths/min with vs. 10.5 ± 2.9 without). Using VBF yielded higher duty cycles than unguided free breathing (34.4% ± 5.8% vs. 28.1% ± 6.6%, respectively). Image grading showed that out of 40 paired evaluations, 20 cases had equivalent and 17 had improved image quality scores with VBF, particularly for mid-exhale and EI. Increased liver excursion was observed with VBF, where superior-inferior, anterior-posterior, and left-right EE-EI displacements were 14.1± 5.8, 4.9 ± 2.1, and 1.5 ± 1.0 mm, respectively, with VBF compared to 11.9

  13. Exome sequencing identifies PDE4D mutations in acrodysostosis.

    PubMed

    Lee, Hane; Graham, John M; Rimoin, David L; Lachman, Ralph S; Krejci, Pavel; Tompson, Stuart W; Nelson, Stanley F; Krakow, Deborah; Cohn, Daniel H

    2012-04-01

    Acrodysostosis is a dominantly-inherited, multisystem disorder characterized by skeletal, endocrine, and neurological abnormalities. To identify the molecular basis of acrodysostosis, we performed exome sequencing on five genetically independent cases. Three different missense mutations in PDE4D, which encodes cyclic AMP (cAMP)-specific phosphodiesterase 4D, were found to be heterozygous in three of the cases. Two of the mutations were demonstrated to have occurred de novo, providing strong genetic evidence of causation. Two additional cases were heterozygous for de novo missense mutations in PRKAR1A, which encodes the cAMP-dependent regulatory subunit of protein kinase A and which has been recently reported to be the cause of a form of acrodysostosis resistant to multiple hormones. These findings demonstrate that acrodysostosis is genetically heterogeneous and underscore the exquisite sensitivity of many tissues to alterations in cAMP homeostasis. PMID:22464252

  14. Intelligent Vehicle Systems: A 4D/RCS Approach

    SciTech Connect

    Madhavan, Raj

    2007-04-01

    This book presents new research on autonomous mobility capabilities and shows how technological advances can be anticipated in the coming two decades. An in-depth description is presented on the theoretical foundations and engineering approaches that enable these capabilities. Chapter 1 provides a brief introduction to the 4D/RCS reference model architecture and design methodology that has proven successful in guiding the development of autonomous mobility systems. Chapters 2 through 7 provide more detailed descriptions of research that has been conducted and algorithms that have been developed to implement the various aspects of the 4D/RCS reference model architecture and design methodology. Chapters 8 and 9 discuss applications, performance measures, and standards. Chapter 10 provides a history of Army and DARPA research in autonomous ground mobility. Chapter 11 provides a perspective on the potential future developments in autonomous mobility.

  15. Brain tissue segmentation in 4D CT using voxel classification

    NASA Astrophysics Data System (ADS)

    van den Boom, R.; Oei, M. T. H.; Lafebre, S.; Oostveen, L. J.; Meijer, F. J. A.; Steens, S. C. A.; Prokop, M.; van Ginneken, B.; Manniesing, R.

    2012-02-01

    A method is proposed to segment anatomical regions of the brain from 4D computer tomography (CT) patient data. The method consists of a three step voxel classification scheme, each step focusing on structures that are increasingly difficult to segment. The first step classifies air and bone, the second step classifies vessels and the third step classifies white matter, gray matter and cerebrospinal fluid. As features the time averaged intensity value and the temporal intensity change value were used. In each step, a k-Nearest-Neighbor classifier was used to classify the voxels. Training data was obtained by placing regions of interest in reconstructed 3D image data. The method has been applied to ten 4D CT cerebral patient data. A leave-one-out experiment showed consistent and accurate segmentation results.

  16. 4D embryonic cardiography using gated optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Jenkins, M. W.; Rothenberg, F.; Roy, D.; Nikolski, V. P.; Hu, Z.; Watanabe, M.; Wilson, D. L.; Efimov, I. R.; Rollins, A. M.

    2006-01-01

    Simultaneous imaging of very early embryonic heart structure and function has technical limitations of spatial and temporal resolution. We have developed a gated technique using optical coherence tomography (OCT) that can rapidly image beating embryonic hearts in four-dimensions (4D), at high spatial resolution (10-15 μm), and with a depth penetration of 1.5 - 2.0 mm that is suitable for the study of early embryonic hearts. We acquired data from paced, excised, embryonic chicken and mouse hearts using gated sampling and employed image processing techniques to visualize the hearts in 4D and measure physiologic parameters such as cardiac volume, ejection fraction, and wall thickness. This technique is being developed to longitudinally investigate the physiology of intact embryonic hearts and events that lead to congenital heart defects.

  17. Review: Melatonin stimulates the synthesis and release of gonadotropin-inhibitory hormone in birds.

    PubMed

    Chowdhury, Vishwajit S; Ubuka, Takayoshi; Tsutsui, Kazuyoshi

    2013-01-15

    Gonadotropin-inhibitory hormone (GnIH), a neuropeptide that inhibits gonadotropin synthesis and release, was first identified in the quail hypothalamus. To understand the physiological role of GnIH, this review will demonstrate the mechanisms that regulate GnIH synthesis and release. Pinealectomy (Px) combined with orbital enucleation (Ex) decreased the synthesis of GnIH precursor mRNA and content of mature GnIH peptide in the diencephalon. Melatonin administration to Px plus Ex birds caused a dose-dependent increase in the synthesis of GnIH precursor mRNA and production of mature peptide. A melatonin receptor subtype, Mel(1c,) was expressed in GnIH-immunoreactive neurons, suggesting direct action of melatonin on GnIH neurons. Melatonin administration further increased GnIH release in a dose-dependent manner from hypothalamic explants in vitro. GnIH mRNA expression and GnIH release during the dark period were greater than those during the light period in explants from quail exposed to long-day photoperiods. Conversely, plasma luteinizing hormone (LH) concentration decreased during the dark period. This review summarizes that melatonin appears to act on GnIH neurons in stimulating not only GnIH synthesis but also its release, thus inhibiting plasma LH concentration in birds.

  18. 4D flow cardiovascular magnetic resonance consensus statement.

    PubMed

    Dyverfeldt, Petter; Bissell, Malenka; Barker, Alex J; Bolger, Ann F; Carlhäll, Carl-Johan; Ebbers, Tino; Francios, Christopher J; Frydrychowicz, Alex; Geiger, Julia; Giese, Daniel; Hope, Michael D; Kilner, Philip J; Kozerke, Sebastian; Myerson, Saul; Neubauer, Stefan; Wieben, Oliver; Markl, Michael

    2015-01-01

    Pulsatile blood flow through the cavities of the heart and great vessels is time-varying and multidirectional. Access to all regions, phases and directions of cardiovascular flows has formerly been limited. Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) has enabled more comprehensive access to such flows, with typical spatial resolution of 1.5×1.5×1.5 - 3×3×3 mm(3), typical temporal resolution of 30-40 ms, and acquisition times in the order of 5 to 25 min. This consensus paper is the work of physicists, physicians and biomedical engineers, active in the development and implementation of 4D Flow CMR, who have repeatedly met to share experience and ideas. The paper aims to assist understanding of acquisition and analysis methods, and their potential clinical applications with a focus on the heart and greater vessels. We describe that 4D Flow CMR can be clinically advantageous because placement of a single acquisition volume is straightforward and enables flow through any plane across it to be calculated retrospectively and with good accuracy. We also specify research and development goals that have yet to be satisfactorily achieved. Derived flow parameters, generally needing further development or validation for clinical use, include measurements of wall shear stress, pressure difference, turbulent kinetic energy, and intracardiac flow components. The dependence of measurement accuracy on acquisition parameters is considered, as are the uses of different visualization strategies for appropriate representation of time-varying multidirectional flow fields. Finally, we offer suggestions for more consistent, user-friendly implementation of 4D Flow CMR acquisition and data handling with a view to multicenter studies and more widespread adoption of the approach in routine clinical investigations. PMID:26257141

  19. Phosphodiesterase 4D gene polymorphisms in sudden sensorineural hearing loss.

    PubMed

    Chien, Chen-Yu; Tai, Shu-Yu; Wang, Ling-Feng; Hsi, Edward; Chang, Ning-Chia; Wang, Hsun-Mo; Wu, Ming-Tsang; Ho, Kuen-Yao

    2016-09-01

    The phosphodiesterase 4D (PDE4D) gene has been reported as a risk gene for ischemic stroke. The vascular factors are between the hypothesized etiologies of sudden sensorineural hearing loss (SSNHL), and this genetic effect might be attributed for its role in SSNHL. We hypothesized that genetic variants of the PDE4D gene are associated with susceptibility to SSNHL. We conducted a case-control study with 362 SSNHL cases and 209 controls. Three single nucleotide polymorphisms (SNPs) were selected. The genotypes were determined using TaqMan technology. Hardy-Weinberg equilibrium (HWE) was tested for each SNP, and genetic effects were evaluated according to three inheritance modes. We carried out sex-specific analysis to analyze the overall data. All three SNPs were in HWE. When subjects were stratified by sex, the genetic effect was only evident in females but not in males. The TT genotype of rs702553 exhibited an adjusted odds ratio (OR) of 3.83 (95 % confidence interval = 1.46-11.18) (p = 0.006) in female SSNHL. The TT genotype of SNP rs702553 was associated with female SSNHL under the recessive model (p = 0.004, OR 3.70). In multivariate logistic regression analysis, TT genotype of rs702553 was significantly associated with female SSNHL (p = 0.0043, OR 3.70). These results suggest that PDE4D gene polymorphisms influence the susceptibility for the development of SSNHL in the southern Taiwanese female population.

  20. A 4D Hyperspherical Interpretation of q-Space

    PubMed Central

    Hosseinbor, A. Pasha; Chung, Moo K.; Wu, Yu-Chien; Bendlin, Barbara B.; Alexander, Andrew L.

    2015-01-01

    3D q-space can be viewed as the surface of a 4D hypersphere. In this paper, we seek to develop a 4D hyperspherical interpretation of q-space by projecting it onto a hypersphere and subsequently modeling the q-space signal via 4D hyperspherical harmonics (HSH). Using this orthonormal basis, we derive several well-established q-space indices and numerically estimate the diffusion orientation distribution function (dODF). We also derive the integral transform describing the relationship between the diffusion signal and propagator on a hypersphere. Most importantly, we will demonstrate that for hybrid diffusion imaging (HYDI) acquisitions low order linear expansion of the HSH basis is sufficient to characterize diffusion in neural tissue. In fact, the HSH basis achieves comparable signal and better dODF reconstructions than other well-established methods, such as Bessel Fourier orientation reconstruction (BFOR), using fewer fitting parameters. All in all, this work provides a new way of looking at q-space. PMID:25624043

  1. 4D-Flow validation, numerical and experimental framework

    NASA Astrophysics Data System (ADS)

    Sansom, Kurt; Liu, Haining; Canton, Gador; Aliseda, Alberto; Yuan, Chun

    2015-11-01

    This work presents a group of assessment metrics of new 4D MRI flow sequences, an imaging modality that allows for visualization of three-dimensional pulsatile flow in the cardiovascular anatomy through time-resolved three-dimensional blood velocity measurements from cardiac-cycle synchronized MRI acquisition. This is a promising tool for clinical assessment but lacks a robust validation framework. First, 4D-MRI flow in a subject's stenotic carotid bifurcation is compared with a patient-specific CFD model using two different boundary condition methods. Second, Particle Image Velocimetry in a patient-specific phantom is used as a benchmark to compare the 4D-MRI in vivo measurements and CFD simulations under the same conditions. Comparison of estimated and measureable flow parameters such as wall shear stress, fluctuating velocity rms, Lagrangian particle residence time, will be discussed, with justification for their biomechanics relevance and the insights they can provide on the pathophysiology of arterial disease: atherosclerosis and intimal hyperplasia. Lastly, the framework is applied to a new sequence to provide a quantitative assessment. A parametric analysis on the carotid bifurcation pulsatile flow conditions will be presented and an accuracy assessment provided.

  2. Gonadotropin (LH and FSH) response after submaximal GnRH stimulation in depressed premenopausal women and healthy controls.

    PubMed

    Amsterdam, J D; Maislin, G; Rosenzweig, M; Halbrecht, U

    1995-01-01

    Although hormonal response abnormalities in depression have been demonstrated in several hypothalamic-pituitary-target organ axes after a variety of neuroendocrine challenge tests, studies of hypothalamic-pituitary-gonadal (HPG) axis function have been inconsistent in their findings. The use of maximal or supramaximal doses of gonadotropin-releasing hormone (GnRH) in early studies (150-600 micrograms) may have masked the presence of more subtle disturbances in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) responsiveness in depression. We hypothesized that submaximal doses of GnRH might reveal a more subtle dysregulation in gonadotropin responsiveness in depression, and therefore measured LH and FSH responses after GnRH 10 micrograms and 90 micrograms doses in nine premenopausal depressed women and six healthy controls. There were no statistically significant differences between subject groups for mean basal LH, FSH, and estradiol concentrations, nor for any of the LH and FSH response values after either GnRH stimulation dose. The present observations of an intact HPG axis in depression contrast with findings of disturbances in most other hypothalamic-pituitary axes, and suggest that neuroendocrine dysregulation in depression might not represent a generalized limbic system-hypothalamic-pituitary abnormality, but rather a more restricted lesion sparing the medial preoptic and/or arcuate region of the hypothalamus which regulates gonadotropin secretion.

  3. Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma.

    PubMed

    Ge, Xuecai; Milenkovic, Ljiljana; Suyama, Kaye; Hartl, Tom; Purzner, Teresa; Winans, Amy; Meyer, Tobias; Scott, Matthew P

    2015-01-01

    Alterations in Hedgehog (Hh) signaling lead to birth defects and cancers including medulloblastoma, the most common pediatric brain tumor. Although inhibitors targeting the membrane protein Smoothened suppress Hh signaling, acquired drug resistance and tumor relapse call for additional therapeutic targets. Here we show that phosphodiesterase 4D (PDE4D) acts downstream of Neuropilins to control Hh transduction and medulloblastoma growth. PDE4D interacts directly with Neuropilins, positive regulators of Hh pathway. The Neuropilin ligand Semaphorin3 enhances this interaction, promoting PDE4D translocation to the plasma membrane and cAMP degradation. The consequent inhibition of protein kinase A (PKA) enhances Hh transduction. In the developing cerebellum, genetic removal of Neuropilins reduces Hh signaling activity and suppresses proliferation of granule neuron precursors. In mouse medulloblastoma allografts, PDE4D inhibitors suppress Hh transduction and inhibit tumor growth. Our findings reveal a new regulatory mechanism of Hh transduction, and highlight PDE4D as a promising target to treat Hh-related tumors. PMID:26371509

  4. Phosphodiesterase 4D acts downstream of Neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma

    PubMed Central

    Ge, Xuecai; Milenkovic, Ljiljana; Suyama, Kaye; Hartl, Tom; Purzner, Teresa; Winans, Amy; Meyer, Tobias; Scott, Matthew P

    2015-01-01

    Alterations in Hedgehog (Hh) signaling lead to birth defects and cancers including medulloblastoma, the most common pediatric brain tumor. Although inhibitors targeting the membrane protein Smoothened suppress Hh signaling, acquired drug resistance and tumor relapse call for additional therapeutic targets. Here we show that phosphodiesterase 4D (PDE4D) acts downstream of Neuropilins to control Hh transduction and medulloblastoma growth. PDE4D interacts directly with Neuropilins, positive regulators of Hh pathway. The Neuropilin ligand Semaphorin3 enhances this interaction, promoting PDE4D translocation to the plasma membrane and cAMP degradation. The consequent inhibition of protein kinase A (PKA) enhances Hh transduction. In the developing cerebellum, genetic removal of Neuropilins reduces Hh signaling activity and suppresses proliferation of granule neuron precursors. In mouse medulloblastoma allografts, PDE4D inhibitors suppress Hh transduction and inhibit tumor growth. Our findings reveal a new regulatory mechanism of Hh transduction, and highlight PDE4D as a promising target to treat Hh-related tumors. DOI: http://dx.doi.org/10.7554/eLife.07068.001 PMID:26371509

  5. Impact of gonadotropin-releasing hormone antagonist addition on pregnancy rates in gonadotropin-stimulated intrauterine insemination cycles

    PubMed Central

    Jain, Shikha; Majumdar, Abha

    2016-01-01

    OBJECTIVES: The objective of the study is to evaluate the efficacy of gonadotropin-releasing hormone (GnRH) antagonist in improving clinical pregnancy rate in gonadotropin-stimulated intrauterine insemination (IUI) cycles in patients of unexplained infertility. STUDY DESIGN: This was a prospective, randomized case-controlled study. SETTINGS: The study was conducted in the infertility clinic of a tertiary care center. MATERIALS AND METHODS: Four hundred twenty-seven women undergoing IUI following controlled ovarian stimulation with gonadotropins (recombinant follicle-stimulating hormone [r-FSH] 75 IU/day) were randomly divided into two groups. Women in Group I received GnRH antagonist (Cetrorelix 0.25 mg/day) in a multiple dose flexible protocol. Women in Group II received r-FSH alone. Ovulatory trigger was given with human chorionic gonadotropin 5000 IU when dominant follicle was ≥18 mm. IUI was performed within 44–48 h. Both groups received similar luteal phase support. Primary outcome measure was clinical pregnancy rate. The trial was powered to detect an absolute increase in clinical pregnancy rate by 13% from an assumed 20% clinical pregnancy rate in the control group, with an alpha error level of 0.05 and a beta error level of 0.20. RESULTS: Clinical pregnancy rate in Groups I and II was 27.6% (n = 56) and 26.5% (n = 54), respectively (P=0.800). Ongoing pregnancy and multiple pregnancy rates were likewise similar between the groups. CONCLUSIONS: Addition of GnRH antagonist to gonadotropin-stimulated IUI cycles results in no significant difference in clinical pregnancy rate. PMID:27803582

  6. Methoxychlor-induced atresia in the mouse involves Bcl-2 family members, but not gonadotropins or estradiol.

    PubMed

    Borgeest, Christina; Miller, Kimberly P; Gupta, Rupesh; Greenfeld, Chuck; Hruska, Kathleen S; Hoyer, Patricia; Flaws, Jodi A

    2004-06-01

    Methoxychlor (MXC) is an organochlorine pesticide that increases the rate of ovarian atresia. To date, little is known about the mechanism by which MXC induces atresia. Because Bcl-2 (an antiapoptotic factor), Bax (a proapoptotic factor), gonadotropins, and estradiol are important regulators of atresia in the ovary, the purpose of this study was first to examine whether MXC-induced atresia occurred through alterations in Bcl-2 or Bax, and second, to examine the effect of MXC on gonadotropins, estradiol, and their receptors. CD-1 mice were dosed with 8-64 mg kg(-1) day(-1) MXC or vehicle (sesame oil). Ovaries were subjected to analysis of antral follicle numbers, Bcl-2, Bax, estrogen receptor, and follicle-stimulating hormone receptor levels. Blood was used to measure gonadotropins and estradiol. In some experiments, mice that overexpressed Bcl-2 or mice that were deficient in Bax were dosed with MXC or vehicle and their ovaries were analyzed for atresia. MXC caused a dose-dependent increase in the percentage of atretic antral follicles compared with controls at the 32 and 64 mg kg(-1) day(-1) doses of MXC. MXC treatment did not result in changes in Bcl-2 levels, but it did result in an increase in Bax levels in antral follicles. MXC treatment did not affect gonadotropin or estradiol levels, nor did it affect the levels of follicle-stimulating hormone or estrogen receptors. Mice that overexpressed Bcl-2 or mice that were deficient in Bax were protected from MXC-induced atresia. These data suggest that MXC induces atresia through direct effects on the Bax and Bcl-2 signaling pathways in the ovary.

  7. Free β-human chorionic gonadotropin, total human chorionic gonadotropin and maternal risk of breast cancer

    PubMed Central

    Toriola, Adetunji T; Tolockiene, Egle; Schock, Helena; Surcel, Helja-Marja; Zeleniuch-Jacquotte, Anne; Wadell, Goran; Toniolo, Paolo; Lundin, Eva; Grankvist, Kjell; Lukanova, Annekatrin

    2014-01-01

    Background We investigated whether the free β-human chorionic gonadotropin (free β-hCG) would provide additional information to that provided by total hCG alone and thus be useful in future epidemiological studies relating hCG to maternal breast cancer risk. Materials & methods Cases (n = 159) and controls (n = 286) were a subset of our previous study within the Northern Sweden Maternity Cohort on total hCG during primiparous pregnancy and breast cancer risk. Results The associations between total hCG (hazard ratio: 0.79; 95% CI: 0.49–1.27), free β-hCG (hazard ratio: 0.85; 95% CI: 0.33–2.18) and maternal risk of breast cancer were very similar in all analyses and mutual adjustment for either one had minor effects on the risk estimates. Conclusion In the absence of a reliable assay on intact hCG, total hCG alone can be used in epidemiological studies investigating hCG and breast cancer risk, as free β-hCG does not appear to provide any additional information. PMID:24559445

  8. Effects of gonadotropin inhibitory hormone or gonadotropin-releasing hormone on reproduction-related genes in the protandrous cinnamon clownfish, Amphiprion melanopus.

    PubMed

    Choi, Young Jae; Kim, Na Na; Habibi, Hamid R; Choi, Cheol Young

    2016-09-01

    Hypothalamic peptide neurohormones such as gonadotropin-releasing hormones (GnRHs) and gonadotropin-inhibitory hormone (GnIH) play pivotal roles in the control of reproduction and gonadal maturation in teleost fish. To study the effects of GnIH on fish reproduction, we investigated the influence of seabream GnRH (sbGnRH) and GnIH (both alone and in combination) on levels of reproductive genes (GnIH, GnIH-receptor [GnIH-R], melatonin receptor [MT3], sbGnRH, and gonadotropic hormones [GTHs]) during different stages of gonadal maturation in male, female, and immature cinnamon clownfish, Amphiprion melanopus. The results showed that the expression levels of GnIH, GnIH-R, and MT3 genes increased after the GnIH injection, but decreased after the sbGnRH injection. In addition, these gene expression levels gradually lowered after GnIH3 and sbGnRH combination treatment, as compared to the MT3 mRNA levels of GnIH treatment alone. However, the expression levels of the HPG (hypothalamus-pituitary-gonad) axis genes (sbGnRH and GTHs) decreased after the GnIH injection, but increased after the sbGnRH injection. In all cinnamon clownfish groups, HPG axis gene mRNA levels gradually decreased after mixed GnIH3 and sbGnRH treatment, compared to GnIH treatment alone. The present study provides novel information on the effects of GnIH and strongly supports the hypothesis that GnIH plays an important role in the negative regulation of the HPG axis in the protandrous cinnamon clownfish. PMID:27288637

  9. Cleavage pattern and fate map of the mesentoblast, 4d, in the gastropod Crepidula: a hallmark of spiralian development

    PubMed Central

    2012-01-01

    include the adult heart, internal foot tissues, and additional muscle and mesenchymal cells derived from later-born progeny of the left and right teloblasts. To test whether other cells can compensate for the loss of these tissues (that is, undergo regulation), specific cells were ablated in C. fornicata. Conclusions Our results present the first fate map of the 4d micromere sublineages in a mollusk. The fate map reveals that endodermal and mesodermal fates segregate much later than previously thought. We observed little evidence of regulation between sublineages, consistent with a lineage-driven cell specification process. Our results provide a framework for comparisons with other spiralians and lay the groundwork for investigation of the molecular mechanisms of endomesoderm formation, germ line segregation and bilateral differentiation in Crepidula. PMID:22992254

  10. 4D Proton treatment planning strategy for mobile lung tumors

    SciTech Connect

    Kang Yixiu; Zhang Xiaodong; Chang, Joe Y.; Wang He; Wei Xiong; Liao Zhongxing; Komaki, Ritsuko; Cox, James D.; Balter, Peter A.; Liu, Helen; Zhu, X. Ronald; Mohan, Radhe; Dong Lei . E-mail: ldong@mdanderson.org

    2007-03-01

    Purpose: To investigate strategies for designing compensator-based 3D proton treatment plans for mobile lung tumors using four-dimensional computed tomography (4DCT) images. Methods and Materials: Four-dimensional CT sets for 10 lung cancer patients were used in this study. The internal gross tumor volume (IGTV) was obtained by combining the tumor volumes at different phases of the respiratory cycle. For each patient, we evaluated four planning strategies based on the following dose calculations: (1) the average (AVE) CT; (2) the free-breathing (FB) CT; (3) the maximum intensity projection (MIP) CT; and (4) the AVE CT in which the CT voxel values inside the IGTV were replaced by a constant density (AVE{sub R}IGTV). For each strategy, the resulting cumulative dose distribution in a respiratory cycle was determined using a deformable image registration method. Results: There were dosimetric differences between the apparent dose distribution, calculated on a single CT dataset, and the motion-corrected 4D dose distribution, calculated by combining dose distributions delivered to each phase of the 4DCT. The AVE{sub R}IGTV plan using a 1-cm smearing parameter had the best overall target coverage and critical structure sparing. The MIP plan approach resulted in an unnecessarily large treatment volume. The AVE and FB plans using 1-cm smearing did not provide adequate 4D target coverage in all patients. By using a larger smearing value, adequate 4D target coverage could be achieved; however, critical organ doses were increased. Conclusion: The AVE{sub R}IGTV approach is an effective strategy for designing proton treatment plans for mobile lung tumors.

  11. Localization of 4D gravity on pure geometrical thick branes

    SciTech Connect

    Barbosa-Cendejas, Nandinii; Herrera-Aguilar, Alfredo

    2006-04-15

    We consider the generation of thick brane configurations in a pure geometric Weyl integrable 5D spacetime which constitutes a non-Riemannian generalization of Kaluza-Klein (KK) theory. In this framework, we show how 4D gravity can be localized on a scalar thick brane which does not necessarily respect reflection symmetry, generalizing in this way several previous models based on the Randall-Sundrum (RS) system and avoiding both, the restriction to orbifold geometries and the introduction of the branes in the action by hand. We first obtain a thick brane solution that preserves 4D Poincare invariance and breaks Z{sub 2}-symmetry along the extra dimension which, indeed, can be either compact or extended, and supplements brane solutions previously found by other authors. In the noncompact case, this field configuration represents a thick brane with positive energy density centered at y=c{sub 2}, whereas pairs of thick branes arise in the compact case. Remarkably, the Weylian scalar curvature is nonsingular along the fifth dimension in the noncompact case, in contraposition to the RS thin brane system. We also recast the wave equations of the transverse traceless modes of the linear fluctuations of the classical background into a Schroedinger's equation form with a volcano potential of finite bottom in both the compact and the extended cases. We solve Schroedinger equation for the massless zero mode m{sup 2}=0 and obtain a single bound wave function which represents a stable 4D graviton. We also get a continuum gapless spectrum of KK states with m{sup 2}>0 that are suppressed at y=c{sub 2} and turn asymptotically into plane waves.

  12. Phase and amplitude binning for 4D-CT imaging

    NASA Astrophysics Data System (ADS)

    Abdelnour, A. F.; Nehmeh, S. A.; Pan, T.; Humm, J. L.; Vernon, P.; Schöder, H.; Rosenzweig, K. E.; Mageras, G. S.; Yorke, E.; Larson, S. M.; Erdi, Y. E.

    2007-07-01

    We compare the consistency and accuracy of two image binning approaches used in 4D-CT imaging. One approach, phase binning (PB), assigns each breathing cycle 2π rad, within which the images are grouped. In amplitude binning (AB), the images are assigned bins according to the breathing signal's full amplitude. To quantitate both approaches we used a NEMA NU2-2001 IEC phantom oscillating in the axial direction and at random frequencies and amplitudes, approximately simulating a patient's breathing. 4D-CT images were obtained using a four-slice GE Lightspeed CT scanner operating in cine mode. We define consistency error as a measure of ability to correctly bin over repeated cycles in the same field of view. Average consistency error μe ± σe in PB ranged from 18% ± 20% to 30% ± 35%, while in AB the error ranged from 11% ± 14% to 20% ± 24%. In PB nearly all bins contained sphere slices. AB was more accurate, revealing empty bins where no sphere slices existed. As a proof of principle, we present examples of two non-small cell lung carcinoma patients' 4D-CT lung images binned by both approaches. While AB can lead to gaps in the coronal images, depending on the patient's breathing pattern, PB exhibits no gaps but suffers visible artifacts due to misbinning, yielding images that cover a relatively large amplitude range. AB was more consistent, though often resulted in gaps when no data existed due to patients' breathing pattern. We conclude AB is more accurate than PB. This has important consequences to treatment planning and diagnosis.

  13. Non-spherical particle generation from 4D optofluidic fabrication.

    PubMed

    Paulsen, Kevin S; Chung, Aram J

    2016-08-01

    Particles with non-spherical shapes can exhibit properties which are not available from spherical shaped particles. Complex shaped particles can provide unique benefits for areas such as drug delivery, tissue engineering, structural materials, and self-assembly building blocks. Current methods of creating complex shaped particles such as 3D printing, photolithography, and imprint lithography are limited by either slow speeds, shape limitations, or expensive processes. Previously, we presented a novel microfluidic flow lithography fabrication scheme combined with fluid inertia called optofluidic fabrication for the creation of complex shaped three-dimensional (3D) particles. This process was able to address the aforementioned limits and overcome two-dimensional shape limitations faced by traditional flow lithography methods; however, all of the created 3D particle shapes displayed top-down symmetry. Here, by introducing the time dimension into our existing optofluidic fabrication process, we break this top-down symmetry, generating fully asymmetric 3D particles where we termed the process: four-dimensional (4D) optofluidic fabrication. This 4D optofluidic fabrication is comprised of three sequential procedures. First, density mismatched precursor fluids flow past pillars within fluidic channels to manipulate the flow cross sections via fluid inertia. Next, the time dimension is incorporated by stopping the flow and allowing the denser fluids to settle by gravity to create asymmetric flow cross sections. Finally, the fluids are exposed to patterned ultraviolet (UV) light in order to polymerize fully asymmetric 3D-shaped particles. By varying inertial flow shaping, gravity-induced flow shaping, and UV light patterns, 4D optofluidic fabrication can create an infinite set of complex shaped asymmetric particles. PMID:27092661

  14. Non-spherical particle generation from 4D optofluidic fabrication.

    PubMed

    Paulsen, Kevin S; Chung, Aram J

    2016-08-01

    Particles with non-spherical shapes can exhibit properties which are not available from spherical shaped particles. Complex shaped particles can provide unique benefits for areas such as drug delivery, tissue engineering, structural materials, and self-assembly building blocks. Current methods of creating complex shaped particles such as 3D printing, photolithography, and imprint lithography are limited by either slow speeds, shape limitations, or expensive processes. Previously, we presented a novel microfluidic flow lithography fabrication scheme combined with fluid inertia called optofluidic fabrication for the creation of complex shaped three-dimensional (3D) particles. This process was able to address the aforementioned limits and overcome two-dimensional shape limitations faced by traditional flow lithography methods; however, all of the created 3D particle shapes displayed top-down symmetry. Here, by introducing the time dimension into our existing optofluidic fabrication process, we break this top-down symmetry, generating fully asymmetric 3D particles where we termed the process: four-dimensional (4D) optofluidic fabrication. This 4D optofluidic fabrication is comprised of three sequential procedures. First, density mismatched precursor fluids flow past pillars within fluidic channels to manipulate the flow cross sections via fluid inertia. Next, the time dimension is incorporated by stopping the flow and allowing the denser fluids to settle by gravity to create asymmetric flow cross sections. Finally, the fluids are exposed to patterned ultraviolet (UV) light in order to polymerize fully asymmetric 3D-shaped particles. By varying inertial flow shaping, gravity-induced flow shaping, and UV light patterns, 4D optofluidic fabrication can create an infinite set of complex shaped asymmetric particles.

  15. Founding Gravitation in 4D Euclidean Space-Time Geometry

    SciTech Connect

    Winkler, Franz-Guenter

    2010-11-24

    The Euclidean interpretation of special relativity which has been suggested by the author is a formulation of special relativity in ordinary 4D Euclidean space-time geometry. The natural and geometrically intuitive generalization of this view involves variations of the speed of light (depending on location and direction) and a Euclidean principle of general covariance. In this article, a gravitation model by Jan Broekaert, which implements a view of relativity theory in the spirit of Lorentz and Poincare, is reconstructed and shown to fulfill the principles of the Euclidean approach after an appropriate reinterpretation.

  16. Multicolor 4D Fluorescence Microscopy using Ultrathin Bessel Light Sheets.

    PubMed

    Zhao, Teng; Lau, Sze Cheung; Wang, Ying; Su, Yumian; Wang, Hao; Cheng, Aifang; Herrup, Karl; Ip, Nancy Y; Du, Shengwang; Loy, M M T

    2016-01-01

    We demonstrate a simple and efficient method for producing ultrathin Bessel ('non-diffracting') light sheets of any color using a line-shaped beam and an annulus filter. With this robust and cost-effective technology, we obtained two-color, 3D images of biological samples with lateral/axial resolution of 250 nm/400 nm, and high-speed, 4D volume imaging of 20 μm sized live sample at 1 Hz temporal resolution. PMID:27189786

  17. Oblique sounding using the DPS-4D stations in Europe

    NASA Astrophysics Data System (ADS)

    Mosna, Zbysek; Kouba, Daniel; Koucka Knizova, Petra; Arikan, Feza; Arikan, Orhan; Gok, Gokhan; Rejfek, Lubos

    2016-07-01

    The DPS-4D Digisondes are capable of detection of echoes from neighbouring European stations. Currently, a campaign with high-temporal resolution of 5 min is being run. Further, ionograms from regular vertical sounding with 15 min resolution provide us with oblique reflections together with vertical reflections. We analyzed profiles of electron concentration and basic ionospheric parameters derived from the ionograms. We compared results derived from reflections from the ionosphere above the stations (vertical sounding) with information derived from oblique reflections between the stations. This study is supported by the Joint TUBITAK 114E092 and AS CR 14/001 projects.

  18. Lagrangian constraints and renormalization of 4D gravity

    NASA Astrophysics Data System (ADS)

    Park, I. Y.

    2015-04-01

    It has been proposed in [21] that 4D Einstein gravity becomes effectively reduced to 3D after solving the Lagrangian analogues of the Hamiltonian and momentum constraints of the Hamiltonian quantization. The analysis in [21] was carried out at the classical/operator level. We review the proposal and make a transition to the path integral account. We then set the stage for explicitly carrying out the two-loop renormalization procedure of the resulting 3D action. We also address a potentially subtle issue in the gravity context concerning whether renormalizability does not depend on the background around which the original action is expanded.

  19. Multicolor 4D Fluorescence Microscopy using Ultrathin Bessel Light Sheets

    PubMed Central

    Zhao, Teng; Lau, Sze Cheung; Wang, Ying; Su, Yumian; Wang, Hao; Cheng, Aifang; Herrup, Karl; Ip, Nancy Y.; Du, Shengwang; Loy, M. M. T.

    2016-01-01

    We demonstrate a simple and efficient method for producing ultrathin Bessel (‘non-diffracting’) light sheets of any color using a line-shaped beam and an annulus filter. With this robust and cost-effective technology, we obtained two-color, 3D images of biological samples with lateral/axial resolution of 250 nm/400 nm, and high-speed, 4D volume imaging of 20 μm sized live sample at 1 Hz temporal resolution. PMID:27189786

  20. All the supersymmetric configurations of N=4, d=4 supergravity

    NASA Astrophysics Data System (ADS)

    Bellorín, Jorge; Ortín, Tomás

    2005-10-01

    All the supersymmetric configurations of pure, ungauged, N=4, d=4 supergravity are classified in a formalism that keeps manifest the S and T dualities of the theory. We also find simple equations that need to be satisfied by the configurations to be classical solutions of the theory. While the solutions associated to null Killing vectors were essentially classified by Tod (a classification that we refine), we find new configurations and solutions associated to timelike Killing vectors that do not satisfy Tod's rigidity hypothesis (hence, they have a nontrivial U(1) connection) and whose supersymmetry projector is associated to 1-dimensional objects (strings), although they have a trivial axion field.

  1. Actively triggered 4d cone-beam CT acquisition

    SciTech Connect

    Fast, Martin F.; Wisotzky, Eric; Oelfke, Uwe; Nill, Simeon

    2013-09-15

    Purpose: 4d cone-beam computed tomography (CBCT) scans are usually reconstructed by extracting the motion information from the 2d projections or an external surrogate signal, and binning the individual projections into multiple respiratory phases. In this “after-the-fact” binning approach, however, projections are unevenly distributed over respiratory phases resulting in inefficient utilization of imaging dose. To avoid excess dose in certain respiratory phases, and poor image quality due to a lack of projections in others, the authors have developed a novel 4d CBCT acquisition framework which actively triggers 2d projections based on the forward-predicted position of the tumor.Methods: The forward-prediction of the tumor position was independently established using either (i) an electromagnetic (EM) tracking system based on implanted EM-transponders which act as a surrogate for the tumor position, or (ii) an external motion sensor measuring the chest-wall displacement and correlating this external motion to the phase-shifted diaphragm motion derived from the acquired images. In order to avoid EM-induced artifacts in the imaging detector, the authors devised a simple but effective “Faraday” shielding cage. The authors demonstrated the feasibility of their acquisition strategy by scanning an anthropomorphic lung phantom moving on 1d or 2d sinusoidal trajectories.Results: With both tumor position devices, the authors were able to acquire 4d CBCTs free of motion blurring. For scans based on the EM tracking system, reconstruction artifacts stemming from the presence of the EM-array and the EM-transponders were greatly reduced using newly developed correction algorithms. By tuning the imaging frequency independently for each respiratory phase prior to acquisition, it was possible to harmonize the number of projections over respiratory phases. Depending on the breathing period (3.5 or 5 s) and the gantry rotation time (4 or 5 min), between ∼90 and 145

  2. 4D micro-CT using fast prospective gating

    NASA Astrophysics Data System (ADS)

    Guo, Xiaolian; Johnston, Samuel M.; Qi, Yi; Johnson, G. Allan; Badea, Cristian T.

    2012-01-01

    Micro-CT is currently used in preclinical studies to provide anatomical information. But, there is also significant interest in using this technology to obtain functional information. We report here a new sampling strategy for 4D micro-CT for functional cardiac and pulmonary imaging. Rapid scanning of free-breathing mice is achieved with fast prospective gating (FPG) implemented on a field programmable gate array. The method entails on-the-fly computation of delays from the R peaks of the ECG signals or the peaks of the respiratory signals for the triggering pulses. Projection images are acquired for all cardiac or respiratory phases at each angle before rotating to the next angle. FPG can deliver the faster scan time of retrospective gating (RG) with the regular angular distribution of conventional prospective gating for cardiac or respiratory gating. Simultaneous cardio-respiratory gating is also possible with FPG in a hybrid retrospective/prospective approach. We have performed phantom experiments to validate the new sampling protocol and compared the results from FPG and RG in cardiac imaging of a mouse. Additionally, we have evaluated the utility of incorporating respiratory information in 4D cardiac micro-CT studies with FPG. A dual-source micro-CT system was used for image acquisition with pulsed x-ray exposures (80 kVp, 100 mA, 10 ms). The cardiac micro-CT protocol involves the use of a liposomal blood pool contrast agent containing 123 mg I ml-1 delivered via a tail vein catheter in a dose of 0.01 ml g-1 body weight. The phantom experiment demonstrates that FPG can distinguish the successive phases of phantom motion with minimal motion blur, and the animal study demonstrates that respiratory FPG can distinguish inspiration and expiration. 4D cardiac micro-CT imaging with FPG provides image quality superior to RG at an isotropic voxel size of 88 µm and 10 ms temporal resolution. The acquisition time for either sampling approach is less than 5 min. The

  3. Luteinizing hormone and human chorionic gonadotropin: origins of difference.

    PubMed

    Choi, Janet; Smitz, Johan

    2014-03-01

    Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) are widely recognized for their roles in ovulation and the support of early pregnancy. Aside from the timing of expression, however, the differences between LH and hCG have largely been overlooked in the clinical realm because of their similar molecular structures and shared receptor. With technologic advancements, including the development of highly purified and recombinant gonadotropins, researchers now appreciate that these hormones are not as interchangeable as once believed. Although they bind to a common receptor, emerging evidence suggests that LH and hCG have disparate effects on downstream signaling cascades. Increased understanding of the inherent differences between LH and hCG will foster more effective diagnostic and prognostic assays for use in a variety of clinical contexts and support the individualization of treatment strategies for conditions such as infertility.

  4. Effects of dopamine blockade on gonadotropins and testosterone in men.

    PubMed

    Siris, S G; Siris, E S; van Kammen, D P; Docherty, J P; Alexander, P E; Bunney, W E

    1980-02-01

    The authors found that plasma luteinizing hormone (LH), prolactin, and testosterone were initially normal in nine acutely psychotic males with schizophrenia or schizo-affective disorder; follicle-stimulating hormone (FSH) was normal in eight of the nine. When patients were treated with pimozide, a relatively specific dopamine receptor blocker, there were statistically significant declines in FSH and LH, although levels remained within normal limits. Prolactin rose significantly, but testosterone did not change. The observed reductions in FSH and LH concentrations are consistent with the hypotheses that dopamine and/or prolactin play a role in gonadotropin secretion. The maintenance of normal levels of gonadotropins and testosterone, however, suggests that these patients possessed relatively normal hypothalamic-pituitary-gonadal axis function before and during a course of neuroleptic treatment.

  5. Gonadotropins: a cohesive gender-based etiology of Alzheimer disease.

    PubMed

    Webber, Kate M; Casadesus, Gemma; Atwood, Craig S; Bowen, Richard L; Perry, George; Smith, Mark A

    2007-01-01

    While there is ample experimental evidence supporting the role of estrogen in the pathogenesis of Alzheimer disease, recent inconclusive data regarding hormone replacement therapy (HRT), specifically, the unexpected results of the Women's Health Initiative (WHI) Memory Study has raised serious questions regarding the protective effects of estrogen. Because of this and other inconsistencies in the estrogen hypothesis, we propose that another hormone of the hypothalamic-pituitary-gonadal axis, luteinizing hormone, is a major factor in the pathogenesis of Alzheimer disease. Specifically, we suspect that the increase in gonadotropin concentrations, and not the decrease in steroid hormone (e.g., estrogen) production following menopause/andropause, is a primary causative factor for the development of Alzheimer disease. In this review, we examine how the gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, Alzheimer disease.

  6. Gonadotropin-releasing hormone analogs: Understanding advantages and limitations.

    PubMed

    Kumar, Pratap; Sharma, Alok

    2014-07-01

    Pituitary stimulation with pulsatile gonadotropin-releasing hormone (GnRH) analogs induces both follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Pituitary gonadotropin secretions are blocked upon desensitization when a continuous GnRH stimulus is provided by means of an agonist or when the pituitary receptors are occupied with a competitive antagonist. GnRH antagonists were not available originally; therefore, prolonged daily injections of agonist with its desensitizing effect were used. Today, single- and multiple-dose injectable antagonists are also available to block the LH surge and thus to cause desensitization. This review provides an overview of the use of GnRH analogs which is potent therapeutic agents that are considerably useful in a variety of clinical indications from the past to the future with some limitations. These indications include management of endometriosis, uterine leiomyomas, hirsutism, dysfunctional uterine bleeding, premenstrual syndrome, assisted reproduction, and some hormone-dependent tumours, other than ovulation induction.

  7. Binding sites for gonadotropins in human postmenopausal ovaries

    SciTech Connect

    Nakano, R.; Shima, K.; Yamoto, M.; Kobayashi, M.; Nishimori, K.; Hiraoka, J.

    1989-02-01

    The binding of human LH and human FSH to postmenopausal ovarian tissue from 21 patients with cervical carcinoma was analyzed. The binding sites for FSH and LH were demonstrated in postmenopausal ovarian tissue. The surface-binding sites for gonadotropins were localized in the cells of cortical stroma of the postmenopausal ovary. In addition, diffuse cytoplasmic staining of endogenous estrogen and 3 beta-hydroxysteroid dehydrogenase activity were detected immunohistochemically and histochemically in the cells of the cortical stroma. Electron microscopic study also suggested steroidogenic function in the cells of the cortical stroma. The results of the present study suggest that postmenopausal ovaries contain specific binding sites for pituitary gonadotropins and play a role in ovarian steroidogenesis.

  8. Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study

    PubMed Central

    Lee, Alice W.; Tyrer, Jonathan P.; Doherty, Jennifer A.; Stram, Douglas A.; Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Spiewankiewicz, Beata; Myers, Emily J.; Chenevix-Trench, Georgia; Fasching, Peter A.; Beckmann, Matthias W.; Ekici, Arif B.; Hein, Alexander; Vergote, Ignace; Van Nieuwenhuysen, Els; Lambrechts, Diether; Wicklund, Kristine G.; Eilber, Ursula; Wang-Gohrke, Shan; Chang-Claude, Jenny; Rudolph, Anja; Sucheston-Campbell, Lara; Odunsi, Kunle; Moysich, Kirsten B.; Shvetsov, Yurii B.; Thompson, Pamela J.; Goodman, Marc T.; Wilkens, Lynne R.; Dörk, Thilo; Hillemanns, Peter; Dürst, Matthias; Runnebaum, Ingo B.; Bogdanova, Natalia; Pelttari, Liisa M.; Nevanlinna, Heli; Leminen, Arto; Edwards, Robert P.; Kelley, Joseph L.; Harter, Philipp; Schwaab, Ira; Heitz, Florian; du Bois, Andreas; Orsulic, Sandra; Lester, Jenny; Walsh, Christine; Karlan, Beth Y.; Hogdall, Estrid; Kjaer, Susanne K.; Jensen, Allan; Vierkant, Robert A.; Cunningham, Julie M.; Goode, Ellen L.; Fridley, Brooke L.; Southey, Melissa C.; Giles, Graham G.; Bruinsma, Fiona; Wu, Xifeng; Hildebrandt, Michelle A.T.; Lu, Karen; Liang, Dong; Bisogna, Maria; Levine, Douglas A.; Weber, Rachel Palmieri; Schildkraut, Joellen M.; Iversen, Edwin S.; Berchuck, Andrew; Terry, Kathryn L.; Cramer, Daniel W.; Tworoger, Shelley S.; Poole, Elizabeth M.; Olson, Sara H.; Orlow, Irene; Bandera, Elisa V.; Bjorge, Line; Tangen, Ingvild L.; Salvesen, Helga B.; Krakstad, Camilla; Massuger, Leon F.A.G.; Kiemeney, Lambertus A.; Aben, Katja K.H.; van Altena, Anne M.; Bean, Yukie; Pejovic, Tanja; Kellar, Melissa; Le, Nhu D.; Cook, Linda S.; Kelemen, Linda E.; Brooks-Wilson, Angela; Lubinski, Jan; Gronwald, Jacek; Cybulski, Cezary; Jakubowska, Anna; Wentzensen, Nicolas; Brinton, Louise A.; Lissowska, Jolanta; Yang, Hannah; Nedergaard, Lotte; Lundvall, Lene; Hogdall, Claus; Song, Honglin; Campbell, Ian G.; Eccles, Diana; Glasspool, Rosalind; Siddiqui, Nadeem; Carty, Karen; Paul, James; McNeish, Iain A.; Sieh, Weiva; McGuire, Valerie; Rothstein, Joseph H.; Whittemore, Alice S.; McLaughlin, John R.; Risch, Harvey A.; Phelan, Catherine M.; Anton-Culver, Hoda; Ziogas, Argyrios; Menon, Usha; Ramus, Susan J.; Gentry-Maharaj, Aleksandra; Harrington, Patricia; Pike, Malcolm C.; Modugno, Francesmary; Rossing, Mary Anne; Ness, Roberta B.; Pharoah, Paul D.P.; Stram, Daniel O.; Wu, Anna H.; Pearce, Celeste Leigh

    2016-01-01

    Objective Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. Methods Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. Results We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p = 0.045, mucinous), LHCGR (p = 0.046, high-grade serous), GNRH (p = 0.041, high-grade serous), and FSHB (p = 0.036, overall invasive). There was also suggestive evidence for INHA (p = 0.060, overall invasive). Conclusions Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available. PMID:25528498

  9. Atlas construction for dynamic (4D) PET using diffeomorphic transformations.

    PubMed

    Bieth, Marie; Lombaert, Hervé; Reader, Andrew J; Siddiqi, Kaleem

    2013-01-01

    A novel dynamic (4D) PET to PET image registration procedure is proposed and applied to multiple PET scans acquired with the high resolution research tomograph (HRRT), the highest resolution human brain PET scanner available in the world. By extending the recent diffeomorphic log-demons (DLD) method and applying it to multiple dynamic [11C]raclopride scans from the HRRT, an important step towards construction of a PET atlas of unprecedented quality for [11C]raclopride imaging of the human brain has been achieved. Accounting for the temporal dimension in PET data improves registration accuracy when compared to registration of 3D to 3D time-averaged PET images. The DLD approach was chosen for its ease in providing both an intensity and shape template, through iterative sequential pair-wise registrations with fast convergence. The proposed method is applicable to any PET radiotracer, providing 4D atlases with useful applications in high accuracy PET data simulations and automated PET image analysis. PMID:24579121

  10. 488-4D ASH LANDFILL CLOSURE CAP HELP MODELING

    SciTech Connect

    Phifer, M.

    2014-11-17

    At the request of Area Completion Projects (ACP) in support of the 488-4D Landfill closure, the Savannah River National Laboratory (SRNL) has performed Hydrologic Evaluation of Landfill Performance (HELP) modeling of the planned 488-4D Ash Landfill closure cap to ensure that the South Carolina Department of Health and Environmental Control (SCDHEC) limit of no more than 12 inches of head on top of the barrier layer (saturated hydraulic conductivity of no more than 1.0E-05 cm/s) in association with a 25-year, 24-hour storm event is not projected to be exceeded. Based upon Weber 1998 a 25-year, 24-hour storm event at the Savannah River Site (SRS) is 6.1 inches. The results of the HELP modeling indicate that the greatest peak daily head on top of the barrier layer (i.e. geosynthetic clay liner (GCL) or high density polyethylene (HDPE) geomembrane) for any of the runs made was 0.079 inches associated with a peak daily precipitation of 6.16 inches. This is well below the SCDHEC limit of 12 inches.

  11. 4D Dynamic Required Navigation Performance Final Report

    NASA Technical Reports Server (NTRS)

    Finkelsztein, Daniel M.; Sturdy, James L.; Alaverdi, Omeed; Hochwarth, Joachim K.

    2011-01-01

    New advanced four dimensional trajectory (4DT) procedures under consideration for the Next Generation Air Transportation System (NextGen) require an aircraft to precisely navigate relative to a moving reference such as another aircraft. Examples are Self-Separation for enroute operations and Interval Management for in-trail and merging operations. The current construct of Required Navigation Performance (RNP), defined for fixed-reference-frame navigation, is not sufficiently specified to be applicable to defining performance levels of such air-to-air procedures. An extension of RNP to air-to-air navigation would enable these advanced procedures to be implemented with a specified level of performance. The objective of this research effort was to propose new 4D Dynamic RNP constructs that account for the dynamic spatial and temporal nature of Interval Management and Self-Separation, develop mathematical models of the Dynamic RNP constructs, "Required Self-Separation Performance" and "Required Interval Management Performance," and to analyze the performance characteristics of these air-to-air procedures using the newly developed models. This final report summarizes the activities led by Raytheon, in collaboration with GE Aviation and SAIC, and presents the results from this research effort to expand the RNP concept to a dynamic 4D frame of reference.

  12. Complete valvular heart apparatus model from 4D cardiac CT.

    PubMed

    Grbic, Sasa; Ionasec, Razvan; Vitanovski, Dime; Voigt, Ingmar; Wang, Yang; Georgescu, Bogdan; Navab, Nassir; Comaniciu, Dorin

    2012-07-01

    The cardiac valvular apparatus, composed of the aortic, mitral, pulmonary and tricuspid valves, is an essential part of the anatomical, functional and hemodynamic characteristics of the heart and the cardiovascular system as a whole. Valvular heart diseases often involve multiple dysfunctions and require joint assessment and therapy of the valves. In this paper, we propose a complete and modular patient-specific model of the cardiac valvular apparatus estimated from 4D cardiac CT data. A new constrained Multi-linear Shape Model (cMSM), conditioned by anatomical measurements, is introduced to represent the complex spatio-temporal variation of the heart valves. The cMSM is exploited within a learning-based framework to efficiently estimate the patient-specific valve parameters from cine images. Experiments on 64 4D cardiac CT studies demonstrate the performance and clinical potential of the proposed method. Our method enables automatic quantitative evaluation of the complete valvular apparatus based on non-invasive imaging techniques. In conjunction with existent patient-specific chamber models, the presented valvular model enables personalized computation modeling and realistic simulation of the entire cardiac system.

  13. Seasonal Control of Gonadotropin-Inhibitory Hormone (GnIH) in Birds and Mammals

    PubMed Central

    Kriegsfeld, Lance J.; Ubuka, Takayoshi; Bentley, George E.; Tsutsui, Kazuyoshi

    2015-01-01

    Animals inhabiting temperate and boreal latitudes experience marked seasonal changes in the quality of their environments and maximize reproductive success by phasing breeding activities with the most favorable time of year. Whereas the specific mechanisms driving seasonal changes in reproductive function vary across species, converging lines of evidence suggest gonadotropin-inhibitory hormone (GnIH) serves as a key component of the neuroendocrine circuitry driving seasonal changes in reproduction and sexual motivation in some species. In addition to anticipating environmental change through transduction of photoperiodic information and modifying reproductive state accordingly, GnIH is also positioned to regulate acute changes in reproductive status should unpredictable conditions manifest throughout the year. The present overview summarizes the role of GnIH in avian and mammalian seasonal breeding while considering the similarities and disparities that have emerged from broad investigations across reproductively photoperiodic species. PMID:25511257

  14. Heme oxygenase-derived carbon monoxide modulates gonadotropin-releasing hormone release in immortalized hypothalamic neurons.

    PubMed

    Errico, Stefania; Shohreh, Rugia; Barone, Eugenio; Pusateri, Angela; Mores, Nadia; Mancuso, Cesare

    2010-03-01

    Heme oxygenase (HO), the main enzyme deputed to heme metabolism, has been identified as two main isoforms called HO-1 and HO-2 both present in the central nervous system. Heme oxygenase has been shown to regulate the hypothalamic release of neuropeptides such as corticotrophin-releasing hormone and arginin-vasopressin. The aim of this study was to investigate and further characterize the presence of HO in gonadotropin-releasing hormone (GnRH) secreting hypothalamic neurons, GT1-7 and the role of HO by-products on GnRH secretion. The pulsatile release of GnRH from scattered hypothalamic neurons is the key regulator of mammalian fertility in the central nervous system. GT1-7 cells are immortalized hypothalamic neurons, characterized by spontaneous electrical activity and pulsatile GnRH release, resembling the central control pathway of the hypothalamic pituitary gonadal axis (HPG) in mammals. Hemin, the substrate of HO, significantly stimulated HO activity in static cultures, causing a rapid increase in GnRH release. Neither biliverdin nor bilirubin were able to mimic this rapid stimulatory effect, which was instead caused by carbon monoxide. Evidence of a possible involvement of prostaglandin E(2) in the HO by-product modulated GnRH secretion was reported. The hemin-evoked effect on GT1-7 neurons suggests a direct activity of HO by-products on the hypothalamic neuropeptide secretion, and claims for a possible role of CO in both the modulation of gonadotropin secretion and crosstalk among HPG and stress axis within the mammalian hypothalamus.

  15. 4D XCAT phantom for multimodality imaging research

    SciTech Connect

    Segars, W. P.; Sturgeon, G.; Mendonca, S.; Grimes, Jason; Tsui, B. M. W.

    2010-09-15

    Purpose: The authors develop the 4D extended cardiac-torso (XCAT) phantom for multimodality imaging research. Methods: Highly detailed whole-body anatomies for the adult male and female were defined in the XCAT using nonuniform rational B-spline (NURBS) and subdivision surfaces based on segmentation of the Visible Male and Female anatomical datasets from the National Library of Medicine as well as patient datasets. Using the flexibility of these surfaces, the Visible Human anatomies were transformed to match body measurements and organ volumes for a 50th percentile (height and weight) male and female. The desired body measurements for the models were obtained using the PEOPLESIZE program that contains anthropometric dimensions categorized from 1st to the 99th percentile for US adults. The desired organ volumes were determined from ICRP Publication 89 [ICRP, ''Basic anatomical and physiological data for use in radiological protection: reference values,'' ICRP Publication 89 (International Commission on Radiological Protection, New York, NY, 2002)]. The male and female anatomies serve as standard templates upon which anatomical variations may be modeled in the XCAT through user-defined parameters. Parametrized models for the cardiac and respiratory motions were also incorporated into the XCAT based on high-resolution cardiac- and respiratory-gated multislice CT data. To demonstrate the usefulness of the phantom, the authors show example simulation studies in PET, SPECT, and CT using publicly available simulation packages. Results: As demonstrated in the pilot studies, the 4D XCAT (which includes thousands of anatomical structures) can produce realistic imaging data when combined with accurate models of the imaging process. With the flexibility of the NURBS surface primitives, any number of different anatomies, cardiac or respiratory motions or patterns, and spatial resolutions can be simulated to perform imaging research. Conclusions: With the ability to produce

  16. 4D Light Field Imaging System Using Programmable Aperture

    NASA Technical Reports Server (NTRS)

    Bae, Youngsam

    2012-01-01

    Complete depth information can be extracted from analyzing all angles of light rays emanated from a source. However, this angular information is lost in a typical 2D imaging system. In order to record this information, a standard stereo imaging system uses two cameras to obtain information from two view angles. Sometimes, more cameras are used to obtain information from more angles. However, a 4D light field imaging technique can achieve this multiple-camera effect through a single-lens camera. Two methods are available for this: one using a microlens array, and the other using a moving aperture. The moving-aperture method can obtain more complete stereo information. The existing literature suggests a modified liquid crystal panel [LC (liquid crystal) panel, similar to ones commonly used in the display industry] to achieve a moving aperture. However, LC panels cannot withstand harsh environments and are not qualified for spaceflight. In this regard, different hardware is proposed for the moving aperture. A digital micromirror device (DMD) will replace the liquid crystal. This will be qualified for harsh environments for the 4D light field imaging. This will enable an imager to record near-complete stereo information. The approach to building a proof-ofconcept is using existing, or slightly modified, off-the-shelf components. An SLR (single-lens reflex) lens system, which typically has a large aperture for fast imaging, will be modified. The lens system will be arranged so that DMD can be integrated. The shape of aperture will be programmed for single-viewpoint imaging, multiple-viewpoint imaging, and coded aperture imaging. The novelty lies in using a DMD instead of a LC panel to move the apertures for 4D light field imaging. The DMD uses reflecting mirrors, so any light transmission lost (which would be expected from the LC panel) will be minimal. Also, the MEMS-based DMD can withstand higher temperature and pressure fluctuation than a LC panel can. Robotics need

  17. 4D XCAT phantom for multimodality imaging research

    PubMed Central

    Segars, W. P.; Sturgeon, G.; Mendonca, S.; Grimes, Jason; Tsui, B. M. W.

    2010-01-01

    Purpose: The authors develop the 4D extended cardiac-torso (XCAT) phantom for multimodality imaging research. Methods: Highly detailed whole-body anatomies for the adult male and female were defined in the XCAT using nonuniform rational B-spline (NURBS) and subdivision surfaces based on segmentation of the Visible Male and Female anatomical datasets from the National Library of Medicine as well as patient datasets. Using the flexibility of these surfaces, the Visible Human anatomies were transformed to match body measurements and organ volumes for a 50th percentile (height and weight) male and female. The desired body measurements for the models were obtained using the PEOPLESIZE program that contains anthropometric dimensions categorized from 1st to the 99th percentile for US adults. The desired organ volumes were determined from ICRP Publication 89 [ICRP, ‘‘Basic anatomical and physiological data for use in radiological protection: reference values,” ICRP Publication 89 (International Commission on Radiological Protection, New York, NY, 2002)]. The male and female anatomies serve as standard templates upon which anatomical variations may be modeled in the XCAT through user-defined parameters. Parametrized models for the cardiac and respiratory motions were also incorporated into the XCAT based on high-resolution cardiac- and respiratory-gated multislice CT data. To demonstrate the usefulness of the phantom, the authors show example simulation studies in PET, SPECT, and CT using publicly available simulation packages. Results: As demonstrated in the pilot studies, the 4D XCAT (which includes thousands of anatomical structures) can produce realistic imaging data when combined with accurate models of the imaging process. With the flexibility of the NURBS surface primitives, any number of different anatomies, cardiac or respiratory motions or patterns, and spatial resolutions can be simulated to perform imaging research. Conclusions: With the ability to produce

  18. Semaphorin 4D Contributes to Rheumatoid Arthritis by Inducing Inflammatory Cytokine Production: Pathogenic and Therapeutic Implications

    PubMed Central

    Yoshida, Yuji; Kang, Sujin; Ebina, Kousuke; Shi, Kenrin; Nojima, Satoshi; Kimura, Tetsuya; Ito, Daisuke; Morimoto, Keiko; Nishide, Masayuki; Hosokawa, Takashi; Hirano, Toru; Shima, Yoshihito; Narazaki, Masashi; Tsuboi, Hideki; Saeki, Yukihiko; Tomita, Tetsuya; Tanaka, Toshio; Kumanogoh, Atsushi

    2015-01-01

    Objective Semaphorin 4D (Sema4D)/CD100 has pleiotropic roles in immune activation, angiogenesis, bone metabolism, and neural development. We undertook this study to investigate the role of Sema4D in rheumatoid arthritis (RA). Methods Soluble Sema4D (sSema4D) levels in serum and synovial fluid were analyzed by enzyme‐linked immunosorbent assay. Cell surface expression and transcripts of Sema4D were analyzed in peripheral blood cells from RA patients, and immunohistochemical staining of Sema4D was performed in RA synovium. Generation of sSema4D was evaluated in an ADAMTS‐4–treated monocytic cell line (THP‐1 cells). The efficacy of anti‐Sema4D antibody was evaluated in mice with collagen‐induced arthritis (CIA). Results Levels of sSema4D were elevated in both serum and synovial fluid from RA patients, and disease activity markers were correlated with serum sSema4D levels. Sema4D‐expressing cells also accumulated in RA synovium. Cell surface levels of Sema4D on CD3+ and CD14+ cells from RA patients were reduced, although levels of Sema4D transcripts were unchanged. In addition, ADAMTS‐4 cleaved cell surface Sema4D to generate sSema4D in THP‐1 cells. Soluble Sema4D induced tumor necrosis factor α (TNFα) and interleukin‐6 (IL‐6) production from CD14+ monocytes. IL‐6 and TNFα induced ADAMTS‐4 expression in synovial cells. Treatment with an anti‐Sema4D antibody suppressed arthritis and reduced proinflammatory cytokine production in CIA. Conclusion A positive feedback loop involving sSema4D/IL‐6 and TNFα/ADAMTS‐4 may contribute to the pathogenesis of RA. The inhibition of arthritis by anti‐Sema4D antibody suggests that Sema4D represents a potential therapeutic target for RA. PMID:25707877

  19. Identification and distribution of gonadotropin-releasing hormone-like peptides in the brain of horseshoe crab Tachypleus tridentatus

    NASA Astrophysics Data System (ADS)

    Huang, Huiyang; Li, Linming; Ye, Haihui; Feng, Biyun; Li, Shaojing

    2013-03-01

    Gonadotropin-releasing hormone (GnRH) is a crucial peptide for the regulation of reproduction. Using immunological techniques, we investigated the presence of GnRH in horseshoe crab Tachypleus tridentatus. Octopus GnRH-like immunoreactivity, tunicate GnRH-like immunoreactivity, and lamprey GnRH-I-like immunoreactivity were detected in the neurons and fibers of the protocerebrum. However, no mammal GnRH-like immunoreactivity or lamprey GnRH-III-like immunoreactivity was observed. Our results suggest that a GnRH-like factor, an ancient peptide, existed in the brain of T. tridentatus and may be involved in the reproductive endocrine system.

  20. Mapping motion from 4D-MRI to 3D-CT for use in 4D dose calculations: A technical feasibility study

    SciTech Connect

    Boye, Dirk; Lomax, Tony; Knopf, Antje

    2013-06-15

    Purpose: Target sites affected by organ motion require a time resolved (4D) dose calculation. Typical 4D dose calculations use 4D-CT as a basis. Unfortunately, 4D-CT images have the disadvantage of being a 'snap-shot' of the motion during acquisition and of assuming regularity of breathing. In addition, 4D-CT acquisitions involve a substantial additional dose burden to the patient making many, repeated 4D-CT acquisitions undesirable. Here the authors test the feasibility of an alternative approach to generate patient specific 4D-CT data sets. Methods: In this approach motion information is extracted from 4D-MRI. Simulated 4D-CT data sets [which the authors call 4D-CT(MRI)] are created by warping extracted deformation fields to a static 3D-CT data set. The employment of 4D-MRI sequences for this has the advantage that no assumptions on breathing regularity are made, irregularities in breathing can be studied and, if necessary, many repeat imaging studies (and consequently simulated 4D-CT data sets) can be performed on patients and/or volunteers. The accuracy of 4D-CT(MRI)s has been validated by 4D proton dose calculations. Our 4D dose algorithm takes into account displacements as well as deformations on the originating 4D-CT/4D-CT(MRI) by calculating the dose of each pencil beam based on an individual time stamp of when that pencil beam is applied. According to corresponding displacement and density-variation-maps the position and the water equivalent range of the dose grid points is adjusted at each time instance. Results: 4D dose distributions, using 4D-CT(MRI) data sets as input were compared to results based on a reference conventional 4D-CT data set capturing similar motion characteristics. Almost identical 4D dose distributions could be achieved, even though scanned proton beams are very sensitive to small differences in the patient geometry. In addition, 4D dose calculations have been performed on the same patient, but using 4D-CT(MRI) data sets based on

  1. Intraovarian expression of GnRH-1 and gonadotropin mRNA and protein levels in Siberian hamsters during the estrus cycle and photoperiod induced regression/recrudescence.

    PubMed

    Shahed, Asha; Young, Kelly A

    2011-01-15

    The hypothalamic-pituitary-gonadal (HPG) axis is the key reproductive regulator in vertebrates. While gonadotropin releasing hormone (GnRH), follicle stimulating (FSH), and luteinizing (LH) hormones are primarily produced in the hypothalamus and pituitary, they can be synthesized in the gonads, suggesting an intraovarian GnRH-gonadotropin axis. Because these hormones are critical for follicle maturation and steroidogenesis, we hypothesized that this intraovarian axis may be important in photoperiod-induced ovarian regression/recrudescence in seasonal breeders. Thus, we investigated GnRH-1 and gonadotropin mRNA and protein expression in Siberian hamster ovaries during (1) the estrous cycle; where ovaries from cycling long day hamsters (LD;16L:8D) were collected at proestrus, estrus, diestrus I, and diestrus II and (2) during photoperiod induced regression/recrudescence; where ovaries were collected from hamsters exposed to 14 weeks of LD, short days (SD;8L:16D), or 8 weeks post-transfer to LD after 14 weeks SD (PT). GnRH-1, LHβ, FSHβ, and common α subunit mRNA expression was observed in cycling ovaries. GnRH-1 expression peaked at diestrus I compared to other stages (p < 0.05). FSHβ and LHβ mRNA levels peaked at proestrus and diestrus I (p < 0.05), with no change in the α subunit across the cycle (p > 0.05). SD exposure decreased ovarian mass and plasma estradiol concentrations (p<0.05) and increased GnRH-1, LHβ, FSHβ, and α subunit mRNA expression as compared to LD and, except for LH, compared to PT (p < 0.05). GnRH and gonadotropin protein was also dynamically expressed across the estrous cycle and photoperiod exposure. The presence of cycling intraovarian GnRH-1 and gonadotropin mRNA suggests that these hormones may be locally involved in ovarian maintenance during SD regression and/or could potentially serve to prime ovaries for rapid recrudescence.

  2. Biomechanics of DNA structures visualized by 4D electron microscopy

    PubMed Central

    Lorenz, Ulrich J.; Zewail, Ahmed H.

    2013-01-01

    We present a technique for in situ visualization of the biomechanics of DNA structural networks using 4D electron microscopy. Vibrational oscillations of the DNA structure are excited mechanically through a short burst of substrate vibrations triggered by a laser pulse. Subsequently, the motion is probed with electron pulses to observe the impulse response of the specimen in space and time. From the frequency and amplitude of the observed oscillations, we determine the normal modes and eigenfrequencies of the structures involved. Moreover, by selective “nano-cutting” at a given point in the network, it was possible to obtain Young’s modulus, and hence the stiffness, of the DNA filament at that position. This experimental approach enables nanoscale mechanics studies of macromolecules and should find applications in other domains of biological networks such as origamis. PMID:23382239

  3. Myocardial motion and function assessment using 4D images

    NASA Astrophysics Data System (ADS)

    Shi, Peng-Cheng; Robinson, Glynn P.; Duncan, James S.

    1994-09-01

    This paper describes efforts aimed at more objectively and accurately quantifying the local, regional and global function of the left ventricle (LV) of the heart from 4D image data. Using our shape-based image analysis methods, point-wise myocardial motion vector fields between successive image frames through the entire cardiac cycle will be computed. Quantitative LV motion, thickening, and strain measurements will then be established from the point correspondence maps. In the paper, we will also briefly describe an in vivo experimental model which uses implanted imaging-opaque markers to validate the results of our image analysis methods. Finally, initial experimental results using image sequences from two different modalities will be presented.

  4. 4D GPR Experiments--Towards the Virtual Lysimeter

    NASA Astrophysics Data System (ADS)

    Grasmueck, M.; Viggiano, D. A.; Day-Lewis, F. D.; Drasdis, J. B.; Kruse, S. E.; Or, D.

    2006-05-01

    In-situ monitoring of infiltration, water flow and retention in the vadose zone currently rely primarily on invasive methods, which irreversibly disturb original soil structure and alter its hydrologic behavior in the vicinity of the measurement. For example, use of lysimeters requires extraction and repacking of soil samples, and time- domain reflectometry (TDR) requires insertion of probes into the soil profile. This study investigates the use of repeated high-density 3D ground penetrating radar surveys (also known as 4D GPR) as a non-invasive alternative for detailed visualization and quantification of water flow in the vadose zone. Evaluation of the 4D GPR method was based on a series of controlled point-source water injection experiments into undisturbed beach sand deposits at Crandon Park in Miami, Florida. The goal of the GPR surveys was to image the shape and evolution of a wet-bulb as it propagates from the injection points (~0.5 m) towards the water table at 2.2 m depth. The experimental design was guided by predictive modeling using Hydrus 2D and finite-difference GPR waveform codes. Input parameters for the modeling were derived from hydrologic and electromagnetic characterization of representative sand samples. Guided by modeling results, we injected 30 to 40 liters of tap water through plastic-cased boreholes with slotted bottom sections (0.1 m) located 0.4 to 0.6 m below the surface. During and after injection, an area of 25 m2 was surveyed every 20 minutes using 250 and 500 MHz antennas with a grid spacing of 0.05 x 0.025 m. A total of 20 3D GPR surveys were completed over 3 infiltration sites. To confirm wet-bulb shapes measured by GPR, we injected 2 liters of "brilliant blue" dye (~100 mg/l) along with a saline water tracer towards the end of one experiment. After completion of GPR scanning, a trench was excavated to examine the distribution of the saltwater and dye using TDR and visual inspection, respectively. Preliminary analysis of the 4D GPR

  5. Chaos in a 4D dissipative nonlinear fermionic model

    NASA Astrophysics Data System (ADS)

    Aydogmus, Fatma

    2015-12-01

    Gursey Model is the only possible 4D conformally invariant pure fermionic model with a nonlinear self-coupled spinor term. It has been assumed to be similar to the Heisenberg's nonlinear generalization of Dirac's equation, as a possible basis for a unitary description of elementary particles. Gursey Model admits particle-like solutions for the derived classical field equations and these solutions are instantonic in character. In this paper, the dynamical nature of damped and forced Gursey Nonlinear Differential Equations System (GNDES) are studied in order to get more information on spinor type instantons. Bifurcation and chaos in the system are observed by constructing the bifurcation diagrams and Poincaré sections. Lyapunov exponent and power spectrum graphs of GNDES are also constructed to characterize the chaotic behavior.

  6. Parallel Wavefront Analysis for a 4D Interferometer

    NASA Technical Reports Server (NTRS)

    Rao, Shanti R.

    2011-01-01

    This software provides a programming interface for automating data collection with a PhaseCam interferometer from 4D Technology, and distributing the image-processing algorithm across a cluster of general-purpose computers. Multiple instances of 4Sight (4D Technology s proprietary software) run on a networked cluster of computers. Each connects to a single server (the controller) and waits for instructions. The controller directs the interferometer to several images, then assigns each image to a different computer for processing. When the image processing is finished, the server directs one of the computers to collate and combine the processed images, saving the resulting measurement in a file on a disk. The available software captures approximately 100 images and analyzes them immediately. This software separates the capture and analysis processes, so that analysis can be done at a different time and faster by running the algorithm in parallel across several processors. The PhaseCam family of interferometers can measure an optical system in milliseconds, but it takes many seconds to process the data so that it is usable. In characterizing an adaptive optics system, like the next generation of astronomical observatories, thousands of measurements are required, and the processing time quickly becomes excessive. A programming interface distributes data processing for a PhaseCam interferometer across a Windows computing cluster. A scriptable controller program coordinates data acquisition from the interferometer, storage on networked hard disks, and parallel processing. Idle time of the interferometer is minimized. This architecture is implemented in Python and JavaScript, and may be altered to fit a customer s needs.

  7. Dissecting the Roles of Gonadotropin-Inhibitory Hormone in Mammals: Studies Using Pharmacological Tools and Genetically Modified Mouse Models

    PubMed Central

    Leon, Silvia; Tena-Sempere, Manuel

    2016-01-01

    Reproduction is essential for perpetuation of the species and, hence, is controlled by a sophisticated network of regulatory factors of central and peripheral origin that integrate at the hypothalamic–pituitary–gonadal (HPG) axis. Among the central regulators of reproduction, kisspeptins, as major stimulatory drivers of gonadotropin-releasing hormone (GnRH) neurosecretion, have drawn considerable interest in the last decade. However, the dynamic, if not cyclic (in the female), nature of reproductive function and the potency of kisspeptins and other stimulatory signals of the HPG axis make tenable the existence of counterbalance inhibitory mechanisms, which may keep stimulation at check and would allow adaptation of reproductive maturation and function to different endogenous and environmental conditions. In this context, discovery of the gonadotropin-inhibitory hormone (GnIH) in birds, and its mammalian homolog, RFRP, opened up the exciting possibility that this inhibitory signal might operate centrally to suppress, directly or indirectly, GnRH/gonadotropin secretion, thus reciprocally cooperating with other stimulatory inputs in the dynamic regulation of the reproductive hypothalamic–pituitary unit. After more than 15 years of active research, the role of GnIH/RFRP in the control of the HPG axis has been documented in different species. Yet, important aspects of the physiology of this system, especially regarding its relative importance and actual roles in the control of key facets of reproductive function, remain controversial. In the present work, we aim to provide a critical review of recent developments in this area, with special attention to studies in rodent models, using pharmacological tools and functional genomics. In doing so, we intend to endow the reader with an updated view of what is known (and what is not known) about the physiological role of GnIH/RFRP signaling in the control of mammalian reproduction. PMID:26779117

  8. Dissecting the Roles of Gonadotropin-Inhibitory Hormone in Mammals: Studies Using Pharmacological Tools and Genetically Modified Mouse Models.

    PubMed

    Leon, Silvia; Tena-Sempere, Manuel

    2015-01-01

    Reproduction is essential for perpetuation of the species and, hence, is controlled by a sophisticated network of regulatory factors of central and peripheral origin that integrate at the hypothalamic-pituitary-gonadal (HPG) axis. Among the central regulators of reproduction, kisspeptins, as major stimulatory drivers of gonadotropin-releasing hormone (GnRH) neurosecretion, have drawn considerable interest in the last decade. However, the dynamic, if not cyclic (in the female), nature of reproductive function and the potency of kisspeptins and other stimulatory signals of the HPG axis make tenable the existence of counterbalance inhibitory mechanisms, which may keep stimulation at check and would allow adaptation of reproductive maturation and function to different endogenous and environmental conditions. In this context, discovery of the gonadotropin-inhibitory hormone (GnIH) in birds, and its mammalian homolog, RFRP, opened up the exciting possibility that this inhibitory signal might operate centrally to suppress, directly or indirectly, GnRH/gonadotropin secretion, thus reciprocally cooperating with other stimulatory inputs in the dynamic regulation of the reproductive hypothalamic-pituitary unit. After more than 15 years of active research, the role of GnIH/RFRP in the control of the HPG axis has been documented in different species. Yet, important aspects of the physiology of this system, especially regarding its relative importance and actual roles in the control of key facets of reproductive function, remain controversial. In the present work, we aim to provide a critical review of recent developments in this area, with special attention to studies in rodent models, using pharmacological tools and functional genomics. In doing so, we intend to endow the reader with an updated view of what is known (and what is not known) about the physiological role of GnIH/RFRP signaling in the control of mammalian reproduction.

  9. Respiratory triggered 4D cone-beam computed tomography: A novel method to reduce imaging dose

    PubMed Central

    Cooper, Benjamin J.; O’Brien, Ricky T.; Balik, Salim; Hugo, Geoffrey D.; Keall, Paul J.

    2013-01-01

    Purpose: A novel method called respiratory triggered 4D cone-beam computed tomography (RT 4D CBCT) is described whereby imaging dose can be reduced without degrading image quality. RT 4D CBCT utilizes a respiratory signal to trigger projections such that only a single projection is assigned to a given respiratory bin for each breathing cycle. In contrast, commercial 4D CBCT does not actively use the respiratory signal to minimize image dose. Methods: To compare RT 4D CBCT with conventional 4D CBCT, 3600 CBCT projections of a thorax phantom were gathered and reconstructed to generate a ground truth CBCT dataset. Simulation pairs of conventional 4D CBCT acquisitions and RT 4D CBCT acquisitions were developed assuming a sinusoidal respiratory signal which governs the selection of projections from the pool of 3600 original projections. The RT 4D CBCT acquisition triggers a single projection when the respiratory signal enters a desired acquisition bin; the conventional acquisition does not use a respiratory trigger and projections are acquired at a constant frequency. Acquisition parameters studied were breathing period, acquisition time, and imager frequency. The performance of RT 4D CBCT using phase based and displacement based sorting was also studied. Image quality was quantified by calculating difference images of the test dataset from the ground truth dataset. Imaging dose was calculated by counting projections. Results: Using phase based sorting RT 4D CBCT results in 47% less imaging dose on average compared to conventional 4D CBCT. Image quality differences were less than 4% at worst. Using displacement based sorting RT 4D CBCT results in 57% less imaging dose on average, than conventional 4D CBCT methods; however, image quality was 26% worse with RT 4D CBCT. Conclusions: Simulation studies have shown that RT 4D CBCT reduces imaging dose while maintaining comparable image quality for phase based 4D CBCT; image quality is degraded for displacement based RT 4D

  10. Parallel Infrastructure Modeling and Inversion Module for E4D

    SciTech Connect

    2014-10-09

    Electrical resistivity tomography ERT is a method of imaging the electrical conductivity of the subsurface. Electrical conductivity is a useful metric for understanding the subsurface because it is governed by geomechanical and geochemical properties that drive subsurface systems. ERT works by injecting current into the subsurface across a pair of electrodes, and measuring the corresponding electrical potential response across another pair of electrodes. Many such measurements are strategically taken across an array of electrodes to produce an ERT data set. These data are then processed through a computationally demanding process known as inversion to produce an image of the subsurface conductivity structure that gave rise to the measurements. Data can be inverted to provide 2D images, 3D images, or in the case of time-lapse 3D imaging, 4D images. ERT is generally not well suited for environments with buried electrically conductive infrastructure such as pipes, tanks, or well casings, because these features tend to dominate and degrade ERT images. This reduces or eliminates the utility of ERT imaging where it would otherwise be highly useful for, for example, imaging fluid migration from leaking pipes, imaging soil contamination beneath leaking subusurface tanks, and monitoring contaminant migration in locations with dense network of metal cased monitoring wells. The location and dimension of buried metallic infrastructure is often known. If so, then the effects of the infrastructure can be explicitly modeled within the ERT imaging algorithm, and thereby removed from the corresponding ERT image. However,there are a number of obstacles limiting this application. 1) Metallic infrastructure cannot be accurately modeled with standard codes because of the large contrast in conductivity between the metal and host material. 2) Modeling infrastructure in true dimension requires the computational mesh to be highly refined near the metal inclusions, which increases

  11. 4D Dynamic RNP Annual Interim Report-Year 1

    NASA Technical Reports Server (NTRS)

    Finkelsztein, Daniel M.; Sturdy, James L.; Alaverdi, Omeed; Chung, William W.; Salvano, Daniel; Klooster, Joel; Hochwarth, Joachim K.

    2010-01-01

    This Annual Interim Report summarizes the activities led by Raytheon, in collaboration with GE Aviation and SAIC, and presents the results obtained during the first year of this research effort to expand the RNP concept to 4 dimensions relative to a dynamic frame of reference. Joint Program Development Office (JPDO)Concepts of Operations for the Next Generation Air Transportation System (NextGen) considers 4 Dimension Trajectory (4DT) procedures a key enabler to Trajectory Based Operations (TBO). The JPDO defines 4DT as a precise description of an aircraft path in space and time . While NextGen assumes that this path is defined within an Earth-reference frame, many 4DT procedure implementations will require an aircraft to precisely navigate relative to a moving reference such as another aircraft to form aggregate flows or a weather cell to allow for flows to shift. Current methods of implementing routes and flight paths rely on aircraft meeting a Required Navigation Performance (RNP) specification and being equipped with a monitoring and alerting capability to annunciate when the aircraft system is unable to meet the performance specification required for the operation. Since all aircraft today operate within the NAS relative to fixed reference points, the current RNP definition is deemed satisfactory. However, it is not well understood how the current RNP construct will support NextGen 4DT procedures where aircraft operate relative to each other or to other dynamic frames of reference. The objective of this research effort is to analyze candidate 4DT procedures from both an Air Navigation Service Provider (ANSP) and aircraft perspective, to identify their specific navigational requirements, assess the shortcomings of the current RNP construct to meet these requirements, to propose an extended 4 Dimensional Dynamic RNP (4D Dynamic RNP) construct that accounts for the dynamic spatial and temporal nature of the selected 4DT procedures, and finally, to design an

  12. Effects of a pure antiandrogen on gonadotropin secretion in normal women and in polycystic ovarian disease.

    PubMed

    Couzinet, B; Thomas, G; Thalabard, J C; Brailly, S; Schaison, G

    1989-07-01

    To assess the role of androgens in gonadotropin regulation in women, we studied the effects of a pure nonsteroidal antiandrogen, Anandron (Cassenne, Paris, France). Nine normally cycling women (group 1) with acne and/or seborrhoea and nine patients with polycystic ovarian disease (PCOD) (group 2) received Anandron (100 mg twice a day) and a placebo. Both treatments were administered orally, in a cross-over randomized design, for two consecutive cycles (group 1) or months (group 2) separated by one cycle or 1 month. Luteinizing hormone (LH) pulse frequency and amplitude (cluster analysis), basal and gonadotropin-releasing hormone (GnRH)-stimulated plasma LH/follicle-stimulating hormone (FSH) levels were determined on day 5 of each treatment or placebo cycle. On days 5, 10, 20, and 24 of each cycle or month, plasma estradiol (E2), estrone (E1), testosterone (T), dihydrotestosterone (DHT), androstenedione (A), dehydroepiandrosterone sulfate (DHAS), sex hormone-binding globulin (SHBG) levels, and urinary androstanediol glucuronide (3 alpha-diol G) were measured. Plasma progesterone (P) levels were determined on days 20 and 24 of each cycle (group 1) and on days 5, 10, 20, and 24 (group 2). In both groups, seborrhea and acne decreased markedly within the first month and practically disappeared after 2 months of Anandron treatment. No adverse side effects were reported. None of the normal patients had any disturbance of menstrual cycles as assessed by basal body temperature shift, ultrasonography, and plasma P levels. In PCOD patients, cycles remained anovulatory.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2744186

  13. Three gonadotropin-releasing hormone genes in one organism suggest novel roles for an ancient peptide.

    PubMed Central

    White, S A; Kasten, T L; Bond, C T; Adelman, J P; Fernald, R D

    1995-01-01

    Gonadotropin-releasing hormone (GnRH) is known and named for its essential role in vertebrate reproduction. Release of this decapeptide from neurons in the hypothalamus controls pituitary gonadotropin levels which, in turn, regulate gonadal state. The importance of GnRH is underscored by its widespread expression and conservation across vertebrate taxa: five amino acids are invariant in all nine known forms, whereas two others show only conservative changes. In most eutherian mammals, only one form, expressed in the hypothalamus, is thought to exist, although in a recent report, antibody staining in developing primates suggests an additional form. In contrast, multiple GnRH forms and expression loci have been reported in many non-mammalian vertebrates. However, evidence based on immunological discrimination does not always agree with analysis of gene expression, since GnRH forms encoded by different genes may not be reliably distinguished by antibodies. Here we report the expression of three distinct GnRH genes in a teleost fish brain, including the sequence encoding a novel GnRH preprohormone. Using in situ hybridization, we show that this form is found only in neurons that project to the pituitary and exhibit changes in soma size depending on social and reproductive state. The other two GnRH genes are expressed in other, distinct cell populations. All three genes share the motif of encoding a polypeptide consisting of GnRH and a GnRH-associated peptide. Whereas the GnRH moiety is highly conserved, the GnRH-associated peptides are not, reflecting differential selective pressure on different parts of the gene. GnRH forms expressed in nonhypothalamic regions may serve to coordinate reproductive activities of the animal. Images Fig. 3 PMID:7667296

  14. Altered pulsatile gonadotropin signaling in nutritional deficiency in the male.

    PubMed

    Bergendahl, M; Veldhuis, J D

    1995-07-01

    Reproduction cannot occur without adequate nutrition. Diets that are nutritionally inadequate delay and disrupt the pubertal development of the reproductive processes of immature experimental animals and humans, and impair the function of the hypothalamic-pituitary-gonadal axis in adults. Although there is a general understanding of the linkages between nutrition and reproduction, there is a lack of detailed knowledge of the exact mechanisms that couple these two systems. The major effects of malnutrition on the hypothalamic-pituitary-gonadal axis reported in the literature are, for the most part, manifested as reduced gonadotropin secretion. Malnutrition results in decreased circulating gonadotropin concentrations. These changes in the reproductive system are associated with impaired gonadal function and subsequent secondary sex organ atrophy and lead, ultimately, to poor reproduction. Decreased hypothalamic release of gonadotropin-releasing hormone (GnRH) has been proposed as the most important etiologic factor for the fasting-induced suppression of pituitary-testicular function. In the human, hypogonadism and infertility develop in both sexes during chronic malnutrition. Most studies on the effects of malnutrition on the reproductive hormones have been performed in women, perhaps because malnutrition in women is promptly accompanied by amenorrhea, whereas in men hypogonadism develops gradually and becomes clinically evident only during more severe malnutrition. With the advent of sensitive assays for measuring reproductive hormones and of modern computerized methods for analyzing the pulsatile secretion of these hormones, however, the function of the hypothalamic-pituitary-testicular axis has been scrutinized and it has, indeed, been observed that this system is disturbed even during acute malnutrition. Here, we review the effects of malnutrition on reproductive function, especially on the pulsatile pattern of LH secretion, in humans and in experimental animals.

  15. Gonadotropins in doping: pharmacological basis and detection of illicit use

    PubMed Central

    Stenman, U-H; Hotakainen, K; Alfthan, H

    2008-01-01

    Parenteral administration of human chorionic gonadotropin (hCG) or luteinizing hormone (LH) stimulates the production of testosterone in males and these gonadotropins can therefore be used by athletes to enhance muscle strength. However, they are more expensive and less efficient than testosterone and anabolic steroids. Therefore their main use is probably to stimulate gonadal testosterone production during and after self-administration of testosterone or anabolic steroids. A positive effect of hCG on muscle strength has not been demonstrated in women and elevated concentrations of hCG in females are often caused by pregnancy. The use of gonadotropins is therefore prohibited only in males but not in females. HCG occurs at low but measurable concentrations in plasma and urine of healthy males and can be measured by sensitive methods. However, the characteristics of the method to be used for doping control have not been defined. Virtually all commercially available hCG assays have been designed for determination of hCG in serum rather than urine, which is used for doping control. Methods based on mass spectrometric detection of fragments derived from hCG extracted from urine by immunoadsorption have been developed but their suitability for doping control remains to be determined. The concentrations of LH in serum and urine are variable and more then 10-fold higher than those hCG. It is therefore difficult to detect illicit use of LH. The characteristics and reference values for hCG and LH assays used in doping control and the cutoff values need to be defined. PMID:18414398

  16. Multitasking in Gonadotropin-Releasing Hormone Neuron Dendrites.

    PubMed

    Iremonger, Karl J; Herbison, Allan E

    2015-01-01

    Gonadotropin-releasing hormone (GnRH) neurons integrate synaptic information in their dendrites in order to precisely control GnRH secretion and hence fertility. Recent discoveries concerning the structure and function of GnRH neuron dendrites have shed new light on the control of GnRH neuron excitability and GnRH secretion. This work suggests that GnRH neurons have a unique projection to the median eminence that possesses both dendritic and axonal properties. We propose that this 'dendron' projection allows GnRH neurons to multitask and integrate information in ways that would not be possible in a classically envisioned axon projection. PMID:25300776

  17. Active immunization of gilts against gonadotropin-releasing hormone: effects on secretion of gonadotropins, reproductive function, and responses to agonists of gonadotropin-releasing hormone.

    PubMed

    Esbenshade, K L; Britt, J H

    1985-10-01

    Sexually mature gilts were actively immunized against gonadotropin-releasing hormone (GnRH) by conjugating GnRH to bovine serum albumin, emulsifying the conjugate in Freund's adjuvant, and giving the emulsion as a primary immunization at Week 0 and as booster immunizations at Weeks 10 and 14. Antibody titers were evident by 2 wk after primary immunization and increased markedly in response to booster immunizations. Active immunization against GnRH caused gonadotropins to decline to nondetectable levels, gonadal steroids to decline to basal levels, and the gilts to become acyclic. Prolactin concentrations in peripheral circulation were unaffected by immunization against GnRH. The endocrine status of the hypothalamic-pituitary-ovarian axis was examined by giving GnRH and two agonists to GnRH and by ovariectomy. An i.v. injection of 100 micrograms GnRH caused release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in control animals, but not in gilts immunized against GnRH. In contrast, administration of 5 micrograms D-(Ala6, des-Gly-NH2(10] ethylamide or 5 micrograms D-(Ser-t-But6, des-Gly-NH2(10] ethylamide resulted in immediate release of LH and FSH in both control and GnRH-immunized gilts. Circulating concentrations of LH and FSH increased after ovariectomy in the controls, but remained at nondetectable levels in gilts immunized against GnRH. Prolactin concentrations did not change in response to ovariectomy. We conclude that cyclic gilts can be actively immunized against GnRH and that this causes cessation of estrous cycles and inhibits secretion of LH, FSH, and gonadal steroids.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Ovarian hyperstimulation syndrome prevention strategies: oral contraceptive pills-dual gonadotropin-releasing hormone agonist suppression with step-down gonadotropin protocols.

    PubMed

    Damario, Mark A

    2010-11-01

    The identification of patients at high risk for excessive responses to ovarian stimulation for in vitro fertilization and embryo transfer is essential in the tailoring of safe and effective treatment strategies. Known factors associated with increased sensitivity to gonadotropins include polycystic ovary syndrome, young age, prior ovarian hyperstimulation syndrome (OHSS), high baseline antral follicle count, and high baseline ovarian volume. Although several treatment strategies have been proposed for these patients, this report describes the experience using the dual suppression with gonadotropin step-down protocol. This protocol uses oral contraceptive pretreatment in combination with a long gonadotropin-releasing hormone agonist followed by a programmed step-down in gonadotropin dosing. Hormonal characteristics of dual suppression include an improved luteinizing hormone-to-follicle-stimulating hormone ratio and lower serum androgens, particularly dehydroepiandrosterone sulfate. Clinical characteristics of the protocol include a lower cancellation rate and favorable clinical and ongoing pregnancy rates per initiated cycle while mitigating the risk of OHSS.

  19. Multimaterial 4D Printing with Tailorable Shape Memory Polymers.

    PubMed

    Ge, Qi; Sakhaei, Amir Hosein; Lee, Howon; Dunn, Conner K; Fang, Nicholas X; Dunn, Martin L

    2016-08-08

    We present a new 4D printing approach that can create high resolution (up to a few microns), multimaterial shape memory polymer (SMP) architectures. The approach is based on high resolution projection microstereolithography (PμSL) and uses a family of photo-curable methacrylate based copolymer networks. We designed the constituents and compositions to exhibit desired thermomechanical behavior (including rubbery modulus, glass transition temperature and failure strain which is more than 300% and larger than any existing printable materials) to enable controlled shape memory behavior. We used a high resolution, high contrast digital micro display to ensure high resolution of photo-curing methacrylate based SMPs that requires higher exposure energy than more common acrylate based polymers. An automated material exchange process enables the manufacture of 3D composite architectures from multiple photo-curable SMPs. In order to understand the behavior of the 3D composite microarchitectures, we carry out high fidelity computational simulations of their complex nonlinear, time-dependent behavior and study important design considerations including local deformation, shape fixity and free recovery rate. Simulations are in good agreement with experiments for a series of single and multimaterial components and can be used to facilitate the design of SMP 3D structures.

  20. Multimaterial 4D Printing with Tailorable Shape Memory Polymers

    NASA Astrophysics Data System (ADS)

    Ge, Qi; Sakhaei, Amir Hosein; Lee, Howon; Dunn, Conner K.; Fang, Nicholas X.; Dunn, Martin L.

    2016-08-01

    We present a new 4D printing approach that can create high resolution (up to a few microns), multimaterial shape memory polymer (SMP) architectures. The approach is based on high resolution projection microstereolithography (PμSL) and uses a family of photo-curable methacrylate based copolymer networks. We designed the constituents and compositions to exhibit desired thermomechanical behavior (including rubbery modulus, glass transition temperature and failure strain which is more than 300% and larger than any existing printable materials) to enable controlled shape memory behavior. We used a high resolution, high contrast digital micro display to ensure high resolution of photo-curing methacrylate based SMPs that requires higher exposure energy than more common acrylate based polymers. An automated material exchange process enables the manufacture of 3D composite architectures from multiple photo-curable SMPs. In order to understand the behavior of the 3D composite microarchitectures, we carry out high fidelity computational simulations of their complex nonlinear, time-dependent behavior and study important design considerations including local deformation, shape fixity and free recovery rate. Simulations are in good agreement with experiments for a series of single and multimaterial components and can be used to facilitate the design of SMP 3D structures.

  1. Multimaterial 4D Printing with Tailorable Shape Memory Polymers

    PubMed Central

    Ge, Qi; Sakhaei, Amir Hosein; Lee, Howon; Dunn, Conner K.; Fang, Nicholas X.; Dunn, Martin L.

    2016-01-01

    We present a new 4D printing approach that can create high resolution (up to a few microns), multimaterial shape memory polymer (SMP) architectures. The approach is based on high resolution projection microstereolithography (PμSL) and uses a family of photo-curable methacrylate based copolymer networks. We designed the constituents and compositions to exhibit desired thermomechanical behavior (including rubbery modulus, glass transition temperature and failure strain which is more than 300% and larger than any existing printable materials) to enable controlled shape memory behavior. We used a high resolution, high contrast digital micro display to ensure high resolution of photo-curing methacrylate based SMPs that requires higher exposure energy than more common acrylate based polymers. An automated material exchange process enables the manufacture of 3D composite architectures from multiple photo-curable SMPs. In order to understand the behavior of the 3D composite microarchitectures, we carry out high fidelity computational simulations of their complex nonlinear, time-dependent behavior and study important design considerations including local deformation, shape fixity and free recovery rate. Simulations are in good agreement with experiments for a series of single and multimaterial components and can be used to facilitate the design of SMP 3D structures. PMID:27499417

  2. Effortless assignment with 4D covariance sequential correlation maps.

    PubMed

    Harden, Bradley J; Mishra, Subrata H; Frueh, Dominique P

    2015-11-01

    Traditional Nuclear Magnetic Resonance (NMR) assignment procedures for proteins rely on preliminary peak-picking to identify and label NMR signals. However, such an approach has severe limitations when signals are erroneously labeled or completely neglected. The consequences are especially grave for proteins with substantial peak overlap, and mistakes can often thwart entire projects. To overcome these limitations, we previously introduced an assignment technique that bypasses traditional pick peaking altogether. Covariance Sequential Correlation Maps (COSCOMs) transform the indirect connectivity information provided by multiple 3D backbone spectra into direct (H, N) to (H, N) correlations. Here, we present an updated method that utilizes a single four-dimensional spectrum rather than a suite of three-dimensional spectra. We demonstrate the advantages of 4D-COSCOMs relative to their 3D counterparts. We introduce improvements accelerating their calculation. We discuss practical considerations affecting their quality. And finally we showcase their utility in the context of a 52 kDa cyclization domain from a non-ribosomal peptide synthetase.

  3. Multimaterial 4D Printing with Tailorable Shape Memory Polymers.

    PubMed

    Ge, Qi; Sakhaei, Amir Hosein; Lee, Howon; Dunn, Conner K; Fang, Nicholas X; Dunn, Martin L

    2016-01-01

    We present a new 4D printing approach that can create high resolution (up to a few microns), multimaterial shape memory polymer (SMP) architectures. The approach is based on high resolution projection microstereolithography (PμSL) and uses a family of photo-curable methacrylate based copolymer networks. We designed the constituents and compositions to exhibit desired thermomechanical behavior (including rubbery modulus, glass transition temperature and failure strain which is more than 300% and larger than any existing printable materials) to enable controlled shape memory behavior. We used a high resolution, high contrast digital micro display to ensure high resolution of photo-curing methacrylate based SMPs that requires higher exposure energy than more common acrylate based polymers. An automated material exchange process enables the manufacture of 3D composite architectures from multiple photo-curable SMPs. In order to understand the behavior of the 3D composite microarchitectures, we carry out high fidelity computational simulations of their complex nonlinear, time-dependent behavior and study important design considerations including local deformation, shape fixity and free recovery rate. Simulations are in good agreement with experiments for a series of single and multimaterial components and can be used to facilitate the design of SMP 3D structures. PMID:27499417

  4. Effortless assignment with 4D covariance sequential correlation maps

    NASA Astrophysics Data System (ADS)

    Harden, Bradley J.; Mishra, Subrata H.; Frueh, Dominique P.

    2015-11-01

    Traditional Nuclear Magnetic Resonance (NMR) assignment procedures for proteins rely on preliminary peak-picking to identify and label NMR signals. However, such an approach has severe limitations when signals are erroneously labeled or completely neglected. The consequences are especially grave for proteins with substantial peak overlap, and mistakes can often thwart entire projects. To overcome these limitations, we previously introduced an assignment technique that bypasses traditional pick peaking altogether. Covariance Sequential Correlation Maps (COSCOMs) transform the indirect connectivity information provided by multiple 3D backbone spectra into direct (H, N) to (H, N) correlations. Here, we present an updated method that utilizes a single four-dimensional spectrum rather than a suite of three-dimensional spectra. We demonstrate the advantages of 4D-COSCOMs relative to their 3D counterparts. We introduce improvements accelerating their calculation. We discuss practical considerations affecting their quality. And finally we showcase their utility in the context of a 52 kDa cyclization domain from a non-ribosomal peptide synthetase.

  5. 2,4-D and IAA Amino Acid Conjugates Show Distinct Metabolism in Arabidopsis

    PubMed Central

    Eyer, Luděk; Vain, Thomas; Pařízková, Barbora; Oklestkova, Jana; Barbez, Elke; Kozubíková, Hana; Pospíšil, Tomáš; Wierzbicka, Roksana; Kleine-Vehn, Jürgen; Fránek, Milan; Strnad, Miroslav; Robert, Stéphanie

    2016-01-01

    The herbicide 2,4-D exhibits an auxinic activity and therefore can be used as a synthetic and traceable analog to study auxin-related responses. Here we identified that not only exogenous 2,4-D but also its amide-linked metabolite 2,4-D-Glu displayed an inhibitory effect on plant growth via the TIR1/AFB auxin-mediated signaling pathway. To further investigate 2,4-D metabolite conversion, identity and activity, we have developed a novel purification procedure based on the combination of ion exchange and immuno-specific sorbents combined with a sensitive liquid chromatography-mass spectrometry method. In 2,4-D treated samples, 2,4-D-Glu and 2,4-D-Asp were detected at 100-fold lower concentrations compared to 2,4-D levels, showing that 2,4-D can be metabolized in the plant. Moreover, 2,4-D-Asp and 2,4-D-Glu were identified as reversible forms of 2,4-D homeostasis that can be converted to free 2,4-D. This work paves the way to new studies of auxin action in plant development. PMID:27434212

  6. 2,4-D and IAA Amino Acid Conjugates Show Distinct Metabolism in Arabidopsis.

    PubMed

    Eyer, Luděk; Vain, Thomas; Pařízková, Barbora; Oklestkova, Jana; Barbez, Elke; Kozubíková, Hana; Pospíšil, Tomáš; Wierzbicka, Roksana; Kleine-Vehn, Jürgen; Fránek, Milan; Strnad, Miroslav; Robert, Stéphanie; Novak, Ondrej

    2016-01-01

    The herbicide 2,4-D exhibits an auxinic activity and therefore can be used as a synthetic and traceable analog to study auxin-related responses. Here we identified that not only exogenous 2,4-D but also its amide-linked metabolite 2,4-D-Glu displayed an inhibitory effect on plant growth via the TIR1/AFB auxin-mediated signaling pathway. To further investigate 2,4-D metabolite conversion, identity and activity, we have developed a novel purification procedure based on the combination of ion exchange and immuno-specific sorbents combined with a sensitive liquid chromatography-mass spectrometry method. In 2,4-D treated samples, 2,4-D-Glu and 2,4-D-Asp were detected at 100-fold lower concentrations compared to 2,4-D levels, showing that 2,4-D can be metabolized in the plant. Moreover, 2,4-D-Asp and 2,4-D-Glu were identified as reversible forms of 2,4-D homeostasis that can be converted to free 2,4-D. This work paves the way to new studies of auxin action in plant development. PMID:27434212

  7. Digit ratio (2D:4D) and hand preference for writing in the BBC Internet Study.

    PubMed

    Manning, J T; Peters, M

    2009-09-01

    The ratio of the length of the second to the fourth digit (2D:4D) may be negatively correlated with prenatal testosterone. Hand preference has been linked with prenatal testosterone and 2D:4D. Here we show that 2D:4D is associated with hand preference for writing in a large internet sample (n>170,000) in which participants self-reported their finger lengths. We replicated a significant association between right 2D:4D and writing hand preference (low right 2D:4D associated with left hand preference) as well as a significant correlation between writing hand preference and the difference between left and right 2D:4D or Dr-l (low Dr-l associated with left hand preference). A new significant correlation between left 2D:4D and writing hand preference was also shown (high left 2D:4D associated with left hand preference). There was a clear interaction between writing hand preference and 2D:4D: The left 2D:4D was significantly larger than the right 2D:4D in male and female left-handed writers, and the right hand 2D:4D was significantly larger than the left hand 2D:4D in male and female right-handed writers.

  8. Efficacy of exogenous gonadotropins on the maintenance of spermatogenesis in pethidine treated albino rats.

    PubMed

    Patil, S R; Sonar, A; Londonkar, R; Patil, S R; Patil, S B

    1998-10-01

    An attempt is made to induce the pethidine suppressed gonadal activities by the administration of exogenous gonadotropins (hCG, PMSG, hCG + PMSG). Administration of 5 IU gonadotropins either separately or in combination to the rats treated with pethidine for 30 days resulted in the significant increase in the weight of testis, diameter of testis and seminiferous tubules. Gonadotropin(s) treatment stimulated the spermatogenic activity which was inhibited by pethidine. Therefore the number of spermatogonia, spermatocytes, spermatids in the seminiferous tubules and spermatozoa in cauda epididymis is increased significantly. Decreased testicular cholesterol, increased protein content and weight of accessory sex organs indicate the rejuvenation of steroidogenesis. Combination of both the gonadotropins is more effective in bringing all these activities.

  9. 4D imaging of protein aggregation in live cells.

    PubMed

    Spokoini, Rachel; Shamir, Maya; Keness, Alma; Kaganovich, Daniel

    2013-01-01

    ubiquitinated are diverted to the IPOD, where they are actively aggregated in a protective compartment. Up until this point, the methodological paradigm of live-cell fluorescence microscopy has largely been to label proteins and track their locations in the cell at specific time-points and usually in two dimensions. As new technologies have begun to grant experimenters unprecedented access to the submicron scale in living cells, the dynamic architecture of the cytosol has come into view as a challenging new frontier for experimental characterization. We present a method for rapidly monitoring the 3D spatial distributions of multiple fluorescently labeled proteins in the yeast cytosol over time. 3D timelapse (4D imaging) is not merely a technical challenge; rather, it also facilitates a dramatic shift in the conceptual framework used to analyze cellular structure. We utilize a cytosolic folding sensor protein in live yeast to visualize distinct fates for misfolded proteins in cellular aggregation quality control, using rapid 4D fluorescent imaging. The temperature sensitive mutant of the Ubc9 protein (Ubc9(ts)) is extremely effective both as a sensor of cellular proteostasis, and a physiological model for tracking aggregation quality control. As with most ts proteins, Ubc9(ts) is fully folded and functional at permissive temperatures due to active cellular chaperones. Above 30 ° C, or when the cell faces misfolding stress, Ubc9(ts) misfolds and follows the fate of a native globular protein that has been misfolded due to mutation, heat denaturation, or oxidative damage. By fusing it to GFP or other fluorophores, it can be tracked in 3D as it forms Stress Foci, or is directed to JUNQ or IPOD. PMID:23608881

  10. GRAM 88 - 4D GLOBAL REFERENCE ATMOSPHERE MODEL-1988

    NASA Technical Reports Server (NTRS)

    Johnson, D. L.

    1994-01-01

    the Jacchia values. Below 25km the atmospheric parameters are computed by the 4-D worldwide atmospheric model of Spiegler and Fowler (1972). This data set is not included. GRAM-88 incorporates a hydrostatic/gas law check in the 0-30 km altitude range to flag and change any bad data points. Between 5km and 30km, an interpolation scheme is used between the 4-D results and the modified Groves values. The output parameters consist of components for: (1) latitude, longitude, and altitude dependent monthly and annual means, (2) quasi-biennial oscillations (QBO), and (3) random perturbations to partially simulate the variability due to synoptic, diurnal, planetary wave, and gravity wave variations. Quasi-biennial and random variation perturbations are computed from parameters determined by various empirical studies and are added to the monthly mean values. The GRAM-88 program is for batch execution on the IBM 3084. It is written in STANDARD FORTRAN 77 under the MVS/XA operating system. The IBM DISPLA graphics routines are necessary for graphical output. The program was developed in 1988.

  11. 4D measurement system for automatic location of anatomical structures

    NASA Astrophysics Data System (ADS)

    Witkowski, Marcin; Sitnik, Robert; Kujawińska, Małgorzata; Rapp, Walter; Kowalski, Marcin; Haex, Bart; Mooshake, Sven

    2006-04-01

    Orthopedics and neurosciences are fields of medicine where the analysis of objective movement parameters is extremely important for clinical diagnosis. Moreover, as there are significant differences between static and dynamic parameters, there is a strong need of analyzing the anatomical structures under functional conditions. In clinical gait analysis the benefits of kinematical methods are undoubted. In this paper we present a 4D (3D + time) measurement system capable of automatic location of selected anatomical structures by locating and tracing the structures' position and orientation in time. The presented system is designed to help a general practitioner in diagnosing selected lower limbs' dysfunctions (e.g. knee injuries) and also determine if a patient should be directed for further examination (e.g. x-ray or MRI). The measurement system components are hardware and software. For the hardware part we adapt the laser triangulation method. In this way we can evaluate functional and dynamic movements in a contact-free, non-invasive way, without the use of potentially harmful radiation. Furthermore, opposite to marker-based video-tracking systems, no preparation time is required. The software part consists of a data acquisition module, an image processing and point clouds (point cloud, set of points described by coordinates (x, y, z)) calculation module, a preliminary processing module, a feature-searching module and an external biomechanical module. The paper briefly presents the modules mentioned above with the focus on the feature-searching module. Also we present some measurement and analysis results. These include: parameters maps, landmarks trajectories in time sequence and animation of a simplified model of lower limbs.

  12. Infrared PINEM developed by diffraction in 4D UEM

    PubMed Central

    Liu, Haihua; Baskin, John Spencer; Zewail, Ahmed H.

    2016-01-01

    The development of four-dimensional ultrafast electron microscopy (4D UEM) has enabled not only observations of the ultrafast dynamics of photon–matter interactions at the atomic scale with ultrafast resolution in image, diffraction, and energy space, but photon–electron interactions in the field of nanoplasmonics and nanophotonics also have been captured by the related technique of photon-induced near-field electron microscopy (PINEM) in image and energy space. Here we report a further extension in the ongoing development of PINEM using a focused, nanometer-scale, electron beam in diffraction space for measurements of infrared-light-induced PINEM. The energy resolution in diffraction mode is unprecedented, reaching 0.63 eV under the 200-keV electron beam illumination, and separated peaks of the PINEM electron-energy spectrum induced by infrared light of wavelength 1,038 nm (photon energy 1.2 eV) have been well resolved for the first time, to our knowledge. In a comparison with excitation by green (519-nm) pulses, similar first-order PINEM peak amplitudes were obtained for optical fluence differing by a factor of more than 60 at the interface of copper metal and vacuum. Under high fluence, the nonlinear regime of IR PINEM was observed, and its spatial dependence was studied. In combination with PINEM temporal gating and low-fluence infrared excitation, the PINEM diffraction method paves the way for studies of structural dynamics in reciprocal space and energy space with high temporal resolution. PMID:26848135

  13. Binary 4D seismic history matching, a metric study

    NASA Astrophysics Data System (ADS)

    Chassagne, Romain; Obidegwu, Dennis; Dambrine, Julien; MacBeth, Colin

    2016-11-01

    This paper explores 4D seismic history matching and it specifically focuses on the objective function used during the optimisation with seismic data. The objective function is calculated by using binary maps, where one map is obtained from the observed seismic data and the other is from one realisation of the optimisation algorithm from the simulation model. In order to decide which set of parameters is a relevant update for the simulation model, an efficient way is required to measure how similar these two binary images are, during their evaluation within the objective function. Behind this aspect of quantification of the similarities or dissimilarities lies the metric notion, or the art of measuring distances. Four metrics are proposed with this study, the well-known Hamming distance, two widely used metrics, the Hausdorff distance and Mutual Information and a recent metric, called the Current Measure Metric. These metrics will be tested and compared on different case scenarios, designed in accordance to a real field case (gas exsolution) before being used in the second part of the paper. Despite its simplicity, the Hamming distance gives positive results, but the Current Measure Metric appears to be a more efficient choice to cover a wider range of scenarios, these conclusions remain true when tested on synthetic and real dataset in a history matching exercise. Some practical aspects of binary map processes will be examined through the paper, as it is shown that it is more proper to use a derivative free optimisation algorithm and a proper metric should be more inclined to capture global features than local features.

  14. Fast interactive exploration of 4D MRI flow data

    NASA Astrophysics Data System (ADS)

    Hennemuth, A.; Friman, O.; Schumann, C.; Bock, J.; Drexl, J.; Huellebrand, M.; Markl, M.; Peitgen, H.-O.

    2011-03-01

    1- or 2-directional MRI blood flow mapping sequences are an integral part of standard MR protocols for diagnosis and therapy control in heart diseases. Recent progress in rapid MRI has made it possible to acquire volumetric, 3-directional cine images in reasonable scan time. In addition to flow and velocity measurements relative to arbitrarily oriented image planes, the analysis of 3-dimensional trajectories enables the visualization of flow patterns, local features of flow trajectories or possible paths into specific regions. The anatomical and functional information allows for advanced hemodynamic analysis in different application areas like stroke risk assessment, congenital and acquired heart disease, aneurysms or abdominal collaterals and cranial blood flow. The complexity of the 4D MRI flow datasets and the flow related image analysis tasks makes the development of fast comprehensive data exploration software for advanced flow analysis a challenging task. Most existing tools address only individual aspects of the analysis pipeline such as pre-processing, quantification or visualization, or are difficult to use for clinicians. The goal of the presented work is to provide a software solution that supports the whole image analysis pipeline and enables data exploration with fast intuitive interaction and visualization methods. The implemented methods facilitate the segmentation and inspection of different vascular systems. Arbitrary 2- or 3-dimensional regions for quantitative analysis and particle tracing can be defined interactively. Synchronized views of animated 3D path lines, 2D velocity or flow overlays and flow curves offer a detailed insight into local hemodynamics. The application of the analysis pipeline is shown for 6 cases from clinical practice, illustrating the usefulness for different clinical questions. Initial user tests show that the software is intuitive to learn and even inexperienced users achieve good results within reasonable processing

  15. Negative feedback effects of chlormadinone acetate and ethynylestradiol on gonadotropin secretion in patients with prostatic cancer and male rats.

    PubMed

    Noguchi, K; Nishimura, R; Takai, S; Arita, J; Higuchi, T; Kawakami, M

    1980-06-01

    Serum LH and FSH levels were determined before and after LH-RH injection (100 micrograms, i.m.) in patients with prostatic cancer who were chronically treated with either chlormadinone acetate (CMA, 100 mg/day) or ethynylestradiol (EE, 1 mg/day). In patients treated with EE, the levels of serum LH and FSH before and after injection of LH-RH were significantly lower than those in controls. On the other hand in patients treated with CMA, the basal levels of serum gonadotropins did not differ from those in controls, and the increase in gonadotropin after LH-RH injection was comparable to that in controls. To examine the effects of these steroids on the hypothalamo-hypophysial axis in the regulation of gonadotropin secretion, CMA or EE was implanted in castrated male rats. CMA, EE or cholesterol (control) was implanted in the hypothalamic median eminence-arcuate nucleus region through a stainless doublecannula. EE implantation resulted in a 75% decrease in serum LH (p < 0.001) and a 38% decrease in serum FSH (p < 0.05) from the control levels on day 5 of implantation. On the other hand, CMA implantation induced a 33% decrease in serum LH (p < 0.05) from the control level on day 3 of implantation, but no significant change in serum FSH levels. The injection of 2 micrograms/kg of LH-RH on day 7 of implantation induced significant lowering of LH and FSH levels. There was no significant difference between serum levels of the hormones 20 min after LH-RH injection for these two groups and those for the control group. These studies suggest that EE has a potent negative feedback effect on both LH and FSH secretion, and that CMA has a mild negative feedback effect on LH secretion.

  16. Vessels as 4-D curves: global minimal 4-D paths to extract 3-D tubular surfaces and centerlines.

    PubMed

    Li, Hua; Yezzi, Anthony

    2007-09-01

    In this paper, we propose an innovative approach to the segmentation of tubular structures. This approach combines all of the benefits of minimal path techniques such as global minimizers, fast computation, and powerful incorporation of user input, while also having the capability to represent and detect vessel surfaces directly which so far has been a feature restricted to active contour and surface techniques. The key is to represent the trajectory of a tubular structure not as a 3-D curve but to go up a dimension and represent the entire structure as a 4-D curve. Then we are able to fully exploit minimal path techniques to obtain global minimizing trajectories between two user supplied endpoints in order to reconstruct tubular structures from noisy or low contrast 3-D data without the sensitivity to local minima inherent in most active surface techniques. In contrast to standard purely spatial 3-D minimal path techniques, however, we are able to represent a full tubular surface rather than just a curve which runs through its interior. Our representation also yields a natural notion of a tube's "central curve." We demonstrate and validate the utility of this approach on magnetic resonance (MR) angiography and computed tomography (CT) images of coronary arteries. PMID:17896594

  17. Superovulation in cattle: practical aspects of gonadotropin treatment and insemination.

    PubMed

    Kanitz, Wilhelm; Becker, Frank; Schneider, Falk; Kanitz, Ellen; Leiding, Claus; Nohner, Hans-Peter; Pöhland, Ralf

    2002-01-01

    Embryo transfer (ET) in cattle has been used for the realisation of breeding programmes world-wide for more than 20 years. The efficiency of breeding technology, i.e. the breeding progress and costs, depends to a large extent on the results of superovulatory treatment and artificial insemination (A.I.). The results of this step are characterised by a high degree of variation. Numerous attempts have been undertaken to explain the reason(s) for this. Numerous attempts have also been made to clarify the importance of different factors affecting the results. Undoubtedly, the applied hormones and the scheme of insemination itself are main factors, which influence the number and the portion of transferable embryos. Therefore this paper is focused on the following aspects of superovulatory treatment with FSH: dose-response relations, bioactivity of the glycoprotein, FSH/LH ratio, ovulation time and time-oriented insemination, frequency of gonadotropin administration and follicular population at the time of gonadotropin application. PMID:12625423

  18. Advances in the molecular understanding of gonadotropins-receptors interactions.

    PubMed

    el Tayar, N

    1996-12-20

    The extracellular domain (ECD) of gonadotropin receptors belong to the leucine-rich repeat (LRR) protein superfamily and their transmembrane domain (TMD) is characteristic of the seven alpha-helices G-protein-coupled receptors (GPCR). The availability of the X-ray structures of porcine ribonuclease inhibitor (RI), a LRR protein, and bacteriorhodopsin (bR) allows the construction of 3D models of the ECD and the TMD of gonadotropin receptors, respectively. The predicted models are to a large extent consistent with currently available biochemical and mutational data. The models provide a reliable basis for understanding how the hormone binds and activates its receptor. The ECD, in particular the LRR region, serves as a baseball glove which efficiently catches the large hormone and optimally orient the appropriate parts of it for interaction with the seven-transmembrane-helix domain of the receptor. This in turn is expected to lead to a conformational change to be sensed by the appropriate G-protein complex leading to the stimulation of cAMP synthesis and steroids production.

  19. 32 CFR 1630.43 - Class 4-D: Minister of religion.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 6 2010-07-01 2010-07-01 false Class 4-D: Minister of religion. 1630.43 Section... CLASSIFICATION RULES § 1630.43 Class 4-D: Minister of religion. In accord with part 1645 of this chapter any registrant shall be placed in Class 4-D who is a: (a) Duly ordained minister of religion; or (b)...

  20. 32 CFR 1630.43 - Class 4-D: Minister of religion.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 6 2013-07-01 2013-07-01 false Class 4-D: Minister of religion. 1630.43 Section... CLASSIFICATION RULES § 1630.43 Class 4-D: Minister of religion. In accord with part 1645 of this chapter any registrant shall be placed in Class 4-D who is a: (a) Duly ordained minister of religion; or (b)...

  1. 32 CFR 1630.43 - Class 4-D: Minister of religion.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 6 2014-07-01 2014-07-01 false Class 4-D: Minister of religion. 1630.43 Section... CLASSIFICATION RULES § 1630.43 Class 4-D: Minister of religion. In accord with part 1645 of this chapter any registrant shall be placed in Class 4-D who is a: (a) Duly ordained minister of religion; or (b)...

  2. 32 CFR 1630.43 - Class 4-D: Minister of religion.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 6 2011-07-01 2011-07-01 false Class 4-D: Minister of religion. 1630.43 Section... CLASSIFICATION RULES § 1630.43 Class 4-D: Minister of religion. In accord with part 1645 of this chapter any registrant shall be placed in Class 4-D who is a: (a) Duly ordained minister of religion; or (b)...

  3. 32 CFR 1630.43 - Class 4-D: Minister of religion.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 6 2012-07-01 2012-07-01 false Class 4-D: Minister of religion. 1630.43 Section... CLASSIFICATION RULES § 1630.43 Class 4-D: Minister of religion. In accord with part 1645 of this chapter any registrant shall be placed in Class 4-D who is a: (a) Duly ordained minister of religion; or (b)...

  4. Gonadotropin-I and -II subunit gene expression of male striped bass (Morone saxatilis) after gonadotropin-releasing hormone analogue injection: quantitation using an optimized ribonuclease protection assay.

    PubMed

    Hassin, S; Gothilf, Y; Blaise, O; Zohar, Y

    1998-05-01

    In fish, both gonadotropin (GtH)-I and -II are involved in the spermatogenic process, but the differential regulation of these hormones by GnRH is still poorly understood. To gain further insight into the GnRH regulation of GtH-I and -II gene expression in the male striped bass, we have developed and optimized a ribonuclease protection assay for the simultaneous measurement of all GtH subunit mRNAs in a single pituitary gland. The RNA extraction protocol enables the determination of GtH protein content in the same sample, thus enhancing the power of the method. Maturing striped bass males were injected intramuscularly with [D-Ala6,Pro9Net]-LHRH (GnRHa) and sampled at 6 and 24 h postinjection. The mRNA levels of the alpha subunit and GtH-IIbeta increased after 6 h (4- and 6-fold, respectively), while the GtH-Ibeta mRNA levels increased only 2-fold after 24 h. Interestingly, GnRHa stimulation caused a significant increase in beta-actin mRNA levels. GnRHa treatment also resulted in a 2-fold decrease in pituitary GtH-II content, associated with a dramatic increase of plasma GtH-II levels from undetectable levels (< 0.2 ng/ml) to 13+/-2 ng/ml after 6 h. These results demonstrate that both GtH-Ibeta and -Ilbeta are expressed during striped bass spermatogenesis and that the two genes are subjected to differential regulation by GnRHa.

  5. Mineralization of 2,4-dichlorophenoxyacetic acid (2,4-D) and mixtures of 2,4-D and 2,4,5-trichlorophenoxyacetic acid by Phanerochaete chrysosporium

    SciTech Connect

    Yadav, J.S.; Reddy, C.A. )

    1993-09-01

    2,4-dichloropheonxyacetic Acid (2,4-D) is one of the most commonly used phenoxyalkanoic herbicides for selective control of weeds and for defoliation. Since these toxic chemical are manufactured and used each year in massive quantities, effective handling of their production wastes and the contaminated environment is needed. A number of bacterial general are known to degrade 2,4-D, but no naturally occuring bacterium is know to be capable of mineralizing 2,4,5-trichlorophenoxyacetic acid. Mutual inhibition of degradation has been reported when 2,4-D and 2,4,5-T are presented in a mixture to degrading bacteria. This paper investigates the ability of Pseudomonas chrysosporium to mineralize 2,4-D individually and in combination with 2,4,5-T. Results indicate that P. chrysosporium effectively mineralizes 2,4-D alone as well as in combination with 2,4,5-T. 31 refs., 4 figs., 1 tab.

  6. Influence of estradiol, progesterone, and nutrition on concentrations of gonadotropins and GnRH receptors, and abundance of mRNA for GnRH receptors and gonadotropin subunits in pituitary glands of beef cows.

    PubMed

    Looper, M L; Vizcarra, J A; Wettemann, R P; Malayer, J R; Braden, T D; Geisert, R D; Morgan, G L

    2003-01-01

    Nutritionally induced anovulatory cows (n = 28) were used to determine the effect of steroids on regulation of synthesis and secretion of gonadotropins. Anovulatory cows were ovariectomized and received intravaginal inserts containing estradiol (E2), progesterone (P4), E2 and P4 (E2P4), or a sham intravaginal insert (C) for 7 d. Concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were quantified in serum and E2 and P4 were quantified in plasma. Cows were exsanguinated within 1 to 2 h after removal of intravaginal inserts and pituitary glands were collected and stored at -80 degrees C until messenger ribonucleic acid (mRNA) for gonadotropin-releasing hormone receptor (GnRH-R) and gonadotropin subunits, pituitary content of GnRH-R, and LH and FSH were quantified. Pituitary glands from five proestrous cows were harvested to compare gonadotropin characteristics between ovariectomized, anovulatory cows and intact cows. Plasma concentrations of E2 were greater (P < 0.05) in E2-treated cows than in sham-treated cows. Concentrations of P4 were greater (P < 0.05) in cows treated with P4 than in sham-treated cows. Mean serum concentrations of LH and FSH were not significantly influenced by steroid treatments. However, frequency of LH pulses of ovariectomized, nutritionally induced anovulatory cows was increased (P < 0.05) by treatment with E2 and amplitude of LH pulses was greater (P < 0.05) in cows treated with E2 or P4 than in cows treated with E2P4 or sham-treated. Quantity of mRNA for LHbeta in the pituitary gland was greater when cows were treated with P4. Concentrations of LH in the pituitary gland were not affected by steroid treatments; however, pituitary concentrations of FSH were less (P < 0.1) in E2 cows than in sham-treated cows. The number of GnRH-R was increased (P < 0.05) in cows treated with E2, but P4 treatment did not influence the number of GnRH-R. Abundance of mRNA for GnRH-R, common alpha-subunit, and FSHbeta were not

  7. Familial idiopathic gonadotropin deficiency not linked to gene for gonadotropin-releasing hormone (GnRH) in Brazilian kindred

    SciTech Connect

    Faraco, J.; Francke, U.; Toledo, S.

    1994-09-01

    Familial idiopathic gonadotropin deficiency (FIGD) is an autosomal recessive disorder which results in failure to develop secondary sexual characteristics. The origin is a hypothalamic defect resulting in insufficient secretion of gonadotropin-releasing hormone GnRH (also called LHRH, luteinizing hormone releasing hormone) and follicle-stimuating hormone (FSH). FIGD has been determined to be a separate entity from Kallmann syndrome which presents with hypogonadism as well as anosmia. The FIGD phenotype appears to be analogous to the phenotype of the hpg (hypogonadal) mouse. Because the hpg phenotype is the result of a structurally abnormal GnRH gene, we have studied the GnRH gene in individuals from a previously reported Brazilian FIGD family. An informative dimorphic marker in the signal peptide sequence of the GnRH gene allowed assessment of linkage between the disease gene and the GnRH locus in this pedigree. We have concluded that the GnRH locus is not linked to the disease-causing mutation in these hypogonadal individuals. Recent evidence suggests that neuropeptide Y (NPY) may play a role in the initiation of puberty. We hypothesize that mutations in NPY may result in failure to secrete GnRH. We have characterized three diallelic frequent-cutter restriction fragment length polymorphisms within the human NPY locus, and are currently using these markers to determine if the NPY gene is linked to, and possibly the site of the disease mutation in this kindred.

  8. Fertility Rates of Ewes Treated with Medroxyprogesterone and Injected with Equine Chorionic Gonadotropin plus Human Chorionic Gonadotropin in Anoestrous Season

    PubMed Central

    Santos, I. W.; Binsfeld, L. C.; Weiss, R. R.; Kozicki, L. E.

    2010-01-01

    The aim of the present paper was to investigate the efficiency of the equine chorionic gonadotropin (eCG) plus human chorionic gonadotropin (hCG) associated with medroxyprogesterone acetate (MAP) to estrous ewes synchronization. Ninety Texel ewes were investigated during seasonal anoestrous. The ewes received intravaginal sponges containing MAP (60 mg) for nine days. At the time of sponges' withdrawal, the ewes were divided into three groups (G): (1) receiving 2 mL of saline i.m. (n = 30), (2) receiving eCG 400 IU i.m. (n = 30), and (3) receiving eCG 400 IU plus hCG 200 IU i.m. (n = 30). Twelve h after sponges' removal, teaser rams were used to estrus check and remained with the ewes for 96 h. The artificial insemination was made with fresh semen 10 h after estrus detection. The effect of the treatment was not significant for the estrous rates among the groups: 73%, 90%, and 86%, respectively. The main effect was observed in the pregnancy and lambing rates among the groups: 70%, 86%, 56%, and 80%, 120%, 56%, respectively. Based on these results from our study, the use of the MAP—eCG is the best choice to improve the fertility rate on ewes. PMID:20953333

  9. 4D motion animation of coronary arteries from rotational angiography

    NASA Astrophysics Data System (ADS)

    Holub, Wolfgang; Rohkohl, Christopher; Schuldhaus, Dominik; Prümmer, Marcus; Lauritsch, Günter; Hornegger, Joachim

    2011-03-01

    Time-resolved 3-D imaging of the heart is a major research topic in the medical imaging community. Recent advances in the interventional cardiac 3-D imaging from rotational angiography (C-arm CT) are now also making 4-D imaging feasible during procedures in the catheter laboratory. State-of-the-art reconstruction algorithms try to estimate the cardiac motion and utilize the motion field to enhance the reconstruction of a stable cardiac phase (diastole). The available data offers a handful of opportunities during interventional procedures, e.g. the ECG-synchronized dynamic roadmapping or the computation and analysis of functional parameters. In this paper we will demonstrate that the motion vector field (MVF) that is output by motion compensated image reconstruction algorithms is in general not directly usable for animation and motion analysis. Dependent on the algorithm different defects are investigated. A primary issue is that the MVF needs to be inverted, i.e. the wrong direction of motion is provided. A second major issue is the non-periodicity of cardiac motion. In algorithms which compute a non-periodic motion field from a single rotation the in depth motion information along viewing direction is missing, since this cannot be measured in the projections. As a result, while the MVF improves reconstruction quality, it is insufficient for motion animation and analysis. We propose an algorithm to solve both problems, i.e. inversion and missing in-depth information in a unified framework. A periodic version of the MVF is approximated. The task is formulated as a linear optimization problem where a parametric smooth motion model based on B-splines is estimated from the MVF. It is shown that the problem can be solved using a sparse QR factorization within a clinical feasible time of less than one minute. In a phantom experiment using the publicly available CAVAREV platform, the average quality of a non-periodic animation could be increased by 39% by applying the

  10. Experimenting with the GMAO 4D Data Assimilation

    NASA Technical Reports Server (NTRS)

    Todling, R.; El Akkraoui, A.; Errico, R. M.; Guo, J.; Kim, J.; Kliest, D.; Parrish, D. F.; Suarez, M.; Trayanov, A.; Tremolet, Yannick; Whitaker, J.

    2012-01-01

    The Global Modeling and Assimilation Office (GMAO) has been working to promote its prototype four-dimensional variational (4DVAR) system to a version that can be exercised at operationally desirable configurations. Beyond a general circulation model (GeM) and an analysis system, traditional 4DV AR requires availability of tangent linear (TL) and adjoint (AD) models of the corresponding GeM. The GMAO prototype 4DVAR uses the finite-volume-based GEOS GeM and the Grid-point Statistical Interpolation (GSI) system for the first two, and TL and AD models derived ITom an early version of the finite-volume hydrodynamics that is scientifically equivalent to the present GEOS nonlinear GeM but computationally rather outdated. Specifically, the TL and AD models hydrodynamics uses a simple (I-dimensional) latitudinal MPI domain decomposition, which has consequent low scalability and prevents the prototype 4DV AR ITom being used in realistic applications. In the near future, GMAO will be upgrading its operational GEOS GCM (and assimilation system) to use a cubed-sphere-based hydrodynamics. This versions of the dynamics scales to thousands of processes and has led to a decision to re-derive the TL and AD models for this more modern dynamics, thus taking advantage of a two-dimensional MPI decomposition and improved scalability properties. With the aid of the Transformation of Algorithms in FORTRAN (l'AF) automatic adjoint generation tool and some hand-coding, a version of the cubed-sphere-based TL and AD models, with a simplified vertical diffusion scheme, is now available, enabling multiple configurations of standard implementations of 4DV AR in GEOS. Concurrent to this development, collaboration with the National Centers for Environmental Prediction (NCEP) and the Earth System Research Laboratory (ESRL) has allowed GMAO to implement a hybrid-ensemble capability within the GEOS data assimilation system. Both 3Dand 4D-ensemble capabilities are presently available thus allowing

  11. A dose error evaluation study for 4D dose calculations

    NASA Astrophysics Data System (ADS)

    Milz, Stefan; Wilkens, Jan J.; Ullrich, Wolfgang

    2014-10-01

    Previous studies have shown that respiration induced motion is not negligible for Stereotactic Body Radiation Therapy. The intrafractional breathing induced motion influences the delivered dose distribution on the underlying patient geometry such as the lung or the abdomen. If a static geometry is used, a planning process for these indications does not represent the entire dynamic process. The quality of a full 4D dose calculation approach depends on the dose coordinate transformation process between deformable geometries. This article provides an evaluation study that introduces an advanced method to verify the quality of numerical dose transformation generated by four different algorithms. The used transformation metric value is based on the deviation of the dose mass histogram (DMH) and the mean dose throughout dose transformation. The study compares the results of four algorithms. In general, two elementary approaches are used: dose mapping and energy transformation. Dose interpolation (DIM) and an advanced concept, so called divergent dose mapping model (dDMM), are used for dose mapping. The algorithms are compared to the basic energy transformation model (bETM) and the energy mass congruent mapping (EMCM). For evaluation 900 small sample regions of interest (ROI) are generated inside an exemplary lung geometry (4DCT). A homogeneous fluence distribution is assumed for dose calculation inside the ROIs. The dose transformations are performed with the four different algorithms. The study investigates the DMH-metric and the mean dose metric for different scenarios (voxel sizes: 8 mm, 4 mm, 2 mm, 1 mm 9 different breathing phases). dDMM achieves the best transformation accuracy in all measured test cases with 3-5% lower errors than the other models. The results of dDMM are reasonable and most efficient in this study, although the model is simple and easy to implement. The EMCM model also achieved suitable results, but the approach requires a more complex

  12. Predicting lower mantle heterogeneity from 4-D Earth models

    NASA Astrophysics Data System (ADS)

    Flament, Nicolas; Williams, Simon; Müller, Dietmar; Gurnis, Michael; Bower, Dan J.

    2016-04-01

    basal layer ˜ 4% denser than ambient mantle. Increasing convective vigour (Ra ≈ 5 x 108) or decreasing the density of the basal layer decreases both the accuracy and sensitivity of the predicted lower mantle structure. References: D. J. Bower, M. Gurnis, N. Flament, Assimilating lithosphere and slab history in 4-D Earth models. Phys. Earth Planet. Inter. 238, 8-22 (2015). V. Lekic, S. Cottaar, A. Dziewonski, B. Romanowicz, Cluster analysis of global lower mantle tomography: A new class of structure and implications for chemical heterogeneity. Earth Planet. Sci. Lett. 357, 68-77 (2012).

  13. 4D Visualization of Experimental Procedures in Rock Physics

    NASA Astrophysics Data System (ADS)

    Vanorio, T.; di Bonito, C.

    2010-12-01

    Engaging students in laboratory classes in geophysics is becoming more and more difficult. This is primarily because of an ever-widening gap between the less appealing aspects that characterize these courses (e.g., lengthiness of the experimental operations, high student/instrument ratio, limited time associated with lack of previous hands-on experiences, and logistical and safety concerns) and the life style of the 21st century generations (i.e., extensive practice to high-tech tools, high-speed communications and computing, 3D graphics and HD videos). To bridge the gap and enhance the teaching strategy of laboratory courses in geophysics, we have created simulator-training tools for use in preparation for the actual experimental phase. We are using a modeling, animation, and rendering package to create (a) 3D models that accurately reproduce actual scenarios and instruments used for the measurement of rock physics properties and (b) 4D interactive animations that simulate hands-on demonstrations of the experimental procedures. We present here a prototype describing step-by-step the experimental protocol and the principles behind the measurement of rock porosity. The tool reproduces an actual helium porosimeter and makes use of interactive animations, guided text, and a narrative voice guiding the audience through the different phases of the experimental process. Our strategy is to make the most of new technologies while preserving the accuracy of classical laboratory methods and practices. These simulations are not intended to replace traditional lab work; rather they provide students with the opportunity for review and repetition. The primary goal is thus to help students familiarize themselves during their earlier curricula with lab methodologies, thus minimizing apparent hesitation and frustration in later classes. This may also increase the level of interest and involvement of undergraduate students and, in turn, enhance their keenness to pursue their

  14. Interactive 4D Visualization of Sediment Transport Models

    NASA Astrophysics Data System (ADS)

    Butkiewicz, T.; Englert, C. M.

    2013-12-01

    Coastal sediment transport models simulate the effects that waves, currents, and tides have on near-shore bathymetry and features such as beaches and barrier islands. Understanding these dynamic processes is integral to the study of coastline stability, beach erosion, and environmental contamination. Furthermore, analyzing the results of these simulations is a critical task in the design, placement, and engineering of coastal structures such as seawalls, jetties, support pilings for wind turbines, etc. Despite the importance of these models, there is a lack of available visualization software that allows users to explore and perform analysis on these datasets in an intuitive and effective manner. Existing visualization interfaces for these datasets often present only one variable at a time, using two dimensional plan or cross-sectional views. These visual restrictions limit the ability to observe the contents in the proper overall context, both in spatial and multi-dimensional terms. To improve upon these limitations, we use 3D rendering and particle system based illustration techniques to show water column/flow data across all depths simultaneously. We can also encode multiple variables across different perceptual channels (color, texture, motion, etc.) to enrich surfaces with multi-dimensional information. Interactive tools are provided, which can be used to explore the dataset and find regions-of-interest for further investigation. Our visualization package provides an intuitive 4D (3D, time-varying) visualization of sediment transport model output. In addition, we are also integrating real world observations with the simulated data to support analysis of the impact from major sediment transport events. In particular, we have been focusing on the effects of Superstorm Sandy on the Redbird Artificial Reef Site, offshore of Delaware Bay. Based on our pre- and post-storm high-resolution sonar surveys, there has significant scour and bedform migration around the

  15. p19INK4d Controls Hematopoietic Stem Cells in a Cell-Autonomous Manner during Genotoxic Stress and through the Microenvironment during Aging

    PubMed Central

    Hilpert, Morgane; Legrand, Céline; Bluteau, Dominique; Balayn, Natalie; Betems, Aline; Bluteau, Olivier; Villeval, Jean-Luc; Louache, Fawzia; Gonin, Patrick; Debili, Najet; Plo, Isabelle; Vainchenker, William; Gilles, Laure; Raslova, Hana

    2014-01-01

    Summary Hematopoietic stem cells (HSCs) are characterized by the capacity for self-renewal and the ability to reconstitute the entire hematopoietic compartment. Thrombopoietin maintains adult HSCs in a quiescent state through the induction of cell cycle inhibitors p57Kip2 and p19INK4d. Using the p19INK4d−/− mouse model, we investigated the role of p19INK4d in basal and stress-induced hematopoiesis. We demonstrate that p19INK4d is involved in the regulation of HSC quiescence by inhibition of the G0/G1 cell cycle transition. Under genotoxic stress conditions, the absence of p19INK4d in HSCs leads to accelerated cell cycle exit, accumulation of DNA double-strand breaks, and apoptosis when cells progress to the S/G2-M stages of the cell cycle. Moreover, p19INK4d controls the HSC microenvironment through negative regulation of megakaryopoiesis. Deletion of p19INK4d results in megakaryocyte hyperproliferation and increased transforming growth factor β1 secretion. This leads to fibrosis in the bone marrow and spleen, followed by loss of HSCs during aging. PMID:25458892

  16. WNT5a is required for normal ovarian follicle development and antagonizes gonadotropin responsiveness in granulosa cells by suppressing canonical WNT signaling.

    PubMed

    Abedini, Atefeh; Zamberlam, Gustavo; Lapointe, Evelyne; Tourigny, Catherine; Boyer, Alexandre; Paquet, Marilène; Hayashi, Kanako; Honda, Hiroaki; Kikuchi, Akira; Price, Christopher; Boerboom, Derek

    2016-04-01

    Whereas the roles of the canonical wingless-type MMTV (mouse mammary tumor virus) integration site family (WNT) signaling pathway in the regulation of ovarian follicle growth and steroidogenesis are now established, noncanonical WNT signaling in the ovary has been largely overlooked. Noncanonical WNTs, including WNT5a and WNT11, are expressed in granulosa cells (GCs) and are differentially regulated throughout follicle development, but their physiologic roles remain unknown. Using conditional gene targeting, we found that GC-specific inactivation ofWnt5a(but notWnt11) results in the female subfertility associated with increased follicular atresia and decreased rates of ovulation. Microarray analyses have revealed that WNT5a acts to down-regulate the expression of FSH-responsive genesin vitro, and corresponding increases in the expression of these genes have been found in the GCs of conditional knockout mice. Unexpectedly, we found that WNT5a regulates its target genes not by signalingviathe WNT/Ca(2+)or planar cell polarity pathways, but rather by inhibiting the canonical pathway, causing both β-catenin (CTNNB1) and cAMP responsive element binding (CREB) protein levels to decreaseviaa glycogen synthase kinase-3β-dependent mechanism. We further found that WNT5a prevents follicle-stimulating hormone and luteinizing protein from up-regulating the CTNNB1 and CREB proteins and their target genes, indicating that WNT5a functions as a physiologic inhibitor of gonadotropin signaling. Together, these findings identify WNT5a as a key regulator of follicle development and gonadotropin responsiveness.-Abedini, A., Zamberlam, G., Lapointe, E., Tourigny, C., Boyer, A., Paquet, M., Hayashi, K., Honda, H., Kikuchi, A., Price, C., Boerboom, D. WNT5a is required for normal ovarian follicle development and antagonizes gonadotropin responsiveness in granulosa cells by suppressing canonical WNT signaling. PMID:26667040

  17. Androgen receptor repression of gonadotropin-releasing hormone gene transcription via enhancer 1.

    PubMed

    Brayman, Melissa J; Pepa, Patricia A; Mellon, Pamela L

    2012-11-01

    Gonadotropin-releasing hormone (GnRH) plays a major role in the hypothalamic-pituitary-gonadal (HPG) axis, and synthesis and secretion of GnRH are regulated by gonadal steroid hormones. Disruptions in androgen levels are involved in a number of reproductive defects, including hypogonadotropic hypogonadism and polycystic ovarian syndrome. Androgens down-regulate GnRH mRNA synthesis in vivo and in vitro via an androgen receptor (AR)-dependent mechanism. Methyltrienolone (R1881), a synthetic AR agonist, represses GnRH expression through multiple sites in the proximal promoter. In this study, we show AR also represses GnRH transcription via the major enhancer (GnRH-E1). A multimer of the -1800/-1766 region was repressed by R1881 treatment. Mutation of two bases, -1792 and -1791, resulted in decreased basal activity and a loss of AR-mediated repression. AR bound to the -1796/-1791 sequence in electrophoretic mobility shift assays, indicating a direct interaction with DNA or other transcription factors in this region. We conclude that AR repression of GnRH-E1 acts via multiple AR-responsive regions, including the site at -1792/-1791.

  18. Androgen receptor repression of gonadotropin-releasing hormone gene transcription via enhancer 1.

    PubMed

    Brayman, Melissa J; Pepa, Patricia A; Mellon, Pamela L

    2012-11-01

    Gonadotropin-releasing hormone (GnRH) plays a major role in the hypothalamic-pituitary-gonadal (HPG) axis, and synthesis and secretion of GnRH are regulated by gonadal steroid hormones. Disruptions in androgen levels are involved in a number of reproductive defects, including hypogonadotropic hypogonadism and polycystic ovarian syndrome. Androgens down-regulate GnRH mRNA synthesis in vivo and in vitro via an androgen receptor (AR)-dependent mechanism. Methyltrienolone (R1881), a synthetic AR agonist, represses GnRH expression through multiple sites in the proximal promoter. In this study, we show AR also represses GnRH transcription via the major enhancer (GnRH-E1). A multimer of the -1800/-1766 region was repressed by R1881 treatment. Mutation of two bases, -1792 and -1791, resulted in decreased basal activity and a loss of AR-mediated repression. AR bound to the -1796/-1791 sequence in electrophoretic mobility shift assays, indicating a direct interaction with DNA or other transcription factors in this region. We conclude that AR repression of GnRH-E1 acts via multiple AR-responsive regions, including the site at -1792/-1791. PMID:22877652

  19. Molecular Characterization of Three Gonadotropin Subunits and Their Expression Patterns during Ovarian Maturation in Cynoglossus semilaevis

    PubMed Central

    Shi, Bao; Liu, Xuezhou; Xu, Yongjiang; Wang, Shanshan

    2015-01-01

    The endocrine regulation of reproduction in a multiple spawning flatfish with an ovary of asynchronous development remains largely unknown. The objectives of this study were to monitor changes in mRNA expression patterns of three gonadotropin hormone (GTH) subunits (FSHβ, LHβ and CGα) and plasma GTH levels during ovarian maturation of half-smooth tongue sole Cynoglossus semilaevis. Cloning and sequence analysis revealed that the cDNAs of FSHβ, LHβ and CGα were 541, 670 and 685 bp in length, and encode for peptides of 130, 158 and 127 amino acids, respectively. The number of cysteine residues and potential N-linked glycosylation sites of the flatfish GTHs were conserved among teleosts. However, the primary structure of GTHs in Pleuronectiformes appeared to be highly divergent. The FSHβ transcriptional level in the pituitary remained high during the vitellogenic stage while plasma levels of FSH peaked and oocyte development was stimulated. The LHβ expression in the pituitary and ovary reached the maximum level during oocyte maturation stages when the plasma levels of LH peaked. The brain GTHs were expressed at the different ovarian stages. These results suggested that FSH and LH may simultaneously regulate ovarian development and maturation through the brain-pituitary-ovary axis endocrine system in tongue sole. PMID:25633101

  20. Gonadotropin and estradiol secretion during the week of placebo therapy in oral contraceptive pill users.

    PubMed

    van der Spuy, Z M; Sohnius, U; Pienaar, C A; Schall, R

    1990-12-01

    The changes in the hypothalamic-pituitary-ovarian axis during the placebo week in oral contraceptive pill users were assessed. Fifteen women using the combined oral contraceptive pill were studied for eight hours at the start and at the end of the placebo week and gonadotropin secretion and estradiol concentrations were compared with those in control women in the follicular phase of an unmedicated menstrual cycle. Both gonadotropin and estradiol concentrations were suppressed at the start of the placebo week. By day 7 of placebo, gonadotropin concentrations and pulse patterns were indistinguishable from those of the control subjects although estradiol concentrations were still significantly lower.

  1. Profiles of gonadotropin-inhibitory hormone and melatonin during the sex change and maturation of cinnamon clownfish, Amphiprion melanopus.

    PubMed

    Choi, Young Jae; Habibi, Hamid R; Choi, Cheol Young

    2016-06-24

    The present study aimed to determine the relationship between melatonin and gonadotropin-inhibitory hormone (GnIH) and their effect on reproduction in cinnamon clownfish, Amphiprion melanopus. Accordingly, we investigated the expression pattern of GnIH, GnIH receptor (GnIH-R), and melatonin receptor (MT-R1) mRNA and protein, as well as the plasma levels of melatonin, during sex change in cinnamon clownfish. We found that GnIH and MT-R1 mRNA and melatonin activity were higher in fish with mature brain than in fish with developing gonads, and using double immunofluorescence staining, we found that both GnIH and MT-R1 proteins were co-expressed in the hypothalamus of cinnamon clownfish. These findings support the hypothesis that melatonin plays an important role in the negative regulation of maturation and GnIH regulation during reproduction. PMID:27208779

  2. Targeted disruption of the heat shock protein 20–phosphodiesterase 4D (PDE4D) interaction protects against pathological cardiac remodelling in a mouse model of hypertrophy

    PubMed Central

    Martin, Tamara P.; Hortigon-Vinagre, Maria P.; Findlay, Jane E.; Elliott, Christina; Currie, Susan; Baillie, George S.

    2014-01-01

    Phosphorylated heat shock protein 20 (HSP20) is cardioprotective. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a mouse model of pressure overload mediated hypertrophy, we show that peptide disruption of the HSP20–phosphodiesterase 4D (PDE4D) complex results in attenuation of action potential prolongation and protection against adverse cardiac remodelling. The later was evidenced by improved contractility, decreased heart weight to body weight ratio, and reduced interstitial and perivascular fibrosis. This study demonstrates that disruption of the specific HSP20–PDE4D interaction leads to attenuation of pathological cardiac remodelling. PMID:25426411

  3. Kisspeptin signaling is indispensable for neurokinin B, but not glutamate, stimulation of gonadotropin secretion in mice.

    PubMed

    García-Galiano, David; van Ingen Schenau, Dorette; Leon, Silvia; Krajnc-Franken, Magda A M; Manfredi-Lozano, Maria; Romero-Ruiz, Antonio; Navarro, Victor M; Gaytan, Francisco; van Noort, Paula I; Pinilla, Leonor; Blomenröhr, Marion; Tena-Sempere, Manuel

    2012-01-01

    Kisspeptins (Kp), products of the Kiss1 gene that act via Gpr54 to potently stimulate GnRH secretion, operate as mediators of other regulatory signals of the gonadotropic axis. Mouse models of Gpr54 and/or Kiss1 inactivation have been used to address the contribution of Kp in the central control of gonadotropin secretion; yet, phenotypic and hormonal differences have been detected among the transgenic lines available. We report here a series of neuroendocrine analyses in male mice of a novel Gpr54 knockout (KO) model, generated by heterozygous crossing of a loxP-Gpr54/Protamine-Cre double mutant line. Gpr54-null males showed severe hypogonadotropic hypogonadism but retained robust responsiveness to GnRH. Gonadotropic responses to the agonist of ionotropic glutamate receptors, N-methyl-d-aspartate, were attenuated, but persisted, in Gpr54-null mice. In contrast, LH secretion after activation of metabotropic glutamate receptors was totally preserved in the absence of Gpr54 signaling. Detectable, albeit reduced, LH responses were also observed in Gpr54 KO mice after intracerebroventricular administration of galanin-like peptide or RF9, putative antagonist of neuropeptide FF receptors for the mammalian ortholog of gonadotropin-inhibiting hormone. In contrast, the stimulatory effect of senktide, agonist of neurokinin B (NKB; cotransmitter of Kiss1 neurons), was totally abrogated in Gpr54 KO males. Lack of Kp signaling also eliminated feedback LH responses to testosterone withdrawal. However, residual but sustained increases of FSH were detected in gonadectomized Gpr54 KO males, in which testosterone replacement failed to fully suppress circulating FSH levels. In sum, our study provides novel evidence for the relative importance of Kp-dependent vs. -independent actions of several key regulators of GnRH secretion, such as glutamate, galanin-like peptide, and testosterone. In addition, our data document for the first time the indispensable role of Kp signaling in mediating

  4. Assessing Gonadotropin Receptor Function by Resonance Energy Transfer-Based Assays

    PubMed Central

    Ayoub, Mohammed Akli; Landomiel, Flavie; Gallay, Nathalie; Jégot, Gwenhael; Poupon, Anne; Crépieux, Pascale; Reiter, Eric

    2015-01-01

    Gonadotropin receptors belong to the super family of G protein-coupled receptors and mediate the physiological effects of follicle-stimulating hormone (FSHR) and luteinizing hormone (LHR). Their central role in the control of reproductive function has made them the focus of intensive studies. Upon binding to their cognate hormone, they trigger complex signaling and trafficking mechanisms that are tightly regulated in concentration, time, and space. Classical cellular assays often fail to capture all these dynamics. Here, we describe the use of various bioluminescence and fluorescence resonance energy transfer (BRET and FRET) assays to investigate the activation and regulation of FSHR and LHR in real-time, in living cells (i.e., transiently expressed in human embryonic kidney 293 cells). Indeed, the dynamics of hormone-mediated heterotrimeric G protein activation, cyclic adenosine-monophosphate (cAMP) production, calcium release, β-arrestin 2 recruitment, and receptor internalization/recycling was assessed. Kinetics and dose–response analyses confirmed the expected pharmacological and signaling properties of hFSHR and hLHR but revealed interesting characteristics when considering the two major pathways (cAMP and β-arrestin 2) of the two receptors assessed by BRET. Indeed, the EC50 values were in picomolar range for cAMP production while nanomolar range was observed for β-arrestin 2 recruitment as well as receptor internalization. Interestingly, the predicted receptor occupancy indicates that the maximal G protein activation and cAMP response occur at <10% of receptor occupancy whereas >90% of activated receptors is required to achieve full β-arrestin 2 recruitment and subsequent receptor internalization. The rapid receptor internalization was also followed by a recycling phase. Collectively, our data reveal that β-arrestin-mediated desensitization, internalization, and the subsequent fast recycling of receptors at the plasma membrane may provide a mechanistic

  5. Cysteamine reduces serum gonadotropin concentrations in adult male rats.

    PubMed

    Badger, T M; Sagar, S M; Millard, W J; Martin, J B; Rosenblum, P

    1982-01-18

    We have examined the effects of cysteamine on the hypothalamic-pituitary-gonadal axis of the adult male rat. A single subcutaneous injection of cysteamine (300 mg/kg) reduces significantly (p less than or equal to 0.05 serum concentrations of LH, FSH and T. Cysteamine blocked LH secretion induced by castration and administration of naloxone and LHRH. Neither acute nor chronic treatment (7 days) altered the hypothalamic LHRH content. These results suggest that cysteamine acts to reduce pituitary responsiveness to LHRH, resulting in lower mean serum gonadotropin and testosterone concentrations. It is possible, however, that cysteamine acts also at the hypothalamus to reduce LHRH secretion and/or at the testes to reduce testosterone release.

  6. Pulsatile gonadotropin-releasing hormone therapy for ovulatory disorders.

    PubMed

    Santoro, N; Elzahr, D

    1993-09-01

    Pulsatile GnRH remains a physiologic method of inducing ovulation that is effective and safer than other parenteral preparations. Its lower rate of acceptance in the United States stands in curious contrast to its widespread usage in other countries as a second-line (postclomiphene) technique of choice for ovulation induction. In a high-technology era such as ours, women who may benefit from pulsatile GnRH therapy should not be forgotten. By far the most favorable results are obtained in women with primary or secondary hypothalamic amenorrhea. In such women, pregnancy rates appear comparable to those achieved with exogenous gonadotropins with a much lower risk of multiple pregnancy and ovarian hyperstimulation. These positive aspects, combined with the decreased need for clinical monitoring and the increased sense of control imparted to the patient, lead to the conclusion that women with uncomplicated hypothalamic-pituitary disorders are the ideal patient group to consider for therapy. The application of pulsatile GnRH therapy to other groups of women relies on limited data. By all means, women with polycystic ovarian syndrome who have not ovulated or conceived after other forms of treatment should be considered because reasonable pregnancy salvage can be obtained. We have noted a first-cycle successful pregnancy after failure of exogenous gonadotropins, with or without a superimposed GnRH agonist, and even in vitro fertilization with multiple embryo transfers. Before such invasive, high-technology procedures are entertained, it would appear prudent to consider this simple alternative in women with an overactive hypothalamic-pituitary axis, as seen in polycystic ovarian syndrome. Other ovulatory defects also may be amenable to treatment with pulsatile GnRH, but their practical usefulness will await further clinical study.

  7. Gonadotropin-releasing hormone agonist-induced pituitary apoplexy

    PubMed Central

    Keane, Fergus; Navin, Patrick; Brett, Francesca; Dennedy, Michael C

    2016-01-01

    Summary Pituitary apoplexy represents an uncommon endocrine emergency with potentially life-threatening consequences. Drug-induced pituitary apoplexy is a rare but important consideration when evaluating patients with this presentation. We describe an unusual case of a patient with a known pituitary macroadenoma presenting with acute-onset third nerve palsy and headache secondary to tumour enlargement and apoplexy. This followed gonadotropin-releasing hormone (GNRH) agonist therapy used to treat metastatic prostate carcinoma. Following acute management, the patient underwent transphenoidal debulking of his pituitary gland with resolution of his third nerve palsy. Subsequent retrospective data interpretation revealed that this had been a secretory gonadotropinoma and GNRH agonist therapy resulted in raised gonadotropins and testosterone. Hence, further management of his prostate carcinoma required GNRH antagonist therapy and external beam radiotherapy. This case demonstrates an uncommon complication of GNRH agonist therapy in the setting of a pituitary macroadenoma. It also highlights the importance of careful, serial data interpretation in patients with pituitary adenomas. Finally, this case presents a unique insight into the challenges of managing a hormonal-dependent prostate cancer in a patient with a secretory pituitary tumour. Learning points While non-functioning gonadotropinomas represent the most common form of pituitary macroadenoma, functioning gonadotropinomas are exceedingly rare. Acute tumour enlargement, with potential pituitary apoplexy, is a rare but important adverse effect arising from GNRH agonist therapy in the presence of both functioning and non-functioning pituitary gonadotropinomas. GNRH antagonist therapy represents an alternative treatment option for patients with hormonal therapy-requiring prostate cancer, who also have diagnosed with a pituitary gonadotropinoma. PMID:27284452

  8. SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease.

    PubMed

    Smith, Ernest S; Jonason, Alan; Reilly, Christine; Veeraraghavan, Janaki; Fisher, Terrence; Doherty, Michael; Klimatcheva, Ekaterina; Mallow, Crystal; Cornelius, Chad; Leonard, John E; Marchi, Nicola; Janigro, Damir; Argaw, Azeb Tadesse; Pham, Trinh; Seils, Jennifer; Bussler, Holm; Torno, Sebold; Kirk, Renee; Howell, Alan; Evans, Elizabeth E; Paris, Mark; Bowers, William J; John, Gareth; Zauderer, Maurice

    2015-01-01

    Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by immune cell infiltration of CNS, blood-brain barrier (BBB) breakdown, localized myelin destruction, and progressive neuronal degeneration. There exists a significant need to identify novel therapeutic targets and strategies that effectively and safely disrupt and even reverse disease pathophysiology. Signaling cascades initiated by semaphorin 4D (SEMA4D) induce glial activation, neuronal process collapse, inhibit migration and differentiation of oligodendrocyte precursor cells (OPCs), and disrupt endothelial tight junctions forming the BBB. To target SEMA4D, we generated a monoclonal antibody that recognizes mouse, rat, monkey and human SEMA4D with high affinity and blocks interaction between SEMA4D and its cognate receptors. In vitro, anti-SEMA4D reverses the inhibitory effects of recombinant SEMA4D on OPC survival and differentiation. In vivo, anti-SEMA4D significantly attenuates experimental autoimmune encephalomyelitis in multiple rodent models by preserving BBB integrity and axonal myelination and can be shown to promote migration of OPC to the site of lesions and improve myelin status following chemically-induced demyelination. Our study underscores SEMA4D as a key factor in CNS disease and supports the further development of antibody-based inhibition of SEMA4D as a novel therapeutic strategy for MS and other neurologic diseases with evidence of demyelination and/or compromise to the neurovascular unit. PMID:25461192

  9. SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease.

    PubMed

    Smith, Ernest S; Jonason, Alan; Reilly, Christine; Veeraraghavan, Janaki; Fisher, Terrence; Doherty, Michael; Klimatcheva, Ekaterina; Mallow, Crystal; Cornelius, Chad; Leonard, John E; Marchi, Nicola; Janigro, Damir; Argaw, Azeb Tadesse; Pham, Trinh; Seils, Jennifer; Bussler, Holm; Torno, Sebold; Kirk, Renee; Howell, Alan; Evans, Elizabeth E; Paris, Mark; Bowers, William J; John, Gareth; Zauderer, Maurice

    2015-01-01

    Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by immune cell infiltration of CNS, blood-brain barrier (BBB) breakdown, localized myelin destruction, and progressive neuronal degeneration. There exists a significant need to identify novel therapeutic targets and strategies that effectively and safely disrupt and even reverse disease pathophysiology. Signaling cascades initiated by semaphorin 4D (SEMA4D) induce glial activation, neuronal process collapse, inhibit migration and differentiation of oligodendrocyte precursor cells (OPCs), and disrupt endothelial tight junctions forming the BBB. To target SEMA4D, we generated a monoclonal antibody that recognizes mouse, rat, monkey and human SEMA4D with high affinity and blocks interaction between SEMA4D and its cognate receptors. In vitro, anti-SEMA4D reverses the inhibitory effects of recombinant SEMA4D on OPC survival and differentiation. In vivo, anti-SEMA4D significantly attenuates experimental autoimmune encephalomyelitis in multiple rodent models by preserving BBB integrity and axonal myelination and can be shown to promote migration of OPC to the site of lesions and improve myelin status following chemically-induced demyelination. Our study underscores SEMA4D as a key factor in CNS disease and supports the further development of antibody-based inhibition of SEMA4D as a novel therapeutic strategy for MS and other neurologic diseases with evidence of demyelination and/or compromise to the neurovascular unit.

  10. Geometric validation of self-gating k-space-sorted 4D-MRI vs 4D-CT using a respiratory motion phantom

    SciTech Connect

    Yue, Yong Yang, Wensha; McKenzie, Elizabeth; Tuli, Richard; Wallace, Robert; Fraass, Benedick; Fan, Zhaoyang; Pang, Jianing; Deng, Zixin; Li, Debiao

    2015-10-15

    Purpose: MRI is increasingly being used for radiotherapy planning, simulation, and in-treatment-room motion monitoring. To provide more detailed temporal and spatial MR data for these tasks, we have recently developed a novel self-gated (SG) MRI technique with advantage of k-space phase sorting, high isotropic spatial resolution, and high temporal resolution. The current work describes the validation of this 4D-MRI technique using a MRI- and CT-compatible respiratory motion phantom and comparison to 4D-CT. Methods: The 4D-MRI sequence is based on a spoiled gradient echo-based 3D projection reconstruction sequence with self-gating for 4D-MRI at 3 T. Respiratory phase is resolved by using SG k-space lines as the motion surrogate. 4D-MRI images are reconstructed into ten temporal bins with spatial resolution 1.56 × 1.56 × 1.56 mm{sup 3}. A MRI-CT compatible phantom was designed to validate the performance of the 4D-MRI sequence and 4D-CT imaging. A spherical target (diameter 23 mm, volume 6.37 ml) filled with high-concentration gadolinium (Gd) gel is embedded into a plastic box (35 × 40 × 63 mm{sup 3}) and stabilized with low-concentration Gd gel. The phantom, driven by an air pump, is able to produce human-type breathing patterns between 4 and 30 respiratory cycles/min. 4D-CT of the phantom has been acquired in cine mode, and reconstructed into ten phases with slice thickness 1.25 mm. The 4D images sets were imported into a treatment planning software for target contouring. The geometrical accuracy of the 4D MRI and CT images has been quantified using target volume, flattening, and eccentricity. The target motion was measured by tracking the centroids of the spheres in each individual phase. Motion ground-truth was obtained from input signals and real-time video recordings. Results: The dynamic phantom has been operated in four respiratory rate (RR) settings, 6, 10, 15, and 20/min, and was scanned with 4D-MRI and 4D-CT. 4D-CT images have target

  11. IMRT treatment planning on 4D geometries for the era of dynamic MLC tracking.

    PubMed

    Suh, Yelin; Murray, Walter; Keall, Paul J

    2014-12-01

    The problem addressed here was to obtain optimal and deliverable dynamic multileaf collimator (MLC) leaf sequences from four-dimensional (4D) geometries for dynamic MLC tracking delivery. The envisaged scenario was where respiratory phase and position information of the target was available during treatment, from which the optimal treatment plan could be further adapted in real time. A tool for 4D treatment plan optimization was developed that integrates a commercially available treatment planning system and a general-purpose optimization system. The 4D planning method was applied to the 4D computed tomography planning scans of three lung cancer patients. The optimization variables were MLC leaf positions as a function of monitor units and respiratory phase. The objective function was the deformable dose-summed 4D treatment plan score. MLC leaf motion was constrained by the maximum leaf velocity between control points in terms of monitor units for tumor motion parallel to the leaf travel direction and between phases for tumor motion parallel to the leaf travel direction. For comparison and a starting point for the 4D optimization, three-dimensional (3D) optimization was performed on each of the phases. The output of the 4D IMRT planning process is a leaf sequence which is a function of both monitor unit and phase, which can be delivered to a patient whose breathing may vary between the imaging and treatment sessions. The 4D treatment plan score improved during 4D optimization by 34%, 4%, and 50% for Patients A, B, and C, respectively, indicating 4D optimization generated a better 4D treatment plan than the deformable sum of individually optimized phase plans. The dose-volume histograms for each phase remained similar, indicating robustness of the 4D treatment plan to respiratory variations expected during treatment delivery. In summary, 4D optimization for respiratory phase-dependent treatment planning with dynamic MLC motion tracking improved the 4D treatment plan

  12. Short-term use of gonadotropin-releasing hormone agonist (leuprolide) for in vitro fertilization.

    PubMed

    Katayama, K P; Roesler, M; Gunnarson, C; Stehlik, E; Jagusch, S

    1988-12-01

    A common problem encountered by in vitro fertilization (IVF) programs is the premature occurrence of the spontaneous luteinizing hormone (LH) surge during ovarian stimulation cycles. Administration of gonadotropin-releasing hormone agonists (GnRH-a) for 2 to 3 weeks produces a state of hypogonadotropic hypogonadism, thus allowing ovarian stimulation to proceed uncomplicated by a spontaneous LH surge. We have elected to treat seven patients with GnRH-a in a "short-term" protocol, with GnRH-a initiated on cycle day 3 along with exogenous gonadotropins. In this series, we found that the spontaneous LH surge was abolished, while ovarian responsiveness seemed to be improved. These results suggest that the initial surge of gonadotropins elicited by GnRH-a administration may enhance ovarian stimulation and that spontaneous LH surge is blocked when GnRH-a and exogenous gonadotropins are initiated concomitantly.

  13. Suppression of Gonadotropins and Estradiol in Premenopausal Women by Oral Administration of the Nonpeptide Gonadotropin-Releasing Hormone Antagonist Elagolix

    PubMed Central

    Struthers, R. Scott; Nicholls, Andrew J.; Grundy, John; Chen, Takung; Jimenez, Roland; Yen, Samuel S. C.; Bozigian, Haig P.

    2009-01-01

    Context: Parenteral administration of peptide GnRH analogs is widely employed for treatment of endometriosis and fibroids and in assisted-reproductive therapy protocols. Elagolix is a novel, orally available nonpeptide GnRH antagonist. Objective: Our objective was to evaluate the safety, pharmacokinetics, and inhibitory effects on gonadotropins and estradiol of single-dose and 7-d elagolix administration to healthy premenopausal women. Design: This was a first-in-human, double-blind, placebo-controlled, single- and multiple-dose study with sequential dose escalation. Participants: Fifty-five healthy, regularly cycling premenopausal women participated. Interventions: Subjects were administered a single oral dose of 25–400 mg or placebo. In a second arm of the study, subjects received placebo or 50, 100, or 200 mg once daily or 100 mg twice daily for 7 d. Treatment was initiated on d 7 (±1) after onset of menses. Main Outcome Measures: Safety, tolerability, pharmacokinetics, and serum LH, FSH, and estradiol concentrations were assessed. Results: Elagolix was well tolerated and rapidly bioavailable after oral administration. Serum gonadotropins declined rapidly. Estradiol was suppressed by 24 h in subjects receiving at least 50 mg/d. Daily (50–200 mg) or twice-daily (100 mg) administration for 7 d maintained low estradiol levels (17 ± 3 to 68 ± 46 pg/ml) in most subjects during late follicular phase. Effects of the compound were rapidly reversed after discontinuation. Conclusions: Oral administration of a nonpeptide GnRH antagonist, elagolix, suppressed the reproductive endocrine axis in healthy premenopausal women. These results suggest that elagolix may enable dose-related pituitary and gonadal suppression in premenopausal women as part of treatment strategies for reproductive hormone-dependent disease states. PMID:19033369

  14. 2D:4D digit ratio predicts delay of gratification in preschoolers.

    PubMed

    Da Silva, Sergio; Moreira, Bruno; Da Costa, Newton

    2014-01-01

    We replicate the Stanford marshmallow experiment with a sample of 141 preschoolers and find a correlation between lack of self-control and 2D:4D digit ratio. Children with low 2D:4D digit ratio are less likely to delay gratification. Low 2D:4D digit ratio may indicate high fetal testosterone. If this hypothesis is true, our finding means high fetal testosterone children are less likely to delay gratification.

  15. 2D:4D Digit Ratio Predicts Delay of Gratification in Preschoolers

    PubMed Central

    Da Silva, Sergio; Moreira, Bruno; Da Costa, Newton

    2014-01-01

    We replicate the Stanford marshmallow experiment with a sample of 141 preschoolers and find a correlation between lack of self-control and 2D:4D digit ratio. Children with low 2D:4D digit ratio are less likely to delay gratification. Low 2D:4D digit ratio may indicate high fetal testosterone. If this hypothesis is true, our finding means high fetal testosterone children are less likely to delay gratification. PMID:25490040

  16. 4D VMAT, gated VMAT, and 3D VMAT for stereotactic body radiation therapy in lung.

    PubMed

    Chin, E; Loewen, S K; Nichol, A; Otto, K

    2013-02-21

    Four-dimensional volumetric modulated arc therapy (4D VMAT) is a treatment strategy for lung cancers that aims to exploit relative target and tissue motion to improve organ at risk (OAR) sparing. The algorithm incorporates the entire patient respiratory cycle using 4D CT data into the optimization process. Resulting treatment plans synchronize the delivery of each beam aperture to a specific phase of target motion. Stereotactic body radiation therapy treatment plans for 4D VMAT, gated VMAT, and 3D VMAT were generated on three patients with non-small cell lung cancer. Tumour motion ranged from 1.4-3.4 cm. The dose and fractionation scheme was 48 Gy in four fractions. A B-spline transformation model registered the 4D CT images. 4D dose volume histograms (4D DVH) were calculated from total dose accumulated at the maximum exhalation. For the majority of OARs, gated VMAT achieved the most radiation sparing but treatment times were 77-148% longer than 3D VMAT. 4D VMAT plan qualities were comparable to gated VMAT, but treatment times were only 11-25% longer than 3D VMAT. 4D VMAT's improvement of healthy tissue sparing can allow for further dose escalation. Future study could potentially adapt 4D VMAT to irregular patient breathing patterns.

  17. A sinogram warping strategy for pre-reconstruction 4D PET optimization.

    PubMed

    Gianoli, Chiara; Riboldi, Marco; Fontana, Giulia; Kurz, Christopher; Parodi, Katia; Baroni, Guido

    2016-03-01

    A novel strategy for 4D PET optimization in the sinogram domain is proposed, aiming at motion model application before image reconstruction ("sinogram warping" strategy). Compared to state-of-the-art 4D-MLEM reconstruction, the proposed strategy is able to optimize the image SNR, avoiding iterative direct and inverse warping procedures, which are typical of the 4D-MLEM algorithm. A full-count statistics sinogram of the motion-compensated 4D PET reference phase is generated by warping the sinograms corresponding to the different PET phases. This is achieved relying on a motion model expressed in the sinogram domain. The strategy was tested on the anthropomorphic 4D PET-CT NCAT phantom in comparison with the 4D-MLEM algorithm, with particular reference to robustness to PET-CT co-registrations artefacts. The MLEM reconstruction of the warped sinogram according to the proposed strategy exhibited better accuracy (up to +40.90 % with respect to the ideal value), whereas images reconstructed according to the 4D-MLEM reconstruction resulted in less noisy (down to -26.90 % with respect to the ideal value) but more blurred. The sinogram warping strategy demonstrates advantages with respect to 4D-MLEM algorithm. These advantages are paid back by introducing approximation of the deformation field, and further efforts are required to mitigate the impact of such an approximation in clinical 4D PET reconstruction.

  18. 4D VMAT, gated VMAT, and 3D VMAT for stereotactic body radiation therapy in lung

    NASA Astrophysics Data System (ADS)

    Chin, E.; Loewen, S. K.; Nichol, A.; Otto, K.

    2013-02-01

    Four-dimensional volumetric modulated arc therapy (4D VMAT) is a treatment strategy for lung cancers that aims to exploit relative target and tissue motion to improve organ at risk (OAR) sparing. The algorithm incorporates the entire patient respiratory cycle using 4D CT data into the optimization process. Resulting treatment plans synchronize the delivery of each beam aperture to a specific phase of target motion. Stereotactic body radiation therapy treatment plans for 4D VMAT, gated VMAT, and 3D VMAT were generated on three patients with non-small cell lung cancer. Tumour motion ranged from 1.4-3.4 cm. The dose and fractionation scheme was 48 Gy in four fractions. A B-spline transformation model registered the 4D CT images. 4D dose volume histograms (4D DVH) were calculated from total dose accumulated at the maximum exhalation. For the majority of OARs, gated VMAT achieved the most radiation sparing but treatment times were 77-148% longer than 3D VMAT. 4D VMAT plan qualities were comparable to gated VMAT, but treatment times were only 11-25% longer than 3D VMAT. 4D VMAT's improvement of healthy tissue sparing can allow for further dose escalation. Future study could potentially adapt 4D VMAT to irregular patient breathing patterns.

  19. SU-D-17A-04: The Impact of Audiovisual Biofeedback On Image Quality During 4D Functional and Anatomic Imaging: Results of a Prospective Clinical Trial

    SciTech Connect

    Keall, P; Pollock, S; Yang, J; Diehn, M; Berger, J; Graves, E; Loo, B; Yamamoto, T

    2014-06-01

    Purpose: The ability of audiovisual (AV) biofeedback to improve breathing regularity has not previously been investigated for functional imaging studies. The purpose of this study was to investigate the impact of AV biofeedback on 4D-PET and 4D-CT image quality in a prospective clinical trial. We hypothesized that motion blurring in 4D-PET images and the number of artifacts in 4D-CT images are reduced using AV biofeedback. Methods: AV biofeedback is a real-time, interactive and personalized system designed to help a patient self-regulate his/her breathing using a patient-specific representative waveform and musical guides. In an IRB-approved prospective clinical trial, 4D-PET and 4D-CT images of 10 lung cancer patients were acquired with AV biofeedback (AV) and free breathing (FB). The 4D-PET images in 6 respiratory bins were analyzed for motion blurring by: (1) decrease of GTVPET and (2) increase of SUVmax in 4-DPET compared to 3D-PET. The 4D-CT images were analyzed for artifacts by: (1) comparing normalized cross correlation-based scores (NCCS); and (2) quantifying a visual assessment score (VAS). A two-tailed paired t-test was used to test the hypotheses. Results: The impact of AV biofeedback on 4D-PET and 4D-CT images varied widely between patients, suggesting inconsistent patient comprehension and capability. Overall, the 4D-PET decrease of GTVPET was 2.0±3.0cm3 with AV and 2.3±3.9cm{sup 3} for FB (p=0.61). The 4D-PET increase of SUVmax was 1.6±1.0 with AV and 1.1±0.8 with FB (p=0.002). The 4D-CT NCCS were 0.65±0.27 with AV and 0.60±0.32 for FB (p=0.32). The 4D-CT VAS was 0.0±2.7 (p=ns). Conclusion: A 10-patient study demonstrated a statistically significant reduction of motion blurring of AV over FB for 1/2 functional 4D-PET imaging metrics. No difference between AV and FB was found for 2 anatomic 4D-CT imaging metrics. Future studies will focus on optimizing the human-computer interface and including patient training sessions for improved

  20. Significance of the secretion of human prolactin and gonadotropin for puerperal lactational infertility.

    PubMed

    Tyson, J E; Freedman, R S; Perez, A; Zacur, H A; Zanartu, J

    1976-01-01

    The causes of puerperal infertility in lactating women are poorly understood. The controlling centres may be either the hypothalamic-pituitary axis or the ovary (or both). We studied the secretory dynamics of prolactin and gonadotropins in healthy, normal, lactating and non-lactating women after administering either gonadoliberin to assess pituitary responsiveness or human menopausal gonadotropins to assess ovarian responsiveness during the puerperium. A reciprocal relationship was observed between the secretion of gonadotropins and the secretion of prolactin after the nipples of mothers who were breast-feeding had been stimulated for 30 min. The absence of a short-loop negative feedback control by prolactin for gonadotropin secretion was not confirmed because cyclic secretion of gonadotropin was not necessarily impaired by hyperprolactinaemia. Hyperprolactinaemia did, however, appear to impair the function of the corpus luteum in women suffering from non-puerperal galactorrhoea. We postulate a multifactorial mechanism for puerperal infertility based initially on the peripheral concentration of prolactin and gonadotropins and, in some poorly defined way, on the cerebral concentration of catecholamines.

  1. Development of Gonadotropin-Releasing Hormone-Secreting Neurons from Human Pluripotent Stem Cells.

    PubMed

    Lund, Carina; Pulli, Kristiina; Yellapragada, Venkatram; Giacobini, Paolo; Lundin, Karolina; Vuoristo, Sanna; Tuuri, Timo; Noisa, Parinya; Raivio, Taneli

    2016-08-01

    Gonadotropin-releasing hormone (GnRH) neurons regulate human puberty and reproduction. Modeling their development and function in vitro would be of interest for both basic research and clinical translation. Here, we report a three-step protocol to differentiate human pluripotent stem cells (hPSCs) into GnRH-secreting neurons. Firstly, hPSCs were differentiated to FOXG1, EMX2, and PAX6 expressing anterior neural progenitor cells (NPCs) by dual SMAD inhibition. Secondly, NPCs were treated for 10 days with FGF8, which is a key ligand implicated in GnRH neuron ontogeny, and finally, the cells were matured with Notch inhibitor to bipolar TUJ1-positive neurons that robustly expressed GNRH1 and secreted GnRH decapeptide into the culture medium. The protocol was reproducible both in human embryonic stem cells and induced pluripotent stem cells, and thus provides a translational tool for investigating the mechanisms of human puberty and its disorders. PMID:27426041

  2. Adrenocorticotropic Hormone Suppresses Gonadotropin-Stimulated Estradiol Release from Zebrafish Ovarian Follicles

    PubMed Central

    Alsop, Derek; Ings, Jennifer S.; Vijayan, Mathilakath M.

    2009-01-01

    While stress is known to impact reproductive performance, the pathways involved are not entirely understood. Corticosteroid effects on the functioning of the hypothalamus-pituitary-gonadal axis are thought to be a key aspect of stress-mediated reproductive dysfunction. A vital component of the stress response is the pituitary secretion of adrenocorticotropic hormone (ACTH), which binds to the melanocortin 2 receptor (MC2R) in the adrenal glands and activates cortisol biosynthesis. We recently reported MC2R mRNA abundance in fish gonads leading to the hypothesis that ACTH may be directly involved in gonadal steroid modulation. Using zebrafish (Danio rerio) ovarian follicles, we tested the hypothesis that acute ACTH stimulation modulates cortisol and estradiol (E2) secretion. ACTH neither affected cortisol nor unstimulated E2 release from ovarian follicles. However, ACTH suppressed human chorionic gonadotropin (hCG)-stimulated E2 secretion in a dose-related manner, with a maximum decrease of 62% observed at 1 I.U. ACTH mL−1. This effect of ACTH on E2 release was not observed in the presence of either 8-bromo-cAMP or forskolin, suggesting that the mechanism(s) involved in steroid attenuation was upstream of adenylyl cyclase activation. Overall, our results suggest that a stress-induced rise in plasma ACTH levels may initiate a rapid down-regulation of acute stimulated E2 biosynthesis in the zebrafish ovary, underscoring a novel physiological role for this pituitary peptide in modulating reproductive activity. PMID:19649243

  3. Folliculostatins, gonadotropins and a model for control of growth in the grey fleshfly, Neobellieria (sarcophaga) bullata.

    PubMed

    De Loof, A; Bylemans, D; Schoofs, L; Janssen, I; Spittaels, K; Vanden Broeck, J; Huybrechts, R; Borovsky, D; Hua, Y J; Koolman, J

    1995-06-01

    The sequences of two folliculostatic peptides of the fleshfly Neobellieria bullata have been determined recently. The first peptide (Neb-TMOF: H-NPTNLH-OH), originates from a 75 kDa precursor protein found in vitellogenic oocytes. The hexapeptide directly inhibits the synthesis of trypsin-like enzymes in the gut, and thus lowers the concentration of yolk polypeptides in the hemolymph. It also inhibits the biosynthesis of ecdysone in the larval ring gland. Therefore, it could also be named prothoracicostatic hormone (Neb-PTSH). The second peptide (Neb-colloostatin: H-SIV-PLGLPVPIGPIVVGPR-OH) acts on previtellogenic follicles and is a cleaved product of a collagen-like precursor molecule. Our results indicate that peptides that are cleaved from matrix proteins could act as growth-inhibiting factors. Gonadotropin releasing hormone (GnRH)-immunolike peptides were not identified, but progress is being made in the isolation and characterization of factors which stimulate cAMP production by the ovary. Using these results, a novel model of growth control in which matrix proteins play an important role as a potential source of growth regulators has been developed.

  4. Primary cilia enhance kisspeptin receptor signaling on gonadotropin-releasing hormone neurons

    PubMed Central

    Koemeter-Cox, Andrew I.; Sherwood, Thomas W.; Green, Jill A.; Steiner, Robert A.; Berbari, Nicolas F.; Yoder, Bradley K.; Kauffman, Alexander S.; Monsma, Paula C.; Brown, Anthony; Askwith, Candice C.; Mykytyn, Kirk

    2014-01-01

    Most central neurons in the mammalian brain possess an appendage called a primary cilium that projects from the soma into the extracellular space. The importance of these organelles is highlighted by the fact that primary cilia dysfunction is associated with numerous neuropathologies, including hyperphagia-induced obesity, hypogonadism, and learning and memory deficits. Neuronal cilia are enriched for signaling molecules, including certain G protein-coupled receptors (GPCRs), suggesting that neuronal cilia sense and respond to neuromodulators in the extracellular space. However, the impact of cilia on signaling to central neurons has never been demonstrated. Here, we show that the kisspeptin receptor (Kiss1r), a GPCR that is activated by kisspeptin to regulate the onset of puberty and adult reproductive function, is enriched in cilia projecting from mouse gonadotropin-releasing hormone (GnRH) neurons. Interestingly, GnRH neurons in adult animals are multiciliated and the percentage of GnRH neurons possessing multiple Kiss1r-positive cilia increases during postnatal development in a progression that correlates with sexual maturation. Remarkably, disruption of cilia selectively on GnRH neurons leads to a significant reduction in kisspeptin-mediated GnRH neuronal activity. To our knowledge, this result is the first demonstration of cilia disruption affecting central neuronal activity and highlights the importance of cilia for proper GPCR signaling. PMID:24982149

  5. Anterior cingulate cortex gray matter volume mediates an association between 2D:4D ratio and trait aggression in women but not men.

    PubMed

    Gorka, Adam X; Norman, Rachel E; Radtke, Spenser R; Carré, Justin M; Hariri, Ahmad R

    2015-06-01

    Previous research demonstrates that prenatal testosterone exposure increases aggression, possibly through its effects on the structure and function of neural circuits supporting threat detection and emotion regulation. Here we examined associations between regional gray matter volume, trait aggression, and the ratio of the second and fourth digit of the hand (2D:4D ratio) as a putative index of prenatal testosterone exposure in 464 healthy young adult volunteers. Our analyses revealed a significant positive correlation between 2D:4D ratio and gray matter volume of the dorsal anterior cingulate cortex (dACC), a brain region supporting emotion regulation, conflict monitoring, and behavioral inhibition. Subsequent analyses demonstrated that reduced (i.e., masculinized) gray matter volume in the dACC mediated the relationship between 2D:4D ratio and aggression in women, but not men. Expanding on this gender-specific mediation, additional analyses demonstrated that the shared variance between 2D:4D ratio, dACC gray matter volume, and aggression in women reflected the tendency to engage in cognitive reappraisal of emotionally provocative stimuli. Our results provide novel evidence that 2D:4D ratio is associated with masculinization of dACC gray matter volume, and that this neural phenotype mediates, in part, the expression of trait aggression in women.

  6. Sema4D, the ligand for Plexin B1, suppresses c-Met activation and migration and promotes melanocyte survival and growth.

    PubMed

    Soong, Joanne; Chen, Yulin; Shustef, Elina M; Scott, Glynis A

    2012-04-01

    Semaphorins are secreted and membrane-bound proteins involved in neural pathfinding, organogenesis, and tumor progression, through Plexin and neuropilin receptors. We recently reported that Plexin B1, the Semaphorin 4D (Sema4D) receptor, is a tumor-suppressor protein for melanoma, which functions, in part, through inhibition of the oncogenic c-Met tyrosine kinase receptor. In this report, we show that Sema4D is a protective paracrine factor for normal human melanocyte survival in response to UV irradiation, and that it stimulates proliferation and regulates the activity of the c-Met receptor. c-Met receptor signaling stimulates melanocyte migration, partly through downregulation of the cell adhesion molecule E-cadherin. Sema4D suppressed activation of c-Met in response to its ligand, hepatocyte growth factor (HGF), and partially blocked the suppressive effects of HGF on E-cadherin expression in melanocytes and HGF-dependent migration. These data demonstrate a role for Plexin B1 in maintenance of melanocyte survival and proliferation in the skin, and suggest that Sema4D and Plexin B1 act cooperatively with HGF and c-Met to regulate c-Met-dependent effects in human melanocytes. Because our data show that Plexin B1 is profoundly downregulated by UVB in melanocytes, loss of Plexin B1 may accentuate HGF-dependent effects on melanocytes, including melanocyte migration.

  7. Müllerian inhibiting substance production and cleavage is modulated by gonadotropins and steroids.

    PubMed

    Kuroda, T; Lee, M M; Ragin, R C; Hirobe, S; Donahoe, P K

    1991-12-01

    Analysis of the ontogeny and localization of the amino (N)-terminal and carboxy (C)-terminal cleavage products of Müllerian Inhibiting Substance (MIS) and their modulation by hormones of the hypothalamic-pituitary gonadal axis by immunohistochemistry and Northern analysis led to the discovery of a novel mode of posttranslational regulation of this differentiating agent. Antibody to both holo- and C-terminal MIS identically stained the cytosol of testicular Sertoli cells from 21-day fetal rats, whereas staining of antibody to N-terminal MIS localized to the basement membrane of seminiferous tubules. In addition, when studied longitudinally, basement membrane staining for N-terminal MIS persisted; cytosolic staining for C-terminal MIS was no longer detectable in post-natal testes, but marked basement membrane staining for the N-terminal fragment could still be observed in the testes of untreated 7-day postnatal animals. When 19-day fetuses were injected with FSH, testes collected 2 days later showed less immunohistochemical staining for holo-, N-, and C-terminal MIS, and less MIS messenger RNA. This suggested that FSH downregulates MIS transcription, as had been shown previously in neonatal testes treated with FSH. Testes collected at 21 days from fetuses treated at day 19 in utero with human CG or testosterone, also showed less staining for holo-MIS, but, surprisingly, increased staining for the N- and C-terminal fragments. These changes in MIS protein were accompanied by no or minimal changes in MIS messenger RNA levels, indicating that human CG and testosterone do not affect transcription, but may regulate the cleavage and/or dissociation of MIS. This study describes a form of post-translational regulation of MIS and shows that both transcription and processing of MIS may be differentially modulated by gonadotropins and sex steroids.

  8. Estrus behavior and fecal steroid profiles in the Asiatic lion (Panthera leo persica) during natural and gonadotropin-induced estrus.

    PubMed

    Umapathy, Govindhaswamy; Sontakke, Sadanand D; Srinivasu, K; Kiran, Thomas; Kholkute, S D; Shivaji, S

    2007-10-01

    In this paper the behavior of the Asiatic lion was studied during natural and gonadotropin-induced estrus in relation to fecal estradiol and progesterone concentration. The average length of estrus was 5.4 days and no significant difference was observed between natural and gonadotropin-induced estrus. Vocalization and rolling were the major estrus behavioral activities of Asiatic lions and the frequency of these activities were similar in both natural and gonadotropin-induced estrus and treatment with exogenous gonadotropin did not alter estrus behavioral activities. A significant positive correlation was observed between fecal estradiol and frequency of estrus behavior during natural and gonadotropin-induced estrus. Following gonadotropin treatment estrus could be induced in 69% of animals and these induced animals ovulated following hCG treatment. This study reports for the first time the successful use of the non-invasive fecal steroid assay for monitoring the induction of estrus and ovulation in the Asiatic lion.

  9. Teaching Tip: Managing Software Engineering Student Teams Using Pellerin's 4-D System

    ERIC Educational Resources Information Center

    Doman, Marguerite; Besmer, Andrew; Olsen, Anne

    2015-01-01

    In this article, we discuss the use of Pellerin's Four Dimension Leadership System (4-D) as a way to manage teams in a classroom setting. Over a 5-year period, we used a modified version of the 4-D model to manage teams within a senior level Software Engineering capstone course. We found that this approach for team management in a classroom…

  10. Elite collegiate tennis athletes have lower 2D: 4D ratios than those of nonathlete controls.

    PubMed

    Hsu, Cheng-Chen; Su, Borcherng; Kan, Nai-Wen; Lai, Su-Ling; Fong, Tsorng-Harn; Chi, Chung-Pu; Chang, Ching-Chyuan; Hsu, Mei-Chich

    2015-03-01

    The ratio of the length of the second finger (index finger) to the fourth finger (ring finger) (2D:4D ratio) is a putative marker for prenatal hormones. Physiological research has suggested a low 2D:4D ratio correlates with high athletic ability. Athletes of specific sports (e.g., American football) have lower 2D:4D ratios than those of nonathletes, whereas athletes of some sports (e.g., rowing, gymnastics, and soccer) do not. This study investigated the 2D:4D ratios among collegiate tennis athletes, elite collegiate tennis athletes, and nonelite collegiate tennis athletes and compared them with nonathletes of both sexes. The participants included 43 elite collegiate tennis athletes (Level I intercollegiate athletes in Taiwan; 27 males and 16 females), 107 nonelite collegiate tennis athletes (Level II athletes; 55 males and 52 females), and 166 nonathlete college students (80 males and 86 females). The principle findings suggest that (a) regardless of sex, collegiate tennis athletes have lower 2D:4D values than those of nonathletes; (b) elite collegiate tennis athletes have lower 2D:4D values than those of nonathletes; (c) among females but not males, athletes and nonelite athletes have lower 2D:4D values than those of nonathletes; and (d) males have lower 2D:4D values than those of females. PMID:25226321

  11. Elite collegiate tennis athletes have lower 2D: 4D ratios than those of nonathlete controls.

    PubMed

    Hsu, Cheng-Chen; Su, Borcherng; Kan, Nai-Wen; Lai, Su-Ling; Fong, Tsorng-Harn; Chi, Chung-Pu; Chang, Ching-Chyuan; Hsu, Mei-Chich

    2015-03-01

    The ratio of the length of the second finger (index finger) to the fourth finger (ring finger) (2D:4D ratio) is a putative marker for prenatal hormones. Physiological research has suggested a low 2D:4D ratio correlates with high athletic ability. Athletes of specific sports (e.g., American football) have lower 2D:4D ratios than those of nonathletes, whereas athletes of some sports (e.g., rowing, gymnastics, and soccer) do not. This study investigated the 2D:4D ratios among collegiate tennis athletes, elite collegiate tennis athletes, and nonelite collegiate tennis athletes and compared them with nonathletes of both sexes. The participants included 43 elite collegiate tennis athletes (Level I intercollegiate athletes in Taiwan; 27 males and 16 females), 107 nonelite collegiate tennis athletes (Level II athletes; 55 males and 52 females), and 166 nonathlete college students (80 males and 86 females). The principle findings suggest that (a) regardless of sex, collegiate tennis athletes have lower 2D:4D values than those of nonathletes; (b) elite collegiate tennis athletes have lower 2D:4D values than those of nonathletes; (c) among females but not males, athletes and nonelite athletes have lower 2D:4D values than those of nonathletes; and (d) males have lower 2D:4D values than those of females.

  12. Plasma kisspeptin levels are elevated in cord blood and present sexual dimorphism in the adult population: relation with leptin, gonadotropins and anthropometrical data.

    PubMed

    Pita, Jimena; Rado-Peralta, Sandra; Gavela-Pérez, Teresa; Aragón, Isabel; Barrios, Vicente; Rovira, Adela; Argente, Jesús; Soriano-Guillén, Leandro

    2011-05-01

    Kisspeptin, the product of the hypothalamic KISS1 gene, is a main regulator of the hypothalamic-pituitary-gonadal axis and could be a link between metabolism and reproduction through its interaction with leptin. Kisspeptin could be involved in gonadotropin regulation and responsive to leptin levels from the first stages of life, exhibiting, as does leptin, sexual dimorphism. To test our hypothesis, we have analyzed plasma kisspeptin levels and their possible relationship with gonadotropins and leptin in a cohort composed of newborns (n = 86) and adults (n = 55). Plasma kisspeptin, gonadotropin and leptin levels were measured by RIA and multiplexed bead immunoassays, respectively. We have built a multivariate linear regression model (analyzing kisspeptin and LH separately as dependent variables) by stepwise analysis, incorporating the variables that had shown significant correlation in the univariate analysis. Cord blood samples exhibited high kisspeptin levels 127.01(113-141.02 pmol/l), but these were not sexually dimorphic. The adult population exhibited sexual dimorphism (3.72(2.95-4.49) vs. 1.77(1.23-2.31)pmol/l women vs. men, p<0.05). Leptin levels showed sexual dimorphism in cord blood samples and also in the adult population. Furthermore, there was a significant interaction between LH and kisspeptin levels and kisspeptin was negatively correlated with age. The high kisspeptin levels observed in cord blood, with no sexual dimorphism, suggest a placental source. The sexual dimorphism exhibited in adulthood supports the notion that there are different sources and/or differential kisspeptin regulation between men and women.

  13. GnRH-Induced Ca2+ Signaling Patterns and Gonadotropin Secretion in Pituitary Gonadotrophs. Functional Adaptations to Both Ordinary and Extraordinary Physiological Demands

    PubMed Central

    Durán-Pastén, Maria Luisa; Fiordelisio, Tatiana

    2013-01-01

    Pituitary gonadotrophs are a small fraction of the anterior pituitary population, yet they synthesize gonadotropins: luteinizing (LH) and follicle-stimulating (FSH), essential for gametogenesis and steroidogenesis. LH is secreted via a regulated pathway while FSH release is mostly constitutive and controlled by synthesis. Although gonadotrophs fire action potentials spontaneously, the intracellular Ca2+ rises produced do not influence secretion, which is mainly driven by Gonadotropin-Releasing Hormone (GnRH), a decapeptide synthesized in the hypothalamus and released in a pulsatile manner into the hypophyseal portal circulation. GnRH binding to G-protein-coupled receptors triggers Ca2+ mobilization from InsP3-sensitive intracellular pools, generating the global Ca2+ elevations necessary for secretion. Ca2+ signaling responses to increasing (GnRH) vary in stereotyped fashion from subthreshold to baseline spiking (oscillatory), to biphasic (spike-oscillatory or spike-plateau). This progression varies somewhat in gonadotrophs from different species and biological preparations. Both baseline spiking and biphasic GnRH-induced Ca2+ signals control LH/FSH synthesis and exocytosis. Estradiol and testosterone regulate gonadotropin secretion through feedback mechanisms, while FSH synthesis and release are influenced by activin, inhibin, and follistatin. Adaptation to physiological events like the estrous cycle, involves changes in GnRH sensitivity and LH/FSH synthesis: in proestrus, estradiol feedback regulation abruptly changes from negative to positive, causing the pre-ovulatory LH surge. Similarly, when testosterone levels drop after orquiectomy the lack of negative feedback on pituitary and hypothalamus boosts both GnRH and LH secretion, gonadotrophs GnRH sensitivity increases, and Ca2+ signaling patterns change. In addition, gonadotrophs proliferate and grow. These plastic changes denote a more vigorous functional adaptation in response to an extraordinary functional

  14. The Influence of Facial Characteristics on the Relation between Male 2D:4D and Dominance

    PubMed Central

    Ryckmans, Jan; Millet, Kobe; Warlop, Luk

    2015-01-01

    Although relations between 2D:4D and dominance rank in both baboons and rhesus macaques have been observed, evidence in humans is mixed. Whereas behavioral patterns in humans have been discovered that are consistent with these animal findings, the evidence for a relation between dominance and 2D:4D is weak or inconsistent. The present study provides experimental evidence that male 2D:4D is related to dominance after (fictitious) male-male interaction when the other man has a dominant, but not a submissive or neutral face. This finding provides evidence that the relationship between 2D:4D and dominance emerges in particular, predictable situations and that merely dominant facial characteristics of another person are enough to activate supposed relationships between 2D:4D and dominance. PMID:26600255

  15. Simultaneous motion estimation and image reconstruction (SMEIR) for 4D cone-beam CT

    SciTech Connect

    Wang, Jing; Gu, Xuejun

    2013-10-15

    Purpose: Image reconstruction and motion model estimation in four-dimensional cone-beam CT (4D-CBCT) are conventionally handled as two sequential steps. Due to the limited number of projections at each phase, the image quality of 4D-CBCT is degraded by view aliasing artifacts, and the accuracy of subsequent motion modeling is decreased by the inferior 4D-CBCT. The objective of this work is to enhance both the image quality of 4D-CBCT and the accuracy of motion model estimation with a novel strategy enabling simultaneous motion estimation and image reconstruction (SMEIR).Methods: The proposed SMEIR algorithm consists of two alternating steps: (1) model-based iterative image reconstruction to obtain a motion-compensated primary CBCT (m-pCBCT) and (2) motion model estimation to obtain an optimal set of deformation vector fields (DVFs) between the m-pCBCT and other 4D-CBCT phases. The motion-compensated image reconstruction is based on the simultaneous algebraic reconstruction technique (SART) coupled with total variation minimization. During the forward- and backprojection of SART, measured projections from an entire set of 4D-CBCT are used for reconstruction of the m-pCBCT by utilizing the updated DVF. The DVF is estimated by matching the forward projection of the deformed m-pCBCT and measured projections of other phases of 4D-CBCT. The performance of the SMEIR algorithm is quantitatively evaluated on a 4D NCAT phantom. The quality of reconstructed 4D images and the accuracy of tumor motion trajectory are assessed by comparing with those resulting from conventional sequential 4D-CBCT reconstructions (FDK and total variation minimization) and motion estimation (demons algorithm). The performance of the SMEIR algorithm is further evaluated by reconstructing a lung cancer patient 4D-CBCT.Results: Image quality of 4D-CBCT is greatly improved by the SMEIR algorithm in both phantom and patient studies. When all projections are used to reconstruct a 3D-CBCT by FDK, motion

  16. Interpreting digit ratio (2D:4D)-behavior correlations: 2D:4D sex difference, stability, and behavioral correlates and their replicability in young children.

    PubMed

    Wong, Wang I; Hines, Melissa

    2016-02-01

    The popularity of using the ratio of the second to the fourth digit (2D:4D) to study influences of early androgen exposure on human behavior relies, in part, on a report that the ratio is sex-dimorphic and stable from age 2 years (Manning etal., 1998). However, subsequent research has rarely replicated this finding. Moreover, although 2D:4D has been correlated with many behaviors, these correlations are often inconsistent. Young children's 2D:4D-behavior correlations may be more consistent than those of older individuals, because young children have experienced fewer postnatal influences. To evaluate the usefulness of 2D:4D as a biomarker of prenatal androgen exposure in studies of 2D:4D-behavior correlations, we assessed its sex difference, temporal stability, and behavioral correlates over a 6- to 8-month period in 126, 2- to 3-year-old children, providing a rare same-sample replicability test. We found a moderate sex difference on both hands and high temporal stability. However, between-sex overlap and within-sex variability were also large. Only 3 of 24 correlations with sex-typed behaviors-scores on the Preschool Activities Inventory (PSAI), preference for a boy-typical toy, preference for a girl-typical toy, were significant and in the predicted direction, all of which involved the PSAI, partially confirming findings from another study. Correlation coefficients were larger for behaviors that showed larger sex differences. But, as in older samples, the overall pattern showed inconsistency across time, sex, and hand. Therefore, although sex-dimorphic and stable, 2D:4D-behavior correlations are no more consistent for young children than for older samples. Theoretical and methodological implications are discussed.

  17. Weight of the evidence on the human carcinogenicity of 2,4-D*

    PubMed Central

    Ibrahim, M. A.; Bond, G. G.; Burke, T. A.; Cole, P.; Dost, F. N.; Enterline, P. E.; Gough, M.; Greenberg, R. S.; Halperin, W. E.; McConnell, E.; Munro, I. C.; Swenberg, J. A.; Zahm, S. H.; Graham, J. D.

    1991-01-01

    The phenoxy herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) is widely used to control the growth of weeds and broadleaf plants. We convened a panel of 13 scientists to weigh the evidence on the human carcinogenicity of 2,4-D. The panel based its findings on a review of the toxicological and epidemiological literature on 2,4-D and related phenoxy herbicides. The toxicological data do not provide a strong basis for predicting that 2,4-D is a human carcinogen. Although a cause–effect relationship is far from being established, the epidemiological evidence for an association between exposure to 2,4-D and non–Hodgkin's lymphoma is suggestive and requires further investigation. There is little evidence of an association between use of 2,4-D and soft-tissue sarcoma or Hodgkin's disease, and no evidence of an association between 2,4-D use and any other form of cancer. Scientists on the panel were asked to categorize 2,4-D as a “known,” “probable,” “possible,” or “unlikely” carcinogen or as a noncarcinogen in humans. The predominant opinion among the panel members was that the weight of the evidence indicates that it is possible that exposure to 2,4-D can cause cancer in humans, although not all of the panelists believed the possibility was equally likely: one thought the possibility was strong, leaning toward probable, and five thought the possibility was remote, leaning toward unlikely. Two panelists believed it unlikely that 2,4-D can cause cancer in humans. PMID:1820267

  18. Serum Soluble Semaphorin 4D is Associated with Left Atrial Diameter in Patients with Atrial Fibrillation

    PubMed Central

    Xiang, Li; You, Tao; Chen, Jianchang; Xu, Weiting; Jiao, Yang

    2015-01-01

    Background The aim of this study was to evaluate the serum soluble semaphorin 4D (sSema4D) in patients with atrial fibrillation and to investigate the relationship of serum sSema4D with left atrial diameter (LAD). Material/Methods We studied a total of 113 patients who were subdivided into paroxysmal and non-paroxysmal (included persistent and permanent) atrial fibrillation groups, respectively. Another 55 subjects without atrial fibrillation were enrolled as the healthy control group. Serum levels of soluble semaphorin 4D (Sema4D) were measured in all subjects using the enzyme-labeled immunosorbent assay method. We also evaluated the coagulation parameters and left atrial diameters. Results Patients with paroxysmal and non-paroxysmal atrial fibrillation had significantly higher sSema4D level compared with controls (8.50±2.19 ng/mL and 9.30±2.28 ng/mL vs. 6.56±1.27 ng/ml, P<0.05). Serum sSema4D concentrations were elevated in patients with non-paroxysmal atrial fibrillation compared to those with paroxysmal atrial fibrillation (P<0.001). The level of sSema4D was positively correlated with LAD (r=0.606, P<0.001). Multivariate logistic regression analysis revealed that serum sSema4D, LAD, male sex, heart rate, hypertension, and coronary artery disease were associated with atrial fibrillation (P<0.05). Conclusions Serum sSema4D levels are increased in patients with atrial fibrillation and are independently associated with atrial remodeling. PMID:26417899

  19. TU-C-BRD-01: Image Guided SBRT I: Multi-Modality 4D Imaging

    SciTech Connect

    Cai, J; Mageras, G; Pan, T

    2014-06-15

    Motion management is one of the critical technical challenges for radiation therapy. 4D imaging has been rapidly adopted as essential tool to assess organ motion associated with respiratory breathing. A variety of 4D imaging techniques have been developed and are currently under development based on different imaging modalities such as CT, MRI, PET, and CBCT. Each modality provides specific and complementary information about organ and tumor respiratory motion. Effective use of each different technique or combined use of different techniques can introduce a comprehensive management of tumor motion. Specifically, these techniques have afforded tremendous opportunities to better define and delineate tumor volumes, more accurately perform patient positioning, and effectively apply highly conformal therapy techniques such as IMRT and SBRT. Successful implementation requires good understanding of not only each technique, including unique features, limitations, artifacts, imaging acquisition and process, but also how to systematically apply the information obtained from different imaging modalities using proper tools such as deformable image registration. Furthermore, it is important to understand the differences in the effects of breathing variation between different imaging modalities. A comprehensive motion management strategy using multi-modality 4D imaging has shown promise in improving patient care, but at the same time faces significant challenges. This session will focuses on the current status and advances in imaging respiration-induced organ motion with different imaging modalities: 4D-CT, 4D-MRI, 4D-PET, and 4D-CBCT/DTS. Learning Objectives: Understand the need and role of multimodality 4D imaging in radiation therapy. Understand the underlying physics behind each 4D imaging technique. Recognize the advantages and limitations of each 4D imaging technique.

  20. Impact of gonadotropins on oocyte maturation, fertilisation and developmental competence in vitro.

    PubMed

    Wang, Xuemei; Tsai, Tony; Qiao, Jie; Zhang, Zhan; Feng, Huai L

    2014-06-01

    The aim of the present study was to evaluate the dose-dependent effects of gonadotropins, either singly (Bravelle (B), Luveris (L), Menupur (M), Repronex (R), Gonal-F (G), Follism (F) and Norvarel (N)) or in combination (Menupur+Bravelle; Repronext+Bravelle; and Bravelle+Norvarel), on rates of oocyte maturation, fertilisation and early embryo development in vitro in an animal model. Bovine cumulus-oocyte complexes (COCs) were purchased commercially and cultured in TCM-199 with 10% fetal bovine serum supplemented with varying concentrations of gonadotropin (0, 5, 10, 20, 40IU or United States Pharmacopoeia (USP) mL-1) for 24 and 48h according to current IVF clinical stimulation protocols. All gonadotropins enhanced oocyte maturation in vitro in a dose-dependent manner. Individually, Gonal-F (Merck KGaA, Darmstadt, Germany), Follism (Merck Co, Whitehouse Station, NJ, USA) and Repronext (Ferring, Parsippany, NJ, USA) promoted oocyte maturation; in combination, they effectively enhanced COC expansion and increased the maturation competence of MII oocytes. However, high concentrations of gonadotropins may result in maturation arrest. Specific combinations of gonadotropins may change the rate of early embryonic development (8-16-cells) and morula-blastocyst formation. These data provide support for the responsiveness of bovine oocytes to gonadotropins in vitro and the need to consider variations in the relative concentrations and ratio of combinations (FSH/LH or human chorionic gonadotropin) for optimisation of oocyte developmental competence. The results of the present study could be applied to therapeutic clinical stimulation protocols and help improve IVF success rates.

  1. 4D subject-specific inverse modeling of the chick embryonic heart outflow tract hemodynamics.

    PubMed

    Goenezen, Sevan; Chivukula, Venkat Keshav; Midgett, Madeline; Phan, Ly; Rugonyi, Sandra

    2016-06-01

    Blood flow plays a critical role in regulating embryonic cardiac growth and development, with altered flow leading to congenital heart disease. Progress in the field, however, is hindered by a lack of quantification of hemodynamic conditions in the developing heart. In this study, we present a methodology to quantify blood flow dynamics in the embryonic heart using subject-specific computational fluid dynamics (CFD) models. While the methodology is general, we focused on a model of the chick embryonic heart outflow tract (OFT), which distally connects the heart to the arterial system, and is the region of origin of many congenital cardiac defects. Using structural and Doppler velocity data collected from optical coherence tomography, we generated 4D ([Formula: see text]) embryo-specific CFD models of the heart OFT. To replicate the blood flow dynamics over time during the cardiac cycle, we developed an iterative inverse-method optimization algorithm, which determines the CFD model boundary conditions such that differences between computed velocities and measured velocities at one point within the OFT lumen are minimized. Results from our developed CFD model agree with previously measured hemodynamics in the OFT. Further, computed velocities and measured velocities differ by [Formula: see text]15 % at locations that were not used in the optimization, validating the model. The presented methodology can be used in quantifications of embryonic cardiac hemodynamics under normal and altered blood flow conditions, enabling an in-depth quantitative study of how blood flow influences cardiac development.

  2. Rapid Anti-Inflammatory Effects of Gonadotropin-Releasing Hormone Antagonism in Rheumatoid Arthritis Patients with High Gonadotropin Levels in the AGRA Trial

    PubMed Central

    Kåss, Anita; Hollan, Ivana; Fagerland, Morten Wang; Gulseth, Hans Christian; Torjesen, Peter Abusdal; Førre, Øystein Torleiv

    2015-01-01

    Objectives Gonadotropin-releasing hormone (GnRH) and pituitary gonadotropins, which appear to be proinflammatory, undergo profound secretory changes during events associated with rheumatoid arthritis (RA) onset, flares, or improvement e.g. menopausal transition, postpartum, or pregnancy. Potential anti-inflammatory effects of GnRH-antagonists may be most pronounced in patients with high GnRH and gonadotropin levels. Therefore, we investigated the efficacy and safety of a GnRH-antagonist, cetrorelix, in RA patients with high gonadotropin levels. Methods We report intention-to-treat post hoc analyses among patients with high gonadotropin levels (N = 53), i.e. gonadotropin levels>median, from our proof-of-concept, double-blind AGRA-study (N = 99). Patients with active longstanding RA, randomized to subcutaneous cetrorelix (5mg days1–2; 3mg days 3–5) or placebo, were followed through day 15. Only predefined primary and secondary endpoints were analyzed. Results The primary endpoint, Disease Activity Score of 28-joint counts with C-reactive protein (DAS28-CRP), improved with cetrorelix compared with placebo by day 5 (-1.0 vs. -0.4, P = 0∙010). By day 5, more patients on cetrorelix achieved at least a 20% improvement in the American College of Rheumatology scale (44% vs. 19%, P = 0.049), DAS28-CRP≤3.2 (24% vs. 0%, P = 0.012), and European League against Rheumatism ‘Good-responses’ (19% vs. 0%, P = 0.026). Tumor necrosis factor-α, interleukin-1β, interleukin-10, and CRP decreased with cetrorelix (P = 0.045, P = 0.034, P = 0.020 and P = 0.042 respectively) compared with placebo by day 15. Adverse event rates were similar between groups. Conclusions GnRH-antagonism produced rapid anti-inflammatory effects in RA patients with high gonadotropin levels. GnRH should be investigated further in RA. Trial Registration ClinicalTrials.gov NCT00667758 PMID:26460564

  3. Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats.

    PubMed

    Kirby, Elizabeth D; Geraghty, Anna C; Ubuka, Takayoshi; Bentley, George E; Kaufer, Daniela

    2009-07-01

    The subjective experience of stress leads to reproductive dysfunction in many species, including rodents and humans. Stress effects on reproduction result from multilevel interactions between the hormonal stress response system, i.e., the hypothalamic-pituitary-adrenal (HPA) axis, and the hormonal reproductive system, i.e., the hypothalamic-pituitary-gonadal (HPG) axis. A novel negative regulator of the HPG axis known as gonadotropin-inhibitory hormone (GnIH) was recently discovered in quail, and orthologous neuropeptides known as RFamide-related peptides (RFRPs) have also been identified in rodents and primates. It is currently unknown, however, whether GnIH/RFRPs influence HPG axis activity in response to stress. We show here that both acute and chronic immobilization stress lead to an up-regulation of RFRP expression in the dorsomedial hypothalamus (DMH) of adult male rats and that this increase in RFRP is associated with inhibition of downstream HPG activity. We also show that adrenalectomy blocks the stress-induced increase in RFRP expression. Immunohistochemistry revealed that 53% of RFRP cells express receptors for glucocorticoids (GCs), indicating that adrenal GCs can mediate the stress effect through direct action on RFRP cells. It is thought that stress effects on central control of reproduction are largely mediated by direct or indirect effects on GnRH-secreting neurons. Our data show that stress-induced increases in adrenal GCs cause an increase in RFRP that contributes to hypothalamic suppression of reproductive function. This novel insight into HPA-HPG interaction provides a paradigm shift for work on stress-related reproductive dysfunction and infertility, and indicates that future work on stress and reproductive system interactions must include investigation of the role of GnIH/RFRP.

  4. Four-dimensional (4D) PET/CT imaging of the thorax

    SciTech Connect

    Nehmeh, S.A.; Erdi, Y.E.; Pan, T.

    2004-12-01

    We have reported in our previous studies on the methodology, and feasibility of 4D-PET (Gated PET) acquisition, to reduce respiratory motion artifact in PET imaging of the thorax. In this study, we expand our investigation to address the problem of respiration motion in PET/CT imaging. The respiratory motion of four lung cancer patients were monitored by tracking external markers placed on the thorax. A 4D-CT acquisition was performed using a 'step-and-shoot' technique, in which computed tomography (CT) projection data were acquired over a complete respiratory cycle at each couch position. The period of each CT acquisition segment was time stamped with an 'x-ray ON' signal, which was recorded by the tracking system. 4D-CT data were then sorted into 10 groups, according to their corresponding phase of the breathing cycle. 4D-PET data were acquired in the gated mode, where each breathing cycle was divided into ten 0.5 s bins. For both CT and PET acquisitions, patients received audio prompting to regularize breathing. The 4D-CT and 4D-PET data were then correlated according to respiratory phase. The effect of 4D acquisition on improving the co-registration of PET and CT images, reducing motion smearing, and consequently increase the quantitation of the SUV, were investigated. Also, quantitation of the tumor motions in PET, and CT, were studied and compared. 4D-PET with matching phase 4D-CTAC showed an improved accuracy in PET-CT image co-registration of up to 41%, compared to measurements from 4D-PET with clinical-CTAC. Gating PET data in correlation with respiratory motion reduced motion-induced smearing, thereby decreasing the observed tumor volume, by as much as 43%. 4D-PET lesions volumes showed a maximum deviation of 19% between clinical CT and phase- matched 4D-CT attenuation corrected PET images. In CT, 4D acquisition resulted in increasing the tumor volume in two patients by up to 79%, and decreasing it in the other two by up to 35%. Consequently, these

  5. Qualitative grading of aortic regurgitation: a pilot study comparing CMR 4D flow and echocardiography.

    PubMed

    Chelu, Raluca G; van den Bosch, Annemien E; van Kranenburg, Matthijs; Hsiao, Albert; van den Hoven, Allard T; Ouhlous, Mohamed; Budde, Ricardo P J; Beniest, Kirsten M; Swart, Laurens E; Coenen, Adriaan; Lubbers, Marisa M; Wielopolski, Piotr A; Vasanawala, Shreyas S; Roos-Hesselink, Jolien W; Nieman, Koen

    2016-02-01

    Over the past 10 years there has been intense research in the development of volumetric visualization of intracardiac flow by cardiac magnetic resonance (CMR).This volumetric time resolved technique called CMR 4D flow imaging has several advantages over standard CMR. It offers anatomical, functional and flow information in a single free-breathing, ten-minute acquisition. However, the data obtained is large and its processing requires dedicated software. We evaluated a cloud-based application package that combines volumetric data correction and visualization of CMR 4D flow data, and assessed its accuracy for the detection and grading of aortic valve regurgitation using transthoracic echocardiography as reference. Between June 2014 and January 2015, patients planned for clinical CMR were consecutively approached to undergo the supplementary CMR 4D flow acquisition. Fifty four patients(median age 39 years, 32 males) were included. Detection and grading of the aortic valve regurgitation using CMR4D flow imaging were evaluated against transthoracic echocardiography. The agreement between 4D flow CMR and transthoracic echocardiography for grading of aortic valve regurgitation was good (j = 0.73). To identify relevant,more than mild aortic valve regurgitation, CMR 4D flow imaging had a sensitivity of 100 % and specificity of 98 %. Aortic regurgitation can be well visualized, in a similar manner as transthoracic echocardiography, when using CMR 4D flow imaging. PMID:26498478

  6. 2,4-D resistance in wild radish: reduced herbicide translocation via inhibition of cellular transport

    PubMed Central

    Goggin, Danica E.; Cawthray, Gregory R.; Powles, Stephen B.

    2016-01-01

    Resistance to auxinic herbicides is increasing in a range of dicotyledonous weed species, but in most cases the biochemical mechanism of resistance is unknown. Using 14C-labelled herbicide, the mechanism of resistance to 2,4-dichlorophenoxyacetic acid (2,4-D) in two wild radish (Raphanus raphanistrum L.) populations was identified as an inability to translocate 2,4-D out of the treated leaf. Although 2,4-D was metabolized in wild radish, and in a different manner to the well-characterized crop species wheat and bean, there was no difference in metabolism between the susceptible and resistant populations. Reduced translocation of 2,4-D in the latter was also not due to sequestration of the herbicide, or to reduced uptake by the leaf epidermis or mesophyll cells. Application of auxin efflux or ABCB transporter inhibitors to 2,4-D-susceptible plants caused a mimicking of the reduced-translocation resistance phenotype, suggesting that 2,4-D resistance in the populations under investigation could be due to an alteration in the activity of a plasma membrane ABCB-type auxin transporter responsible for facilitating long-distance transport of 2,4-D. PMID:26994475

  7. Generation and preclinical characterization of an antibody specific for SEMA4D

    PubMed Central

    Fisher, Terrence L.; Reilly, Christine A.; Winter, Laurie A.; Pandina, Tracy; Jonason, Alan; Scrivens, Maria; Balch, Leslie; Bussler, Holm; Torno, Sebold; Seils, Jennifer; Mueller, Loretta; Huang, He; Klimatcheva, Ekaterina; Howell, Alan; Kirk, Renee; Evans, Elizabeth; Paris, Mark; Leonard, John E.; Smith, Ernest S.; Zauderer, Maurice

    2016-01-01

    Semaphorin 4D (SEMA4D or CD100) is a member of the semaphorin family of proteins and an important mediator of the movement and differentiation of multiple cell types, including those of the immune, vascular, and nervous systems. Blocking the binding of SEMA4D to its receptors can result in physiologic changes that may have implications in cancer, autoimmune, and neurological disease. To study the effects of blocking SEMA4D, we generated, in SEMA4D-deficient mice, a panel of SEMA4D-specific hybridomas that react with murine, primate, and human SEMA4D. Utilizing the complementarity-determining regions from one of these hybridomas (mAb 67-2), we generated VX15/2503, a humanized IgG4 monoclonal antibody that is currently in clinical development for the potential treatment of various malignancies and neurodegenerative disorders, including multiple sclerosis and Huntington's disease. This work describes the generation and characterization of VX15/2503, including in vitro functional testing, epitope mapping, and an in vivo demonstration of efficacy in an animal model of rheumatoid arthritis. PMID:26431358

  8. Fluorescent caged compounds of 2,4-dichlorophenoxyacetic acid (2,4-d): photorelease technology for controlled release of 2,4-D.

    PubMed

    Atta, Sanghamitra; Jana, Avijit; Ananthakirshnan, Rajakumar; Narayana Dhuleep, Pradeep Singh

    2010-11-24

    A novel controlled-release formulation (CRF) of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) was developed to reduce its negative environmental impacts by improving its herbicidal efficacy. The 2,4-D was chemically caged by coupling with photoremovable protecting groups (PRPGs) of coumarin derivatives. Photophysical studies of caged compounds showed that they all exhibited strong fluorescence properties. Controlled release of 2,4-D was achieved by irradiating the caged compounds using UV-vis light (310, 350, and 410 nm). The effect of various factors such as pH, solvent, and different substituents at the seventh position of coumarin moiety on the rate of photorelease was studied. The herbicidal activity of caged compounds and 4-(hydroxymethyl)-7-substituted coumarins was studied against Vigna radiata . The new formulation provided greater control over the release of 2,4-D by UV-vis light and also demonstrated the potential of the PRPGs not only to act as a delivery device but also to possess herbicidal activity after photorelease.

  9. Clinical evaluation of 4D PET motion compensation strategies for treatment verification in ion beam therapy

    NASA Astrophysics Data System (ADS)

    Gianoli, Chiara; Kurz, Christopher; Riboldi, Marco; Bauer, Julia; Fontana, Giulia; Baroni, Guido; Debus, Jürgen; Parodi, Katia

    2016-06-01

    A clinical trial named PROMETHEUS is currently ongoing for inoperable hepatocellular carcinoma (HCC) at the Heidelberg Ion Beam Therapy Center (HIT, Germany). In this framework, 4D PET-CT datasets are acquired shortly after the therapeutic treatment to compare the irradiation induced PET image with a Monte Carlo PET prediction resulting from the simulation of treatment delivery. The extremely low count statistics of this measured PET image represents a major limitation of this technique, especially in presence of target motion. The purpose of the study is to investigate two different 4D PET motion compensation strategies towards the recovery of the whole count statistics for improved image quality of the 4D PET-CT datasets for PET-based treatment verification. The well-known 4D-MLEM reconstruction algorithm, embedding the motion compensation in the reconstruction process of 4D PET sinograms, was compared to a recently proposed pre-reconstruction motion compensation strategy, which operates in sinogram domain by applying the motion compensation to the 4D PET sinograms. With reference to phantom and patient datasets, advantages and drawbacks of the two 4D PET motion compensation strategies were identified. The 4D-MLEM algorithm was strongly affected by inverse inconsistency of the motion model but demonstrated the capability to mitigate the noise-break-up effects. Conversely, the pre-reconstruction warping showed less sensitivity to inverse inconsistency but also more noise in the reconstructed images. The comparison was performed by relying on quantification of PET activity and ion range difference, typically yielding similar results. The study demonstrated that treatment verification of moving targets could be accomplished by relying on the whole count statistics image quality, as obtained from the application of 4D PET motion compensation strategies. In particular, the pre-reconstruction warping was shown to represent a promising choice when combined with intra

  10. Simultaneous motion estimation and image reconstruction (SMEIR) for 4D cone-beam CT

    NASA Astrophysics Data System (ADS)

    Wang, Jing; Gu, Xuejun

    2014-03-01

    Image reconstruction and motion model estimation in four dimensional cone-beam CT (4D-CBCT) are conventionally handled as two sequential steps. Due to the limited number of projections at each phase, the image quality of 4D-CBCT is degraded by view aliasing artifacts, and the accuracy of subsequent motion modeling is decreased by the inferior 4DCBCT. The objective of this work is to enhance both the image quality of 4D-CBCT and the accuracy of motion model estimation with a novel strategy enabling simultaneous motion estimation and image reconstruction (SMEIR). The proposed SMEIR algorithm consists of two alternating steps: 1) model-based iterative image reconstruction to obtain a motion-compensated primary CBCT (m-pCBCT) and 2) motion model estimation to obtain an optimal set of deformation vector fields (DVFs) between the m-pCBCT and other 4D-CBCT phases. The motion-compensated image reconstruction is based on the simultaneous algebraic reconstruction (SART) technique coupled with total variation minimization. During the forward- and back-projection of SART, measured projections from an entire set of 4D-CBCT are used for reconstruction of the m-pCBCT by utilizing the updated DVF. The DVF is estimated by matching the forward projection of the deformed m-pCBCT and measured projections of other phases of 4D-CBCT. The performance of the SMEIR algorithm is quantitatively evaluated on a 4D NCAT phantom. The SMEIR algorithm improves image reconstruction accuracy of 4D-CBCT and tumor motion trajectory estimation accuracy as compared to conventional sequential 4D-CBCT reconstruction and motion estimation.

  11. Clinical evaluation of 4D PET motion compensation strategies for treatment verification in ion beam therapy.

    PubMed

    Gianoli, Chiara; Kurz, Christopher; Riboldi, Marco; Bauer, Julia; Fontana, Giulia; Baroni, Guido; Debus, Jürgen; Parodi, Katia

    2016-06-01

    A clinical trial named PROMETHEUS is currently ongoing for inoperable hepatocellular carcinoma (HCC) at the Heidelberg Ion Beam Therapy Center (HIT, Germany). In this framework, 4D PET-CT datasets are acquired shortly after the therapeutic treatment to compare the irradiation induced PET image with a Monte Carlo PET prediction resulting from the simulation of treatment delivery. The extremely low count statistics of this measured PET image represents a major limitation of this technique, especially in presence of target motion. The purpose of the study is to investigate two different 4D PET motion compensation strategies towards the recovery of the whole count statistics for improved image quality of the 4D PET-CT datasets for PET-based treatment verification. The well-known 4D-MLEM reconstruction algorithm, embedding the motion compensation in the reconstruction process of 4D PET sinograms, was compared to a recently proposed pre-reconstruction motion compensation strategy, which operates in sinogram domain by applying the motion compensation to the 4D PET sinograms. With reference to phantom and patient datasets, advantages and drawbacks of the two 4D PET motion compensation strategies were identified. The 4D-MLEM algorithm was strongly affected by inverse inconsistency of the motion model but demonstrated the capability to mitigate the noise-break-up effects. Conversely, the pre-reconstruction warping showed less sensitivity to inverse inconsistency but also more noise in the reconstructed images. The comparison was performed by relying on quantification of PET activity and ion range difference, typically yielding similar results. The study demonstrated that treatment verification of moving targets could be accomplished by relying on the whole count statistics image quality, as obtained from the application of 4D PET motion compensation strategies. In particular, the pre-reconstruction warping was shown to represent a promising choice when combined with intra

  12. Restoration of Dioxin-Induced Damage to Fetal Steroidogenesis and Gonadotropin Formation by Maternal Co-Treatment with α-Lipoic Acid

    PubMed Central

    Koga, Takayuki; Ishida, Takumi; Takeda, Tomoki; Ishii, Yuji; Uchi, Hiroshi; Tsukimori, Kiyomi; Yamamoto, Midori; Himeno, Masaru; Furue, Masutaka; Yamada, Hideyuki

    2012-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an endocrine disruptor, causes reproductive and developmental toxic effects in pups following maternal exposure in a number of animal models. Our previous studies have demonstrated that TCDD imprints sexual immaturity by suppressing the expression of fetal pituitary gonadotropins, the regulators of gonadal steroidogenesis. In the present study, we discovered that all TCDD-produced damage to fetal production of pituitary gonadotropins as well as testicular steroidogenesis can be repaired by co-treating pregnant rats with α-lipoic acid (LA), an obligate co-factor for intermediary metabolism including energy production. While LA also acts as an anti-oxidant, other anti-oxidants; i.e., ascorbic acid, butylated hydroxyanisole and edaravone, failed to exhibit any beneficial effects. Neither wasting syndrome nor CYP1A1 induction in the fetal brain caused through the activation of aryl hydrocarbon receptor (AhR) could be attenuated by LA. These lines of evidence suggest that oxidative stress makes only a minor contribution to the TCDD-induced disorder of fetal steroidogenesis, and LA has a restorative effect by targeting on mechanism(s) other than AhR activation. Following a metabolomic analysis, it was found that TCDD caused a more marked change in the hypothalamus, a pituitary regulator, than in the pituitary itself. Although the components of the tricarboxylic acid cycle and the ATP content of the fetal hypothalamus were significantly changed by TCDD, all these changes were again rectified by exogenous LA. We also provided evidence that the fetal hypothalamic content of endogenous LA is significantly reduced following maternal exposure to TCDD. Thus, the data obtained strongly suggest that TCDD reduces the expression of fetal pituitary gonadotropins to imprint sexual immaturity or disturb development by suppressing the level of LA, one of the key players serving energy production. PMID:22911699

  13. Environmental impacts on the gonadotropic system in female Atlantic salmon (Salmo salar) during vitellogenesis: Photothermal effects on pituitary gonadotropins, ovarian gonadotropin receptor expression, plasma sex steroids and oocyte growth.

    PubMed

    Taranger, Geir Lasse; Muncaster, Simon; Norberg, Birgitta; Thorsen, Anders; Andersson, Eva

    2015-09-15

    The gonadotropic system and ovarian growth and development were studied during vitellogenesis in female Atlantic salmon subjected to either simulated natural photoperiod and ambient water temperature (NL-amb), or an accelerating photoperiod (short day of LD8:16 from May 10) combined with either warmed (ca 2°C above ambient; 8L-warm) or cooled water (ca 2°C below ambient; 8L-cold) from May to September. Monthly samples were collected from 10 females/group for determination of transcript levels of pituitary gonadotropin subunits (fshb and lhb) and ovarian gonadotropin receptors (fshr and lhr), plasma sex steroids (testosterone: T and estradiol-17β: E2), gonadosomatic index (GSI) and oocyte size. Short day in combination with either warmed or cooled water induced an earlier increase in pituitary fshb and lhb levels compared with NL-amb controls, and advanced ovarian growth and the seasonal profiles of T, E2. By contrast only minor effects were seen of the photothermal treatments on ovarian fshr and lhr. The 8L-cold had earlier increase in fshb, lhb and E2, but similar oocyte and gonadal growth as 8L-warm, suggesting that the 8L-cold group tried to compensate for the lower water temperature during the period of rapid gonadal growth by increasing fshb and E2 production. Both the 8L-warm and 8L-cold groups showed incomplete ovulation in a proportion of the females, possibly due to the photoperiod advancement resulting in earlier readiness of spawning occurring at a higher ambient temperature, or due to some reproductive dysfunction caused by photothermal interference with normal neuroendocrine regulation of oocyte development and maturation.

  14. SU-E-J-241: Creation of Ventilation CT From Daily 4D CTs Or 4D Conebeam CTs Acquired During IGRT for Thoracic Cancers

    SciTech Connect

    Tai, A; Ahunbay, E; Li, X

    2014-06-01

    Purpose: To develop a method to create ventilation CTs from daily 4D CTs or 4D KV conebeam CTs (4DCBCT) acquired during image-guided radiation therapy (IGRT) for thoracic tumors, and to explore the potential for using the ventilation CTs as a means for early detection of lung injury during radiation treatment. Methods: 4DCT acquired using an in-room CT (CTVision, Siemens) and 4DCBCT acquired using the X-ray Volume Imaging (XVI) system (Infinity, Elekta) for representative lung cancer patients were analyzed. These 4D data sets were sorted into 10 phase images. A newly-available deformable image registration tool (ADMIRE, Elekta) is used to deform the phase images at the end of exhale (EE) to the phase images at the end of inhale (EI). The lung volumes at EI and EE were carefully contoured using an intensity-based auto-contour tool and then manually edited. The ventilation images were calculated from the variations of CT numbers of those voxels masked by the lung contour at EI between the registered phase images. The deformable image registration is also performed between the daily 4D images and planning 4DCT, and the resulting deformable field vector (DFV) is used to deform the planning doses to the daily images by an in-house Matlab program. Results: The ventilation images were successfully created. The tide volumes calculated using the ventilation images agree with those measured through volume difference of contours at EE and EI, indicating the accuracy of ventilation images. The association between the delivered doses and the change of lung ventilation from the daily ventilation CTs is identified. Conclusions: A method to create the ventilation CT using daily 4DCTs or 4D KV conebeam CTs was developed and demonstrated.

  15. Maturational steroids and gonadotropin in upstream migratory sockeye salmon.

    PubMed

    Truscott, B; Idler, D R; So, Y P; Walsh, J M

    1986-04-01

    The circulating serum concentrations of various steroid hormones in mature sockeye salmon were measured at four different developmental stages in their upstream migration to spawn at Adams River in British Columbia, Canada. In females, a high level of estradiol-17 beta was found in fish at the first location, and it persisted until immediately before reaching the spawning grounds, 485 km upstream, where it decreased to a minimal level. Free testosterone was extremely high throughout the migration but decreased significantly after spawning while its glucuronide changed reciprocally. Free and conjugated 17 alpha, 20 beta-dihydroxy-4-pregnen-3-one (17 alpha, 20 beta-P) peaked at the last location before spawning with the glucuronide only 20% of the free steroid in concentration. After spawning, the concentration of free steroid declined but the glucuronide remained constant. 17 alpha-hydroxyprogesterone increased significantly in serum before and after the fish had spawned. During the migration 11-deoxycortisol was present in the serum at all stages but maximal levels were found in postspawned fish. Throughout the migration, the males had high serum levels of 11-ketotestosterone. Lesser amounts of free testosterone were also consistently present but the ratio of free: conjugated decreased from 1.7 at the beginning of the migration to 0.15 on the arrival at the Adams River and 0.10 in postspawned fish. Only low levels of 11 beta-hydroxytestosterone were found except in the postspawned males where the value was equal to one-half that of free testosterone. As in the females, there was a substantial increase in the levels of 17 alpha, 20 beta-P and its glucuronide in the males captured at the spawning grounds. In both sexes gonadotropin levels were low during the migration and high in the postspawned fish.

  16. Early-Life Social Isolation Impairs the Gonadotropin-Inhibitory Hormone Neuronal Activity and Serotonergic System in Male Rats.

    PubMed

    Soga, Tomoko; Teo, Chuin Hau; Cham, Kai Lin; Idris, Marshita Mohd; Parhar, Ishwar S

    2015-01-01

    Social isolation in early life deregulates the serotonergic system of the brain, compromising reproductive function. Gonadotropin-inhibitory hormone (GnIH) neurons in the dorsomedial hypothalamic nucleus are critical to the inhibitory regulation of gonadotropin-releasing hormone neuronal activity in the brain and release of luteinizing hormone by the pituitary gland. Although GnIH responds to stress, the role of GnIH in social isolation-induced deregulation of the serotonin system and reproductive function remains unclear. We investigated the effect of social isolation in early life on the serotonergic-GnIH neuronal system using enhanced green fluorescent protein (EGFP)-tagged GnIH transgenic rats. Socially isolated rats were observed for anxious and depressive behaviors. Using immunohistochemistry, we examined c-Fos protein expression in EGFP-GnIH neurons in 9-week-old adult male rats after 6 weeks post-weaning isolation or group housing. We also inspected serotonergic fiber juxtapositions in EGFP-GnIH neurons in control and socially isolated male rats. Socially isolated rats exhibited anxious and depressive behaviors. The total number of EGFP-GnIH neurons was the same in control and socially isolated rats, but c-Fos expression in GnIH neurons was significantly reduced in socially isolated rats. Serotonin fiber juxtapositions on EGFP-GnIH neurons were also lower in socially isolated rats. In addition, levels of tryptophan hydroxylase mRNA expression in the dorsal raphe nucleus were significantly attenuated in these rats. These results suggest that social isolation in early-life results in lower serotonin levels, which reduce GnIH neuronal activity and may lead to reproductive failure. PMID:26617573

  17. Gonadotropin-Inhibitory Hormone Reduces Sexual Motivation But Not Lordosis Behavior In Female Syrian Hamsters (Mesocricetus auratus)

    PubMed Central

    Piekarski, David J.; Zhao, Sheng; Jennings, Kimberly J.; Iwasa, Takeshi; Legan, Sandra J.; Mikkelsen, Jens D.; Tsutsui, Kazuyoshi; Kriegsfeld, Lance J.

    2014-01-01

    Reproductive success is maximized when female sexual motivation and behavior coincide with the time of optimal fertility. Both processes depend upon coordinated hormonal events, beginning with signaling by the gonadotropin-releasing hormone (GnRH) neuronal system. Two neuropeptidergic systems that lie upstream of GnRH, gonadotropin-inhibitory hormone (GnIH; also known as RFamide related peptide-3) and kisspeptin, are potent inhibitory and excitatory modulators of GnRH, respectively, participate in the timing of the preovulatory luteinizing hormone (LH) surge and ovulation. Whether these neuropeptides serve as neuromodulators to coordinate female sexual behavior with the limited window of fertility has not been thoroughly explored. In the present study, either intact or ovariectomized, hormonetreated female hamsters were implanted for fifteen days with chronic release osmotic pumps filled with GnIH or saline. The effect of GnIH on sexual motivation, vaginal scent marking, and lordosis was examined. Following mating, FOS activation was quantified in brain regions implicated in the regulation of female sexual behavior. Intracerebroventricular administration of GnIH reduced sexual motivation and vaginal scent marking, but not lordosis behavior. GnIH administration altered FOS expression in key neural loci implicated in female reproductive behavior, including the medial preoptic area, medial amygdala and bed nucleus of the stria terminalis, independent of changes in circulating gonadal steroids and kisspeptin cell activation. Together, these data point to GnIH as an important modulator of female proceptive sexual behavior and motivation, independent of downstream alterations in sex steroid production. PMID:23827890

  18. Early-Life Social Isolation Impairs the Gonadotropin-Inhibitory Hormone Neuronal Activity and Serotonergic System in Male Rats

    PubMed Central

    Soga, Tomoko; Teo, Chuin Hau; Cham, Kai Lin; Idris, Marshita Mohd; Parhar, Ishwar S.

    2015-01-01

    Social isolation in early life deregulates the serotonergic system of the brain, compromising reproductive function. Gonadotropin-inhibitory hormone (GnIH) neurons in the dorsomedial hypothalamic nucleus are critical to the inhibitory regulation of gonadotropin-releasing hormone neuronal activity in the brain and release of luteinizing hormone by the pituitary gland. Although GnIH responds to stress, the role of GnIH in social isolation-induced deregulation of the serotonin system and reproductive function remains unclear. We investigated the effect of social isolation in early life on the serotonergic–GnIH neuronal system using enhanced green fluorescent protein (EGFP)-tagged GnIH transgenic rats. Socially isolated rats were observed for anxious and depressive behaviors. Using immunohistochemistry, we examined c-Fos protein expression in EGFP–GnIH neurons in 9-week-old adult male rats after 6 weeks post-weaning isolation or group housing. We also inspected serotonergic fiber juxtapositions in EGFP–GnIH neurons in control and socially isolated male rats. Socially isolated rats exhibited anxious and depressive behaviors. The total number of EGFP–GnIH neurons was the same in control and socially isolated rats, but c-Fos expression in GnIH neurons was significantly reduced in socially isolated rats. Serotonin fiber juxtapositions on EGFP–GnIH neurons were also lower in socially isolated rats. In addition, levels of tryptophan hydroxylase mRNA expression in the dorsal raphe nucleus were significantly attenuated in these rats. These results suggest that social isolation in early-life results in lower serotonin levels, which reduce GnIH neuronal activity and may lead to reproductive failure. PMID:26617573

  19. Relation between the 4d superconformal index and the S 3 partition function

    NASA Astrophysics Data System (ADS)

    Imamura, Yosuke

    2011-09-01

    A relation between the 4d superconformal index and the S 3 partition function is studied with focus on the 4d and 3d actions used in localization. In the case of vanishing Chern-Simons levels and round S 3 we explicitly show that the 3d action is obtained from the4d action by dimensional reduction up to terms which do not affect the exact results. By combining this fact and a recent proposal concerning a squashing of S 3 and SU(2) Wilson line, we obtain a formula which gives the partition function depending on the Weyl weight of chiral multiplets, real mass parameters, FI parameters, and a squashing parameter as a limit of the index of a parent 4d theory.

  20. Dissipation and residue of 2,4-D in citrus under field condition.

    PubMed

    Chen, Weijun; Jiao, Bining; Su, Xuesu; Zhao, Qiyang; Sun, Dali

    2015-05-01

    The dissipation, residues, and risks of 2,4-dicholrophenoxyacetic acid (2,4-D) in citrus under field condition were investigated based on a simple ultra-performance LC (UPLC)-MS/MS method. The results indicated that the residue level of 2,4-D in citrus did not degrade gradually with sampling time under field condition. At pre-harvest intervals (PHI) of 20-40 days, 2,4-D residues were 0.021-0.269 mg/kg in citrus flesh, 0.028-0.337 mg/kg in whole citrus, and 0.028-0.376 mg/kg in citrus peel, all bellow the China maximum residue limit in citrus (1 mg/kg). Risks of 2,4-D were assessed by calculation of risk quotient, and the results revealed no significant health risks after consumption of citrus.

  1. Effect of gonadotropin-releasing hormone II receptor (GnRHR-II) knockdown on testosterone secretion in the boar

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Unlike the classical gonadotropin-releasing hormone (GnRH-I), the second mammalian GnRH isoform (GnRH-II; His5, Trp7, Tyr8) is a poor stimulator of gonadotropin secretion. In addition, GnRH-II is ubiquitously expressed, with transcript levels highest in tissues outside of the brain. A receptor speci...

  2. Effect of gonadotropin secretion rate on the radiosensitivity of the rat luteinizing hormone-releasing hormone neuron and gonadotroph

    SciTech Connect

    Winterer, J.; Barnes, K.M.; Lichter, A.S.; Deluca, A.M.; Loriaux, D.L.; Cutler, G.B. Jr.

    1988-03-01

    To test the hypothesis that the functional state of hypothalamic LHRH neurons and pituitary gonadotrophs might alter their radiosensitivity, we determined the experimental conditions under which the gonadotropin response to castration could be impaired by a single dose of cranial irradiation. Single doses of cranial irradiation greater than 2000 rads were lethal to unshielded rats. Shielding of the oropharynx and esophagus allowed the animals to survive doses up to 5000 rads. Doses between 2000 and 5000 rads had no effect on basal gonadotropin levels for as long as 3 months after irradiation. Irradiation caused a dose- and time-dependent impairment, however, in the gonadotropin response to castration. Impairment of the gonadotropin levels of castrate animals occurred in animals that were irradiated either before or after castration. However, rats irradiated in the castrate state showed a decreased susceptibility to irradiation damage. Additionally, stimulation of the pituitary by LHRH agonist (LHRHa) 3 h before irradiation significantly reduced the impairment of gonadotropin secretion 12-20 weeks after irradiation (P less than 0.05). Thus, increased functional activity of the rat hypothalamus or pituitary at the time of irradiation, induced by either castration or acute LHRHa administration, was associated with some protection against the gonadotropin-lowering effect of irradiation. Based upon these data, we hypothesize that stimulation of gonadotropin secretion at the time of therapeutic cranial irradiation in humans might protect against subsequent impairment of gonadotropin secretion.

  3. Residues of 2, 4-D in air samples from Saskatchewan: 1966-1975.

    PubMed

    Grover, R; Kerr, L A; Wallace, K; Yoshida, K; Maybank, J

    1976-01-01

    Residues of 2,4-D (2,4-dichlorophenoxyacetic acid) in air samples from several sampling sites in central and southern Saskatchewan during the spraying seasons in the 1966-68 and 1970-75 periods were determined by gas-liquid chromatographic techniques. Initially, individual esters of 2,4-D were characterized by retention times and confirmed further by co-injection and dual column procedures. Since 1973, however, only total 2,4-D acid levels in air samples have been determined after esterification to the methyl ester and confirmed by gc/ms techniques whenever possible. Up to 50% of the daily samples collected during the spraying season at any of the locations and during any given year contained 2,4-D, with butyl esters being found most frequently. The daily 24-hr mean atmospheric concentrations of 2,4-D ranged from 0.01 to 1.22 mug/m3, 0.01 to 13.50 mug/m3, and 0.05 to 0.59 mug/m3 for the iso-propyl, mixed butyl and iso-octyl esters, respectively. Even when the samples were analysed for the total 2,4-D content, i.e. from 1973 onwards, the maximum level of the total acid reached only 23.14 mug/m3. In any given year and at any of the sampling sites, about 30% of the samples contained less than 0.01 mug/m3 of 2,4-D. In another 40% of the samples, the levels of 2,4-D ranged from 0.01 to 0.099 mug/m3. Only about 30% of the samples contained 2,4-D concentrations higher than 0.1 mug/m3, with only 10% or less exceeding 1 mug/m3. None of the samples, obtained with the high volume particulate sampler, showed any detectable levels of 2,4-D, indicating little or no transport of 2,4-D adsorbed on dust particles or as crystals of amine salts. PMID:1002953

  4. Energy levels in Ag-like (4d{sup 10}4f, 4d{sup 10}5l (l = 0-3)), Pd-like (4d{sup 9}4f [J = 1], 4d{sup 9}5p [J = 1], 4d{sup 9}5f [J = 1]), and Rh-like (4d{sup 9} [J = 5/2, 3/2]) ions with Z {<=} 86

    SciTech Connect

    Ivanova, E.P.

    2009-11-15

    Relativistic perturbation theory with a model potential is used for the calculation of energy levels of the states 4f{sub 5/2}, 4f{sub 7/2}, 5s{sub 1/2}, 5p{sub 1/2}, 5p{sub 3/2}, 5d{sub 3/2}, 5d{sub 5/2}, 5f{sub 5/2}, and 5f{sub 7/2} above the 1s{sup 2}2s{sup 2}2p{sup 6}3s{sup 2}3p{sup 6}3d{sup 10}4s{sup 2}4p{sup 6}4d{sup 10} core, with one vacancy 4d{sub 5/2}{sup 9}, 4d{sub 7/2}{sup 9} in the same core, in the silver and rhodium isoelectronic sequences with the maximum nuclear charge Z = 86. The method of extrapolation of the model potential parameter is applied to calculate one-electron and one-vacancy wavefunctions. The wavefunctions of Ag- and Rh-like ions were used to calculate the energies of resonance transitions to the ground state {sup 1}S{sub 0} in Pd-like ions. Good agreement between the theoretical and the experimental energies of the resonance transitions in Pd-like ions indicates the reliability of the results obtained.

  5. Effect of pH and Electrolytes on Adsorption of 2,4-D onto Kaolinite

    NASA Astrophysics Data System (ADS)

    Sharma, A.; Kawamoto, K.; Komatsu, T.; Moldrup, P.

    2006-12-01

    The fate and transport of pesticides in soil can be greatly influenced by adsorption onto clay minerals such as kaolinite. The ionic pesticide 2,4-D (2,4-dichlorophenoxyacetic acid) is one of the most commonly used herbicides. The purpose of this study is to investigate the effect of electrolytes and pH on the adsorption of 2,4- D onto kaolinite. The adsorption coefficient (Kd) of 2,4-D on two types of kaolinite was measured in batch experiments using water and 4 different electrolytes (0.005M CaSO4, 0.005M CaCl2, 0.01M KCl, and 0.01M NaCl). The experiments were carried out with 0.5 g kaolinite at a solid:liquid ratio of 1:20 and at different pH (1.9-6.3). The pH of the solution was controlled by addition of 0.2N of HCl. X-ray diffraction analysis of both kaolinite with and without adsorbed 2,4-D was also done to understand the location of 2,4-D adsorption. The effects of pH and electrolytes on Kd were compared and possible adsorption mechanisms were revealed for 2,4-D adsorption onto the two different types of kaolinite. The results implied that 2,4-D adsorption was higher for an electrolyte solution with monovalent cation than with divalent cation for one type of kaolinite, while no such trend was observed for the other kaolinite. The adsorption of 2,4-D increased significantly with decreasing pH for both types of kaolinite.

  6. Decreased hypothalamic gonadotropin-releasing hormone secretion in male marathon runners.

    PubMed

    MacConnie, S E; Barkan, A; Lampman, R M; Schork, M A; Beitins, I Z

    1986-08-14

    Hypogonadotropic hypogonadism due to a deficiency in hypothalamic gonadotropin-releasing hormone is common in female athletes ("hypothalamic amenorrhea"). It is not known, however, whether a similar phenomenon occurs in male athletes. We investigated the integrity of the hypothalamic-pituitary-gonadal axis in six highly trained male marathon runners (who were running 125 to 200 km per week). The mean (+/- SEM) frequency of spontaneous luteinizing hormone pulses was diminished in the runners, as compared with healthy controls (2.2 +/- 0.48 vs. 3.6 +/- 0.24 pulses per eight hours, P less than 0.05). The amplitude of the pulses was also low in the runners (0.9 +/- 0.24 vs. 1.6 +/- 0.15 mlU per milliliter; P less than 0.05), and the responses of luteinizing hormone to gradually increasing doses of exogenous gonadotropin-releasing hormone were decreased. Plasma testosterone levels were similar in the two groups and increased equally in response to an intramuscular injection of 2000 units of human chorionic gonadotropin. During short-term intense physical exercise (a treadmill run at 72 percent of maximal oxygen consumption for two hours), the plasma gonadotropin levels in the athletes remained stable, but significant elevations in plasma levels of cortisol, prolactin, and testosterone occurred. We conclude that highly trained male athletes, like their female counterparts, may have a deficiency of hypothalamic gonadotropin-releasing hormone. This condition may be caused by the prolonged, repetitive elevations of gonadal steroids and other hormones known to suppress gonadotropin-releasing hormone secretion that are elicited by their daily exercise.

  7. Biolabeling with 2,4-dichlorophenoxyacetic acid derivatives: the 2,4-D tag.

    PubMed

    Bade, Steffen; Röckendorf, Niels; Franek, Milan; Gorris, Hans H; Lindner, Buko; Olivier, Verena; Schaper, Klaus-Jürgen; Frey, Andreas

    2009-12-01

    Many bioanalytic and diagnostic procedures rely on labels with which the molecule of interest can be tracked in or discriminated from accompanying like substances. Herein, we describe a new labeling and detection system based on derivatives of 2,4-dichlorophenoxyacetic acid (2,4-D) and anti-2,4-D antibodies. The 2,4-D system is highly sensitive with a K(D) of 7 x 10(-11) M for the hapten-antibody pair, can be used on a large variety of biomolecules such as proteins, peptides, carbohydrates, and nucleic acids, is not hampered by endogenous backgrounds because 2,4-D is a xenobiotic, and is robust because 2,4-D is a very stable compound that withstands the conditions of most reactions usually performed on biomolecules. With this unique blend of properties, the 2,4-D system compares favorably with its rivals digoxigenin (DIG)/anti-DIG and biotin/(strept)avidin and provides an interesting and powerful tool in biomolecular labeling.

  8. Marked suppression of gonadotropins and testosterone by an antagonist analog of gonadotropin-releasing hormone in men.

    PubMed

    Salameh, W; Bhasin, S; Steiner, B; McAdams, L A; Peterson, M; Swerdloff, R

    1991-01-01

    To study the dose response characteristics of a gonadotropin-releasing hormone (GnRH) antagonist ([Ac-D2-Nal1,D4-Cl-Phe2,D3-Pal3,Arg5,dGlu6 (AA), d-Ala10] GnRH; Nal-Glu), 1.5 or 5.0 mg of Nal-Glu were administered to two groups of five normal men by daily subcutaneous injection for 21 days. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (T) were determined on multiple occasions before, during, and after the antagonist treatment. Five milligrams Nal-Glu markedly suppressed mean serum immunoreactive LH to a mean of 1.5 +/- 0.4 IU/L (+/- SEM), immunoreactive FSH to the limit of assay detection (1 IU/L), and lowered basal mean serum T to castrate range (less than 2 nmol/L). Serum bioactive LH levels also showed a marked decrease in the 5.0-mg group similar to that seen in immunoreactive LH levels. Amplitude of immunoreactive LH pulses was markedly reduced in the 5.0-mg group on day 21. A 1.5-mg dose of Nal-Glu transiently suppressed serum immunoreactive LH levels on day 1. There was a subsequent escape on the rest of the days sampled. Serum immunoreactive FSH levels were not significantly changed over the 21-day treatment period. Serum T levels were transiently suppressed only on day 1 paralleling immunoreactive LH suppression. No adverse systemic side effects occurred. Thus, the 5.0-mg dose of this GnRH antagonist provides a pharmacological means of markedly suppressing the hypothalamic-pituitary-gonadal axis and, therefore, has potential as a male contraceptive.

  9. Early development of the gonadotropin-releasing hormone neuronal network in transgenic zebrafish.

    PubMed

    Zhao, Yali; Lin, Meng-Chin A; Farajzadeh, Matthew; Wayne, Nancy L

    2013-01-01

    Understanding development of gonadotropin-releasing hormone (GnRH) neuronal circuits is fundamental to our understanding of reproduction, but not yet well understood. Most studies have been focused on GnRH neurons located in the hypothalamus and preoptic area (POA), which directly regulate the pituitary-gonadal axis. In zebrafish (Danio rerio), two forms of GnRH have been identified: GnRH2 and GnRH3. GnRH3 neurons in this species plays two roles: hypophysiotropic and neuromodulatory, depending on their location. GnRH3 neurons in the ventral telencephalon, POA, and hypothalamus control pituitary-gonadal function; in other areas (e.g., terminal nerve), they are neuromodulatory and without direct action on reproduction. To investigate the biology of GnRH neurons, a stable line of transgenic zebrafish was generated in which the GnRH3 promoter drives expression of a bright variant of green fluorescent protein (Emerald GFP, or EMD). This provides unprecedented sensitivity in detecting and imaging GnRH3 neurons during early embryogenesis in the transparent embryo. Using timelapse confocal imaging to monitor the time course of GnRH3:EMD expression in the live embryo, we describe the emergence and development of GnRH3 neurons in the olfactory region, hypothalamus, POA, and trigeminal ganglion. By 50 h post fertilization, these diverse groups of GnRH3 neurons project broadly in the central and peripheral nervous systems and make anatomical connections with each other. Immunohistochemistry of synaptic vesicle protein 2 (a marker of synaptic transmission) in this transgenic model suggests synaptic formation is occurring during early development of the GnRH3 neural network. Electrophysiology reveals early emergence of responsiveness to the stimulatory effects of kisspeptin in terminal nerve GnRH3 neurons. Overall, our findings reveal that the GnRH3 neuronal system is comprised of multiple populations of neurons as a complicated network. PMID:24009601

  10. Gonadotropin-releasing hormone receptor system: modulatory role in aging and neurodegeneration.

    PubMed

    Wang, Liyun; Chadwick, Wayne; Park, Sung-Soo; Zhou, Yu; Silver, Nathan; Martin, Bronwen; Maudsley, Stuart

    2010-11-01

    Receptors for hormones of the hypothalamic-pituitary-gonadal axis are expressed throughout the brain. Age-related decline in gonadal reproductive hormones cause imbalances of this axis and many hormones in this axis have been functionally linked to neurodegenerative pathophysiology. Gonadotropin-releasing hormone (GnRH) plays a vital role in both central and peripheral reproductive regulation. GnRH has historically been known as a pituitary hormone; however, in the past few years, interest has been raised in GnRH actions at non-pituitary peripheral targets. GnRH ligands and receptors are found throughout the brain where they may act to control multiple higher functions such as learning and memory function and feeding behavior. The actions of GnRH in mammals are mediated by the activation of a unique rhodopsin-like G protein-coupled receptor that does not possess a cytoplasmic carboxyl terminal sequence. Activation of this receptor appears to mediate a wide variety of signaling mechanisms that show diversity in different tissues. Epidemiological support for a role of GnRH in central functions is evidenced by a reduction in neurodegenerative disease after GnRH agonist therapy. It has previously been considered that these effects were not via direct GnRH action in the brain, however recent data has pointed to a direct central action of these ligands outside the pituitary. We have therefore summarized the evidence supporting a central direct role of GnRH ligands and receptors in controlling central nervous physiology and pathophysiology.

  11. Immunological properties of prolactin and studies on a gonadotropin binding inhibitor

    SciTech Connect

    Chang, Y.S.

    1985-01-01

    The physiological role of prolactin in horses has not yet been well defined. With the availability of highly purified ePRL for inducing antibody formation in rabbits and for radiolabeling with Na/sup 125/I, a very sensitive (0.4-0.6 ng/ml) and highly specific homologous RIA for ePRL was developed. A heterologous RIA using /sup 125/I-labeled ovine PRL and anti-ePRL antiserum was also developed and compared to the homologous RIA for ePRL. Of the two systems, it is concluded that this homologous RIA system is more suitable and more reliable for measuring prolactin concentration in horse serum samples. Until now, biochemical information on PRL has not been available for reptilian species. Sea turtle (Chelonia mydas) prolactin was purified from pituitary extracts by selective precipitation, DEAE-cellulose chromatography and gel filtration. Similar to other species of PRL, sea turtle PRL is a 22,000-24,000 daltons protein and contains a high content of glutamic acid, aspartic acid, serine and leucine, the N-terminal amino acid residue. Gonadotropin (FSH) binding inhibitor was partially purified from sheep testes by ammonium sulfate fractionation and ion exchange chromatography. The FSH-BI (molecular weight: 50,000 daltons, estimated by gel filtration) contains a protein moiety necessary for binding inhibitory activity. The inhibition of the binding of /sup 125/I-labeled ovine FSH to its receptor by the FSH-BI is not competitive. Both in vivo and in vitro biological studies of FSH-BI preparations in rats indicated various effects on FSH and LH activities at the gonadal level. These findings suggest a physiological role for FSH-BI in the regulation of reproduction.

  12. Early Development of the Gonadotropin-Releasing Hormone Neuronal Network in Transgenic Zebrafish

    PubMed Central

    Zhao, Yali; Lin, Meng-Chin A.; Farajzadeh, Matthew; Wayne, Nancy L.

    2013-01-01

    Understanding development of gonadotropin-releasing hormone (GnRH) neuronal circuits is fundamental to our understanding of reproduction, but not yet well understood. Most studies have been focused on GnRH neurons located in the hypothalamus and preoptic area (POA), which directly regulate the pituitary-gonadal axis. In zebrafish (Danio rerio), two forms of GnRH have been identified: GnRH2 and GnRH3. GnRH3 neurons in this species plays two roles: hypophysiotropic and neuromodulatory, depending on their location. GnRH3 neurons in the ventral telencephalon, POA, and hypothalamus control pituitary-gonadal function; in other areas (e.g., terminal nerve), they are neuromodulatory and without direct action on reproduction. To investigate the biology of GnRH neurons, a stable line of transgenic zebrafish was generated in which the GnRH3 promoter drives expression of a bright variant of green fluorescent protein (Emerald GFP, or EMD). This provides unprecedented sensitivity in detecting and imaging GnRH3 neurons during early embryogenesis in the transparent embryo. Using timelapse confocal imaging to monitor the time course of GnRH3:EMD expression in the live embryo, we describe the emergence and development of GnRH3 neurons in the olfactory region, hypothalamus, POA, and trigeminal ganglion. By 50 h post fertilization, these diverse groups of GnRH3 neurons project broadly in the central and peripheral nervous systems and make anatomical connections with each other. Immunohistochemistry of synaptic vesicle protein 2 (a marker of synaptic transmission) in this transgenic model suggests synaptic formation is occurring during early development of the GnRH3 neural network. Electrophysiology reveals early emergence of responsiveness to the stimulatory effects of kisspeptin in terminal nerve GnRH3 neurons. Overall, our findings reveal that the GnRH3 neuronal system is comprised of multiple populations of neurons as a complicated network. PMID:24009601

  13. Role of p19ink4d in the pathogenesis of hearing loss

    PubMed Central

    Lai, Ruosha; Li, Jingkun; Hu, Peng; Wen, Jie; Jie, Qing; Dong, Yunpeng; Peng, Tao; Liu, Xuezhong; Xie, Dinghua

    2015-01-01

    This study aimed to investigate the p19 expression in cisplatin-treated rats and the role of p19 in the degeneration of inner ear cells. It also searched for p19 gene alterations in patients with profound sensorineural deafness. P19ink4d is essential for the postmitotic maintenance of hair cells. It is presumed that a mutation in the functional homolog of p19 or a disturbance in its regulated expression can be the underlying cause of hearing loss. Experiments were conducted on male and female Sprague-Dawley rats (aged 6-7 weeks, 280-320 g) with thresholds of auditory brainstem responses <30 dB in the sound pressure level, and signs of middle ear infection were used for the experiment. For clinical evaluation, 400 children (age less than 13 years) from unrelated families with severe or profound sensorineural hearing loss (SNHL) were recruited at the second Xiangya Hospital of Central South University between 2005 and 2013, and genomic DNA for deafness gene analysis was obtained from peripheral blood samples of the patients and their lineal relatives. It was found that the p19 expression increased over time in the inner ear cells after cisplatin administration, but the p19 mRNA and protein levels significantly decreased in rats with manifested hearing loss induced by cisplatin. However, no mutation existed within the coding exons of p19 in the patients with profound sensorineural deafness. To conclude, the results support the concept that p19 may play an important role in the ototoxic effects of cisplatin and is probably involved in the pathogenesis of hearing loss. PMID:26722409

  14. RNA interference-mediated knockdown of long-form phosphodiesterase-4D (PDE4D) enzyme reverses amyloid-β42-induced memory deficits in mice.

    PubMed

    Zhang, Cong; Cheng, Yufang; Wang, Haitao; Wang, Chuang; Wilson, Steven P; Xu, Jiangping; Zhang, Han-Ting

    2014-01-01

    Phosphodiesterase-4 (PDE4) inhibitors enhance memory, increase hippocampal neurogenesis, and reverse amyloid-β (Aβ)-induced memory deficits. Here, we examined whether long-form PDE4D knockdown by lentiviral RNA construct containing a specific microRNA/miRNA-mir hairpin structure (4DmiRNA) reversed memory impairment caused by amyloid-β1-42 (Aβ42) in mice using the Morris water maze (MWM) and novelty object recognition tests. Western blotting analysis was used to assess protein levels of cAMP response element-binding protein (CREB, unphosphorylated and phosphorylated [pCREB]), brain-derived neurotrophic factor (BDNF), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB) to explore the neurochemical mechanisms. Aggregated Aβ42 (0.5 μg/side) bilaterally infused in dentate gyrus decreased cAMP levels (p < 0.01) and produced memory deficits in the MWM (p < 0.01) and object recognition tests (p < 0.01). Microinfusions of lentiviruses resulted in downregulated expression of PDE4D4 and 4D5 proteins and reversed Aβ42-induced cAMP decline (p < 0.05) and memory deficits. Treatment also concomitantly increased pCREB (p < 0.05) and BDNF (p < 0.01) and reduced IL-1β (p < 0.05), TNF-α (p < 0.01), and NF-κB (p65) (p < 0.05) in the hippocampus of Aβ42-challenged mice. These results suggest that long-form PDE4D knockdown may offer a promising treatment for memory loss associated with Alzheimer's disease.

  15. Dynamically accumulated dose and 4D accumulated dose for moving tumors

    SciTech Connect

    Li Heng; Li Yupeng; Zhang Xiaodong; Li Xiaoqiang; Liu Wei; Gillin, Michael T.; Zhu, X. Ronald

    2012-12-15

    Purpose: The purpose of this work was to investigate the relationship between dynamically accumulated dose (dynamic dose) and 4D accumulated dose (4D dose) for irradiation of moving tumors, and to quantify the dose uncertainty induced by tumor motion. Methods: The authors established that regardless of treatment modality and delivery properties, the dynamic dose will converge to the 4D dose, instead of the 3D static dose, after multiple deliveries. The bounds of dynamic dose, or the maximum estimation error using 4D or static dose, were established for the 4D and static doses, respectively. Numerical simulations were performed (1) to prove the principle that for each phase, after multiple deliveries, the average number of deliveries for any given time converges to the total number of fractions (K) over the number of phases (N); (2) to investigate the dose difference between the 4D and dynamic doses as a function of the number of deliveries for deliveries of a 'pulsed beam'; and (3) to investigate the dose difference between 4D dose and dynamic doses as a function of delivery time for deliveries of a 'continuous beam.' A Poisson model was developed to estimate the mean dose error as a function of number of deliveries or delivered time for both pulsed beam and continuous beam. Results: The numerical simulations confirmed that the number of deliveries for each phase converges to K/N, assuming a random starting phase. Simulations for the pulsed beam and continuous beam also suggested that the dose error is a strong function of the number of deliveries and/or total deliver time and could be a function of the breathing cycle, depending on the mode of delivery. The Poisson model agrees well with the simulation. Conclusions: Dynamically accumulated dose will converge to the 4D accumulated dose after multiple deliveries, regardless of treatment modality. Bounds of the dynamic dose could be determined using quantities derived from 4D doses, and the mean dose difference

  16. Low external pH replaces 2,4-D in maintaining and multiplying 2,4-D-initiated embryogenic cells of carrot

    NASA Technical Reports Server (NTRS)

    Smith, D. L.; Krikorian, A. D.

    1990-01-01

    A mixed culture comprised of both embryonic globules and nonembryogenic callus was derived from seedling hypocotyls of Daucus carota cv. Scarlet Nantes on 2,4-D- containing medium using well-established methods. Then the mixed cultures were transferred to, and serially subcultured on, a hormone-free medium near pH 4. The medium contained 1 mM NH4+ as the sole nitrogen source. When cultured in this way, embryonic globules were able to multiply without development into later embryo stages. Nonembryogenic callus did not survive. Continuous culture of embryonic globules on this low pH hormone-free medium yielded cultures consisting entirely of preglobular stage proembryos (PGSPs). PGSP cultures have been maintained as such with continuous multiplication for nearly 2 years without loss of embryogenic potential. These hormone-free-maintained PGSPs continue their development to later embryo stages when cultured on the same hormone-free medium buffered at pH 5.8. We show that hormone-free medium near pH 4 can replace 2,4-D in its ability to sustain multiplication of 2,4-D-initiated embryogenic cells of carrot at an acceptable growth rate without their development into later embryo stages. This procedure provides selective conditions that do not permit the growth of non-embryogenic cells while providing an adequate environment for embryogenic cell proliferation and should prove invaluable in studying habituation.

  17. 2,4-D toxicosis.III: An attempt to produce 2,4-D toxicosis in dogs on treated grass plots.

    PubMed

    Arnold, E K; Lovell, R A; Beasley, V R; Parker, A J; Stedelin, J R

    1991-10-01

    Eighteen English pointer dogs were randomly assigned to 3 outdoor grass-plot enclosures (6/enclosure) uniformly sprayed once with either the 2,4-dichlorophenoxyacetic acid (2,4-D) dimethylamine formulation (DMA-4) at the maximum recommended application rate, DMA-4 at 4 times the maximum recommended application rate, or the DMA-4 vehicle alone at 4 times the maximum recommended application rate. A heavy rain shower occurred 24 h after application. The dogs were observed for clinical signs and evaluated using an electroencephalograph, electrocardiograph (lead I), and electromyograph prior to exposure, and either 1 or 7 d after continuous exposure. Clinical examination, hematologic and serum biochemical data were obtained, and serum, urine and kidney 2,4-D were quantified. Half of the dogs from each group were killed after 1 d of continuous exposure, while the other half were killed after 7 d. Gross postmortem and histologic examinations were conducted on each dog. No obvious 2,4-D effects were detected in any of the dogs.

  18. Serum progesterone and estradiol-17beta concentrations, and lapaloscopic observations of the ovary in the cheetah (Acinonyxjubatus) with pregnant mare serum gonadotropin and human chorionic gonadotropin treatments.

    PubMed

    Doi, O; Kusunoki, H; Sato, T; Kawakami, S; Fukuoka, T; Okuda, K; Ito, O; Saito, E; Hayashi, T; Hase, T; Kamiyosh, M

    2001-12-01

    In 3 adult female cheetahs, induced-superovulation treatment was conducted, by means of 200 IU of pregnant mare serum gonadotropin (PMSG) and 100 IU of human chorionic gonadotropin (hCG) 80 hr after PMSG. The administration of PMSG created a sharp increase in the estradiol-17beta concentration, resulting in 232 pg/ml 8 hr later in one specimen out of three. The hCG administration showed an increase in the progesterone concentration of 2.29 ng/ml 46 hr later. In addition, after direct observation of the ovary surface by laparoscopy, 5 follicles in the right ovary over 2 mm in diameter, and 7 corpora lutea (5 in the right ovary and 2 in the left) were found. It is assumed that ovulation can be induced with hCG after 80 hr on PMSG during a cheetah's diestrus or proestrus.

  19. Molecular cloning, expression pattern, and chromosomal localization of human CDKN2D/INK4d, an inhibitor of cyclin D-dependent kinases

    SciTech Connect

    Okuda, Tsukasa; Shurtleff, S.A.; Downing, J.R.

    1995-10-10

    Progression through the G1 phase of the cell cycle is dependent on the activity of holoenzymes formed between D-type cyclins and their catalytic partners, the cyclin-dependent kinases cdk4 and cdk6. p16{sup INK4a} p15{sup INK4b}, and p18{sup INK4c}, a group of structurally related proteins, function as specific inhibitors of the cyclin D-dependent kinases and are likely to play physiologic roles as specific regulators of these kinases in vivo. A new member of the INK4 gene family, murine INK4d, has recently been identified. Here we report the isolation of human INK4d (gene symbol CDKN2D), which is 86 identical at the amino acid level to the murine clone and {approximately}44% identical to each of the other human INK4 family members. The INK4d gene is ubiquitously expressed as a single 1.4-kb mRNA with the highest levels detected in thymus, spleen, peripheral blood leukocytes, fetal liver, brain, and testes. The abundance of INK4d mRNA oscillates in a cell-cycle-dependent manner with expression lowest at mid G1 and maximal during S phase. Using a P1-phage genomic clone of INK4d for fluorescence in situ hybridization analysis, the location of this gene was mapped to chromosome 19p13. No rearrangements or deletions of the INK4d gene were observed in Southern blot analysis of selected cases of pediatric acute lymphoblastic leukemia (ALL) containing a variant (1;19)(q23;p13) translocation that lacks rearrangement of either E2A or PBX1, or in ALL cases containing homozygous or hemizygous deletions of the related genes, INK4a and INK4b. 39 refs., 3 figs.

  20. Evaluation of a 4D cone-beam CT reconstruction approach using a simulation framework.

    PubMed

    Hartl, Alexander; Yaniv, Ziv

    2009-01-01

    Current image-guided navigation systems for thoracic abdominal interventions utilize three dimensional (3D) images acquired at breath-hold. As a result they can only provide guidance at a specific point in the respiratory cycle. The intervention is thus performed in a gated manner, with the physician advancing only when the patient is at the same respiratory cycle in which the 3D image was acquired. To enable a more continuous workflow we propose to use 4D image data. We describe an approach to constructing a set of 4D images from a diagnostic CT acquired at breath-hold and a set of intraoperative cone-beam CT (CBCT) projection images acquired while the patient is freely breathing. Our approach is based on an initial reconstruction of a gated 4D CBCT data set. The 3D CBCT images for each respiratory phase are then non-rigidly registered to the diagnostic CT data. Finally the diagnostic CT is deformed based on the registration results, providing a 4D data set with sufficient quality for navigation purposes. In this work we evaluate the proposed reconstruction approach using a simulation framework. A 3D CBCT dataset of an anthropomorphic phantom is deformed using internal motion data acquired from an animal model to create a ground truth 4D CBCT image. Simulated projection images are then created from the 4D image and the known CBCT scan parameters. Finally, the original 3D CBCT and the simulated X-ray images are used as input to our reconstruction method. The resulting 4D data set is then compared to the known ground truth by normalized cross correlation(NCC). We show that the deformed diagnostic CTs are of better quality than the gated reconstructions with a mean NCC value of 0.94 versus a mean 0.81 for the reconstructions. PMID:19964143

  1. Capillary Deposition of Complement C4d and C3d in Chinese Renal Allograft Biopsies

    PubMed Central

    Lv, Rong; Zhang, Wei; Han, Fei; Liu, Guangjun; Xie, Wenqing

    2015-01-01

    Background. C3d is a product of both the classic and the alternative complement cascades; however, few studies have addressed the role of C3d in renal biopsies and its relationship with long-term graft survival rate is not very clear. Methods. 94 patients with biopsy-proven acute rejection episodes were included in the study. We investigated the associations between histological findings, clinical examinations, and outcome. Results. The overall prevalence for C4dPTC and C3dPTC was 42.6% and 29.8%. There was a significant association between C3dPTC and C4dPTC (P < 0.001). C3dPTC and C4dPTC were related with histological types (P = 0.024 and P < 0.001, resp.). The long-term survival rate for C4dPTC positive transplants was lower than that of C4dPTC negative transplants, but it was not statistic significant in our study (P = 0.150). The survival rate of C3dPTC positive group was much lower than the negative group (P = 0.014). Patients with double positives for C4dPTC and C3dPTC exhibited the lowest survival rate significantly different from those of the C3dPTC only and C4dPTC only groups (P = 0.01 and P = 0.0037). Conclusions. This longitudinal cohort study has demonstrated that C3d deposition in the PTC was closely related to renal dysfunction and pathological changes. PMID:25821339

  2. Evaluation of 4D CT acquisition methods designed to reduce artifacts.

    PubMed

    Castillo, Sarah J; Castillo, Richard; Castillo, Edward; Pan, Tinsu; Ibbott, Geoffrey; Balter, Peter; Hobbs, Brian; Guerrero, Thomas

    2015-03-08

    Four-dimensional computed tomography (4D CT) is used to account for respiratory motion in radiation treatment planning, but artifacts resulting from the acquisition and postprocessing limit its accuracy. We investigated the efficacy of three experimental 4D CT acquisition methods to reduce artifacts in a prospective institutional review board approved study. Eighteen thoracic patients scheduled to undergo radiation therapy received standard clinical 4D CT scans followed by each of the alternative 4D CT acquisitions: 1) data oversampling, 2) beam gating with breathing irregularities, and 3) rescanning the clinical acquisition acquired during irregular breathing. Relative values of a validated correlation-based artifact metric (CM) determined the best acquisition method per patient. Each 4D CT was processed by an extended phase sorting approach that optimizes the quantitative artifact metric (CM sorting). The clinical acquisitions were also postprocessed by phase sorting for artifact comparison of our current clinical implementation with the experimental methods. The oversampling acquisition achieved the lowest artifact presence among all acquisitions, achieving a 27% reduction from the current clinical 4D CT implementation (95% confidence interval = 34-20). The rescan method presented a significantly higher artifact presence from the clinical acquisition (37%; p < 0.002), the gating acquisition (26%; p < 0.005), and the oversampling acquisition (31%; p < 0.001), while the data lacked evidence of a significant difference between the clinical, gating, and oversampling methods. The oversampling acquisition reduced artifact presence from the current clinical 4D CT implementation to the largest degree and provided the simplest and most reproducible implementation. The rescan acquisition increased artifact presence significantly, compared to all acquisitions, and suffered from combination of data from independent scans over which large internal anatomic shifts occurred.

  3. 4D optimization of scanned ion beam tracking therapy for moving tumors

    NASA Astrophysics Data System (ADS)

    Eley, John Gordon; Newhauser, Wayne David; Lüchtenborg, Robert; Graeff, Christian; Bert, Christoph

    2014-07-01

    Motion mitigation strategies are needed to fully realize the theoretical advantages of scanned ion beam therapy for patients with moving tumors. The purpose of this study was to determine whether a new four-dimensional (4D) optimization approach for scanned-ion-beam tracking could reduce dose to avoidance volumes near a moving target while maintaining target dose coverage, compared to an existing 3D-optimized beam tracking approach. We tested these approaches computationally using a simple 4D geometrical phantom and a complex anatomic phantom, that is, a 4D computed tomogram of the thorax of a lung cancer patient. We also validated our findings using measurements of carbon-ion beams with a motorized film phantom. Relative to 3D-optimized beam tracking, 4D-optimized beam tracking reduced the maximum predicted dose to avoidance volumes by 53% in the simple phantom and by 13% in the thorax phantom. 4D-optimized beam tracking provided similar target dose homogeneity in the simple phantom (standard deviation of target dose was 0.4% versus 0.3%) and dramatically superior homogeneity in the thorax phantom (D5-D95 was 1.9% versus 38.7%). Measurements demonstrated that delivery of 4D-optimized beam tracking was technically feasible and confirmed a 42% decrease in maximum film exposure in the avoidance region compared with 3D-optimized beam tracking. In conclusion, we found that 4D-optimized beam tracking can reduce the maximum dose to avoidance volumes near a moving target while maintaining target dose coverage, compared with 3D-optimized beam tracking.

  4. Resolution enhancement of lung 4D-CT data using multiscale interphase iterative nonlocal means

    SciTech Connect

    Zhang Yu; Yap, Pew-Thian; Wu Guorong; Feng Qianjin; Chen Wufan; Lian Jun; Shen Dinggang

    2013-05-15

    Purpose: Four-dimensional computer tomography (4D-CT) has been widely used in lung cancer radiotherapy due to its capability in providing important tumor motion information. However, the prolonged scanning duration required by 4D-CT causes considerable increase in radiation dose. To minimize the radiation-related health risk, radiation dose is often reduced at the expense of interslice spatial resolution. However, inadequate resolution in 4D-CT causes artifacts and increases uncertainty in tumor localization, which eventually results in extra damages of healthy tissues during radiotherapy. In this paper, the authors propose a novel postprocessing algorithm to enhance the resolution of lung 4D-CT data. Methods: The authors' premise is that anatomical information missing in one phase can be recovered from the complementary information embedded in other phases. The authors employ a patch-based mechanism to propagate information across phases for the reconstruction of intermediate slices in the longitudinal direction, where resolution is normally the lowest. Specifically, the structurally matching and spatially nearby patches are combined for reconstruction of each patch. For greater sensitivity to anatomical details, the authors employ a quad-tree technique to adaptively partition the image for more fine-grained refinement. The authors further devise an iterative strategy for significant enhancement of anatomical details. Results: The authors evaluated their algorithm using a publicly available lung data that consist of 10 4D-CT cases. The authors' algorithm gives very promising results with significantly enhanced image structures and much less artifacts. Quantitative analysis shows that the authors' algorithm increases peak signal-to-noise ratio by 3-4 dB and the structural similarity index by 3%-5% when compared with the standard interpolation-based algorithms. Conclusions: The authors have developed a new algorithm to improve the resolution of 4D-CT. It outperforms

  5. The Use of Gated and 4D CT Imaging in Planning for Stereotactic Body Radiation Therapy

    SciTech Connect

    D'Souza, Warren D. . E-mail: wdsou001@umaryland.edu; Nazareth, Daryl P.; Zhang Bin; Deyoung, Chad; Suntharalingam, Mohan; Kwok, Young; Yu, Cedric X.; Regine, William F.

    2007-07-01

    The localization of treatment targets is of utmost importance for patients receiving stereotactic body radiation therapy (SBRT), where the dose per fraction is large. While both setup or respiration-induced motion components affect the localization of the treatment volume, the purpose of this work is to describe our management of the intrafraction localization uncertainty induced by normal respiration. At our institution, we have implemented gated computed tomography (CT) acquisition with an active breathing control system (ABC), and 4-dimensional (4D) CT using a skin-based marker and retrospective respiration phase-based image sorting. During gated simulation, 3D CT images were acquired corresponding to end-inhalation and end-exhalation. For 4D CT imaging, 3D CT images were acquired corresponding to 8 phases of the respiratory cycle. In addition to gated or 4D CT images, we acquired a conventional free-breathing CT (FB). For both gated and 4D CT images, the target contours were registered to the FB scan in the planning system. These contours were then combined in the FB image set to form the internal target volume (ITV). Dynamic conformal arc treatment plans were generated for the ITV using the FB scan and the gated or 4D scans with an additional 7-mm margin for patient setup uncertainty. We have described our results for a pancreas and a lung tumor case. Plans were normalized so that the PTV received 95% of the prescription dose. The dose distribution for all the critical structures in the pancreas and lung tumor cases resulted in increased sparing when the ITV was defined using gated or 4D CT images than when the FB scan was used. Our results show that patient-specific target definition using gated or 4D CT scans lead to improved normal tissue sparing.

  6. Isolation and 2,4-D-degrading characteristics of Cupriavidus campinensis BJ71

    PubMed Central

    Han, Lizhen; Zhao, Degang; Li, Cuicui

    2015-01-01

    An indigenous bacterial strain capable of utilizing 2,4-dichlorophenoxyacetic acid as the sole carbon and energy source was isolated from a soil used for grown wheat with a long-term history of herbicide use in Beijing, China. The strain BJ71 was identified as Cupriavidus campinensis based on its 16S rRNA sequence analysis and morphological, physiological, and biochemical characteristics. The degradation characteristics of strain BJ71 were evaluated. The optimal conditions for 2,4-D degradation were as follows: pH 7.0, 30 °C, 3% (v/v) inoculum size, and an initial 2,4-D concentration of 350 mg L−1. Up to 99.57% of the 2,4-D was degraded under optimal conditions after 6 days of incubation. Strain BJ71 was also able to degrade quizalofop and fluroxypyr. This is the first report of a 2,4-D-degrader containing tfdA gene that can utilize these two herbicides. In a biodegradation experiment, 87.13% and 42.53% of 2,4-D (initial concentration, 350 mg kg−1) was degraded in non-sterile and sterilized soil inoculated with BJ71, respectively, after 14 days. The 2,4-D degradation was more rapid in a soil microcosm including BJ71 than in a soil microcosm without BJ71. These results indicate that strain BJ71 is a potential candidate for the bioremediation of soil contaminated with the herbicide 2,4-D. PMID:26273258

  7. Cloning and expression of the 4D8 gene from Hyalomma asiaticum tick.

    PubMed

    Liu, Z Q; Xia, J; Wang, G L; Kuermanali, N

    2016-01-01

    Hyalomma asiaticum tick, an important ectozoic parasite causes tickle, pain, anemia, weight loss, and paralysis in its hosts, which include humans, cattle, sheep, horses, camels, and hares. The 4D8 gene can be a potential vaccine candidate antigen for H. asiaticum. In the present study, we cloned and expressed the 4D8 gene of H. asiaticum from Xinjiang Province. Primers were designed according to the H. asiaticum tick 4D8 gene sequence available in GenBank. The gene was amplified by reverse transcription-polymerase chain reaction and the fragments were subcloned into the prokaryotic expression vector pET30a and the recombinant vector pET30a-4D8 was constructed. The expressed recombinant protein was purified and its biological activity was investigated by western blot. Results revealed that the recombinant protein was a biologically active fusion protein with a molecular weight of 20 kDa. The purified 4D8 protein would provide a strong foundation for further studies on this protein. PMID:27323189

  8. 4D cone-beam CT reconstruction using multi-organ meshes for sliding motion modeling.

    PubMed

    Zhong, Zichun; Gu, Xuejun; Mao, Weihua; Wang, Jing

    2016-02-01

    A simultaneous motion estimation and image reconstruction (SMEIR) strategy was proposed for 4D cone-beam CT (4D-CBCT) reconstruction and showed excellent results in both phantom and lung cancer patient studies. In the original SMEIR algorithm, the deformation vector field (DVF) was defined on voxel grid and estimated by enforcing a global smoothness regularization term on the motion fields. The objective of this work is to improve the computation efficiency and motion estimation accuracy of SMEIR for 4D-CBCT through developing a multi-organ meshing model. Feature-based adaptive meshes were generated to reduce the number of unknowns in the DVF estimation and accurately capture the organ shapes and motion. Additionally, the discontinuity in the motion fields between different organs during respiration was explicitly considered in the multi-organ mesh model. This will help with the accurate visualization and motion estimation of the tumor on the organ boundaries in 4D-CBCT. To further improve the computational efficiency, a GPU-based parallel implementation was designed. The performance of the proposed algorithm was evaluated on a synthetic sliding motion phantom, a 4D NCAT phantom, and four lung cancer patients. The proposed multi-organ mesh based strategy outperformed the conventional Feldkamp-Davis-Kress, iterative total variation minimization, original SMEIR and single meshing method based on both qualitative and quantitative evaluations.

  9. Improvement of the cine-CT based 4D-CT imaging

    SciTech Connect

    Pan Tinsu; Sun Xiaojun; Luo Dershan

    2007-11-15

    An improved 4D-CT utility has been developed on the GE LightSpeed multislice CT (MSCT) and Discovery PET/CT scanners, which have the cine CT scan capability. Two new features have been added in this 4D-CT over the commercial Advantage 4D-CT from GE. One feature was a new tool for disabling parts of the respiratory signal with irregular respiration and improving the accuracy of phase determination for the respiratory signal from the Varian real-time positioning and monitoring (RPM) system before sorting of the cine CT images into the 4D-CT images. The second feature was to allow generation of the maximum-intensity-projection (MIP), average (AVG) and minimum-intensity-projection (mip) CT images from the cine CT images without a respiratory signal. The implementation enables the assessment of tumor motion in treatment planning with the MIP, AVG, and mip CT images on the GE MSCT and PET/CT scanners without the RPM and the Advantage 4D-CT with a GE Advantage windows workstation. Several clinical examples are included to illustrate this new application.

  10. Review of 2,4-dichlorophenoxyacetic acid (2,4-D) biomonitoring and epidemiology

    PubMed Central

    Burns, Carol J.; Swaen, Gerard M. H.

    2012-01-01

    A qualitative review of the epidemiological literature on the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) and health after 2001 is presented. In order to compare the exposure of the general population, bystanders and occupational groups, their urinary levels were also reviewed. In the general population, 2,4-D exposure is at or near the level of detection (LOD). Among individuals with indirect exposure, i.e. bystanders, the urinary 2,4-D levels were also very low except in individuals with opportunity for direct contact with the herbicide. Occupational exposure, where exposure was highest, was positively correlated with behaviors related to the mixing, loading and applying process and use of personal protection. Information from biomonitoring studies increases our understanding of the validity of the exposure estimates used in epidemiology studies. The 2,4-D epidemiology literature after 2001 is broad and includes studies of cancer, reproductive toxicity, genotoxicity, and neurotoxicity. In general, a few publications have reported statistically significant associations. However, most lack precision and the results are not replicated in other independent studies. In the context of biomonitoring, the epidemiology data give no convincing or consistent evidence for any chronic adverse effect of 2,4-D in humans. PMID:22876750

  11. Impact of 4D image quality on the accuracy of target definition.

    PubMed

    Nielsen, Tine Bjørn; Hansen, Christian Rønn; Westberg, Jonas; Hansen, Olfred; Brink, Carsten

    2016-03-01

    Delineation accuracy of target shape and position depends on the image quality. This study investigates whether the image quality on standard 4D systems has an influence comparable to the overall delineation uncertainty. A moving lung target was imaged using a dynamic thorax phantom on three different 4D computed tomography (CT) systems and a 4D cone beam CT (CBCT) system using pre-defined clinical scanning protocols. Peak-to-peak motion and target volume were registered using rigid registration and automatic delineation, respectively. A spatial distribution of the imaging uncertainty was calculated as the distance deviation between the imaged target and the true target shape. The measured motions were smaller than actual motions. There were volume differences of the imaged target between respiration phases. Imaging uncertainties of >0.4 cm were measured in the motion direction which showed that there was a large distortion of the imaged target shape. Imaging uncertainties of standard 4D systems are of similar size as typical GTV-CTV expansions (0.5-1 cm) and contribute considerably to the target definition uncertainty. Optimising and validating 4D systems is recommended in order to obtain the most optimal imaged target shape.

  12. Hydrophobic metabolites of 2,4-dichlorophenoxyacetic acid (2,4-D) in cultured coconut tissue.

    PubMed

    López-Villalobos, Arturo; Hornung, Roland; Dodds, Peter F

    2004-10-01

    Cultures of inflorescence and plumular tissues of coconut palm (Cocos nucifera L.) were maintained in the presence of the auxin, [14C]2,4-dichlorophenoxyacetic acid (2,4-D), so that its metabolic fate could be studied. Thin layer chromatography of methanol extracts of the plumular tissue showed that four classes of metabolites, as well as the unchanged acid, were recovered in the extract. In inflorescence tissue, only the unchanged acid and the most polar class of metabolites (metabolite I) were recovered. Metabolite I was shown to consist mostly of a mixture of sugar conjugates and metabolite II (the next most polar) was an unidentified basic metabolite. Metabolites III and IV were both novel triacylglycerol analogues in which one of the natural fatty acids was replaced with a chain-elongated form of 2,4-D. Reversed-phase thin layer chromatography was used to identify the 2,4-D-derived acids and it was found that metabolite III contained the 2,4-dichlorophenoxy-moiety attached to a chain-length of between 2 and 12 carbons, whereas metabolite IV contained 12, 14 and 16 carbon chain lengths. In inflorescence tissue, and in plumular tissue at low sucrose or 2,4-D concentrations and after short periods in culture, metabolite I predominated. The other metabolites increased as a percentage when plumular culture was prolonged or when sucrose or 2,4-D concentrations were raised. These changes correlated with better development of the explant.

  13. Allowing for model error in strong constraint 4D-Var

    NASA Astrophysics Data System (ADS)

    Howes, Katherine; Lawless, Amos; Fowler, Alison

    2016-04-01

    Four dimensional variational data assimilation (4D-Var) can be used to obtain the best estimate of the initial conditions of an environmental forecasting model, namely the analysis. In practice, when the forecasting model contains errors, the analysis from the 4D-Var algorithm will be degraded to allow for errors later in the forecast window. This work focusses on improving the analysis at the initial time by allowing for the fact that the model contains error, within the context of strong constraint 4D-Var. The 4D-Var method developed acknowledges the presence of random error in the model at each time step by replacing the observation error covariance matrix with an error covariance matrix that includes both observation error and model error statistics. It is shown that this new matrix represents the correct error statistics of the innovations in the presence of model error. A method for estimating this matrix using innovation statistics, without requiring prior knowledge of the model error statistics, is presented. The method is demonstrated numerically using a non-linear chaotic system with erroneous parameter values. We show that that the new method works to reduce the analysis error covariance when compared with a standard strong constraint 4D-Var scheme. We discuss the fact that an improved analysis will not necessarily provide a better forecast.

  14. Review of 2,4-dichlorophenoxyacetic acid (2,4-D) biomonitoring and epidemiology.

    PubMed

    Burns, Carol J; Swaen, Gerard M H

    2012-10-01

    A qualitative review of the epidemiological literature on the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) and health after 2001 is presented. In order to compare the exposure of the general population, bystanders and occupational groups, their urinary levels were also reviewed. In the general population, 2,4-D exposure is at or near the level of detection (LOD). Among individuals with indirect exposure, i.e. bystanders, the urinary 2,4-D levels were also very low except in individuals with opportunity for direct contact with the herbicide. Occupational exposure, where exposure was highest, was positively correlated with behaviors related to the mixing, loading and applying process and use of personal protection. Information from biomonitoring studies increases our understanding of the validity of the exposure estimates used in epidemiology studies. The 2,4-D epidemiology literature after 2001 is broad and includes studies of cancer, reproductive toxicity, genotoxicity, and neurotoxicity. In general, a few publications have reported statistically significant associations. However, most lack precision and the results are not replicated in other independent studies. In the context of biomonitoring, the epidemiology data give no convincing or consistent evidence for any chronic adverse effect of 2,4-D in humans.

  15. 4D cone-beam CT reconstruction using multi-organ meshes for sliding motion modeling

    NASA Astrophysics Data System (ADS)

    Zhong, Zichun; Gu, Xuejun; Mao, Weihua; Wang, Jing

    2016-02-01

    A simultaneous motion estimation and image reconstruction (SMEIR) strategy was proposed for 4D cone-beam CT (4D-CBCT) reconstruction and showed excellent results in both phantom and lung cancer patient studies. In the original SMEIR algorithm, the deformation vector field (DVF) was defined on voxel grid and estimated by enforcing a global smoothness regularization term on the motion fields. The objective of this work is to improve the computation efficiency and motion estimation accuracy of SMEIR for 4D-CBCT through developing a multi-organ meshing model. Feature-based adaptive meshes were generated to reduce the number of unknowns in the DVF estimation and accurately capture the organ shapes and motion. Additionally, the discontinuity in the motion fields between different organs during respiration was explicitly considered in the multi-organ mesh model. This will help with the accurate visualization and motion estimation of the tumor on the organ boundaries in 4D-CBCT. To further improve the computational efficiency, a GPU-based parallel implementation was designed. The performance of the proposed algorithm was evaluated on a synthetic sliding motion phantom, a 4D NCAT phantom, and four lung cancer patients. The proposed multi-organ mesh based strategy outperformed the conventional Feldkamp-Davis-Kress, iterative total variation minimization, original SMEIR and single meshing method based on both qualitative and quantitative evaluations.

  16. Hydrophobic metabolites of 2,4-dichlorophenoxyacetic acid (2,4-D) in cultured coconut tissue.

    PubMed

    López-Villalobos, Arturo; Hornung, Roland; Dodds, Peter F

    2004-10-01

    Cultures of inflorescence and plumular tissues of coconut palm (Cocos nucifera L.) were maintained in the presence of the auxin, [14C]2,4-dichlorophenoxyacetic acid (2,4-D), so that its metabolic fate could be studied. Thin layer chromatography of methanol extracts of the plumular tissue showed that four classes of metabolites, as well as the unchanged acid, were recovered in the extract. In inflorescence tissue, only the unchanged acid and the most polar class of metabolites (metabolite I) were recovered. Metabolite I was shown to consist mostly of a mixture of sugar conjugates and metabolite II (the next most polar) was an unidentified basic metabolite. Metabolites III and IV were both novel triacylglycerol analogues in which one of the natural fatty acids was replaced with a chain-elongated form of 2,4-D. Reversed-phase thin layer chromatography was used to identify the 2,4-D-derived acids and it was found that metabolite III contained the 2,4-dichlorophenoxy-moiety attached to a chain-length of between 2 and 12 carbons, whereas metabolite IV contained 12, 14 and 16 carbon chain lengths. In inflorescence tissue, and in plumular tissue at low sucrose or 2,4-D concentrations and after short periods in culture, metabolite I predominated. The other metabolites increased as a percentage when plumular culture was prolonged or when sucrose or 2,4-D concentrations were raised. These changes correlated with better development of the explant. PMID:15474562

  17. Investigation of the accumulation of 2,4-dichlorophenoxyacetic acid (2,4-D) in rat kidneys.

    PubMed

    Aydin, Handan; Ozdemir, Nurullah; Uzunören, Nuray

    2005-10-01

    The accumulation of 2,4-dichlorophenoxyacetic acid (2,4-D) and its metabolite 2,4-dichlorophenol (2,4-DCP) in the kidneys of rats was investigated. Male and female Sprague-Dawley rats were given 2,4-D in drinking water and food for 30 days. Group A (control group) was fed a normal diet, Group B was fed 50 ppm 2,4-D in 15 g food, Group C received 100 ppm 2,4-D in 15 g food, Group D received 25 ppm 2,4-D in 15 ml drinking water and Group E was given 50 ppm 2,4-D in 15 ml of drinking water. Levels of 2,4-D and 2,4-DCP in kidneys were determined using high performance liquid chromatography (HPLC). It was observed that at low doses of 2,4-D, the metabolite, 2,4-DCP found in the kidneys.

  18. Metabolic status, gonadotropin secretion, and ovarian function during acute nutrient restriction of beef heifers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The effect of acute nutritional restriction on metabolic status, gonadotropin secretion, and ovarian function of heifers was determined in 2 experiments. In Exp. 1, 14-mo-old heifers were fed a diet supplying 1.2 × maintenance energy requirements (1.2M). After 10 d, heifers were fed 1.2M or were res...

  19. Gonadotropin and estrogen responses in freshwater turtle (Chrysemys picta) from Cape Cod, Massachusetts.

    PubMed

    Kitana, Noppadon; Khonsue, Wichase; Won, Seung Jae; Lance, Valentine A; Callard, Ian P

    2006-10-01

    As a result of chemical waste disposal on the Massachusetts Military Reservation, a Superfund site on Cape Cod, MA, contaminated groundwater plumes have formed. These plumes are of concern due to the widespread use of groundwater wells as a drinking water source by the local population. Prior observations on a sentinel species Chrysemys picta field-trapped from ponds on Cape Cod suggested deficits in reproductive processes including lower levels of vitellogenin, estradiol-17beta, oviduct weights, and oocyte numbers in females and lower testicular weight and sperm count in males. Possible loci in the hypothalamic-pituitary-gonadal-liver axis at which xenobiotics may act were determined in turtles trapped from Moody Pond (a test site) and Washburn Pond (a reference site). Specifically, gonadotropin and estrogen responses were assessed using plasma steroids and vitellogenin as markers. Basal vitellogenin levels were significantly lower in Moody Pond females; however, vitellogenin responses to estradiol-17beta were the same in both groups, indicating a normal hepatic response to estrogen. In contrast, estradiol-17beta secretion was not stimulated by gonadotropin in Moody Pond females, compared to Washburn animals. Basal plasma testosterone and the response to gonadotropin in males were similar, although steroid levels in Moody Pond animals were slower to return to baseline after gonadotropin injection. The results suggest that a low-level mixture of xenobiotic contaminants may interfere with the steroid metabolic pathways in turtles exposed to the test site, but not the reference site, environment.

  20. Rapid enlargement of an intracranial germ cell tumor after gonadotropin hormone therapy.

    PubMed

    Sasagawa, Yasuo; Tachibana, Osamu; Nakagawa, Athushi; Nakada, Satoko; Nojima, Takayuki; Koya, Daisuke; Iizuka, Hideaki

    2016-09-01

    We report a case of an intracranial germ cell tumor (iGCT) that showed rapid enlargement after human chorionic gonadotropin (hCG) hormone therapy for pituitary hypogonadism. A 16-year-old boy presented with headache and was diagnosed with a suprasellar tumor. He was initially observed without surgery. Intranasal desmopressin therapy was started for central diabetes insipidus, but there was no change in the tumor size on MRI. The diagnosis of the tumor remained unknown for 4years. Levels of serum gonadotropin hormones (follicle-stimulating and luteinizing hormone) and testosterone progressively decreased, and the patient developed pituitary hypogonadism and complained about his undeveloped beard, lack of underarm hair, and erectile dysfunction. Intramuscular gonadotropin injection (hCG 5000U×2/week) was started at age 20. Eight months after the first gonadotropin injection, the MRI showed tumor growth with vivid enhancement. Craniotomy was performed and the tumor was partially resected. The histological diagnosis was immature teratoma. After surgery, the patient was treated with 5 cycles of chemotherapy with carboplatin and etoposide. He also received radiation therapy of 50Gy (20Gy tumor bed and 30Gy whole ventricles) to the residual tumor, after which the tumor decreased in size. We postulate that iGCT may be at risk of progression during hCG hormone therapy. Thus, careful monitoring is required for a patient with iGCT who receives this therapy.

  1. A review of luteinising hormone and human chorionic gonadotropin when used in assisted reproductive technology.

    PubMed

    Ezcurra, Diego; Humaidan, Peter

    2014-01-01

    Gonadotropins extracted from the urine of post-menopausal women have traditionally been used to stimulate folliculogenesis in the treatment of infertility and in assisted reproductive technology (ART). Products, such as human menopausal gonadotropin (hMG), consist not only of a mixture of the hormones, follicle-stimulating hormone (FSH), luteinising hormone (LH) and human chorionic gonadotropin (hCG), but also other biologically active contaminants, such as growth factors, binding proteins and prion proteins. The actual amount of molecular LH in hMG preparations varies considerably due to the purification process, thus hCG, mimicking LH action, is added to standardise the product. However, unlike LH, hCG plays a different role during the natural human menstrual cycle. It is secreted by the embryo and placenta, and its main role is to support implantation and pregnancy. More recently, recombinant gonadotropins (r-hFSH and r-hLH) have become available for ART therapies. Recombinant LH contains only LH molecules. In the field of reproduction there has been controversy in recent years over whether r-hLH or hCG should be used for ART. This review examines the existing evidence for molecular and functional differences between LH and hCG and assesses the clinical implications of hCG-supplemented urinary therapy compared with recombinant therapies used for ART. PMID:25280580

  2. Neutralization of gonadotropin-releasing hormone in neonatal rats with permanent impairment of the hypothalamic-pituitary-testicular axis.

    PubMed

    Bercu, B B

    1982-05-01

    Males rats were passively immunized at 5 days of age with a single 0.25 ml i.p. injection of gonadotropin-releasing hormone (GnRH) antiserum. Control animals were given an equal volume of normal rabbit serum (NRS). Serial blood determinations of gonadotropins, testosterone and dihydrotestosterone (DHT) were obtained at intervals ranging from early in life through adult life. Gonadotropin secretion was reduced (P less than 0.025) up to 35 days of age. Androgen secretion (testosterone) was reduced (P less than 0.05) at 10 and 33 days of age. When hCG was given to 54-day-old (young adult), and 100-day-old and 15-month-old animals, testosterone concentrations were similar in both experimental and control groups 1 h after hCG stimulation. As adults, basal gonadotropins were the same in both groups; however, after GnRH stimulation, the GnRH antiserum-treated groups showed an increased gonadotropin response when compared to the NRS control group. In order to determine whether there was an alteration in steroid feedback, other animals were castrated at adult age (approximately 100 days old), and exogenous testosterone was given in increasing increments. However, serum gonadotropins decreased similarly in treated and control groups. These data indicate that a single injection of GnRH antiserum early in life decreased gonadotropin secretion temporarily during prepubertal sexual development and caused a permanent alteration in hypothalamic-pituitary-testicular function.

  3. 2D:4D finger ratio positively correlates with total cerebral cortex in males.

    PubMed

    Darnai, Gergely; Plózer, Enikő; Perlaki, Gábor; Orsi, Gergely; Nagy, Szilvia Anett; Horváth, Réka; Schwarcz, Attila; Kovács, Norbert; Altbäcker, Anna; Janszky, József; Clemens, Zsófia

    2016-02-26

    Although there is evidence that the ratio of 2nd-4th digit length (2D:4D) correlates with prenatal testosterone level, psychological and health traits only two studies have assessed the relationship with brain morphological features. Here we investigated the association between the 2D:4D ratio and several brain subvolumes. Seventy-five subjects between the ages of 18 and 30 were included in the study. The length of the 2nd and 4th digits were measured with an electronic vernier caliper while MRI measurements were performed on a Siemens Magnetom Trio Tim (3T) system. Freesurfer software suite was used for volumetric segmentation. Finger ratio significantly positively correlated with total cerebral cortex, total cerebellar white matter and total cerebellar cortex in males but not in females. Our results indicate that prenatal testosterone, as estimated by the 2D:4D ratio has an effect on adult brain morphology in males. PMID:26780566

  4. Proximal femoral focal deficiency of the fetus - early 3D/4D prenatal ultrasound diagnosis.

    PubMed

    Kudla, Marek J; Beczkowska-Kielek, Aleksandra; Kutta, Katarzyna; Partyka-Lasota, Justyna

    2016-09-01

    Proximal Femoral Focal Deficiency (PFFD) is a rare congenital syndrome of unknown etiology. Additional disorders can be present up to 70% of PFFD cases. Management (including termination) depends on the severity of the malformation. We present a case of a 32-year-old woman referred for routine ultrasound examination in the 12th week of pregnancy. Detailed 3D/4D evaluation revealed asymmetry of lower limbs and diagnosis of isolated PFFD was established. Parents were fully informed and decided to continue the pregnancy. We stress here the importance of early 3D/4D ultrasound diagnosis. Our paper presents the earliest case where the diagnosis of PFFD was established with 3D/4D ultrasound. PMID:27622419

  5. Interaction of 2,4-dichlorophenoxyacetic acid (2,4-D) with cell and model membranes.

    PubMed

    Suwalsky, M; Benites, M; Villena, F; Aguilar, F; Sotomayor, C P

    1996-12-01

    2,4-dichlorophenoxyacetic acid (2,4-D), a widely used herbicide, is a component of the "agent orange' whose toxicity has been extensively studied without definite conclusions. In order to evaluate its perturbing effect upon cell membranes, 2,4-D was made to interact with human erythrocytes and molecular models. These studies were performed by scanning electron microscopy on red cells, fluorescence spectroscopy on dimyristoylphosphatidylcholine (DMPC) large unilamellar vesicles and X-ray diffraction on multilayers of DMPC and dimyristoylphosphatidylethanolamine (DMPE). It was observed that 2,4-D induced a pronounced shape change to the erythrocytes. This effect is explained by the herbicide interaction with the outer monolayer of the red cell membrane. PMID:8972711

  6. Synthesis, biological activities and pharmacokinetic properties of new fluorinated derivatives of selective PDE4D inhibitors.

    PubMed

    Brullo, Chiara; Massa, Matteo; Villa, Carla; Ricciarelli, Roberta; Rivera, Daniela; Pronzato, Maria Adelaide; Fedele, Ernesto; Barocelli, Elisabetta; Bertoni, Simona; Flammini, Lisa; Bruno, Olga

    2015-07-01

    A new series of selective PDE4D inhibitors has been designed and synthesized by replacing 3-methoxy group with 3-difluoromethoxy isoster moiety in our previously reported cathecolic structures. All compounds showed a good PDE4D3 inhibitory activity, most of them being inactive toward other PDE4 isoforms (PDE4A4, PDE4B2 and PDE4C2). Compound 3b, chosen among the synthesized compounds as the most promising in terms of inhibitory activity, selectivity and safety, showed an improved pharmacokinetic profile compared to its non fluorinated analogue. Spontaneous locomotor activity, assessed in an open field apparatus, showed that, differently from rolipram and diazepam, selective PDE4D inhibitors, such as compounds 3b, 5b and 7b, did not affect locomotion, whereas compound 1b showed a tendency to reduce the distance traveled and to prolong the immobility period, possibly due to a poor selectivity.

  7. A practical introduction to the hemodynamic analysis of the cardiovascular system with 4D Flow MRI.

    PubMed

    Pineda Zapata, J A; Delgado de Bedout, J A; Rascovsky Ramírez, S; Bustamante, C; Mesa, S; Calvo Betancur, V D

    2014-01-01

    The 4D Flow MRI technique provides a three-dimensional representation of blood flow over time, making it possible to evaluate the hemodynamics of the cardiovascular system both qualitatively and quantitatively. In this article, we describe the application of the 4D Flow technique in a 3T scanner; in addition to the technical parameters, we discuss the advantages and limitations of the technique and its possible clinical applications. We used 4D Flow MRI to study different body areas (chest, abdomen, neck, and head) in 10 volunteers. We obtained 3D representations of the patterns of flow and quantitative hemodynamic measurements. The technique makes it possible to evaluate the pattern of blood flow in large and midsize vessels without the need for exogenous contrast agents.

  8. Uptake of 2,4-D in higher plants from artificial rain.

    PubMed

    Løkke, H

    1984-02-01

    Sinapis alba L., Lapsana communis L., Achillea millefolium L., Brassica napus L., Lactuca sativa L., and Lycopersicum esculentum L. were exposed to 2,4-dichlorophenoxy [2-14C]acetic acid (2,4-D) at 10 micrograms liter-1 in artificial rain, pH 6.5 and 3.3. The 2,4-D was absorbed in all species tested. Concentrations of parent 2,4-D appeared at the highest level in Achillea (0.1 mg kg-1 dry wt), and at zero level in Lycopersicum. Twenty-one daily treatments at pH 6.5 for 30-min periods increased dry-matter concentrations (P less than or equal to 0.05) in the leaves of Achillea and decreased those in Brassica. No change in dry-matter concentration was observed in the leaves of Brassica by seven daily treatments for 30-min periods at pH 3.3.

  9. Uptake of 2,4-D in higher plants from artificial rain

    SciTech Connect

    Lokke, H.

    1984-02-01

    Sinapis alba L., Lapsana communis L., Achillea millefolium L., Brassica napus L., Lactuca sativa L., and Lycopersicum esculentum L. were exposed to 2,4-dichlorophenoxy (2-/sup 14/C)acetic acid (2,4-D) at 10 micrograms liter-1 in artificial rain, pH 6.5 and 3.3. The 2,4-D was absorbed in all species tested. Concentrations of parent 2,4-D appeared at the highest level in Achillea (0.1 mg kg-1 dry wt), and at zero level in Lycopersicum. Twenty-one daily treatments at pH 6.5 for 30-min periods increased dry-matter concentrations in the leaves of Achillea and decreased those in Brassica. No change in dry-matter concentration was observed in the leaves of Brassica by seven daily treatments for 30-min periods at pH 3.3.

  10. Live 4D optical coherence tomography for early embryonic mouse cardiac phenotyping

    NASA Astrophysics Data System (ADS)

    Lopez, Andrew L.; Wang, Shang; Larin, Kirill V.; Overbeek, Paul A.; Larina, Irina V.

    2016-03-01

    Studying embryonic mouse development is important for our understanding of normal human embryogenesis and the underlying causes of congenital defects. Our research focuses on imaging early development in the mouse embryo to specifically understand cardiovascular development using optical coherence tomography (OCT). We have previously developed imaging approaches that combine static embryo culture, OCT imaging and advanced image processing to visualize the whole live mouse embryos and obtain 4D (3D+time) cardiodynamic datasets with cellular resolution. Here, we present the study of using 4D OCT for dynamic imaging of early embryonic heart in live mouse embryos to assess mutant cardiac phenotypes during development, including a cardiac looping defect. Our results indicate that the live 4D OCT imaging approach is an efficient phenotyping tool that can reveal structural and functional cardiac defects at very early stages. Further studies integrating live embryonic cardiodynamic phenotyping with molecular and genetic approaches in mouse mutants will help to elucidate the underlying signaling defects.

  11. Attosecond delay of xenon 4 d photoionization at the giant resonance and Cooper minimum

    NASA Astrophysics Data System (ADS)

    Magrakvelidze, Maia; Madjet, Mohamed El-Amine; Chakraborty, Himadri S.

    2016-07-01

    A Kohn-Sham time-dependent local-density-functional scheme is utilized to predict attosecond time delays of xenon 4 d photoionization that involves the 4 d giant dipole resonance and Cooper minimum. The fundamental effect of electron correlations to uniquely determine the delay at both regions is demonstrated. In particular, for the giant dipole resonance, the delay underpins strong collective effect, emulating the recent prediction at C60 giant plasmon resonance [T. Barillot et al., Phys. Rev. A 91, 033413 (2015), 10.1103/PhysRevA.91.033413]. For the Cooper minimum, a qualitative similarity with a photorecombination experiment near argon 3 p minimum [S. B. Schoun et al., Phys. Rev. Lett. 112, 153001 (2014), 10.1103/PhysRevLett.112.153001] is found. The result should encourage attosecond measurements of Xe 4 d photoemission.

  12. The 2D:4D-Ratio and Neuroticism Revisited: Empirical Evidence from Germany and China

    PubMed Central

    Sindermann, Cornelia; Li, Mei; Sariyska, Rayna; Lachmann, Bernd; Duke, Éilish; Cooper, Andrew; Warneck, Lidia; Montag, Christian

    2016-01-01

    The 2D:4D-Ratio, as an indirect measure of the fetal testosterone to estradiol ratio, is potentially very important for understanding and explaining different personality traits. It was the aim of the present study to replicate the findings from Fink et al. (2004) about the relation between individual differences in 2D:4D-Ratios and the Five Factor Model in different cultural groups. Therefore a sample of n = 78 Chinese and n = 370 German participants was recruited. Every participant provided hand scans of both hands, from which 2D:4D-Ratios were computed. Moreover, all participants filled in the NEO Five Factor Inventory (NEO-FFI). Significant sex differences were found for ratios of both hands in the expected direction, with females showing higher ratios than males. With respect to links between personality and the digit ratio, a positive association was observed between 2D:4D-Ratio and Neuroticism in females, as shown in the earlier study. These findings were observed in both female subsamples from China and Germany, as well as in the full sample of participants. But in contrast to the results for the whole and the German female sample, where 2D:4D-Ratio of both hands were related to Neuroticism, in the Chinese female sample only left hand 2D:4D-Ratio was significantly and positively related to Neuroticism. There were no significant correlations found in any of the male samples. Thus, prenatal exposure to sex steroids appears to influence the personality factor Neuroticism in females specifically. This finding potentially has implications for mental health, as Neuroticism has been shown to be a risk factor for various forms of psychopathology. PMID:27375513

  13. Respiratory motion correction in 4D-PET by simultaneous motion estimation and image reconstruction (SMEIR).

    PubMed

    Kalantari, Faraz; Li, Tianfang; Jin, Mingwu; Wang, Jing

    2016-08-01

    In conventional 4D positron emission tomography (4D-PET), images from different frames are reconstructed individually and aligned by registration methods. Two issues that arise with this approach are as follows: (1) the reconstruction algorithms do not make full use of projection statistics; and (2) the registration between noisy images can result in poor alignment. In this study, we investigated the use of simultaneous motion estimation and image reconstruction (SMEIR) methods for motion estimation/correction in 4D-PET. A modified ordered-subset expectation maximization algorithm coupled with total variation minimization (OSEM-TV) was used to obtain a primary motion-compensated PET (pmc-PET) from all projection data, using Demons derived deformation vector fields (DVFs) as initial motion vectors. A motion model update was performed to obtain an optimal set of DVFs in the pmc-PET and other phases, by matching the forward projection of the deformed pmc-PET with measured projections from other phases. The OSEM-TV image reconstruction was repeated using updated DVFs, and new DVFs were estimated based on updated images. A 4D-XCAT phantom with typical FDG biodistribution was generated to evaluate the performance of the SMEIR algorithm in lung and liver tumors with different contrasts and different diameters (10-40 mm). The image quality of the 4D-PET was greatly improved by the SMEIR algorithm. When all projections were used to reconstruct 3D-PET without motion compensation, motion blurring artifacts were present, leading up to 150% tumor size overestimation and significant quantitative errors, including 50% underestimation of tumor contrast and 59% underestimation of tumor uptake. Errors were reduced to less than 10% in most images by using the SMEIR algorithm, showing its potential in motion estimation/correction in 4D-PET. PMID:27385378

  14. The 2D:4D-Ratio and Neuroticism Revisited: Empirical Evidence from Germany and China.

    PubMed

    Sindermann, Cornelia; Li, Mei; Sariyska, Rayna; Lachmann, Bernd; Duke, Éilish; Cooper, Andrew; Warneck, Lidia; Montag, Christian

    2016-01-01

    The 2D:4D-Ratio, as an indirect measure of the fetal testosterone to estradiol ratio, is potentially very important for understanding and explaining different personality traits. It was the aim of the present study to replicate the findings from Fink et al. (2004) about the relation between individual differences in 2D:4D-Ratios and the Five Factor Model in different cultural groups. Therefore a sample of n = 78 Chinese and n = 370 German participants was recruited. Every participant provided hand scans of both hands, from which 2D:4D-Ratios were computed. Moreover, all participants filled in the NEO Five Factor Inventory (NEO-FFI). Significant sex differences were found for ratios of both hands in the expected direction, with females showing higher ratios than males. With respect to links between personality and the digit ratio, a positive association was observed between 2D:4D-Ratio and Neuroticism in females, as shown in the earlier study. These findings were observed in both female subsamples from China and Germany, as well as in the full sample of participants. But in contrast to the results for the whole and the German female sample, where 2D:4D-Ratio of both hands were related to Neuroticism, in the Chinese female sample only left hand 2D:4D-Ratio was significantly and positively related to Neuroticism. There were no significant correlations found in any of the male samples. Thus, prenatal exposure to sex steroids appears to influence the personality factor Neuroticism in females specifically. This finding potentially has implications for mental health, as Neuroticism has been shown to be a risk factor for various forms of psychopathology. PMID:27375513

  15. Respiratory motion correction in 4D-PET by simultaneous motion estimation and image reconstruction (SMEIR)

    NASA Astrophysics Data System (ADS)

    Kalantari, Faraz; Li, Tianfang; Jin, Mingwu; Wang, Jing

    2016-08-01

    In conventional 4D positron emission tomography (4D-PET), images from different frames are reconstructed individually and aligned by registration methods. Two issues that arise with this approach are as follows: (1) the reconstruction algorithms do not make full use of projection statistics; and (2) the registration between noisy images can result in poor alignment. In this study, we investigated the use of simultaneous motion estimation and image reconstruction (SMEIR) methods for motion estimation/correction in 4D-PET. A modified ordered-subset expectation maximization algorithm coupled with total variation minimization (OSEM-TV) was used to obtain a primary motion-compensated PET (pmc-PET) from all projection data, using Demons derived deformation vector fields (DVFs) as initial motion vectors. A motion model update was performed to obtain an optimal set of DVFs in the pmc-PET and other phases, by matching the forward projection of the deformed pmc-PET with measured projections from other phases. The OSEM-TV image reconstruction was repeated using updated DVFs, and new DVFs were estimated based on updated images. A 4D-XCAT phantom with typical FDG biodistribution was generated to evaluate the performance of the SMEIR algorithm in lung and liver tumors with different contrasts and different diameters (10-40 mm). The image quality of the 4D-PET was greatly improved by the SMEIR algorithm. When all projections were used to reconstruct 3D-PET without motion compensation, motion blurring artifacts were present, leading up to 150% tumor size overestimation and significant quantitative errors, including 50% underestimation of tumor contrast and 59% underestimation of tumor uptake. Errors were reduced to less than 10% in most images by using the SMEIR algorithm, showing its potential in motion estimation/correction in 4D-PET.

  16. The 2D:4D-Ratio and Neuroticism Revisited: Empirical Evidence from Germany and China.

    PubMed

    Sindermann, Cornelia; Li, Mei; Sariyska, Rayna; Lachmann, Bernd; Duke, Éilish; Cooper, Andrew; Warneck, Lidia; Montag, Christian

    2016-01-01

    The 2D:4D-Ratio, as an indirect measure of the fetal testosterone to estradiol ratio, is potentially very important for understanding and explaining different personality traits. It was the aim of the present study to replicate the findings from Fink et al. (2004) about the relation between individual differences in 2D:4D-Ratios and the Five Factor Model in different cultural groups. Therefore a sample of n = 78 Chinese and n = 370 German participants was recruited. Every participant provided hand scans of both hands, from which 2D:4D-Ratios were computed. Moreover, all participants filled in the NEO Five Factor Inventory (NEO-FFI). Significant sex differences were found for ratios of both hands in the expected direction, with females showing higher ratios than males. With respect to links between personality and the digit ratio, a positive association was observed between 2D:4D-Ratio and Neuroticism in females, as shown in the earlier study. These findings were observed in both female subsamples from China and Germany, as well as in the full sample of participants. But in contrast to the results for the whole and the German female sample, where 2D:4D-Ratio of both hands were related to Neuroticism, in the Chinese female sample only left hand 2D:4D-Ratio was significantly and positively related to Neuroticism. There were no significant correlations found in any of the male samples. Thus, prenatal exposure to sex steroids appears to influence the personality factor Neuroticism in females specifically. This finding potentially has implications for mental health, as Neuroticism has been shown to be a risk factor for various forms of psychopathology.

  17. Advances in 4D Treatment Planning for Scanned Particle Beam Therapy — Report of Dedicated Workshops

    PubMed Central

    Bert, Christoph; Graeff, Christian; Riboldi, Marco; Nill, Simeon; Baroni, Guido; Knopf, Antje-Christin

    2014-01-01

    We report on recent progress in the field of mobile tumor treatment with scanned particle beams, as discussed in the latest editions of the 4D treatment planning workshop. The workshop series started in 2009, with about 20 people from 4 research institutes involved, all actively working on particle therapy delivery and development. The first workshop resulted in a summary of recommendations for the treatment of mobile targets, along with a list of requirements to apply these guidelines clinically. The increased interest in the treatment of mobile tumors led to a continuously growing number of attendees: the 2012 edition counted more than 60 participants from 20 institutions and commercial vendors. The focus of research discussions among workshop participants progressively moved from 4D treatment planning to complete 4D treatments, aiming at effective and safe treatment delivery. Current research perspectives on 4D treatments include all critical aspects of time resolved delivery, such as in-room imaging, motion detection, beam application, and quality assurance techniques. This was motivated by the start of first clinical treatments of hepato cellular tumors with a scanned particle beam, relying on gating or abdominal compression for motion mitigation. Up to date research activities emphasize significant efforts in investigating advanced motion mitigation techniques, with a specific interest in the development of dedicated tools for experimental validation. Potential improvements will be made possible in the near future through 4D optimized treatment plans that require upgrades of the currently established therapy control systems for time resolved delivery. But since also these novel optimization techniques rely on the validity of the 4DCT, research focusing on alternative 4D imaging technique, such as MRI based 4DCT generation will continue. PMID:24354749

  18. Respiratory motion correction in 4D-PET by simultaneous motion estimation and image reconstruction (SMEIR).

    PubMed

    Kalantari, Faraz; Li, Tianfang; Jin, Mingwu; Wang, Jing

    2016-08-01

    In conventional 4D positron emission tomography (4D-PET), images from different frames are reconstructed individually and aligned by registration methods. Two issues that arise with this approach are as follows: (1) the reconstruction algorithms do not make full use of projection statistics; and (2) the registration between noisy images can result in poor alignment. In this study, we investigated the use of simultaneous motion estimation and image reconstruction (SMEIR) methods for motion estimation/correction in 4D-PET. A modified ordered-subset expectation maximization algorithm coupled with total variation minimization (OSEM-TV) was used to obtain a primary motion-compensated PET (pmc-PET) from all projection data, using Demons derived deformation vector fields (DVFs) as initial motion vectors. A motion model update was performed to obtain an optimal set of DVFs in the pmc-PET and other phases, by matching the forward projection of the deformed pmc-PET with measured projections from other phases. The OSEM-TV image reconstruction was repeated using updated DVFs, and new DVFs were estimated based on updated images. A 4D-XCAT phantom with typical FDG biodistribution was generated to evaluate the performance of the SMEIR algorithm in lung and liver tumors with different contrasts and different diameters (10-40 mm). The image quality of the 4D-PET was greatly improved by the SMEIR algorithm. When all projections were used to reconstruct 3D-PET without motion compensation, motion blurring artifacts were present, leading up to 150% tumor size overestimation and significant quantitative errors, including 50% underestimation of tumor contrast and 59% underestimation of tumor uptake. Errors were reduced to less than 10% in most images by using the SMEIR algorithm, showing its potential in motion estimation/correction in 4D-PET.

  19. Respiratory motion correction in 4D-PET by simultaneous motion estimation and image reconstruction (SMEIR)

    NASA Astrophysics Data System (ADS)

    Kalantari, Faraz; Li, Tianfang; Jin, Mingwu; Wang, Jing

    2016-08-01

    In conventional 4D positron emission tomography (4D-PET), images from different frames are reconstructed individually and aligned by registration methods. Two issues that arise with this approach are as follows: (1) the reconstruction algorithms do not make full use of projection statistics; and (2) the registration between noisy images can result in poor alignment. In this study, we investigated the use of simultaneous motion estimation and image reconstruction (SMEIR) methods for motion estimation/correction in 4D-PET. A modified ordered-subset expectation maximization algorithm coupled with total variation minimization (OSEM-TV) was used to obtain a primary motion-compensated PET (pmc-PET) from all projection data, using Demons derived deformation vector fields (DVFs) as initial motion vectors. A motion model update was performed to obtain an optimal set of DVFs in the pmc-PET and other phases, by matching the forward projection of the deformed pmc-PET with measured projections from other phases. The OSEM-TV image reconstruction was repeated using updated DVFs, and new DVFs were estimated based on updated images. A 4D-XCAT phantom with typical FDG biodistribution was generated to evaluate the performance of the SMEIR algorithm in lung and liver tumors with different contrasts and different diameters (10–40 mm). The image quality of the 4D-PET was greatly improved by the SMEIR algorithm. When all projections were used to reconstruct 3D-PET without motion compensation, motion blurring artifacts were present, leading up to 150% tumor size overestimation and significant quantitative errors, including 50% underestimation of tumor contrast and 59% underestimation of tumor uptake. Errors were reduced to less than 10% in most images by using the SMEIR algorithm, showing its potential in motion estimation/correction in 4D-PET.

  20. The hypoxia-inducible factor-responsive proteins semaphorin 4D and vascular endothelial growth factor promote tumor growth and angiogenesis in oral squamous cell carcinoma

    SciTech Connect

    Zhou, Hua; Yang, Ying-Hua; Binmadi, Nada O.; Proia, Patrizia; Basile, John R.

    2012-08-15

    Growth and metastasis of solid tumors requires induction of angiogenesis to ensure the delivery of oxygen, nutrients and growth factors to rapidly dividing transformed cells. Through either mutations, hypoxia generated by cytoreductive therapies, or when a malignancy outgrows its blood supply, tumor cells undergo a change from an avascular to a neovascular phenotype, a transition mediated by the hypoxia-inducible factor (HIF) family of transcriptional regulators. Vascular endothelial growth factor (VEGF) is one example of a gene whose transcription is stimulated by HIF. VEGF plays a crucial role in promoting tumor growth and survival by stimulating new blood vessel growth in response to such stresses as chemotherapy or radiotherapy-induced hypoxia, and it therefore has become a tempting target for neutralizing antibodies in the treatment of advanced neoplasms. Emerging evidence has shown that the semaphorins, proteins originally associated with control of axonal growth and immunity, are regulated by changes in oxygen tension as well and may play a role in tumor-induced angiogenesis. Through the use of RNA interference, in vitro and in vivo angiogenesis assays and tumor xenograft experiments, we demonstrate that expression of semaphorin 4D (SEMA4D), which is under the control of the HIF-family of transcription factors, cooperates with VEGF to promote tumor growth and vascularity in oral squamous cell carcinoma (OSCC). We use blocking antibodies to show that targeting SEMA4D function along with VEGF could represent a novel anti-angiogenic therapeutic strategy for the treatment of OSCC and other solid tumors. -- Highlights: Black-Right-Pointing-Pointer Similar to VEGF, SEMA4D promotes angiogenesis in vitro and in vivo. Black-Right-Pointing-Pointer Both VEGF and SEMA4D are produced by OSCC cells in a HIF-dependent manner. Black-Right-Pointing-Pointer These factors combine to elicit a robust pro-angiogenic phenotype in OSCC. Black-Right-Pointing-Pointer Anti-SEMA4D

  1. Gonadotropin ratio affects the in vitro growth of rhesus ovarian preantral follicles.

    PubMed

    Kim, Yoon Young; Yun, Jun-Won; Kim, Jong Min; Park, Chung Gyu; Rosenwaks, Zev; Liu, Hung Ching; Kang, Byeong-Cheol; Ku, Seung-Yup

    2016-04-01

    In vitro follicle growth (IVFG) strategy is critical in the fertility preservation of cancer survivors; however, its optimal protocol needs to be developed using primate models since the availability of human samples is limited. Only a few previous studies have reported the successful IVFG of rhesus monkey ovaries using low-dose follicle-stimulating hormone (FSH) (0.3 or 3 ng/mL) and long-term culture (up to 5 weeks) and it is still uncertain in regard to the optimal culture duration and effective dose of treated gonadotropins applicable to the IVFG of rhesus preantral follicles. Recently, we have reported that the FSH to luteinizing hormone (LH) ratio affects the in vitro growth of murine ovarian follicles. We aimed to investigate whether gonadotropin ratios affect the efficiency of rhesus follicular growth in vitro Ovaries were collected from six necropsied rhesus macaques (4-9 years) and preantral follicles were retrieved and cultured for 14 days using 200 mIU/mL FSH. The characteristics of follicular growth were compared between the FSH:LH=1:1 (n=24) and FSH:LH=2:1 (n=24) groups. High concentration gonadotropin treatment shortened the duration required for in vitro maturation of rhesus preantral follicles. The FSH:LH=2:1 group showed a faster follicular growth and enabled the acquisition of mature oocytes, although the expression of growth differentiation factor (GDF)-9 and anti-Müllerian hormone (AMH) did not differ significantly between the two groups. Taken together, high dose gonadotropin treatment can shorten the duration of IVFG and the gonadotropin ratio is important in the IVFG of rhesus monkey ovaries.

  2. Utility of gonadotropin-releasing hormone agonists in programs of ovarian hyperstimulation with intrauterine insemination.

    PubMed

    Gagliardi, C L

    1993-09-01

    The GnRH agonists have practical and theoretic advantages for adjunctive use in ovulation induction. The IVF cycles demonstrate a decrease in the cancellation rate, an increase in the ease of scheduling, and an increase in the number of oocytes obtained per retrieval when GnRH agonists are employed. Other advantages, such as an improvement in the fertilization and cleavage rate, an increased length of the luteal phase, and an increased pregnancy rate, are suggested but not universally accepted. The utility of adding GnRH agonists to human menopausal gonadotropin-intrauterine insemination cycles is similarly in dispute. Although controlled ovarian hyperstimulation with both human menopausal gonadotropins alone and in conjunction with GnRH agonists have produced pregnancies when coupled with intrauterine insemination, it was demonstrated that there was a significantly greater pregnancy rate per cycle with the use of a GnRH agonist in a recalcitrant infertile population. Others did not substantiate this improvement in pregnancy rate per cycle in their patient population of regularly ovulating women undergoing their first controlled ovarian stimulation cycle either with or without GnRH agonist therapy. This suggests that women with ovulatory dysfunction, and particularly women who previously have not responded to therapy with human menopausal gonadotropin therapy, will reap the most benefits from the addition of a GnRH agonist to their ovulation induction regimen. The addition of a GnRH agonist to controlled ovarian hyperstimulation is a highly effective method of inducing pregnancy in a recalcitrant infertile population. Patients who did not conceive with human menopausal gonadotropins-intrauterine insemination may conceive with GnRH agonist-human menopausal gonadotropins-intrauterine insemination therapy.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8403617

  3. Gonadotropin ratio affects the in vitro growth of rhesus ovarian preantral follicles

    PubMed Central

    Kim, Yoon Young; Yun, Jun-Won; Kim, Jong Min; Park, Chung Gyu; Rosenwaks, Zev; Liu, Hung Ching; Kang, Byeong-Cheol; Ku, Seung-Yup

    2016-01-01

    In vitro follicle growth (IVFG) strategy is critical in the fertility preservation of cancer survivors; however, its optimal protocol needs to be developed using primate models since the availability of human samples is limited. Only a few previous studies have reported the successful IVFG of rhesus monkey ovaries using low-dose follicle-stimulating hormone (FSH) (0.3 or 3 ng/mL) and long-term culture (up to 5 weeks) and it is still uncertain in regard to the optimal culture duration and effective dose of treated gonadotropins applicable to the IVFG of rhesus preantral follicles. Recently, we have reported that the FSH to luteinizing hormone (LH) ratio affects the in vitro growth of murine ovarian follicles. We aimed to investigate whether gonadotropin ratios affect the efficiency of rhesus follicular growth in vitro. Ovaries were collected from six necropsied rhesus macaques (4–9 years) and preantral follicles were retrieved and cultured for 14 days using 200 mIU/mL FSH. The characteristics of follicular growth were compared between the FSH:LH=1:1 (n=24) and FSH:LH=2:1 (n=24) groups. High concentration gonadotropin treatment shortened the duration required for in vitro maturation of rhesus preantral follicles. The FSH:LH=2:1 group showed a faster follicular growth and enabled the acquisition of mature oocytes, although the expression of growth differentiation factor (GDF)-9 and anti-Müllerian hormone (AMH) did not differ significantly between the two groups. Taken together, high dose gonadotropin treatment can shorten the duration of IVFG and the gonadotropin ratio is important in the IVFG of rhesus monkey ovaries. PMID:26980777

  4. Etiology and therapeutic outcomes of children with gonadotropin-independent precocious puberty

    PubMed Central

    Kang, Eungu; Cho, Ja Hyang; Choi, Jin-Ho

    2016-01-01

    Purpose This study was performed to investigate the etiology, clinical features, and outcomes of patients with gonadotropin-independent precocious puberty (GIPP). Methods The study included 16 patients (14 female and 2 male patients) who manifested secondary sexual characteristics, elevated sex hormones, or adrenal androgens with prepubertal luteinizing hormone levels after gonadotropin releasing hormone stimulation diagnosed between May 1994 and December 2015. Patients with congenital adrenal hyperplasia were excluded. Clinical features, laboratory findings, treatment modalities, and outcomes were retrospectively reviewed. Results The median age at diagnosis was 2.6 years (range, 0.7–7.9 years) and median follow-up duration was 4.6 years (range, 1 month–9.8 years). Patients with McCune-Albright syndrome (n=5) and functional ovarian cysts (n=4) presented with vaginal bleeding and elevated estradiol levels (23.3±17.5 pg/mL); adrenocortical tumors (n=4) with premature pubarche and elevated dehydroepiandrosterone sulfate levels (87.2–6,530 µg/dL); and human chorionic gonadotropin (hCG)-producing tumor (n=1) with premature pubarche and elevated β-human chorionic gonadotropin levels (47.4 mIU/mL). Two patients were idiopathic. Six patients transited to gonadotropin-dependent precocious puberty median 3.3 years (range, 0.3–5.1 years) after the onset of GIPP. Initial and follow-up height standard deviation scores (0.99±0.84 vs. 1.10±1.10, P=0.44) and bone age advancement (1.49±1.77 years vs. 2.02±1.95 years, P=0.06) were not significantly different. Conclusion The etiologies of GIPP are heterogeneous, and treatment and prognosis is quite different according to the etiology. Efficacy of treatment with aromatase inhibitors needs to be evaluated after long-term follow-up. PMID:27777905

  5. Four-dimensional (4D) tracking of high-temperature microparticles

    NASA Astrophysics Data System (ADS)

    Wang, Zhehui; Liu, Q.; Waganaar, W.; Fontanese, J.; James, D.; Munsat, T.

    2016-11-01

    High-speed tracking of hot and molten microparticles in motion provides rich information about burning plasmas in magnetic fusion. An exploding-wire apparatus is used to produce moving high-temperature metallic microparticles and to develop four-dimensional (4D) or time-resolved 3D particle tracking techniques. The pinhole camera model and algorithms developed for computer vision are used for scene calibration and 4D reconstructions. 3D positions and velocities are then derived for different microparticles. Velocity resolution approaches 0.1 m/s by using the local constant velocity approximation.

  6. Impact of Petrophysical Experiments on Quantitative Interpretation of 4D Seismic Data at Ketzin, Germany

    NASA Astrophysics Data System (ADS)

    Ivanova, A.; Lueth, S.

    2015-12-01

    Petrophysical investigations for CCS concern relationships between physical properties of rocks and geophysical observations for understanding behavior of injected CO2 in a geological formation. In turn 4D seismic surveying is a proven tool for CO2 monitoring. At the Ketzin pilot site (Germany) 4D seismic data have been acquired by means of a baseline (pre-injection) survey in 2005 and monitor surveys in 2009 and 2012. At Ketzin CO2 was injected in supercritical state from 2008 to 2013 in a sandstone saline aquifer (Stuttgart Formation) at a depth of about 650 m. The 4D seismic data from Ketzin reflected a pronounced effect of this injection. Seismic forward modeling using results of petrophysical experiments on two core samples fromthe target reservoir confirmed that effects of the injected CO2 on the 4D seismic data are significant. The petrophysical data were used in that modeling in order to reflect changes due to the CO2 injection in acoustic parameters of the reservoir. These petrophysical data were further used for a successful quantitative interpretation of the 4D seismic data at Ketzin. Now logs from a well (drilled in 2012) penetrating the reservoir containing information about changes in the acoustic parameters of the reservoir due to the CO2 injection are available. These logs were used to estimate impact of the petrophysical data on the qualitative and quantitative interpretation of the 4D seismic data at Ketzin. New synthetic seismograms were computed using the same software and the same wavelet as the old ones apart from the only difference and namely the changes in the input acoustic parameters would not be affected with any petrophysical experiments anymore. Now these changes were put in computing directly from the logs. In turn the new modelled changes due to the injection in the newly computed seismograms do not include any effects of the petrophysical data anymore. Key steps of the quantitative and qualitative interpretation of the 4D seismic

  7. A hybrid reconstruction algorithm for fast and accurate 4D cone-beam CT imaging

    SciTech Connect

    Yan, Hao; Folkerts, Michael; Jiang, Steve B. E-mail: steve.jiang@UTSouthwestern.edu; Jia, Xun E-mail: steve.jiang@UTSouthwestern.edu; Zhen, Xin; Li, Yongbao; Pan, Tinsu; Cervino, Laura

    2014-07-15

    Purpose: 4D cone beam CT (4D-CBCT) has been utilized in radiation therapy to provide 4D image guidance in lung and upper abdomen area. However, clinical application of 4D-CBCT is currently limited due to the long scan time and low image quality. The purpose of this paper is to develop a new 4D-CBCT reconstruction method that restores volumetric images based on the 1-min scan data acquired with a standard 3D-CBCT protocol. Methods: The model optimizes a deformation vector field that deforms a patient-specific planning CT (p-CT), so that the calculated 4D-CBCT projections match measurements. A forward-backward splitting (FBS) method is invented to solve the optimization problem. It splits the original problem into two well-studied subproblems, i.e., image reconstruction and deformable image registration. By iteratively solving the two subproblems, FBS gradually yields correct deformation information, while maintaining high image quality. The whole workflow is implemented on a graphic-processing-unit to improve efficiency. Comprehensive evaluations have been conducted on a moving phantom and three real patient cases regarding the accuracy and quality of the reconstructed images, as well as the algorithm robustness and efficiency. Results: The proposed algorithm reconstructs 4D-CBCT images from highly under-sampled projection data acquired with 1-min scans. Regarding the anatomical structure location accuracy, 0.204 mm average differences and 0.484 mm maximum difference are found for the phantom case, and the maximum differences of 0.3–0.5 mm for patients 1–3 are observed. As for the image quality, intensity errors below 5 and 20 HU compared to the planning CT are achieved for the phantom and the patient cases, respectively. Signal-noise-ratio values are improved by 12.74 and 5.12 times compared to results from FDK algorithm using the 1-min data and 4-min data, respectively. The computation time of the algorithm on a NVIDIA GTX590 card is 1–1.5 min per phase

  8. Fast X-ray micro-CT for real-time 4D observation

    NASA Astrophysics Data System (ADS)

    Takano, H.; Yoshida, K.; Tsuji, T.; Koyama, T.; Tsusaka, Y.; Kagoshima, Y.

    2009-09-01

    Fast X-ray computed tomography (CT) system with sub-second order measurement for single CT acquisition has been developed. The system, consisting of a high-speed sample rotation stage and a high-speed X-ray camera, is constructed at synchrotron radiation beamline in order to utilize fully intense X-rays. A time-resolving CT movie (i.e. 4D CT) can be available by operating the fast CT system continuously. Real-time observation of water absorbing process of super-absorbent polymer (SAP) has been successfully performed with the 4D CT operation.

  9. No relation between 2D : 4D fetal testosterone marker and dyslexia.

    PubMed

    Boets, Bart; De Smedt, Bert; Wouters, Jan; Lemay, Katrien; Ghesquière, Pol

    2007-09-17

    It has been suggested that high levels of prenatal testosterone exposure are implied in the aetiology of dyslexia and its frequently co-occurring sensory problems. This study examined 2D : 4D digit ratio (a marker of fetal testosterone exposure) in dyslexic and normal reading children. No group differences in 2D : 4D were observed. Digit ratio did not show the postulated relation with reading, spelling, phonological ability, speech perception, auditory processing and visual processing. These findings challenge the validity of theories that allocate a prominent role to fetal testosterone exposure in the aetiology of dyslexia and its sensory impairments. PMID:17712280

  10. Clinical Utility of 4D FDG-PET/CT Scans in Radiation Treatment Planning

    SciTech Connect

    Aristophanous, Michalis; Sher, David J.; Allen, Aaron M.; Larson, Elysia; Chen, Aileen B.

    2012-01-01

    Purpose: The potential role of four-dimensional (4D) positron emission tomography (PET)/computed tomography (CT) in radiation treatment planning, relative to standard three-dimensional (3D) PET/CT, was examined. Methods and Materials: Ten patients with non-small-cell lung cancer had sequential 3D and 4D [{sup 18}F]fluorodeoxyglucose PET/CT scans in the treatment position prior to radiation therapy. The gross tumor volume and involved lymph nodes were contoured on the PET scan by use of three different techniques: manual contouring by an experienced radiation oncologist using a predetermined protocol; a technique with a constant threshold of standardized uptake value (SUV) greater than 2.5; and an automatic segmentation technique. For each technique, the tumor volume was defined on the 3D scan (VOL3D) and on the 4D scan (VOL4D) by combining the volume defined on each of the five breathing phases individually. The range of tumor motion and the location of each lesion were also recorded, and their influence on the differences observed between VOL3D and VOL4D was investigated. Results: We identified and analyzed 22 distinct lesions, including 9 primary tumors and 13 mediastinal lymph nodes. Mean VOL4D was larger than mean VOL3D with all three techniques, and the difference was statistically significant (p < 0.01). The range of tumor motion and the location of the tumor affected the magnitude of the difference. For one case, all three tumor definition techniques identified volume of moderate uptake of approximately 1 mL in the hilar region on the 4D scan (SUV maximum, 3.3) but not on the 3D scan (SUV maximum, 2.3). Conclusions: In comparison to 3D PET, 4D PET may better define the full physiologic extent of moving tumors and improve radiation treatment planning for lung tumors. In addition, reduction of blurring from free-breathing images may reveal additional information regarding regional disease.

  11. CPU-12, a novel synthesized oxazolo[5,4-d]pyrimidine derivative, showed superior anti-angiogenic activity.

    PubMed

    Liu, Jiping; Deng, Ya-Hui; Yang, Ling; Chen, Yijuan; Lawali, Manzo; Sun, Li-Ping; Liu, Yu

    2015-09-01

    Angiogenesis is a crucial requirement for malignant tumor growth, progression and metastasis. Tumor-derived factors stimulate formation of new blood vessels which actively support tumor growth and spread. Various of drugs have been applied to inhibit tumor angiogenesis. CPU-12, 4-chloro-N-(4-((2-(4-methoxyphenyl)-5-methyloxazolo[5,4-d] pyrimidin-7-yl)amino)phenyl)benzamide, is a novel oxazolo[5,4-d]pyrimidine derivative that showed potent activity in inhibiting VEGF-induced angiogenesis in vitro and ex-vivo. In cell toxicity experiments, CPU-12 significantly inhibited the human umbilical vein endothelial cell (HUVEC) proliferation in a dose-dependent manner with a low IC50 value at 9.30 ± 1.24 μM. In vitro, CPU-12 remarkably inhibited HUVEC's migration, chemotactic invasion and capillary-like tube formation in a dose-dependent manner. In ex-vivo, CPU-12 effectively inhibited new microvessels sprouting from the rat aortic ring. In addition, the downstream signalings of vascular endothelial growth factor receptor-2 (VEGFR-2), including the phosphorylation of PI3K, ERK1/2 and p38 MAPK, were effectively down-regulated by CPU-12. These evidences suggested that angiogenic response via the induction of VEGFR through distinct signal transduction pathways regulating proliferation, migration and tube formation of endothelial cells was significantly inhibited by the novel small molecule compound CPU-12 in vitro and ex-vivo. In conclusion, CPU-12 showed superior anti-angiogenic activity in vitro.

  12. Identification and localization of gonadotropin-inhibitory hormone (GnIH) orthologs in the hypothalamus of the red-eared slider turtle, Trachemys scripta elegans.

    PubMed

    Ukena, Kazuyoshi; Iwakoshi-Ukena, Eiko; Osugi, Tomohiro; Tsutsui, Kazuyoshi

    2016-02-01

    Gonadotropin-inhibitory hormone (GnIH) was discovered in 2000 as a novel hypothalamic neuropeptide that inhibited gonadotropin release in the Japanese quail. GnIH and its orthologs have a common C-terminal LPXRFamide (X=L or Q) motif, and have been identified in vertebrates from agnathans to humans, apart from reptiles. In the present study, we characterized a cDNA encoding GnIH orthologs in the brain of the red-eared slider turtle. The deduced precursor protein consisted of 205 amino-acid residues, encoding three putative peptide sequences that included the LPXRFamide motif at their C-termini. In addition, the precursor sequence was most similar to those of avian species. Immunoaffinity purification combined with mass spectrometry confirmed that three mature peptides were produced in the brain. In situ hybridization and immunohistochemistry showed that turtle GnIH-containing cells were restricted to the periventricular hypothalamic nucleus. Immunoreactive fibers were densely distributed in the median eminence. Thus, GnIH and related peptides may act on the pituitary to regulate pituitary hormone release in turtles as well as other vertebrates.

  13. WE-G-BRF-09: Force- and Image-Adaptive Strategies for Robotised Placement of 4D Ultrasound Probes

    SciTech Connect

    Kuhlemann, I; Bruder, R; Ernst, F; Schweikard, A

    2014-06-15

    Purpose: To allow continuous acquisition of high quality 4D ultrasound images for non-invasive live tracking of tumours for IGRT, image- and force-adaptive strategies for robotised placement of 4D ultrasound probes are developed and evaluated. Methods: The developed robotised ultrasound system is based on a 6-axes industrial robot (adept Viper s850) carrying a 4D ultrasound transducer with a mounted force-torque sensor. The force-adaptive placement strategies include probe position control using artificial potential fields and contact pressure regulation by a PD controller strategy. The basis for live target tracking is a continuous minimum contact pressure to ensure good image quality and high patient comfort. This contact pressure can be significantly disturbed by respiratory movements and has to be compensated. All measurements were performed on human subjects under realistic conditions. When performing cardiac ultrasound, rib- and lung shadows are a common source of interference and can disrupt the tracking. To ensure continuous tracking, these artefacts had to be detected to automatically realign the probe. The detection is realised by multiple algorithms based on entropy calculations as well as a determination of the image quality. Results: Through active contact pressure regulation it was possible to reduce the variance of the contact pressure by 89.79% despite respiratory motion of the chest. The results regarding the image processing clearly demonstrate the feasibility to detect image artefacts like rib shadows in real-time. Conclusion: In all cases, it was possible to stabilise the image quality by active contact pressure control and automatically detected image artefacts. This fact enables the possibility to compensate for such interferences by realigning the probe and thus continuously optimising the ultrasound images. This is a huge step towards fully automated transducer positioning and opens the possibility for stable target tracking in

  14. A method for deriving a 4D-interpolated balanced planning target for mobile tumor radiotherapy

    SciTech Connect

    Roland, Teboh; Hales, Russell; McNutt, Todd; Wong, John; Simari, Patricio; Tryggestad, Erik

    2012-01-15

    Purpose: Tumor control and normal tissue toxicity are strongly correlated to the tumor and normal tissue volumes receiving high prescribed dose levels in the course of radiotherapy. Planning target definition is, therefore, crucial to ensure favorable clinical outcomes. This is especially important for stereotactic body radiation therapy of lung cancers, characterized by high fractional doses and steep dose gradients. The shift in recent years from population-based to patient-specific treatment margins, as facilitated by the emergence of 4D medical imaging capabilities, is a major improvement. The commonly used motion-encompassing, or internal-target volume (ITV), target definition approach provides a high likelihood of coverage for the mobile tumor but inevitably exposes healthy tissue to high prescribed dose levels. The goal of this work was to generate an interpolated balanced planning target that takes into account both tumor coverage and normal tissue sparing from high prescribed dose levels, thereby improving on the ITV approach. Methods: For each 4DCT dataset, 4D deformable image registration was used to derive two bounding targets, namely, a 4D-intersection and a 4D-composite target which minimized normal tissue exposure to high prescribed dose levels and maximized tumor coverage, respectively. Through definition of an ''effective overlap volume histogram'' the authors derived an ''interpolated balanced planning target'' intended to balance normal tissue sparing from prescribed doses with tumor coverage. To demonstrate the dosimetric efficacy of the interpolated balanced planning target, the authors performed 4D treatment planning based on deformable image registration of 4D-CT data for five previously treated lung cancer patients. Two 4D plans were generated per patient, one based on the interpolated balanced planning target and the other based on the conventional ITV target. Plans were compared for tumor coverage and the degree of normal tissue sparing

  15. Time-of-day-dependent changes in GnRH1 neuronal activities and gonadotropin mRNA expression in a daily spawning fish, medaka.

    PubMed

    Karigo, Tomomi; Kanda, Shinji; Takahashi, Akiko; Abe, Hideki; Okubo, Kataaki; Oka, Yoshitaka

    2012-07-01

    GnRH neurons in the preoptic area and hypothalamus control the secretion of GnRH and form the final common pathway for hypothalamic-pituitary-gonadal axis regulation in vertebrates. Temporal regulation of reproduction by coordinating endogenous physiological conditions and behaviors is important for successful reproduction. Here, we examined the temporal regulation of reproduction by measuring time-of-day-dependent changes in the electrical activity of GnRH1 neurons and in levels of expression of pituitary gonadotropin mRNA using a daily spawning teleost, medaka (Oryzias latipes). First, we performed on-cell patch-clamp recordings from GnRH1 neurons that directly project to the pituitary, using gnrh1-green fluorescent protein transgenic medaka. The spontaneous firing activity of GnRH1 neurons showed time-of-day-dependent changes: overall, the firing activity in the afternoon was higher than in the morning. Next, we examined the daily changes in the pituitary gonadotropin transcription level. The expression levels of lhb and fshb mRNA also showed changes related to time of day, peaking during the lights-off period. Finally, we analyzed effects of GnRH on the pituitary. We demonstrated that incubation of isolated pituitary with GnRH increases lhb mRNA transcription several hours after GnRH stimulation, unlike the well-known immediate LH releasing effect of GnRH. From these results, we propose a working hypothesis concerning the temporal regulation of the ovulatory cycle in the brain and pituitary of female medaka.

  16. ADULT AND CHILDREN'S EXPOSURE TO 2,4-D FROM MULTIPLE SOURCES AND PATHWAYS

    EPA Science Inventory

    In this study, we investigated the 2,4-dichlorophenoxyacetic acid (2,4-D) herbicide exposures of 135 preschool-aged children and their adult caregivers at 135 homes in North Carolina (NC) and Ohio (OH). Participants were randomly recruited from six NC and six OH counties. Monito...

  17. Inverse planning for four-dimensional (4D) volumetric modulated arc therapy

    SciTech Connect

    Ma Yunzhi; Chang, Daniel; Keall, Paul; Xie Yiaoqin; Park, Jae-yoon; Suh, Tae-Suk; Xing Lei

    2010-11-15

    Purpose: To develop a 4D volumetric modulated arc therapy (VMAT) inverse planning framework. Methods: 4D VMAT inverse planning aims to derive an aperture and weight modulated arc therapy treatment plan that optimizes the accumulated dose distribution from all gantry angles and breathing phases. Under an assumption that the gantry rotation and patient breathing are synchronized (i.e., there is a functional relationship between the phase of the patient breathing cycle and the beam angle), the authors compute the contribution from different respiration phases through the registration of the phased CT images. The accumulative dose distribution is optimized by iteratively adjusting the aperture shape and weight of each beam through the minimization of the planning objective function. For comparison, traditional 3D VMAT plans are also performed for the two cases and the performance of the proposed technique is demonstrated. Results: A framework for 4D VMAT inverse planning has been proposed. With the consideration of the extra dimension of time in VMAT, a tighter target margin can be achieved with a full duty cycle, which is otherwise not achievable simultaneously by either 3D VMAT optimization or gated VMAT. Conclusions: The 4D VMAT planning formulism proposed here provides useful insight on how the ''time'' dimension can be exploited in rotational arc therapy to maximally compensate for the intrafraction organ motion.

  18. Experimental investigation of irregular motion impact on 4D PET-based particle therapy monitoring.

    PubMed

    Tian, Y; Stützer, K; Enghardt, W; Priegnitz, M; Helmbrecht, S; Bert, C; Fiedler, F

    2016-01-21

    Particle therapy positron emission tomography (PT-PET) is an in vivo and non-invasive imaging technique to monitor treatment delivery in particle therapy. The inevitable patient respiratory motion during irradiation causes artefacts and inaccurate activity distribution in PET images. Four-dimensional (4D) maximum likelihood expectation maximisation (4D MLEM) allows for a compensation of these effects, but has up to now been restricted to regular motion for PT-PET investigations. However, intra-fractional motion during treatment might differ from that during acquisition of the 4D-planning CT (e.g. amplitude variation, baseline drift) and therefore might induce inaccurate 4D PET reconstruction results. This study investigates the impact of different irregular analytical one-dimensional (1D) motion patterns on PT-PET imaging by means of experiments with a radioactive source and irradiated moving phantoms. Three sorting methods, namely phase sorting, equal amplitude sorting and event-based amplitude sorting, were applied to manage the PET list-mode data. The influence of these sorting methods on the motion compensating algorithm has been analysed. The event-based amplitude sorting showed a superior performance and it is applicable for irregular motions with ⩽ 4 mm amplitude elongation and drift. For motion with 10 mm baseline drift, the normalised root mean square error was as high as 10.5% and a 10 mm range deviation was observed.

  19. Can exposure to prenatal sex hormones (2D:4D) predict cognitive reflection?

    PubMed

    Bosch-Domènech, Antoni; Brañas-Garza, Pablo; Espín, Antonio M

    2014-05-01

    The Cognitive Reflection Test (CRT) is a test introduced by Frederick (2005). The task is designed to measure the tendency to override an intuitive response that is incorrect and to engage in further reflection that leads to the correct response. The consistent sex differences in CRT performance may suggest a role for prenatal sex hormones. A now widely studied putative marker for relative prenatal testosterone is the second-to-fourth digit ratio (2D:4D). This paper tests to what extent 2D:4D, as a proxy for the prenatal ratio of testosterone/estrogens, can predict CRT scores in a sample of 623 students. After controlling for sex, we observe that a lower 2D:4D (reflecting a relative higher exposure to testosterone) is significantly associated with a higher number of correct answers. The result holds for both hands' 2D:4Ds. In addition, the effect appears to be stronger for females than for males. We also control for patience and math proficiency, which are significantly related to performance in the CRT. But the effect of 2D:4D on performance in CRT is not reduced with these controls, implying that these variables are not mediating the relationship between digit ratio and CRT.

  20. Clastogenicity of pentachlorophenol, 2,4-D and butachlor evaluated by Allium root tip test.

    PubMed

    Ateeq, Bushra; Abul Farah, M; Niamat Ali, M; Ahmad, Waseem

    2002-02-15

    The meristematic mitotic cells of Allium cepa is an efficient cytogenetic material for chromosome aberration assay on environmental pollutants. For assessing genotoxicity of pentachlorophenol (PCP), 2,4-dichlorophenoxyacetic acid (2,4-D) and 2-chloro-2,6-diethyl-N-(butoxymethyl) acetanilide (butachlor), 50% effective concentration (EC(50)), c-mitosis, stickiness, chromosome breaks and mitotic index (MI) were used as endpoints of genotoxicity. EC(50) values for PCP and butachlor are 0.73 and 5.13 ppm, respectively. 2,4-D evidently induced morphological changes at higher concentrations. Some changes like crochet hooks, c-tumours and broken roots were unique to 2,4-D at 5-20 ppm. No such abnormalities were found in PCP and butachlor treated groups, however, root deteriorated and degenerated at higher concentrations (<3 ppm) in PCP. MI in 2,4-D showed a low average of 14.32% followed by PCP (19.53%), while in butachlor it was recorded 71.6%, which is near to the control value. All chemicals induced chromosome aberrations at statistically significant level. The highest chromosome aberration frequency (11.90%) was recorded in PCP at 3 ppm. Large number of c-mitotic anaphases indicated that butachlor acts as potent spindle inhibitor, whereas, breaks, bridges, stickiness and laggards were most frequently found in PCP showing that it is a potent clastogen. PMID:11815249

  1. 77 FR 23135 - 2,4-D; Order Denying NRDC's Petition To Revoke Tolerances

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-18

    ... and thyroid hormonal pathways and ecological effects. (63 FR 71542, 71544, December 28, 1998). The... battery of screening assays in a Federal Register Notice issued January 24, 2008 (73 FR 4216). EPA... October 21, 2009 for 67 chemicals including 2,4-D. (74 FR 54422, 54425). With regard to endocrine...

  2. Clastogenicity of pentachlorophenol, 2,4-D and butachlor evaluated by Allium root tip test.

    PubMed

    Ateeq, Bushra; Abul Farah, M; Niamat Ali, M; Ahmad, Waseem

    2002-02-15

    The meristematic mitotic cells of Allium cepa is an efficient cytogenetic material for chromosome aberration assay on environmental pollutants. For assessing genotoxicity of pentachlorophenol (PCP), 2,4-dichlorophenoxyacetic acid (2,4-D) and 2-chloro-2,6-diethyl-N-(butoxymethyl) acetanilide (butachlor), 50% effective concentration (EC(50)), c-mitosis, stickiness, chromosome breaks and mitotic index (MI) were used as endpoints of genotoxicity. EC(50) values for PCP and butachlor are 0.73 and 5.13 ppm, respectively. 2,4-D evidently induced morphological changes at higher concentrations. Some changes like crochet hooks, c-tumours and broken roots were unique to 2,4-D at 5-20 ppm. No such abnormalities were found in PCP and butachlor treated groups, however, root deteriorated and degenerated at higher concentrations (<3 ppm) in PCP. MI in 2,4-D showed a low average of 14.32% followed by PCP (19.53%), while in butachlor it was recorded 71.6%, which is near to the control value. All chemicals induced chromosome aberrations at statistically significant level. The highest chromosome aberration frequency (11.90%) was recorded in PCP at 3 ppm. Large number of c-mitotic anaphases indicated that butachlor acts as potent spindle inhibitor, whereas, breaks, bridges, stickiness and laggards were most frequently found in PCP showing that it is a potent clastogen.

  3. 4D numerical observer for lesion detection in respiratory-gated PET

    PubMed Central

    Lorsakul, Auranuch; Li, Quanzheng; Trott, Cathryn M.; Hoog, Christopher; Petibon, Yoann; Ouyang, Jinsong; Laine, Andrew F.; El Fakhri, Georges

    2014-01-01

    Purpose: Respiratory-gated positron emission tomography (PET)/computed tomography protocols reduce lesion smearing and improve lesion detection through a synchronized acquisition of emission data. However, an objective assessment of image quality of the improvement gained from respiratory-gated PET is mainly limited to a three-dimensional (3D) approach. This work proposes a 4D numerical observer that incorporates both spatial and temporal informations for detection tasks in pulmonary oncology. Methods: The authors propose a 4D numerical observer constructed with a 3D channelize