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See detailThe presentation of neuroendocrine self in the thymus: a necessity for an integrated evolution of the immune and neuroendocrine systems.
Geenen, Vincent ULg

in Annals of the New York Academy of Sciences (2012), 1261

During evolution, from ancestor thymoids scattered in gill baskets of the lamprey, the first unique thymus appeared in jawed cartilaginous fishes around 450-500 millions years ago, concomitantly or ... [more ▼]

During evolution, from ancestor thymoids scattered in gill baskets of the lamprey, the first unique thymus appeared in jawed cartilaginous fishes around 450-500 millions years ago, concomitantly or shortly after the emergence of recombinase-dependent adaptive immunity. The major biological function of the thymus is to generate a diverse repertoire of T-cell receptors that are self-tolerant. The thymus achieves this role by using two complementary and intimately associated mechanisms: 1) Apoptotic deletion of T-cell clones bearing a TCR with high affinity for self-antigens presented by MHC proteins on thymic epithelial cells (TECs) and dendritic cells (DCs); and 2) Generation of self-antigen specific natural regulatory T (nTreg) cells. Moreover, the escape from thymic central self-tolerance plays a primary role in the development of autoimmune diseases that are a significant burden for the quality of life and health care cost. Our new knowledge in thymus physiology and physiopathology is currently translated into innovative therapeutic strategies against these devastating chronic diseases. [less ▲]

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See detailThymosin beta4 in multiple myeloma: friend or foe
Caers, Jo ULg; Otjacques, Eléonore ULg; Hose, Dirk et al

in Annals of the New York Academy of Sciences (2010), 1194(1), 125-130

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See detailDualism persists in the science of mind.
Demertzi, Athina ULg; Liew, Charlene; Ledoux, Didier ULg et al

in Annals of the New York Academy of Sciences (2009), 1157

The relationship between mind and brain has philosophical, scientific, and practical implications. Two separate but related surveys from the University of Edinburgh (University students, n= 250) and the ... [more ▼]

The relationship between mind and brain has philosophical, scientific, and practical implications. Two separate but related surveys from the University of Edinburgh (University students, n= 250) and the University of Liege (health-care workers, lay public, n= 1858) were performed to probe attitudes toward the mind-brain relationship and the variables that account for differences in views. Four statements were included, each relating to an aspect of the mind-brain relationship. The Edinburgh survey revealed a predominance of dualistic attitudes emphasizing the separateness of mind and brain. In the Liege survey, younger participants, women, and those with religious beliefs were more likely to agree that the mind and brain are separate, that some spiritual part of us survives death, that each of us has a soul that is separate from the body, and to deny the physicality of mind. Religious belief was found to be the best predictor for dualistic attitudes. Although the majority of health-care workers denied the distinction between consciousness and the soma, more than one-third of medical and paramedical professionals regarded mind and brain as separate entities. The findings of the study are in line with previous studies in developmental psychology and with surveys of scientists' attitudes toward the relationship between mind and brain. We suggest that the results are relevant to clinical practice, to the formulation of scientific questions about the nature of consciousness, and to the reception of scientific theories of consciousness by the general public. [less ▲]

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See detailBehavioral effects of brain-derived estrogens in birds.
Balthazart, Jacques ULg; Taziaux, Mélanie ULg; Holloway, Kevin et al

in Annals of the New York Academy of Sciences (2009), 1163

In birds as in other vertebrates, estrogens produced in the brain by aromatization of testosterone have widespread effects on behavior. Research conducted with male Japanese quail demonstrates that ... [more ▼]

In birds as in other vertebrates, estrogens produced in the brain by aromatization of testosterone have widespread effects on behavior. Research conducted with male Japanese quail demonstrates that effects of brain estrogens on all aspects of sexual behavior, including appetitive and consummatory components as well as learned aspects, can be divided into two main classes based on their time course. First, estrogens via binding to estrogen receptors regulate the transcription of a variety of genes involved primarily in neurotransmission. These neurochemical effects ultimately result in the activation of male copulatory behavior after a latency of a few days. Correlatively, testosterone and its aromatized metabolites increase the transcription of the aromatase mRNA, resulting in an increased concentration and activity of the enzyme that actually precedes behavioral activation. Second, recent studies with quail demonstrate that brain aromatase activity can also be modulated within minutes by phosphorylation processes regulated by changes in intracellular calcium concentration, such as those associated with glutamatergic neurotransmission. The rapid upregulations or downregulations of brain estrogen concentration (presumably resulting from these changes in aromatase activity) affect, by nongenomic mechanisms with relatively short latencies (frequency increases or decreases respectively within 10-15 min), the expression of male sexual behavior in quail and also in rodents. Brain estrogens thus affect behavior on different time scales by genomic and nongenomic mechanisms similar to those of a hormone or a neurotransmitter. [less ▲]

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See detailRecent discoveries of new hantaviruses widen their range and question their origins.
Henttonen, Heikki; Buchy, Philippe; Suputtamongkol, Yupin et al

in Annals of the New York Academy of Sciences (2008), 1149

Hantaviruses belong to the Bunyaviridae family. While usually hosted by wild mammals, they are potentially pathogenic for humans, and several serologically distinct groups associated with different ... [more ▼]

Hantaviruses belong to the Bunyaviridae family. While usually hosted by wild mammals, they are potentially pathogenic for humans, and several serologically distinct groups associated with different syndromes have been identified. Yet, investigations have mostly been conducted where human infections by hantaviruses constitute a real and well-identified public health problem, i.e., the holarctic and neotropical areas. Some hantaviruses have also been described from a Suncus murinus in India and a Bandicota indica in Thailand. In addition, recent investigations in Cambodia revealed new Hantavirus types. More recently, two new Hantavirus species were described: Sangassou from a Hylomyscus simus, and Tanganya from a Crocidura theresae, both from Africa (Guinea), thus strongly questioning the current views about geographic range, evolution, and epidemiology of hantaviruses. In such a framework, we have conducted a survey of Hantavirus diversity in Southeast Asia which allows us to isolate the Thailand virus and address questions about the taxonomy of their rodent hosts. Here we present a molecular analysis of representatives of all currently known Hantavirus species, thus allowing the comparison between the newly described ones with a large range sample of rodent hantaviruses. Our results clearly point to the presence of a particular lineage of hantaviruses in Southeast Asia. It also strongly suggests that new viruses, additional mammalian hosts and different related syndromes in humans are likely to be discovered in the near future, particularly in Southeast Asia and in Africa, where Muridae rodents are highly diversified. Furthermore, additional work is also urgently needed to investigate the hantaviruses associated with Crociduridae and Soricidae. [less ▲]

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See detailIntrinsic brain activity in altered states of consciousness: how conscious is the default mode of brain function?
Boly, Mélanie ULg; Phillips, Christophe ULg; Tshibanda, Luaba ULg et al

in Annals of the New York Academy of Sciences (2008), 1129

Spontaneous brain activity has recently received increasing interest in the neuroimaging community. However, the value of resting-state studies to a better understanding of brain-behavior relationships ... [more ▼]

Spontaneous brain activity has recently received increasing interest in the neuroimaging community. However, the value of resting-state studies to a better understanding of brain-behavior relationships has been challenged. That altered states of consciousness are a privileged way to study the relationships between spontaneous brain activity and behavior is proposed, and common resting-state brain activity features observed in various states of altered consciousness are reviewed. Early positron emission tomography studies showed that states of extremely low or high brain activity are often associated with unconsciousness. However, this relationship is not absolute, and the precise link between global brain metabolism and awareness remains yet difficult to assert. In contrast, voxel-based analyses identified a systematic impairment of associative frontoparieto-cingulate areas in altered states of consciousness, such as sleep, anesthesia, coma, vegetative state, epileptic loss of consciousness, and somnambulism. In parallel, recent functional magnetic resonance imaging studies have identified structured patterns of slow neuronal oscillations in the resting human brain. Similar coherent blood oxygen level-dependent (BOLD) systemwide patterns can also be found, in particular in the default-mode network, in several states of unconsciousness, such as coma, anesthesia, and slow-wave sleep. The latter results suggest that slow coherent spontaneous BOLD fluctuations cannot be exclusively a reflection of conscious mental activity, but may reflect default brain connectivity shaping brain areas of most likely interactions in a way that transcends levels of consciousness, and whose functional significance remains largely in the dark. [less ▲]

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See detailThymus-dependent T cell tolerance of neuroendocrine functions - Principles, reflections, and implications for tolerogenic/negative self-vaccination
Geenen, Vincent ULg

in Annals of the New York Academy of Sciences (2006), 1088

Under the evolutionary pressure exerted by the emergence of adaptive immunity and its inherent risk of horror autotoxicus, the thymus appeared some 500 million years ago as a novel lymphoid structure able ... [more ▼]

Under the evolutionary pressure exerted by the emergence of adaptive immunity and its inherent risk of horror autotoxicus, the thymus appeared some 500 million years ago as a novel lymphoid structure able to prevent autoimmunity and to orchestrate self-tolerance as a cornerstone in the physiology of the immune system. Also, the thymus plays a prominent role in T cell education to neuroendocrine principles. Some self-antigens (oxytocin, neurotensin, insulin-like growth factor 2 [IGF-2]) have been selected to be predominantly expressed in thymic epithelium and to be presented to thymus T cells for educating them to tolerate other antigens related to them. In the insulin family, IGF2 is dominantly transcribed in cortical (c) and medullary (m) thymic epithelial cells (TECs), whereas the insulin gene (INS) is expressed at low level by only a few subsets of mTECs. Intrathymic transcription of both IGF2 and INS is under the control of the autoimmune regulator (Aire) gene. The highest concentrations of IGF-2 in the thymus explain why this peptide is much more tolerated than insulin, and why tolerance to IGF-2 is so difficult to break by active immunization. The high level of tolerance to IGF-2 is correlated to the development of a tolerogenic/regulatory profile when the sequence B11-25 of IGF-2 (homologous to the autoantigen insulin B9-23) is presented to DQ8+ type 1 diabetic patients. Since subcutaneous and oral insulin does not exert any tolerogenic properties, IGF-2 and other thymus self-antigens related to type I diabetes (T1D) should be preferred to insulin for the design of novel specific antigen-based preventive approaches against T1D. [less ▲]

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See detailMultiple roles of Hoxc8 in skeletal development
Juan, A. H.; Lei, H. Y.; Bhargava, P. et al

in Annals of the New York Academy of Sciences (2006), 1068

We are interested in investigating the function of Hoxc8 in skeletogenesis during mouse development. Previous studies have shown that deregulation of Hoxc8 expression in the mouse leads to several ... [more ▼]

We are interested in investigating the function of Hoxc8 in skeletogenesis during mouse development. Previous studies have shown that deregulation of Hoxc8 expression in the mouse leads to several skeletal defects, such as homeotic transformation in the thoracic vertebrae, abnormal development of the rib cage, and overproliferation of chondrocytes in the hypertrophic area. By deleting a crucial enhancer of Hoxc8 in vivo, we found that precise temporal expression of Hoxc8 is important for determining the correct identity of the vertebral column in early embryos. We also identified downstream targets of Hoxc8 relevant to osteoblast differentiation at later developmental stages. [less ▲]

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See detailDescriptive and spatial epidemiology of Rift valley fever outbreak in Yemen 2000-2001
Abdo-Salem, S.; Gerbier, G.; Bonnet, Pascal et al

in Annals of the New York Academy of Sciences (2006), 1081

Rift valley fever (RVF) is an arboviral disease produced by a bunyavirus belonging to the genus Phlebovirus. Several species of Aedes and Culex are the vectors of this virus that affects sheep, goats ... [more ▼]

Rift valley fever (RVF) is an arboviral disease produced by a bunyavirus belonging to the genus Phlebovirus. Several species of Aedes and Culex are the vectors of this virus that affects sheep, goats, buffalos, cattle, camels and human beings. The human disease is well known, especially during periods of intense epizootic activity. The initial description of the disease dates back to 1930, when animals and human outbreaks appeared on a farm in Lake Naivasha, in the Great Rift Valley of Kenya. Until 2000, this disease was only described in Africa, and then outbreaks were also declared in the Kingdom of Saudi Arabia (2000-2001 and 2004) and in Yemen (2000-2001). Animal and human cases were recorded. This work presents a retrospective summary of the data collected on animal RVF cases during this epidemic in Yemen. Results from several RVF surveys were gathered from the Yemeni vet services and FAO experts. Geographical data (topographic maps and data freely available on internet) were used for the location of outbreaks. After cleaning and standardization of location names, all the data were introduced into a GIS database. The spatial distribution of outbreaks was then studied at two scales: at the national level and at a local scale in the particular area of Wadi Mawr in the Tihama plain, Western coast of Yemen. [less ▲]

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See detailHLA-DQA is associated with abdominal aortic aneurysms in the Belgian population
Tromp, Gerard; Ogata, Toru; Grégoire, Lucie et al

in Annals of the New York Academy of Sciences (2006), 1085

Chronic inflammation and autoimmunity likely contribute to the pathogenesis of abdominal aortic aneurysms (AAAs). The aim of this study was to investigate the role of autoimmunity in the etiology of AAAs ... [more ▼]

Chronic inflammation and autoimmunity likely contribute to the pathogenesis of abdominal aortic aneurysms (AAAs). The aim of this study was to investigate the role of autoimmunity in the etiology of AAAs using a genetic association study approach with human leukocyte antigen (HLA) polymorphisms (HLA-DQA1, -DQB1, -DRB1 and -DRB3-5 alleles) in 387 AAA cases and 426 controls. We observed an association with the HLA-DQA1 locus among Belgian males, and found a significant difference in the HLA-DQA1 *0102 allele frequencies between AAA cases and controls. In conclusion, this study showed potential evidence that the HLA-DQA1 locus harbors a genetic risk factor for AAAs suggesting that autoimmunity plays a role in the pathogenesis of AAAs. [less ▲]

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See detailNitric oxide and the heart: update on new paradigms.
Belge, C.; MASSION, Paul ULg; Pelat, M. et al

in Annals of the New York Academy of Sciences (2005), 1047

The role of nitric oxide (NO) as a regulator of cardiac contraction was suggested in the early nineties, but a consensual view of its main functions in cardiac physiology has only recently emerged with ... [more ▼]

The role of nitric oxide (NO) as a regulator of cardiac contraction was suggested in the early nineties, but a consensual view of its main functions in cardiac physiology has only recently emerged with the help of experiments using genetic deletion or overexpression of the three nitric oxide synthase (NOS) isoforms in cardiomyocytes. Contrary to the effects of exogenous, pharmacologic NO donors, signaling by endogenous NO is restricted to intracellular effectors co-localized with NOS in specific subcellular compartments. This both ensures coordinate signaling by the three NOS isoforms on different aspects of the cardiomyocyte function and helps to reconcile previous apparently contradictory observations based on the use of non-isoform-specific NOS inhibitors. This review will emphasize the role of NOS on excitation-contraction coupling in the normal and diseased heart. Endothelial NOS and neuronal NOS contribute to maintain an adequate balance between adrenergic and vagal input to the myocardium and participate in the early and late phases of the Frank-Starling adaptation of the heart. At the early phases of cardiac diseases, inducible NOS reinforces these effects, which may become maladaptive as disease progresses. [less ▲]

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See detailAn insulin-like growth factor 2-derived self-antigen inducing a regulatory cytokine profile after presentation to peripheral blood mononuclear cells from DQ8(+) type 1 diabetic adolescents - Preliminary design of a thymus-based tolerogenic self-vaccination
Geenen, Vincent ULg; Louis, Céline ULg; Martens, Henri ULg

in Annals of the New York Academy of Sciences (2004), 1037

This work aims to evaluate the potential use of insulin-like growth factor 2 (IGF-2) as the dominant thymic self-antigen precursor of the insulin family in designing a tolerogenic approach to type 1 ... [more ▼]

This work aims to evaluate the potential use of insulin-like growth factor 2 (IGF-2) as the dominant thymic self-antigen precursor of the insulin family in designing a tolerogenic approach to type 1 diabetes (T1D) prevention. This evaluation was primarily based on cytokine profile driven by MHC presentation of insulin and IGF-2-derived antigens to PBMC cultures derived from 16 T1D DQ8(+) adolescents. Insulin B9-23, one dominant P-cell autoantigen, and the homologous sequence B11-25 of IGF-2 display the same affinity and fully compete for binding to DQ8, a MHC-II allele conferring major genetic susceptibility to type 1 diabetes (T1D). However, compared to insulin beta 9-23, presentation of IGF-2 B11-25 elicits a suppressive/regulatory cytokine profile with a higher number of IL-10-secreting cells (P < 0.05), a much higher ratio of IL-10/IFN-gamma (P < 0.01), as well as a lower number of IL-4-secreting cells (P < 0.05). Thus, with regard to T1D prevention, administration of IGF-2-derived self-antigen(s) seems to be an efficient approach that combines both antagonism for binding to a major susceptibility MHC-II allele, as well as downstream promotion of an antigen-driven tolerogenic response. [less ▲]

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See detailSeasonal plasticity in the song control system - Multiple brain sites of steroid hormone action and the importance of variation in song behavior
Ball, Gregory F.; Auger, Catherine J.; Bernard, Daniel J. et al

in Annals of the New York Academy of Sciences (2004), 1016

Birdsong, in non-tropical species, is generally more common in spring and summer when males sing to attract mates and/or defend territories. Changes in the volumes of song control nuclei, such as HVC and ... [more ▼]

Birdsong, in non-tropical species, is generally more common in spring and summer when males sing to attract mates and/or defend territories. Changes in the volumes of song control nuclei, such as HVC and the robust nucleus of the arcopallium (RA), are observed seasonally. Long photoperiods in spring stimulate the recrudescence of the testes and the release of testosterone. Androgen receptors, and at times estrogen receptors, are present in HVC and RA as are co-factors that facilitate the transcriptional activity of these receptors. Thus testosterone can act directly to induce changes in nucleus volume. However, dissociations have been identified at times among long photoperiods, maximal concentrations of testosterone, large song control nuclei, and high rates of song. One explanation of these dissociations is that song behavior itself can influence neural plasticity in the song system. Testosterone can act via brain-derived neurotrophic factor (BDNF) that is also released in HVC as a result of song activity. Testosterone could enhance song nucleus volume indirectly by acting in the preoptic area, a region regulating sexual behaviors, including song, that connects to the song system through catecholaminergic cells. Seasonal neuroplasticity in the song system involves an interplay among seasonal state, testosterone action, and behavioral activity. [less ▲]

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See detailAromatase (estrogen synthase) activity in the dorsal horn of the spinal cord: Functional implications
Evrard, H. C.; Balthazart, Jacques ULg

in Annals of the New York Academy of Sciences (2003), 1007

The presence of aromatase (estrogen synthase) in neurons in the dorsal horn of the spinal cord in Japanese quail suggests that estrogens produced locally from androgens could control spinal sensory ... [more ▼]

The presence of aromatase (estrogen synthase) in neurons in the dorsal horn of the spinal cord in Japanese quail suggests that estrogens produced locally from androgens could control spinal sensory processes including nociception. We used the hot water nociceptive test (54 degreesC) to appraise the longterm effect of an inhibition of aromatization on the foot withdrawal latency in male quail. Four weeks after the ablation of their main source of testosterone (testes), castrated males displayed a significantly higher foot withdrawal latency than gonadally intact males. A prolonged treatment with subcutaneous capsules filled with testosterone or 17 beta-estradiol restored the baseline latency within 2 weeks. The effect of testosterone in castrated quail was almost completely blocked by systemic injections of Vorozole((TM)), a nonsteroidal aromatase inhibitor or tamoxifen, an estrogen receptor antagonist (one injection per day for 10 days). Taken together, these data demonstrate for the first time to our knowledge an effect of estrogens formed by aromatization of androgens on nociception. Because aromatase-immunoreactive neurons and aromatase activity are present in the dorsal horns of the spinal cord, this control of pain thresholds is presumably mediated, at least in part, by estrogens produced at the spinal level that act locally via slow, presumably genomic, mechanisms mediated by the activation of spinal nuclear estrogen receptors. [less ▲]

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See detailThe aromatase knockout (ArKO) mouse provides new evidence that estrogens are required for the development of the female brain
Bakker, Julie ULg; Honda, S.; Harada, N. et al

in Annals of the New York Academy of Sciences (2003), 1007

The classic view of sexual differentiation is that the male brain develops under the influence of testicular secretions, whereas the female brain develops in the absence of any hormonal stimulation ... [more ▼]

The classic view of sexual differentiation is that the male brain develops under the influence of testicular secretions, whereas the female brain develops in the absence of any hormonal stimulation. However, several studies have suggested a possible role of estradiol in female neural development, although they did not provide unequivocal evidence that estradiol is indispensable for the development of the female brain and behavior. As a result, the hypothesis subsequently languished because of the lack of a suitable animal model to test estrogen's possible contribution to female differentiation. The recent introduction of the aromatase knockout (ArKO) mouse, which is deficient in aromatase activity because of a targeted mutation in the CYP19 gene and therefore cannot aromatize androgen to estrogen, has provided a new opportunity to reopen the debate of whether estradiol contributes to the development of the female brain. Female ArKO mice showed reduced levels of lordosis behavior after adult treatment with estradiol and progesterone, suggesting that estradiol is required for the development of the neural mechanisms controlling this behavior in female mice. The neural systems affected may include the olfactory systems in that ArKO females also showed impairments in olfactory investigation of odors from conspecifics. Thus, the classic view of sexual differentiation, that is, the female brain develops in the absence of any hormonal secretion, needs to be re-examined. [less ▲]

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See detailRole of the thymus in the development of tolerance and autoimmunity towards the neuroendocrine system
Geenen, Vincent ULg; Brilot, Fabienne

in Annals of the New York Academy of Sciences (2003), 992

The thymus is the unique lymphoid organ inside which a confrontation occurs throughout life between neuroendocrine self-antigens and a recently evolved system with original recombination machinery driving ... [more ▼]

The thymus is the unique lymphoid organ inside which a confrontation occurs throughout life between neuroendocrine self-antigens and a recently evolved system with original recombination machinery driving random generation of immune response diversity. Through transcription of neuroendocrine genes in the thymus stromal network and expression of cognate receptors by immature T cells, the neuroendocrine system regulates early T cell differentiation. In addition and more specifically, intrathymic presentation of neuroendocrine self-antigens by, or in close association with, major histocompatibility complex (MHC) proteins is responsible for the establishment of central immune self-tolerance of neuroendocrine principles. All members of the insulin gene (INS) family are expressed in the thymus stroma according to a precise hierarchy and cell topography: IGF2 (thymic epithelial cells) > IGF1 (thymic macrophages) much greater than INS (thymic medullary epithelial cells and/or dendritic cells). Given this hierarchical pattern in gene expression, the protein IGF-2 is more tolerated than INS. Igf2 transcription is defective in the thymus of bio-breeding (BB) rat, one animal model of type 1 diabetes (T1DM). This thymus-specific defect in Igf2 expression may explain both the absence of central tolerance to INS-secreting beta cells and the lymphopenia (including lack of regulatory RT6(+) T cells) in diabetes-prone BB rats. INS B:9-23 and the homologous sequence of IGF-2 compete for binding to DQ8, an MHC class II allele conferring major susceptibility to T1DM. In young DQ8(+) T1DM patients, INS B:9-23 presentation by DQ8 elicits a dominant IFN-gamma secretion by isolated PBMCs, whereas presentation of the IGF-2 self-antigen promotes a dominant regulatory interleukin-10 secretion. These data demonstrate that opposite immune responses are driven by MHC presentation of a self-antigen (here, IGF-2) and an autoantigen (INS, as "altered" self). The important tolerogenic properties of thymic self-antigens deserve now to be exploited for prevention and/or cure of devastating autoimmune diseases such as T1DM. [less ▲]

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See detailThe activation of birdsong by testosterone - Multiple sites of action and role of ascending catecholamine projections
Ball, G. F.; Castelino, C. B.; Maney, D. L. et al

in Annals of the New York Academy of Sciences (2003), 1007

Birdsong is a species-typical stereotypic vocalization produced in the context of reproduction and aggression. Among temperate-zone songbirds, it is produced primarily by males, and its frequency and ... [more ▼]

Birdsong is a species-typical stereotypic vocalization produced in the context of reproduction and aggression. Among temperate-zone songbirds, it is produced primarily by males, and its frequency and quality are enhanced by the presence of the gonadal steroid hormone testosterone in the plasma. In the brain, the effects of testosterone on song behavior involve both estrogenic and androgenic metabolites of testosterone that are locally produced and act via their cognate receptors. Androgen, and in some cases estrogen, receptors are present in many specialized forebrain song control nuclei. Testosterone can regulate catecholamine steady-state levels and turnover in these song control regions. Tracing studies combined with immunocytochemistry for tyrosine hydroxylase (a marker of catecholamine synthesis) reveal several catecholamine cell groups that project to forebrain song control nuclei. These brain areas also express the mRNA for either androgen receptors or estrogen receptor alpha, and androgens enhance the expression of tyrosine hydroxylase. Dopaminergic cell groups that project to song nuclei express the protein product of the immediate early gene fos in association with the production of territorial song. Thus, testosterone may be acting on song behavior via these ascending catecholamine cell groups. Chemical lesioning studies suggest that noradrenergic projections to the song system are involved in the latency to produce song and the ability to discriminate conspecific from heterospecific song. The song control circuit may thus be modulated in significant ways via the androgen regulation of forebrain catecholamine systems. [less ▲]

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See detailTranscription of the human prolactin gene in mammary cells
Baudhuin, A.; Manfroid, Isabelle ULg; Van de Weerdt, Cécile ULg et al

in Annals of the New York Academy of Sciences (2002), 973

Expression of human prolactin in the Mammary gland, one of the main target organs of this hormone, leads to the formation of an autocrine-paracrine proliferative loop in this tissue. Involvement of ... [more ▼]

Expression of human prolactin in the Mammary gland, one of the main target organs of this hormone, leads to the formation of an autocrine-paracrine proliferative loop in this tissue. Involvement of prolactin in normal and neoplastic mammary development triggered the interest in transcriptional regulation of the human prolactin gene in mammary cells. Analysis of this regulation, and comparison to that in the pituitary, will contribute to a better understanding of mammary gland development and tumor formation. Here we present the first extensive analysis of the transcriptional regulation of the human prolactin gene in human mammary tumor cells. [less ▲]

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See detailCoCl2, a chemical inducer of hypoxia-inducible factor-1, and hypoxia reduce apoptotic cell death in hepatoma cell line HepG2.
Piret, Jean-Pascal; Mottet, Denis ULg; Raes, Martine et al

in Annals of the New York Academy of Sciences (2002), 973

HIF-1 (hypoxia-inducible factor-1) is the major transcription factor that is specifically activated during hypoxia. This transcription factor is composed of two subunits: HIF-1alpha and ARNT (aryl ... [more ▼]

HIF-1 (hypoxia-inducible factor-1) is the major transcription factor that is specifically activated during hypoxia. This transcription factor is composed of two subunits: HIF-1alpha and ARNT (aryl hydrocarbon receptor nuclear translocator). ARNT is constitutively expressed, whereas HIF-1alpha is targeted to proteasome degradation by ubiquitination during normoxia. In hypoxia, HIF-1alpha is stabilized and translocates to the nucleus, where it binds to ARNT. The active HIF-1 induces expression of various genes whose products play an adaptive role to the new conditions induced by hypoxia. Besides the role played by HIF-1 in the adaptation to hypoxia, recent data describe a possible role for HIF-1 in the modulation of apoptosis. According to some authors, hypoxia induces apoptosis. However, it has also been reported that hypoxia could protect cells against apoptotic cell death induced by various agents such as serum deprivation and incubation in the presence of chemotherapy agents. These contradictory data suggest that HIF-1 could display either a proapoptotic or an antiapoptotic role according to the conditions. In order to study how HIF-1 can modulate apoptosis, we studied whether hypoxia or cobalt chloride, a chemical inducer of HIF-1, could influence apoptosis induced by tert-butyl hydroperoxide (t-BHP), serum deprivation, or both in hepatoma cell line HepG2. HepG2 cells were incubated 8 hours under normoxia or hypoxia in the presence of t-BHP with or without CoCl2. CoCl2 reduced the apoptotic death of HepG2 cells induced by t-BHP and serum deprivation, as measured by DNA fragmentation. This effect was confirmed by measurement of the caspase activity. Moreover, hypoxia also prevented t-BHP- or serum deprivation-induced DNA fragmentation and caspase activation-however, to a lower extent than CoCl2. These different data suggest a possible antiapoptotic role of HIF-1. More experiments are needed to define if HIF-1 actually plays an active role in cell death protection and to determine the exact mechanism underlying this effect. [less ▲]

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See detailERK and calcium in activation of HIF-1.
Mottet, Denis ULg; Michel, Gaetan; Renard, Patricia et al

in Annals of the New York Academy of Sciences (2002), 973

HIF-1 (hypoxia-inducible factor-1) is the main transcription factor responsible for increased gene expression in hypoxia. The oxygen-dependent regulation of HIF-1 activity occurs at multiple levels in ... [more ▼]

HIF-1 (hypoxia-inducible factor-1) is the main transcription factor responsible for increased gene expression in hypoxia. The oxygen-dependent regulation of HIF-1 activity occurs at multiple levels in vivo. The mechanisms regulating HIF-1alpha protein expression have been most extensively analyzed, but the ones modulating HIF-1 transcriptional activity remain unclear. Changes in the phosphorylation and/or redox status of HIF-1alpha certainly play a role. Here, we show that ionomycin could activate HIF-1 transcriptional activity in a way that is additive to the effect of hypoxia without affecting HIF-1alpha protein level and HIF-1 DNA binding capacity. In addition, a calmodulin dominant-negative mutant as well as BAPTA, an intracellular calcium chelator, inhibited the hypoxia-induced HIF-1 activation. These results indicate that elevated calcium in hypoxia could participate in HIF-1 activation. PD98059, an inhibitor of the ERK pathway, but not KN-93, an inhibitor of calmodulin kinases II and IV, also blocked HIF-1 activation by hypoxia and by ionomycin. Altogether, these results suggest that calcium and calmodulin would act upstream of ERK in the hypoxia signal transduction pathway leading to enhanced HIF-1 transcriptional activity. [less ▲]

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