165 research outputs found
Orexin 2 receptor regulation of the hypothalamic–pituitary–adrenal (HPA) response to acute and repeated stress
Orexins are hypothalamic neuropeptides that have a documented role in mediating the acute stress response. However, their role in habituation to repeated stress, and the role of orexin receptors (OX1R and OX2R) in the stress response, has yet to be defined. Orexin neuronal activation and levels in the cerebrospinal fluid were found to be stimulated with acute restraint, but were significantly reduced by day five of repeated restraint. As certain disease states such as panic disorder are associated with increased central orexin levels and failure to habituate to repeated stress, the effect of activating orexin signaling via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) on the hypothalamic-pituitary-adrenal (HPA) response was evaluated after repeated restraint. While vehicle-treated rats displayed habituation of Adrenocorticotropic Hormone (ACTH) from day 1 to day 5 of restraint, stimulating orexins did not further increase ACTH beyond vehicle levels for either acute or repeated restraint. We delineated the roles of orexin receptors in acute and repeated stress by using a selective OX2R antagonist (MK-1064). Pretreatment with MK-1064 reduced day 1 ACTH levels, but did not allow further habituation on day 5 compared with vehicle-treated rats, indicating that endogenous OX2R activity plays a role in acute stress, but not in habituation to repeated stress. However, in restrained rats with further stimulated orexins by DREADDs, MK-1064 decreased ACTH levels on day 5. Collectively, these results indicate that the OX2R plays a role in acute stress, and can prevent habituation to repeated stress under conditions of high orexin release
Orexin signaling during social defeat stress influences subsequent social interaction behaviour and recognition memory
Orexins are neuropeptides synthesized in the lateral hypothalamus that influence arousal, feeding, reward pathways, and the response to stress. However, the role of orexins in repeated stress is not fully characterized. Here, we examined how orexins and their receptors contribute to the coping response during repeated social defeat and subsequent anxiety-like and memory-related behaviors. Specifically, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to stimulate orexins prior to each of five consecutive days of social defeat stress in adult male rats. Additionally, we determined the role of the orexin 2 receptor in these behaviors by using a selective orexin 2 receptor antagonist (MK-1064) administered prior to each social defeat. Following the 5 day social defeat conditioning period, rats were evaluated in social interaction and novel object recognition paradigms to assess anxiety-like behavior and recognition memory, respectively. Activation of orexin neurons by DREADDs prior to each social defeat decreased the average latency to become defeated across 5 days, indicative of a passive coping strategy that we have previously linked to a stress vulnerable phenotype. Moreover, stimulation of orexin signaling during defeat conditioning decreased subsequent social interaction and performance in the novel object recognition test indicating increased subsequent anxiety-like behavior and reduced working memory. Blocking the orexin 2 receptor during repeated defeat did not alter these effects. Together, our results suggest that orexin neuron activation produces a passive coping phenotype during social defeat leading to subsequent anxiety-like behaviors and memory deficits
Orexin 2 receptor regulation of the hypothalamic–pituitary–adrenal (HPA) response to acute and repeated stress
Orexins are hypothalamic neuropeptides that have a documented role in mediating the acute stress response. However, their role in habituation to repeated stress, and the role of orexin receptors (OX1R and OX2R) in the stress response, has yet to be defined. Orexin neuronal activation and levels in the cerebrospinal fluid were found to be stimulated with acute restraint, but were significantly reduced by day five of repeated restraint. As certain disease states such as panic disorder are associated with increased central orexin levels and failure to habituate to repeated stress, the effect of activating orexin signaling via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) on the hypothalamic-pituitary-adrenal (HPA) response was evaluated after repeated restraint. While vehicle-treated rats displayed habituation of Adrenocorticotropic Hormone (ACTH) from day 1 to day 5 of restraint, stimulating orexins did not further increase ACTH beyond vehicle levels for either acute or repeated restraint. We delineated the roles of orexin receptors in acute and repeated stress by using a selective OX2R antagonist (MK-1064). Pretreatment with MK-1064 reduced day 1 ACTH levels, but did not allow further habituation on day 5 compared with vehicle-treated rats, indicating that endogenous OX2R activity plays a role in acute stress, but not in habituation to repeated stress. However, in restrained rats with further stimulated orexins by DREADDs, MK-1064 decreased ACTH levels on day 5. Collectively, these results indicate that the OX2R plays a role in acute stress, and can prevent habituation to repeated stress under conditions of high orexin release
Stochastic Eulerian Lagrangian Methods for Fluid-Structure Interactions with Thermal Fluctuations
We present approaches for the study of fluid-structure interactions subject
to thermal fluctuations. A mixed mechanical description is utilized combining
Eulerian and Lagrangian reference frames. We establish general conditions for
operators coupling these descriptions. Stochastic driving fields for the
formalism are derived using principles from statistical mechanics. The
stochastic differential equations of the formalism are found to exhibit
significant stiffness in some physical regimes. To cope with this issue, we
derive reduced stochastic differential equations for several physical regimes.
We also present stochastic numerical methods for each regime to approximate the
fluid-structure dynamics and to generate efficiently the required stochastic
driving fields. To validate the methodology in each regime, we perform analysis
of the invariant probability distribution of the stochastic dynamics of the
fluid-structure formalism. We compare this analysis with results from
statistical mechanics. To further demonstrate the applicability of the
methodology, we perform computational studies for spherical particles having
translational and rotational degrees of freedom. We compare these studies with
results from fluid mechanics. The presented approach provides for
fluid-structure systems a set of rather general computational methods for
treating consistently structure mechanics, hydrodynamic coupling, and thermal
fluctuations.Comment: 24 pages, 3 figure
From bi-layer to tri-layer Fe nanoislands on Cu3Au(001)
Self assembly on suitably chosen substrates is a well exploited root to
control the structure and morphology, hence magnetization, of metal films. In
particular, the Cu3Au(001) surface has been recently singled out as a good
template to grow high spin Fe phases, due to the close matching between the
Cu3Au lattice constant (3.75 Angstrom) and the equilibrium lattice constant for
fcc ferromagnetic Fe (3.65 Angstrom). Growth proceeds almost layer by layer at
room temperature, with a small amount of Au segregation in the early stage of
deposition. Islands of 1-2 nm lateral size and double layer height are formed
when 1 monolayer of Fe is deposited on Cu3Au(001) at low temperature. We used
the PhotoElectron Diffraction technique to investigate the atomic structure and
chemical composition of these nanoislands just after the deposition at 140 K
and after annealing at 400 K. We show that only bi-layer islands are formed at
low temperature, without any surface segregation. After annealing, the Fe atoms
are re-aggregated to form mainly tri-layer islands. Surface segregation is
shown to be inhibited also after the annealing process. The implications for
the film magnetic properties and the growth model are discussed.Comment: Revtex, 5 pages with 4 eps figure
Orexin receptors in GtoPdb v.2021.3
Orexin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Orexin receptors [42]) are activated by the endogenous polypeptides orexin-A and orexin-B (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, preproorexin or orexin precursor, by proteolytic cleavage and some typical peptide modifications [109]. Currently the only orexin receptor ligands in clinical use are suvorexant and lemborexant, which are used as hypnotics. Orexin receptor crystal structures have been solved [134, 133, 54, 117, 46]
Orexin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database
Orexin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Orexin receptors [39]) are activated by the endogenous polypeptides orexin-A and orexin-B (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, preproorexin or orexin precursor, by proteolytic cleavage and some typical peptide modifications [102]. Currently the only orexin receptor ligand in clinical use is suvorexant, which is used as a hypnotic. Orexin receptor crystal structures have been solved [124, 123]
Potential conservation of circadian clock proteins in the phylum Nematoda as revealed by bioinformatic searches
Although several circadian rhythms have been described in C. elegans, its molecular clock remains elusive. In this work we employed a novel bioinformatic approach, applying probabilistic methodologies, to search for circadian clock proteins of several of the best studied circadian model organisms of different taxa (Mus musculus, Drosophila melanogaster, Neurospora crassa, Arabidopsis thaliana and Synechoccocus elongatus) in the proteomes of C. elegans and other members of the phylum Nematoda. With this approach we found that the Nematoda contain proteins most related to the core and accessory proteins of the insect and mammalian clocks, which provide new insights into the nematode clock and the evolution of the circadian system.Fil: Romanowski, AndrĂ©s. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Parque Centenario. Instituto de Investigaciones BioquĂmicas de Buenos Aires. FundaciĂłn Instituto Leloir. Instituto de Investigaciones BioquĂmicas de Buenos Aires; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y TecnologĂa. Laboratorio de CronobiologĂa; ArgentinaFil: Garavaglia, MatĂas Javier. Universidad Nacional de Quilmes. Departamento de Ciencia y TecnologĂa. Laboratorio de Ing.genĂ©tica y Biolog.molecular y Celular. Area Virus de Insectos; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Goya, MarĂa Eugenia. Universidad Nacional de Quilmes. Departamento de Ciencia y TecnologĂa. Laboratorio de CronobiologĂa; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Ghiringhelli, Pablo Daniel. Universidad Nacional de Quilmes. Departamento de Ciencia y TecnologĂa. Laboratorio de Ing.genĂ©tica y Biolog.molecular y Celular. Area Virus de Insectos; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Golombek, Diego Andres. Universidad Nacional de Quilmes. Departamento de Ciencia y TecnologĂa. Laboratorio de CronobiologĂa; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; Argentin
Notch signaling during human T cell development
Notch signaling is critical during multiple stages of T cell development in both mouse and human. Evidence has emerged in recent years that this pathway might regulate T-lineage differentiation differently between both species. Here, we review our current understanding of how Notch signaling is activated and used during human T cell development. First, we set the stage by describing the developmental steps that make up human T cell development before describing the expression profiles of Notch receptors, ligands, and target genes during this process. To delineate stage-specific roles for Notch signaling during human T cell development, we subsequently try to interpret the functional Notch studies that have been performed in light of these expression profiles and compare this to its suggested role in the mouse
Timeless Links Replication Termination to Mitotic Kinase Activation
The mechanisms that coordinate the termination of DNA replication with progression through mitosis are not completely understood. The human Timeless protein (Tim) associates with S phase replication checkpoint proteins Claspin and Tipin, and plays an important role in maintaining replication fork stability at physical barriers, like centromeres, telomeres and ribosomal DNA repeats, as well as at termination sites. We show here that human Tim can be isolated in a complex with mitotic entry kinases CDK1, Auroras A and B, and Polo-like kinase (Plk1). Plk1 bound Tim directly and colocalized with Tim at a subset of mitotic structures in M phase. Tim depletion caused multiple mitotic defects, including the loss of sister-chromatid cohesion, loss of mitotic spindle architecture, and a failure to exit mitosis. Tim depletion caused a delay in mitotic kinase activity in vivo and in vitro, as well as a reduction in global histone H3 S10 phosphorylation during G2/M phase. Tim was also required for the recruitment of Plk1 to centromeric DNA and formation of catenated DNA structures at human centromere alpha satellite repeats. Taken together, these findings suggest that Tim coordinates mitotic kinase activation with termination of DNA replication
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