The organizational effects of oxytocin on the central expression of estrogen receptor α and oxytocin in adulthood

Background: Previous studies have demonstrated that neonatal manipulation of oxytocin (OT) has effects on the expression of estrogen receptor alpha (ER alpha) and the central production of oxytocin observed in juveniles ( at weaning, 21 days of age). The goal of this study was to determine whether the effects of neonatal manipulation of OT last into adulthood, and if the effects differ from those observed during the early postnatal period. On the first day of life, prairie voles ( Microtus ochrogaster) received one of three doses of OT (High, 3 mu g; Med, 0.3 mu g; Low, 0.03 mu g), an OT antagonist, or isotonic saline. Another group was handled, but not injected. Then as adults, brains were collected, sectioned, and stained for ERa or OT using immunocytochemistry. Results: In females, treatment with OT increased the expression of ERa immunoreactivity in the ventral lateral septum (0.03 mu g) and the ventromedial nucleus of the hypothalamus and central amygdala ( 0.3 g). In males, OT antagonist increased ERa expression in the bed nucleus of the stria terminalis. There was no apparent effect of OT on the number of cells producing OT in the paraventricular nucleus of the hypothalamus. Conclusion: The current results suggest that neonatal manipulation of OT has long-term organizational effects on the expression of ERa in both males and females. The lack of effect on OT neurons in the paraventricular nucleus suggests that some developmental effects of OT previously observed in weanlings do not persist into adulthood. Developmental effects of OT on ERa patterns were sexually dimorphic, dose-dependent, and site-specific

The Organizational Effects of Oxytocin on the Central Expression of Estrogen Receptor Alpha and Oxytocin in Adulthood

Background: Previous studies have demonstrated that neonatal manipulation of oxytocin (OT) has effects on the expression of estrogen receptor alpha (ER alpha) and the central production of oxytocin observed in juveniles ( at weaning, 21 days of age). The goal of this study was to determine whether the effects of neonatal manipulation of OT last into adulthood, and if the effects differ from those observed during the early postnatal period. On the first day of life, prairie voles ( Microtus ochrogaster) received one of three doses of OT (High, 3 mu g; Med, 0.3 mu g; Low, 0.03 mu g), an OT antagonist, or isotonic saline. Another group was handled, but not injected. Then as adults, brains were collected, sectioned, and stained for ERa or OT using immunocytochemistry. Results: In females, treatment with OT increased the expression of ERa immunoreactivity in the ventral lateral septum (0.03 mu g) and the ventromedial nucleus of the hypothalamus and central amygdala ( 0.3 g). In males, OT antagonist increased ERa expression in the bed nucleus of the stria terminalis. There was no apparent effect of OT on the number of cells producing OT in the paraventricular nucleus of the hypothalamus. Conclusion: The current results suggest that neonatal manipulation of OT has long-term organizational effects on the expression of ERa in both males and females. The lack of effect on OT neurons in the paraventricular nucleus suggests that some developmental effects of OT previously observed in weanlings do not persist into adulthood. Developmental effects of OT on ERa patterns were sexually dimorphic, dose-dependent, and site-specific

Creation and annihilation of topological meron pairs in in-plane magnetized films

Merons which are topologically equivalent to one-half of skyrmions can exist only in pairs or groups in two-dimensional (2D) ferromagnetic (FM) systems. The recent discovery of meron lattice in chiral magnet Co8Zn9Mn3 raises the immediate challenging question that whether a single meron pair, which is the most fundamental topological structure in any 2D meron systems, can be created and stabilized in a continuous FM film? Utilizing winding number conservation, we develop a new method to create and stabilize a single pair of merons in a continuous Py film by local vortex imprinting from a Co disk. By observing the created meron pair directly within a magnetic field, we determine its topological structure unambiguously and explore the topological effect in its creation and annihilation processes. Our work opens a pathway towards developing and controlling topological structures in general magnetic systems without the restriction of perpendicular anisotropy and Dzyaloshinskii-Moriya interaction

Severity-based treatment for Japanese patients with MPO-ANCA-associated vasculitis: the JMAAV study

We (JMAAV [Japanese patients with MPO-ANCA-associated vasculitis] Study Group) performed a prospective, open-label, multi-center trial to evaluate the usefulness of severity-based treatment in Japanese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA)-associated vasculitis. Patients with MPO-ANCA-associated vasculitis received a severity-based regimen according to the appropriate protocol: low-dose corticosteroid and, if necessary, cyclophosphamide or azathioprine in patients with mild form; high-dose corticosteroid and cyclophosphamide in those with severe form; and the severe-form regimen plus plasmapheresis in those with the most severe form. We followed up the patients for 18 months. The primary end points were the induction of remission, death, and end-stage renal disease (ESRD). Fifty-two patients were registered, and 48 patients were enrolled in this study (mild form, n = 23; severe form, n = 23; most severe form, n = 2). Among the 47 patients who received the predefined therapies, 42 achieved remission within 6 months, 5 died, and 1 developed ESRD. Disease flared up in 8 of the 42 patients with remission during the 18-month follow-up period. The JMAAV trial is the first prospective trial for MPO-ANCA-associated vasculitis to be performed in Japan. The remission and death rates were comparable to those in several previous clinical trials performed in western counties. The regimen employed in this trial was tailor-made based on patients’ disease severity and disease type, and it seems that standardization can be consistent with treatment choices made according to severity

Parents’ differential susceptibility to the effects of marital quality on sensitivity across the first year

The current investigation examined the differential susceptibility of parents to the effects of marital quality on changes in parenting. We predicted that parents who were high on the personality constructs Negative Affect and Constraint would be more susceptible to the effects of marital quality on their level of sensitivity. Sensitivity was assessed at 3.5 and 13 months for both mothers and fathers during a triadic interaction. Consistent with the differential susceptibility theory, results suggested that when mothers were high on Negative Affect and when fathers were high on Constraint, their marital quality was associated with changes in sensitivity. This investigation suggests that personality factors may create “vulnerabilities” in parents that make them differentially susceptible to the effects of the family environment on parentin

Vibrational energy redistribution during donor-acceptor electronic energy transfer: criteria to identify subsets of active normal modes

Photoinduced electronic energy transfer in conjugated donor-acceptor systems is naturally accompanied by intramolecular vibrational energy redistributions accepting an excess of electronic energy. Herein, we simulate these processes in a covalently linked donor-acceptor molecular dyad system by using nonadiabatic excited state molecular dynamics simulations. We analyze different complementary criteria to systematically identify the subset of vibrational normal modes that actively participate on the donoracceptor (S2S1) electronic relaxation. We analyze energy transfer coordinates in terms ofstate-specific normal modes defined according to the different potential energy surfaces (PESs) involved. On one hand, we identify those vibrations that contribute the most to the direction of the main driving force on the nuclei during electronic transitions, represented by the non-adiabatic derivative coupling vector between donor and acceptor electronic states. On the other hand, we monitor normal mode transient accumulations of excess energy and their intramolecular energy redistribution fluxes. We observe that the subset of active modes varies according to the PES on which they belong and these modes experience the most significant rearrangements and mixing. Whereas the nuclear motions that promote donoracceptor energy funneling can be localized mainly on one or two normal modes of the S2 state, they become spread out across multiple normal modes of the S1 state following the energy transfer eventThis work was partially supported by CONICET, UNQ, ANPCyT (PICT-2018-2360), the Universidad Carlos III de Madrid, the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement No. 600371, el Ministerio de Economía, Industria y Competitividad (COFUND2014-51509), el Ministerio de Educación, cultura y Deporte (CEI-15-17), Banco Santander and el Ministerio de Ciencia, Innovación y Universidades (RTI2018-101020-B-I00). We also acknowledge support from the Bavarian University Centre for Latin America (BAYLAT). The work at Los Alamos National Laboratory (LANL) was supported by the Laboratory Directed Research and Development Funds (LDRD) program. This work was done in part at the Center for Nonlinear Studies (CNLS) and the Center for Integrated Nanotechnologies (CINT), a U.S. Department of Energy and Office of Basic Energy Sciences user facility, at LANL. This research used resources provided by the LANL Institutional Computing Program. Los Alamos National Laboratory is operated by Triad National Security, LLC, for the National Nuclear Security Administration of the U.S. Department of Energy. This work has received finantial support provided by the Spanish Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, UE) under Project CTQ2016-79345-P and by the Funda-ción Séneca under Project 20789/PI/18

GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of mouse and human pancreatic islet glucagon secretion.

Diabetes mellitus is associated with impaired insulin secretion, often aggravated by oversecretion of glucagon. Therapeutic interventions should ideally correct both defects. Glucagon-like peptide 1 (GLP-1) has this capability but exactly how it exerts its glucagonostatic effect remains obscure. Following its release GLP-1 is rapidly degraded from GLP-1(7-36) to GLP-1(9-36). We hypothesised that the metabolite GLP-1(9-36) (previously believed to be biologically inactive) exerts a direct inhibitory effect on glucagon secretion and that this mechanism becomes impaired in diabetes. We used a combination of glucagon secretion measurements in mouse and human islets (including islets from donors with type 2 diabetes), total internal reflection fluorescence microscopy imaging of secretory granule dynamics, recordings of cytoplasmic Ca <sup>2+</sup> and measurements of protein kinase A activity, immunocytochemistry, in vivo physiology and GTP-binding protein dissociation studies to explore how GLP-1 exerts its inhibitory effect on glucagon secretion and the role of the metabolite GLP-1(9-36). GLP-1(7-36) inhibited glucagon secretion in isolated islets with an IC <sub>50</sub> of 2.5 pmol/l. The effect was particularly strong at low glucose concentrations. The degradation product GLP-1(9-36) shared this capacity. GLP-1(9-36) retained its glucagonostatic effects after genetic/pharmacological inactivation of the GLP-1 receptor. GLP-1(9-36) also potently inhibited glucagon secretion evoked by β-adrenergic stimulation, amino acids and membrane depolarisation. In islet alpha cells, GLP-1(9-36) led to inhibition of Ca <sup>2+</sup> entry via voltage-gated Ca <sup>2+</sup> channels sensitive to ω-agatoxin, with consequential pertussis-toxin-sensitive depletion of the docked pool of secretory granules, effects that were prevented by the glucagon receptor antagonists REMD2.59 and L-168049. The capacity of GLP-1(9-36) to inhibit glucagon secretion and reduce the number of docked granules was lost in alpha cells from human donors with type 2 diabetes. In vivo, high exogenous concentrations of GLP-1(9-36) (>100 pmol/l) resulted in a small (30%) lowering of circulating glucagon during insulin-induced hypoglycaemia. This effect was abolished by REMD2.59, which promptly increased circulating glucagon by >225% (adjusted for the change in plasma glucose) without affecting pancreatic glucagon content. We conclude that the GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of glucagon secretion. We propose that the increase in circulating glucagon observed following genetic/pharmacological inactivation of glucagon signalling in mice and in people with type 2 diabetes reflects the removal of GLP-1(9-36)'s glucagonostatic action