Connollycoates8833

This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.BACKGROUND AND PURPOSE Hispidulin is a flavonoid isolated from Clerodendrum inerme that was found to remit intractable motor tics. Previously, we have found that hispidulin attenuates hyperlocomotion and the disrupted prepulse inhibition (PPI) induced by methamphetamine and N-methyl-d-aspartate (NMDA) receptor blockers, two phenotypes of schizophrenia resembling positive symdromes. Hispidulin can inhibit catechol-O-methyltransferase (COMT), a dopamine-metabolizing enzyme in the prefrontal cortex (PFC) that is important for social interaction. Here, we investigated whether hispidulin would affect social withdrawal, one dimension of negative symptoms in schizophrenia. EXPERIMENTAL APPROACH We examined whether acute administration of hispidulin would attenuate social withdrawal in two mouse models, juvenile isolated disrupted-in-schizophrenia-1 mutant (mutDISC1) mice and chronic phencyclidine (PCP)-treated naïve mice. KEY RESULTS In chronic PCP-treated mice, hispidulin (10 mg/kg, i.p.) attenuated social withdrawal in a manner prevented by a dopamine D1 receptor (D1 R) antagonist (SCH 23390, 0.02 mg/kg, i.p.) and mimicked by a selective COMT inhibitor, OR-486 (10 mg/kg, i.p.). Hispidulin increased extracellular dopamine levels in the PFC of chronic PCP-treated mice. In isolated mutDISC1 mice, hispidulin also rescued social withdrawal. In both models, intra-PFC microinjection of a D1 R agonist (SKF81297 10 nmol/mouse/bilateral) reversed the impairment of Ser897 phosphorylation at the NR1 subunit of NMDA receptors, suggesting the association between NR1 Ser897 -phosphorylation and D1 R activation in the PFC exits in both models. CONCLUSIONS AND IMPLICATIONS Hispidulin rescues social withdrawal by activating D1 Rs indirectly through elevated dopamine levels in the PFC by COMT inhibition. This nature of hispidulin renders it a potential novel therapeutic candidate for negative symptoms in schizophrenia. This article is protected by copyright. All rights reserved.Retroperitoneal ectopic pregnancy (REP) is an extremely rare type of abdominal ectopic pregnancy, with fewer than 25 cases reported worldwide up to 2017.[1] REP is considered to be high risk and life-threatening because it is often located close to large blood vessels. Early diagnosis is usually problematic due to its non-specific symptoms and varied clinical presentation. This article is protected by copyright. All rights reserved.BACKGROUND AND PURPOSE Acute intermittent porphyria (AIP) results from haploinsufficiency of the porphobilinogen deaminase (PBGD) gene encoding the third enzyme in the heme biosynthesis pathway. As liver is the main organ of pathology for AIP, emerging therapies that restore enzyme hepatic levels are appealing. The objective of this work was to develop a mechanistic-based computational framework to describe the effects of novel PBGD mRNA therapy on the accumulation of neurotoxic heme precursors in small and large animal models. EXPERIMENTAL APPROACH Liver PBGD activity data and/or 24-h urinary heme precursors were obtained from genetic AIP mice and wild-type mice, rats, rabbits and macaques. To mimic acute attacks, porphyrogenic drugs were administered over one or multiple challenges and animals were used as controls or treated with different PBGD mRNA products. Available experimental data was sequentially used to build and validate a semi-mechanistic mathematical model using non-linear mixed effects approach. KEY RESULTS The developed framework accounts for the different involved biological processes (i.e. mRNA sequence, release from lipid nanoparticle and degradation, mRNA translation, increased PBGD activity in liver, and heme precursor metabolism) in a simplified mechanistic fashion. The model, validated using external data, shows robustness in the extrapolation of PBGD activity data in rat, rabbit and non-human primate species. CONCLUSION AND IMPLICATIONS This quantitative framework provides a valuable tool to compare PBGD mRNA drug products during early preclinical stages, optimize the amount of experimental data required, and project results to humans, thus supporting drug development and clinical dose and dosing regimen selection. This article is protected by copyright. All rights reserved.KEY POINTS While it has been well described that prolonged rotational stepping will adapt the podokinetic sense of rotation, the mechanisms involved are not clearly understood. By studying podokinetic after-rotations following conditioning rotations not previously reported we have shown that slower rotational velocities are more readily adapted than faster velocities and adaptation occurs more quickly than previously thought. We propose a dynamic feedback model of vestibular and podokinetic adaptation that can fit rotation trajectories across multiple conditions and data sets. Two adaptation processes were identified that may reflect central and peripheral processes and the discussion unifies prior findings in the podokinetic literature under this new framework. The findings show the technique is feasible for people with locomotor turning problems. ABSTRACT After a prolonged period stepping in circles, people walk with a curved trajectory when attempting to walk in a straight line without vision. Podokinetic reasing power function. The response then decayed exponentially. The feedback model of podokinetic and vestibular adaptive processes had a good fit with the data and suggested that podokinetic adaptation is explained by a short (141 s) and a long (27 min) time constant. The podokinetic system adapts more quickly than previously thought and slower rotation is more readily adapted than faster rotation. These findings will have implications for clinical applications of the technique. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.A decade ago, the General Stress Paradigm (GSP) aimed to develop a predictive framework linking predator effects to ecosystem function. ATM/ATR inhibitor The GSP was based on the notion that animals, across taxa, exhibit similar physiological responses to predation risk that divert resources from growth and reproduction [which require N-rich biomolecules (i.e., protein)] to emergency functions [which require C-rich biomolecules (e.g., carbohydrates)]. The GSP predicts that stressed prey should have a greater dietary demand for C-rich resources, a higher body CN ratio, and elevated N excretion. Now, ten years later, we aim to revisit the GSP- using quantitative meta-analysis to test the original predictions of the GSP and how 1) predator hunting mode, 2) multiple stressors, and 3) prey dietary shifts affect prey stoichiometric responses to predation-risk. Our dataset was consistent with previous work showing that predation-risk increases prey glucocorticoid levels and metabolic rates and decreases prey growth rates. We found that predation-risk tended to decrease the fat, carbohydrate, and protein content of prey bodies; increased the CP and NP of prey bodies; but had no effect on the C, N, P or CN content of prey bodies.