Aberrant NMDA receptor (NMDAR) activity contributes to several neurological disorders, but direct antagonism is poorly tolerated therapeutically. The GluN2B cytoplasmic C-terminal domain (CTD) ...represents an alternative therapeutic target since it potentiates excitotoxic signaling. The key GluN2B CTD-centred event in excitotoxicity is proposed to involve its phosphorylation at Ser-1303 by Dapk1, that is blocked by a neuroprotective cell-permeable peptide mimetic of the region. Contrary to this model, we find that excitotoxicity can proceed without increased Ser-1303 phosphorylation, and is unaffected by Dapk1 deficiency in vitro or following ischemia in vivo. Pharmacological analysis of the aforementioned neuroprotective peptide revealed that it acts in a sequence-independent manner as an open-channel NMDAR antagonist at or near the Mg
site, due to its high net positive charge. Thus, GluN2B-driven excitotoxic signaling can proceed independently of Dapk1 or altered Ser-1303 phosphorylation.
Recurrence is frequent in pediatric ependymoma (EPN). Our longitudinal integrated analysis of 30 patient-matched repeated relapses (3.67 ± 1.76 times) over 13 years (5.8 ± 3.8) reveals stable ...molecular subtypes (RELA and PFA) and convergent DNA methylation reprogramming during serial relapses accompanied by increased orthotopic patient derived xenograft (PDX) (13/27) formation in the late recurrences. A set of differentially methylated CpGs (DMCs) and DNA methylation regions (DMRs) are found to persist in primary and relapse tumors (potential driver DMCs) and are acquired exclusively in the relapses (potential booster DMCs). Integrating with RNAseq reveals differentially expressed genes regulated by potential driver DMRs (CACNA1H, SLC12A7, RARA in RELA and HSPB8, GMPR, ITGB4 in PFA) and potential booster DMRs (PLEKHG1 in RELA and NOTCH, EPHA2, SUFU, FOXJ1 in PFA tumors). DMCs predicators of relapse are also identified in the primary tumors. This study provides a high-resolution epigenetic roadmap of serial EPN relapses and 13 orthotopic PDX models to facilitate biological and preclinical studies.
Background Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well ...studied in models of these disorders, however differences in fear response behaviours are often overlooked. We aim to examine fear behaviour and its cellular underpinnings in a rat model of ASD/ID lacking Nlgn3. Methods This study uses a range of behavioural tests to understand differences in fear response behaviour in Nlgn3.sup.-/y rats. Following this, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in flight-or-freeze responses. We used whole-cell patch-clamp recordings from ex vivo PAG slices, in addition to in vivo local-field potential recordings and electrical stimulation of the PAG in wildtype and Nlgn3.sup.-/y rats. We analysed behavioural data with two- and three-way ANOVAS and electrophysiological data with generalised linear mixed modelling (GLMM). Results We observed that, unlike the wildtype, Nlgn3.sup.-/y rats are more likely to response with flight rather than freezing in threatening situations. Electrophysiological findings were in agreement with these behavioural outcomes. We found in ex vivo slices from Nlgn3.sup.-/y rats that neurons in dorsal PAG (dPAG) showed intrinsic hyperexcitability compared to wildtype. Similarly, stimulating dPAG in vivo revealed that lower magnitudes sufficed to evoke flight behaviour in Nlgn3.sup.-/y than wildtype rats, indicating the functional impact of the increased cellular excitability. Limitations Our findings do not examine what specific cell type in the PAG is likely responsible for these phenotypes. Furthermore, we have focussed on phenotypes in young adult animals, whilst the human condition associated with NLGN3 mutations appears during the first few years of life. Conclusions We describe altered fear responses in Nlgn3.sup.-/y rats and provide evidence that this is the result of a circuit bias that predisposes flight over freeze responses. Additionally, we demonstrate the first link between PAG dysfunction and ASD/ID. This study provides new insight into potential pathophysiologies leading to anxiety disorders and changes to fear responses in individuals with ASD. Keywords: Fear, Freezing, Flight, Autism, Intellectual disability, Periaqueductal grey, Neuroligin-3
The selection of low-radioactive construction materials is of the utmost importance for rare-event searches and thus critical to the XENONnT experiment. Results of an extensive radioassay program are ...reported, in which material samples have been screened with gamma-ray spectroscopy, mass spectrometry, and
222
Rn emanation measurements. Furthermore, the cleanliness procedures applied to remove or mitigate surface contamination of detector materials are described. Screening results, used as inputs for a XENONnT Monte Carlo simulation, predict a reduction of materials background (
∼
17%) with respect to its predecessor XENON1T. Through radon emanation measurements, the expected
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Rn activity concentration in XENONnT is determined to be 4.2 (
-
0.7
+
0.5
)
μ
Bq/kg, a factor three lower with respect to XENON1T. This radon concentration will be further suppressed by means of the novel radon distillation system.
Abstract Gram-positive pathogens isolated in 15 Canadian hospital laboratories between 2011 and 2013 were tested for susceptibility to oritavancin and comparative antimicrobial agents using the ...Clinical and Laboratory Standards Institute broth microdilution method. Oritavancin demonstrated in vitro activity equivalent to, or more potent than, vancomycin, daptomycin, linezolid, and tigecycline against the isolates of methicillin-susceptible Staphylococcus aureus ( n = 1460; oritavancin MIC90 , 0.06 μg/mL; 99.7% oritavancin-susceptible), methicillin-resistant S. aureus ( n = 427; oritavancin MIC90 , 0.06 μg/mL; 99.5% oritavancin-susceptible), Streptococcus pyogenes ( n = 132; oritavancin MIC90 , 0.25 μg/mL; 99.2% oritavancin-susceptible), Streptococcus agalactiae ( n = 156; oritavancin MIC90 , 0.12 μg/mL; 100% oritavancin-susceptible), and Enterococcus faecalis ( n = 304; oritavancin MIC90 , 0.06 μg/mL; 98.7% oritavancin-susceptible) tested.
Objectives
Observational studies have suggested that a higher 25-hydroxyvitamin D concentration may be associated with longer telomere length; however, this has not been investigated in randomised ...controlled trials. We conducted an ancillary study within a randomised, double-blind, placebo-controlled trial of monthly vitamin D (the D-Health Trial) for the prevention of all-cause mortality, conducted from 2014 to 2020, to assess the effect of vitamin D supplementation on telomere length (measured as the telomere to single copy gene (T/S) ratio).
Design, Setting, Participants, and Intervention
Participants were Australians aged 60–84 years and we randomly selected 1,519 D-Health participants (vitamin D: n=744; placebo: n=775) for this analysis. We used quantitative polymerase chain reaction to measure the relative telomere length (T/S ratio) at 4 or 5 years after randomisation. We compared the mean T/S ratio between the vitamin D and placebo groups to assess the effect of vitamin D supplementation on relative telomere length, using a linear regression model with adjustment for age, sex, and state which were used to stratify the randomisation.
Results
The mean T/S ratio was 0.70 for both groups (standard deviation 0.18 and 0.16 for the vitamin D and placebo groups respectively). The adjusted mean difference (vitamin D minus placebo) was −0.001 (95% CI −0.02 to 0.02). There was no effect modification by age, sex, body mass index, or predicted baseline 25-hydroxyvitamin D concentration.
Conclusion
In conclusion, routinely supplementing older adults, who are largely vitamin D replete, with monthly doses of vitamin D is unlikely to influence telomere length.
The recent discovery that peroxisome proliferator-activated receptor γ (PPARγ) targeted anti-diabetic drugs function by inhibiting Cdk5-mediated phosphorylation of the receptor has provided a new ...viewpoint to evaluate and perhaps develop improved insulin-sensitizing agents. Herein we report the development of a novel thiazolidinedione that retains similar anti-diabetic efficacy as rosiglitazone in mice yet does not elicit weight gain or edema, common side effects associated with full PPARγ activation. Further characterization of this compound shows GQ-16 to be an effective inhibitor of Cdk5-mediated phosphorylation of PPARγ. The structure of GQ-16 bound to PPARγ demonstrates that the compound utilizes a binding mode distinct from other reported PPARγ ligands, although it does share some structural features with other partial agonists, such as MRL-24 and PA-082, that have similarly been reported to dissociate insulin sensitization from weight gain. Hydrogen/deuterium exchange studies reveal that GQ-16 strongly stabilizes the β-sheet region of the receptor, presumably explaining the compound's efficacy in inhibiting Cdk5-mediated phosphorylation of Ser-273. Molecular dynamics simulations suggest that the partial agonist activity of GQ-16 results from the compound's weak ability to stabilize helix 12 in its active conformation. Our results suggest that the emerging model, whereby “ideal” PPARγ-based therapeutics stabilize the β-sheet/Ser-273 region and inhibit Cdk5-mediated phosphorylation while minimally invoking adipogenesis and classical agonism, is indeed a valid framework to develop improved PPARγ modulators that retain antidiabetic actions while minimizing untoward effects.
Background: PPARγ agonists improve insulin sensitivity but also evoke weight gain.
Results: GQ-16 is a PPARγ partial agonist that blocks receptor phosphorylation by Cdk5 and improves insulin sensitivity in diabetic mice in the absence of weight gain.
Conclusion: The unique binding mode of GQ-16 appears to be responsible for the compound's advantageous pharmacological profile.
Significance: Similar compounds could have promise as anti-diabetic therapeutics.
Individuals with Down syndrome (DS; trisomy 21) display hyperactivation of interferon (IFN) signaling and chronic inflammation, which could potentially be explained by the extra copy of four IFN ...receptor (IFNR) genes encoded on chromosome 21. However, the clinical effects of IFN hyperactivity in DS remain undefined. Here, we report that a commonly used mouse model of DS overexpresses IFNR genes and shows hypersensitivity to IFN ligands in diverse immune cell types. When treated repeatedly with a TLR3 agonist to induce chronic inflammation, these animals overexpress key IFN-stimulated genes, induce cytokine production, exhibit liver pathology, and undergo rapid weight loss. Importantly, the lethal immune hypersensitivity and cytokine production and the ensuing pathology are ameliorated by JAK1 inhibition. These results indicate that individuals with DS may experience harmful hyperinflammation upon IFN-inducing immune stimuli, as observed during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, pointing to JAK1 inhibition as a strategy to restore immune homeostasis in DS.
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•A mouse model of Down syndrome displays lethal immune hypersensitivity•A heightened inflammatory response is associated with rapid wasting•Liver pathology is revealed in this mouse model and exacerbated by immune activation•JAK1 and JAK1/2 inhibitors provide therapeutic benefits in this mouse model
Individuals with Down syndrome (DS) display hyperactivation of interferon (IFN) signaling and chronic inflammation. Using a mouse model of DS, Tuttle et al. demonstrate a dysregulated antiviral response associated with heightened inflammation, liver pathology, and lethal weight loss. JAK inhibitors counteract this immune hypersensitivity and provide therapeutic benefits in mice.
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