Recent human clinical studies with the NMDA receptor (NMDAR) antagonist ketamine have revealed profound and long-lasting antidepressant effects with rapid onset in several clinical trials, but ...antidepressant effects were preceded by dissociative side effects. Here we show that GLYX-13, a novel NMDAR glycine-site functional partial agonist, produces an antidepressant-like effect in the Porsolt, novelty induced hypophagia, and learned helplessness tests in rats without exhibiting substance abuse-related, gating, and sedative side effects of ketamine in the drug discrimination, conditioned place preference, pre-pulse inhibition and open-field tests. Like ketamine, the GLYX-13-induced antidepressant-like effects required AMPA/kainate receptor activation, as evidenced by the ability of NBQX to abolish the antidepressant-like effect. Both GLYX-13 and ketamine persistently (24 h) enhanced the induction of long-term potentiation of synaptic transmission and the magnitude of NMDAR-NR2B conductance at rat Schaffer collateral-CA1 synapses in vitro. Cell surface biotinylation studies showed that both GLYX-13 and ketamine led to increases in both NR2B and GluR1 protein levels, as measured by Western analysis, whereas no changes were seen in mRNA expression (microarray and qRT-PCR). GLYX-13, unlike ketamine, produced its antidepressant-like effect when injected directly into the medial prefrontal cortex (MPFC). These results suggest that GLYX-13 produces an antidepressant-like effect without the side effects seen with ketamine at least in part by directly modulating NR2B-containing NMDARs in the MPFC. Furthermore, the enhancement of 'metaplasticity' by both GLYX-13 and ketamine may help explain the long-lasting antidepressant effects of these NMDAR modulators. GLYX-13 is currently in a Phase II clinical development program for treatment-resistant depression.
Introduction:
The N-methyl-d-aspartate receptor-ionophore complex plays a key role in learning and memory and has efficacy in animals and humans with affective disorders. GLYX-13 is an ...N-methyl-d-aspartate receptor (NMDAR) glycine-site functional partial agonist and cognitive enhancer that also shows rapid antidepressant activity without psychotomimetic side effects.
Areas covered:
The authors review the mechanism of action of GLYX-13 that was investigated in preclinical studies and evaluated in clinical studies. Specifically, the authors review its pharmacology, pharmacokinetics, and drug safety that were demonstrated in clinical studies.
Expert opinion:
NMDAR full antagonists can produce rapid antidepressant effects in treatment-resistant subjects; however, they are often accompanied by psychotomimetic effects that make chronic use outside of a clinical trial inpatient setting problematic. GLYX-13 appears to exert its antidepressant effects in the frontal cortex via NMDAR-triggered synaptic plasticity. Understanding the mechanistic underpinning of GLYX-13's antidepressant action should provide both novel insights into the role of the glutamatergic system in depression and identify new targets for therapeutic development.
Purpose Concern about possible false-negative prostate biopsy histopathology findings often leads to rebiopsy. A quantitative methylation specific polymerase chain reaction assay panel, including ...GSTP1 , APC and RASSF1 , could increase the sensitivity of detecting cancer over that of pathological review alone, leading to a high negative predictive value and a decrease in unnecessary repeat biopsies. Materials and Methods The MATLOC study blindly tested archived prostate biopsy needle core tissue samples of 498 subjects from the United Kingdom and Belgium with histopathologically negative prostate biopsies, followed by positive (cases) or negative (controls) repeat biopsy within 30 months. Clinical performance of the epigenetic marker panel, emphasizing negative predictive value, was assessed and cross-validated. Multivariate logistic regression was used to evaluate all risk factors. Results The epigenetic assay performed on the first negative biopsies of this retrospective review cohort resulted in a negative predictive value of 90% (95% CI 87–93). In a multivariate model correcting for patient age, prostate specific antigen, digital rectal examination and first biopsy histopathological characteristics the epigenetic assay was a significant independent predictor of patient outcome (OR 3.17, 95% CI 1.81–5.53). Conclusions A multiplex quantitative methylation specific polymerase chain reaction assay determining the methylation status of GSTP1 , APC and RASSF1 was strongly associated with repeat biopsy outcome up to 30 months after initial negative biopsy in men with suspicion of prostate cancer. Adding this epigenetic assay could improve the prostate cancer diagnostic process and decrease unnecessary repeat biopsies.
Cerebral small vessel disease (SVD) is the major cause of intracerebral hemorrhage (ICH). There is no comprehensive, easily applicable classification of ICH subtypes according to the presumed ...underlying SVD using MRI. We developed an MRI-based classification for SVD-related ICH.
We performed a retrospective study in the prospectively collected Swiss Stroke Registry (SSR, 2013-2019) and the Stroke InvestiGation in North And central London (SIGNAL) cohort. Patients with nontraumatic, SVD-related ICH and available MRI within 3 months were classified as Cerebral Amyloid angiopathy (CAA), Deep perforator arteriopathy (DPA), Mixed CAA-DPA, or Undetermined SVD using hemorrhagic and nonhemorrhagic MRI markers (CADMUS classification). The primary outcome was inter-rater reliability using Gwet's AC1. Secondary outcomes were recurrent ICH/ischemic stroke at 3 months according to the CADMUS phenotype. We performed Firth penalized logistic regressions and competing risk analyses.
The SSR cohort included 1,180 patients (median age interquartile range 73 62-80 years, baseline NIH Stroke Scale 6 2-12, 45.6% lobar hematoma, systolic blood pressure on admission 166 145-185 mm Hg). The CADMUS phenotypes were as follows: mixed CAA-DPA (n = 751 patients, 63.6%), undetermined SVD (n = 203, 17.2%), CAA (n = 154, 13.1%), and DPA (n = 72, 6.3%), with a similar distribution in the SIGNAL cohort (n = 313). Inter-rater reliability was good (Gwet's AC1 for SSR/SIGNAL 0.69/0.74). During follow-up, 56 patients had 57 events (28 ICH, 29 ischemic strokes). Three-month event rates were comparable between the CADMUS phenotypes.
CADMUS, a novel MRI-based classification for SVD-associated ICH, is feasible and reproducible and may improve the classification of ICH subtypes in clinical practice and research.
Selective serotonin reuptake inhibitors (SSRIs) are the only effective pharmacological treatments for obsessive-compulsive disorder (OCD). Nonetheless, their generally limited efficacy, side-effects, ...and delayed onset of action require improved medications for this highly prevalent disorder. Preclinical and clinical findings have suggested serotonin2C (5-HT
) receptors as a potential drug target. Data in rats and mice are presented here on the effects of a novel 5-HT
receptor agonist ((3S)-3-Methyl-1-4-(trifluoromethyl)-7-benzofuranyl-piperazine) (CPD 1) with high potency and full efficacy at 5-HT
receptors and less potency and partial agonism at 5-HT
and 5-HT
receptors. Effects of CPD 1 on consummatory (schedule-induced polydipsia in rats) and non-consummatory behaviors (marble-burying and nestlet-shredding in mice) that are repetitive and non-habituating were studied. We also evaluated the effects of CPD 1 in rats with isoproterenol- and deprivation-induced drinking in rats to compare with the polydipsia studies. The SSRIs, fluoxetine, and chlomipramine decreased the high rates of drinking in rats engendered by a schedule of intermittent food delivery (schedule-induced polydipsia). The effects of fluoxetine, but not of d-amphetamine, were prevented by the selective 5-HT
receptor antagonist SB242084. The 5-HT
receptor agonists Ro 60-0175 and CPD 1 also decreased drinking, but unlike the SSRIs and Ro 60-0175, CPD 1 dose-dependently decreased excessive drinking without affecting lever press responses that produced food. The effects of CPD 1 were prevented by SB242084. CPD 1 also suppressed drinking induced by isoproterenol and by water deprivation without affecting normative drinking behavior. CPD 1, like fluoxetine, also suppressed marble-burying and nestlet-shredding in mice at doses that did not affect rotarod performance or locomotor activity. The behavioral specificity of effects of CPD 1 against repetitive and excessive behaviors suggests a potential therapeutic application in OCD.
Energy system models underpin decisions by energy system planners and operators. Energy system modeling faces a transformation: accounting for changing meteorological conditions imposed by climate ...change. To enable that transformation, a community of practice in energy-climate modeling has started to form that aims to better integrate energy system models with weather and climate models. Here, we evaluate the disconnects between the energy system and climate modeling communities, then lay out a research agenda to bridge those disconnects. In the near-term, we propose interdisciplinary activities for expediting uptake of future climate data in energy system modeling. In the long-term, we propose a transdisciplinary approach to enable development of (1) energy-system-tailored climate datasets for historical and future meteorological conditions and (2) energy system models that can effectively leverage those datasets. This agenda increases the odds of meeting ambitious climate mitigation goals by systematically capturing and mitigating climate risk in energy sector decision-making.
Display omitted
An emerging body of literature highlights diverse threats that climate change might pose to reliable, resilient, affordable, and clean energy provision. The potential consequences of these threats are underscored by recent real-world events, like rolling blackouts in California and Texas. In recognition of these threats, a community of practice in energy-climate modeling has started to form that aims to better coordinate two types of models: (1) energy system models and (2) weather and climate models. Several disconnects between these two modeling communities hinder the use of the full potential of climate expertise and information in energy system modeling.
To overcome these disconnects, we propose a research agenda consisting of near-term interdisciplinary activities and long-term transdisciplinary activities among the energy and climate modeling communities. In the near-term, our proposed interdisciplinary activities aim to expedite the use of climate data in energy system modeling, generating much-needed insights for decision-makers. In the long-term, our proposed transdisciplinary activities aim to enable two developments: energy-system-tailored climate datasets for historical and future meteorological conditions and energy system models that can effectively leverage those datasets. Achieving this research agenda will require global energy and climate modeling communities and their funders to reframe and reconsider their methods and processes.
Disconnects between energy and climate modeling communities prevent the use of the full potential of climate expertise and information in energy system modeling. This perspective details those disconnects by describing the work of a member of each community and proposes near- and long-term interdisciplinary and transdisciplinary activities among the energy and climate modeling communities to overcome them. Proposed actions will require reframing and reconsidering methods and processes currently used to create and share data and knowledge between climate and energy modeling communities.
An endogenous cannabinoid system may play an important role in controlling memory processes. SR141716A ...(N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride), a selective cannabinoid CB(1) receptor antagonist, was studied in an eight-arm radial maze task in which either deficits or improvements in memory could be detected. This task required well-trained rats to recall after either a relatively short (3 h) or long (7 h) delay period where they had received rewards during an information phase in order to obtain the remaining rewards during a retention phase. SR141716A was administered intraperitoneally immediately after the information phase in order to determine the drug's effects on memory consolidation. Although SR141716A had no effect on the number of errors committed after a short interval, SR141716A significantly reduced the number of errors that occurred after 7 h. These results suggest that a cannabinoid CB(1) receptor antagonist can improve consolidation processes and thus may be useful in treating memory disorders.
Introduction:
Deep perforator arteriolopathy (DPA) causes intracerebral haemorrhage (ICH) and lacunar strokes (LS). We compare patient characteristics, MRI findings and clinical outcomes among ...patients with deep ICH and LS.
Patients and methods:
We included patients with MRI-confirmed LS or ICH in the basal ganglia, thalamus, internal capsule or brainstem from the Bernese Stroke Registry. We assessed MRI small vessel disease (SVD) markers, SVD burden score, modified Rankin Scale (mRS) and ischaemic stroke or ICH at 3 months.
Results:
We included 716 patients, 117 patients (16.3%) with deep ICH (mean age (SD) 65.1 (±15.2) years, 37.1% female) and 599 patients (83.7%) with LS (mean age (SD) 69.7 (±13.6) years, 39.9% female). Compared to LS, deep ICH was associated with a higher SVD burden score (median (IQR) 2 (1–2) vs 1 (0–2)), aORshift 3.19, 95%CI 2.15–4.75). Deep ICH patients had more often cerebral microbleeds (deep ICH: 71.6% vs LS: 29.2%, p < 0.001, median count (IQR) 4(2–12) vs 2(1–6)) and a higher prevalence of lacunes (deep ICH: 60.5% vs LS: 27.4% p < 0.001). At 3 months, deep ICH was associated with higher mRS (aORshift 2.16, 95%CI 1.21–3.87). Occurrence of ischaemic stroke was numerically but not significantly higher in deep ICH (4.3% vs 2.9%; p = 0.51). One patient (1.1%) with ICH but none with LS suffered ICH recurrence.
Discussion/Conclusion:
DPA manifesting as ICH is associated with more severe MRI SVD burden and worse outcome compared to LS. The short-term risks of subsequent ischaemic stroke and recurrent ICH are similar in ICH and LS patients. This implies potential consequences for future secondary prevention strategies.
Graphical abstract
PIEZO1 is a subunit of mechanically-activated, nonselective cation channels. Gain-of-function PIEZO1 mutations are associated with dehydrated hereditary stomatocytosis (DHS), a type of anaemia, due ...to abnormal red blood cell function. Here, we hypothesised additional effects on the heart. Consistent with this hypothesis, mice engineered to contain the M2241R mutation in PIEZO1 to mimic a DHS mutation had increased cardiac mass and interventricular septum thickness at 8-12 weeks of age, without altered cardiac contractility. Myocyte size was greater and there was increased expression of genes associated with cardiac hypertrophy (
,
and
). There was also cardiac fibrosis, increased expression of
(a gene associated with fibrosis) and increased responses of isolated cardiac fibroblasts to PIEZO1 agonism. The data suggest detrimental effects of excess PIEZO1 activity on the heart, mediated in part by amplified PIEZO1 function in cardiac fibroblasts.
PDF
