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Mohr diagrams are a simple and effective method that can help geoscientists consider, model, and predict the ranges of mechanical properties of rock, stresses, fluid pressures, and the resultant fractures that are likely to occur in the sub-surface. Mohr diagrams can be used to make predictions about how rocks may respond to change, with a transition from a stable state to fracturing occurring if there are changes in (1) the failure envelope, (2) stresses, and/or (3) fluid pressure. This article uses Mohr diagrams to address two questions of significance to the energy transition. First, how will metasedimentary rocks, which are potential geothermal reservoir rocks, respond to thermal stimulation? Second, will fractures that may influence the underground storage of radioactive waste develop in a clay sequence during exhumation? Mohr diagrams are shown to be useful for highlighting misconceptions and input data problems, leading to improved understanding of how structures develop., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

The temporal bisection procedure has been used to assess theories of time perception. A problem with the procedure for measuring the perceived midpoint of two durations is that the spacing of probe durations affects the length of the bisection point. Linear spacing results in longer bisection points closer to the arithmetic mean of the durations than logarithmic spacing. In three experiments, the influence of probe duration distribution was avoided by presenting a single probe duration of either the arithmetic or geometric mean of the trained durations. It was found that the number of participants that categorised the arithmetic mean as long was significantly larger than those that categorised it as short. The number of participants that categorised the geometric mean as either short or long did not significantly differ. This was true for trained durations of 0.4 s vs. 1.6 s (Experiments 1-3), 0.2 s vs. 3.2 s (Experiment 2) and 0.4 s vs. 6.4 s (Experiment 3). In Experiment 4, the probe trial distribution effect was replicated with logarithmic and linearly distributed probe durations, demonstrating that bisection occurs close to the arithmetic mean with linearly spaced probe durations. The results provide evidence against bisection at the arithmetic mean when probe spacing bias is avoided and, instead, the results are consistent with logarithmic encoding of time, or a comparison rule based on relative rather than absolute differences., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier B.V.)

The hippocampus has been implicated in temporal learning. Plasticity within the hippocampus requires NMDA receptor-dependent glutamatergic neurotransmission. We tested the prediction that hippocampal NMDA receptors are required for learning about time by testing mice that lack postembryonal NMDARs in the CA1 and dentate gyrus (DG) hippocampal subfields on three different appetitive temporal learning procedures. The conditional knockout mice (Grin1 ΔDCA1 ) showed normal sensitivity to cue duration, responding at a higher level to a short duration cue than compared to a long duration cue. Knockout mice also showed normal precision and accuracy of response timing in the peak procedure in which reinforcement occurred after 10 s delay within a 30 s cue presentation. Mice were tested on the matching of response rates to reinforcement rates on instrumental conditioning with two levers reinforced on a concurrent variable interval schedule. Pressing on one lever was reinforced at a higher rate than the other lever. Grin1 ΔDGCA1 mice showed normal sensitivity to the relative reinforcement rates of the levers. In contrast to the lack of effect of hippocampal NMDAR deletion on measures of temporal sensitivity, Grin1 ΔDGCA1 mice showed increased baseline measures of magazine activity and lever pressing. Furthermore, reversal learning was enhanced when the reward contingencies were switched in the lever pressing task, but this was true only for mice trained with a large difference between relative reinforcement rates between the levers. The results failed to demonstrate a role for NMDARs in excitatory CA1 and DG neurons in learning about temporal information., (© 2023 The Authors. Hippocampus published by Wiley Periodicals LLC.)

Psychosis in disorders like schizophrenia is commonly associated with aberrant salience and elevated striatal dopamine. However, the underlying cause(s) of this hyper-dopaminergic state remain elusive. Various lines of evidence point to glutamatergic dysfunction and impairments in synaptic plasticity in the etiology of schizophrenia, including deficits associated with the GluA1 AMPAR subunit. GluA1 knockout (Gria1 -/- ) mice provide a model of impaired synaptic plasticity in schizophrenia and exhibit a selective deficit in a form of short-term memory which underlies short-term habituation. As such, these mice are unable to reduce attention to recently presented stimuli. In this study we used fast-scan cyclic voltammetry to measure phasic dopamine responses in the nucleus accumbens of Gria1 -/- mice to determine whether this behavioral phenotype might be a key driver of a hyper-dopaminergic state. There was no effect of GluA1 deletion on electrically-evoked dopamine responses in anaesthetized mice, demonstrating normal endogenous release properties of dopamine neurons in Gria1 -/- mice. Furthermore, dopamine signals were initially similar in Gria1 -/- mice compared to controls in response to both sucrose rewards and neutral light stimuli. They were also equally sensitive to changes in the magnitude of delivered rewards. In contrast, however, these stimulus-evoked dopamine signals failed to habituate with repeated presentations in Gria1 -/- mice, resulting in a task-relevant, hyper-dopaminergic phenotype. Thus, here we show that GluA1 dysfunction, resulting in impaired short-term habituation, is a key driver of enhanced striatal dopamine responses, which may be an important contributor to aberrant salience and psychosis in psychiatric disorders like schizophrenia., (© 2022. The Author(s).)

The mono-ADP-ribosyltransferase PARP7 has emerged as a key negative regulator of cytosolic NA-sensors of the innate immune system. We apply a rational design strategy for converting a pan-PARP inhibitor into a potent selective PARP7 inhibitor (KMR-206). Consistent with studies using the structurally distinct PARP7 inhibitor RBN-2397, co-treatment of mouse embryonic fibroblasts with KMR-206 and NA-sensor ligands synergistically induced the expression of the type I interferon, IFN-β. In mouse colon carcinoma (CT-26) cells, KMR-206 alone induced IFN-β. Both KMR-206 and RBN-2397 increased PARP7 protein levels in CT-26 cells, demonstrating that PARP7's catalytic activity regulates its own protein levels. Curiously, treatment with saturating doses of KMR-206 and RBN-2397 achieved different levels of PARP7 protein, which correlated with the magnitude of type I interferon gene expression. These latter results have important implications for the mechanism of action of PARP7 inhibitors and highlights the usefulness of having structurally distinct chemical probes for the same target., Competing Interests: Declaration of interests M.S.C, D.J.S, K.M.R, and S.S are co-inventors on a provisional patent describing the inhibitors in this study., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

PARP7 is an enzyme that catalyzes mono-ADP-ribosylation (MARylation), is a critical regulator of type I interferon signaling, and has emerged as an immune-oncology drug candidate. PARP7 is a labile protein that is regulated in a proteasome-dependent manner. Indeed, endogenous PARP7 levels are undetectable by western blot in most cells. Intriguingly, treatment of cells with orthosteric small molecule inhibitors of PARP7 can increase endogenous PARP7 protein to detectable levels. This characteristic of PARP7 inhibitors could potentially be exploited to assess target engagement-and thus cellular efficacy-of PARP7 inhibitors; however, no method exists to quantitatively monitor endogenous PARP7 levels in a high-throughput manner. In this protocol, we describe an assay using a split Nanoluciferase (NanoLuc) system for quantifying endogenous PARP7 protein levels and PARP7 inhibitor target engagement in cells in a 96-well plate format. We show that this assay can be used to quantify PARP7 protein levels under various cellular treatments and can assess cellular PARP7 inhibitor target engagement. We envision this split NanoLuc PARP7 assay can be used not only for evaluating the cellular efficacy of PARP7 inhibitors in a high-throughput manner but also for uncovering the mechanisms regulating PARP7 protein levels in cells., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Allosteric coupling between the DNA binding site to the NAD + -binding pocket drives PARP-1 activation. This allosteric communication occurs in the reverse direction such that NAD + mimetics can enhance PARP-1's affinity for DNA, referred to as type I inhibition. The cellular effects of type I inhibition are unknown, largely because of the lack of potent, membrane-permeable type I inhibitors. Here we identify the phthalazinone inhibitor AZ0108 as a type I inhibitor. Unlike the structurally related inhibitor olaparib, AZ0108 induces replication stress in tumorigenic cells. Synthesis of analogs of AZ0108 revealed features of AZ0108 that are required for type I inhibition. One analog, Pip6, showed similar type I inhibition of PARP-1 but was ∼90-fold more cytotoxic than AZ0108. Washout experiments suggest that the enhanced cytotoxicity of Pip6 compared with AZ0108 is due to prolonged target residence time on PARP-1. Pip6 represents a new class of PARP-1 inhibitors that may have unique anticancer properties., Competing Interests: Declaration of interests M.R.A. and M.S.C. are inventors on a patent related to the compounds generated from this manuscript. M.S.C. is a founder of Tilikum Therapeutics., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Conditioned responding is sensitive to reinforcement rate. This rate-sensitivity is impaired in genetically modified mice that lack the GluA1 subunit of the AMPA receptor. A time-dependent application of the Rescorla-Wagner learning rule can be used to derive an account of rate-sensitivity by reflecting the balance of excitatory and inhibitory associative strength over time. By applying this analysis, the impairment in GluA1 knockout mice may be explained by reduced sensitivity to negative prediction error and thus, impaired inhibitory learning, such that excitatory associative strength is not reduced during the nonreinforced periods of a conditioned stimulus. The article describes a test of the role of GluA1 in inhibitory learning that requires summing of the associative strengths of cues presented in compound. Mice were trained on a feature negative discrimination of the form A+/AX-. GluA1 knockout mice acquired the discrimination to a similar extent as controls. The inhibitory properties of cue X were verified in a summation test that included a control for nonassociative, external inhibition. The performance of GluA1 knockout mice was similar to that of controls. However, in line with previous findings, GluA1 deletion impaired the precision of timing of conditioned responding. These results provide further evidence that impaired sensitivity to reinforcement rate is not a consequence of impaired inhibitory learning. The results may more readily fit with accounts of rate sensitivity that propose that it reflects encoding of temporal and numeric information rather than being a consequence of changes in associative strength over time. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

To establish the economic value of simple robotic hysterectomy vs laparoscopic hysterectomy and assess the impact of surgeon's experience. Retrospective cohort study. University-affiliated US regional healthcare system. Reproductive and post-menopausal women undergoing hysterectomy for benign indications. Robotic or laparoscopic hysterectomy. Between January 2018 and December 2019, a total of 985 simple laparoscopic and robotic hysterectomies were performed by 47 different gynecologists. Overall, the mean payment, direct cost, and profit were comparable (p value > 0.05) among simple robotic and laparoscopic hysterectomy. However, the mean operative time was significantly shorter for robotic hysterectomy compared to laparoscopic hysterectomy (106 min vs 127 min, respectively, p < 0.05). Operative time decreased as a surgeon's annual robotic case volume increased. Per-minute profitability of robotic hysterectomy increased significantly when a surgeon performed greater than 45 cases annually (p = 0.04). This effect became most pronounced when a surgeon performed 60 or more cases per year (p = 0.01). Simple robotic hysterectomy has shorter operative time compared to laparoscopic hysterectomy, with direct costs being similar. Robotic hysterectomy has higher per-minute profit compared to laparoscopic hysterectomy when a surgeon performs > 45 cases per year., (© 2021. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Objective: The objective of this study is to characterize an acceptable health state, using the patient acceptable symptom state (PASS) question, in adult women with urinary incontinence., Methods: This is a prospective multicenter cohort study determining PASS thresholds from condition-specific measures using an electronic research platform in English-speaking women seeking nonsurgical treatment of urinary incontinence between March 2019 and May 2020. Exclusions included pregnancy, isolated overactive bladder, and pelvic organ prolapse greater than stage II. The cohort was described and then grouped based on achievement of PASS. The PASS thresholds were determined using the 75th percentile and univariate regression methods. Multivariable regression modeling was used to understand the influence of covariates on PASS achievement., Results: The study was completed by 100 (80%) of the 125 enrolled subjects. Of these, 45% (n = 45) achieved PASS after a median of 7 weeks of treatment (range, 6-13 weeks). The corresponding questionnaire score for PASS was estimated to be 6 for the Incontinence Severity Index, 3 for the Patient Global Impression of Severity and Improvement, 37.5 using the Urinary Distress Inventory 6, and 33.3 using the Incontinence Impact Questionnaire 7. Increasing age was independently associated with achieving PASS after adjusting for treatment adherence and outcomes scores (adjusted odds ratio, 1.05 [95% confidence interval, 1.01-1.10]; P = 0.02)., Conclusions: PASS was achieved in 45% of women after conservative treatment of urinary incontinence. PASS offers a new perspective for analysis and interpretation of outcome measures used in pelvic floor disorders and can serve as a reference for future research and clinical care pathways., Competing Interests: D.J.S. is a consultant to InterPRO Urology. M.D.B. receives royalties from Elsevier and UpToDate. The other authors have declared they have no conflicts of interest., (Copyright © 2021 American Urogynecologic Society. All rights reserved.)