Search

The process of relearning locomotor skills is a complex one for the person with a lower-limb amputation. Tracking individuals from the moment they are fitted with a prosthesis until they become competent walkers is a difficult task to achieve with a group of lower-limb amputees. To counter this difficulty, a prosthetic simulator (PS) was designed and created in-house to allow able-bodied individuals to walk in a novel situation. The purpose of the current study was to follow the changes in gait variables during a novel walking task when lower-limb mechanics were altered. Kinematic data were collected from ten able-bodied individuals during 30 minutes of continuous walking with the PS without any instructions. Walking speed, body support times, step characteristics, and the vertical orientation of body segments were analyzed during one time constant, equivalent to 63% of final walking speed. Separate repeated-measures analyses of variance were conducted with p < 0.05. Participants were immediately able to walk unassisted with the PS. Walking speed was initially slow but increased significantly with time (p < 0.000). Time in stance was significantly greater on the intact limb (p < 0.000) and significantly decreased over distance (p < 0.000). Prosthetic step length was significantly longer than intact step length (p < 0.000). Lower-limb segments were significantly less vertically oriented at prosthetic/intact foot contact over time (p < 0.000). Participants were able to adapt quickly to the new locomotor constraints imposed by a PS by modifying kinematic variables. Changes in gait parameters occurred quickly and were retained throughout a 1-week period, suggesting that adaptive strategies were developed early in the task. [ABSTRACT FROM AUTHOR]

STUDY DESIGN: Human subjects were exposed experimentally to a single whiplash-like perturbation. OBJECTIVE: To determine how awareness of the presence and timing of a whiplash-like perturbation affects the onset and amplitude of the neck muscle response and the peak magnitude of head and neck kinematics. SUMMARY OF BACKGROUND DATA: Although most whiplash injuries are sustained in rear-end collisions, which occur without warning, most studies of whiplash injury have used subjects aware of the imminent perturbation. METHODS: Seated subjects (35 women and 31 men) underwent a single forward horizontal perturbation (peak acceleration, 1.5 g). Surface electromyography measured the sternocleidomastoid and cervical paraspinal muscle activity. Three awareness conditions were tested: a countdown for subjects alerted to their perturbation, a perturbation without an alert for subjects who expected it within 60 seconds, and an unexpected perturbation for surprised subjects who were deceived. RESULTS: The muscle and kinematic responses of aware (alerted and unalerted) subjects were not significantly different. Sternocleidomastoid activation occurred 7 ms later in surprised subjects than in aware subjects (P < 0.0002). Cervical paraspinal amplitudes were 260% larger and angular head accelerations in flexion were 180% larger in surprised male subjects than in alerted male subjects. Surprised female subjects exhibited a 25% larger head retraction and a 30% lower forward acceleration of the mastoid process than aware female subjects. CONCLUSIONS: The larger retractions observed in surprised females likely produce larger tissue strains and may increase injury potential. Aware human subjects may not replicate the muscle response, kinematic response, or whiplash injury potential of unprepared occupants in real collisions. [ABSTRACT FROM AUTHOR]

Background and Purpose. Recently, there has been a trend for designers to reduce the weight of wheelchairs. Wheelchair performance is frequently evaluated in clinical as well as laboratory settings by kinematic motion analysis. The purpose of this study was to examine the effect of weight on the kinematics of wheelchair propulsion in nonathletic adults and children with spinal cord injury. Subjects and Methods. The weight of identical new low-weight test chairs (9.3 kg) was manipulated by adding weight (5 and 10 kg) in two matched groups (n= 10) of adults and children with spinal cord injury. The three-dimensional coordinates of reflective markers were obtained as the subjects performed level wheeling at a speed of 2 m/s. Results. The pediatric group was found to have significantly lower wheeling speeds than the adult group. The addition of weight, however, did not alter the wheeling speeds in either group. Neither the proportions of the wheeling cycle spent in propulsion (24%) nor the angular (shoulder flexion-extension, elbow flexion-extension, shoulder abduction, and trunk flexion-extension) kinematics of wheeling changed with additions of weight in either group. The angular kinematics of the pediatric group, however, were different than those of the adult group. Conclusion and Discussion. These results indicate that adding weight in the range of 5 to 10 kg did not affect wheeling style under the level-wheeling, low-speed conditions of the study. It is possible that performance in wheelchair propulsion may be more appropriately determined by kinetic and energetic outcome measures than by kinematic measures. [ABSTRACT FROM AUTHOR]

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.)

Objectives: To evaluate if age and medical comorbidities are associated with progression to implantation of sacral neuromodulation devices in women with symptomatic chronic urinary retention., Methods: This multisite retrospective cohort included women with symptomatic chronic urinary retention who had a trial phase of sacral neuromodulation. The primary outcome was progression to implantation. Post-implantation outcomes were assessed as stable response versus decreased efficacy. A sub-analysis of catheter-reliant (intermittent-self catheterization or indwelling) patients was performed. Age was analyzed by 10-year units (decades of age). Multivariate logistic regression determined odds ratios for outcomes of implantation and for post-implantation stable response., Results: Implantation occurred in 86% (243/284) women across six academic institutions. Most patients (160/243, 66%) were catheter reliant at the time of trial phase. Increased decade of age was associated with reduced implantation in all women [OR 0.54 (95% CI 0.42, 0.70)] and in the subgroup of catheter-reliant women [OR 0.52 (95% CI 0.37, 0.73)]. Post-implantation stable response occurred in 68% (193/243) of women at median follow-up of 2 years (range 0.3-15 years). Medical comorbidities present at the time of trials did not impact progression to implantation or post-implantation success., Conclusions: Increasing decade of age is associated with reduced implantation in women with symptomatic chronic urinary retention. There is no age cutoff at which outcomes change. Post-implantation stable response was not associated with age or medical comorbidities., (© 2020. The International Urogynecological Association.)

[Correction Notice: An Erratum for this article was reported online in Journal of Experimental Psychology: General on Jan 14 2021 (see record 2021-07705-001). In the article, formatting for UK Research Councils funding was omitted. The author note and copyright line now reflect the standard acknowledgment of and formatting for the funding received for this article. All versions of this article have been corrected.] Attention determines which cues receive processing and are learned about. Learning, however, leads to attentional biases. In the study of animal learning, in some circumstances, cues that have been previously predictive of their consequences are subsequently learned about more than are nonpredictive cues, suggesting that they receive more attention. In other circumstances, cues that have previously led to uncertain consequences are learned about more than are predictive cues. In human learning, there is a clear role for predictiveness, but a role for uncertainty has been less clear. Here, in a human learning task, we show that cues that led to uncertain outcomes were subsequently learned about more than were cues that were previously predictive of their outcomes. This effect occurred when there were few uncertain cues. When the number of uncertain cues was increased, attention switched to predictive cues. This pattern of results was found for cues (1) that were uncertain because they led to 2 different outcomes equally often in a nonpredictable manner and (2) that were used in a nonlinear discrimination and were not predictive individually but were predictive in combination with other cues. This suggests that both the opposing predictiveness and uncertainty effects were determined by the relationship between individual cues and outcomes rather than the predictive strength of combined cues. These results demonstrate that learning affects attention; however, the precise nature of the effect on attention depends on the level of task complexity, which reflects a potential switch between exploration and exploitation of cues. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Objective: To identify risk factors associated with surgical revision of midurethral sling (MUS) due to mesh extrusion., Materiald and Methods: This is a case-control study identifying women who underwent primary surgical revision of polypropylene MUS for vaginal mesh extrusion from 2001 to 2016. Cases of surgical revision were compared to a randomly selected control group in a 1:5 ratio. Patient demographics and clinical characteristics were compared and multivariate logistic regression modeling was performed to analyze the relationships between risk factors and vaginal mesh extrusion., Results: In total, 64 cases were identified and compared to 400 controls. The average subject was 51.7 years old (range, 30-78) with a body mass index (BMI) of 27.9 kg/m 2 (range, 23.6-30.2) at the time of surgical revision. The median time to MUS revision was 318 days (interquartile range, 144-1355 days). Surgical revision was associated with current smokers (odds ratio [OR] = 5.43 [95% confidence interval [CI] 2.86, 10.31]), a BMI under 30 kg/m 2 (OR = 4.37 [95% CI = 2.05, 9.36]), age under 55 years (OR = 2.02, [95% CI = 1.13, 3.61]), a retropubic sling (OR = 2.10 [95% CI = 1.14, 3.88]), and fibromyalgia (OR = 3.33 [95% CI 1.12, 9.95])., Conclusion: Smoking status, age under 55 years, BMI below 30 kg/m 2 , fibromyalgia, and retropubic approach were factors associated with surgical revision of MUS due to vaginal mesh extrusion. These findings may improve counseling and patient selection., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Small-molecule inhibitors have been instrumental in uncovering the biological importance of poly-ADP-ribose polymerases (PARPs), a family of enzymes involved in wide-ranging aspects of cell biology. However, few PARP inhibitors are tested against the entire family of PARPs. This makes it impossible to confidently assess the role of a single PARP in cellular processes using small molecules. Here, we detail a PARP activity screening and inhibitor testing assay (PASTA) for determining relative selectivity of PARP inhibitors. For complete details on the use and execution of this protocol, please refer to Kirby et al. (2018)., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Theories of learning differ in whether they assume that learning reflects the strength of an association between memories or symbolic encoding of the statistical properties of events. We provide novel evidence for symbolic encoding of informational variables by demonstrating that sensitivity to time and number in learning is dissociable. Whereas responding in normal mice was dependent on reinforcement rate, responding in mice that lacked the GluA1 AMPA receptor subunit was insensitive to reinforcement rate and, instead, dependent on the number of times a cue had been paired with reinforcement. This suggests that GluA1 is necessary for weighting numeric information by temporal information in order to calculate reinforcement rate. Sample sizes per genotype varied between seven and 23 across six experiments and consisted of both male and female mice. The results provide evidence for explicit encoding of variables by animals rather than implicit encoding via variations in associative strength.

Objective: To evaluate if age and comorbidities are associated with progression from trial phase to implantation of an implantable pulse generator in women with overactive bladder., Methods: This multisite retrospective cohort included women with overactive bladder with or without urinary incontinence who had a trial phase for sacral neuromodulation. The primary outcome was progression to implantation. A sub-analysis of implanted patients was performed for the outcome of additional therapies or "implant only" for the duration of follow-up. Multivariate logistic regression models including potential predictors of implantation and post-implantation addition of therapies were performed., Results: At six academic institutions, 91% (785/864) of patients progressed to implantation. Post-implantation success was achieved by 69% (536/782) of patients at median follow-up of 2 (range 0.3 to 15) years. Odds of implantation [OR 0.73 (CI 0.61, 0.88)] and post-implantation success [OR 0.78 (CI 0.98, 0.97)] were lower with increasing decades of age. Medical comorbidities evaluated did not affect implantation rates or post-implant success., Conclusions: Most women have successful sacral neuromodulation trials despite older age and comorbidities. Higher decade of age has a negative effect on odds of implantation and is associated with addition of therapies post-implantation. Comorbidities assessed in this study did not affect implantation or addition of therapies post-implantation. Most women add therapies to improve efficacy post-implantation, and explantation rates are low.

The GluA1 subunit of the AMPA receptor has been implicated in anhedonia. Mice that lack GluA1 (Gria1 knockout mice) show reduced lick cluster size, a measure of palatability in feeding behaviour. This deficit may reflect a role for GluA1 in encoding the hedonic value of palatable substances or instead a role for GluA1 in the behavioural expression of hedonic value. We tested the role of GluA1 in hedonic value by assessing sensitivity to changes in the rewarding property of sucrose as a consequence of negative/positive contrast effects in female mice. During training, on half of the days consumption of a flavour (CS+) mixed with 4% sucrose was preceded by consumption of 1% sucrose (positive contrast). On the other half of days consumption of a different flavour (CS-) mixed with 4% sucrose was preceded by consumption of 16% sucrose (negative contrast). In the test session both wild-type, controls and Gria1 knockout mice consumed more of the CS+ flavour than the CS- flavour. While Gria1 knockout mice showed reduced lick cluster sizes, both genotypes made larger lick clusters for the CS+ flavour than the CS- flavour suggesting that the CS+ was more palatable than the CS-. A follow up experiment in normal mice demonstrated that the negative contrast procedure resulted in a conditioned reduction of palatability of the CS- in comparison to an associatively neutral, novel flavour. The results failed to demonstrate a role for GluA1 in hedonic value suggesting that, instead, GluA1 is necessary for hedonic responding., (Copyright © 2020. Published by Elsevier Inc.)

Poly(ADP-ribose) polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using NAD as the source of ADPR. Although the well-known poly(ADP-ribosylating) (PARylating) PARPs primarily function in the DNA damage response, many noncanonical mono(ADP-ribosylating) (MARylating) PARPs are associated with cellular antiviral responses. We recently demonstrated robust up-regulation of several PARPs following infection with murine hepatitis virus (MHV), a model coronavirus. Here we show that SARS-CoV-2 infection strikingly up-regulates MARylating PARPs and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while down-regulating other NAD biosynthetic pathways. We show that overexpression of PARP10 is sufficient to depress cellular NAD and that the activities of the transcriptionally induced enzymes PARP7, PARP10, PARP12 and PARP14 are limited by cellular NAD and can be enhanced by pharmacological activation of NAD synthesis. We further demonstrate that infection with MHV induces a severe attack on host cell NAD + and NADP + Finally, we show that NAMPT activation, NAM, and NR dramatically decrease the replication of an MHV that is sensitive to PARP activity. These data suggest that the antiviral activities of noncanonical PARP isozyme activities are limited by the availability of NAD and that nutritional and pharmacological interventions to enhance NAD levels may boost innate immunity to coronaviruses., Competing Interests: Conflict of interest—C. B. is chief scientific adviser of ChromaDex and owns shares of ChromaDex stock. C. B., S. A. J. T., S. P., and A. R. F. filed an invention disclosure on uses of NAD-boosting with respect to protection against coronavirus infection., (© 2020 Heer et al.)

Objective: To evaluate changes in self-reported depression after treatment of fecal incontinence (FI) with sacral neuromodulation., Materials and Methods: This is a subanalysis of data collected from March 2016 to October 2017 for an Institutional Review Board-approved retrospective cohort study. Demographic information, medical history, psychiatric comorbidities, and the Patient-Reported Outcomes Measurement Information System item bank t-scores were extracted from the electronic medical record. The differences in t-scores were compared with a two-sided paired t-test, and a p value <0.05 was considered statistically significant., Results: Of the cohort (n = 24), most were Caucasian (88%), female (92%), nonsmokers (92%). Median age was 63.5 years (interquartile range 57.5-71.0 years) and median body mass index was 27.7 kg/m 2 (range 18.3-42.9 kg/m 2 ). A significant decrease in mean depression t-scores occurred after implantation of a sacral neuromodulation device, -4.5 (95% confidence interval [CI]: -8.7, -0.2, p = 0.04). Self-reported pain interference (p = 0.37) and physical function (p = 0.47) scores were similar following implantation. Individuals with comorbid anxiety reported the greatest improvement in depression (-6.5, 95% CI: -11.8, -1.1, p = 0.02)., Conclusions: Treatment of FI with sacral neuromodulation was associated with improvement in self-reported depression with the greatest improvement in those with anxiety. Further prospective research is needed to corroborate these findings., (© 2020 International Neuromodulation Society.)

Poly-(ADP)-ribose polymerases (PARPs) are a family of 17 enzymes in humans that have diverse roles in cell physiology including DNA damage repair, transcription, innate immunity, and regulation of signaling pathways. The modular domain architecture of PARPs gives rise to this functional diversity. PARPs catalyze the transfer of ADP-ribose from nicotinamide adenine dinucleotide (NAD + ) to targets-proteins and poly-nucleic acids. This enigmatic post-translational modification comes in two varieties: the transfer of a single unit of ADP-ribose, known as mono-ADP-ribosylation (MARylation) or the transfer of multiple units of ADP-ribose, known as poly-ADP-ribosylation (PARylation). Emerging data shows that PARPs are regulated at multiple levels to control when and where PARP-mediated M/PARylation occurs in cells. In this review, we will discuss the latest knowledge regarding the regulation of PARPs in cells: from transcription and protein stability to subcellular localization and modulation of catalytic activity.

Objective: This study aimed to determine the incidence and risk factors associated with revision or removal of a sacral nerve stimulation device for treatment of lower urinary tract dysfunction or fecal incontinence., Materials and Methods: This is a single-center multidisciplinary retrospective cohort study conducted at a university hospital from January 2013 through October 2017. Subjects who underwent successful sacral neuromodulation were identified via procedural codes. Clinical and demographic data regarding device revision or removal were extracted from the medical record. When testing differences between groups, t-test or Mann-Whitney U test was used to compare continuous variables. Categorical variables were compared by Chi-square test. Risk factors with a p value <0.2 in univariate investigation were included in the multivariate analysis. Logistic regression modeling was used to compare associations between risk factors and re-operation rates., Results: Of the 219 subjects analyzed, 35 (16%) had revision or explantation of the sacral nerve stimulation device. Median time to re-operation was 164 days (interquartile range [IQR]: 29, 525). Subjects with device revised or explanted were younger, with a median age of 50 years vs. 62 years (p < 0.01) for those who did not undergo explantation. Patient demographics and co-morbidities were otherwise similar. Multivariate analysis identified age under 55 years (odds ratio [OR]: 2.51; 95% confidence interval [CI]: 1.18-5.33) as a significant risk factor. Our regression model showed that neither preimplantation diagnosis of chronic pain (OR: 0.60; 95% CI: 0.28-1.27) nor the specialty of the surgeon (OR 1.04; 95% CI 0.66-1.62) was associated with stimulation device revision or explantation., Conclusions: This study found a 16% incidence of revision or explantation. Age under 55 years was identified as a significant risk factor. Our analysis did not find further demographic characteristics, co-morbid disorders, or behavioral diagnoses that were associated with revision or removal. Identification of risk factors may aid in patient selection for sacral nerve stimulation device implantation., (© 2019 International Neuromodulation Society.)

We examined the role of the hippocampus and the dorsolateral striatum in the representation of environmental geometry using a spontaneous object recognition procedure. Rats were placed in a kite-shaped arena and allowed to explore two distinctive objects in each of the right-angled corners. In a different room, rats were then placed into a rectangular arena with two identical copies of one of the two objects from the exploration phase, one in each of the two adjacent right-angled corners that were separated by a long wall. Time spent exploring these two objects was recorded as a measure of recognition memory. Since both objects were in different locations with respect to the room (different between exploration and test phases) and the global geometry (also different between exploration and test phases), differential exploration of the objects must be a result of initial habituation to the object relative to its local geometric context. The results indicated an impairment in processing the local geometric features of the environment for both hippocampus and dorsolateral striatum lesioned rats compared with sham-operated controls, though a control experiment showed these rats were unimpaired in a standard object recognition task. The dorsolateral striatum has previously been implicated in egocentric route-learning, but the results indicate an unexpected role for the dorsolateral striatum in processing the spatial layout of the environment. The results provide the first evidence that lesions to the hippocampus and dorsolateral striatum impair spontaneous encoding of local environmental geometric features., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

The duration of a conditioned stimulus (CS) is a key determinant of Pavlovian conditioning. Rate estimation theory (RET) proposes that reinforcement rate is calculated over cumulative exposure to a cue and the reinforcement rate of a cue, relative to the background reinforcement rate, determines the speed of acquisition of conditioned responding. Consequently, RET predicts that shorter-duration cues require fewer trials to acquisition than longer-duration cues due to the difference in reinforcement rates. We tested this prediction by reanalysing the results of a previously published experiment. Mice received appetitive Pavlovian conditioning of magazine approach behaviour with a 10-s CS and a 40-s CS. Cue duration did not affect the rate at which responding emerged or the rate at which it peaked. The 10-s CS did elicit higher levels of responding than the 40-s CS. These results are not consistent with rate estimation theory. Instead, they are consistent with an associative analysis that assumes that asymptotic levels of responding reflect the balance between increments and decrements in associative strength across cumulative exposure to a cue.

Manipulation of host ubiquitin signaling is becoming an increasingly apparent evolutionary strategy among bacterial and viral pathogens. By removing host ubiquitin signals, for example, invading pathogens can inactivate immune response pathways and evade detection. The ovarian tumor (OTU) family of deubiquitinases regulates diverse ubiquitin signals in humans. Viral pathogens have also extensively co-opted the OTU fold to subvert host signaling, but the extent to which bacteria utilize the OTU fold was unknown. We have predicted and validated a set of OTU deubiquitinases encoded by several classes of pathogenic bacteria. Biochemical assays highlight the ubiquitin and polyubiquitin linkage specificities of these bacterial deubiquitinases. By determining the ubiquitin-bound structures of two examples, we demonstrate the novel strategies that have evolved to both thread an OTU fold and recognize a ubiquitin substrate. With these new examples, we perform the first cross-kingdom structural analysis of the OTU fold that highlights commonalities among distantly related OTU deubiquitinases., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Purpose: The aim of this study is to evaluate changes in sleep disturbance following treatment of overactive bladder with sacral neuromodulation., Materials and Methods: This is a sub-analysis of data collected from an institutional review board approved retrospective cohort study evaluating women with Patient-Reported Outcomes Measurement Information System-Sleep Disturbance (PROMIS-SD) before and after sacral neuromodulation for overactive bladder between March 2016 and October 2017. Data collected included demographics, clinical characteristics, and additional PROMIS item banks. Within-group analysis was performed with paired t-tests. Groups based up on PROMIS-SD improvement (change <0) were then compared using Fisher's exact test, t-test, or Mann-Whitney U-test as appropriate., Results: Those with improved sleep disturbance (n=7) noted a significant mean improvement of -3.99 (95% confidence interval, -6.32, -1.65; p<0.01). Both pre- and post-procedure PROMIS-Physical Function (38.86±2.35 vs. 34.13±5.58, p=0.07 and 37.14±5.10 vs. 35.44±4.74, p=0.53), Pain Interference (60.04±6.34 vs. 65.50±6.20, p=0.13 and 57.89±5.08 vs. 64.73±7.35, p=0.07), Depression (44.2±4.73 vs. 61.29±9.53, p=0.17 and 54.29±6.25 vs. 57.96±11.42, p=0.47) t-scores were similar between sleep response groups., Conclusions: Those with improved sleep disturbance reported significant changes after sacral neuromodulation for overactive bladder. However, no significant differences were identified between those with and without improvement. Further investigation of changes in sleep disturbance and factors affecting change are needed within this population., Competing Interests: CONFLICTS OF INTEREST: Derrick J. Sanderson is a consultant for InterPro Bioscience. This relationship began in July of 2019 after completion of this research., (© The Korean Urological Association, 2020.)

NMDA receptor-dependent synaptic plasticity has been proposed to be important for encoding of memories. Consistent with this hypothesis, the non-competitive NMDA receptor antagonist, MK-801, has been found to impair performance on tests of memory. Interpretation of some of these findings has, however, been complicated by the fact that the drug-state of animals has differed during encoding and tests of memory. Therefore, it is possible that MK-801 may result in state-dependent retrieval or expression of memory rather than actually impairing encoding itself. We tested this hypothesis in mice using tests of object recognition memory with a 24-hour delay between the encoding and test phase. Mice received injections of either vehicle or MK-801 prior to the encoding phase and the test phase. In Experiment 1, a low dose of MK-801 (0.01 mg/kg) impaired performance when the drug-state (vehicle or MK-801) of mice changed between encoding and test, but there was no significant effect of MK-801 on encoding. In Experiment 2, a higher dose of MK-801 (0.1 mg/kg) failed to impair object recognition memory when mice received the drug prior to both encoding and test compared to mice that received vehicle. MK-801 did not affect object exploration, but it did induce locomotor hyperactivity at the higher dose. These results suggest that some previous demonstrations of MK-801 effects may reflect a failure to express or retrieve memory due to the state-dependency of memory rather than impaired encoding of memory., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Clinical practice has drastically changed following the 2014 U.S. Food and Drug Administration (FDA) warning statement regarding power morcellation during laparoscopic hysterectomy and myomectomy. Despite investigation into alternative tissue extraction techniques, there remain a paucity of data associated with contained manual morcellation techniques. The goal of this study was to investigate the associated perioperative outcomes of contained manual morcellation compared to power morcellation in women undergoing robotic myomectomy. Performing manual morcellation (n = 38) resulted in a 21-min decrease in mean operative time (105.4 ± 42.2 vs 126.1 ± 44.1 min, p = 0.02) compared to power morcellation (n = 62). Women were younger (33 vs 36 years, p = 0.03) in the manual morcellation group, with all other patient demographics being similar. Median specimen weight (82 vs 104 g, p = 0.13), number of fibroids removed (2 vs 1, p = 0.16), estimated blood loss (10 vs 50 mL, p = 0.25), and post-operative morphine equivalents administered (5.57 ± 4.57 vs 5.29 ± 4.39, p = 0.76) were similar. The same-day discharge rate was not significantly different between the groups (86 vs 90%, p = 0.74). Linear regression modeling identified specimen weight, number of fibroids removed, and use of power morcellation as significant contributors to surgical time. Contained manual morcellation during robotic myomectomy is associated with a significant decrease in surgical time when compared to power morcellation, with similar post-operative narcotic administration and length of stay.

Conditioned stimulus (CS) duration is a determinant of conditioned responding, with increases in duration leading to reductions in response rates. The CS duration effect has been proposed to reflect sensitivity to the reinforcement rate across cumulative exposure to the CS, suggesting that the delay of reinforcement from the onset of the cue is not crucial. Here, we compared the effects of delay and rate of reinforcement on Pavlovian appetitive conditioning in mice. In Experiment 1, the influence of reinforcement delay on the timing of responding was removed by making the duration of cues variable across trials. Mice trained with variable duration cues were sensitive to differences in the rate of reinforcement to a similar extent as mice trained with fixed duration cues. Experiments 2 and 3 tested the independent effects of delay and reinforcement rate. In Experiment 2, food was presented at either the termination of the CS or during the CS. In Experiment 3, food occurred during the CS for all cues. The latter experiment demonstrated an effect of delay, but not reinforcement rate. Experiment 4 ruled out the possibility that the lack of effect of reinforcement rate in Experiment 3 was due to mice failing to learn about the nonreinforced CS exposure after the presentation of food within a trial. These results demonstrate that although the CS duration effect is not simply a consequence of timing of conditioned responses, it is dependent on the delay of reinforcement. The results provide a challenge to current associative and nonassociative, time-accumulation models of learning. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Introduction and Hypothesis: In the United States, vesicovaginal fistula (VVF) most often results from gynecologic surgery causing significant morbidity and distress to both the patient and surgeon. The use of tissue interposition at time of primary repair has been advocated to decrease the risk of recurrence. The aim of this study is to describe our experience with interposition of sigmoid epiploica during robotic extravesical repair of supratrigonal VVF., Methods: This is a retrospective case series from June 2015 to September 2016. Features of the surgical technique include 1) cystoscopic ureteral catheterization, 2) cannulation of the fistula, 3) mobilization of the bladder from the vagina, 4) removal of the epithelialized edges of the fistulous tract, 5) single-layer closure of the vagina, 6) tension-free layered closure of the bladder, 7) retrograde fill of the bladder to ensure water-tight repair, 8) interposition of sigmoid epiploica appendage(s), and 9) prolonged bladder drainage with indwelling transurethral catheter., Results: In total, 5 women underwent successful robotic VVF repair with epiploic appendage interposition. Mean surgical time was 218 minutes with an average console time of 147 minutes and an estimated blood loss of 49 mL. Most the patients were discharged to home on postoperative day 1 with no untoward effects due to the epiploica interposition. There have been no recurrences to date., Conclusions: Robotic repair of VVF with sigmoid epiploica interposition is efficient and well tolerated. Use of this technique may increase the number of patients eligible for tissue interposition., Competing Interests: Conflicts of Interest: All authors declare no conflict of interest regarding the publication of this article.

Spontaneous recognition tasks are widely used as a laboratory measure of memory in animals but give rise to high levels of behavioral noise leading to a lack of reliability. Previous work has shown that a modification of the procedure to allow continual trials testing (in which many trials are run concurrently in a single session) decreases behavioral noise and thus significantly reduces the numbers of rats required to retain statistical power. Here, we demonstrate for the first time that this improved method of testing extends to mice, increasing the overall power of the approach. Moreover, our results show that the new continual trials approach provides the additional benefits of heightened sensitivity and thus provides greater insight into the mechanisms at play. Standard (c57) and transgenic Alzheimer model (TASTPM) mice were tested both at 7 and 10 months of age in both object recognition (OR) and object-location (OL) spontaneous recognition tasks using the continual trials methodology. Both c57 and TASTPM mice showed age-dependent changes in performance in OR. While c57 mice also showed age-related changes in performance of OL, TASTPM mice were unable to perform OL at either age. Significantly, we demonstrate that differences in OL performance in c57s and TASTPM animals is a result of proactive interference rather than an absolute inability to recognize OL combinations. We argue that these continual trials approaches provide overall improved reliability and better interpretation of the memory ability of mice, as well as providing a significant reduction in overall animal use.

Pathological over-activity of the CA1 subfield of the human anterior hippocampus has been identified as a potential predictive marker for transition from a prodromal state to overt schizophrenia. Psychosis, in turn, is associated with elevated activity in the anterior subiculum, the hippocampal output stage directly activated by CA1. Over-activity in these subfields may represent a useful endophenotype to guide translationally predictive preclinical models. To recreate this endophenotype and study its causal relation to deficits in the positive and cognitive symptom domains, we optogenetically activated excitatory neurons of the ventral hippocampus (vHPC; analogous to the human anterior hippocampus), targeting the ventral subiculum. Consistent with previous studies, we found that vHPC over-activity evokes hyperlocomotion, a rodent correlate of positive symptoms. vHPC activation also impaired performance on the spatial novelty preference (SNP) test of short-term memory, regardless of whether stimulation was applied during the encoding or retrieval stage of the task. Increasing dopamine transmission with amphetamine produced hyperlocomotion, but was not associated with SNP impairments. This suggests that short-term memory impairments resulting from hippocampal over-activity likely arise independently of a hyperdopaminergic state, a finding that is consistent with the pharmaco-resistance of cognitive symptoms in patients.

Consumption of foods results in a transient reduction in hedonic value that influences the extent and nature of feeding behavior. The time course of this effect, however, is poorly specified. In an initial experiment, using an analysis of the microstructure of licking in mice we found that consumption of sucrose led to a rapid reduction in lick cluster size, a measure of palatability, which recovered after 10 min, but reemerged 60min after initial consumption. We then replicated the finding that lick cluster size is reduced after 60min, but not 10min, under conditions in which a number of potential behavioural confounds were removed. In Experiment 2 the effect was replicated using a between-subjects design that ruled out the possibility that the effect was a specific consequence of the within-subjects procedures used in the first experiment, in which mice may have come to expect sucrose at different time points within the feeding session. While Experiments 1 and 2 confounded the time between periods of access to sucrose with time since the start of the feeding session, this confound was removed in Experiment 3, and, similar to the previous experiments, it was found that a second reduction in palatability occurred after 60min. Therefore, the effect was dependent only on the time since the previous exposure to sucrose, demonstrating that sucrose consumption initiates a biphasic reduction in palatability. The reduction in lick cluster size after 60min was not typically accompanied by a reduction in consumption suggesting that the more slowly developing reduction in the palatability measure was not simply a consequence of post-ingestive satiety. The cause of the biphasic change is not yet clear, and may reflect independent processes or the consequence of a single process that initiates multiple changes in palatability over time., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The GluA1 subunit of the AMPA receptor has been implicated in schizophrenia. While GluA1 is important for cognition, it is not clear what the role of GluA1 is in hedonic responses that are relevant to the negative symptoms of disorders such as schizophrenia. Here, we tested mice that lack GluA1 (Gria1 -/- mice) on consumption of sucrose solutions using a licking microstructure analysis. GluA1 deletion drastically reduced palatability (as measured by the mean lick cluster size) across a range of sucrose concentrations. Although initial lick rates were reduced, measures of consumption across long periods of access to sucrose solutions were not affected by GluA1 deletion and Gria1 -/- mice showed normal satiety responses to high sucrose concentrations. GluA1 deletion also failed to impair flavour conditioning, in which increased intake of a flavour occurred as a consequence of prior pairing with a high sucrose concentration. These results demonstrate that GluA1 plays a role in responding on the basis of palatability rather than other properties, such as the automatic and learnt post-ingestive, nutritional consequences of sucrose. Therefore, Gria1 -/- mice provide a potential model of anhedonia, adding converging evidence to the role of glutamatergic dysfunction in various symptoms of schizophrenia and related disorders.

The GluA1 AMPAR subunit (encoded by the Gria1 gene) has been implicated in schizophrenia. Gria1 knockout in mice results in recently experienced stimuli acquiring aberrantly high salience. This suggests that GluA1 may be important for learning that is sensitive to the temporal contiguity between events. To test this, mice were trained on a Pavlovian trace conditioning procedure in which the presentation of an auditory cue and food were separated by a temporal interval. Wild-type mice initially learnt, but with prolonged training came to withhold responding during the trace-conditioned cue, responding less than for another cue that was nonreinforced. Gria1 knockout mice, in contrast, showed sustained performance over training, responding more to the trace-conditioned cue than the nonreinforced cue. Therefore, the trace-conditioned cue acquired inhibitory properties (signalling the absence of food) in wild-type mice, but Gria1 deletion impaired the acquisition of inhibition, thus maintaining the stimulus as an excitatory predictor of food. Furthermore, when there was no trace both groups showed successful learning. These results suggest that cognitive abnormalities in disorders like schizophrenia in which gluatamatergic signalling is implicated may be caused by aberrant salience leading to a change in the nature of the information that is encoded.

Background: The Perioperative Surgical Home is a novel care model designed to provide patient-centered, high-quality surgical care. In 2013, we implemented POSH, a pilot Peri-Operative Surgical Home at Phoenix Indian Medical Center (PIMC), an Indian Health Service hospital, as a quality improvement project. After 2 y, we sought to quantify the impact of POSH on the quality of surgical care at PIMC., Materials and Methods: We conducted a retrospective review of 33 surgical patients who underwent surgery at PIMC through the POSH process between 2013 and 2015 matched to 64 historical controls with similar operations. Study patients underwent surgery via the POSH treatment process. Primary outcomes were composite measures of (1) care standards and (2) care goals. Success was defined as meeting seven of nine care standards and six of eight care goals., Results and Discussion: The mean number of care standards met was 8.1 ± 1.0 versus 4.2 ± 1.4 (P < 0.001) and the mean number of care goals met was 6.7 ± 0.8 versus 6.1 ± 1.1 (P = 0.005) for POSH patients and historical controls, respectively. Patients participating in the POSH model were 8.6 (95% confidence interval: 3.5-22.3) and 1.5 (95% confidence interval: 1.2-1.9) times more likely to meet the minimum number of care standards and goals, respectively. Fourteen of the study patients (42%) would not have been offered surgery at PIMC before POSH due to elevated surgical risk., Conclusions: POSH may have improved quality of surgical care at PIMC while expanding services to more complex patients. POSH may present an opportunity for improved surgical quality in resource-constrained environments., (Published by Elsevier Inc.)

Given the widespread use of nonsteroidal anti-inflammatory drugs, physicians should recognize the symptoms of colonic diaphragm disease, a rare but serious complication that can affect the large and small intestines., Competing Interests: Author disclosures The authors report no actual or potential conflicts of interest with regard to this article.

While palatability depends on the properties of particular foods, it is also determined by prior experience, suggesting that memory affects the hedonic value of a substance. Here, we report two procedures that affect palatability in mice: negative contrast and flavour habituation. A microstructure analysis of licking behaviour was employed, with the lick cluster size (the number of licks made in quick succession before a pause) used as a measure of palatability. It was first confirmed that lick cluster size increased monotonically as a function of sucrose concentration, whereas consumption followed an inverted U-shaped function. In a successive negative contrast procedure it was found that when shifted from a high sucrose concentration (32%) to a low sucrose concentration (4%), mice made smaller lick clusters than a group that only received the low concentration. Mice exposed to flavours (cherry or grape Kool Aid) mixed with sucrose (16%) made larger lick clusters for familiar flavours compared to novel flavours. This habituation effect was evident after short (5min) and long (24h) test intervals. Both successive negative contrast and flavour habituation failed to affect levels of consumption. Collectively, the results show that prior experience can have effects on lick cluster size that are equivalent to increasing or decreasing the sweetness of a solution. Thus, palatability is not a fixed property of a substance but is dependent on expectation or familiarity that occurs as a result of memory., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)