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The Australian Community Climate and Earth System Simulator (ACCESS) has contributed to the World Climate Research Programme’s Coupled Model Intercomparison Project Phase 6 (CMIP6) using two fully coupled model versions (ACCESS-CM2 and ACCESS-ESM1.5) and two ocean–sea-ice model versions (1° and 0.25° resolution versions of ACCESS-OM2). The fully coupled models differ primarily in the configuration and version of their atmosphere components (including the aerosol scheme), with smaller differences in their sea-ice and land model versions. Additionally, ACCESS-ESM1.5 includes biogeochemistry in the land and ocean components and can be run with an interactive carbon cycle. CMIP6 comprises core experiments and associated thematic Model Intercomparison Projects (MIPs). This paper provides an overview of the CMIP6 submission, including the methods used for the preparation of input forcing datasets and the post-processing of model output, along with a comprehensive list of experiments performed, detailing their initialisation, duration, ensemble number and computational cost. A small selection of model output is presented, focusing on idealised experiments and their variants at global scale. Differences in the climate simulation of the two coupled models are highlighted. ACCESS-CM2 produces a larger equilibrium climate sensitivity (4.7°C) than ACCESS-ESM1.5 (3.9°C), likely a result of updated atmospheric parameterisation in recent versions of the atmospheric component of ACCESS-CM2. The idealised experiments run with ACCESS-ESM1.5 show that land and ocean carbon fluxes respond to both changing atmospheric CO2 and to changing temperature. ACCESS data submitted to CMIP6 are available from the Earth System Grid Federation (https://doi.org/10.22033/ESGF/CMIP6.2281 and https://doi.org/10.22033/ESGF/CMIP6.2288). The information provided in this paper should facilitate easier use of these significant datasets by the broader climate community.

The Australian Community Climate and Earth System Simulator (ACCESS) has contributed to the World Climate Research Programme’s Coupled Model Intercomparison Project Phase 6 (CMIP6) using two fully coupled model versions (ACCESS-CM2 and ACCESS-ESM1.5) and two ocean–sea-ice model versions (1° and 0.25° resolution versions of ACCESS-OM2). The fully coupled models differ primarily in the configuration and version of their atmosphere components (including the aerosol scheme), with smaller differences in their sea-ice and land model versions. Additionally, ACCESS-ESM1.5 includes biogeochemistry in the land and ocean components and can be run with an interactive carbon cycle. CMIP6 comprises core experiments and associated thematic Model Intercomparison Projects (MIPs). This paper provides an overview of the CMIP6 submission, including the methods used for the preparation of input forcing datasets and the post-processing of model output, along with a comprehensive list of experiments performed, detailing their initialisation, duration, ensemble number and computational cost. A small selection of model output is presented, focusing on idealised experiments and their variants at global scale. Differences in the climate simulation of the two coupled models are highlighted. ACCESS-CM2 produces a larger equilibrium climate sensitivity (4.7°C) than ACCESS-ESM1.5 (3.9°C), likely a result of updated atmospheric parameterisation in recent versions of the atmospheric component of ACCESS-CM2. The idealised experiments run with ACCESS-ESM1.5 show that land and ocean carbon fluxes respond to both changing atmospheric CO2 and to changing temperature. ACCESS data submitted to CMIP6 are available from the Earth System Grid Federation (https://doi.org/10.22033/ESGF/CMIP6.2281 and https://doi.org/10.22033/ESGF/CMIP6.2288). The information provided in this paper should facilitate easier use of these significant datasets by the broader climate community.

Background: Intrinsic resistance to androgen receptor signalling inhibitors (ARSI) occurs in 20-30% of men with metastatic castration-resistant prostate cancer (mCRPC). Ceramide metabolism may have a role in ARSI resistance. Our study's aim is to investigate the association of the ceramide-sphingosine-1-phosphate (ceramide-S1P) signalling axis with ARSI resistance in mCRPC. Method(s): Lipidomic analysis (~700 lipids) was performed on plasma collected from 132 men with mCRPC, before commencing enzalutamide or abiraterone. AR gene aberrations in 77 of these men were identified by deep sequencing of circulating tumour DNA. Associations between circulating lipids, radiological progression-free survival (rPFS) and overall survival (OS) were examined by Cox regression. Inhibition of ceramide-S1P signalling with sphingosine kinase (SPHK) inhibitors (PF-543 and ABC294640) on enzalutamide efficacy was investigated with in vitro assays, and transcriptomic and lipidomic analyses of prostate cancer (PC) cell lines (LNCaP, C42B, 22Rv1). Finding(s): Men with elevated circulating ceramide levels had shorter rPFS (HR=2.3, 95% CI=1.5-3.6, p = 0.0004) and shorter OS (HR=2.3, 95% CI=1.4-36, p = 0.0005). The combined presence of an AR aberration with elevated ceramide levels conferred a worse prognosis than the presence of only one or none of these characteristics (median rPFS time = 3.9 vs 8.3 vs 17.7 months; median OS time = 8.9 vs 19.8 vs 34.4 months). SPHK inhibitors enhanced enzalutamide efficacy in PC cell lines. Transcriptomic and lipidomic analyses indicated that enzalutamide combined with SPHK inhibition enhanced PC cell death by SREBP-induced lipotoxicity. Interpretation(s): Ceramide-S1P signalling promotes ARSI resistance, which can be reversed with SPHK inhibitors.Copyright © 2021 The Authors

Circulating lipids or cytokines are associated with prognosis in metastatic castration-resistant prostate cancer (mCRPC). This study aimed to understand the interactions between lipid metabolism and immune response in mCRPC by investigating the relationship between the plasma lipidome and cytokines. Plasma samples from two independent cohorts of men with mCRPC (n = 146, 139) having life-prolonging treatments were subjected to lipidomic and cytokine profiling (290, 763 lipids; 40 cytokines). Higher baseline levels of sphingolipids, including ceramides, were consistently associated with shorter overall survival in both cohorts, whereas the associations of cytokines with overall survival were inconsistent. Increasing levels of IL6, IL8, CXCL16, MPIF1, and YKL40 correlated with increasing levels of ceramide in both cohorts. Men with a poor prognostic 3- lipid signature at baseline had a shorter time to radiographic progression (poorer treatment response) if their lipid profile at progression was similar to that at baseline, or their cytokine profile at progression differed to that at baseline. In conclusion, baseline levels of circulating lipids were more consistent as prognostic biomarkers than cytokines. The correlation between circulating ceramides and cytokines suggests the regulation of immune responses by ceramides. The association of treatment response with the change in lipid profiles warrants further research into metabolic interventions.Copyright © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

BACKGROUND: Dysregulated lipid metabolism is associated with more aggressive pathology and poorer prognosis in prostate cancer (PC). The primary aim of the study is to assess the relationship between the plasma lipidome and clinical outcomes in localised and metastatic PC. The secondary aim is to validate a prognostic circulating 3-lipid signature specific to metastatic castration-resistant PC (mCRPC). PATIENTS AND METHODS: Comprehensive lipidomic analysis was performed on pre-treatment plasma samples from men with localised PC (N = 389), metastatic hormone-sensitive PC (mHSPC)(N = 44), or mCRPC (validation cohort, N = 137). Clinical outcomes from our previously published mCRPC cohort (N = 159) that was used to derive the prognostic circulating 3-lipid signature, were updated. Associations between circulating lipids and clinical outcomes were examined by Cox regression and latent class analysis. RESULTS: Circulating lipid profiles featuring elevated levels of ceramide species were associated with metastatic relapse in localised PC (HR 5.80, 95% CI 3.04-11.1, P = 1 × 10-6), earlier testosterone suppression failure in mHSPC (HR 3.70, 95% CI 1.37-10.0, P = 0.01), and shorter overall survival in mCRPC (HR 2.54, 95% CI 1.73-3.72, P = 1 × 10-6). The prognostic significance of circulating lipid profiles in localised PC was independent of standard clinicopathological and metabolic factors (P < 0.0002). The 3-lipid signature was verified in the mCRPC validation cohort (HR 2.39, 95% CI 1.63-3.51, P = 1 × 10-5). CONCLUSIONS: Elevated circulating ceramide species are associated with poorer clinical outcomes across the natural history of PC. These clinically actionable lipid profiles could be therapeutically targeted in prospective clinical trials to potentially improve PC outcomes.

BACKGROUND: Intrinsic resistance to androgen receptor signalling inhibitors (ARSI) occurs in 20-30% of men with metastatic castration-resistant prostate cancer (mCRPC). Ceramide metabolism may have a role in ARSI resistance. Our study's aim is to investigate the association of the ceramide-sphingosine-1-phosphate (ceramide-S1P) signalling axis with ARSI resistance in mCRPC. METHODS: Lipidomic analysis (∼700 lipids) was performed on plasma collected from 132 men with mCRPC, before commencing enzalutamide or abiraterone. AR gene aberrations in 77 of these men were identified by deep sequencing of circulating tumour DNA. Associations between circulating lipids, radiological progression-free survival (rPFS) and overall survival (OS) were examined by Cox regression. Inhibition of ceramide-S1P signalling with sphingosine kinase (SPHK) inhibitors (PF-543 and ABC294640) on enzalutamide efficacy was investigated with in vitro assays, and transcriptomic and lipidomic analyses of prostate cancer (PC) cell lines (LNCaP, C42B, 22Rv1). FINDINGS: Men with elevated circulating ceramide levels had shorter rPFS (HR=2·3, 95% CI=1·5-3·6, p = 0·0004) and shorter OS (HR=2·3, 95% CI=1·4-36, p = 0·0005). The combined presence of an AR aberration with elevated ceramide levels conferred a worse prognosis than the presence of only one or none of these characteristics (median rPFS time = 3·9 vs 8·3 vs 17·7 months; median OS time = 8·9 vs 19·8 vs 34·4 months). SPHK inhibitors enhanced enzalutamide efficacy in PC cell lines. Transcriptomic and lipidomic analyses indicated that enzalutamide combined with SPHK inhibition enhanced PC cell death by SREBP-induced lipotoxicity. INTERPRETATION: Ceramide-S1P signalling promotes ARSI resistance, which can be reversed with SPHK inhibitors. FUNDING: None.

Circulating lipids or cytokines are associated with prognosis in metastatic castration-resistant prostate cancer (mCRPC). This study aimed to understand the interactions between lipid metabolism and immune response in mCRPC by investigating the relationship between the plasma lipidome and cytokines. Plasma samples from two independent cohorts of men with mCRPC (n = 146, 139) having life-prolonging treatments were subjected to lipidomic and cytokine profiling (290, 763 lipids; 40 cytokines). Higher baseline levels of sphingolipids, including ceramides, were consistently associated with shorter overall survival in both cohorts, whereas the associations of cytokines with overall survival were inconsistent. Increasing levels of IL6, IL8, CXCL16, MPIF1, and YKL40 correlated with increasing levels of ceramide in both cohorts. Men with a poor prognostic 3-lipid signature at baseline had a shorter time to radiographic progression (poorer treatment response) if their lipid profile at progression was similar to that at baseline, or their cytokine profile at progression differed to that at baseline. In conclusion, baseline levels of circulating lipids were more consistent as prognostic biomarkers than cytokines. The correlation between circulating ceramides and cytokines suggests the regulation of immune responses by ceramides. The association of treatment response with the change in lipid profiles warrants further research into metabolic interventions.

Background: Incidence of neonatal bacterial meningitis is around 0.3 per 1000 live births. Complications of neonatal meningitis can be lifelong leading to a significant disability including cerebral palsy. Inflammatory markers have poor prediction on deciding lumbar puncture in neonatal meningitis. Viral Meningitis specially Enterovirus and Prechovirus can present in the neonatal period. Method(s): It is a multicentre retrospective study across all the Eastern health sites. Analysed all the lumbar puncture results performed on neonates less than 30 days old during the 6-year period from 1st January 2013 to 31st December 2018. Total of 243 patients recruited to the study. We compared the CSF results positivity by defined CSF pleocytosis, positive viral PCR, and association between PCR to positive lumbar punctures. Data are presented as numbers, percentages, Chi-square tests and a P value <0.05 considered significant. Result(s): Total 243 CSF samples were analyzed and 10% of samples were traumatic. Incidence of neonatal bacterial meningitis in this group is 0.03 per 1000 live births. Less than half (48%) (106/219) had CSF viral PCR testing. 36% (39/106) positive for Viral PCR including Entero and Parecho virus. CRP has no correlation in predicting meningitis Pvalue = 1.0 Conclusion(s): CSF microscopy results in isolation difficult to interpret without clinical correlation. Our study supports the findings of previous studies that CRP is a poor predictor of neonatal meningitis. Viral meningitis more common than bacterial culture positive meningitis in this group. We need to consider CSF viral PCR for Enterovirus and Parechovirus as a routine test.

Smartwatches and other wearables are characterized by small-scale touchscreens that complicate the interaction with content. In this paper, we present Force9, the first optimized miniature keyboard leveraging force-sensitive touchscreens on wrist-worn computers. Force9 enables character selection in an ambiguous layout by analyzing the trade-off between interaction space and the easiness of force-assisted interaction. We argue that dividing the screen’s pressure range into three contiguous force levels is sufficient to differentiate characters for fast and accurate text input. Our pilot study captures and calibrates the ability of users to perform force-assisted touches on miniature-sized keys on touchscreen devices. We then optimize the keyboard layout considering the goodness of character pairs (with regards to the selected English corpus) under the force-based configuration and the users? familiarity with the QWERTY layout. We finally evaluate the performance of the trimetric optimized Force9 layout, and achieve an average of 10.18 WPM by the end of the final session. Compared to the other state-of-the-art approaches, Force9 allows for single-gesture character selection without addendum sensors.

Item does not contain fulltext, People can switch quickly and flexibly from one task to another, but suffer the effects of between-task competition when they do so: After switching, they tend to be distracted by irrelevant stimulus information and hampered by incorrect actions associated with recently performed tasks. This competition results in performance costs of switching, as well as a bias against switching when there is choice over which task to perform, particularly when switching from a difficult task to an easier one. Two experiments investigated the locus of these between-task competition effects in voluntary task switching. Participants switched between an easy location classification and a harder shape classification, making two responses on each trial: the first to register their task choice, the second to perform the chosen task on a subsequently presented stimulus. The results indicated that participants chose to perform the difficult shape task more often than the easier location task, evidence that between-task competition affects intentions that are expressed independently of task-specific actions. The bias was stronger in participants with faster choice speed, suggesting that these influences are relatively automatic. Moreover, even though participants had unlimited time to choose and prepare a task before stimulus presentation, their subsequent performance was nonetheless sensitive to persisting effects of between-task competition. Altogether these results indicate the pervasive influence of between-task competition, which affects both the expression of global task intentions and the production of task-specific actions.

Contains fulltext : 102383.pdf (publisher's version ) (Open Access), Impairments in cognitive control generating deviant adaptive cognition have been proposed to account for the strong preference for repetitive behavior in autism. We examined if this preference reflects intentional deficits rather than problems in task execution in the broader autism phenotype using the Autism-Spectrum Quotient (AQ). Participants chose between two tasks differing in their relative strength by indicating first their voluntary task choice and then responding to the subsequently presented stimulus. We observed a stronger repetition bias for the harder task in high AQ participants, with no other differences between the two groups. These findings indicate that the interference between competing tasks significantly contributes to repetitive behavior in autism by modulating the formation of task intentions when choosing tasks voluntarily.

Item does not contain fulltext, This electroencephalographic (EEG) study investigated the impact of between-task competition on intentional control in voluntary task switching. Anticipatory preparation for an upcoming task switch is a hallmark of top-down intentional control. Meanwhile, asymmetries in performance and voluntary choice when switching between tasks differing in relative strength reveal the effects of between-task competition, reflected in a surprising bias against switching to an easier task. Here, we assessed the impact of this bias on EEG markers of intentional control during preparation for an upcoming task switch. The results revealed strong and varied effects of between-task competition on EEG markers of global task preparation - a frontal contingent negative variation (CNV), a posterior slow positive wave, and oscillatory activity in the alpha band (8-12 Hz) over posterior scalp sites. In contrast, we observed no between-task differences in motor-specific task preparation, as indexed by the lateralized readiness potential and by motor-related amplitude asymmetries in the mu (9-13 Hz) and beta (18-26 Hz) frequency bands. Collectively, these findings demonstrate that between-task competition directly influences the formation of top-down intentions, not only their expression in overt behavior. Specifically, this influence occurs at the level of global task intention rather than the preparation of specific actions.

Contains fulltext : 55984.pdf (Publisher’s version ) (Closed access), Functional neuroimaging research in humans has identified a number of brain areas that are activated by the delivery of primary and secondary reinforcers. The present study investigated how activity in these reward-sensitive regions is modulated by the context in which rewards and punishments are experienced. Fourteen healthy volunteers were scanned during the performance of a simple monetary gambling task that involved a "win" condition (in which the possible outcomes were a large monetary gain, a small gain, or no gain of money) and a "lose" condition (in which the possible outcomes were a large monetary loss, a small loss, or no loss of money). We observed reward-sensitive activity in a number of brain areas previously implicated in reward processing, including the striatum, prefrontal cortex, posterior cingulate, and inferior parietal lobule. Critically, activity in these reward-sensitive areas was highly sensitive to the range of possible outcomes from which an outcome was selected. In particular, these regions were activated to a comparable degree by the best outcomes in each condition-a large gain in the win condition and no loss of money in the lose condition-despite the large difference in the objective value of these outcomes. In addition, some reward-sensitive brain areas showed a binary instead of graded sensitivity to the magnitude of the outcomes from each distribution. These results provide important evidence regarding the way in which the brain scales the motivational value of events by the context in which these events occur.

How are we able to focus our attention on the task at hand while ignoring myriad distractions? An elegant neuroimaging study in this issue finds that, contrary to a held view, the prefrontal cortex implements attentional control by amplifying task-relevant information, rather than by inhibiting distracting stimuli. © 2005 Nature Publishing Group.

Contains fulltext : 64211.pdf (publisher's version ) (Closed access), An event-related functional magnetic resonance imaging experiment was conducted in which participants learned to select between response options by trial-and-error, using feedback stimuli that indicated monetary gains and losses. The results of the experiment indicated that error responses and error feedback activate the same region of dorsal anterior cingulate cortex, suggesting that this region is sensitive to both internal and external sources of error information.

Contains fulltext : 126331.pdf (publisher's version ) (Open Access), Previous research has shown that two components of the event-related brain potential, the P300 and feedback negativity, are sensitive to information about rewards and penalties. The present study investigated the properties of these components in a simple gambling game that required participants to choose between cards that were unpredictably associated with monetary gains and losses of variable magnitude. The aim was to determine the sensitivity of each component to two critical features of reward stimuli: magnitude ( small or large) and valence ( win or loss). A double dissociation was observed, with the P300 sensitive to reward magnitude but insensitive to reward valence and the feedback negativity showing the opposite pattern, suggesting that these two fundamental features of rewarding stimuli are evaluated rapidly and separately in the human brain. Subsequent analyses provided additional evidence of functional dissociations between the feedback negativity and P300. First, the P300 ( but not the feedback negativity) showed sensitivity to the reward value of alternative, nonselected stimuli. Second, individual differences in the amplitude of the feedback negativity correlated with individual differences in risk-taking behavior observed after monetary losses, whereas individual differences in P300 amplitude were related to behavioral adjustments observed in response to alternative, unchosen outcomes.

Stimuli that elicit a prepotent but incorrect response are typically associated with an enhanced electrophysiological N2 that is thought to index the operation of a control process such as inhibition or conflict detection. However, recent studies reporting the absence of the N2 modulation in go/no-go tasks involving auditory stimuli challenge this view: It is not clear why inhibition or conflict detection should be sensitive to the modality of the stimulus. Here we present electrophysiological data from a go/no-go task suggesting that the relative size of the N2 modulation in visual and auditory tasks depends on the perceptual overlap between the go and no-go stimuli. Stimuli that looked similar but sounded different were associated with a typical visual N2 modulation and the absence of an auditory N2 modulation, consistent with previous findings. However, when we increased the perceptual overlap between the auditory stimuli, a large no-go N2 was observed. These findings are discussed in terms of existing hypotheses of the N2, and clarify why previous studies have not found an N2 modulation in auditory go/no-go tasks.

A recent study has reported the observation in humans of an event-related brain potential component that is sensitive to the value of outcomes in a gambling task. This component, labeled medial frontal negativity (MFN), was most pronounced following monetary losses as opposed to monetary gains. In this study, we investigate the relationship between the MFN and the error-related negativity (ERN), a component elicited by feedback indicating incorrect choice performance. We argue that the two components can be understood in terms of a recently proposed theory that predicts the occurrence of such scalp negativities following stimuli that indicate that ongoing events are worse than expected. The results from two experiments using a gambling task demonstrate that the sensitivity of the MFN/ERN to the utilitarian and performance aspect of the feedback depends on which aspect is most salient. The results are consistent with the view that the two components are manifestations of the same underlying cognitive and neural process.

In our event-related functional magnetic resonance imaging (fMRI) experiment, participants learned to select between two response options by trial-and-error, using feedback stimuli that indicated monetary gains and losses. The results of the experiment indicate that error responses and error feedback activate the same region of dorsal anterior cingulate cortex, suggesting that this region is sensitive to both internal and external sources of error information.