Post-encoding task engagement not attentional load is detrimental to awake consolidation.

The fate of new memories depends partly on the cognitive state experienced immediately following encoding. Wakeful rest, relative to task engagement, benefits retention and this effect is typically explained through a consolidation account: rest is theorised to provide a state of minimal interference, which would otherwise disrupt consolidation. Yet, the determinants of consolidation interference, notably the contribution of attention, remain poorly characterised. Through a repeated measures design, we investigated attention load's impact on consolidation. In three phases, participants encountered a set of nonwords and underwent immediate recognition testing, experienced a 5-min delay condition, and completed a delayed recognition test for the nonwords. This cycle repeated for each phase before proceeding to the next. Delay conditions comprised of wakeful rest and two sustained attention to response tasks (SART) that were of low (SART-fixed) and high (SART-random) attention load. Immediate memory was matched across conditions, but delayed recognition was poorer after completing the SART-fixed and SART-random conditions, relative to rest. There was no difference between the two SART conditions. These data provide insights into the factors that contribute to the success of consolidation and indicate that the attention load of a task does not determine the magnitude of consolidation interference and associated forgetting.

Real-World Molecular Out-Of-Distribution: Specification and Investigation.

This study presents a rigorous framework for investigating molecular out-of-distribution (MOOD) generalization in drug discovery. The concept of MOOD is first clarified through a problem specification that demonstrates how the covariate shifts encountered during real-world deployment can be characterized by the distribution of sample distances to the training set. We find that these shifts can cause performance to drop by up to 60% and uncertainty calibration by up to 40%. This leads us to propose a splitting protocol that aims to close the gap between the deployment and testing. Then, using this protocol, a thorough investigation is conducted to assess the impact of model design, model selection, and data set characteristics on MOOD performance and uncertainty calibration. We find that appropriate representations and algorithms with built-in uncertainty estimation are crucial to improving performance and uncertainty calibration. This study sets itself apart by its exhaustiveness and opens an exciting avenue to benchmark meaningful algorithmic progress in molecular scoring.

The prevalence of premenstrual dysphoric disorder: Systematic review and meta-analysis.

BACKGROUND: Premenstrual dysphoric disorder is characterised by symptoms confined to the premenstrual phase of the menstrual cycle. Confirmed diagnosis requires prospective monitoring of symptoms over two cycles, otherwise the diagnosis is provisional. We aimed to measure the point prevalence of premenstrual dysphoric disorder. METHODS: We searched for studies of prevalence using MEDLINE, EMBASE, PsycINFO and PubMed. For each study, the total sample size and number of cases were extracted. The prevalence across studies was calculated using random effects meta-analysis with a generalised linear mixed model. Potential sources of heterogeneity were explored by meta-regression and subgroup analyses. Pre-registration was with PROSPERO (CRD42021249249). RESULTS: 44 studies with 48 independent samples met inclusion criteria, consisting of 50,659 participants. The pooled prevalence was 3.2 % (95 % confidence intervals: 1.7 %-5.9 %) for confirmed and 7.7 % (95 % confidence intervals: 5.3 %-11.0 %) for provisional diagnosis. There was high heterogeneity across all studies (I2 = 99 %). Sources of heterogeneity identified by meta-regression were continent of sample (p < 0.0001), type of sample (community-based, university, high school) (p = 0.007), risk of bias (p = 0.009), and method of diagnosis (p = 0.017). Restricting the analysis to community-based samples using confirmed diagnosis resulted in a prevalence of 1.6 % (95 % confidence intervals: 1.0 %-2.5 %), with low heterogeneity (I2 = 26 %). LIMITATIONS: A small number of included studies used full DSM criteria in community settings. CONCLUSIONS: The point prevalence of premenstrual dysphoric disorder using confirmed diagnosis is lower compared with provisional diagnosis. Studies relying on provisional diagnosis are likely to produce artificially high prevalence rates.

Source-based morphometry reveals structural brain pattern abnormalities in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism.

An online experiment that presents challenges for translating rest-related gains in visual detail memory from the laboratory to naturalistic settings.

New memories are labile and consolidate over time. Contemporary findings demonstrate that, like sleep, awake quiescence supports consolidation: people remember more new memories if they experience a brief period of post-encoding quiet rest than sensory processing. Furthermore, it was recently demonstrated that the quality of new memories can also be enhanced significantly by awake quiescence. This phenomenon offers great applied potential, for example, in education and eyewitness testimony settings. However, the translation of rest-related gains from the laboratory to everyday life remains poorly characterised and findings are mixed. Here, we report follow-on evidence demonstrating that rest-related gains in visual detail memory may be more challenging to achieve in naturalistic than laboratory-based settings. In contrast to established laboratory findings, using an online version of an established consolidation paradigm, we observed no memory benefit of post-encoding quiescence, relative to an engaging perceptual task, in the retention of detailed visual memories as measured through a lure discrimination task. This null finding could not be explained by intentional rehearsal in those who rested or between-group differences in participants' demographics or mental state, including fatigue and mood. Crucially, post-experimental reports indicated that those in the rest group experienced challenges in initiating and maintaining a state of quiescence, which may account for our null finding. Based on these findings, we propose three areas of focus for future work should rest-related gains in memory be translated from the lab to field: (1) to establish the specific environmental and individual conditions that are conducive and detrimental to awake consolidation, (2) to understand the barriers to initiating and maintaining a state of quiescence in naturalistic settings, and (3) to examine how knowledge of quiescence and its cognitive benefits can encourage the initiation and maintenance of states that are conductive to awake consolidation.

Rapid white matter changes in children with conduct problems during a parenting intervention.

Studies report that the microstructural integrity of the uncinate fasciculus (UF; connecting the anterior temporal lobe to the orbitofrontal cortex) is abnormal in adults with psychopathy and children with conduct problems (CP), especially those with high callous-unemotional (CU) traits. However, it is unknown if these abnormalities are 'fixed' or 'reversible'. Therefore, we tested the hypothesis that a reduction in CP symptoms, following a parenting intervention, would be associated with altered microstructural integrity in the UF. Using diffusion tensor imaging tractography we studied microstructural differences (mean diffusivity (MD) and radial diffusivity (RD)) in the UF of 43 typically developing (TD) and 67 boys with CP before and after a 14-week parenting intervention. We also assessed whether clinical response in CP symptoms or CU traits explained changes in microstructure following the intervention. Prior to intervention, measures of MD and RD in the UF were increased in CP compared to TD boys. Following intervention, we found that the CP group had a significant reduction in RD and MD. Further, these microstructural changes were driven by the group of children whose CU traits improved (but not CP symptoms as hypothesized). No significant microstructural changes were observed in the TD group. Our findings suggest, for the first time, that microstructural abnormalities in the brains of children with CP may be reversible following parenting intervention.

Different whole-brain functional connectivity correlates of reactive-proactive aggression and callous-unemotional traits in children and adolescents with disruptive behaviors.

BACKGROUND: Disruptive behavior in children and adolescents can manifest as reactive aggression and proactive aggression and is modulated by callous-unemotional traits and other comorbidities. Neural correlates of these aggression dimensions or subtypes and comorbid symptoms remain largely unknown. This multi-center study investigated the relationship between resting state functional connectivity (rsFC) and aggression subtypes considering comorbidities. METHODS: The large sample of children and adolescents aged 8-18 years (n = 207; mean age = 13.30±2.60 years, 150 males) included 118 cases with disruptive behavior (80 with Oppositional Defiant Disorder and/or Conduct Disorder) and 89 controls. Attention-deficit/hyperactivity disorder (ADHD) and anxiety symptom scores were analyzed as covariates when assessing group differences and dimensional aggression effects on hypothesis-free global and local voxel-to-voxel whole-brain rsFC based on functional magnetic resonance imaging at 3 Tesla. RESULTS: Compared to controls, the cases demonstrated altered rsFC in frontal areas, when anxiety but not ADHD symptoms were controlled for. For cases, reactive and proactive aggression scores were related to global and local rsFC in the central gyrus and precuneus, regions linked to aggression-related impairments. Callous-unemotional trait severity was correlated with ICC in the inferior and middle temporal regions implicated in empathy, emotion, and reward processing. Most observed aggression subtype-specific patterns could only be identified when ADHD and anxiety were controlled for. CONCLUSIONS: This study clarifies that hypothesis-free brain connectivity measures can disentangle distinct though overlapping dimensions of aggression in youths. Moreover, our results highlight the importance of considering comorbid symptoms to detect aggression-related rsFC alterations in youths.

Aspacytarabine for the treatment of patients with AML unfit for intensive chemotherapy: a phase 2 study.

High-dose cytarabine is associated with gastrointestinal and cerebellar toxicity, precluding its use for older or unfit patients with acute myeloid leukemia (AML). Aspacytarabine, an inactive prodrug of cytarabine, was evaluated as monotherapy in a phase 2b study of patients unfit for intensive chemotherapy (NCT03435848). Sixty-five patients with AML were treated with aspacytarabine 4.5 g/m2 per day (equimolar to 3 g/m2 per day cytarabine) for 6 doses per treatment. The median age was 75 years; 60.6% of patients had de novo AML, 28.8% had AML secondary to myelodysplastic syndrome, and 10.6% had therapy-related AML. Overall, 36.9% achieved complete remission (CR) with full count recovery. CR rates in patients with secondary AML, patients with prior treatment with hypomethylating agents, and patients with TP53 mutation were 26.7%, 25%, and 36%, respectively. Median overall survival was 9 months (range, 6-15.9) and was not reached among responders. Hematologic recovery was observed in all responding patients by day 26 without prolonged cytopenias. Adverse events typically precluding the use of high-dose cytarabine in older or unfit patients were not observed. These data suggest that aspacytarabine may be an effective regimen with a reduction in the attendant toxicities associated with high-dose cytarabine, an important consideration when treating AML and other hematologic disorders that use high-dose cytarabine. This trial was registered at www.clinicaltrials.gov as #NCT03435848.

Meteorological drivers of resource adequacy failures in current and high renewable Western U.S. power systems.

Power system resource adequacy (RA), or its ability to continually balance energy supply and demand, underpins human and economic health. How meteorology affects RA and RA failures, particularly with increasing penetrations of renewables, is poorly understood. We characterize large-scale circulation patterns that drive RA failures in the Western U.S. at increasing wind and solar penetrations by integrating power system and synoptic meteorology methods. At up to 60% renewable penetration and across analyzed weather years, three high pressure patterns drive nearly all RA failures. The highest pressure anomaly is the dominant driver, accounting for 20-100% of risk hours and 43-100% of cumulative risk at 60% renewable penetration. The three high pressure patterns exhibit positive surface temperature anomalies, mixed surface solar radiation anomalies, and negative wind speed anomalies across our region, which collectively increase demand and decrease supply. Our characterized meteorological drivers align with meteorology during the California 2020 rolling blackouts, indicating continued vulnerability of power systems to these impactful weather patterns as renewables grow.

Characterizing Subcortical Structural Heterogeneity in Autism.

Autism presents with significant phenotypic and neuroanatomical heterogeneity, and neuroimaging studies of the thalamus, globus pallidus and striatum in autism have produced inconsistent and contradictory results. These structures are critical mediators of functions known to be atypical in autism, including sensory gating and motor function. We examined both volumetric and fine-grained localized shape differences in autism using a large (n=3145, 1045-1318 after strict quality control), cross-sectional dataset of T1-weighted structural MRI scans from 32 sites, including both males and females (assigned-at-birth). We investigated three potentially important sources of neuroanatomical heterogeneity: sex, age, and intelligence quotient (IQ), using a meta-analytic technique after strict quality control to minimize non-biological sources of variation. We observed no volumetric differences in the thalamus, globus pallidus, or striatum in autism. Rather, we identified a variety of localized shape differences in all three structures. Including age, but not sex or IQ, in the statistical model improved the fit for both the pallidum and striatum, but not for the thalamus. Age-centered shape analysis indicated a variety of age-dependent regional differences. Overall, our findings help confirm that the neurodevelopment of the striatum, globus pallidus and thalamus are atypical in autism, in a subtle location-dependent manner that is not reflected in overall structure volumes, and that is highly non-uniform across the lifespan.

Ecological Considerations When Designing Mitigation Translocations: An Australian Reptile Case Study.

Translocation science has made considerable progress over the last two decades; however, reptile translocations still frequently fail around the world. Major knowledge gaps surround the basic ecology of reptile species, including basic factors such as habitat preference, which have a critical influence on translocation success. The western spiny-tailed skink (Egernia stokesii badia) is used here as a case study to exemplify how empirical research can directly inform on-ground management and future translocation planning. A combination of studies, including LiDAR scanning of microhabitat structures, camera trapping, plasticine replica model experiments and unbounded point count surveys to assess predation risk, and visual and DNA analysis of dietary requirements, were all used to better understand the ecological requirements of E. s. badia. We found that the skinks have specific log pile requirements, both native and non-native predator management requirements, and a largely herbivorous, broad diet, which all influence translocation site selection and management planning. The use of E. s. badia as an Australian case study provides a clear strategic framework for the targeted research of meaningful ecological factors that influence translocation decision-making. Similar approaches applied to other reptile species are likely to fundamentally increase the capacity for effective management, and the likelihood of future successful translocations.

No evidence from complementary data sources of a direct glutamatergic projection from the mouse anterior cingulate area to the hippocampal formation.

The connectivity and interplay between the prefrontal cortex and hippocampus underpin various key cognitive processes, with changes in these interactions being implicated in both neurodevelopmental and neurodegenerative conditions. Understanding the precise cellular connections through which this circuit is organised is, therefore, vital for understanding these same processes. Overturning earlier findings, a recent study described a novel excitatory projection from anterior cingulate area to dorsal hippocampus. We sought to validate this unexpected finding using multiple, complementary methods: anterograde and retrograde anatomical tracing, using anterograde and retrograde adeno-associated viral vectors, monosynaptic rabies tracing, and the Fast Blue classical tracer. Additionally, an extensive data search of the Allen Projection Brain Atlas database was conducted to find the stated projection within any of the deposited anatomical studies as an independent verification of our own results. However, we failed to find any evidence of a direct, monosynaptic glutamatergic projection from mouse anterior cingulate cortex to the hippocampus proper.

Alterations to parvalbumin-expressing interneuron function and associated network oscillations in the hippocampal - medial prefrontal cortex circuit during natural sleep in AppNL-G-F/NL-G-F mice.

In the early stages of Alzheimer's disease (AD), the accumulation of the peptide amyloid-ß (Aß) damages synapses and disrupts neuronal activity, leading to the disruption of neuronal oscillations associated with cognition. This is thought to be largely due to impairments in CNS synaptic inhibition, particularly via parvalbumin (PV)-expressing interneurons that are essential for generating several key oscillations. Research in this field has largely been conducted in mouse models that over-express humanised, mutated forms of AD-associated genes that produce exaggerated pathology. This has prompted the development and use of knock-in mouse lines that express these genes at an endogenous level, such as the AppNL-G-F/NL-G-F mouse model used in the present study. These mice appear to model the early stages of Aß-induced network impairments, yet an in-depth characterisation of these impairments in currently lacking. Therefore, using 16 month-old AppNL-G-F/NL-G-F mice, we analysed neuronal oscillations found in the hippocampus and medial prefrontal cortex (mPFC) during awake behaviour, rapid eye movement (REM) and non-REM (NREM) sleep to assess the extent of network dysfunction. No alterations to gamma oscillations were found to occur in the hippocampus or mPFC during either awake behaviour, REM or NREM sleep. However, during NREM sleep an increase in the power of mPFC spindles and decrease in the power of hippocampal sharp-wave ripples was identified. The latter was accompanied by an increase in the synchronisation of PV-expressing interneuron activity, as measured using two-photon Ca2+ imaging, as well as a decrease in PV-expressing interneuron density. Furthermore, although changes were detected in local network function of mPFC and hippocampus, long-range communication between these regions appeared intact. Altogether, our results suggest that these NREM sleep-specific impairments represent the early stages of circuit breakdown in response to amyloidopathy.

One Dose Is Not Enough: The Beneficial Effect of Corrective COVID-19 Information Is Diminished If Followed by Misinformation.

The World Health Organization (WHO) released a series of mythbuster infographics to combat misinformation during the COVID-19 infodemic. While the corrective effects of such debunking interventions have typically been examined in the immediate aftermath of intervention delivery; the durability of these corrective effects and their resilience against subsequent misinformation remains poorly understood. To this end, we asked younger and older adults to rate the truthfulness and credibility of 10 statements containing misinformation about common COVID-19 myths, as well as their willingness to share the statements through social media. They did this three times, before and after experimental interventions within a single study session. In keeping with established findings, exposure to the WHO's myth-busting infographics-(a) improved participants' ratings of the misinformation statements as untruthful and uncredible and (b) reduced their reported willingness to share the statements. However, within-subject data revealed these beneficial effects were diminished if corrective information was presented shortly by misinformation, but the effects remained when further corrective information was presented. Throughout the study, younger adults rated the misinformation statements as more truthful and credible and were more willing to share them. Our data reveal that the benefit of COVID-19 debunking interventions may be short-lived if followed shortly by misinformation. Still, the effect can be maintained in the presence of further corrective information. These outcomes provide insights into the effectiveness and durability of corrective information and can influence strategies for tackling health-related misinformation, especially in younger adults.

Demonstrating the source of inherent instability in NiFe LDH-based OER electrocatalysts.

Nickel-iron layered double hydroxides are known to be one of the most highly active catalysts for the oxygen evolution reaction in alkaline conditions. The high electrocatalytic activity of the material however cannot be sustained within the active voltage window on timescales consistent with commercial requirements. The goal of this work is to identify and prove the source of inherent catalyst instability by tracking changes in the material during OER activity. By combining in situ and ex situ Raman analyses we elucidate long-term effects on the catalyst performance from a changing crystallographic phase. In particular, we attribute electrochemically stimulated compositional degradation at active sites as the principal cause of the sharp loss of activity from NiFe LDHs shortly after the alkaline cell is turned on. EDX, XPS, and EELS analyses performed after OER also reveal noticeable leaching of Fe metals compared to Ni, principally from highly active edge sites. In addition, post-cycle analysis identified a ferrihydrite by-product formed from the leached Fe. Density functional theory calculations shed light on the thermodynamic driving force for the leaching of Fe metals and propose a dissolution pathway which involves [FeO4]2- removal at relevant OER potentials.

Chemotherapeutic Activity of Pitavastatin in Vincristine Resistant B-Cell Acute Lymphoblastic Leukemia.

B-cell acute lymphoblastic leukemia (ALL) is derived from an accumulation of malignant, immature B cells in the bone marrow and blood. Relapse due, in part, to the emergence of tumor cells that are resistant to front line standard chemotherapy is associated with poor patient outcomes. This challenge highlights the need for new treatment strategies to eliminate residual chemoresistant tumor cells. Based on the use of pitavastatin in acute myeloid leukemia (AML), we evaluated its efficacy in an REH ALL cell line derived to be resistant to vincristine. We found that pitavastatin inhibited the proliferation of both parental and vincristine-resistant REH tumor cells at an IC50 of 449 nM and 217 nM, respectively. Mitochondrial bioenergetic assays demonstrated that neither vincristine resistance nor pitavastatin treatment affected cellular oxidative phosphorylation, beta-oxidation, or glycolytic metabolism in ALL cells. In a co-culture model of ALL cells with bone marrow stromal cells, pitavastatin significantly decreased cell viability more robustly in the vincristine-resistant ALL cells compared with their parental controls. Subsequently, NSG mice were used to develop an in vivo model of B-cell ALL using both parental and vincristine-resistant ALL cells. Pitavastatin (10 mg/kg i.p.) significantly reduced the number of human CD45+ REH ALL cells in the bone marrow of mice after 4 weeks of treatment. Mechanistic studies showed that pitavastatin treatment in the vincristine-resistant cells led to apoptosis, with increased levels of cleaved PARP and protein-signaling changes for AMP-activated protein kinase/FoxO3a/Puma. Our data suggest the possible repurposing of pitavastatin as a chemotherapeutic agent in a model of vincristine-resistant B-cell ALL.

Reduced emergent character of neural dynamics in patients with a disrupted connectome.

High-level brain functions are widely believed to emerge from the orchestrated activity of multiple neural systems. However, lacking a formal definition and practical quantification of emergence for experimental data, neuroscientists have been unable to empirically test this long-standing conjecture. Here we investigate this fundamental question by leveraging a recently proposed framework known as "Integrated Information Decomposition," which establishes a principled information-theoretic approach to operationalise and quantify emergence in dynamical systems - including the human brain. By analysing functional MRI data, our results show that the emergent and hierarchical character of neural dynamics is significantly diminished in chronically unresponsive patients suffering from severe brain injury. At a functional level, we demonstrate that emergence capacity is positively correlated with the extent of hierarchical organisation in brain activity. Furthermore, by combining computational approaches from network control theory and whole-brain biophysical modelling, we show that the reduced capacity for emergent and hierarchical dynamics in severely brain-injured patients can be mechanistically explained by disruptions in the patients' structural connectome. Overall, our results suggest that chronic unresponsiveness resulting from severe brain injury may be related to structural impairment of the fundamental neural infrastructures required for brain dynamics to support emergence.

Selective Amygdala Hypoactivity to Fear in Boys With Persistent Conduct Problems After Parent Training.

BACKGROUND: Parenting interventions reduce antisocial behavior (ASB) in some children with conduct problems (CPs), but not others. Understanding the neural basis for this disparity is important because persistent ASB is associated with lifelong morbidity and places a huge burden on our health and criminal justice systems. One of the most highly replicated neural correlates of ASB is amygdala hypoactivity to another person's fear. We aimed to assess whether amygdala hypoactivity to fear in children with CPs is remediated following reduction in ASB after successful treatment and/or if it is a marker for persistent ASB. METHODS: We conducted a prospective, case-control study of boys with CPs and typically developing (TD) boys. Both groups (ages 5-10 years) completed 2 magnetic resonance imaging sessions (18 ± 5.8 weeks apart) with ASB assessed at each visit. Participants included boys with CPs following referral to a parenting intervention group and TD boys recruited from the same schools and geographical regions. Final functional magnetic resonance imaging data were available for 36 TD boys and 57 boys with CPs. Boys with CPs were divided into those whose ASB improved (n = 27) or persisted (n = 30) following the intervention. Functional magnetic resonance imaging data assessing fear reactivity were then analyzed using a longitudinal group (TD/improving CPs/persistent CPs) × time point (pre/post) design. RESULTS: Amygdala hypoactivity to fear was observed only in boys with CPs who had persistent ASB and was absent in those whose ASB improved following intervention. CONCLUSIONS: Our findings suggest that amygdala hypoactivity to fear is a marker for ASB that is resistant to change following a parenting intervention and a putative target for future treatments.