Solvent-Controlled Separation of Integratively Self-Sorted Pd2LA2LB2 Coordination Cages.

The integrative implementation of multiple different components into metallosupramolecular self-assemblies requires sophisticated strategies to avoid the formation of statistical mixtures. Previously, the key focus was set on thermodynamically driven reactions of simple homoleptic into complex heteroleptic structures. Using Pd2LA2LB2-type coordination cages, we herein show that integrative self-sorting can be reversed by a change of solvent (from DMSO to MeCN) to favor narcissistic re-segregation into coexisting homoleptic species Pd2LA4 and Pd3LB6. Full separation ("unsorting") back to a mixture of the homoleptic precursors was finally achieved by selective precipitation of Pd3LB6with anionic guest G1 from MeCN, keeping pure Pd2LA4 in solution. When a mixture of homoleptic Pd3LB6 and heteroleptic Pd2LA2LB2 is exposed to a combination of two different di-anions (G1 and G2) in DMSO, selective guest uptake gives rise to two defined coexisting host-guest complexes. A joint experimental and deep theoretical investigation via liquid-state integral equation theory of the reaction thermodynamics on a molecular level accompanied by solvent distribution analysis hints at solvent expulsion from Pd2LA4 to favor the formation of Pd2LA2LB2 in DMSO as the key entropic factor for determining the solvent-specific modulation of the cage conversion equilibrium.

Molecular and clinical heterogeneity within MYC-family amplified medulloblastoma is associated with survival outcomes: A multicenter cohort study.

BACKGROUND: MYC/MYCN are the most frequent oncogene amplifications in medulloblastoma (MB) and its primary biomarkers of high-risk (HR) disease. However, while many patients' MYC(N)-amplified tumors are treatment-refractory, some achieve long-term survival. We therefore investigated clinicobiological heterogeneity within MYC(N)-amplified MB and determined its relevance for improved disease management. METHODS: We characterized the clinical and molecular correlates of MYC- (MYC-MB; n = 64) and MYCN-amplified MBs (MYCN-MB; n = 95), drawn from >1600 diagnostic cases. RESULTS: Most MYC-MBs were molecular group 3 (46/58; 79% assessable) and aged ≥3 years at diagnosis (44/64 [69%]). We identified a "canonical" very high-risk (VHR) MYC-amplified group (n = 51/62; 82%) with dismal survival irrespective of treatment (11% 5-year progression-free survival [PFS]), defined by co-occurrence with ≥1 additional established risk factor(s) (subtotal surgical-resection [STR], metastatic disease, LCA pathology), and commonly group 3/4 subgroup 2 with a high proportion of amplified cells. The majority of remaining noncanonical MYC-MBs survived (i.e. non-group 3/group 3 without other risk features; 11/62 (18%); 61% 5-year PFS). MYCN survival was primarily related to molecular group; MYCN-amplified SHH MB, and group 3/4 MB with additional risk factors, respectively defined VHR and HR groups (VHR, 39% [35/89]; 20% 5-year PFS/HR, 33% [29/89]; 46% 5-year PFS). Twenty-two out of 35 assessable MYCN-amplified SHH tumors harbored TP53 mutations; 9/12 (75%) with data were germline. MYCN-amplified group 3/4 MB with no other risk factors (28%; 25/89) had 70% 5-year PFS. CONCLUSIONS: MYC(N)-amplified MB displays significant clinicobiological heterogeneity. Diagnostics incorporating molecular groups, subgroups, and clinical factors enable their risk assessment. VHR "canonical" MYC tumors are essentially incurable and SHH-MYCN-amplified MBs fare extremely poorly (20% survival at 5 years); both require urgent development of alternative treatment strategies. Conventional risk-adapted therapies are appropriate for more responsive groups, such as noncanonical MYC and non-SHH-MYCN MB.

Evaluating the halogen bonding strength of a iodoloisoxazolium(III) salt.

Diaryliodonium(III) salts have been established as powerful halogen-bond donors in recent years. Herein, a new structural motif for this compound class was developed: iodoloisoxazolium salts, bearing a cyclic five-membered iodolium core fused with an isoxazole ring. A derivative of this class was synthesized and investigated in the solid state by X-ray crystallography. Finally, the potential as halogen-bonding activator was benchmarked in solution in the gold-catalyzed cyclization of a propargyl amide.

Comparison of surgical and conservative therapy in older patients with distal radius fracture: a prospective randomized clinic al trial.

INTRODUCTION: The distal radius fracture is considered the most common fracture in humans. For fractures classified as Arbeitsgemeinschaft für Osteosynthese (AO) 23-C1 + C2, there is no consensus on treatment in older patients due to inconsistent study results. The aim of this study was to compare conservative and surgical treatment in relation to wrist function and satisfaction in patients older than 65 years. METHODS: In this prospective randomized clinical trial, patients aged older than 65 years who suffered an isolated AO-classified C1 or C2 distal radius fracture were randomized to surgical treatment using palmar plate osteosynthesis or conservative treatment. Patient-rated wrist evaluation (PRWE) score and disabilities of arm, shoulder, and hand (DASH) was assessed 3, 6 and 12 months post-interventionally. Satisfaction, range of motion (ROM) and pain scores were evaluated at 6 weeks and 3, 6 and 12 months post-interventionally. RESULTS: A total of 80 patients with a mean age of 77.3 years (± 6.1 years) in the conservative group and 72.5 years (± 5.3 years) in the surgery group were included. Both the PRWE score, and the DASH score showed a statistically significant difference between the two groups after 3 months, 6 months and 12 months (p < 0.001). Patients in the surgical cohort showed a statistically significant higher satisfaction at the 6-week, 6-month and 12-month follow-up (p < 0.001 6 weeks + 12 months; p = 0.004 6 months). CONCLUSION: In this prospective randomized study, surgical treatment proved to be superior to conservative treatment in terms of the primary outcome variable PRWE score. Satisfaction was significantly better in the surgical group.

Under the influence: exogenous testosterone influences men's cross-sex perceptions of sexual interest.

The sexual misperception bias is a cognitive bias in which men tend to overestimate sexual interest from women, potentially shaped by evolutionary mating strategies. Testosterone, often linked to mating behaviors, might play a role in sustaining sexual overperceptions. To explore this possibility, we conducted a placebo-controlled study with 190 heterosexual men, administering either 11 mg of testosterone or a placebo. Participants interacted with an attractive female confederate, while naïve raters assessed the confederate's affiliative behaviors. Our findings suggest that exogenous testosterone did not broadly impact sexual overperception. However, we found that affiliative behavior from the confederate was positively correlated with perceived sexual interest among testosterone-treated, but not placebo-treated men. In addition, we found that this effect among testosterone-treated men was contingent on their self-perceived attractiveness. Specifically, the confederate's affiliative behaviors were positively correlated with perceived sexual interest, but only for testosterone-treated men with average or above average self-perceived attractiveness. Furthermore, our data revealed that men's tendency to project their own short-term and long-term mating interests increases as a function of self-perceived attractiveness, and this coupling is enhanced by testosterone for long-term interest. Taken together, these results suggest that testosterone may potentiate existing biases, particularly when sexual motivation is high, and bias perceptions of friendly behavior when engaging in cross-sex mindreading. This study adds to the understanding of the neuroendocrine bases of social cognition, suggesting that testosterone can affect men's perceptions of potential mates.

Barriers and facilitators to next-generation sequencing use in United States oncology settings: a systematic review.

Aim: Next-generation sequencing (NGS) of solid tumors can inform treatment decisions; however, uptake remains low. This objective of this systematic review was to identify barriers to and facilitators of NGS in US oncology settings.Materials & methods: Embase and MEDLINE were searched in March 2023 for articles published from 2012 to 2023 on barriers and facilitators of NGS adoption for solid tumors. Surveys, interviews and observational studies were eligible. Studies on genetic testing for hereditary cancers and non-US studies were excluded. The Motheral scale, Joanna Briggs Institute critical appraisal checklist and McGill Mixed Methods Appraisal Tool were used to assess study quality. Data were synthesized narratively.Results: Twenty-one studies were included. Study participants were clinicians, payers and administrators. Key barriers included complex reimbursement processes and uncertainties around clinical utility. Including recommendations for NGS in clinical practice guidelines was a key facilitator, although insurance policies were often more restrictive than guideline recommendations.Conclusion: Uptake of NGS is increasing but barriers remain. Changes to the current reimbursement frameworks are needed to increase access to NGS. The impact of implementing the 2018 National Coverage Determination, which allows access to NGS for all Medicare beneficiaries with advanced cancer, is not yet evident in the published literature.

[Box: see text].

How large language models can reshape collective intelligence.

Collective intelligence underpins the success of groups, organizations, markets and societies. Through distributed cognition and coordination, collectives can achieve outcomes that exceed the capabilities of individuals-even experts-resulting in improved accuracy and novel capabilities. Often, collective intelligence is supported by information technology, such as online prediction markets that elicit the 'wisdom of crowds', online forums that structure collective deliberation or digital platforms that crowdsource knowledge from the public. Large language models, however, are transforming how information is aggregated, accessed and transmitted online. Here we focus on the unique opportunities and challenges this transformation poses for collective intelligence. We bring together interdisciplinary perspectives from industry and academia to identify potential benefits, risks, policy-relevant considerations and open research questions, culminating in a call for a closer examination of how large language models affect humans' ability to collectively tackle complex problems.

Effectiveness of a digital lifestyle management intervention (levidex) to improve quality of life in people with multiple sclerosis: results of a randomized controlled trial.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory neurodegenerative disease with diverse symptomatology, significantly impacting patients' quality of life (QoL). While pharmacological therapies focus primarily on reducing inflammation and relapse rates, non-pharmacological interventions, including digital health applications, have shown promise in improving QoL among persons with MS (PwMS). Pilot studies had shown the feasibility and acceptability of levidex, a digital health application based on cognitive behavioral therapy (CBT) principles, a broad set of behavior change techniques, and relevant lifestyle-change advice. This randomized controlled trial aimed to examine the effects of levidex on MS-related QoL over 6 months. METHODS: Participants who were diagnosed with MS for at least one year were recruited via the internet in Germany, using a secure survey software platform, and were randomly assigned to the intervention group (IG), in which they received standard care + levidex, or an active control group (CG), in which they received standard care and were offered web-adapted material on the topic of lifestyle change from the German Multiple Sclerosis Society (DMSG). The primary outcome was MS-related QoL after 6 months, measured by the Hamburg Quality of Life Questionnaire in MS (HAQUAMS); secondary outcomes included QoL subscales, sick days, and health behavior, among others. Analyses of Covariance (ANCOVA) were used to examine intervention effects at 6 months. Participants were recruited between November 2020 and February 2022. RESULTS: A total of 421 adult participants (mean age: 47.5, 78.1% women) were included and randomized (IG, n = 195, CG, n = 226). After 6 months, the IG exhibited significantly higher MS-related QoL, compared to the CG (total score HAQUAMS, adjusted group mean difference = -0.14, 95% CI: [-0.22, -0.06], p = 0.001; Cohen's d = 0.23), with significant effects also observed on the cognitive and mood subscales. At 6 months, IG participants also reported significantly fewer sick days (median = 2 days in IG vs. 6 days in CG; W = 3939, p = 0.012) and significantly higher levels of daily activities, as measured by the Frenchay Activity Index, adjusted group mean difference = 1.37, 95% CI = [0.33, 2.40], p = 0.010; Cohen's d = 0.16. Safety analyses showed no adverse events and good satisfaction. CONCLUSIONS: Compared to the control group, levidex facilitated clinically relevant improvements in MS-related QoL, reduced sick days, and enhanced activity in PwMS over 6 months. These findings suggest that levidex can serve as an effective non-pharmacological adjunctive treatment element to standard care and could help improve QoL among PwMS. TRIAL REGISTRATION: Registered on 22.09.2020 at the German Clinical Trials Register DRKS00023023.

Calculated hydration free energies become less accurate with increases in molecular weight.

In order for computer-aided drug design to fulfil its long held promise of delivering new medicines faster and cheaper, extensive development and validation work must be done first. This pertains particularly to molecular dynamics force fields where one important aspect-the hydration free energy (HFE) of small molecules-is often insufficiently analyzed. While most benchmarking studies report excellent accuracies of calculated hydration free energies-usually within 2 kcal/mol of experimental values-we find that deeper analysis reveals significant shortcomings. Herein, we report a dependence of HFE prediction errors on ligand molecular weight-the higher the weight, the bigger the prediction error and the higher the probability the calculated result is erroneous by a large amount. We show that in the drug-like molecular weight region, HFE predictions can easily be off by 5 kcal/mol or more. This is likely to be highly problematic in a drug discovery and development setting. We make our HFE results and molecular descriptors freely and fully available in order to encourage deeper analysis of future molecular dynamics results and facilitate development of the next generation of force fields.

MYB immunohistochemistry as a predictor of MYB::NFIB fusion in the diagnosis of adenoid cystic carcinoma of the head and neck.

OBJECTIVES: Diagnosing adenoid cystic carcinoma (AdCC) is challenging due to histopathological variability and similarities with other tumors. In AdCC pathogenesis, the cellular myeloblastosis gene (c-MYB) often exhibits a MYB::NFIB fusion from a reciprocal translocation. This study aimed to assess the predictive accuracy of MYB immunohistochemistry for detecting this translocation compared to fluorescence in situ hybridization (FISH). STUDY DESIGN: This study included 110 AdCC patients (1999-2017) from two Dutch head and neck centers using tissue microarrays and full slides. Median MYB expression levels by immunohistochemistry were compared based on translocation status by FISH, and differences within clinicopathological parameters were examined. An immunohistochemical cut-off was established to estimate the translocation. RESULTS: MYB immunohistochemistry was available in 90/110 patients, with a median expression of 27%. FISH was interpretable in 79/108 tumors, identifying MYB::NFIB fusion in 44 (56%). Among 62 patients with both MYB expression and translocation data, the fusion was present in 38 (61%). These tumors had higher MYB expression (30%) than nontranslocated tumors (6%); P = .02. A 60% MYB expression cut-off yielded 100% specificity for detecting the translocation but had no prognostic value. CONCLUSIONS: Although MYB protein expression alone lacks diagnostic precision, protein expression >60% predicted the MYB::NFIB fusion in all tumors.

Activation induces shift in nutrient utilization that differentially impacts cell functions in human neutrophils.

Neutrophils utilize a variety of metabolic sources to support their crucial functions as the first responders in innate immunity. Here, through in vivo and ex vivo isotopic tracing, we examined the contributions of different nutrients to neutrophil metabolism under specific conditions. Human peripheral blood neutrophils, in contrast to a neutrophil-like cell line, rely on glycogen storage as a major metabolic source under resting state but rapidly switch to primarily using extracellular glucose upon activation with various stimuli. This shift is driven by a substantial increase in glucose uptake, enabled by rapidly increased GLUT1 on cell membrane, that dominates the simultaneous increase in gross glycogen cycling capacity. Shifts in nutrient utilization impact neutrophil functions in a function-specific manner: oxidative burst depends on glucose utilization, whereas NETosis and phagocytosis can be flexibly supported by either glucose or glycogen, and neutrophil migration and fungal control are enhanced by the shift from glycogen utilization to glucose utilization. This work provides a quantitative and dynamic understanding of fundamental features in neutrophil metabolism and elucidates how metabolic remodeling shapes neutrophil functions, which has broad health relevance.

Strenuous training combined with erythropoietin induces red cell volume expansion-mediated hypervolemia and alters systemic and skeletal muscle iron homeostasis.

Strenuous physical training increases total blood volume (BV) through expansion of plasma (PV) and red cell volumes (RCV). In contrast, exogenous erythropoietin (EPO) treatment increases RCV but decreases PV, rendering BV stable or slightly decreased. This study aimed to determine the combined effects of strenuous training and EPO treatment on BV and markers of systemic and muscle iron homeostasis. In this longitudinal study, 8 healthy non-anemic males were treated with EPO (50 IU/kg body mass, 3x/week, subcutaneously) across 28 days of strenuous training (4d/week, exercise energy expenditures of 1334±24 kcal/d) while consuming a controlled, energy-balanced diet providing 39±4 mg/d iron. Before (PRE) and after (POST) intervention, BV compartments were measured using carbon monoxide rebreathing, and markers of iron homeostasis were assessed in blood and skeletal muscle (vastus lateralis). Training + EPO increased (p<0.01) RCV (13±6%) and BV (5±4%), whereas PV remained unchanged (p=0.86). The expansion of RCV was accompanied by a large decrease in whole-body iron stores, as indicated by decreased (p<0.01) ferritin (-77±10%) and hepcidin (-49±23%) concentrations in plasma. Training + EPO decreased (p<0.01) muscle protein abundance of ferritin (-25±20%) and increased (p<0.05) transferrin receptor (47±56%). These novel findings illustrate that strenuous training combined with EPO results in both increased total oxygen carrying capacity and hypervolemia in young healthy males. The decrease in plasma and muscle ferritin suggests that the marked upregulation of erythropoiesis alters systemic and tissue iron homeostasis, resulting in a decline in whole-body and skeletal muscle iron stores.

Control of innate immunity and lipid biosynthesis in neurodegeneration.

The cGAS-STING innate immunity pathway and the SREBP-activated cholesterol and fatty acid synthesis pathway are abnormally co-regulated in neurodegenerative disease. Activation of STING signaling occurs at the endoplasmic reticulum (ER) membrane with STING anchored by INSIG1 along with SREBP and the sterol-bound SREBP cleavage activating protein (SCAP) when sterols are in abundance. When sterols are low, the INSIG-dependent STING pathway is inactivated and the SREBP-SCAP complex is translocated to the Golgi where SREBP is cleaved and translocated to the nucleus to transactivate genes for cholesterol and fatty acid synthesis. Thus, there is inverse activation of STING vs. SREBP: when innate immunity is active, pathways for cholesterol and fatty acid synthesis are suppressed, and vice versa. The STING pathway is stimulated by foreign viral cytoplasmic nucleic acids interacting with the cyclic GMP-AMP synthase (cGAS) DNA sensor or RIG-I and MDA5 dsRNA sensors, but with neurodegeneration innate immunity is also activated by self-DNAs and double-stranded RNAs that accumulate with neuronal death. Downstream, activated STING recruits TBK1 and stimulates the transactivation of interferon stimulated genes and the autophagy pathway, which are both protective. However, chronic activation of innate immunity contributes to microglia activation, neuroinflammation and autophagy failure leading to neurodegeneration. STING is also a proton channel that when activated stimulates proton exit from STING vesicles leading to cell death. Here we review the salient features of the innate immunity and cholesterol and fatty acid synthesis pathways, observations of abnormal STING and SREBP signaling in neurodegenerative disease, and relevant therapeutic approaches.

Controlling photothermoelectric directional photocurrents in graphene with over 400 GHz bandwidth.

Photodetection in the near- and mid-infrared spectrum requires a suitable absorbing material able to meet the respective targets while ideally being cost-effective. Graphene, with its extraordinary optoelectronic properties, could provide a material basis simultaneously serving both regimes. The zero-band gap offers almost wavelength independent absorption which lead to photodetectors operating in the infrared spectrum. However, to keep noise low, a detection mechanism with fast and zero bias operation would be needed. Here, we show a self-powered graphene photodetector with a > 400 GHz frequency response. The device combines a metamaterial perfect absorber architecture with graphene, where asymmetric resonators induce photothermoelectric directional photocurrents within the graphene channel. A quasi-instantaneous response linked to the photothermoelectric effect is found. Typical drift/diffusion times optimization are not needed for a high-speed response. Our results demonstrate that these photothermoelectric directional photocurrents have the potential to outperform the bandwidth of many other graphene photodetectors and most conventional technologies.

Real-time fMRI neurofeedback of the anterior insula using arterial spin labelling.

Arterial spin labelling (ASL) is the only non-invasive technique that allows absolute quantification of perfusion and is increasingly used in brain activation studies. Contrary to the blood oxygen level-dependent (BOLD) effect ASL measures the cerebral blood flow (CBF) directly. However, the ASL signal has a lower signal-to-noise ratio (SNR), than the BOLD signal, which constrains its utilization in neurofeedback studies. If successful, ASL neurofeedback can be used to aid in the rehabilitation of health conditions with impaired blood flow, for example, stroke. We provide the first ASL-based neurofeedback study incorporating a double-blind, sham-controlled design. A pseudo-continuous ASL (pCASL) approach with background suppression and 3D GRASE readout was combined with a real-time post-processing pipeline. The real-time pipeline allows to monitor the ASL signal and provides real-time feedback on the neural activity to the subject. In total 41 healthy adults (19-56 years) divided into three groups underwent a neurofeedback-based emotion imagery training of the left anterior insula. Two groups differing only in the explicitness level of instruction received real training and a third group received sham feedback. Only those participants receiving real feedback with explicit instruction showed significantly higher absolute CBF values in the trained region during neurofeedback than participants receiving sham feedback. However, responder analyses of percent signal change values show no differences in activation between the three groups. Persisting limitations, such as the lower SNR, confounding effects of arterial transit time and partial volume effects still impact negatively the implementation of ASL neurofeedback.

Comments and Controversies in Oncology: The Tribulations of Trials Developing ONC201.

Our international team highlights issues with efficacy reports in several studies on DMG with the new drug ONC201.

Associations between Essential Amino Acid Intake and Functional Health Outcomes in Older Adults: Analysis of the National Health and Nutrition Examination Survey, 2001-2018.

Background: The relationships between habitual essential amino acid (EAA) intake and body composition, muscle strength, and physical function in older US adults are not well defined. Objectives: This cross-sectional study evaluated associations between usual EAA intakes and body composition, muscle strength, and physical function in US adults ≥65 y. Methods: The Food and Nutrient Database for Dietary Studies (FNDDS) 2001-2018 was linked to the US Department of Agriculture Standard Reference database to access existing amino acid composition data for FNDDS ingredients. FNDDS ingredients without existing amino acid composition data were matched to similar ingredient codes with available data. Usual EAA, leucine, lysine, and sulfur-containing amino acid (SAA; methionine + cysteine) intakes (g/d) from National Health and Nutrition Examination Survey 2001-2018 were calculated for individuals ≥65 y (n = 10,843). Dependent variables included muscle strength measured by isometric grip test, body mass index (BMI), waist circumference, dual-energy X-ray absorptiometry-measured appendicular lean mass and whole-body fat mass, and self-reported physical function (that is, tasks of daily living). Regression analyses were used to determine covariate-adjusted relationships between EAA, leucine, lysine, and SAA intake and functional health outcomes. P < 0.0013 was considered significant. Results: EAA, leucine, lysine, and SAA intakes, covaried with physical activity level and usual protein intake, were not associated with muscle strength or self-reported physical function in males or females or with body composition in males. EAA intakes were positively associated with waist circumference in females (ß ± SEM, 2.1 ± 0.6 cm, P = 0.0007). Lysine intakes were positively associated with BMI (3.0 ± 0.7 kg/m2, P < 0.0001) and waist circumference (7.0 ± 1.7 cm, P = 0.0001) in females. Conclusions: Habitual EAA, leucine, lysine, and SAA intakes, covaried with physical activity level and usual protein intake, were not associated with lean mass, muscle strength, or physical function in adults ≥65 y. However, EAA intakes, particularly lysine, were positively associated with measures of adiposity in older females.This trial was registered with the Open Science Framework (https://doi.org/10.17605/OSF.IO/25V63) as osf.io/25v63).

From emotional arousal to executive action. Role of the prefrontal cortex.

Emotional arousal is caused by the activity of two parallel ascending systems targeting mostly the subcortical limbic regions and the prefrontal cortex. The aversive, negative arousal system is initiated by the activity of the mesolimbic cholinergic system and the hedonic, appetitive, arousal is initiated by the activity of the mesolimbic dopaminergic system. Both ascending projections have a diffused nature and arise from the rostral, tegmental part of the brain reticular activating system. The mesolimbic cholinergic system originates in the laterodorsal tegmental nucleus and the mesolimbic dopaminergic system in the ventral tegmental area. Cholinergic and dopaminergic arousal systems have converging input to the medial prefrontal cortex. The arousal system can modulate cortical EEG with alpha rhythms, which enhance synaptic strength as shown by an increase in long-term potentiation (LTP), whereas delta frequencies are associated with decreased arousal and a decrease in synaptic strength as shown by an increase in long-term depotentiation (LTD). It is postulated that the medial prefrontal cortex is an adaptable node with decision making capability and may control the switch between positive and negative affect and is responsible for modifying or changing emotional state and its expression.

The political (a)symmetry of metacognitive insight into detecting misinformation.

Political misinformation poses a major threat to democracies worldwide, often inciting intense disputes between opposing political groups. Despite its central role for informed electorates and political decision making, little is known about how aware people are of whether they are right or wrong when distinguishing accurate political information from falsehood. Here, we investigate people's metacognitive insight into their own ability to detect political misinformation. We use data from a unique longitudinal study spanning 12 waves over 6 months that surveyed a representative U.S. sample (N = 1,191) on the most widely circulating political (mis)information online. Harnessing signal detection theory methods to model metacognition, we found that people from both the political left and the political right were aware of how well they distinguished accurate political information from falsehood across all news. However, this metacognitive insight was considerably lower for Republicans and conservatives-than for Democrats and liberals-when the information in question challenged their ideological commitments. That is, given their level of knowledge, Republicans' and conservatives' confidence was less likely to reflect the correctness of their truth judgments for true and false political statements that were at odds with their political views. These results reveal the intricate and systematic ways in which political preferences are linked to the accuracy with which people assess their own truth discernment. More broadly, by identifying a specific political asymmetry-for discordant relative to concordant news-our findings highlight the role of metacognition in perpetuating and exacerbating ideological divides. (PsycInfo Database Record (c) 2024 APA, all rights reserved).