Background:HIV and cocaine use (CU) each relate to cognitive deficits and brain abnormalities, yet their combined impact on brain aging remains unclear. This study examined how comorbid HIV and CU relate to brain aging and cognitive impairment. Methods:We trained a morphometry-based brain-age model using harmonized Human Connectome Project-Aging data (HCP-A; n=725) with Gaussian Process Regression. The model was applied to an independent cohort with varying HIV/CU burden (HIV-/CU-, n=34; one disorder [HIV+/CU- or HIV-/CU+], n=72; HIV+/CU+, n=80). Brain age gap (BAG; predicted minus chronological age) was examined in relation to comorbidity burden and neurocognitive impairment (NCI; NIH Toolbox), adjusting for age, sex, education, depression, and image-quality indices. Analyses on SHapley Additive exPlanation (SHAP) values characterized network-wise feature-level contributions to brain age estimates. Results:A dose-dependent effect of comorbidity burden on BAG was observed, with the HIV+/CU+ group showing the highest BAG. Greater BAG was associated with increased likelihood of NCI, and BAG partially mediated the relationship between comorbidity burden and NCI, with a stronger mediation effect in the two-disorder group than in the one-disorder group. Structural contributors to elevated BAG in the HIV/CU cohort included cortical thickness in the visual, ventral attention, and frontoparietal networks, and sulcal depth in the sensorimotor network. Conclusion:Comorbid HIV/CU is linked to accelerated structural brain aging. BAG may reflect brain-level alterations underlying the association between comorbid HIV/CU and cognitive impairment, and may help identify network-specific targets for intervention.

Mycobacterium tuberculosis (Mtb) is a facultative intracellular pathogen that thrives primarily inside the phagosome of macrophages. A key Mtb survival strategy is to exploit and manipulate metal cation trafficking inside macrophages. Copper plays dual roles in host-pathogen interactions, i.e., as a bactericidal toxin for the host, as well as micronutrients for the bacteria. In contrast to the well-studied copper resistance pathways, the copper uptake machinery of Mtb remains poorly characterized. We here show that Rv1273c and Rv1272c form a heterodimeric copper influx ABC transporter in Mtb, and their expression is induced by copper and phagocytosis. Intracellular copper imported by Rv1273c-Rv1272c promotes mycobacterial sedimentation and alters bacterial envelope structure. Moreover, copper broadly affects the mycobacterial transcriptome and metabolome, as well as glycolipid and phospholipid contents of the mycobacterial envelope, thereby contributing to mycobacterial survival in macrophages. Finally, the murine model results show that the deletion of Rv1273c-Rv1272c causes lower bacterial burdens in the lungs and spleens, suggesting that Rv1273c-Rv1272c is essential for Mtb virulence. Taken together, these findings demonstrate that mycobacteria utilize the copper uptake ABC transport system to facilitate pathogenesis.

Cognitive function, psychological processes, mental states and behaviors are key dimensions of mental disorders across diagnostic categories, but whether they are linked to common or distinct brain morphological patterns underlying risk or resilience remains unclear. The current study is a longitudinal investigation of 8,672 youths from the Adolescent Brain Cognitive Development (ABCD) study aged 9–10 years at baseline (4,412 male; 4,260 female). A machine learning approach based on canonical correlation analysis was used to identify latent dimensional associations of cortical morphology (surface area, cortical and subcortical volume, cortical thickness and sulcal/gyral depth) with multidomain behavioral assessments, including cognitive scores and psychological measures indexing motivation, impulse control, mental states and behaviors across a continuum from healthy to pathological. We identified a robust latent brain structural variate across morphological measures that correlated positively with cognitive performance and negatively with psychological measures indexing greater psychopathology. Higher scores on this brain variate reflected larger cortical surface area and cortical volume, especially in the temporal gyri, together with a posterior–anterior gradient in cortical thickness, showing greater thickness in occipital, parietal and temporal cortices and lower thickness in cingulate and frontal regions. This brain variate and the related cognitive–psychological–behavioral variate remained stable and showed a dose-dependent relationship with cumulative psychiatric diagnoses assessed concurrently and at the 2-year follow-up, with lower brain variate scores associated with higher numbers of comorbid diagnoses. Brain scores were also associated with longitudinal transitions between healthy and diagnosed states: lower baseline scores associated with persistent psychiatric diagnoses and higher baseline scores associated with persistent healthy states, suggesting a vulnerability–resilience continuum for psychopathology. These findings advance the neurodevelopmental understanding of psychiatric disorders and highlight the potential utility of morphology-informed approaches for early screening and intervention in youth. This study investigates the relationship of brain morphology with cognitive and psychological dimensions in 8,672 youths, using machine learning to reveal significant correlations between cortical metrics and behavioral assessments, indicating a continuum of vulnerability and resilience for psychiatric disorders.

Many psychiatric disorders begin during adolescence, coinciding with the rapid development of brain white matter (WM). However, it remains unclear whether deviations from normal WM maturation during this age period contribute to the development of psychopathology. In this study, we developed and validated normative models of brain age based on specific WM tracts using three large-scale developmental datasets (a total of ∼10,000 subjects). We found that tract-specific deviations in WM development of association and limbic/subcortical systems were linked to concurrent cognition and psychopathology. The spatial pattern of the association system aligned closely with distributions of high-order brain networks, and with mitochondrial content and respiratory capacity. The maturation of the association system contributed significantly to better cognitive performance assessed two or three years later. Importantly, delayed WM development especially in dorsal association tracts predicted psychiatric disorders across diagnoses and disorder onset over a 2-year follow-up. By identifying tract-specific WM development during preadolescence as a predictor of cognitive capacity and psychiatric disorder risks, this study provides a valuable framework for tracking individualized brain maturation and understanding the neurobiological underpinnings of cognitive performance and transdiagnostic psychopathology.

A high risk of relapse triggered by craving during abstinence remains a main challenge in opioid addiction treatment. Multiple brain regions have been implicated in opioid craving, but the brain-wide neural mechanisms underlying this process remain poorly understood. Using resting-state fMRI and connectome-based predictive modeling, we identified a whole-brain connectome that predicted the time-dependent increases (incubation) in oxycodone craving in individual rats after voluntary abstinence induced by exposure to an electric barrier. Incubation of oxycodone craving was operationally defined as the increase in nonreinforced lever pressing during relapse tests from early (day 1) to late (day 15) abstinence (incubation score). We found that changes in whole-brain functional connectivity during abstinence, but not during oxycodone self-administration, predicted the incubation score. Greater decreases in functional connectivity were associated with higher incubation scores. The predictive connectome involved complex interactions across multiple brain systems, including frontal-striatal, frontal-insula, insula-striatal, and hippocampal and sensorimotor circuits. To test causality of the predictive connectome, we examined the effect of pharmacological inactivation of dorsomedial striatum (DMS), which significantly decreased oxycodone seeking after electric barrier-induced abstinence. DMS inactivation increased connectivity strength within the predictive connectome, supporting a causal role of this connectome in incubation of oxycodone craving. The predictive connectome did not predict food-reward seeking after electric barrier-induced abstinence, indicating specificity to oxycodone craving. Our findings identify a brain-wide connectome marker that predicts individual differences in the incubation of opioid craving and provide potential targets for developing personalized interventions and monitoring therapeutic outcomes in opioid addiction treatment.

Bacterial pathogens such as Salmonella enterica serovar Typhimurium can resist phagocytosis by macrophages. Here we explored the role of bacterial haem biosynthesis in phagocytosis resistance. Using transposon sequencing (Tn-seq) during Salmonella infection of macrophages, we identify a methyltransferase, SirM, that indirectly inhibits phagocytosis of bacteria. Mechanistically, sirM is activated upon interaction with macrophages and methylates HemL, a key enzyme in haem biosynthesis, resulting in upregulation of haem synthesis by Salmonella. Salmonella-derived haem inhibits Cdc42 activation in a Toll-like receptor 4 (TLR4)-dependent manner to inhibit phagocytosis. Moreover, sirM promotes macrophage death by increasing haem synthesis. Experiments in mouse models show that sirM is required for virulence and confers a competitive advantage over intestinal commensal bacteria during infection. We also found that sirM is distributed among enteric pathogens. Collectively, our findings show that bacterial haem promotes evasion of phagocyte responses and pathogenesis to confer an advantage in the host.

[This corrects the article DOI: 10.1371/journal.ppat.1013136.].

e20146 Background: Extensive-stage small cell lung cancer (ES-SCLC) is a highly aggressive malignancy with limited treatment options. While immunochemotherapy constitutes standard first-line therapy, predictive biomarkers for treatment response remain undefined, impeding personalized therapeutic strategies. Methods: We investigated circulating small extracellular vesicle (sEV)-derived microRNAs (miRNAs) as non-invasive predictive biomarkers in treatment-naïve ES-SCLC patients receiving immunochemotherapy. Plasma samples from a training cohort (n = 33) and an independent prospective cohort (n = 5) were collected pre-treatment. sEVs were isolated, characterized, and subjected to small RNA sequencing to quantify miRNA expression. Results: Small RNA sequencing revealed 23 differentially expressed sEV miRNAs between responders (n = 19) and non-responders (n = 14). Machine learning refined these candidates into a predictive model. Recursive feature elimination (RFE) yielded an 11-sEV-miRNA signature. The top-performing model (Extra Trees Gini) incorporated 5 sEV miRNAs and 1 clinical feature, demonstrating high predictive accuracy in the training set (AUC = 0.855, sensitivity = 95%, specificity = 80%). Preliminary validation in the prospective cohort achieved 80% accuracy (4/5 correct classifications). Conclusions: We established a novel sEV-miRNA biomarker panel that robustly predicts immunochemotherapy response in ES-SCLC. High discriminatory performance and initial prospective validation underscore its clinical utility for guiding treatment decisions and optimizing outcomes by avoiding ineffective therapy in non-responders.

People often use external tools to offload cognitive demands associated with remembering future intentions. While previous research has established a causal role of metacognition in cognitive offloading, the neural basis of white matter tracts supporting this metacognitive control process remains unclear. To address this, we conducted a study with 34 participants using diffusion tensor imaging (DTI) to examine how white matter connectivity supports metacognition driven cognitive offloading. Behaviorally, we replicated prior findings showing that under-confidence in internal memory predicts a bias toward using external reminders. At the neural level, we used diffusion tensor imaging to quantify fractional anisotropy (FA), a measure of microstructural integrity in white matter. We found the microstructural integrity of the superior longitudinal fasciculus (SLF) and cingulum bundle (CB) predicted deviations from the optimal use of reminders. The microstructural integrity of the fornix negatively predicted participants’ confidence in performing the task when restricted to internal memory. Our findings reveal the microstructural organization of the white-matter tracts in the fronto-temporal-parietal network are related to metacognition driven cognitive offloading. We discuss several aspects of metacognition driven cognitive offloading from a white matter microstructural perspective.

Background:Treatment of tyrosine kinase inhibitor (TKI)-resistant anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC) remains an unmet need. Among these patients, the efficacy of immunotherapy has not been thoroughly investigated. The purpose of our study was to evaluate the efficacy of immunotherapy in patients with ALK-TKI-resistant NSCLC, stratified by programmed cell death ligand-1 (PD-L1) expression. Methods:We retrospectively collected the data of advanced NSCLC patients with ALK-rearrangement, who were treated with immunotherapy or chemotherapy after the development of ALK-TKI resistance at the Shanghai Chest Hospital. Progression-free survival (PFS) was used to evaluate the outcomes. Results:The final analysis included 89 patients between June 1, 2018, and December 31, 2022, who met the selection criteria. The entire cohort had a median follow-up time of 33.4 months. The patients who received immunotherapy had better PFS than those who received non-immunotherapy (median PFS: 5.3 vs. 2.5 months; P=0.009). The PD-L1-positive patients who received immunotherapy had a median PFS of 7.1 months, while those who received non-immunotherapy had a median PFS of 2.5 months (P=0.02). No such statistically significant difference was observed in the PD-L1-negative patients (median PFS for with immunotherapy vs. without immunotherapy: 1.5 vs. 2.9 months; P=0.68). The PD-L1-positive patients who underwent re-biopsy after the development of TKI resistance and who received immunotherapy had a PFS of 7.8 months, while those who received non-immunotherapy had a PFS of 2.7 months (P=0.002). Conclusions:This was the first real-world retrospective study to show that some patients with positive PD-L1 expression may benefit from immune-based therapy after the development of ALK-TKI resistance. However, we still recommend biopsy for patients who develop ALK-TKI resistance to provide further treatment guidance.

Importance:Adverse childhood experiences (ACEs) are common and account for more than 25% of psychiatric disorders in youths, but the underlying neurobiological mechanisms associated with risk and resilience among children exposed to ACEs are poorly understood. Objectives:To examine associations between ACEs and transdiagnostic psychopathology during the transition to adolescence and to test whether these associations are modified by whole-brain functional connectivity. Design, Setting, and Participants:This cohort study used data from the longitudinal Adolescent Brain Cognitive Development (ABCD) Study's baseline through 2-year follow-up assessments. A total of 6813 children aged 9 to 11 years at baseline were recruited from 21 US sites between June 1, 2016, and October 31, 2018. Data were analyzed from September 2023 to April 2025. Exposure:Lifetime ACEs, assessed from child and parent reports, through 2-year follow-up. Main Outcomes and Measures:Cumulative number of current DSM-5 psychiatric disorders obtained from the computerized self-administered Kiddie Schedule for Affective Disorders and Schizophrenia for DSM-5 (KSADS-5) through 2-year follow-up and a machine learning-based latent connectome variate (CV) score derived from baseline resting-state functional magnetic resonance imaging data. Results:Among 6813 children (mean [SD] age at baseline, 10.0 [0.6] years; 3413 girls [50.1%]) with available baseline neuroimaging, behavioral, and covariate data, the mean (SD) ACE score was 2.3 (1.7) at baseline. ACE scores were significantly associated with the cumulative number of KSADS-5 diagnoses at baseline (β = 0.11; 95% CI, 0.10-0.12; P < .001) and 2-year follow-up (β = 0.14; 95% CI, 0.12-0.15; P < .001). Baseline CV score modified associations between ACEs and psychiatric disorders across the 2 years (β = -0.02; 95% CI, -0.03 to -0.01; t = -3.34; P < .001). Post hoc investigation showed that the modification of the CV score on associations between ACEs and psychopathology was specific to the threat-related ACEs (β = -0.04; 95% CI, -0.06 to -0.02; t = -3.67; P < .001) and was pronounced for girls (β = -0.06; 95% CI, -0.09 to -0.02; t = -3.33; P < .001). Conclusions and Relevance:In this cohort study of children, a whole-brain functional connectivity score derived from neuroimaging data modified the association between ACEs and psychiatric disorders. This modification was particularly seen against threat-related ACEs and was pronounced for female youths. These findings suggest that functional connectivity strength in a broad system relevant to cognitive control may protect preadolescents who have experienced lifetime ACEs-especially girls and those experiencing threat-related ACEs-from developing transdiagnostic psychopathology.

Deficits in behavioral or cognitive flexibility that are linked to altered activity in both cortical and subcortical brain regions, are often observed across multiple neuropsychiatric disorders. The medial prefrontal cortex (mPFC)-nucleus accumbens (NAc) pathway in rats plays a critical role in flexible control of behavior. However, the modulation of this pathway on activity and functional connectivity with the rest of the brain remains unclear. In this study, we first confirmed the role of the mPFC-NAc pathway in behavioral flexibility using a set-shifting task in rats and then evaluated the causal effects of mPFC-NAc activation induced by chemogenetic stimulation of the terminal axons of the NAc with DREADD expression on whole-brain activity and functional connectivity measured by functional MRI. mPFC-NAc activation improved performance on the set-shifting task by reducing perseverative errors. Additionally, stimulation of this pathway increased activity in a set of brain regions within the basal ganglia-thalamus-cortical loop network including NAc, thalamus, hypothalamus and various connected cortical regions, while also decreased functional connectivity strength of NAc-mPFC, NAc-secondary motor cortex (M2), and various cortical circuits. Moreover, performance on the set-shifting task was related to the functional connectivity strength of the above frontostriatal and cortical circuits. These findings provide insights into the link between specific frontostriatal circuits on decision making flexibility, which may inform potential future interventions for behavioral flexibility deficits.

Pseudomonas aeruginosa is a globally prevalent multidrug-resistant pathogen that causes severe infections, particularly in immunocompromised individuals. This review focuses on the dual role of iron in P. aeruginosa infections: as a critical nutrient for bacterial growth and as a mediator of host cell ferroptosis, a form of iron-dependent cell death. We summarize how P. aeruginosa manipulates iron metabolism to induce ferroptosis in host cells, thereby promoting its own survival and pathogenicity. Additionally, we explore therapeutic strategies targeting iron metabolism, including interfering with acquisition of iron ions from the environment, disrupting bacterial iron metabolism and iron homeostasis, using ferroptosis inhibitors to suppress host cell ferroptosis, and employing high iron concentrations to induce bacterial ferroptosis. These insights provide innovative approaches to combat drug-resistant P. aeruginosa infections.

Importance:Identifying brain-based markers of resiliency that reliably predict who is and is not at elevated risk for developing psychopathology among children who experience adverse childhood experiences (ACEs) is important for improving our mechanistic understanding of these etiological links between child adversity and psychopathology and guiding precision medicine and prevention efforts for reducing psychiatric impact of ACEs. Objective:To examine associations between ACEs and transdiagnostic psychopathology during the transition from preadolescence to early adolescence and test whether these associations are moderated by a hypothesized resilience factor, a previously identified connectome variate (CV) that is associated with higher cognitive function and lower psychopathology. Design Setting and Participants:This study was conducted in a longitudinal design based on multicenter data from a community cohort of U.S. youth aged of 9-11 at baseline, who participated in the Adolescent Brain Cognitive Development (ABCD) study (N=7,382 at baseline and 6,813 at 2-year follow-up). Linear regression models and moderation analyses were used to characterize concurrent and prospective associations between lifetime ACEs and number of DSM-5 psychiatric disorders (indexing transdiagnostic psychopathology) and to determine if individual variations in these associations were moderated by the CV derived from resting-state fMRI at baseline. Main Outcomes and Measures:Cumulative number of current DSM-5 psychiatric disorders assessed using the computerized self-admin version Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS-5) and lifetime ACEs assessed from child and parent reports at baseline (9-10 years) and 2-year-follow-up (11-12 years). Results:ACE total scores correlated positively with the cumulative number of current DSM-5 psychiatric disorders at both baseline (r =.258, p < .001) and 2-year follow-up (r =.257, p < .001). The baseline CV score moderated the ACE-disorder associations at baseline (B = -0.021, p < .001) and at 2-year follow-up (B = -0.018, p = .008), as well as the association between the changes in ACE and in the number of disorders from baseline to year 2 (B = -0.012, p = .045). Post-hoc analyses further showed that the moderation effect of CV on ACE-psychopathology associations was specific to the threat-related ACEs and to female youth. Conclusions and Relevance:These findings provide preliminary evidence for a connectome-based resiliency marker and suggest that functional connectivity strength in a broad system including frontal-parietal cortices and subcortical nuclei relevant to cognitive control may protect preadolescents who have experienced lifetime ACEs--especially females and those experiencing threat-related ACEs--from developing transdiagnostic psychopathology.

Ubiquitination plays vital roles in modulating pathogen-host cell interactions. RNF213, a unique E3 ligase, can catalyze the ubiquitination of lipopolysaccharide (LPS) and is crucial for antibacterial immunity in mammals. Shigella flexneri, an LPS-containing pathogenic bacterium, has developed mechanisms to evade host antibacterial defenses during infection. However, the precise strategies by which S. flexneri circumvents RNF213-mediated antibacterial immunity remain poorly understood. Here, through comprehensive biochemical, structural and cellular analyses, we reveal that the E3 effector IpaH1.4 of S. flexneri can directly target human RNF213 via a specific interaction between the IpaH1.4 LRR domain and the RING domain of RNF213, and mediate the ubiquitination and proteasomal degradation of RNF213 in cells. Furthermore, we determine the cryo-EM structure of human RNF213 and the crystal structure of the IpaH1.4 LRR/RNF213 RING complex, elucidating the molecular mechanism underlying the specific recognition of RNF213 by IpaH1.4. Finally, our cell-based function asaays demonstrate that the targeting of host RNF213 by IpaH1.4 promotes S. flexneri proliferation within infected cells. In summary, our work uncovers a novel strategy employed by S. flexneri to subvert the key host immune factor RNF213, thereby facilitating bacterial proliferation during invasion.

People often use external tools to offload cognitive demands in remembering future intentions. While previous research has identified the causal role of metacognition in cognitive offloading, the neural mechanisms underlying this metacognitive control process remain unclear. To address this gap, we conducted a study with 34 participants using diffusion tensor imaging (DTI) to investigate how connections between brain regions support metacognition-driven cognitive offloading. Behaviorally, we confirmed that under-confidence in using internal memory to execute delayed intentions predicts a bias towards using external reminders. At the brain level we found that the fractional anisotropy (FA) of the fornix, a memory-related white matter tract connected to the hippocampus, positively correlated with the bias in setting up reminders. Additionally, the FA of the left uncinate fasciculus, which links the hippocampus to the prefrontal cortex and is involved in memory error monitoring, negatively correlated with deviations from optimal reminder use. Furthermore, the FA of the superior longitudinal fasciculus, a tract involved in metacognitive monitoring, moderated how confidence influenced the use of reminders. Taken together, our findings reveal a temporal-frontal neural circuit underlying metacognition-driven cognitive offloading, and provide new insights into the interaction between metacognitive monitoring and control.