Childhood adversity and adolescent mental health: Examining cumulative and specificity effects across contexts and developmental timing.

Associations between adversity and youth psychopathology likely vary based on the types and timing of experiences. Major theories suggest that the impact of childhood adversity may either be cumulative in type (the more types of adversity, the worse outcomes) or in timing (the longer exposure, the worse outcomes) or, alternatively, specific concerning the type (e.g., parenting, home, neighborhood) or the timing of adversity (e.g., specific developmental periods). In a longitudinal sample from the Future of Families and Wellbeing Study (N = 4,210), we evaluated these competing hypotheses using a data-driven structured life-course modeling approach using risk factors examined at child age 1 (infancy), 3 (toddlerhood), 5 (early childhood), and 9 (middle childhood). Results showed that exposures to more types of adversity for longer durations (i.e., cumulative in both type and timing) best predicted youth psychopathology. Adversities that occurred at age 9 were better predictors of youth psychopathology as compared to those experienced earlier, except for neglect, which was predictive of internalizing symptoms when experienced at age 3. Throughout childhood (across ages 1-9), aside from the accumulation of all adversities, parental stress and low collective efficacy were the strongest predictors of internalizing symptoms, whereas psychological aggression was predictive of externalizing symptoms.

Inherent symmetry and flexibility in hepatitis B virus subviral particles.

Chronic hepatitis B virus (HBV) infection poses a major global health challenge with massive morbidity and mortality. Despite a preventive vaccine, current treatments provide limited virus clearance, necessitating lifelong commitment. The HBV surface antigen (HBsAg) is crucial for diagnosis and prognosis, yet its high-resolution structure and assembly on the virus envelope remain elusive. Utilizing extensive datasets and advanced cryo-electron microscopy analysis, we present structural insights into HBsAg at a near-atomic resolution of 3.7 angstroms. HBsAg homodimers assemble into subviral particles with D2- and D4-like quasisymmetry, elucidating the dense-packing rules and structural adaptability of HBsAg. These findings provide insights into how HBsAg assembles into higher-order filaments and interacts with the capsid to form virions.

The dynamic and relational nature of parent-child conflict from childhood into emerging adulthood.

Although the parent-child relationship is widely regarded as a foundational context for youth development, the developmental origins of this relationship remain unknown. The present study addressed these gaps, leveraging longitudinal and genetically informed methods to illuminate the developmental origins of mother-child conflict as it unfolds from middle childhood into emerging adulthood. Participants consisted of 2,060 twins in 1,030 twin families (51% male, 49% female; 82% White, 10% Black, 1% Asian, 1% Indigenous, 6% multiracial) from the Michigan State University Twin Registry. Families were assessed up to five times. We fitted a series of latent growth curve models (univariate and parallel process) to data from mothers and children, after which we estimated genetic and environmental sources of variance within and covariance among the intercepts and slopes. Parallel process analyses indicated that maternal reports of conflict at baseline shaped their own and their children's perceptions of change in conflict over time but that children's reports of conflict at baseline predicted only their own rate of change in conflict. Subsequent biometric analyses indicated substantial environmental contributions to the intercepts in childhood, as well as prominent environmental origins to the overlap between maternal and child intercepts. By contrast, we observed robust genetically influenced child effects on maternal rate of change and on the association between the maternal and child slopes. Such findings collectively illuminate the dynamic and relational nature of mother-child conflict from childhood into emerging adulthood. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A reference genome, mitochondrial genome and associated transcriptomes for the critically endangered swift parrot ( Lathamus discolor).

The swift parrot ( Lathamus discolor) is a Critically Endangered migratory parrot that breeds in Tasmania and winters on the Australian mainland. Here we provide a reference genome assembly for the swift parrot. We sequence PacBio HiFi reads to create a high-quality reference assembly and identify a complete mitochondrial sequence. We also generate a reference transcriptome from five organs to inform genome annotation. The genome was 1.24 Gb in length and consisted of 847 contigs with a contig N50 of 18.97 Gb and L50 of 20 contigs. This study provides an annotated reference assembly and transcriptomic resources for the swift parrot to assist in future conservation genomic research.

Methylome-wide association study of multidimensional resilience.

Although resilient youth provide an important model of successful adaptation to adversity, we know relatively little about the origins of their positive outcomes, particularly the role of biological mechanisms. The current study employed a series of methylome-wide association studies to identify methylomic biomarkers of resilience in a unique sample of 276 twins within 141 families residing in disadvantaged neighborhoods. Results revealed methylome-wide significant differentially methylated probes (DMPs) for social and academic resilience and suggestive DMPs for psychological resilience and resilience across domains. Pathway analyses informed our understanding of the biological underpinnings of significant differentially methylated probes. Monozygotic twin difference analyses were then employed to narrow in on DMPs that were specifically environmental in origin. Our findings suggest that alterations in the DNA methylome may be implicated in youth resilience to neighborhood adversity and that some of the suggestive DMPs may be environmentally engendered. Importantly, our ability to replicate our findings in a well-powered sample was hindered by the scarcity of twin samples with youth exposed to moderate to substantial levels of adversity. Thus, although preliminary, the present study is the first to identify DNA methylation biomarkers of academic and social resilience.

Cryo-EM structures of a mycobacterial ABC transporter that mediates rifampicin resistance.

Drug-resistant Tuberculosis (TB) is a global public health problem. Resistance to rifampicin, the most effective drug for TB treatment, is a major growing concern. The etiological agent, Mycobacterium tuberculosis (Mtb), has a cluster of ATP-binding cassette (ABC) transporters which are responsible for drug resistance through active export. Here, we describe studies characterizing Mtb Rv1217c-1218c as an ABC transporter that can mediate mycobacterial resistance to rifampicin and have determined the cryo-electron microscopy structures of Rv1217c-1218c. The structures show Rv1217c-1218c has a type V exporter fold. In the absence of ATP, Rv1217c-1218c forms a periplasmic gate by two juxtaposed-membrane helices from each transmembrane domain (TMD), while the nucleotide-binding domains (NBDs) form a partially closed dimer which is held together by four salt-bridges. Adenylyl-imidodiphosphate (AMPPNP) binding induces a structural change where the NBDs become further closed to each other, which downstream translates to a closed conformation for the TMDs. AMPPNP binding results in the collapse of the outer leaflet cavity and the opening of the periplasmic gate, which was proposed to play a role in substrate export. The rifampicin-bound structure shows a hydrophobic and periplasm-facing cavity is involved in rifampicin binding. Phospholipid molecules are observed in all determined structures and form an integral part of the Rv1217c-1218c transporter system. Our results provide a structural basis for a mycobacterial ABC exporter that mediates rifampicin resistance, which can lead to different insights into combating rifampicin resistance.

A Novel Surgical Approach to Synovial Sarcoma of the Esophagus: New Possibilities for the Management of a Rare Tumor.

Synovial sarcoma (SS) is an uncommon soft tissue malignancy that typically occurs in surrounding joints. Rarely, this malignancy may occur in the gastrointestinal (GI) tract, including the esophagus. Given the rarity of this malignancy, treatment recommendations are limited. In all reviewed cases, surgical resection was performed via some variation of esophagectomy. Here, we present a novel approach to the treatment of esophageal SS. A 30-year-old patient was found to have a large upper esophageal mass after developing symptoms of dysphagia, cough, and regurgitation. Otolaryngology was consulted for the removal of the mass. A CO2 laser was used to remove the pedicled mass from the esophageal wall. Given the size of the mass, it could not be removed through the upper esophageal sphincter despite significant effort. The decision was made to allow the mass to pass to the stomach to be digested. The patient had an uncomplicated postoperative course with seemingly complete spontaneous digestion of the tumor and no evidence of residual tumor, metastasis, or recurrence. Frozen section pathology confirmed SS of the esophagus. SS of the esophagus is a rare malignancy that presents unique treatment challenges. This case represents a novel strategy for resecting esophageal SS utilizing transoral esophagoscopy. The preservation of the upper esophageal sphincter may also be accomplished using this approach by allowing for the autodigestion of tumors in some cases. This case also suggests that esophagectomy may not be necessary for all cases of esophageal SS.

Socioeconomic resources in youth are linked to divergent patterns of network integration/segregation across the brain's transmodal axis.

Socioeconomic resources (SER) calibrate the developing brain to the current context, which can confer or attenuate risk for psychopathology across the lifespan. Recent multivariate work indicates that SER levels powerfully relate to intrinsic functional connectivity patterns across the entire brain. Nevertheless, the neuroscientific meaning of these widespread neural differences remains poorly understood, despite its translational promise for early risk identification, targeted intervention, and policy reform. In the present study, we leverage graph theory to precisely characterize multivariate and univariate associations between SER across household and neighborhood contexts and the intrinsic functional architecture of brain regions in 5,821 youth (9-10 years) from the Adolescent Brain Cognitive Development Study. First, we establish that decomposing the brain into profiles of integration and segregation captures more than half of the multivariate association between SER and functional connectivity with greater parsimony (100-fold reduction in number of features) and interpretability. Second, we show that the topological effects of SER are not uniform across the brain; rather, higher SER levels are associated with greater integration of somatomotor and subcortical systems, but greater segregation of default mode, orbitofrontal, and cerebellar systems. Finally, we demonstrate that topological associations with SER are spatially patterned along the unimodal-transmodal gradient of brain organization. These findings provide critical interpretive context for the established and widespread associations between SER and brain organization. This study highlights both higher-order and somatomotor networks that are differentially implicated in environmental stress, disadvantage, and opportunity in youth.

Sustained Performance of Cardiac Arrest Prevention in Pediatric Cardiac Intensive Care Units.

Importance: The Pediatric Cardiac Critical Care Consortium (PC4) cardiac arrest prevention (CAP) quality improvement (QI) project facilitated a decreased in-hospital cardiac arrest (IHCA) incidence rate across multiple hospitals. The sustainability of this outcome has not been determined. Objective: To examine the IHCA incidence rate at participating hospitals after the QI project ended and discern which factors best aligned with sustained improvement. Design, Setting, and Participants: This observational cohort study compared IHCA data from the CAP era (July 1, 2018, to December 31, 2019) with data from the 2-year follow-up era (March 1, 2020, to February 28, 2022). Data were obtained from pediatric cardiac intensive care units (CICUs) from 17 PC4 CAP-participating hospitals. Intervention: The CAP practice bundle was designed to facilitate local practice integration, with the intention to implement, adapt, and continue CAP processes beyond the CAP era. A web-based survey was administered 2 years after the end of the project to estimate CAP-specific QI work. Main Outcomes and Measures: Risk-adjusted IHCA incidence rates across all admissions were compared between study eras. The survey generated a novel hospital-specific QI sustainability score, which is generally reflective of the sum of local CAP work performed. Results: There were no clinically important differences in demographic and admission characteristics between the 13 082 CAP era admissions and 16 284 follow-up admissions (total mean [SD] age, 5.1 [8.4] years; 56.1% male). Risk-adjusted IHCA incidences were not different between the CAP vs follow-up eras (2.8% vs 2.8%; odds ratio, 1.03; 95% CI, 0.89-1.19), suggesting sustained prevention improvement. There was also no difference between eras in risk-adjusted IHCA incidence within medical, surgical, or high-risk subgroups. A lower hospital QI sustainability score was correlated with higher odds for IHCA in the follow-up vs CAP era (correlation coefficient, -0.58; P = .02). Five hospitals had increases of 1% or greater in risk-adjusted IHCA rates in the follow-up era; these hospitals had significantly lower QI sustainability scores and were less likely to have adopted sustainability elements during the CAP era or report persistent engagement for CAP-related QI processes during follow-up. Conclusions and Relevance: In this cohort study of all CICU admissions across 17 hospitals, IHCA prevention was feasible and sustainable; the established reduction in risk-adjusted IHCA rate was maintained for at least 2 years after the end of the CAP project. Both implementation strategies and continued engagement in CAP processes during the follow-up era were associated with sustained improvement.

The Promise and Challenges of Integrating Biological and Prevention Sciences: A Community-Engaged Model for the Next Generation of Translational Research.

Beginning with the successful sequencing of the human genome two decades ago, the possibility of developing personalized health interventions based on one's biology has captured the imagination of researchers, medical providers, and individuals seeking health care services. However, the application of a personalized medicine approach to emotional and behavioral health has lagged behind the development of personalized approaches for physical health conditions. There is potential value in developing improved methods for integrating biological science with prevention science to identify risk and protective mechanisms that have biological underpinnings, and then applying that knowledge to inform prevention and intervention services for emotional and behavioral health. This report represents the work of a task force appointed by the Board of the Society for Prevention Research to explore challenges and recommendations for the integration of biological and prevention sciences. We present the state of the science and barriers to progress in integrating the two approaches, followed by recommended strategies that would promote the responsible integration of biological and prevention sciences. Recommendations are grounded in Community-Based Participatory Research approaches, with the goal of centering equity in future research aimed at integrating the two disciplines to ultimately improve the well-being of those who have disproportionately experienced or are at risk for experiencing emotional and behavioral problems.

Molecular Alterations Associated with Histologically Overt Stromal Response in Patients with Prostate Cancer.

Prostate cancer has substantial heterogeneity in clinical outcomes and therapeutic responses, posing challenges in predicting disease progression and tailoring treatment strategies. Recent studies have highlighted the potential prognostic value of evaluating the tumor microenvironment, including the presence of a histologically overt stromal response (HOST-response) characterized by peri-glandular stromal changes and architectural distortions. This retrospective study examined patient records from The Cancer Genome Atlas database to identify genomic alterations associated with the HOST-response in prostate cancer. Among 348 patients who underwent radical prostatectomy, 160 (45.98%) were identified as having a HOST-response. A gene expression analysis revealed 1263 genes with significantly higher expression in patients with a HOST-response. A protein-protein interaction network analysis identified seven hub genes (KIF2C, CENPA, CDC20, UBE2C, ESPL1, KIF23, and PLK1) highly interconnected in the network. A functional enrichment analysis revealed alterations in the cell division, cytoskeletal organization, cytokinesis, and interleukin-16 signaling pathways in patients with a HOST-response, suggesting dysregulated proliferation and inflammation. The distinct molecular signature associated with the HOST-response provides insights into the tumor-stroma interactions driving adverse outcomes and potential targets for tailored therapeutic interventions in this subset of patients with prostate cancer.

Latent Profiles of Childhood Adversity, Adolescent Mental Health, and Neural Network Connectivity.

Importance: Adverse childhood experiences are pervasive and heterogeneous, with potential lifelong consequences for psychiatric morbidity and brain health. Existing research does not capture the complex interplay of multiple adversities, resulting in a lack of precision in understanding their associations with neural function and mental health. Objectives: To identify distinct childhood adversity profiles and examine their associations with adolescent mental health and brain connectivity. Design, Setting, and Participants: This population-based birth cohort used data for children who were born in 20 large US cities between 1998 and 2000 and participated in the Future Families and Child Well-Being Study. Families were interviewed when children were born and at ages 1, 3, 5, 9, and 15 years. At age 15 years, neuroimaging data were collected from a subset of these youths. Data were collected from February 1998 to April 2017. Analyses were conducted from March to December 2023. Exposures: Latent profiles of childhood adversity, defined by family and neighborhood risks across ages 0 to 9 years. Main Outcomes and Measures: Internalizing and externalizing symptoms at age 15 years using parent- and youth-reported measures. Profile-specific functional magnetic resonance imaging connectivity across the default mode network (DMN), salience network (SN), and frontoparietal network (FPN). Results: Data from 4210 individuals (2211 [52.5%] male; 1959 [46.5%] Black, 1169 [27.7%] Hispanic, and 786 [18.7%] White) revealed 4 childhood adversity profiles: low-adversity (1230 individuals [29.2%]), medium-adversity (1973 [46.9%]), high-adversity (457 [10.9%]), and high maternal depression (MD; 550 [13.1%]). High-adversity, followed by MD, profiles had the highest symptoms. Notably, internalizing symptoms did not differ between these 2 profiles (mean difference, 0.11; 95% CI, -0.03 to 0.26), despite the MD profile showing adversity levels most similar to the medium-adversity profile. In the neuroimaging subsample of 167 individuals (91 [54.5%] female; 128 [76.6%] Black, 11 [6.6%] Hispanic, and 20 [12.0%] White; mean [SD] age, 15.9 [0.5] years), high-adversity and MD profiles had the highest DMN density relative to other profiles (F(3,163) = 11.14; P < .001). The high-adversity profile had lower SN density relative to the low-adversity profile (mean difference, -0.02; 95% CI, -0.04 to -0.003) and the highest FPN density among all profiles (F(3,163) = 18.96; P < .001). These differences were specific to brain connectivity during an emotion task, but not at rest. Conclusions and Relevance: In this cohort study, children who experienced multiple adversities, or only elevated MD, had worse mental health and different neural connectivity in adolescence. Interventions targeting multiple risk factors, with a focus on maternal mental health, could produce the greatest benefits.

The Association between the Substitution of Red Meat with Legumes and the Risk of Primary Liver Cancer in the UK Biobank: A Cohort Study.

Primary liver cancer is globally on the rise, partially due to poor diets and sedentary lifestyles. Shifting to more plant-based diets may lower the risk. We aimed to estimate the effect of replacing total red meat, unprocessed red meat and processed red meat with legumes on primary liver cancer in a free-living population. We analyzed data from 126,744 UK Biobank participants who completed ≥ two 24 h diet recalls. Baseline characteristics were collected from the initial assessment visit. Information on liver cancer diagnoses was collected via external linkage to inpatient hospital episodes or central cancer registries. Cox proportional hazards regression models were used to estimate the substitution of 15 g/day of legumes with 15 g/day of total red meat, unprocessed red meat or processed red meat on liver cancer risk, using the leave-one-out food substitution model. During a median follow-up time of 11.1 years, 173 participants developed liver cancer. In the fully adjusted models, no association was observed when substituting 15 g/day of legumes with total red meat (HR: 1.02 (95% CI 0.96-1.08)), unprocessed red meat (HR: 1.00 (95% CI 0.94-1.06)) or processed red meat (HR: 1.09 (95% CI 0.99-1.21)). Overall, little evidence of an association between replacing red meat with legumes and liver cancer was observed. Further research in other study populations with longer follow-up time is warranted.

MYC Induces Oncogenic Stress through RNA Decay and Ribonucleotide Catabolism in Breast Cancer.

Upregulation of MYC is a hallmark of cancer, wherein MYC drives oncogenic gene expression and elevates total RNA synthesis across cancer cell transcriptomes. Although this transcriptional anabolism fuels cancer growth and survival, the consequences and metabolic stresses induced by excess cellular RNA are poorly understood. Herein, we discover that RNA degradation and downstream ribonucleotide catabolism is a novel mechanism of MYC-induced cancer cell death. Combining genetics and metabolomics, we find that MYC increases RNA decay through the cytoplasmic exosome, resulting in the accumulation of cytotoxic RNA catabolites and reactive oxygen species. Notably, tumor-derived exosome mutations abrogate MYC-induced cell death, suggesting excess RNA decay may be toxic to human cancers. In agreement, purine salvage acts as a compensatory pathway that mitigates MYC-induced ribonucleotide catabolism, and inhibitors of purine salvage impair MYC+ tumor progression. Together, these data suggest that MYC-induced RNA decay is an oncogenic stress that can be exploited therapeutically. Significance: MYC is the most common oncogenic driver of poor-prognosis cancers but has been recalcitrant to therapeutic inhibition. We discovered a new vulnerability in MYC+ cancer where MYC induces cell death through excess RNA decay. Therapeutics that exacerbate downstream ribonucleotide catabolism provide a therapeutically tractable approach to TNBC (Triple-negative Breast Cancer) and other MYC-driven cancers.

One-HIIT wonder: Can music make high-intensity interval training more pleasant?

The use of music as an aid to recovery during and after exercise is an area of growing scientific interest. We investigated the effects of in-task, asynchronous music and respite-active music (i.e., music used for active recovery in between high-intensity exercise bouts) on a range of psychological, psychophysical and psychophysiological outcomes. Participants (N = 28; 14 females) made five laboratory visits for: (a) pre-test/familiarisation; (b) fast-tempo music during supramaximal exercise bouts and medium-tempo music during active-recovery periods; (c) fast-tempo music during exercise and no music during recovery; (d) no music during exercise and medium-tempo music during recovery; and (e) a no-music (throughout) control. A cycle ergometer-based HIIT protocol comprising 6 × 60-s bouts at 100% Wmax with 75-s active recovery was administered. Measures were taken at the end of supramaximal bouts and active recovery periods (RPE, state attention, core affect, state motivation), then upon cessation of the protocol (remembered pleasure and exercise enjoyment). Heart rate and heart rate variability (HRV) measures were taken throughout. The music manipulations only had an effect on state motivation, which was higher (p = 0.036) in the fast tempo-medium tempo condition compared to no-music control (Cohen's d = 0.49), and the SDNN component of HRV, which was lower (p = 0.007) in the fast-tempo-no-music condition compared to control (Cohen's d = 0.32). Collectively, the present findings do not support any of the study hypotheses regarding the music-related manipulations, and do not concur with the findings of related studies (e.g., Karageorghis et al., 2021). The unexpected results are discussed with reference to extant theory, and recommendations are offered in regard to music-related applications.

Plethora of New Marsupial Genomes Informs Our Knowledge of Marsupial MHC Class II.

The major histocompatibility complex (MHC) plays a vital role in the vertebrate immune system due to its role in infection, disease and autoimmunity, or recognition of "self". The marsupial MHC class II genes show divergence from eutherian MHC class II genes and are a unique taxon of therian mammals that give birth to altricial and immunologically naive young providing an opportune study system for investigating evolution of the immune system. Additionally, the MHC in marsupials has been implicated in disease associations, including susceptibility to Chlamydia pecorum infection in koalas. Due to the complexity of the gene family, automated annotation is not possible so here we manually annotate 384 class II MHC genes in 29 marsupial species. We find losses of key components of the marsupial MHC repertoire in the Dasyuromorphia order and the Pseudochiridae family. We perform PGLS analysis to show the gene losses we find are true gene losses and not artifacts of unresolved genome assembly. We investigate the associations between the number of loci and life history traits, including lifespan and reproductive output in lineages of marsupials and hypothesize that gene loss may be linked to the energetic cost and tradeoffs associated with pregnancy and reproduction. We found support for litter size being a significant predictor of the number of DBA and DBB loci, indicating a tradeoff between the energetic requirements of immunity and reproduction. Additionally, we highlight the increased susceptibility of Dasyuridae species to neoplasia and a potential link to MHC gene loss. Finally, these annotations provide a valuable resource to the immunogenetics research community to move forward and further investigate diversity in MHC genes in marsupials.

Inhibition of M. tuberculosis and human ATP synthase by BDQ and TBAJ-587.

Bedaquiline (BDQ), a first-in-class diarylquinoline anti-tuberculosis drug, and its analogue, TBAJ-587, prevent the growth and proliferation of Mycobacterium tuberculosis by inhibiting ATP synthase1,2. However, BDQ also inhibits human ATP synthase3. At present, how these compounds interact with either M. tuberculosis ATP synthase or human ATP synthase is unclear. Here we present cryogenic electron microscopy structures of M. tuberculosis ATP synthase with and without BDQ and TBAJ-587 bound, and human ATP synthase bound to BDQ. The two inhibitors interact with subunit a and the c-ring at the leading site, c-only sites and lagging site in M. tuberculosis ATP synthase, showing that BDQ and TBAJ-587 have similar modes of action. The quinolinyl and dimethylamino units of the compounds make extensive contacts with the protein. The structure of human ATP synthase in complex with BDQ reveals that the BDQ-binding site is similar to that observed for the leading site in M. tuberculosis ATP synthase, and that the quinolinyl unit also interacts extensively with the human enzyme. This study will improve researchers' understanding of the similarities and differences between human ATP synthase and M. tuberculosis ATP synthase in terms of the mode of BDQ binding, and will allow the rational design of novel diarylquinolines as anti-tuberculosis drugs.

Consortium Profile: The Methylation, Imaging and NeuroDevelopment (MIND) Consortium.

Epigenetic processes, such as DNA methylation, show potential as biological markers and mechanisms underlying gene-environment interplay in the prediction of mental health and other brain-based phenotypes. However, little is known about how peripheral epigenetic patterns relate to individual differences in the brain itself. An increasingly popular approach to address this is by combining epigenetic and neuroimaging data; yet, research in this area is almost entirely comprised of cross-sectional studies in adults. To bridge this gap, we established the Methylation, Imaging and NeuroDevelopment (MIND) Consortium, which aims to bring a developmental focus to the emerging field of Neuroimaging Epigenetics by (i) promoting collaborative, adequately powered developmental research via multi-cohort analyses; (ii) increasing scientific rigor through the establishment of shared pipelines and open science practices; and (iii) advancing our understanding of DNA methylation-brain dynamics at different developmental periods (from birth to emerging adulthood), by leveraging data from prospective, longitudinal pediatric studies. MIND currently integrates 15 cohorts worldwide, comprising (repeated) measures of DNA methylation in peripheral tissues (blood, buccal cells, and saliva) and neuroimaging by magnetic resonance imaging across up to five time points over a period of up to 21 years (Npooled DNAm = 11,299; Npooled neuroimaging = 10,133; Npooled combined = 4,914). By triangulating associations across multiple developmental time points and study types, we hope to generate new insights into the dynamic relationships between peripheral DNA methylation and the brain, and how these ultimately relate to neurodevelopmental and psychiatric phenotypes.

Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes.

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation in specific brain regions is associated with declines in human-specialized social-emotional and language functions. In most patients, disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD-associated regional degeneration patterns relate to regional gene expression of human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution. To this end, we used structural neuroimaging from patients with FTLD and human brain regional transcriptomic data from controls to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions linked to expression levels of recently evolved genes. In addition, we asked whether genes whose expression correlates with FTLD atrophy are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired. We found that FTLD-TDP and FTLD-tau subtypes target brain regions with overlapping and distinct gene expression correlates, highlighting many genes linked to neuromodulatory functions. FTLD atrophy-correlated genes were strongly enriched for HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes and genes with more numerous TDP-43 binding sites compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes. Overall, our findings suggest that FTLD targets brain regions that have undergone recent evolutionary specialization and provide intriguing potential leads regarding the transcriptomic basis for selective vulnerability in distinct FTLD molecular-anatomical subtypes.