SMARCB1 loss interacts with neuronal differentiation state to block maturation and impact cell stability.

Atypical teratoid rhabdoid tumors (ATRTs) are challenging pediatric brain cancers that are predominantly associated with inactivation of the gene SMARCB1, a conserved subunit of the chromatin remodeling BAF complex, which has known contributions to developmental processes. To identify potential interactions between SMARCB1 loss and the process of neural development, we introduced an inducible SMARCB1 loss-of-function system into human induced pluripotent stem cells (iPSCs) that were subjected to either directed neuronal differentiation or differentiation into cerebral organoids. Using this system, we identified substantial differences in the downstream effects of SMARCB1 loss depending on differentiation state and identified an interaction between SMARCB1 loss and neural differentiation pressure that causes a resistance to terminal differentiation and a defect in maintenance of a normal cell state. Our results provide insight into how SMARCB1 loss might interact with neural development in the process of ATRT tumorigenesis.

Germline Elongator mutations in Sonic Hedgehog medulloblastoma.

Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children1,2, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma3. Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype4 and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U34) position5,6. Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems7-9. Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.

Using the Doughnut Economics framework to structure whole-system thinking in socioecological wellbeing with multidisciplinary stakeholders: an applied case study in Glasgow, Scotland.

BACKGROUND: Human and environmental health are inseparable and interdependent. Doughnut Economics is a conceptual framework combining the Sustainable Development Goals with Planetary Boundaries, thereby simultaneously considering human and planetary wellbeing. The vision is to "meet the needs of all people within the means of the living planet, for the benefit of both current and future generations". Glasgow City Council has committed to becoming a Green Wellbeing Economy, with a socially just transition to Net Zero by 2030. Through our City-University partnership, we are exploring whether Doughnut Economics can drive transformative action towards a sustainable, healthy, and equitable future. METHODS: Glasgow is a pilot site for the C40 Cities' Thriving City Portrait methodology that downscales Doughnut Economics to cities. The Portrait process combined desk-based research and policy review (from January to April, 2022) with participatory workshops to enrich initial findings. The five participatory workshops took place between April, 2022, and February, 2023, and involved about 130 stakeholders. Participants included civil servants, politicians, scientists, community representatives, employees and representatives of private and third-sector organisations, and social enterprises, identified through an iterative stakeholder mapping process with City Council partners. Workshop aims were to create pluralistic definitions of what thriving means for each of the Doughnut's social and ecological dimensions. Ethics approval for the study was granted by The University of Glasgow, College of Medical Veterinary and Life Sciences. FINDINGS: The workshops produced a shared, holistic vision for Glasgow's future as a thriving city. The Doughnut demonstrated potential as a tool for both understanding the city's socioecological impacts, and as a compass by which the city might set its policy agenda. It allows the multiple goals and priorities of a city system to congregate around a cohesive goal. The Portrait process led to a widening of stakeholders' perspectives, applying systems thinking to policy priorities, cross-sector discussion and collaboration, and significant buy-in from a diverse range of changemakers. INTERPRETATION: The Doughnut framework offered a starting point for Public and Planetary Health researchers to understand connections, co-benefits and trade-offs across different parts of the policy and intervention system. Applying this framework in cities could generate support for whole-system interventions and sustainable solutions to the complex and interconnected climate and social challenges we face. One of the limitations is that we do not yet know whether stakeholders can translate support for this co-created framework into tangible whole-systems action. FUNDING: UKRI Natural Environment Research Council and University of Glasgow.

Differential viral RNA methylation contributes to pathogen blocking in Wolbachia-colonized arthropods.

Arthropod endosymbiont Wolbachia pipientis is part of a global biocontrol strategy to reduce the replication of mosquito-borne RNA viruses such as alphaviruses. We previously demonstrated the importance of a host cytosine methyltransferase, DNMT2, in Drosophila and viral RNA as a cellular target during pathogen-blocking. Here we report a role for DNMT2 in Wolbachia-induced alphavirus inhibition in Aedes species. Expression of DNMT2 in mosquito tissues, including the salivary glands, is elevated upon virus infection. Notably, this is suppressed in Wolbachia-colonized animals, coincident with reduced virus replication and decreased infectivity of progeny virus. Ectopic expression of DNMT2 in cultured Aedes cells is proviral, increasing progeny virus infectivity, and this effect of DNMT2 on virus replication and infectivity is dependent on its methyltransferase activity. Finally, examining the effects of Wolbachia on modifications of viral RNA by LC-MS show a decrease in the amount of 5-methylcytosine modification consistent with the down-regulation of DNMT2 in Wolbachia colonized mosquito cells and animals. Collectively, our findings support the conclusion that disruption of 5-methylcytosine modification of viral RNA is a vital mechanism operative in pathogen blocking. These data also emphasize the essential role of epitranscriptomic modifications in regulating fundamental alphavirus replication and transmission processes.

Saccades and presaccadic stimulus repetition alter cortical network topology and dynamics: evidence from EEG and graph theoretical analysis.

Parietal and frontal cortex are involved in saccade generation, and their output signals modify visual signals throughout cortex. Local signals associated with these interactions are well described, but their large-scale progression and network dynamics are unknown. Here, we combined source localized electroencephalography (EEG) and graph theory analysis (GTA) to understand how saccades and presaccadic visual stimuli interactively alter cortical network dynamics in humans. Twenty-one participants viewed 1-3 vertical/horizontal grids, followed by grid with the opposite orientation just before a horizontal saccade or continued fixation. EEG signals from the presaccadic interval (or equivalent fixation period) were used for analysis. Source localization-through-time revealed a rapid frontoparietal progression of presaccadic motor signals and stimulus-motor interactions, with additional band-specific modulations in several frontoparietal regions. GTA analysis revealed a saccade-specific functional network with major hubs in inferior parietal cortex (alpha) and the frontal eye fields (beta), and major saccade-repetition interactions in left prefrontal (theta) and supramarginal gyrus (gamma). This network showed enhanced segregation, integration, synchronization, and complexity (compared with fixation), whereas stimulus repetition interactions reduced synchronization and complexity. These cortical results demonstrate a widespread influence of saccades on both regional and network dynamics, likely responsible for both the motor and perceptual aspects of saccades.

Associations of Osteoarthritis with Prevalence and Incidence of Cardiovascular Disease over 10 Years in Community-Dwelling Older Adults: The Sydney Memory and Ageing Study.

INTRODUCTION: The data are limited for the association between osteoarthritis (OA) and cardiovascular disease (CVD) in community-based older populations and whether there is sex difference. This study aimed to examine the relationship between OA and prevalence and incidence of CVD over 10 years in community-dwelling older adults. METHODS: Data on self-reported OA, high cholesterol, hypertension, and type 2 diabetes were collected from 1,025 community-dwelling participants aged 70-90 years in the Sydney Memory and Ageing Study. The presence of CVD at baseline was defined as self-reported presence of stroke, heart attack, transient ischaemic attack, angina, aortic aneurysm, or claudication. The incidence of CVD was defined by a combination of incident self-reported CVD or CVD mortality at different follow-up timepoints over 10 years. RESULTS: At baseline, 395 (38.5%) participants self-reported OA (252 [44.6%] women, 143 [31.1%] men). Self-reported OA was associated with increased prevalence of CVD in women (OR 1.67, 95% CI 1.12-2.47) but not men (1.26, 0.80-1.98). In the total population, self-reported OA at baseline was associated with increased incidence of CVD at 4 years (OR 1.77, 95% CI 1.10-2.83), 6 years (1.59, 1.03-2.46), 8 years (1.56, 1.02-2.38), and 10 years (1.66, 1.10-2.50), but not at 2 years (1.43, 0.79-2.57). Significant associations were observed in female participants at 4, 8, and 10 years, with no significant associations seen in male participants. CONCLUSION: OA was associated with increased prevalence at baseline and incidence of CVD over 10 years in community-based older adults, especially women. Identifying those with OA to target their cardiovascular risk factors while managing their OA has the potential to reduce the burden of CVD in older people, particularly women.

Longitudinal alcohol-related brain changes in older adults: The Sydney Memory and Ageing Study.

Increases in harmful drinking among older adults indicate the need for a more thorough understanding of the relationship between later-life alcohol use and brain health. The current study investigated the relationships between alcohol use and progressive grey and white matter changes in older adults using longitudinal data. A total of 530 participants (aged 70 to 90 years; 46.0% male) were included. Brain outcomes assessed over 6 years included total grey and white matter volume, as well as volume of the hippocampus, thalamus, amygdala, corpus callosum, orbitofrontal cortex and insula. White matter integrity was also investigated. Average alcohol use across the study period was the main exposure of interest. Past-year binge drinking and reduction in drinking from pre-baseline were additional exposures of interest. Within the context of low-level average drinking (averaging 11.7 g per day), higher average amount of alcohol consumed was associated with less atrophy in the left (B = 7.50, pFDR = 0.010) and right (B = 5.98, pFDR = 0.004) thalamus. Past-year binge-drinking was associated with poorer white matter integrity (B = -0.013, pFDR = 0.024). Consuming alcohol more heavily in the past was associated with greater atrophy in anterior (B = -12.73, pFDR = 0.048) and posterior (B = -17.88, pFDR = 0.004) callosal volumes over time. Across alcohol exposures and neuroimaging markers, no other relationships were statistically significant. Within the context of low-level drinking, very few relationships between alcohol use and brain macrostructure were identified. Meanwhile, heavier drinking was negatively associated with white matter integrity.

Surgical management of Rathke cleft cysts in pediatric patients: a single institution experience.

OBJECTIVE: Rathke cleft cysts (RCCs) are benign, epithelial-lined sellar lesions that arise from remnants of the craniopharyngeal duct. Due to their rarity in the pediatric population, data are limited regarding the natural history and optimal management of growing or symptomatic RCCs. We present our institutional experience with the surgical management of RCCs. METHODS: We performed a retrospective study of consecutive RCC patients ≤ 18 years old treated surgically at our institution between 2006 and 2022. RESULTS: Overall, 567 patients with a diagnosis of pituitary mass or cyst were identified. Of these, 31 had a histopathological diagnosis of RCC, 58% female and 42% male. The mean age was 13.2 ± 4.2 years. Presenting symptoms included headache (58%), visual changes (32%), and endocrinopathies or growth delay (26%); 13% were identified incidentally and subsequently demonstrated growth on serial imaging. Six percent presented with symptomatic intralesional hemorrhage. Surgical approach was transsphenoidal for 90% of patients and orbitozygomatic for 10%. Preoperative headaches resolved in 61% of patients and preoperative visual deficits improvement in 55% after surgery. New pituitary axis deficits were seen in 9.7% of patients. Only two complications occurred from a first-time surgery: one cerebrospinal fluid leak requiring lumbar drain placement, and one case of epistaxis requiring cauterization. No patients experienced new visual or neurological deficits. Patients were followed postoperatively with serial imaging at a mean follow-up was 62.9 ± 58.4 months. Recurrence requiring reoperation occurred in 32% of patients. Five-year progression-free survival was 47.9%. Except for one patient with multiple neurological deficits from a concurrent tectal glioma, all patients had a modified Rankin Scale score of 0 or 1 (good outcome) at last follow-up. CONCLUSION: Due to their secretory epithelium, pediatric RCCs may demonstrate rapid growth and can cause symptoms due to local mass effect. Surgical management of symptomatic or growing pediatric RCCs via cyst fenestration or partial resection of the cyst wall can be performed safely, with good neurologic outcomes. There is a nontrivial risk of endocrinologic injury, and long-term follow up is needed due to high recurrence rates.

Network analysis of neuropsychiatric, cognitive, and functional complications of stroke: implications for novel treatment targets.

AIM: Recovery from stroke is adversely affected by neuropsychiatric complications, cognitive impairment, and functional disability. Better knowledge of their mutual relationships is required to inform effective interventions. Network theory enables the conceptualization of symptoms and impairments as dynamic and mutually interacting systems. We aimed to identify interactions of poststroke complications using network analysis in diverse stroke samples. METHODS: Data from 2185 patients were sourced from member studies of STROKOG (Stroke and Cognition Consortium), an international collaboration of stroke studies. Networks were generated for each cohort, whereby nodes represented neuropsychiatric symptoms, cognitive deficits, and disabilities on activities of daily living. Edges characterized associations between them. Centrality measures were used to identify hub items. RESULTS: Across cohorts, a single network of interrelated poststroke complications emerged. Networks exhibited dissociable depression, apathy, fatigue, cognitive impairment, and functional disability modules. Worry was the most central symptom across cohorts, irrespective of the depression scale used. Items relating to activities of daily living were also highly central nodes. Follow-up analysis in two studies revealed that individuals who worried had more densely connected networks than those free of worry (CASPER [Cognition and Affect after Stroke: Prospective Evaluation of Risks] study: S = 9.72, P = 0.038; SSS [Sydney Stroke Study]: S = 13.56, P = 0.069). CONCLUSION: Neuropsychiatric symptoms are highly interconnected with cognitive deficits and functional disabilities resulting from stroke. Given their central position and high level of connectedness, worry and activities of daily living have the potential to drive multimorbidity and mutual reinforcement between domains of poststroke complications. Targeting these factors early after stroke may have benefits that extend to other complications, leading to better stroke outcomes.

Clinical Characteristics and Delayed Diagnosis of Pediatric Patients Presenting to the Emergency Department With a Newly Diagnosed Central Nervous System Tumor: A Single Institutional Experience.

BACKGROUND: Due to the varied symptomatology and inconsistent features on neurologic exam, central nervous system (CNS) tumors are difficult to diagnosis in a timely manner. OBJECTIVE: To determine the clinical, neurological, and neuroimaging features of newly diagnosed CNS tumors presenting to the emergency department (ED). METHODS: We evaluated a retrospective cohort of 121 consecutive patients presenting to a tertiary care pediatric ED over 7 consecutive years with newly diagnosed CNS tumors. Clinical symptomatology, neurologic findings reported by emergency room and neurology physicians, neuroimaging features, and time to diagnosis were analyzed. RESULTS: A total of 116 (48 female, median age 8.0 years (interquartile range, 4.4-12.6), 52% Hispanic) presented to the ED (64% self-referred) diagnosed with a brain tumor (54% posterior fossa, 24% embryonal, 24% low-grade glioma, 16% high-grade glioma) resulting in hospital admission in 92% of cases. Five were diagnosed with extradural spinal, clivus, or orbital apex tumors. Symptomatology or duration did not differ when stratified by demographics, location, or histologic subtype. Moderate degree of concordance was observed among neurologic examinations performed by ED physicians and neurologists. Delayed diagnosis (median delay = 3.5 [1-7] months) was seen in 14% of patients, 13 with primary brain tumors (11 hemispheric, 2 brain stem). Six children with delayed diagnosis of low-grade glial tumors had a nonfocal neurologic examination in comparison to 5 patients with abnormal examinations observed with primary spinal or extradural CNS tumors. Four patients with posterior fossa tumors (3 medulloblastoma, 1 ependymoma) had normal/near normal neurologic examination at presentation despite posterior fossa symptomatology related to increased intracranial pressure. CONCLUSIONS: Our series highlights the complexity of symptomology and neurologic findings in children presenting to the ED with newly diagnosed CNS tumors who may have a normal neurologic examination. Standardization of symptom assessment and focused neurologic examinations may lead to earlier neuroimaging and prevent delayed diagnosis.