Faculty Bibliography

OBJECTIVE/UNASSIGNED:Gender-diverse individuals often face a burden of poor mental health. This study examined whether gender-diverse experiences were associated with higher levels of loneliness in adolescents, over and above depression and anxiety, and how family environmental factors, including maladaptive parenting, being bullied by a sibling at home (victimization), and bullying a sibling at home (perpetration), moderate the associations between gender-diverse and loneliness experiences among 4,424 adolescents in a population-based cohort. METHOD/UNASSIGNED:This cross-sectional study was embedded in Generation R, a multiethnic population-based cohort from fetal life onward. Adolescents with information on self-reported or parent-reported gender diversity and loneliness at ages 13 to 15 years were included. RESULTS/UNASSIGNED:s > .10). CONCLUSION/UNASSIGNED:Gender diversity is associated with higher levels of loneliness in adolescents. Being a target of bullying modified the association of gender diversity with loneliness experiences, suggesting that gender-diverse adolescents who are bullied by siblings experience particularly higher levels of loneliness.

Animals can initiate movements either in response to external cues or from internal drive, yet how the brain flexibly supports both remains unclear. Disorders such as Parkinson's disease disrupt these modes differently, suggesting distinct underlying mechanisms. These differences could arise from specialized circuits or from shared neuronal populations that shift their dynamics across contexts. To distinguish between these possibilities, we performed two-photon calcium imaging in the dorsolateral striatum as mice executed the same lever press either spontaneously or in response to a cue. Unsupervised clustering identified neurons modulated during cue, movement, or postaction periods. Critically, the same neurons encoded movement across initiation contexts, but their population dynamics diverged before movement. Both D1- and D2-expressing spiny projection neurons contributed to these dynamics, with D1-SPNs more active at the time of the sensory stimulus. These results show that context shapes neural dynamics within a shared movement-encoding population, revealing a context-generalizable striatal code that supports flexible movement initiation across internal and external drives.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Degeneration of the central autonomic network with relative sparing of peripheral autonomic neurons underlies neurogenic orthostatic hypotension in patients with multiple system atrophy (MSA). Ampreloxetine, a novel, selective, norepinephrine (NE) reuptake inhibitor, allows once-daily dosing to precisely target residual peripheral autonomic neurons. Based on the hypothesis that patients with MSA would be most responsive and the substantial unmet need for symptomatic therapy in this population, an MSA subgroup analysis was prespecified. METHODS:We conducted a run-in 4-week, parallel-group, randomized controlled trial (SEQUOIA), followed by a pivotal enriched randomized withdrawal (RW) trial with 16-week open-label treatment and 6 weeks of 1:1 RW (REDWOOD). Inclusion criteria for the MSA subgroup included (1) probable or possible MSA, (2) 3-minute orthostatic blood pressure (BP) fall >20/10 mm Hg, and (3) dizziness or lightheadedness score >4 points. Outcome measures included self-reported symptom burden captured on the 10-item OH Questionnaire (OHQ). Differences were analyzed using logistic regression and mixed-model repeated measures analysis. RESULTS:= 0.015). Standing BP remained unchanged from open-label in the ampreloxetine group (systolic: 5.6 ± 4.1; diastolic: 3.7 ± 2.9 [SE] mm Hg) but fell after placebo withdrawal (systolic: -10.0 ± 4.5; diastolic: -6.0 ± 3.1 mm Hg). The catecholamine profile was consistent with NE transporter inhibition. There were no observed increases in supine BP. DISCUSSION/CONCLUSIONS:In a prespecified subgroup analysis of MSA participants in the REDWOOD trial, patients randomized to placebo worsened, whereas those who were randomized to treatment maintained their open-label level of function. TRIAL REGISTRATION INFORMATION/UNASSIGNED:REDWOOD trial, NCT03829657; first submitted to registry January 10, 2019; first participant enrolled February 22, 2019. SEQUOIA trial, NCT03750552; first submitted to registry November 20, 2018; first participant enrolled January 24, 2019. See ClinicalTrials.gov for full-protocol and statistical analysis plan. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class III evidence that in patients with MSA who had symptomatic benefit on orthostatic hypotension with ampreloxetine, there was no difference in the odds of treatment failures between those maintained on ampreloxetine and those withdrawn to placebo.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Circumferential minimally invasive surgery (cMIS) techniques in adult spinal deformity (ASD) surgery may reduce physiological burden compared with open technique, but their utility in octogenarians has not been previously assessed. METHODS:Operative ASD patients aged 80 years or older with complete baseline (BL) and 2-year postoperative radiographic and health-related quality of life data were assessed and compared by surgical technique: open vs cMIS. Propensity score matching aligned groups by BL Charlson Comorbidity Index (CCI), C7-S1 sagittal vertical axis, pelvic incidence minus lumbar lordosis mismatch, and C7 plumb line. BL and peri/postoperative factors were assessed using analysis of variance and Bonferroni-adjusted analysis of covariance while controlling for BL CCI and posterior fusion length. RESULTS:Thirty-four octogenarian ASD patients met inclusion criteria, of whom 29.4% underwent cMIS and 70.6% underwent open correction. cMIS patients were less likely to require surgical intensive care unit (10% vs 75%, P < .001) and had shorter hospital stays (4.6 vs 10.1 days, P = .013). Open patients reported higher Scoliosis Research Society-22 Appearance and Mental domain scores (both P < .005) and more frequently reached minimal clinically important difference in both domains by 2 years (P = .025, .024). cMIS patients more often required reoperation for radiographic sagittal imbalance by 2 years when controlling for CCI and levels fused (20.0% vs 8.3%, P < .001). No deaths occurred in either group by 2 years. CONCLUSION/CONCLUSIONS:In octogenarians undergoing ASD surgery, cMIS reduced physiological burden but had higher reoperation rates, whereas open surgery showed greater durability.

Alston's singing mouse has emerged as an intriguing model for the comparative study of vocal control. New work on the species sets the stage to understand the proximate mechanisms and evolutionary roots of novel acoustic communication traits.

Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer that frequently presents with disseminated disease. The PDA metastatic microenvironment imposes distinct metabolic stressors, potentially generating context-dependent vulnerabilities. Therefore, we employed CRISPR-based genetic screening in a model of PDA liver metastasis to identify novel and possibly targetable liabilities. Remarkably, ferritin heavy chain (FTH1) emerged as the most prominent liver-specific dependency - loss of FTH1 suppressed tumor growth specifically in the liver microenvironment. FTH1 deletion and subsequent disruption of iron handling triggers mitochondrial dysfunction and ionic imbalance, including cytosolic calcium overload. These perturbations result in the activation of a transcriptional program that triggers anti-tumor immunity mediated by immunostimulatory cytokine IL36G. Mechanistically, FTH1 deletion and subsequent ionic imbalance causes decreased protein levels of the tumor suppressor Stk11 (LKB1) which we propose to be mediated by an RNA G-quadruplex located in the 5'-UTR of LKB1. The loss of LKB1 protein levels alters signaling cascades resulting in reduced SIK signaling and inhibition of nonsense mediated decay, ultimately leading to Il36g mRNA stabilization. Taken together, this work elucidates novel ionic disruptions that regulate the translation of LKB1 through a previously undescribed quadruplex in the 5'UTR, altering signaling axes that can be targeted to generate an anti-tumor immune response in PDA.

Astrocytes, long considered supportive cells of the central nervous system (CNS), have critical roles in innate immunity. This Review explores immune signaling pathways in astrocytes, including pattern recognition through Toll-like receptors, nucleic acid sensors and inflammasomes. These pathways enable the detection of danger signals and initiate protective responses and endogenous innate immune functions. Downstream signaling pathways, including the interferon, NF-κB and STAT3 pathways, mediate astrocyte reactivity and drive cytokine secretion, antiviral responses, phagocytosis and many other immune functions. While these responses are crucial for CNS health, their dysregulation can contribute to chronic inflammation and neurodegeneration in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis. Additionally, astrocytes exhibit regional heterogeneity in their immune behaviors, which may influence disease trajectories. We highlight unresolved questions regarding the immune functions of astrocytes, their interplay with professional immune cells and their dual protective and pathological roles.