Research square最新文献

{"title":"Evaluating Patient Representation Strategies for Early Prediction of Alzheimer's Disease and Related Dementias from Longitudinal EHRs.","authors":"Shahla Farzana, Ash Arian, Moïse Desvarieux, Tatjana Rundek, Habibul Ahsan","doi":"10.21203/rs.3.rs-10988118/v1","DOIUrl":"10.21203/rs.3.rs-10988118/v1","url":null,"abstract":"<p><p>The neurodegenerative processes underlying Alzheimer's disease and related dementias (ADRD) begin years before clinical diagnosis, motivating scalable approaches for earlier identification. Electronic health records (EHRs) provide longitudinal clinical information for early ADRD prediction but are sparse, temporal, and hierarchical, and alternative EHR representations encode these characteristics differently. We systematically evaluated how EHR representation and temporal distance from diagnosis influence ADRD prediction and whether representation-specific performance generalizes across health systems. Using All of Us EHRs, we compared interpretable count-based representations with pretrained clinical foundation-model representations at clinically meaningful lead times across multiple ADRD case definitions. Count-based models achieved the strongest overall discrimination and calibration. Performance generally declined with increasing prediction horizons, while differences between representations narrowed; at 36 months, pretrained representations achieved comparable AUROC (0.719 versus 0.738) with higher sensitivity and F1 at a fixed operating threshold. Temporal feature attribution showed greater model reliance on healthcare-utilization indicators at longer horizons and increasing importance of cognitive phenotypes, including amnesia and mild cognitive impairment, nearer diagnosis. Zero-shot evaluation on independent UChicago Medicine EHRs showed substantial performance degradation across representations, demonstrating challenges in cross-institutional transportability. These findings characterize representation-dependent tradeoffs in early ADRD prediction across temporal horizons and healthcare systems.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rho GTPase-driven stress granules enable anchorage-independent survival under adhesion stress.","authors":"Seungwon Yang, Anaïs Aulas, Paul J Anderson, Pavel Ivanov","doi":"10.21203/rs.3.rs-10284597/v1","DOIUrl":"10.21203/rs.3.rs-10284597/v1","url":null,"abstract":"<p><p>Cells that lose adhesion to their native extracellular matrix must either adapt to impaired adhesion signaling or undergo anoikis. How cells convert loss of adhesion into translational stress responses and survival signaling remains incompletely understood. Here, we define adhesion stress as a cellular stress state triggered by impaired adhesion signaling and show that this state induces stress granule (SG) assembly as an adaptive survival mechanism. We modeled adhesion stress through cell detachment, reduced adhesion strength, and pharmacologic inhibition of focal adhesion kinase (FAK). Across these models, adhesion stress activated a RhoA-ROCK-PERK-eIF2α signaling pathway that drove SG assembly. PERK was the principal eIF2α kinase required for this adhesion-stress response. Proteomic profiling further showed that adhesion-stress SGs represent a previously unrecognized SG subtype characterized by a Rho GTPase-associated protein signature and selective enrichment of CASP4, an inflammatory caspase linked to cell-death signaling. Functionally, SG assembly limited CASP4 activation and reduced apoptotic signaling during FAK inhibitor-induced adhesion stress. In parallel, PERK contributed to sustained AKT-mTOR survival signaling during anoikis. Genetic loss of SG assembly or pharmacologic inhibition of G3BP-dependent SG formation increased anoikis sensitivity and sensitized cancer cells to multiple FAK inhibitors. SGs were also enriched in invading cancer cells in human breast tumors, consistent with a role for adhesion-stress adaptation in invasive tumor contexts. Together, these findings identify adhesion-stress SGs as a RhoA-ROCK-PERK-driven survival program that limits anoikis and enables anchorage-independent cancer cell survival.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic Connectivity and Adaptive Gene Flow of <i>Anopheles gambiae s. s</i>. Across East and Central Africa.","authors":"Fekadu Gemechu, Kelly L Bennett, Araya Eukubay, Sisay Dugassa, Anastasia Hernandez-Koutoucheva, Luna Kamau, Tadesse Kebede Zeleke, Alistair Miles, Deriba Abera, Chris S Clarkson, Lemu Golassa","doi":"10.21203/rs.3.rs-10571451/v1","DOIUrl":"10.21203/rs.3.rs-10571451/v1","url":null,"abstract":"<p><p>Population connectivity influences the adaptive capacity of disease vectors by mediating the spread of insecticide resistance alleles. High gene flow poses challenges for tailored intervention strategies targeting localised populations, but connectivity is often poorly characterised for particular geographical regions. This study uses whole-genome data to investigate the population connectivity of the <i>Anopheles gambiae</i> malaria vector across East-Central Africa, including understudied populations from Ethiopia. We also investigated adaptive gene flow using Diplotype clustering at known insecticide resistance loci. Population structure analyses revealed that Ethiopian populations experience high gene flow with inland East African <i>An. gambiae</i> including Uganda, inland Kenya, inland Tanzania, and the northern DRC, likely reflecting ecological continuity across the region. In contrast, coastal populations of East Africa and south-central DRC were subject to restricted gene flow, consistent with geographical and ecological barriers to dispersal. Diplotype clustering of the <i>Cyp6aa/p</i> gene cluster and <i>Cyp9k1</i> revealed that CNV-variant sharing broadly mirrored genome-wide connectivity patterns, with shared variation present in inland East Africa and the northern DRC, but distinct CNV-associated clusters in more isolated populations in southeastern DRC. On the other hand, allele sharing at the <i>Vgsc</i> gene did not follow patterns of population connectivity, with the <i>Vgsc</i>-L995S allele broadly shared across East Africa and the <i>Vgsc</i>-L995F allele shared between Ethiopia and populations throughout the DRC. Notably, Ethiopia emerges as a crossover point where resistance alleles from East and Central Africa can converge, suggesting it is an important region for the monitoring of emergent and/or expanding adaptations. Findings highlight the importance of cross-border collaboration and the development of resistance management strategies that respond to both regional connectivity and local divergence.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Divergent PML and Nucleolar Body Programs Distinguish Protected from Vulnerable Neurons in FTLD-TDP.","authors":"Oseas Medina, Alissa Nana Li, Lily Talley, Stephanie E Gaus, Joel H Kramer, Jennifer S Yokoyama, Howard J Rosen, Maria Luisa Gorno Tempini, Salvatore Spina, Lea T Grinberg, Bruce L Miller, William W Seeley","doi":"10.21203/rs.3.rs-11089898/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-11089898/v1","url":null,"abstract":"<p><p>TDP-43 nuclear depletion and cytoplasmic aggregation are hallmarks of frontotemporal lobar degeneration (FTLD) and motor neuron disease, yet the events preceding depletion remain poorly characterized. PML nuclear bodies and the nucleolus are phase-separated protein quality control (PQC) compartments; SUMO1 is integral to PML nuclear body assembly and accumulates in the nucleolus under proteostatic stress. How they remodel in relation to TDP-43 pathobiology has not been examined at single-cell resolution in human tissue. We analyzed 18,742 anterior cingulate cortex neurons across 29 subjects (10 sporadic FTLD-TDP, 10 C9orf72-associated FTLD-TDP, 9 controls) by multichannel confocal immunofluorescence, scoring each neuron for five nuclear body phenomena and TDP-43 nuclear depletion. Three phenomena were elevated in nuclear TDP-43-preserved patient neurons relative to controls and returned to approximately control levels in depleted neurons, consistent with a protective role (control → preserved → depleted): SUMO1 nucleolar granules (3.2% → 13.9% → 5.0%), SUMO1 nucleolar puncta (0.2% → 11.0% → 3.1%), and PML nucleolar contacts (2.5% → 6.4% → 1.7%). In contrast, PML nuclear membrane contacts (0.1% → 2.6% → 19.9%) and macro-PML bodies (0.0% → 0.9% → 15.6%) increased progressively, and both were associated with depletion (odds ratio 9.2, 95% CI 6.1-14.0 and 20.2, 95% CI 13.9-29.4), consistently across sporadic and C9orf72-associated disease. Within nuclear TDP-43-preserved neurons, protection-associated phenomena rarely co-occurred with PML nuclear membrane contacts (odds ratio 0.39-0.54, all p < 0.05) but co-occurred with each other (odds ratio 3.3-4.0), defining two segregated remodeling programs; depletion fell from 15.3% in neurons bearing no protection-associated phenomenon to 2.3% in those bearing all three (Kendall's τ = -0.135). These findings identify opposing nuclear body remodeling programs in FTLD-TDP, expand the spectrum of pre-depletion changes, implicate phase-separated nuclear PQC compartments as determinants of neuronal fate, and raise the possibility that SUMO1 nucleolar accumulation is a general marker of neuronal stress.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Language of Hope in Conversations between Pediatric Oncologists, Children with Advanced Cancer, and their Families.","authors":"Nidhi Vij Mali, Carolyn Humphrey, Amy Porter, Erica Carmen Kaye, Alexandra Kathleen Superdock","doi":"10.21203/rs.3.rs-10617761/v1","DOIUrl":"10.21203/rs.3.rs-10617761/v1","url":null,"abstract":"<p><strong>Purpose: </strong>Hope is a key driver of coping and decision-making for children with cancer and their families. Prior studies have shown that hope is bolstered, not fractured, by high-quality prognostic communication. However, clinicians describe a tension between conveying hope and honestly discussing poor prognosis. This prospective longitudinal observational study aimed to identify and characterize communication approaches used by oncologists and parents to navigate hope in the context of poor prognosis.</p><p><strong>Methods: </strong>Serial conversations between pediatric patients with poor-prognosis brain tumors, their families, and their medical teams were audio-recorded at disease reevaluation timepoints for up to 24 months or until death. Rapid qualitative analysis was used to characterize the frequency and content of hope-related dialogue.</p><p><strong>Results: </strong>132 conversations were recorded for 30 brain tumor patient-parent-oncologist triads.Hope-related dialogue was identified in 73 (55%) of encounters. Oncologists introduced hope language in about two-thirds of these conversations. Hope dialogue could be described along two dimensions: temporal orientation and desired outcomes. Temporally, hope appeared in conversations as prospective, retrospective, or negated. Desired outcomes included hope for cure, hope for remission, hope for life prolongation and meaningful experiences, and hope for symptom management and comfort at the end of life.</p><p><strong>Conclusion: </strong>Hope dialogue may be an entry point for aligning with families, exploring prognostic understanding, and opening the door to deeper conversations about reframing hopes and goals of care. Future work should explore development of strategies to elicit and respond to patient and family hopes across the cancer trajectory.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adapting on-the-go in NYC: Ongoing implementation strategy and cultural adaptations of Problem Management Plus (PM+), a non-clinician delivered mental health intervention.","authors":"Manaswi Sangraula, Selam Kidane, Ari Holman, Chynere Best, Farhana Alam, Kelly Andrew, Alejandra Cid-Vega, Laure Experton, Ruta Rangel, Ruth Marie de Jong Montero, Sophia Ryder, Francesca Ungureanu, Eliot Assoudeh, Lemlem Baraki, Heather Day, Eva Wong, Ilana Yamin, Adam Brown, Brandon Kohrt","doi":"10.21203/rs.3.rs-10419563/v1","DOIUrl":"10.21203/rs.3.rs-10419563/v1","url":null,"abstract":"<p><strong>Introduction: </strong>Mental health service utilization remains disproportionately low among racial and ethnic minority populations, due to structural barriers and a lack of culturally responsive mental health programming in community settings. Adapting both intervention content and implementation strategies is essential to improving the fit and effectiveness of task-shared mental health interventions, yet most adaptation research focuses on pre-implementation changes rather than ongoing adjustments throughout a program's lifecycle. This paper examines adaptations to Problem Management Plus (PM+), a task-shared intervention delivered by non-clinicians across 19 community-based organizations in New York City as part of a cluster randomized controlled trial, drawing on implementation science and cultural adaptation frameworks to guide documentation of adaptations before, during, and after implementation.</p><p><strong>Methods: </strong>Three implementation science and two cultural adaptation frameworks were used to guide the documentation, analysis, and reporting of implementation strategy and cultural adaptations. A seven-step adaptation process was conducted before, during, and after intervention implementation and data was collected throughout each of these steps. Qualitative methods and descriptive statistics were used to characterize and summarize implementation strategy and cultural adaptations.</p><p><strong>Results: </strong>Of the 139 adaptations documented, most (63%, n = 88) occurred during implementation, and most concerned program delivery (69%, n = 96) rather than training/supervision (10%, n = 14) or recruitment and CBO integration (21%, n = 29). Adaptations were made mainly at the individual level (43%, n = 59), followed by across all CBO sites (38%, n = 53) and select sites (19%, n = 27). Priority adaptations included adjusting the training model to increase trainee retention, integration of implementation strategy-related topics such as participant reach within clinical supervision, delivering the intervention in community settings such as parks and cafes, and integration of culturally appropriate practices such as meditation and prayer within the intervention.</p><p><strong>Conclusion: </strong>This paper offers guidance on documenting implementation strategies and cultural adaptations throughout program delivery in real-world settings-specifically, how to conduct and document adaptations pre-, during, and post-implementation, and what to adapt. By consolidating implementation science and cultural adaptation frameworks, this study aims to bridge dialogue between the two disciplines and serve as a guiding example for documenting adaptations across the program lifecycle.</p><p><strong>Trial registration: </strong>NCT04913766; Clinicaltrials.gov; Registration date 06/03/2021.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"μ-Opioid receptors negatively regulate striatal dopamine D₁ receptor signaling through heteromerization.","authors":"Arantzazu Alonso-Carrasco, William N Sánchez, Natàlia Llopart, Marta Valle-León, Marc Ciruela-Jardí, César Quiroz, Ning-Sheng Cai, Cèlia Rodríguez-Casas, Christopher J Earley, Estefanía Moreno, Verònica Casadó-Anguera, Leonardo Pardo, Vicent Casadó, Sergi Ferré","doi":"10.21203/rs.3.rs-10628538/v1","DOIUrl":"10.21203/rs.3.rs-10628538/v1","url":null,"abstract":"<p><p>Integrating biophysical, computational, <i>in situ</i>, and <i>in vivo</i> approaches with selective heteromer-disrupting transmembrane peptides, this study demonstrates that μ-opioid receptors (MORs) and dopamine D₁ receptors (D₁Rs) assemble into functional heteromers. Furthermore, real-time <i>in vivo</i> fiber photometry using a genetically encoded cAMP biosensor directly demonstrates that MORs regulate striatal D₁Rs via heteromerization in the intact mouse brain. Our findings support a tetrameric structure composed of Gi-coupled MOR and Gs-coupled D₁R homodimers, which enables both canonical Gi-Gs antagonistic interaction at the level of adenylyl cyclase and receptor-level cross-antagonism, by which MOR agonists and antagonists counteract D₁R agonist-induced signaling. Located predominantly within striosomal GABAergic projection neurons, MOR-D₁R heteromers constitute mechanistically defined signaling units that integrate dopaminergic and opioid neurotransmission governing motor control and reward processing. Collectively, these findings establish MOR-D₁R heteromers as a previously unrecognized therapeutic target for the treatment of opioid withdrawal-associated restlessness and restless legs syndrome.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-Throughput Screening Identifies Novel Antileishmanial Scaffolds and Reveals Cross-Species Activity of Structurally Diverse Compounds.","authors":"Juan P Gonzalez, Hannah N Corman, Douglas A Shoue, Mohanna Sadat Sajjadi Oskouei, Theodore O Schroder, Chaniay O'Brien, Bruce J Melancon, Mary Ann McDowell","doi":"10.21203/rs.3.rs-10898149/v1","DOIUrl":"10.21203/rs.3.rs-10898149/v1","url":null,"abstract":"<p><strong>Background: </strong>Leishmaniasis remains a neglected tropical disease with limited therapeutic options and a continued need for new and effective treatments. High-throughput phenotypic screening provides an approach for identifying chemically diverse compounds with antileishmanial activity that can serve as a starting point for drug development. This study further characterized compounds identified through a previous high-throughput phenotypic screen to prioritize promising antileishmanial chemical scaffolds and evaluate their potential for continued drug development.</p><p><strong>Methods: </strong>Compounds belonging to two enriched scaffolds, 1,4-diaryl-pyrazolo-pyridinone (1,4-DAPP) and pyrazolo-[5,1-c][1,2,4]triazine (PTZ), along with structurally diverse singleton compounds, were evaluated for antileishmanial activity across <i>Leishmania</i> parasite life stages by determining half-maximal inhibitory concentrations (IC₅₀). Host-cell cytotoxicity was evaluated against THP-1 macrophages by determining half-maximal cytotoxic concentrations (CC₅₀). The IC₅₀ and CC₅₀ values were determined by nonlinear regression analysis. Selected lead compounds underwent preliminary <i>in vitro</i> absorption, distribution, metabolism, and excretion (ADME) profiling. Synthesized analogs of both scaffolds were evaluated to investigate structure-activity relationships and opportunities for chemical optimization.</p><p><strong>Results: </strong>1,4-DAPP #9279817 and PTZ #9234527 were prioritized as lead compounds based on their combined antileishmanial activity and host-cell selectivity, exhibiting intracellular amastigote IC₅₀ values of 3.50 and 3.12 μM and selectivity indices (SI) of 14.29 and 16.03, respectively. Singleton compounds exhibited variable parasite stage-specific activity, with host-cell cytotoxicity limiting the selectivity of several candidates. Both lead scaffolds retained activity across multiple <i>Leishmania</i> species, although compound susceptibility varied among species. Preliminary ADME profiling revealed distinct properties of the two leads, highlighting strengths and limitations for further optimization. Structural modifications of both scaffolds generated analogs with improved intracellular antileishmanial activity and selectivity.</p><p><strong>Conclusions: </strong>The 1,4-DAPP and PTZ scaffolds represent promising candidates for continued antileishmanial development. These findings support continued optimization of both scaffolds while emphasizing the importance of evaluating antileishmanial activity in disease-relevant parasite models.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vestibulo-sympathetic Reflex and Pupillary Responses Elicited by Vertical Semicircular Canal Stimulation.","authors":"Fumihiro Mochizuki, Yoshiyuki Sasano, Alexander Kiderman, Bernat Miro, Madison Hawthorne, Michael Hoffer, Erin Williams","doi":"10.21203/rs.3.rs-10833093/v1","DOIUrl":"10.21203/rs.3.rs-10833093/v1","url":null,"abstract":"<p><p>The vestibulo-sympathetic reflex has been studied mainly using horizontal semicircular canal and otolith stimulation, whereas the autonomic role of the vertical canals remains unclear. We quantified cardiovascular and pupillary responses to vertical canal stimulation and compared stimulus-frequency-locked pupil oscillations between vertical and horizontal rotations in 18 healthy adults. Vertical stimulation used a 70°-tilted rotary chair aligning the vertical canal planes with the earth-horizontal axis. Participants underwent sinusoidal harmonic acceleration at 0.08, 0.16, and 0.64 Hz and the vertical velocity step test at 100°/s. Systolic blood pressure rose 5.8-7.8 mmHg with medium-to-large effect sizes but did not survive multiple-comparison correction. Pupil area increased significantly at all frequencies, and vertical stimulation produced larger stimulus-frequency-locked oscillation amplitude compared to horizontal stimulation (β = 0.568 mm², p = 0.018). Additionally, the pupillary oscillation was phase-locked to the stimulus per canal plane, reaching significance at 0.64 Hz (sign-aligned cross-plane phase-locking value 0.27-0.37; Rayleigh p = 0.015). A two-stage gain model (cupula velocity transduction filtered by iris smooth-muscle dynamics; gain ≈ 0.09 mm²/(deg/s); iris corner ≈ 0.71 Hz) was more consistent with a velocity-coded than an acceleration-coded drive, although the sample size precluded resolving the absolute phase. These findings suggest that vertical canal inputs may engage human vestibulo-autonomic pathways and that spectral pupillometry may provide a noninvasive index of vestibulo-sympathetic reflex function.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The balloon model revisited.","authors":"John C Gore, Tzu-Wei Li, Yang Jiao, Abbe L Knutsson, Warren W Boschen, Muwei Li, Kurt Schilling, Adam W Anderson, Zhaohua Ding, Yurui Gao","doi":"10.21203/rs.3.rs-11197888/v1","DOIUrl":"10.21203/rs.3.rs-11197888/v1","url":null,"abstract":"<p><p>Functional MRI based on the blood oxygenation level-dependent (BOLD) effect infers neural activity from hemodynamic changes through a hemodynamic response function (HRF). We revisit the balloon model of the BOLD effect and show that Grubb's empirical flow-volume power law can be used to determine how vascular transit time varies with flow and is governed by a single index of venous distensibility. Linearizing the resulting equations yields an explicit closed-form HRF, expressed in physiologically recognizable parameters, that reproduces the canonical response. The initial dip, time to peak and poststimulus undershoot are each traced to identifiable terms, and the relations assumed in calibrated BOLD signals emerge as outputs. When oxygen consumption is specified independently of flow, as in earlier generalizations, the analytic solution quantifies the specific relationships between the latency and depth of an initial dip and a neurovascular delay. The new model will prove useful for explaining variations in HRF in white matter, across the brain, and between different populations.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}