Research square最新文献

{"title":"KinoViz: A User-Friendly Web Application for High-Throughput Kinome Profiling Analysis and Visualization in Cancer Research.","authors":"Ehsan Saghapour, Joshua C Anderson, Jake Y Chen, Christopher D Willey","doi":"10.21203/rs.3.rs-6431257/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6431257/v1","url":null,"abstract":"<p><p>Kinases, at the signaling level, dynamically mediate uncontrolled cellular growth, survival and other cancer supporting processes. This, paired with the inherent druggability of kinases, points to the importance of measuring kinase activity, and that of inhibitors against them, directly, and to analyze this accurately. High-throughput kinome profiling technologies, such as the PamStation®12, allow researchers to kinetically capture kinase activity, against a multitude of peptide targets simultaneously. Yet, the complex datasets produced often require advanced computational tools and bioinformatics expertise to properly analyze that are not intuitive or readily available. To address this gap, we developed KinoViz, a web-based application to simplify analysis and visualization of kinome array data. KinoViz offers a suite of interactive tools that enables users to upload raw peptide phosphorylation datasets and conduct in-depth analyses without the need for coding knowledge. Key features include modules for visualizing kinetic phosphorylation curves, identifying statistically significant peptide changes, exploring individual peptide profiles, and generating insightful visualizations such as heatmaps, network diagrams, and dimensionality reduction plots (PCA, UMAP). By making complex kinomic data more accessible and interpretable, KinoViz allows researchers to rapidly generate interactive visualizations and comparative analyses. We aim to expand KinoViz's analytical capabilities for more advanced use, including use in direct translational drug discovery.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236925/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593711","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":"Cell Line-Specific Estrogen Responses Uncover Functional Sex Differences in Murine Macrophages.","authors":"Alison M Veintimilla, Zoe Turner, Nana Owusu-Boaitey, Varun Deshpande, Margaret McCarthy, Erika Moore","doi":"10.21203/rs.3.rs-6925474/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6925474/v1","url":null,"abstract":"<p><p>Background RAW 264.7 (male-derived) and J774A.1 (female-derived), are widely used in immunology research, yet their responses to gonadal hormones remain poorly understood. Gonadal hormones, particularly estrogen, shape immune cell function and contribute to sex differences in disease outcomes, with macrophages playing a central role through their expression of intracellular estrogen receptors (ERs). Herein, we investigated ER expression and functional responses to 17β-estradiol (E2) in male-derived RAW 264.7 and female-derived J774A.1 macrophages, in 2D culture. Additionally we looked at sex-matched and mismatched media conditions in a 3D hydrogel system. Our results reveal distinct phenotypic and functional differences between the cell lines, emphasizing the need for sex-aware approaches in immunological research and model design. Methods RAW 264.7 and J774A.1 macrophages were cultured in basal media for 24 hours, then treated with varying concentrations of 17β-estradiol (5, 25, 100 nM), as well as hormone-free and control media. Post-treatment analyses included viability, estrogen receptor expression, phenotype skewing, matrix metalloprotease 9 (MMP9) levels, and phagocytosis. These macrophages were also used to condition sex-specific media environments and were encapsulated in a hydrogel network containing adhesive and cleavable sites. Encapsulated cells were then exposed to sex-matched or sex-mismatched conditioned media, and proliferation and MMP9 production were assessed. Results Our results revealed distinct differences in estrogen receptor gene and protein expression, as well as in core macrophage functions such as proliferation, inflammation, matrix remodeling, and phenotype skewing. Additionally, the sex-derivation of the surrounding molecular environment affected macrophage behavior in a 3D hydrogel system. Female-derived macrophages were more sensitive in terms of proliferation to sex-mismatched environments, while male-derived macrophages exhibited altered enzyme activity when exposed to female-conditioned media. Conclusions These findings underscore the importance of accounting for both the origin of immune cells as well as the hormonal and environmental context in which they are studied. Without these considerations, experimental models risk missing critical biological differences that shape immune responses and disease outcomes.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593672","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":"Deep Learning of Suboptimal Spirometry to Predict Respiratory Outcomes and Mortality.","authors":"Michael Cho, Davin Hill, Max Torop, Aria Masoomi, Peter Castaldi, Edwin Silverman, Sandeep Bodduluri, Surya Bhatt, Taedong Yun, Cory McLean, Farhad Hormozdiari, Jennifer Dy, Brian Hobbs","doi":"10.21203/rs.3.rs-6296752/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6296752/v1","url":null,"abstract":"<p><strong>Importance: </strong>Obtaining spirometry requires repeated testing and using the maximal values based on quality control criteria. Whether the suboptimal efforts are useful for the prediction of respiratory outcomes is not clear.</p><p><strong>Objective: </strong>To determine whether a machine learning model could predict respiratory outcomes and mortality based on suboptimal spirometry.</p><p><strong>Design: </strong>Observational cohorts (UK Biobank and COPDGene).</p><p><strong>Setting: </strong>Multi-center; population, and disease-enriched.</p><p><strong>Participants: </strong>UK aged 40-69; US aged 45-80, >10 pack-years smoking, without respiratory diseases other than COPD or asthma.</p><p><strong>Exposures: </strong>Raw spirograms (volume-time).</p><p><strong>Main outcomes and measures: </strong>To create a combined representation of lung function we implemented a contrastive learning approach, Spirogram-based Contrastive Learning Framework (Spiro-CLF), which utilized all recorded volume-time curves per participant and applied different transformations (e.g. flow-volume, flow-time). We defined \"maximal\" efforts as those passing quality control (QC) with the maximum FVC; all other efforts, including submaximal and QC-failing efforts, were defined as \"suboptimal\". We trained the Spiro-CLF model using both maximal and suboptimal efforts from the UK Biobank. We tested the model in a held-out 20% testing UK Biobank subset and COPDGene, on 1) binary predictions of FEV1/FVC <0.7, and FEV1 Percent Predicted (FEV1PP) <80%, 2) Cox regression for all-cause mortality, and 3) prediction of respiratory phenotypes.</p><p><strong>Results: </strong>We trained Spiro-CLF on 940,705 volume-time curves from 352,684 UKB participants with 2-3 spirometry efforts per individual (66.7% with 3 efforts) and at least one QC-passing spirometry effort. Of all spirometry efforts, 61.6% were suboptimal (37.5% submaximal and 24.1% QC-failing). In the UK Biobank, Spiro-CLF using QC-failing and submaximal efforts predicted FEV1/FVC < 0.7 with an Area under the Receiver Operating Characteristics (AUROC) of 0.956, mortality with a concordance index of 0.647, and asthma with a 9-42% improvement versus baseline models. In COPDGene (n=10,110 participants), adding QC-passing, submaximal efforts did not improve the prediction of lung function or mortality; however, Spiro-CLF representations predicted asthma and respiratory phenotypes (joint test P ≤ 2 × 10-3).</p><p><strong>Conclusions and relevance: </strong>A machine-learning model can predict respiratory phenotypes using suboptimal spirometry; results from all spirometry efforts may contain valuable data. Additional studies are required to determine performance and utility in specific clinical scenarios.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593687","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":"Polygenic score for C-reactive protein is associated with accelerated cortical thinning and increased psychopathology in adolescents: a population-based longitudinal cohort study.","authors":"Haixia Zheng, Jonathan Savitz, Ebrahim Haroon, Jonathan Ahern, Robert Loughnan, Firas Nabber, Bohan Xu, Katherine Forthman, Robin Aupperle, Leanne Williams, Martin Paulus, Chun Chieh Fan, Wesley Thompson","doi":"10.21203/rs.3.rs-6823364/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6823364/v1","url":null,"abstract":"<p><p>Adolescence is a critical neurodevelopmental window characterized by rapid cortical thinning, during which vulnerability to psychiatric disorders significantly increases. Although increased rates of cortical thinning have been associated with adverse mental health outcomes, the biological mechanisms underlying atypical neurodevelopment remain unclear. This study investigates whether genetic predisposition to systemic inflammation, assessed via polygenic scores for C-reactive protein (PGS_CRP), influences cortical thinning trajectories and psychopathology risk in adolescents. Using longitudinal data from the Adolescent Brain Cognitive Development (ABCD) Study (baseline n=11,214; follow-up n=7,823), we found that higher genetic susceptibility to inflammation was associated with accelerated cortical thinning, particularly in medial temporal and insular regions (β = -0.013 ~ -0.018, p.FDR < 0.05), and increased externalizing psychopathology symptoms (β = 0.167, p.FDR < 0.05). Early-life infections independently predicted greater depressive and externalizing symptoms (β = 0.511 ~ 0.608, p.FDR < 0.05) but did not interact significantly with genetic predisposition. Structural equation modeling revealed that cortical thinning partially mediated the relationship between genetic inflammation risk and externalizing symptoms. Moreover, neurobiological annotation showed regional overlaps between inflammation-linked cortical thinning and neurotransmitter receptor gradients involving serotonin, GABA, cannabinoid, and glutamate systems. These findings provide evidence for genetic predisposition to inflammation as a factor in adolescent cortical maturation and behavioral outcomes, highlighting potential neuroimmune mechanisms underpinning vulnerability to mental health disorders during this sensitive developmental period.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593714","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 association of medical mistrust, clinical trial knowledge, and perceived clinical trial risk with willingness to participate in health research among historically marginalized individuals living in New York City.","authors":"Isabel Inez Curro, Laura C Wyatt, Victoria Foster, Yousra Yusuf, Sonia Sifuentes, Perla Chebli, Julie A Kranick, Simona C Kwon, Chau Trinh-Shevrin, Madison N LeCroy","doi":"10.21203/rs.3.rs-6699898/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6699898/v1","url":null,"abstract":"<p><p>Medical mistrust, clinical trial knowledge, and clinical trial risk impact research participation, yet are rarely studied among racial and ethnic groups. Data were from a cross-sectional survey (n = 1,788). Multinomial logistic regression models examined associations of medical mistrust, clinical trial knowledge, and clinical trial risk with willingness to participate in health research (Yes, No, Unsure) among Chinese, Korean, South Asian, Haitian, North American Latiné, South American Latiné, and Southwest Asian and North African (SWANA) NYC residents with one model per group Overall, 46.1% of participants reported willingness to participate, ranging from 35.8% (Chinese participants) to 58.7% (South Asian participants). Increased mistrust was associated with less willingness among Chinese (OR: 1.06, 95%CI: 1.00, 1.12) and South American Latiné (OR: 1.15, 95%CI: 1.01, 1.30) participants; more willingness among Haitian participants (OR: 0.87, 95%CI: 0.81, 0.94); more uncertainty among Korean (OR: 1.13, 95%CI: 1.05, 1.22), South Asian (OR: 1.07 95%CI: 1.01, 1.12), and North American Latiné (OR: 1.18, 95%CI: 1.09, 1.27) participants; and less uncertainty among Haitian (OR: 0.91, 95%CI: 0.84, 0.99) and SWANA (OR: 0.91, 95%CI:0.86, 0.97) participants. Knowledge was associated with more willingness for Haitian participants (OR: 2.77, 95%CI: 1.15, 6.65), less willingness for Chinese participants (OR: 0.55, 95%CI: 0.34, 0.88), and more uncertainty among South Asian (OR: 2.09, 95%CI: 1.07, 4.07) and SWANA (OR: 2.71, 95%CI: 1.21, 6.03) participants. Some risk and more willingness were linked for South American Latiné participants (OR: 0.14, 95%CI: 0.02, 0.85). Associations varied by group. Studying diverse groups advances equitable research representation.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236929/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593726","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 pancreatic β-cell incretin response is modulated by mitochondrial transaminase GPT2.","authors":"Sabyasachi Sen, Andrea Rozo, Matthew Haemmerle, Jeffrey Roman, Andrea Scota, Xiaodun Yang, Christine Juliana, Sarah Tersey, Eric Morrow, Nicolai Doliba, Doris Stoffers","doi":"10.21203/rs.3.rs-6950998/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-6950998/v1","url":null,"abstract":"<p><p>The effect of the incretin hormones GLP-1 and GIP to promote pancreatic β-cell function is exploited by an expansive menu of incretin mimetics for the treatment of type 2 diabetes (T2D); however, the incretin effect is well known to diminish as T2D progresses. Here, we show that silencing of stress-inducible mitochondrial protein glutamic pyruvate transaminase 2 (GPT2) enhances the β-cell incretin response. Mice with β-cell specific Gpt2 deficiency (Gpt2βKO) have improved oral glucose tolerance and insulin secretion due to enhanced β-cell incretin sensitivity. In the diet induced obesity (DIO) model of T2D, Gpt2βKO mice maintained lower non-fasting glucose and improved oral glucose tolerance and insulin secretion. The effect of GLP-1 receptor (GLP-1R) agonism on β-cell survival was also enhanced in Gpt2βKO islets. GPT2 was markedly induced in human islets from donors with type 2 diabetes and in non-diabetic donor islets exposed to glucolipotoxicity. Silencing GPT2 in human β-cells enhanced β-cell incretin sensitivity and survival, and it reversed incretin unresponsiveness in T2D islets. These findings raise GPT2 as a therapeutic target to mitigate β-cell dysfunction in T2D.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593728","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":"Cerebellar pathology contributes to neurodevelopmental deficits in spinal muscular atrophy.","authors":"Florian Gerstner, Sandra Wittig, Christian Menedo, Sayan Ruwald, Maria J Carlini, Adela Vankova, Leonie Sowoidnich, Gerardo Martín-López, Vanessa Dreilich, Andrea Alonso Collado, John G Pagiazitis, Oumayma Aousji, Chloe Grzyb, Amy Smith, Mu Yang, Francesco Roselli, George Z Mentis, Charlotte J Sumner, Livio Pellizzoni, Christian M Simon","doi":"10.21203/rs.3.rs-6819992/v2","DOIUrl":"10.21203/rs.3.rs-6819992/v2","url":null,"abstract":"<p><p>Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by ubiquitous SMN deficiency and loss of motor neurons. The persistence of motor and communication impairments, together with emerging cognitive and social deficits in severe Type I SMA patients treated early with SMN-restoring therapies, suggests a broader dysfunction involving neural circuits of the brain. To explore the potential supraspinal contributions to these emerging phenotypes, we investigated the cerebellum, a brain region critical for both motor and cognitive behaviors. Here, we identify cerebellar pathology in both <i>post-mortem</i> tissue from Type I SMA patients and a severe mouse model, which is characterized by lobule-specific Purkinje cell (PC) death driven by cell-autonomous, non-apoptotic p53-dependent mechanisms. Loss and dysfunction of excitatory parallel fiber synapses onto PC further contribute to cerebellar circuit disruption and altered PC firing. Furthermore, we identified impaired ultrasonic vocalization (USV) in a severe SMA mouse model-a proxy for early-developing social communication skills that depend on cerebellar function. Cell-specific rescue experiments demonstrate that intrinsic cerebellar pathology contributes to motor and social communication impairments independently of spinal motor circuit abnormalities. Together, these findings establish cerebellar dysfunction as a pathogenic driver of motor and social deficits, providing a link between brain involvement and the emerging neurodevelopmental phenotypes of SMA.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532604","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":"A Next-Generation Human Lymphatic Filariasis Vaccine Candidate, r<i>Bm</i>HAXT, for Clinical Development.","authors":"Nithila Saravanan, Sean Gray, Jennifer Davis, Conrad M Puff-Carter, Vishal Khatri, Nikhil Chauhan, Darrick Carter, Ramaswamy Kalyanasundaram","doi":"10.21203/rs.3.rs-6572437/v1","DOIUrl":"10.21203/rs.3.rs-6572437/v1","url":null,"abstract":"<p><p>This study was conducted to yield a robust and scalable manufacturing process for a candidate vaccine for human lymphatic filariasis (LF) - a tropical parasitic infection transmitted by mosquitoes. In previous studies, we demonstrated that removing an affinity purification tag from the fusion protein did not affect immunogenicity or vaccine efficacy. During scaled-up production of r<i>Bm</i>HAXT, we noticed that significant amounts of the antigen aggregated, resulting in the loss of purified vaccine antigens. Thus, this project aimed to create new r<i>Bm</i>HAXT forms more suitable for industrial-scale production while maintaining robust protection. We generated three different variants: one with all the cysteinyl residues mutated to serinyl residues (delta-Cys), a second one with a flexible glycine-serine linker inserted between each of the component antigens (GS), and finally, a third variant with a combination of both the cysteine deletion and the addition of linkers (delta-Cys GS). We then evaluated the immunogenicity and efficacy of each variant in a mouse model. We demonstrated that the delta-Cys mutant retained immunogenicity and vaccine efficacy similar to the parent tag-free r<i>Bm</i>HAXT protein. We also evaluated the proteins in an accelerated stability study at five (5) different temperatures (-80°C, -20°C, 4°C, 25°C, and 40°C). We concluded that all preparations were stable at 4°C, and the delta-Cys variant was stable even at 25°C up to the completion of the study (6 weeks). In addition to improved stability, the delta-Cys protein exhibited reduced aggregation and equivalent potency in mice and, therefore, is an optimal candidate for progression to cGMP manufacturing and human clinical trials as a vaccine for lymphatic filariasis.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532581","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":"Determinants of Adherence and Satisfaction in Parkinson's Disease Exercise Programs: A Comparison of 16-Months of Adapted Tango vs. Supervised Walking.","authors":"Haneul Kim, Forouzan Rafiei, Meghan E Kazanski, Amir Hossein Nekouei, Madeleine E Hackney","doi":"10.21203/rs.3.rs-6908014/v1","DOIUrl":"10.21203/rs.3.rs-6908014/v1","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Moderate aerobic activities are promising treatment modalities for mitigating motor and cognitive deficits associated with Parkinson's disease (PD). This study aims to characterize the association of PD-specific characteristics with compliance and satisfaction to the moderate-aerobic activity. Thirty-six participants with PD engaged in either adapted Argentine tango (TANGO) (n=20) or supervised walking (WALK) (n=16) classes for 16 months. Participants attended between59 to 76 classes to be fully compliant. Metrics associated with PD characteristics, including frequency and duration of dyskinesia and OFF state, freezing of gait status (FOG), years since PD diagnosis, Hoehn-Yahr Stage and motor and cognitive function, were collected. Linear regression models were used to examine the association of the PD metrics with treatment compliance (number of completed classes) and self-reported program satisfaction composites. Program engagement analysis revealed a wide attendance distribution (range: 1-76 sessions; mean ± SD: 39.1 ± 26.0 sessions) over the 16-month intervention period. Overall participant satisfaction was favorable (mean ± SD: 4.0 ± 0.8 on a 5-point scale) across motor-cognitive, emotional, and psychosocial domains. Multivariate analysis identified significant negative correlations between dyskinesia metrics and program compliance, with both percentage of waking time with dyskinesia (β = -0.381, R&lt;sup&gt;2&lt;/sup&gt; = 0.145, p = 0.055) and total dyskinesia duration (β = -0.377, R&lt;sup&gt;2&lt;/sup&gt; = 0.142, p =0.058) emerging as key predictors. Program compliance demonstrated a positive association with participant satisfaction (β = 0.378, R&lt;sup&gt;2&lt;/sup&gt; = 0.143, p = 0.063). Hierarchical regression analysis of clinical predictors revealed cognitive function (MoCA scores) as the strongest predictor of participant satisfaction (β = 0.396, R&lt;sup&gt;2&lt;/sup&gt; = 0.157, p = 0.050), followed by non-motor daily living scores (UPDRS Part I; β = -0.343, R&lt;sup&gt;2&lt;/sup&gt; = 0.118, p = 0.093) and dyskinesia duration (β = -0.346, R&lt;sup&gt;2&lt;/sup&gt; = 0.120, p = 0.134). Secondary outcome measures including OFF-time duration, MDS-UPDRS total score, and disease duration showed minimal predictive value (all R&lt;sup&gt;2&lt;/sup&gt; &lt; 0.10, p &gt; 0.15). Notably, FOG demonstrated no significant impact on either program satisfaction (R&lt;sup&gt;2&lt;/sup&gt; = 0.022, p = 0.514) or attendance patterns (FOG-positive: 59.1 ± 21.4 vs. FOG-negative: 60.4 ± 18.9 sessions; t-test, p = 0.79). This study demonstrates that PD-related motor and cognitive characteristics significantly influence engagement in moderate-intensity aerobic interventions. While overall satisfaction was high, dyskinesia frequency and duration were associated with reduced compliance, indicating key barriers to participation. In contrast, cognitive functions emerged as the strongest predictor of satisfaction. However, FOG did not show any effect on program compliance or satisfaction. These findings highlight the need for tailored exercise prog","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532610","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":"Boosting AlphaFold Protein Tertiary Structure Prediction through MSA Engineering and Extensive Model Sampling and Ranking in CASP16.","authors":"Jian Liu, Pawan Neupane, Jianlin Cheng","doi":"10.21203/rs.3.rs-6845168/v1","DOIUrl":"10.21203/rs.3.rs-6845168/v1","url":null,"abstract":"<p><p>AlphaFold2 and AlphaFold3 have revolutionized protein structure prediction by enabling high-accuracy tertiary structure predictions for most single-chain proteins (monomers). However, obtaining high-quality predictions for some hard protein targets with shallow or noisy multiple sequence alignments (MSAs) and complicated multi-domain architectures remains challenging. Here, we present MULTICOM4, an integrative protein structure prediction system that uses diverse MSA generation, large-scale model sampling, and an ensemble model quality assessment (QA) strategy of combining individual QA methods to improve model generation and ranking of AlphaFold2 and AlphaFold3. In the 16th Critical Assessment of Techniques for Protein Structure Prediction (CASP16), our predictors built on MULTICOM4 ranked among the top performers out of 120 predictors in tertiary structure prediction and outperformed a standard AlphaFold3 predictor. The average TM-score of our best performing predictor MULTCOM's top-1 prediction for 84 CASP16 domain is 0.902. It achieved high accuracy (TM-score > 0.9) for 73.8% of the 84 domains and correct fold predictions (TM-score > 0.5) for 97.6% domains in terms of top-1 prediction. In terms of best-of-top-5 prediction, it predicted correct folds for all the domains. The results show that MSA engineering through the use of different protein sequence databases, alignment tools, and domain segmentation as well as extensive model sampling are the key to generate accurate and correct structural models. Additionally, using multiple complementary QA methods and model clustering can improve the robustness and reliability of model ranking.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532592","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}