Pub Date : 2025-08-08DOI: 10.21203/rs.3.rs-2407778/v2
Rita Sianga-Mete, Penelope Hartnady, Wimbai Caroline Mandikumba, Kayleigh Rutherford, Christopher Brian Currin, Florence Phelanyane, Sabina Stefan, Steven Weaver, Sergei L Kosakovsky Pond, Darren P Martin
Most phylogenetic trees are inferred using time-reversible evolutionary models that assume that the relative rates of substitution for any given pair of nucleotides are the same regardless of the direction of the substitutions. However, there is no reason to assume that the underlying biochemical mutational processes that cause substitutions are similarly symmetrical. We consider two non-reversible nucleotide substitution models: (1) a 6-rate non-reversible model (NREV6) that is applicable to analyzing mutational processes in double-stranded genomes in that complementary substitutions occur at identical rates; and (2) a 12-rate non-reversible model (NREV12) that is applicable to analyzing mutational processes in single-stranded (ss) genomes in that all substitution types are free to occur at different rates. Using likelihood ratio and Akaike Information Criterion-based model tests, we show that, surprisingly, NREV12 provided a significantly better fit than the General Time Reversible (GTR) and NREV6 models to 21/31 dsRNA and 20/30 dsDNA datasets. As expected, however, NREV12 provided a significantly better fit to 24/33 ssDNA and 40/47 ssRNA datasets. We tested how non-reversibility impacts the accuracy with which phylogenetic trees are inferred. As simulated degrees of non-reversibility (DNR) increased, the tree topology inferences using both NREV12 and GTR became more accurate, whereas inferred tree branch lengths became less accurate. We conclude that while non-reversible models should be helpful in the analysis of mutational processes in most virus species, there is no pressing need to use these models for routine phylogenetic inference.
{"title":"Viral genome sequence datasets display pervasive evidence of strand-specific substitution biases that are best described using non-reversible nucleotide substitution models.","authors":"Rita Sianga-Mete, Penelope Hartnady, Wimbai Caroline Mandikumba, Kayleigh Rutherford, Christopher Brian Currin, Florence Phelanyane, Sabina Stefan, Steven Weaver, Sergei L Kosakovsky Pond, Darren P Martin","doi":"10.21203/rs.3.rs-2407778/v2","DOIUrl":"10.21203/rs.3.rs-2407778/v2","url":null,"abstract":"<p><p>Most phylogenetic trees are inferred using time-reversible evolutionary models that assume that the relative rates of substitution for any given pair of nucleotides are the same regardless of the direction of the substitutions. However, there is no reason to assume that the underlying biochemical mutational processes that cause substitutions are similarly symmetrical. We consider two non-reversible nucleotide substitution models: (1) a 6-rate non-reversible model (NREV6) that is applicable to analyzing mutational processes in double-stranded genomes in that complementary substitutions occur at identical rates; and (2) a 12-rate non-reversible model (NREV12) that is applicable to analyzing mutational processes in single-stranded (ss) genomes in that all substitution types are free to occur at different rates. Using likelihood ratio and Akaike Information Criterion-based model tests, we show that, surprisingly, NREV12 provided a significantly better fit than the General Time Reversible (GTR) and NREV6 models to 21/31 dsRNA and 20/30 dsDNA datasets. As expected, however, NREV12 provided a significantly better fit to 24/33 ssDNA and 40/47 ssRNA datasets. We tested how non-reversibility impacts the accuracy with which phylogenetic trees are inferred. As simulated degrees of non-reversibility (DNR) increased, the tree topology inferences using both NREV12 and GTR became more accurate, whereas inferred tree branch lengths became less accurate. We conclude that while non-reversible models should be helpful in the analysis of mutational processes in most virus species, there is no pressing need to use these models for routine phylogenetic inference.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9810213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10005642","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}
Pub Date : 2024-10-23DOI: 10.21203/rs.3.rs-3150186/v2
Shan Qi, Abhay Kumar, Shuang Chen, Shuo Zhou, Manish Parihar, Carmen Villalobos, Navom Gupta, Siu-Hong Chan, Manjeet K Rao, Stanton F McHardy, Shozeb Haider, Yogesh K Gupta
The nuclear METTL3-METTL14 transfers a methyl group from SAM to convert the N6 of adenosine (A) in RNA to m6A and in ssDNA to 6mA. m6A marks are prevalent in eukaryotic mRNAs and lncRNAs and modulate their stability and fate in a context-dependent manner. The cytoplasmic METTL3 can act as a m6A reader. However, the precise mechanism during m6A writing, reading, or sensing is unclear. Here, we present a ~2.5 Å structure of the methyltransferase core of human METTL3-METTL14 in complex with the reaction product mimic, N6 -methyladenosine monophosphate (m6A), representing a state post-catalysis but before the release of m6A. m6A occupies an evolutionarily conserved RNA-binding pocket ~16 Å away from the SAM pocket that also frequently mutates in cancer. We propose a two-step model of swiveling of target A upon conversion to m6A and sensing its methylation status by this pocket, enabling it to actuate enzymes' switch from writer to an m6A-sensor. Cancer-associated mutations show impaired RNA binding dynamics, de-stacking, and defective m6A writing and sensing.
{"title":"Structure of METTL3-METTL14 with an m6A nucleotide reveals insights into m6A conversion and sensing.","authors":"Shan Qi, Abhay Kumar, Shuang Chen, Shuo Zhou, Manish Parihar, Carmen Villalobos, Navom Gupta, Siu-Hong Chan, Manjeet K Rao, Stanton F McHardy, Shozeb Haider, Yogesh K Gupta","doi":"10.21203/rs.3.rs-3150186/v2","DOIUrl":"10.21203/rs.3.rs-3150186/v2","url":null,"abstract":"<p><p>The nuclear METTL3-METTL14 transfers a methyl group from SAM to convert the <i>N</i> <sup><i>6</i></sup> of adenosine (A) in RNA to m<sup>6</sup>A and in ssDNA to 6mA. m<sup>6</sup>A marks are prevalent in eukaryotic mRNAs and lncRNAs and modulate their stability and fate in a context-dependent manner. The cytoplasmic METTL3 can act as a m<sup>6</sup>A reader. However, the precise mechanism during m6A writing, reading, or sensing is unclear. Here, we present a ~2.5 Å structure of the methyltransferase core of human METTL3-METTL14 in complex with the reaction product mimic, <i>N</i> <sup><i>6</i></sup> -methyladenosine monophosphate (m<sup>6</sup>A), representing a state post-catalysis but before the release of m<sup>6</sup>A. m<sup>6</sup>A occupies an evolutionarily conserved RNA-binding pocket ~16 Å away from the SAM pocket that also frequently mutates in cancer. We propose a two-step model of <i>swiveling</i> of target A upon conversion to m<sup>6</sup>A and <i>sensing</i> its methylation status by this pocket, enabling it to actuate enzymes' switch from writer to an m<sup>6</sup>A-sensor. Cancer-associated mutations show impaired RNA binding dynamics, de-stacking, and defective m<sup>6</sup>A writing and sensing.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10441475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10491988","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}
Pub Date : 2024-08-20DOI: 10.21203/rs.3.rs-3243336/v2
Kaitlyn Fessler, Jiaqi Zhang, Avinaash K Sandhu, Yinan Hui, Aakanksha R Kapoor, Samuel K Ayeh, Styliani Karanika, Petros C Karakousis, Richard B Markham, James T Gordy
Previous studies in the B16F10 mouse melanoma model have demonstrated that combining a DNA vaccine comprised of regions of gp100 and tyrosinase-related protein 2 fused to Macrophage-inflammatory protein 3-alpha (MIP3α) with recombinant Interferon alpha (IFN) and 5-Aza-2'-Deoxycytidine (5Aza) treatments resulted in significantly greater anti-tumor activity and immunogenicity in the tumor microenvironment (TME). This brief report details that the combination of vaccine with treatments IFN and 5Aza results in both the upregulation of genes expressing CD11c-interacting proteins and an increase in the TME of a distinct CD11c+ CD8+ T cell population. This cell population correlates with tumor size, is primarily comprised of effector or effector memory T cells, and has a more robust response to ex vivo stimulation as compared to CD11c- CD8+ T cells as measured by surface activation markers 4-1BB (CD137) and KLRG1 (Killer cell lectin-like receptor G1) and intracellular IFNγ production. In conclusion, this combination therapy results in greater presence of highly active effector CD8+ T-cells expressing CD11c in the TME that correlate with and are likely primary contributors to treatment efficacy.
{"title":"Combination of a MIP3α-antigen fusion therapeutic DNA vaccine with treatments of IFNα and 5-Aza-2'Deoxycytidine enhances activated effector CD8+ T cells expressing CD11c in the B16F10 melanoma model.","authors":"Kaitlyn Fessler, Jiaqi Zhang, Avinaash K Sandhu, Yinan Hui, Aakanksha R Kapoor, Samuel K Ayeh, Styliani Karanika, Petros C Karakousis, Richard B Markham, James T Gordy","doi":"10.21203/rs.3.rs-3243336/v2","DOIUrl":"10.21203/rs.3.rs-3243336/v2","url":null,"abstract":"<p><p>Previous studies in the B16F10 mouse melanoma model have demonstrated that combining a DNA vaccine comprised of regions of gp100 and tyrosinase-related protein 2 fused to Macrophage-inflammatory protein 3-alpha (MIP3α) with recombinant Interferon alpha (IFN) and 5-Aza-2'-Deoxycytidine (5Aza) treatments resulted in significantly greater anti-tumor activity and immunogenicity in the tumor microenvironment (TME). This brief report details that the combination of vaccine with treatments IFN and 5Aza results in both the upregulation of genes expressing CD11c-interacting proteins and an increase in the TME of a distinct CD11c+ CD8+ T cell population. This cell population correlates with tumor size, is primarily comprised of effector or effector memory T cells, and has a more robust response to ex vivo stimulation as compared to CD11c- CD8+ T cells as measured by surface activation markers 4-1BB (CD137) and KLRG1 (Killer cell lectin-like receptor G1) and intracellular IFNγ production. In conclusion, this combination therapy results in greater presence of highly active effector CD8+ T-cells expressing CD11c in the TME that correlate with and are likely primary contributors to treatment efficacy.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10462250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10165883","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}
Pub Date : 2024-06-26DOI: 10.21203/rs.3.rs-3251741/v5
Wenyu Tu, Samuel R Cramer, Nanyin Zhang
Resting-state brain networks (RSNs) have been widely applied in health and disease, but the interpretation of RSNs in terms of the underlying neural activity is unclear. To address this fundamental question, we conducted simultaneous recordings of whole-brain resting-state functional magnetic resonance imaging (rsfMRI) and electrophysiology signals in two separate brain regions of rats. Our data reveal that for both recording sites, spatial maps derived from band-specific local field potential (LFP) power can account for up to 90% of the spatial variability in RSNs derived from rsfMRI signals. Surprisingly, the time series of LFP band power can only explain to a maximum of 35% of the temporal variance of the local rsfMRI time course from the same site. In addition, regressing out time series of LFP power from rsfMRI signals has minimal impact on the spatial patterns of rsfMRI-based RSNs. This disparity in the spatial and temporal relationships between resting-state electrophysiology and rsfMRI signals suggests that electrophysiological activity alone does not fully explain the effects observed in the rsfMRI signal, implying the existence of an rsfMRI component contributed by "electrophysiology-invisible" signals. These findings offer a novel perspective on our understanding of RSN interpretation.
{"title":"Disparity in temporal and spatial relationships between resting-state electrophysiological and fMRI signals.","authors":"Wenyu Tu, Samuel R Cramer, Nanyin Zhang","doi":"10.21203/rs.3.rs-3251741/v5","DOIUrl":"10.21203/rs.3.rs-3251741/v5","url":null,"abstract":"<p><p>Resting-state brain networks (RSNs) have been widely applied in health and disease, but the interpretation of RSNs in terms of the underlying neural activity is unclear. To address this fundamental question, we conducted simultaneous recordings of whole-brain resting-state functional magnetic resonance imaging (rsfMRI) and electrophysiology signals in two separate brain regions of rats. Our data reveal that for both recording sites, spatial maps derived from band-specific local field potential (LFP) power can account for up to 90% of the spatial variability in RSNs derived from rsfMRI signals. Surprisingly, the time series of LFP band power can only explain to a maximum of 35% of the temporal variance of the local rsfMRI time course from the same site. In addition, regressing out time series of LFP power from rsfMRI signals has minimal impact on the spatial patterns of rsfMRI-based RSNs. This disparity in the spatial and temporal relationships between resting-state electrophysiology and rsfMRI signals suggests that electrophysiological activity alone does not fully explain the effects observed in the rsfMRI signal, implying the existence of an rsfMRI component contributed by \"electrophysiology-invisible\" signals. These findings offer a novel perspective on our understanding of RSN interpretation.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10462190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10168633","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}
Pub Date : 2024-05-10DOI: 10.21203/rs.3.rs-4344678/v1
P. Afulani, Monica Getahun, L. Ongeri, Raymond A Aborigo, J. Kinyua, Beryl A Ogolla, Jaffer Okiring, Ali Moro, Iscar Oluoch, Maxwell Dalaba, Osamuede Odiase, Jerry Nutor, Wendy Berry Mendes, Dilys Walker, Torsten B. Neilands
Abstract Background Poor person-centered maternal care (PCMC) contributes to high maternal mortality and morbidity, directly and indirectly, through lack of, delayed, inadequate, unnecessary, or harmful care. While evidence on poor PCMC prevalence, as well as inequities, expanded in the last decade, there is still a significant gap in evidence-based interventions to address PCMC. We describe the protocol for a trial to test the effectiveness of the “Caring for Providers to Improve Patient Experience” (CPIPE) intervention, which includes five strategies for provider behavior change, targeting provider stress and bias as intermediate factors to improve PCMC and to address inequities. Methods The trial will assess the effect of CPIPE on PCMC, as well as on intermediate and distal outcomes, using a two-arm cluster randomized controlled trial in 40 health facilities in Migori and Homa Bay Counties in Kenya and Upper East and Northeast Regions in Ghana. Twenty facilities in each country will be randomized to 10 intervention and 10 control sites. The primary intervention targets are all healthcare workers who provide maternal health services. The intervention impact will also be assessed first among providers, and then among women who give birth in health facilities. The primary outcome is PCMC measured with the PCMC scale, via multiple cross-sectional surveys of mothers who gave birth in the preceding 12 weeks in study facilities at baseline (prior to the intervention), midline (6 months after intervention start), and endline (12 months post-baseline) (N = 2000 across both countries at each time point). Additionally, 400 providers in the study facilities across both countries will be followed longitudinally at baseline, midline, and endline, to assess intermediate outcomes. The trial incorporates a mixed-methods design; survey data alongside in-depth interviews (IDIs) with healthcare facility leaders, providers, and mothers to qualitatively explore factors influencing the outcomes. Finally, we will collect process and cost data to assess intervention fidelity and cost-effectiveness. Discussion This trial will be the first to rigorously assess an intervention to improve PCMC that addresses both provider stress and bias and will advance the evidence base for interventions to improve PCMC and contribute to equity in maternal and neonatal health.
{"title":"A cluster randomized controlled trial to assess the impact of the ‘Caring for Providers to Improve Patient Experience’ intervention on person-centered maternity care in Kenya and Ghana: Study Protocol","authors":"P. Afulani, Monica Getahun, L. Ongeri, Raymond A Aborigo, J. Kinyua, Beryl A Ogolla, Jaffer Okiring, Ali Moro, Iscar Oluoch, Maxwell Dalaba, Osamuede Odiase, Jerry Nutor, Wendy Berry Mendes, Dilys Walker, Torsten B. Neilands","doi":"10.21203/rs.3.rs-4344678/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4344678/v1","url":null,"abstract":"Abstract Background Poor person-centered maternal care (PCMC) contributes to high maternal mortality and morbidity, directly and indirectly, through lack of, delayed, inadequate, unnecessary, or harmful care. While evidence on poor PCMC prevalence, as well as inequities, expanded in the last decade, there is still a significant gap in evidence-based interventions to address PCMC. We describe the protocol for a trial to test the effectiveness of the “Caring for Providers to Improve Patient Experience” (CPIPE) intervention, which includes five strategies for provider behavior change, targeting provider stress and bias as intermediate factors to improve PCMC and to address inequities. Methods The trial will assess the effect of CPIPE on PCMC, as well as on intermediate and distal outcomes, using a two-arm cluster randomized controlled trial in 40 health facilities in Migori and Homa Bay Counties in Kenya and Upper East and Northeast Regions in Ghana. Twenty facilities in each country will be randomized to 10 intervention and 10 control sites. The primary intervention targets are all healthcare workers who provide maternal health services. The intervention impact will also be assessed first among providers, and then among women who give birth in health facilities. The primary outcome is PCMC measured with the PCMC scale, via multiple cross-sectional surveys of mothers who gave birth in the preceding 12 weeks in study facilities at baseline (prior to the intervention), midline (6 months after intervention start), and endline (12 months post-baseline) (N = 2000 across both countries at each time point). Additionally, 400 providers in the study facilities across both countries will be followed longitudinally at baseline, midline, and endline, to assess intermediate outcomes. The trial incorporates a mixed-methods design; survey data alongside in-depth interviews (IDIs) with healthcare facility leaders, providers, and mothers to qualitatively explore factors influencing the outcomes. Finally, we will collect process and cost data to assess intervention fidelity and cost-effectiveness. Discussion This trial will be the first to rigorously assess an intervention to improve PCMC that addresses both provider stress and bias and will advance the evidence base for interventions to improve PCMC and contribute to equity in maternal and neonatal health.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":" 32","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140993730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-10DOI: 10.21203/rs.3.rs-4355589/v1
Hanmin Guo, Alexander Eckehart Urban, Wing Hung Wong
Abstract Rare variants, comprising a vast majority of human genetic variations, are likely to have more deleterious impact on human diseases compared to common variants. Here we present carrier statistic, a statistical framework to prioritize disease-related rare variants by integrating gene expression data. By quantifying the impact of rare variants on gene expression, carrier statistic can prioritize those rare variants that have large functional consequence in the diseased patients. Through simulation studies and analyzing real multi-omics dataset, we demonstrated that carrier statistic is applicable in studies with limited sample size (a few hundreds) and achieves substantially higher sensitivity than existing rare variants association methods. Application to Alzheimer's disease reveals 16 rare variants within 15 genes with extreme carrier statistics. We also found strong excess of rare variants among the top prioritized genes in diseased patients compared to that in healthy individuals. The carrier statistic method can be applied to various rare variant types and is adaptable to other omics data modalities, offering a powerful tool for investigating the molecular mechanisms underlying complex diseases.
{"title":"Prioritizing disease-related rare variants by integrating gene expression data","authors":"Hanmin Guo, Alexander Eckehart Urban, Wing Hung Wong","doi":"10.21203/rs.3.rs-4355589/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4355589/v1","url":null,"abstract":"Abstract Rare variants, comprising a vast majority of human genetic variations, are likely to have more deleterious impact on human diseases compared to common variants. Here we present carrier statistic, a statistical framework to prioritize disease-related rare variants by integrating gene expression data. By quantifying the impact of rare variants on gene expression, carrier statistic can prioritize those rare variants that have large functional consequence in the diseased patients. Through simulation studies and analyzing real multi-omics dataset, we demonstrated that carrier statistic is applicable in studies with limited sample size (a few hundreds) and achieves substantially higher sensitivity than existing rare variants association methods. Application to Alzheimer's disease reveals 16 rare variants within 15 genes with extreme carrier statistics. We also found strong excess of rare variants among the top prioritized genes in diseased patients compared to that in healthy individuals. The carrier statistic method can be applied to various rare variant types and is adaptable to other omics data modalities, offering a powerful tool for investigating the molecular mechanisms underlying complex diseases.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":" 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140992746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-10DOI: 10.21203/rs.3.rs-4356493/v1
Nicholas Hertz, Randall Chin, Rishi Rakhit, D. Ditsworth, Chengzhong Wang, Johan Bartholomeus, Song Liu, Akash Mody, Alex Laihsu, A. Eastes, Chao Tai, Roy Kim, Jessica Li, Saurabh Khasnavis, Victoria Rafalski, Donald Heerendeen, Virginia Garda, Jennie Phung, Daniel de Roulet, A. Ordureau, J. W. Harper, Shawn Johnstone, Jan Stöhr
Abstract PINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinson’s disease (PD) and Parkinsonism, respectively. We demonstrate that pathological α-synuclein deposition, the hallmark pathology of idiopathic PD, induces mitochondrial dysfunction, and impairs mitophagy as evidenced by the accumulation of the PINK1 substrate pS65-Ubiquitin (pUb). We discovered MTK458, a brain penetrant small molecule that binds to PINK1 and stabilizes its active complex, resulting in increased rates of mitophagy. Treatment with MTK458 mediates clearance of accumulated pUb and α-synuclein pathology in α-synuclein pathology models in vitro and in vivo. Our findings from preclinical PD models suggest that pharmacological activation of PINK1 warrants further clinical evaluation as a therapeutic strategy for disease modification in PD.
{"title":"Pharmacological PINK1 activation ameliorates Pathology in Parkinson’s Disease models","authors":"Nicholas Hertz, Randall Chin, Rishi Rakhit, D. Ditsworth, Chengzhong Wang, Johan Bartholomeus, Song Liu, Akash Mody, Alex Laihsu, A. Eastes, Chao Tai, Roy Kim, Jessica Li, Saurabh Khasnavis, Victoria Rafalski, Donald Heerendeen, Virginia Garda, Jennie Phung, Daniel de Roulet, A. Ordureau, J. W. Harper, Shawn Johnstone, Jan Stöhr","doi":"10.21203/rs.3.rs-4356493/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4356493/v1","url":null,"abstract":"Abstract PINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinson’s disease (PD) and Parkinsonism, respectively. We demonstrate that pathological α-synuclein deposition, the hallmark pathology of idiopathic PD, induces mitochondrial dysfunction, and impairs mitophagy as evidenced by the accumulation of the PINK1 substrate pS65-Ubiquitin (pUb). We discovered MTK458, a brain penetrant small molecule that binds to PINK1 and stabilizes its active complex, resulting in increased rates of mitophagy. Treatment with MTK458 mediates clearance of accumulated pUb and α-synuclein pathology in α-synuclein pathology models in vitro and in vivo. Our findings from preclinical PD models suggest that pharmacological activation of PINK1 warrants further clinical evaluation as a therapeutic strategy for disease modification in PD.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":" 83","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140991079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-10DOI: 10.21203/rs.3.rs-4356062/v1
Brady E Hanson, Joshua F Lee, R. Garten, Zachary Barrett O'Keefe, G. Layec, Bradley A Ruple, D. Wray, Russell S. Richardson, J. Trinity
Abstract Heightened muscle sympathetic nerve activity (MSNA) contributes to impaired vasodilatory capacity and vascular dysfunction associated with aging and cardiovascular disease. The contribution of elevated MSNA to the vasodilatory response during passive leg movement (PLM) has not been adequately addressed. This study sought to test the hypothesis that elevated MSNA diminishes the vasodilatory response to PLM in healthy young males (n = 11, 25 ± 2 year). Post exercise circulatory occlusion (PECO) following 2 min of isometric handgrip (HG) exercise performed at 25% (ExPECO 25%) and 40% (ExPECO 40%) of maximum voluntary contraction was used to incrementally engage the metaboreceptors and augment MSNA. Control trials were performed without PECO (ExCON 25% and ExCON 40%) to account for changes due to HG exercise. PLM was performed 2 min after the cessation of exercise and central and peripheral hemodynamics were assessed. MSNA was directly recorded by microneurography in the peroneal nerve (n = 8). Measures of MSNA (i.e., burst incidences) increased during ExPECO 25% (+ 15 ± 5 burst/100 bpm) and ExPECO 40% (+ 22 ± 4 burst/100 bpm) and returned to pre-HG levels during ExCON trials. Vasodilation, assessed by the change in leg vascular conductance during PLM, was reduced by 16% and 44% during ExPECO 25% and ExPECO 40%, respectively. These findings indicate that elevated MSNA attenuates the vasodilatory response to PLM and that the magnitude of reduction in vasodilation during PLM is graded in relation to the degree of sympathoexcitation.
{"title":"Acute sympathetic activation blunts the hyperemic and vasodilatory response to passive leg movement","authors":"Brady E Hanson, Joshua F Lee, R. Garten, Zachary Barrett O'Keefe, G. Layec, Bradley A Ruple, D. Wray, Russell S. Richardson, J. Trinity","doi":"10.21203/rs.3.rs-4356062/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4356062/v1","url":null,"abstract":"Abstract Heightened muscle sympathetic nerve activity (MSNA) contributes to impaired vasodilatory capacity and vascular dysfunction associated with aging and cardiovascular disease. The contribution of elevated MSNA to the vasodilatory response during passive leg movement (PLM) has not been adequately addressed. This study sought to test the hypothesis that elevated MSNA diminishes the vasodilatory response to PLM in healthy young males (n = 11, 25 ± 2 year). Post exercise circulatory occlusion (PECO) following 2 min of isometric handgrip (HG) exercise performed at 25% (ExPECO 25%) and 40% (ExPECO 40%) of maximum voluntary contraction was used to incrementally engage the metaboreceptors and augment MSNA. Control trials were performed without PECO (ExCON 25% and ExCON 40%) to account for changes due to HG exercise. PLM was performed 2 min after the cessation of exercise and central and peripheral hemodynamics were assessed. MSNA was directly recorded by microneurography in the peroneal nerve (n = 8). Measures of MSNA (i.e., burst incidences) increased during ExPECO 25% (+ 15 ± 5 burst/100 bpm) and ExPECO 40% (+ 22 ± 4 burst/100 bpm) and returned to pre-HG levels during ExCON trials. Vasodilation, assessed by the change in leg vascular conductance during PLM, was reduced by 16% and 44% during ExPECO 25% and ExPECO 40%, respectively. These findings indicate that elevated MSNA attenuates the vasodilatory response to PLM and that the magnitude of reduction in vasodilation during PLM is graded in relation to the degree of sympathoexcitation.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":" 84","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140991027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-10DOI: 10.21203/rs.3.rs-4350156/v1
Sricharan S. Veeturi, Arshaq Saleem, Diego Ojeda, Elena Sagues, Sebastian Sanchez, Andres S Gudino, E. Levy, David Hasan, Adnan H Siddiqui, V. Tutino, Edgar A Samaniego
Abstract Background: Aneurysm wall enhancement (AWE) has the potential to be used as an imaging biomarker for the risk stratification of intracranial aneurysms (IAs). Radiomics provides a refined approach to quantify and further characterize AWE's textural features. This study examines the performance of AWE quantification combined with clinical information in detecting symptomatic IAs. Methods: Ninety patients harboring 104 IAs (29 symptomatic and 75 asymptomatic) underwent high-resolution magnetic resonance imaging (HR-MRI). The assessment of AWE was performed using two different methods: 3D-AWE mapping and composite radiomics-based score (RadScore). The dataset was split into training and testing subsets. The testing set was used to build two different nomograms using each modality of AWE assessment combined with patients’ demographic information and aneurysm morphological data. Finally, each nomogram was evaluated on an independent testing set. Results: A total of 22 radiomic features were significantly different between symptomatic and asymptomatic IAs. The 3D-AWE Mapping nomogram achieved an area under the curve (AUC) of 0.77 (63% accuracy, 78% sensitivity and 58% specificity). The RadScore nomogram exhibited a better performance, achieving an AUC of 0.83 (77% accuracy, 89% sensitivity and 73% specificity). Conclusions : Combining AWE quantification through radiomic analysis with patient demographic data in a clinical nomogram achieved high accuracy in detecting symptomatic IAs.
{"title":"Radiomics-Based Predictive Nomogram for Assessing the Risk of Intracranial Aneurysms","authors":"Sricharan S. Veeturi, Arshaq Saleem, Diego Ojeda, Elena Sagues, Sebastian Sanchez, Andres S Gudino, E. Levy, David Hasan, Adnan H Siddiqui, V. Tutino, Edgar A Samaniego","doi":"10.21203/rs.3.rs-4350156/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4350156/v1","url":null,"abstract":"Abstract Background: Aneurysm wall enhancement (AWE) has the potential to be used as an imaging biomarker for the risk stratification of intracranial aneurysms (IAs). Radiomics provides a refined approach to quantify and further characterize AWE's textural features. This study examines the performance of AWE quantification combined with clinical information in detecting symptomatic IAs. Methods: Ninety patients harboring 104 IAs (29 symptomatic and 75 asymptomatic) underwent high-resolution magnetic resonance imaging (HR-MRI). The assessment of AWE was performed using two different methods: 3D-AWE mapping and composite radiomics-based score (RadScore). The dataset was split into training and testing subsets. The testing set was used to build two different nomograms using each modality of AWE assessment combined with patients’ demographic information and aneurysm morphological data. Finally, each nomogram was evaluated on an independent testing set. Results: A total of 22 radiomic features were significantly different between symptomatic and asymptomatic IAs. The 3D-AWE Mapping nomogram achieved an area under the curve (AUC) of 0.77 (63% accuracy, 78% sensitivity and 58% specificity). The RadScore nomogram exhibited a better performance, achieving an AUC of 0.83 (77% accuracy, 89% sensitivity and 73% specificity). Conclusions : Combining AWE quantification through radiomic analysis with patient demographic data in a clinical nomogram achieved high accuracy in detecting symptomatic IAs.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":" 15","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140992044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-10DOI: 10.21203/rs.3.rs-4314004/v1
Iracema Lua, Laio Magno, Andréa Silva, P. Pinto, João Luiz Bastos, Gabriela S Jesus, Ronaldo Coelho, Maria Ichihara, M. Barreto, Carlos Teles Santos, C. Moucheraud, Pamina Gorbach, James Macinko, Luis Souza, Inês Dourado, D. Rasella
Abstract The relationships between race, education, wealth, their intersections and AIDS morbidity/mortality were analyzed in retrospective cohort of 28.3 million individuals followed for 9 years (2007-2015). Together with several sensitivity analyses, a wide range of interactions on additive and multiplicative scales were estimated. Race, education, and wealth were each strongly associated with all of the AIDS-related outcomes, and the magnitude of the associations increased as intersections were included. A significantly higher risk of illness (aRR: 3.07, 95%CI:2.67-3.53) and death (aRR: 4.96, 95%CI:3.99-6.16) from AIDS was observed at the intersection of Black race, lower educational attainment, and less wealth. A higher case-fatality rate (aRR: 1.62, 95%CI:1.18-2.21) was also seen for the same intersectional group. Historically oppressed groups lying at the intersections of race, education, and wealth, had a considerably higher risk of illness and death from AIDS. AIDS-related interventions will require the implementation of comprehensive intersectoral policies that follow an intersectionality perspective.
{"title":"The intersecting effects of race, wealth, and education on AIDS incidence, mortality, and case-fatality rate: a Brazilian cohort study of 28.3 million individuals","authors":"Iracema Lua, Laio Magno, Andréa Silva, P. Pinto, João Luiz Bastos, Gabriela S Jesus, Ronaldo Coelho, Maria Ichihara, M. Barreto, Carlos Teles Santos, C. Moucheraud, Pamina Gorbach, James Macinko, Luis Souza, Inês Dourado, D. Rasella","doi":"10.21203/rs.3.rs-4314004/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4314004/v1","url":null,"abstract":"Abstract The relationships between race, education, wealth, their intersections and AIDS morbidity/mortality were analyzed in retrospective cohort of 28.3 million individuals followed for 9 years (2007-2015). Together with several sensitivity analyses, a wide range of interactions on additive and multiplicative scales were estimated. Race, education, and wealth were each strongly associated with all of the AIDS-related outcomes, and the magnitude of the associations increased as intersections were included. A significantly higher risk of illness (aRR: 3.07, 95%CI:2.67-3.53) and death (aRR: 4.96, 95%CI:3.99-6.16) from AIDS was observed at the intersection of Black race, lower educational attainment, and less wealth. A higher case-fatality rate (aRR: 1.62, 95%CI:1.18-2.21) was also seen for the same intersectional group. Historically oppressed groups lying at the intersections of race, education, and wealth, had a considerably higher risk of illness and death from AIDS. AIDS-related interventions will require the implementation of comprehensive intersectoral policies that follow an intersectionality perspective.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":" 45","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140993490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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