Pub Date : 2024-05-06DOI: 10.21203/rs.3.rs-4277591/v1
Wayne Hicks, S. Jana, Tigist Kassa, Richard Prince, Pedro Cabrales, Joel Friedman, A. Alayash
Abstract Blood storage lesion induces cytosolic and membrane changes driven in part by hemoglobin (Hb) oxidation reactions within red blood cells (RBCs). A novel gel formulation containing the antioxidant curcuminoids in a biocompatible solvent system was used to deliver curcumin into RBCs. Incubation of peroxide treated RBCs stored in PBS with curcumin gel led to a reduction in prooxidant ferrylHb and recovery in ATP. Curcumin treatment prevented band 3 tyrosine (Y359 and Y21) phosphorylation. RBCs stored in AS-3 solutions for 28, 35, 42 and 49 days, following a single-dose of 100µM curcuminoids at each time points, caused reduction in protein carbonylation and considerable recovery in ATP levels. Proteomic analysis revealed minimal changes in the proteomic landscape in 35 days. However, a downregulation in fibrinogen was observed in the treated samples which may reduce RBC aggregation. Additionally, we used a guinea pig model where the circulation of infused aged RBCs can be extended (approximately 10%) when treated with curcumin gel at the start of storage. Our data therefore provide mechanistic insights and supportive animal data into benefits of treating stored RBCs with a novel curcuminoid formulation based on the biopreservation of RBC membrane integrity, redox balance, and increased longevity in circulation.
{"title":"Biopreservation and Reversal of Oxidative Injury During Blood Storage by a Novel Curcumin-based Gel Formulation","authors":"Wayne Hicks, S. Jana, Tigist Kassa, Richard Prince, Pedro Cabrales, Joel Friedman, A. Alayash","doi":"10.21203/rs.3.rs-4277591/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4277591/v1","url":null,"abstract":"Abstract Blood storage lesion induces cytosolic and membrane changes driven in part by hemoglobin (Hb) oxidation reactions within red blood cells (RBCs). A novel gel formulation containing the antioxidant curcuminoids in a biocompatible solvent system was used to deliver curcumin into RBCs. Incubation of peroxide treated RBCs stored in PBS with curcumin gel led to a reduction in prooxidant ferrylHb and recovery in ATP. Curcumin treatment prevented band 3 tyrosine (Y359 and Y21) phosphorylation. RBCs stored in AS-3 solutions for 28, 35, 42 and 49 days, following a single-dose of 100µM curcuminoids at each time points, caused reduction in protein carbonylation and considerable recovery in ATP levels. Proteomic analysis revealed minimal changes in the proteomic landscape in 35 days. However, a downregulation in fibrinogen was observed in the treated samples which may reduce RBC aggregation. Additionally, we used a guinea pig model where the circulation of infused aged RBCs can be extended (approximately 10%) when treated with curcumin gel at the start of storage. Our data therefore provide mechanistic insights and supportive animal data into benefits of treating stored RBCs with a novel curcuminoid formulation based on the biopreservation of RBC membrane integrity, redox balance, and increased longevity in circulation.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"43 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141008191","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 : 2024-05-06DOI: 10.21203/rs.3.rs-4319658/v1
Youstina Soliman*, Chino Eke, Xiaojia Guo, Melinda Wang, Tatiana Silva, Gary V. Désir, Liza Konnikova
Abstract Preeclampsia (PEC) is a complication of pregnancy associated with hypertension and the risk of eclampsia. The pathophysiology of PEC is unknown and identifying factors associated with PEC during pregnancy is crucial for placental, fetal, and maternal health. Renalase (RNLS) is an anti-inflammatory secretory flavoprotein associated with hypertension. Recent data demonstrated a correlation between maternal serum RNLS and PEC, and work from our group identified RNLS expression in the placenta. However, it remains unknown whether RNLS levels in placenta are altered by preeclampsia. Additionally, it is unclear if there is a differential effect of preterm and term PEC on RNLS. We demonstrate that serum RNLS was reduced in preterm cases of PEC. Similarly, placental RNLS was diminished in the chorion of preterm cases of PEC. However, a reduction of RNLS in the decidua was observed with all cases of PEC, while the levels of RNLS within the placental villi were similar in all cases. Overall, we demonstrate that RNLS correlates with PEC both systemically in maternal serum and locally within the placenta, with variable effects on the different layers of the placenta and more pronounced in preterm cases.
{"title":"Renalase Levels are Decreased in Maternal Blood and Placental Tissues in Pregnancies Associated with Preterm Preeclampsia","authors":"Youstina Soliman*, Chino Eke, Xiaojia Guo, Melinda Wang, Tatiana Silva, Gary V. Désir, Liza Konnikova","doi":"10.21203/rs.3.rs-4319658/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4319658/v1","url":null,"abstract":"Abstract Preeclampsia (PEC) is a complication of pregnancy associated with hypertension and the risk of eclampsia. The pathophysiology of PEC is unknown and identifying factors associated with PEC during pregnancy is crucial for placental, fetal, and maternal health. Renalase (RNLS) is an anti-inflammatory secretory flavoprotein associated with hypertension. Recent data demonstrated a correlation between maternal serum RNLS and PEC, and work from our group identified RNLS expression in the placenta. However, it remains unknown whether RNLS levels in placenta are altered by preeclampsia. Additionally, it is unclear if there is a differential effect of preterm and term PEC on RNLS. We demonstrate that serum RNLS was reduced in preterm cases of PEC. Similarly, placental RNLS was diminished in the chorion of preterm cases of PEC. However, a reduction of RNLS in the decidua was observed with all cases of PEC, while the levels of RNLS within the placental villi were similar in all cases. Overall, we demonstrate that RNLS correlates with PEC both systemically in maternal serum and locally within the placenta, with variable effects on the different layers of the placenta and more pronounced in preterm cases.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"7 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141005922","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 : 2024-05-06DOI: 10.21203/rs.3.rs-4308293/v1
Alexander P. Glaser, Abigail R. Smith, Dacey Maglaque, Brian T. Helfand, Rowida Mohamed, Hosanna An, Melissa Marquez, P. Talaty, Padraig Carolan, Aaron M. Geller, Francesca R. Farina, Sally E. Jensen, James W Griffith
Abstract Background Lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) significantly impact quality of life among older men. Despite the prevalent use of the American Urological Association Symptom Index (AUA-SI) for BPH, this measure overlooks key symptoms such as pain and incontinence, underscoring the need for more comprehensive patient-reported outcome (PRO) tools. This study aims to integrate enhanced PROs into routine clinical practice to better capture the spectrum of LUTS, thereby improving clinical outcomes and patient care. Methods This prospective observational study will recruit men with LUTS secondary to BPH aged ≥ 50 years from urology clinics. Participants will be stratified into medical and surgical management groups, with PRO assessments scheduled at regular intervals to monitor LUTS and other health outcomes. The study will employ the LURN Symptom Index (SI)-29 alongside the traditional AUA-SI and other non-urologic PROs to evaluate a broad range of symptoms. Data on comorbidities, symptom severity, and treatment efficacy will be collected through a combination of electronic health records and PROs. Analyses will focus on the predictive power of these tools in relation to symptom trajectories and treatment responses. Aims are to: (1) integrate routine clinical tests with PRO assessment to enhance screening, diagnosis, and management of patients with BPH; (2) examine psychometric properties of the LURN SIs, including test-retest reliability and establishment of clinically meaningful differences; and (3) create care-coordination recommendations to facilitate management of persistent symptoms and common comorbidities measured by PROs. Discussion By employing comprehensive PRO measures, this study expects to refine symptom assessment and enhance treatment monitoring, potentially leading to improved personalized care strategies. The integration of these tools into clinical settings could revolutionize the management of LUTS/BPH by providing more nuanced insights into patient experiences and outcomes. The findings could have significant implications for clinical practices, potentially leading to updates in clinical guidelines and better health management strategies for men with LUTS/BPH. Trial registration: This study is registered in ClinicalTrials.gov (NCT05898932).
{"title":"Enhanced Clinical Decisions for Management of Benign Prostatic Hyperplasia using Patient-Reported Outcomes: Protocol for a Prospective Observational Study","authors":"Alexander P. Glaser, Abigail R. Smith, Dacey Maglaque, Brian T. Helfand, Rowida Mohamed, Hosanna An, Melissa Marquez, P. Talaty, Padraig Carolan, Aaron M. Geller, Francesca R. Farina, Sally E. Jensen, James W Griffith","doi":"10.21203/rs.3.rs-4308293/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4308293/v1","url":null,"abstract":"Abstract Background Lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) significantly impact quality of life among older men. Despite the prevalent use of the American Urological Association Symptom Index (AUA-SI) for BPH, this measure overlooks key symptoms such as pain and incontinence, underscoring the need for more comprehensive patient-reported outcome (PRO) tools. This study aims to integrate enhanced PROs into routine clinical practice to better capture the spectrum of LUTS, thereby improving clinical outcomes and patient care. Methods This prospective observational study will recruit men with LUTS secondary to BPH aged ≥ 50 years from urology clinics. Participants will be stratified into medical and surgical management groups, with PRO assessments scheduled at regular intervals to monitor LUTS and other health outcomes. The study will employ the LURN Symptom Index (SI)-29 alongside the traditional AUA-SI and other non-urologic PROs to evaluate a broad range of symptoms. Data on comorbidities, symptom severity, and treatment efficacy will be collected through a combination of electronic health records and PROs. Analyses will focus on the predictive power of these tools in relation to symptom trajectories and treatment responses. Aims are to: (1) integrate routine clinical tests with PRO assessment to enhance screening, diagnosis, and management of patients with BPH; (2) examine psychometric properties of the LURN SIs, including test-retest reliability and establishment of clinically meaningful differences; and (3) create care-coordination recommendations to facilitate management of persistent symptoms and common comorbidities measured by PROs. Discussion By employing comprehensive PRO measures, this study expects to refine symptom assessment and enhance treatment monitoring, potentially leading to improved personalized care strategies. The integration of these tools into clinical settings could revolutionize the management of LUTS/BPH by providing more nuanced insights into patient experiences and outcomes. The findings could have significant implications for clinical practices, potentially leading to updates in clinical guidelines and better health management strategies for men with LUTS/BPH. Trial registration: This study is registered in ClinicalTrials.gov (NCT05898932).","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"32 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141010444","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 : 2024-05-06DOI: 10.21203/rs.3.rs-4294058/v1
Jason S Wasserman, Holly A. Fowle, Rumesa Hashmi, Diba Atar, Kishan Patel, Amir Yarmahmoodi, Alexander W. Macfarlane, Yinfei Tan, Edna Cukierman, Bojana Gligorijevic, Adam Karami, Kelly A. Whelan, Kerry S. Campbell, Xavier Graña
Abstract Prostate cancer (PCa) is the most common cancer diagnosed in men worldwide and the second leading cause of cancer-related deaths in US males in 2022. Prostate cancer also represents the second highest cancer mortality disparity between non-Hispanic blacks and whites. However, there is a relatively small number of prostate normal and cancer cell lines compared to other cancers. To identify the molecular basis of PCa progression, it is important to have prostate epithelial cell (PrEC) lines as karyotypically normal as possible. Our lab recently developed a novel methodology for the rapid and efficient immortalization of normal human PrEC that combines simultaneous CRISPR-directed inactivation of CDKN2A exon 2 (which directs expression of p16INK4A and p14ARF) and ectopic expression of an hTERT transgene. To optimize this methodology to generate immortalized lines with minimal genetic alterations, we sought to target exon 1α of the CDKN2A locus so that p16INK4A expression is ablated while p14ARF expression remains unaltered. Here we describe the establishment of two cell lines: one with the above-mentioned p16INK4A only loss, and a second line targeting both products in the CDKN2A locus. We characterize the potential lineage origin of these new cell lines along with our previously obtained clones, revealing distinct gene expression signatures. Based on the analyses of protein markers and RNA expression signatures, these cell lines are most closely related to a subpopulation of basal prostatic cells. Given the simplicity of this one-step methodology and the fact that it uses only the minimal genetic alterations necessary for immortalization, it should also be suitable for the establishment of cell lines from primary prostate tumor samples, an urgent need given the limited number of available prostate cancer cell lines.
{"title":"Derivation of human primary prostate epithelial cell lines by differentially targeting the CDKN2A locus along with expression of hTERT","authors":"Jason S Wasserman, Holly A. Fowle, Rumesa Hashmi, Diba Atar, Kishan Patel, Amir Yarmahmoodi, Alexander W. Macfarlane, Yinfei Tan, Edna Cukierman, Bojana Gligorijevic, Adam Karami, Kelly A. Whelan, Kerry S. Campbell, Xavier Graña","doi":"10.21203/rs.3.rs-4294058/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-4294058/v1","url":null,"abstract":"Abstract Prostate cancer (PCa) is the most common cancer diagnosed in men worldwide and the second leading cause of cancer-related deaths in US males in 2022. Prostate cancer also represents the second highest cancer mortality disparity between non-Hispanic blacks and whites. However, there is a relatively small number of prostate normal and cancer cell lines compared to other cancers. To identify the molecular basis of PCa progression, it is important to have prostate epithelial cell (PrEC) lines as karyotypically normal as possible. Our lab recently developed a novel methodology for the rapid and efficient immortalization of normal human PrEC that combines simultaneous CRISPR-directed inactivation of CDKN2A exon 2 (which directs expression of p16INK4A and p14ARF) and ectopic expression of an hTERT transgene. To optimize this methodology to generate immortalized lines with minimal genetic alterations, we sought to target exon 1α of the CDKN2A locus so that p16INK4A expression is ablated while p14ARF expression remains unaltered. Here we describe the establishment of two cell lines: one with the above-mentioned p16INK4A only loss, and a second line targeting both products in the CDKN2A locus. We characterize the potential lineage origin of these new cell lines along with our previously obtained clones, revealing distinct gene expression signatures. Based on the analyses of protein markers and RNA expression signatures, these cell lines are most closely related to a subpopulation of basal prostatic cells. Given the simplicity of this one-step methodology and the fact that it uses only the minimal genetic alterations necessary for immortalization, it should also be suitable for the establishment of cell lines from primary prostate tumor samples, an urgent need given the limited number of available prostate cancer cell lines.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"51 47","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141009864","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 : 2024-04-24DOI: 10.21203/rs.3.rs-3342413/v2
Reji Babygirija, Michelle M Sonsalla, Jericha Mill, Isabella James, Jessica H Han, Cara L Green, Mariah F Calubag, Gina Wade, Anna Tobon, John Michael, Michaela M Trautman, Ryan Matoska, Chung-Yang Yeh, Isaac Grunow, Heidi H Pak, Michael J Rigby, Dominique A Baldwin, Natalie M Niemi, John M Denu, Luigi Puglielli, Judith Simcox, Dudley W Lamming
Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and many independent groups of researchers have shown that dietary protein restriction (PR) extends the lifespan and healthspan of mice. Here, we examined the effect of PR on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. We found that PR has metabolic benefits for 3xTg mice and non-transgenic controls of both sexes, promoting leanness and glycemic control in 3xTg mice and rescuing the glucose intolerance of 3xTg females. We found that PR induces sex-specific alterations in circulating metabolites and in the brain metabolome and lipidome, downregulating sphingolipid subclasses including ceramides, glucosylceramides, and sphingomyelins in 3xTg females. Consumption of a PR diet starting at 6 months of age reduced AD pathology in conjunction with reduced mTORC1 activity, increased autophagy, and had cognitive benefits for 3xTg mice. Finally, PR improved the survival of 3xTg mice. Our results demonstrate that PR slows the progression of AD at molecular and pathological levels, preserves cognition in this mouse model of AD, and suggests that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.
{"title":"Protein restriction slows the development and progression of Alzheimer's disease in mice.","authors":"Reji Babygirija, Michelle M Sonsalla, Jericha Mill, Isabella James, Jessica H Han, Cara L Green, Mariah F Calubag, Gina Wade, Anna Tobon, John Michael, Michaela M Trautman, Ryan Matoska, Chung-Yang Yeh, Isaac Grunow, Heidi H Pak, Michael J Rigby, Dominique A Baldwin, Natalie M Niemi, John M Denu, Luigi Puglielli, Judith Simcox, Dudley W Lamming","doi":"10.21203/rs.3.rs-3342413/v2","DOIUrl":"10.21203/rs.3.rs-3342413/v2","url":null,"abstract":"<p><p>Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and many independent groups of researchers have shown that dietary protein restriction (PR) extends the lifespan and healthspan of mice. Here, we examined the effect of PR on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. We found that PR has metabolic benefits for 3xTg mice and non-transgenic controls of both sexes, promoting leanness and glycemic control in 3xTg mice and rescuing the glucose intolerance of 3xTg females. We found that PR induces sex-specific alterations in circulating metabolites and in the brain metabolome and lipidome, downregulating sphingolipid subclasses including ceramides, glucosylceramides, and sphingomyelins in 3xTg females. Consumption of a PR diet starting at 6 months of age reduced AD pathology in conjunction with reduced mTORC1 activity, increased autophagy, and had cognitive benefits for 3xTg mice. Finally, PR improved the survival of 3xTg mice. Our results demonstrate that PR slows the progression of AD at molecular and pathological levels, preserves cognition in this mouse model of AD, and suggests that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10543316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41133091","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 : 2024-04-01DOI: 10.21203/rs.3.rs-3272974/v2
Azam Yazdani
The full text of this preprint has been withdrawn, as it was submitted in error. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.
{"title":"WITHDRAWN: Broadcasters, receivers, functional groups of metabolites and the link to heart failure using polygenic factors.","authors":"Azam Yazdani","doi":"10.21203/rs.3.rs-3272974/v2","DOIUrl":"10.21203/rs.3.rs-3272974/v2","url":null,"abstract":"<p><p>The full text of this preprint has been withdrawn, as it was submitted in error. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10479558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10208057","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 : 2024-02-09DOI: 10.21203/rs.3.rs-3922129/v1
Vijjayalakshmi Santhakumar, Deepak Subramanian, C. Eisenberg, Andrew Huang, Jiyeon Baek, Haniya Naveed, Samiksha Komatireddy, Michael Shiflett, Tracy Tran
Abstract Dysregulation of development, migration, and function of interneurons, collectively termed interneuronopathies, have been proposed as a shared mechanism for autism spectrum disorders (ASDs) and childhood epilepsy. Neuropilin-2 (Nrp2), a candidate ASD gene, is a critical regulator of interneuron migration from the median ganglionic eminence (MGE) to the pallium, including the hippocampus. While clinical studies have identified Nrp2 polymorphisms in patients with ASD, whether dysregulation of Nrp2-dependent interneuron migration contributes to pathogenesis of ASD and epilepsy has not been tested. We tested the hypothesis that the lack of Nrp2 in MGE-derived interneuron precursors disrupts the excitation/inhibition balance in hippocampal circuits, thus predisposing the network to seizures and behavioral patterns associated with ASD. Embryonic deletion of Nrp2 during the developmental period for migration of MGE derived interneuron precursors (iCKO) significantly reduced parvalbumin, neuropeptide Y, and somatostatin positive neurons in the hippocampal CA1. Consequently, when compared to controls, the frequency of inhibitory synaptic currents in CA1 pyramidal cells was reduced while frequency of excitatory synaptic currents was increased in iCKO mice. Although passive and active membrane properties of CA1 pyramidal cells were unchanged, iCKO mice showed enhanced susceptibility to chemically evoked seizures. Moreover, iCKO mice exhibited selective behavioral deficits in both preference for social novelty and goal-directed learning, which are consistent with ASD-like phenotype. Together, our findings show that disruption of developmental Nrp2 regulation of interneuron circuit establishment, produces ASD-like behaviors and enhanced risk for epilepsy. These results support the developmental interneuronopathy hypothesis of ASD epilepsy comorbidity.
{"title":"Dysregulation of Neuropilin-2 Expression in Inhibitory Neurons Impairs Hippocampal Circuit Development Leading to Autism-Epilepsy Phenotype","authors":"Vijjayalakshmi Santhakumar, Deepak Subramanian, C. Eisenberg, Andrew Huang, Jiyeon Baek, Haniya Naveed, Samiksha Komatireddy, Michael Shiflett, Tracy Tran","doi":"10.21203/rs.3.rs-3922129/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3922129/v1","url":null,"abstract":"Abstract Dysregulation of development, migration, and function of interneurons, collectively termed interneuronopathies, have been proposed as a shared mechanism for autism spectrum disorders (ASDs) and childhood epilepsy. Neuropilin-2 (Nrp2), a candidate ASD gene, is a critical regulator of interneuron migration from the median ganglionic eminence (MGE) to the pallium, including the hippocampus. While clinical studies have identified Nrp2 polymorphisms in patients with ASD, whether dysregulation of Nrp2-dependent interneuron migration contributes to pathogenesis of ASD and epilepsy has not been tested. We tested the hypothesis that the lack of Nrp2 in MGE-derived interneuron precursors disrupts the excitation/inhibition balance in hippocampal circuits, thus predisposing the network to seizures and behavioral patterns associated with ASD. Embryonic deletion of Nrp2 during the developmental period for migration of MGE derived interneuron precursors (iCKO) significantly reduced parvalbumin, neuropeptide Y, and somatostatin positive neurons in the hippocampal CA1. Consequently, when compared to controls, the frequency of inhibitory synaptic currents in CA1 pyramidal cells was reduced while frequency of excitatory synaptic currents was increased in iCKO mice. Although passive and active membrane properties of CA1 pyramidal cells were unchanged, iCKO mice showed enhanced susceptibility to chemically evoked seizures. Moreover, iCKO mice exhibited selective behavioral deficits in both preference for social novelty and goal-directed learning, which are consistent with ASD-like phenotype. Together, our findings show that disruption of developmental Nrp2 regulation of interneuron circuit establishment, produces ASD-like behaviors and enhanced risk for epilepsy. These results support the developmental interneuronopathy hypothesis of ASD epilepsy comorbidity.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"44 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139964983","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 : 2024-02-09DOI: 10.21203/rs.3.rs-3640878/v1
Guo-Wei Wei, Dong Chen, Jian Liu
Abstract Pre-trained deep Transformers have had tremendous success in a wide variety of disciplines. However, in computational biology, essentially all Transformers are built upon the biological sequences, which ignores vital stereochemical information and may result in crucial errors in downstream predictions. On the other hand, three-dimensional (3D) molecular structures are incompatible with the sequential architecture of Transformer and natural language processing (NLP) models in general. This work addresses this foundational challenge by a topological Transformer (TopoFormer). TopoFormer is built by integrating NLP and a multiscale topology techniques, the persistent topological hyperdigraph Laplacian (PTHL), which systematically converts intricate 3D protein-ligand complexes at various spatial scales into a NLP-admissible sequence of topological invariants and homotopic shapes. Element-specific PTHLs are further developed to embed crucial physical, chemical, and biological interactions into topological sequences. TopoFormer surges ahead of conventional algorithms and recent deep learning variants and gives rise to exemplary scoring accuracy and superior performance in ranking, docking, and screening tasks in a number of benchmark datasets. The proposed topological sequences can be extracted from all kinds of structural data in data science to facilitate various NLP models, heralding a new era in AI-driven discovery.
{"title":"TopoFormer: Multiscale Topology-enabled Structure-to-Sequence Transformer for Protein-Ligand Interaction Predictions","authors":"Guo-Wei Wei, Dong Chen, Jian Liu","doi":"10.21203/rs.3.rs-3640878/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3640878/v1","url":null,"abstract":"Abstract Pre-trained deep Transformers have had tremendous success in a wide variety of disciplines. However, in computational biology, essentially all Transformers are built upon the biological sequences, which ignores vital stereochemical information and may result in crucial errors in downstream predictions. On the other hand, three-dimensional (3D) molecular structures are incompatible with the sequential architecture of Transformer and natural language processing (NLP) models in general. This work addresses this foundational challenge by a topological Transformer (TopoFormer). TopoFormer is built by integrating NLP and a multiscale topology techniques, the persistent topological hyperdigraph Laplacian (PTHL), which systematically converts intricate 3D protein-ligand complexes at various spatial scales into a NLP-admissible sequence of topological invariants and homotopic shapes. Element-specific PTHLs are further developed to embed crucial physical, chemical, and biological interactions into topological sequences. TopoFormer surges ahead of conventional algorithms and recent deep learning variants and gives rise to exemplary scoring accuracy and superior performance in ranking, docking, and screening tasks in a number of benchmark datasets. The proposed topological sequences can be extracted from all kinds of structural data in data science to facilitate various NLP models, heralding a new era in AI-driven discovery.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"51 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139964808","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 : 2024-02-09DOI: 10.21203/rs.3.rs-3914483/v1
Samuel Kawuma, Rogers Katwesigye, H. Walusaga, Praise Akatukunda, J. Nangendo, Charles Kabugo, Moses R. Kamya, Fred C. Semitala
Abstract Background Female sex workers (FSWs) have the highest HIV prevalence in Uganda. Pre exposure prophylaxis (PrEP) has been recommended as part of the HIV combination prevention strategy, with improved patient initiation, but continuation on the service is low. We evaluated PrEP continuation among FSWs and explored potential determinants of PrEP continuation within a public referral hospital in Urban Uganda. Methods An explanatory sequential mixed method study was conducted at Kiruddu National referral hospital in Uganda. Secondary data on social demographic characteristics and follow up outcomes of at least one year was collected for all FSWs who were initiated PrEP between May 2020 and April 2021.We used Kaplan–Meier survival analysis to evaluate continuation on PrEP from time of initiation and follow-up period. The capability, opportunity, and motivation to change behaviour model was used to explore perspectives and practices of FSWs (n = 24) and health care providers (n = 8) on continuation on PrEP among FSWs, using semi structured interviews. The qualitative data was deductively coded and analyzed thematically, categorizing the themes related to PrEP continuation as facilitators and barriers. Results Of the 292 FSWs initiated on PrEP during this period, 101 (34.6) % were active on PrEP, 137 (46.9%) were lost to follow-up, 45 (15.4%) were no longer eligible to continue PrEP, eight (2.7%) were transferred out and one (0.3%) had died. Median survival time on PrEP was 15 months (Interquartile range IQR, 3–21). The continuation rates on PrEP at six (6) and 12 months were, 61.1% and 53.1%, respectively. Facilitators of PrEP continuation included awareness of risk associated with sex work, integration of PrEP with other HIV prevention services, presence of PrEP Peer support and use of Drop-in centers. The barriers included low community awareness about PrEP, high mobility of sex workers, substance abuse, and the unfavorable daytime clinic schedules. Conclusion Continuation on PrEP remains low among FSWs. Interventions for PrEP continuation should address barriers such as low community awareness on PrEP, substance abuse and restrictive health facility policies for scale of the PrEP program among FSWs in Uganda. Integration of PrEP with other services and scale up of community PrEP delivery structures may improve its continuation.
{"title":"Determinants to Continuation on Hiv Pre-exposure Propylaxis Among Female Sex Workers at a Referral Hospital in Uganda: a Mixed Methods Study Using Com-b Model","authors":"Samuel Kawuma, Rogers Katwesigye, H. Walusaga, Praise Akatukunda, J. Nangendo, Charles Kabugo, Moses R. Kamya, Fred C. Semitala","doi":"10.21203/rs.3.rs-3914483/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3914483/v1","url":null,"abstract":"Abstract Background Female sex workers (FSWs) have the highest HIV prevalence in Uganda. Pre exposure prophylaxis (PrEP) has been recommended as part of the HIV combination prevention strategy, with improved patient initiation, but continuation on the service is low. We evaluated PrEP continuation among FSWs and explored potential determinants of PrEP continuation within a public referral hospital in Urban Uganda. Methods An explanatory sequential mixed method study was conducted at Kiruddu National referral hospital in Uganda. Secondary data on social demographic characteristics and follow up outcomes of at least one year was collected for all FSWs who were initiated PrEP between May 2020 and April 2021.We used Kaplan–Meier survival analysis to evaluate continuation on PrEP from time of initiation and follow-up period. The capability, opportunity, and motivation to change behaviour model was used to explore perspectives and practices of FSWs (n = 24) and health care providers (n = 8) on continuation on PrEP among FSWs, using semi structured interviews. The qualitative data was deductively coded and analyzed thematically, categorizing the themes related to PrEP continuation as facilitators and barriers. Results Of the 292 FSWs initiated on PrEP during this period, 101 (34.6) % were active on PrEP, 137 (46.9%) were lost to follow-up, 45 (15.4%) were no longer eligible to continue PrEP, eight (2.7%) were transferred out and one (0.3%) had died. Median survival time on PrEP was 15 months (Interquartile range IQR, 3–21). The continuation rates on PrEP at six (6) and 12 months were, 61.1% and 53.1%, respectively. Facilitators of PrEP continuation included awareness of risk associated with sex work, integration of PrEP with other HIV prevention services, presence of PrEP Peer support and use of Drop-in centers. The barriers included low community awareness about PrEP, high mobility of sex workers, substance abuse, and the unfavorable daytime clinic schedules. Conclusion Continuation on PrEP remains low among FSWs. Interventions for PrEP continuation should address barriers such as low community awareness on PrEP, substance abuse and restrictive health facility policies for scale of the PrEP program among FSWs in Uganda. Integration of PrEP with other services and scale up of community PrEP delivery structures may improve its continuation.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"51 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139964809","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 : 2024-02-09DOI: 10.21203/rs.3.rs-3748581/v1
Tibor Harkany, Evgenii Tretiakov, Luis Varela, Jasna Jarc, Patrick Rebernik, Sylvia Newbold, Erik Keimpema, Alexei Verkhratsky, Tamas Horvath, Roman Romanov
Abstract Astrocytes safeguard the homeostasis of the central nervous system 1,2 . Despite their prominent morphological plasticity under conditions that challenge the brain’s adaptive capacity 3–5 , the classification of astrocytes, and relating their molecular make-up to spatially devolved neuronal operations that specify behavior or metabolism, remained mostly futile 6,7 . Although it seems unexpected in the era of single-cell biology, the lack of a major advance in stratifying astrocytes under physiological conditions rests on the incompatibility of ‘neurocentric’ algorithms that rely on stable developmental endpoints, lifelong transcriptional, neurotransmitter, and neuropeptide signatures for classification 6–8 with the dynamic functional states, anatomic allocation, and allostatic plasticity of astrocytes 1 . Simplistically, therefore, astrocytes are still grouped as ‘resting’ vs. ‘reactive’, the latter referring to pathological states marked by various inducible genes 3,9,10 . Here, we introduced a machine learning-based feature recognition algorithm that benefits from the cumulative power of published single-cell RNA-seq data on astrocytes as a reference map to stepwise eliminate pleiotropic and inducible cellular features. For the healthy hypothalamus, this walk-back approach revealed gene regulatory networks (GRNs) that specified subsets of astrocytes, and could be used as landmarking tools for their anatomical assignment. The core molecular censuses retained by astrocyte subsets were sufficient to stratify them by allostatic competence, chiefly their signaling and metabolic interplay with neurons. Particularly, we found differentially expressed mitochondrial genes in insulin-sensing astrocytes and demonstrated their reciprocal signaling with neurons that work antagonistically within the food intake circuitry. As a proof-of-concept, we showed that disrupting Mfn2 expression in astrocytes reduced their ability to support dynamic circuit reorganization, a time-locked feature of satiety in the hypothalamus, thus leading to obesity in mice. Overall, our results suggest that astrocytes in the healthy brain are fundamentally more heterogeneous than previously thought and topologically mirror the specificity of local neurocircuits.
{"title":"Molecularly stratified hypothalamic astrocytes are cellular foci for obesity","authors":"Tibor Harkany, Evgenii Tretiakov, Luis Varela, Jasna Jarc, Patrick Rebernik, Sylvia Newbold, Erik Keimpema, Alexei Verkhratsky, Tamas Horvath, Roman Romanov","doi":"10.21203/rs.3.rs-3748581/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3748581/v1","url":null,"abstract":"Abstract Astrocytes safeguard the homeostasis of the central nervous system 1,2 . Despite their prominent morphological plasticity under conditions that challenge the brain’s adaptive capacity 3–5 , the classification of astrocytes, and relating their molecular make-up to spatially devolved neuronal operations that specify behavior or metabolism, remained mostly futile 6,7 . Although it seems unexpected in the era of single-cell biology, the lack of a major advance in stratifying astrocytes under physiological conditions rests on the incompatibility of ‘neurocentric’ algorithms that rely on stable developmental endpoints, lifelong transcriptional, neurotransmitter, and neuropeptide signatures for classification 6–8 with the dynamic functional states, anatomic allocation, and allostatic plasticity of astrocytes 1 . Simplistically, therefore, astrocytes are still grouped as ‘resting’ vs. ‘reactive’, the latter referring to pathological states marked by various inducible genes 3,9,10 . Here, we introduced a machine learning-based feature recognition algorithm that benefits from the cumulative power of published single-cell RNA-seq data on astrocytes as a reference map to stepwise eliminate pleiotropic and inducible cellular features. For the healthy hypothalamus, this walk-back approach revealed gene regulatory networks (GRNs) that specified subsets of astrocytes, and could be used as landmarking tools for their anatomical assignment. The core molecular censuses retained by astrocyte subsets were sufficient to stratify them by allostatic competence, chiefly their signaling and metabolic interplay with neurons. Particularly, we found differentially expressed mitochondrial genes in insulin-sensing astrocytes and demonstrated their reciprocal signaling with neurons that work antagonistically within the food intake circuitry. As a proof-of-concept, we showed that disrupting Mfn2 expression in astrocytes reduced their ability to support dynamic circuit reorganization, a time-locked feature of satiety in the hypothalamus, thus leading to obesity in mice. Overall, our results suggest that astrocytes in the healthy brain are fundamentally more heterogeneous than previously thought and topologically mirror the specificity of local neurocircuits.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":"50 24","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139964814","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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