Pub Date : 2023-12-13DOI: 10.21203/rs.3.rs-2836905/v1
Ziv Avizemer, Carlos Martí-Gómez, Shlomo Yakir Hoch, David M McCandlish, Sarel J Fleishman
Some protein binding pairs exhibit extreme specificities that functionally insulate them from homologs. Such pairs evolve mostly by accumulating single-point mutations, and mutants are selected if their affinity exceeds the threshold required for function1-4. Thus, homologous and high-specificity binding pairs bring to light an evolutionary conundrum: how does a new specificity evolve while maintaining the required affinity in each intermediate5,6? Until now, a fully functional single-mutation path that connects two orthogonal pairs has only been described where the pairs were mutationally close thus enabling experimental enumeration of all intermediates2. We present an atomistic and graph-theoretical framework for discovering low molecular strain single-mutation paths that connect two extant pairs, enabling enumeration beyond experimental capability. We apply it to two orthogonal bacterial colicin endonuclease-immunity pairs separated by 17 interface mutations7. We were not able to find a strain-free and functional path in the sequence space defined by the two extant pairs. But including mutations that bridge amino acids that cannot be exchanged through single-nucleotide mutations led us to a strain-free 19-mutation trajectory that is completely viable in vivo. Our experiments show that the specificity switch is remarkably abrupt, resulting from only one radical mutation on each partner. Furthermore, each of the critical specificity-switch mutations increases fitness, demonstrating that functional divergence could be driven by positive Darwinian selection. These results reveal how even radical functional changes in an epistatic fitness landscape may evolve.
{"title":"Evolutionary paths that link orthogonal pairs of binding proteins.","authors":"Ziv Avizemer, Carlos Martí-Gómez, Shlomo Yakir Hoch, David M McCandlish, Sarel J Fleishman","doi":"10.21203/rs.3.rs-2836905/v1","DOIUrl":"10.21203/rs.3.rs-2836905/v1","url":null,"abstract":"<p><p>Some protein binding pairs exhibit extreme specificities that functionally insulate them from homologs. Such pairs evolve mostly by accumulating single-point mutations, and mutants are selected if their affinity exceeds the threshold required for function<sup>1-4</sup>. Thus, homologous and high-specificity binding pairs bring to light an evolutionary conundrum: how does a new specificity evolve while maintaining the required affinity in each intermediate<sup>5,6</sup>? Until now, a fully functional single-mutation path that connects two orthogonal pairs has only been described where the pairs were mutationally close thus enabling experimental enumeration of all intermediates<sup>2</sup>. We present an atomistic and graph-theoretical framework for discovering low molecular strain single-mutation paths that connect two extant pairs, enabling enumeration beyond experimental capability. We apply it to two orthogonal bacterial colicin endonuclease-immunity pairs separated by 17 interface mutations<sup>7</sup>. We were not able to find a strain-free and functional path in the sequence space defined by the two extant pairs. But including mutations that bridge amino acids that cannot be exchanged through single-nucleotide mutations led us to a strain-free 19-mutation trajectory that is completely viable <i>in vivo</i>. Our experiments show that the specificity switch is remarkably abrupt, resulting from only one radical mutation on each partner. Furthermore, each of the critical specificity-switch mutations increases fitness, demonstrating that functional divergence could be driven by positive Darwinian selection. These results reveal how even radical functional changes in an epistatic fitness landscape may evolve.</p>","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10153392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9855429","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 : 2023-12-02DOI: 10.21203/rs.3.rs-3592604/v1
Nami Tajima, Nebojša Bogdanović, Guadalupe Segura-Covarrubias, Lisa Zhang
Abstract Kainate receptors (KARs) belong to the family of ionotropic glutamate receptors (iGluRs) and are tetrameric ligand-gated ion channels that regulate neurotransmitter release and excitatory synaptic transmission in the central nervous system. While KARs share overall architectures with other iGluR subfamilies, their dynamics are significantly different from those of other iGluRs. KARs are activated by both full and partial agonists. While there is less efficacy with partial agonists than with full agonists, the detailed mechanism has remained elusive. Here, we used cryo-electron microscopy to determine the structures of homomeric rat GluK2 KARs in the absence of ligands (apo) and in complex with a partial agonist. Intriguingly, the apo state KARs were captured in desensitized conformation. This structure confirms the KAR desensitization prior to activation. Structures of KARs complexed to the partial agonist domoate populate in domoate bound desensitized and non-active/non-desensitized states. These previously unseen intermediate structures highlight the molecular mechanism of partial agonism in KARs. Additionally, we show how N -glycans stabilized the ligand-binding domain dimer via cation/anion binding and modulated receptor gating properties using electrophysiology. Our findings provide vital structural and functional insights into the unique KAR gating mechanisms.
{"title":"Structural dynamics of GluK2 kainate receptors in apo and partial agonist bound states.","authors":"Nami Tajima, Nebojša Bogdanović, Guadalupe Segura-Covarrubias, Lisa Zhang","doi":"10.21203/rs.3.rs-3592604/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3592604/v1","url":null,"abstract":"Abstract Kainate receptors (KARs) belong to the family of ionotropic glutamate receptors (iGluRs) and are tetrameric ligand-gated ion channels that regulate neurotransmitter release and excitatory synaptic transmission in the central nervous system. While KARs share overall architectures with other iGluR subfamilies, their dynamics are significantly different from those of other iGluRs. KARs are activated by both full and partial agonists. While there is less efficacy with partial agonists than with full agonists, the detailed mechanism has remained elusive. Here, we used cryo-electron microscopy to determine the structures of homomeric rat GluK2 KARs in the absence of ligands (apo) and in complex with a partial agonist. Intriguingly, the apo state KARs were captured in desensitized conformation. This structure confirms the KAR desensitization prior to activation. Structures of KARs complexed to the partial agonist domoate populate in domoate bound desensitized and non-active/non-desensitized states. These previously unseen intermediate structures highlight the molecular mechanism of partial agonism in KARs. Additionally, we show how N -glycans stabilized the ligand-binding domain dimer via cation/anion binding and modulated receptor gating properties using electrophysiology. Our findings provide vital structural and functional insights into the unique KAR gating mechanisms.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138607646","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 : 2023-12-02DOI: 10.21203/rs.3.rs-3677630/v1
Marisol Herrera-Rivero, M. Adli, K. Akiyama, N. Akula, Azmeraw T. Amare, R. Ardau, Bárbara Arias, Jean-Michel Aubry, L. Backlund, F. Bellivier, A. Benabarre, S. Bengesser, A. Bhattacharjee, Joanna M. Biernacka, A. Birner, Micah Cearns, P. Cervantes, Hsi-Chung Chen, C. Chillotti, S. Cichon, Scott R. Clark, F. Colom, C. Cruceanu, P. Czerski, N. Dalkner, Franziska Degenhardt, M. Zompo, J. DePaulo, Bruno Etain, Peter Falkai, E. Ferensztajn-Rochowiak, A. Forstner, J. Frank, L. Frisén, Mark A. Frye, Janice M. Fullerton, Carla Gallo, S. Gard, J. Garnham, F. Goes, M. Grigoroiu-Serbanescu, P. Grof, Ryota Hashimoto, R. Hasler, Joanna Hauser, U. Heilbronner, S. Herms, Per Hoffmann, Liping Hou, Yi-Hsiang Hsu, S. Jamain, E. Jiménez, J. Kahn, L. Kassem, Tadafumi Kato, J. Kelsoe, Sarah Kittel-Schneider, Po-Hsiu kuo, I. Kusumi, B. König, G. Laje, M. Landén, C. Lavebratt, M. Leboyer, S. Leckband, M. Maj, Mirko Manchia, C. Marie-Claire, Lina Martinsson, Michael J. McCarthy, Susan L. McElroy, V. Millischer, M. Mitjans, Franci
Abstract Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.
{"title":"Exploring the genetics of lithium response in bipolar disorders","authors":"Marisol Herrera-Rivero, M. Adli, K. Akiyama, N. Akula, Azmeraw T. Amare, R. Ardau, Bárbara Arias, Jean-Michel Aubry, L. Backlund, F. Bellivier, A. Benabarre, S. Bengesser, A. Bhattacharjee, Joanna M. Biernacka, A. Birner, Micah Cearns, P. Cervantes, Hsi-Chung Chen, C. Chillotti, S. Cichon, Scott R. Clark, F. Colom, C. Cruceanu, P. Czerski, N. Dalkner, Franziska Degenhardt, M. Zompo, J. DePaulo, Bruno Etain, Peter Falkai, E. Ferensztajn-Rochowiak, A. Forstner, J. Frank, L. Frisén, Mark A. Frye, Janice M. Fullerton, Carla Gallo, S. Gard, J. Garnham, F. Goes, M. Grigoroiu-Serbanescu, P. Grof, Ryota Hashimoto, R. Hasler, Joanna Hauser, U. Heilbronner, S. Herms, Per Hoffmann, Liping Hou, Yi-Hsiang Hsu, S. Jamain, E. Jiménez, J. Kahn, L. Kassem, Tadafumi Kato, J. Kelsoe, Sarah Kittel-Schneider, Po-Hsiu kuo, I. Kusumi, B. König, G. Laje, M. Landén, C. Lavebratt, M. Leboyer, S. Leckband, M. Maj, Mirko Manchia, C. Marie-Claire, Lina Martinsson, Michael J. McCarthy, Susan L. McElroy, V. Millischer, M. Mitjans, Franci","doi":"10.21203/rs.3.rs-3677630/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3677630/v1","url":null,"abstract":"Abstract Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138607939","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 : 2023-12-02DOI: 10.21203/rs.3.rs-3667486/v1
S. Mbalinda, M. Kaddumukasa, J. Najjuma, Doreen Birungi, M. Kaddumukasa, Jennifer Levin, Carolyn Still, C. Burant, Avani Modi, Elly T Katabira, Martha Sajatovic
Abstract Background: Epilepsy is a common chronic brain disorder globally affecting people of all ages, with the majority living in developing countries. The introduction of epilepsy self-management approaches to help people with epilepsy is urgently needed to influence epilepsy-related outcomes. This 2-site randomised controlled trial building on promising preliminary data is intended to explore this further. Methods: A total of 188 adult people with epilepsy (PWE) attending the neurology clinics at Mulago and Mbarara hospitals and consent to participate in the study. They will be randomised into intervention versus enhanced treatment control (eTAU) study groups. The intervention group will receive 12-week “intensive” educational sessions and a 12-week remotely accessed telephone follow-up stage. The controls will continue in their usual care supplemented by written materials on epilepsy in their preferred language and tailored to the reading level of most patients at the clinic. SMART-U consists of 2 main components: a 12-week “intensive” group format stage and a 12-week remotely accessed telephone follow-up stage. SMART-U will be assessed for acceptability, fidelity, and efficacy compared to eTAU. The primary study outcome is the mean change in cumulative past 24-week seizure frequency (24 weeks prior to the study baseline compared to the 24-week follow-up). Seizure frequency will be via self-report with corroboration by family/support system informants whenever possible. Participants will self-report their seizure frequency (numeric count) that they experienced between baseline and 13 weeks and again between 13 and 24 weeks and the mean change from baseline to 24 weeks in QOL. Discussion: The curriculum-guided Self-Management intervention for Reducing The epilepsy burden among Ugandans (SMART-U) program is anticipated to reduce the epilepsy burden seizure frequency and improve other health outcomes, including depression, functional status and health resource use. Trial Registration Number (TRN): NCT06139198 Date of registration: 14 th November 2023
{"title":"Self-management Intervention for Reducing Epilepsy Burden Among Adult Ugandans With Epilepsy (Smart-u), Randomised Clinical Trial Protocol","authors":"S. Mbalinda, M. Kaddumukasa, J. Najjuma, Doreen Birungi, M. Kaddumukasa, Jennifer Levin, Carolyn Still, C. Burant, Avani Modi, Elly T Katabira, Martha Sajatovic","doi":"10.21203/rs.3.rs-3667486/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3667486/v1","url":null,"abstract":"Abstract Background: Epilepsy is a common chronic brain disorder globally affecting people of all ages, with the majority living in developing countries. The introduction of epilepsy self-management approaches to help people with epilepsy is urgently needed to influence epilepsy-related outcomes. This 2-site randomised controlled trial building on promising preliminary data is intended to explore this further. Methods: A total of 188 adult people with epilepsy (PWE) attending the neurology clinics at Mulago and Mbarara hospitals and consent to participate in the study. They will be randomised into intervention versus enhanced treatment control (eTAU) study groups. The intervention group will receive 12-week “intensive” educational sessions and a 12-week remotely accessed telephone follow-up stage. The controls will continue in their usual care supplemented by written materials on epilepsy in their preferred language and tailored to the reading level of most patients at the clinic. SMART-U consists of 2 main components: a 12-week “intensive” group format stage and a 12-week remotely accessed telephone follow-up stage. SMART-U will be assessed for acceptability, fidelity, and efficacy compared to eTAU. The primary study outcome is the mean change in cumulative past 24-week seizure frequency (24 weeks prior to the study baseline compared to the 24-week follow-up). Seizure frequency will be via self-report with corroboration by family/support system informants whenever possible. Participants will self-report their seizure frequency (numeric count) that they experienced between baseline and 13 weeks and again between 13 and 24 weeks and the mean change from baseline to 24 weeks in QOL. Discussion: The curriculum-guided Self-Management intervention for Reducing The epilepsy burden among Ugandans (SMART-U) program is anticipated to reduce the epilepsy burden seizure frequency and improve other health outcomes, including depression, functional status and health resource use. Trial Registration Number (TRN): NCT06139198 Date of registration: 14 th November 2023","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138606372","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 : 2023-12-02DOI: 10.21203/rs.3.rs-3683218/v1
Kitty Lui, Abhishek Dave, K. Sprecher, M. Chappel-Farley, B. Riedner, Margo Heston, Chase E. Taylor, C. Carlsson, O. Okonkwo, S. Asthana, Sterling Johnson, B. Bendlin, B. Mander, Ruth M. Benca
Abstract Background : Obstructive sleep apnea (OSA) increases risk for cognitive decline and Alzheimer’s disease (AD). While the underlying mechanisms remain unclear, hypoxemia during OSA has been implicated in cognitive impairment. OSA during rapid eye movement (REM) sleep is usually more severe than in non-rapid eye movement (NREM) sleep, but the relative effect of oxyhemoglobin desaturation during REM versus NREM sleep on memory is not completely characterized. Here, we examined the impact of OSA, as well as the moderating effects of AD risk factors, on verbal memory in a sample of middle-aged and older adults with heightened AD risk. Methods : Eighty-one adults (mean age:61.7±6.0 years, 62% females, 32% a polipoprotein E ε4 allele ( APOE4) carriers, and 70% with parental history of AD) underwent clinical polysomnography including assessment of OSA. OSA features were derived in total, NREM, and REM sleep. REM-NREM ratios of OSA features were also calculated. Verbal memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT). Multiple regression models evaluated the relationships between OSA features and RAVLT scores while adjusting for sex, age, time between assessments, education years, body mass index (BMI), and APOE4 status or parental history of AD. The significant main effects of OSA features on RAVLT performance and the moderating effects of AD risk factors (i.e., sex, age, APOE4 status, and parental history of AD) were examined. Results : Apnea-hypopnea index (AHI), respiratory disturbance index (RDI), and oxyhemoglobin desaturation index (ODI) during REM sleep were negatively associated with RAVLT total learning and long-delay recall. Further, greater REM-NREM ratios of AHI, RDI, and ODI (i.e., more events in REM than NREM) were related to worse total learning and recall. We found specifically that the negative association between REM ODI and total learning was driven by adults 60+ years old. In addition, the negative relationships between REM-NREM ODI ratio and total learning and REM-NREM RDI ratio and long-delay recall were driven by APOE4 carriers. Conclusion : Greater OSA severity, particularly during REM sleep, negatively affects verbal memory, especially for people with greater AD risk. These findings underscore the potential importance of proactive screening and treatment of REM OSA even if overall AHI appears low.
{"title":"Older adults at greater risk for Alzheimer’s disease show stronger associations between sleep apnea severity and verbal memory","authors":"Kitty Lui, Abhishek Dave, K. Sprecher, M. Chappel-Farley, B. Riedner, Margo Heston, Chase E. Taylor, C. Carlsson, O. Okonkwo, S. Asthana, Sterling Johnson, B. Bendlin, B. Mander, Ruth M. Benca","doi":"10.21203/rs.3.rs-3683218/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3683218/v1","url":null,"abstract":"Abstract Background : Obstructive sleep apnea (OSA) increases risk for cognitive decline and Alzheimer’s disease (AD). While the underlying mechanisms remain unclear, hypoxemia during OSA has been implicated in cognitive impairment. OSA during rapid eye movement (REM) sleep is usually more severe than in non-rapid eye movement (NREM) sleep, but the relative effect of oxyhemoglobin desaturation during REM versus NREM sleep on memory is not completely characterized. Here, we examined the impact of OSA, as well as the moderating effects of AD risk factors, on verbal memory in a sample of middle-aged and older adults with heightened AD risk. Methods : Eighty-one adults (mean age:61.7±6.0 years, 62% females, 32% a polipoprotein E ε4 allele ( APOE4) carriers, and 70% with parental history of AD) underwent clinical polysomnography including assessment of OSA. OSA features were derived in total, NREM, and REM sleep. REM-NREM ratios of OSA features were also calculated. Verbal memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT). Multiple regression models evaluated the relationships between OSA features and RAVLT scores while adjusting for sex, age, time between assessments, education years, body mass index (BMI), and APOE4 status or parental history of AD. The significant main effects of OSA features on RAVLT performance and the moderating effects of AD risk factors (i.e., sex, age, APOE4 status, and parental history of AD) were examined. Results : Apnea-hypopnea index (AHI), respiratory disturbance index (RDI), and oxyhemoglobin desaturation index (ODI) during REM sleep were negatively associated with RAVLT total learning and long-delay recall. Further, greater REM-NREM ratios of AHI, RDI, and ODI (i.e., more events in REM than NREM) were related to worse total learning and recall. We found specifically that the negative association between REM ODI and total learning was driven by adults 60+ years old. In addition, the negative relationships between REM-NREM ODI ratio and total learning and REM-NREM RDI ratio and long-delay recall were driven by APOE4 carriers. Conclusion : Greater OSA severity, particularly during REM sleep, negatively affects verbal memory, especially for people with greater AD risk. These findings underscore the potential importance of proactive screening and treatment of REM OSA even if overall AHI appears low.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138607250","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 : 2023-12-02DOI: 10.21203/rs.3.rs-3449868/v1
Min Kyung Kim, Grace S. Su, Angel N.Y. Chan, Yuxin Fu, Yanqing Huang, Chien-Chi Huang, Ben Hires, MyDzung Chu
Abstract Background The COVID-19 pandemic and rise in anti-Asian racism have had adverse mental health impacts in Asian communities. The lack of culturally-responsive and linguistically-accessible mental health trainings hinders access to mental health services for Asian populations. In this study, we assessed the mental health needs of Asian communities in Greater Boston and evaluated cultural responsiveness of the Mental Health First Aid (MHFA), a first-responder training teaching participants skills to recognize signs of mental health and substance use challenges, and how to appropriately respond. Methods This community-based participatory research with the Boston Chinatown Neighborhood Center (BCNC), Asian Women For Health (AWFH), and the Addressing Disparities in Asian Populations through Translational Research (ADAPT) Coalition employed two phases. In phase 1, we conducted focus groups with BCNC and AWFH staff and peer educators to assess mental health priorities of Asian populations in Boston. Findings informed phase 2, which evaluated cultural responsiveness of the MHFA through pre- and post-training questionnaires and focus groups with community participants. The pre-training questionnaire asked about mental health needs and barriers, help-seeking behaviors, and literacy; and personal and Asian community stigma. The post-training questionnaire and focus group with community participants asked about cultural competence of MHFA training for Asian populations. Paired t-tests were used to evaluate questionnaire responses. Thematic analysis was used to analyze interviews. Results In total, 10 staff/educators and 8 community members participated in focus groups. They identified common mental health needs and workforce and culturally-responsive community strategies to support persons with mental health issues. Twenty-four community participants completed pre- and post-training questionnaires. They reported the MHFA training reduced mental health care stigma and increased mental health literacy. Recommendations to increase cultural-responsiveness of the MHFA were to include mental health case studies common in Asian populations and provide the training in other languages (e.g., Chinese, Vietnamese). Conclusion Cultural responsiveness of the MHFA for Asian populations could be improved with the inclusion of case studies specific to the Asian communities and accessibility of the training in other languages. Increasing the cultural relevance and language accessibility of these trainings could help reduce mental health stigma and gaps in mental health awareness and service utilization among Asian populations.
{"title":"Cultural-Responsiveness of the Mental Health First Aid Training for Asian Immigrant Populations in Greater Boston, Massachusetts","authors":"Min Kyung Kim, Grace S. Su, Angel N.Y. Chan, Yuxin Fu, Yanqing Huang, Chien-Chi Huang, Ben Hires, MyDzung Chu","doi":"10.21203/rs.3.rs-3449868/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3449868/v1","url":null,"abstract":"Abstract Background The COVID-19 pandemic and rise in anti-Asian racism have had adverse mental health impacts in Asian communities. The lack of culturally-responsive and linguistically-accessible mental health trainings hinders access to mental health services for Asian populations. In this study, we assessed the mental health needs of Asian communities in Greater Boston and evaluated cultural responsiveness of the Mental Health First Aid (MHFA), a first-responder training teaching participants skills to recognize signs of mental health and substance use challenges, and how to appropriately respond. Methods This community-based participatory research with the Boston Chinatown Neighborhood Center (BCNC), Asian Women For Health (AWFH), and the Addressing Disparities in Asian Populations through Translational Research (ADAPT) Coalition employed two phases. In phase 1, we conducted focus groups with BCNC and AWFH staff and peer educators to assess mental health priorities of Asian populations in Boston. Findings informed phase 2, which evaluated cultural responsiveness of the MHFA through pre- and post-training questionnaires and focus groups with community participants. The pre-training questionnaire asked about mental health needs and barriers, help-seeking behaviors, and literacy; and personal and Asian community stigma. The post-training questionnaire and focus group with community participants asked about cultural competence of MHFA training for Asian populations. Paired t-tests were used to evaluate questionnaire responses. Thematic analysis was used to analyze interviews. Results In total, 10 staff/educators and 8 community members participated in focus groups. They identified common mental health needs and workforce and culturally-responsive community strategies to support persons with mental health issues. Twenty-four community participants completed pre- and post-training questionnaires. They reported the MHFA training reduced mental health care stigma and increased mental health literacy. Recommendations to increase cultural-responsiveness of the MHFA were to include mental health case studies common in Asian populations and provide the training in other languages (e.g., Chinese, Vietnamese). Conclusion Cultural responsiveness of the MHFA for Asian populations could be improved with the inclusion of case studies specific to the Asian communities and accessibility of the training in other languages. Increasing the cultural relevance and language accessibility of these trainings could help reduce mental health stigma and gaps in mental health awareness and service utilization among Asian populations.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138607573","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 : 2023-12-02DOI: 10.21203/rs.3.rs-3627637/v1
S. Kang, Jeyeon Lee, Sun Choi, J. Nesbitt, Paul H Min, Eugenia Trushina, Doo-Sup Choi
Abstract Background Alcohol use disorder (AUD) has been associated with the development of neurodegenerative diseases, including Alzheimer's disease (AD). However, recent studies demonstrate that moderate alcohol consumption may be protective against dementia and cognitive decline. Methods We examined astrocyte function, low-density lipoprotein (LDL) receptor-related protein 1 (LRP1), and the NF-κB p65 and IKK-α/β signaling pathways in modulating neuroinflammation and amyloid beta (Aβ) deposition. We assessed apolipoprotein E (ApoE) in the mouse brain using IHC and ELISA in response to moderate ethanol exposure (MEE). First, to confirm the intracerebral distribution of ApoE, we co-stained with GFAP, a marker for astrocytes that biosynthesize ApoE. We sought to investigate whether the ethanol-induced upregulation of LRP1 could potentially inhibit the activity of IL-1β and TNF-α induced IKK-α/β towards NF-κB p65, resulting in a reduction of pro-inflammatory cytokines. To evaluate the actual Aβ load in the brains of APP/PS1 mice, we performed with a specific antibody Aβ (Thioflavin S) on both air- and ethanol-exposed groups, subsequently analyzing Aβ levels. We also measured glucose uptake activity using 18F-FDG in APP/PS1 mice. Finally, we investigated whether MEE induced cognitive and memory changes using the Y maze, noble objective recognition (NOR) test, and Morris water maze (MWM). Results Our findings demonstrate that MEE reduced astrocytic glial fibrillary acidic protein (GFAP) and ApoE levels in the cortex and hippocampus in presymptomatic APP/PS1 mice. Interestingly, increased LRP1 protein expression is accompanied by dampening the IKK-α/β-NF-κB p65 pathway, resulting in decreased IL-1β and TNF-α levels in male mice. Notably, female mice show reduced anti-inflammatory cytokines, IL-4, and IL-10 levels without altering IL-1β and TNF-α concentrations. In both males and females, Aβ plaques, a hallmark of AD, were reduced in the cortex and hippocampus of ethanol-exposed presymptomatic APP/PS1 mice. Consistently, MEE increased fluorodeoxyglucose (FDG)-positron emission tomography (PET)-based brain activities and normalized cognitive and memory deficits in the APP/PS1 mice. Conclusions Our findings suggest that MEE may benefit AD pathology via modulating LRP1 expression, potentially reducing neuroinflammation and attenuating Aβ deposition. Our study implies that reduced astrocyte derived ApoE and LDL cholesterol levels are critical for attenuating AD pathology.
{"title":"Moderate ethanol exposure reduces astrocyte-induced neuroinflammatorysignaling and cognitive decline in presymptomatic APP/PS1 mice","authors":"S. Kang, Jeyeon Lee, Sun Choi, J. Nesbitt, Paul H Min, Eugenia Trushina, Doo-Sup Choi","doi":"10.21203/rs.3.rs-3627637/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3627637/v1","url":null,"abstract":"Abstract Background Alcohol use disorder (AUD) has been associated with the development of neurodegenerative diseases, including Alzheimer's disease (AD). However, recent studies demonstrate that moderate alcohol consumption may be protective against dementia and cognitive decline. Methods We examined astrocyte function, low-density lipoprotein (LDL) receptor-related protein 1 (LRP1), and the NF-κB p65 and IKK-α/β signaling pathways in modulating neuroinflammation and amyloid beta (Aβ) deposition. We assessed apolipoprotein E (ApoE) in the mouse brain using IHC and ELISA in response to moderate ethanol exposure (MEE). First, to confirm the intracerebral distribution of ApoE, we co-stained with GFAP, a marker for astrocytes that biosynthesize ApoE. We sought to investigate whether the ethanol-induced upregulation of LRP1 could potentially inhibit the activity of IL-1β and TNF-α induced IKK-α/β towards NF-κB p65, resulting in a reduction of pro-inflammatory cytokines. To evaluate the actual Aβ load in the brains of APP/PS1 mice, we performed with a specific antibody Aβ (Thioflavin S) on both air- and ethanol-exposed groups, subsequently analyzing Aβ levels. We also measured glucose uptake activity using 18F-FDG in APP/PS1 mice. Finally, we investigated whether MEE induced cognitive and memory changes using the Y maze, noble objective recognition (NOR) test, and Morris water maze (MWM). Results Our findings demonstrate that MEE reduced astrocytic glial fibrillary acidic protein (GFAP) and ApoE levels in the cortex and hippocampus in presymptomatic APP/PS1 mice. Interestingly, increased LRP1 protein expression is accompanied by dampening the IKK-α/β-NF-κB p65 pathway, resulting in decreased IL-1β and TNF-α levels in male mice. Notably, female mice show reduced anti-inflammatory cytokines, IL-4, and IL-10 levels without altering IL-1β and TNF-α concentrations. In both males and females, Aβ plaques, a hallmark of AD, were reduced in the cortex and hippocampus of ethanol-exposed presymptomatic APP/PS1 mice. Consistently, MEE increased fluorodeoxyglucose (FDG)-positron emission tomography (PET)-based brain activities and normalized cognitive and memory deficits in the APP/PS1 mice. Conclusions Our findings suggest that MEE may benefit AD pathology via modulating LRP1 expression, potentially reducing neuroinflammation and attenuating Aβ deposition. Our study implies that reduced astrocyte derived ApoE and LDL cholesterol levels are critical for attenuating AD pathology.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138606058","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 : 2023-12-01DOI: 10.21203/rs.3.rs-3126261/v1
The full text of this preprint has been withdrawn by the authors due to author disagreement with the posting of the preprint. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.
{"title":"WITHDRAWN: Elevated glucose promotes DNA replication and cancer cell growth through pRB-E2F1.","authors":"","doi":"10.21203/rs.3.rs-3126261/v1","DOIUrl":"10.21203/rs.3.rs-3126261/v1","url":null,"abstract":"<p><p>The full text of this preprint has been withdrawn by the authors due to author disagreement with the posting of the preprint. 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":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10371085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10315614","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 : 2023-12-01DOI: 10.21203/rs.3.rs-1297358/v3
V. Feichtenschlager, Linan Chen, Yixuan Zheng, Wilson Ho, Martina Sanlorenzo, I. Vujic, Eleanor Fewings, Albert Lee, Christopher Chen, Ciara Callanan, Kevin Lin, Tiange Qu, Dasha Hohlova, M. Vujic, Yeonjoo Hwang, Kevin Lai, Stephanie Chen, Thuan Nguyen, Denise P Muñoz, Y. Kohwi, C. Posch, Adil Daud, Klemens Rappersberger, T. Kohwi-Shigematsu, Jean-Philippe Coppé, S. Ortiz-Urda
Abstract Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA ( AC004540.4 ) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS . Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS . T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impacton normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.
{"title":"The therapeutically actionable long non-coding RNA ‘T-RECS’ is essential to cancer cells’ survival in NRAS/MAPK-driven melanoma","authors":"V. Feichtenschlager, Linan Chen, Yixuan Zheng, Wilson Ho, Martina Sanlorenzo, I. Vujic, Eleanor Fewings, Albert Lee, Christopher Chen, Ciara Callanan, Kevin Lin, Tiange Qu, Dasha Hohlova, M. Vujic, Yeonjoo Hwang, Kevin Lai, Stephanie Chen, Thuan Nguyen, Denise P Muñoz, Y. Kohwi, C. Posch, Adil Daud, Klemens Rappersberger, T. Kohwi-Shigematsu, Jean-Philippe Coppé, S. Ortiz-Urda","doi":"10.21203/rs.3.rs-1297358/v3","DOIUrl":"https://doi.org/10.21203/rs.3.rs-1297358/v3","url":null,"abstract":"Abstract Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA ( AC004540.4 ) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS . Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS . T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impacton normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138624644","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 : 2023-11-07DOI: 10.21203/rs.3.rs-3546693/v2
Khandoker Rahad, Kianna Martin, Ihunna Amugo, Shania Ferguson, Angela Curtis, Anniya Davis, P. Gangula, Qingguo Wang
Abstract The recent rise of powerful large language model (LLM)-based AI tools, exemplified by ChatGPT and Bard, poses a great challenge to contemporary dental education while simultaneously offering a unique resource and approach that potentially complements today’s teaching and learning, where existing widely available learning resources have often fallen short. Although both the clinical and educational aspects of dentistry will be shaped profoundly by the LLM tools, the didactic curricula, which primarily rely on lecture-based courses where instructors impart knowledge through presentations and discussions, need to be upgraded urgently. In this paper, we used dental course materials, syllabi, and textbooks adopted currently in the School of Dentistry (SOD) at Meharry Medical College to assess the potential utility and effectiveness of ChatGPT in dental education. We collected the responses of the chatbot to questions as well as students' interactions with it for assessment. Our results showed that ChatGPT can assist in dental essay writing and generate relevant content for dental students, in addition to other benefits. The limitations of ChatGPT were also discussed in the paper.
{"title":"ChatGPT to enhance learning in dental education at a historically black medical college","authors":"Khandoker Rahad, Kianna Martin, Ihunna Amugo, Shania Ferguson, Angela Curtis, Anniya Davis, P. Gangula, Qingguo Wang","doi":"10.21203/rs.3.rs-3546693/v2","DOIUrl":"https://doi.org/10.21203/rs.3.rs-3546693/v2","url":null,"abstract":"Abstract The recent rise of powerful large language model (LLM)-based AI tools, exemplified by ChatGPT and Bard, poses a great challenge to contemporary dental education while simultaneously offering a unique resource and approach that potentially complements today’s teaching and learning, where existing widely available learning resources have often fallen short. Although both the clinical and educational aspects of dentistry will be shaped profoundly by the LLM tools, the didactic curricula, which primarily rely on lecture-based courses where instructors impart knowledge through presentations and discussions, need to be upgraded urgently. In this paper, we used dental course materials, syllabi, and textbooks adopted currently in the School of Dentistry (SOD) at Meharry Medical College to assess the potential utility and effectiveness of ChatGPT in dental education. We collected the responses of the chatbot to questions as well as students' interactions with it for assessment. Our results showed that ChatGPT can assist in dental essay writing and generate relevant content for dental students, in addition to other benefits. The limitations of ChatGPT were also discussed in the paper.","PeriodicalId":21039,"journal":{"name":"Research Square","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139285671","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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