Research square最新文献

{"title":"Oral Health Status and Cardinal Symptoms of Depression in the Old Order Amish: a cross-sectional study.","authors":"Teodor T Postolache, Abhishek Wadhawan, Kathy A Ryan, Melanie L Daue, Stefanie Malan-Müller, Aline Dagdag, Hina Makkar, Janna Volkov, Julie Kreyenbuhl, Andrew J Hoisington, Lisa A Brenner, Robert K Ernst, Braxton D Mitchell, Mark A Reynolds","doi":"10.21203/rs.3.rs-10470389/v1","DOIUrl":"10.21203/rs.3.rs-10470389/v1","url":null,"abstract":"<p><strong>Background: </strong>Although results have been mixed, possibly owing to high confounding heterogeneity within and across studies, multiple efforts suggest that tooth loss and periodontitis are associated with depression.</p><p><strong>Methods: </strong>We analyzed questionnaires on dental health and depression obtained as a component of a Wellness study in 4,288 Old Order Amish (mean age = 43.5 ± 16.8 years; 57% women), a population with relatively high genetic and lifestyle homogeneity. Specifically, we obtained questionnaires reporting the use of removable partial/complete dentures (false teeth) and cardinal symptoms of depression (dysphoria/hopelessness and anhedonia), and we analyzed their associations using multivariable logistic regression, with adjustment for age, sex, smoking status, and occupation (farmer vs. non-farmer).</p><p><strong>Results: </strong>We report statistically significant associations between dentures and current (but not \"ever\") depression symptom ratings (p < 0.05). The most robust associations were between current anhedonia AND dysphoria/hopelessness and the presence of any dentures (versus no dentures) (OR 1.760 [1.131, 2.737], p = 0.012), and the presence of complete dentures (versus partial or no dentures) (OR 1.794 [1.008, 3.193], p = 0.047).</p><p><strong>Conclusions: </strong>In this relatively homogeneous population, denture use-particularly complete dentures-was associated with current anhedonia and dysphoria/hopelessness. A primary strength of the study is its relatively homogeneous population, with a low prevalence of smoking-an important confounding factor-and limited access to both prophylactic dental care and fluoridated water, which collectively enhance the reliability of the findings. Limitations include the cross-sectional design and reliance on self-reported data. These findings warrant replication in future longitudinal studies incorporating dental and clinical examinations, imaging, and laboratory biomarkers.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protonation- and substrate-regulated dimer opening couples brain-type creatine kinase to vesicular and actin-remodeling membranes.","authors":"Samantha Gies, Nolan K McLaughlin, Ahmed Shubbar, Chen Kong, Tianqi Wu, Sana Khan, Alessandro Ustione, Ian Miller, David W Piston, Mahmoud Moradi, Michael L Gross, Reza Dastvan","doi":"10.21203/rs.3.rs-10582165/v1","DOIUrl":"10.21203/rs.3.rs-10582165/v1","url":null,"abstract":"<p><p>Brain-type creatine kinase (CK-BB) buffers local ATP demand through reversible phosphotransfer between ATP and phosphocreatine, yet how this soluble metabolic enzyme couples to dynamic membrane compartments remains unclear. Here, we integrate immunofluorescence microscopy, DEER spectroscopy, hydrogen-deuterium exchange and native mass spectrometry, DEER- and AlphaFold-guided modeling, and long-timescale molecular dynamics to define the acid- and substrate-regulated conformational landscape of human CK-BB. Acidification redistributes endogenous and recombinant CK-BB from a diffuse cytosolic pool to punctate vesicular structures and membrane ruffles. DEER and modeling reveal a spatially asymmetric dimer in which the convex surface remains comparatively restrained, whereas the concave catalytic-regulatory surface samples pH- and substrate-dependent conformational intermediates. We identify progressive dimer opening as a novel regulatory mechanism by which acidic pH and substrate binding increase dynamics across the convex surface and NTD-NTD interface and sensitize the His191/Ser199 module to graded pH-dependent exchange. Substrate binding buffers acid-induced deprotection while preserving localized dynamics near this regulatory interface. Together, these data support a model in which protonation and substrate occupancy generate membrane-competent CK-BB conformations, coupling local ATP regeneration to curved vesicular and actin-remodeling membranes.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbiota as a biomarker of tuberculosis treatment response: association with clinical history, inflammation and outcome.","authors":"Grant Theron, Charissa Marsh, Loide Shipingana, Adam Cantor, Suventha Moodley, Happy Tshivhula, Tariq Webber, Zaida Palmer, Tinaye Chiyaka, Hilary Monaco, Benjamin Wu, Yonghua Li, Destiny Collazo, Shivani Singh, Robin Warren, Leanie Kleynhans, Jose Clemente, Leopoldo Segal","doi":"10.21203/rs.3.rs-11050242/v1","DOIUrl":"10.21203/rs.3.rs-11050242/v1","url":null,"abstract":"<p><p>Tuberculosis requires prolonged multidrug therapy. Whether this disrupts the microbiota in ways reflecting previous treatment exposure and outcome is unknown. We performed 16S rRNA gene sequencing on sputum and stool from 107 people with tuberculosis (cases) in a longitudinal cohort, sampled at baseline, month 2, end-of-treatment (month 6), and months 12 and 18, and ≤2 close contacts per case (n=180) at baseline, months 6 and 18. Serum cytokines were quantified in cases (baseline, months 6 and 18) and contacts (baseline). Treatment outcome was defined by month 2 culture-conversion and month 6 culture/smear status. Longitudinal microbial time-series were clustered using LoClust and linked to clinical data. Cases' α-diversity declined initially, recovering by month 6 in sputum and month 12 in stool. Stool β-diversity reductions, driven by Dialister-enrichment and Clostridiales-depletion, persisted to month 18; close contacts remained stable throughout. Unfavourable outcomes showed sputum Pseudomonas- and Mycobacterium gordonae-enrichment and Porphyromonas endodontalis-depletion, and stool Clostridiales-enrichment and Dialister-depletion. Clustering identified five α-diversity trajectories, with declining-diversity trajectories enriched for previous TB. Microbiota-inflammation associations persisted beyond treatment, with Clostridiales independently predicting IP-10 and TNF-α, and Dialister predicting C-reactive protein. Microbiota recovery trajectories are linked to previous tuberculosis, and specific taxa to outcome and inflammation, highlighting biomarker potential.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Device-based measures of physical activity are associated with cognitive function but do not inoculate against later cognitive decline.","authors":"Robert Eves, Justin Hachenberger, Fabio Franzese, Claudia Voelcker-Rehage, Angelina Sutin, David Richter, Sakari Lemola","doi":"10.21203/rs.3.rs-10975193/v1","DOIUrl":"10.21203/rs.3.rs-10975193/v1","url":null,"abstract":"<p><p>Physical activity and sleep are thought to be key protective factors against cognitive decline. However, longitudinal studies with objective measures of physical activity and sleep are still missing. 719 older adults from the Survey of Health, Ageing and Retirement in Europe (SHARE) wore accelerometers over an 8-day period. Cognitive function was measured at baseline and 26 months later. In unadjusted analyses, steps per day and intensity minutes per day at baseline were associated both contemporaneously and longitudinally with cognitive function (betas = 0.22 and 0.23, both <i>p</i> < 0.001). However, in longitudinal analyses that controlled for age, education, and cognitive function at the prior wave, physical activity was no longer significantly associated with cognitive function (beta = 0.04, <i>p</i> = 0.131). Sleep metrics of sleep duration and sleep efficiency were not significantly associated with cognitive function (all betas < 0.21, all <i>p values</i> > 0.090). Alongside other interpretations such as reverse causality, the results are consistent with a concurrent effect of physical activity but not with inoculation effects against cognitive decline 26 months later.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise inhibits doxorubicin-induced cardiotoxicity by preventing cardiac and endothelial cell senescence by activating FNDC5/Irisin signaling.","authors":"Prince Jeyabal, Pradeep Shrestha, Yuanzheng Yang, Fei Wang, Zhanglong Peng, You Zhou, Yan Zheng, Eugenie S Kleinerman","doi":"10.21203/rs.3.rs-10910107/v1","DOIUrl":"10.21203/rs.3.rs-10910107/v1","url":null,"abstract":"<p><p>Exercise's effect on Dox-induced cardiac senescence in the heart was investigated using p16-3MR transgenic mice. Mice treated with doxorubicin (Dox) had decreased cardiac function, increased p16INK4a+ and b-Galactosidase+ senescent cells in the heart, decreased HMGB1 and calreticulin expression, endothelial cell senescence, and decreased TUJ1 expression (indicating reduced axonal density), increased expression of Semaphorin3A and p-cofilin with impaired F-actin depolarization and cytoskeleton disorganization. None of these changes were seen in mice treated with Dox + Exercise. Exercise sustained the levels of FNDC5 in the heart compared with the Dox-treated hearts suggesting a link between exercise, decreased senescence, and the FNDC5/ irisin pathway. In vitro studies using human cardiomyocytes and endothelial cells confirmed that irisin attenuated Dox-induced senescence. Taken together, these data provide evidence that exercise mitigates Dox-induced cardiotoxicity by suppressing cardiovascular senescence via a mechanism involving the exercise-induced myosin irisin, and that exercise is a potential intervention for preventing Dox-induced cardiotoxicity.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunological Correlate of Protection by PHV02 Live, Attenuated Recombinant VSV Vaccine Against Nipah Virus Disease Using an Improved Neutralizing Antibody Method, with Considerations for Future Research.","authors":"Thomas P Monath, Richard Nichols, Wasima Rida, Joan S Fusco","doi":"10.21203/rs.3.rs-10860842/v1","DOIUrl":"https://doi.org/10.21203/rs.3.rs-10860842/v1","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Establishing the immune correlate of protection for a vaccine could be the basis for regulatory approval. The immune correlate of PHV02, a clinical-stage recombinant vesicular stomatitis (rVSV) vaccine against Nipah virus (NiV) disease, was investigated in the African green monkey (AGM) model. Although a mechanistic immune correlate is not required, the focus was on neutralizing antibody, which is the mediator of protection against future viral infection. Two experimental approaches were used to determine the correlation between neutralizing antibody levels, survival, and viral and clinical outcomes after 100% lethal intranasal/intratracheal (IN/IT) challenge with NiV (Bangladesh): 1) reduction in vaccine dose given 28 days before challenge; and 2) challenge at early times after vaccination. In a previous publication of the results of these studies, a neutralization test employing wild type NiV (wt NT) under high (BSL-4) biocontainment was employed. Since this is not sustainable for immunological testing in multiple clinical trials, we developed and qualified a pseudovirus microneutralization test (VNA) using a non-replicating rVSV expressing NiV F and G envelope proteins and luciferase that can be performed at BSL-2. Sera from the two studies in the AGM model were re-tested using the VNA method. There was a high correlation between the VNA and wt NT. We confirmed that reduction in PHV02 vaccine dose to very low levels led to primary vaccine failure rather than a sub-protective level of antibody, a feature common to other replication-competent live vaccines. All AGMs survived when vaccinated with PHV02 at a dose (2 x 10 &lt;sup&gt;7&lt;/sup&gt; pfu) employed in clinical trials 21, 14 or 7 days before challenge. Neutralizing antibodies by VNA appeared by Day 13-14 after vaccination and increased by Day 20-21, reaching high titers (GMT &gt; 1000). AGMs vaccinated 7 days before challenge had low or undetectable neutralizing antibody titers pre-challenge but also survived; these animals were on the cusp of an immune response when subjected to NiV challenge. AGMs vaccinated on Day - 21 were protected against illness whereas 4 (67%) of 6 survivor AGMs vaccinated on Day - 14 before challenge and 5 (83%) of 6 survivor AGMs vaccinated on Day - 7 before challenge had signs of illness from which they recovered. Thus, the frequency and severity of sub-lethal clinical illness decreased as time between vaccination and challenge was increased. Since high titers of VNA antibody were already present by Day 13/14, other factors such as affinity maturation of neutralizing antibody likely played a role in preventing clinical signs. A simple logistic regression model of the combined studies was used in which the sole explanatory variable was pre-challenge neutralizing antibody titers. For a pre-challenge VNA titer of 1:12 [the lower level of quantitation and representing a two-fold rise (seroresponse) from the imputed baseline of LLOQ/2], the predicted survival probability is","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence and genotype distribution of human papillomavirus (HPV) among adolescent girls and young women in a high HIV burden rural area of South Africa: a cross-sectional survey.","authors":"Maphe Mthembu, Kathy Baisley, Jacob Busang, Nqobile Ngoma, Nonsikelelo Ndlela, Nonhlanhla Okesola, Carina Herbst, Thandeka Khoza, Jaco Dreyer, Lenine Liebenberg, Zaza Ndhlovu, Maryam Shahmanesh","doi":"10.21203/rs.3.rs-10548481/v1","DOIUrl":"10.21203/rs.3.rs-10548481/v1","url":null,"abstract":"<p><strong>Background: </strong>Human papillomavirus (HPV) is the primary cause of cervical cancer, with women living with HIV at increased risk of HPV infection and HPV-related disease. Data on HPV prevalence and genotype distribution among adolescent girls and young women (AGYW) in rural South African settings remain limited. We estimated HPV prevalence, genotype distribution, and factors associated with HPV infection among AGYW in a high HIV prevalence district of KwaZulu-Natal, South Africa.</p><p><strong>Methods: </strong>This cross-sectional study was nested within the baseline survey of the Thetha Nami population-based trial among young people aged 15-30 years in rural uMkhanyakude District, KwaZulu-Natal. Survey participants were asked to provide dried blood spots for HIV testing and genital swabs for STI testing. For this study, we selected AGYW living with HIV with available vaginal swabs and a frequency-matched sample of AGYW without HIV. HPV genotyping was done using the HPV Direct Flow Chip Kit (Master Diagnostica, Spain). Genotype-specific HPV prevalence was described overall and by HIV status. Logistic regression was used to identify factors associated with HPV infection.</p><p><strong>Results: </strong>Among 187 AGYW with valid HPV results, 90 (48.1%) were living with HIV. Overall HPV prevalence was 69.1% (95% confidence interval (CI) = 54.5-80.7%) and high-risk (hr)HPV prevalence was 57.3% (95%CI = 44.1-69.6%). HPV prevalence was higher among AGYW living with HIV than among AGYW without HIV (84.6% vs 64.6%, p = 0.02). HPV genotype distribution varied by HIV status: HPV35, HPV45 and HPV58 were the most prevalent hrHPV genotypes among AGYW living with HIV, vs HPV52, HPV56 and HPV31 among AGYW without HIV. No HPV16 or HPV18 infections were detected among participants who were age-eligible for the national HPV vaccination programme. Reported condomless sex (adjusted odds ratio (1) 2.23, 95%CI = 1.06-4.70) and the presence of another sexually transmitted infection (aOR = 4.30, 95%CI = 1.52-12.20) were associated with HPV infection.</p><p><strong>Conclusions: </strong>AGYW in rural uMkhanyakude experience a high burden of hrHPV infection, especially those living with HIV. Regardless of HPV vaccination status not being confirmed, no HPV 16/18 was detected among vaccine-eligible AGYW. The higher prevalence of non-HPV16/18 hrHPV genotypes covered by the nonavalent vaccine highlights the potential value of vaccines with broader genotype coverage. These findings support expanding HPV screening and cervical cancer prevention programmes in high HIV prevalence settings.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting transitions between functional and financial vulnerability states and death in older Chinese adults: a longitudinal CHARLS study with temporal evaluation.","authors":"Tianrun Piao, Aiqun He, Jingbo Li","doi":"10.21203/rs.3.rs-10694017/v1","DOIUrl":"10.21203/rs.3.rs-10694017/v1","url":null,"abstract":"<p><strong>Background: </strong>Functional decline can increase care needs at the same time that out-of-pocket spending constrains continued treatment and rehabilitation. Existing studies usually predict these outcomes separately and therefore cannot identify older adults moving into joint functional and financial vulnerability. We developed a multistate model and tested whether its predictions remained informative in later CHARLS waves.</p><p><strong>Methods: </strong>We used 2011-2018 Harmonized China Health and Retirement Longitudinal Study data. Adults aged at least 60 years contributed adjacent-wave observations. Four living states combined basic-activity difficulty and household catastrophic health expenditure, defined as out-of-pocket health spending at least 40% of non-food expenditure; death was the fifth state. Penalized multinomial regression and XGBoost were developed in 2011-2015 and evaluated without updating in 2015-2018. Penalized regression was primary because it matched XGBoost while remaining transparent. The locked model was applied to 2018 origins for exploratory 2020 validation of observable death and ADL components.</p><p><strong>Results: </strong>The analysis comprised 12,866 transitions from 7,353 participants; 5,175 formed the 2015-2018 evaluation set, including 361 dual-vulnerability outcomes and 389 deaths. Penalized regression achieved a macro-AUROC of 0.722 (95% CI 0.712-0.734) and Brier score of 0.570 (0.557-0.583). AUROCs were 0.728 for dual vulnerability, 0.755 for death, and 0.629 for CHE alone. XGBoost did not improve macro-AUROC (0.720). Of 8,532 eligible 2018 origins, 8,004 had death or ADL status observed in 2020. Exploratory component AUROCs were 0.813 for death and 0.801 for ADL difficulty or death. The highest-risk 20% contained 53.5% of deaths and 46.1% of dual-vulnerability-or-death outcomes.</p><p><strong>Conclusions: </strong>Joint functional-financial states were dynamic and prognostically distinct. A transparent penalized model provided moderate discrimination for dual vulnerability and death in the complete five-state evaluation and identified a manageable high-risk stratum for coordinated functional and financial review. The 2020 analysis supported only the observable clinical components. Isolated CHE remained difficult to forecast without detailed reimbursement, local-cost, and long-term-care information.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changes in Menopause Stage, Body Mass, and Fat Mass as Drivers of Midlife Changes in C-reactive Protein Levels: A Prospective Cohort Study.","authors":"Arun S Karlamangla, Wei Juan Han, Duncan Thomas, Samar El Khoudary, Sherri-Ann Burnett-Bowie, Carrie Karvonen-Gutierrez, Sybil Crawford, Gail Greendale","doi":"10.21203/rs.3.rs-10924459/v1","DOIUrl":"10.21203/rs.3.rs-10924459/v1","url":null,"abstract":"<p><strong>Background: </strong>Serum levels of C-reactive protein (CRP), a marker of chronic inflammation, increase in many, but not all, women going through the menopause transition (MT). It is not known whether this is driven entirely by changes in body mass and fat mass in midlife or by other physiological changes during the MT.</p><p><strong>Methods: </strong>We use individual fixed effects analysis of repeated measurements across the MT, in a multi-ethnic cohort of 1681 women followed for over two decades (1996-2018), to address this knowledge gap; we also test whether associations between body mass increase (likewise fat mass increase) and CRP increase differ by race/ethnicity.</p><p><strong>Results: </strong>Adjusted for changes in body mass index (BMI), change in menopause stage was not associated with change in CRP. Every kg/m² within-woman increase in BMI was associated with 16% increase in serum CRP (p<.0001). Similarly, every kg/m² within-woman increase in fat mass index (total fat mass divided by square of height, FMI) was associated with 23% increase in serum CRP (p<.0001). The association of BMI increase with CRP increase was smaller in Black than in White women: 12% vs. 18% per kg/m² (p = 0.03 for test of difference), but not statistically different in Chinese and Japanese women relative to White women. On the other hand, race/ethnicity did not modify the association of FMI increase with CRP increase, but the association was modestly smaller in natural and surgical postmenopause than in premenopause: 20% and 15% vs. 22% per kg/m², respectively (p = 0.001 and 0.05 for tests of difference).</p><p><strong>Conclusions: </strong>Midlife increases in CRP levels in women are not directly related to menopause stage but appear to be driven by increases in body mass, particularly fat mass. While changes in body mass have different implications for CRP changes in Black vs. White women, increases in fat mass have similar associations with CRP increases in Black and White women. However, changes in fat mass have modestly smaller associations with CRP changes in postmenopause than before the MT.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early emergence of contractility and mechanotransduction during human megakaryopoiesis.","authors":"Oleg V Kim, Rustem I Litvinov, Deborah L French, Lawrence F Brass, Giulia Pavani, John W Weisel","doi":"10.21203/rs.3.rs-10882232/v1","DOIUrl":"10.21203/rs.3.rs-10882232/v1","url":null,"abstract":"<p><p>The ability to contract blood clots is a hallmark of functional platelets. Proteins that support agonist-induced platelet contraction are expressed in megakaryocytes (MKs) and transferred to platelets during thrombopoiesis. Here, we investigated when during MK development the functional machinery for contraction emerges. Human induced pluripotent stem cells (iPSCs) were differentiated into embryonic hematopoietic progenitor cells (HPCs) and further matured into MKs (iMKs) to map the emergence of contractility and mechanotransduction across differentiation. Expression of total (CD41) and activated (mAb PAC-1) αIIbβ3 integrin, the thrombin receptor PAR1, and the MK marker CD42b was quantified by flow cytometry. Cell contractility was assessed by optically tracking human plasma clot shrinkage following thrombin stimulation. Undifferentiated iPSCs lacked detectable αIIbβ3 and were non-contractile. Both HPCs and iMKs exhibited agonist-induced contractility, integrin activation, and force transmission to extracellular fibrin, although at different levels. Following thrombin stimulation, activated αIIbβ3 on the cell surface was approximately 5-fold lower in HPCs and restricted to the MK-committed CD42b⁺ subset, indicating that integrin activation is linked to MK commitment. Functionally, both HPCs and iMKs induced clot contraction but with distinct kinetics and magnitude, with HPCs exhibiting approximately 2.5-fold lower contraction rates and final extent. Depletion of CD42b⁺ cells from HPCs reduced contraction to baseline, identifying early MK-lineage progenitors as the principal contractile population at this stage. These findings demonstrate that cellular contractility and αIIbβ3-mediated mechanotransduction emerge early during MK lineage commitment, establishing contractility as an early functional hallmark of megakaryocyte differentiation.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169474","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}