bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of long-term rapamycin treatment on age-related osteoarthritis in common marmoset
Authors: Minton Dennis M. , Ailiani Aditya R. , Focht Michael D.K. , Kersh Mariana E. , Marolf Angela J. , Santangelo Kelly S , Salmon Adam B. , Konopka Adam R. 
Published: May 2024

AbstractObjectivePharmacologic inhibition of the mechanistic target of rapamycin (mTOR) can attenuate experimental osteoarthritis (OA) in young, male preclinical models. However, the potential of mTOR inhibition as a therapeutic mechanism for OA remains unknown. The goal of this study was to determine if mTOR-inhibition by oral rapamycin can modify OA pathology in the common marmoset, a translational model of age-associated OA.MethodsmicroCT and histopathologic assessments of the knee were performed on formalin-fixed hindlimbs obtained from common marmosets treated with oral rapamycin (n=24; 1mg/kg/day) or parallel control group (n=41). Rapamycin started at 9.2±3.0 years old and lasted until death (2.1±1.5 years). In a subset of marmosets, contralateral hind limbs were collected to determine mTOR signaling in several joint tissues.ResultsRapamycin decreased P-RPS6Ser235/36and increased P-Akt2Ser473in cartilage, meniscus, and infrapatellar fat pad, suggesting inhibition of mTORC1 but not mTORC2 signaling. Rapamycin-treated marmosets had lower lateral synovium score versus control but there was no difference in the age-related increase in microCT or cartilage OA scores. Subchondral bone thickness and thickness variability were not different with age but were lower in rapamycin-treated geriatric marmosets, which was largely driven by females. Rapamycin also tended to worsen age-related meniscus calcification in female marmosets.ConclusionOral rapamycin attenuated mTORC1 signaling and may have caused feedback activation of mTORC2 signaling in joint tissues. Despite modifying site-specific aspects of synovitis, rapamycin did not modify the age-associated increase in OA in geriatric marmosets. Conversely, rapamycin may have had deleterious effects on meniscus calcification and lateral tibia subchondral bone, primarily in geriatric female marmosets.
TGFβ1 plasma levels and clot lysis assay to better characterize patients after a first unprovoked episode of pulmonary embolism
Authors: des Deserts Marc Danguy , de Moreuil Claire , Elhasnaoui Jamal , Gourhant Lenaïck , Gourdou-Latyszenok Virginie , Espinasse Benjamin , Menguy Juliette , Tromeur Cécile , Le Corre Rozenn , Le Mao Raphael , Kraemmer Daniel , Sanchez Olivier ,   PADIS-PE investigators, Couturaud Francis , Lemarié Catherine A. 
Published: May 2024

AbstractIntroductionThe pathophysiology of residual pulmonary vascular obstruction (RPVO) and recurrent venous thromboembolism (VTE) after unprovoked pulmonary embolism (PE) remains poorly understood. The purpose was to evaluate fibrinolytic and tissue remodeling markers as indicators of RPVO and recurrence after a first unprovoked PE.MethodsAnalyses were conducted in the 18 to 70-year-old patients included in the PADIS-PE trial, with a pulmonary vascular obstruction (PVO) index ≥30% at PE diagnosis. After an initial six-month vitamin K antagonist treatment, patients were randomised to receive placebo or warfarin for 18 months, assessed for the absence or presence of residual pulmonary vascular obstruction (RPVO < or ≥5%, respectively) and followed during two years. Quantitative assessment of fibrinolytic (D-dimer, tPA, uPA, TFPI) and tissue remodeling (TGFß1) markers, and a tissue-factor-based turbidimetric clot lysis assay (CLA) were performed one month after warfarin discontinuation.ResultsAmong the 371 patients included in PADIS-PE, 23 were eligible. Six (26%) patients presented RPVO ≥ 5%, symptomatic recurrent VTE occurred in nine (39%) patients. Clot formation and lysis parameters were not associated with RPVO. TGFß1 plasma levels were higher in patients with RPVO. Clot formation potential measured with CLA was higher in patients with recurrent VTE. No association between recurrent VTE and TGFß1 was observed. In multivariable analysis, time to peak was associated with VTE recurrence.ConclusionIn adult patients with a first unprovoked PE and a PVO index ≥30%, TGFß1 plasma level was associated with RPVO, whereas clot formation parameters measured with CLA were associated with VTE recurrence.
Bias in the estimated reporting fraction due to vaccination in the time-series SIR model
Authors: Leung Tiffany , Ferrari Matthew 
Published: May 2024

AbstractThe time-series Susceptible-Infectious-Recovered (TSIR) model has been a standard tool for studying the non-linear dynamics of acute, immunizing infectious diseases. The standard assumption of the TSIR model, that vaccination is equivalent to a reduction in the recruitment of susceptible individuals, or the birth rate, can lead to a bias in the estimate of the reporting fraction and of the total incidence. We show that this bias increases with the level of vaccination due to a double-counting of individuals who are infected prior to the age of vaccination. We present a simple correction for this bias by discounting the observed number of cases by the product of the number that occur prior to the average age of vaccination and the vaccination coverage during the initial susceptible reconstruction step of the TSIR model fitting. We generate a time series of measles cases using an age-structured SIR transmission model with vaccination after birth (at 9 months of age) and illustrate the bias with the standard TSIR fitting method. We then illustrate that our proposed correction eliminates the bias in the estimated reporting fraction and total incidence. We note further that this bias does not impact the estimates of the seasonality of transmission.
Association between BMI and cause-specific long-term mortality in acute myocardial infarction patients
Authors: Schmitz Timo , Freuer Dennis , Raake Philip , Linseisen Jakob , Meisinger Christa 
Published: May 2024

AbstractBackgroundTo investigate the association between body mass index (BMI) at acute myocardial infarction (AMI) and all-cause as well as cause-specific long-term mortality.MethodsThe analysis was based on 10,651 hospitalized AMI patients (age 25-84 years) recorded by the population-based Myocardial Infarction Registry Augsburg between 2000 and 2017. The median follow-up time was 6.7 years [IQR: 3.5-10.0)]. Cause-specific mortality was obtained by evaluating the death certificates. In multivariable-adjusted COX regression models using cubic splines for the variable BMI, the association between BMI and cause-specific mortality (all-cause, cardiovascular, ischemic heart diseases, cancer) was investigated. Additionally, a subgroup analysis in three age groups was performed for all-cause mortality.ResultsOverall, there was a statistically significant U-shaped association between BMI at AMI and long-term mortality with the lowest hazard ratios (HR) found for BMI values between 25 and 30 kg/m². For cancer mortality, higher BMI values > 30 kg/m² were not associated with higher mortality. In patients aged <60 years, there was a significant association between BMI values > 35 kg/m² and increased all-cause mortality; this association was missing in 60 to 84 years old patients. For all groups and for each specific cause of mortality, lower BMI (< 25kg/m²) values were significantly associated with higher mortality.ConclusionsOverall, a lower BMI – and also a high BMI in patients younger than 60 years - seem to be a risk factors for increased all-cause mortality after AMI. A BMI in a mid-range between 25 and 30 kg/m² is favorable in terms of long-term survival after AMI.What is Known?Obesity is considered a major risk factor for cardiovascular diseases and coronary artery disease.Nonetheless, the results of prior studies indicated lower mortality for overweight and obese individuals after acute myocardial infarction (AMI); a phenomenon often called ‘obesity paradox’.What the Study AddsThis study analyzed the association between body mass index (BMI) and cause-specific long-term mortality after AMI in a population-based cohort of 10.000 AMI patients recorded by the Myocardial Infarction Registry Augsburg.The obesity paradox was partially confirmed, as we found a U-shaped association between BMI and long-term mortality with the lowest risk of mortality in overweight individuals.For cancer mortality and in elderly, obesity (BMI > 30 kg/m²) was not associated with mortality. Lower BMI < 25 kg/m² went along with significantly higher mortality in all age groups and for all causes of death (all-cause, cardiovascular, ischemic heart disease, cancer)
The dynamic impact of location and resection on the glioma CSF proteome
Authors: Riviere-Cazaux Cecile , Graser Christopher J. , Warrington Arthur E. , Hoplin Matthew D. , Andersen Katherine M. , Malik Noor , Palmer Elizabeth A. , Carlstrom Lucas P. , Dasari Surendra , Munoz-Casabella Amanda , Ikram Samar , Ghadimi Keyvan , Himes Benjamin T. , Jusue-Torres Ignacio , Sarkaria Jann N. , Meyer Fredric B. , Van Gompel Jamie J. , Kizilbash Sani H. , Sener Ugur , Michor Franziska , Campian Jian L. , Parney Ian F. , Burns Terry C. 
Published: May 2024

ABSTRACTWhile serial sampling of glioma tissue is rarely performed prior to recurrence, cerebrospinal fluid (CSF) is an underutilized longitudinal source of candidate glioma biomarkers for understanding therapeutic impacts. However, the impact of key variables to consider in longitudinal CSF samples, including anatomical location and post-surgical changes, remains unknown. To that end, pre- versus post-resection intracranial CSF samples were obtained at early (1-16 days; n=20) or delayed (86-153 days; n=11) timepoints for patients with glioma. Paired lumbar-versus-intracranial glioma CSF samples were also obtained (n=14). Using aptamer-based proteomics, we identify significant differences in the CSF proteome between lumbar, subarachnoid, and ventricular CSF. Our analysis of serial intracranial CSF samples suggests the early potential for disease monitoring and evaluation of pharmacodynamic impact of targeted therapies. Importantly, we found that resection had a significant, evolving longitudinal impact on the CSF proteome. Proteomic data are provided with individual clinical annotations as a resource for the field.One Sentence SummaryGlioma cerebrospinal fluid (CSF) accessed intra-operatively and longitudinally via devices can reveal impacts of treatment and anatomical location.
The number of effectors limits the relative sleep gain: Insights from seven finger tapping experiments
Authors: Erlacher Daniel , Schmid Daniel 
Published: May 2024

AbstractThe role of sleep in motor memory consolidation is still a matter of ongoing debate. A classic task to investigate mechanisms of motor memory consolidation is the finger tapping task, which reliably shows small effects in performance enhancement after sleep but not after a corresponding wake interval. However, variants of the task with a varying number of effectors (e.g., one hand) failed to demonstrate this effect on motor memory consolidation. Thus, in a series of seven experiments we investigate five variants of the classic finger tapping task in which the number of effectors (1 or 2 hands combined with 1, 2 or 4 fingers) used to perform the task are systematically varied. For the groups, where sleep immediately followed learning, a beneficial effect of sleep in comparison with a corresponding wake interval was found, except for the task variant where the finger tapping task was performed with 1 hand and 1 finger. However, no clear-cut pattern could be identified for the numbers of effectors used to perform the task and the magnitude of offline motor memory consolidation. Furthermore, for groups with an intervening wake interval between learning and sleep no differences between the post-sleep and post-wake gain were observed.HighlightsIn a variation of the classical finger tapping task with one hand and one finger, no sleep-dependent enhancement was found.In all other variations, small to large effects of sleep-dependent offline-gains were found.An interposed wake interval between learning and sleep substantially diminishes the post-sleep enhancement.Motor skill complexity, with respect to the coordination of more than one effector, does partially play a role in predicting sleep-dependent motor memory enhancement.
Crystal structure determination of the antipsychotic drug of olanzapine form III
Authors: Anyfanti Goulielmina , Husanu Elena , Andrusenko Iryna , Marchetti Danilo , Gemmi Mauro 
Published: May 2024

AbstractOlanzapine, an antipsychotic drug, is well known for its complex polymorphism. Although widely investigated, the crystal structure of one of its anhydrous polymorphs, form III, is still unknown. Its appearance, always in concomitance with form II and I, and the impossibility of isolating it from that mixture, has prevented its structure determination so far. The scenario has changed with the emerging field of 3D electron diffraction (3D ED) technique and its great advantages in the characterization of polyphasic mixture of nanosized crystals. In this study we show how the application of 3D ED allows the ab-initio structure determination and dynamical refinement of this elusive crystal structure unknown for more than 20 years. Olanzapine form III is monoclinic and shows a similar but shifted packing with respect to form II. It is remarkably different from the lowest energy structures predicted by the energy minimization algorithms of crystal structure prediction.
TbpB-based oral mucosal vaccine provides heterologous protection against Glässer’s disease caused by different serovars of Spanish field isolates ofGlaesserella parasuis
Authors: González-Fernández Alba , Mencía-Ares Oscar , García-Iglesias María José , Petrocchi-Rilo Máximo , Miguélez-Pérez Rubén , Perelló Jiménez Alberto , Herencia-Lagunar Elena , Acebes-Fernández Vanessa , Gutiérrez-Martín César B. , Martínez-Martínez Sonia 
Published: May 2024

AbstractBackgroundGlaesserella parasuishas a substantial impact on the pig production as the primary agent of Glässer’s disease, particularly affecting nursery and early fattening stages. Current prophylactic measures, mainly based in serovar-specific bacterins administered parenterally to sows, face limitations due to maternal immunity, which may interfere with the active immunization of piglets. The mucosal administration of TbpB-based subunit vaccines offers a promising approach to overcome these limitations for the control of the disease in weaning piglets. This study evaluates the immunogenicity and heterologous protection of the oral mucosal TbpBY167Asubunit vaccine in colostrum-deprived piglets challenged with fourG. parasuisclinical isolates belonging to different TbpB clusters and serovars (SVs) recovered from Spanish pig farms.ResultsThe mucosal administration of a two-dose TbpB-based vaccine induced a robust humoral immune response in immunized colostrum-deprived piglets, significantly increasing IgA (p <0.01) and IgM (p <0.01) concentration 15 days after the second dose. Subsequent infection challenge with fourG. parasuisclinical isolates demonstrated heterologous protection, markedly improving survival rates (OR: 8.45; CI 95%: 4.97-14.36) and significantly reducing clinical signs and lesions, regardless of theG. parasuisTbpB cluster and serovar. The vaccine not only reducedG. parasuiscolonization in the respiratory tract of immunized piglets (p< 0.0001), but also in systemic target tissues, such as the tarsus and carpus joints, liver, and brain (p< 0.05). Further immunohistochemical analysis in different lung locations revealed a significantly lower macrophage count in immunized piglets (p< 0.0001).ConclusionsOverall, this study demonstrates that the oral mucosal administration of the TbpBY167Asubunits vaccine in piglets provides effective heterologous protection against different virulent EuropeanG. parasuisfield isolates, significantly reducing bacterial colonization and dissemination. These facts position this TbpB-based vaccine as a leading candidate for a universal vaccine against Glässer’s disease.
Gynura procumbensLeaf Extract-Loaded Self-Microemulsifying Drug Delivery System Offers Enhanced Protective Effects in the Hepatorenal Organs of the Experimental Rats
Authors: Shill Manik Chandra , Jalal Md. Faisal Bin , Shuma Madhabi Lata , Mollick Patricia Prova , Muhit Md. Abdul , Halder Shimul 
Published: May 2024

AbstractGynura procumbens, known as longevity spinach, is a plant traditionally used in tropical Asian countries for its anti-inflammatory, hepatoprotective, anti-hypertensive, anti-hyperglycemic, and anti-inflammatory properties. The current study aimed to enhance the hepatorenal protective activity ofGynura procumbensleaf extract (GLE) by developing a self-microemulsifying drug delivery system (SMEDDS). SMEDDS-GLE exhibited the formation of small micelles with a mean droplet size of 231 nm. This resulted in a significant enhancement in the dispersion of GLE in water, as evidenced by a dispersibility that was at least 4.8 times greater than that of GLE alone. In the rat model of hepatic injury induced by cisplatin (7.5 mg/kg,i.p.), the administration of SMEDDS-GLE (75 mg-GLE/kg,p.o.) significantly reduced liver damage, observed by histological examination and reduced levels of plasma biomarkers associated with hepatic injury. Furthermore, according to histological examination findings and plasma biomarkers assessment, SMEDDS-GLE enhanced nephroprotective benefits of GLE in the rat model of acute kidney injury. Based on these findings, a strategic application of the SMEDDS-based approach could be a viable choice to enhance GLE’s nutraceutical properties.
Mitochondria-targeted hydrogen sulfide donor reduces atherogenesis by reprogramming macrophages and increasing UCP1 expression in vascular smooth muscle cells
Authors: Stachowicz Aneta , Wiśniewska Anna , Czepiel Klaudia , Pomierny Bartosz , Skórkowska Alicja , Kuśnierz-Cabala Beata , Surmiak Marcin , Kuś Katarzyna , Wood Mark E. , Torregrossa Roberta , Whiteman Matthew , Olszanecki Rafał 
Published: May 2024

AbstractAimsAtherosclerosis is a leading cause of morbidity and mortality in the Western countries. A growing body of evidence points to the role of mitochondrial dysfunction in the pathogenesis of atherosclerosis. Recently, it has been shown that mitochondrial hydrogen sulfide (H2S) can complement the bioenergetic role of Krebs cycle leading to improved mitochondrial function. However, controlled, direct delivery of H2S to mitochondria was not investigated as a therapeutic strategy in atherosclerosis. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with mitochondrial H2S donor AP39 on the development of atherosclerotic lesions in apolipoprotein E knockout (apoE-/-) mice.ResultsOur results indicated that AP39 reduced atherosclerosis in apoE-/-mice and stabilized atherosclerotic lesions through decreased total macrophage content and increased collagen depositions. Moreover, AP39 reprogrammed macrophages from proinflammatory M1 to anti-inflammatory M2 in atherosclerotic lesions. It also upregulated pathways related to mitochondrial function, such as cellular respiration, fatty acid β-oxidation and thermogenesis while downregulated pathways associated with immune system, platelet aggregation and complement and coagulation cascades in the aorta. Furthermore, treatment with AP39 increased the expression of mitochondrial brown fat uncoupling protein 1 (UCP1) in vascular smooth muscle cells (VSMCs) in atherosclerotic lesions and upregulated mRNA expression of other thermogenesis-related genes in the aorta but not perivascular adipose tissue (PVAT) of apoE-/-mice. Finally, AP39 treatment decreased markers of activated endothelium and increased endothelial nitric oxide synthase (eNOS) expression and activation.ConclusionsTaken together, mitochondrial H2S donor AP39 could provide potentially a novel therapeutic approach to the treatment/prevention of atherosclerosis.
Learning precise segmentation of neurofibrillary tangles from rapid manual point annotations
Authors: Ghandian Sina , Albarghouthi Liane , Nava Kiana , Sharma Shivam R. Rai , Minaud Lise , Beckett Laurel , Saito Naomi , DeCarli Charles , Rissman Robert A. , Teich Andrew F. , Jin Lee-Way , Dugger Brittany N. , Keiser Michael J. 
Published: May 2024

AbstractAccumulation of abnormal tau protein into neurofibrillary tangles (NFTs) is a pathologic hallmark of Alzheimer disease (AD). Accurate detection of NFTs in tissue samples can reveal relationships with clinical, demographic, and genetic features through deep phenotyping. However, expert manual analysis is time-consuming, subject to observer variability, and cannot handle the data amounts generated by modern imaging. We present a scalable, open-source, deep-learning approach to quantify NFT burden in digital whole slide images (WSIs) of post-mortem human brain tissue. To achieve this, we developed a method to generate detailed NFT boundaries directly from single-point-per-NFT annotations. We then trained a semantic segmentation model on 45 annotated 2400µm by 1200µm regions of interest (ROIs) selected from 15 unique temporal cortex WSIs of AD cases from three institutions (University of California (UC)-Davis, UC-San Diego, and Columbia University). Segmenting NFTs at the single-pixel level, the model achieved an area under the receiver operating characteristic of 0.832 and an F1 of 0.527 (196-fold over random) on a held-out test set of 664 NFTs from 20 ROIs (7 WSIs). We compared this to deep object detection, which achieved comparable but coarser-grained performance that was 60% faster. The segmentation and object detection models correlated well with expert semi-quantitative scores at the whole-slide level (Spearman’s rho ρ=0.654 (p=6.50e-5) and ρ=0.513 (p=3.18e-3), respectively). We openly release this multi-institution deep-learning pipeline to provide detailed NFT spatial distribution and morphology analysis capability at a scale otherwise infeasible by manual assessment.
Endocardial primary cilia and blood flow are required for regulation of EndoMT during endocardial cushion development
Authors: Berg Kathryn , Gorham Joshua , Lundt Faith , Seidman Jonathan , Brueckner Martina 
Published: May 2024

SummaryBlood flow is critical for heart valve formation, and cellular mechanosensors are essential to translate flow into transcriptional regulation of development. Here, we identify a role for primary ciliain vivoin the spatial regulation of cushion formation, the first stage of valve development, by regionally controlling endothelial to mesenchymal transition (EndoMT) via modulation ofKruppel-like Factor 4 (Klf4). We find that high shear stress intracardiac regions decrease endocardial ciliation over cushion development, correlating with KLF4 downregulation and EndoMT progression. Mouse embryos constitutively lacking cilia exhibit a blood-flow dependent accumulation of KLF4 in these regions, independent of upstream left-right abnormalities, resulting in impaired cushion cellularization. snRNA-seq revealed that cilia KO endocardium fails to progress to late-EndoMT, retains endothelial markers and has reduced EndoMT/mesenchymal genes that KLF4 antagonizes. Together, these data identify a mechanosensory role for endocardial primary cilia in cushion development through regional regulation of KLF4.