bluuebunny/crossref_metadata_2025_split huggingface dataset:
LTBK-08. Inferring cell type and cell state composition in glioblastoma from bulk DNA methylation profiles using multi-omic single-cell analyses
Authors: Silverbush Dana , Suva Mario , Hovestadt Volker 
Published: November 2022

Abstract

OBJECTIVE
Cellular heterogeneity determines tumor phenotype and response to therapy. This is particularly pronounced in glioblastoma (GBM), which is characterized by multiple malignant cell states with distinct proliferation potentials, and different cell types of the microenvironment. Ideally, cellular heterogeneity is characterized using single cell genomic profiling techniques. However, these techniques remain challenging to apply in a diagnostic setting and to large retrospective patient cohorts (TCGA, GLASS, DKFZ and clinical trials). Instead, clinicians routinely support their diagnosis with bulk DNA methylation profiling, which generates robust results from low quality material but does not inform on cellular heterogeneity. We have developed a powerful new computational method to deconvolute bulk DNA methylation data and infer cellular heterogeneity within individual tumors, to support prognostic accuracy and personalized treatment decisions.

METHODS
Using both bulk and single-cell multi-omic datasets, we created a DNA methylation-based reference of cell types (malignant, glial, neuronal, and immune) within GBM tumors, and the state of malignant cells therein (stem-like vs. differentiated-like). Using this reference, our computational approach accurately deconvolutes bulk DNA methylation profiles of individual query samples.

RESULTS
High deconvolution accuracy of GBM heterogeneity was achieved from frozen and FFPE tissue samples, including those of low quality or purity (Jensen Shannon divergence for composition similarity &lt; 0.05). Our approach eliminates bias derived from the microenvironment, and results in patient stratification that harmonizes the DNA methylation- and RNA-based classifications of GBM. It also reveals the inter- and intra-tumoral links between the genetic, DNA methylation, and transcriptomic components of GBM pathology, and suggests their specific impacts on treatment efficacy. To facilitate clinical translation, we created a public website that allows clinicians to infer the relative abundance of different cell states within a tumor at the click of a button.
Stable HIV Reservoir Despite Prolonged Low-Dose Mycophenolate to Limit CD4+ T-cell Proliferation
Authors: Schiffer Joshua T , Levy Claire , Hughes Sean M , Pandey Urvashi , Padullo Mel , Jerome Keith R , Zhu Haiying , Puckett Katrina , Helgeson Eric , Harrington Robert D , Hladik Florian 
Published: November 2022

Abstract

Background
The HIV reservoir of latently infected CD4+ T cells represents the barrier to cure. CD4+ T-cell proliferation is a mechanism that sustains the reservoir even during prolonged antiretroviral therapy (ART). Blocking proliferation may therefore deplete the reservoir.

Methods
We conducted an unblinded, uncontrolled clinical trial of mycophenolate, a T-cell antiproliferative compound, in people with HIV on chronic suppressive ART. Study drug dose selection was based on calibration to an observed ex vivo antiproliferative effect. The primary outcome was clinically significant reduction (&gt;0.25 log10) in the HIV reservoir, measured by total and intact HIV DNA per million T cells in blood over 48 weeks.

Results
Five participants enrolled in the trial. Four participants took mycophenolate mofetil (MMF). One had a per-protocol switch to enteric-coated mycophenolate sodium (Myfortic) due to nausea but left the study for personal reasons. One participant developed finger cellulitis, but there were no opportunistic infections. In the 4 participants who completed the protocol, there was no clinically significant reduction in total or intact HIV DNA. There was no change in blood CD4+ T-cell subset composition within the HIV reservoir or the entire CD4+ T-cell population, although total CD4+ T cells decreased slightly in all 4 participants. An ex vivo antiproliferative effect was observed using participant serum obtained 1 hour after dosing, but this effect was severely diminished at drug trough.

Conclusions
Mycophenolate given over 48 weeks did not reduce the volume or composition of the HIV reservoir.

Clinical Trials registration
NCT03262441.
Male-linked geneTsRPL10a′in androdioecious treeTapiscia sinensis: implications for sex differentiation by influencing gynoecium development
Authors: Wang Feng , Ren Xiaolong , Jiang Minggao , Hou Kunpeng , Xin Guiliang , Yan Feng , Zhao Peng , Liu Wenzhe 
Published: November 2022

AbstractThe mechanism of sex differentiation in androdioecy is of great significance for illuminating the origin and evolution of dioecy. Tapiscia sinensis Oliv. is a functionally androdioecious species with both male and hermaphroditic individuals. Male flowers of T. sinensis lack the ovules of gynoecia compared with hermaphrodites. To identify sex simply and accurately, and further find the potential determinants of sex differentiation in T. sinensis, we found that TsRPL10a′, a duplicate of TsRPL10a, was a male-linked gene. The promoter (5′ untranslated region and the first intron) of TsRPL10a′ can be used to accurately identify sex in T. sinensis. TsRPL10a is a ribosomal protein that is involved in gynoecium development, and sufficient ribosomal levels are necessary for female gametogenesis. The expression level of TsRPL10a was significantly downregulated in male flower primordia compared with hermaphrodites. The RNA fluorescence in situ hybridization (FISH) assay demonstrated that TsRPL10a was almost undetectable in male gynoecia at the gynoecial ridge stage, which was a key period of ovule formation by scanning electron microscope observation. In male flowers, although the promoter activity of TsRPL10a was significantly higher than TsRPL10a′ verified by transgenic Arabidopsis thaliana, the transcriptional expression ratio of TsRPL10a was obviously lower than TsRPL10a′ and reached its lowest at the gynoecial ridge stage, indicating the existence of a female suppressor. The promoter similarity of TsRPL10a and TsRPL10a′ was only 45.29%; the genomic sequence similarity was 89.8%; four amino acids were altered in TsRPL10a′. The secondary structure of TsRPL10a′ was different from TsRPL10a, and TsRPL10a′ did not exhibit FISH and GUS expression in the gynoecium the way TsRPL10a did. From the perspective of RT-qPCR, its high expression level, followed by the low expression level of TsRPL10a in male flowers, indicates its antagonism function with TsRPL10a. The evolutionary analysis, subcellular localization and flower expression pattern suggested that TsRPL10a might be functionally conserved with AtRPL10aA, AtRPL10aB and AtRPL10aC in A. thaliana. Overall, we speculated that TsRPL10a and its duplicate TsRPL10a′ might be involved in sex differentiation by influencing gynoecium development in T. sinensis.
Fatigue of hybrid fibre-reinforced plastics
Authors: Carvelli Valter , Lomov Stepan V. , Sapozhnikov Sergei B. , Breite Christian , Swolfs Yentl 
Published: November 2022

Understanding the fatigue behaviour of hybrid fibre-reinforced plastics is desirable for exploiting their features in safe, durable and reliable industrial components. The fatigue performance of hybrid composites has not been extensively investigated yet. The paper presents an overview of the available knowledge on the fatigue of hybrid fibre-reinforced plastics, and, more specifically, reports the fatigue behaviour of a quasi-isotropic pseudo-ductile all-carbon fibre interlayer hybrid composite by experimental measurements and observations, with emphasis on the damage development. The fatigue conditions are tension-tension stress- and strain-controlled cyclic loading. The results include fatigue life for different maximum stress and strain levels, stiffness evolution and damage observations by X-ray micro-computed tomography. The studied hybrid all-carbon fibre quasi-isotropic composite exhibits pseudo-ductility in quasi-static testing. For stress-controlled fatigue, the fatigue load over the limit of elastic response is not sustained. Contrary to that, the composite retains its load-carrying ability in the pseudo-ductile regime for a strain-controlled regime, albeit with lowered stiffness.
This article is part of the theme issue 'Ageing and durability of composite materials'.
Evaluation of the reliability and applicability of human unbound brain-to-plasma concentration ratios
Authors: Fagerholm Urban 
Published: November 2022

ABSTRACTBackgroundBlood-brain barrier permeability (BBB Pe) and unbound brain-to-plasma concentration ratio (Kp,uu,brain) are relevant parameters describing the brain uptake potential of compounds. BBB efflux by transporter proteins, mainly MDR-1 and BCRP, is an essential factor determining Kp,uu,brain. Kp,uu,brain-values are commonly estimatedin vivoin rats and monkeys and predicted usingin silicomethodology. Such estimates can be used to predict corresponding human clinical values.ObjectiveThe objective of the study was to evaluate the reliability and applicability of human clinical Kp,uu,brain-data for understanding and predictions of brain uptake in man.MethodologyKp,uu,brainin rats, monkeys and humans, measured andin silicopredicted MDR-1 and BCRP substrate specificities andin silicopredicted passive Pewere used for the analysis.In silicopredictions were done using the ANDROMEDA by Prosilico ADME/PK-prediction software.Results and DiscussionRat and monkey Kp,uu,brain-values were highly correlated (R^2=0.74; n=17). Based on this finding a correlation between rat and human Kp,uu,brainwas expected. However, no correlation between rat and human Kp,uu,brainwas found (R^2=0.01; n=13). There was no (as also anticipated) correlation between passive Peand human Kp,uu,brain(R^2=0.04; n=16) and compounds with measured or predicted efflux did not have lower Kp,uu,brainthan compounds without efflux. The compound with highest Kp,uu,brainin man (2.8) is effluxed and predicted to have high passive Peand has no apparent efflux at the rat BBB. The MDR-1 substrate with highest Kp,uu,brainin rat (2.4) has very low Kp,uu,brainin man (0.15) is predicted to have high passive Pe.ConclusionResults indicate that available human Kp,uu,brain-data are too uncertain to be applicable for validation of predictions and understanding of clinical brain uptake of drugs and drug candidates.
The impact of a gamified intervention on daily steps in real-life conditions: a retrospective analysis of 4800 individuals
Authors: Mazéas Alexandre , Forestier Cyril , Harel Guillaume , Duclos Martine , Chalabaev Aïna 
Published: November 2022

AbstractBackgroundDigital interventions integrating gamification features hold promise to promote daily steps. However, results regarding the effectiveness of this type of intervention are heterogeneous and not yet confirmed in real-life contexts.ObjectiveThis study aimed to examine the effectiveness of a gamified intervention and its potential moderators in a large sample using real-world data. Specifically, we tested (1) whether a gamified intervention enhanced daily steps during the intervention and follow-up periods compared to baseline, (2) whether this enhancement was higher in participants to the intervention than in nonparticipants, and (3) what participants’ characteristics or intervention parameters moderated the effect of the program.MethodsData from 4819 individuals who registered for a mHealth Kiplin program between 2019 and 2022 were retrospectively analyzed. In this intervention, participants could take part in one or several games where their daily step count was tracked, allowing individuals to play with their overall activity. Nonparticipants are people who registered to the program but did not take part in the intervention and were considered as a control group. Daily step counts were measured via accelerometers embedded in either commercial wearables or smartphones of the participants. Exposure to the intervention, the intervention content, and participants’ characteristics were included in multilevel models to test the study objectives.ResultsParticipants in the intervention group demonstrated a significantly greater increase in mean daily steps from baseline compared to nonparticipants (p<.0001). However, intervention effectiveness depended on participants’ initial physical activity. Whereas the daily steps of participants with <7500 baseline daily steps significantly improved from baseline both during the Kiplin intervention (+3291 daily steps) and during follow-up periods (+945 daily steps), participants with a higher baseline had no improvement or significant decreases in daily steps after the intervention. Age (p<.0001) and exposure (p<.0001) positively moderated the intervention effect.ConclusionsIn real-world settings and among a large sample, the Kiplin intervention was significantly effective to increase the daily steps of participants from baseline, during intervention and follow-up periods, compared to nonparticipants. Interestingly, responses to the intervention differed based on participant’ initial steps with the existence of a plateau effect. Drawing on the insights of the self-determination theory, we can assume that the effect of gamification could depend of the initial motivation and activity of participants.
Factors associated with release relief of Long COVID symptoms at 12-Months and their impact on daily life
Authors: Salmon Dominique , Slama Dorsaf , Linard Françoise , Dumesges Nicolas , Lebaut Valérie , Hakim Florence , Oustric Pauline , Seyrat Emilie , Thoreux Patricia , Marshall Esaie 
Published: November 2022

AbstractIntroductionOur purpose was to describe the course of Long COVID symptoms after 12-month follow-up, their impact on daily life and the factors associated with the relief of symptoms.MethodsA cross-sectional survey was conducted within an out-patient clinic for Long COVID patients. Participants, who had experienced their initial COVID-19 episode between January, 15 2020 and May 21, 2021, were contacted 12-months post onset. Their characteristics, symptom course at initial COVID-19 episode, Long COVID phase and one year follow-up along with remission status were collected through a questionnaire and a specific post COVID remission scale from complete remission to persistence of symptoms and dependence in daily life activities.ResultsAmong the 231 long COVID participants who answered the 12-month follow-up questionnaire, 63.2% had developed SARS-CoV-2 antibodies before COVID-19 vaccination. At 12-month follow-up, only 8.7% of the participants felt in complete remission while 28.6% noted a significant improvement of their symptoms. The prevalence rate of most symptoms remained high at 12 months: asthenia 83.1%, neurocognitive and neurological symptoms 91.8%, cardiothoracic symptoms 77.9%, musculoskeletal 78.8%. During Long COVID phase, 62.2% had to stop working at least once and only 32.5% resumed professional activities full time at one year follow-up. The presence of SARS-CoV-2 antibodies before COVID-19 vaccination was associated with an increased probability of significant improvement at one year (aPRR: 1.60, p=0.028) while ageusia at initial Long COVID phase was associated with a lower probability of improvement (aPRR: 0.38, p=0.007).ConclusionWhile observing a trend towards some improvement in a majority of long COVID patients at a 12-month follow-up, fatigue, musculoskeletal pain, cardiothoracic symptoms and neurocognitive impairment persisted in most of them. Having developed SARS-CoV-2 antibodies was associated with a better prognosis while persistent ageusia at long COVID phase seems to be associated with the persistence of symptoms.
Maternally-derived antibody titer dynamics and risk of hospitalised infant dengue disease
Authors: O’Driscoll Megan , Buddhari Darunee , Huang Angkana , Waikman Adam , Kaewhirun Surachai , Iamsirithaworn Sopon , Khampaen Direk , Farmer Aaron , Fernandez Stefan , Rodriguez-Barraquer Isabel , Srikiatkhachorn Anon , Thomas Stephen , Endy Timothy , Rothman Alan L. , Anderson Kathryn , Cummings Derek A.T. , Salje Henrik 
Published: November 2022

AbstractDengue virus (DENV) immunity is complex. Maternally-derived DENV antibodies initially provide protection against infection, however, as antibodies decay they can enhance disease severity upon infection. Quantifying antibody titers that are associated with disease risk is complicated by their dynamic nature and imperfect measurement processes. It also remains unknown whether long-term trends in birth rates, population-level infection risks, and maternal ages have altered immune profiles in child-bearing women, leading to shifts in age-specific infant disease risks. Here, we analyse DENV antibody data from two infant cohorts (N=165 infants with 665 blood draws) and 40 years of infant dengue hospitalisation data from Thailand. We use mathematical models to reconstruct maternally-derived antibody dynamics and estimate hospitalisation risk by titer. We find the relative risk of dengue hospitalisation ranges from 0.13 (0.00-0.89) in 1 month olds to 3.52 (3.25-3.79) in 8 month olds, compared to the risk in 12 month olds. We estimate the highest risk of infant dengue hospitalisation occurs at PRNT50titers of 6.0 (5.7-6.6). Our inferred titer-related risk estimates are consistent with previously identified titer-based correlates of severe disease among older individuals experiencing secondary DENV infections, suggesting a common mechanism of risk enhancement from pre-existing antibodies. Finally, we describe how the shifting epidemiology of dengue in Thailand, combined with declining birth rates, have decreased the absolute risk of infant dengue disease by 64% over a 40 year period while having minimal impact on the mean age of infant hospital-attended dengue disease.
Mapping the African Tobacco Control Network
Authors: Leischow Scott J. , Ayo-Yusuf Olalekan , Okamoto Janet , Warner Mary , Twesten Jenny E. , Stecher Chad , Valente Thomas W. , Parascandola Mark 
Published: November 2022

ABSTRACTBackgroundTo understand the state of tobacco control efforts across Africa, a first-ever survey was implemented to assess the nature and activities of tobacco control stakeholders across the African continent.MethodsA survey in English, Arabic, and French was made available to individuals and organizations to assess the types and scope of tobacco control efforts and experience with tobacco control programs based on FCTC articles/MPOWER components.ResultsThere were 219 respondents from 32 African and 6 non-African countries. Research and advocacy were the most reported activities, and several organizations emerged as network nodes for connecting tobacco control efforts across multiple African countries. The most common FCTC articles/MPOWER components worked on were (W) warning about the dangers of tobacco (58%), (M) monitor tobacco use and policies (49%), and (P) protection against secondhand smoke exposure (47%). Significant between-country differences were also found on some FCTC articles/MPOWER components: (1) (R) price and tax measures [Articles 6 and 15] (F=1.57, p=0.048), (2) industry interference [Article 5.3] (F=1.62, p=0.038), and (3) economically viable alternatives to tobacco growing [Article 17] (F=1.94, p=0.007).DiscussionThis study found a broad and robust tobacco control network across Africa, with multiple organizations serving those networks and having overlapping collaborations. There is considerable variability in tobacco control priorities and networking, and multiple barriers were identified to expanding the network and to fostering increased tobacco control efforts. The results point to important directions for increasing collaboration across FCTC articles/MPOWER components to improve tobacco control efforts; potential research opportunities, including an analysis of tobacco industry activities, an exploration of ways to help people quit tobacco, and approaches to elevate the cost of tobacco; and a solid tobacco control network foundation on which to build. However, exploring creative approaches to increase research most relevant to specific countries and their cultural characteristics is essential.
Longitudinal analysis at three oral sites links oral microbiota to clinical outcomes in allogeneic hematopoietic stem-cell transplant
Authors: Heidrich Vitor , Knebel Franciele H. , Bruno Julia S. , de Molla Vinícius C. , Miranda-Silva Wanessa , Asprino Paula F. , Tucunduva Luciana , Rocha Vanderson , Novis Yana , Fregnani Eduardo R. , Arrais-Rodrigues Celso , Camargo Anamaria A. 
Published: November 2022

AbstractBackgroundAllogeneic hematopoietic stem-cell transplant (allo-HSCT) is a potentially curative therapy for several hematological disorders. Before stem-cell infusion, recipients undergo a conditioning regimen with chemo/radiotherapy and immunosuppressants, requiring the use of antibiotics to treat and prevent infections. This regimen promotes drastic alterations in the recipient’s microbiotas, including the oral microbiota, which have been associated with allo-HSCT complications and poor outcomes. However, long-term longitudinal studies on the oral microbiota of allo-HSCT recipients are scarce and disregard the existence of distinct microbiotas within the oral cavity. Here, we used 16S rRNA gene sequencing to characterize the microbiota dynamics (during and after allo-HSCT) of 31 allo-HSCT recipients at 3 oral sites (gingival crevicular fluid, oral mucosa, and supragingival biofilm).ResultsAnalysis of the oral microbiota dynamics during allo-HSCT revealed a significant decline in bacterial diversity and major shifts in microbiota composition in all oral sites, including blooms of potentially pathogenic genera. These blooms in some cases preceded respiratory infections caused by the blooming genera. We also noticed that differences in microbiota diversity and composition between oral sites were lost during allo-HSCT. Overall, oral microbiotas returned to their preconditioning state after engraftment. However, the ability to recover the initial bacterial composition varied between patients. After stratifying patients based on their ability to recover their preconditioning microbiota composition, we found that recovery of the oral mucosa microbiota composition was not associated with antibiotic usage but was associated with higher preconditioning diversity and earlier reconstitution of normal leukocyte counts. Most notably, oral mucosa microbiota composition recovery was an independent biomarker of better allo-HSCT outcomes.ConclusionWe observed clear patterns of microbiota dysbiosis in all three oral sites during allo-HSCT, however each oral site responded differently to the perturbations associated with allo-HSCT. Oral microbiota injury and recovery patterns were associated with allo-HSCT complications and outcomes. This study highlights the potential clinical impact of the oral microbiota in the allo-HSCT setting and the clinical value of tracking oral microbiota changes during allo-HSCT.