bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrin-αVβ3 is a fundamental factor in medulloblastoma tumorigenicity and radioresistance: A new game for an old player
Authors: Echavidre William , Durivault Jérôme , Gotorbe Célia , Blanchard Thays , Pagnuzzi-Boncompagni Marina , Vial Valérie , Raes Florian , Broisat Alexis , Villeneuve Rémy , Amblard Régis , Garnier Nicolas , Ortholan Cécile , Faraggi Marc , Serrano Benjamin , Picco Vincent , Montemagno Christopher 
Published: March 2023

ABSTRACTMedulloblastoma (MB) is the most frequent solid tumor in children, localized in the brain’s posterior fossa. Its standard of care comprises maximal resection surgery followed by craniospinal irradiation and chemotherapy. Despite a long-term survival rate of 70%, wide disparities among patients have been observed. Relevant targets for naive and recurrent MB are urgently needed. Primary and recurrent MBs are characterized by aggressive invasion into surrounding brain tissue, active angiogenesis, and radioresistance. Integrin-αvβ3 was a major driver of these features in glioblastoma. Nevertheless, such observations have not yet been reported in MB. Integrin-αvβ3 was found to be expressed in a subset of MB patients. We investigated the role of integrin-αvβ3 using MB-derived cell lines with β3-subunit depletion or overexpression both in vitro and in vivo. Radioresistant MB cell lines were generated and showed increased integrin-αvβ3 expression, which correlated with increased susceptibility to pharmacological integrin-αvβ3 inhibition with cilengitide, a competitive ligand mimetic. Finally, we conducted single-photon emission computed tomography (SPECT)/magnetic resonance imaging (MRI) studies on orthotopic models using a radiolabeled integrin-αvβ3 ligand (99mTc-RAFT-RGD). This approach offers the prospect of a novel predictive imaging modality in MB. Altogether, our data pave the way for SPECT/MRI-based selection of a subpopulation of MB patients eligible for integrin-αvβ3-directed therapies.SIGNIFICANCEThis study demonstrates integrin-αvβ3’s fundamental role in MB tumorigenicity and radioresistance and the effect of its expression on cilengitide functional activity.
The fork restart factor PHF6 interacts with RRM2 and binds to H3K56ac marked nascent DNA
Authors: Depestel Lisa , Bekaert Sarah-Lee , Sanders Ellen , Damme Carolien Van , Eggermont Aline , Loontiens Siebe , Tilleman Laurentijn , Nieuwerburgh Filip Van , Delhaye Louis , Vlierberghe Pieter Van , Eyckerman Sven , Speleman Frank , Durinck Kaat 
Published: March 2023

AbstractThe PHF6 protein is a presumed chromatin reader implicated in disease through germline loss-of-function mutations causing cognitive disability syndromes and somatic mutations are predominantly observed in acute T-cell leukemia. Previous reports support a role for PHF6 in DNA damage repair, replication fork restart as well as hematopoietic precursor cell self-renewal capacity and lineage commitment. To explore better how PHF6 mediates these functions, we mapped the PHF6 interactome and identified RRM2 as a consistent binding partner across different normal and malignant cell types. Next, PHF6 knockdown imposed increased replicative stress/DNA damage and suggested possible binding of PHF6 to H3K56ac, a marker for nascent DNA at sites of DNA damage repair. Genome-wide mapping of PHF6 chromatin binding indeed revealed overlap with sites of active DNA damage, binding sites of replication fork proteins and functional crosstalk with the neuroblastoma transcription core regulatory circuitry. Altogether, we show a canonical PHF6-RRM2 interaction enabling active transport of RRM2 to genomic sites of PHF6 mediated fork restart and PHF6 localization to H3K56ac at highly transcribed genes facilitating fork restart following replication-transcription conflicts.
BE3 is the major branching enzyme isoform required for amylopectin synthesis in Chlamydomonas reinhardtii
Authors: Courseaux Adeline , George Océane , Deschamps Philippe , Bompard Coralie , Duchêne Thierry , Dauvillée David 
Published: March 2023

AbstractStarch-branching enzymes (BEs) are essential for starch synthesis in both plants and algae where they influence the architecture and physical properties of starch granules. Within Embryophytes, BEs are classified as type 1 and type 2 depending on their substrate preference. In this article, we report the characterization of the three BE isoforms encoded in the genome of the starch producing green algaeChlamydomonas reinhardtii: two type 2 BEs (BE2 and BE3) and a single type 1 BE (BE1). Using single mutant strains, we analyzed the consequences of the lack of each isoform on both transitory and storage starches. The transferred glucan substrate and the chain length specificities of each isoform were also determined. We show that only BE2 and BE3 isoforms are involved in starch synthesis and that, although both isoforms possess similar enzymatic properties, BE3 is critical for both transitory and storage starch metabolism. Finally, we propose putative explanations for the strong phenotype differences evidenced between theC. reinhardtii be2andbe3mutants, including functional redundancy, enzymatic regulation or alterations in the composition of multimeric enzyme complexes.
Evaluating targeted COVID-19 vaccination strategies with agent-based modeling
Authors: Hladish Thomas J. , Pillai Alexander N. , Pearson Carl A. B. , Toh Kok Ben , Tamayo Andrea , Stoltzfus Arlin , Longini Ira M. 
Published: March 2023

We evaluate approaches to vaccine distribution using an agent-based model of human activity and COVID-19 transmission calibrated to detailed trends in cases, hospitalizations, deaths, seroprevalence, and vaccine breakthrough infections in Florida, USA. We compare the incremental effectiveness for four different distribution strategies at four different levels of vaccine availability, reflecting different income settings’ historical COVID-19 vaccine distribution. Our analysis indicates that the best strategy to reduce severe outcomes is to actively target high disease-risk individuals. This was true in every scenario, although the advantage was greatest for the middle-income-country availability assumptions, and relatively modest compared to a simple mass vaccination approach for rapid, high levels of vaccine availability. Ring vaccination, while generally the most effective strategy for reducing infections, ultimately proved least effective at preventing deaths. We also consider using age group as a practical, surrogate measure for actual disease-risk targeting; this approach still outperforms both simple mass distribution and ring vaccination.We also find that the magnitude of strategy effectiveness depends on when assessment occurs (e.g., after delta vs. after omicron variants). However, these differences in absolute benefit for the strategies do not change the ranking of their performance at preventing severe outcomes across vaccine availability assumptions.
Global landscape ofStreptococcus pneumoniaeserotypes colonising healthy individuals worldwide before vaccine introduction; a systematic review and meta-analysis
Authors: Clifford Samuel , Knoll Maria D , O’Brien Katherine L , Pollington Timothy M , Moodley Riya , Prieto-Merino David ,   RESPICAR Consortium, Edmunds W John , Flasche Stefan , de Waroux Olivier le Polain 
Published: March 2023

AbstractBackgroundMonitoring pneumococcal carriage prevalence and serotype distribution is critical to understanding pneumococcal transmission dynamics and vaccine impact, particularly where routine disease surveillance is limited. This study aimed to describe and interpret heterogeneity in serotype-specific carriage globally before widespread use of pneumococcal conjugate vaccines (PCVs).MethodsA systematic literature review was undertaken to summarise all pneumococcal carriage studies across continents and age groups before PCV introduction. Serotype distributions were assessed via Bayesian nested meta-regression and hierarchical clustering.FindingsIn total 237 studies from 74 countries were included, comprising 492 age-specific datasets that contained 47,769 serotyped isolates.The modelled carriage prevalence differed substantially across regions, ranging in <5y from 35% (95%CrI 34%-35%) in Europe to 69% (95%CrI 69-70%) in Africa. Serotypes 19F, 6B, 6A, 23F, and 14 were the five most prevalent in children <5 years. The modelled proportion of Synflorix-10 (PCV10) serotypes carried by <5y ranged from 45% (95% CrI: 44% to 46%) in Asia to 59% (58% to 60%) in Europe, and that of Prevenar-13 (PCV13) from 60% (59% to 61%) in Asia to 76% (75% to 77%) in Europe. The diversity of carried serotypes increased with age, and so did the prevalence of vaccine-type serotypes. However, variation in serotype distribution did not cluster by age, ethnicity, region, or overall carriage prevalence.InterpretationGlobally, pre-PCV pneumococcal carriage was dominated by a few serotypes. Serotype distribution variability was not easily attributable to a single discriminatory factor.FundingThe review was funded by a grant to OlPdW from the World Health Organisation (grant number: SPHQ14-APW-2639) and by a Fellowship to SF jointly funded by the Wellcome Trust and the Royal Society (grant number: 208812/Z/17/Z).
Cause of Death by Race and Ethnicity in Minnesota Before and During the COVID-19 Pandemic, 2019-2020
Authors: Blake Madelyn J. , Marka Nicholas A. , Steer Clifford J. , Ravdin Jonathan I. 
Published: March 2023

ABSTRACTObjectivesTo measure changes in cause of death dynamics in 2019 and 2020 and the relationship between concurrent occurrence of the COVID-19 pandemic and mortality outcome by race and ethnicity.Patients and MethodsWe used resident mortality data from the Minnesota Department of Health (MDH) to conduct retrospective statistical analysis of deaths in Minnesota in 2019 relative to 2020 to assess changes in mortality in a pre-pandemic and pandemic period.ResultsCOVID-19 strongly contributed to ethnicity-related mortality disparities in Minnesota. Not only was there a greater proportion of COVID-19 decedents within the Black and Hispanic populations, but their average decedent age was markedly lower relative to the White population. The Black population experienced a disproportionate increase in decedents with a 34% increase during 2020 compared to 2019.ConclusionsThis retrospective analysis of death dynamics and mortality outcomes in Minnesota from 2019 to 2020 demonstrated an increase in adverse mortality outcomes relative to the pre-pandemic period that disproportionately impacted Black and Hispanic minority populations. Access to non-pharmaceutical interventions combating COVID-19 infection in Black and Hispanic communities should be expanded in Minnesota.
Clinical performance of a chemiluminescence SARS-CoV-2 antibody assay in a cohort of healthcare workers, blood donors and COVID-19 patients
Authors: Rangel Giselle , Lopez Daysa , Chavarría Athneris , Mudarra Laiss , Britton Gabrielle , Villarreal Alcibiades 
Published: March 2023

ABSTRACTIntroductionSerological detection of antibodies against SARS-CoV-2 has become an essential tool to test vaccine efficacy and epidemiological surveillance of COVID-19. There have been limited published studies documenting the performance of SARS-CoV-2 antibody assays within hispanic populations.Materials and methodsWe evaluated the diagnostic performance of a chemiluminescence enzyme immunoassay (CLIA) on a set of 1,035 samples including pre-pandemic samples, healthcare workers (HCW), blood donors (BD) and COVID-19 positive confirmed by RT-PCR collected from April to December 2020.ResultsThrough a ROC curve the CLIA test had a high diagnostic performance, with an AUC of 0.9854 (CI95%95.68-100), P <0.0001. The analysis yielded a cut-off point 0.1950, sensitivity of 98.4% (CI95%95 91.54-99.9), and specificity of 93.8% (CI95%79.8 - 98.9). The diagnostic performance was also evaluated comparing the results with those obtained using other diagnostic techniques. Substantial agreement with the lateral flow chromatography and RT-PCR tests was found, and a high level of agreement with ELISA, with %PPA of 91.3 (CI95%84.0-95.5), % NPA of 97.7 (CI95%96.3-98.6), % OPA of 97.7 (CI95%96.3-98.6) and Cohen’s kappa value of 90.4 (CI95%85.8-94.9). A logistic regression was used to determine which of the independent variables predicted reactivity to CLIA test. A higher age was associated with an odds ratio (OR) of 1.043 (CI95%1.022-1.065), while the presence of at least one chronic disease was associated with an OR of 5.649 (CI95%3.089-10.329) greater likelihood of reactivity.ConclusionsCLIA test exhibited excellent performance making it a suitable test for seroprevalence surveillance at the community level.
Families Experience of a Relatives Brain Stem Death Diagnosis: A Systematic Review
Authors: Cade-Smith Ella , Mackay Liam , Wijayatilake Dhuleep Sanjay , Kingsley Marc , Shaikh Madiha 
Published: March 2023

AbstractAIMBeing diagnosed as Brain Stem Dead is a very challenging experience for families. Most research regarding brain stem death focuses on Organ Donation and there is currently little research into families’ experience of brain stem death. The aim is to review the family’s experience of brain stem death.DESIGNSystematic reviewMETHODA narrative synthesis was conducted for 9 studies including qualitative and quantitative study designs. Four electronic databases: AHMED (Allied and Complimentary Medicine), Emcare (1995-present), Medline (Ovid) and APA Psych Info (Ovid) were searched. No limit was placed on date of publishing due to this being a relatively under researched topic. The original search was conducted on 4thNovember 2021 and rerun on 6thDecember 2022 to ensure the inclusion of any new published studies.RESULTSSix main themes were identified, including: The Unexpected Prognosis; Coming to terms with brain stem death- grieving process; Request for organ donation; Observing brain stem death testing; The impact of staff on families’ experience; and the lasting impact.CONCLUSIONFamilies of patients with brain stem death are often left with a lack of understanding surrounding the diagnosis, the process, and the short and long term distress it can cause. There is need for research into family’s experiences and brain stem death testing specifically so that more reliable data can be produced. There is a need to establish national, or international practice surrounding family care in intensive care in cases of brain stem death. This review highlights the importance of establishing specific brain stem death protocols, enabling more effective and consistent support for families.
Sex-stratified GWAS of Body Fat Percentage after Adjusting for Testosterone and SHBG in the UK Biobank
Authors: Roshandel Delnaz , Paterson Andrew D. , Dash Satya 
Published: March 2023

ABSTRACTIntroductionAdiposity, particularly centripetal adiposity/reduced gluteofemoral adiposity, increases dyslipidemia, type 2 diabetes (T2D) and coronary artery disease (CAD). Genome-wide association studies (GWAS) to date have identified 12 loci associated with body fat percentage (BFP). Biological sex influences both overall adiposity and fat distribution. Further, testosterone and sex hormone binding globulin (SHBG) influence adiposity and metabolic function, with differential effects of testosterone in men and women.MethodsWe performed sex-stratified GWAS of BFP in white British individuals from the UK biobank adjusting for SHBG and testosterone. We further investigated association of the identified loci with high density cholesterol (HDL), triglyceride (TG), T2D, CAD, and MRI-derived abdominal subcutaneous adipose tissue (ASAT), visceral adipose tissue (VAT) and gluteofemoral adipose tissue (GFAT) using publicly available data from large GWAS. We also performed 2-sample Mendelian Randomization (MR) using identified BFP variants as instruments to investigate causal effect of BFP on HDL, TG, T2D and CAD in males and females separately.ResultsWe identified 193 and 174 autosomal loci explaining 3.35% and 2.60% of the variation in BFP in males and females, respectively. In addition, we identified 2 Chr X loci in men. Only 38 of these loci associated with BFP in both males and females. Seven loci in men including the 2 loci on Chr X and ten loci in females have not been associated with any adiposity or cardiometabolic traits previously. The majority of BFP loci did not associate with cardiometabolic traits. Of the BFP loci associated with cardiometabolic traits several had paradoxically beneficial cardiometabolic effects with favourable fat distribution. Consistent with that sex-stratified MR analyses using identified BFP variants as instruments did not find convincing supportive evidence that increased BFP has deleterious cardiometabolic effects in either sex with highly significant heterogeneity.ConclusionsAdjusting for testosterone and SHBG with sex-stratified analyses substantially increased the number of BFP associated loci. Despite this adjustment, there was limited genetic overlap in BFP in males and females. Further identified loci in general did not have adverse cardiometabolic effects which may reflect the protective effect of favourable fat distribution and the modulation of cardiometabolic risk by testosterone and SHBG.
Fit by design: Developing substrate-specific seed mixtures for functional dike grasslands
Authors: Bauer Markus , Huber Jakob K. , Kollmann Johannes 
Published: March 2023

AbstractSowing is a well-established restoration technique to overcome dispersal limitation. Site-specific seed mixtures are most effective to achieve functional communities. This is especially important if the restored vegetation has to protect critical infrastructure like roadsides and dikes. Here, an improved seed–substrate combination will secure slope stability, reduce mowing efforts, and generate species-rich grasslands.A factorial field experiment addressed this topic on a dike at River Danube in SE Germany in 2018–2021. Within 288 plots, we tested three sand admixtures, two substrate depths, two seed densities and two seed mixture types (mesic hay meadow, semi-dry calcareous grassland) in north and south exposition, and measured the recovery completeness by calculating the successional distance to reference sites, the persistence of sown species, and the Favourable Conservation Status (FCS) of target species.Overall, the sown vegetation developed in the desired direction, but a recovery debt remained after four years, and some plots still showed similarities to negative references from ruderal sites. In north exposition, hay meadow-seed mixtures developed closer to the respective reference communities than dry-grassland mixtures.In south exposition, the sown communities developed poorly which might be due to a severe drought during establishment. This initial negative effect remained over the entire observation period.Sand admixture had a slightly positive effect on target variables, while substrate depth, seed density and mixture type had no effects on species persistence or FCS.Synthesis and applications: Site-adapted seed mixtures make restoration more effective. However, applying several seed–substrate combinations might foster beta diversity. Furthermore, additional management efforts are recommended, as they might be necessary to reduce the recovery debt, as well as re-sowing after unfavourable conditions.
Sub-clinical triiodothyronine levels predict health, demographic, and socioeconomic outcomes
Authors: Lawton Ralph I. , Sabatini Bernardo L. , Hochbaum Daniel R. 
Published: March 2023

AbstractThe Hypothalamic-Pituitary-Thyroid (HPT) axis is fundamental to human biology, exerting central control over energy expenditure, metabolic rate, and body temperature. However, the consequences of “normal” physiologic HPT-axis variation in non-clinical populations are poorly understood. Using nationally-representative data from the 2007-2012 NHANES, we explore relationships with demographics, mortality, and socio-economic factors. We find much larger variation across age in free T3 than other HPT-axis hormones. T3 and T4 have opposite effects on mortality: free T3 is inversely related and free T4 is positively related with likelihood of death. Free T3 and household income are negatively related, particularly at lower incomes. Finally, free T3 among older adults is associated with labor both on the extensive margin (unemployment) and intensive margin (hours worked). Physiologic TSH/T4 explain only 1% of T3 variation, and neither are appreciably correlated to socio-economic outcomes. Taken together, our data suggest an unappreciated complexity and non-linearity of the HPT-axis signaling cascade broadly such that TSH and T4 may not be accurate surrogates of free T3. Furthermore, we find that sub-clinical variation in the HPT-axis effector hormone T3 is an important and overlooked factor linking socio-economic forces, human biology, and aging.
Circadian clock-gated cell renewal controls time-dependent changes in taste sensitivity
Authors: Matsu-ura Toru , Matsuura Kaoru 
Published: March 2023

AbstractCircadian regulation of the cell cycle progression produces a diurnal supply of newborn cells to replace the ones that were lost in the organs and tissues. Here we analyzed time-dependent changes in the cell types in the mouse tongue epithelium. We observed circadian regulated alternate oscillations of the stem/progenitor cell maker genes and the differentiated cell marker genes expressions in mouse tongue epithelial organoids. The cell cycle progression was regulated time-dependent manner in the tongue organoids and mice tongue. Single-cell RNA sequencing revealed time-dependent population changes of the stem/progenitor cells and the differentiated cells in mice tongues. Remarkably, we observed time-dependent type II taste cell population changes, resulting in time-dependent taste sensitivity changes. We also found the same population changes in mice intestines and uteruses, suggesting the contributions of the diurnal supply of newborn cells to the time-dependent physiological controls in the broad types of organs and tissues.
Comparative analysis of syngeneic mouse models of high-grade serous ovarian cancer
Authors: Cook David P , Galpin Kristianne JC , Rodriguez Galaxia M , Shakfa Noor , Wilson-Sanchez Juliette , Pereira Madison , Matuszewska Kathy , Haagsma Jacob , Murshed Humaira , Cudmore Alison O , MacDonald Elizabeth , Tone Alicia , Shepherd Trevor G. , Petrik James J , Koti Madhuri , Vanderhyden Barbara C. 
Published: March 2023

AbstractOvarian cancers often exhibit high rates of recurrence and poor treatment response. Preclinical models that recapitulate the heterogeneity of human disease are critical to develop new therapeutic approaches. While patient-derived models are a powerful tool for testing various therapeutics, their dependence on immune-compromised mice is severely limiting. Syngeneic mouse models, however, allow for the generation of tumours comprising the full repertoire of non-malignant cell types. Here we have performed a comparative analysis of diverse models of high-grade serous ovarian cancer based on transcriptomic profiling of 22 cell line models, and intrabursal and intraperitoneal tumours from 12 models. Among cell lines, we identify distinct features in signalling activity, such as elevated inflammatory signalling in STOSE and OVE16 models, and MAPK/ERK signalling in ID8 and OVE4 models; metabolic features, such as predicted reduction in glycolysis associated with subsets of engineered ID8 subclones; and relevant functional properties, including differences in EMT activation, PD-L1 and MHC class I expression, and predicted chemosensitivity. Finally, we evaluate variability in properties of the tumour microenvironment among models. We anticipate that this work will serve as a valuable resource, providing new insight to help in the selection of models for specific experimental objectives.