bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insight into spatial intratumoral genomic evolution in glioblastoma
Authors: Anand Atul , Petersen Jeanette Krogh , Andersen Lars van Brakel , Burton Mark , Larsen Martin Jakob , Pedersen Christian Bonde , Poulsen Frantz Rom , Grupe Peter , Kruse Torben A. , Thomassen Mads , Kristensen Bjarne Winther 
Published: September 2023

AbstractGlioblastoma undergoes a complex and dynamic evolution involving genetic and epigenetic changes. Understanding the mechanisms underlying this evolution is vital for the development of efficient therapeutic strategies. Although treatment resistance is associated with intratumoral heterogeneity in glioblastoma, it remains uncertain whether hypometabolic and hypermetabolic lesions observed through positron emission tomography (PET) imaging are influenced by spatial intratumoral genomic evolution. In this study, we precisely isolated autologous hypometabolic and hypermetabolic lesions from glioblastoma using advanced neurosurgical and brain tumor imaging technologies, followed by comprehensive whole-genome exome and transcriptome analyses. Our findings revealed that hypermetabolic lesions evolved from hypometabolic lesions, harbored shrewd focal amplifications and deletions, and exhibited a higher frequency of critical genomic alterations linked to increased aggressiveness, upregulated APOBEC3 and hypoxic genes, and downregulated putative tumor suppressors. This study highlights spatial genomic evolution with diagnostic implications and unveils the obstacles and possibilities that should be considered in the development of novel therapeutic strategies.Statement of significance:Glioblastoma is a multifaceted disease that is difficult to treat, and insights into the metabolic gradient observed in imaging and the underlying role of genomic evolution are lacking. This study is the first to investigate the molecular basis of hypermetabolic tumor lesions in glioblastoma using precise three-dimensional biopsy isolation, whole genome/exome, and mRNA sequencing. These findings have diagnostic significance, provide insights into therapeutic resistance, and shed light on the obstacles encountered by precision therapeutics for glioblastoma.
Identifying latent genetic interactions in genome-wide association studies using multiple traits
Authors: Bass Andrew J. , Bian Shijia , Wingo Aliza P. , Wingo Thomas S. , Cutler David J. , Epstein Michael P. 
Published: September 2023

AbstractGenome-wide association studies of complex traits frequently find that SNP-based estimates of heritability are considerably smaller than estimates from classic family-based studies. This ‘missing’ heritability may be partly explained by genetic variants interacting with other genes or environments that are difficult to specify, observe, and detect. To circumvent these challenges, we propose a new method to detect genetic interactions that leverages pleiotropy from multiple related traits without requiring the interacting variable to be specified or observed. Our approach, Latent Interaction Testing (LIT), uses the observation that correlated traits with shared latent genetic interactions have trait variance and covariance patterns that differ by genotype. LIT examines the relationship between trait variance/covariance patterns and genotype using a flexible kernel-based framework that is computationally scalable for biobank-sized datasets with a large number of traits. We first use simulated data to demonstrate that LIT substantially increases power to detect latent genetic interactions compared to a trait-by-trait univariate method. We then apply LIT to four obesity-related traits in the UK Biobank and detect genetic variants with interactive effects near known obesity-related genes. Overall, we show that LIT, implemented in the R packagelit, uses shared information across traits to improve detection of latent genetic interactions compared to standard approaches.
Deep mutational scans of XBB.1.5 and BQ.1.1 reveal ongoing epistatic drift during SARS-CoV-2 evolution
Authors: Taylor Ashley L. , Starr Tyler N. 
Published: September 2023

AbstractSubstitutions that fix between SARS-CoV-2 variants can transform the mutational landscape of future evolution via epistasis. For example, large epistatic shifts in mutational effects caused by N501Y underlied the original emergence of Omicron variants, but whether such large epistatic saltations continue to define ongoing SARS-CoV-2 evolution remains unclear. We conducted deep mutational scans to measure the impacts of all single amino acid mutations and single-codon deletions in the spike receptor-binding domain (RBD) on ACE2-binding affinity and protein expression in the recent Omicron BQ.1.1 and XBB.1.5 variants, and we compared mutational patterns to earlier viral strains that we have previously profiled. As with previous RBD deep mutational scans, we find many mutations that are tolerated or even enhance binding to ACE2 receptor. The tolerance of sites to single-codon deletion largely conforms with tolerance to amino acid mutation. Though deletions in the RBD have not yet been seen in dominant lineages, we observe many tolerated deletions including at positions that exhibit indel variation across broader sarbecovirus evolution and in emerging SARS-CoV-2 variants of interest, most notably the well-tolerated Δ483 deletion in BA.2.86. The substitutions that distinguish recent viral variants have not induced as dramatic of epistatic perturbations as N501Y, but we identify ongoing epistatic drift in SARS-CoV-2 variants, including interaction between R493Q reversions and mutations at positions 453, 455, and 456, including mutations like F456L that define the newly emerging EG.5 lineage. Our results highlight ongoing drift in the effects of mutations due to epistasis, which may continue to direct SARS-CoV-2 evolution into new regions of sequence space.
The Effect of Mechanical Stimuli on the Phenotypic Plasticity of Induced Pluripotent Stem Cell-Derived Vascular Smooth Muscle Cells in a 3D Hydrogel
Authors: Meijer Elana M. , Giles Rachel , van Dijk Christian G.M. , Maringanti Ranganath , Wissing Tamar B. , Appels Ymke , Chrifi Ihsan , Crielaard Hanneke , Verhaar Marianne C. , Smits Anthal I.P.M. , Cheng Caroline 
Published: September 2023

AbstractIntroductionVascular smooth muscle cells (VSMCs) play a pivotal role in vascular homeostasis, with dysregulation leading to vascular complications. Human induced pluripotent stem cell (hiPSC)-derived VSMCs offer prospects for personalized disease modeling and regenerative strategies. Current research lacks comparative studies on the impact of 3D substrate properties under cyclic strain on phenotype adaptation in hiPSC-derived VSMCs. Here we investigated the potential of human mural cells derived from hiPSC-derived organoids (ODMCs) to undergo phenotypical adaptation under various biological and 3D mechanical stimuli.Methods and resultsODMCs were cultured in 2D conditions with synthetic or contractile differentiation medium, or 3D Gelatin Methacryloyl (GelMa) substrates with varying degrees of functionalization and percentages to modulate material stiffness, elasticity, and crosslink density. Cells in 3D substrates were exposed to cyclic unidirectional strain. Phenotype characterization was conducted using specific markers through immunofluorescence and gene expression analysis. Under static 2D culture, ODMCs derived from hiPSCs exhibited a VSMC phenotype, expressing key mural markers, and demonstrated a level of phenotypic plasticity like primary human vSMCs. In static 3D culture, higher substrate stiffness, lower elasticity and higher crosslink density promoted a contractile phenotype in ODMCs and vSMCs. Dynamic stimulation in 3D substrate promoted a switch towards a contractile phenotype in both cell types.ConclusionOur study demonstrates a phenotypic plasticity of human ODMCs in response to 2D biological and 3D mechanical stimuli that equals that of primary human vSMCs. These findings may contribute to the advancement of tailored approaches for vascular disease modelling and regenerative strategies
Position-independent functional refinement within the vagus motor topographic map
Authors: Kaneko Takuya , Boulanger-Weill Jonathan , Isabella Adam J , Moens Cecilia B 
Published: September 2023

SUMMARYMotor neurons in the central nervous system often lie in a continuous topographic map, where neurons that innervate different body parts are spatially intermingled. This is the case for the efferent neurons of the vagus nerve, which innervate diverse muscle and organ targets in the head and viscera for brain-body communication. It remains elusive how neighboring motor neurons with different fixed peripheral axon targets develop the separate somatodendritic (input) connectivity they need to generate spatially precise body control. Here we show that vagus motor neurons in the zebrafish indeed generate spatially appropriate peripheral responses to focal sensory stimulation even when they are transplanted into ectopic positions within the topographic map, indicating that circuit refinement occurs after the establishment of coarse topography. Refinement depends on motor neuron synaptic transmission, suggesting that an experience-dependent periphery-to-brain feedback mechanism establishes specific input connectivity amongst intermingled motor populations.
Determination of glomerular filtration rate, a spin off after contrast-enhanced computed tomography among critically ill patients – proof of concept
Authors: Kågedal Bertil , Helldén Anders , Dernroth Dženeta Nezirevic , Andersen Anders , Ekman Andreas , Haglund Mats , Kataria Bharti , Oskarsson Frida , Tobieson Lovisa , Östholm Balkhed Åse , Hanberger Håkan 
Published: September 2023

AbstractBackgroundRecently, Gong et al. (Gong et al. 2022) showed, in nine heathy subjects, that plasma clearance of high doses of iohexol given as contrast enhanced computed tomography (CT) could be used for determination of glomerular filtration rate (GFR). We utilized high doses of iohexol from angiographic or other contrast enhanced CT given to critical ill patients for calculation of GFRiohexoland compared these data with standard low dose iohexol GFR determinations.MethodPatients at intensive care units (ICUs) in Southeast Sweden intended for radiographic investigations that included injection of 45-120 ml of iohexol (Omnipaque) were included, and the concentration of iohexol in plasma was measured by HPLC. Iohexol clearance was calculated by the method of Bröchner-Mortensen. The following days was iohexol clearance determined using the standard low dose of 5 mL of iohexol. Sixteen patients admitted to ICUs were included in this pilot study.ResultsGFR after high dosing of iohexol at contrast enhanced CT could be measured for all sixteen critically ill patients. Patients with normal or increased renal function had neglectable iohexol concentrations the day following the CT scan. There was excellent correlation between GFR determination with high and standard low iohexol dosing among these 6 patients. Ten patients had decreased renal function and delayed elimination of iohexol, thus was not GFR measurement with low dose iohexol possible to analyse the day after CT scan with high dose iohexol.ConclusionThis pilot study showed that GFR can be measured after high doses of iohexol at enhanced CT and compare well with the standard low dose of iohexol clearance determinations.
Estimation of the infection attack rate of mumps in an outbreak among college students using paired serology
Authors: van Boven Michiel , Backer Jantien A. , Veldhuijzen Irene , Gomme Justin , van Binnendijk Rob , Kaaijk Patricia 
Published: September 2023

AbstractMumps virus is a highly transmissible pathogen that is effectively controlled in countries with high vaccination coverage. Nevertheless, outbreaks have occurred worldwide over the past decades in vaccinated populations. Here we analyse serological data from outbreaks of mumps virus genotype G among college students in the Netherlands over the period 2009-2012. To identify infections in the presence of preexisting antibodies we compared mumps specific serum IgG concentrations in two consecutive samples (n= 746), whereby the first sample was taken when students started their study prior to the outbreaks, and the second sample was taken 2-5 years later. We fit a binary mixture model to the data. The two mixing distributions represent uninfected and infected classes. Throughout we assume that the infection probability increases with the ratio of antibody concentrations of the second to first sample. The estimated infection attack rate is higher than reported earlier (0.095 versus 0.042). The analyses yield probabilistic classifications of participants, which are mostly quite precise owing to the high intraclass correlation in uninfected participants (0.85, 95%CrI: 0.82 − 0.87). The estimated probability of infection increases with decreasing antibody concentration in the pre-outbreak sample, such that the probability of infection is 0.12 (95%CrI: 0.10 − 0.13) for the lowest quartile of the pre-outbreak samples and 0.056 (95%CrI: 0.044 − 0.068) for the highest quartile. We discuss the implications of these insights for the design of booster vaccination strategies.HighlightsWe use paired pre- and post-outbreak serological data to estimate mumps infection rates in college students.We use a two-component mixture model to provide individual estimates of infection for each participant.The estimated population infection attack rate is higher than reported earlier (9.5% vs 4.2%).The estimated individual probability of infection increases with decreasing pre-outbreak antibody concentrations, from 12% in the lowest to 5.6% in the highest quartile.
Social Determinants of Genetics Referral and Completion Rates Among Child Neurology Patients
Authors: Cole Jordan J. , Sellitto Angela D. , Baratta Laura Rosa , Huecker Julia B. , Balls-Berry Joyce E. , Gurnett Christina A. 
Published: September 2023

AbstractObjectiveTo investigate clinical, social, and systems-level determinants predictive of genetics clinic referral and completion of genetics clinic visits among child neurology patients.MethodsElectronic health record data were extracted from patients 0-18 years old who were evaluated in child neurology clinics at a single tertiary care institution between July 2018 to January 2020. Variables aligned with the Health Equity Implementation Framework. Referral and referral completion rates to genetics and cardiology clinics were compared among Black vs White patients using bivariate analysis. Demographic variables associated with genetics clinic referral and visit completion were identified using logistic regressions.ResultsIn a cohort of 11,371 child neurology patients, 304 genetics clinic referrals and 82 cardiology clinic referrals were placed. In multivariate analysis of patients with Black or White ethnoracial identity (n=10,601), genetics clinic referral rates did not differ by race, but were significantly associated with younger age, rural address, neurodevelopmental disorder diagnosis, number of neurology clinic visits, and provider type. The only predictors of genetics clinic visit completion number of neurology clinic visits and race/ethnicity, with White patients being twice as likely as Black patients to complete the visit. Cardiology clinic referrals and visit completion did not differ by race/ethnicity.InterpretationAlthough race/ethnicity was not associated with differences in genetics clinic referral rates, White patients were twice as likely as Black patients to complete a genetics clinic visit after referral. Further work is needed to determine whether this is due to systemic/structural racism, differences in attitudes toward genetic testing, or other factors.
Do dietary habits, dietary patterns, and macronutrient intakes affect aging? Multi-dimensional evidence from UK Biobank
Authors: Zhu Chen , Wang Youfa , Yang Xiaosong , Zhao Qiran , Xu Wenyan , Wang Xiaolu , Liang Yanjun , Chen Qihui , Fan Shenggen 
Published: September 2023

AbstractThe role of diet in aging is pivotal, yet existing research offers inconsistent findings regarding the impact of specific diets on human aging. We conducted a systematic investigation into the relationship between dietary factors and aging, exploring potential causal links between macronutrient intake and aging. Utilizing data from the UK Biobank baseline survey and a 24-hour dietary assessment survey, we employed a High-dimensional Fixed Effects (HDFE) model to examine dietary factors’ association with aging. Multivariable Mendelian Randomization (MVMR) and Semiparametric Nonlinear Mendelian Randomization (NLMR) techniques assessed causal links between macronutrient consumption and aging. HDFE analysis indicated that a healthier diet was generally linked to better aging outcomes, with various dietary components correlating with aging. For instance, plant-based food intake was associated with increased telomere length and/or reduced phenotypic age, while animal-based food consumption correlated with adverse aging effects. MVMR revealed the benefits of carbohydrate intake on aging, reducing phenotypic age (βC=C-0.0025; 95% CI=[-0.0047, -0.0003];p= 0.026) and increasing whole-brain grey matter volume (βC=C0.0262; 95% CI=[0.007, 0.046];p= 0.008). Overall, our study underscores diet’s significant role in biological aging, highlighting the potential advantages of a carbohydrate-rich diet in promoting healthy aging.
Dissociable contributions of the medial parietal cortex to recognition memory
Authors: Koslov Seth R. , Kable Joseph W. , Foster Brett L. 
Published: September 2023

AbstractHuman neuroimaging studies of episodic memory retrieval routinely observe the engagement of specific cortical regions beyond the medial temporal lobe. Of these, medial parietal cortex (MPC) is of particular interest given its ubiquitous, and yet distinct, functional characteristics during different types of retrieval tasks. Specifically, while recognition memory and autobiographical recall tasks are both used to probe episodic retrieval, these paradigms consistently drive distinct patterns of response within MPC. This dissociation adds to growing evidence suggesting a common principle of functional organization across memory related brain structures, specifically regarding the control or content demands of memory-based decisions. To carefully examine this putative organization, we used a high-resolution fMRI dataset collected at ultra-high field (7T) while subjects performed thousands of recognition-memory trials to identify MPC regions responsive to recognition-decisions or semantic content of stimuli within and across individuals. We observed interleaving, though distinct, functional subregions of MPC where responses were sensitive to either recognition decisions or the semantic representation of stimuli, but rarely both. In addition, this functional dissociation within MPC was further accentuated by distinct profiles of connectivity bias with the hippocampus during task and rest. Finally, we show that recent observations of person and place selectivity within MPC reflect category specific responses from within identified semantic regions that are sensitive to mnemonic demands. Together, these data better account for how distinct patterns of MPC responses can occur as a result of task demands during episodic retrieval and may reflect a common principle of organization throughout hippocampal-neocortical memory systems.Significance statementMedial parietal cortex (MPC) plays a growing role in contemporary theories of episodic memory, as it is reliably observed in human neuroimaging to be engaged during tasks of recognition and retrieval. However, the spatial pattern of MPC engagement consistently differs across these putatively similar episodic memory tasks. Despite a large literature indicating that the MPC is important for episodic memory, there is little consensus about its specific role. Here, we employed ‘precision-neuroimaging’ to identify dissociable interleaving MPC subregions, where activity reflected either memory-based decision-making or stimulus content. This dissociation within MPC provides a better understanding for how retrieval demands shape response patterns and speaks to growing evidence for a common principle of organization across memory structures of the human brain.
Digital holo-tomographic 3D maps of COVID-19 microclots in blood to assess disease severity
Authors: Bergaglio Talia , Synhaivska Olena , Nirmalraj Peter Niraj 
Published: September 2023

AbstractThe coronavirus disease 2019 (COVID-19) has impacted health globally. Cumulative evidence points to long-term effects of COVID-19 such as cardiovascular and cognitive disorders diagnosed in patients even after the recovery period. In particular, micrometer-sized blood clots and hyperactivated platelets have been identified as potential indicators of long COVID. Here we resolve individual microclot structures in platelet-rich plasma of donors with different subphenotypes of COVID-19 in a label-free manner, using 3D digital holo-tomographic microscopy (DHTM). Based on 3D refractive index (RI) tomograms, the size, dry mass, and prevalence of microclot composites were quantified and then parametrically differentiated from fibrin-rich microclots and platelet aggregates in the plasma of COVID-19 donors. Importantly, fewer microclots and platelet aggregates were detected in the plasma of healthy controls when compared to COVID-19 donors. Our work highlights the utility of integrating DHTM in clinical settings that may allow the detection of individuals at risk of developing microvascular thrombotic disorders and for monitoring the efficiency of prescribed treatments by screening plasma samples.
Single-cell epigenomic reconstruction of developmental trajectories in human neural organoid systems from pluripotency
Authors: Zenk Fides , Fleck Jonas Simon , Jansen Sophie Martina Johanna , Kashanian Bijan , Eisinger Benedikt , Santel Małgorzata , Dupre Jean , Camp J. Gray , Treutlein Barbara 
Published: September 2023

AbstractHuman cell type diversity emerges through a highly regulated series of fate restrictions from pluripotent progenitors. Fate restriction is orchestrated in part through epigenetic modifications at genes and regulatory elements, however it has been difficult to study these mechanisms in humans. Here, we use organoid models of the human central nervous system and establish single-cell profiling of histone modifications (H3K27ac, H3K27me3, H3K4me3) in organoid cells over a time course to reconstruct epigenomic trajectories governing cell identity acquisition from human pluripotency. We capture transitions from pluripotency through neuroepithelium, to retinal and brain region specification, as well as differentiation from progenitors to neuronal and glial terminal states. We find that switching of repressive and activating epigenetic modifications can precede and predict decisions at each stage, providing a temporal census of gene regulatory elements and transcription factors that we characterize in a gene regulatory network underlying human cerebral fate acquisition. We use transcriptome and chromatin accessibility measurements in the same cell from a human developing brain to validate this regulatory mode in a primary tissue. We show that abolishing histone 3 lysine 27 trimethylation (H3K27me3) through inhibition of the polycomb group protein Embryonic Ectoderm Development (EED) at the neuroectoderm stage disrupts fate restriction and leads to aberrant cell fate acquisition, ultimately influencing cell type composition in brain organoids. Altogether, our single-cell genome wide map of histone modifications during human neural organoid development serves as a blueprint (https://episcape.ethz.ch) to explore human cell fate decisions in normal physiology and in neurodevelopmental disorders. More broadly, this approach can be used to study human epigenomic trajectory mechanisms in any human organoid system.SummaryUnguided neural organoids reveal widespread and dynamic switching of epigenetic modifications during development and recapitulate fate restriction from pluripotency to terminally differentiated cells of the human central nervous system.