bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomic and Metabolomic analyses in Monozygotic and Dizygotic twins
Authors: Hubers Nikki , Drouard Gabin , Jansen Rick , Pool René , Hottenga Jouke Jan , Ollikainen Miina , Wang Xiaoling , Willemsen Gonneke , Kaprio Jaakko , Boomsma Dorret I. , van Dongen Jenny 
Published: June 2024

AbstractMonozygotic (MZ) and dizygotic (DZ) twins are studied to understand genetic and environmental influences on complex traits, however the mechanisms behind twinning are not completely understood. (Epi)genomic studies identified SNPs associated with DZ twinning and DNA methylation sites with MZ twinning. To find molecular biomarkers of twinning, we compared transcriptomics and metabolomics data from MZ and DZ twins. We analyzed 42,663 RNA transcripts in 1,453 MZ twins and 1,294 DZ twins from the Netherlands Twin Register (NTR), followed by sex-stratified analyses. The top 5% transcripts with lowest p-values were analyzed for replication in 217 MZ and 158 DZ twins from the older Finnish Twin cohort (FTC). In the NTR, one transcript (PURG)was significantly differentially expressed between MZ and DZ twins; but this did not replicate in FTC. Pathway analyses highlighted the WNT-pathway, previously associated with MZ twinning, and the TGF-B and SMAD pathway, previously associated with DZ twinning. Meta-analysis of 169 serum metabolites in 2,797 MZ and 2,040 DZ twins from the NTR, FTC and FinnTwin12, showed no metabolomic differences. Overall, we did not find replicable transcript-level expression differences in blood between MZ and DZ twins, but highlighted the TGF-B/SMAD pathway as a potential transcriptional biomarker for DZ twinning.
Development and validation of risk prediction models for childhood, teenage and young adult cancers: research protocol and statistical analysis plan
Authors: Saatci Defne , Harnden Anthony , Hippisley-Cox Julia 
Published: June 2024

AbstractBackgroundChildhood, teenage and young adult (CTYA, 0-24 years) cancers are rare and diverse, making timely diagnosis challenging. Studies based on adult cancers suggest that the development and integration of clinical decision tools in primary care aid earlier cancer detection, yet, these have not been explored for CTYA cancers.AimTo develop and validate a primary care-based risk prediction tool to identify CTYA who are at increased risk of cancer.Methods and analysisUsing the QResearch Database, a nationally representative primary care database, we will generate an open cohort of children, teenagers and young adults (0-24 years) who were registered with a GP between 1stJanuary 1998 and 31stDecember 2019. CTYA will be followed up from the date at which the first cancer-relevant symptom is recorded in the records (index date) until the date of cancer diagnosis/6-months, whichever comes first. Candidate variables will include symptoms, signs, blood test results and demographic factors. Model derivation will include two approaches, Cox regression and logistic regression. Apparent performance of the derived model will be explored and subsequently internally-externally cross-validated to investigate performance heterogeneity and geographical transportability.
Development and verification of non-supervised smartphone-based methods for assessing pure-tone thresholds and loudness perception
Authors: Xu Chen , Schell-Majoor Lena , Kollmeier Birger 
Published: June 2024

ObjectiveThe benefit of using smartphones for hearing tests in a non-supervised, rapid, and contactless way has drawn a lot of interest, especially if supra-threshold measures are assessed that go beyond audiogram-based measures alone. It is unclear, nevertheless, how well these measures compare to more supervised and regulated manual audiometric assessments. The aim of this study is to validate such smartphone-based methods against standardized laboratory assessments.DesignPure-tone audiometry and categorical loudness scaling (CLS) were used. Three conditions with varying degrees of supervision were created and compared. In order to assess binaural and spectral loudness summation, both narrowband monaural and broadband binaural noise have been examined as CLS test stimuli.Study sampleN = 21 individuals with normal hearing and N = 16 participants with mild-to-moderate hearing loss.ResultsThe tests conducted here did not show any distinctions between smartphone-based and laboratory-based methods.ConclusionsNon-supervised listening tests via smartphone may serve as a valid, reliable, and cost-effective approach, e.g., for pure-tone audiometry, CLS, and the evaluation of binaural and spectral loudness summation. In addition, the supra-threshold tests can be constructed to be invariant against missing calibration and external noise which makes them more robust for smartphone usage than audiogram measures.
Fingerprint method applied to data from a phase III clinical trial
Authors: Edenbrandt Lars 
Published: June 2024

AbstractResearchers in the RECOMIA network have been developing AI tools for the automated analysis of PET/CT studies in lymphoma patients. To enhance these AI tools, the CALGB 50303 dataset from The Cancer Imaging Archive was identified for inclusion in their project. Ensuring the quality of databases used for AI training is crucial, and one quality control (QC) measure involves the AI-based Fingerprint method to verify correct de-identification of clinical trial images. The study applied the Fingerprint method to PET/CT studies from 130 patients, successfully detecting an incorrectly de-identified study and identifying its correct trial identification number. This demonstrates the feasibility of using AI for QC in clinical trials. AI-based methods offer significant opportunities for enhancing QC, providing automated, consistent, and objective analyses that reduce the workload on human annotators. Integrating AI into QC processes promises to improve accuracy, consistency, and efficiency, thereby enhancing data integrity and the reliability of clinical trial results. This study underscores the importance of further developing AI-based QC methods in clinical trials.
A mechanistic model of curative combination therapy explains lymphoma clinical trial results
Authors: Pomeroy Amy E. , Palmer Adam C. 
Published: June 2024

ABSTRACTCombinations of chemotherapies are used to treat many cancer types as they elicit higher cure rates and longer responses than single drugs. Several rationales contribute to the efficacy of combinations, including overcoming inter-patient and intra-tumor heterogeneity and improving efficacy through additive or synergistic pharmacological effects. We present a quantitative model that unifies these phenomena to simulate the clinical activity of curative combination therapies. This mechanistic simulation describes kinetics of tumor growth and death in response to treatment and outputs progression-free survival (PFS) distributions in patient populations. We applied this model to first-line combination therapy for Diffuse Large B-Cell Lymphoma, which is cured in most patients by the 5-drug combination RCHOP. This mechanistic model reproduced clinically observed PFS distributions, kinetics of tumor killing measured by circulating tumor DNA, and the adverse prognostic effect of tumor proliferation rate. The outcomes of nine phase 3 trials of new therapies combined with RCHOP were accurately predicted by the model, based on new therapies’ efficacies in trials in patients with relapsed or refractory disease. Finally, we used the model to explore how drug synergy and predictive biomarkers affect the chance of success of randomized trials. These findings show that curative combination therapies can be understood in quantitative and kinetic detail, and that predictive simulations can be used to aid the design of new treatment regimens and clinical trials in curative-intent settings.SIGNIFICANCEA novel model that incorporates pharmacological interactions in the presence of inter-patient and intra-tumor heterogeneity explains and predicts combination clinical trial outcomes of curative regimes used to treat Diffuse Large B-cell lymphoma. This model can be used to understand and inform optimal design of drug combinations and clinical trials.
Environmental Risk Factors Influence the Natural History of Familial Dilated Cardiomyopathy
Authors: Peters Stacey A. , Wright Leah , Yao Jess , McCall Lauren , Thompson Tina , Thompson Bryony , Johnson Renee , Huynh Quan , Santiago Celine F , Trainer Alison , Perrin Mark , James Paul , Zentner Dominica , Kalman Jon , Marwick Thomas H. , Fatkin Diane 
Published: June 2024

AbstractBackgroundFamilial dilated cardiomyopathy (DCM) is characterized by marked variability in phenotypic penetrance. The extent to which this is determined by patient-specific environmental factors is unknown.MethodsA retrospective longitudinal cohort study was performed in families with DCM-causing genetic variants. Environmental factors were classified into two subsets based on evidence for a causal link to depressed myocardial contractility, termed (1) DCM-promoting factors and (2) heart failure (HF) comorbidities. These factors were correlated with DCM diagnosis, disease trajectory, and adverse events.Results105 probands and family members were recruited: 51 genotype-positive, phenotype-positive (G+P+), 24 genotype-positive, phenotype-negative (G+P-), and 30 genotype-negative, phenotype-negative (G-P-). Baseline characteristics were similar between the 3 genotype groups. DCM-promoting environmental factors (eg. alcohol excess) were enriched in G+P+ individuals compared to G+P-(P<0.001) and G-P-(P=0.003) and were significantly associated with age at DCM onset (HR 2.01,P=0.014). HF comorbidities (eg. Diabetes) had a similar prevalence in G+P+ and G-P-but were significantly reduced in the G+P-group. Fluctuations in left ventricular ejection fraction during follow-up were linked to changes in environmental factors in 35/45 (78%) of instances: 32 (91%) of these were DCM-promoting factors. HF comorbidities, but not DCM-promoting factors, were associated with adverse events in G+ individuals (OR 4.9,P=0.004).ConclusionWe identified distinct subsets of environmental factors that affect DCM penetrance and adverse outcomes respectively. Our data highlight DCM-promoting environmental factors as key determinants of penetrance and disease trajectory. Collectively, these findings provide a new framework for risk factor assessment in familial DCM and have important implications for clinical management.
Nuclear assembly in giant unilamellar vesicles encapsulatingXenopusegg extract
Authors: Takamori Sho , Mimura Hisatoshi , Osaki Toshihisa , Kondo Tomo , Shintomi Miyuki , Shintomi Keishi , Ohsugi Miho , Takeuchi Shoji 
Published: June 2024

AbstractThe reconstitution of a cell nucleus in a lipid bilayer-enclosed synthetic cell makes great strides in bottom-up synthetic biology. In this study, we propose a method for assembling a nucleus in giant unilamellar vesicles (GUVs). To induce reconstitution of the nucleus, we utilize interphase egg extract of African clawed frogsXenopus laevis, known as a biochemically controllable cell-free system capable of transforming an added sperm chromatin into a nucleusin vitro. We enhanced GUV formation efficiency by the inverted emulsion method through incorporating prolonged waiting time and adding chloroform into lipid-dispersed oil, facilitating subsequent nuclear assembly reactions in the GUVs.Characterization of nucleus-like structures formed in the GUVs revealed the presence of dense DNA and accumulated GFP-NLS in the structure, indicative of functional nuclear import. Immunostaining further validated the presence of nuclear pore complexes on the surfaces of these nucleus-like structures. Our approach offers a versatile platform for constructing artificial cellular systems that closely mimic eukaryotic cells.TeaserA cell nucleus is reconstituted in lipid bilayer-enclosed confinements using egg extract from African clawed frogs.
Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C
Authors: Arseni Diana , Nonaka Takashi , Jacobsen Max H. , Murzin Alexey G. , Cracco Laura , Peak-Chew Sew Y. , Garringer Holly J. , Kawakami Ito , Suzuki Hisaomi , Onaya Misumoto , Saito Yuko , Murayama Shigeo , Geula Changiz , Vidal Ruben , Newell Kathy L. , Mesulam Marsel , Ghetti Bernardino , Hasegawa Masato , Ryskeldi-Falcon Benjamin 
Published: June 2024

SUMMARYNeurodegenerative diseases are characterised by the abnormal filamentous assembly of specific proteins in the central nervous system1. Human genetic studies established a causal role for protein assembly in neurodegeneration2. However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in electron cryo-microscopy (cryo-EM) have enabled the structures of the protein filaments to be determined from patient brains1. All diseases studied to date have been characterised by the self-assembly of a single intracellular protein in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) Types A and B3,4. Here, we used cryo-EM to determine filament structures from the brains of individuals with FTLD-TDP Type C, one of the most common forms of sporadic FTLD-TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/284–N345 and ANXA11 residues L39–L74 from their respective low-complexity domains (LCDs). Regions of TDP-43 and ANXA11 previously implicated in protein-protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as a ∼22 kDa N-terminal fragment (NTF) lacking the annexin core domain. Immunohistochemistry of brain sections confirmed the co-localisation of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP Type C. This work establishes a central role for ANXA11 in FTLD-TDP Type C. The unprecedented formation of heteromeric amyloid filaments in human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.
Airway basal stem cells are necessary for the maintenance of functional intraepithelial airway macrophages
Authors: Kooistra Tristan , Saez Borja , Roche Marly , Egea-Zorrilla Alejandro , Li Dongzhu , Anketell Dilanjan , Nguyen Nhan , Villoria Jorge , Gillis Jacob , Petri Eva , Vera Laura , Blasco-Iturri Zuriñe , Smith Neal P. , Alladina Jehan , Zhang Yanting , Vinarsky Vladimir , Shivaraju Manjunatha , Sheng Susan L. , Gonzalez-Celeiro Meryem , Mou Hongmei , Waghray Avinash , Lin Brian , Paksa Azadeh , Yanger Kilangsungla , Tata Purushotama Rao , Zhao Rui , Causton Benjamin , Zulueta Javier J. , Prosper Felipe , Cho Josalyn L. , Villani Alexandra-Chloe , Haber Adam , Rajagopal Jayaraj , Medoff Benjamin D. , Pardo-Saganta Ana 
Published: June 2024

SUMMARYAdult stem cells play a crucial role in tissue homeostasis and repair through multiple mechanisms. In addition to being able to replace aged or damaged cells, stem cells provide signals that contribute to the maintenance and function of neighboring cells. In the lung, airway basal stem cells also produce cytokines and chemokines in response to inhaled irritants, allergens, and pathogens, which affect specific immune cell populations and shape the nature of the immune response. However, direct cell-to-cell signaling through contact between airway basal stem cells and immune cells has not been demonstrated. Recently, a unique population of intraepithelial airway macrophages (IAMs) has been identified in the murine trachea. Here, we demonstrate that IAMs require Notch signaling from airway basal stem cells for maintenance of their differentiated state and function. Furthermore, we demonstrate that Notch signaling between airway basal stem cells and IAMs is required for antigen-induced allergic inflammation only in the trachea where the basal stem cells are located whereas allergic responses in distal lung tissues are preserved consistent with a local circuit linking stem cells to proximate immune cells. Finally, we demonstrate that IAM-like cells are present in human conducting airways and that these cells display Notch activation, mirroring their murine counterparts. Since diverse lung stem cells have recently been identified and localized to specific anatomic niches along the proximodistal axis of the respiratory tree, we hypothesize that the direct functional coupling of local stem cell-mediated regeneration and immune responses permits a compartmentalized inflammatory response.
Characterising cancer cell responses to cyclic hypoxia using mathematical modelling
Authors: Celora Giulia , Nixson Ruby , Pitt-Francis Joe , Maini Philip , Byrne Helen 
Published: June 2024

AbstractIn vivo observations show that oxygen levels in tumours can fluctuate on fast and slow timescales. As a result, cancer cells can be periodically exposed to pathologically low oxygen levels; a phenomenon known as cyclic hypoxia. Yet, little is known about the response and adaptation of cancer cells to cyclic, rather than, constant hypoxia. Further, existing in vitro models of cyclic hypoxia fail to capture the complex and heterogeneous oxygen dynamics of tumours growingin vivo. Mathematical models can help to overcome current experimental limitations and, in so doing, offer new insights into the biology of tumour cyclic hypoxia by predicting cell responses to a wide range of cyclic dynamics. We develop an individual-based model to investigate how cell cycle progression and cell fate determination of cancer cells are altered following exposure to cyclic hypoxia. Our model can simulate standardin vitroexperiments, such as clonogenic assays and cell cycle experiments, allowing for efficient screening of cell responses under a wide range of cyclic hypoxia conditions. Simulation results show that the same cell line can exhibit markedly different responses to cyclic hypoxia depending on the dynamics of the oxygen fluctuations. We also use our model to investigate the impact of changes to cell cycle checkpoint activation and damage repair on cell responses to cyclic hypoxia. Our simulations suggest that cyclic hypoxia can promote heterogeneity in cellular damage repair activity within vascular tumours.
CRISPR screen decodes SWI/SNF chromatin remodeling complex assembly
Authors: Schwaemmle Hanna , Soldati Hadrien , Lykoskoufis Nikolaos M. R. , Docquier Mylène , Hainard Alexandre , Braun Simon M. G. 
Published: June 2024

AbstractThe SWI/SNF (or BAF) complex is an essential chromatin remodeler that regulates DNA accessibility at developmental genes and enhancers. SWI/SNF subunits are among the most frequently mutated genes in cancer and neurodevelopmental disorders. These mutations are often heterozygous loss-of-function alleles, indicating a dosage-sensitive role for SWI/SNF subunits in chromatin regulation. However, the molecular mechanisms that regulate SWI/SNF subunit dosage to ensure proper complex assembly remain largely unexplored. We performed a genome-wide CRISPR KO screen, using epigenome editing in mouse embryonic stem cells, and identifiedMlf2andRbm15as regulators of SWI/SNF complex activity. First, we show that MLF2, a poorly characterized chaperone protein, regulates a subset of SWI/SNF target genes by promoting chromatin remodeling activity. Next, we find that RBM15, part of the m6A RNA methylation writer complex, controls m6A modifications on specific SWI/SNF mRNAs to regulate protein levels of these subunits. Misregulation of m6A methylation causes overexpression of core SWI/SNF subunits leading to the assembly of incomplete complexes lacking the catalytic ATPase/ARP subunits. These data indicate that targeting modulators of SWI/SNF complex assembly may offer a potent therapeutic strategy for diseases associated with impaired chromatin remodeling.
Co-Metabolic Growth and Microbial Diversity: Keys for the depletion of the α, δ, β and γ-HCH isomers
Authors: Bernabei Giacomo , De Simone Giampiero , Becarelli Simone , Di Mambro Riccardo , Gentini Alessandro , Di Gregorio Simona 
Published: June 2024

AbstractThe objective of this study was to select and enhance microbiomes capable of degrading the α, δ, β and γ-HCH isomers. These microbiomes were isolated and enriched from an HCH-contaminated dumpsite in Italy, both in the presence of HCH isomers (1:1:1:1) as the sole carbon sources and under co-metabolic growth conditions in presence of glucose (0.1%). Four microbiomes were assessed for their relevant metabolic capabilities. A quantitative metabarcoding approach was employed to analyze the compositional evolution of the four microbiomes during the enrichment phase and the phase of tsting of the HCH isomers degradation kinetics. The use of a co-metabolic substrate during enrichment process was essential for selecting microbiomes with higher biodiversity. All microbiomes efficiently degraded the α, δ, and γ-HCH isomers. The highest efficiency in the β-HCH degradation capacity was associated to the highest biodiversity of the microbiome, and the involvement ofChryseobacteriumandAsinibacteriumsps. has been proposed for a recorded increment in bacterial load during the HCH degradation process.Statement of environmental implicationsSoil contaminated with hexachlorocyclohexane (HCH), including all four isomers, poses a significant risk to environmental and public health. This study isolates and selects microbiomes capable of degrading HCH, demonstrating their degradation efficiency using GC-MS analysis, and studies the microbial communities through metabarcoding of both the initial soils and the selected microbiomes. The contaminated soil originates from the historically polluted area of Italy known as SIN-Valle del Sacco. Developing and optimizing microbiome selection techniques for application on contaminated sites can significantly enhance soil bioremediation, thereby reducing contamination and protecting the environment.
Sensitive quantification of fibroblast activation protein and high-throughput screening for inhibition by FDA-approved compounds
Authors: Čermáková Kateřina , Šimková Adéla , Wichterle Filip , Kryštůfek Robin , Staňurová Jana , Bušek Petr , Konvalinka Jan , Šácha Pavel 
Published: June 2024

AbstractFibroblast activation protein (FAP) has been extensively studied as a cancer biomarker for decades. Recently, small-molecule FAP inhibitors have been widely adopted as a targeting moiety of experimental theranostic radiotracers. Here we present a fast qPCR-based analytical method allowing FAP inhibition screening in a high-throughput regime. In order to identify clinically relevant compounds that might interfere with FAP-targeted approaches, we focused on the library of FDA-approved drugs. Using theDNA-linkedInhibitorAntibodyAssay (DIANA), we tested a library of 2,667 compounds within just few hours and identified numerous FDA-approved drugs as novel FAP inhibitors. Notably, prodrugs of cephalosporin antibiotics, reverse-transcriptase inhibitors, and one elastase inhibitor were the most potent FAP inhibitors in our dataset. In addition, by employing FAP DIANA in quantification mode, we were able to determine FAP concentrations in human plasma samples. Together, our work expands the repertoire of FAP inhibitors, underscores the potential interference of co-administered drugs with FAP-targeting strategies, and presents a sensitive and low-consumption ELISA alternative for FAP quantification with a detection limit of 50 pg/ml.Graphical abstract