bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of head motion on brain age prediction using deep convolutional neural networks
Authors: Vakli Pál , Weiss Béla , Rozmann Dorina , Erőss György , Nárai Ádám , Hermann Petra , Vidnyánszky Zoltán 
Published: November 2023

AbstractDeep learning can be used effectively to predict participants’ age from brain magnetic resonance imaging (MRI) data, and a growing body of evidence suggests that the difference between predicted and chronological age—referred to as brain-predicted age difference (brain-PAD)—is related to various neurological and neuropsychiatric disease states. A crucial aspect of the applicability of brain-PAD as a biomarker of individual brain health is whether and how brain-predicted age is affected by MR image artifacts commonly encountered in clinical settings. To investigate this issue, we trained and validated two different 3D convolutional neural network architectures (CNNs) from scratch and tested the models on a separate dataset consisting of motion-free and motion-corrupted T1-weighted MRI scans from the same participants, the quality of which were rated by neuroradiologists from a clinical diagnostic point of view. Our results revealed a systematic increase in brain-PAD with worsening image quality for both models. This effect was also observed for images that were deemed usable from a clinical perspective, with brains appearing older in medium than in good quality images. These findings were also supported by significant associations found between the brain-PAD and standard image quality metrics indicating larger brain-PAD for lower-quality images. Our results demonstrate a spurious effect of advanced brain aging as a result of head motion and underline the importance of controlling for image quality when using brain-predicted age based on structural neuroimaging data as a proxy measure for brain health.HighlightsTwo 3D CNNs trained from scratch and validated to predict age from T1-w brain MRITesting on motion-free and motion-corrupted scans from the same participantsImage quality assessed by neuroradiologists and using standard image quality metricsSystematic increase in brain-predicted age difference with worsening image qualitySpurious advanced brain aging effect in scans deemed usable for clinical diagnostics
Distress symptoms of old age and mild cognitive impairment are two distinct dimensions in older adults without major depression: effects of adverse childhood experiences and negative life events
Authors: Tran-Chi Vinh-Long , Maes Michael , Nantachai Gallayaporn , Hemrungrojn Solaphat , Solmi Marco , Tunvirachaisakul Chavit 
Published: November 2023

AbstractBackgroundStudies in old adults showed bidirectional interconnections between amnestic mild cognitive impairment (aMCI) and affective symptoms and that adverse childhood experiences (ACE) may affect both factors. Nevertheless, these associations may be confined to older adults with clinical depression.AimsTo delineate the relationship between clinical symptoms of aMCI and affective symptoms in older adults without major depression (MDD) or dysfunctions in activities of daily living (ADL).MethodsThis case-control study recruited 61 participants with aMCI (diagnosed using Petersen’s criteria) and 59 older adults without aMCI and excluded subjects with MDD and ADL dysfunctions.ResultsWe uncovered 2 distinct dimensions, namely distress symptoms of old age (DSOA) comprising anxiety, depression, perceived stress and neuroticism scores, and mild cognitive dysfunctions (mCoDy) comprising episodic memory test scores, and the total Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores. A large part of the variance (37.9%) in DSOA scores was explained by ACE, negative life events (health and financial problems), a subjective feeling of cognitive decline, and education (all positively). While ACE and NLE have a highly significant impact on the DSOA, they are not associated with the mCoDy scores. Cluster analysis showed that the diagnosis of aMCI is overinclusive because some subjects with DSOA symptoms may be incorrectly classified as aMCI.ConclusionsThe clinical impact is that clinicians should carefully screen older adults for DSOA after excluding MDD. DSOA might be misinterpreted as aMCI.
Characterization of highly active mutational signatures in tumors from a large Chinese population
Authors: Chevalier Aaron , Guo Tao , Gurevich Natasha Q. , Xu Jingwen , Yajima Masanao , Campbell Joshua D. 
Published: November 2023

AbstractThe majority of mutational signatures have been characterized in tumors from Western countries and the degree to which mutational signatures are similar or different in Eastern populations has not been fully explored. We leveraged a large-scale clinical sequencing cohort of tumors from a Chinese population containing 25 tumor types and found that the highly active mutational signatures were similar to those previously characterized1,2. The aristolochic acid signature SBS22 was observed in four soft tissue sarcomas and the POLE-associated signature SBS10 was observed in a gallbladder carcinoma. In lung adenocarcinoma, the polycyclic aromatic hydrocarbon (PAH) signature SBS4 was significantly higher in males compared to females but not associated with smoking status. The UV-associated signature SBS7 was significantly lower in cutaneous melanomas from the Chinese population compared to a similar American cohort. Overall, these results add to our understanding of the mutational processes that contribute to tumors from the Chinese population.
General population screening for type 1 diabetes using islet autoantibodies at the preschool vaccination visit: a proof-of-concept study (the T1Early study)
Authors: Scudder Claire , Townson Julia , Gillespie Kathleen M , Bowen-Morris Jane , Evans Philip , Jones Sarah , Thomas Nicholas P B , Stanford Jane , Fox Robin , Todd John A , Greenfield Sheila , Dayan Colin M , Besser Rachel E J 
Published: November 2023

ABSTRACTObjectiveType 1 diabetes (T1D) screening programmes testing islet autoantibodies (IAbs) in childhood can reduce life-threatening diabetic ketoacidosis. General population screening is required to detect the majority of children with T1D, since in >85% there is no family history. Age 3-5 has been proposed as an optimal age for a single screen approach.DesignCapillary samples were collected from children attending their pre-school vaccination and analysed for IAbs to insulin, glutamic acid decarboxylase, islet antigen-2, and zinc transporter 8, using Radiobinding/Luciferase Immunoprecipitation Systems assays. Acceptability was assessed using semi-structured interviews and open-ended postcard questionnaires with parents.SettingTwo primary care practices in Oxfordshire, UK.Main outcome measuresThe ability to collect capillary blood to test IAbs in children at the routine pre-school vaccination (3.5-4 years).ResultsOf 134 parents invited, 66 (49%) were recruited (median age 3.5y (IQR 3. 4-3.6), 26(39.4%) male); 63 provided a sample (97% successfully). Parents (n=15 interviews, n=29 postcards) were uniformly positive about screening aligned to vaccination and stated they would have been less likely to take part had screening been a separate visit. Themes identified included preparedness for T1D, and the long-term benefit outweighing short-term upset. The perceived volume of the capillary sample was a potential concern and needs optimising.ConclusionsCapillary IAb testing is a possible method to screen children for T1D. Aligning collection to the pre-school vaccination visit can be convenient for families and allows a universal approach without the need for an additional visit.KEY MESSAGESWhat is already known on this topic?Screening children for type 1 diabetes by measuring islet autoantibodies (IAbs) may reduce life-threatening diabetic ketoacidosis. The optimal age for screening children at a single timepoint has been proposed as age 3-5. Routine immunisations are given at a similar age.What does this study add?Aligning IAb testing with the pre-school vaccination visit (age 3.5-4y) is feasible and acceptable. Potential barriers and facilitators of this approach are explored.How this study might affect research, practice or policy?The routine vaccination programme is a potential opportunity to screen children for future type 1 diabetes, offering improved engagement and potentially reducing the costs associated with a screening programme; all of which need exploration in a large and definitive study.
Ventricular volume asymmetry as a novel imaging biomarker for disease discrimination and outcome prediction
Authors: McCracken Celeste , Szabo Liliana , Abdulelah Zaid A. , Vago Hajnalka , Nichols Thomas E. , Petersen Steffen E. , Neubauer Stefan , Raisi-Estabragh Zahra 
Published: November 2023

BackgroundThe utility of ventricular asymmetry as an imaging biomarker for cardiovascular risk has not been assessed in population cohorts.ObjectivesThis study presents a comprehensive assessment of the population distribution of ventricular asymmetry and its relationships across a range of prevalent and incident cardiorespiratory diseases.MethodsCardiovascular magnetic resonance (CMR) imaging metrics derived from automated image analysis were examined, along with clinical outcomes ascertained through linked health records. Ventricular asymmetry was expressed as the ratio of left and right ventricular (LV, RV) end-diastolic volumes. The normal range for ventricular symmetry was defined in a healthy subset without cardiorespiratory disease. Participants with values outside the 5th-95thpercentiles of the healthy distribution were classed as either LV dominant (LV/RV > 112%) or RV dominant (LV/RV < 80%) asymmetry. Associations of LV and RV dominant asymmetry with vascular risk factors, CMR features, and prevalent and incident cardiovascular diseases were examined using regression models, adjusting for vascular risk factors, prevalent diseases, and conventional CMR measures.ResultsThe analysis includes 44,796 participants (average age 64.1±7.7 years; 51.9% women). Ventricular asymmetry, in either direction, was associated with older age and adverse cardiovascular remodeling. LV-dominance was linked to an array of pre-existing vascular risk factors and cardiovascular diseases, and a two-fold increased risk of incident heart failure, non-ischemic cardiomyopathies, and left-sided valvular disorders. RV dominance was associated with an elevated risk of all-cause mortality.ConclusionsVentricular asymmetry has clinical utility for cardiovascular risk assessment, providing information that is incremental to traditional risk factors and conventional CMR metrics.Condensed abstractHealthy hearts have a predictable symmetry. Asymmetry produced when one, e.g. the left ventricular (LV) volume outweighs the right, or vice versa, could be an important indicator of underlying disorders, and powerful risk indicator for future disease. In this study of 44,796 UK Biobank participants, we show that LV dominance associates significantly with clinical risk factors, existing heart disease, and a two-fold increased risk for future heart failure, non-ischemic cardiomyopathies, and left-sided valvular disorders. RV dominance was associated with an increased risk of all-cause mortality. Ventricular asymmetry is easily calculated from conventional imaging metrics and could be a highly useful addition to the clinician’s toolkit.Central illustration:Ventricular volume asymmetry associates with adverse outcomes
Rational Empiric Antibiotic Escalation Applied to Specific Patient Groups
Authors: Bamber Ranjeet , Sullivan Brian , Gorman Léo , Lee Winnie WY , Avison Matthew B , Dowsey Andrew W , Williams Philip 
Published: November 2023

AbstractBackgroundClinicians commonly escalate empiric antibiotic therapy due to poor clinical progress, without microbiology guidance. When escalating, they should take account of how resistance to an initial antibiotic affects the probability of resistance to subsequent options. The term Escalation Antibiogram (EA) has been coined to describe this concept. One difficulty when applying the EA concept to clinical practice is understanding the uncertainty in results and how this changes for specific patient subgroups.MethodsA Bayesian model was developed to estimate antibiotic resistance rates in Gram-negative bloodstream infections based on phenotypic resistance data. It provides an expected value (posterior mean) with 95% credible interval to illustrate uncertainty, based on the size of the patient subgroup, and estimates probability of inferiority between two antibiotics. This model can be applied to specific patient groups where resistance rates and underlying microbiology may differ from the whole hospital population.ResultsRates of resistance to empiric first choice and potential escalation antibiotics were calculated for the whole hospitalised population based on 10,486 individual bloodstream infections, and for a range of specific patient groups, including ICU, haematology-oncology, and paediatric patients. Differences in optimal escalation antibiotic options between specific patient groups were noted.ConclusionsEA analysis informed by our Bayesian model is a useful tool to support empiric antibiotic switches, providing an estimate of local resistances rates, and a comparison of antibiotic options with a measure of the uncertainty in the data. We demonstrate that EAs calculated for the whole population cannot be assumed to apply to specific patient groups.
Lower activity of cholesteryl ester transfer protein (CETP) and the risk of dementia: a Mendelian randomization analysis
Authors: Schmidt Amand F , Davidson Michael H , Ditmarsch Marc , Kastelein John J. , Finan Chris 
Published: November 2023

AbstractElevated levels of low-density lipoprotein cholesterol (LDL-C) are linked to dementia risk, and conversely, increased plasma concentrations of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein-A1 (Apo-A1) associate with decreased dementia risk. Inhibition of cholesteryl ester transfer protein (CETP) meaningfully affects the concentrations of these blood lipids and may therefore provide an opportunity to treat dementia. Drug target Mendelian randomization (MR) was employed to anticipate the on-target effects of lower CETP concentration (µg/mL) on plasma lipids, cardiovascular disease outcomes, Lewy body dementia (LBD) as well as Parkinson’s dementia. MR analysis of lower CETP concentration recapitulated the blood lipid effects observed in clinical trials of CETP-inhibitors, as well as protective effects on CHD (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.89; 0.96), heart failure, abdominal aortic aneurysm any stroke, ischemic stroke, and small vessel stroke (0.90, 95%CI 0.85; 0.96). Consideration of dementia related traits indicated that lower CETP concentrations were associated higher total brain volume (0.04 per standard deviation, 95%CI 0.02; 0.06), lower risk of LBD (OR 0.81, 95%CI 0.74; 0.89) and Parkinson’s dementia risk (OR 0.26, 95%CI 0.14; 0.48).APOE4stratified analyses suggested the LBD effect was most pronounced inAPOE-ε4+ participants (OR 0.61 95%CI 0.51; 0.73), compared toAPOE-ε4-(OR 0.89 95%CI 0.79; 1.01); interaction p-value 5.81×10-4. Additionally, MR was employed to link plasma CETP concentration to the levels of cerebrospinal fluid and brain proteins previously implicated in neurodegenerative pathways These results suggest that inhibition of CETP may be a viable strategy to treat dementia.
Spatially resolved proteomics of the stomatal lineage: polarity complexes for cell divisions and stomatal pores
Authors: Wallner Eva-Sophie , Mair Andrea , Handler Dominik , McWhite Claire , Xu Shou-Ling , Dolan Liam , Bergmann Dominique C. 
Published: November 2023

AbstractCell polarity is used to guide asymmetric divisions and create morphologically diverse cells. We find that two oppositely oriented cortical polarity domains present during the asymmetric divisions in the Arabidopsis stomatal lineage are reconfigured into polar domains marking ventral (pore-forming) and outward facing domains of maturing stomatal guard cells. Proteins that define these opposing polarity domains were used as baits in miniTurboID-based proximity labeling. Among differentially enriched proteins we find kinases, putative microtubule-interacting proteins, polar SOSEKIs with their effector ANGUSTIFOLIA, and using AI-facilitated protein structure prediction models, we identify their potential interaction interfaces. Functional and localization analysis of polarity protein OPL2 and its newly discovered partners suggest a positive interaction with mitotic microtubules and a potential role in cytokinesis. This combination of cutting-edge proteomics and structural modeling with live cell imaging provides insights into how polarity is rewired in different cell types and cell cycle stages.
Leveraging a self-cleaving peptide for tailored control in proximity labeling proteomics
Authors: Delhaye Louis , Moschonas George D. , Fijalkowska Daria , Verhee Annick , De Sutter Delphine , Van de Steene Tessa , De Meyer Margaux , Van Moortel Laura , De Bosscher Karolien , Jacobs Thomas , Eyckerman Sven 
Published: November 2023

SummaryProtein-protein interactions play an important biological role in every aspect of cellular homeostasis and functioning. Proximity labeling mass spectrometry-based proteomics overcomes challenges typically associated with other methods, and has quickly become the current state-of-the-art in the field. Nevertheless, tight control of proximity labeling enzymatic activity and expression levels is crucial to accurately identify protein interactors. Here, we leverage a T2A self-cleaving peptide and a non-cleaving mutant to accommodate the protein-of-interest in the experimental and control TurboID setup. To allow easy and streamlined plasmid assembly, we built a Golden Gate modular cloning system to generate plasmids for transient expression and stable integration. To highlight our T2A Split-link design, we applied it to identify protein interactions of the glucocorticoid receptor and SARS-CoV-2 nucleocapsid and NSP7 proteins by TurboID proximity labeling. Our results demonstrate that our T2A split-link provides an opportune control that builds upon previously established control requirements in the field.MotivationIn proximity labeling proteomics protein-protein interactions are identified byin vivobiotinylation. However, the current lack of a universally applicable negative control for differential analysis affects accurate mapping of the interactome. To bridge this gap, we conceptualized a system based on the T2A self-cleaving peptide to match expression levels between control and bait protein setups while using the same bait protein. In addition, we implemented a versatile modular cloning system to build mammalian expression vectors for, but not limited to, proximity labeling assays.
Conserved patterns of sequence diversification provide insight into the evolution of two-component systems in Enterobacteriaceae
Authors: Barretto Luke A.F. , Van Patryc-Khang T. , Fowler Casey C. 
Published: November 2023

ABSTRACTTwo-component regulatory systems (TCS) are a major mechanism used by bacteria to sense and respond to their environments. Many of the same TCS are used by biologically diverse organisms with different regulatory needs, suggesting that the functions of TCS must adapt over evolution. To explore this topic, we analyzed the amino acid sequence divergence patterns of a large set of broadly conserved TCS across different branches of Enterobacteriaceae, a family of Gram-negative bacteria that includes biomedically important genera such asSalmonella,Escherichia,Klebsiella, and others. Our analysis revealed trends in how TCS sequences change across different proteins or functional domains of the TCS, and across different lineages. Based on these trends, we identified individual TCS that exhibit atypical evolutionary patterns. We observed a strong correlation for the extent of sequence variation of a given TCS across different lineages, unveiling a hierarchy TCS sequence conservation with EnvZ/OmpR as the most conserved TCS. We provide evidence that, for the most divergent of the TCS analyzed, PmrA/PmrB, different alleles were horizontally acquired by different branches of this family, and that different PmrA/PmrB sequence variants have highly divergent signal sensing domains. Collectively, this study sheds light on how TCS evolve, and serves as a compendium for how the sequences of the TCS in this family have diverged over the course of evolution.
UsingVibrio natriegensfor high-yield production of challenging expression targets and for protein deuteration
Authors: Mojica Natalia , Kersten Flore , Montserrat-Canals Mateu , Huhn G. Robb , Tislevoll Abelone M. , Cordara Gabriele , Teter Ken , Krengel Ute 
Published: November 2023

ABSTRACTProduction of soluble proteins is essential for structure/function studies, however, this usually requires milligram amounts of protein, which can be difficult to obtain with traditional expression systems. Recently, the Gram-negative bacteriumVibrio natriegensappeared as a novel and alternative host platform for production of proteins in high yields. Here, we used a commercial strain derived fromV. natriegens(VmaxTMX2) to produce soluble bacterial and fungal proteins in milligram scale, which we struggled to achieve inEscherichia coli. These proteins include the cholera toxin (CT) andN-acetyl glucosamine binding protein A (GbpA) fromVibrio cholerae, the heat-labile enterotoxin (LT) fromE. coliand the fungal nematotoxin CCTX2 fromCoprinopsis cinerea. CT, GbpA and LT are secreted by the Type II secretion system in their natural hosts. When these three proteins were produced in Vmax, they were also secreted, and could be recovered from the growth media. This simplified the downstream purification procedure and resulted in considerably higher protein yields compared to production inE. coli(6– to 26-fold increase). We also tested Vmax for protein deuteration using deuterated minimal media with deuterium oxide as solvent, and achieved a 3-fold increase in yield compared to the equivalent protocol inE. coli. This is good news since isotopic labeling is expensive and often ineffective, but represents a necessary prerequisite for some structural techniques. Thus, Vmax represents a promising host for production of challenging expression targets and for protein deuteration in amounts suitable for structural biology studies.
Quantification of influenza virus mini viral RNA dynamics using Cas13
Authors: Lamb Caitlin H. , Pitré Emmanuelle M. , Elshina Elizaveta , Rigby Charlotte V. , Bisht Karishma , Oade Michael S. , Jalal Hamid , Myhrvold Cameron , Velthuis Aartjan J.W. te 
Published: November 2023

AbstractInfluenza A virus RNA synthesis produces full-length and aberrant RNA molecules, which include defective viral genomes (DVG) and mini viral RNAs (mvRNA). Sequencing approaches have shown that aberrant RNA species may be present during infection, and that they can vary in size, segment origin, and sequence. Moreover, a subset of aberrant RNA molecules can bind and activate host pathogen receptor retinoic acid-inducible gene I (RIG-I), leading to innate immune signaling and the expression of type I and III interferons. Understanding the kinetics and distribution of these immunostimulatory aberrant RNA sequences is important for understanding their function in IAV infection. Here, we use an amplification-free LbuCas13a-based detection method to quantify mvRNA amplification dynamics and subcellular distributions. We show that our assay can quantify the copy numbers of specific mvRNA sequences in infected tissue culture cells, ferret upper and lower respiratory tract tissue infected with two different pandemic H1N1 IAV strains, or clinical nasopharyngeal swab extracts of hospitalized patients infected with seasonal H1N1 or H3N2 strains. In addition, we find dynamic differences between immunostimulatory and non-immunostimulatory mvRNAs, as well as among mvRNAs derived from different segments, during IAV infection. Overall, our results reveal a hitherto hidden diversity in the behavior of IAV mvRNAs and suggest that individual aberrant RNAs are not produced stochastically.