bluuebunny/crossref_metadata_2025_split huggingface dataset:
Membrane-bound Interleukin-1α mediates leukocyte adhesion during atherogenesis
Authors: Mäder Christina , Speer Thimoteus , Wirth Angela , Boeckel Jes-Niels , Fatima Sameen , Shahzad Khurrum , Freichel Marc , Laufs Ulrich , Gaul Susanne 
Published: June 2023

AbstractBackgroundThe interleukin-1 (IL-1) family and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome contribute to atherogenesis but the underlying mechanism are incompletely understood. Unlike IL-1β, IL-1α is not dependent on the NLRP3 inflammasome to exert its pro-inflammatory effects. Here, a non-genetic model was applied to characterize the role of IL-1α, IL-1β and NLRP3 for the pathogenesis of atherosclerosis.MethodsAtherogenesis was induced by gain-of-function PCSK9-AAV8 mutant viruses and feeding of a high-fat western diet (WTD) for 12 weeks in C57Bl6/J wildtype mice (control) and in Il1a-/-, Nlrp3-/-, and Il1b-/-mice.ResultsIl1a-/-mice showed reduced atherosclerotic plaque area in the aortic root with lower lipid accumulation, while no difference was observed between wildtype, Nlrp3-/-and Il1b-/-mice. Serum proteomic analysis showed a reduction of pro-inflammatory cytokines (e.g. IL-1β, IL-6) in Il1a-/-as well as in Nlrp3-/-and Il1b-/-mice. Bone marrow dendritic cells (BMDC) of WT, Nlrp3-/-and Il1b-/-mice and primary human monocytes showed translocation of IL-1α to the plasma membrane (csIL-1α) upon stimulation with LPS. The translocation of IL-1α to the cell surface was regulated by myristoylation and increased in mice with hypercholesterolemia. CsIL-1α and IL1R1 protein-protein interaction on endothelial cells induced VCAM1 expression and monocyte adhesion, which was abrogated by the administration of neutralizing antibodies against IL-1α and IL1R1.ConclusionsIl1a-/-mice, but not Nlrp3-/-or Il1b-/-mice, are protected from atherosclerosis after induction of hypercholesterolemia independent of circulating cytokines. Myristoylation and translocation of IL-1α to the cell surface in myeloid cells facilitates leukocyte adhesion and contributes to the development of atherosclerosis.Abstract FigureGraphical abstract.The role of cell-surface (cs) IL-1a in the initiation of atherosclerosis.
Coiled-coil domains are sufficient to drive liquid-liquid phase separation of proteins in molecular models
Authors: Ramirez Dominique A. , Hough Loren E. , Shirts Michael R. 
Published: June 2023

ABSTRACTLiquid-liquid phase separation (LLPS) is thought to be a main driving force in the formation of membraneless organelles. Examples of such organelles include the centrosome, central spindle, and stress granules. Recently, it has been shown that coiled-coil (CC) proteins, such as the centrosomal proteins pericentrin, spd-5, and centrosomin, might be capable of LLPS. CC domains have physical features that could make them the drivers of LLPS, but it is unknown if they play a direct role in the process. We developed a coarse-grained simulation framework for investigating the LLPS propensity of CC proteins, in which interactions which support LLPS arise solely from CC domains. We show, using this framework, that the physical features of CC domains are sufficient to drive LLPS of proteins. The framework is specifically designed to investigate how the number of CC domains, as well as multimerization state of CC domains, can affect LLPS. We show that small model proteins with as few as two CC domains can phase separate. Increasing the number of CC domains up to four per protein can somewhat increase LLPS propensity. We demonstrate that trimer-forming and tetramer-forming CC domains have a dramatically higher LLPS propensity than dimer-forming coils, which shows that multimerization state has a greater effect on LLPS than the number of CC domains per protein. These data support the hypothesis of CC domains as drivers of protein LLPS, and has implications in future studies to identify the LLPS-driving regions of centrosomal and central spindle proteins.STATEMENT OF SIGNIFICANCEThe liquid-liquid phase separation of coiled-coil proteins has been implicated in the formation of membraneless organelles such as the centrosome and central spindle. Little is known about the features of these proteins that might drive their phase separation. We developed a modeling framework to investigate the potential role of coiled-coil domains in phase separation, and show that these domains are sufficient to drive the phenomenon in simulation. We additionally show the importance of multimerization state on the ability for such proteins to phase separate. This work suggests that coiled-coil domains should be considered for their contribution to protein phase separation.
Quantifying collective interactions in biomolecular phase separation
Authors: Ausserwöger Hannes , Qian Daoyuan , Krainer Georg , de Csilléry Ella , Welsh Timothy J. , Sneideris Tomas , Franzmann Titus M. , Qamar Seema , Erkamp Nadia A. , Nixon-Abell Jonathon , Kar Mrityunjoy , George-Hyslop Peter St , Hyman Anthony A. , Alberti Simon , Pappu Rohit V. , Knowles Tuomas P. J. 
Published: June 2023

AbstractBiomolecular phase separation plays a pivotal role in governing critical biological functions and arises from the collective interactions of large numbers of molecules. Characterising the underlying collective interactions of phase separation, however, has proven to be challenging with currently available tools. Here, we propose a general and easily accessible strategy to quantify collective interactions in biomolecular phase separation with respect to composition and energetics. By measuring the dilute phase concentration of one species only, we determine tie line gradients and free energy dominance as dedicated descriptors of collective interactions. We apply this strategy to dissect the role of salts and small molecules on phase separation of the protein fused in sarcoma (FUS). We discover that monovalent salts can display both exclusion from or preferential partitioning into condensates to either counteract charge screening or enhance non-ionic interactions. Moreover, we show that the common hydrophobic interaction disruptor 1,6-hexanediol inhibits FUS phase separation by acting as a solvation agent capable of expanding the protein polypeptide chain. Taken together, our work presents a widely applicable strategy that enables quantification of collective interactions and provides unique insights into the underlying mechanisms of condensate formation and modulation.
ACCELEROMETER-BASED SEDENTARY BEHAVIOUR AND PHYSICAL ACTIVITY ARE ASSOCIATED WITH THE GUT MICROBIOTA IN 8507 INDIVIDUALS FROM THE POPULATION-BASED SCAPIS
Authors: Baldanzi Gabriel , Sayols-Baixeras Sergi , Ekblom-Bak Elin , Ekblom Örjan , Dekkers Koen F. , Hammar Ulf , Nguyen Diem , Ahmad Shafqat , Ericson Ulrika , Arvidsson Daniel , Börjesson Mats , Johanson Peter J. , Smith J Gustav , Bergström Göran , Lind Lars , Engström Gunnar , Ärnlöv Johan , Kennedy Beatrice , Orho-Melander Marju , Fall Tove 
Published: June 2023

ABSTRACTObjectivePopulation-based studies investigating the relationship between physical activity and the gut microbiota composition have mainly relied on self-reported activity, potentially influenced by reporting bias. Here, we investigated associations of accelerometer-based sedentary behaviour and physical activity with the gut microbiota composition and functional profile in the large Swedish CArdioPulmonary bioImage Study.MethodsIn 8507 participants aged 50-65, the proportion of time in sedentary (SED), moderate-intensity (MPA), and vigorous-intensity (VPA) physical activity were estimated with hip-worn accelerometer. The gut microbiota was profiled using shotgun metagenomics of fecal samples. We fitted multivariable regression models, and adjusted for sociodemographic, lifestyle, and technical covariates while also accounting for multiple testing.ResultsOverall, SED and MPA were associated with microbiota species in opposite directions. For example, the strongest positive regression coefficient for MPA and the strongest negative for SED were withPrevotella copri, a plant-polysaccharide-degrading bacteria. Species associated with VPA aligned with the MPA associations, although with clear discrepancies. For instance,Phocaeicola vulgatuswas negatively associated with MPA, while the association with VPA was non-significant and in the positive direction. Additional adjustment for dietary variables or adiposity attenuated some of the associations. For the functional profile, MPA and VPA were generally associated with lower capacity for amino acid degradation.ConclusionOur findings suggest that sedentary behaviour and physical activity are associated with a similar set of gut microbiota species and functions, but in opposite directions. Furthermore, the intensity of physical activity may have specific effects on certain species of the gut microbiota.
On the Atrial Fibrillation Detection Performance of ECG-DualNet
Authors: Reich Christoph , Rohr Maurice , Kircher Tim , Antink Christoph Hoog 
Published: June 2023

AbstractAtrial Fibrillation (AF) is a severe cardiac arrhythmia affecting a significant amount of the human population [1]. Quick diagnosis and treatment are critical in reducing the risk of severe sequelae such as stroke or heart failure. Rohret al. [2] recently proposed ECG-DualNet, a neural network for accurate AF detection in single-lead electrocardiogram (ECG) data. This short paper reports additional empirical results of ECG-DualNet to gain new insights on AF detection in single-lead ECG data with deep neural networks. We systematically analyze which ingredients of ECG-DualNet are crucial for achieving competitive AF detection results. We also scale the ECG-DualNet architecture to 130M parameters and perform large-scale supervised pre-training, providing additional empirical results. Finally, we provide recommendations for future research toward accurate and robust AF detection.
A multi-step analysis and co-produced principles to support Equitable Partnership with Liverpool School of Tropical Medicine, 125 years on
Authors: Karuga Robinson , Steege Rosie , Chowdhury Shahreen , Squire Bertie , Theobald Sally , Otiso Lilian 
Published: June 2023

AbstractTransboundary health partnerships are shaped by global inequities. Voices from “global South” research partners are critical to understand and redress power asymmetries in research partnerships. We undertook research with Liverpool School of Tropical Medicine (LSTM) partners to inform LSTM’s equitable partnership strategy and co-develop principles for equitable partnerships.We applied mixed methods and participatory approaches. An online survey (n=21) was conducted with transboundary partners on fairness of opportunity, fair process, and fair sharing of benefits in partnership with LSTM-Liverpool. We triangulated the survey with key informant interviews (n=12). Qualitative narratives were coded and analysed using the thematic framework approach. These findings were presented in a participatory workshop with transboundary partners to co-develop principles for equitable partnership, which were then refined and validated.Transboundary partners identified being involved in agenda setting from the outset, shaping the design of research projects and theories of change as mechanisms to support fair opportunity however, funding mechanisms that shape power structures was reported as limiting fair opportunities. Fair process was supported by multi-directional, long-term collaborations with opportunities for capacity strengthening. Participants raised concerns about funder requirements and outdated language in contracting process that hindered equity. Fair benefit sharing was facilitated by early discussions on authorship to promote equity and policy influence. Funding also influenced the ability to travel and network, important for benefit sharing and fair opportunity. High paywalls limit sharing of research findings and access to research findings for many “global-South” partners.The co-developed principles are part of ongoing reflections and dialogue to improve and undo harmful power structures that perpetuate coloniality within global health. While this process was conducted with LSTM-Liverpool partners, the principles to strengthen equity are applicable to other institutions engaged in transboundary research partnerships and relevant for funders.
The clinical, genomic, and microbiological profile of invasive multi-drug resistant Escherichia coli in a major teaching hospital in the United Kingdom
Authors: Hamilton William L. , Coscione Suny , Maes Mailis , Warne Ben , Pike Lindsay J. , Khokhar Fahad A. , Blane Beth , Brown Nicholas M. , Gouliouris Theodore , Dougan Gordon , Török M. Estée , Baker Stephen 
Published: June 2023

AbstractEscherichia coliis a ubiquitous component of the human gut microbiome, but is also a common pathogen, causing around 40,000 bloodstream infections (BSI) in the UK annually. The number ofE. coliBSI has increased over the last decade in the UK, and emerging antimicrobial resistance (AMR) profiles threaten treatment options. Here, we combined clinical, epidemiological, and whole genome sequencing data with high content imaging to characterise over 300E. coliisolates associated with BSI in a large UK teaching hospital. Overall, only a limited number of sequence types (ST) were responsible for the majority of organisms causing invasive disease. The most abundant (20% of all isolates) was ST131, of which around 90% comprised the pandemic O25:H4 group. ST131-O25:H4 isolates were frequently multi-drug resistant (MDR), with a high prevalence of extended spectrum β-lactamases (ESBL) and fluoroquinolone resistance. There was no association between AMR phenotypes and the source ofE. colibacteraemia or whether the infection was healthcare-associated. Several clusters of ST131 were genetically similar, potentially suggesting a shared transmission network. However, there was no clear epidemiological associations between these cases, and they included organisms from both healthcare-associated and non-healthcare-associated origins. The majority of ST131 genetic clusters exhibited strong binding with an anti-O25b antibody, raising the possibility of developing rapid diagnostics targeting this pathogen. In summary, our data suggest that a restricted set of MDRE. colipopulations can be maintained and spread across both community and healthcare settings in this location, contributing disproportionately to invasive disease and AMR.Impact statementThe pandemic ST131-O25:H4 lineage was a common cause ofE. colibloodstream infections in this location, and carried multiple AMR mechanisms including ESBL and fluoroquinolone resistance. The conserved antigenicity of ST131-O25:H4 raises the possibility of developing targeted immune therapeutics and rapid diagnostics for this common and frequently multi-drug resistant pathogen.
HIV prevalence and associated factors among married women, Mozambique, 2015
Authors: Nuvunga Samuel , Langa Denise Chitsondzo , Baltazar Cynthia Semá , Sacarlal Jahit , Rossetto Erika 
Published: June 2023

AbstractBackgroundThe 2021 human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) global report indicated that women and girls in sub-Saharan Africa remained the most affected groups, accounting for 62% of new infections in the region. In 2021 in Mozambique, the HIV prevalence rate among the adult population was 12.5%, with a rate of 15.4% among women of reproductive age. Our study assessed HIV prevalence and associated factors among married women in Mozambique.MethodologyA cross-sectional epidemiological study was carried out using secondary data extracted from the 2015 Immunization, Malaria and HIV/AIDS (IMASIDA) survey in Mozambique. Married women (civil marriage and common law marriage) of reproductive age (15-49 years) were included. We applied sample weights for data analysis.ResultsOut of the 3,006 married women included in the study, 20.1% fell within the 20-24 age group (n=603), and the average age was 30 years (SD=8.9 years). HIV prevalence was 6.9%. Factors significantly associated with HIV infection were age group 35-49 years (aOR=2.5; CI[1.3-4.6]; p=0.005) compared to age group 15-24 years, lack of formal education and primary education compared to higher education (aOR 7.7; CI [1.1-52.9], p=0.038 and aOR=9.8; CI [1.6-60.1]; p=0.014 respectively), having an uncircumcised partner (aOR=1.9; CI [1.2-3.1]; p=0.008), and having three or more lifetime sex partners compared to one sex partner (aOR=3.6; CI [2.9-7.3]; p< 0.001). Women who were in one lifelong union had a lower risk of HIV positivity compared to women who hadmore than one union (aOR=0.5; CI[0.3-0.8] p=0.005).ConclusionThe factors that contributed to a greater odds of HIV-positivity in this group of married Mozambican women were older age, low levels of education, having an uncircumcised partner and having more than one sexual partner throughout one’s lifetime. In order to have maximum effect, HIV prevention and control campaigns in Mozambique should be tailored tothese “higher-risk” populations.
Performance evaluation of artificial neural network and multiple linear regression in the prediction of body mass index in children
Authors: Asif Muhammad , Khosa Ghazi Khan , Alomair Abdullah Mohammad , Alomair Mohammad Ahmed , Aslam Muhammad , Arslan Muhammad , Sanaullah Muhammad , Wyszyńska Justyna 
Published: June 2023

AbstractThe body mass index (BMI) provides essential medical information related to body weight for the treatment and prognosis prediction of different diseases. The main goal of the present study was to evaluate the performance of artificial neural network (ANN) and multiple linear regression (MLR) model in the prediction of BMI in children. The data from a total of 5,964 children aged 5 to 12 years were included in study. Age, gender, neck circumference (NC), waist circumference (WC), hip circumference (HpC), and mid upper arm circumference (MUAC) measurements were used to estimate the BMI of children. The ANN and MLR were utilized to predict the BMI. The predictive performance of these methods was also evaluated. Gender-wise average comparison showed that median values of all the anthropometric measurements (except BMI) were significantly higher in boys as compared to girls. For the overall sample, the BMI prediction model was,― 0.147 X Age ― 0.367 X Gender + 0.176 X NC + 0.041 X WC + 0.060 X HpC + 0.404 X MUAC. A high R2value and lower RMSE, MAPE, and MAD indicated that the ANN is the best method for predicting BMI in children. Our results confirm that the BMI of children can be predicted by using ANN and MLR regression methods. However, the ANN method has a higher predictive performance than MLR.
In search of disentanglement in tandem mass spectrometry datasets
Authors: Abram Krzysztof Jan , McCloskey Douglas 
Published: June 2023

AbstractGenerative modeling and representation learning of tandem mass spectrometry data aim to learn an interpretable and instrument-agnostic digital representation of metabolites directly from MS/MS spectra. Interpretable and instrument-agnostic digital representations would facilitate comparisons of MS/MS spectra between instrument vendors and enable better and more accurate queries of large MS/MS spectra databases for metabolite identification. In this study, we apply generative modeling and representation learning using variational autoencoders to understand the extent to which tandem mass spectra can be disentangled into its factors of generation (e.g., collision energy, ionization mode, instrument type, etc.) with minimal prior knowledge of the factors. We find that variational autoencoders can disentangle tandem mass spectra data with the proper choice of hyperparameters into meaningful latent representations aligned with known factors of variation. We develop a two-step approach to facilitate the selection of models that are disentangled which could be applied to other complex and high-dimensional data sets.
Monitoring GPCR Conformation with GFP-Inspired Dyes
Authors: Belousov Anatoliy , Maslov Ivan , Orekhov Philipp , Khorn Polina , Kuzmichev Pavel , Baleeva Nadezhda , Motov Vladislav , Bogorodskiy Andrey , Krasnova Svetlana , Mineev Konstantin , Zinchenko Dmitry , Zernii Evgeni , Ivanovich Valentin , Permyakov Sergei , Hofkens Johan , Hendrix Jelle , Cherezov Vadim , Gensch Thomas , Mishin Alexander , Baranov Mikhail , Mishin Alexey , Borshchevskiy Valentin 
Published: June 2023

AbstractSolvatochromic compounds have emerged as valuable environment-sensitive probes for biological research, with the chromophore of the green fluorescent protein (GFP) being a well-studied example. In this study, we demonstrate that synthetic analogues of the GFP chromophore can be used to investigate ligand-induced conformational changes in proteins. We synthesized thiol-reactive derivatives of four analogues of the GFP chromophore that exhibit notable solvatochromism. We used these derivatives to label two proteins: the soluble calcium sensor recoverin (Rec) and the transmembrane G protein-coupled A2Aadenosine receptor (A2AAR), via cysteines located or introduced in the regions that undergo structural changes upon ligand binding. Two of these dyes showed Ca2+-induced fluorescence changes when attached to Rec. Notably, our best-performing dye, DyeC, when attached to A2AAR, revealed agonist-induced changes in both fluorescence intensity and shape of the emission spectrum. Molecular dynamics (MD) simulations provided mechanistic insights into these changes showing the activation of A2AAR transfers DyeC to a more confined and more hydrophilic environment. Additionally, an allosteric modulator, HMA, induces changes in DyeC fluorescence spectra, indicating a distinct receptor conformation from apo, antagonist, or agonist-bound receptors. Our study demonstrates that GFP-inspired dyes are effective for detecting structural changes in GPCR (G protein-coupled receptors), with advantages such as the ability to perform both intensity-based and ratiometric tracking, red-shifted fluorescence spectra, high extinction coefficient, and sensitivity to allosteric modulation. These dyes expand the toolbox for tracking ligand-induced changes and facilitate new insights into conformational changes induced by allosteric modulators in GPCRs.
Novel histones and histone variant families in prokaryotes
Authors: Schwab Samuel , Hu Yimin , van Erp Bert , Cajili Marc K. M. , Hartmann Marcus D. , Alvarez Birte Hernandez , Alva Vikram , Boyle Aimee L. , Dame Remus T. 
Published: June 2023

AbstractHistones are important chromatin-organizing proteins in eukaryotes and archaea. They form superhelical structures around which DNA is wrapped. Recent studies have shown that some archaea and bacteria contain alternative histones that exhibit different DNA binding properties, in addition to highly divergent sequences. However, the vast majority of these new histones are identified in metagenomes and thus are difficult to studyin vivo. The recent revolutionary breakthroughs in computational protein structure prediction by AlphaFold2 and RoseTTAfold allow for unprecedented insights into the potential function and structure of previously uncharacterized proteins. Here, we categorize the prokaryotic histone space into 17 distinct groups based on AlphaFold2 predictions. We identify a new superfamily of histones, termedα3 histones, which are common in archaea and present in several bacteria. Importantly, we establish the existence of a large family of histones throughout archaea and in some bacteriophages that, instead of wrapping DNA, bridge DNA, thereby diverging from conventional nucleosomal histones.