bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determinants of COVID-19 booster uptake in the Netherlands, autumn 2022: how well were those at risk for severe disease reached?
Authors: van Roekel Caren , Labuschagne Lisanne , Pijpers Joyce , van Roon Annika , Smagge Bente , Ferreira José A. , Hahné Susan , de Melker Hester 
Published: August 2023

ABSTRACTBackgroundA booster with bivalent COVID-19 vaccine was offered in the Netherlands in autumn, 2022. We aimed to investigate vaccine uptake during the autumn 2022 booster round among the population subgroups at risk for severe COVID-19 that were specifically targeted by this campaign: the medical risk group aged 18-59 years and individuals ≥60 years. We calculated booster uptake in both populations and analyzed determinants of booster uptake among those who had received at least one prior COVID-19 vaccination.MethodsHaving had an autumn 2022 booster dose was defined as having received a COVID-19 vaccination between 19 September 2022 and 7 March 2023. The study population included individuals who received at least one previous COVID-19 vaccination. National registries of sociodemographic determinants and COVID-19 vaccination were linked by a unique person identifier. Voting proportions for political parties were included at neighborhood level. Determinants of COVID-19 vaccine autumn booster uptake were ranked by importance by random forest analyses.ResultsBooster uptake was 68% among those aged ≥60 and 30% among those aged 18-59 years with a medical risk factor for severe disease. For both target groups the most important determinant for booster uptake was age (15% in 18-29 years to 72% in 80+ years). Voting proportions for progressive liberal political parties ranked second in the random forest analysis in both groups, with an increasing proportion of votes associated with higher uptake. In the 60+ group, household type ranked third, with highest vaccine uptake among married couples without children (72%) and the lowest uptake among unmarried couples with children (47%). In the medical risk group, migration status ranked third. Migrants with two parents born abroad had the lowest uptake (18%), whereas migrants with both parents born in the Netherlands had the highest uptake (35%).ConclusionAmong individuals who had received at least one prior COVID-19 vaccination, the autumn 2022 COVID-19 booster uptake was 68% in people ≥60 years and 30% in in the medical risk group aged 18-59 years. The most important determinant of booster uptake was age, followed by political preference and household type (60+ group) or migration status (medical risk group). Uptake varied considerably among subgroups in both target groups. Further research should be aimed at understanding the drivers and barriers of vaccine uptake among the subgroups with notably low uptake.
Shared and distinct molecular effects of regulatory genetic variants provide insight into mechanisms of distal enhancer-promoter communication
Authors: Ray-Jones Helen , Song Zeji , Chan Lai Ting , Haglund Alexander , Artemov Pavel , Rosa Monica Della , Ruje Luminita , Burden Frances , Kreuzhuber Roman , Litovskikh Anna , Weyenbergh Eline , Brusselaers Zoï , Tan Vanessa Xue Hui , Frontini Mattia , Wallace Chris , Malysheva Valeriya , Bottolo Leonardo , Vigorito Elena , Spivakov Mikhail 
Published: August 2023

AbstractGene enhancers often form long-range contacts with promoters, but it remains unclear if enhancer activity and their chromosomal contacts are mediated by the same DNA sequences and recruited factors. We studied the effects of expression quantitative trait loci (eQTLs) on enhancer activity and promoter contacts in primary monocytes isolated from 34 individuals. Using eQTL-Capture Hi-C and a Bayesian approach considering both intra- and inter-individual variation, we initially detected 19 eQTLs associated with enhancer-eGene promoter contacts, most of which also associated with enhancer accessibility and activity. Capitalising on these shared effects, we devised a multi-modality Bayesian strategy, which identified 629 “trimodal QTLs” jointly associated with enhancer accessibility, eGene promoter contact, and gene expression. Causal mediation analysis and CRISPR interference revealed causal relationships between these three modalities. Many detected QTLs overlapped disease susceptibility loci and influenced the predicted binding of myeloid transcription factors, including SPI1, GABPB and STAT3. Additionally, a variant associated withPCK2promoter contact directly disrupted a CTCF binding motif and impacted promoter insulation from downstream enhancers. Jointly, our findings suggest an inherent genetic link between the activity and connectivity of enhancers with relevance for human disease, and highlight the role of genetically-determined chromatin boundaries in gene control.
Differential substrate affinity and catabolite repression enable preferential use of urea by ammonia-oxidizing bacteria
Authors: Qin Wei , Wei Stephany P. , Zheng Yue , Choi Eunkyung , Li Xiangpeng , Johnston Juliet , Wan Xianhui , Abrahamson Britt , Flinkstrom Zachary , Wang Baozhan , Li Hanyan , Hou Lei , Tao Qing , Chlouber Wyatt W. , Sun Xin , Wells Michael , Ngo Long , Hunt Kristopher A. , Urakawa Hidetoshi , Tao Xuanyu , Wang Dongyu , Yan Xiaoyuan , Wang Dazhi , Pan Chongle , Weber Peter K. , Jiang Jiandong , Zhou Jizhong , Zhang Yao , Stahl David A. , Ward Bess B. , Mayali Xavier , Martens-Habbena Willm , Winkler Mari-Karoliina H. 
Published: August 2023

AbstractFour distinct lineages of ammonia-oxidizing microorganisms (AOM) collectively contribute to one of the largest nitrogen fluxes in the global nitrogen budget. AOM possess widely different specific affinities for ammonia, thought to determine their niche differentiation. Nevertheless, ammonia-oxidizing archaea and bacteria (AOA, AOB), and complete ammonia oxidizers (comammox) co-occur in soils, freshwater sediments, and aquifers, suggesting that other factors must drive their coexistence. Here, we show that representatives of four AOM lineages employ distinct regulatory strategies for ammonia or urea utilization, thereby minimizing direct competition for either substrate. The tested AOA and comammox species preferentially used ammonia over urea, while beta-proteobacterial AOB favored urea utilization, repressed ammonia transport in the presence of urea, and showed higher affinity for urea than ammonia, whereas gamma-proteobacterial AOB co-utilized both substrates. Stable isotope tracing, kinetics, and transcriptomics experiments revealed that both assimilation and oxidation of ammonia are transport-dependent. These results reveal novel mechanisms of nitrogen metabolism regulation and transporter-based affinity underlying the contrasting niche adaptation and coexistence patterns among the major AOM lineages.
Prediction of A. thaliana’s MCTP4 Structure using Deep Learning-Based tools and Exploration of Transmembrane domain Dynamics using Coarse-Grained Molecular Dynamics Simulations
Authors: Sritharan Sujith , Versini Raphaelle , Petit Jules , Bayer Emmanuelle , Taly Antoine 
Published: August 2023

AbstractMultiple C2 Domains and Transmembrane region Proteins (MCTPs) in plants have been identified as important functional and structural components of plasmodesmata cytoplasmic bridges, which are vital for cell-cell communication. MCTPs are endoplasmic reticulum (ER)-associated proteins which contain three to four C2 domains and two transmembrane regions. In this study, we created structural models ofArabidopsisMCTP4 ER-anchor transmembrane region (TMR) domain using several prediction methods based on deep learning (DL). This region, critical for driving ER association, presents a complex domain organization and remains largely unknown. Our study demonstrates that using a single deep-learning method to predict the structure of membrane proteins can be challenging. Our deep learning models presented three different conformations for the MCTP4 structure, provided by different deep learning methods, indicating the potential complexity of the protein’s conformational landscape. For the first time, we used simulations to explore the behaviour of the TMR of MCTPs within the lipid bilayer. We found that the TMR of MCTP4 is not rigid, but can adopt various conformations including some not identified by deep learning tools. These findings underscore the complexity of predicting protein structures. We learned that combining different methods, such as deep learning and simulations, enhances our understanding of complex proteins.
Discovery of an APP-Selective BACE1 Inhibitor for Alzheimer’s Disease
Authors: Campagna Jesus , Jagodzinska Barbara , Wi Dongwook , Zhu Chunni , Lee Jessica , Cohn Whitaker , Jun Michael , Elias Chris , Descamps Olivier , Zhang Qiang , Gorostiza Olivia , Poksay Karen , Spilman Patricia , Bredesen Dale , John Varghese 
Published: August 2023

ABSTRACTInhibition of amyloid precursor protein (APP) beta-site cleaving enzyme 1 (BACE1; BACE) has been a target for Alzheimer’s disease (AD) therapeutic development, but has been impaired by off-target effects of clinically evaluated inhibitors, including inhibition of cleavage of non-APP substrates. Here, we report our identification of a BACE inhibitors series that are not only selective for the APP substrate, but also for BACE1 as the targeted enzyme. These APP-selective fluoro aminohydantoin (FAH) inhibitor compounds were identified by screening a compound library for inhibition of BACE cleavage of a maltose binding protein (MBP)-conjugated-APPC125 substrate followed by IC50 determination using the P5-P5’ substrate assay. In multiple substrate and enzyme cell-free assays, the lead compound FAH65 displayed substrate selectivity for inhibition of APP cleavage, with little activity against BACE substrates neuregulin 1 (NRG1) or p-selectin glycoprotein ligand -1 (PSGL1). We also demonstrate FAH65 shows little inhibitory activity against the enzyme cathepsin D (Cat D) or BACE2. FAH65 inhibits production of BACE cleavage products soluble APPβ (sAPPβ) and the β C-terminal fragment (βCTF), as well as amyloid-β (Aβ)1-40 and 1-42,in vitroin cells andin vivoin an animal model of AD. In a murine model of AD, FAH65 improved the discrimination score in the Novel Object Recognition (NOR) memory testing paradigm. The active enantiomer of FAH65, FAH65E(-), was obtained and tested in in vivo pharmacokinetic and pharmacodynamic (PK/PD) analysis, wherein it displayed good brain-penetrance and target engagement. Given its demonstrated selectivity for both enzyme and substrate, along with evidence it can improve cognitive performance in an animal model, FAH65 and its E(-) enantiomer merit continued pre-clinical development towards clinical testing as an APP-selective BACE1 inhibitor. Such a candidate would reduce Aβ levels and overcome the deleterious effects of the non-selective BACE1 inhibitors that have failed in the clinic and potentially could be used as a maintenance therapy along with or following clearance of Aβ from the brain with the approved antibody therapy for AD.
Altered primary somatosensory neuron development in aPtenheterozygous model for autism spectrum disorder
Authors: Fernandez Alejandra , Sarn Nick , Eng Charis , Wright Kevin M. 
Published: August 2023

SummaryAutism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social interactions, repetitive behaviors, and hyper- or hyposensitivity to sensory stimuli. The mechanisms underlying the emergence of sensory features in ASD are not fully understood, but recent studies in rodent models highlight that these may result from differences in primary sensory neurons themselves. We examined sensory behaviors in aPtenhaploinsufficient mouse model (PtenHet) for syndromic ASD and identified elevated responses to mechanical stimuli and a higher threshold to thermal responses. Transcriptomic andin vivoanatomical analysis identified alterations in subtype-specific markers of primary somatosensory neurons inPtenHetdorsal root ganglia (DRG). These defects emerge early during DRG development and involve dysregulation of multiple signaling pathways downstream ofPten. Finally, we show that mice harboring an ASD-associated mutation (PtenY69H) also show altered expression of somatosensory neuron subtype-specific markers. Together, these results show that precise levels ofPtenare required for proper somatosensory development and provide insight into the molecular and cellular basis of sensory abnormalities in a model for syndromic ASD.
Decoding auditory working memory content from intracranial high frequency activity in humans
Authors: Uluç Işıl , Peled Noam , Paulk Angelique C. , Bush Alan , Gumenyuk Valentina , Kotlarz Parker , Lankinen Kaisu , Mamashli Fahimeh , Matsuda Nao , Richardson Mark R. , Stufflebeam Steven M. , Cash Sydney S. , Ahveninen Jyrki 
Published: August 2023

AbstractHow the human brain maintains information in working memory (WM), a process critical for all our goal-directed function, has been debated for decades. Classic neurophysiological models, which argue that WM is maintained via persistent content-specific “delay activity,” have been challenged by alternative ideas suggesting a combination of dynamic activity patterns and activity-silent mechanisms. Here, utilizing human intracranial stereo-EEG (sEEG) recordings and machine learning techniques, we tested understudied auditory WM in multiple cortical and subcortical brain areas. Neuronal activity was quantified as broadband high frequency activity (HFA, 70-190 Hz) which has been shown to be highly correlated with multiunit activity of neuron populations. Our multivariate pattern analysis (MVPA) results, validated via robust non-parametric permutation testing, show that information can be decoded from multiple brain regions, including prefrontal regions, superior temporal auditory cortices, and the hippocampus. However, the recording sites with high WM decoding accuracies were not accompanied by statistically significant increases in HFA power. In contrast, HFA power was reduced relative to the period preceding WM encoding in many frontal, superior temporal, and hippocampal sEEG recording sites. These results are in line with the hypothesis that WM maintenance can be supported by highly dynamic, “activity silent” processes rather than via persistent activity only.
Mucilage Produced by Sorghum (Sorghum bicolor) Aerial Roots Hosts Diazotrophs that Provide Significant Amounts of Nitrogen to the Plant
Authors: Venado Rafael E. , Wilker Jennifer , Pankievicz Vania , Infante Valentina , MacIntyre April , Wolf Emily S. A. , Vela Saddie , Robbins Fletcher , Fernandes-Júnior Paulo Ivan , Vermerris Wilfred , Ané Jean-Michel 
Published: August 2023

AbstractSorghum (Sorghum bicolor) is a significant crop globally, serving as an important source of food, feed, and fodder, and is increasingly recognized as an energy crop due to its high potential for biomass production. Certain sorghum accessions exhibit prolific aerial root development and produce abundant carbohydrate-rich mucilage after precipitation. This aerial root mucilage bears resemblance to that found in landraces of maize (Zea mays) from southern Mexico, which have previously been found to harbor diazotrophs. In this study, we examined the aerial root development of specific sorghum accessions and investigated the influence of humidity on this trait. Our microbiome analysis of the aerial root mucilage of maize and sorghum revealed the presence of numerous diazotrophs in sorghum mucilage, withPseudomonadota,Bacillota, andBacteriodotabeing the predominant phyla observed. However, the community composition varied significantly depending on the host plant and location. Through acetylene reduction,15N2gas feeding, and15N isotope dilution assays, we determined that these sorghum accessions can acquire approximately 40% of their nitrogen from the atmosphere through these symbiotic associations on aerial roots. The nitrogen fixation occurring in sorghum aerial root mucilage presents a promising opportunity to reduce reliance on synthetic fertilizers and advance sustainable agricultural practices for food, feed, fodder, and bioenergy production.
Mitochondrial DNA released by senescent cells triggers immunosuppression in cancer
Authors: Lai Ping , Liu Lei , Bancaro Nicolò , Troiani Martina , Calì Bianca , Chen Jingjing , Singh Prafull Kumar , Arzola Rydell Alvarez , Attanasio Giuseppe , Pernigoni Nicolò , Pasquini Emiliano , Mosole Simone , Rinaldi Andrea , Sgrignani Jacopo , Li Yuxin , Qiu Shi , Song Pan , Li Yingrui , Desbats Maria Andrea , Ángel Azucena Rendón , Mestre Ricardo Pereira , Barile Lucio , Cavalli Andrea , de Bono Johann , Alimonti Andrea 
Published: August 2023

AbstractDNA is a potent damage-associated molecular pattern signaling that, once in the extracellular space, triggers the activation of the innate immune system. Here we find that senescent cells release mtDNA to both the cytosol and the extracellular space. In cells undergoing cellular senescence, the release of mtDNA precedes that of nuclear DNA resulting in the activation of the cGAS/STING pathway and establishment of cellular senescence. Intriguingly, by exploiting co-culture and in vivo cross-species experiments, we show that extracellular mtDNA released by senescent tumors cells is specifically captured by polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in the tumor microenvironment (TME). Mechanistically we find that PMN-MDSCs uptake mtDNA to enhance their immunosuppressive ability. Pharmacological inhibition of mtDNA released from senescent tumor cells blocks the PMN-MDSCs immunosuppressive activity, improving the efficacy of therapy-induced senescence (TIS) in cancer. These results reveal the crucial role of mtDNA in initiating cellular senescence and immunosuppression independently of the SASP. Thus, targeting mtDNA release-mediated pathway may hold promise to reprogram the immune suppressive microenvironment in patients treated with chemotherapy.
TREM2 Alteration Increases AD Biomarkers and is Associated with Key Genes with 5xFAD Mice Model Analysis on MODEL-AD Database
Authors: Budyak Elena I. , Kwon Jihoon , Messenger Evan J , Maharjan Surendra , Koothur Juan J 
Published: August 2023

AbstractAlzheimer Disease is a multifactorial disorder characterized by cognitive decline and memory loss. A key gene associated with AD is the TREM2 gene which has been identified as a risk factor for AD. Studies show that TREM2 functions in microglia regulation that controls the amount of AB proteins by the mechanisms of clearance and degradation. However, the exact mechanism of how the TREM2 variations like TREM2 KO and TREM2 R47H contribute to the progression of Alzheimer is still debated. Moreover, research into the levels of gene expression and measurements of biomarkers that contribute to progression of AD is very limited. In this paper, we conduct a comprehensive analysis of the biomarker concentration and gene regulatory behavior in TREM2 KO and TREM2 R47H mutated mice models from the MODEL AD database in order to gain understanding of how these variations contribute to the formation of biomarkers and contribute to AD progression.Our research indicates a correlation between the mutated mice model and the different biomarker concentrations in the brain like insoluble AB40 and 42 proteins, soluble AB40 and 42 proteins, and NFL, which shows that TREM2 gene may be associated with multiple biomarkers. Moreover, we identified some key genes that were associated with the downregulation of the TREM2 gene with the TREM2 KO mice model gene analysis. Finally, we took the confocal images of the TREM2 KO mice model to analyze the effect that the lack of TREM2 extracellular receptor has on the neuritic dystrophy in the brain. Overall, we analyzed the biomarker concentration, gene regulatory activity, and the neuritic effects of the TREM2 KO and TREM2 R47H mutated variants of the TREM2 gene.
Bayesian modeling disentangles language versus executive control disruption in stroke
Authors: Hartwigsen Gesa , Lim Jae-Sung , Bae Hee-Joon , Yu Kyung-Ho , Kuijf Hugo J. , Weaver Nick A. , Biesbroek J. Matthijs , Kopal Jakub , Bzdok Danilo 
Published: August 2023

AbstractStroke is the leading cause of long-term disability worldwide. Incurred brain damage disrupts cognition, often with persisting deficits in language and executive capacities. Despite their clinical relevance, the commonalities, and differences of language versus executive control impairments remain under-specified. We tailored a Bayesian hierarchical modeling solution in a largest-of-its-kind cohort (1080 stroke patients) to deconvolve language and executive control in the brain substrates of stroke insults. Four cognitive factors distinguished left- and right-hemispheric contributions to ischemic tissue lesion. One factor delineated language and general cognitive performance and was mainly associated with damage to left-hemispheric brain regions in the frontal and temporal cortex. A factor for executive control summarized control and visual-constructional abilities. This factor was strongly related to right-hemispheric brain damage of posterior regions in the occipital cortex. The interplay of language and executive control was reflected in two factors: executive speech functions and verbal memory. Impairments on both were mainly linked to left-hemispheric lesions. These findings shed light onto the causal implications of hemispheric specialization for cognition; and make steps towards subgroup-specific treatment protocols after stroke.
A genome-wide atlas of human cell morphology
Authors: Ramezani Meraj , Bauman Julia , Singh Avtar , Weisbart Erin , Yong John , Lozada Maria , Way Gregory P. , Kavari Sanam L. , Diaz Celeste , Haghighi Marzieh , Batista Thiago M. , Pérez-Schindler Joaquín , Claussnitzer Melina , Singh Shantanu , Cimini Beth A. , Blainey Paul C. , Carpenter Anne E. , Jan Calvin H. , Neal James T. 
Published: August 2023

AbstractA key challenge of the modern genomics era is developing data-driven representations of gene function. Here, we present the first unbiased morphology-based genome-wide perturbation atlas in human cells, containing three genome-scale genotype-phenotype maps comprising >20,000 single-gene CRISPR-Cas9-based knockout experiments in >30 million cells. Our optical pooled cell profiling approach (PERISCOPE) combines a de-stainable high-dimensional phenotyping panel (based on Cell Painting1,2) with optical sequencing of molecular barcodes and a scalable open-source analysis pipeline to facilitate massively parallel screening of pooled perturbation libraries. This approach provides high-dimensional phenotypic profiles of individual cells, while simultaneously enabling interrogation of subcellular processes. Our atlas reconstructs known pathways and protein-protein interaction networks, identifies culture media-specific responses to gene knockout, and clusters thousands of human genes by phenotypic similarity. Using this atlas, we identify the poorly-characterized disease-associated transmembrane protein TMEM251/LYSET as a Golgi-resident protein essential for mannose-6-phosphate-dependent trafficking of lysosomal enzymes, showing the power of these representations. In sum, our atlas and screening technology represent a rich and accessible resource for connecting genes to cellular functions at scale.