bluuebunny/crossref_metadata_2025_split huggingface dataset:
Grey and white matter metrics demonstrate distinct and complementary prediction of differences in cognitive performance in children: Findings from ABCD (N= 11 876)
Authors: Michel Lea C. , McCormick Ethan M. , Kievit Rogier A. 
Published: March 2023

AbstractIndividual differences in cognitive performance in childhood are a key predictor of significant life outcomes such as educational attainment and mental health. Differences in cognitive ability are governed in part by variations in brain structure. However, studies commonly focus on either grey or white matter metrics in humans, leaving open the key question as to whether grey or white matter microstructure play distinct or complementary roles supporting cognitive performance.To compare the role of grey and white matter in supporting cognitive performance, we used regularized structural equation models to predict cognitive performance with grey and white matter measures. Specifically, we compared how grey matter (volume, cortical thickness and surface area) and white matter measures (volume, fractional anisotropy and mean diffusivity) predicted individual differences in cognitive performance. The models were tested in 11,876 children (ABCD Study, 5680 female; 6196 male) at 10 years old.We found that grey and white matter metrics bring partly non-overlapping information to predict cognitive performance. The models with only grey or white matter explained respectively 15.4% and 12.4% of the variance in cognitive performance, while the combined model explained 19.0%. Zooming in we additionally found that different metrics within grey and white matter had different predictive power, and that the tracts/regions that were most predictive of cognitive performance differed across metric.These results show that studies focusing on a single metric in either grey or white matter to study the link between brain structure and cognitive performance are missing a key part of the equation.Significance StatementThis paper enriches the recent debates on the challenges of linking variation in brain structure to phenotypic differences (Marek et al., 2022). We demonstrate that using latent variables (to improve power), structural equation modelling (to allow greater flexibility in linking brain to behaviour), and by simultaneously incorporating multiple measures of grey and white matter in a large sample, we demonstrate relatively strong and robust brain-behaviour associations, which highlight the complementarity of grey and white matter metrics in predicting cognitive performance as well as the importance of incorporating the full complexity of these associations over 1-to-1 linkages. This finding should lead researchers to consider integrating both grey and white matter measures when demonstrating a more comprehensive picture of brain-cognition relationships.
Demographic Modeling of Admixed Latin American Populations from Whole Genomes
Authors: Medina-Muñoz Santiago G. , Ortega-Del Vecchyo Diego , Cruz-Hervert Luis Pablo , Ferreyra-Reyes Leticia , García-García Lourdes , Moreno-Estrada Andrés , Ragsdale Aaron P. 
Published: March 2023

ABSTRACTDemographic models of Latin American populations often fail to fully capture their complex evolutionary history, which has been shaped by both recent admixture and deeper-in-time demographic events. To address this gap, we used high-coverage whole genome data from Indigenous American ancestries in present-day Mexico and existing genomes from across Latin America to infer multiple demographic models that capture the impact of different timescales on genetic diversity. Our approach, which combines analyses of allele frequencies and ancestry tract length distributions, represents a significant improvement over current models in predicting patterns of genetic variation in admixed Latin American populations. We jointly modeled the contribution of European, African, East Asian, and Indigenous American ancestries into present-day Latin American populations to capture the historical demographic events that have shaped genetic variation. Our inferred demographic histories are consistent across different genomic regions and annotations, suggesting that our inferences are robust to the potential effects of linked selection. In conjunction with published distributions of fitness effects for new nonsynonymous mutations in humans, we show in large-scale simulations that our models recover important features of both neutral and deleterious variation. By providing a more realistic framework for understanding the evolutionary history of Latin American populations, our models can help address the historical under-representation of admixed groups in genomics research, and can be a valuable resource for future studies of populations with complex admixture and demographic histories.
Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD-CC protein family
Authors: Staal Jens , Driege Yasmine , Van Gaever Femke , Steels Jill , Beyaert Rudi 
Published: March 2023

AbstractCARD9, -10, -11 and -14 all belong to the CARD-coiled coil (CC) protein family and originated from a single common ancestral protein early in vertebrate evolution. All four proteins form CARD-CC/BCL10/MALT1 (CBM) complexes leading to NF-κB activation after upstream phosphorylation by various protein kinase C (PKC) isoforms. CBM complex signaling is critical for innate and adaptive immunity, but aberrant activation can cause autoimmune or autoinflammatory diseases, or be oncogenic. CARD9 shows a superior auto-inhibition with very low spontaneous activity when overexpressed in HEK293T cells. In contrast, the poor auto-inhibition of other CARD-CC family proteins, especially CARD10 (CARMA3) and CARD14 (CARMA2), is hampering characterization of upstream activators or activating mutations in overexpression studies. We grafted different domains from CARD10, -11 and 14 on CARD9 to generate chimeric CARD9 backbones for functional characterization of activating mutants using NF-κB reporter gene activation in HEK293T cells as readout. CARD11 (CARMA1) activity was not further reduced by grafting on CARD9 backbones. The chimeric CARD9 approach was subsequently validated by using several known disease-associated mutations in CARD10 and CARD14, and additional screening allowed us to identify several novel activating natural variants in human CARD9 and CARD10. Using Genebass as a resource of exome-based disease association statistics, we found that activated alleles of CARD9 correlate with irritable bowel syndrome (IBS), constipation, osteoarthritis, fibromyalgia, insomnia, anxiety and depression, which can occur as comorbidities.
Computational modeling of reinforcement learning and functional neuroimaging of probabilistic reversal dissociates compulsive behaviors in Gambling and Cocaine Use Disorders
Authors: Zühlsdorff Katharina , Verdejo-Román Juan , Clark Luke , Albein-Urios Natalia , Soriano-Mas Carles , Cardinal Rudolf N. , Robbins Trevor W. , Dalley Jeffrey W. , Verdejo-García Antonio , Kanen Jonathan W. 
Published: March 2023

AbstractCognitive flexibility refers to the ability to adjust to changes in the environment and is essential for adaptive behavior. It can be investigated using laboratory tests such as probabilistic reversal learning (PRL). In individuals with both Cocaine Use Disorder (CUD) and Gambling Disorder (GD), overall impairments in PRL flexibility are observed. However, it is poorly understood whether this impairment depends on the same brain mechanisms in cocaine and gambling addictions. Reinforcement learning (RL) is the process by which rewarding or punishing feedback from the environment is used to adjust behavior, to maximise reward and minimise punishment. Using RL models, a deeper mechanistic explanation of the latent processes underlying cognitive flexibility can be gained. Here, we report results from a re-analysis of PRL data from control participants (n=18) and individuals with either GD (n=18) or CUD (n=20) using a hierarchical Bayesian RL approach. We observed significantly reduced ‘stimulus stickiness’ (i.e., stimulus-bound perseveration) in GD, which may reflect increased exploratory behavior that is insensitive to outcomes. RL parameters were unaffected in CUD. We relate the behavioral findings to their underlying neural substrates through an analysis of task-based fMRI data. We report differences in tracking reward and punishment expected values (EV) in individuals with GD compared to controls, with greater activity during reward EV tracking in the cingulate gyrus and amygdala. In CUD, we observed reduced responses to positive punishment prediction errors (PPE) and increased activity following negative PPEs in the superior frontal gyrus compared to controls. Thus, an RL framework serves to differentiate behavior in a probabilistic learning paradigm in two compulsive disorders, GD and CUD.
Pioneer factor Foxa2 mediates chromatin conformation changes in ligand-dependent activation of nuclear receptor FXR
Authors: Hao Yi , Han Lu , Wu Anqi , Bochkis Irina M. 
Published: March 2023

ABSTACTActivation of nuclear receptors, a family of ligand-dependent transcription factors, is used extensively in development of drug targets. We have previously shown that pioneer factor Foxa2 opens chromatin for binding of nuclear receptors FXR and LXRα during acute ligand activation. FXR is activated by bile acids and deletion of Foxa2 in the liver results in intrahepatic cholestasis. We hypothesized that Foxa2 also enables chromatin conformational changes during ligand activation. We performed Foxa2 HiChIP to assess Foxa2-dependent long-range interactions in mouse livers treated with either vehicle control or FXR agonist GW4064. HiChIP contact analysis shows that global chromatin interactions are dramatically increased during FXR activation. Ligand-treated livers exhibit extensive redistribution of topological associated domains (TAD and substantial increase in Foxa2-anchored loops, suggesting Foxa2 is involved in dynamic chromatin conformational changes. We demonstrate that chromatin conformation, including genome-wide interactions, TADs, intra-chromosomal and inter-chromosomal Foxa2-anchored loops, drastically changes upon addition of FXR agonist. Hence, we determine a novel role for Foxa2 in enabling these conformational changes, extending its function in bile acid metabolism.
DNA-PK and the TRF2 iDDR inhibit MRN-initiated resection at leading-end telomeres
Authors: Myler Logan R. , Toia Beatrice , Vaughan Cara K. , Takai Kaori , Matei Andreea M. , Wu Peng , Paull Tanya T. , de Lange Titia , Lottersberger Francisca 
Published: March 2023

AbstractTelomeres replicated by leading-strand synthesis lack the 3’ overhang required for telomere protection. Surprisingly, resection of these blunt telomere is initiated by the telomere-specific 5’ exonuclease Apollo rather than the Mre11-Rad50-Nbs1 (MRN) complex, the nuclease that acts at DNA breaks. Without Apollo, leading-end telomeres undergo fusion, which, as demonstrated here, are mediated by alternative End Joining. Here, we show that DNA-PK and TRF2 coordinate the repression of MRN at blunt telomeres. DNA-PK represses an MRN-dependent long range resection at blunt telomeres, while the endonuclease activity of MRN/CtIP, which could cleave DNA-PK off of blunt telomere ends, is inhibitedin vitroandin vivoby the iDDR of TRF2. AlphaFold-Multimer predicts a conserved association of the iDDR with Rad50 potentially interfering with CtIP binding and MRN endonuclease activation. We propose that repression of MRN-mediated resection is a conserved aspect of telomere maintenance and represents an ancient feature of DNA-PK and the iDDR.
Symbiotic acacia ants drive nesting behavior by birds in an African savanna
Authors: Ema Lujan , Nielsen Ryen , Short Zoe , Wicks Samuel , Watetu Wilson Nderitu , Khasoha Leo M. , Palmer Todd M. , Goheen Jacob R. , Alston Jesse M. 
Published: March 2023

AbstractMutualisms between plants and ants are common features of tropical ecosystems around the globe and can have cascading effects on interactions with the ecological communities in which they occur. In an African savanna, we assessed whether acacia ants influence nest site selection by tree-nesting birds. Birds selected nest sites in trees inhabited by ant species that vigorously defend against browsing mammals. Future research could address the extent to which hatching and fledging rates depend on the species of ant symbiont, and why ants tolerate nesting birds but not other tree associates (especially insects).
Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection throughout aging
Authors: Serrano Isabel M. , Hirose Misa , Valentine Charles C. , Roesner Sharon , Schmidt Elizabeth , Pratt Gabriel , Williams Lindsey , Salk Jesse , Ibrahim Saleh , Sudmant Peter H. 
Published: March 2023

AbstractMitochondrial genomes co-evolve with the nuclear genome over evolutionary timescales and are shaped by selection in the female germline. Here, we investigate how mismatching between nuclear and mitochondrial ancestry impacts the somatic evolution of the mt-genome in different tissues throughout aging. We used ultra-sensitive Duplex Sequencing to profile ∼2.5 million mt-genomes across five mitochondrial haplotypes and three tissues in young and aged mice, cataloging ∼1.2 million mitochondrial somatic and ultra low frequency inherited mutations, of which 81,097 are unique. We identify haplotype-specific mutational patterns and several mutational hotspots, including at the Light Strand Origin of Replication, which consistently exhibits the highest mutation frequency. We show that rodents exhibit a distinct mitochondrial somatic mutational spectrum compared to primates with a surfeit of reactive oxygen species-associated G>T/C>A mutations, and that somatic mutations in protein coding genes exhibit signatures of negative selection. Lastly, we identify an extensive enrichment in somatic reversion mutations that “re-align” mito-nuclear ancestry within an organism’s lifespan. Together, our findings demonstrate that mitochondrial genomes are a dynamically evolving subcellular population shaped by somatic mutation and selection throughout organismal lifetimes.
Unfolded Protein Response Factor ATF6 Augments T Helper Cell Responses and Promotes Mixed Granulocytic Airway Inflammation
Authors: Wu Dandan , Zhang Xing , Zimmerly Kourtney M. , Wang Ruoning , Wang Chunqing , Wu Xiang , Liu Meilian , Yang Xuexian O. 
Published: March 2023

AbstractThe unfolded protein response (UPR) is associated with the risk of asthma, including treatment- refractory severe asthma. Several recent studies demonstrated a pathogenic role of activating transcription factor 6α (ATF6α or ATF6), one of the essential arms of UPR, in airway structural cells. However, its role in T helper (TH) cells has not been well examined. In this study, we found that ATF6 was selectively induced by STAT6 and STAT3 in TH2 and TH17 cells, respectively. ATF6 upregulated UPR genes and promoted the differentiation and cytokine secretion of TH2 and TH17 cells. T cell-specificAtf6-deficiency impaired TH2 and TH17 responsesin vitroandin vivoand attenuated mixed granulocytic experimental asthma. ATF6 inhibitor Ceapin A7 suppressed ATF6 downstream gene expression and TH cell cytokine expression in both murine and human memory CD4+T cells. At the chronic stage of asthma, administration of Ceapin A7 lessened TH2 and TH17 responsesin vivo, leading to alleviation of both airway neutrophilia and eosinophilia. Thus, our results demonstrate a critical role of ATF6 in TH2 and TH17 cell-driven mixed granulocytic airway disease, suggesting a novel option to combat steroid-resistant mixed and even T2-low endotypes of asthma by targeting ATF6.
Evaluation of Antinociceptive and Anti-Inflammatory Activities of Solvent Fraction of the Roots ofEchinops keberichoMesfin (Asteraceae) In Mice Model
Authors: Tadesse Tesfaye Yimer , Dagnew Samuel Berihun , Yiblet Tesfagegn Gobezie , Addis Getu Tesfaw , Kiflie Zemene Demelash 
Published: March 2023

AbstractBackgroundSince ancient times, pain and inflammation have been treated using herbal remedies, which are essentially a stockroom of phytochemical components. Due to the numerous adverse effects of the already available anti-pain and anti-inflammatory medications, the search for new potential pharmaceuticals used to relieve pain and inflammation from natural sources is an ongoing process. The present study was therefore, aimed at investigating the antinociceptive and antiinflammatory activities of the solvent fractions of the roots ofE. keberichoM. in mice model.MethodsSuccessive maceration was used as a method of extraction using solvents of increasing polarity: methanol and water. The crude extract was then further fractionated using distilled water, ethyl acetate, and chloroform. Each solvent fraction was then evaluated for its peripheral analgesic activities using an acetic acid-induced writing test and central analgesic activities using the hot plate method. The acute and chronic anti-inflammatory activities of the solvent fractions were detected using carrageenan induced paw edema and cotton pellet ear granuloma respectively. The detected doses were 100mg/kg, 200mg/kg, and 400mg/kg. The positive control groups received ASA (150mg/kg) for the writing test, morphine (10mg/kg) for the hot plate method, diclofenac Na for carrageenan induced paw edema and dexamethasone (10mg/kg) for granuloma, while the negative control group received distilled water.ResultEA fraction at all test doses employed (100mg/kg, 200mg/kg and 400mg/kg) showed statistical significant (p < 0.05, p < 0.01, p < 0.001 respectively) analgesic effects in both chemical and thermal induced pain stimuli in dose dependant manner. Likewise, EA fraction also exhibited anti-inflammatory activities on carrageenan induced paw edema and cotton pellet-induced granuloma in a dose-dependent manner. The AQ fraction on the other hand produced statistical significant (p < 0.05, p < 0.012) analgesic and anti-inflammatory activities at the doses of 200mg/kg and 400mg/kg, while the CH fraction exhibited statistical significant (p < 0.05) analgesic and anti-inflammatory activity at the dose of 400mg/kg.ConclusionIn general, the data obtained from the present study elucidated that the solvent fractions possessed significant analgesic and anti-inflammatory activities and recommended further investigations.
A SLiM-dependent conformational change in baculovirus IE1 controls its focus formation ability
Authors: Nagamine Toshihiro , Sako Yasushi 
Published: March 2023

ABSTRACTThe baculovirus IE1 gene encodes a multifunctional protein that is essential for both DNA replication and RNA transcription of the virus. Prior to viral DNA replication, IE1 promotes early gene transcription when localized inhr-dependent foci. During viral DNA replication, the IE1 foci expand and fuse to generate the virogenic stroma (VS) with IE1 forming the VS reticulum. To explore the IE1 structural features essential for this coordinated localization, we constructed various IE1 mutants based on three putative domains (N, I, and C). We determined that a BDI motif located in the intrinsic disorder region (IDR) between the N and I domains acts as a nuclear localization signal, whereas BDII and HLH in the C domain are required for VS localization in infected cells or for chromosomal association in uninfected mitotic cells. Deletion of the SLiM (shortlinearmotif) located in the I domain restrains both nuclear- and VS localization. Intra-molecular fluorescence resonance energy transfer (FRET) probes of IE1 mutants revealed a conformational change of the I-C two-domain fragment during infection, which was inhibited by aphidicolin, suggesting that IE1 undergoes a stage-dependent conformational change. Further, homo-dimerization of the I domain and stage-dependent conformational changes require an intact SLiM. Mutational analysis of SLiM revealed that VS localization and chromosomal association were retained following S291A and S291E substitutions, buthr-dependent focus formation differed between the two mutations. These results suggest that coordinated IE1 localization is controlled by SLiM-dependent conformational changes and that are dependent on the SLiM phosphorylation state.ImportanceSLiMs (shortlinearmotifs) are compact non-globular protein interaction interfaces that mediate various cellular functions and as such are often mimicked by viruses to rewire cellular pathways. Here, we found that an unusual type of viral SLiM acts as a conformational switch rather than a cellular mimic. Prior to viral DNA replication, the baculovirus IE1 protein promotes early gene transcription within its focus. During viral DNA replication, the IE1 foci expand and fuse to form the virogenic stroma where late virus replication events occur. Our results indicate that IE1 undergoes a conformational change that is dependent on the infection stage and SLiM phosphorylation. This work provides new insights into the role SLiMs play in heterotypic and homotypic protein-protein interactions.
Localisation and tissue tropism of the symbiont Microsporidia MB in the germ line and somatic tissues of Anopheles arabiensis
Authors: Makhulu Edward E. , Onchuru Thomas O. , Gichuhi Joseph , Otieno Fidel G. , Wairimu Anne W. , Muthoni Joseph .N. , Koekoemoer Lizette , Herren Jeremy K. 
Published: March 2023

AbstractTheAnophelessymbiont,Microsporidia MB, is maternally inherited and has a strong malaria transmission-blocking phenotype inAnopheles arabiensis. Microsporidia MBis also vertically transmitted, sexually transmitted and avirulent. These characteristics are expected to promote its spread through mosquito populations, enhancing the potential ofMicrosporidia MBas a candidate for the development of a symbiont-mediated malaria transmission blocking strategy. We found that the patterns ofMicrosporidia MBlocalisation over the development ofAn. arabiensisindicate accumulation in tissues linked to its transmission, specifically the male and female gonadal tissues. Transovarial vertical transmission ofMicrosporidia MBoccurs in the femaleAn. arabiensisovary whenMicrosporidia MBbecomes localised to the cytoplasm of the developing oocyte. In maleAn. arabiensis, Microsporidia MBis localised in the testis and vas deferens. Notably, a high intensity ofMicrosporidia MBcan also be observed in theAn. arabiensisadult but not larval gut. The levels ofMicrosporidia MBfound in the female ovary are linked to the progression of oogenesis, increasing after blood feeding initiates the development of eggs. The levels ofMicrosporiodia MBin the male and female gonadal and gut tissue do not increase as mosquitoes age. Altogether, the high specificity ofMicrosporidia MBtissue localisation patterns and changes in infection prevalence and intensity suggest adaptation to maximise transmission and avirulence inAnopheles arabiensis.ImportanceMicrosporidia MBis a symbiont with strong malaria transmission-blocking phenotype inAnopheles arabiensis. It spreads in mosquito populations through mother-to-offspring and sexual transmission. The ability ofMicrosporidia MBto blockPlasmodiumtransmission together with its ability to spread withinAnophelespopulations and its avirulence to the host makes it a very attractive candidate for developing a key strategy to stop malaria transmissions. Here, we report the basis ofMicrosporidia MBtransmission. We find thatMicrosporidia MBaccumulates inAnopheles arabiensistissues linked to its sexual and vertical transmission. Its prevalence and intensity in the tissues over the mosquito life cycle suggest adaptation to maximise transmission and avirulence inAnopheles arabiensis. These findings provide the foundation for understanding the factors that affectMicrosporidia MBtransmission efficiency. This will contribute to the establishment of strategies to maximizeMicrosporidia MBtransmission forAnophelesmosquito population replacement and malaria transmission blocking.