bluuebunny/crossref_metadata_2025_split huggingface dataset:
A FOXN1 mutation competitively displaces wild-type FOXN1 from higher-order nuclear condensates to cause immunodeficiency
Authors: Rota Ioanna A. , Handel Adam E. , Klein Fabian , Maio Stefano , Dhalla Fatima , Deadman Mary E. , Cheuk Stanley , Newman Joseph A , Michaels Yale S. , Zuklys Saulius , Prevot Nicolas , Hublitz Philip , Charles Philip D. , Gkazi Athina Soragia , Adamopoulou Eleni , Qasim Waseem , Davies E. Graham , Hanson Celine , Pagnamenta Alistair T. , Camps Carme , Dreau Helene M. , White Andrea , James Kieran , Fischer Roman , Gileadi Opher , Taylor Jenny C. , Fulga Tudor , Lagerholm B. Christoffer , Anderson Graham , Sezgin Erdinc , Holländer Georg A. 
Published: March 2021

AbstractThe transcription factor FOXN1 is a master regulator of thymic epithelial cell development and function. Here we demonstrate that FOXN1 expression is differentially regulated during organogenesis and participates in multi-molecular nuclear condensates essential for the factor’s transcriptional activity. FOXN1’s C-terminal sequence regulates the diffusion velocity within these aggregates and modulates the binding to proximal gene regulatory regions. These dynamics are significantly altered in a patient with a mutant FOXN1 which is modified in its C-terminal sequence. This mutant is transcriptionally inactive and acts as a dominant negative factor displacing wild-type FOXN1 from condensates and causing athymia and severe lymphopenia in heterozygotes. Expression of the mutated mouse ortholog, selectively impairs mouse thymic epithelial cell (TEC) differentiation revealing a gene dose dependency for individual TEC subtypes. We have therefore identified the cause for a primary immunodeficiency disease and determined the mechanism by which this FOXN1 gain-of-function mutant mediates its dominant negative effect.
Associations Between Task-Related Modulation of Motor-Evoked Potentials and EEG Event-Related Desynchronization in Children with ADHD
Authors: Ewen Joshua B. , Puts Nicolaas A. , Mostofsky Stewart H. , Horn Paul S. , Gilbert Donald L. 
Published: March 2021

ABSTRACTChildren with attention-deficit/hyperactivity disorder (ADHD) have previously shown a decreased magnitude of event-related desynchronization (ERD) during a finger-tapping task, with a large between-group effect. Because the neurobiology underlying several TMS measures have been studied in multiple contexts, we compared ERD and three TMS measures (Resting Motor Threshold [RMT], Short-Interval Cortical Inhibition [SICI] and Task-Related Up-Modulation [TRUM]) within 14 participants with ADHD (ages 8-12y) and 17 control children. The TD group showed a correlation between greater RMT and greater magnitude of alpha (10-13Hz, here) ERD, and there was no diagnostic interaction effect, consistent with a rudimentary model of greater needed energy input to stimulate movement. Similarly, inhibition measured by SICI was also greater in the TD group when the magnitude of movement-related ERD was higher; there was a miniscule diagnostic interaction effect. Finally, TRUM during a response-inhibition task showed an unanticipated pattern: in TD children, the greater TMS task modulation (TRUM) was associated with a smaller magnitude of ERD during finger-tapping. The ADHD group showed the opposite direction of association: greater TRUM was associated with larger-magnitude ERD. Prior EEG results have demonstrated specific alterations of task-related modulation of cortical physiology, and the current results provide a fulcrum for multimodal study.
Perceiving and remembering speech depend on multifractal nonlinearity in movements producing and exploring speech
Authors: Bloomfield Lauren , Lane Elizabeth , Mangalam Madhur , Kelty-Stephen Damian G. 
Published: March 2021

AbstractSpeech perception and memory for speech require active engagement. Gestural theories have emphasized mainly the effect of speaker’s movements on speech perception. They fail to address the effects of listener movement, focusing on communication as a boundary condition constraining movement among interlocutors. The present work attempts to break new ground by using multifractal geometry of physical movement as a common currency for supporting both sides of the speaker-listener dyads. Participants self-paced their listening to a narrative, after which they completed a test of memory querying their narrative comprehension and their ability to recognize words from the story. The multifractal evidence of nonlinear interactions across timescales predicted the fluency of speech perception. Self-pacing movements that enabled listeners to control the presentation of speech sounds constituted a rich exploratory process. The multifractal nonlinearity of this exploration supported several aspects of memory for the perceived spoken language. These findings extend the role of multifractal geometry in the speaker’s movements to the narrative case of speech perception. In addition to posing novel basic research questions, these findings make a compelling case for calibrating multifractal structure in text-to-speech synthesizers for better perception and memory of speech.
Large-scale phylogenomics of the genus Macrostomum (Platyhelminthes) reveals cryptic diversity and novel sexual traits
Authors: Brand Jeremias N. , Viktorin Gudrun , Wiberg R. Axel W. , Beisel Christian , Schärer Lukas 
Published: March 2021

AbstractFree-living flatworms of the genus Macrostomum are small and transparent animals, representing attractive study organisms for a broad range of topics in evolutionary, developmental, and molecular biology. The genus includes the model organism M. lignano for which extensive molecular resources are available, and recently there is a growing interest in extending work to additional species in the genus. These endeavours are currently hindered because, even though >200 Macrostomum species have been taxonomically described, molecular phylogenetic information and geographic sampling remain limited. We report on a global sampling campaign aimed at increasing taxon sampling and geographic representation of the genus. Specifically, we use extensive transcriptome and single-locus data to generate phylogenomic hypotheses including 145 species. Across different phylogenetic methods and alignments used, we identify several consistent clades, while their exact grouping is less clear, possibly due to a radiation early in Macrostomum evolution. Moreover, we uncover a large undescribed diversity, with 94 of the studied species likely being new to science, and we identify multiple novel morphological traits. Furthermore, we identify cryptic speciation in a taxonomically challenging assemblage of species, suggesting that the use of molecular markers is a prerequisite for future work, and we describe the distribution of possible synapomorphies and suggest taxonomic revisions based on our finding. Our large-scale phylogenomic dataset now provides a robust foundation for comparative analyses of morphological, behavioural and molecular evolution in this genus.
Epigenomic and transcriptomic differences between low-grade and acute inflammation in LPS-induced murine immune cells
Authors: Naler Lynette B. , Hsieh Yuan-Pang , Geng Shuo , Zhou Zirui , Li Liwu , Lu Chang 
Published: March 2021

AbstractChronic, low-grade inflammation has a widespread and significant impact on health, especially in Western society. While inflammation is beneficial for the removal of microbes, low-grade inflammation never resolves and can cause or worsen other diseases. The process by which low-grade inflammation occurs remains poorly understood. Here we exposed murine bone-marrow derived monocytes to chronic lipopolysaccharide (LPS) stimulation at low dose or high dose, as well as a PBS control. The cells were profiled for genome-wide H3K27ac modification and gene expression. The gene expression of TRAM-deficient and IRAK-M-deficient monocytes with LPS exposure was also analyzed. We discover that low-grade inflammation preferentially utilizes the TRAM/TRIF-dependent pathway of TLR4 signaling, and induces the expression of interferon response genes. In contrast, acute inflammation uniquely upregulates metabolic and proliferative pathways that also appear to be TRAM-dependent. The extensive differences in the epigenomic landscape between low-dose and high-dose conditions suggest the importance of epigenetic regulations in driving differential responses. Our data provide potential targets for future mechanistic or therapeutic studies.
A dynamical model of TGF-βactivation in asthmatic airways
Authors: Pybus Hannah J. , O’Dea Reuben D. , Brook Bindi S. 
Published: March 2021

AbstractExcessive activation of the regulatory cytokine transforming growth factorβ(TGF-β) via contraction of airway smooth muscle (ASM) is associated with the development of asthma. In this study, we develop an ordinary differential equation model that describes the change in density of the key airway wall constituents, ASM and extracellular matrix (ECM), and their interplay with subcellular signalling pathways leading to the activation of TGF-β. We identify bistable parameter regimes where there are two positive steady states, corresponding to either reduced or elevated TGF-βconcentration, with the latter leading additionally to increased ASM and ECM density. We associate the former with a healthy homeostatic state and the latter with a diseased (asthmatic) state. We demonstrate that external stimuli, inducing TGF-βactivation via ASM contraction (mimicking an asthmatic exacerbation), can perturb the system irreversibly from the healthy state to the diseased one. We show that the properties of the stimuli, such as their frequency or strength, and the clearance of surplus active TGF-β, are important in determining the long-term dynamics and the development of disease. Finally we demonstrate the utility of this model in investigating temporal responses to bronchial thermoplasty, a therapeutic intervention in which ASM is ablated by applying thermal energy to the airway wall. The model predicts the parameter-dependent threshold damage required to obtain irreversible reduction in ASM content suggesting that certain asthma phenotypes are more likely to benefit from this intervention.
Transcriptome profiling of embryonic retinal pigment epithelium reprogramming
Authors: Tangeman Jared A , Luz-Madrigal Agustín , Sreeskandarajan Sutharzan , Esquivel Erika Grajales- , Liu Lin , Liang Chun , Tsonis Panagiotis A. , Rio-Tsonis Katia Del 
Published: March 2021

AbstractThe plasticity of human retinal pigment epithelium (RPE) has been observed during proliferative vitreoretinopathy, a defective repair process during which injured RPE gives rise to fibrosis. In contrast, following injury, the RPE of the embryonic chicken can be reprogrammed to regenerate neural retina in an FGF2-dependent manner. To characterize the mechanisms underlying embryonic RPE reprogramming, we used laser capture microdissection to isolate RNA from 1) intact RPE, 2) transiently reprogrammed RPE (t-rRPE) 6 hours post-retinectomy, and 3) reprogrammed RPE (rRPE) 6 hours post-retinectomy with FGF2 treatment. Using RNA-seq, we observed the acute repression of genes related to cell cycle progression in the injured t-rRPE, as well as up-regulation of genes associated with injury. In contrast, the rRPE was strongly enriched for MAPK-responsive genes and retina development factors, confirming that FGF2 and the downstream MAPK cascade are the main drivers of embryonic RPE reprogramming. Clustering and pathway enrichment analysis were used to create an integrated network of the core processes associated with RPE reprogramming, including key terms pertaining to injury response, migration, actin dynamics, and cell cycle progression. Finally, we employed gene set enrichment analysis to suggest a previously uncovered role for epithelial-mesenchymal transition (EMT) machinery in the initiation of embryonic chick RPE reprogramming. The EMT program is accompanied by extensive, coordinated regulation of extracellular matrix (ECM) regulators, and these observations together suggest an early role for ECM and EMT-like dynamics during reprogramming. Our study provides for the first time an in-depth transcriptomic analysis of embryonic RPE reprogramming and will prove useful in guiding future efforts to understand proliferative disorders of the RPE and to promote retinal regeneration.
Comprehensive machine-learning-based analysis of microRNA-target interactions reveals variable transferability of interaction rules across species
Authors: Or Gilad Ben , Veksler-Lublinsky Isana 
Published: March 2021

AbstractBackgroundMicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally via base-pairing with complementary sequences on messenger RNAs (mRNAs). Due to the technical challenges involved in the application of high-throughput experimental methods, datasets of direct bona-fide miRNA targets exist only for a few model organisms. Machine learning (ML) based target prediction methods were successfully trained and tested on some of these datasets. There is a need to further apply the trained models to organisms where experimental training data is unavailable. However, it is largely unknown how the features of miRNA-target interactions evolve and whether there are features that have been fixed during evolution, questioning the general applicability of these ML methods across species.ResultsIn this paper, we examined the evolution of miRNA-target interaction rules and used data science and ML approaches to investigate whether these rules are transferable between species. We analyzed eight datasets of direct miRNA-target interactions in four organisms (human, mouse, worm, cattle). Using ML classifiers, we achieved high accuracy for intra-dataset classification and found that the most influential features of all datasets significantly overlap. To explore the relationships between datasets we measured the divergence of their miRNA seed sequences and evaluated the performance of cross-datasets classification. We showed that both measures coincide with the evolutionary distance of the compared organisms.ConclusionsOur results indicate that the transferability of miRNA-targeting rules between organisms depends on several factors, the most associated factors being the composition of seed families and evolutionary distance. Furthermore, our feature importance results suggest that some miRNA-target features have been evolving while some have been fixed during evolution. Our study lays the foundation for the future developments of target prediction tools that could be applied to “non-model” organisms for which minimal experimental data is available.Availability and implementation The code is freely available at https://github.com/gbenor/TPVOD
Bioinformatics analysis of potential key genes and mechanisms in type 2 diabetes mellitus
Authors: Vastrad Basavaraj , Vastrad Chanabasayya 
Published: March 2021

AbstractType 2 diabetes mellitus (T2DM) is etiologically related to metabolic disorder. The aim of our study was to screen out candidate genes of T2DM and to elucidate the underlying molecular mechanisms by bioinformatics methods. Expression profiling by high throughput sequencing data of GSE154126 was downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between T2DM and normal control were identified. And then, functional enrichment analyses of gene ontology (GO) and REACTOME pathway analysis was performed. Protein–protein interaction (PPI) network and module analyses were performed based on the DEGs. Additionally, potential miRNAs of hub genes were predicted by miRNet database. Transcription factors (TFs) of hub genes were detected by NetworkAnalyst database. Further, validations were performed by receiver operating characteristic curve (ROC) analysis and real-time polymerase chain reaction (RT-PCR). In total, 925 DEGs were identified in T2DM, including 447 up regulated genes and 478 down-regulated genes. Functional enrichment analysis results showed that up regulated DEGs were significantly enriched in defense response, neutrophil degranulation, cell adhesion and extracellular matrix organization. The top 10 hub genes, JUN, VCAM1, RELA, U2AF2, ADRB2, FN1, CDK1, TK1, A2M and ACTA2 were identified from the PPI network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network. Furthermore, ROC analysis and RT-PCR revealed that JUN, VCAM1, RELA, U2AF2, ADRB2, FN1, CDK1, TK1, A2M and ACTA2 might serve as biomarkers in T2DM. Bioinformatics analysis is a useful tool to explore the molecular mechanism and pathogenesis of T2DM. The identified hub genes may participate in the onset and advancement of T2DM and serve as therapeutic targets.
Brain-wide neuronal activation and functional connectivity are modulated by prior exposure to repetitive learning episodes
Authors: Terstege Dylan J. , Durante Isabella M. , Epp Jonathan R. 
Published: March 2021

ABSTRACTMemory storage and retrieval are shaped by past experiences. Prior learning and memory episodes have numerous impacts on brain structure from micro to macroscale. Previous experience with specific forms of learning increases the efficiency of future learning. It is less clear whether such practice effects on one type of memory might also have transferable effects to other forms of memory. Different forms of learning and memory rely on different brain-wide networks but there are many points of overlap in these networks. Enhanced structural or functional connectivity caused by one type of learning may be transferable to another type of learning due to overlap in underlying memory networks. Here, we investigated the impact of prior chronic spatial training on the task-specific functional connectivity related to subsequent contextual fear memory recall in mice. Our results show that mice exposed to prior spatial training exhibited decreased brain-wide activation compared to control mice during the retrieval of a context fear memory. With respect to functional connectivity, we observed changes in several network measures notably an increase in global efficiency. Interestingly, we also observed an increase in network resilience based on simulated targeted node deletion. Overall, this study suggests that chronic learning has transferable effects on the functional connectivity networks of other types of learning and memory. The generalized enhancements in network efficiency and resilience suggest that learning itself may protect brain networks against deterioration.
Turnip crinkle virus targets host ATG8 proteins to attenuate antiviral autophagy
Authors: Shukla Aayushi , Hoffmann Gesa , Hofius Daniel , Hafrén Anders 
Published: March 2021

SUMMARYAutophagy has emerged as a central player in plant virus disease and resistance. In this study we have addressed the potential roles of autophagy in Turnip crinkle virus (TCV) infection. We found that autophagy attenuates disease severity and contributes to resistance against TCV by limiting virus accumulation. These autophagy-dependent disease phenotypes intensify further when combined with defects in RNA silencing, suggesting that these two major defence pathways are largely uncoupled in TCV disease. Intriguingly, as a counterdefence, TCV employs the viral silencing suppressor protein P38 to suppress antiviral autophagy, likely by directly sequestering ATG8 proteins. This strategy appears to be novel for plant viruses, yet resembles mechanisms described for other pathogen classes. Together, these results broaden our understanding of autophagy in plant virus disease, and strengthens our view of virus-specific adaptation to the autophagy pathway.
Evidence of an additional wild contributor,Malus orientalisUglitzk., to the genome of cultivated apple varieties in the Caucasus and Iran
Authors: Hamid Bina , Hamed Yousefzadeh , Anthony Venon , Carine Remoué , Agnès Rousselet , Matthieu Falque , Faramarzi Shadab , Chen Xilong , Samanchina Jarkyn , Gill David , Kabaeva Akylai , Tatiana Giraud , Batool Hossainpour , Hamid Abdollahi , Ivan Gabrielyan , Anush Nersesyan , Cornille A. 
Published: March 2021

AbstractAnthropogenic and natural divergence processes remain poorly studied in crop-wild fruit tree complexes, especially in the Caucasus, a pivotal region for plant domestication. We investigated anthropogenic and natural divergence processes in apples in the Caucasus using 26 microsatellite markers amplified in 550 wild and cultivated samples. We found two genetically distinct cultivated populations in Iran that are differentiated fromMalus domestica, the standard cultivated apple worldwide. Coalescent-based inferences showed that these two cultivated populations originated from specific domestication events ofM. orientalisin Iran. One of the Iranian clusters comprised both cultivated and forest trees, suggesting that either farmers use local wild apple for cultivation or that some forest trees are feral cultivars. We found evidence of substantial wild-crop and crop-crop gene flow in the Caucasus, as has been described in apple in Europe. In the Caucasus, we identified seven genetically differentiated populations of wild apple (Malus orientalis). Niche modeling combined with genetic diversity estimates indicated that these populations likely resulted from range changes during past glaciations. This study identifies Iran as a key region in the domestication of apple andM. orientalisas an additional contributor to the cultivated apple gene pool. Domestication of the apple tree therefore involved multiple origins of domestication in different geographic locations and substantial crop-wild hybridization, as found in other fruit trees. This study also highlights the impact of climate change on the natural divergence of a wild fruit tree and provides a starting point for apple conservation and breeding programs in the Caucasus.
TOR represses stress responses through global regulation of H3K27 trimethylation in plants
Authors: Dong Yihan , Uslu Veli V. , Berr Alexandre , Singh Gaurav , Papdi Csaba , Steffens Victor A , Heitz Thierry , Ryabova Lyubov 
Published: March 2021

AbstractTarget of Rapamycin (TOR) functions as a central sensory hub to link a wide range of external stimuli to gene expression. However, the mechanisms underlying stimulus-specific transcriptional reprogramming by TOR remains elusive. Ourin silicoanalysis in Arabidopsis demonstrates that TOR-repressed genes are associated with either bistable or silent chromatin states. Both states regulated by TOR signaling pathway are associated with high level of H3K27me3 deposited by CURLY LEAF (CLF) in specific context with LIKE HETEROCHROMATIN PROTEIN1 (LHP1). Combinations of epigenetic modifications H3K4me3 and H3K27me3 implicate bistable feature which alternates between on and off state allowing rapid transcriptional changes upon external stimuli. Chromatin remodeler SWI2/SNF2 ATPase BRAHMA (BRM) activates TOR-repressed genes only at bistable chromatin domains to rapidly induce biotic stress responses. Here we demonstrated bothin silicoandin vivothat TOR represses transcriptional stress responses through global maintenance of H3K27me3.