bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of autotetraploidy and microbiome associations mediate differential responses to pathogens
Authors: Mehlferber Elijah C , Song Michael J , Pelaez Julianne Naomi , Jaenisch Johan , Coate Jeremy E , Koskella Britt , Rothfels Carl J 
Published: October 2021

AbstractIt has become increasingly clear that the microbiome plays a critical role in shaping the host organism’s response to disease. There also exists mounting evidence that an organism’s ploidy level is important in their response to pathogens and parasites. However, no study has determined if or how these two factors influence one another. We investigate the effect of whole-genome duplication in Arabidopsis thaliana on their above-ground (phyllosphere) microbiome, and determine the interacting impacts of ploidy and the microbiome on disease outcome. Using seven independently derived synthetic auto-tetraploid Arabidopsis accessions, a synthetic leaf-associated bacterial community, and the model pathogen Pseudomonas syringae pv. Tomato DC3000, we confirm that polyploids are generally more resistant to pathogens, but illustrate that this resistance may be in part due to a decrease in the reliance on beneficial bacteria. Polyploids fare better against the pathogen than diploids regardless of microbial inoculation, while we observed that diploids harboring an intact microbiome have lower pathogen densities than those without. We then use RNA sequencing to show that diploids have many more differentially expressed defense-related genes in the presence of their phyllosphere microbiota, while polyploids exhibit constitutively activated defenses regardless of exposure to the synthetic community. These results imply that whole-genome duplication can disrupt historical host-microbiome associations, and suggest that a potential cause or consequence of disruption is a heightened capacity for pathogen defense that is less impacted by the microbiome.
Loss of α-actinin-3 confers protection from eccentric contraction damage in fast-twitch EDL muscles from aged mdx dystrophic mice by reducing pathological fibre branching
Authors: Kiriaev Leonit , Houweling Peter J. , North Kathryn N. , Head Stewart I. 
Published: October 2021

ABSTRACTThe common null polymorphism (R577X) in the ACTN3 gene is present in over 1.5 billion people worldwide and results in the absence of the protein α-actinin-3 from the Z-discs of fast-twitch skeletal muscle fibres. We have previously reported that this polymorphism is a modifier of dystrophin deficient Duchenne Muscular Dystrophy. To investigate the mechanism underlying this we use a double knockout (dk)Actn3KO/mdx (dKO) mouse model which lacks both dystrophin and sarcomere α-actinin-3. We used dKO mice and mdx dystrophic mice at 12 months (aged) to investigate the correlation between morphological changes to the fast-twitch dKO EDL and the reduction in force deficit produced by an in vitro eccentric contraction protocol. In the aged dKO mouse we found a marked reduction in fibre branching complexity that correlated with protection from eccentric contraction induced force deficit. Complex branches in the aged dKO EDL fibres (28%) were substantially reduced compared to aged mdx EDL fibres (68%) and this correlates with a graded force loss over three eccentric contractions for dKO muscles (∼35% after first contraction, ∼66% overall) compared to an abrupt drop in mdx upon the first eccentric contraction (∼73% after first contraction, ∼89% after three contractions). In dKO protection from eccentric contraction damage was linked with a doubling of SERCA1 pump density the EDL. We propose that the increased oxidative metabolism of fast-twitch glycolytic fibres characteristic of the null polymorphism (R577X) and increase in SR Ca2+ pump proteins reduces muscle fibre branching and decreases susceptibility to eccentric injury in the dystrophinopathies.
A comprehensive atlas of fetal splicing patterns in the brain of adult myotonic dystrophy type 1 patients
Authors: Degener Max J. F. , van Cruchten Remco T.P. , Otero Brittney A. , Wang Eric T. , Wansink Derick G. , ‘t Hoen Peter A.C. 
Published: October 2021

ABSTRACTIn patients with myotonic dystrophy type 1 (DM1), dysregulation of RNA-binding proteins like MBNL and CELF1 leads to alternative splicing of exons and is thought to induce a return to fetal splicing patterns in adult tissues, including the central nervous system (CNS). To comprehensively evaluate this, we created an atlas of developmentally regulated splicing patterns in the frontal cortex of healthy individuals and DM1 patients by combining RNA-seq data from BrainSpan, GTEx and DM1 patients. Thirty four splice events displayed an inclusion pattern in DM1 patients that is typical for the fetal situation in healthy individuals. The regulation of DM1-relevant splicing patterns could partly be explained by changes in mRNA expression of the splice regulators MBNL1, MBNL2 and CELF1. On the contrary, interindividual differences in splicing patterns between healthy adults could not be explained by differential expression of these splice regulators. Our findings lend transcriptome-wide evidence to the previously noted shift to fetal splicing patterns in the adult DM1 brain as a consequence of an imbalance in antagonistic MBNL and CELF1 activities. Our atlas serves as a solid foundation for further study and understanding of the cognitive phenotype in patients.
Coordination chemogenetics for activation of GPCR-type glutamate receptors in brain tissue
Authors: Ojima Kento , Kakegawa Wataru , Ito Masayuki , Miura Yuta , Michibata Yukiko , Kubota Ryou , Doura Tomohiro , Yamasaki Tokiwa , Miura Eriko , Nonaka Hiroshi , Mizuno Seiya , Takahashi Satoru , Yuzaki Michisuke , Hamachi Itaru , Kiyonaka Shigeki 
Published: October 2021

AbstractDirect activation of cell-surface receptors is highly desirable for elucidating the physiological roles of receptors. However, subtype-selective ligands are very limited because of the high homology among receptor subtypes. A potential approach for selective activation of a receptor subtype is chemogenetics, in which both point mutagenesis of the receptors and designed ligands are used. However, ligand-binding properties are affected in most current methods. Here, we developed a chemogenetic method for direct activation of metabotropic glutamate receptor 1 (mGlu1), which plays essential roles in cerebellar functions in the brain. Our screening identified a mGlu1 mutant, mGlu1(N264H), that was directly activated by palladium complexes. Notably, a palladium complex showing low cytotoxicity successfully activated mGlu1 in mGlu1(N264H) knock-in mice, revealing that activation of endogenous mGlu1 is sufficient to evoke the critical cellular mechanism of synaptic plasticity, a basis of motor learning in the cerebellum.
The role of parasympathetic mechanisms in the infarct-limiting effect of SGLT2 inhibitor ertugliflozin
Authors: Basalay MV , Arjun S , Davidson SM , Yellon DM 
Published: October 2021

AbstractIntroductionBased on data that outcome in patients with acute myocardial infarction is predicted by final infarct size (IS), reducing IS is of paramount importance. Recent experimental studies have demonstrated a strong infarct-sparing effect of SGLT2 inhibitors – a class of drugs which have proved to be safe and beneficial in patients with heart failure. Repurposing SGLT2 inhibitors for the benefit of patients presenting with acute myocardial infarction should be preceded by investigation of the underlying mechanisms of this infarct limitation. Experimental and clinical data indicate a potential role for autonomic modulation in these mechanisms, specifically sympatho-inhibition. The aim of this study was to investigate the role of the parasympathetic mechanism in the infarct-limiting effect of SGLT2 inhibition.MethodsFortyeight Sprague Dawley male rats were fed with a standard diet containing either the SGLT2 inhibitor ertugliflozin or vehicle, for 5-7 days. Myocardial ischaemia/reperfusion injury was initiated by a 40-min occlusion of the left anterior descending coronary artery followed by a 2hr period of reperfusion under isoflurane anaesthesia. Bilateral cervical vagotomy was performed 10min prior to myocardial ischaemia. Alternatively, muscarinic receptors were blocked systemically with the non-selective blocker atropine sulphate (2 mg/kg bolus, then 1 mg/kg/h) or the M3-selective blocker 4-DAMP (2 mg/kg bolus).ResultsPre-treatment with ertugliflozin reduced IS in comparison with the vehicle-treated controls (p<0.001). Bilateral vagotomy, atropine sulphate and 4-DAMP all abolished this infarct-limiting effect (IS 35±10%, 44±8%, and 35±4% respectively; P<0.01vs. Ertu for vagotomy, P<0.001vs. Ertu for both atropine sulphate and 4-DAMP).ConclusionThese results suggest that the Infarct-limiting effect of the SGLT2 inhibitor ertugliflozin, may be mediated via activation of the vagus nerve and M3-cholinoreceptors.
HERBS: Histological E-data Registration in rodent Brain Spaces
Authors: Fuglstad Jingyi Guo , Saldanha Pearl , Paglia Jacopo , Whitlock Jonathan R. 
Published: October 2021

AbstractRecording technologies for rodents have seen huge advances in the last decade, allowing users to sample thousands of neurons simultaneously from multiple brain regions. This has prompted the need for digital tool kits to aid in curating anatomical data, however, existing tools either provide limited functionality or require users to be proficient in coding to use them. To address this we created HERBS, a comprehensive new tool for rodent users that offers a broad range of functionalities through a user-friendly graphical user interface. Prior to experiments, HERBS can be used to plan coordinates for implanting electrodes, targeting viral injections or tracers. After experiments, users can register recording electrode locations (e.g. Neuropixels, tetrodes), viral expression or other anatomical features, and visualize the results in 2D or 3D. Additionally, HERBS can delineate expression from multiple injections across tissue sections and obtain individual cell counts. Regional delineations in HERBS are based either on annotated 3D volumes from the Waxholm Space Atlas of the Sprague Dawley Rat Brain or the Allen Mouse Brain Atlas. HERBS allows users to scroll through the digital brain atlases and provides custom-angle slice cuts through the volumes, and supports free-transformation of tissue sections to atlas slices. Furthermore, HERBS allows users to reconstruct a 3D brain mesh with tissue from individual animals. HERBS is a multi-platform open-source Python package that is available on PyPI and GitHub.
Towards mouse genetic-specific RNA-sequencing read mapping
Authors: Gobet Nastassia , Jan Maxime , Franken Paul , Xenarios Ioannis 
Published: October 2021

AbstractGenetic variations affect behavior and cause disease but understanding how these variants drive complex traits is still an open question. A common approach is to link the genetic variants to intermediate molecular phenotypes such as the transcriptome using RNA-sequencing (RNA-seq). Paradoxically, these variants between the samples are usually ignored at the beginning of RNA-seq analyses of many model organisms. This can skew the transcriptome estimates that are used later for downstream analyses, such as expression quantitative trait locus (eQTL) detection. Here, we assessed the impact of reference-based analysis on the transcriptome and eQTLs in a widely-used mouse genetic population: the BXD panel of recombinant inbred lines. We highlight existing reference bias in the transcriptome data analysis and propose practical solutions which combine available genetic variants, genotypes, and genome reference sequence. The use of custom BXD line references improved downstream analysis compared to classical genome reference. These insights would likely benefit genetic studies with a transcriptomic component and demonstrate that genome references might need to be reassessed and improved.
Stimulating music supports attention in listeners with attentional difficulties
Authors: Woods Kevin JP , Sampaio Gonçalo , James Tedra , Przysinda Emily , Hewett Adam , Spencer Andrea E , Morillon Benjamin , Loui Psyche 
Published: October 2021

ABSTRACTBackground music is widely used to sustain attention, but little is known about what musical properties aid attention. This may be due to inter-individual variability in neural responses to music. We test the hypothesis that music can sustain attention by affecting oscillations via acoustic amplitude modulation, differentially for those with varying levels of attentional difficulty. We first show that heavily-modulated music improves sustained attention for participants with more ADHD symptoms. FMRI showed this music elicited greater activity in attentional networks in this group only, and EEG showed greater stimulus-brain coupling for this group in response to the heavily-modulated music. Finally, we parametrically manipulated the depth and rate of amplitude modulations inserted in otherwise-identical music, and found that beta-range modulations helped more than other frequency ranges for participants with more ADHD symptoms. Results suggest the possibility of an oscillation-based neural mechanism for targeted music to support improved cognitive performance.
A general theoretical framework for trait-based eco-evolutionary dynamics: population structure, intraspecific variation, and community assembly
Authors: Wickman Jonas , Koffel Thomas , Klausmeier Christopher A. 
Published: October 2021

AbstractTo understand how functional traits shape ecological communities it is necessary to understand both how traits across the community affect its functioning and how eco-evolutionary dynamics within the community change the traits over time. Of particular interest are so-called evolutionarily stable communities (ESCs), since these are the end points of eco-evolutionary dynamics and can persist over long time scales. One theoretical framework that has successfully been used for assembling ESCs is adaptive dynamics. However, this framework cannot account for intraspecific variation— neither locally nor across structured populations. On the other hand, in moment-based approaches, intraspecific variation is accommodated, but community assembly has been neglected. This is unfortunate as some questions regarding for example local adaptation vis-a-vis diversification into multiple species requires both facets. In this paper we develop a general theoretical framework that bridges the gap between these two approaches. We showcase how ESCs can be assembled using the framework, and illustrate various aspects of the framework using two simple models of resource competition. We believe this unifying framework could be of great use to address questions regarding the role of functional traits in communities where population structure, intraspecific variation, and eco-evolutionary dynamics are all important.
It is the Locus Coeruleus! Or… is it? : A proposition for analyses and reporting standards for structural and functional magnetic resonance imaging of the noradrenergic Locus Coeruleus
Authors: Yi Yeo-Jin , Lüsebrink Falk , Maaß Anne , Ziegler Gabriel , Yakupov Renat , Kreißl Michael C. , Betts Matthew , Speck Oliver , Düzel Emrah , Hämmerer Dorothea 
Published: October 2021

AbstractThe noradrenergic locus coeruleus (LC) in the brainstem shows early signs of protein pathologies in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. As the LC’s small size (approximately 2.5 mm in width) presents a challenge for molecular imaging, the past decade has seen a steep rise in structural and functional Magnetic Resonance (MR) studies aiming to characterise the LC’s changes in ageing and neurodegeneration. However, given its position in the brainstem and small volume, great care must be taken to yield methodologically reliable MR results as spatial deviations in transformations can greatly reduce the statistical power of the analyses at the group level. Here, we suggest a spatial transformation procedure and a set of quality assessment methods which allow LC researchers to achieve the spatial precision necessary for investigating this small but potentially impactful brain structure.Using a combination of available toolboxes (SPM12, ANTs, FSL, FreeSurfer), individual structural and functional 3T LC scans are transformed into MNI space via a study-specific anatomical template. Following this, the precision of spatial alignment in individual MNI-transformed images is quantified using in-plane distance measures based on slice-specific centroids of structural LC segmentations and based on landmarks of salient anatomical features in mean functional images, respectively.Median in-plane distance of all landmarks on the transformed structural as well as functional LC imaging data were below 2 mm, thereby falling below the typical LC width of 2.5 mm suggested by post-mortem data.With the set of spatial post-processing steps outlined in this paper and available for download, we hope to give readers interested in LC imaging a starting point for a reliable analysis of structural and functional MR data of the LC and to have also taken a first step towards establishing reporting standards of LC imaging data.
Finding and Keeping the Beat: Neural Mechanisms Differ as Beat Perception Unfolds
Authors: Cameron Daniel J. , Grahn Jessica A. 
Published: October 2021

AbstractPerception of a regular beat is essential to our ability to synchronize movements to music in an anticipatory fashion. Beat perception requires multiple, distinct neural functions, corresponding to the perceptual stages that occur over time, including 1) detection that regularity is present (beat finding), 2) prediction of future regular events to enable anticipation (beat continuation), and 3) dynamic adjustment of predictions as the rhythmic stimulus changes (beat adjustment). The striatum has been shown to be crucial for beat perception generally, although it is unclear how, or whether, distinct regions of the striatum contribute to these different stages of beat perception. Here, we used fMRI to investigate the activity of striatal subregions during the different stages of beat perception. Participants listened to pairs of rhythms (polyrhythms) whose temporal structure induced distinct perceptual stages—finding, continuation, and adjustment of the beat. Dorsal putamen was preferentially active during beat finding, whereas the ventral putamen was preferentially active during beat adjustment. We also observed that anterior insula activity was sensitive to metrical structure (greater when polyrhythms were metrically incongruent than when they were congruent). These data implicate the dorsal putamen in the detection of regularity, possibly by detection of coincidences between cortical oscillations, and the ventral putamen in the adjustment of regularity perception, possibly by integration of prediction errors in ongoing beat predictions. Additionally, activity in the supramarginal and superior temporal gyri correlated with beat tapping performance, and activity in the superior temporal gyrus correlated with beat perception (performance on the Beat Alignment Test).
Ruminant-specific retrotransposons shape regulatory evolution of bovine immunity
Authors: Kelly Conor J. , Chitko-McKown Carol , Chuong Edward B. 
Published: October 2021

ABSTRACTCattle are an important livestock species, and mapping the genomic architecture of agriculturally relevant traits such as disease susceptibility is a major challenge in the bovine research community. Lineage-specific transposable elements (TEs) are increasingly recognized to contribute to gene regulatory evolution and variation, but this possibility has been largely unexplored in ruminant genomes. We conducted epigenomic profiling of the type II interferon (IFN) response in bovine cells, and found thousands of ruminant-specific TEs including MER41_BT and Bov-A2 elements predicted to act as IFN-inducible enhancer elements. CRISPR knockout experiments in bovine cells established that critical immune factors including IFNAR2 and IL2RB are transcriptionally regulated by TE-derived enhancers. Finally, population genomic analysis of 38 individuals revealed that a subset of TE-derived enhancers represent polymorphic insertion sites in modern cattle. Our study reveals that lineage-specific TEs have shaped the evolution of ruminant IFN responses, and potentially continue to contribute to immune gene regulatory differences across modern breeds and individuals. Together with previous work in human cells, our findings demonstrate that lineage-specific TEs have been independently co-opted to regulate IFN-inducible gene expression in multiple species, supporting TE co-option as a recurrent mechanism driving the evolution of IFN-inducible transcriptional networks.
High-throughput RNA isoform sequencing using programmable cDNA concatenation
Authors: Al’Khafaji Aziz M. , Smith Jonathan T. , Garimella Kiran V , Babadi Mehrtash , Sade-Feldman Moshe , Gatzen Michael , Sarkizova Siranush , Schwartz Marc A. , Popic Victoria , Blaum Emily M. , Day Allyson , Costello Maura , Bowers Tera , Gabriel Stacey , Banks Eric , Philippakis Anthony A. , Boland Genevieve M. , Blainey Paul C. , Hacohen Nir 
Published: October 2021

AbstractAlternative splicing is a core biological process that enables profound and essential diversification of gene function. Short-read RNA sequencing approaches fail to resolve RNA isoforms and therefore primarily enable gene expression measurements - an isoform unaware representation of the transcriptome. Conversely, full-length RNA sequencing using long-read technologies are able to capture complete transcript isoforms, but their utility is deeply constrained due to throughput limitations. Here, we introduce MAS-ISO-seq, a technique for programmably concatenating cDNAs into single molecules optimal for long-read sequencing, boosting the throughput >15 fold to nearly 40 million cDNA reads per run on the Sequel IIe sequencer. We validated unambiguous isoform assignment with MAS-ISO-seq using a synthetic RNA isoform library and applied this approach to single-cell RNA sequencing of tumor-infiltrating T cells. Results demonstrated a >30 fold boosted discovery of differentially spliced genes and robust cell clustering, as well as canonical PTPRC splicing patterns across T cell subpopulations and the concerted expression of the associated hnRNPLL splicing factor. Methods such as MAS-ISO-seq will drive discovery of novel isoforms and the transition from gene expression to transcript isoform expression analyses.