bluuebunny/crossref_metadata_2025_split huggingface dataset:
KaryoCreate: a new CRISPR-based technology to generate chromosome-specific aneuploidy by targeting human centromeres
Authors: Bosco Nazario , Goldberg Aleah , Johnson Adam F , Zhao Xin , Mays Joseph C , Cheng Pan , Bianchi Joy J , Toscani Cecilia , Katsnelson Lizabeth , Annuar Dania , Mei Sally , Faitelson Roni E , Pesselev Ilan Y , Mohamed Kareem S , Mermerian Angela , Camacho-Hernandez Elaine M , Gionco Courtney A , Manikas Julie , Tseng Yi-Shuan , Sun Zhengxi , Fani Somayeh , Keegan Sarah , Lippman Scott M , Fenyö David , Santaguida Stefano , Davoli Teresa 
Published: September 2022

SUMMARYAneuploidy, the presence of chromosome gains or losses, is a hallmark of cancer and congenital syndromes. Here, we describe KaryoCreate (Karyotype CRISPR Engineered Aneuploidy Technology), a system that enables generation of chromosome-specific aneuploidies by co-expression of a sgRNA targeting chromosome-specific CENPA-binding ɑ-satellite repeats together with dCas9 fused to a mutant form of KNL1. We designed unique and highly specific sgRNAs for 19 out of 24 chromosomes. Expression of these sgRNAs with KNL1Mut-dCas9 leads to missegregation and induction of gains or losses of the targeted chromosome in cellular progeny with an average efficiency of 8% and 12% for gains and losses, respectively (up to 20%), tested and validated across 9 chromosomes. Using KaryoCreate in colon epithelial cells, we show that chromosome 18q loss, a frequent occurrence in gastrointestinal cancers, promotes resistance to TGFβ, likely due to synergistic hemizygous deletion of multiple genes. Altogether, we describe a novel technology to create and study chromosome missegregation and aneuploidy in the context of cancer and beyond.HighlightsWe designed sgRNAs targeting chromosome-specific centromeres across 19 human chromosomesKaryoCreate combines chromosome-specific centromeric sgRNAs with dCas9 fused to a mutant form of KNL1.KaryoCreate allows engineering gains and losses of specific human chromosomes.Engineered Chromosome 18q loss promotes tumor-associated phenotypes in colon-derived cells.KaryoCreate is a CRISPR-based technology to foster the study of centromere biology and aneuploidy.
Edaphic specialization onto bare, rocky outcrops as a factor in the evolution of desert angiosperms
Authors: Lichter Marck Isaac H. , Baldwin Bruce G. 
Published: September 2022

AbstractUnderstanding the processes that enable organisms to shift into more arid environments as they emerge is critical for gauging resilience to climate change, yet these forces remain poorly known. In a comprehensive clade-based study, we investigate recent shifts into North American deserts in the rock daisies (Perityleae), a diverse tribe of desert sunflowers (Compositae). We sample Perityleae across two separate contact zones between tropical deciduous forest and desert biomes in western North America and infer a time-calibrated phylogeny based on target capture sequence data. We reconstruct biome shifts using Bayesian inference with paleobiome-informed models and find evidence for seven independent shifts into desert habitats since the onset of aridification in the late Miocene epoch. The earliest shift occurred out of tropical deciduous forests and led to an extensive radiation throughout North American deserts that accounts for the majority of extant desert Perityleae. Reconstructions of life history and micro-habitat in Perityleae reveal a correlation between a suffrutescent perennial life history and edaphic endemism onto rocky outcrops, an ecological specialization that evolved prior to establishment and diversification in deserts. That the insular radiation of desert rock daisies stemmed from ancestors pre-adapted for dry conditions as edaphic endemics in otherwise densely vegetated tropical deciduous forests in northwest Mexico underscores the crucial role of exaptation and dispersal for shifts into arid environments.Significance StatementThe environmentally stressful conditions found in desert regions have often been implicated as the main factor in the evolution of drought tolerance in desert plants. Yet many iconic desert plant lineages evolved prior to the recent emergence of widespread arid climates, suggesting an important role for pre-adaptation (exaptation). In the desert rock daisies (Perityleae), we provide empirical support for this view by showing that life history evolution associated with their ecological specialization onto rock outcrops was a precursor to their establishment and extensive diversification in North American deserts. We caution against assuming the presence of ancient dry biomes based on time-calibrated phylogenies and we emphasize the fundamental roles that exaptation and dispersal play during community assembly in novel environments.
Specific connectivity optimizes learning in thalamocortical loops
Authors: Lakshminarasimhan Kaushik , Xie Marjorie , Cohen Jeremy , Sauerbrei Britton , Hantman Adam , Litwin-Kumar Ashok , Escola Sean 
Published: September 2022

1AbstractCortico-thalamo-cortical loops have a central role in cognition and motor control, but precisely how thalamus contributes to these processes is unclear. Recent studies showing evidence of plasticity in thalamocortical synapses indicate a role for thalamus in shaping cortical dynamics – and thus behavior – through learning. Since corticothalamic projections compress cortical activity into a lower-dimensional thalamic activity space, we hypothesized that the computational role of thalamus would depend critically on the structure of corticothalamic connectivity. To test this, we identified the optimal corticothalamic structure that promotes biologically plausible learning in thalamocortical synapses. We found that corticothalamic structures specialized to carry an efference copy of the cortical output benefit motor control, while corticothalamic connections that communicate the directions of highest variance in cortical activity are optimal for working memory tasks. We analyzed neural recordings from mice performing grasping and delayed discrimination, and found corticothalamic interactions consistent with these predictions. These results suggest that thalamus orchestrates cortical dynamics in a functionally precise manner through structured connectivity.
Caveolin-1 protects endothelial cells from extensive expansion of transcellular tunnel by stiffening the plasma membrane
Authors: Morel Camille , Lemerle Eline , Tsai Feng-Ching , Obadia Thomas , Srivastava Nishit , Marechal Maud , Salles Audrey , Albert Marvin , Stefani Caroline , Benito Yvonne , Vandenesch François , Lamaze Christophe , Vassilopoulos Stéphane , Piel Matthieu , Bassereau Patricia , Gonzalez-Rodriguez David , Leduc Cécile , Lemichez Emmanuel 
Published: September 2022

AbstractLarge transcellular pores elicited by bacterial mono-ADP-ribosyltransferase (mART) exotoxins inhibiting the small RhoA GTPase compromise the endothelial barrier. Recent advances in biophysical modeling point towards membrane tension and bending rigidity as the minimal set of mechanical parameters determining the nucleation and maximal size of transendothelial cell macroaperture (TEM) tunnels induced by bacterial RhoA-targeting mART exotoxins. We report that cellular depletion of caveolin-1, the membrane-embedded building block of caveolae, and depletion of cavin-1, the master regulator of caveolae invaginations, increase the number of TEMs per cell. The enhanced occurrence of TEM nucleation events correlates with a reduction of cell height, due to the increase of cell spreading and decrease of cell volume, which, together with the disruption of RhoA-driven F-actin meshwork, favor membrane apposition for TEM nucleation. Strikingly, caveolin-1 specifically controls the opening speed of TEMs leading to their dramatic 5.4-fold larger widening. Consistent with the increase of TEM density and width in siCAV1 cells, we record a higher lethality in caveolin-1-deficient mice subjected to a catalytically active mART exotoxin targeting RhoA during staphylococcal bloodstream infection. Combined theoretical modeling with independent biophysical measurements of plasma membrane bending rigidity point toward a specific contribution of caveolin-1 to membrane stiffening in addition to the role of cavin-1/caveolin-1-dependent caveolae in the control of membrane tension homeostasis.
The TBX20-TLE Interaction is Essential for the Second Heart Field
Authors: Edwards Whitney , Bussey Olivia K. , Conlon Frank L. 
Published: September 2022

ABSTRACTTbx20 plays a multifaceted role in cardiac morphogenesis and controls a broad gene regulatory network. However, the mechanism by which Tbx20 activates and represses target genes in a tissue-specific and temporal manner remains unclear. Studies show that Tbx20 directly interacts with the Transducin-like Enhancer of Split (TLE) family of proteins to mediate transcriptional repression of downstream target genes. However, a functional role for the Tbx20-TLE transcriptional repression complex during heart development is not established. To this end, we generated a mouse model with a two-amino acid substitution in the Tbx20 EH1 domain, thereby disrupting the Tbx20-TLE interaction (Tbx20EH1mut). We demonstrate that disruption of this interaction impairs critical morphogenic events, including cardiac looping and chamber formation, and ultimately leads to embryonic lethality. Transcriptional profiling of Tbx20EH1mut hearts and analysis of putative Tbx20 direct targets reveals misexpression of the retinoic acid pathway and cardiac progenitor genes, demonstrating that the Tbx20-TLE interaction serves to inhibit cardiac progenitor programs in the developing heart. We find that loss of this interaction also results in perturbations of the second heart field progenitor population, implying that altered cardiac progenitor function may underly the observed cardiac defects in our model. Our studies indicate that TLE-mediated repression is a primary mechanism by which Tbx20 systematically controls gene expression.
Analysis of the abomasal transcriptome of LDA affected cattle
Authors: Gál Zoltán , Biró Bálint , Nagy Zsófia , Kontra Levente , Horváth András , Hoffmann Orsolya Ivett 
Published: September 2022

AbstractLeft displacement of the abomasum (LDA) is a common condition in Holstein population mainly occur around the time of parturition. The entrapped abomasum located between the rumen and the abdominal wall caused by the abomasal hypomotility. The heritability of LDA estimated higher than for other bovine diseases but a number of management and nutritional conditions are also affecting the disease appearance. Genome studies revealed many significant genomic regions associated with LDA, although an RNA sequencing analysis of abomasum is missing from the literature. Within the framework of this research, we tried to patch up this area missing from the literature and to reveal the genetic causes and a complex interaction between the endocrine and neuromuscular pathways behind the symptoms of the disease with the help of transcriptomic analysis.
Small-molecule Polθ inhibitors provide safe and effective tumor radiosensitization in preclinical models
Authors: Rodriguez-Berriguete Gonzalo , Ranzani Marco , Prevo Remko , Puliyadi Rathi , Machado Nicole , Bolland Hannah R. , Millar Val , Ebner Daniel , Boursier Marie , Cerutti Aurora , Cicconi Alessandro , Galbiati Alessandro , Grande Diego , Grinkevich Vera , Majithiya Jayesh , Piscitello Desiree , Rajendra Eeson , Stockley Martin , Boulton Simon J. , Hammond Ester M. , Heald Robert , Smith Graeme C. M. , Robinson Helen , Higgins Geoff S. 
Published: September 2022

ABSTRACTDNA polymerase theta (Polθ) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Polθ has limited expression in normal tissues but is frequently overexpressed in cancer cells and, therefore, represents an ideal target for tumor-specific radiosensitization. Here, we show that ART558 and ART899, two novel and specific allosteric inhibitors of the Polθ DNA polymerase domain, potently radiosensitize tumor cells, particularly when combined with fractionated radiation. Importantly, normal fibroblasts are not radiosensitized by Polθ inhibition. Mechanistically, we show that the radiosensitization caused by Polθ inhibition is most effective in replicating cells and is due to impaired DNA damage repair. We also show that radiosensitization is still effective under hypoxia, suggesting that these inhibitors may help overcome hypoxia-induced radioresistance. In addition, we describe for the first time ART899 and characterize it as a potent and specific Polθ inhibitor with improved metabolic stability. In vivo, the combination of Polθ inhibition using ART899 with fractionated radiation is well tolerated and results in a significant reduction in tumor growth compared to radiation alone. These results pave the way for future clinical trials of Polθ inhibitors in combination with radiotherapy.
Single cell transcriptomics delineates the immune-cell landscape in equine lower airways and reveals upregulation of the FKBP5 gene in horses with asthma
Authors: Riihimäki Miia , Fegraeus Kim , Nordlund Jessica , Waern Ida , Wernersson Sara , Akula Srinivas , Hellman Lars , Raine Amanda 
Published: September 2022

AbstractBackgroundEquine asthma (EA) is a heterogenous, complex disease with a significant negative impact on horse welfare and performance. EA and human asthma have fundamental similarities, making EA a useful large animal disease model. Bronchoalveolar lavage (BAL) fluid provides a snapshot sample of the immune cells occupying the alveolar space and is one of the most relevant sample types for studies of chronic inflammation in the lung. In this study, we sequenced single equine BAL-cells in order to study the immune cell landscape of the respiratory tract of horses diagnosed with mild-to-moderate EA and healthy controls.ResultsScRNA-seq analysis of ~63,000 cells from eleven horses diagnosed with mild-moderate asthma (mEA) and eight healthy controls were performed using the Drop-Seq technology. We identified five major immune cell populations in equine BAL; alveolar macrophages (AM), T cells, neutrophils, mast cells and dendritic cells, as well as subtypes thereof. The cellular subtypes demonstrated herein have previously not been characterized in horses. Differential gene expression analysis revealed upregulation of genes in mEA horses, including FKBP5 and CCL24, which have previously been associated with asthma in other species. The most significantly upregulated gene across the cell types in EA was FKBP5, a chaperone protein involved in regulating the assembly, activity, and sensitivity of the glucocorticoid receptorConclusionHerein we demonstrate the first comprehensive scRNA-seq map of the immune-cell populations in BAL from horses with asthma and healthy individuals. The glucocorticoid receptor associated protein FKBP5 was identified as a potential biomarker for EA.
Deep Learning from Phylogenies for Diversification Analyses
Authors: Lambert Sophia , Voznica Jakub , Morlon Hélène 
Published: September 2022

ABSTRACTBirth-death models are widely used in combination with species phylogenies to study past diversification dynamics. Current inference approaches typically rely on likelihood-based methods. These methods are not generalizable, as a new likelihood formula must be established each time a new model is proposed; for some models such formula is not even tractable. Deep learning can bring solutions in such situations, as deep neural networks can be trained to learn the relation between simulations and parameter values as a regression problem. In this paper, we adapt a recently developed deep learning method from pathogen phylodynamics to the case of diversification inference, and we extend its applicability to the case of the inference of state-dependent diversification models from phylogenies associated with trait data. We demonstrate the accuracy and time efficiency of the approach for the time constant homogeneous birth-death model and the Binary-State Speciation and Extinction model. Finally, we illustrate the use of the proposed inference machinery by reanalyzing a phylogeny of primates and their associated ecological role as seed dispersers. Deep learning inference provides at least the same accuracy as likelihood-based inference while being faster by several orders of magnitude, offering a promising new inference approach for deployment of future models in the field.
The development of compulsive coping behaviors depends on the engagement of dorsolateral striatum dopamine-dependent mechanisms
Authors: Giuliano Chiara , Marti-Prats Lucia , Domi Ana , Puaud Mickaël , Pena-Oliver Yolanda , McKenzie Colin , Everitt Barry J. , Belin David 
Published: September 2022

AbstractHumans greatly differ in how they cope with stress, a natural behavior learnt through negative reinforcement. Some individuals engage in displacement activities, others in exercise or comfort eating, and others still in alcohol use. Across species, adjunctive behaviors, such as polydipsic drinking, are used as a form of displacement activity that reduces distress. Some individuals, in particular those that use alcohol to self-medicate, tend to lose control over such coping behaviors, which become excessive and compulsive. However, the psychological and neural mechanisms underlying this individual vulnerability have not been elucidated. Here we tested the hypothesis that the development of compulsive adjunctive behaviors stems from the functional engagement of the dorsolateral striatum (DLS) dopamine-dependent habit system after a prolonged history of adjunctive responding. We measured in longitudinal studies in male Sprague Dawley rats the sensitivity of early established vs compulsive polydipsic water or alcohol drinking to a bilateral infusion of the dopamine receptor antagonist α-flupentixol into the anterior DLS (aDLS). While most rats acquired a polydipsic drinking response with water, others only did so with alcohol. Whether reliant on water or alcohol, the acquisition of this coping response was insensitive to aDLS dopamine receptor blockade. In contrast, after prolonged experience, adjunctive drinking became dependent on the aDLS dopamine-dependent habit system at a time it was compulsive in vulnerable individuals. These data suggest that habits may develop out of negative reinforcement and that the engagement of their underlying striatal system is necessary for the manifestation of adjunctive behaviors.Significance statementHarnessing the individual variability that rodents, like humans, show to engage in adaptive or maladaptive coping strategies, which can result in the development of compulsive disorders, here we demonstrate that the functional engagement of the dorsolateral striatum-dependent habit system precipitates the transition to compulsion in rats that have acquired a polydipsic adjunctive drinking response with water or alcohol as a means to cope with distress. The results of this study not only provide evidence for the emergence of instrumental habits under negative reinforcement, but they also reveal that compulsive behaviors that originate from the loss of control over coping strategies are mediated by the dorsolateral striatum-dependent habit system.
The Uniqueness of Human Vulnerability to Brain Aging in Great Ape Evolution
Authors: Vickery Sam , Patil Kaustubh R. , Dahnke Robert , Hopkins William D. , Sherwood Chet C. , Caspers Svenja , Eickhoff Simon B. , Hoffstaedter Felix 
Published: September 2022

AbstractAging is associated with robust decline of the brain’s gray matter. This spatially specific, morphological change in humans has recently been found in chimpanzees. Direct comparison of age-related brain deterioration between these great ape species can provide a unique evolutionary perspective on human brain aging. Here, we present a data-driven, cross-species comparative framework to explore the relationship between gray matter atrophy with age and cross-species cerebral expansion in chimpanzees and humans. In humans, we found a positive relationship between cerebral aging and cortical expansion, whereas, in chimpanzees no such relationship was found. The greater aging and expansion effects in higher-order cognitive regions like the orbito-frontal cortex were observed to be unique to humans. This resembles the last in, first out hypothesis for neurodevelopment and may represent a biological cost for recent evolutionary developments of human faculties.
The human MRS2 magnesium binding domain is a regulatory feedback switch for channel activity
Authors: Uthayabalan Sukanthathulse , Vishnu Neelanjan , Madesh Muniswamy , Stathopulos Peter B. 
Published: September 2022

AbstractMitochondrial RNA splicing protein 2 (MRS2) forms a major magnesium (Mg2+) entry channel into the matrix. While MRS2 contains two transmembrane domains that constitute a pore, most of the protein resides within the matrix. Yet, the precise structural and functional role of this obtrusive amino terminal domain (NTD) in human MRS2 function is unknown. Here, we show that the MRS2 NTD self-associates into a homodimer, contrasting the pentameric assembly of CorA, an orthologous bacterial channel. Mg2+and calcium suppress lower and higher order oligomerization of MRS2 NTD, while cobalt has no effect on the NTD but disassembles full-length MRS2. Mutating pinpointed residues mediating Mg2+binding to the NTD, not only selectively decreases Mg2+binding affinity ∼7-fold but also abrogates Mg2+binding-induced changes in secondary, tertiary and quaternary structures. Disruption of NTD Mg2+binding strikingly potentiates mitochondrial Mg2+uptake in wild-type and Mrs2 knockout cells. Our work exposes a mechanism for human MRS2 autoregulation by negative feedback from the NTD and identifies a novel gain of function mutant with broad applicability to future Mg2+signaling research.