bluuebunny/crossref_metadata_2025_split huggingface dataset:
ARPC5 deficiency leads to severe early onset systemic inflammation and early mortality
Authors: Sindram Elena , Caballero-Oteyza Andrés , Kogata Naoko , Huang Shaina , Alizadeh Zahra , Gamez-Diaz Laura , Fazlollhi Mohammad Reza , Peng Xiao , Grimbacher Bodo , Way Michael , Proietti Michele 
Published: January 2023

AbstractThe seven subunit Arp2/3 complex drives the formation of branched actin networks that are essential for many cellular processes including cell migration. In humans, the ARPC5 subunit of the Arp2/3 complex is encoded by two paralogous genes (ARPC5andARPC5L), resulting in proteins with 67% identity. Through whole-exome sequencing, we identified a biallelic ARPC5 frameshift variant in a female child who presented with recurrent infections, multiple congenital anomalies, diarrhea, and thrombocytopenia, and suffered early demise from sepsis. Her consanguineous parents also had a previous child who died with similar clinical features. Using CRISPR/Cas9-mediated approaches, we demonstrate that loss of ARPC5 affects actin cytoskeleton organization and function, as well as chemokine-dependent cell migrationin vitro. HomozygousArpc5-/- mice do not survive past embryonic day 9 due to severe developmental defects, including loss of the second pharyngeal arch which contributes to craniofacial and heart development. Our results indicate that ARPC5 is important for both prenatal development and postnatal immune signaling, in a non-redundant manner with ARPC5L. Moreover, our observations add theARPC5locus to the list of genes that should be considered when patients present with syndromic early-onset immunodeficiency, particularly if recessive inheritance is suspected.
Long-term methylome changes after experimental seed demethylation and their interaction with recurrent water stress inErodium cicutarium(Geraniaceae)
Authors: Balao Francisco , Medrano Mónica , Bazaga Pilar , Paun Ovidiu , Alonso Conchita 
Published: January 2023

SummaryThe frequency and length of drought periods are increasing in subtropical and temperate regions worldwide. Epigenetic responses to water stress could be key for plant resilience to this largely unpredictable challenge. Experimental DNA demethylation together with application of a stress factor stands as a suitable strategy to uncover the contribution of epigenetics to plant responses to stress.We analysed leaf cytosine methylation changes in adult plants of the Mediterranean weed,Erodium cicutarium, after seed demethylation with 5-Azacytidine and/or recurrent water stress in a greenhouse. We used bisulfite RADseq (BsRADseq) and a newly reported reference genome forE. cicutariumto characterize methylation changes in a 2×2 factorial design, controlling for plant relatedness.In the long-term, 5-Azacytidine treatment alone caused both hypo and hyper-methylation at individual cytosines, with substantial hypomethylation in CG contexts. In control conditions, drought resulted in a decrease in methylation level in all but CHH contexts. In contrast, the genome of plants that experienced recurrent water stress and had been treated with 5-Azacytidine increased DNA methylation level by ca. 5%.Seed demethylation and recurrent drought exhibited a highly significant interaction in terms of global and context-specific cytosine methylation supporting an epigenetic contribution in response to stress at molecular level.
Modulatory feedback determines attentional object segmentation in a model of the ventral stream
Authors: Papale Paolo , Williford Jonathan R. , Balk Stijn , Roelfsema Pieter R. 
Published: January 2023

AbstractStudies in neuroscience inspired progress in the design of artificial neural networks (ANNs), and, vice versa, ANNs provide new insights into the functioning of brain circuits. So far, the focus has been on how ANNs can help to explain the tuning of neurons at various stages of the visual cortical hierarchy. However, the role of modulatory feedback connections, which play a role in attention and perceptual organization, has not been resolved yet. The present study presents a biologically plausible neural network that performs scene segmentation and can shift attention using modulatory feedback connections from higher to lower brain areas. The model replicates several neurophysiological signatures of recurrent processing. Specifically, figural regions elicit more activity in model units than background regions. The modulation of activity by figure and ground occurs at a delay after the first feedforward response, because it depends on a loop through the higher model areas. Importantly, the figural response enhancement is enhanced by object-based attention, which stays focused on the figural regions and does not spill over to the adjacent background, just as is observed in the visual cortex. Our results indicate how progress in artificial intelligence can be used to garner insight into the recurrent cortical processing for scene segmentation and object-based attention.Author SummaryRecent feedforward networks in artificial intelligence provide unmatched models of tuning of neurons in the visual cortex. However, these feedforward models do not explain the influences of object-based attention and image segmentation on neuronal responses, which rely on feedback interactions between cortical regions that are not included in the feedforward networks. In particular, the role of feedback connections from higher brain regions that modulate neural activity in lower cortical regions has not yet been studied extensively so that we still lack anin silicomodel of the role of these connections. Here, we present a biologically plausible neural network that successfully performs image segmentation and can shift object-based attention using modulatory feedback connections. The model evolved representations that mirror the properties of neurons in the visual cortex, including orientation tuning, shape-selectivity, surround suppression and a sensitivity to figure-ground organization, while trained only on a segmentation task. The new model provides insight into how the perception of coherent objects can emerge from the interaction between lower and higher visual cortical areas.
Resistance to vincristine in cancerous B-cells by disruption of p53-dependent mitotic surveillance
Authors: Rovsing Anne Bruun , Thomsen Emil Aagaard , Nielsen Ian , Skov Thomas Wisbech , Luo Yonglun , Dybkær Karen , Mikkelsen Jacob Giehm 
Published: January 2023

AbstractThe frontline therapy R-CHOP for patients with diffuse large B-cell lymphoma (DLBCL) has remained unchanged for two decades despite numerous phase III clinical trials investigating new alternatives. Multiple large studies have uncovered genetic subtypes of DLBCL enabling a targeted approach. To further pave the way for precision oncology, we perform genome-wide CRISPR screening to uncover the cellular response to one of the components of R-CHOP, vincristine, in the DLBCL cell line SU-DHL-5. We discover important pathways and subnetworks using gene-set enrichment analysis and protein-protein interaction networks and identify genes related to mitotic spindle organization that are essential during vincristine treatment. Inhibition of KIF18A, a mediator of chromosome alignment, using the small molecule inhibitor BTB-1 causes complete cell death in a synergistic manner when administered together with vincristine. We also identify the genesKIF18BandUSP28for which CRISPR/Cas9-directed knockout induces vincristine resistance across two DLBCL cell lines. Mechanistic studies show that lack ofKIF18BorUSP28counteracts a vincristine-induced p53 response involving the mitotic surveillance pathway (USP28-53BP1-p53). Collectively, our CRISPR screening data uncover potential drug targets and mechanisms behind vincristine resistance, which may support the development of future drug regimens.Key pointsInhibition of the mitotic surveillance pathway (USP28-53BP1-p53) and KIF18B induces resistance to vincristineSubstantial synergistic effects observed when using the KIF18A-inhibitor BTB-1 with vincristine in eradicating GCB-subtype DLBCL cells
Ferroptosis Integrates Mitochondrial Derangements and Pathological Inflammation to Promote Pulmonary Hypertension
Authors: Kazmirczak Felipe , Vogel Neal T. , Prisco Sasha Z. , Patterson Michael T. , Annis Jeffrey , Moon Ryan T. , Hartweck Lynn M , Mendelson Jenna B. , Kim Minwoo , Calixto Mancipe Natalia , Markowski Todd , Higgins LeAnn , Guerrero Candace , Kremer Ben , Blake Madelyn L. , Rhodes Christopher J. , Williams Jesse W. , Brittain Evan L. , Prins Kurt W. 
Published: January 2023

AbstractBackgroundMitochondrial dysfunction, characterized by impaired lipid metabolism and heightened reactive oxygen species (ROS) generation, results in lipid peroxidation and ferroptosis. Ferroptosis is an inflammatory mode of cell death that promotes complement activation and macrophage recruitment. In pulmonary arterial hypertension (PAH), pulmonary arterial endothelial cells (PAEC) exhibit cellular phenotypes that promote ferroptosis. Moreover, there is ectopic complement deposition and inflammatory macrophage accumulation in the pulmonary vasculature. However, the effects of ferroptosis inhibition on these pathogenic mechanisms and the cellular landscape of the pulmonary vasculature are incompletely defined.MethodsMulti-omics and physiological analyses evaluated how ferroptosis inhibition modulated preclinical PAH. The impact of AAV1-mediated expression of the pro-ferroptotic protein ACSL4 on PAH was determined, and a genetic association study in humans further probed the relationship between ferroptosis and pulmonary hypertension (PH).ResultsFerrostatin-1, a small-molecule ferroptosis inhibitor, mitigated PAH severity in monocrotaline rats. RNA-seq and proteomics analyses demonstrated ferroptosis was associated with PAH severity. RNA-seq, proteomics, and confocal microscopy revealed complement activation and pro-inflammatory cytokines/chemokines were suppressed by ferrostatin-1. Additionally, ferrostatin-1 combatted changes in endothelial, smooth muscle, and interstitial macrophage abundance and gene activation patterns as revealed by deconvolution RNA-seq. Ferroptotic PAEC damage associated molecular patterns restructured the transcriptomic signature, mitochondrial morphology, and promoted proliferation of pulmonary artery smooth muscle cells, and created a pro-inflammatory phenotype in monocytesin vitro. AAV1-Acsl4induced an inflammatory PAH phenotype in rats. Finally, single-nucleotide polymorphisms in six ferroptosis genes identified a potential link between ferroptosis and PH severity in the Vanderbilt BioVU repository.ConclusionsFerroptosis promotes PAH through metabolic and inflammatory mechanisms in the pulmonary vasculature.
Effects of Inbreeding on Microbial Community Diversity ofZea mays
Authors: Schultz Corey R , Johnson Matthew , Wallace Jason G 
Published: January 2023

AbstractHeterosis, also known as hybrid vigor, is the basis of modern maize production. The effect of heterosis on maize phenotypes has been studied for decades, but its effect on the maize-associated microbiome is much less characterized. To determine the effect of heterosis on the maize microbiome, we sequenced and compared the bacterial communities of inbred, open pollinated, and hybrid maize. Samples covered three tissue types (Stalk, Root, and Rhizosphere) in two field experiments and one greenhouse experiment. Bacterial diversity was affected by location and tissue type, but not genetic background, for both within-sample (alpha) and between-sample (beta) diversity. PERMANOVA analysis similarly showed that tissue type and location had significant effects on the overall community structure, whereas the genetic background and individual plant genotypes did not. Differential abundance analysis identified only 18 bacterial ASVs that significantly differed between inbred and hybrid maize. Predicted metagenome content was inferred with Picrust2, and it also showed a significantly larger effect of tissue and location than genetic background. Overall, these results indicate that the bacterial communities of inbred and hybrid maize are often more similar than they are different, and that non-genetic effects are generally the largest influences on the maize microbiome.
Rare disease research workflow using multilayer networks elucidates the molecular determinants of severity in Congenital Myasthenic Syndromes
Authors: Núñez-Carpintero Iker , O’Connor Emily , Rigau Maria , Bosio Mattia , Spendiff Sally , Azuma Yoshiteru , Topf Ana , Thompson Rachel , ’t Hoen Peter A.C. , Chamova Teodora , Tournev Ivailo , Guergueltcheva Velina , Laurie Steven , Beltran Sergi , Capella Salvador , Cirillo Davide , Lochmüller Hanns , Valencia Alfonso 
Published: January 2023

AbstractExploring the molecular basis of disease severity in rare disease scenarios is a challenging task provided the limitations on data availability. Causative genes have been described for Congenital Myasthenic Syndromes (CMS), a group of diverse minority neuromuscular junction (NMJ) disorders; yet a molecular explanation for the phenotypic severity differences remains unclear. Here, we present a workflow to explore the functional relationships between CMS causal genes and altered genes from each patient, based on multilayer network analysis of protein-protein interactions, pathways and metabolomics.Our results show that CMS severity can be ascribed to the personalized impairment of extracellular matrix components and postsynaptic modulators of acetylcholine receptor (AChR) clustering. We explore this in more detail for one of the proteins not previously associated with the NMJ, USH2A. Loss of the zebrafish USH2A ortholog revealed some effects on early movement and gross NMJ morphology.This work showcases how coupling multilayer network analysis with personalized -omics information provides molecular explanations to the varying severity of rare diseases; paving the way for sorting out similar cases in other rare diseases.
The effectiveness of pseudomagic traits in promoting premating isolation
Authors: Aubier Thomas G. , Bürger Reinhard , Servedio Maria R. 
Published: January 2023

AbstractUpon the secondary contact of populations, speciation with gene flow is greatly facilitated when the same pleiotropic loci are both subject to divergent ecological selection and induce non-random mating, leading to loci with this fortuitous combination of functions being referred to as “magic trait” loci. We use a population genetics model to examine whether “pseudomagic trait” complexes, composed of physically linked loci fulfilling these two functions, are as efficient in promoting premating isolation as magic traits. We specifically measure the evolution of choosiness, which controls the strength of assortative mating. We show that, surprisingly, pseudomagic trait complexes, and to a lesser extent also physically unlinked loci, can lead to the evolution of considerably stronger assortative mating preferences than do magic traits, provided polymorphism at the involved loci is maintained. This is because assortative mating preferences are generally favored when there is a risk of producing maladapted recombinants, as occurs with nonmagic trait complexes but not with magic traits (since pleiotropy precludes recombination). Contrary to current belief, magic traits may not be the most effective genetic architecture for promoting strong premating isolation. Distinguishing between magic traits and pseudomagic trait complexes is therefore important when inferring their role in premating isolation. This calls for further fine-scale genomic research on speciation genes.
Graph-pMHC: Graph Neural Network Approach to MHC Class II Peptide Presentation and Antibody Immunogenicity
Authors: Thrift William John , Perera Jason , Cohen Sivan , Lounsbury Nicolas W. , Gurung Hem , Rose Chris , Chen Jieming , Jhunjhunwala Suchit , Liu Kai 
Published: January 2023

AbstractAntigen presentation on MHC Class II (pMHCII presentation) plays an essential role in the adaptive immune response to extracellular pathogens and cancerous cells. But it can also reduce the efficacy of large-molecule drugs by triggering an anti-drug response. Significant progress has been made in pMHCII presentation modeling due to the collection of large-scale pMHC mass spectrometry datasets (ligandomes) and advances in deep machine learning. Here, we develop graph-pMHC, a graph neural network approach to predict pMHCII presentation. We derive adjacency matrices for pMHCII using Alphafold2-multimer, and address the peptide-MHC binding groove alignment problem with a simple graph enumeration strategy. We demonstrate that graph-pMHC dramatically outperforms methods with suboptimal inductive biases, such as the multilayer-perceptron-based NetMHCIIan-4.0 (+22.84% average precision). Finally, we create an antibody drug immunogenicity dataset from clinical trial data, and develop a method for measuring anti-antibody immunogenicity risk using pMHCII presentation models. In comparison with BioPhi’s Sapiens score, a deep learning based measure of the humanness of an antibody drug, our strategy achieves a 7.14% ROC AUC improvement in predicting antibody drug immunogenicity.
The mechanics of cephalic furrow formation in theDrosophilaembryo
Authors: Niloy Redowan A. , Holcomb Michael C. , Thomas Jeffrey H. , Blawzdziewicz Jerzy 
Published: January 2023

ABSTRACTCephalic furrow formation (CFF) is a major morphogenetic movement during gastrulation inDrosophila melanogasterembryos that gives rise to a deep, transitory epithelial invagination. Recent studies have identified the individual cell shape changes that drive the initiation and progression phases of CFF; however, the underlying mechanics of these changes are not yet well understood. During the progression phase, the furrow deepens as columnar cells from both the anterior and posterior directions fold inwards rotating by 90°. To analyze the mechanics of this process, we have developed an advanced 2D vertex model, which introduces multi-node representation of cellular membranes and allows us to capture the membrane curvature associated with pressure variation. Our investigations reveal some key mechanical features of CFF. As cells begin to roll over the cephalic furrow cleft, they become wedge-shaped as their apical cortices and overlying membranes expand, lateral cortices and overlying membranes release tension, internal pressures drop, and basal cortices and membranes contract. Cells then reverse the process by shortening apical cortices and membranes, increasing lateral tension, and causing internal pressures to rise. Since the basal membranes expand, the cells recover a rotated columnar shape at the end of this process. Interestingly, our findings indicate that the basal membranes may be passively reactive throughout the progression phase. We also find that the smooth rolling of cells over the cephalic furrow cleft necessitates that internalized cells provide a solid base through high membrane tensions and internal pressure levels, which allows transmission of tensile force that pulls new cells into the furrow. These results lead us to suggest that CFF may help establish a baseline tension across the apical surface of the embryo that would facilitate cellular coordination of other morphogenetic movements via mechanical stress feedback mechanisms.SIGNIFICANCEMechanical forces and stress feedback are essential for the development of morphology and structure in the embryo. Although great progress has been made in understanding the genetic control of patterning and cell fate, mechanical stress contributions are not as well understood. Mechanical analyses of the apical constrictions initiating ventral furrow formation and subsequent invagination dynamics inDrosophilahave shed considerable light on these processes; however, ventral furrow formation is only one of many morphogenetic movements. Cephalic furrow formation occurs simultaneously with ventral furrow formation, but its cell shape changes and invagination dynamics are radically different. This study shows that mechanical forces and feedback operating in cephalic furrow formation also differ considerably from those in ventral furrow, demonstrating a potentially wide array of mechanical processes in morphogenesis.
TCF4 mutations disrupt synaptic function through dysregulation of RIMBP2 in patient-derived cortical neurons
Authors: Davis Brittany A. , Chen Huei-Ying , Ye Zengyou , Ostlund Isaac , Tippani Madhavi , Das Debamitra , Sripathy Srinidhi Rao , Wang Yanhong , Martin Jacqueline M. , Shim Gina , Panchwagh Neel M. , Moses Rebecca L. , Farinelli Federica , Bohlen Joseph F. , Li Meijie , Luikart Bryan W. , Jaffe Andrew E. , Maher Brady J. 
Published: January 2023

AbstractGenetic variation in the transcription factor 4 (TCF4)gene is associated with risk for a variety of developmental and psychiatric conditions, which includes a syndromic form of ASD called Pitt Hopkins Syndrome (PTHS).TCF4encodes an activity-dependent transcription factor that is highly expressed during cortical development and in animal models is shown to regulate various aspects of neuronal development and function. However, our understanding of how disease-causing mutations in TCF4 confer pathophysiology in a human context is lacking. Here we show that cortical neurons derived from patients withTCF4mutations have deficits in spontaneous synaptic transmission, network excitability and homeostatic plasticity. Transcriptomic analysis indicates these phenotypes result from altered expression of genes involved in presynaptic neurotransmission and identifies the presynaptic binding protein, RIMBP2 as the most differentially expressed gene in PTHS neurons. Remarkably, TCF4-dependent deficits in spontaneous synaptic transmission and network excitability were rescued by increasing RIMBP2 expression in presynaptic neurons. Together, these results identify TCF4 as a critical transcriptional regulator of human synaptic development and plasticity and specifically identifies dysregulation of presynaptic function as an early pathophysiology in PTHS.
Novel genetically encoded tools for imaging or silencing neuropeptide release from presynaptic terminalsin vivo
Authors: Kim Dong-Il , Park Sekun , Ye Mao , Chen Jane Y. , Jhang Jinho , Hunker Avery C. , Zweifel Larry S. , Palmiter Richard D. , Han Sung 
Published: January 2023

SUMMARYNeurons produce and release neuropeptides to communicate with one another. Despite their profound impact on critical brain functions, circuit-based mechanisms of peptidergic transmission are poorly understood, primarily due to the lack of tools for monitoring and manipulating neuropeptide releasein vivo. Here, we report the development of two genetically encoded tools for investigating peptidergic transmission in behaving mice: a genetically encoded large dense core vesicle (LDCV) sensor that detects the neuropeptides release presynaptically, and a genetically encoded silencer that specifically degrades neuropeptides inside the LDCV. Monitoring and silencing peptidergic and glutamatergic transmissions from presynaptic terminals using our newly developed tools and existing genetic tools, respectively, reveal that neuropeptides, not glutamate, are the primary transmitter in encoding unconditioned stimulus during Pavlovian threat learning. These results show that our sensor and silencer for peptidergic transmission are reliable tools to investigate neuropeptidergic systems in awake behaving animals.