bluuebunny/crossref_metadata_2025_split huggingface dataset:
Conifers concentrate large numbers of NLR immune receptor genes on one chromosome
Authors: Woudstra Yannick , Tumas Hayley , van Ghelder Cyril , Hung Tin Hang , Ilska Joana J. , Girardi Sebastien , A’Hara Stuart , McLean Paul , Cottrell Joan , Bohlmann Joerg , Bousquet Jean , Birol Inanc , Woolliams John A. , MacKay John J. 
Published: October 2023

AbstractNucleotide-binding domain and Leucine-rich Repeat (NLR) immune receptor genes form a major line of defence in plants, acting in both pathogen recognition and resistance machinery activation. NLRs are reported to form large gene clusters in limber pine (Pinus flexilis) but it is unknown how widespread this genomic architecture may be among the extant species of conifers (Pinophyta). We used comparative genomic analyses to assess patterns in the abundance, diversity and genomic distribution of NLR genes. Chromosome-level whole genome assemblies and high-density linkage maps in the Pinaceae, Cupressaceae, Taxaceae and other gymnosperms were scanned for NLR genes using existing and customised pipelines. Discovered genes were mapped across chromosomes and linkage groups, and analysed phylogenetically for evolutionary history. Conifer genomes are characterised by dense clusters of NLR genes, highly localised on one chromosome. These clusters are rich in TNL-encoding genes, which seem to have formed through multiple tandem duplication events. In contrast to angiosperms and non-coniferous gymnosperms, genomic clustering of NLR genes is ubiquitous in conifers. NLR-dense genomic regions are likely to influence a large part of the plant’s resistance, informing our understanding of adaptation to biotic stress and the development of genetic resources through breeding.Plain language summaryNLR immune receptor genes are important in pest, disease and drought resistance of plants. In the giga-genomes of conifers, they concentrate on very small chromosomal regions. These regions act as important reservoirs for NLR diversity and can be used in breeding to improve the resilience of conifer trees.
Assessing nanobody interaction with SARS-CoV-2 Nsp9
Authors: Esposito Gennaro , Hunashal Yamanappa , Percipalle Mathias , Fogolari Federico , Venit Tomas , Leonchiks Ainars , Gunsalus Kristin C. , Piano Fabio , Percipalle Piergiorgio 
Published: October 2023

AbstractThe interaction between SARS-CoV-2 non-structural protein Nsp9 and the nanobody 2NSP90 was investigated by NMR spectroscopy using the paramagnetic perturbation methodology PENELOP (Paramagnetic Equilibrium vs Nonequilibrium magnetization Enhancement or LOss Perturbation). The Nsp9 monomer is an essential component of the replication and transcription complex (RTC) that reproduces the viral gRNA for subsequent propagation. Therefore preventing Nsp9 recruitment in RTC would represent an efficient antiviral strategy that could be applied to different coronaviruses, given the Nsp9 relative invariance. The NMR results were consistent with a previous characterization suggesting a 4:4 Nsp9-to-nanobody stoichiometry with the occurrence of two epitope pairs on each of the Nsp9 units that establish the inter-dimer contacts of Nsp9 tetramer. The oligomerization state of Nsp9 was also analyzed by molecular dynamics simulations and both dimers and tetramers resulted plausible. However a different distribution of the mapped epitopes on the tetramer surface with respect to the former 4:4 complex could also be possible, as well as different stoichiometries of the Nsp9-nanobody assemblies such as the 2:2 stoichiometry suggested by the recent crystal structure of the Nsp9 complex with 2NSP23 (PDB ID: 8dqu), a nanobody exhibiting essentially the same affinity as 2NSP90. The experimental NMR evidence, however, ruled out the occurrence in liquid state of the relevant Nsp9 conformational change observed in the same crystal structure.
A public resource of single cell transcriptomes and multiscale networks from persons with and without Alzheimer’s disease
Authors: Wang Qi , Antone Jerry , Alsop Eric , Reiman Rebecca , Funk Cory , Bendl Jaroslav , Dudley Joel T , Liang Winnie S , Karr Timothy L , Roussos Panos , Bennett David A , De Jager Philip L , Serrano Geidy E , Beach Thomas G , Keuren-Jensen Kendall Van , Mastroeni Diego , Reiman Eric M , Readhead Benjamin P 
Published: October 2023

AbstractThe emergence of technologies that can support high-throughput profiling of single cell transcriptomes offers to revolutionize the study of brain tissue from persons with and without Alzheimer’s disease (AD). Integration of these data with additional complementary multiomics data such as genetics, proteomics and clinical data provides powerful opportunities to link observed cell subpopulations and molecular network features within a broader disease-relevant context. We report here single nucleus RNA sequencing (snRNA-seq) profiles generated from superior frontal gyrus cortical tissue samples from 101 exceptionally well characterized, aged subjects from the Banner Brain and Body Donation Program in combination with whole genome sequences. We report findings that link common AD risk variants withCR1expression in oligodendrocytes as well as alterations in peripheral hematological lab parameters, with these observations replicated in an independent, prospective cohort study of ageing and dementia. We also observed an AD-associated CD83(+) microglial subtype with unique molecular networks that encompass many known regulators of AD-relevant microglial biology, and which are associated with immunoglobulin IgG4 production in the transverse colon. These findings illustrate the power of multi-tissue molecular profiling to contextualize snRNA-seq brain transcriptomics and reveal novel disease biology. The transcriptomic, genetic, phenotypic, and network data resources described within this study are available for access and utilization by the scientific community.
Presynaptic inhibition selectively suppresses leg proprioception in behavingDrosophila
Authors: Dallmann Chris J. , Luo Yichen , Agrawal Sweta , Chou Grant M. , Cook Andrew , Brunton Bingni W. , Tuthill John C. 
Published: October 2023

SummaryControlling arms and legs requires feedback from proprioceptive sensory neurons that detect joint position and movement. Proprioceptive feedback must be tuned for different behavioral contexts, but the underlying circuit mechanisms remain poorly understood. Using calcium imaging in behavingDrosophila, we find that the axons of position-encoding leg proprioceptors are active across behaviors, whereas the axons of movement-encoding leg proprioceptors are suppressed during walking and grooming. Using connectomics, we identify a specific class of interneurons that provide GABAergic presynaptic inhibition to the axons of movement-encoding proprioceptors. The predominant synaptic inputs to these interneurons are descending neurons, suggesting they are driven by predictions of leg movement originating in the brain. Calcium imaging from both the interneurons and their descending inputs confirmed that their activity is correlated with self-generated but not passive leg movements. Overall, our findings elucidate a neural circuit for suppressing specific proprioceptive feedback signals during self-generated movements.
Cellular rules underlying psychedelic control of prefrontal pyramidal neurons
Authors: Ekins Tyler G , Brooks Isla , Kailasa Sameer , Rybicki-Kler Chloe , Jedrasiak-Cape Izabela , Donoho Ethan , Mashour George A. , Rech Jason , Ahmed Omar J 
Published: October 2023

ABSTRACTClassical psychedelic drugs are thought to increase excitability of pyramidal cells in prefrontal cortex via activation of serotonin 2Areceptors (5-HT2ARs). Here, we instead find that multiple classes of psychedelics dose-dependently suppress intrinsic excitability of pyramidal neurons, and that extracellular delivery of psychedelics decreases excitability significantly more than intracellular delivery. A previously unknown mechanism underlies this psychedelic drug action: enhancement of ubiquitously expressed potassium “M-current” channels that is independent of 5-HT2R activation. Using machine-learning-based data assimilation models, we show that M-current activation interacts with previously described mechanisms to dramatically reduce intrinsic excitability and shorten working memory timespan. Thus, psychedelic drugs suppress intrinsic excitability by modulating ion channels that are expressed throughout the brain, potentially triggering homeostatic adjustments that can contribute to widespread therapeutic benefits.
Multilevel gene expression changes in lineages containing adaptive copy number variants
Authors: Spealman Pieter , de Santana Carolina , De Titir , Gresham David 
Published: October 2023

AbstractCopy-number variants (CNVs) are an important class of recurrent variants that mediate adaptive evolution. While CNVs can increase the relative fitness of the organism, they can also incur a cost. We previously evolved populations ofSaccharomyces cerevisiaeover hundreds of generations in glutamine-limited (Gln-) chemostats and observed the recurrent evolution of CNVs at theGAP1locus. To understand the role that expression plays in adaptation, both in relation to the adaptation of the organism to the selective condition, and as a consequence of the CNV, we measured the transcriptome, translatome, and proteome of 4 strains of evolved yeast, each with a unique CNV, and their ancestor in Gln-conditions. We find CNV-amplified genes correlate with higher RNA abundance; however, this effect is reduced at the level of the proteome, consistent with post-transcriptional dosage compensation. By normalizing each level of expression by the abundance of the preceding step we were able to identify widespread divergence in the efficiency of each step in the gene in the efficiency of each step in gene expression. Genes with significantly different translational efficiency were enriched for potential regulatory mechanisms including either upstream open reading frames, RNA binding sites for SSD1, or both. Genes with lower protein expression efficiency were enriched for genes encoding proteins in protein complexes. Taken together, our study reveals widespread changes in gene expression at multiple regulatory levels in lineages containing adaptive CNVs highlighting the diverse ways in which adaptive evolution shapes gene expression.
A Novel Semi-automated Proofreading and Mesh Error Detection Pipeline for Neuron Extension
Authors: Joyce Justin , Chalavadi Rupasri , Chan Joey , Tanna Sheel , Xenes Daniel , Kuo Nathanael , Rose Victoria , Matelsky Jordan , Kitchell Lindsey , Bishop Caitlyn , Rivlin Patricia K. , Villafañe-Delgado Marisel , Wester Brock 
Published: October 2023

AbstractThe immense scale and complexity of neuronal electron microscopy (EM) datasets pose significant challenges in data processing, validation, and interpretation, necessitating the development of efficient, automated, and scalable error-detection methodologies. This paper proposes a novel approach that employs mesh processing techniques to identify potential error locations near neuronal tips. Error detection at tips is a particularly important challenge since these errors usually indicate that many synapses are falsely split from their parent neuron, injuring the integrity of the connectomic reconstruction. Additionally, we draw implications and results from an implementation of this error detection in a semi-automated proofreading pipeline. Manual proofreading is a laborious, costly, and currently necessary method for identifying the errors in the machine learning based segmentation of neural tissue. This approach streamlines the process of proofreading by systematically highlighting areas likely to contain inaccuracies and guiding proofreaders towards potential continuations, accelerating the rate at which errors are corrected.
Staphylococcal and Non-typhoidalSalmonellainfection statuses in non-human mammals: A potential source of zoonoses in the Greater Accra region of Ghana
Authors: Amoah Linda Ama Owusuaa , Ameade Evans Paul Kwame , Yeboah-Ofori Benjamin , Sampane-Donkor Eric , Bimi Langbong 
Published: October 2023

AbstractBackgroundBacterial zoonoses are readily transmitted from animals to humans and are thrice more likely to lead to emerging or re-emerging diseases. In Ghana, there is a paucity of animal-related bacterial infection surveillance data, significantly affecting how such diseases are accurately targeted for prevention or control. This study sought to investigate the prevalence of two important bacterial infections in some common animals found in two human-dominated landscapes and ascertain if their prevalence was of imminent public health concern. In most Ghanaian communities, dogs, cats and rodents are non-human mammals that are frequently in contact with humans. As such, they were targeted during this cross-sectional study.MethodsBiological samples collected from animals in households and veterinary institutions were processed using molecular techniques targetingStaphylococcusand Non-typhoidalSalmonellaspecies. Additionally, medical records were sourced from three (3) major health institutions to determine if cases of bacterial zoonoses were of imminent concern.ResultsOverall, the prevalence of staphylococcal and Non-typhoidalSalmonellainfections were 72.5% and 22.8%, respectively. More animals from the urban areas tested positive for Staphylococcal (χ2=5.721;p=0.017) and Non-typhoidalSalmonella(χ2=16.151;p< 0.001) infections compared to those from the peri-urban areas. The medical records also revealed that relatively higher cases of staphylococcal infections were reported within three years (2018-2020), although no significant differences were observed between the urban and peri-urban areas.ConclusionThe high prevalence of staphylococcal infections in animals and the high number of hospital cases suggest increased exposure to this bacteria and a higher risk of persons residing in these areas to bacterial zoonoses. Data from the study also suggest that rodents are actively and inactively maintaining the cycle of these two bacterial species and as such, a source of concern. Findings underscore the need for active surveillance of bacterial species with zoonotic potential in non-human mammals regularly found in communities, which is fundamental to developing appropriate disease control strategies.
Inhibitory actions of melanin-concentrating hormone in the lateral septum
Authors: Payant Mikayla A , Spencer C Duncan , Chee Melissa J 
Published: October 2023

AbstractMelanin-concentrating hormone (MCH) neurons can coexpress several neuropeptides or neurotransmitters and send widespread projections throughout the brain. Notably, there is a dense cluster of nerve terminals from MCH neurons in the lateral septum (LS) that innervate LS cells by glutamate release. The LS is also a key region integrating stress- and anxiety-like behaviours that are also emerging roles of MCH neurons. However, it is not known if the MCH peptide acts within the LS or whether MCH target sites are localized. We analysed the projections from MCH neurons in male and female mice anteroposteriorly throughout the LS and found spatial overlap between the distribution pattern of MCH-immunoreactive (MCH-ir) fibers with MCH receptorMchr1mRNA hybridization or MCHR1-ir cells. This overlap was most prominent along the ventral and lateral border of the rostral part of the LS (LSr). Most MCHR1-labeled LS neurons laid adjacent to passing MCH-ir fibers, but some MCH-ir varicosities directly contacted the soma or cilium of MCHR1-labeled LS neurons. We thus performed whole-cell patch-clamp recordings from MCHR1-rich LSr regions to determine if and how LS cells respond to MCH. Bath application of MCH to acute brain slices activated a bicuculline-sensitive chloride current that directly hyperpolarized LS cells. This MCH-mediated hyperpolarization was blocked by calphostin C and suggested that the inhibitory actions of MCH were mediated by protein kinase C-dependent activation of GABAAreceptors. Taken together, these findings defined potential hotspots within the LS that may elucidate the contributions of MCH to stress- or anxiety-related feeding behaviours.Key pointsRESEARCH QUESTION.Melanin-concentrating hormone (MCH) neurons have dense nerve terminals within the lateral septum (LS), a key region underlying stress- and anxiety-like behaviours that are emerging roles of the MCH system, but it is not known if the LS is a MCH target site.NEUROANATOMY.We found spatial overlap between MCH-immunoreactive fibers,Mchr1mRNA, and MCHR1 protein expression especially along the lateral border of the LS.ELECTROPHYSIOLOGY.Within MCHR1-rich regions, MCH directly inhibited LS cells by increasing a chloride conductance in a protein kinase C-dependent manner.SIGNIFICANCE.Electrophysiological MCH effects in brain slices have been elusive and even fewer have described the mechanisms of MCH action. Our findings demonstrated, to our knowledge, the first description of MCHR1 Gq-coupling in brain slices, which was previously predicted in cell or primary culture models only. Together, these findings defined hotspots and mechanistic underpinnings for MCH effects such as in stress- and anxiety-related behaviours.
Architecture and activation of human muscle phosphorylase kinase
Authors: Yang Xiaoke , Zhu Mingqi , Lu Xue , Wang Yuxin , Xiao Junyu 
Published: October 2023

AbstractThe study of phosphorylase kinase (PhK)-regulated glycogen metabolism has contributed to the fundamental understanding of protein phosphorylation. Here we present the high-resolution cryo-electron microscopy structures of human muscle PhK. The 1.3-megadalton PhK α4β4γ4δ4hexadecamer consists of a tetramer of tetramer, wherein four αβγδ modules are connected by the central β4scaffold. The α- and β-subunits possess glucoamylase-like domains, but exhibit no detectable enzyme activities. The α-subunit serves as a bridge between the β-subunit and the γδ subcomplex, and facilitates the γ-subunit to adopt an autoinhibited state. Ca2+-free calmodulin (δ-subunit) binds to the γ-subunit in a compact conformation. Upon binding of Ca2+, a conformational change occurs, allowing for the de-inhibition of the γ-subunit through a spring-loaded mechanism. We also reveal an ADP-binding pocket in the β-subunit, which plays a role in allosterically enhancing PhK activity. These results provide unprecedented molecular insights of this important kinase complex.
Master transcription factor binding sites constitute the core of early replication control elements
Authors: Turner Jesse L. , Hinojosa-Gonzalez Laura , Sasaki Takayo , Uchino Satoshi , Vouzas Athanasios , Soto Mariella S. , Chakraborty Abhijit , Alexander Karen E. , Fitch Cheryl A. , Brown Amber N. , Ay Ferhat , Gilbert David M. 
Published: October 2023

ABSTRACTEukaryotic genomes replicate in a defined temporal order called the replication timing (RT) program. RT is developmentally regulated with potential to drive cell fate transitions, but mechanisms controlling RT remain elusive. We previously identified “Early Replication Control Elements” (ERCEs) necessary for early RT, domain-wide transcription, 3D chromatin architecture and compartmentalization in mouse embryonic stem cells (mESCs) but, deletions identifying ERCEs were large and encompassed many putative regulatory elements. Here, we show that ERCEs are compound elements whose RT activity can largely be accounted for by multiple sites of diverse master transcription factor binding (subERCEs), distinguished from other such sites by their long-range interactions. While deletion of subERCEs had large effects on both transcription and RT, deleting transcription start sites eliminated nearly all transcription with moderate effects on RT. Our results suggest a model in which subERCEs respond to diverse master transcription factors by functioning both as transcription enhancers and as elements that organize chromatin domains structurally and support early RT, potentially providing a feed-forward loop to drive robust epigenomic change during cell fate transitions.
Rare Genomic Copy Number Variants Implicate New Candidate Genes for Bicuspid Aortic Valve
Authors: Carlisle Steven G. , Albasha Hasan , Michelena Hector , Sabate-Rotes Anna , Bianco Lisa , De Backer Julie , Mosquera Laura Muiño , Yetman Anji T. , Bissell Malenka M , Andreassi Maria Grazia , Foffa Ilenia , Hui Dawn S. , Caffarelli Anthony , Kim Yuli Y. , Guo Dong-Chuan , Citro Rodolfo , De Marco Margot , Tretter Justin T. , McBride Kim L. ,   EBAV Investigators,   BAVCon Investigators, Milewicz Dianna M. , Body Simon C. , Prakash Siddharth K. 
Published: October 2023

AbstractBicuspid aortic valve (BAV), the most common congenital heart defect, is a major cause of aortic valve disease requiring valve interventions and thoracic aortic aneurysms predisposing to acute aortic dissections. The spectrum of BAV ranges from early onset valve and aortic complications (EBAV) to sporadic late onset disease. Rare genomic copy number variants (CNVs) have previously been implicated in the development of BAV and thoracic aortic aneurysms. We determined the frequency and gene content of rare CNVs in EBAV probands (n = 272) using genome-wide SNP microarray analysis and three complementary CNV detection algorithms (cnvPartition, PennCNV, and QuantiSNP). Unselected control genotypes from the Database of Genotypes and Phenotypes were analyzed using identical methods. We filtered the data to select large genic CNVs that were detected by multiple algorithms. Findings were replicated in cohorts with late onset sporadic disease (n = 5040). We identified 34 large and rare (< 1:1000 in controls) CNVs in EBAV probands. The burden of CNVs intersecting with genes known to cause BAV when mutated was increased in case-control analysis. CNVs intersecting withGATA4andDSCAMwere enriched in cases, recurrent in other datasets, and segregated with disease in families. In total, we identified potentially pathogenic CNVs in 8% of EBAV cases, implicating alterations of candidate genes at these loci in the pathogenesis of BAV.Author SummaryBicuspid aortic valve (BAV) is the most common form of congenital heart disease and can lead to long-term complications such as aortic stenosis, aortic regurgitation, or thoracic aortic aneurysms. Most BAV-related complications arise in late adulthood, but 10-15% of individuals with BAV develop early onset complications before age 30. Copy number variants (CNVs) are genomic structural variations that have been previously implicated in some types of congenital heart disease, including BAV. Here we demonstrate that individuals with early onset complications of BAV are enriched for specific rare CNVs compared to individuals with late-onset BAV disease. We also describe novel CNVs involvingDSCAM, a gene on chromosome 21 that has not previously been associated with the development of BAV. These results may lead to improved risk stratification and targeted therapies for BAV patients.