bluuebunny/crossref_metadata_2025_split huggingface dataset:
K29-linked unanchored polyubiquitin chains disrupt ribosome biogenesis and direct ribosomal proteins to the Intranuclear Quality control compartment (INQ)
Authors: Suresh Harsha Garadi , Bonneil Eric , Albert Benjamin , Dominique Carine , Costanzo Michael , Pons Carles , David Masinas Myra Paz , Shuteriqi Ermira , Shore David , Henras Anthony K. , Thibault Pierre , Boone Charles , Andrews Brenda J 
Published: May 2023

SummaryRibosome assembly requires precise coordination between the production and assembly of ribosomal components. Mutations in ribosomal proteins that inhibit the assembly process or ribosome function are often associated with Ribosomopathies, some of which are linked to defects in proteostasis. In this study, we examine the interplay between several yeast proteostasis enzymes, including deubiquitylases (DUBs), Ubp2 and Ubp14, and E3 ligases, Ufd4 and Hul5, and we explore their roles in the regulation of the cellular levels of K29-linked unanchored polyubiquitin (polyUb) chains. Accumulating K29-linked unanchored polyUb chains associate with maturing ribosomes to disrupt their assembly, activate the Ribosome assembly stress response (RASTR), and lead to the sequestration of ribosomal proteins at the Intranuclear Quality control compartment (INQ). These findings reveal the physiological relevance of INQ and provide insights into mechanisms of cellular toxicity associated with Ribosomopathies.
Deep immunological imprinting due to the ancestral spike in the current bivalent COVID-19 vaccine
Authors: Wang Qian , Guo Yicheng , Tam Anthony R. , Valdez Riccardo , Gordon Aubree , Liu Lihong , Ho David D. 
Published: May 2023

AbstractWith the aim of broadening immune responses against the evolving SARS-CoV-2 Omicron variants, bivalent COVID-19 mRNA vaccines that encode the ancestral and Omicron BA.5 spike proteins have been authorized for clinical use, supplanting the original monovalent counterpart in numerous countries. However, recent studies have demonstrated that administering either a monovalent or bivalent vaccine as a fourth vaccine dose results in similar neutralizing antibody titers against the latest Omicron subvariants, raising the possibility of immunological imprinting. Utilizing binding immunoassays, pseudotyped virus neutralization assays, and antigenic mapping, we investigated antibody responses from 72 participants who received three monovalent mRNA vaccine doses followed by either a bivalent or monovalent booster, or who experienced breakthrough infections with the BA.5 or BQ subvariant after vaccinations with an original monovalent vaccine. Compared to a monovalent booster, the bivalent booster did not yield noticeably higher binding titers to D614G, BA.5, and BQ.1.1 spike proteins, nor higher virus-neutralizing titers against SARS-CoV-2 variants including the predominant XBB.1.5 and the emergent XBB.1.16. However, sera from breakthrough infection cohorts neutralized Omicron subvariants significantly better. Multiple analyses of these results, including antigenic mapping, made clear that inclusion of the ancestral spike prevents the broadening of antibodies to the BA.5 component in the bivalent vaccine, thereby defeating its intended goal. Our findings suggest that the ancestral spike in the current bivalent COVID-19 vaccine is the cause of deep immunological imprinting. Its removal from future vaccine compositions is therefore strongly recommended.
Genome assembly and analysis ofLactuca virosa: implications for lettuce breeding
Authors: Xiong Wei , van Workum Dirk-Jan M. , Berke Lidija , Bakker Linda V. , Schijlen Elio , Becker Frank F.M. , van de Geest Henri , Peters Sander , Michelmore Richard , van Treuren Rob , Jeuken Marieke , Smit Sandra , Schranz M. Eric 
Published: May 2023

AbstractLettuce (Lactuca sativaL.) is a leafy vegetable crop with ongoing breeding efforts related to quality, resilience, and innovative production systems. Genetic variation of important traits in close relatives is necessary to meet lettuce breeding goals.Lactuca virosa(2x=2n=18), a wild relative assigned to the tertiary lettuce gene pool, has a much larger genome (3.7 Gbp) thanLactuca sativa(2.5 Gbp). It has been used in interspecific crosses and is a donor to modern crisphead lettuce cultivars. Here, we present ade novoreference assembly ofL. virosawith high continuity and complete gene space. This assembly facilitated comparisons to the genome ofL. sativaand to that of the wild speciesL. saligna, a representative of the secondary lettuce gene pool. To assess the diversity in gene content, we classified the genes of the threeLactucaspecies as core, accessory and unique. In addition, we identified three interspecific chromosomal inversions compared toL. sativa, which each may cause recombination suppression and thus hamper future introgression breeding. Using three-way comparisons in both reference-based and reference-free manners, we show that the proliferation of long-terminal repeat elements has driven the genome expansion ofL. virosa. Further, we performed a genome-wide comparison of immune genes, nucleotide-binding leucine-rich repeat, and receptor-like kinases amongLactucaspp. and indicate the evolutionary patterns and mechanisms behind their expansions. These genome analyses greatly facilitate the understanding of genetic variation inL. virosa, which is beneficial for the breeding of improved lettuce varieties.
Is there a latitudinal diversity gradient for symbiotic microbes? A case study with sensitive partridge peas
Authors: Harrison Tia L. , Parshuram Zoe A. , Frederickson Megan E. , Stinchcombe John R. 
Published: May 2023

AbstractMutualism is more prevalent in the tropics than temperate zones and is therefore expected to play an important role in generating and maintaining high species richness found at lower latitudes. However, results on the impact of mutualism on latitudinal diversity gradients are mixed, and few empirical studies sample both temperate and tropical regions. We investigated whether a latitudinal diversity gradient exists in the symbiotic microbial community associated with the legumeChamaecrista nictitans. We sampled bacteria DNA from nodules and the surrounding soil of plant roots across a latitudinal gradient (38.64 °N to 8.68 °N). Using 16S rRNA sequence data, we identified many non-rhizobial species withinC. nictitansnodules that cannot form nodules or fix nitrogen. Species richness increased towards lower latitudes in the non-rhizobial portion of the nodule community but not in the rhizobial community. The microbe community in the soil did not predict the non-rhizobia community inside nodules, indicating that host selection is important for structuring non-rhizobia communities in nodules. We next factorially manipulated the presence of three non-rhizobia strains in greenhouse experiments and found that co-inoculations of non-rhizobia strains with rhizobia had a marginal effect on nodule number and no effect on plant growth. Our results suggest that these non-rhizobia bacteria are likely commensals – species that benefit from associating with a host but are neutral for host fitness. Overall, our study suggests that temperateC. nictitansplants are more selective in their associations with the non-rhizobia community, potentially due to differences in soil nitrogen across latitude.
GARSA: An integrative pipeline for genome wide association studies and polygenic risk score inference in admixed human populations
Authors: Rossi Fernando P. N. , Patané José S. L. , de Souza Vinicius , Neyra Jennifer M. , Rosa Rogério S. , Krieger Jose E. , Teixeira Samantha K. 
Published: May 2023

AbstractGenome-wide association studies (GWAS) and polygenic risk scores (PRS) are multistep analytical tools to identify genetic variants and to assess their contribution to phenotypes/diseases. These analyses are evolving and becoming instrumental to understand the genetic architecture of complex phenotypes/diseases. Nevertheless, to date, there is no single solution incorporating all major steps related to those analyses combined with robust populational bias correction. Here, we describe a semi-automated pipeline unifying steps involved in GWAS and PRS including widely used software. Our pipeline handles quality control (QC), GWAS, and PRS steps, managing different types of input/output files. Furthermore, it includes robust bias correction steps, such as inference of kinship matrix with correction for population structure, use of principal component analysis (PCA) with detection and removal of outlier variant followed by re-projection of related individuals (if desired), generation of PCA figures that assist in setting the best number of principal components (PCs) for association analysis, availability of mixed models, use of recommended software for GWAS based on population size, and a Markov chain Monte Carlo (MCMC) method to estimate best set of PRS parameters. Finally, we tested GARSA pipeline in a family-based Brazilian admixed population and demonstrated that the corrections implemented indeed mitigate bias in downstream analysis. The pipeline can be implemented on personal or server-side environments.AvailabilityThe development version (open-source) is available inhttps://github.com/LGCM-OpenSource/GARSAContactFernando P. N. Rossi -fernando.rossi@hc.fm.usp.br; José S. L. Patané -jose.patane@hc.fm.usp.brSupplementary informationSupplementary tutorial.
A Bayesian Noisy Logic Model for Inference of Transcription Factor Activity from Single Cell and Bulk Transcriptomic Data
Authors: Arriojas Argenis , Patalano Susan , Macoska Jill , Zarringhalam Kourosh 
Published: May 2023

AbstractThe advent of high-throughput sequencing has made it possible to measure the expression of genes at relatively low cost. However, direct measurement of regulatory mechanisms, such as Transcription Factor (TF) activity is still not readily feasible in a high-throughput manner. Consequently, there is a need for computational approaches that can reliably estimate regulator activity from observable gene expression data. In this work, we present a noisy Boolean logic Bayesian model for TF activity inference from differential gene expression data and causal graphs. Our approach provides a flexible framework to incorporate biologically motivated TF-gene regulation logic models. Using simulations and controlled over-expression experiments in cell cultures, we demonstrate that our method can accurately identify TF activity. Moreover, we apply our method to bulk and single cell transcriptomics measurements to investigate transcriptional regulation of fibroblast phenotypic plasticity. Finally, to facilitate usage, we provide user-friendly software packages and a web-interface to query TF activity from user input differential gene expression data:https://umbibio.math.umb.edu/nlbayes/.Author SummaryNextGen RNA sequencing (RNA-Seq) has enabled simultaneous measurement of the expression level of all genes. Measurements can be done at the population level or single-cell resolution. However, direct measurement of regulatory mechanisms, such as Transcription Factor (TF) activity, is still not possible in a high-throughput manner. As such, there is a need for computational models to infer regulator activity from gene expression data. In this work, we introduce a Bayesian methodology that utilizes prior biological knowledge on bio-molecular interactions in conjunction with readily available gene expression measurements to estimate TF activity. The Bayesian model naturally incorporates biologically motivated combinatorial TF-gene interaction logic models and accounts for noise in gene expression data as well as prior knowledge. The method is accompanied by efficiently implemented R and Python software packages as well as a user-friendly web-based interface that allows users to upload their gene expression data and run queries on a TF-gene interaction network to identify and rank putative transcriptional regulators. This tool can be used for a wide range of applications, such as identification of TFs downstream of signaling events and environmental or molecular perturbations, the aberration in TF activity in diseases, and other studies with ‘case-control’ gene expression data.
Pulmonary Matrix Derived Hydrogels from Patients with Idiopathic Pulmonary Fibrosis Induce a Proinflammatory State in Lung FibroblastsIn Vitro
Authors: Fernandez Davila JG , Moore DW , Kim J , Khan JA , Singh AK , Lemma M , King CS , Nathan SD , Rodriguez LR , Grant GM , Moran JL 
Published: May 2023

ABSTRACTIdiopathic pulmonary fibrosis (IPF), one of the most common forms of interstitial lung disease, is a poorly understood, chronic, and often fatal fibroproliferative condition with only two FDA-approved medications. Understanding the pathobiology of the fibroblast in IPF is critical to evaluating and discovering novel therapeutics. Unfortunately, our ability to interrogate this biologyin vitrois greatly limited by the well-documented effects of tissue culture plastic on the fibroblast phenotype. Using a decellularized lung matrix derived from IPF patients, we generate three-dimensional (3D) hydrogels asin vitromodels of lung physiology and characterize the phenotype of fibroblasts seeded into the hydrogels. When cultured in our hydrogels, IPF fibroblasts display differential contractility compared to their normal counterparts, lose the classical myofibroblast marker α-smooth muscle actin, and increase expression of proinflammatory cytokines compared to fibroblasts seeded two-dimensionally (2D) on tissue culture dishes. We validate this proinflammatory state in fibroblast conditioned media studies with monocytes and monocyte-derived macrophages. These findings add to a growing understanding of the lung microenvironment effect on fibroblast phenotypes, shed light on the potential role of fibroblasts as immune signaling hubs during lung fibrosis, and suggest intervention in fibroblast-immune cell crosstalk as a possible novel therapeutic avenue.
Worth the weight: Sub-Pocket EXplorer (SubPEx), a weighted-ensemble method to enhance binding-pocket conformational sampling
Authors: Hellemann Erich , Durrant Jacob D. 
Published: May 2023

1.AbstractStructure-based virtual screening (VS) is an effective method for identifying potential small-molecule ligands, but traditional VS approaches consider only a single binding-pocket conformation. Consequently, they struggle to identify ligands that bind to alternate conformations. Ensemble docking helps address this issue by incorporating multiple conformations into the docking process, but it depends on methods that can thoroughly explore pocket flexibility. We here introduce Sub-Pocket EXplorer (SubPEx), an approach that uses weighted ensemble (WE) path sampling to accelerate binding-pocket sampling. As proof of principle, we apply SubPEx to three proteins relevant to drug discovery: heat shock protein 90, influenza neuraminidase, and yeast hexokinase 2. SubPEx is available free of charge without registration under the terms of the open-source MIT license:http://durrantlab.com/subpex/
Neural responses to reconstructed target pursuits
Authors: Ogawa Yuri , Nicholas Sarah , Thyselius Malin , Leibbrandt Richard , Nowotny Thomas , Knight James C. , Nordström Karin 
Published: May 2023

AbstractMany animals use motion vision information to control dynamic behaviors. Predatory animals, for example, show an exquisite ability to detect rapidly moving prey followed by pursuit and capture. Such target detection is not only used by predators but can also play an important role in conspecific interactions. Male hoverflies (Eristalis tenax), for example, vigorously defend their territories against conspecific intruders. Visual target detection is believed to be subserved by specialized target tuned neurons that are found in a range of species, including cats, zebrafish, and insects. However, how these target-tuned neurons respond to actual pursuit trajectories is currently not well understood. To redress his, we recorded extracellularly from target selective descending neurons (TSDNs) in maleEristalis tenaxhoverflies. We show that the neurons have dorso-frontal receptive fields, with a preferred direction up and away from the visual midline. We next reconstructed visual flow-fields as experienced during pursuits of artificial targets (black beads). We recorded TSDN responses to six reconstructed pursuits and found that each neuron responded consistently at remarkably specific time points, but that these time points differed between neurons. We compared the observed spike probability with the spike probability predicted from each neuron’s receptive field and size tuning, and found a correlation coefficient of 0.35. Interestingly, however, the overall response rate was low, with individual neurons responding to only a small part of each reconstructed pursuit. In contrast, the TSDN population responded to a substantially larger proportion of the pursuits (up to a median of 23%). This large variation between neurons could be useful if different neurons control different parts of the behavioral output.Significance statementDescending neurons constitute less than 1% of the nervous system, yet have to convey all requisite information from the brain to the body. They are therefore a crucial bottleneck in sensorimotor transformation. Descending target tuned neurons in male hoverflies (Eristalis tenax), for example, are believed to play a key role in territory defense and pursuit of conspecifics. However, this has not been tested using visual stimuli resembling reconstructed target pursuits. We here found that the observed neural responses to reconstructed pursuits are stronger than those predicted from responses to simpler stimuli. In addition, while the responses to simple stimuli suggested a homogenous population of neurons, the reconstructed pursuits showed important differences between individual neurons. Our data thus highlight the need for using more naturalistic stimuli when deciphering neural function.
Spatially-resolved single-cell atlas of ascidian endostyle provides insights into the origin of vertebrate pharyngeal organs
Authors: Jiang An , Han Kai , Wei Jiankai , Su Xiaoshan , Wang Rui , Zhang Wei , Liu Xiawei , Qiao Jinghan , Liu Penghui , Liu Qun , Zhang Jin , Zhang Nannan , Ge Yonghang , Zhuang Yuan , Yu Haiyan , Wang Shi , Chen Kai , Xu Xun , Yang Huanming , Fan Guangyi , Dong Bo 
Published: May 2023

AbstractThe pharynx is an endoderm innovation in deuterostome ancestors, the vertebrate descendent structure of which is a pharyngeal developmental organizer involving multi-germ layer and organ derivatives. However, the evolutionary origination of complicated pharynx organs in vertebrates is still largely unknown. Endostyle, a transitional pharyngeal organ exclusively in basal chordates provides an opportunity to reveal the origin of pharyngeal organs. Here, utilizing cutting-edged Stereo-seq and single-cell RNA-seq, we constructed the first spatially-resolved single-cell atlas in the endostyle of urochordate ascidianStyela clava, where the spatial location of Stereo-seq and high capture efficiency of single-cell RNA-seq complement each other and identified 23 highly differentiated cell types. We identified a previously overlooked hemolymphoid region (HLR), which harbors immune and blood cell clusters with enriched stemness capacities, illuminating a mixed rudiment and stem-cell niches for the blood and lymphoid system. More excitingly, we discovered a mechanical-sensitive hair cell candidate in zone 3 homologous to vertebrate acoustico-lateralis system, which was supported by the expression ofin situhybridization-verified inner ear-specific markers, includingPTPRQ,USH2A,WHRN, andADGRV1, ultracellular structure evidence and cross-species comparison. These results thoroughly renewed the comprehension of the basal-chordate pharynx and provides expressional evidence for multiplexed pharyngeal organ evolution.
Probing Conformational Landscapes of Binding and Allostery in the SARS-CoV-2 Omicron Variant Complexes Using Microsecond Atomistic Simulations and Perturbation-Based Profiling Approaches: Hidden Role of Omicron Mutations as Modulators of Allosteric Signaling and Epistatic Relationships
Authors: Verkhivker Gennady , Alshahrani Mohammed , Gupta Grace , Xiao Sian , Tao Peng 
Published: May 2023

AbstractIn this study, we systematically examine the conformational dynamics, binding and allosteric communications in the Omicron BA.1, BA.2, BA.3 and BA.4/BA.5 complexes with the ACE2 host receptor using molecular dynamics simulations and perturbation-based network profiling approaches. Microsecond atomistic simulations provided a detailed characterization of the conformational landscapes and revealed the increased thermodynamic stabilization of the BA.2 variant which is contrasted with the BA.4/BA.5 variants inducing a significant mobility of the complexes. Using ensemble-based mutational scanning of binding interactions, we identified binding affinity and structural stability hotspots in the Omicron complexes. Perturbation response scanning and network-based mutational profiling approaches probed the effect of the Omicron variants on allosteric communications. The results of this analysis revealed specific roles of Omicron mutations as “plastic and evolutionary adaptable” modulators of binding and allostery which are coupled to the major regulatory positions through interaction networks. Through perturbation network scanning of allosteric residue potentials in the Omicron variant complexes, which is performed in the background of the original strain, we identified that the key Omicron binding affinity hotspots N501Y and Q498R could mediate allosteric interactions and epistatic couplings. Our results suggested that the synergistic role of these hotspots in controlling stability, binding and allostery can enable for compensatory balance of fitness tradeoffs with conformationally and evolutionary adaptable immune-escape Omicron mutations. Through integrative computational approaches, this study provides a systematic analysis of the effects of Omicron mutations on thermodynamics, binding and allosteric signaling in the complexes with ACE2 receptor. The findings support a mechanism in which Omicron mutations can evolve to balance thermodynamic stability and conformational adaptability in order to ensure proper tradeoff between stability, binding and immune escape.