bluuebunny/crossref_metadata_2025_split huggingface dataset:
The molecular basis of parental conflict driven regulation of endosperm cellularization
Authors: Butel N. , Qiu Y. , Xu W. , Santos-González J. , Köhler C. 
Published: June 2023

AbstractThe endosperm is a seed tissue supporting embryo growth, similar to the placenta in mammals. It originates after fertilization of the maternal central cell by one of the paternal sperm cells. In the early stages ofArabidopsis thalianaseed development, nuclei divisions in the endosperm are not followed by cellularization. After a defined number of mitotic cycles, the endosperm cellularizes and stops dividing. The timing of endosperm cellularization impacts on final seed size and is differentially controlled by maternal and paternal genome contributions. While increased maternal genome dosage causes early endosperm cellularization and the formation of small seeds, the opposite is caused by increased paternal genome dosage. The parental factors controlling the differential timing of endosperm cellularization remain largely unexplored. Here, we show that a family of maternally expressed auxin response factors (ARFs) promotes endosperm cellularization and regulates final seed size.One-Sentence SummaryEndosperm cellularization is under antagonistic parental control that converges on Auxin Response Factors.
Modeling the motion of disease-associated KIF1A heterodimers
Authors: Kita Tomoki , Sasaki Kazuo , Niwa Shinsuke 
Published: June 2023

ABSTRACTKIF1A is a member of the kinesin-3 family motor protein that transports synaptic vesicle precursors in axons. Mutations in theKif1agene cause neuronal diseases. Most patients are heterozygous and have both mutated and intact KIF1A alleles, suggesting that heterodimers composed of wild-type KIF1A and mutant KIF1A are likely involved in pathogenesis. In this study, we propose mathematical models to describe the motility of KIF1A heterodimers composed of wild-type KIF1A and mutant KIF1A. Our models precisely describe run length, run time, and velocity of KIF1A heterodimers using a few parameters obtained from two homodimers. The independent head model is a simple hand-over-hand model in which stepping and detachment rates from a microtubule of each head are identical to those in the respective homodimers. Although the velocities of heterodimers expected from the independent head model were in good agreement with the experimental results, this model underestimated the run lengths and run times of some heterodimeric motors. To address this discrepancy, we propose the coordinated head model, in which we hypothesize a tethered head, in addition to a microtubule-binding head, contributes to microtubule binding in a vulnerable one-head-bound state. The run lengths and run times of the KIF1A heterodimers predicted by the coordinated head model matched well with experimental results, suggesting a possibility that the tethered head affects the microtubule binding of KIF1A. Our models provide insights into how each head contributes to the processive movement of KIF1A and can be used to estimate motile parameters of KIF1A heterodimers.SIGNIFICANCEKIF1A is responsible for transporting synaptic vesicle precursors in axons. KIF1A mutations are associated with neurodegener-ative diseases. Most of these mutations are de novo and autosomal dominant, suggesting that half of the motors in patients are heterodimers composed of wild-type and mutant KIF1A. However, reliable theoretical models to explain the behavior of heterodimeric motors are lacking. In this study, we obtained exact analytical solutions to describe run length, run time, and velocity of heterodimeric motors which move in a hand-over-hand fashion. Our models provide valuable tools for quantitatively understanding the impact of heterodimerization with mutant KIF1A and the cooperative behavior of KIF1A dimers.
C9orf72 polyPR directly binds to various nuclear transport components
Authors: Jafarinia Hamidreza , Van der Giessen Erik , Onck Patrick R. 
Published: June 2023

AbstractThe disruption of nucleocytoplasmic transport (NCT) is an important mechanism in neurodegenerative diseases. In the case of C9orf72-ALS, trafficking of macromolecules through the nuclear pore complex (NPC) might get frustrated by the binding of C9orf72-translated arginine-containing dipeptide repeat proteins (R-DPRs) to the Kapβ family of nuclear transport receptors. Beside Kapβs, several other types of transport components have been linked to NCT impairments in R-DPRs expressed cells, but the molecular origin of these observations has not been clarified. Here, we adopt a coarse-grained molecular dynamics model at amino-acid resolution to study the direct interaction between polyPR, the most toxic DPR, and various nuclear transport components to elucidate the binding mechanisms and provide a complete picture of potential polyPR-mediated NCT defects. We found polyPR to directly bind to several isoforms of the Impα family, CAS (the specific exporter of Impα) and RanGAP. We observe no binding between polyPR and Ran. Longer polyPRs at lower salt concentrations also make contact with RanGEF and NTF2. Analyzing the polyPR contact sites on the transport components reveals that polyPR potentially interferes with RanGTP/RanGDP binding, with nuclear localization signal (NLS)-containing cargoes (cargo-NLS) binding to Impα, with cargo-NLS release from Impα, and with Impα export from the nucleus. The abundance of polyPR binding sites on multiple transport components combined with the inherent polyPR length dependence makes direct polyPR interference of NCT a potential mechanistic pathway of C9orf72 toxicity.
Unveiling the signaling network of FLT3-ITD AML improves drug sensitivity prediction
Authors: Latini Sara , Venafra Veronica , Massacci Giorgia , Bica Valeria , Graziosi Simone , Pugliese Giusj Monia , Iannuccelli Marta , Frioni Filippo , Minnella Gessica , Marra John Donald , Chiusolo Patrizia , Pepe Gerardo , Helmer-Citterich Manuela , Mougiakakos Dimitrios , Boettcher Martin , Fischer Thomas , Perfetto Livia , Sacco Francesca 
Published: June 2023

SummaryCurrently, the identification of patient-specific therapies in cancer is mainly informed by personalized genomic analysis. In the setting of acute myeloid leukemia (AML), patient-drug treatment matching fails in a subset of patients harboring atypical internal tandem duplications (ITDs) in the tyrosine kinase domain of the FLT3 gene. To address this unmet medical need, here we develop a systems-based strategy that integrates multiparametric analysis of crucial signaling pathways, patient-specific genomic and transcriptomic data with a prior-knowledge signaling network using a Boolean-based formalism. By this approach, we derive personalized predictive models describing the signaling landscape of AML FLT3-ITD positive cell lines and patients. These models enable us to derive mechanistic insight into drug resistance mechanisms and suggest novel opportunities for combinatorial treatments. Interestingly, our analysis reveals that the JNK kinase pathway plays a crucial role in the tyrosine kinase inhibitor response of FLT3-ITD cells through cell cycle regulation. Finally, our work shows that patient-specific logic models have the potential to inform precision medicine approaches.
Reorganization of the Flagellum Scaffolding Induces a Sperm Standstill During Fertilization
Authors: Jabloñski Martina , Luque Guillermina M. , Gómez-Elías Matías D. , Sanchez-Cardenas Claudia , Xu Xinran , de la Vega-Beltran Jose Luis , Corkidi Gabriel , Linares Alejandro , Abonza Amaro Victor X. , Arenas-Hernandez Aquetzalli , Del Pilar Ramos-Godinez María , López-Saavedra Alejandro , Krapf Dario , Krapf Diego , Darszon Alberto , Guerrero Adan , Buffone Mariano G. 
Published: June 2023

AbstractMammalian sperm delve into the female reproductive tract to fertilize the female gamete. The available information about how sperm regulate their motility during the final journey to the fertilization site is extremely limited. In this work, we investigated the structural and functional changes in the sperm flagellum after AE and during the interaction with the eggs. The evidence demonstrates that the double helix actin network surrounding the mitochondrial sheath of the midpiece undergoes structural changes prior to the motility cessation. This structural modification is accompanied by a decrease in diameter of the midpiece and is driven by intracellular calcium changes that occur concomitant with a reorganization of the actin helicoidal cortex. Midpiece contraction occurs in a subset of cells that undergo AE, live-cell imaging during in vitro fertilization showed that the midpiece contraction is required for motility cessation after fusion is initiated. These findings provide the first evidence of the F-actin network’s role in regulating sperm motility, adapting its function to meet specific cellular requirements during fertilization, and highlighting the broader significance of understanding sperm motility.Significant statementIn this work, we demonstrate that the helical structure of polymerized actin in the flagellum undergoes a rearrangement at the time of sperm-egg fusion. This process is driven by intracellular calcium and promotes a decrease in the sperm midpiece diameter as well as the arrest in motility, which is observed after the fusion process is initiated.
The impact of non-lineage defining mutations in the structural stability for variants of concern of SARS-CoV-2
Authors: Martins Yasmmin , da Silva Ronaldo Francisco 
Published: June 2023

AbstractMotivationThe identification of the most important mutations, that lead to a structural and functional change in a highly transmissible virus variants, is essential to understand the impacts and the possible chances of vaccine and antibody escape. Strategies to rapidly associate mutations to functional and conformational properties are needed to rapidly analyze mutations in proteins and their impacts in antibodies and human binding proteins.ResultsComparative analysis showed the main structural characteristics of the essential mutations found for each variant of concern in relation to the reference proteins. The paper presented a series of methodologies to track and associate conformational changes and the impacts promoted by the mutations.Contactyasmmin.c.martins@gmail.com.brSupplementary informationSupplementary data are available atBioinformaticsonline.
Unraveling the mechanisms of PAMless DNA interrogation by SpRY Cas9
Authors: Hibshman Grace N. , Bravo Jack P. K. , Zhang Hongshan , Dangerfield Tyler L. , Finkelstein Ilya J. , Johnson Kenneth A. , Taylor David W. 
Published: June 2023

AbstractCRISPR-Cas9 is a powerful tool for genome editing, but the strict requirement for an “NGG” protospacer-adjacent motif (PAM) sequence immediately adjacent to the DNA target limits the number of editable genes. To overcome the PAM requirement, a recently developed Cas9 variant, called SpRY-Cas9 was engineered to be “PAMless” (1, 2). However, the molecular mechanisms of how SpRY can recognize all potential PAM sequences and still accurately identify DNA targets have not been investigated. Here, we combined enzyme kinetics, cryo-EM, and single-molecule imaging to determine how SpRY interrogates DNA and recognizes target sites for cleavage. Divergent PAM sequences can be accommodated through conformational flexibility within the PAM-interacting region of SpRY, which facilitates tight binding to off-target DNA sequences. Once SpRY correctly identifies a target site, nuclease activation occurs ∼1,000-fold slower than forStreptococcus pyogenesCas9, enabling us to directly visualize multiple on-pathway intermediate states. Insights gained from our intermediate structures prompted rationally designed mutants with improved DNA cleavage efficiency. Our findings shed light on the molecular mechanisms of PAMless genome editing with SpRY and provide a framework for the design of future genome editing tools with improved versatility, precision, and efficiency.
Mitochondrial genome fragmentation is correlated with increased rates of molecular evolution
Authors: Najer Tomáš , Doña Jorge , Buček Aleš , Sweet Andrew D. , Sychra Oldřich , Johnson Kevin P. 
Published: June 2023

AbstractAnimal mitochondrial genomes (mitogenomes) typically exhibit a highly conserved gene content and organisation, with genes encoded on a single circular chromosome. However, many species of parasitic lice (Insecta: Phthiraptera) are notable exceptions, having mitogenomes fragmented into multiple circular chromosomes. To understand the process of mitogenome fragmentation, we conducted a large-scale genomic study of a major group of lice, Amblycera, with extensive taxon sampling. Analyses of the evolution of mitogenome structure across a phylogenomic tree of 90 samples from 53 genera, revealed evidence for multiple independent origins of mitogenome fragmentation, some inferred to have occurred less than five million years ago. We leveraged these many independent origins of fragmentation to compare the rates of DNA substitution and gene rearrangement, specifically contrasting branches with fragmented and non-fragmented mitogenomes. We found that lineages with fragmented mitochondrial genomes had significantly higher rates of mitochondrial sequence evolution. In addition, lineages with fragmented mitochondrial genomes were more likely to have mitogenome gene rearrangements than those with single-chromosome mitochondrial genomes. By combining phylogenomics and mitochondrial genomics we provide a detailed portrait of mitogenome evolution across this group of insects with a remarkably unstable mitogenome structure, identifying processes of molecular evolution that are correlated with mitogenome fragmentation.Author SummaryMitochondria are organelles that play a key role in providing energy to cells essential for life. The structure of the mitochondrial genome is conserved across most animal groups, being a single circular chromosome containing 37 genes. Deviations from this structure are typically detrimental and associated with some human diseases. However, in very few animal groups, the mitochondrial genome is fragmented into multiple circular chromsomes. In one group of insects, parasitic lice, fragmentation varies among species, with some having a complete circular genome and others having their mitochondrial genome fragmented in two or more smaller chromosomes. Here, we use whole genome sequencing reads to analyze an unprecedented number of species from a diverse group of lice (Amblycera) that exhibits both single-chromosome and fragmented mitochondrial genomes to understand how this fragmentation evolved. We found that fragmentation evolved many times independently in this group and this fragmentation is correlated faster rates mitochondrial molecular evolution and with an increased frequency of gene rearrangement. We also provide evidence that the rate of mitochondrial genome fragmentation changes over time. Altogether, our combination of broad sampling and phylogenomic and comparative analyses provide new insights into the mechanisms and dynamics of mitochondrial genome fragmentation.
Longitudinal associations between language network characteristics in the infant brain and school-age reading abilities are mediated by early-developing phonological skills
Authors: Tang Xinyi , Turesky Ted K. , Escalante Elizabeth S. , Loh Megan Yf , Xia Mingrui , Yu Xi , Gaab Nadine 
Published: June 2023

AbstractReading acquisition is a prolonged learning process relying on language development starting in utero. Behavioral longitudinal studies reveal prospective associations between infant language abilities and preschool/kindergarten phonological development that relates to subsequent reading performance. While recent pediatric neuroimaging work has begun to characterize the neural network underlying language development in infants, how this neural network scaffolds long-term language and reading acquisition remains unknown. We addressed this question in a 7-year longitudinal study from infancy to school-age. Seventy-six infants completed resting-state fMRI scanning, and underwent standardized language assessments in kindergarten. Of this larger cohort, forty-one were further assessed on their emergent word reading abilities after receiving formal reading instructions. Hierarchical clustering analyses identified a modular infant language network in which functional connectivity (FC) of the inferior frontal module prospectively correlated with kindergarten-age phonological skills and emergent word reading abilities. These correlations were obtained when controlling for infant age at scan, nonverbal IQ and parental education. Furthermore, kindergarten-age phonological skills mediated the relationship between infant FC and school-age reading abilities, implying a critical mid-way milestone for long-term reading development from infancy. Overall, our findings illuminate the neurobiological mechanisms by which infant language capacities could scaffold long-term reading acquisition.HighlightsClustering analyses revealed a modular language network in the infant brainInfant language network characteristics associate with school-age reading outcomesThese longitudinal associations are mediated by kindergarten-age phonological skills
Response of soil microbiome composition to selection on methane oxidation rate
Authors: Morris Andrew H. , Bohannan Brendan J. M. 
Published: June 2023

AbstractMicrobiomes mediate important ecosystem functions, yet it has proven difficult to determine the relationship between microbiome composition and the rate of ecosystem functions. This challenge remains because it is difficult to manipulate microbiome composition directly, we often cannot knowa prioriwhich microbiome members influence the rate of an ecosystem function, and microbiomes can covary strongly with other drivers of ecosystem function, such as the environment. To address these challenges, we imposed artificial selection on whole soil ecosystems over multiple generations to select for microbial communities with a high rate of CH4oxidation. This approach is potentially powerful because it is biologically “agnostic” in that it makes few assumptions about which taxa are important to function, and repeated passaging with fresh substrate weakens the covariance between microbes and the environment. As a response to selection, we observed a 50.7% increase in CH4oxidation rate per passage relative to a control that experienced random selection. We estimated that 31.5% of the variation in CH4oxidation rate in these soils can be attributed to microbiome variation (though this was not significant). We also found that selection did not enrich for known CH4oxidizers; instead, 12 families not known to oxidize CH4, includingFimbriimonadaceae,Cytophagaceae, andDiplorickettsiaceae, were enriched by selection. This result is in contrast to the typical assumption that the rate of an ecosystem function is limited by the final step in the associated microbial pathway. Our study demonstrates that variation in microbiome composition can contribute to variation in the rate of ecosystem function independent of the environment and that this may not always be limited by the final step in a pathway. This suggests that manipulating microbiome composition directly without altering the environment could be a viable strategy for managing ecosystem functions.
Loss of endothelial cell heterogeneity in arteries after obesogenic diet
Authors: Dunaway Luke S. , Luse Melissa A. , Nyshadham Shruthi , Bulut Gamze , Alencar Gabriel F. , Chavkin Nicholas W. , Cortese-Krott Miriam , Hirschi Karen K. , Isakson Brant E. 
Published: June 2023

AbstractBackgroundIt is well recognized that obesity leads to arterial endothelial dysfunction and cardiovascular disease. However, the progression to endothelial dysfunction is not clear. Endothelial cells (ECs) adapt to the unique needs of their resident tissue and respond to systemic metabolic perturbations. We sought to better understand how obesity affects EC phenotypes in different tissues specifically focusing on mitochondrial gene expression.MethodsWe performed bulk RNA sequencing (RNA-seq) and single cell RNA-seq (scRNA-seq) on mesenteric and adipose ECs isolated from normal chow (NC) and high fat diet (HFD) fed mice. Differential gene expression, gene ontology pathway, and transcription factor analyses were performed. We further investigated our hypothesis in humans using published human adipose single nuclei RNA-seq (snRNA-seq) data.ResultsBulk RNA-seq revealed higher mitochondrial gene expression in adipose ECs compared to mesenteric ECs in both NC and HFD mice. We then performed scRNA-seq and categorized EC clusters as arterial, capillary, venous, or lymphatic. HFD decreased the number of differentially expressed genes between mesenteric and adipose ECs in all subtypes, but the largest effect was seen in arterial ECs. Further analysis of arterial ECs revealed genes coding for mitochondrial oxidative phosphorylation proteins were enriched in adipose compared to mesentery under NC conditions. In HFD mice, these genes were decreased in adipose ECs becoming similar to mesenteric ECs. Transcription factor analysis revealed C/EBPα and PPARγ, both known to regulate lipid handling and metabolism, had high specificity scores in the NC adipose artery ECs. These findings were recapitulated in snRNA-seq data from human adipose.ConclusionsThese data suggest mesenteric and adipose arterial ECs metabolize lipids differently and the transcriptional phenotype of these two vascular beds converge in obesity, in part, due to downregulation of PPARγ and C/EBPα in adipose artery ECs. This work lays the foundation for investigating vascular bed specific adaptations to obesity.
Exploring success factors in food waste prevention initiatives of retailers: the critical role of digital technologies
Authors: Corsini Filippo , Annesi Nora , Annunziata Eleonora , Frey Marco 
Published: June 2023

PurposeFood waste is a severe problem affecting the supply chain due to its significant adverse social and environmental effects. Even if the topic is hotly debated in the literature, there is a lack of research about the success factors influencing food waste prevention initiatives retailers undertake.Design/methodology/approachThe research analyzes how several variables (i.e. product-related variables and technology-enabling variables) might impact the success of the sales of products close to the expiration date that is sold at a discounted price. Data from 390.000 products sold at a discounted price in 2020 and 2021 by a large Italian food retailer were examined with a regression analysis.FindingsThe results highlight that both product-related and technology-enabling variables influence the success of food prevention initiatives aimed at selling products close to the expiration date at a discounted price. In particular, the authors stress the importance of digital technologies in supporting food waste prevention initiatives.Practical implicationsThe study offers several practical implications for managers in structuring a waste prevention initiative. The introduction of digital technologies, the monitoring of specific variables or the ability to find synergies with other food waste prevention initiatives are discussed to support retailers in reducing food losses.Originality/valueThe paper is focused on the retailer perspective, which is barely investigated due to the difficulty in finding data.