bluuebunny/crossref_metadata_2025_split huggingface dataset:
TATDN2 resolution of R-loops is required for survival of BRCA1-mutant cancer cells
Authors: Jaiswal Aruna S , Dutta Arijit , Srinivasan Gayathri , Yuan Yaxia , Zhou Daohong , Shaheen Montaser , Sadideen Doraid T , Kirby Austin , Williamson Elizabeth A , Gupta Yogesh K , Olsen Shaun K , Xu Mingjiang , Loranc Eva , Mukhopadhyay Pramiti , Pertsemlidis Alexander , Bishop Alexander J R , Sung Patrick , Nickoloff Jac A , Hromas Robert 
Published: November 2023

Abstract
BRCA1-deficient cells have increased IRE1 RNase, which degrades multiple microRNAs. Reconstituting expression of one of these, miR-4638–5p, resulted in synthetic lethality in BRCA1-deficient cancer cells. We found that miR-4638-5p represses expression of TATDN2, a poorly characterized member of the TATD nuclease family. We discovered that human TATDN2 has RNA 3′ exonuclease and endonuclease activity on double-stranded hairpin RNA structures. Given the cleavage of hairpin RNA by TATDN2, and that BRCA1-deficient cells have difficulty resolving R-loops, we tested whether TATDN2 could resolve R-loops. Using in vitro biochemical reconstitution assays, we found TATDN2 bound to R-loops and degraded the RNA strand but not DNA of multiple forms of R-loops in vitro in a Mg2+-dependent manner. Mutations in amino acids E593 and E705 predicted by Alphafold-2 to chelate an essential Mg2+ cation completely abrogated this R-loop resolution activity. Depleting TATDN2 increased cellular R-loops, DNA damage and chromosomal instability. Loss of TATDN2 resulted in poor replication fork progression in the presence of increased R-loops. Significantly, we found that TATDN2 is essential for survival of BRCA1-deficient cancer cells, but much less so for cognate BRCA1-repleted cancer cells. Thus, we propose that TATDN2 is a novel target for therapy of BRCA1-deficient cancers.
Splicing factor Prp18p promotes genome-wide fidelity of consensus 3′-splice sites
Authors: Roy Kevin R , Gabunilas Jason , Neutel Dean , Ai Michelle , Yeh Zoe , Samson Joyce , Lyu Guochang , Chanfreau Guillaume F 
Published: November 2023

Abstract
The fidelity of splice site selection is critical for proper gene expression. In particular, proper recognition of 3′-splice site (3′SS) sequences by the spliceosome is challenging considering the low complexity of the 3′SS consensus sequence YAG. Here, we show that absence of the Prp18p splicing factor results in genome-wide activation of alternative 3′SS in S. cerevisiae, including highly unusual non-YAG sequences. Usage of these non-canonical 3′SS in the absence of Prp18p is enhanced by upstream poly(U) tracts and by their potential to interact with the first intronic nucleoside, allowing them to dock in the spliceosome active site instead of the normal 3′SS. The role of Prp18p in 3′SS fidelity is facilitated by interactions with Slu7p and Prp8p, but cannot be fulfilled by Slu7p, identifying a unique role for Prp18p in 3′SS fidelity. This fidelity function is synergized by the downstream proofreading activity of the Prp22p helicase, but is independent from another late splicing helicase, Prp43p. Our results show that spliceosomes exhibit remarkably relaxed 3′SS sequence usage in the absence of Prp18p and identify a network of spliceosomal interactions centered on Prp18p which are required to promote the fidelity of the recognition of consensus 3′SS sequences.
Genome-Enabled Analysis of Population Dynamics and Virulence-Associated Loci in the Oat Crown Rust Fungus Puccinia coronata f. sp. avenae
Authors: Hewitt Tim C. , Henningsen Eva C. , Pereira Danilo , McElroy Kerensa , Nazareno Eric S. , Dugyala Sheshanka , Nguyen-Phuc Hoa , Li Feng , Miller Marisa E. , Visser Botma , Pretorius Zacharias A. , Boshoff Willem H. P. , Sperschneider Jana , Stukenbrock Eva H. , Kianian Shahryar F. , Dodds Peter N. , Figueroa Melania 
Published: November 2023

Puccinia coronata f. sp. avenae ( Pca) is an important fungal pathogen causing crown rust that impacts oat production worldwide. Genetic resistance for crop protection against Pca is often overcome by the rapid virulence evolution of the pathogen. This study investigated the factors shaping adaptive evolution of Pca using pathogen populations from distinct geographic regions within the United States and South Africa. Phenotypic and genome-wide sequencing data of these diverse Pca collections, including 217 isolates, uncovered phylogenetic relationships and established distinct genetic composition between populations from northern and southern regions from the United States and South Africa. The population dynamics of Pca involve a bidirectional movement of inoculum between northern and southern regions of the United States and contributions from clonality and sexuality. The population from South Africa is solely clonal. A genome-wide association study (GWAS) employing a haplotype-resolved Pca reference genome was used to define 11 virulence-associated loci corresponding to 25 oat differential lines. These regions were screened to determine candidate Avr effector genes. Overall, the GWAS results allowed us to identify the underlying genetic factors controlling pathogen recognition in an oat differential set used in the United States to assign pathogen races (pathotypes). Key GWAS findings support complex genetic interactions in several oat lines, suggesting allelism among resistance genes or redundancy of genes included in the differential set, multiple resistance genes recognizing genetically linked Avr effector genes, or potentially epistatic relationships. A careful evaluation of the composition of the oat differential set accompanied by the development or implementation of molecular markers is recommended. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Development of a Large-Scale Soil DNA Extraction Method for Molecular Quantification of Fusarium oxysporum f. sp. fragariae in Soil
Authors: Matson Michael E. H. , Kane Saben M. , Crouch Uma T. , Zepada Sascha K. , Martin Frank N. 
Published: November 2023

The most common soilborne diseases affecting the strawberry industry in California include Verticillium wilt due to Verticillium dahliae, charcoal root rot due to Macrophomina phaseolina, and Fusarium wilt due to Fusarium oxysporum f. sp. fragariae. Detection of these pathogens in soil is an important facet of disease management and fumigation recommendations. Whereas the soil populations of both M. phaseolina and V. dahliae can be readily quantified with quantitative PCR (qPCR) assays using DNA extractions with 500 mg of soil, the single-cell nature of the F. oxysporum chlamydospore does not provide enough pathogen DNA from 500-mg extractions to be reliably quantified. Here, we describe an improved DNA extraction protocol from 10 to 15 g of soil that allows for the quantification of F. oxysporum f. sp. fragariae populations below 10 CFU/g. The relationship between results from the TaqMan qPCR assay and pathogen population density in soil was determined by using this extraction method in pathogen-free soils artificially infested with a hygromycin-resistant strain of F. oxysporum f. sp. fragariae to facilitate accurate colony counts when plated on a selective medium. Although the protocol was developed for F. oxysporum f. sp. fragariae, it is applicable for detection and quantification of other soilborne pathogens.
Evolution and sustainability: gathering the strands for an Anthropocene synthesis
Authors: Søgaard Jørgensen Peter , Weinberger Vanessa P. , Waring Timothy M. 
Published: November 2023

How did human societies evolve to become a major force of global change? What dynamics can lead societies on a trajectory of global sustainability? The astonishing growth in human population, economic activity and environmental impact has brought these questions to the fore. This theme issue pulls together a variety of traditions that seek to address these questions using different theories and methods. In this Introduction, we review and organize the major strands of work on how the Anthropocene evolved, how evolutionary dynamics are influencing sustainability efforts today, and what principles, strategies and capacities will be important to guide us towards global sustainability in the future. We present a set of synthetic insights and highlight frontiers for future research efforts which could contribute to a consolidated synthesis.
This article is part of the theme issue ‘Evolution and sustainability: gathering the strands for an Anthropocene synthesis’.
Towards understanding human–environment feedback loops: the Atacama Desert case
Authors: Gayo Eugenia M. , Lima Mauricio , Gurruchaga Andone , Estay Sergio A. , Santoro Calogero M. , Latorre Claudio , McRostie Virginia 
Published: November 2023

The overall trajectory for the human–environment interaction has been punctuated by demographic boom-and-bust cycles, phases of growth/overshooting as well as of expansion/contraction in productivity. Although this pattern has been explained in terms of an interplay between population growth, social upscaling, ecosystem engineering and climate variability, the evoked demographic–resource-complexity mechanisms have not been empirically tested. By integrating proxy data for population sizes, palaeoclimate and internal societal factors into empirical modelling approaches from the population dynamic theory, we evaluated how endogenous (population sizes, warfare and social upscaling) and exogenous (climate) variables module the dynamic in past agrarian societies. We focused on the inland Atacama Desert, where populations developed agriculture activities by engineering arid and semi-arid landscapes during the last 2000 years. Our modelling approach indicates that these populations experienced a boom-and-bust dynamic over the last millennia, which was coupled to structure feedback between population sizes, hydroclimate, social upscaling, warfare and ecosystem engineering. Thus, the human–environment loop appears closely linked with cooperation, competition, limiting resources and the ability of problem-solving.
This article is part of the theme issue ‘Evolution and sustainability: gathering the strands for an Anthropocene synthesis’.
Long-distance social relationships can both undercut and promote local natural resource management
Authors: Pisor Anne C. , Borgerhoff Mulder Monique , Smith Kristopher M. 
Published: November 2023

The management of large common-pool resources, like fisheries and forests, is more difficult when more people and more communities can access them—a particular problem given increased population sizes, higher mobility and globalized trade in the Anthropocene. Social relationships spanning communities, such as kin relationships, business or trade relationships and friendships, can make management even more challenging by facilitating and transmitting norms of overharvesting. However, these long-distance relationships can also bolster management by transmitting norms for sustainability, promoting interdependence and laying the groundwork for nested management systems. Here, we review the negative and positive impacts of long-distance relationships on local natural resource management (NRM), providing illustrative examples from our field research on forest and fisheries management in Tanzania. Drawing on the evolutionary literature, the development literature and our field data, we offer suggestions for how development partners can avoid the pitfalls of long-distance relationships and how they can use or even deliberately foster long-distance relationships to promote successful local NRM.
This article is part of the theme issue ‘Evolution and sustainability: gathering the strands for an Anthropocene synthesis’.
EVALUATION OF MYCOTOXINS IN GRAINS SOLD IN IDAH, AJAKA AND OGBOGBO AREAS OF NIGERIA
Authors: Ukwuru Michael Ukwuru , Muritala Abdullahi 
Published: November 2023

Mycotoxin contamination in grains is a significant concern due to its adverse effects on human and animal health. Understanding the levels and patterns of mycotoxin contamination in different regions and storage conditions is crucial for developing effective control strategies. This study aimed to assess mycotoxin levels in stored and recently harvested grains in three regions (Idah, Ajaka, and Ogbogbo) and investigate the implications for food safety. The study involved the analysis of mycotoxin levels in maize, rice, sorghum, and millet using appropriate mycotoxin extraction method based on the mycotoxins of interest and a suitable HPLC system. The findings revealed the presence of mycotoxins such as aflatoxins (1±0.2-5±0.4 µg/Kg), deoxynivalenol (520±0.8-700±1.2 µg/Kg) zearalenone (200±0.4-370±0.6 µg/Kg) , ochratoxins (2±0.2-4±0.3 µg/Kg) and fumonisin (0±0.0-4±0.3 µg/Kg) in both recently harvested and stored grains.Patulin was absent in most of the samples. Variations in mycotoxin levels were observed among different grains and regions, highlighting the need for targeted interventions. The European Commission mycotoxin standards in grains for human consumption are: Aflatoxins 4 µg/Kg in maize, millet and sorghum while rice is 8 µg/Kg, Deoxynivalenal 1750 µg/Kg, Zearalenone 100 µg/Kg, for all the grains under study, Ochratoxin A 5 µg/Kg for maize, rice and millet, then 10 µg/Kg for sorghum.Fumonisin is 4000 µg/Kg but no level for rice and patulin is 50 µg/Kg for rice and non for the other grains. This study demonstrates the persistence of mycotoxin contamination in stored grains and the importance of considering specific crop types and geographical locations when addressing mycotoxin contamination. The findings underscore the significance of implementing effective control measures to mitigate mycotoxin contamination and enhance food safety. The study provides valuable insights into mycotoxin contamination and emphasizes the need for comprehensive risk assessment studies and appropriate regulatory measures.
Identification of NpdA as the protein forming the surface layer in Paracidovorax citrulii and evidence of its occurrence as a surface layer protein in diverse genera of the Betaproteobacteria and Gammaproteobacteria
Authors: Gajbhiye Shabda , Gonzales Erin D. , Toso Daniel B. , Kirk Natalie A. , Hickey William James 
Published: November 2023

The phytopathogen Paracidovorax citrulli possesses an ortholog of a newly identified surface layer protein (SLP) termed NpdA but has not been reported to produce a surface layer (S-layer). This study had two objectives. First, to determine if P. citrulli formed a NpdA-based S-layer and, if so, assess the effects of S-layer formation on virulence, production of nanostructures termed nanopods, and other phenotypes. Second, to establish the distribution of npdA orthologs throughout the Pseudomonadota and examine selected candidate cultures for physical evidence of S-layer formation. Formation of a NpdA-based S-layer by P. citrulli AAC-001 was confirmed by gene deletion mutagenesis (ΔnpdA), proteomics, and cryo-electron microscopy. There were no significant differences between the wild type and mutant in virulence assays with detached watermelon fruit. Nanopods contiguous with S-layers of multiple biofilm cells were visualized by transmission electron microscopy. Orthologs of npdA were identified in 62 Betaproteobacteria species and 49 Gammaproteobacteria species. In phylogenetic analyses, NpdA orthologs largely segregated into distinct groups. Cryo-electron microscopy imaging revealed a NpdA-like S-layer in all but one of the 16 additional cultures examined. We conclude that NpdA represents a new family of SLP, forming an S-layer in P. citrulli and other Pseudomonadota. While the S-layer didn’t contribute to virulence in watermelon fruit, a potential role of the P. citrulli S-layer in another dimension of pathogenesis cannot be ruled out. Lastly, formation of cell-bridging nanopods in biofilms is a new property of S-layers; it remains to be determined if nanopods can mediate intercellular movement of materials.
TNFα hinders FGF4 efficacy to mitigate ALS astrocyte dysfunction and cGAS-STING pathway-induced innate immune reactivity
Authors: Velasquez Erika , Savchenko Ekaterina , Marmolejo-Martínez-Artesero Sara , Challuau Désiré , Aebi Aline , Pomeshchik Yuriy , Lamas Nuno Jorge , Vihinen Mauno , Rezeli Melinda , Schneider Bernard , Raoul Cedric , Roybon Laurent 
Published: November 2023

AbstractAstrocytes play an important role in the onset and progression of amyotrophic lateral sclerosis (ALS), a fatal disorder characterized by the relentless degeneration of motor neurons (MNs) in the central nervous system. Despite evidence showing that ALS astrocytes are toxic to MNs, little is understood about the earliest pathological changes that lead to their neurotoxic phenotype. In this study, we generated human astrocytes from induced pluripotent stem cells (iPSCs) harboring the ALS-associated A4V mutation in superoxide dismutase 1 (SOD1), to examine cellular pathways and network changes similar to early stages of the disease. By using proteomics as a molecular indicator, we observed significant alterations in the levels of proteins linked to ALS pathology and the cGAS-STING pathway-induced innate immunity. Interestingly, we found that the protein profile of reactive ALS astrocytes differed from that of wildtype astrocytes treated with the pro-inflammatory cytokine TNFα. Notably, we showed that fibroblast growth factor 4 (FGF4) reversed ALS astrocyte dysfunction and reactivity, but failed to provide protection to MNs when expressed in the spinal cord of the SOD1G93Amouse model of ALS. Further analysis showed that ALS astrocyte reactivity which was rescued by FGF4 was abrogated by TNFα. The latter is capable of exacerbating the dysfunction and reactivity of ALS astrocytes compared to control. Our data show that iPSC-derived ALS astrocytes are dysfunctional and spontaneously exhibit a reactive phenotype when generated from iPSCs. This suggests that this phenotype may resemble the early stages of the disease. Our data also demonstrate that reducing mutant astrocyte reactivity in vivo using FGF4 is not sufficient to prevent MN death in a mouse model of ALS. To mitigate ALS, future studies should investigate whether dual therapies that both lower astrocyte reactivity and reverse disease-associated cellular dysfunction could prevent MN death.Graphic abstractHighlights–ALS astrocytes are dysfunctional and reactive compared to wildtype astrocytes–FGF4 reverses ALS astrocyte dysfunction and reactivity–FGF4 lowers ALS astrocyte reactivity in vivo but fails to protect ALS motor neurons from death–ALS astrocyte reactivity rescued by FGF4 is attenuated by TNFα
Prioritizing genomic variants through neuro-symbolic, knowledge-enhanced learning
Authors: Althagafi Azza , Zhapa-Camacho Fernando , Hoehndorf Robert 
Published: November 2023

AbstractMotivationWhole-exome and genome sequencing have become common tools in diagnosing patients with rare diseases. Despite their success, this approach leaves many patients undiagnosed. A common argument is that more disease variants still await discovery, or the novelty of disease phenotypes results from a combination of variants in multiple disease-related genes. Interpreting the phenotypic consequences of genomic variants relies on information about gene functions, gene expression, physiology, and other genomic features. Phenotype-based methods to identify variants involved in genetic diseases combine molecular features with prior knowledge about the phenotypic consequences of altering gene functions. While phenotype-based methods have been successfully applied to prioritizing variants, such methods are based on known gene–disease or gene–phenotype associations as training data and are applicable to genes that have phenotypes associated, thereby limiting their scope. In addition, phenotypes are not assigned uniformly by different clinicians, and phenotype-based methods need to account for this variability.ResultsWe developed an Embedding-based Phenotype Variant Predictor (EmbedPVP), a computational method to prioritize variants involved in genetic diseases by combining genomic information and clinical phenotypes. EmbedPVP leverages a large amount of background knowledge from human and model organisms about molecular mechanisms through which abnormal phenotypes may arise. Specifically, EmbedPVP incorporates phenotypes linked to genes, functions of gene products, and the anatomical site of gene expression, and systematically relates them to their phenotypic effects through neuro-symbolic, knowledge-enhanced machine learning. We demonstrate EmbedPVP’s efficacy on a large set of synthetic genomes and genomes matched with clinical information.AvailabilityEmbedPVP and all evaluation experiments are freely available athttps://github.com/bio-ontology-research-group/EmbedPVP.Contactrobert.hoehndorf@kaust.edu.saSupplementary informationSupplementary data are available atBioinformatics.
Behavioral adaptation to changing energy constraints via altered frequency of movement selection
Authors: Darveniza Thomas , Zhu Shuyu I. , Pujic Zac , Sun Biao , Levendosky Matthew , Wong Robert , Agarwal Ramesh , McCullough Michael H. , Goodhill Geoffrey J. 
Published: November 2023

AbstractAnimal behavior is strongly constrained by energy consumption. A natural manipulation which provides insight into this constraint is development, where an animal must adapt its movement to a changing energy landscape as its body grows. Unlike many other animals, for fish it is relatively easy to estimate the energy consumed by their movements via fluid mechanics. Here we simulated the fluid mechanics of>100,000 experimentally-recorded movement bouts from larval zebrafish across different ages and fluid conditions as they huntedParamecia. We find that these fish adapt to their changing relationship with the fluid environment as they grow by adjusting the frequency with which they select different types of movements, so that more expensive movements are chosen less often. This strategy was preserved when fish were raised in an unnaturally viscous environment. This work suggests a general principle by which animals could minimize energy consumption in the face of changing energy costs over development.
Microglial NF-κB Signaling Deficiency Protects Against Metabolic Disruptions Caused by Volatile Organic Compound via Modulating the Hypothalamic Transcriptome
Authors: Debarba L.K. , Jayarathne H.S.M. , Stilgenbauer L. , Terra dos Santos A.L. , Koshko L. , Scofield S. , Sullivan R. , Mandal A. , Klueh U. , Sadagurski M. 
Published: November 2023

AbstractProlonged exposure to benzene, a prevalent volatile organic compound (VOC), at concentrations found in smoke, triggers hyperglycemia, and inflammation in mice. Corroborating this with existing epidemiological data, we show a strong correlation between environmental benzene exposure and metabolic impairments in humans. To uncover the underlying mechanisms, we employed a controlled exposure system and continuous glucose monitoring (CGM), revealing rapid blood glucose surges and disturbances in energy homeostasis in mice. These effects were attributed to alterations in the hypothalamic transcriptome, specifically impacting insulin and immune response genes, leading to hypothalamic insulin resistance and neuroinflammation. Moreover, benzene exposure activated microglial transcription characterized by heightened expression of IKKβ/NF-κB-related genes. Remarkably, selective removal of IKKβ in immune cells or adult microglia in mice alleviated benzene-induced hypothalamic gliosis, and protected against hyperglycemia. In summary, our study uncovers a crucial pathophysiological mechanism, establishing a clear link between airborne toxicant exposure and the onset of metabolic diseases.