bluuebunny/crossref_metadata_2025_split huggingface dataset:
ADAR1 Regulates Lipid Remodeling through MDM2 to Dictate Ferroptosis Sensitivity
Authors: Kung Che-Pei , Terzich Nick D. , Ilagen Ma Xenia G. , Prinsen Michael J. , Kaushal Madhurima , Kladney Raleigh D. , Weber Jade H. , Mabry Alex R. , Torres Luisangely Soto , Bramel Emily R. , Freeman Eric C. , Sabloak Thwisha , Cottrell Kyle A. , Ryu Sua , Weber William M. , Maggi Leonard , Shriver Leah P. , Patti Gary J. , Weber Jason D. 
Published: January 2025

AbstractTriple-negative breast cancer (TNBC), lacking expression of estrogen, progesterone, and HER2 receptors, is aggressive and lacks targeted treatment options. An RNA editing enzyme, adenosine deaminase acting on RNA 1 (ADAR1), has been shown to play important roles in TNBC tumorigenesis. We posit that ADAR1 functions as a homeostatic factor protecting TNBC from internal and external pressure, including metabolic stress. We tested the hypothesis that the iron- dependent cell death pathway, ferroptosis, is a ADAR1-protected metabolic vulnerability in TNBC by showing that ADAR1 knockdown sensitizes TNBC cells to GPX4 inhibitors. By performing single-reaction monitoring-based liquid chromatography coupled to mass spectrometry (LC-MS) to measure intracellular lipid contents, we showed that ADAR1 loss increased the abundance of polyunsaturated fatty acid phospholipids (PUFA-PL), of which peroxidation is the primary driver of ferroptosis. Transcriptomic analyses led to the discovery of the proto-oncogene MDM2 contributing to the lipid remodeling in TNBC upon ADAR1 loss. A phenotypic drug screen using a ferroptosis-focused library was performed to identify FDA- approved cobimetinib as a drug-repurposing candidate to synergize with ADAR1 loss to suppress TNBC tumorigenesis. By demonstrating that ADAR1 regulates the metabolic fitness of TNBC through desensitizing ferroptosis, we aim to leverage this metabolic vulnerability to inform basic, pre-clinical, and clinical studies to develop novel therapeutic strategies for TNBC.
Solution conformational differences between conventional and CENP-A nucleosomes are accentuated by reversible deformation under high pressure
Authors: Gupta Kushol , Sekulić Nikolina , Allu Praveen Kumar , Sapp Nicklas , Huang Qingqiu , Sarachan Kathryn , Christensen Mikkel , Lund Reidar , Krueger Susan , Curtis Joseph E. , Gillilan Richard E. , Van Duyne Gregory D. , Black Ben E. 
Published: January 2025

AbstractSolution-based interrogation of the physical nature of nucleosomes has its roots in X-ray and neutron scattering experiments, including those that provided the initial observation that DNA wraps around core histones. In this study, we performed a comprehensive small-angle scattering study to compare canonical nucleosomes with variant centromeric nucleosomes harboring the histone variant, CENP-A. We used nucleosome core particles (NCPs) assembled on an artificial positioning sequence (Widom 601) and compared these to those assembled on a natural α-satellite DNA cloned from human centromeres. We establish the native solution properties of octameric H3 and CENP-A NCPs using analytical ultracentrifugation (AUC), small-angle X-ray scattering (SAXS), and contrast variation small-angle neutron scattering (CV-SANS). Using high-pressure SAXS (HP-SAXS), we discovered that both histone identity and DNA sequence have an impact on the stability of octameric nucleosomes in solution under high pressure (300 MPa), with evidence of reversible unwrapping in these experimental conditions. Both canonical nucleosomes harboring conventional histone H3 and their centromeric counterparts harboring CENP-A have a substantial increase in their radius of gyration, but this increase is much less prominent for centromeric nucleosomes. More broadly for chromosome-related research, we note that as HP-SAXS methodologies expand in their utility, we anticipate this will provide a powerful solution-based approach to study nucleosomes and higher-order chromatin complexes.
Identification of a divergent botulinum neurotoxin like gene cluster inFurfurilactobacillus
Authors: Wei Xin , Lee Pyung-Gang , Dong Min , Doxey Andrew C. 
Published: January 2025

AbstractBotulinum neurotoxins (BoNTs) are among the most potent biological toxins and are traditionally associated withClostridiumspecies. However, recent discoveries have identified BoNT-like proteins in diverse bacterial genera, revealing an expanding family of neurotoxins with unique evolutionary and functional traits. In this study, we report the identification of a novel BoNT-like gene cluster inFurfurilactobacillussp. OKN36, encoding a toxin we tentatively designate as “Furfuritoxin”. Sequence and structural analyses indicate that Furfuritoxin shares key domains with clostridial neurotoxins, including a light chain zinc metalloprotease domain and heavy chain translocase and binding domains, while exhibiting significant sequence divergence. Phylogenetic analysis places Furfuritoxin within a divergent lineage alongside previously reported BoNT/Wo, suggesting a shared ancestral relationship. Gene neighborhood analysis reveals features shared with other BoNT gene clusters including ORFX-related genes and conjugation-associated elements, indicating horizontal gene transfer may have facilitated its distribution. This study adds to the growing family of BoNT-like toxins, providing insights into their evolution and diversity.
Monitoring fungicide resistance frequencies – a case study of barley net blotch
Authors: Knight N. L. , Adhikari K. C. , Mair W. J. , Dodhia K. , Zulak K. G. , Lopez-Ruiz F. J. 
Published: January 2025

AbstractDecreased sensitivity to fungicides impacts the effectiveness of fungicide applications for managing plant disease. Knowledge of the frequency of decreased sensitivity in field populations is critical for evaluating risks for disease control. This study has applied a droplet digital PCR detection approach to assess pathogen populations and quantify the frequencies of alleles associated with decreased sensitivity to either demethylation inhibitor or succinate dehydrogenase inhibitor fungicides inPyrenophora terescausing net blotch on barley in Western Australia.Pyrenophora teresf.maculatawas the most frequent form of the pathogen in the sampled region. Frequencies of decreased fungicide sensitivity alleles varied, being as great as 92% for the PtTi insertion in the CYP51A promoter, 88% for C-S75 and 28% for L489-2. Impacts of cultivar selection and weed hosts on the presence and survival of decreased fungicide sensitivity were observed. Determining the dynamics of alleles within different field populations ofP. teresprovides an important perspective on the impact of fungicides, the fitness associated with decreased fungicide sensitivity alleles and the susceptibility of barley cultivars.
Assessing Generative Diffusion Models for Enhanced Sampling of Folded and Disordered Protein States Across Scales and in All-atom Resolution
Authors: Bera Palash , Mondal Jagannath 
Published: January 2025

AbstractMolecular dynamics (MD) simulations are indispensable for studying the dynamic behavior of biomolecules, yet they are often constrained by timescale challenges that limit sampling efficiency. Generative machine learning (ML) models have recently emerged as promising tools to address these limitations. In this study, we revisit the potential of the Denoising Diffusion Probabilistic Model (DDPM) as an approach for enhancing the sampling and for generation of atomistically accurate conformational ensembles of biomolecules of diverse size, ranging from small folded proteins to large intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs). By training DDPM independently on MD simulation data of torsion angle and all-atom coordinates, we demonstrate their ability to effectively explore conformational space, including sparsely sampled regions, and to generate novel conformations. The performance of DDPM is evaluated on a diverse set of systems, including the Trp-cage mini-protein, the folded protein BPTI, the IDPα-Synuclein, and the IDR Ash1. Our results reveal that DDPM-generated ensembles accurately reproduce key structural features such as secondary structure, radius of gyration, and contact maps, while also capturing the inherent conformational heterogeneity of IDPs. These findings highlight the potential of DDPM to enhance the efficiency and accuracy of biomolecular simulations, offering a scalable framework for gaining deeper insights into protein structure and dynamics.
Recovering ecological interactions by mining non-target data from whole genome re-sequencing projects
Authors: Jones Mirkka , Rastas Pasi , Chacón-Duque J. Camilo , DiLeo Michelle F. , Nair Abhilash , Oostra Vicencio , Saastamoinen Marjo , Duplouy Anne 
Published: January 2025

AbstractThe study of parasitic species can shed light on aspects of their host’s ecology. Such interactions are however often unknown or understudied due to the difficulty to detect and/or quantify many infections. Whole-genome sequencing and re-sequencing data have been generated at an increasing rate and reduced costs over the last two decades. Projects based on whole organisms, like whole insect specimens, provide genomic material for the target taxon, but may also include sequencing reads from associated microbes and other parasites. Here, we screened for the presence of non-host reads in a collection of whole-genome (re-) sequence projects from the Glanville fritillary butterfly,Melitaea cinxia,a model organism in research on the ecology and evolution of species in spatially structured and fragmented landscapes. We identified infections with different bacteria and eukaryotic parasites, which are shared between populations and underly both previously known and new biotic interactions for this butterfly species. The bacterial symbiontWolbachia, usually common in insects, was found at relatively low prevalence, whileSpiroplasmawas ubiquitous across samples from several European populations of the butterfly. Additionally, we confirmed expected rates of larval parasitism by at least two parasitoid wasps. Such results provide proof of principle that key ecological interactions can be uncovered efficiently from existing data, an important first step to characterising the role host-associated organisms play in shaping the ecology and evolutionary history of their host species.
Quantification of spliced and unspliced transcripts by velocyto is inaccurate for 5’-sequencing data
Authors: Klingler Doreen , Schleicher Jan T. , Claassen Manfred 
Published: January 2025

AbstractRNA velocity allows for the prediction of future states of individual cells based on their current transcriptional activity. The technique depends on the separate quantification of spliced and unspliced transcripts in single-cell RNA-sequencing data, first introduced by velocyto in 2018. Since its introduction, significant advances have been made in the field, including new protocols by 10x Genomics that enable sequencing from the 5’-end of mRNA molecules instead of the 3’-end. Despite these advances, velocyto has not been updated since its release but is still commonly used with these new protocols. In this study, we demonstrate that velocyto cannot accurately detect the reversed direction of transcripts, leading to incorrect count assignments. By comparing velocyto to alevin-fry, a quantification method compatible with 5’-sequencing data, we show that this limitation can result in substantial deviations in inferred velocities and differing interpretations. Therefore, we do not recommend the use of velocyto with 5’-sequencing data.
Shifting ecological niches ofPrunusspecies under climate change
Authors: Vanalli Chiara , Gatto Marino , Casagrandi Renato , Bevacqua Daniele 
Published: January 2025

ABSTRACTClimate change is strongly impacting agriculture, reducing crop production and shifting the geographic distribution of suitable areas for crop cultivation. To safeguard future global yield and feed a growing world population, the migration of crop production areas to new suitable sites represents a way to adapt to a changing climate. Here, we aim to identify the ecological niche ofPrunusspecies, namely peach, plum, almond, apricot and sweet cherry, and examine their expected future shifts under climate change. For eachPrunusspecies, we selected from the literature processed-based phenological models for dormancy break, blooming and fruit ripening, whose fulfillment determines whether an area is suitable for crop cultivation. Historically, the ecological niche ofPrunusspecies spans mid-low European latitudes, while higher latitudes fail satisfying the forcing requirements for blooming and fruit ripening. In future, this constraint is expected to become less restrictive with a northwards expansion of the suitable areas. However, this will be contrasted by a contraction of the niche at low latitudes due to dormancy break failures. While bridging established mechanistic knowledge on the climatic effects of plant phenological traits with citizen science observations, our work brings new insights into how fruit crops will respond to global warming.
Longitudinal Trajectories of Cognition and Neural Metrics as Predictors of Persistent Distressing Psychotic-Like Experiences Across Middle Childhood and Early Adolescence
Authors: Karcher Nicole R. , Dong Fanghong , Johnson Emma C. , Paul Sarah E. , Kilciksiz Can Misel , Oh Hans , Schiffman Jason , Agrawal Arpana , Bogdan Ryan , Jackson Joshua J. , Barch Deanna M. 
Published: January 2025

AbstractObjectivesPsychotic-like experiences (PLEs) may arise from genetic and environmental risk leading to worsening cognitive and neural metrics over time, which in turn lead to worsening PLEs. Persistence and distress are factors that distinguish more clinically significant PLEs. Analyses used three waves of unique longitudinal Adolescent Brain Cognitive Development Study data (ages 9-13) to test whether changes in cognition and structural neural metrics attenuate associations between genetic and environmental risk with persistent distressing PLEs.MethodsMultigroup univariate latent growth models examined three waves of cognitive metrics and global structural neural metrics separately for three PLE groups: persistent distressing PLEs (n=356), transient distressing PLEs (n=408), and low-level PLEs (n=7901). Models then examined whether changes in cognitive and structural neural metrics over time attenuated associations between genetic liability (i.e., schizophrenia polygenic risk scores/family history) or environmental risk scores (e.g., poverty) and PLE groups.ResultsPersistent distressing PLEs showed greater decreases (i.e., more negative slopes) of cognition and neural metrics over time compared to those in low-level PLE groups. Associations between environmental risk and persistent distressing PLEs were attenuated when accounting for lowered scores over time on cognitive (e.g., picture vocabulary) and to a lesser extent neural (e.g., cortical thickness, volume) metrics.ConclusionsAnalyses provide novel evidence for extant theories that worsening cognition and global structural metrics may partially account for associations between environmental risk with persistent distressing PLEs.
The Mathematics of Serocatalytic Models with applications to public health data
Authors: Kamau Everlyn , Chen Junjie , Bajaj Sumali , Torres Nicolás , Creswell Richard , Pavlich-Mariscal Jaime A. , Donnelly Christl , Cucunubá Zulma , Lambert Ben 
Published: January 2025

AbstractSerocatalytic models are powerful tools which can be used to infer historical infection patterns from age-structured serological surveys. These surveys are especially useful when disease surveillance is limited and have an important role to play in providing a ground truth gauge of infection burden. In this tutorial, we consider a wide range of serocatalytic models to generate epidemiological insights. With mathematical analysis, we explore the properties and intuition behind these models and include applications to real data for a range of pathogens and epidemiological scenarios. We also include practical steps and code in R and Stan for interested learners to build experience with this modelling framework. Our work highlights the usefulness of serocatalytic models and shows that accounting for the epidemiological context is crucial when using these models to understand infectious disease epidemiology.
Representation of conceptual affordances in eye movements and the entorhinal cortex
Authors: Eperon Alexander , Doeller Christian F. , Theves Stephanie , Bottini Roberto 
Published: January 2025

ABSTRACTStructural representations in the entorhinal cortex are a crucial feature of cognitive maps. However, a complete understanding of task structure often requires knowledge of the actions available at each state (analogous to the moves of different pieces on a chessboard). Moreover, action representations are key to several models of the hippocampal-entorhinal system. In this study, we tested whether the entorhinal cortex represents the actions that allow transitioning between states of a conceptual space. In particular, participants learned to transition between numerically-labelled states using different mathematical operations. Behaviourally, participants learned and generalised action information across states. Action information was also reflected in eye movements, indicating the active processing of the possible actions for a given state during the trials. Importantly, we found that neural pattern similarity in the right entorhinal cortex scaled with the similarity of action affordances across the states. This affordance representation was not explained by other properties of the task space such as link distance between the states or action magnitude. In sum, this study provides first evidence for the integration of action information into ocular and entorhinal representations of conceptual spaces, suggesting that these may not just store experiences, but provide information about how to explore knowledge.
Molecular sorting of nitrogenase catalytic cofactors
Authors: Salinero-Lanzarote Alvaro , Lian Josh , Namkoong Gil , Suess Daniel L. M. , Rubio Luis M. , Dean Dennis R. , Pérez-González Ana 
Published: January 2025

AbstractThe free-living diazotrophAzotobacter vinelandiiproduces three genetically distinct but functionally and mechanistically similar nitrogenase isozymes, designated as Mo-dependent, V-dependent, and Fe-only. They respectively harbor nearly identical catalytic cofactors that are distinguished by a heterometal site occupied by Mo (FeMo-cofactor), V (FeV-cofactor), or Fe (FeFe-cofactor). Completion of FeMo-cofactor and FeV-cofactor formation occurs on molecular scaffolds prior to delivery to their catalytic partners. In contrast, completion of FeFe-cofactor assembly occurs directly within its cognate catalytic partner. Because hybrid nitrogenase species that contain the incorrect cofactor type cannot reduce N2to support diazotrophic growth there must be a way to prevent misincorporation of an incorrect cofactor when different nitrogenase isozyme systems are produced at the same time. Here, we show that fidelity of the Fe-only nitrogenase is preserved by blocking the misincorporation of either FeMo-cofactor or FeV-cofactor during its maturation. This protection is accomplished by a two-domain protein, designated AnfO. It is shown that the N-terminal domain of AnfO binds to an immature form of the Fe-only nitrogenase and the C-terminal domain, tethered to the N-terminal domain by a flexible linker, has the capacity to capture FeMo- and FeV-cofactor. AnfO does not prevent the normal activation of Fe-only nitrogenase because completion of FeFe-cofactor assembly occurs within its catalytic partner and, therefore, is never available for capture by AnfO. These results support a post-translational mechanism involving the molecular sorting of structurally similar metallocofactors that involve both protein-protein interactions and metallocofactor binding while exploiting differential pathways for nitrogenase associated catalytic cofactor assembly.
USP1 acts as a chaperone for HSFA2 and plays a crucial role in thermopriming in Arabidopsis
Authors: Manickam Prabhu , Shekhawat Kirti , Fatima Anam , Alhoraibi Hanna M. , Abulfaraj Aala A. , Rayapuram Naganand , Hirt Heribert 
Published: January 2025

AbstractPlants employ diverse strategies to cope with different types of heat stress. The response to short-term acute heat stress differs significantly from that to moderate heat stress followed by severe stress events. After experiencing moderate heat stress, plants exhibit a more robust response to subsequent severe stress, a phenomenon known as thermopriming or acquired thermotolerance. Thermopriming creates a memory by maintaining the heat stress (HS) memory-related genes in an alert state. In this work, we investigated the role of Arabidopsis Universal Stress Protein 1 (USP1) in plant heat stress responses. CRISPR-Cas9 generated knockoutusp1mutant lines showed no morphological changes during development and normal growth conditions. However,usp1mutant plants showed enhanced levels of apoplast hydrogen peroxide and superoxide reactive oxygen species accumulation upon heat stress. Transcriptome analyses revealed that genes related to protein folding, electron transport, and oxidative phosphorylation are strongly upregulated inusp1mutant plants. USP1 is essential for acquired thermotolerance, asusp1mutants are compromised in heat stress memory but show normal responses to acute heat stress similar tohsfa2mutants. Biochemical assays showed that USP1 functions as a molecular chaperone, protecting the transcription factor HSFA2 from heat-induced denaturation. Moreover,usp1mutant plants show decreased transcript levels of heat stress response genes and reduced H3K4me3 enrichment at memory gene loci. These data show that USP1 plays an important role as a chaperone of HSFA2 in mediating plant heat stress memory.
Small molecule-controlled gene expression: Design of drug-like high affinity small molecule modulators of a custom-made riboswitch
Authors: Hedwig Vera , Spöring Maike , Aspnes Gary , Gottschling Dirk , Klein Holger , Klugmann Matthias , Kreuz Sebastian , Ries Benjamin , Schnapp Gisela , Scharsich Sandra , Hartig Jörg S. , Hucke Oliver 
Published: January 2025

AbstractRiboswitches are regulatory RNA structures that modulate gene expression in response to a small molecule. Until now, efforts to design ligand analogs were motivated by their potential antibiotic activity. However, riboswitches are ideally suited as tools for gene therapy, enabling precise control of gene ex-pression without the need of potentially immunogenic regulatory proteins. Developing synthetic RNA switches starting from natural riboswitches will require engineering both, the ligand and the RNA sequence in order to achieve full orthogonality i.e., sensitivity to the designed small molecule modulator, but not to the natural ligand. We present the structure-based design of a drug-like small molecule ligand of the thiamine pyrophosphate (TPP) aptamer, BI-5232. BI-5232 is structurally highly diverse from the natural ligand TPP but rivals its binding affinity (KD= 1.0 nM). Importantly, in our design the pyrophosphate of TPP was replaced by an uncharged heterocycle that interacts with the PP helix in an unprecedented way, as revealed by Molecular Dynamics simulations. Subsequently, we altered the aptamer sequence to drastically reduce its affinity to TPP while retaining binding properties for our designed ligand. Based on the developed orthogonal small molecule/RNA aptamer interaction we finally constructed orthogonal ribozyme-based ON- and OFF-switches of gene expression in human cell lines. Such systems are valuable additions to the synthetic toolbox for conditionally controlling gene expression with potential applications in next-generation gene therapies.