bluuebunny/crossref_metadata_2025_split huggingface dataset:
The loss of a supergene in obligately polygynousFormicawood ant species
Authors: Sigeman Hanna , Satokangas Ina , De Lamarre Matthieu , Deshmukh Riddhi , Nouhaud Pierre , Helanterä Heikki , Chapuisat Michel , Kulmuni Jonna , Viljakainen Lumi 
Published: September 2024

AbstractSome of the most striking examples of phenotypic variation within species are controlled by supergenes. However, most research on supergenes has focused on their emergence and long-term maintenance, leaving the later stages of their life cycle largely unexplored. Specifically, what happens to a derived supergene haplotype when the trait it controls reaches fixation? Here we answer this question using the ancient supergene system ofFormicaants, where (monogynous) single-queen colonies carry only the ancestral haplotype M while the derived haplotype P is exclusive to (polygynous) colonies with multiple queens. Through comparative genomics of all seven European wood ant species, we found that the P haplotype was present in only one of the three obligate polygynous species (F. polyctena). In the two others (F. aquiloniaandF. paralugubris) the P haplotype was completely missing except for duplicated P-specific paralogs of two genes,Zasp52andTTLL2, withZasp52being directly involved in wing muscle development. We hypothesize that these genes play a direct role in polygyny and contribute to differences in body size and/or dispersal behaviour between monogynous and polygynous queens. A complete lack of P/P genotypes among the 136 workers suggest strong selection against such genotypes. While our analyses did not reveal evidence of increased mutation load on the P, it is possible that this skew in genotype distributions is driven by a few loci with strong fitness effects. We propose that selection to escape P-associated fitness costs underlies the loss of this haplotype in obligate polygynous wood ants.
Structural Insights into the Role of the Proline Rich Region in Tau Function
Authors: Acosta Karen , Brue Christopher R. , Kim Hee Jong , Holubovska Polina , Mayne Leland , Murakami Kenji , Rhoades Elizabeth 
Published: September 2024

ABSTRACTTau is a microtubule-associated protein that plays an important role in modulating axonal microtubules in neurons. Intracellular tau aggregates are found in a broad class of disorders, including Alzheimer’s disease, termed tauopathies. Tau is an intrinsically disordered protein, and its structural disorder appears to be critical to its microtubule-related functions. Tubulin binding sites are found in tau’s proline-rich region (PRR), microtubule binding repeats (MTBR: R1–R4), and pseudo-repeat, R′. While many post-translational modifications have been identified on tau, phosphorylation sites, which both regulate tubulin dimer and microtubule interactions and are correlated with disease, cluster with high frequency within the PRR. Here, we use fluorescence correlation spectroscopy and structural mass spectrometry techniques to characterize the impact of phosphomimic mutations in the PRR on tubulin dimer binding and probe the structure of the PRR-tubulin dimer complex. We find that phosphomimics cumulatively diminish tubulin dimer binding and slow microtubule polymerization. Additionally, we map two ∼15 residue regions of the PRR as primary tubulin dimer binding sites and propose a model in which PRR enhances lateral interactions between tubulin dimers, complementing the longitudinal interactions observed for MTBR. Together these measurements provide insight into the previously overlooked relevance of tau’s PRR in functional interactions with tubulin.GRAPHICAL ABSTRACT
Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma
Authors: Umbaugh Charles S. , Groth Marie , Erkut Cihan , Lee Kwang-Seok , Marinho Joana , Iser Florian , Kapp Jonas N. , Schroeter Petra , Dolaner Simay , Kayserili Asli , Hartmann Julia , Walch Philipp , Barth Thomas F.E. , Mellert Kevin , Dreier Birgit , Schaefer Jonas V. , Plückthun Andreas , Fröhling Stefan , Scholl Claudia 
Published: September 2024

ABSTRACTAberrant expression of the embryonal transcription factor TBXT (also known as brachyury) drives chordoma, a rare spinal neoplasm with no effective drug therapies. The gene network regulated by TBXT is poorly understood, and strategies to disrupt its abnormal activity for therapeutic purposes are lacking. Here, we developed TBXT-targeted designed ankyrin repeat proteins (T-DARPins) that selectively bind TBXT, inhibiting its binding to DNA and expression. In chordoma cells, T-DARPins reduced cell cycle progression, spheroid formation, and tumor growth in mice and induced morphologic changes indicative of senescence and differentiation. Combining T-DARPin-mediated TBXT inhibition with transcriptomic and proteomic analyses, we determined the TBXT regulome in chordoma cells, which comprises in particular networks involved in cell cycle regulation, DNA replication and repair, embryonal cell identity, metabolic processes, and interferon response. The analysis of selected TBXT regulome components provided new insights into chordoma biology, such as the strong upregulation of IGFBP3 upon TBXT inhibition to fine-tune part of TBXT’s downstream effectors. Finally, we assigned each TBXT regulome member a druggability status to create a resource for future translational studies and found high interferon response signaling in chordoma cell lines and patient tumors, which was promoted by TBXT and associated with strong sensitivity to clinically approved JAK2 inhibitors. These findings demonstrate the potential of DARPins to investigate the function of nuclear proteins to understand the regulatory networks of cancers driven by aberrant transcription factor activity, including novel entry points for targeted therapies that warrant testing in patients.
Synonymous and single nucleotide changes facilitate the adaptation of a horizontally transferred gene
Authors: Venkataraman Pavithra , Singh Sudeepta , Ahlawat Neetika , Saini Supreet 
Published: September 2024

AbstractThe movement of genes between microbial species, or horizontal gene transfer, is common. While this process speeds up adaptation, the functionality of horizontally transferred genes is highly constrained in the new hosts due to several reasons, and protein localization is one of them. In this study, we ask what is the minimum number of mutations that can resolve a localization problem faced by a horizontally transferred protein in a new host. Using a directed-evolution approach, we show that SNPs and a synonymous mutation can change the localization patterns of an ammonia transporter (AmtA) moved fromDictyostelium discoideumtoSaccharomyces cerevisiae. Interestingly, the mutations that cause this change in localization, confer different fitness effects, are spread throughout the gene, and do not cause a uniform change in amino acids. In a novel attempt, we show how SNPs or a synonymous mutation can alter the membrane affinity of proteins, and as a result, aiding protein evolution and functional diversification.
Mesoscale Modelling of Fibrin Clots: The Interplay between Rheology and Microstructure at the Gel Point
Authors: Zohravi Elnaz , Moreno Nicolas , Hawkins Karl , Curtis Daniel , Ellero Marco 
Published: September 2024

AbstractThis study presents a numerical model for incipient fibrin-clot formation that captures characteristic rheological and microstructural features of the clot at the gel point. Using a mesoscale-clustering framework, we evaluate the effect of gel concentration or gel volume fraction and branching on the fractal dimension, the gel time, and the viscoelastic properties of the clots. We show that variations in the gel concentration of our model can reproduce the effect of thrombin in the formation of fibrin clots. In particular, the model reproduces the fractal dimension’s dependency on gel concentration and the trends in elasticity and gelation time with varying thrombin concentrations. This approach allows us to accurately recreate the gelation point of fibrin-thrombin gels, highlighting the intricate process of fibrin polymerization and gel network formation. This is critical for applications in the clinical and bioengineering fields where precise control over the gelation process is required.
Transposable elements are prevalent vectors of transgenerational epigenetic inheritance in nature
Authors: Baduel Pierre , De Oliveira Louna , Caillieux Erwann , Bohl-Viallefond Grégoire , El Messaoudi Mounia , Xu Ciana , Barois Matteo , Singh Vipin , Sarazin Alexis , Boccara Martine , Gilbault Elodie , de France Antoine , Quadrana Leandro , Loudet Olivier , Colot Vincent 
Published: September 2024

AbstractTransgenerational epigenetic inheritance (TEI) mediated by transposable elements (TEs) is well established in plants. However, the molecular determinants and functional impact of this additional system of inheritance are poorly characterized. Through comprehensive analyses of severe DNA methylation loss over TEs in an experimental population and in >700 natural strains ofArabidopsis thaliana, we uncovered hundreds of TE epivariants in nature, most of which can be inherited independently of DNA sequence changes and thus are true epialleles. Furthermore, natural epivariants are enriched near genes and we uncovered a novel role for the Paf1 complex as a major facilitator of their prevalence. Conversely, related TE copies limit epiallelic variation, by producing the small RNAs that guide DNA methylation intrans. Crucially, natural epivariants mainly affect stress-responsive genes, making them unique targets for selection. Our findings therefore demonstrate that TEs are important mediators of transgenerational epigenetic variation in nature, with singular properties for plant adaptation.
The molecular arsenal of the key coastal bioturbatorHediste diversicolorfaced with changing oceans
Authors: Beine Kaylee , Feugere Lauric , Fletcher Nichola , Power Megan L. , Connell Liam J. , Bates Adam , Li Jiao , Winter Michael R. , Sellers Graham S. , Mincarelli Luana Fiorella , Vámos Sofia , James Jennifer , Ohnstad Hannah , Bartels-Hardege Helga , Parsons Daniel , Sanders Trystan , Parker Ruth , Bolam Stefan G. , Garcia Clement , Solan Martin , Hardege Jörg , Godbold Jasmin A. , Wollenberg Valero Katharina C. 
Published: September 2024

AbstractThe importance of infaunal bioturbators for the functioning of marine ecosystems cannot be overstated. Inhabitants of estuarine and coastal habitats are expected to show resilience to fluctuations in seawater temperature and pH, which adds complexity to our understanding of the effects of global change drivers. Further, stress responses may be propagated through chemical cues within and across species, which may amplify the costs of life and alter species interactions. Research into the molecular mechanisms underlying this resilience has been limited by a lack of annotated genomes and associated molecular tools. In this study, we present the first chromosome-level, annotated draft genome of the marine ragwormHediste diversicolor, specifically mapping genes important for chemical communication, sensing and pH homeostasis. Using these resources, we then evaluate the transcriptomic and behavioural responses of two distinct populations — one field-sampled from Portugal (Ria Formosa) and one laboratory-acclimated and -bred from the United Kingdom (Humber) — to changes in seawater pH, temperature, and odour cues from a low pH-stressed predator. Both populations displayed adaptive responses to future oceanic conditions, with targeted acid-base regulation in the Ria Formosa population experiment, and broader changes in metabolism and growth genes in the Humber population experiment. Chemical cues from stressed fish predators induced genes related to Schreckstoff biosynthesis in ragworms. Additionally, under future ocean conditions including increased temperature, the Humber population exhibited signs of cellular stress and damage. Our findings using the new annotated genome offer novel insights into the molecular arsenal of acid-base regulation which aids in predicting the impacts of an increasingly acidified and unstable ocean, and to transfer this knowledge to investigate these mechanisms in species with less tolerance.
De novoassembly and annotation of theEmpoasca fabaemitochondrial genome
Authors: Molligan Joshua , Jacques Jordanne , Mukhopadhyay Soham , Perez-Lopez Edel 
Published: September 2024

ABSTRACTThis study presents the assembly and annotation of the full-length mitochondrial genome for the leafhopper speciesEmpoasca fabaeHarris, 1841. The mitogenome was obtained from a contig-level assembly with the identified mitochondrial genome being 14,873 bp in length. The base composition was A (38.8%), T (39.1%), C (11.7%), and G (10.4%). The mitogenome comprised 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), two ribosomal RNA genes (rRNAs), and showed a unique, non-AT-rich D-loop region. Nearly all PCGs being with an ATN start codon, while two begin with TCG and GTG. Phylogenetic analysis confirmed the placement ofE. fabaewithin the subfamily Typhlocybinae, clustering with other species in theEmpoascagenus.
Independent avian epigenetic clocks for aging and development
Authors: Haller Ayke , Risse Judith , Sepers Bernice , van Oers Kees 
Published: September 2024

AbstractInformation on individual age is a fundamental aspect in many ecological and evolutionary studies. However, accurate and non-lethal methods that can be applied to estimate the age of wild animals are often absent. Furthermore, since the process of ageing is accompanied by a physical decline and the deterioration of biological functions, the biological age often deviates from the chronological age. Epigenetic marks are widely suggested to be associated with this age-related physical decline, and especially changes in DNA methylation are suggested to be reliable age-predictive biomarkers. Here, we developed separate epigenetic clocks for ageing for development in a small passerine bird, the great tit (Parus major). The ageing clock was constructed and evaluated using erythrocyte DNA methylation data of 122 post-fledging individuals, and the developmental clock using 67 pre-fledging individuals from a wild population. Using a leave-one-out cross validation approach, we were able to accurately predict the ages of individuals with mediation absolute deviations of 0.40 years for the ageing and 1.06 days for the development clock. Moreover, using existing data from a brood-size manipulation we show that nestlings from reduced broods are estimated to be biologically older compared to control nestlings, while they are expected to have higher fitness. These epigenetic clocks provide further evidence that, as observed in mammals, changes in DNA methylation of certain CpG sites are highly correlated with chronological age in birds and open up new avenues for broad applications in behavioural and evolutionary ecology.
Neural substrates for saccadic modulation of visual representations in mouse superior colliculus
Authors: Hunt Joshua B. , Buteau Anna , Hanson Spencer , Poleg-Polsky Alon , Felsen Gidon 
Published: September 2024

SUMMARYHow do sensory systems account for stimuli generated by natural behavior? We addressed this question by examining how an ethologically relevant class of saccades modulates visual representations in the mouse superior colliculus (SC), a key region for sensorimotor integration. We quantified saccadic modulation by recording SC responses to visual probes presented at stochastic saccade-probe latencies. Saccades significantly impacted population representations of the probes, with early enhancement that began prior to saccades and pronounced suppression for several hundred milliseconds following saccades, independent of units’ visual response properties or directional tuning. To determine the cause of saccadic modulation, we presented fictive saccades that simulated the visual experience during saccades without motor output. Some units exhibited similar modulation by fictive and real saccades, suggesting a sensory-driven origin of saccadic modulation, while others had dissimilar modulation, indicating a motor contribution. These findings advance our understanding of the neural basis of natural visual coding.
Phosphorylation regulated conformational diversity and topological dynamics of an intrinsically disordered nuclear receptor
Authors: Akulov Vasily , Panizo Alba Jiménez , Estébanez-Perpiñá Eva , van Noort John , Mashaghi Alireza 
Published: September 2024

AbstractSite-specific phosphorylation of disordered proteins is often considered as a marker of protein activity, yet it is unclear how phosphorylation alters conformational dynamics of disordered protein chains, such as those in the nuclear receptor superfamily. In the case of disordered human glucocorticoid receptor N-terminal domain (GR NTD), a negatively charged region known as core activation function 1 (AF1c) features three phosphorylation sites, regulating its function and intracellular localization. Deletion of this sequence reduces GR transcriptional activation ability dramatically in cell experiments. By developing a circuit topology-based fold analysis approach, combined with atomistic simulations, we reveal that site-specific phosphorylation facilitates formation of non-local contacts, leading to the emergence of disordered compact topologies with significant entanglement, which are distinct from solvent exposed topologies. While we observe that the topological buildup of solvent-exposed states is similar in different phosphovariants, it depends on the exact phosphorylation site for the disordered compact states. This study thus reveals the complex regulatory role of the GR phosphorylation and introduces a unique analysis framework that can be broadly applied to studying topological dynamics of disordered proteins.
Decoding Protein Dynamics: ProFlex as a Linguistic Bridge in Normal Mode Analysis
Authors: Magill Damian J. , Skvortsov Timofey A. 
Published: September 2024

AbstractArtificial intelligence has revolutionized structural bioinformatics, with AlphaFold being arguably the most impactful development to date. The structural atlases generated by these methods present significant opportunities for unraveling biological mysteries, but also pose challenges in leveraging such massive datasets effectively. In this work, we explore the dynamic landscape of hundreds of thousands of AlphaFold-predicted structures using normal mode analysis. The resulting data is used to define an alphabet summarizing relative protein flexibility, termed ProFlex. We believe that refining and further applying ProFlex-like approaches offers novel opportunities for understanding protein function and enhancing other methods.
Toxicity of extracellular cGAMP and its analogs to T cells is due to SLC7A1-mediated import
Authors: Sudaryo Valentino , Carvalho Dayanne R. , Lee J. Michelle , Carozza Jacqueline A. , Cao Xujun , Cordova Anthony F. , Li Lingyin 
Published: September 2024

AbstractSTING agonists are promising innate immune therapies and can synergize with adaptive immune checkpoint blockade therapies for cancer treatment, but their effectiveness is limited by the toxicity to activated T cells. An important class of STING agonists are analogs of the endogenous STING agonist, cGAMP, and while transporters for these small molecules are known in some cell types, how they enter and kill T cells remains unknown. Here, we identify the cationic amino acid transporter SLC7A1 as the dominant transporter of cGAMP and its analogs in activated primary mouse and human T cells. T cells upregulate this transporter upon activation and rapid proliferation to meet their high metabolic demand, but this comes at the cost of enabling increased transport and toxicity of cGAMP. To circumvent the essentiality of SLC7A1 to proliferating T cells, we found that the residues responsible for cGAMP transport are separate from the arginine binding pocket allowing us to perturb cGAMP transport and STING-activation mediated killing without impacting arginine transport. These results suggest that SLC7A1 is a potential target for alleviating T cell toxicity associated with cGAMP and its analogs.
Super-enhancer profiling reveals ThPOK/ZBTB7B, a CD4+cell lineage commitment factor, as a master regulator that restricts breast cancer cells to a luminal non-migratory phenotype
Authors: Arcuschin Camila D , Kahrizi Kamin , Sayaman Rosalyn W , DiBenedetto Carolina , Shen Yizhuo , Salaberry Pedro J , Zakroui Ons , Schwarzer Cecilia , Scapozza Alessandro , Betancur Paola , Saba Julie D , Coppé Jean-Philippe , Barcellos-Hoff Mary-Helen , Kappes Dietmar , van ‘t Veer Laura , Schor Ignacio E , Muñoz Denise P 
Published: September 2024

AbstractDespite efforts to understand breast cancer biology, metastatic disease remains a clinical challenge. Identifying suppressors of breast cancer progression and mechanisms of transition to more invasive phenotypes could provide game changing therapeutic opportunities. Transcriptional deregulation is central to all malignancies, highlighted by the extensive reprogramming of regulatory elements that underlie oncogenic programs. Among these, super-enhancers (SEs) stand out due to their enrichment in genes controlling cancer hallmarks. To reveal novel breast cancer dependencies, we integrated the analysis of the SE landscape with master regulator activity inference for a series of breast cancer cell lines. As a result, we identifiedT-helper-inducing Poxviruses and Zinc-finger (POZ)/Krüppel-like factor (ThPOK,ZBTB7B), a CD4+cell lineage commitment factor, as a breast cancer master regulator that is recurrently associated with a SE. ThPOK expression is highest in luminal breast cancer but is significantly reduced in the basal subtype. Manipulation of ThPOK levels in cell lines shows that its repressive function restricts breast cancer cells to an epithelial phenotype by suppressing the expression of genes involved in the epithelial-mesenchymal transition (EMT), WNT/β-catenin target genes, and the pro-metastatic TGFβ pathway. Our study reveals ThPOK as a master transcription factor that restricts the acquisition of metastatic features in breast cancer cells.
Pollinator visitation pattern and differential reproductive compatibilities contribute to the unequal morph abundances in a nocturnal ginger from Western Ghats, India
Authors: Shrotri Saket , Gowda Vinita 
Published: September 2024

SummaryPolymorphism, the presence of discrete floral morphs within a population, is often maintained by pollinator-mediated or frequency-dependent selection. While pollinators often act on visual displays, this study investigates hawkmoth-mediated selection in the nocturnalCurcuma caulina(Zingiberaceae), where visual cues play a minimal role. We explore the impact of non-visual traits, such as morph abundance, nectar rewards, and reproductive compatibility, on the maintenance of bract color polymorphism.We measured floral traits, nectar rewards, and abundance of morphs in the natural population, and quantified reproductive compatibility using hand pollination treatments. We next used path analysis to test the effect of morph abundance on reproductive fitness via floral and ecological traits.We identified tri-modal morph abundance with two common morphs and one rare morph. Morphs differed in nectar traits and reproductive compatibility but not in floral morphologies. Rare morphs had high-energy nectar, higher pollinator revisits and self-pollination, and lower seed output, while common morphs had low-energy nectar, lower revisits, higher outcrossing and fitness.Morph abundance inC. caulinais shaped by an interplay between nectar rewards, pollinator attraction, and compatibility. We conclude that in perennial rhizomatic species understanding historical selection regimes and both abiotic and biotic factors are necessary to characterize floral polymorphism.