bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring Arylidene-Indolinone Ligands of Autophagy Proteins LC3B and GABARAP
Authors: Leveille Alexandria N. , Schwarzrock Thomas , Brown Hawley , True Bennett , Plasencia Joanet , Neudecker Philipp , Üffing Alina , Weiergräber Oliver H. , Willbold Dieter , Kritzer Joshua A. 
Published: February 2024

ABSTRACTWe report the first structure-activity studies of arylidene-indolinone compoundGW5074which was reported as a ligand of autophagy-related protein LC3B. The literature has conflicting information on the binding affinity of this compound and there is some debate regarding its use as a component of autophagy-dependent degrader compounds. We developed an AlphaScreen assay to measure competitive inhibition of the binding of known peptide ligands to LC3B and its paralog GABARAP. 18 analogs were synthesized and tested against both proteins. Inhibitory potencies were found to be in the mid- to high micromolar range. 2D-NMR data revealed the binding site on GABARAP as hydrophobic pocket 1, where native peptide ligands bind with an aromatic side chain. Our results suggest thatGW5074binds LC3B and GABARAP with micromolar affinity. These affinities could support further exploration in targeted protein degradation, but only if off-target effects and poor solubility can be appropriately addressed.
Local ecdysone synthesis in a wounded epithelium sustains developmental delay and promotes regeneration inDrosophila
Authors: Terry Douglas , Schweibenz Colby , Moberg Kenneth 
Published: February 2024

SUMMARYRegenerative ability often declines as animals mature past embryonic and juvenile stages, suggesting that regeneration requires redirection of growth pathways that promote developmental growth. Intriguingly, theDrosophilalarval epithelia require the hormone ecdysone (Ec) for growth but require a drop in circulating Ec levels to regenerate. Examining Ec dynamics more closely, we find that transcriptional activity of the Ec-receptor (EcR) drops in uninjured regions of wing discs, but simultaneously rises in cells around the injury-induced blastema. In parallel, blastema depletion of genes encoding Ec biosynthesis enzymes blocks EcR activity and impairs regeneration but has no effect on uninjured wings. We find that local Ec/EcR signaling is required for injury-induced pupariation delay following injury and that key regeneration regulatorsupd3andEts21crespond to Ec levels. Collectively, these data indicate that injury induces a local source of Ec within the wing blastema that sustains a transcriptional signature necessary for developmental delay and tissue repair.
Oxytocin and shared intentionality drive variation in cooperation in children
Authors: McClung Jennifer , Triki Zegni , Lancheros Pompeyo Monica , Fassier Romain , Emery Yasmin , Bangerter Adrian , Clément Fabrice , Bshary Redouan 
Published: February 2024

AbstractWhile humans cooperate with unrelated individuals to an extent that far outstrips any other species, we also display extreme variation in decisions about whether to cooperate or not. A diversity of cognitive, affective, social, and physiological mechanisms interact to shape these decisions. For example, group membership, shared intentionality talk (i.e. talk about shared goals), and natural initial oxytocin levels affect cooperation in adults in an optimal foraging paradigm that is loosely modelled on the iterated prisoner’s dilemma. In this ‘egg hunt’, shared intentionality talk was key to achieve cooperation, and it occurred more between participants who shared the same group membership and had higher initial oxytocin levels. Such complex interactions raise the question of the age at which humans develop the necessary mechanisms to cooperate effectively in the egg hunt game. Here, we tested children in secondary school aged between 10 and 14 years. We found that, as for adults, shared intentionality talk was crucial for successful cooperation. Furthermore, initial oxytocin levels affected cooperation through shared intentionality talk. In contrast, group membership did not affect behaviour. Finally, pre- and post-experiment oxytocin levels showed various interactions with group membership and gender. Thus, children’s performance was relatively similar to adults while showing some differences with respect to underlying mechanisms. Our study is a rare contribution to further our understanding of the role of oxytocin in early adolescent social behaviour.
Stabilization of Integrator/INTAC by the small but versatile DSS1 protein
Authors: Xu Congling , Zhou Qian-Xing , Zheng Hai , Song Aixia , Zhao Wen-Ying , Xiong Yan , Huang Zixuan , Xu Yanhui , Cheng Jingdong , Chen Fei Xavier 
Published: February 2024

AbstractIntegrator-PP2A (INTAC) is a highly modular complex orchestrating the transition of paused RNA polymerase II into productive elongation or promoter-proximal premature termination, with its loss resulting in transcription dysregulation and genome instability. Here, we identify human DSS1—a flexible 70-residue protein found in multiple functionally diverse complexes including the 26S proteasome—as an integral subunit of the INTAC backbone. Structural analysis of DSS1–INTAC, both alone and in association with paused polymerase, demonstrates intimate interactions between DSS1 and the INTAC backbone subunit INTS7. We identify tryptophan 39 of DSS1 as being critical for interacting with INTAC and find that mutating this residue disrupts DSS1’s interaction with INTAC, while maintaining DSS1’s interaction with the proteasome. This substitution not only destabilizes INTAC and therefore INTAC-dependent transcriptional regulation, but also reveals that INTAC is DSS1’s major chromatin-bound form. Together, our findings reveal the essential role of the versatile DSS1 protein in the structure and regulatory functions of INTAC.
Grapevine Rootstock and Scion Genotypes’ Symbiosis with Soil Microbiome: A Machine Learning Revelation for Climate-Resilient Viticulture
Authors: Anand Lakshay , Gentimis Thanos , Downie Allan Bruce , Lopez Carlos M. Rodriguez 
Published: February 2024

AbstractGiven the impact of climate change on agriculture, the development of resilient crop cultivars is imperative. A healthy plant microbiota is key to plant productivity, influencing nutrient absorption, disease resistance, and overall vigor. The plant genetic factors controlling the assembly of microbial communities are still unknown. Here we examine if Machine Learning can predict grapevine rootstock and scion genotypes based on soil microbiota, despite environmental variability. The study utilized soil microbial bacteriome datasets from 281 vineyards across 13 countries and five continents, featuring 34 differentVitis viniferacultivars grafted onto, often ambiguous, rootstocks. Random Forests, Adaptive Boost, Gradient Boost, Support Vector Machines, Gaussian and Bernoulli Naïve Bayes, k-Nearest Neighbor, and Neural Networks algorithms were employed to predict continent, country, scion, and rootstock cultivar, under two filtering criteria: retaining sparse classes, ensuring class diversity, and excluding sparse classes assessing model robustness against overfitting. Both criteria showed remarkable F1-weighted scores (>0.8) for all classes, for most algorithms. Moreover, successful rootstock and scion genotype prediction from soil microbiomes confirms that genotypes of both plant parts shape the microbiome. These insights pave the way for identifying plant genes for use with breeding programs that enhance plant productivity and sustainability by improving the plant-microbiota relationship.
RNA-binding tunes the conformational plasticity and intradomain stability of TDP-43 tandem RNA recognition motifs
Authors: Ozguney Busra , Mohanty Priyesh , Mittal Jeetain 
Published: February 2024

ABSTRACTTAR DNA binding protein 43 (TDP-43) is a nuclear RNA/DNA-binding protein with pivotal roles in RNA-related processes such as splicing, transcription, transport, and stability. The high binding affinity and specificity of TDP-43 towards its cognate RNA sequences (GU-rich) is mediated by highly conserved residues in its tandem RNA recognition motif (RRM) domains (aa:104-263). Importantly, the loss of RNA-binding to the tandem RRMs caused by physiological stressors and chemical modifications promotes cytoplasmic mislocalization and pathological aggregation of TDP-43. Despite the substantial implications of RNA in TDP-43 function and pathology, a comprehensive characterization of the effect of RNA-binding on conformational dynamics, interdomain interactions and intradomain stability of the tandem RRMs has not yet been conducted. Here, we employed all-atom molecular dynamics (MD) simulations to assess the effect of RNA-binding on the conformational landscape and intradomain stability of TDP-43 tandem RRMs. Our simulations reveal a high intrinsic conformational plasticity of the tandem RRMs in the absence of RNA which surprisingly, is accompanied by a tendency of RRM1 to adopt partially-unfolded conformations. While binding to RNA limits the overall conformational space of the tandem RRMs and promotes intradomain stability, several RRM-RNA contacts mediated by highly conserved residues are observed to be far more dynamic than previously inferred from NMR structural ensemble. Overall, our simulations reveal how RNA dynamically tunes the structural and conformational landscape of TDP-43 tandem RRMs, contributing to physiological function and mitigating pathological aggregation.SIGNIFICANCEThe cytoplasmic mislocalization and aggregation of TDP-43 due to loss of its RNA-binding capability is associated with the onset and progression of neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Due to the flexible nature of RNA and the presence of a disordered linker between RRM domains, characterizing the dynamic interactions between RRMs-RNA and/or RRM1-RRM2 by experiments alone has remained challenging. In this study, we performed all-atom simulations initiated from the NMR conformers of RNA-bound tandem RRMs of TDP-43 to investigate their underlying structural and conformational dynamics. Our findings indicate that RNA binding effectively reduces conformational heterogeneity in the tandem RRMs and acts as a protective factor for the unfolding and aggregation of RRM1. These effects are achieved through a combination of stable and dynamic protein-RNA interactions which involve highly conserved amino acids.
Genome Report: The reference genome of an endangered Asteraceae,Deinandra increscenssubsp.villosa, endemic to the Central Coast of California
Authors: McEvoy Susan L. , Meyer Rachel S. , Hasenstab-Lehman Kristen E. , Guilliams C. Matt 
Published: February 2024

AbstractWe present a high-quality reference genome of the federally endangered Gaviota tarplant,Deinandra increscenssubsp.villosa(Madiinae, Asteraceae), an annual herb endemic to the Central California coast. Stewards of remaining populations have planned to apply conservation strategies informed by whole genome approaches. Generating PacBio Hifi, Oxford Nanopore Technologies, and Dovetail Omni-C data, we assembled a genome of 1.67 Gbp as 28.7 K scaffolds with a scaffold N50 of 74.9 Mb. BUSCO completeness for the final assembly was 98.1% with 15.7% duplicate copies. We annotated repeat content in 74.8% of the genome. Long terminal repeats (LTR) covered 44.0% of the genome withCopiafamilies predominant at 22.9% followed byGypsyat 14.2%. BothGypsyandCopiaelements were common in ancestral peaks of LTR, and the most abundant element was aGypsyelement containing nestedCopia/Angelasequenced similarity, reflecting a complex evolutionary history of repeat activity. Gene annotation produced 41,039 genes and 69,563 transcripts, of which >99% were functionally annotated. BUSCO duplication rates remained very high with proteins at 50.4% complete duplicates and 46.0% single copy. Whole genome duplication (WGD) synonymous mutation rates of Gaviota tarplant and sunflower (Helianthus annuus) shared peaks that correspond to the last Asteraceae polyploidization event and subsequent divergence from a common ancestor at ∼27 mya. Tandem genes were twice as prevalent as WGD genes suggesting tandem genes could be an important strategy of environmental adaptation in this species.Article SummaryWe introduce a high-quality reference genome for the endangered Gaviota tarplant. The assembly is 1.67 Gbp with 98.1% BUSCO completeness and 41 K annotated genes. We find extensiveCopialong terminal repeat sequences and tandem genes that suggest environmental adaptation strategies. Comparisons with sunflower suggest a shared polyploidization event around 27 million years ago, close to the date of the common ancestor divergence. This work underlines the importance of genomic studies in accurately understanding adaptations and conservation needs.
Meiotic DSB repair DNA synthesis tracts inArabidopsis thaliana
Authors: Hernández Sánchez-Rebato Miguel , Schubert Veit , White Charles I. 
Published: February 2024

AbstractWe report here the successful labelling of meiotic prophase I DNA synthesis in the flowering plant,Arabidopsis thaliana. Incorporation of the thymidine analogue, EdU, enables visualisation of the footprints of recombinational repair of programmed meiotic DNA double-strand breaks (DSB), with ∼400 discrete, SPO11-dependent, EdU-labelled chromosomal foci clearly visible at pachytene and later stages of meiosis. This number equates well with previous estimations of 200-300 DNA double-strand breaks per meiosis in Arabidopsis, confirming the power of this approach to detect the repair of most or all SPO11-dependent meiotic DSB repair recombination. The chromosomal distribution of these DNA-synthesis foci accords with that of early recombination markers and MLH1, which marks Class I crossover sites, colocalises with the EdU foci.It is currently estimated that ∼10 cross-overs (CO) and an equivalent number of non-cross-overs (NCO) occur in each Arabidopsis male meiosis. Thus, at least 90% of meiotic recombination events, and very probably more, have not previously been accessible for analysis. Visual examination of the patterns of the foci on the synapsed pachytene chromosomes corresponds well with expectations from the different mechanisms of meiotic recombination and notably, no evidence for long Break-Induced Replication DNA synthesis tracts was found. Labelling of meiotic prophase I, SPO11-dependent DNA synthesis holds great promise for further understanding of the molecular mechanisms of meiotic recombination, at the heart of reproduction and evolution of eukaryotes.Author SummarySexual reproduction involves the fusion of two cells, one from each parent. To maintain a stable chromosome complement across generations, these specialized reproductive cells must be produced through a specialized cell division called meiosis. Meiosis halves the chromosome complement of gametes and recombines the parental genetic contributions in each gamete, generating the genetic variation that drives evolution. The complex mechanisms of meiotic recombination have been intensely studied for many years and we now know that it involves the repair of programmed chromosomal breaks through recombination with intact template DNA sequences on another chromatid. At the molecular level, this is known to involve new DNA synthesis at the sites of repair/recombination and we report here the successful identification and characterisation of this DNA neo-synthesis during meiosis in the flowering plant, Arabidopsis. Both the characteristics and numbers of these DNA synthesis tracts accord with expectations from theory and earlier studies. Potentially applicable to studies in many organisms, this approach provides indelible footprints in the chromosomes and has the great advantage of freeing researchers from dependence on indirect methods involving detection of proteins involved in these dynamic processes.
Establishing and evaluating the gradient of item naming difficulty in post-stroke aphasia and semantic dementia
Authors: Nørkær Erling , Halai Ajay D. , Woollams Anna , Lambon Ralph Matthew A. , Schumacher Rahel 
Published: February 2024

AbstractAnomia is a common consequence following brain damage and a central symptom in semantic dementia (SD) and post-stroke aphasia (PSA), for instance. Picture naming tests are often used in clinical assessments and experience suggests that items vary systematically in their difficulty. Despite clinical intuitions and theoretical accounts, however, the existence and determinants of such a naming difficulty gradient remain to be empirically established and evaluated. Seizing the unique opportunity of two large-scale datasets of semantic dementia and post-stroke aphasia patients assessed with the same picture naming test, we applied an Item Response Theory (IRT) approach and we (a) established that an item naming difficulty gradient exists, which (b) partly differs between patient groups, and is (c) related in part to a limited number of psycholinguistic properties - frequency and familiarity for SD, frequency and word length for PSA. Our findings offer exciting future avenues for new, adaptive, time-efficient, and patient-tailored approaches to naming assessment and therapy.
Scenarios for the long-term efficacy of amyloid-targeting therapies in the context of the natural history of Alzheimer’s disease
Authors: Raket Lars Lau , Cummings Jeffrey , Moscoso Alexis , Villain Nicolas , Schöll Michael 
Published: February 2024

AbstractImportanceRecent clinical trials of Aβ-targeting therapies in Alzheimer’s disease (AD) have demonstrated clinical benefit over 18-months, but their long-term impact on disease trajectory is not yet understood. We propose a framework for evaluating realistic long-term scenarios.ObjectiveTo integrate data from recent phase 3 trials of the high-clearance Aβ-targeting antibodies with an estimate of the long-term patient-level natural history trajectory of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, to explore realistic long-term efficacy scenarios.Data SourcesPublished results from recent phase 3 randomized clinical trials of high-clearance Aβ-targeting antibodies with completion between 2019 and 2023.Study SelectionAll phase 3 studies of aducanumab, lecanemab, gantenerumab, and donanemab were included.Main Outcomes and MeasuresReported study results on CDR-SB estimated using categorical-time models.ResultsThree distinct long-term efficacy scenarios were examined, ranging from conservative (enduring short-term delay), over intermediate (fading stage-dependent slowing), to optimistic (continued stage-independent slowing). In a hypothetical framework, we found that even modestly effective therapies with fading stage-dependent slowing could result in major delays of disease progression if initiated in the earliest stages of AD. In long-term scenarios for the treatment effects observed in recent positive phase 3 trials, we found that initiating the treatments in the early symptomatic stages, defined by the respective trial inclusion criteria, could delay the onset of severe dementia by 0.3-0.6 years (conservative), 1.1-1.9 years (intermediate), and 2.0-4.2 years (optimistic).Conclusion and RelevanceThe findings provide insights into hypothetical long-term impact of Aβ-targeting treatments, highlighting the potential of maximizing clinical benefit with earlier intervention. This study underscores some of the complexities of evaluating and comparing Aβ-targeting therapies in the context of AD’s nonlinear disease trajectory and the need for considering both differences in trial populations and duration. Our work calls for studies with longer follow-up and results from early intervention trials to provide a comprehensive assessment of these therapies’ true long-term impact.
Exploring what lies beneath the tip of the gender-based violence iceberg
Authors: Moriña David , Millán Isabel , Fernández-Fontelo Amanda , Puig Pedro , Toran Pere , Gómez-Maldonado Meritxell , Falguera Gemma 
Published: February 2024

ABSTRACTGender-based violence refers to violence directed against a person because of that person’s gender or violence that affects persons of a particular gender disproportionately. It is estimated that 30% of women worldwide have suffered either physical and/or sexual violence in their lifetime. Primary Health Care could be one of the ideal places for the detection of these situations, but most of the cases remain undetected as the victims often decline to seek for medical care after suffering an event. This work shows that public primary health care system in Catalonia might be registering only around 50% of the cases currently, and it will take more than 20 years to see the whole picture of the phenomenon, and the situation could be the same in countries with similar socioeconomic contexts. We found in previous studies that gender-based violence cases are severely underregistered from the public health and judicial perspectives, on the basis of qualitative analyses and survey data. Furthermore, we propose a statistical modelling approach able to estimate the actual burden of this issue accurately. Our results show that awareness training campaigns focused on primary healthcare professionals are very effective in reducing the underreporting issue but should be conducted repeatedly and not only once.
Differential expression analyses on aortic tissue reveal novel genes and pathways associated with abdominal aortic aneurysm onset and progression
Authors: Temprano-Sagrera Gerard , Soto Begoña , Dilmé Jaume , Peypoch Olga , Juscafresa Laura Calsina , Davtian David , Nieto Lluís , Brown Andrew , Escudero José Román , Viñuela Ana , Camacho Mercedes , Sabater-Lleal Maria 
Published: February 2024

ABSTRACTBackgroundAbdominal aortic aneurysms (AAA) are focal dilatations of the abdominal aorta. They are normally asymptomatic and progressively expand, increasing their risk of rupture. Rupture of an AAA is associated with high mortality rates, but the mechanisms underlying the initiation, expansion and rupture of AAA are not yet fully understood. This study aims to characterize and identify new genes associated with the pathophysiology of AAA through differential expression analyses between dilated and non-dilated aortic tissue samples, and between AAA of different diameters. Our study used RNA-seq data on 140 samples, becoming the largest RNA-seq dataset for differential expression studies of AAA.ResultsWe identified 7,454 differentially expressed genes (DEGs) between AAA and controls, 2,851 of which were new compared to previous microarray studies. Notably, a novel cluster on adenosine triphosphate synthesis regulation emerged as strongly associated with AAA. Additionally, exploring AAA of different diameters identified eight genes (EXTL3,ZFR,DUSP8,DISP1,USP33,VPS37C,ZNF784,RFX1) that overlapped with the DEGs between AAA and controls, implying roles in both disease onset and progression. Seven genes (SPP1,FHL1,GNAS,MORF4L2,HMGN1,ARL1,RNASE4) with differential splicing patterns were also DEGs between AAA and controls, suggesting that splicing differences contribute to the observed expression changes and the disease development.ConclusionsThis study identified new genes and pathways associated with AAA onset and progression and validated previous relevant roles of inflammation and intracellular calcium regulation. These findings provide insights into the complex mechanisms underlying AAA and indicate potential targets to limit AAA progression and mortality risk.