bluuebunny/crossref_metadata_2025_split huggingface dataset:
Designing and validating a Hereditary Spastic Paraplegia-specific Quality of Life Rating Scale (HSPQoL)
Authors: Siow Sue Faye , Fleming Jane , Barlow-Stewart Kristine , Kumar Kishore R , Sue Carolyn M 
Published: July 2024

AbstractBackgroundPatients with Hereditary Spastic Paraplegia (HSP) report reduced quality of life (QoL) compared to the general population. Generic QoL measures do not address disease-specific aspects such as spasticity, access to specialty HSP clinics, and bladder symptoms. We designed and validated an HSP-specific QoL scale (HSPQoL), intended for use in standard clinical settings and clinical trials.MethodsHSP-specific items were added to the RAND 36-Item Short Form Health Survey (SF-36) to form HSPQoL. Following literature review/expert input, 23 items were presented to a panel of HSP clinicians, patients, and patient representatives (n=12) using a modified Delphi process. Items were ranked for clarity and relevance (inclusion criteria: 80% consensus). Interviews with patients (n=5) assessed suitability, comprehension, clarity, and response options to additional items. Patients completed the HSPQoL and EQ5D-5L for evaluation of construct validity (correlation, exploratory factor analysis) and test-retest reliability.ResultsFollowing the modified Delphi process, 21/23 items met the inclusion criteria. Based on cognitive interview results, items were modified (n=4), removed (n=7), or added (n=3). Sixty-one participants completed the HSPQoL and EQ5D-5L. The HSPQoL was repeated with 19 patients: 15/17 additional items moderately to strongly correlated with pre-existing SF-36 subscores (Spearman correlation 0.319-0.771, p<0.05). Exploratory factor analyses showed high percentage of variance in the first component (>45%). HSPQoL demonstrated good internal consistency (Cronbach alpha 0.94), test-retest reliability (ICC 0.957), and convergent validity with EQ5D-5L (r=0.725).ConclusionsDemonstrated validity and reliability of the HSPQoL confirms consideration of its use for assessing specific QoL in individuals with HSP.
Functional Movement Disorder Is Associated with Abnormal Interoceptive Brain Activity: A Task-based Functional MRI Study
Authors: Spagnolo Primavera A , Parker Jacob A , Hallett Mark , Horovitz Silvina 
Published: July 2024

AbstractBackgroundAberrant interoceptive processing has been hypothesized to contribute to the pathophysiology of functional neurological disorder, although findings have been inconsistent. Here, we utilized functional magnetic resonance imaging (fMRI) to examine neural correlates of interoceptive attention – the conscious focus and awareness of bodily sensations – in functional movement disorder (FMD).MethodsWe used voxelwise analyses to compare blood oxygenation level-dependent responses between 13 adults with hyperkinetic FMD and 13 healthy controls (HCs) during a task requiring attention to different bodily sensations and to an exteroceptive stimulus. Additionally, we examined between-group differences in self-reported measures of interoception and evaluated their relationship with neural activity.ResultsInteroceptive conditions (heartbeat, stomach and ‘body’, indicating sensations from the body part or limb affected in FMD participants) activated a network involving the precuneus, the posterior cingulate cortex (PCC) and caudate nucleus (CN) bilaterally, and the right anterior insula (aINS) (p<0.05 , corrected). Group differences in brain activity were mainly driven by processing of disease-related interoceptive signals, which in the FMD group was associated with a broader neural activation than monitoring gastric interoception, while no group differences were detected during cardiac interoception. Differences based on interoceptive focus (body vsheartbeat and stomach) between FMD subjects and HCs were found in PCC, CN, angular gyrus, thalamus, and in the mid-insula (p<0.05, corrected).ConclusionsThis is, to our knowledge, the first study showing that FMD is associated with abnormal interoceptive processing in regions involved in monitoring body state, attentional focus, and homeostatic inference.
Amortized template-matching of molecular conformations from cryo-electron microscopy images using simulation-based inference
Authors: Dingeldein Lars , Silva-Sánchez David , Evans Luke , D’Imprima Edoardo , Grigorieff Nikolaus , Covino Roberto , Cossio Pilar 
Published: July 2024

AbstractBiomolecules undergo conformational changes to perform their function. Cryo-electron microscopy (cryo-EM) can capture snapshots of biomolecules in various conformations. However, these images are noisy and display the molecule in unknown orientations, making it difficult to separate conformational differences from differences due to noise or projection directions. Here, we introduce cryo-EM simulation-based inference (cryoSBI) to infer the conformations of biomolecules and the uncertainties associated with the inference from individual cryo-EM images. CryoSBI builds on simulation-based inference, a combination of physics-based simulations and probabilistic deep learning, allowing us to use Bayesian inference even when likelihoods are too expensive to calculate. We begin with an ensemble of conformations, which can be templates from molecular simulations or modelling, and use them as structural hypotheses. We train a neural network approximating the Bayesian posterior using simulated images from these templates, and then use it to accurately infer the conformations of biomolecules from experimental images. Training is only done once, and after that, it takes just a few milliseconds to make inference on an image, making cryoSBI suitable for arbitrarily large datasets. CryoSBI eliminates the need to estimate particle pose and imaging parameters, significantly enhancing the computational speed in comparison to explicit likelihood methods. We illustrate and benchmark cryoSBI on synthetic data and showcase its promise on experimental single-particle cryo-EM data.
Improved constructs for bait RNA display in a bacterial three-hybrid assay
Authors: Nguyen Linh D. , LeBlanc Hannah , Berry Katherine E. 
Published: July 2024

ABSTRACTWe have previously developed a transcription-based bacterial three-hybrid (B3H) assay as a genetic approach to probe RNA-protein interactions inside ofE. colicells. This system offers a straightforward path to identify and assess the consequences of mutations in RBPs with molecular phenotypes of interest. One limiting factor in detecting RNA-protein interactions in the B3H assay is RNA misfolding arising from incorrect base-pair interactions with neighboring RNA sequences in a hybrid RNA. To support correct folding of hybrid bait RNAs, we have explored the use of a highly stable stem (“GC clamp”) to isolate regions of a hybrid RNA as discrete folding units. In this work, we introduce new bait RNA constructs to 1) insulate the folding of individual components of the hybrid RNA with GC clamps and 2) express bait RNAs that do not encode their own intrinsic terminator. We find that short GC clamps (5 or 7 bp long) are more effective than a longer 13bp GC clamp in the B3H assay. These new constructs increase the number of Hfq-sRNA and -5′UTR interactions that are detectable in the B3H system and improve the signal-to-noise ratio of many of these interactions. We therefore recommend the use of constructs containing short GC clamps for the expression of future B3H bait RNAs. With these new constructs, a broader range of RNA-protein interactions are detectable in the B3H assay, expanding the utility and impact of this genetic tool as a platform to search for and interrogate mechanisms of additional RNA-protein interactions.
The Biochemical Effects of Carotenoids in Orange Carrots on the Colonic Proteome in a Mouse Model of Diet-induced Obesity
Authors: Balbuena Emilio , Milhem Fadia , Kiremitci Buse Zeren , Williams Taufika Islam , Collins Leonard , Shu Qingbo , Eroglu Abdulkerim 
Published: July 2024

AbstractCarotenoids are naturally occurring pigments in plants and are responsible for the orange, yellow, and red color of fruits and vegetables. Carrots are one of the primary dietary sources of carotenoids. The biological activities of carotenoids in higher organisms are well documented in most tissues but not the large intestine. The gastrointestinal barrier acts as a line of defense against the systemic invasion of pathogenic bacteria, especially at the colonic level. Proteins involved in tight junction assembly between epithelial cells and mucus secretion from goblet cells are essential for maintaining intestinal barrier homeostasis. A high-fat diet can cause gut impairment by inducing barrier permeability, leading to low-grade chronic inflammation via metabolic endotoxemia. Our hypothesis for this study is that the dietary intake of carotenoid-rich foods can alleviate obesity-associated gut inflammation and strengthen the intestinal barrier function. Male C57BL/6J mice were randomized to one of four experimental diets for 20 weeks (n = 20 animals/group): Low-fat diet (LFD, 10% calories from fat), high-fat diet (HFD, 45% calories from fat), HFD with white carrot powder (HFD + WC), or HFD with orange carrot powder (HFD + OC). Colon tissues were harvested to analyze the biochemical effects of carotenoids in carrots. The distal sections were subjected to isobaric labeling-based quantitative proteomics in which tryptic peptides were labeled with tandem mass tags, followed by fractionation and LC-MS/MS analysis in an Orbitrap Eclipse Tribrid instrument. High-performance liquid chromatography results revealed that the HFD+WC pellets were carotenoid-deficient, and the HFD+OC pellets contained high concentrations of provitamin A carotenoids, specifically α-carotene and β-carotene. As a result of the quantitative proteomics, a total of 4410 differentially expressed proteins were identified. Intestinal barrier-associated proteins were highly upregulated in the HFD+OC group, particularly mucin-2 (MUC-2). Upon closer investigation into mucosal activity, other proteins related to MUC-2 functionality and tight junction management were upregulated by the HFD+OC dietary intervention. Collectively, our findings suggest that carotenoid-rich foods can prevent high-fat diet-induced intestinal barrier disruption by promoting colonic mucus synthesis and secretion in mammalian organisms. Data are available via ProteomeXchange with identifier PXD054150.
Comparative analysis of 43 distinct RNA modifications by nanopore tRNA sequencing
Authors: White Laura K. , Dobson Kezia , del Pozo Samantha , Bilodeaux Jill M. , Andersen Shelby E. , Baldwin Amber , Barrington Chloe , Körtel Nadine , Martinez-Seidel Federico , Strugar Saylor M. , Watt Kristin E.N. , Mukherjee Neelanjan , Hesselberth Jay R. 
Published: July 2024

AbstractTransfer RNAs are the fundamental adapter molecules of protein synthesis and the most abundant and heterogeneous class of noncoding RNA molecules in cells. The study of tRNA repertoires remains challenging, complicated by the presence of dozens of post transcriptional modifications. Nanopore sequencing is an emerging technology with promise for both tRNA sequencing and the detection of RNA modifications; however, such studies have been limited by the throughput and accuracy of direct RNA sequencing methods. Moreover, detection of the complete set of tRNA modifications by nanopore sequencing remains challenging. Here we show that recent updates to nanopore direct RNA sequencing chemistry (RNA004) combined with our own optimizations to tRNA sequencing protocols and analysis workflows enable high throughput coverage of tRNA molecules and characterization of nanopore signals produced by 43 distinct RNA modifications. We share best practices and protocols for nanopore sequencing of tRNA and further report successful detection of low abundance mitochondrial and viral tRNAs, providing proof of concept for use of nanopore sequencing to study tRNA populations in the context of infection and organelle biology. This work provides a roadmap to guide future efforts towardsde novodetection of RNA modifications across multiple organisms using nanopore sequencing.
WITHDRAWN: Experimental verification on “Telomere DNA and ribosomal DNA co-regulation model for cell senescence”
Authors: Huang Bilu , Wu Zhengzhi 
Published: July 2024

Withdrawal StatementThis manuscript has been withdrawn as it was submitted and made public without the full consent of all the authors. Therefore, this work should not be cited as reference for the project. If you have any questions, please contact the corresponding author.
Different timescales of neural activities introduce different representations of task-relevant information
Authors: Kurikawa Tomoki 
Published: July 2024

AbstractRecent findings indicate significant variations in neuronal activity timescales across and within cortical areas, yet their impact on cognitive processing remains inadequately understood. This study explores the role of neurons with different timescales in information processing within the neural system, particularly during the execution of context-dependent working memory tasks. Especially, we hypothesized that neurons with varying timescales contribute distinctively to task performance by forming diverse representations of task-relevant information. To test this, the model was trained to perform a context-dependent working memory task with a machine-learning technique. Results revealed that slow timescale neurons maintained stable representations of contextual information throughout the trial, whereas fast timescale neurons responded transiently to immediate stimuli. This differentiation in neuronal function suggests a fundamental role for timescale diversity in supporting the neural system’s ability to integrate and process information dynamically. Our findings contribute to understanding how neural timescale diversity underpins cognitive flexibility and task-specific information processing, highlighting implications for both theoretical neuroscience and practical applications in designing artificial neural networks.
Evolutionary plasticity and functional repurposing of the essential metabolic enzyme MoeA
Authors: Megrian Daniela , Martinez Mariano , Alzari Pedro M , Wehenkel Anne Marie 
Published: July 2024

AbstractMoeA, or gephyrin in higher eukaryotes, is crucial for molybdenum cofactor biosynthesis required in redox reactions. Gephyrin is a moonlighting protein also involved in postsynaptic receptor clustering, a feature thought to be a recent evolutionary trait. We showed previously that a repurposed copy of MoeA (Glp) is involved in bacterial cell division. To investigate how MoeA acquired multifunctionality, we used phylogenetic inference and protein structure analyses to understand the diversity and evolutionary history of MoeA. Glp-expressing Bacteria have at least two copies of the gene, and our analysis suggests that Glp has lost its enzymatic role. In Archaea we identified an ancestral duplication where one of the paralogs might bind tungsten instead of molybdenum. In eukaryotes, the acquisition of the moonlighting activity of gephyrin comprised three major events: first, MoeA was obtained from Bacteria by early eukaryotes, second, MogA was fused to the N-terminus of MoeA in the ancestor of opisthokonts, and finally, it acquired the function of anchoring GlyR receptors in neurons. Our results support the functional versatility and adaptive nature of the MoeA scaffold, which has been repurposed independently both in eukaryotes and bacteria to carry out analogous functions in network organization at the cell membrane.
Graph-structured populations elucidate the role of deleterious mutations in long-term evolution
Authors: Sharma Nikhil , Das Suman G. , Krug Joachim , Traulsen Arne 
Published: July 2024

AbstractBirth-death models have long been employed to understand the interplay of genetic drift and natural selection. While well-mixed populations remain unaffected by the choice of replacement rules, the evolutionary outcomes in spatially structured populations are strongly impacted by this choice. Moving parent individuals to vacant sites gives rise to new update rules, leading to new fixation categories for spatial graphs. We discover a new category of graphs, amplifiers of fixation, where a structure has a higher probability of fixation for mutants than the well-mixed population, regardless of their fitness value. Under death-Birth updating with parents moving to vacant sites, the star graph is an amplifier of fixation. For very large population sizes, the probability to fix deleterious mutants on the star graph converges to a non-zero value, in contrast to the result from well-mixed populations where the probability goes to zero. Additionally, most random graphs are amplifiers of fixation for death-Birth updating, with parent individuals replacing dead individuals. Conversely, most random graphs are suppressors of fixation− graphs with lower fixation probability for mutants regardless of their fitnesses− for Birth-death updating with offspring replacing dead individuals. When subjected to long-term evolution, amplifiers of fixation, despite being more efficient at fixing beneficial mutants, attain lower fitness than the well-mixed population, whereas suppressors attain higher fitness despite their inferior ability to fix beneficial mutants. These surprising findings can be explained by their deleterious mutant regime. Therefore, the deleterious mutant regime can be as crucial as the beneficial mutant regime for adaptive evolution.
QCM: real-time quantitative quality control of single-molecule localization microscopy acquisitions
Authors: Mailfert Sébastien , Djendli Meriem , Fabre Roxane , Marguet Didier , Bertaux Nicolas 
Published: July 2024

AbstractSingle molecule localization microscopy (SMLM) has revolutionized the understanding of cellular organization by reconstructing informative images with quantifiable spatial distributions of molecules far beyond the optical diffraction limit. Much effort has been devoted to optimizing localization accuracy. Among them, assessing the quality of SMLM data in real-time, rather than after lengthy post-acquisition analysis, represent a computational challenge.Here, we overcome this difficulty by implementing an innovative mathematical approach to drastically reduce the computational analysis of particle localization. We have therefore designed the Quality Control Map (QCM) workflow to process data at a much higher rate than that limited by the frequency required by current cameras. Moreover, QCM requires no parameters other than the PSF radius characteristic of the optical system and only a GPU card to reach its computational speed. Thus, QCM is robust and adaptable to any type of input data. Finally, the QCM off-line mode can be used to evaluate synthetic or previously acquired data, and as a tool for teaching the basic concepts of the SMLM approach.TeaserQCM, a parameter-free algorithm, calculates indicators for instant feedback on single-molecule localization precision experiments
Mapping fitness landscapes to interpret sex allocation in hermaphrodites
Authors: Chen Kai-Hsiu , Pannell John R. 
Published: July 2024

AbstractSex allocation theory successfully predicts sex-ratio variation among organisms with separate sexes, but it has been much less successful in explaining variation in sex allocation in hermaphrodites because the assumption of a direct tradeoff between male and female functions is often violated. Here, we show that sex-allocation theory can be applied to hermaphrodites simply by mapping components of seasonal reproductive success onto a fitness landscape defined by potentially independent measures of allocation to male and female functions on orthogonal axes. Taking this approach allowed us to interpret the complex variation in the reproductive strategy of a long-lived perennial herb (Pulsatilla alpina) that produces both male and bisexual flowers and that shifts between male and female allocation among seasons. We find that components of reproductive success forP. alpinamap onto a rugged landscape with peaks that reflect an interactive effect of male and female allocations on self-fertilization and total reproductive success and that correspond to the observed sex-allocation strategies adopted by the species in nature. This simple approach should be widely applicable to problems in the study of hermaphroditic reproduction in other plants and animals.Significance StatementSex allocation theory has helped to explain sex-ratio variation in numerous dioecious species, but it has been difficult to apply to hermaphrodites, in which male-female tradeoffs are often obscure. Here, we show that by mapping fitness estimates for plants with complex allocation patterns on a two-dimensional landscape defined by both male and female allocations, we sidestep the tradeoff assumption. Our analysis reveals fitness peaks that correspond precisely to the strategic allocation decisions adopted by the species in nature. Our simple but novel approach provides a rescue-line for a powerful body of theory that has been criticized for being too difficult to apply to the messy world of hermaphrodites, both in plants and animals.
Genome admixture among four hare species in Iberia: focus on the broom hare (Lepus castroviejoi)
Authors: Souto João , Marques João P. , Farelo Liliana , Costa José , Queirós João , Pietri Christian , Ballesteros Fernando , Alves Paulo C. , Boursot Pierre , Melo-Ferreira José 
Published: July 2024

AbstractPleistocene climatic fluctuations have often driven range shifts and hybridization among related species, leaving present-day genomic footprints. In the Iberian Peninsula,Lepus timidus, after its post-deglaciation retreat, has left extensive mitochondrial DNA traces in three other hare species, but the genomic correlates and underlying biogeographic scenarios are still incompletely understood. This study focuses onLepus castroviejoi, endemic to the Cantabrian region, using its non-Iberian sister species,L. corsicanus, for comparison. By analyzing coalescent patterns from 10 genomes, we estimate that these species remained isolated since their divergence, around 50,000 years ago, consistent with their current allopatry. Further analyses with 25 additional genomes indicate that small fractions of theL. castroviejoigenome originate fromL. granatensis,L. timidus, andL. europaeus(0.72%, 0.08%, and 0.04%, respectively). Introgression dating based on tract lengths suggestsL. granatensiswas already admixed withL. timiduswhen it hybridized withL. castroviejoi, which could explain thegranatensis-timidusancestry tract junctions detected inL. castroviejoi. Genomic segments with such junctions contain genes enriched for cell signaling and olfactory receptor activity, possibly facilitating genetic exchange. This research demonstrates how genomic ancestry inferences can reveal complex multiway admixture histories and illuminate past biogeographic events.