bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical trials in Leber hereditary optic neuropathy: outcomes and opportunities
Authors: Chen Benson S. , Newman Nancy J. 
Published: December 2024

Purpose of review
Leber hereditary optic neuropathy (LHON) is a mitochondrial DNA disease characterised by sequential bilateral vision loss due to loss of retinal ganglion cells. The purpose of this review is to provide an update on the results of recent clinical trials for LHON, focusing on studies of idebenone and lenadogene nolparvovec gene therapy.

Recent findings
Evidence from three clinical studies (RHODOS, RHODOS-OFU, and LEROS) suggest that idebenone should be started early and continued for at least 24 months. Treatment effect varies according to the stage of LHON and the underlying mutation. Favourable outcomes are associated with the m.11778G>A mutation and chronic eyes with the m.14484T>C mutation. Caution should be taken in subacute/dynamic eyes with the m.3460G>A mutation, due to possible clinical worsening with idebenone. Compared to eyes from an external natural history cohort, pooled data from four clinical studies (RESCUE, REVERSE, RESTORE and REFLECT) show that a single intravitreal injection of lenadogene nolparvovec can result in sustained bilateral visual improvement in m.11778G>A LHON patients aged ≥15 years when treated within 1 year of onset. Although the treatment effect is modest, the final visual acuity of treated patients (∼1.2 logMAR) significantly differs from the published natural history of LHON and the treatment benefit is more pronounced than the effect of idebenone alone in patients with the m.11778G>A mutation.

Summary
There is increasing evidence for the potential therapeutic benefit of idebenone and lenadogene nolparvovec gene therapy.
MEGA12: Molecular Evolutionary Genetic Analysis version 12 for adaptive and green computing
Authors: Kumar Sudhir , Stecher Glen , Suleski Michael , Sanderford Maxwell , Sharma Sudip , Tamura Koichiro 
Published: December 2024

AbstractWe introduce the 12th version of the Molecular Evolutionary Genetics Analysis (MEGA) software. This latest version brings many significant improvements by reducing the computational time needed for selecting optimal substitution models and conducting bootstrap tests on phylogenies using maximum likelihood (ML) methods. These improvements are achieved by implementing heuristics that minimize likely unnecessary computations. Analyses of empirical and simulated datasets show substantial time savings by using these heuristics without compromising the accuracy of results.MEGA12also implements an evolutionary sparse learning approach to identify fragile clades and associated sequences in evolutionary trees inferred through phylogenomic analyses. In addition, this version includes fine-grained parallelization for ML analyses, support for high-resolution monitors, and an enhancedTree Explorer. TheMEGA12beta version can be downloaded fromhttps://www.megasoftware.net/beta_download.
Inbreeding and demography interact to impact population recovery from bottlenecks
Authors: Zheng Jia , Rees-Baylis Ella , Janzen Thijs , Zhang Zhengwang , Zhan Xiangjiang , Wang Daiping , Li Richter Xiang-Yi 
Published: December 2024

AbstractBiodiversity loss driven by climate change and human activities poses a critical global challenge. Population restoration and reintroduction programs are essential for mitigating this threat, yet their outcomes are often unpredictable due to poorly understood success factors. The conservation program of the crested ibis (Nipponia nippon) marks a successful example where the population rose from seven survivors to over 9,000 in the past four decades. To learn whether this successful restoration was due to chance or largely repeatable, we developed an individual-based model that simulates the restoration process by incorporating life-history parameters from empirical data. Our simulation results closely mirror empirical findings, including the time taken to reach the current population size and population-level inbreeding coefficients. We further analyzed the model to compare the effectiveness of two reintroduction strategies and analyzed how inbreeding depression interacts with demography to influence the chance of recovery from bottlenecks. The reintroduction simulations reveal that the ‘firework’ approach (one-source translocations) outperforms the ‘stepping-stone’ (serial translocations) approach in restoration effectiveness. Our simulations over broad demographic parameters demonstrate that the net effect of inbreeding varies with species-specific demography, and highlight the importance of considering this interaction when interpreting conservation outcomes and designing future reintroduction programs.
Machine Learning Predictions Surpass Individual mRNAs as a Proxy of Single-cell Protein Expression
Authors: Fisher Josephine , Wood Oliver , Bullers Samuel , Murray Lynne , Li Li , Jackson-Wood Matthew A. 
Published: December 2024

AbstractBackgroundExpansive repositories of single-cell RNA-seq data are now available. These data are often analysed assuming that mRNA abundance reflects the expression of their cognate proteins. However, post-transcriptional and translational regulation make mRNA an inadequate proxy for protein. High sparsity in low abundance mRNAs from single-cell transcriptomics data further complicates the extrapolation of protein expression levels. Although methods for single-cell surface protein quantification exist, they incur additional technical steps at greater expense and have yet to see wide-spread adoption. Computational approaches for protein imputation from scRNAseq data have been published, which learn transcriptome-wide patterns that predict protein expression. These models can then be applied to infer surface protein expression on RNA-seq only data, to increase the utility of existing data repositories.ResultsWe tested 8 such methods and compared the accuracy of predictions between approaches, and against cognate mRNAs as a direct proxy. Predictions from the trained models outperformed the use of mRNA expression as a proxy. We identify notable cases of cell surface proteins with very poor correlation with their mRNA that were predicted very successfully by imputation using the whole transcriptome. We find cell type signatures are a major determinant of predicted protein levels and, as such, prediction methods require representative training data.ConclusionsThese results reiterate that mRNA level is not a reliable predictor of cell surface protein expression, and that whole-transcriptome informed imputation can improve protein estimations given appropriately trained models.
Sending mixed signals: convergent iridescence and divergent chemical signals in sympatric sister-species of Amazonian butterflies
Authors: Ledamoisel Joséphine , Buatois Bruno , Mauxion Rémi , Andraud Christine , McClure Melanie , Debat Vincent , Llaurens Violaine 
Published: December 2024

AbstractClosely-related species are often partitioned into different geographic areas or micro-habitats as a result of competition and reproductive interference. Here, we investigate how the evolution of shared adaptive traits may shape ecological interactions and genetic divergence, and facilitate co-existence in sympatry. In closely-relatedMorphobutterfly species living in the understory of the neo-tropical rainforest, the blue iridescent coloration of the wings is likely involved in predation evasion as well as in mating recognition and courtship. These contrasted selective pressures acting on this visual trait shared between closely-related species has likely shaped their coexistence. We used spectrophotometry, behavioral experiments, visual modeling and chemical analyses applied to samples from allopatric and sympatric populations ofMorpho helenorandMorpho achillesto characterize how the evolution of visual and chemical traits might favor their coexistence in sympatry: we quantified the differences in wing iridescence and tested for variations in the sexual preference for this trait between allopatricvs.sympatric populations. We found a strong similarity in iridescence among species in sympatry, suggesting convergence driven by predation. Although behavioral results suggest that iridescent signals could also be used as visual cues during mate choice, convergent iridescent signals may impair the visual recognition of sympatricMorphospecies. In contrast, divergent chemical bouquets among species suggest that the visual similarity of sympatricMorphospecies might have favored the divergence of alternative traits involved in species recognition such as chemical cues. This study underlines how ecological interactions and trait evolution can shape species coexistence in sympatry.
Biomechanics of stem cell fate decisions in multilayered tissues
Authors: Sahu Preeti , Canato Sara , Soares Raquel , Sánchez-Danés Adriana , Hannezo Edouard 
Published: December 2024

AbstractTissue homeostasis relies on a precise balance of fate choices between renewal and differentiation, which is dysregulated during tumor initiation. Although much progress has been done over recent years to characterize the dynamics of cellular fate choices at the single cell level, their underlying mechanistic basis often remains unclear. In particular, although physical forces are increasingly characterized as regulators of cell behaviors, a unifying description of how global tissue mechanics interplays with local cellular fate choices is missing. Concentrating on skin epidermis as a paradigm for multilayered tissues with complex fate choices, we develop a 3D vertex-based model with proliferation restrained in the basal layer, showing that mechanics and competition for space naturally gives rise to homeostasis and neutral drift dynamics that are seen experimentally. We then explore the effect of introducing mechanical inhomogeneities, whereby subpopulations have differential tensions. We uncover that relatively small mechanical disparities can be sufficient to heavily tilt cellular towards symmetric renewal and exponential growth. Importantly, the simulations predict that such mechanical inhomogeneities are reflected by distinct morphological changes in single-cell shapes. This led us to derive a master relationship between two very different experimentally measurable parameters, cell shape and long-term clonal dynamics, which we validated using a model of basal cell carcinoma (BCC) consisting in clonal Smoothened overexpression in mouse tail epidermis. Altogether, we propose a theoretical framework to link mechanical forces, quantitative cellular morphologies and cellular fate outcomes in complex tissues.
Modulatory Effects of Mdivi-1 on OxLDL-Induced Metabolic Alterations, Inflammatory Responses, and Foam Cell Formation in Human Monocytes
Authors: Mosalmanzadeh Negin , Maurmann Rafael Moura , Davis Kierstin , Schmitt Brenda Landvoigt , Makowski Liza , Pence Brandt D. 
Published: December 2024

AbstractAtherosclerosis, a major contributor to cardiovascular disease, involves lipid accumulation and inflammatory processes in arterial walls, with oxidized low-density lipoprotein (OxLDL) playing a central role. OxLDL is increased during aging and stimulates monocyte transformation into foam cells and induces metabolic reprogramming and pro-inflammatory responses, accelerating atherosclerosis progression and contributing to other age-related diseases. This study investigated the effects of Mdivi-1, a mitochondrial fission inhibitor, and S1QEL, a selective complex I-associated reactive oxygen species (ROS) inhibitor, on OxLDL-induced responses in monocytes. Healthy monocytes isolated from participants were treated with OxLDL, with or without Mdivi-1 or S1QEL, and assessed for metabolic shifts, inflammatory cytokine expression, foam cell formation, and ROS production. OxLDL treatment elevated glycolytic activity (ECAR) and expression of pro-inflammatory cytokines IL1B and CXCL8, promoting foam cell formation and mitochondrial ROS (mtROS) production. Mdivi-1 and S1QEL effectively reduced OxLDL-induced glycolytic reprogramming, inflammatory cytokine levels, and foam cell formation while limiting mtROS. These findings suggest that both Mdivi-1 and S1QEL modulate key monocyte responses to OxLDL, providing insights into potential therapeutic approaches for age-related diseases.
Epigenomics of embryogenesis in turbot (Scophthalmus maximus)
Authors: Aramburu Oscar , Pardo Belén G. , Jimenez-Gonzalez Ada , Blanco-Hortas Andrés , Macqueen Daniel J. , Bouza Carmen , Martínez Paulino 
Published: December 2024

ABSTRACTEmbryogenesis is the crucial first step of ontogeny, where an organism with a complex body plan arises from a single undifferentiated totipotent cell. This process is orchestrated by dynamic changes in transcriptional regulation, influenced by chromatin accessibility and nucleotide and histone modifications constituting epigenetic signals enabling access to transcription factors. The epigenomic regulation of embryogenesis has been studied in model fishes, but little attention has been paid to farmed fish - where traits of importance to aquaculture rely on early developmental processes. This study, framed within the AQUA-FAANG consortium, reports a comprehensive regulatory atlas of embryogenesis for turbot (Scophthalmus maximus), a farmed flatfish representing order Pleuronectiformes. 14,560 genes were expressed in the embryonic transcriptome with > 90% showing differential expression across consecutive stages. By integrating multi-histone ChIP-Seq marks with ATAC-Seq, we built a genome-wide chromatin state model, defining promoter and enhancer activity across stages. Transcription factor binding motif (TFBM) analysis of differentially active promoters and enhancers revealed dynamism in regulated gene functions, with more than half the TFBM enriched in a single developmental transition. Significant shifts in chromatin accessibility occurred across stages, most notably during the transition from shield to early segmentation, suggesting a profound chromatin reorganization underpins somitogenesis and early organ development. Most changes in chromatin accessibility across stages did not involve promoter regions of differentially expressed genes, suggesting a trend of promoter accessibility preceding gene transcriptional activity. Comparative analyses with zebrafish revealed a global transcriptomic correlation of single copy orthologs at matched stages of embryogenesis across species. While conserved expression dynamics were revealed for many orthologous Hox genes, notable cross-species differences were identified from before zygotic genome activation leading up to hatching. This multi-omics investigation provides a novel atlas of non-coding regulatory elements controlling turbot development, with key applications for flatfish biology and enhancing sustainable aquaculture.
Condensates act as translation hubs to coordinate multinucleate cell growth
Authors: Geisterfer Zachary M. , Jalihal Ameya P. , Cole Sierra J. , Gladfelter Amy S. 
Published: December 2024

AbstractCoordination between growth and division is a fundamental feature of cells. In many syncytia, cell growth must couple with multiple nuclear divisions in one cytoplasm. In the fungus,Ashbya gossypii,cell-cycle progression and hyphal elongation require condensates formed by the protein Whi3 in complex with distinct mRNA species. We hypothesized the condensates may act through local translation regulation and find that Whi3 target mRNAs show distinct spatial biases in translation in vivo. Whi3-RNA condensates can both promote and repress RNA translation in an RNA- and condensate size-dependent manner in vitro. Interestingly, we observe a sub-condensate enrichment of translation that is tunable by RNA valency and protein phospho-state. Together, these data suggest that Whi3 condensates generate a continuum of translation states, resulting in asynchronous nuclear divisions coordinated with growth. This local regulation requires a minimal complement of molecular components at the nano scale to support global coordination at the cell scale.
SpecificSOX10enhancer elements modulate phenotype plasticity and drug resistance in melanoma
Authors: DeGeorgia Sophia “Noah” , Kaufman Charles K. 
Published: December 2024

AbstractRecent studies indicate that the development of drug resistance and increased invasiveness in melanoma is largely driven by transcriptional plasticity rather than canonical coding mutations. Understanding the mechanisms behind cell identity shifts in oncogenic transformation and cancer progression is crucial for advancing our understanding of melanoma and other aggressive cancers. While distinct melanoma phenotypic states have been well characterized, the processes and transcriptional controls that enable cells to shift between these states remain largely unknown. In this study, we initially leverage the well-established zebrafish melanoma model as a high-throughput system to dissect and analyze transcriptional control elements that are hijacked by melanoma. We identify key characteristics of these elements, making them translatable to human enhancer identification despite the lack of direct sequence conservation. Building on our identification of a zebrafishsox10enhancer necessary for melanoma initiation, we extend these findings to human melanoma, identifying two human upstream enhancer elements that are critical for fullSOX10expression. Stable biallelic deletion of these enhancers using CRISPR-Cas9 induces a distinct phenotype shift across multiple human melanoma cell lines from a melanocytic phenotype towards an undifferentiated phenotype and is also characterized by an increase in drug resistance that mirrors clinical data including an upregulation of NTRK1, a tyrosine kinase, and potential therapeutic target. These results provide new insights into the transcriptional regulation ofSOX10in human melanoma and underscore the role of individual enhancer elements and potentially NTRK1 in driving melanoma phenotype plasticity and drug resistance. Our work lays the groundwork for future gene-based and combination kinase-inhibitor therapies targetingSOX10regulation and NTRK1 as a potential avenue for enhancing the efficacy of current melanoma treatments.
Plasmo3Net: A Convolutional Neural Network-Based Algorithm for Detecting Malaria Parasites in Thin Blood Smear Images
Authors: Owoloye Afolabi J. , Ligali Funmilayo C. , Enejoh Ojochenemi A. , Agosile Oluwafemi , Musa Adesola Z. , Aina Oluwagbemiga , Idowu Emmanuel T. , Oyebola Kolapo M. 
Published: December 2024

ABSTRACTEarly diagnosis of malaria is crucial for effective control and elimination efforts. Microscopy is a reliable field-adaptable malaria diagnostic method. However, microscopy results are only as good as the quality of slides and images obtained from thick and thin smears. In this study, we developed deep learning algorithms to identify malaria-infected red blood cells (RBCs) in thin blood smears. Three algorithms were developed based on a convolutional neural network (CNN). The CNN was trained on 15,060 images and evaluated using 4,000 images. After a series of fine-tuning and hyperparameter optimization experiments, we selected the top-performing algorithm, which was named Plasmo3Net. The Plasmo3Net architecture was made up of 13 layers: three convolutional, three max-pooling, one flatten, four dropouts, and two fully connected layers, to obtain an accuracy of 99.3%, precision of 99.1%, recall of 99.6%, and F1 score of 99.3%. The maximum training accuracy of 99.5% and validation accuracy of 97.7% were obtained during the learning phase. Four pre-trained deep learning models (InceptionV3, VGG16, ResNet50, and ALexNet) were selected and trained alongside our model as baseline techniques for comparison due to their performance in malaria parasite identification. The topmost transfer learning model was the ResNet50 with 97.9% accuracy, 97.6% precision, 98.3 % recall, and 97.9% F1 score. The accuracy of the Plasmo3Net in malaria parasite identification highlights its potential for automated malaria diagnosis in the future. With additional validation using more extensive and diverse datasets, Plasmo3Net could evolve into a diagnostic workflow suitable for field applications.
Assessing group size and the demographic composition of unhabituated northern muriqui (Brachyteles hypoxanthus) using non-invasive biomonitoring
Authors: Kaizer Mariane C. , Sales Naiara G. , Alvim Thiago H. G. , Strier Karen B. , de Melo Fabiano R. , Boubli Jean P. , Young Robert J. , McDevitt Allan D. 
Published: December 2024

AbstractObtaining accurate population measures of endangered species is critical for effective conservation and management actions and to evaluate their success overtime. However, determining the population size and demographic composition of most canopy forest-dwelling species has proven to be challenging. Here, we apply two non-invasive biomonitoring methods, arboreal camera trap and genetic tagging of faecal samples, to estimate the population size of a critically endangered primate, the northern muriqui (Brachyteles hypoxanthus), in the Caparaó National Park, Brazil. When comparing population sizes between camera trapping and genetic tagging, the genetic tagging survey estimated fewer individuals for one of the muriqui groups studied but showed slightly higher population size estimates for the other group. In terms of the cost-efficiency of both methods, arboreal camera trapping had high initial costs but was more cost-effective in the long-term. Genetic tagging on the other hand did not require expensive equipment for data collection but had higher associated expenses for laboratory consumables and data processing. We recommend the use of both methods for northern muriqui monitoring and provide suggestions for improving the implementation of these non-invasive methods for future routine monitoring. Our findings also highlight the potential of arboreal camera trapping and genetic tagging to other arboreal mammals in tropical forests.
Targeting and anchoring the mechanosensitive ion channel Piezo to facilitate its inhibition of axon regeneration
Authors: Wang Qin , Miles Leanne , Wang Shuo , Noristani Harun N. , Monahan Vargas Ernest J. , Powell Jackson , O’Rourke-Ibach Sean J , Li Shuxin , Song Yuanquan 
Published: December 2024

AbstractMechanical force orchestrates a myriad of cellular events including inhibition of axon regeneration, by locally activating the mechanosensitive ion channel Piezo enriched at the injured axon tip. However, the cellular mechanics underlying Piezo localization and function remains poorly characterized. We show that the RNA repair/splicing enzyme Rtca acts upstream of Piezo to modulate its expression and transport/targeting to the plasma membrane via Rab10 GTPase, whose expression also relies on Rtca. Loss or gain of function of Rab10 promotes or impedesDrosophilasensory neuron axon regeneration, respectively. Rab10 mediates the cell surface expression of integrin β1 (Itgb1)/mys, which colocalizes and genetically interacts with Piezo, facilitating its anchorage and engagement with the microenvironment, and subsequent activation of mechanotransduction to inhibit regeneration. Importantly, loss of Rtca, Rab10 or Itgb1 promotes CNS axon regeneration after spinal cord injury or optic nerve crush in adult mice, indicating the evolutionary conservation of the machinery.