bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early exposure to Western Diet exacerbates visual outcomes in female mice
Authors: Meseguer David , Furtado Jessica , Zapadka Thomas , Rodriguez Amanda , Na Daxiang , Grajales-Reyes Jose G. , Demb Jonathan , Eichmann Anne , Schneeberger Marc 
Published: December 2024

AbstractObesity, a growing pandemic in Western societies, significantly impacts metabolic health and contributes to visual disorders. While the systemic consequences of obesity, such as chronic inflammation and insulin resistance, are well-studied in adults, its early-life effects on retinal health remain underexplored. Using a maternal Western Diet (WD) exposure model, we investigated the developmental impact of early-life metabolic disturbances on retinal and cognitive function. Our findings reveal that WD exposure from gestation to early adulthood accelerates the onset of features resembling diabetic retinopathy, including increased retinal vascularization, inflammation, and compromised blood-retina barrier integrity, observed within just four months. Females exhibited heightened vulnerability, showing pronounced ocular defects such as anophthalmia, microphthalmia, and congenital cataracts. These results underscore a critical developmental window during which metabolic disruptions predispose to sex-specific retinal and neurovascular pathologies. This work bridges the link between pediatric and adult obesity, highlighting the urgent need for early interventions to mitigate long-term visual impairments that could further impair recognition memory.
Reshaping the Landscape of Locoregional Treatments for Breast Cancer Liver Metastases: A novel, intratumoral, p21-targeted percutaneous therapy increases survival in BALB/c mice inoculated with 4T1 triple negative breast cancer cells in the liver
Authors: Margulies Bryan S. , Likhitpanichkul Morakot , Tripathy Debu 
Published: December 2024

AbstractPatients with disseminated metastatic disease from breast cancer are likely to have liver involvement in >50% of cases at some point during disease progression. These patients have a poor prognosis; and, when treated with the standard of care systemic therapy they have a median survival of <9-months. Increasing survival in breast cancer patients will likely require the administration of better therapies that are specifically targeted to treat distant metastases. One approach to increasing treatment efficacy for breast cancer liver metastases is through the application locoregional therapies. Locoregional therapies are an appealing interventional approach for breast cancer patients with liver metastases since these tumor lesions are accessible via minimally invasive procedures that can be administered using either ultrasound or CT imaging. Current locoregional therapies to treat breast cancer liver metastases are non-specific and have not produced significant increases in survival. The goal of this study was to design and test a targeted locoregional therapeutic intervention for breast cancer liver metastases. The lead candidate, a fixed-dose small-molecule drug called MBC-005, was testedin vitroand then the efficacy was evaluated in a BALB/c mouse liver metastases model. A novel formulation of N-allyl noroxymorphone hydrochloride incorporated into an alginate-based gel overcomes many of the limitations associated with the administration of small-molecule drugs, which include solubility, off-target toxicity, and enzymatic degradation.In vitroresults demonstrated that MBC-005 mediated its anti-tumorigenic effect through a p21-dependent mechanism via a novel molecular pathway, in which N-allyl noroxymorphone component of MBC-005 stimulated the opioid growth factor receptor to increase p21 expression. Intratumoral administration of MBC-005 increased survival 3.9-fold in mice and significantly decreased tumor volume 4-fold. While many cytotoxic therapies increase p21 expression as a response to DNA damage, MBC-005 increased p21 expression independent cytotoxic DNA damage. MBC-005 did not induce off-target toxicity; and, as such, would be amenable to multiple rounds of administration. Nevertheless, it is notable that the positive effects of MBC-005 treatment on increasing survival and decreasing tumor volume in mice was achieved using a single dose.
Genetic Control of Prickles in Tetraploid Blackberry
Authors: Johns Carmen A. , Silva Alexander , Chizk T. Mason , Nelson Lacy , Clark John R. , Aryal Rishi , Ashrafi Hudson , Thompson Ellen , Hardigan Michael , Worthington Margaret 
Published: December 2024

AbstractPrickle-free blackberry (RubussubgenusRubus) canes are strongly preferred by growers due to food and worker safety concerns and damage to fruit from mechanical injury by prickles. This project was conducted to identify the genetic region responsible for prickle-free canes derived from the recessive ’Merton Thornless’ source in autotetraploid blackberry using a genome-wide association study, develop diagnostic KASP markers for prickle-free canes, and determine the effects of allele dosage at the prickle-free locus on prickle density in two biparental populations. The prickle locus was located on chromosome Ra04 from 30.48 to 36.04 Mb in an extensive LD block, with the peak SNP located at 33.64 Mb. Two diagnostic KASP markers were developed that correctly predicted the phenotype of 97% and 96% of 626 diverse fresh-market blackberry genotypes from multiple breeding programs, respectively. Allele dosage at the prickle-free locus had a significant impact on prickle density, with duplex prickly genotypes having significantly higher prickle density than simplex genotypes in both biparental populations studied. Five potential candidate genes with functional annotations related to epidermal, trichome, and/or prickle development were identified within the prickle-free locus, but no nonsynonymous polymorphism within these genes were identified.Article SummaryBlackberry cultivars with prickle-free canes are strongly preferred by growers and shipper marketers. The objectives of this study were to map the prickle-free locus in tetraploid fresh- market blackberries using a genome-wide association approach and develop diagnostic molecular markers that breeders can use to plan crosses and screen seedlings for prickle-free canes. The prickle-free locus was mapped to a 5.6 Mb region on chromosome Ra04. Two molecular markers developed in this region correctly predicted the phenotype of 96% or more of the breeding selections and cultivars in a large validation panel composed of germplasm from three breeding programs.
One score to rule them all: regularized ensemble polygenic risk prediction with GWAS summary statistics
Authors: Zhao Zijie , Dorn Stephen , Wu Yuchang , Yang Xiaoyu , Jin Jin , Lu Qiongshi 
Published: December 2024

AbstractEnsemble learning has been increasingly popular for boosting the predictive power of polygenic risk scores (PRS), with almost every recent multi-ancestry PRS approach employing ensemble learning as a final step. Existing ensemble approaches rely on individual-level data for model training, which severely limits their real-world applications, especially in non-European populations without sufficient genomic samples. Here, we introduce a statistical framework to construct regularized ensemble PRS, which allows us to combine a large number of candidate PRS models using only summary statistics from genome-wide association studies. We demonstrate its robust and substantial improvement over many existing PRS models in both within- and cross-ancestry applications. We believe this is truly “one score to rule them all” due to its capability to continuously combine newly developed PRS models with existing models to improve prediction performance, which makes it a universal approach that should always be employed in future PRS applications.
Potential antiviral and immunomodulatory Amazonian medicinal plant compounds
Authors: Napoleão Sarah Maria da Silva , Bernardes João Paulo Romualdo Alarcão , Tenório Bernardo Guerra , Cardenas Calisto Moreno , Dallago Bruno Stéfano Lima , Çiçek Serhat Sezai , Bezerra Roberto Messias , Segovia Jorge Federico Orellana , Kanzaki Elida Cleyse Gomes da Mata , Kanzaki Isamu 
Published: December 2024

AbstractBackgroundNovel antiretroviral drugs are in constant need for HIV/AIDS patients to face the continuous emerging resistance to the commonly prescribed combination of anti-HIV synthetic agents and their side effects.MethodsAmazonian medicinal plants,Licania macrophylla(Chrysobalanaceae) andOuratea hexasperma(Ochnaceae) were assayed for antiretroviral and immunomodulatory activity, utilizing an established human leukocyte cell line and the Simian Immunodeficiency Virus. The IL-4, IL-6, IL-8, IL-10 and IFN-y cytokines were quantified after leukocyte culture stimulation with ethanolic plant extracts and challenged with lentivirus infection.ResultsMitotic activity induced byO. hexaspermaextract was significatively more pronounced thanL. macrophyllaextract. Cytokine modulation was recorded in SIV infected cells under independent treatment withO. hexaspermaandL. macrophyllaextracts. Betulinic acid, ninuriflavone, (-)epigallocathechine, (-)gallocatechine and 4-O-methyl-epigallocatechin were isolated fromL. macrophyla.ConclusionsCellular proliferative activity and cytokine modulation by the extracts assayed have potential applications in the therapy of HIV/AIDS pathology, as the isolated compounds of these plants have been reported for antiviral activity.
A Comparative Review of Deep Learning Methods for RNA Tertiary Structure Prediction
Authors: Martinović Ivona , Vlašić Tin , Li Yang , Hooi Bryan , Zhang Yang , Šikić Mile 
Published: December 2024

AbstractSeveral deep learning-based tools for RNA 3D structure prediction have recently emerged, including DRfold, DeepFoldRNA, RhoFold, RoseTTAFoldNA, trRosettaRNA, and AlphaFold3. In this study, we systematically evaluate these six models on three datasets: RNA Puzzles, CASP15 RNA targets, and a newly generated large dataset of sequentially distinct RNAs, which serves as a benchmark for generalization capabilities. To ensure a robust evaluation, we also introduce a fourth, more stringent dataset that contains both sequentially and structurally distinct RNAs. We observed that each model predicts the best structure for certain RNAs, and evaluated whether commonly used scoring functions, Rosetta score and ARES, can reliably identify the most accurate structure from the predictions. Finally, since many RNA chains in the Protein Data Bank are part of complexes, we compare the performance of RoseTTAFoldNA and AlphaFold3 in predicting RNA structures within complexes versus isolated RNA chains extracted from these complexes. This comprehensive evaluation highlights the strengths and limitations of current deep learning-based tools and provides valuable insights for advancing RNA 3D structure prediction.
Effect of levodopa/carbidopa on the progression of Machado-Joseph disease /spinocerebellar ataxia type 3 (MJD/SCA3)
Authors: Raposo Mafalda , Sárkány Zsuzsa , Damásio Joana ,   CRC-SCA Consortium, Lima Manuela , Macedo-Ribeiro Sandra , Martins Pedro M. 
Published: December 2024

Background and ObjectivesIn Machado-Joseph disease or spinocerebellar ataxia type 3 (MJD/SCA3), ataxin-3 accumulates as neuronal nuclear inclusions in specific regions of the brain such as the substantia nigra and the dentate cerebellar nucleus. Ataxin-3 aggregation is strongly inhibited by dopamine, a neurotransmitter whose brain levels can be increased through the use of medication containing levodopa/carbidopa (LA/CA). Here we perform a retrospective study to determine whether exposition to LA/CA is associated with a decreased progression of MJD/SCA3.MethodsWe assessed the natural history of individuals with MJD/SCA3 and also SCA1, 2, 6, 7, 8, and 10 enrolled by the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA). Our initial analysis focused on individuals with all spinocerebellar ataxias (SCAs) whose ataxia progression was assessed by the Scale for the Assessment and Rating of Ataxia (SARA) between 2010 and 2023. To account for important covariates affecting the time evolution of SARA scores, our study was then limited to MJD/SCA3 cases with genetic and age information available. A linear mixed model was used to determine the effects of LA/CA and other anti-parkinsonian drugs at 6 and 13 years of MJD/SCA3 progression.ResultsAmong the group of 716 individuals with SCAs with monitored SARA scores, 58 (8.1%) had taken LA/CA formulations, whereas 26 (3.6%) had taken other anti-parkinsonian drugs, mainly dopamine receptor agonists. A non-parametric analysis suggested a positive effect of LA/CA on the probability of major disease decline during the initial 6 years of patient monitoring. A multivariate analysis of 262 MJD/SCA3 cases (of which 30 were taken LA/CA) showed statistically significant effects in favor of LA/CA exposition: after adjusting for age and number of CAG repeats in the expanded allele, the yearly SARA response demonstrated a positive effect at 6 years (linear mixed model coefficientβ = −0.651[95% confidence interval−1.141 to −0.161],P = 0.009) and 13 years (β = −0.274[−0.547to−0.002],P = 0.048).ConclusionsThe use of LA/CA to treat non-cerebellar symptoms had a beneficial effect on the SARA score progression in MJD/SCA3. This observation supports the hypothesis that restoring the dopamine levels in the brains of MJD/SCA3 patients might slow down disease progression. Our findings warrant further investigation on whether individuals with MJD/SCA3, even in the absence of Parkinsonian symptoms should also be treated with LA/CA and at what doses.
Scaling Dense Representations for Single Cell with Transcriptome-Scale Context
Authors: Ho Nicholas , Ellington Caleb N. , Hou Jinyu , Addagudi Sohan , Mo Shentong , Tao Tianhua , Li Dian , Zhuang Yonghao , Wang Hongyi , Cheng Xingyi , Song Le , Xing Eric P. 
Published: December 2024

AbstractDeveloping a unified model of cellular systems is a canonical challenge in biology. Recently, a wealth of public single-cell RNA sequencing data as well as rapid scaling of self-supervised learning methods have provided new avenues to address this longstanding challenge. However, rapid parameter scaling has been essential to the success of large language models in text and images, while similar scaling has not been attempted with Transformer architectures for cellular modeling. To produce accurate, transferable, and biologically meaningful representations of cellular systems, we develop AIDO.Cell, a pretrained module for representing gene expression and cellular systems in an AI-driven Digital Organism [1]. AIDO.Cell contains a series of 3M, 10M, 100M, and 650M parameter encoder-only dense Transformer models pre-trained on 50 million human cells from diverse tissues using a read-depth-aware masked gene expression pretraining objective. Unlike previous models, AIDO.Cell is capable of handling the entire human transcriptome as input without truncation or sampling tricks, thus learning accurate and general representations of the human cell’s entire transcriptional context. This pretraining with a longer context was enabled through FlashAttention-2, mixed precision, and large-scale distributed systems training. AIDO.Cell (100M) achieves state-of-the-art results in tasks such as zero-shot clustering, cell-type classification, and perturbation modeling. Our findings reveal interesting loss scaling behaviors as we increase AIDO.Cell’s parameters from 3M to 650M, providing insights for future directions in single-cell modeling. Models and code are available through ModelGenerator inhttps://github.com/genbio-ai/AIDOand on Hugging Face.
Superspreaders have lower gut microbial alpha-diversity and distinct gut microbial composition in a natural rodent population
Authors: Wanelik Klara M. , Begon Mike , Bradley Janette E. , Fenn Jonathan , Jackson Joseph A. , Paterson Steve 
Published: December 2024

AbstractThe microbiome is well-known to drive variation in host states (e.g., behaviour, or immunity) that would be expected to modulate the spread of infectious disease - but the role of microbiotal interactions in promoting superspreading by individuals is poorly understood. Superspreaders are individuals with a strongly disproportionate contribution to pathogen transmission, and they come in two forms. Supershedders transmit infection to more individuals because they shed higher levels of a pathogen. Supercontacters transmit infection to more individuals because they have a larger number of social contacts. We explore associations between the gut microbiota and these two forms of superspreading in a wild rodent model –Bartonellaspp. bacteraemia in the field vole (Microtus agrestis). We find evidence that, first, individuals fall into distinct shedding and contacting clusters, and second, that higher-contacters have lower and more variable gut microbial alpha-diversity than lower-contacters. We also show evidence that both higher-shedders and higher-contacters have distinct gut microbial composition, and identify OTUs which are differentially abundant in the gut microbiota of these two classes of individuals when compared to lower-shedders and lower-contacters respectively. We find that theMuribaculaceaeare associated with differences in both shedding and contacting, and discuss potential mechanisms by which they may be acting on these host traits.
ACE: a versatile contrastive learning framework for single-cell mosaic integration
Authors: Yan Xuhua , Chen Jinmiao , Zheng Ruiqing , Li Min 
Published: December 2024

AbstractThe integration of single-cell multi-omics datasets is critical for deciphering cellular heterogeneities. Mosaic integration, the most general integration task, poses a greater challenge regarding disparity in modality abundance across datasets. Here, we present ACE, a mosaic integration framework that assembles two types of strategies to handle this problem: modality-alignment based strategy (ACE-align) and regression-based strategy (ACE-spec). ACE-align utilizes a novel contrastive learning objective for explicit modality alignment to uncover the shared latent representations behind modalities. ACE-spec combines the modality-alignment results and modality-specific representations to construct complete multi-omics representations for all datasets. Extensive experiments across various mosaic integration scenarios demonstrate the superiority of ACE’s two strategies over existing methods. Application of ACE-spec to bi-modal and tri-modal integration scenarios showcases that ACE-spec is able to enhance the representation of cellular heterogeneities for datasets with incomplete modalities. The source code of ACE can be accessed athttps://github.com/CSUBioGroup/ACE-main.
A digital DNA system reveals the superiority of unidirectional inheritance over ‘Lamarckian’ inheritance
Authors: Shiju Aswathi , Arras Samantha D. M. , Rodrigo Allen G. , Poole Anthony M. 
Published: December 2024

ABSTRACTIn biology, changes to a DNA sequence can impact protein sequence but changes to protein sequence (phenotype) do not flow back into DNA (genotype). A system with bidirectional information flow (i.e. both translation and ‘reverse translation’) remains a theoretical possibility for an independent origin of life or an artificial biosystem, but the recent development of digital data storage in DNA does just this: changes made to a digital file can be written back into DNA, meaning changes to ‘phenotype’ can be written back to ‘genotype’. To explore the evolutionary properties of such a system, we created an artificial system where synthetic DNA serves as genotype and music as phenotype. Audio can be output from a DNA sequence, then recorded and written to DNA as ‘codons’, enabling bidirectional information flow (DNA→music and music→DNA). Our results show that the mutation rate in a bidirectional system is much higher than for unidirectional information flow, and that, under reverse translation there is no mechanism for preservation of codon choice across generations. This has the effect of eliminating the impact of spontaneous synonymous mutations, a key the benefit of a redundant genetic code. As a result, non-synonymous mutations are the only DNA-level changes that are transmitted across generations, and, as non-synonymous mutation can emerge at both ‘genotypic’ and ‘phenotypic’ levels, these occur at a two-fold higher frequency than in a unidirectional system. Our system holds some practical insight. First, for DNA read/write systems, it may be wise to avoid designing systems with ‘de novoreverse translation’ because the opportunities for mutation are higher; tracking genotype information from the preceding generation to guide this process may reduce error. Second, our system helps clarify how a ‘Lamarckian’ biological system might operate. We conclude that, were a ‘Lamarckian’ system of inheritance a feature of early genetic systems, it would likely have been short lived as the high frequency of mutation would risk driving the system to extinction. A system based on unidirectional information flow thus appears superior as there are fewer opportunities for mutational error.
Age-dependent differential iron deficiency responses of rosette leaves during reproductive stages inArabidopsis thaliana
Authors: Ngigi Mary , Khan Mather , Remus Ricarda , Gupta Shishir K , Bauer Petra 
Published: December 2024

AbstractIron is essential for plant development throughout the life cycle. When plants lack the crucial micronutrient iron (Fe), they develop interveinal leaf chlorosis and stunted growth. To cope with this, they adjust gene expression and manage Fe and other metal ions accordingly. Rosette leaves may act as Fe sources and Fe sinks. Little is known about the dynamics of Fe deficiency (-Fe) responses in theArabidopsis thalianarosette leaves during the reproductive stages.We studied the dynamics of Fe-dependent responses at four consecutive reproductive stages (rosette, bolting, flowering, mature silique stages, hereby named RS, BS, FS, MS). We examined the growth of rosette leaves, elemental contents and gene expression patterns of Fe homeostasis genes belonging to differently regulated groups. We determined individual leaf sizes during seven days of +Fe and -Fe treatment at the RS.Young leaves responded rapidly to -Fe with growth inhibition and yellowing. Old and young leaves differed in gene expression patterns and elemental contents. Differences were also noted between the early and late reproductive stages (primarily RS and BS versus MS) and correlations between ionomic contents and gene expression were detected. Although all leaves had induced Fe recycling genes at -Fe, the expression patterns of “High Fe” and other Fe marker genes together with elemental contents indicate that old leaves at the RS and BS might serve as Fe sources, while young leaves might be Fe sinks at +Fe.Our findings highlight a developmental stage-dependent modulation of +Fe and -Fe responses in leaves. We discuss possible leaf signaling mechanisms accounting for the distinct responses between old and young leaves. This insight is informative for iron management in crops.One-sentence summaryThis study explores reproductive stage-dependent responses of rosette leaves to iron availability, revealing distinct growth, elemental contents, and gene expression patterns between young and old leaves and stages.Major findingsYoung leaves but not old leaves exhibited rapid growth inhibition and chlorosis under -Fe conditions.Significant differences in gene expression and ionomics profile were observed between old and young leaves.Contrasts were noted between the early reproductive stages (RS, BS) and the late ones (FS, MS).Correlations between ionomics profiles and gene expression indicated a complex interaction.