bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diaminopurine in Nonenzymatic RNA Template Copying
Authors: Jia Xiwen , Fang Ziyuan , Kim Seohyun Chris , Ding Dian , Zhou Lijun , Szostak Jack W. 
Published: February 2024

AbstractIn the primordial RNA World, before the advent of ribozymes, nonenzymatic template copying would have been essential for the transmission of genetic information. However, the products of chemical copying with the canonical nucleotides are heavily biased towards the incorporation of G and C. Diaminopurine (D) can form a D:U base pair that is almost as strong as a G:C base pair. We therefore asked whether replacing A with D might lead to more efficient and less biased nonenzymatic template copying. As expected, primer extension substrates containing D bind to U in the template more tightly than substrates containing A. However, primer extension with D exhibited elevated reaction rates on a C template, leading to concerns about fidelity. To investigate the nature of the D:C mismatch, we solved the crystal structure of RNA duplexes containing D:C mismatches, and showed that D can form a wobble-type base pair with C. We then asked whether competition with G would decrease mismatched primer extension. We performed nonenzymatic primer extension with all four activated nucleotides on randomized RNA templates containing all four letters, and used deep sequencing to analyze the products. We found that the DUCG genetic system exhibited a more even product distribution and a lower mismatch frequency than the canonical AUCG system. Furthermore, primer extension is greatly reduced following all mismatches, including the D:C mismatch. Our study suggests that diaminopurine deserves further attention for its possible role in the RNA World, and as a potentially useful component of artificial nonenzymatic RNA replication systems.
Fast and accurate short read alignment with hybrid hash-tree data structure
Authors: Makino Junichiro , Ebisuzaki Toshikazu , Himeno Ryutaro , Hayashizaki Yoshihide 
Published: February 2024

ABSTRACTRapidly increasing amount of short read data generated by NGSs (new-generation sequencers) calls for the development of fast and accurate read alignment programs. The programs based on hash table (BLAST) and Burrows-Wheeler transform (bwa-mem) are used, and the latter is known to give superior performance. We here present a new algorithm, a hybrid of hash table and suffix tree, which we designed to speed up the alignment of short reads against large reference sequences such as human genome. The total turnaround time for processing one human genome sample (read depth of 30) is just 31 minutes with our system while that was more than 25 hours with bwa-mem/gatk. The time for aligner alone is 28 minutes for our system but around 2 hours for bwa-mem. Our new algorithm is 4.4 times faster than bwa-mem while achieving similar accuracy. Variant calling and other downstream analyses after the alignment can be done with open-source tools such as SAMtools and Genome Analysis Toolkit (gatk) packages, as well as our own fast variant caller, which is well parallelized and much faster than gatk.
An Engineered IGF2 Mutant for Lysosomal Targeting Chimeras Development and Membrane Proteins Degradation
Authors: Pan Yanchao , Xiang Qing , Deng Kai , Anwar Muhammad , Wang Leiming , Wang Yuan , Liang Qiulian , Shen Lirou , Yang Jing , Shen Weijun 
Published: February 2024

AbstractLysosome-targeting chimeras (LYTACs) have emerged as a promising strategy for targeted degradation of membrane proteins, offering potential applications in drug development. Currently, two main methods for developing LYTACs exist: chemically modified antibodies[1-2]and wild-type insulin-like growth factor 2 (IGF2) fusion proteins (iLYTACs)[3]. However, the fusion of the IGF2 arm within iLYTACs carries the risk of activating IGF1R tyrosine kinase activity and promoting tumor development. To address this concern, we introduce eiLYTACs, a technology that employs engineered IGF2 fusion antibodies to induce degradation of endogenous membrane proteins. Compared to the wild-type IGF2, the engineered IGF2 mutant exhibited minimal binding affinity for IGF1R but demonstrated a significant 100-fold increase in its binding affinity for IGF2R. In contrast to wild-type IGF2, which promotes tumor growth, the cells incubated with the engineered IGF2 showed no stimulation of tumor growth. The eiLYTACs strategy effectively inhibits tumor cell proliferation by degrading specific targets, resulting in a significant reduction in xenograft tumor size in experimental nude mice. More interestingly, our research revealed that eiLYTACs simultaneously degrade both homo- and heterodimers of disease-relevant proteins,which offer a promising strategy to address the activation of compensatory bypass signaling pathways, drug resistance, and tumor heterogeneity.
An analysis of contractile and protrusive cell behaviours at the superficial surface of the zebrafish neural plate
Authors: Araya Claudio , Boekemeyer Raegan , Farlie Francesca , Moon Lauren , Darwish Freshta , Rookyard Chris , Allison Leanne , Vizcay-Barrena Gema , Fleck Roland , Aranda Millaray , Tada Masa , Clarke Jonathan D W 
Published: February 2024

AbstractThe motive forces underlying convergence and internalisation of the teleost neural plate remain unknown. To help understand this crucial morphogenetic movement we have analysed collective and individual cell behaviours at the superficial surface of the neural plate. Convergence to the midline does not rely on mediolateral cell intercalation, it is characterised by oscillatory contractile behaviours, a punctate distribution of Cdh2 and medially polarised actin-rich protrusions at the surface of the neural plate. Additionally, we characterise and discuss the intimate relationship and dynamic cell surfaces between the motile neural plate and the stationary overlying non-neural enveloping layer.
Theileria annulataInfection Promotes p53 suppression, Genomic Instability and DNA deaminase APOBEC3H upregulation leading to cancer-like phenotype in host cells
Authors: Dandesena Debabrata , Suresh Akash , Budhwar Roli , Godwin Jeffrey , Singh Sakshi , Subudhi Madhusmita , T Amruthanjali , Roy Sonti , A Vengatachala Moorthy , Bhandari Vasundhra , Sharma Paresh 
Published: February 2024

AbstractTheileria annulata-infected host leukocytes display cancer-like phenotypes, though the precise mechanism is yet to be fully understood. The occurrence of cancer-like phenotypes inTheileria-infected leukocytes may be attributed to various factors, including genomic instability and acquired mutations, a crucial trait that underpins the genetic foundation of cancer. This paper presents WGS data and bioinformatic analyses to reveal point mutations and large-scale alterations in six clinically relevantT. annulata-infected cell lines. We identified 7867 exon-linked somatic mutations common to all cell lines, and cancer association analysis showed significant accumulation in oncogenes (FLT4, NOTCH2, MAP3K1, DAXX, FCGR2B, ROS1) and tumor suppressor genes (BARD1, KMT2C, GRIN2A, BAP1) implicated in established critical cancer processes. We demonstrated that a crizotinib-induced blockade of the ROS1 oncogenic protein, which harbored the most mutations, led to the death of infected leukocytes. This is consistent with the significant role of ROS1 in parasite-induced leukocyte transformation. In addition, we found somatic mutations in genes involved in genome instability and the DDR pathway. Our findings support the notion that ROS1 and Nutulin 3a are valid targets for intervention, and the suppression of TP53, a crucial tumor suppressor gene, may play a significant role in cell immortalization. We also show that upon infection with the parasite, bovine cells upregulate the expression of APOBEC3H, a DNA mutator likely responsible for the detected mutations. Our study highlights howT. annulatatransforms leukocytes to gain selective advantage via mutation, and our observations could steer future research towards a mechanistic understanding of disease pathogenesis.
Long-read sequencing reveals novel isoform-specific eQTLs and regulatory mechanisms of isoform expression
Authors: Nagura Yuya , Shimada Mihoko , Kuribayashi Ryoji , Kiyose Hiroki , Igarashi Arisa , Kaname Tadashi , Unoki Motoko , Fujimoto Akihiro 
Published: February 2024

AbstractGenetic variations linked to changes in gene expression are known as expression quantitative loci (eQTLs). The identification of eQTLs provides a profound understanding of the mechanisms governing gene expression. However, prior studies have primarily utilized short-read sequencing techniques, and the analysis of eQTLs on isoforms has been relatively limited. In this study, we employed long-read sequencing technology (Oxford Nanopore) on B cells from 67 healthy Japanese individuals to explore genetic variations associated with isoform expression levels, referred to as isoform eQTLs (ieQTLs). Our analysis revealed 33,928 ieQTLs, with 69.0% remaining undetected by a gene-level analysis. Additionally, we identified ieQTLs that have significantly different effects on isoform expression levels within a gene. A functional feature analysis demonstrated a significant enrichment of ieQTLs at splice sites and specific histone marks, such as H3K36me3, H3K4me1, H3K4me3, and H3K79me3. Through an experimental validation using genome editing, we observed that a distant genomic region can modulate isoform-specific expression. Moreover, an ieQTL analysis and minigene splicing assays unveiled functionally crucial variants in splicing, which software-based predictions failed to anticipate. A comparison with GWAS data revealed a higher number of colocalizations between ieQTLs and GWAS findings compared to gene eQTLs. These findings highlight the substantial contribution of ieQTLs identified through long-read analysis in our understanding of the functional implications of genetic variations and the regulatory mechanisms governing isoforms.
Empowering Personalized Pharmacogenomics with Generative AI Solutions
Authors: Murugan Mullai , Yuan Bo , Venner Eric , Ballantyne Christie M. , Robinson Katherine M. , Coons James C. , Wang Liwen , Empey Philip E. , Gibbs Richard A. 
Published: February 2024

AbstractObjectiveThis study evaluates an AI assistant developed using OpenAI’s GPT-4 for interpreting pharmacogenomic (PGx) testing results, aiming to improve decision-making and knowledge sharing in clinical genetics, and to enhance patient care with equitable access.MethodsThe AI assistant employs Retrieval Augmented Generation (RAG) combining retrieval and generative techniques. It employs a Knowledge Base (KB) comprising Clinical Pharmacogenetics Implementation Consortium (CPIC) data, with context-aware GPT-4 generating tailored responses to user queries from this KB, refined through prompt engineering and guardrails.ResultsEvaluated against a specialized PGx question catalog, the AI assistant showed high efficacy in addressing user queries. Compared with OpenAI’s ChatGPT 3.5, it demonstrated better performance, especially in provider-specific queries requiring specialized data and citations. Key areas for improvement include enhancing accuracy, relevancy, and representative language in responses.DiscussionThe integration of context-aware GPT-4 with RAG significantly enhanced the AI assistant’s utility. RAG’s ability to incorporate domain-specific CPIC data, including recent literature, proved beneficial. Challenges persist, such as the need for specialized genetic/PGx models to improve accuracy and relevancy and addressing ethical, regulatory, and safety concerns.ConclusionThis study underscores generative AI’s potential for transforming healthcare provider support and patient accessibility to complex pharmacogenomic information. While careful implementation of large language models like GPT-4 is necessary, it is clear that they can substantially improve understanding of pharmacogenomic data. With further development, these tools could augment healthcare expertise, provider productivity, and the delivery of equitable, patient-centered healthcare services.
Development of an orthotopic medulloblastoma zebrafish model for rapid drug testing
Authors: van Bree Niek , Oppelt Ann-Sophie , Lindström Susanne , Zhou Leilei , Boutin Lola , Johnsen John Inge , Bräutigam Lars , Wilhelm Margareta 
Published: February 2024

AbstractMedulloblastoma (MB) is one of the most common malignant brain tumors in children. Current preclinicalin vivomodel systems for MB have increased our understanding of molecular mechanisms regulating MB development; however, they may not be suitable for high-throughput screening efforts. We demonstrate here that transplantation of seven different MB cell lines or patient-derived cells into the blastula stage of zebrafish embryos leads to orthotopic tumor cell growth that can be observed within 24 hours after transplantation. Importantly, the homing of transplanted cells to the hindbrain region and the aggressiveness of tumor growth are enhanced by pre-culturing cells in a neural stem cell-like medium. The change in culture conditions rewires the transcriptome towards a more migratory and neuronal progenitor phenotype, including the expression of guidance molecules SEMA3A and EFNB1, both of which correlate with lower overall survival in MB patients. Furthermore, we highlight that the orthotopic zebrafish MB xenograft model has the potential to be used for high-throughput drug screening.Key pointsMedulloblastoma cells home to the hindbrain region in developing zebrafish embryos.Neural stem cell culture conditions improve the homing capacity of MB tumor cells.Medulloblastoma-transplanted zebrafish embryos can be used as a high-throughputin vivomodel for drug screening.Importance of the StudyOne of the challenges of accurately modeling medulloblastoma is the large heterogeneity in tumor characteristics. To accurately model this heterogeneous disease, patient-derived xenograft mouse models are currently the standard. However, such mouse models are labor intensive, time-consuming, and not suitable for high-throughput studies. Here, we describe a quick and straightforward zebrafish xenograft model that provides a promising alternative to these existing mouse models. We demonstrate that this model can be utilized to study tumor cell growth of several major medulloblastoma subgroups. More importantly, our model facilitates high-throughput drug testing, providing a scalable opportunity forin vivodrug screenings that will support the discovery of novel therapeutic compounds against medulloblastoma.
Metavinculin mediates differentiation cues into myogenic gene expression
Authors: Murugan Abinayaselvi , Nanjegowda Nandeesh Bevinahalli , Jothi Mathivanan 
Published: February 2024

SUMMARYIsoform switching in deciphering differentiation signals into myogenic transcriptional output remains unexplored. Here, we report a distinct function of muscle-specific metavinculin isoform in switching canonical to non-canonical Wnt-pathways to establish skeletal muscle differentiation. Metavinculin expression is specifically associated with muscle differentiation, regeneration and absent in proliferating myoblasts. During differentiation, metavinculin-specific exon retention is facilitated by the direct binding of Rbfox1 to its downstream intron. Depletion of metavinculin impairs skeletal muscle differentiation, while its ectopic expression induces genes associated with differentiation even in proliferating myoblasts. Subsequent results revealed that pharmacological activation of canonical Wnt impedes muscle differentiation, whereas its inhibition stimulates differentiation. Canonical Wnt inhibition or ectopic non-canonical Wnt7b expression restores muscle differentiation programs in metavinculin-depleted cells. These results indicates a dynamic interplay between Rbfox1-generated metavinculin and Wnt-signaling pathways. This advancement sheds light on the intricate molecular mechanisms underlying skeletal muscle differentiation and suggests potential therapeutic targets for muscle-related disorders.
Exposure to bilingual or monolingual maternal speech during pregnancy affects the neurophysiological encoding of speech sounds in neonates differently
Authors: Arenillas-Alcón Sonia , Gorina-Careta Natàlia , Puertollano Marta , Mondéjar-Segovia Alejandro , Ijjou-Kadiri Siham , Costa-Faidella Jordi , Gómez-Roig María Dolores , Escera Carles 
Published: February 2024

AbstractExposure to maternal speech during the prenatal period shapes speech perception and linguistic preferences, allowing neonates to recognize stories heard frequently in utero and demonstrating an enhanced preference for their mother’s voice and native language. Yet, with a high prevalence of bilingualism worldwide, it remains an open question whether monolingual or bilingual maternal speech during pregnancy influence differently the fetus’ neural mechanisms underlying speech sound encoding. In the present study, the frequency-following response (FFR), an auditory evoked potential that reflects the complex spectrotemporal dynamics of speech sounds, was recorded to a two-vowel /oa/ stimulus in a sample of 131 healthy term neonates within the 1-3 days after birth. Newborns were divided into two groups according to maternal language usage during the last trimester of gestation (monolingual; bilingual). Spectral amplitudes and spectral signal-to-noise ratios (SNR) at the stimulus fundamental (F0) and first formant (F1) frequencies of each vowel were respectively taken as measures of pitch and formant structure neural encoding. Our results reveal that while spectral amplitudes at F0did not differ between groups, neonates from bilingual mothers exhibited a lower spectral SNR. Additionally, monolingually exposed neonates exhibited a higher spectral amplitude and SNR at F1frequencies. We interpret our results under the consideration that bilingual maternal speech, as compared to monolingual, is characterized by a greater complexity in the speech sound signal, rendering newborns from bilingual mothers more sensitive to a wider range of speech frequencies without generating a particularly strong response at any of them. Our results contribute to an expanding body of research indicating the influence of prenatal experiences on language acquisition and underscore the necessity of including prenatal language exposure in developmental studies on language acquisition, a variable often overlooked yet capable of influencing research outcomes.
Land-use impacts on plant functional diversity throughout Europe
Authors: Rosa Francesca , van Bodegom Peter M. , Hellweg Stefanie , Pfister Stephan , Biurrun Idoia , Boch Steffen , Chytrý Milan , Ćušterevska Renata , Dalle Fratte Michele , Damasceno Gabriella , Garbolino Emmanuel , Lenoir Jonathan , Ozinga Wim A , Penuelas Josep , Sabatini Francesco Maria , Schrodt Franziska , Uogintas Domas , Byun Chaeho , Dolezal Jiri , Dziuba Tetiana , Hérault Bruno , Martín-Forés Irene , Niinemets Ülo , Peyre Gwendolyn , Scherer Laura 
Published: February 2024

AbstractAimGlobal biodiversity loss resulting from anthropogenic land-use activities is a pressing concern, requiring precise assessments of impacts at large spatial extents. Existing models mainly focus on species richness and abundance, lacking insights into ecological mechanisms and species’ roles in ecosystem functioning. To bridge this gap, we conducted an extensive analysis of the impact of human land use on vascular plant functional diversity, across diverse land-use classes and bioregions in Europe, comparing it to traditional metrics.Location: EuropeTime period: 1992-2019Major taxa studied: Vascular plantsMethodsIntegrating extensive databases of vegetation plots with spatial data on land use and land cover, we paired plots from areas actively used and modified by humans with plots from natural habitats under similar environmental conditions. Using species occurrences and traits, in each plot we computed three complementary functional diversity metrics (functional richness, evenness, and divergence), species richness and abundance. We assessed the impact of land use by comparing the metrics in the paired plots.ResultsOur findings revealed that, compared to natural habitats, anthropogenic land use exhibits lower functional richness and divergence but higher functional evenness across most land-use classes and bioregions. The response of functional richness was more marked than the other two metrics and especially pronounced in croplands and urban areas and in northern bioregions. Functional richness exhibited a pattern that did not fully overlap with the trend in species richness, providing useful complementary information.Main conclusionsWe provide a large-scale precise assessment of anthropogenic land-use impacts on functional diversity across Europe. Our findings indicate that: (i) human disturbance significantly alters plant functional diversity compared to natural habitats; (ii) this alteration goes in the direction of functional homogenization; (i) functional diversity metrics complement traditional metrics by offering deeper insights into the ecological mechanisms in response to anthropogenic land use.
DDR1 regulates RUNX1-CBFβ to control breast stem cell differentiation
Authors: Trepicchio Colin , Rauner Gat , Traugh Nicole , Parrish Meadow , Fein Daniel E.C. , Mal Youssof , Kuperwasser Charlotte 
Published: February 2024

AbstractThe human breast is complex and comprised of multi-lineage and multi-structural elements. Recent work has shown that epithelial stem and progenitor cells use the collagen receptor Discoidin Domain Receptor 1 (DDR1) for differentiation into both basal and luminal cell lineages, which together are necessary for both ductal and alveolar morphogenesis. We developed a next-generation single cell derived organoid model that generates miniaturized breast tissue, to study how single stem cells can give rise to multiple cell types and compound tissue structures. We show that DDR1 activation triggers stem cell differentiation via RUNX1 in turn driving multilineage differentiation as well as complex ductal-lobular development. Mechanistically, DDR1 affects the interaction and expression of RUNX1 and its cofactor CBFβ thereby regulating its activity. Together, these findings contribute to the current understanding of how the extracellular matrix component within the stem cell niche drives organogenesis and tissue regeneration.
Asiatic acid improves mitochondrial function, activates antioxidant response in the mouse brain and improves cognitive function in beta-amyloid overexpressing mice
Authors: Varada Samantha , Chamberlin Steve R , Bui Lillie , Brandes Mikah S , Gladen-Kolarsky Noah , Harris Christopher J , Hack Wyatt , Brumbach Barbara H , Quinn Joseph F , Gray Nora E 
Published: February 2024

AbstractExtracts of the plantCentella asiaticacan enhance mitochondrial function, promote antioxidant activity and improve cognitive deficits. Asiatic acid (AA) is one of the constituent triterpene compounds present in the plant. In this study we explore the effects of increasing concentrations of AA on brain mitochondrial function, antioxidant response and cognition in healthy mice and a single concentration of AA in the beta-amyloid overexpressing 5xFAD mouse line. Associative memory and overall activity were assessed. Hippocampal mitochondrial bioenergetics and the expression of mitochondrial and antioxidant response genes was determined. In the 5xFAD line, total beta-amyloid plaque burden after AA treatment was also evaluated. In healthy mice, we report dose responsive effects of increasing concentrations of AA on enhanced associative memory and a dose dependent increase in basal and maximal mitochondrial respiration, mitochondrial gene expression and antioxidant gene expression. Results from the highest AA dose (1% AA) were similar to what was observed with CAW. The high AA dose was then evaluated in the context of Aβ accumulation in 5xFAD mice. Improvements in mitochondrial and antioxidant response genes were favored in females over males without significant alleviation of Aβ plaque burden.