bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pre-existing Subclones Determine Radioresistance in Rectal Cancer Organoids
Authors: Andel D. , Viergever B.J. , Peters N.A. , Raats D.A.E. , van Schelven S.J. , Intven M.P.W. , Zandvliet M. , Hagendoorn J. , Rinkes I.H.M. Borel , Kranenburg O. 
Published: November 2023

SummaryMore than half of all cancer patients receive radiation therapy, but resistance is commonly observed. Currently, it is unknown whether resistance to radiation therapy is acquired or inherently present. Here, we employed organoids derived from rectal cancer and single-cell whole genome sequencing to investigate the long-term evolution of subclones in response to radiation. Comparing single-cell whole genome karyotypes between unirradiated and irradiated organoids revealed three patterns of subclonal evolution: (i) subclonal persistence, (ii) subclonal extinction, and (iii) subclonal expansion. Only organoids in which subclonal shifts occurred (i.e., expansion or extinction) became more resistant to radiation. Although radioresistant subclones did not share recurrent copy number alterations that could explain their radioresistance, resistance was associated with reduced chromosomal instability; an association that was also observed in 529 human cancer cell lines. These data suggest resistance to radiation is inherently present and associated with reduced chromosomal instability.
Unveiling the Microbial Diversity and Associated Secondary Metabolism on Black Apples
Authors: Cowled Michael S. , Phippen Christopher B. W. , Kromphardt Kresten J. K. , Clemmensen Sidsel E. , Frandsen Rasmus J. N. , Frisvad Jens C. , Larsen Thomas O. 
Published: November 2023

AbstractBlack apples are the late-stage microbial decomposition of apples after having fallen to the ground. This phenomenon is highly comparable from year to year, with the filamentous fungusMonilinia fructigenamost commonly being the first invader, followed byPenicillium expansum. Motivated by the fact that only little chemistry has been reported from apple microbiomes, we set out to investigate the chemical diversity and potential ecological roles of secondary metabolites (SMs) in a total of 38 black apples. Metabolomics analyses were conducted on either whole apples or small excisions of fungal biomass derived from black apples. Annotation of fungal SMs in black apple extracts was aided by cultivation of 15 recently isolated fungal strains on 9 different substrates in an OSMAC approach, leading to identification of 3319 unique chemical features. Only 6.8% were attributable to known compounds based on analysis of HPLC-HRMS/MS data using spectral library matching tools. Of the 1606 features detected in the black apple extracts, 32% could be assigned as fungal-derived, due to their presence in the OSMAC-based training dataset. Notably, the detection of several antifungal compounds clearly indicates the importance of such compounds for invasion of and control of other microbial competitors on apples. In conclusion, the diversity and abundance of microbial SMs on black apples was found to be much higher than that typically observed for other environmental microbiomes. Detection of SMs known to be produced by the six fungal species tested also highlights a succession of fungal growth following the initial invaderM. fructigena.ImportanceMicrobial secondary metabolites constitute a significant reservoir of biologically potent and clinically valuable chemical scaffolds. However, their usefulness is hampered by rapidly developing resistance, resulting in reduced profitability of such research endeavours. Hence, it is vital that the ecological role of such microbial secondary metabolites be considered to understand how best to utilise such compounds as chemotherapeutics. Here, we explore an under-investigated environmental microbiome in the case of black apples; a veritable “low-hanging fruit”, with relatively high abundances and diversity of microbially produced secondary metabolites. Using both a targeted and untargeted metabolomics approach, the interplay between metabolites, other microbes and the apple host itself was investigated. This study highlights the surprisingly low incidence of known secondary metabolites in such a system, highlighting the need to study the functionality of secondary metabolites in microbial interactions and complex microbiomes.
Plant-like heliotropism in a photosymbiotic animal
Authors: Lintnerova Eliska , Shaw Callum , Keys Matthew , Brownlee Colin , Modepalli Vengamanaidu 
Published: November 2023

AbstractBeing photosynthetic sessile organisms, plants established heliotropism to track the sun’s position across the sky and allow their vegetative parts to orient accordingly. Here, we report plant-like heliotropic movement in a photosymbiotic sea anemoneAnemonia viridis. Like plants, photosynthesis represents a key energy source in endosymbiotic cnidarians bearing microalgae. We observed thatA. viridisin their natural habitats under sunlight displayed heliotropism or solar tracking by pointing their tentacles towards the sun while remaining sessile, facing east at dawn and west at dusk as they track the sun’s relative position through the day, a phenomenon previously only observed in plants. Solar tracking movements inA. viridisare driven by a light wavelength that prompts photosynthesis in their endosymbionts. The heliotropic response was absent in both bleached (aposymbiotic)A. viridisand in symbioticA. viridiswith chemically inhibited photosynthesis. We revealed a direct correlation between heliotropism and endosymbiont oxygen production inA. viridis. Our findings suggest that photosymbioticA. viridishas likely evolved plant-like heliotropism as an effective way to modulate exposure to solar irradiation for photosynthesis. The study exemplifies how photosynthetic organisms such as plants and photosymbiotic sea anemones, display similar behaviour in response to similar environmental pressures.
Microbial Metamorphosis: Symbiotic bacteria and fungi proliferate during diapause and may enhance overwintering survival in a solitary bee
Authors: Christensen S. M. , Srinivas S. , McFrederick Q. , Danforth B. , Buchmann S. L. , Vannette R. L. 
Published: November 2023

AbstractHost-microbe interactions underlie the development and fitness of many macroorganisms including bees. While many social bees benefit from vertically transmitted gut bacteria, solitary bees, which comprise the vast majority of species diversity within bees, lack a specialized gut microbiome. Here we examine the composition and abundance of bacteria and fungi throughout the complete life cycle of a ground-nesting solitary beeAnthophora bomboides standfordiana. In contrast to expectations, immature bee stages maintain a distinct core microbiome consisting of Actinobacteria and fungi in the genusMoniliella. Diapausing larval bees hosted the most abundant and distinctive bacteria and fungi, attaining 33 and 52 times their initial copy number, respectively. We tested two adaptive hypotheses regarding microbial functions for overwintering bees. First, using isolated bacteria and fungi, we found thatStreptomycesfrom brood cells inhibited the growth of multiple pathogenic filamentous fungi, suggesting a role in pathogen protection during the long period of diapause. Second, sugar alcohol composition changed in tandem with major changes in microbial abundance suggesting links with bee metabolism or overwintering biology. Our results suggest thatAnthophora bomboideshosts a conserved core microbiome that may provide key fitness advantages through larval development and overwintering, and raises the question of how this microbiome is transmitted between generations. The present work suggests that focus on adult gut microbiomes in solitary bees may overlook microbial symbionts within brood cells that could play diverse roles in bee fitness, and that exploration of microbes associated with immature bees may uncover novel microbial effects on insect hosts.
Engineered immunomodulatory extracellular vesicles derived from epithelial cells acquire capacity for positive and negative T cell co-stimulation in cancer and autoimmunity
Authors: Kugeratski Fernanda G. , LeBleu Valerie S. , Dowlatshahi Dara P. , Sugimoto Hikaru , Arian Kent A. , Fan Yibo , Huang Li , Wells Danielle , Lilla Sergio , Hodge Kelly , Zanivan Sara , McAndrews Kathleen M. , Kalluri Raghu 
Published: November 2023

AbstractExtracellular vesicles (EVs) are generated by all cells and systemic administration of allogenic EVs derived from epithelial and mesenchymal cells have been shown to be safe, despite carrying an array of functional molecules, including thousands of proteins. To address whether epithelial cells derived EVs can be modified to acquire the capacity to induce immune response, we engineered 293T EVs to harbor the immunomodulatory CD80, OX40L and PD-L1 molecules. We demonstrated abundant levels of these proteins on the engineered cells and EVs. Functionally, the engineered EVs efficiently elicit positive and negative co-stimulation in human and murine T cells. In the setting of cancer and auto-immune hepatitis, the engineered EVs modulate T cell functions and alter disease progression. Moreover, OX40L EVs provide additional benefit to anti-CTLA-4 treatment in melanoma-bearing mice. Our work provides evidence that epithelial cell derived EVs can be engineered to induce immune responses with translational potential to modulate T cell functions in distinct pathological settings.
Netrin1 patterns the dorsal spinal cord through modulation of Bmp signaling
Authors: Alvarez Sandy , Gupta Sandeep , Honeychurch Kaitlyn , Mercado-Ayon Yesica , Kawaguchi Riki , Butler Samantha J. 
Published: November 2023

SummaryWe have identified an unexpected role for netrin1 as a suppressor of bone morphogenetic protein (Bmp) signaling in the developing dorsal spinal cord. Using a combination of gain- and loss-of-function approaches in chicken, embryonic stem cell (ESC), and mouse models, we have observed that manipulating the level of netrin1 specifically alters the patterning of the Bmp-dependent dorsal interneurons (dIs), dI1-dI3. Altered netrin1 levels also change Bmp signaling activity, as measured by bioinformatics, and monitoring phosophoSmad1/5/8 activation, the canonical intermediate of Bmp signaling, and Id levels, a known Bmp target. Together, these studies support the hypothesis that netrin1 acts from the intermediate spinal cord to regionally confine Bmp signaling to the dorsal spinal cord. Thus, netrin1 has reiterative activities shaping dorsal spinal circuits, first by regulating cell fate decisions and then acting as a guidance cue to direct axon extension.
A global atlas of soil viruses reveals unexplored biodiversity and potential biogeochemical impacts
Authors: Graham Emily B. , Camargo Antonio Pedro , Wu Ruonan , Neches Russell Y. , Nolan Matt , Paez-Espino David , Kyrpides Nikos C. , Jansson Janet K. , McDermott Jason E. , Hofmockel Kirsten S. ,   the Soil Virosphere Consortium
Published: November 2023

ABSTRACTHistorically neglected by microbial ecologists, soil viruses are now thought to be critical to global biogeochemical cycles. However, our understanding of their global distribution, activities, and interactions with the soil microbiome remains limited. Here, we present the Global Soil Virus (GSV) Atlas, a comprehensive dataset compiled from 2,953 previously sequenced soil metagenomes and comprised of 616,935 uncultivated viral genomes (UViGs) and 38,508 unique viral operational taxonomic units (vOTUs). Rarefaction curves from the GSV Atlas indicate that most soil viral diversity remains unexplored, further underscored by high spatial turnover and low rates of shared vOTUs across samples. By examining genes associated with biogeochemical functions, we also demonstrate the viral potential to impact soil carbon and nutrient cycling. This study represents an extensive characterization of soil viral diversity and provides a foundation for developing testable hypotheses regarding the role of the virosphere in the soil microbiome and global biogeochemistry.
Bio-Mol:Pretraining Multimodality Bioactivity Profile for Enhancing Small Molecule Property Prediction
Authors: Yip Hiu Fung , Wei Xiao , Li Zeming , Ren Qing , Cao DongSheng , Zhang Lu , Lu Aiping 
Published: November 2023

AbstractNon-optimized pharmacokinetic parameters serve as the primary cause of failure in clinical trials of drugs. Therefore, the successful prediction of pharmacokinetic parameters during the pre-clinical stage is crucial for the success of drug candidates. Conventional methods primarily rely on 2D structural information, while advanced models extend the features to other structural-related information or use advanced computational models to improve prediction accuracy. However, to gain a comprehensive understanding of small molecules, integrating bioactivity profiles with chemical structural information is essential. One significant challenge in this integration is the high proportion of missing values within experimentally validated bioactivity profiles for most small molecules. To address this challenge, we introduce Bio-Mol, an artificial intelligence model designed to effectively handle this issue. Bio-Mol utilizes a pretrain and finetune strategy, enabling the incorporation of a large proportion of missing bioactivity profiles during the small molecule representation learning process.Comprehensive evaluations of Bio-Mol demonstrate a notable improvement in predicting molecule properties. The integration of missing bioactivity profiles enhances the AUROC of average 5.2% compared to the previous state-of-the-art model’s predictions. Furthermore, we explore the potential of Bio-Mol in predicting synergistic drug combinations, highlighting its versatility and broader applications in the field of drug discovery.The successful implementation of Bio-Mol showcases its efficacy in over-coming the challenges posed by missing bioactivity profile data. This model paves the way for optimizing small molecule pharmacokinetics prediction, providing valuable insights for drug development and discovery processes.
Quantitative Three-dimensional Label-free Digital Holographic Imaging of Cardiomyocyte Size, Ploidy, and Cell Division
Authors: Park Sangsoon , Huang Herman , Ross Ines , Moreno Joseph , Khyeam Sheamin , Simmons Jacquelyn , Huang Guo N. , Payumo Alexander Y. 
Published: November 2023

ABSTRACTCardiac regeneration in newborn rodents depends on the ability of pre-existing cardiomyocytes to proliferate and divide. This capacity is lost within the first week of postnatal development when these cells rapidly switch from hyperplasia to hypertrophy, withdraw from the cell cycle, become binucleated, and increase in size. How these dynamic changes in size and ploidy impact cardiomyocyte proliferative potential is not well understood. In this study, we innovate the application of a commercially available digital holographic imaging microscope, the Holomonitor M4, to evaluate the proliferative responses of mononucleated diploid and binucleated tetraploid cardiomyocytes. This instrument coupled with the powerful Holomonitor App Suite software enables long-term label-free quantitative three-dimensional tracking of primary cardiomyocyte dynamics in real-time with single-cell resolution. Our digital holographic imaging results provide direct evidence that mononucleated cardiomyocytes retain significant proliferative potential as most can successfully divide with high frequency. In contrast, binucleated cardiomyocytes exhibit a blunted response to a proliferative stimulus with the majority not attempting to divide at all. Nevertheless, some binucleated cardiomyocytes were capable of complete division, suggesting that these cells still do retain limited proliferative capacity. By quantitatively tracking cardiomyocyte volume dynamics during these proliferative responses, we reveal that both mononucleated and binucleated cells reach a unique size threshold prior to attempted cell division. The absolute threshold is increased by binucleation, which may limit the ability of binucleated cardiomyocytes to divide. By defining the interrelationship between cardiomyocyte size, ploidy, and cell cycle control, we will better understand the cellular mechanisms that drive the loss of mammalian cardiac regenerative capacity after birth.
Prebiotic membrane structures mimic the morphology of purported early traces of life on Earth
Authors: Jordan Seán F. , van Zuilen Mark A. , Rouillard Joti , Martins Zita , Lane Nick 
Published: November 2023

AbstractElucidating the most probable compositions of the first cell membranes prior to the origin of life, within a laboratory setting, requires experiments with organic molecules and chemical conditions representative of those present on the early Earth. As such, the membrane forming molecules used in these experiments are described as ‘prebiotically plausible’, i.e., they could have formed through abiotic reactions and be available for membrane formation prior to the emergence of biology. Similarly, the chemical properties of solutions in which these membranes are formed (e.g., pH, temperature, ionic strength) must represent the early Earth environmental conditions under investigation. Here, using a combined confocal and transmission electron microscopy approach, we show that prebiotically plausible organic molecules, in solutions representative of Hadean submarine alkaline hydrothermal vents, form aggregated structures with substantial morphological diversity. The structures hold the potential for use as traces of prebiotic processes in the ancient rock record. In addition, many of the structures are morphologically similar to those which are presented as early microfossils, thus highlighting the limitations of morphological interpretation in these types of studies. Detailed analyses of abiotic organic structures are essential for our understanding of the earliest living organisms on Earth, as well as for our interpretation of any potential biosignatures recovered in the future from extra-terrestrial bodies.
Machine Learning-GWAS reveals the role ofWSD1gene for cuticular wax ester biosynthesis and key genomic regions controlling early maturity in bread wheat
Authors: Tekeu Honoré , Jean Martine , Ngonkeu Eddy L. M. , Belzile François 
Published: November 2023

AbstractThis study employed Machine Learning-Genome-Wide Association Study (ML-GWAS) to identify genomic regions linked to cuticular wax ester biosynthesis (SW) and early maturity (DM) in wheat. Using a dataset with 170 wheat accessions and 74K SNPs, four GWAS tools (MLM, CMLM, FarmCPU, and BLINK) and five machine learning techniques (RF, ANN, SVR, CNN, and SVM) were applied. A highly significant SW association was found on chromosome 1A, with the peak SNP (chr1A:556842331) explaining 50% of the phenotypic variation. A promising candidate gene,TraesCS1A01G385500, was identified as an ortholog of Arabidopsis thaliana’sWSD1gene, which plays a crucial role in very long-chain (VLC) wax ester biosynthesis. For DM, four QTLs were detected on chromosomes 4B (two QTLs), 2A, and 5A. Haplotype analysis revealed that alleles TT significantly contribute to cuticular wax ester biosynthesis and early maturity in wheat varieties. The study underscores the superior performance of ML models, especially when combined with advanced multi-locus GWAS models like BLINK and FarmCPU, with significantly lower p-values for identifying relevant QTLs compared to traditional methods. ML approaches hold potential for revolutionizing the study of complex genetic traits, offering insights to enhance wheat crops’ resilience and quality. ML-GWAS emerges as a compelling tool for genomic-based breeding, enabling breeders to develop improved wheat varieties with greater precision and efficiency.
The hepatocyte Epidermal Growth Factor Receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche
Authors: Gonzalez-Sanchez Ester , Vaquero Javier , Caballero-Diaz Daniel , Grzelak Jan , Fusté Noel P , Bertran Esther , Amengual Josep , Garcia-Saez Juan , Martín-Mur Beatriz , Gut Marta , Esteve-Codina Anna , Alay Ania , Coulouarn Cedric , Calero Silvia , Valdecantos Pilar , Valverde Angela M. , Sánchez Aránzazu , Herrera Blanca , Fabregat Isabel 
Published: November 2023

ABSTRACTBackground & AimsLiver fibrosis is the consequence of chronic liver injury in the presence of an inflammatory component. Although the main executors of this activation are known, the mechanisms that lead to the inflammatory process that mediates the production of profibrotic factors are not well characterized. The Epidermal Growth Factor Receptor (EGFR) signaling in hepatocytes is essential for the regenerative process of the liver; however, its potential role in regulating the fibrotic niche is not yet clear.Approach & ResultsOur group generated a mouse model that expresses an inactive truncated form of the EGFR specifically in hepatocytes (ΔEGFR mice). Here, we have analyzed the response of WT and ΔEGFR mice to chronic treatment with CCl4.Resultsindicated that the hallmarks of liver fibrosis were attenuated in CCl4-treated ΔEGFR mice when compared to WT mice, coinciding with a faster resolution of the fibrotic process and an ameliorated damage. The absence of EGFR activity in hepatocytes induced changes in the pattern of immune cells in the liver, with a notable change in the population of M2 macrophages, more related to fibrosis resolution, as well as an increase in the population of lymphocytes related to eradication of the damage. Transcriptomic analysis of hepatocytes and secretome studies from extracellular media inin vitrostudies allowed to elucidate the specific molecular mechanisms regulated by EGFR that mediate hepatocyte production of both pro-inflammatory and pro-fibrotic mediators.ConclusionsOur results support a pro-inflammatory and pro-fibrogenic role for the hepatocyte EGFR pathway during chronic liver damage.
Targeting cellular cathepsins inhibits hepatitis E virus infection
Authors: Klöhn Mara , Burkard Thomas , Janzen Juliana , Schrader Jil Alexandra , Gömer André , Brown Richard J. P. , Dao Thi Viet Loan , Kinast Volker , Brüggemann Yannick , Todt Daniel , Steinmann Eike 
Published: November 2023

AbstractBackground and AimsThe hepatitis E virus (HEV) is estimated to be responsible for 70,000 deaths annually, yet therapy options remain limited. In the pursuit of effective antiviral therapies, targeting viral entry holds promise and has proven effective for other hepatotropic viruses. However, the precise mechanisms and host factors required during HEV entry remain unclear. Cellular proteases have emerged as a class of host factors required for viral surface protein activation and productive cell entry by many viruses. Hence, we investigated the functional requirement and therapeutic potentials of cellular proteases during HEV infection.Approach and ResultsUsing our recently established HEV cell culture model and subgenomic HEV replicons, we found that blocking lysosomal cathepsins (CTS) with small molecule inhibitors, impedes HEV infection without affecting replication. Most importantly, the pan-cathepsin inhibitor K11777 robustly suppressed HEV infections with an EC50of ∼ 0.01 nM. Inhibition by K11777, devoid of notable toxicity in hepatoma cells until micromolar concentrations, was also observed in differentiated HepaRG andex vivoin primary human hepatocytes. Furthermore, through time-of-addition experiments, we confirmed that HEV entry is potently blocked by inhibition of cathepsins and cathepsin L (CTSL) knockout cells were less permissive to HEV suggesting that CTSL is critical for HEV infection.ConclusionsIn summary, our study highlights the pivotal role of lysosomal cathepsins, especially CTSL, in the HEV entry process. The profound anti-HEV efficacy of the pan-cathepsin inhibitor, K11777, especially with its notable safety profile in primary cells, further underscores its potential as a promising therapeutic candidate.