bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reciprocal links between methionine metabolism, DNA repair and therapy resistance in glioblastoma
Authors: Korimerla Navyateja , Meghdadi Baharan , Haq Isra , Wilder-Romans Kari , Xu Jie , Becker Nicole , Zhu Ziqing , Kalev Peter , Qi Nathan , Evans Charles , Kachman Maureen , Zhao Zitong , Lin Angelica , Scott Andrew J , O’Brien Alexandra , Kothari Ayesha , Sajjakulnukit Peter , Zhang Li , Palavalasa Sravya , Peterson Erik R , Hyer Marc L , Marjon Katya , Sleger Taryn , Morgan Meredith A , Lyssiotis Costas A , Stone Everett M. , Ferris Sean P. , Lawrence Theodore S , Nagrath Deepak , Zhou Weihua , Wahl Daniel R 
Published: November 2024

ABSTRACTGlioblastoma (GBM) is uniformly lethal due to profound treatment resistance. Altered cellular metabolism is a key mediator of GBM treatment resistance. Uptake of the essential sulfur-containing amino acid methionine is drastically elevated in GBMs compared to normal cells, however, it is not known how this methionine is utilized or whether it relates to GBM treatment resistance.Here, we find that radiation acutely increases the levels of methionine-related metabolites in a variety of treatment-resistant GBM models. Stable isotope tracing studies further revealed that radiation acutely activates methionine to S-adenosyl methionine (SAM) conversion through an active signaling event mediated by the kinases of the DNA damage response.In vivotumor SAM synthesis increases after radiation, while normal brain SAM production remains unchanged, indicating a tumor- specific metabolic alteration to radiation. Pharmacological and dietary strategies to block methionine to SAM conversion slowed DNA damage response and increased cell death following radiation in vitro. Mechanistically, these effects are due to depletion of DNA repair proteins and are reversed by SAM supplementation. These effects are selective to GBMs lacking the methionine salvage enzyme methylthioadenosine phosphorylase. Pharmacological inhibition of SAM synthesis hindered tumor growth in flank and orthotopicin vivoGBM models when combined with radiation. By contrast, methionine depletion does not reduce tumor SAM levels and fails to radiosensitize intracranial models, indicating depleting SAM, as opposed to simply lowering methionine, is critical for hindering tumor growth in intracranial models of GBM.These results highlight a new signaling link between DNA damage and SAM synthesis and define the metabolic fates of methionine in GBMin vivo. Inhibiting radiation-induced SAM synthesis slows DNA repair and augments radiation efficacy in GBM. Using MAT2A inhibitors to deplete SAM may selectively overcome treatment resistance in GBMs with defective methionine salvage while sparing normal brain.
Targeting eIF4G1-dependent translation in melanoma
Authors: Feng Yongmei , Radaeva Mariia , Amiri Mehdi , Deshpande Aniruddha J. , Olson Steven , Jovanovic Predrag , Pass Ian , Deng Qiyun , Lazar Ikrame , Murad Rabi , Molinolo Alfredo , Kim Hyungsoo , Sergienko Eduard , Villaneuva Jessie , Topisirovic Ivan , Jackson Michael , Sonenberg Nahum , Cherkasov Artem , Ronai Ze’ev A. 
Published: November 2024

AbstractElevated expression of components of eIF4F translation initiation complex has been documented in cancer, resulting in enhanced translation of mRNAs encoding pro-tumorigenic factors, including oncogenic proteins. We previously identified SBI-756, a small molecule that interferes with the eIF4F assembly and overcomes melanoma resistance to BRAF inhibitors. SBI-756 enhanced anti-tumor immunity in pancreatic cancer and was effective in the treatment of diffuse large B cell lymphoma. Here, we identified the eIF4G1 MA3 (4G1-MA3) domain as the target of SBI-756, attenuating eIF4F complex assembly. Melanoma cells expressing a mutant form of 4G1-MA3 exhibited polysome profiles resembling those of melanoma cells treated with SBI-756. A structure-basedin silicoscreen against the eIF4G1 MA3 domain identified M19, a small molecule inhibitor that exhibited anti-melanoma effects. RNA sequencing (RNA-seq) revealed upregulation of UPR, mTOR, p53, and ROS signaling in M19-treated melanoma cells. Ribosome sequencing identified changes in ribosomal structure and electron transport chain components following M19-6 treatment of melanoma cells. Autophagy and histone deacetylase inhibitors were found to enhance anti-neoplastic activities of M19 or its analog, M19-6. M19-6 conferred a greater effect on melanoma than melanocytes and overcame melanoma resistance to BRAF or MEK inhibitors. Alone, M19-6 reduced melanoma growth and metastasis in a xenograft model. M19-6 offers a new therapeutic modality to overcome resistance and metastasis.
A droplet digital PCR assay for quantification of bacteriophage viral vector titer and purity
Authors: Voorhees Peter J. , Ponek Ronni M. , Liu Jamie D. , Lai Samuel K. 
Published: November 2024

ABSTRACTBacteriophage (phage) vectors, bacterial viruses engineered to deliver specific transgenes into target bacteria, offer considerable promise as tools for tuning the microbiome. However, the field currently lacks standardized methods for characterizing phage vectors with the same rigor as those for viral vectors used in human gene therapy. To develop a robust and reproducible viral vector system, it is critical to measure both transduction efficiency and the true dose of vector particles used. Here, we use central composite design to develop a digital droplet PCR (ddPCR) assay for precise quantification of transgene and vector genome-packed phage vector titers following an established production process. This duplex assay uses probes specific to 2 unique DNA barcodes inserted into the vector genome and transgene cassette, enabling precise quantitation of each population with a dynamic range of nearly 3 orders of magnitude. We show biological activity assays can consistently underestimate the number of transgene-packed vectors, potentially greatly overestimating the true transduction efficiency, particularly when contamination by genome-packed vectors is high. This ddPCR approach can be broadly adopted to characterize phage particles for a variety of biomedical applications.
Urban microbial communities shift towards carotenoid-producing species under constant anthropogenic stress
Authors: Sedova V. V. , Demin K. A. , Kulikov M. P. , Prazdnova E.V. , Gorovtsov A.V. 
Published: November 2024

AbstractDuring years of investigating soil microbial communities, our research group consistently observed a predominance of carotenoid-producing microbes – characteristically pigmented in hues typical of carotenoids – in urban soil samples, as compared to those from recreational, rural, or non-urban areas. To validate this observation as non-random and to explore the ecological role of carotenoid-producing microorganisms in urban soils, we conducted a series of experiments. Additionally, we extended our study to other components of the urban ecosystem that may harbor and transfer microbial communities, including dust and snow samples. Through ecological monitoring, we assessed the proportion of culturable carotenoid-producing bacteria in those samples. It was found that in urban soils >60% of the isolates are pigmented, and in natural soils only about 30% exhibit carotenoid pigmentation. For snow and dust samples, all sites have shown pigmented bacteria predominance. Further, we analyzed both the physiological traits of individual isolates and the broader characteristics of entire culturomes (comprising all isolates from a single aliquot plated onto Petri dishes). Metagenomic analysis of the culturome washes was also performed to provide deeper insights into the microbial communities present. Metagenome of urban isolates clearly show elevated biodiversity of carotenoid biosynthesis genes and carotenoid-producing taxa, as compared to metagenome of natural habitat. In this study,Flavobacteriumwas identified as the most abundant pigmented genus of urban settings.Based on data obtained in this work, and similar literature data on urban microbial communities, we propose that the unique combination of environmental factors in urban settings fosters the selective enrichment of carotenoid-producing microorganisms. Finally, we offer a model to explain this selective process.
Agouti and BMP signaling drive a naturally occurring fate conversion of melanophores to leucophores in zebrafish
Authors: Huang Delai , Kapadia Emaan , Liang Yipeng , Shriver Leah P. , Dai Shengkun , Patti Gary J. , Humbel Bruno M. , Laudet Vincent , Parichy David M. 
Published: November 2024

The often-prominent pigment patterns of vertebrates are varied in form and function and depend on several types of pigment cells derived from embryonic neural crest or latent stem cells of neural crest origin. These cells and the patterns they produce have been useful for uncovering features of differentiation and morphogenesis that underlie adult phenotypes, and they offer opportunities to discover how patterns and the cell types themselves have diversified. In zebrafish, a body pattern of stripes arises by self organizing interactions among three types of pigment cells. Yet these fish also exhibit white ornamentation on their fins that depends on the transdifferentiation of black melanophores to white cells, “melanoleucophores.” To identify mechanisms underlying this conversion we used ultrastructural, transcriptomic, mutational and other approaches. We show that melanophore– melanoleucophore transition depends on regional BMP signals transduced through non-canonical receptors (Rgmb-Neo1a-Lrig2) as well as BMP-dependent signaling by Agouti genes,asip1andasip2b. These signals lead to expression of transcription factor genes includingfoxd3andrunx3that are necessary to induce loss of melanin by an autophagy-like process, curtail new melanin production, and deploy a pathway for accumulating guanine crystals that, together, confer a white phenotype. These analyses uncover an important role for positional information in specifying ornamentation in zebrafish and show how tissue environmental cues and a novel gene regulatory program have allowed terminal addition of a distinct phenotype to a pre-existing cell type.SignificanceFish often have striking color patterns with important functions in behavior. In zebrafish, the familiar striped pattern forms through self-organizing interactions between pigment cells, yet the white highlights on their fins arise differently—through the transformation of black pigment cells into white ones. This study reveals how this dramatic cell transformation happens: signals from the surrounding tissue, specifically BMP and Agouti proteins, instruct black cells to change their fate. These signals trigger expression of specific genes that cause the cells to break down their black pigment while acquiring white, crystal-like structures. This work shows how local signals in tissues can drive the development of ornamental features and provides insights into how new cell types evolve.
A systematic assessment of phylogenomic approaches for microbial species tree reconstruction
Authors: Weiner Samson , Feng Yutian , Gogarten J. Peter , Bansal Mukul S. 
Published: November 2024

AbstractA key challenge in microbial phylogenomics is that microbial gene families are often affected by extensive horizontal gene transfer (HGT). As a result, most existing methods for microbial phylogenomics can only make use of a small subset of the gene families present in the microbial genomes under consideration, potentially biasing their results and affecting their accuracy. To address this challenge, several methods have recently been developed for inferring microbial species trees from genome-scale datasets of gene families affected by evolutionary events such as HGT, gene duplication, and gene loss.In this work, we use extensive simulated and real biological datasets to systematically assess the accuracies of four recently developed methods for microbial phylogenomics, SpeciesRax, ASTRAL-Pro 2, PhyloGTP, and AleRax, under a range of different conditions. Our analysis reveals important insights into the relative performance of these methods on datasets with different characteristics, identifies shared weaknesses when analyzing complex biological datasets, and demonstrates the importance of accounting for gene tree inference error/uncertainty for improved species tree reconstruction. Among other results, we find that (i) AleRax, the only method that explicitly accounts for gene tree inference error/uncertainty, shows the best species tree reconstruction accuracy among all tested methods, (ii) PhyloGTP shows the best overall accuracy among methods that do not account for gene tree error and uncertainty, (iii) ASTRAL-Pro 2 is less accurate than the other methods across nearly all tested conditions, and (iv) explicitly accounting for gene tree inference error/uncertainty can lead to substantial improvements in species tree reconstruction accuracy. Importantly, we also find that all methods, including AleRax and PhyloGTP, are susceptible to biases present in complex real biological datasets and can sometimes yield misleading phylogenies.
Vaccination with a Replication-Dead Murine Gammaherpesvirus Lacking Viral Pathogenesis Genes Inhibits WT Virus Infection
Authors: Mitra Dipanwita , Oldenburg Darby , Forrest J. Craig , Krug Laurie T. 
Published: November 2024

AbstractGammaherpesviruses are oncogenic pathogens that establish lifelong infections. There are no FDA-approved vaccines against Epstein-Barr virus or Kaposi sarcoma herpesvirus. Murine gammaherpesvirus-68 (MHV68) infection of mice provides a system for investigating of gammaherpesvirus pathogenesis and testing vaccine strategies. Prime-boost vaccination with a replication-dead virus (RDV) that does not express the essential replication and transactivator protein (RTA) encoded byORF50 (RDV-50.stop) protected against WT virus replication and reduce latency in C57BL/6 mice and prevented lethal disease inIfnar1-/-mice. To further improve the RDV vaccine and more closely model KSHV vaccine design, we generated an RDV lacking the unique M1-M4 genes and the non-coding tRNA-miRNA-encoded RNAs (TMERs) 6, 7, and 8 that collectively promote latency of MHV68in vivo. Prime-boost vaccination of mice with RDV-50.stopΔM1-M4 elicited neutralizing antibodies and virus-specific CD8 T-cell responses in lungs and spleens, the respective sites of acute replication and latency, that were comparable to RDV-50.stop vaccination. When challenged with WT MHV68, vaccinated mice exhibited a near-complete block of lytic replication and a reduction in latency and reactivation. We conclude that major determinants of MHV68 pathogenesis are not required components for eliciting a protective immune response.
Mechanisms of growth-dependent regulation of the Gin4 kinase
Authors: Diaz Francisco Mendez , Godinez David Sanchez , Solano Francisco , Jasani Akshi , Alcaide Maria , Kellogg Douglas R. 
Published: November 2024

AbstractCell cycle progression is dependent upon cell growth. Cells must therefore translate growth into a proportional signal that can be used to determine when there has been sufficient growth for cell cycle progression. In budding yeast, the protein kinase Gin4 is required for normal control of cell growth and undergoes gradual hyperphosphorylation and activation that are dependent upon growth and proportional to the extent of growth, which suggests that Gin4 could function in mechanisms that measure cell growth. However, the molecular mechanisms that drive hyperphosphorylation of Gin4 are poorly understood. Here, we used biochemical reconstitution and genetic analysis to test hypotheses for the mechanisms that drive phosphorylation of Gin4. We ruled out a previous model in which phosphatidylserine delivered to sites of plasma membrane growth binds Gin4 to initiate autophosphorylation. Instead, we show that Elm1, a homolog of the mammalian Lkb1 tumor suppressor kinase, is sufficient to promote hyperphosphorylation of Gin4 in vitro, likely via initiation of Gin4 autophosphorylation. Furthermore, we show that casein kinase I is required for growth-dependent hyperphosphorylation of Gin4 and also for normal regulation of Elm1. Together, these discoveries lead to new insight into mechanisms that link cell cycle progression to cell growth.
The human claustrum activates across multiple cognitive tasks
Authors: Huang Celine H.L. , Stewart Brent W. , Liu Chun Yin , Phylactou Phivos , Mathur Brian N. , Seminowicz David A. 
Published: November 2024

AbstractCognitive control, the ability to manage information during purposeful actions, is crucial for everyday functioning and can become impaired in a variety of neuropsychiatric disorders. The claustrum, a subcortical brain structure, has recently been implicated in functional mechanisms underlying cognitive control. A current theory on the claustrum’s function, the Network Instantiation in Cognitive Control (NICC) model, proposes that the claustrum acts as a cortical network hub synchronizing distant parts of the brain to optimize task performance across cognitive domains. Testing this in this study, we examined the claustrum signal within a dataset (n = 55) that includes functional MRI (fMRI) of healthy participants engaged in four well-established cognitive tasks: the Stroop task, AX-continuous performance task (AX-CPT), cued task-switching, and Sternberg working memory task. Bilateral claustrum activation was observed during certain conditions and trial phases of all four tasks, particularly during active use of cognitive control, and coinciding with task-positive cortical network activations. These findings provide further support for the NICC model of claustrum function, demonstrating claustrum activation across multiple cognitive tasks, and potentially paving the way for new insights into how cognitive processes can become compromised in neuropsychiatric disorders.
Ezh2 Delays Activation of Differentiation Genes During Normal Cerebellar Granule Neuron Development and in Medulloblastoma
Authors: Purzner James , Brown Alexander S. , Purzner Teresa , Ellis Lauren , Broski Sara , Litzenburger Ulrike , Andrews Kaytlin , Sharma Aryaman , Wang Xin , Taylor Michael D. , Cho Yoon-Jae , Fuller Margaret T. , Scott Matthew P. 
Published: November 2024

AbstractMedulloblastoma (MB) is the most common malignant brain tumour in children. The Sonic Hedgehog (SHH)-medulloblastoma subtype arises from the cerebellar granule neuron lineage. Terminally differentiated neurons are incapable of undergoing further cell division, so an effective treatment for this tumour could be to force neuronal differentiation. Differentiation therapy provides a potential alternative for patients with medulloblastoma who harbor mutations that impair cell death pathways (TP53), which is associated a with high mortality. To this end, our goal was to explore epigenetic regulation of cerebellar granule neuron differentiation in medulloblastoma cells. Key regulators were discovered using chromatin immunoprecipitation with high-throughput sequencing. DNA-bound protein and chromatin protein modifications were investigated across all genes. We discovered that Ezh2-mediated tri-methylation of the H3 histone (H3K27me3), occurred on more than half of the 787 genes whose transcription normally increases as granule neurons terminally differentiate. Conditional knockout ofEzh2led to early initiation of differentiation in granule neuron precursors (GNPs), but only after cell cycle exit had occurred. Similarly, in MB cells, neuronal differentiation could be induced by preventing H3K27me3 modifications using an Ezh2 inhibitor (UNC1999), but only when UNC1999 was combined with forced cell cycle exit driven by a CDK4/6 inhibitor (Palbociclib). Ezh2 emerges as a powerful restraint upon post-mitotic differentiation during normal GNP development and combination of Ezh2 inhibition with cell cycle exit leads to MB cell differentiation.
Anthropogenic noise can decrease tomato reproductive success by hindering bumblebee-mediated pollination
Authors: Varga-Szilay Zsófia , Szövényi Gergely , Pozsgai Gábor 
Published: November 2024

AbstractAnthropogenic noise is a little-studied type of pollution that negatively affects the physiology, nervous function and development of insects, thereby it has the potential to disrupt even key ecological services such as pollination. Here, we investigate the effects of anthropogenic noise on the pollination success of theBombus terrestrison tomatoes in controlled conditions. We expect that bumblebees avoid flowers exposed to noise more than flowers in non-noisy environments, leading to less efficient pollination and lower fruit quality. The experiment was conducted in Hungary, in 2023. Three treatments were applied to randomly chosen flowers: noisy (with played traffic noise); and two non-noisy, one allowing bumblebees and one excluding them. The flowers were enclosed with nets before maturity to avoid pollination, opened exclusively during treatment, and re-enclosed for three more days post-treatment. We recorded the marketing value of the fruits and the number of seeds they produced. We found no significant differences in the marketing value of fruits among treatments, but the number of seeds differed significantly suggesting that anthropogenic noise has a substantial effects on bumblebee-mediated pollination. Although these effects may be mitigated by habituation, loud external noise of various machines (e.g. irrigation systems) within polytunnels is still likely to contribute to the everyday noise exposure of bumblebees and could thus potentially lead to hidden economic losses in production. Therefore, further research is needed to understand the behavioural effects of both direct and indirect noise pollution on bumblebees.
Modeling Mountain Pine Beetle Abundance in Novel Hosts
Authors: Xie Xiaoqi , Brush Micah , Johnson Evan , Cullingham Catherine , Duffy Jessica , Lewis Mark A. 
Published: November 2024

AbstractThe mountain pine beetle has recently expanded its range into northern and central Alberta, posing an immediate threat to the novel host, jack pine. To date, some experiments suggest that jack pine has limited defensive capabilities despite of the restrictions from the physical environment. In this work, we explore the susceptibility of jack pine compared to the primary host, lodgepole pine, evaluating the risk of potential range expansion into Canada’s boreal forest. We employ a hierarchical model, incorporating environmental and ecological covariates, to examine mountain pine beetle dynamics in a pine forest with lodgepole, hybrid and jack pines. Our results show that pine species significantly influence the probability of being killed, with jack pine being less likely to be infested than lodgepole pine, all else being equal. The hierarchical model demonstrates that beetles perform poorer in jack pine, characterized by a reproduction rate 0.16 times that of non-jack pine. Although jack pine is a suitable host, our results indicate that the number of infestations in jack pine could be lower than in lodgepole pine, with a reduced probability of emerging beetles.