bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cancer Prevalence Across Vertebrates
Authors: Compton Zachary T. , Mellon Walker , Harris Valerie , Rupp Shawn , Mallo Diego , Kapsetaki Stefania E. , Wilmot Mallory , Kennington Ryan , Noble Kathleen , Baciu Cristina , Ramirez Lucia , Peraza Ashley , Martins Brian , Sudhakar Sushil , Aksoy Selin , Furukawa Gabriela , Vincze Orsolya , Giraudeau Mathieu , Duke Elizabeth G. , Spiro Simon , Flach Edmund , Davidson Hannah , Li Christopher , Zehnder Ashley , Graham Trevor A. , Troan Brigid , Harrison Tara M. , Tollis Marc , Schiffman Joshua D. , Aktipis Athena , Abegglen Lisa M. , Maley Carlo C. , Boddy Amy M. 
Published: February 2023

AbstractCancer is pervasive across multicellular species, but what explains differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades (amphibians, sauropsids and mammals) we found that neoplasia and malignancy prevalence increases with adult weight (contrary to Peto’s Paradox) and somatic mutation rate, but decreases with gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%) the black-footed penguin (<0.4%), ferrets (63%) and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer.Statement of SignificanceEvolution has discovered mechanisms for suppressing cancer in a wide variety of species. By analyzing veterinary necropsy records we can identify species with exceptionally high or low cancer prevalence. Discovering the mechanisms of cancer susceptibility and resistance may help improve cancer prevention and explain cancer syndromes.
Actin Dysregulation Induces Neuroendocrine Plasticity and Immune Evasion: A Vulnerability of Small Cell Lung Cancer
Authors: Seo Yoojeong , Zhang Shengzhe , Jang Jinho , Ko Kyung-Pil , Kim Kee-Beom , Huang Yuanjian , Kim Dong-Wook , Kim Bongjun , Zou Gengyi , Zhang Jie , Jun Sohee , Chu Wonhong , Kirk Nicole A. , Hwang Ye Eun , Ban Young Ho , Dhar Shilpa S. , Chan Joseph M. , Lee Min Gyu , Rudin Charles M. , Park Kwon-Sik , Park Jae-Il 
Published: February 2023

AbstractSmall cell lung cancer (SCLC) is aggressive with limited therapeutic options. Despite recent advances in targeted therapies and immunotherapies, therapy resistance is a recurring issue, which might be partly due to tumor cell plasticity, a change in cell fate. Nonetheless, the mechanisms underlying tumor cell plasticity and immune evasion in SCLC remain elusive. CRACD, a capping protein inhibitor that promotes actin polymerization, is frequently inactivated in SCLC.Cracdknockout (KO) transforms preneoplastic cells into SCLC tumor-like cells and promotes in vivo SCLC development driven byRb1,Trp53, andRbl2triple KO.CracdKO induces neuroendocrine (NE) plasticity and increases tumor cell heterogeneity of SCLC tumor cells via dysregulated NOTCH1 signaling by actin cytoskeleton disruption. CRACD depletion also reduces nuclear actin and induces EZH2-mediated H3K27 methylation. This nuclear event suppresses the MHC-I genes and thereby depletes intratumoral CD8+T cells for accelerated SCLC tumorigenesis. Pharmacological blockade of EZH2 inhibits CRACD-negative SCLC tumorigenesis by restoring MHC-I expression and immune surveillance. Unsupervised single-cell transcriptomics identifies SCLC patient tumors with concomitant inactivation of CRACD and downregulated MHC-I pathway. This study defines CRACD, an actin regulator, as a tumor suppressor that limits cell plasticity and immune evasion and proposes EZH2 blockade as a viable therapeutic option for CRACD-negative SCLC.
A diverse repertoire of anti-defense systems is encoded in the leading region of plasmids
Authors: Samuel Bruria , Burstein David 
Published: February 2023

AbstractPlasmids are an important source of antibiotic-resistance genes that mobilize horizontally between bacteria, including many human pathogens. Bacteria express various defense mechanisms, such as CRISPR-Cas, restriction-modification systems, and SOS-response genes, to prevent the invasion of mobile elements. Yet, plasmids efficiently and robustly overcome these defenses during conjugation. Here, we show that the leading region of plasmids, which is the first to enter recipient cells, is a hotspot for an extensive repertoire of anti-defense systems, encoding anti-CRISPR, anti-restriction, anti-SOS, and other counter-defense proteins. We further demonstrate that focusing on these specific functional regions can lead to the discovery of diverse anti-defense genes. Promoters known to allow expression from ssDNA were prevalent in the leading regions, potentially facilitating rapid protection against bacterial immunity in the early stages of plasmid invasion. These findings reveal a new facet of plasmid dissemination and provide theoretical foundations for developing conjugative delivery systems for natural microbial communities.
Fish microbiota repels ovipositing mosquitoes
Authors: Shteindel Nimrod , Gerchman Yoram , Silberbush Alon 
Published: February 2023

AbstractThe mere presence of predators causes prey organisms to enact predation-avoidance strategies. This presence is often reveled through predator-released kairomones. It was previously suggested that in many cases, the predator’s microbiota composition plays an important role in the release of these kairomones, however this mechanism is still poorly understood. Ovipositing mosquito females of several species are repelled by kairomones released from larvivorous fish. In this study we looked into the effects of the microbiota originated byGambusia affinis(Baird and Girard) on the ovipisition behavior of gravid mosquito females in an outdoor mesocosm experiment. We show that interference with the fish microbiota significantly reduces its repellant effect. We further show that the bacteriumPantoea pleurotiisolated from the skin of the fish repels oviposition ofCulex laticinctus(Edwards) andCuliseta longiareolataMacquart mosquitoes similarly to the effect of live fish. These results highlight the importance of bacteria in the interspecies interactions of their hosts and the potential conflict of interests in this system, where bacteria may benefit from the absence of the bacterivore mosquito larvae, but the fish loose access to prey.
Clustering rare diseases within an ontology-enriched knowledge graph
Authors: Sanjak Jaleal , Zhu Qian , Mathé Ewy A. 
Published: February 2023

Structured AbstractObjectiveIdentifying sets of rare diseases with shared aspects of etiology and pathophysiology may enable drug repurposing and/or platform based therapeutic development. Toward that aim, we utilized an integrative knowledge graph-based approach to constructing clusters of rare diseases.Materials and MethodsData on 3,242 rare diseases were extracted from the National Center for Advancing Translational Science (NCATS) Genetic and Rare Diseases Information center (GARD) internal data resources. The rare disease data was enriched with additional biomedical data, including gene and phenotype ontologies, biological pathway data and small molecule-target activity data, to create a knowledge graph (KG). Node embeddings were used to convert nodes into vectors upon which k-means clustering was applied. We validated the disease clusters through semantic similarity and feature enrichment analysis.ResultsA node embedding model was trained on the ontology enriched rare disease KG and k-means clustering was applied to the embedding vectors resulting in 37 disease clusters with a mean size of 87 diseases. We validate the disease clusters quantitatively by looking at semantic similarity of clustered diseases, using the Orphanet Rare Disease Ontology. In addition, the clusters were analyzed for enrichment of associated genes, revealing that the enriched genes within clusters were shown to be highly related.DiscussionWe demonstrate that node embeddings are an effective method for clustering diseases within a heterogenous KG. Semantically similar diseases and relevant enriched genes have been uncovered within the clusters. Connections between disease clusters and approved or investigational drugs are enumerated for follow-up efforts.ConclusionOur study lays out a method for clustering rare diseases using the graph node embeddings. We develop an easy to maintain pipeline that can be updated when new data on rare diseases emerges. The embeddings themselves can be paired with other representation learning methods for other data types, such as drugs, to address other predictive modeling problems. Detailed subnetwork analysis and in-depth review of individual clusters may lead to translatable findings. Future work will focus on incorporation of additional data sources, with a particular focus on common disease data.
Functional networks in the infant brain during sleep and wake states
Authors: Yates Tristan S. , Ellis Cameron T. , Turk-Browne Nicholas B. 
Published: February 2023

AbstractFunctional brain networks are assessed differently early in development than at maturity: infants are almost universally scanned during sleep, whereas adults are typically scanned awake while resting or performing tasks. Observed differences between infant and adult functional networks may thus reflect these differing states of consciousness rather than or in addition to developmental changes. We explore this question by comparing functional networks in fMRI scans acquired from infants during natural sleep and awake movie-watching. As a reference, we also acquired fMRI scans in adults during awake rest and awake movie-watching. Whole-brain functional connectivity was more similar within-state (sleep-sleep, wake-wake) than across-state (sleep-wake) in infants, demonstrating that movies elicit a different network configuration than typical sleep acquisitions. Indeed, a classifier trained on patterns of functional connectivity during infant sleep versus wake robustly decoded the state of additional infants and even generalized to decode rest versus movie in adults; interestingly, a classifier trained on rest versus movie in adults did not generalize nearly as well to sleep versus wake in infants. Moreover, the overall level of similarity between infant and adult functional connectivity was modulated by adult state (stronger for movie than rest) but not infant state (equivalent for sleep and wake). Nevertheless, the network connections that drove similarity between infants and adults, particularly in frontoparietal network, were modulated by infant state. In sum, infant functional connectivity can differ between sleep and wake states, highlighting the potential value of awake data for studying the early development of functional brain networks.Significance statementFunctional networks in the infant brain provide a foundation for early cognitive abilities and act as a marker of brain maturation and developmental disorders. What we know about these networks comes from fMRI data acquired during sleep, given the challenges of awake infant fMRI. This contrasts with the dominant approach in older populations of assessing networks during awake rest or tasks. These differing levels of consciousness cloud the interpretation of developmental changes. Here we show that whole-brain functional connectivity differs between sleeping and awake infants, and that the similarity of these infant states to adults loads on dissociable network connections. This research suggests that a full understanding of early functional brain networks will benefit from complementary insights in awake infants.
Construction of Fosmid-based SARS-CoV-2 replicons for antiviral drug screening and replication analyses in biosafety level 2 facilities
Authors: Takazawa Shunta , Kotaki Tomohiro , Nakamura Satsuki , Utsubo Chie , Kameoka Masanori 
Published: February 2023

AbstractThe coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has necessitated the global development of countermeasures since its outbreak. However, current therapeutics and vaccines to stop the pandemic are insufficient and this is mainly because of the emergence of resistant variants, which requires the urgent development of new countermeasures, such as antiviral drugs. Replicons, self-replicating RNAs that do not produce virions, are a promising system for this purpose because they safely recreate viral replication, enabling antiviral screening in biosafety level (BSL)-2 facilities. We herein constructed three pCC2Fos-based RNA replicons lacking some open reading frames (ORF) of SARS-CoV-2: the Δorf2-8, Δorf2.4, and Δorf2 replicons, and validated their replication in Huh-7 cells. The functionalities of the Δorf2-8 and Δorf2.4 replicons for antiviral drug screening were also confirmed. We conducted puromycin selection following the construction of the Δorf2.4-puro replicon by inserting a puromycin-resistant gene into the Δorf2.4 replicon. We observed the more sustained replication of the Δorf2.4-puro replicon by puromycin pressure. The present results will contribute to the establishment of a safe and useful replicon system for analyzing SARS-CoV-2 replication mechanisms as well as the development of novel antiviral drugs in BSL-2 facilities.
Molecular basis for potent B cell responses to antigen displayed on particles of viral size
Authors: Brooks Jeremy F. , Riggs Julianne , Mueller James L. , Mathenge Raisa , Wholey Wei-Yun , Yoda Sekou-Tidiane , Vykunta Vivasvan S. , Cheng Wei , Zikherman Julie 
Published: February 2023

AbstractAlthough it has long been appreciated that multivalent antigens – and particularly viral epitope display – produce extremely rapid, robust, and T-independent humoral immune responses, the biochemical basis for such potency has been incompletely understood. Here we take advantage of a set of neutral liposomes of viral size that are engineered to display affinity mutants of the model antigen (Ag) hen egg lysozyme at precisely varied density. We show that particulate Ag display by liposomes induces highly potent B cell responses that are dose-and density-dependent but affinity-independent. Titrating dose of particulate, but not soluble, Ag reveals bimodal Erk phosphorylation and cytosolic calcium increases. Particulate Ag induces signal amplification downstream of the B cell receptor (BCR) by selectively evading LYN-dependent inhibitory pathways, butin vitropotency is independent of CD19. Importantly, Ag display on viral-sized particles signals independently of MYD88 and IRAK1/4, but activates NF-κB robustly in a manner that mimics T cell help. Together, such biased signaling by particulate Ag promotes MYC expression and reduces the threshold required for B cell proliferation relative to soluble Ag. These findings uncover a molecular basis for highly sensitive B cell response to viral Ag display and remarkable potency of virus-like particle vaccines that is not merely accounted for by avidity and BCR cross-linking, and is independent of the contribution of B cell nucleic acid-sensing machinery.
The mitochondrial regulation of smooth muscle cell proliferation in type 2 diabetes
Authors: Koval Olha M. , Nguyen Emily K. , Mittauer Dylan J. , Ait-Aissa Karima , Chinchankar William , Qian Lan , Madesh Muniswamy , Dai Dao-Fu , Grumbach Isabella M. 
Published: February 2023

ABSTRACTBackgroundType 2 diabetes (T2D) is associated with a strongly increased risk for restenosis after angioplasty driven by proliferation of vascular smooth muscle cells (VSMCs). Here, we sought to determine whether and how mitochondrial dysfunction in T2D drives VSMC proliferation with a focus on ROS and intracellular [Ca2+] that both drive cell proliferation, occur in T2D and are regulated by mitochondrial activity.MethodsUsing a diet-induced mouse model of T2D, the inhibition of the mitochondrial Ca2+/calmodulin-dependent kinase II (mtCaMKII), a regulator of Ca2+entry via the mitochondrial Ca2+uniporter selectively in VSMCs, we performed in vivo phenotyping after mechanical injury and established the mechanisms of excessive proliferation in cultured VSMCs.ResultsIn T2D, the inhibition of mtCaMKII reduced both neointima formation after mechanical injury and the proliferation of cultured VSMCs. VSMCs from T2D mice displayed accelerated proliferation, reduced mitochondrial Ca2+entry and membrane potential with elevated baseline [Ca2+]cytocompared to cells from normoglycemic mice. Accelerated proliferation after PDGF treatment was driven by activation of Erk1/2 and its upstream regulators. Hyperactivation of Erk1/2 was Ca2+-dependent rather than mitochondrial ROS-driven Ca2+-dependent and included the activation of CaMKII in the cytosol. The inhibition of mtCaMKII exaggerated the Ca2+imbalance by lowering mitochondrial Ca2+entry and increasing baseline [Ca2+]cyto, further enhancing baseline Erk1/2 activation. With inhibition of mtCaMKII, PDGF treatment had no additional effect on cell proliferation. Inhibition of activated CaMKII in the cytosol decreased excessive Erk1/2 activation and reduced VSMC proliferation.ConclusionsCollectively, our results provide evidence for the molecular mechanisms of enhanced VSMC proliferation after mechanical injury by mitochondrial Ca2+entry in T2D.
Start codon-associated ribosomal frameshifting mediates nutrient stress adaptation
Authors: Mao Yuanhui , Jia Longfei , Dong Leiming , Shu Xin Erica , Qian Shu-Bing 
Published: February 2023

AbstractA translating ribosome is typically thought to follow the reading frame defined by the selected start codon. Using super-resolution ribosome profiling, here we report pervasive out-of-frame translation immediately from the start codon. The start codon-associated ribosome frameshifting (SCARF) stems from the slippage of ribosomes during the transition from initiation to elongation. Using a massively paralleled reporter assay, we uncovered sequence elements acting as SCARF enhancers or repressors, implying that start codon recognition is coupled with reading frame fidelity. This finding explains thousands of mass spectrometry spectra unannotated from human proteome. Mechanistically, we find that the eukaryotic initiation factor 5B (eIF5B) maintains the reading frame fidelity by stabilizing initiating ribosomes. Intriguingly, amino acid starvation induces SCARF by proteasomal degradation of eIF5B. The stress-induced SCARF protects cells from starvation by enabling amino acid recycling and selective mRNA translation. Our findings illustrate a beneficial effect of translational “noise” in nutrient stress adaptation.
Dominant and Genome-Wide Formation of DNA:RNA Hybrid G-Quadruplexes in Living Yeast Cells
Authors: Ren Chen-xia , Duan Rui-fang , Wang Jia , Hao Yu-hua , Tan Zheng 
Published: February 2023

AbstractGuanine-rich nucleic acids form G-quadruplex (G4) structures that play a critical role in cellular processes. Previous studies have mostly focused on monomeric intramolecular G4s with four consecutive guanine tracts (G-tracts) from a single strand. However, this structural form has never been confirmed in eukaryotic cells. Here, we report the formation of hybrid G4s (hG4s), consisting of G-tracts from both DNA and RNA, in the genome of living yeast cells. Analysis of Okazaki fragment syntheses and G4-specific probing reveals that hG4s can efficiently form with as few as a single DNA guanine-guanine (GG) tract due to the participation of G-tracts from RNA. This finding increases the number of G4-forming sites in the yeast genome from 38 to 587,694, a more than 15,000-fold increase. Interestingly, hG4s still form and even dominate at genomic G4 sites that are theoretically capable of forming the monomeric intramolecular DNA G4s by themselves. Compared to DNA G4s (dG4s), hG4s exhibit a wider range of kinetics, higher prevalence, and greater structural diversity and stability. Most importantly, hG4 formation is tightly coupled to transcription through the involvement of RNA, allowing hG4s to function in a transcription-dependent manner. Overall, our study establishes hG4s as the overwhelmingly dominant G4 species in the yeast genome and emphasizes a renewal of the current perception of the structural form, formation mechanism, prevalence, and functional role of G4s in eukaryotic genomes. It also provides a sensitive and currently the only method for detecting the structural form of G4s in living cells.SignificanceThe identification of hybrid G-quadruplexes (hG4s) has disclosed a previously unrecognized structural form of G4s as the most common and abundant G4 species in the yeast genome. It reveals not only a dominant rule governing the formation of G4s in eukaryotic genomes, but also a unique genotype that allows G4-mediated transcriptional regulation to take feedback from the output as input, thus allowing the creation of feedback loops at the transcriptome scale.
SNP profile for quantitative trait nucleotide in populations with small effective size and its impact on mapping and genomic predictions
Authors: Misztal Ignacy , Pocrnic Ivan , Lourenco Daniela 
Published: February 2023

ABSTRACTIn animal populations, increasing the SNP density by incorporating sequence information only marginally increases prediction accuracies. To find out why, we used statistical models and simulations to investigate the profile or distribution of SNP around Quantitative Trait Nucleotides (QTN) in populations with small effective population size (Ne). A QTN profile created by averaging SNP solutions around each QTN was similar to the shape of expected pairwise linkage disequilibrium (PLD) based on Neand genetic distance between SNP, with a distinct peak for the QTN. Populations with smaller Neshowed lower but wider QTN profiles; however, adding more genotyped individuals with phenotypes dragged the profile closer to the QTN; the QTN profile was higher and narrower for populations with larger compared to smaller Ne. Assuming the PLD curve for the QTN profile, 80% of the additive genetic variance explained by each QTN is contained in 8 “Stam” segments (one segment = 1/4NeMorgans), corresponding to 1.6 Mb in cattle, and 5 Mb in pigs and broiler chickens. With such large segments, identifying QTN is difficult even if all of them are in the data and the assumed genetic architecture is simplistic. Additional complexity in QTN detection arises from confounding of QTN profiles with signals due to relationships, overlapping profiles with closely-spaced QTN, and spurious signals due to imputation errors. However, small Neallows for accurate prediction with large data even without QTN identification because QTN are accounted for by QTN profiles if SNP density is sufficient to saturate the segments.