bluuebunny/crossref_metadata_2025_split huggingface dataset:
Methods to study xenografted human cancer in genetically diverse mice
Authors: Hasham Muneer G. , Sargent Jennifer K. , Warner Mark A. , Farley Shawnna R. , Hoffmann Brian R. , Stodola Timothy J. , Brunton Catherine J. , Munger Steven C. 
Published: January 2024

ABSTRACTXenografting human cancer tissues into mice to test new cures against cancers is critical for understanding and treating the disease. However, only a few inbred strains of mice are used to study cancers, and derivatives of mainly one strain, mostly NOD/ShiLtJ, are used for therapy efficacy studies. As it has been demonstrated when human cancer cell lines or patient-derived tissues (PDX) are xenografted into mice, the neoplastic cells are human but the supporting cells that comprise the tumor (the stroma) are from the mouse. Therefore, results of studies of xenografted tissues are influenced by the host strain. We previously published that when the same neoplastic cells are xenografted into different mouse strains, the pattern of tumor growth, histology of the tumor, number of immune cells infiltrating the tumor, and types of circulating cytokines differ depending on the strain. Therefore, to better comprehend the behavior of cancerin vivo, one must xenograft multiple mouse strains. Here we describe and report a series of methods that we used to reveal the genes and proteins expressed when the same cancer cell line, MDA-MB-231, is xenografted in different hosts. First, using proteomic analysis, we show how to use the same cell linein vivoto reveal the protein changes in the neoplastic cell that help it adapt to its host. Then, we show how different hosts respond molecularly to the same cell line. We also find that using multiple strains can reveal a more suitable host than those traditionally used for a “difficult to xenograft” PDX. In addition, using complex trait genetics, we illustrate a feasible method for uncovering the alleles of the host that support tumor growth. Finally, we demonstrate that Diversity Outbred mice, the epitome of a model of mouse-strain genetic diversity, can be xenografted with human cell lines or PDX using 2-deoxy-D-glucose treatment.
A reduced vernalization requirement is a key component of the early-bolting trait in globe artichoke (Cynara cardunculusvar.scolymus)
Authors: Berentsen Rick , Benlloch Reyes , Visser Peter , Madueño Francisco , Balanzà Vicente 
Published: January 2024

SummaryEarly-bolting is a major breeding objective for globe artichoke (Cynara cardunculusvar.scolymusL.). It has been suggested that globe artichoke bolting time is linked to a vernalization requirement, although environmental conditions under which vernalized plants and controls have been grown may not always allow for proper comparison. Here, we defined morphological markers to monitor the vegetative-to- reproductive phase transition at the shoot apex and linked these to expression changes of homologues of key Arabidopsis flowering regulatorsSOC1,FUL, andAP1. Importantly, we developed an experimental setup where control and vernalized plants grow under comparable conditions. These tools together allowed for comparison of the vegetative-to-reproductive phase transition between early- and late-bolting genotypes and how they respond to vernalization. Our results show that vernalization requirement is significantly lower in early-bolting genotypes, supporting the view that the early-bolting trait is partly underlain by alterations in the network controlling vernalization response.
Regulatory genome annotation of 33 insect species
Authors: Asma Hasiba , Tieke Ellen , Deem Kevin D. , Rahmat Jabale , Dong Tiffany , Huang Xinbo , Tomoyasu Yoshinori , Halfon Marc S. 
Published: January 2024

ABSTRACTAnnotation of newly-sequenced genomes frequently includes genes, but rarely covers important non-coding genomic features such as thecis-regulatory modules—e.g., enhancers and silencers—that regulate gene expression. Here, we begin to remedy this situation by developing a workflow for rapid initial annotation of insect regulatory sequences, and provide a searchable database resource with enhancer predictions for 33 genomes. Using our previously-developed SCRMshaw computational enhancer prediction method, we predict over 2.8 million regulatory sequences along with the tissues where they are expected to be active, in a set of insect species ranging over 360 million years of evolution. Extensive analysis and validation of the data provides several lines of evidence suggesting that we achieve a high true-positive rate for enhancer prediction. One, we show that our predictions target specific loci, rather than random genomic locations. Two, we predict enhancers in orthologous loci across a diverged set of species to a significantly higher degree than random expectation would allow. Three, we demonstrate that our predictions are highly enriched for regions of accessible chromatin. Four, we achieve a validation rate in excess of 70% using in vivo reporter gene assays. As we continue to annotate both new tissues and new species, our regulatory annotation resource will provide a rich source of data for the research community and will have utility for both small-scale (single gene, single species) and large-scale (many genes, many species) studies of gene regulation. In particular, the ability to search for functionally-related regulatory elements in orthologous loci should greatly facilitate studies of enhancer evolution even among distantly related species.
Linking phenotypic and genotypic variation: a relaxed phylogenetic approach using the probabilistic programming language Stan
Authors: Gemmell Patrick 
Published: January 2024

AbstractPhyloG2P methods link genotype and phenotype by integrating evidence from across a phylogeny. I introduce a Bayesian approach to jointly modelling a continuous trait and a multiple sequence alignment, given a background tree and substitution rate matrix. The aim is to ask whether faster sequence evolution is linked to faster phenotypic evolution. Per-branch substitution rate multipliers (for the alignment) are linked to per-branch variance rates of a Brownian diffusion process (for the trait) via the flexible logistic function. The Brownian diffusion process can evolve on the same tree used to describe the alignment, or on a second tree, for example a tree with branch lengths in units of time. Simulation studies suggest the model can be well estimated using relatively short alignments and reasonably sized trees. An application of the model in both its one-tree and two-tree variants is provided as an example. Notably, the method is implemented concisely using the general-purpose probabilistic programming language Stan.
Declining reservoir elevations following a two-decade drought increase water temperatures and non-native fish passage facilitating a downstream invasion
Authors: Eppehimer D.E. , Yackulic C.B. , Bruckerhoff L.A. , Wang J. , Young K.L. , Bestgen K.R. , Mihalevich B.A. , Schmidt J.C. 
Published: January 2024

AbstractRiver ecosystems are threatened by interactions among river regulation, non-native species, and climate change. Water use has exceeded supply for two decades in the USA’s Colorado River basin draining its two largest storage reservoirs (Lake Powell and Lake Mead). In 2022, after more than two decades of declining reservoir levels and warming downstream river water temperatures, Lake Powell began releasing water from its lower epilimnion into the Grand Canyon segment of the Colorado River. While managers were concerned about the risk of non-native, predatory smallmouth bass (Micropterus dolomieu) entrainment and reproduction, they lacked a quantitative tool to understand entrainment rates and population growth potential under different reservoir management strategies. To fill this void, we developed models in spring 2022 that: 1) predicted propagule pressure at different reservoir elevations, and 2) linked reservoir storage/operations, water temperatures, and smallmouth bass population dynamics to forecast population growth rates under different hydrologic and management scenarios. In the summers of 2022 and 2023, smallmouth bass were documented reproducing in the lower Colorado River for the first time. Our models accurately forecasted adult catch of smallmouth bass in 2022 and 2023 and forecasted that reproduction would occur in both years for the first time in the history of this river segment. Above average runoff in 2023 increased reservoir elevations, however the potential for smallmouth bass establishment remains high because of long-term forecasts of reduced reservoir inflows and lake levels significantly below full pool. Maintaining Lake Powell elevations above 1,088 m (3,570 ft) would likely minimize propagule pressure from the reservoir and would likely create downstream conditions that minimize smallmouth bass population growth.
Predicting COVID-19 cases across a large university campus using complementary built environment and wastewater surveillance approaches
Authors: Hinz Aaron , Moggridge Jason A. , Ke Hanna , Hicks Alexandra M. A. , Doukhanine Evgueni , Fralick Michael , Hug Laura , MacFadden Derek , Mejbel Hebah , Nott Caroline , Raudanskis Ashley , Thampi Nisha , Wong Alex , Kassen Rees 
Published: January 2024

ABSTRACTBackgroundEnvironmental surveillance of SARS-CoV-2 via wastewater has become an invaluable tool for population-level surveillance. Built environment sampling may provide complementary spatially-refined detection for viral surveillance in congregate settings such as universities.MethodsWe conducted a prospective environmental surveillance study at the University of Ottawa between September 2021 and April 2022. Floor surface samples were collected twice weekly from six university buildings. Samples were analyzed for the presence of SARS-CoV-2 using RT-qPCR. A Poisson regression was used to model the campus-wide COVID-19 cases predicted from the fraction of floor swabs positive for SARS-CoV-2 RNA, building CO2levels, Wi-Fi usage, and SARS-CoV-2 RNA levels in regional wastewater. We used a mixed-effects Poisson regression analysis to model building-level cases using viral copies detected in floor samples as a predictor. A random intercepts logistic regression model tested whether floor samples collected in high-traffic areas were more likely to have SARS-CoV-2 present than low-traffic areas.ResultsOver the 32-week study period, we collected 554 floor swabs at six university buildings. Overall, 13% of swabs were PCR-positive for SARS-CoV-2, with positivity ranging between 4.8% and 32.7% among university buildings. Both floor swab positivity (Spearman r = 0.74, 95% CI: 0.53-0.87) and regional wastewater signal (Spearman r = 0.50, 95% CI: 0.18-0.73) were positively correlated with on-campus COVID-19 cases. In addition, built environment detection was a predictor of cases linked to individual university buildings (IRlog10(copies)+1= 17, 95% CI: 7-44). There was no significant difference in detection between floors sampled in high-traffic versus low-traffic areas (OR = 1.3, 95% CI: 0.8-2.1).ConclusionsDetection of SARS-CoV-2 RNA on floors and viral RNA levels found in wastewater were strongly associated with the incidence of COVID-19 cases on a university campus. These data suggest a potential role for institutional built environment sampling, used together with wastewater surveillance, for predicting COVID-19 cases at both campus-wide and building level scales.
Plxnd1-mediated mechanosensing of blood flow controls the caliber of the Dorsal Aorta via the transcription factor Klf2
Authors: He Jia , Blazeski Adriana , Nilanthi Uthayanan , Menéndez Javier , Pirani Samuel C. , Levic Daniel S. , Bagnat Michel , Singh Manvendra K. , Raya José G , García-Cardeña Guillermo , Torres-Vázquez Jesús 
Published: January 2024

SUMMARYThe cardiovascular system generates and responds to mechanical forces. The heartbeat pumps blood through a network of vascular tubes, which adjust their caliber in response to the hemodynamic environment. However, how endothelial cells in the developing vascular system integrate inputs from circulatory forces into signaling pathways to define vessel caliber is poorly understood. Using vertebrate embryos andin vitro-assembled microvascular networks of human endothelial cells as models, flow and genetic manipulations, and custom software, we reveal that Plexin-D1, an endothelial Semaphorin receptor critical for angiogenic guidance, employs its mechanosensing activity to serve as a crucial positive regulator of the Dorsal Aorta’s (DA) caliber. We also uncover that the flow-responsive transcription factor KLF2 acts as a paramount mechanosensitive effector of Plexin-D1 that enlarges endothelial cells to widen the vessel. These findings illuminate the molecular and cellular mechanisms orchestrating the interplay between cardiovascular development and hemodynamic forces.HighlightsPlexin-D1 mechanosensing of blood flow tunes the caliber of the Dorsal Aorta (DA)The DA widens without raising endothelial cell numbers, which can change separate from the caliberThe Kruppel-like transcription factor 2 (KLF2) is a key Plexin-D1 mechano-effector during developmentKLF2 increases endothelial cell size to expand the DA caliber
The effect of semantic content on the perception of audiovisual movieclips
Authors: Kesoglou Anastasia Maria , Mikellidou Kyriaki 
Published: January 2024

AbstractOur brain is skilled with the ability to perceive and process multimodal stimuli. This process known as crossmodal perceptual integration, has been in the research spotlight for a long time, providing evidence for the integration of information coming from different modalities. Prior research mostly utilized pictures and focused on the semantic content of a single sound or word. The present study aims to investigate crossmodal perceptual integration in realistic conditions using short movieclips (1500ms) and auditory meaningful three-word sentences to evaluate target detection in terms of accuracy and response times. Two experimental tasks were developed using PsychoPy, where participants had to indicate whether a target (noun for Experiment 1, verb for Experiment 2) was present or absent. In trials without a target, target-related information was always present, either through one of the two senses (vision or audition; incongruent condition) or through both senses (congruent condition). We observed superior performance when the target was absent generally (Mexp1=93.9%, SDexp1=0.04, Mexp2=84.2%, SDexp2=0.182) compared to when it was present (Mexp1=82.3%, SDexp1=0.143, Mexp2=73.7%, SDexp2=0.184). Moreover, superior performance was noted in incongruent target-related movieclips, which significantly decreased during congruent target-related movieclips. In Experiment 1, we observed that in the audio condition when the target-related word was a noun, participant performance was superior compared to when it was a verb (M=99.4% vs. M=86.7%; tincVerb vs. incNoun=-8.428, p=.001). In Experiment 2, the judgment scores were similarly high in incongruent movieclips and significantly lower in congruent ones regardless of whether the target-related information presented was a verb or noun. The present results provide evidence regarding the role of complexity of semantics, and especially the diverse role verbs and nouns could play in crossmodal perceptual integration in more realistic situations. Our findings can enrich the content of learning techniques, as well as the design of AI models, by taking advantage of the supporting role of semantic audiovisual information, while taking into consideration the potential confusion that the complexity of semantic information can induce to perception experience.
Interferon-γas a Potential Inhibitor of SARS-CoV-2 ORF6 Accessory Protein
Authors: Krachmarova Elena , Petkov Peicho , Lilkova Elena , Stoynova Dayana , Malinova Kristina , Hristova Rossitsa , Gospodinov Anastas , Ilieva Nevena , Nacheva Genoveva , Litov Leandar 
Published: January 2024

AbstractORF6 protein of the SARS-CoV-2 virus plays a crucial role in blocking the innate immune response of the infected cells by inhibiting interferon pathways. Additionally, it binds and immobilises the RAE1 protein onto the cytoplasmic membranes, thereby blocking the transport of mRNA from the nucleus to the cytoplasm. In all these cases the host cell proteins are tethered by the flexible C-terminus of ORF6. A possible strategy to inhibit the biological activity of ORF6 is to bind its C-terminus with suitable ligands. Our in silico experiments suggest that hIFNγbinds the ORF6 protein with high affinity, thus impairing its interactions with RAE1 and, consequently, its activity in viral invasion. The here reported in vitro studies reveal a shift of the localization of RAE1 in ORF6 overexpressing cells upon treatment with hIFNγfrom predominantly cytoplasmic to mainly nuclear, resulting in restoration of the export of mRNA from the nucleus. We also explored the expression of GFP in transfected with ORF6 cells by means of fluorescence microscopy and qRT-PCR, finding that treatment with hIFNγunblocks the mRNA trafficking and reinstates the GFP expression level. The ability of the cytokine to block ORF6 is also reflected in minimising its negative effects on DNA replication by reducing accumulated RNA-DNA hybrids. Our results, therefore, suggest hIFNγas a promising inhibitor of the most toxic SARS-CoV-2 protein.
Wnt7a is Required for Regeneration of Dystrophic Skeletal Muscle
Authors: Gurriaran-Rodriguez Uxia , Kodippili Kasun , Datzkiw David , Javandoost Ehsan , Xiao Fan , Rejas Maria Teresa , Rudnicki Michael A. 
Published: January 2024

AbstractIntramuscular injection of Wnt7a has been shown to accelerate and augment skeletal muscle regeneration and to ameliorate dystrophic progression inmdxmuscle, a model for Duchenne muscular dystrophy (DMD). However, loss-of-function studies to investigate the requirement for Wnt7a in muscle regeneration has not been evaluated. Here, we assessed muscle regeneration and function in wild type (WT) andmdxmice where Wnt7a was specifically deleted in muscle using a conditionalWnt7afloxed allele and aMyf5-Credriver. We found that both WT andmdxmice with deletion of Wnt7a in muscle, exhibited marked deficiencies in muscle regeneration at 21 d following cardiotoxin (CTX) induced injury. Unlike WT, deletion of Wnt7a inmdxresulted in a marked decrease in specific force generation prior to CTX injury. However, both WT andmdxmuscle lacking Wnt7a displayed decreased specific force generation following CTX injection. Notably the regeneration deficit observed inmdxmice lacking Wnt7a in muscle was rescued by a single tail vein injection of an extracellular vesicle preparation containing Wnt7a (Wnt7a-EVs). Therefore, we conclude that the regenerative capacity of muscle inmdxmice is due to the upregulation of endogenous Wnt7a following injury, and that systemic delivery of Wnt7a-EVs represents a therapeutic strategy for treating DMD.
Diverse Database and Machine Learning Model to Narrow the Generalization Gap in RNA Structure Prediction
Authors: de Lajarte Albéric A. , Martin des Taillades Yves J. , Kalicki Colin , Fuchs Wightman Federico , Aruda Justin , Salazar Dragui , Allan Matthew F. , L’Esperance-Kerckhoff Casper , Kashi Alex , Jossinet Fabrice , Rouskin Silvi 
Published: January 2024

AbstractUnderstanding macromolecular structures of proteins and nucleic acids is critical for discerning their functions and biological roles. Advanced techniques—crystallography, NMR, and CryoEM—have facilitated the determination of over 180,000 protein structures, all cataloged in the Protein Data Bank (PDB). This comprehensive repository has been pivotal in developing deep learning algorithms for predicting protein structures directly from sequences. In contrast, RNA structure prediction has lagged, and suffers from a scarcity of structural data. Here, we present the secondary structure models of 1098 pri-miRNAs and 1456 human mRNA regions determined through chemical probing. We develop a novel deep learning architecture, inspired from the Evoformer model of Alphafold and traditional architectures for secondary structure prediction. This new model, eFold, was trained on our newly generated database and over 300,000 secondary structures across multiple sources. We benchmark eFold on two new test sets of long and diverse RNA structures and show that our dataset and new architecture contribute to increasing the prediction performance, compared to similar state-of-the-art methods. All together, our results reveal that merely expanding the database size is insufficient for generalization across families, whereas incorporating a greater diversity and complexity of RNAs structures allows for enhanced model performance.
Herpes Simplex Virus-1 targets the 2’-3’cGAMP importer SLC19A1 as an antiviral countermeasure
Authors: Szemere Zsuzsa K. , Murphy Eain A. 
Published: January 2024

ABSTRACTTo establish a successful infection, herpes simplex virus-1 (HSV-1), a virus with high seropositivity in the human population, must undermine host innate and intrinsic immune defense mechanisms, including the stimulator of interferon genes (STING) pathway. Recently it was discovered that not onlyde novoproduced intracellular 2’-3’cGAMP, but also extracellular 2’-3’cGAMP activates the STING pathway by being transported across the cell membrane via the folate transporter, SLC19A1, the first identified extracellular antiporter of this signaling molecule. We hypothesized that the import of exogenous 2’-3’cGAMP functions to establish an antiviral state like that seen with the paracrine antiviral activities of interferon. Further, to establish a successful infection, HSV-1 must undermine this induction of the STING pathway by inhibiting the biological functions of SLC19A1. Herein, we report that treatment of the monocytic cell line, THP-1 cells, epithelial cells (ARPE-19) and SH-SY5Y neuronal cell line with exogenous 2’-3’cGAMP induces interferon production and establishes an antiviral state. Using either pharmaceutical inhibition or genetic knockout of SLC19A1 blocks the 2’-3’cGAMP-induced antiviral state. Additionally, HSV-1 infection results in the reduction of SLC19A1 transcription, translation, and importantly, the rapid removal of SLC19A1 from the cell surface of infected cells. Our data indicate SLC19A1 functions as a newly identified antiviral mediator for extracellular 2’-3’cGAMP which is undermined by HSV-1. This work presents novel and important findings about how HSV-1 manipulates the host’s immune environment for viral replication and discovers details about an antiviral mechanism which information could aid in the development of better antiviral drugs in the future.ImportanceHSV-1 has evolved multiple mechanisms to neutralize of the host’s innate and intrinsic defense pathways, such as the STING pathway. Here, we identified an antiviral response in which extracellular 2’-3’cGAMP triggers IFN production via its transporter SLC19A1. Moreover, we report that HSV-1 blocks the functions of this transporter thereby impeding the antiviral response, suggesting exogenous 2’-3’cGAMP can act as an immunomodulatory molecule in uninfected cells to activate the STING pathway, and priming an antiviral state, similar to that seen in interferon responses. The details of this mechanism highlight important details about HSV-1 infections. This work presents novel findings about how HSV-1 manipulates the host’s immune environment for viral replication and reveals details about a novel antiviral mechanism. These findings expand our understanding of how viral infections undermine host responses and may help in the development of better broad based antiviral drugs in the future.