bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ras/MAPK signalling intensity defines subclonal fitness in a mouse model of primary and metastatic hepatocellular carcinoma
Authors: Lozano Anthony , Souche François-Régis , Ramirez Christel , Vegna Serena , Desandré Guillaume , Riviere Anaïs , Dardalhon Valérie , El Aabidine Amal Zine , Fort Philippe , Akkari Leila , Hibner Urszula , Grégoire Damien 
Published: August 2021

AbstractQuantitative differences in signal transduction are to date an understudied feature of tumour heterogeneity. The MAPK Erk pathway, which is activated in a large proportion of human tumours, is a prototypic example of distinct cell fates being driven by signal intensity. We have used primary hepatocyte precursors transformed with different dosages of an oncogenic form of Ras to model subclonal variations in MAPK signalling. Orthotopic allografts of Ras-transformed cells in immunocompromised mice gave rise to fast-growing aggressive tumours, both at the primary location and in the peritoneal cavity. Fluorescent labelling of cells expressing different oncogene levels, and consequently varying levels of MAPK Erk activation, highlighted the selection processes operating at the two sites of tumour growth. Indeed, significantly higher Ras expression was observed in primary as compared to metastatic tumours, despite the evolutionary trade-off of increased apoptotic death in the liver that correlated with high Ras dosage. Analysis of the immune tumoral microenvironment at the two locations suggests that fast metastatic growth in the immunocompromised setting is abrogated in immunocompetent animals due to efficient antigen presentation by peritoneal dendritic cells. Furthermore, our data indicate that, in contrast to the metastatic outgrowth, strong MAPK signalling is required in the primary liver tumours to resist elimination by NK cells. Overall, this study describes a quantitative aspect of tumour heterogeneity and highlights potential vulnerability of a subtype of hepatocellular carcinoma as a function of MAPK Erk signalling intensity.
Autophagy coordinates chondrocyte development and early joint formation in zebrafish
Authors: Moss Joanna J. , Wirth Martina , Tooze Sharon A. , Lane Jon D. , Hammond Chrissy L. 
Published: August 2021

ABSTRACTAutophagy is a catabolic process responsible for the removal of waste and damaged cellular components by lysosomal degradation. It plays a key role in fundamental cell processes, including ER stress mitigation, control of cell metabolism, and cell differentiation and proliferation, all of which are essential for cartilage cell (chondrocyte) development and survival, and for the formation of cartilage. Correspondingly, autophagy dysregulation has been implicated in several skeletal disorders such as osteoarthritis and osteoporosis. To test the requirement for autophagy during skeletal development in zebrafish, we generated an atg13 CRISPR knockout zebrafish line. This line showed a complete loss of atg13 expression, and restricted autophagic activity in vivo. In the absence of autophagy, chondrocyte maturation was accelerated, with chondrocytes exhibiting signs of premature hypertrophy. Focussing on the jaw element, autophagy disruption affected joint articulation causing restricted mouth opening. This gross behavioural phenotype corresponded with a failure to thrive, and death in homozygote atg13 nulls within 17 days. Taken together, our results are consistent with autophagy contributing to the timely regulation of chondrocyte maturation and for extracellular matrix formation.
Response of Posidonia oceanica (L.) Delile and its associated N2 fixers to different combinations of temperature and light levels
Authors: García-Márquez Manuela Gertrudis , Fernández-Juárez Víctor , Rodríguez-Castañeda José Carlos , Agawin Nona S. R. 
Published: August 2021

AbstractOcean warming and water turbidity are threats for the persistence of seagrass meadows and their effects on the productivity of seagrasses and the functioning of their associated microorganisms have not been studied extensively. The purpose of this study was to assess the effects of different light levels and temperatures on Posidonia oceanica, the endemic seagrass species in the Mediterranean Sea, and their N2 fixing community, which contributes importantly to the nitrogen requirements and high productivity of the plants. Aquarium experiments were conducted in winter when the plants are more vulnerable to changes in temperature, subjecting them to short-term exposures to ambient (15.5 °C) and elevated temperatures (ambient+5.5 °C) and at limited (13 μmol photons m-2 s-1) and saturating light conditions (124 μmol photons m-2 s-1). Primary production, chlorophyll content, reactive oxygen species production, polyphenols content, the nifH gene expression, N2 fixation and alkaline phosphatase activities were measured in different plant tissues. Plants incubated at ambient temperature and high light exhibited enhanced total chlorophyll production and significantly higher gross and net primary production, which were approximately two-fold compared to the rest of the treatments. The oxidative stress analyses revealed increased production of reactive oxygen species in young leaves incubated at ambient temperature and saturating light, while the polyphenols content in top leaves was considerably higher under elevated temperatures. In contrast, N2 fixation and alkaline phosphatase rates were significantly higher under elevated temperature and low light levels. The presence of the N2 fixing phylotypes UCYN-A, -B and -C was detected through genetic analyses, with UCYN-B demonstrating the highest nifH gene transcription levels at elevated temperatures. These findings emphasize the significant role of irradiance on the productivity of P. oceanica and the temperature dependence of the N2 fixation process in winter.
Engineering Bacillus subtilis for the formation of a durable living biocomposite material
Authors: Kang Sun-Young , Pokhrel Anaya , Bratsch Sara , Benson Joey J. , Seo Seung-Oh , Quin Maureen B. , Aksan Alptekin , Schmidt-Dannert Claudia 
Published: August 2021

ABSTRACTEngineered living materials (ELMs) are a fast-growing area of research that combine approaches in synthetic biology and material science. Here, we engineer B. subtilis to become a living component of a silica material composed of self-assembling protein scaffolds for functionalization and cross-linking of cells. B. subtilis was engineered to display SpyTags on polar flagella for cell attachment and cross-linking of SpyCatcher modified secreted scaffolds. Through deletion of the autolysis LytC, endospore limited B. subtilis cells become a structural component of the material with spores for long-term storage of genetic programming. Known silica biomineralization peptides were screened and scaffolds designed for silica polymerization to fabricate biocomposite materials with enhanced mechanical properties. We show that the resulting ELM can be regenerated from a piece of silica material and that new functions can be readily incorporated by co-cultivation of engineered B. subtilis strains. We believe that this work will serve as a framework for the future design of resilient ELMs as functional, self-healing materials for use as responsive coatings and plasters.
Gpnmb inhibits oligodendrocyte differentiation of adult neural stem cells by amplifying TGFβ1 signaling
Authors: Radecki Daniel Z. , Wang Albert R. , Johnson Abigail S. , Overman Christian A. , Thatcher Madison M. , Iyer Gopal , Samanta Jayshree 
Published: August 2021

SummaryGli1 expressing neural stem cells, in the subventricular zone of the adult mammalian brain, respond to demyelination injury by differentiating into oligodendrocytes. We have identified Gpnmb as a novel regulator of oligodendrogenesis in Gli1 neural stem cells, whose expression is induced by TGFβ1 signaling via Gli1, in response to a demyelinating injury. Upregulation of Gpnmb further activates the TGFβ1 pathway by increasing the expression of the TGFβ1 binding receptor subunit, TGFβR2. Thus the TGFβ1→Gli1→Gpnmb→TGFβR2 signaling pathway forms a feed forward loop for sustained activation of TGFβ1 signaling in Gli1 neural stem cells, resulting in inhibition of their differentiation into mature oligodendrocytes following demyelination.
Severe inbreeding and gene loss in the historical and extant population of the critically endangered Devils Hole pupfish
Authors: Tian David , Turner Bruce J. , Martin Christopher H. 
Published: August 2021

AbstractSmall populations with limited geographic distributions are predicted to be threatened by inbreeding and lack of genetic diversity, both of which may negatively impact fitness and exacerbate population decline. One of the most extreme natural examples is the Devils Hole pupfish (Cyprinodon diabolis), an iconic and critically endangered species with the smallest known habitat range of any vertebrate. This imperiled species has experienced severe declines in population size over the last thirty years and suffered major, repeated bottlenecks in 2007 and 2013, when the population sunk to 38 and 35 individuals, respectively. Here we sequenced contemporary and historical genomes of Devils Hole and neighboring Death Valley and Ash Meadows desert pupfishes to examine the genomic consequences of small population size. We found extreme inbreeding (FROH = 0.71 - 0.82) and increased genetic load in the Devils Hole pupfish. We also document unique fixed loss-of-function (LOF) alleles and deletions in genes associated with sperm motility, stress, and hypoxia within the extant Devils Hole pupfish population that likely reduce fitness. Comparisons between contemporary samples (2008 – 2012) and a genome sequenced from a 1980 formalin-fixed museum specimen suggest that inbreeding has increased 6% as the population has declined, but that many putatively deleterious variants have been segregating in the population since at least 1980. This includes a fixed early stop codon in cfap43 (n = 8/8 samples), which is associated with sperm flagellum defects and causes infertility in humans and mice. Out of ninety-four unique deletions, fifteen were detected within 2 kb of annotated genes. Five have roles in physiological responses to hypoxia and mitochondrial activity, such as redd1 (n = 7/7 samples), suggesting impaired hypoxia tolerance in this species despite the low oxygen concentrations of Devils Hole. We thus document one of the most extreme inbreeding events in a natural population and a set of candidate deleterious variants to inform management and potential genetic rescue in this conservation icon.
Using Oxford Nanopore Technology direct RNA sequencing to identify depurination events induced by ricin and other ribosome inactivating proteins
Authors: Ryan Yan , Harrison Abbie , Trivett Hannah , Hartley Catherine , David Jonathan , Clark Graeme , Hiscox Julian A. 
Published: August 2021

AbstractDepurination is a frequent modification to both DNA and RNA, in DNA causing point mutations through misincorporation, in RNA, disabling ribosomes and halting protein synthesis. Some modifications of nucleic acids can be determined by direct sequencing using Oxford Nanopore Technologies (ONT). However, the identification of modifications is often limited by noise and their variety and number. Ricin is a toxin which enters cells and depurinates an adenine base in the sarcin-ricin loop of the large ribosomal subunit. This leaves only a ribose backbone, thus inhibiting protein translation. In humans, biological threat agents and ribosome inactivating proteins, such as ricin and saporin, depurinate base 4605 on the 28S rRNA providing a single defined target to try and identify. We postulated that the depurination event could be detected using ONT direct RNA sequencing through a change in charge in the ricin loop. A software tool was developed, RIPpore, that quantified the adenine modification from direct RNA sequencing data of ribosomal RNA purified from respiratory epithelial cells exposed to ricin. This provided a novel method of directly identifying ricin exposure and a basis for ONT’s utility in detecting lesions in nucleic acids caused by depurination events.
Analysis of Mouse Vocal Communication (AMVOC): A deep, unsupervised method for rapid detection, analysis, and classification of ultrasonic vocalizations
Authors: Stoumpou Vasiliki , Vargas César D. M. , Schade Peter F. , Giannakopoulos Theodoros , Jarvis Erich D. 
Published: August 2021

AbstractSome aspects of the neural mechanisms underlying mouse ultrasonic vocalizations (USVs) are a useful model for the neurobiology of human speech and speech-related disorders. Much of the research on vocalizations and USVs is limited to offline methods and supervised classification of USVs, hindering the discovery of new types of vocalizations and the study of real-time free behavior. To address these issues, we developed AMVOC (Analysis of Mouse VOcal Communication) as a free, open-source software to analyze and detect USVs in both online and offline modes. When compared to hand-annotated ground-truth USV data, AMVOC’s detection functionality (both offline and online) has high accuracy, and outperforms leading methods in noisy conditions, thus allowing for broader experimental use. AMVOC also includes the implementation of an unsupervised deep learning approach that facilitates discovery and analysis of USV data by clustering USVs using latent features extracted by a convolutional autoencoder and isimplemented in a graphical user interface (GUI), also enabling user’s evaluation. These results can be used to explore the vocal repertoire space of the analyzed vocalizations. In this way, AMVOC will facilitate vocal analyses in a broader range of experimental conditions and allow users to develop previously inaccessible experimental designs for the study of mouse vocal behavior.
Novel murine models of post-implantation and midgestional malaria-induced preterm birth
Authors: Andrew Alicer K. , Cooper Caitlin A. , Moore Julie M. 
Published: August 2021

AbstractDespite major advances made in malaria treatment and control over recent decades, the development of new models for studying disease pathogenesis remains a vital part of malaria research efforts. The study of malaria infection during pregnancy is particularly reliant on mouse models, as a means of circumventing many challenges and costs associated with pregnancy studies in endemic human populations. Here, we introduce three novel murine models that will further our understanding of how post-implantation and midgestional malaria infection affects pregnancy outcomes. When C57BL/6J (B6) mice are infected with Plasmodium chabaudi chabaudi AS on either embryonic day (E) 6.5, 8.5, or 10.5, preterm birth occurs in all animals by E16.5, E17.5, or E18.5 respectively, with no evidence of intrauterine growth restriction. We found that the time to delivery, placental inflammatory and antioxidant transcript upregulation, and the relationships between parasitemia and transcript expression prior to preterm birth are different based on the embryonic day of infection. On the day before preterm delivery, E6.5 infected mice did not experience significant upregulation of the inflammatory or antioxidant gene transcripts examined; however, parasitemia correlated positively with Il1β, Cox1, and Hmox1 placental transcript abundance. E8.5 infected mice had elevated transcripts for Ifnγ, Tnf, Il10, Cox1, Cox2, Sod1, Sod2, Cat, and Nrf2, while Sod3 was the only transcript that correlated with parasitemia. Finally, E10.5 infected mice had elevated transcripts for Ifnγ only, with a tendency for Tnf transcripts to correlate with parasitemia. Tumor necrosis factor deficient (TNF-/-) and TNF receptor 1 deficient (TNFR1-/-) mice infected on E8.5 experienced preterm birth at the same time as B6 controls. Further characterization of these models is necessary to discover new and/or existing mechanism(s) or trigger(s) responsible for malaria-driven preterm birth that is determined by gestational age upon maternal infection, parasite-host dynamics, or both.
Effects of aqueous antioxidants extracts from ginger, garlic and onion on 2-thiobarbituric Acid Reactive Substances and total volatile basic nitrogen content in chevon (goat meat) and pork during frozen storage
Authors: Chatepa Lesten Eliez Chisomo , Masamba Kingsley George , Tanganyika Jonathan 
Published: August 2021

AbstractThe study investigated the effect of 10% aqueous extracts of ginger (Zingiber officinale L.), garlic (Allium sativum L.) and onion (Allium cepa L.) on the quality of frozen chevon and pork as reflected by changes in values of 2-thiobartituric Acid Reactive Substances (2-TBARS), pH and total volatile basic nitrogen (TVB-N) over a 14 day storage under frozen conditions. Fresh samples each weighing 2 kg from chevon and pork were bought from the local slaughter houses in two locations 24hrs after slaughtering while ginger roots, garlic and onion bulbs were purchased from Mitundu local market in Lilongwe district, Malawi. The pH, total 2-TBARS and TVB-N of the thigh chevon and pork were measured from frozen storage at −20 °C after 14 days. The 10% aqueous extracts resulted in low pH values of 5.63, 5.79 and 5.67 at 14 d for chevon mixed with ginger, garlic and onion respectively. However, treated pork had higher pH content compared to treated chevon at 14 d. At day14 of frozen storage, the 2-TBARS expressed as mg MDA/kg meat, for chevon mixed with ginger, garlic and onion aqueous extracts were 2.62±0.01, 0 and 4.71±0.03 which was lower compared to the value of 5.93±0.01 for raw chevon. The TBARS values of chevon and pork mixed with ginger, garlic and onion and control chevon decreased from day 0 to 7 which eventually increased on 14 d. On 14 d, pork mixed with garlic extracts had lower TBARS value of 2.13±0.01 compared to 3.50±0.20, 2.26±0.01 and 3.92±0.01 for pork mixed with extracts of onion, ginger and control pork sample respectively. TVB-N, in mg/100g, was highest in control raw chevon and pork registering 95.70±0.32 and 84.00±0.40 at 14 d. Low values of TVB-N of 7.24±0.23, 12.37±0.23 and 16.61v±0.50 were registered in chevon mixed with aqueous extracts of ginger, garlic and onion compared to the values of 14.23±0.62, 22.87±0.47 and 18.86±0.14 for pork mixed with aqueous extracts of ginger, garlic and onion. The results of the study have revealed that natural aqueous antioxidant extracts of ginger, garlic and onion have antioxidative effect on lipid peroxidation in frozen stored fresh chevon and pork signifying that the use of these extracts can maintain quality.
CureSCi Metadata Catalog – Making sickle cell studies findable
Authors: Pan H. , Ives C. , Mandal M. , Qin Y. , Hendershot T. , Popovic J.R. , Brambilla D. , Stratford J.K. , Treadwell M. , Wu X. , Kroner B. 
Published: August 2021

AbstractObjectivesTo adopt the FAIR principles (Findable, Accessible, Interoperable, Reusable) to enhance data sharing, the Cure Sickle Cell Initiative (CureSCi) MetaData Catalog (MDC) was developed to make Sickle Cell Disease (SCD) study datasets more Findable by curating study metadata and making them available through an open-access web portal.MethodsStudy metadata, including study protocol, data collection forms, and data dictionaries, describe information about study patient-level data. We curated key metadata of 16 SCD studies in a three-tiered conceptual framework of category, subcategory, and data element using ontologies and controlled vocabularies to organize the study variables. We developed the CureSCi MDC by indexing study metadata to enable effective browse and search capabilities at three levels: study, Patient-Reported Outcome (PRO) Measures, and data element levels.ResultsThe CureSCi MDC offers several browse and search tools to discover studies by study level, PRO Measures, and data elements. The “Browse Studies,” “Browse Studies by PRO Measures,” and “Browse Studies by Data Elements” tools allow users to identify studies through pre-defined conceptual categories. “Search by Keyword” and “Search Data Element by Concept Category” can be used separately or in combination to provide more granularity to refine the search results. This resource helps investigators find information about specific data elements across studies using public browsing/search tools, before going through data request procedures to access controlled datasets. The MDC makes SCD studies more Findable through browsing/searching study information, PRO Measures, and data elements, aiding in the reuse of existing SCD data.
Modeling toes contributes to realistic stance knee mechanics in three-dimensional predictive simulations of walking
Authors: Falisse Antoine , Afschrift Maarten , De Groote Friedl 
Published: August 2021

AbstractPhysics-based predictive simulations have been shown to capture many salient features of human walking. Yet they often fail to produce realistic stance knee mechanics and terminal stance ankle plantarflexion. While the influence of the performance criterion on the predicted walking pattern has been previously studied, the influence of the mechanics has been less explored. Here, we investigated the influence of two mechanical assumptions on the predicted walking pattern: the complexity of the foot segment and the stiffness of the Achilles tendon. We found, through three-dimensional muscle-driven predictive simulations of walking, that modeling the toes and metatarsophalangeal joints, and thus using two-segment instead of single-segment foot models, contributed to robustly eliciting physiological stance knee flexion angles, knee extension torques, and knee extensor activity. Yet modeling toe joints did not improve ankle kinematics, nor did decreasing the Achilles tendon stiffness. The lack of predicted terminal stance ankle plantarflexion thereby remains an open question. Overall, this simulation study shows that not only the performance criterion but also mechanical assumptions affect predictive simulations of walking. Improving the realism of predictive simulations is required for their application in clinical contexts. Here, we suggest that using complex models is needed to yield such realism.
The diazepam binding inhibitor’s modulation of the GABA-A receptor is subunit-dependent
Authors: Borchardt Jennifer S. , Blecker Lucas M. , Tung Anton , Satyshur Kenneth A. , Czajkowski Cynthia 
Published: August 2021

AbstractFirst synthesized in the 1950s, benzodiazepines are widely prescribed drugs that exert their anxiolytic, sedative and anticonvulsant actions by binding to GABA-A receptors, the main inhibitory ligand-gated ion channel in the brain. Scientists have long theorized that there exists an endogenous benzodiazepine, or endozepine, in the brain. While there is indirect evidence suggesting a peptide, the diazepam binding inhibitor, is capable of modulating the GABA-A receptor, direct evidence of the modulatory effects of the diazepam binding inhibitor is limited.Here we take a reductionist approach to understand how purified diazepam binding inhibitor interacts with and affects GABA-A receptor activity. We used two-electrode voltage clamp electrophysiology to study how the effects of diazepam binding inhibitor vary with GABA-A receptor subunit composition, and found that GABA-evoked currents from α3-containing GABA-A receptors are weakly inhibited by the diazepam binding inhibitor, while currents from α5-containing receptors are positively modulated. We also used in silico protein-protein docking to visualize potential diazepam binding inhibitor/GABA-A receptor interactions that revealed diazepam binding inhibitor bound at the benzodiazepine α/γ binding site interface, which provides a structural framework for understanding diazepam binding inhibitor effects on GABA-A receptors. Our results provide novel insights into mechanisms underlying how the diazepam binding inhibitor modulates GABA-mediated inhibition in the brain.