bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Pancreatic Tumor Microenvironment Compensates for Loss of GOT2
Authors: Kerk Samuel A. , Lin Lin , Myers Amy L. , Zhang Yaqing , Jiménez Jennifer A. , Sajjakulnukit Peter , Nelson Barbara S. , Chen Brandon , Robinson Anthony , Thurston Galloway , Kemp Samantha B. , Steele Nina G. , Hoffman Megan T. , Wen Hui-Ju , Long Daniel , Ackenhusen Sarah E. , Ramos Johanna , Gao Xiaohua , Zhang Li , Andren Anthony , Nwosu Zeribe C. , Galbán Stefanie , Halbrook Christopher J. , Lombard David B. , Piwnica-Worms David R. , Ying Haoqiang , Crawford Howard C. , di Magliano Marina Pasca , Shah Yatrik M. , Lyssiotis Costas A. 
Published: August 2020

ABSTRACTThe tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) restricts vascularization and, consequently, access to blood-derived nutrients and oxygen, which impacts tumor growth. Intracellular redox imbalance is another restraint on cellular proliferation, yet it is unknown if the TME contributes to the maintenance of redox homeostasis in PDA cells. Here, we demonstrate that the loss of mitochondrial glutamate-oxaloacetate transaminase 2 (GOT2), a component in the malate-aspartate shuttle, disturbs redox homeostasis and halts proliferation of PDA cells in vitro. In contrast, GOT2 inhibition has no effect on in vivo tumor growth or tumorigenesis in an autochthonous model. We propose that this discrepancy is explained by heterocellular pyruvate exchange from the TME, including from cancer associated fibroblasts. More broadly, pyruvate similarly confers resistance to inhibitors of mitochondrial respiration. Genetic or pharmacologic inhibition of pyruvate uptake or metabolism abrogated pyruvate-mediated alleviation of reductive stress from NADH buildup. In sum, this work describes a potential resistance mechanism mediated by metabolic crosstalk within the pancreatic TME. These findings have important implications for metabolic treatment strategies since several mitochondrial inhibitors are currently in clinical trials for PDA and other cancers.
Interstitial spaces are continuous across tissue and organ boundaries in humans
Authors: Cenaj Odise , Allison Douglas H. R. , Imam R , Zeck Briana , Drohan Lilly M. , Chiriboga Luis , Llewellyn Jessica , Liu Cheng Z , Park Young Nyun , Wells Rebecca G. , Theise Neil D. 
Published: August 2020

AbstractBodies have “reticular networks” comprising collagens, elastin, glycosaminoglycans, and other extracellular matrix components, that are continuous within and around all organs. Fibrous tissue coverings of nerves and blood vessels create structural continuity beyond organ boundaries. We recently described fluid flow through such human fibrous tissues. It remains unclear whether these interstitial spaces are continuous through the body or are discontinuous, confined within individual organs. We investigated IS continuity using two approaches. Non-biological particles (tattoo pigment, colloidal silver) were tracked within colon and skin interstitial spaces and into adjacent fascia. We also exploited hyaluronic acid, a macromolecular component of interstitial spaces. Both techniques demonstrate continuity of interstitial spaces within and across organ boundaries, including within perineurium and vascular adventitia traversing organs and the spaces between them. We suggest a body-wide network of fluid-filled interstitial spaces with significant implications for molecular signaling, cell trafficking, and the spread of malignant and infectious disease.
Engineered sex distortion in the global agricultural pestCeratitis capitata
Authors: Meccariello Angela , Krsticevic Flavia , Colonna Rita , Del Corsano Giuseppe , Fasulo Barbara , Papathanos Philippos Aris , Windbichler Nikolai 
Published: August 2020

AbstractGenetic sex ratio distorters have potential for the area-wide control of harmful insect populations. Endonucleases targeting the X-chromosome and whose activity is restricted to male gametogenesis have recently been pioneered as a means to engineer such traits. Here we enabled endogenous CRISPR/Cas9 and CRISPR/Cas12a activity during spermatogenesis of the Mediterranean fruit flyCeratitis capitata, a worldwide agricultural pest of extensive economic significance. In the absence of a chromosome-level assembly, we analysed long and short-read genome sequencing data from males and females to identify two clusters of abundant and X-chromosome specific sequence repeats. When targeted by gRNAs in conjunction with Cas9 they yielded a significant and consistent distortion of the sex ratio in independent transgenic strains and a combination of distorters induced a strong bias towards males (~80%). Our results demonstrate the design of sex distorters in a non-model organism and suggest that strains with characteristics suitable for field application could be developed for a range of medically or agriculturally relevant insect species.
Impaired Fetal Lung Development can be Rescued by Administration of Extracellular Vesicles Derived from Amniotic Fluid Stem Cells
Authors: Antounians Lina , Catania Vincenzo D. , Montalva Louise , Liu Benjamin D. , Hou Huayun , Chan Cadia , Matei Andreea C. , Tzanetakis Areti , Li Bo , Figueira Rebeca Lopes , da Costa Karina Miura , Wong Amy P. , Mitchell Robert , David Anna L. , Patel Ketan , De Coppi Paolo , Neto Lourenço Sbragia , Wilson Michael D. , Rossant Janet , Zani Augusto 
Published: August 2020

AbstractIncomplete lung development, also known as pulmonary hypoplasia, is a recognized cause of neonatal death and poor outcome for survivors. To date, there is no effective treatment that promotes fetal lung growth and maturation. Herein, we describe a novel stem cell-based approach that enhances fetal lung development via the administration of extracellular vesicles (EVs) derived from amniotic fluid stem cells (AFSCs). In experimental models of pulmonary hypoplasia, administration of AFSC-EVs promoted lung branching morphogenesis and alveolarization, and stimulated pulmonary epithelial cell and fibroblast differentiation. This regenerative ability was confirmed in two models of injured human lung cells, where human AFSC-EVs obtained following good manufacturing practices restored pulmonary epithelial homeostasis. AFSC-EV beneficial effects were exerted via the release of RNA cargo, primarily miRNAs, that regulate the expression of genes involved in fetal lung development. Our findings suggest that AFSC-EVs hold regenerative ability for underdeveloped fetal lungs, demonstrating potential for therapeutic application.One Sentence SummaryFetal lung regeneration via administration of extracellular vesicles derived from amniotic fluid stem cells
Extrasynaptic volume transmission: A novel route for neuropeptide signaling in nematodes
Authors: Atkinson Louise E. , Liu Yang , McKay Fiona , Vandewyer Elke , Viau Charles , Irvine Allister , Rosa Bruce A. , Li Zihui , Marks Nikki J. , Maule Aaron G. , Mitreva Makedonka , Beets Isabel , Li Lingjun , Mousley Angela 
Published: August 2020

AbstractNeural circuit synaptic connectivities (the connectome) provide the anatomical foundation for our understanding of nematode nervous system function. However, other non-synaptic routes of communication are known in invertebrates including extrasynaptic volume transmission (EVT), which enables short- and/or long-range communication in the absence of synaptic connections. Although EVT has been highlighted as a facet ofCaenorhabditis elegansneurosignaling, no experimental evidence identifies body cavity fluid (pseudocoelomic fluid; PCF) as a vehicle for either neuropeptide or biogenic amine transmission. In the parasitic nematodeAscaris suumFMRFamide-like peptides encoded onflp-18 potently stimulate female reproductive organs but are only expressed in cells that are anatomically distant from the reproductive organ, with no known synaptic connections to this tissue. Here we report a new non-synaptic mode of signaling in nematodes mediated by neuropeptides within the PCF. Our data show that: (i)A. suumPCF (As-PCF) contains a catalogue of neuropeptides including FMRFamide-like peptides and neuropeptide-like proteins; (ii) theA. suumFMRFamide-like peptide As-FLP-18A dominates the As-PCF peptidome; (iii) As-PCF potently modulates nematode reproductive muscle functionex vivo, mirroring the effects of synthetic FLP-18 peptides; (iv) As-PCF activates theC. elegansFLP-18 receptors NPR-4 and -5; (v) As-PCF altersC. elegansbehavior and, (vi) FLP-18 and FLP-18 receptors display pan-phylum distribution in nematodes. Here we provide the first direct experimental evidence that supports an extrasynaptic volume route for neuropeptide transmission in nematodes. These data demonstrate non-synaptic signaling within the nematode functional connectome and are pertinent to receptor deorphanisation approaches underpinning drug discovery programs for nematode pathogens.
Sialylation and fucosylation changes of cytidine monophosphate-Nacetylneuraminic acid hydroxylase (CMAH) and glycoprotein, alpha1,3-galactosyltransferase(GGTA1) knockout pig erythrocyte membranes
Authors: Choe Hak Myong , Luo Zhao-Bo , Xuan Mei-Fu , Quan Biao-Hu , Kang Jin-Dan , Oh Myung Jin , An Hyun Joo , Yin Xi-jun 
Published: August 2020

AbstractThe recent GGTA1 and CMAH DKO pigs have made it possible to resolve the immune barriers which are duo to xenoantigens on RBC such as αGal and Neu5Gc. Nevertheless, it still requires the detection of glycosylation alternation on the pig RBCs because even the minor changes would be unexpected xenoantigens.DKO RBC immune reactivity with human serum was assessed by hemagglutination assay. Glycosylation alteration of RBC membranes was characterized by NanoLC-Q-TOF-MS system and lectin blotting assay.Twelve GGTA1/CMAH DKO piglets were successfully produced. The immunoreactivity with human serum was remarkably reduced in DKO (less than 1:2 dilution), whereas wild type(WT) pigs showed agglutination (the least 1:256 dilution). The MS results showed that DKO increased neutral N-glycans as well as decreased total sialylated N-glycans, especially suggesting significant decrease of di-sialylated N-glycans (P < 0.05). Moreover, lectin blotting assay revealed that DKO pigs reduced the binding signals with AAL, AOL, LCA and SNA and increased the binding signal with MAL.DKO pigs decreased the expression of total fucosylation and sialylated N-glycans on the erythrocyte membrane. Our findings will support further investigation into DKO pig RBC glycosylation and contribute to uncover the roles of glycan changes for xenotransfusion.Summary statementTo detect glycosylation changes in red blood cells(RBC) of GGTA1/CMAH double knockout(DKO) pigs, comparative analysis of the glycan profiling was done.
Specification and epigenetic resetting of the pig germline exhibit conservation with the human lineage
Authors: Zhu Qifan , Sang Fei , Withey Sarah , Tang Walfred , Dietmann Sabine , Klisch Doris , Ramos-Ibeas Priscila , Zhang Haixin , Requena Cristina E. , Hajkova Petra , Loose Matt , Surani M. Azim , Alberio Ramiro 
Published: August 2020

SummaryInvestigations on the human germline and programming are challenging due to limited access to embryonic material. However, the pig as a model may provide insight on transcriptional network and epigenetic reprogramming applicable to both species. Here we show that during the pre- and early migratory stages pig primordial germ cells (PGCs) initiate large-scale epigenetic reprogramming, including DNA demethylation involving TET-mediated hydroxylation and potentially base excision repair (BER). There is also macroH2A1 depletion and increased H3K27me3, as well as X chromosome reactivation (XCR) in females. Concomitantly, there is dampening of glycolytic metabolism genes and re-expression of some pluripotency genes like those in preimplantation embryos. We identified evolutionarily young transposable elements and gene coding regions resistant to DNA demethylation in acutely hypomethylated gonadal PGCs, with potential for transgenerational epigenetic inheritance. Detailed insights into the pig germline will likely contribute significantly to advances in human germline biology, includingin vitrogametogenesis.
The influence of eye movements and their retinal consequences on bistable motion perception
Authors: Brych Mareike , Murali Supriya , Händel Barbara 
Published: August 2020

AbstractEye related movements such as blinks and microsaccades are modulated during bistable perceptual tasks, however, the role of such movements in these purely internal perceptual switches is not known. We conducted two experiments involving an ambiguous plaid stimulus, wherein participants had to continuously report their motion percept. To dissociate the effect of blinks and microsaccades from the visual consequences of such eye movements, we added external blanks and microshifts.Our results showed that while blanks facilitated a switch to the coherent motion percept, this was not the case for a switch to component percept. A similar difference was found with respect to blinks. While both types of perceptual switches were preceded by a decrease in blinks, only the switch to coherent percept was followed by an increase in blinks. These blink related findings, which we largely replicated and refined in a second study, indicate distinct internal processes underlying the two perceptual switches. Microsaccade rates, on the other hand, only showed a weak relation with perceptual switches but their direction was modulated by the perceived motion direction. Additionally, our data showed that microsaccades are differently modulated around internal (blinks) and external events (blanks, microshifts), indicating an interaction between different eye related movements.This study shows that eye movements such as blinks and microsaccades are modulated by purely internal perceptual events independent of task related motor or attentional demands. Eye movements therefore can uncover distinct internal perceptual processes that might otherwise be hard to dissociate.
The Response of Culturally Important Plants to Experimental Warming and Grazing in Pakistan Himalayas
Authors: Karimi Saira , Nawaz Muhammad Ali , Naseem Saadia , Akrem Ahmed , Dangles Olivier , Ali Zahid 
Published: August 2020

AbstractThe response of wild plants towards climate warming is taxa specific, but overgrazing could also be a determining factor for the alpine ecosystems. Overgrazing and climate warming are important drivers of alpine grassland degradation worldwide. Local indigenous peoples will be the first impacted by such degradation due to impacts on animal production and the availability of local medicinal plants. Studies on plant responses to overgrazing and climate change are rarely performed to assess threats to these biological and cultural systems. Long-term observations or manipulative experiments are promising, but rarely use strategies to evaluate the sensitivity and vulnerability of such ecosystems to climatic change. We studied the combined effects of overgrazing and increased temperatures on culturally important medicinal plants of Khunjerab National Park, Pakistan. Three experimental treatments were used (control, warming through an open-top chamber, and exclusion of grazing animals vs. the control). These experimental plots were installed at different elevations (3352-4969 m) and were monitored routinely. Grazing reduced vegetation cover & biomass by 2.3% and 6.26%, respectively, but that was not significant due to the high variability among study plots. However, warming significantly increased the overall percentage cover and biomass of all target plant species, ranging from 1±0.6% inBistorta officinalisto 18.7 ± 4.9% inPoa alpina. Thus, warming may increase the availability of therapeutic plants for indigenous people while overgrazing would have deteriorating effects locally. This research illustrates that vegetation sensitivity to warming and overgrazing is likely to affect man– environment relationships, and traditional knowledge on a regional scale.
UsingPlasmodium knowlesias a model for screeningPlasmodium vivaxblood-stage malaria vaccine targets reveals new candidates
Authors: Ndegwa Duncan N. , Hostetler Jessica B. , Marin-Menendez Alejandro , Sanderson Theo , Mwikali Kioko , Verzier Lisa H. , Coyle Rachael , Adjalley Sophie , Rayner Julian C. 
Published: August 2020

ABSTRACTPlasmodium vivaxis responsible for the majority of malaria cases outside Africa. UnlikeP. falciparum, theP. vivaxlife-cycle includes a dormant liver stage, the hypnozoite, which can cause infection in the absence of mosquito transmission. An effective vaccine againstP. vivaxblood stages would limit symptoms and pathology from such recurrent infections, and therefore could play a critical role in the control of this species. Vaccine development inP. vivax, however, lags considerably behindP. falciparum, which has many identified targets with several having transitioned to Phase II testing. By contrast only oneP. vivaxblood-stage vaccine candidate based on the Duffy Binding Protein (PvDBP), has reached Phase Ia, in large part because the lack of a continuousin vitroculture system forP. vivaxlimits systematic screening of new candidates. We used the close phylogenetic relationship betweenP. vivaxandP. knowlesi, for which anin vitroculture system in human erythrocytes exists, to test the scalability of systematic reverse vaccinology to identify and prioritiseP. vivaxblood-stage targets. A panel ofP. vivaxproteins predicted to function in erythrocyte invasion were expressed as full-length recombinant ectodomains in a mammalian expression system. Eight of these antigens were used to generate polyclonal antibodies, which were screened for their ability to recognize orthologous proteins inP. knowlesi. These antibodies were then tested for inhibition of growth and invasion of both wild typeP. knowlesiand chimericP. knowlesilines modified using CRISPR/Cas9 to exchangeP. knowlesigenes with theirP. vivaxorthologues. Candidates that induced antibodies that inhibited invasion to a similar level as PvDBP were identified, confirming the utility ofP. knowlesias a model forP. vivaxvaccine development and prioritizing antigens for further follow up.AUTHOR SUMMARYMalaria parasites cause disease after invading human red blood cells, implying that a vaccine that interrupts this process could play a significant role in malaria control. MultiplePlasmodiumparasite species can cause malaria in humans, and most malaria outside Africa is caused byPlasmodium vivax. There is currently no effective vaccine against the blood stage of any malaria parasite, and progress inP. vivaxvaccine development has been particularly hampered because this parasite species cannot be cultured for prolonged periods of time in the lab. We explored whether a related species,P. knowlesi, which can be propagated in human red blood cellsin vitro, can be used to screen for potentialP. vivaxvaccine targets. We raised antibodies against selectedP. vivaxproteins and testedtheir ability to recognize and preventP. knowlesiparasites from invading human red blood cells, thereby identifying multiple novel vaccine candidates.
Family variation in surface feeding behavior of steelhead fry predicts growth rate under hatchery conditions
Authors: Wrey Madeleine C. , Skaar James C. , Cates Stanley B. , Bollmann Stephanie R. , Fuentes Claudio , Blouin Michael S. 
Published: August 2020

AbstractHatchery reared salmonid fish often have lower fitness than their natural-origin counterparts when spawning in the wild. Although this difference appears to result from rapid adaptation to captivity, it is not known what traits are under selection. We hypothesize that variation in traits that confer a growth rate advantage to some individuals in the novel hatchery environment are under strong selection because survival at sea is correlated with size at release. Here we show that full sibling families of steelhead trout (Oncorhynchus mykiss) show substantial variation in propensity to feed at the surface as fry, and that the more surface-oriented families grew faster under hatchery conditions. We hypothesize that surface-oriented fry gain an initial growth advantage that persists through size at release. Because surface orientation is a correlate of generalized boldness, hatcheries may inadvertently select for that phenotype, which could explain the fitness differences observed between hatchery and natural-origin fish in the wild.
Successful introduction of the Colour Test into inexperienced settings
Authors: Klaos Kadri , Agejeva Anna , Kummik Tiina , Laks Sirje , Remets Olesja , Sasi Sirje , Tann Anneli , Viiklepp Piret , Altraja Alan 
Published: August 2020

AbstractImplementation of non-commercial in-house methods into routine clinical diagnostics becomes more challenging, because these methods are not internationally standardized, most of the research in that field is underfunded and recommendations for their use is lacking. We conducted a study, where all the technicians were previously unfamiliar to the Colour Test (CT), a colorimetric redox indicator and thin-layer agar basedMycobacterium tuberculosiscomplex diagnosis and direct drug susceptibility testing (DST) method, and tested whether the performance of this in-house method is dependent on experience of the laboratory personnel.After a two-day hands-on training, six panels of 150M. tuberculosisisolates were cultured onto CT plates prepared in-house by six technicians in two laboratories. Finally, triplicate readings of 900 CT plates resulted 18 DST patterns for each of the initial isolates. The results were compared to each other and the gold standard of BACTEC MGIT 960 DST results.The median time to produceM. tuberculosisCT DST results for three antituberculosis drugs was 13 days. The overall ability to correctly define phenotypic resistance ranged from 94.7% for levofloxacin to 95.8% and 97.3% for isoniazid and rifampicin, respectively. The test specificities were even higher exceeding 97% for all three drugs tested. Interobserver agreement reached 100% in one of the laboratories and exceeded 97% for levofloxacin and 99% for isoniazid and rifampicin in the second laboratory.The implementation of the CT into a new laboratory was straightforward with only minimal guidance. This study proves that the CT is highly reproducible and easily interpreted by previously inexperienced personnel.
Cyp33 Binds AU-Rich RNA Motifs via an Extended Interface that Competitively Disrupts the Gene Repressive Cyp33-MLL1 Interactionin vitro
Authors: Lloyd Neil R. , Wuttke Deborah S. 
Published: August 2020

AbstractCyp33 is an essential human cyclophilin prolyl isomerase that plays myriad roles in splicing and chromatin remodeling. In addition to a canonical cyclophilin (Cyp) domain, Cyp33 contains an RNA-recognition motif (RRM) domain, and RNA-binding triggers proline isomerase activity. One prominent role for Cyp33 is through a direct interaction with the mixed lineage leukemia protein 1 (MLL1, also known as KMT2A) complex, which is a histone methyltransferase that serves as a global regulator of human transcription. MLL activity is regulated by Cyp33, which isomerizes a key proline in the linker between the PHD3 and Bromo domains of MLL1, acting as a switch between gene activation and repression. The direct interaction between MLL1 and Cyp33 is critical, as deletion of the MLL1-PHD3 domain responsible for this interaction results in oncogenesis. The Cyp33 RRM is central to these activities, as it binds both the PHD3 domain and RNA. To better understand how RNA binding drives the action of Cyp33, we performed RNA-SELEX against full-length Cyp33 accompanied by deep sequencing. We have identified an enriched Cyp33 binding motif (AAUAAUAA) broadly represented in the cellular RNA pool as well as tightly binding RNA aptamers with affinities comparable and competitive with the Cyp33 MLL1-PHD3 interaction. RNA binding extends beyond the canonical RRM domain, but not to the Cyp domain, suggesting an indirect mechanism of interaction. NMR chemical shift mapping confirms an overlapping, but not identical, interface on Cyp33 for RNA and PHD3 binding. This finding suggests RNA can disrupt the gene repressive Cyp33-MLL1 complex providing another layer of regulation for chromatin remodeling by MLL1.