bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of Notch1 drives the development of radiation-induced thymic lymphoma in p53 wild-type mice
Authors: Lee Chang-Lung , Brock Kennedy Davis , Hasapis Stephanie , Zhang Dadong , Sibley Alexander B. , Qin Xiaodi , Gresham Jeremy , Caraballo Isibel , Luo Lixia , Daniel Andrea R. , Hilton Matthew J. , Owzar Kouros , Kirsch David G. 
Published: August 2020

ABSTRACTMouse models of radiation-induced thymic lymphoma are widely used to study the development of radiation-induced blood cancers and to gain insights into the biology of human T-lymphoblastic leukemia/lymphoma. Here, we aimed to determine key oncogenic drivers for the development of radiation-induced thymic lymphoma by performing whole-exome sequencing using tumors and paired normal tissues from mice with and without irradiation. Thymic lymphomas from irradiated wild-type (WT), p53+/-and KrasLA1mice were not observed to harbor significantly higher numbers of non-synonymous somatic mutations compared to thymic lymphomas from unirradiated p53-/-mice. However, we observed distinct patterns of recurrent mutations in genes that control the Notch1 signaling pathway based on the mutational status of p53. Preferential activation of Notch1 signaling in p53 WT lymphomas was also observed at the RNA and protein level. Using reporter mice for activation of the Notch1 signaling we observed that TBI enriched Notch1hiCD44+thymocytes, which are capable of self-renewalin vivo. Mechanistically, genetic inhibition of Notch1 signaling in thymocytes prevented the formation of radiation-induced thymic lymphoma in p53 WT mice. Taken together, our results demonstrate a critical role of activated Notch1 signaling in driving multi-step carcinogenesis of thymic lymphoma following total-body irradiation in p53 WT mice.
In vivo metabolite tracing of T cells
Authors: Sheldon Ryan D. , Ma Eric H. , DeCamp Lisa M. , Williams Kelsey S. , Jones Russell G. 
Published: August 2020

AbstractT cells are integral players in the adaptive immune system that readily adapt their metabolism to meet their energetic and biosynthetic needs. A major hurdle to understand physiologic T cell metabolism has been the differences between in vitro cell culture conditions and the complex in vivo milieu. To address this, we have developed a protocol that merges traditional immunology infection models with whole-body metabolite infusion and mass spectrometry (MS)-based metabolomic profiling to assess T cell metabolismin vivo. In this protocol, pathogen-infected mice are infused via the tail vein with an isotopically labeled metabolite, followed by rapid magnetic bead isolation to purify T cell populations and then stable isotope labeling (SIL) analysis conducted by MS. This procedure enables researchers to evaluate metabolic substrate utilization by specific T cell subpopulations in the context of physiological immune responses in vivo.
A long read optimizedde novotranscriptome pipeline reveals novel ocular developmentally regulated gene isoforms and disease targets
Authors: Swamy Vinay S. , Fufa Temesgen D. , Hufnagel Robert B. , McGaughey David M. 
Published: August 2020

AbstractDe novotranscriptome construction from short-read RNA-seq is a common method for reconstructing mRNA transcripts within a given sample. However, the precision of this process is unclear as it is difficult to obtain a ground-truth measure of transcript expression. With advances in third generation sequencing, full length transcripts of whole transcriptomes can be accurately sequenced to generate a ground-truth transcriptome. We generated long-read PacBio and short-read Illumina RNA-seq data from a human induced pluripotent stem cell- derived retinal pigmented epithelium (iPSC-RPE) cell line. We use long-read data to identify simple metrics for assessingde novotranscriptome construction and optimize a short-read basedde novotranscriptome construction pipeline. We apply this this pipeline to construct transcriptomes for 340 short-read RNA-seq samples originating from healthy adult and fetal human retina, cornea, and RPE. We identify hundreds of novel gene isoforms and examine their significance in the context of ocular development and disease.
Detection of Discordant Peptide Quantities in Shotgun Proteomics Data by Peptide Correlation Analysis (PeCorA)
Authors: Meyer Jesse G. 
Published: August 2020

ABSTRACTShotgun proteomics techniques infer the presence and quantity of proteins using peptide proxies, which are produced by cleavage of all isolated protein by a protease. Most protein quantitation strategies assume that multiple peptides derived from a protein will behave quantitatively similar across treatment groups, but this assumption may be false for biological or technical reasons. Here, I describe a strategy called peptide correlation analysis (PeCorA) that detects quantitative disagreements between peptides mapped to the same protein. Simple linear models are used to assess whether the slope of a peptide’s change across treatment groups differs from the slope of all other peptides assigned to the same protein. Reanalysis of proteomic data from primary mouse microglia with PeCorA revealed that about 15% of proteins contain one discordant peptide. Inspection of the discordant peptides shows utility of PeCorA for direct and indirect detection of regulated PTMs, and also for discovery of poorly quantified peptides that should be excluded. PeCorA can be applied to an arbitrary list of quantified peptides, and is freely available as a script written in R.
Computationally Guided Design of Novel Selective Serotonin Reuptake Inhibitors
Authors: Achyutuni Kavya G. , Adhikari Sambid , Huang Peishan , Siegel Justin B. 
Published: August 2020

ABSTRACTCurrent selective serotonin reuptake inhibitor (SSRI) drugs such as paroxetine, fluoxetine and escitalopram are prescribed for mental health conditions such as anxiety and depression. However, there are still several unpleasant side effects which fuels the need for new designs. In this work, computational studies were conducted to design two novel drug candidates with improved docking scores than paroxetine, an existing SSRI drug. Homology analysis was carried out to determine the suitability of an organism for preclinical trials and revealed laboratory mouse (Mus musculus) to be a good candidate.
Auxetic Two-Dimensional Nanostructures from DNA
Authors: Li Ruixin , Chen Haorong , Choi Jong Hyun 
Published: August 2020

ABSTRACTArchitectured materials exhibit negative Poisson’s ratios and enhanced mechanical properties compared with regular materials. Their auxetic behaviors should emerge from periodic cellular structures regardless of the materials used. The majority of such metamaterials are constructed by top-down approaches and macroscopic with unit cells of microns or larger. On the other extreme, there are molecular-scale auxetics including naturally-occurring crystals which are not designable. There is a gap from few nanometers to microns, which may be filled by bottom-up biomolecular self-assembly. Here we demonstrate two-dimensional auxetic nanostructures using DNA origami. Structural reconfiguration experiments are performed by strand displacement and complemented by mechanical deformation studies using coarse-grained molecular dynamics (MD) simulations. We find that the auxetic properties of DNA nanostructures are mostly defined by geometrical designs, yet materials’ chemistry also plays an important role. From elasticity theory, we introduce a set of design principles for auxetic DNA metamaterials, which should find diverse applications.
geneRFinder: gene finding in distinct metagenomic data complexities
Authors: Silva Raíssa , Padovani Kleber , Góes Fabiana , Alves Ronnie 
Published: August 2020

AbstractMotivationMicrobes perform a fundamental economic, social and environmental role in our society. Metagenomics makes it possible to investigate microbes in their natural environments (the complex communities) and their interactions. The way they act is usually estimated by looking at the functions they play in those environments and their responsibility is measured by their genes. The advances of next-generation sequencing technology have facilitated metagenomics research however it also create a heavy computational burden. Large and complex biological datasets are available as never before. There are many gene predictors available which can aid gene annotation process though they lack of handling appropriately metagenomic data complexities. There is no standard metagenomic benchmark data for gene prediction. Thus, gene predictors may inflate their results by obfuscating low false discovery rates.ResultsWe introduce geneRFinder, a ML-based gene predictor able to outperform state-of-the-art gene prediction tools across this benchmark by using only one pre-trained Random Forest model. Average prediction rates of geneRFinder differed in percentage terms by 54% and 64%, respectively, against Prodigal and FragGeneScan while handling high complexity metagenomes. The specificity rate of geneRFinder had the largest distance against FragGeneScan, 79 percentage points, and 66 more than Prodigal. According to McNemar’s test, all percentual differences between predictors performances are statistically significant for all datasets with a 99% confidence interval.ConclusionsWe provide geneRFinder, a approach for gene prediction in distinct metagenomic complexities, available at github.com/railorena/geneRFinder, and also we provide a novel, comprehensive benchmark data for gene prediction — which is based on The Critical Assessment of Metagenome Interpretation (CAMI) challenge, and contains labeled data from gene regions – avaliable at sourceforge.net/p/generfinder-benchmark.
Hallucination of moving objects revealed by a dynamic noise background
Authors: Nakayama Ryohei , Holcombe Alex O. 
Published: August 2020

AbstractWe show that on a dynamic noise background, the perceived disappearance location of a moving object is shifted in the direction of motion. This “twinkle goes” illusion has little dependence on the luminance- or chromaticity-based confusability of the object with the background, or on the amount of background motion energy in the same direction as the object motion. This suggests that the illusion is enabled by the dynamic noise masking the offset transients that otherwise accompany an object’s disappearance. While these results are consistent with an anticipatory process that pre-activates positions ahead of the object’s current position, additional findings suggest an alternative account: a continuation of attentional tracking after the object disappears. First, the shift was greatly reduced when attention was divided between two moving objects. Second, the illusion was associated with a prolonging of the perceived duration of the object, by an amount that matched the extent of extrapolation inferred from the effect of speed on the size of the illusion (~50 ms). While the anticipatory extrapolation theory does not predict this, the continuation of attentional tracking theory does. Specifically, we propose that in the absence of offset transients, attentional tracking keeps moving for several tens of milliseconds after the target disappearance, and this causes one to hallucinate a moving object at the position of attention.
Bacterial-like nonribosomal peptide synthetases produce cyclopeptides in the zygomycetous fungusMortierella alpina
Authors: Wurlitzer Jacob M. , Stanišić Aleksa , Wasmuth Ina , Jungmann Sandra , Fischer Dagmar , Kries Hajo , Gressler Markus 
Published: August 2020

AbstractFungi are traditionally considered as reservoir of biologically active natural products. However, an active secondary metabolism has long not been attributed to early diverging fungi such asMortierella spec. Here, we report on the biosynthesis of two series of cyclic pentapeptides, the malpicyclins and malpibaldins, as products ofMortierella alpinaATCC32222. The molecular structures of malpicyclins were elucidated by HR-MS/MS, Marfey’s method, and 1D and 2D NMR spectroscopy. In addition, malpibaldin biosynthesis was confirmed by HR-MS. Genome mining and comparative qRT-PCR expression analysis pointed at two pentamodular nonribosomal peptide synthetases (NRPS), malpicyclin synthetase MpcA and malpibaldin synthetase MpbA, as candidate biosynthetic enzymes. Heterologous production of the respective adenylation domains and substrate specificity assays proved promiscuous substrate selection and confirmed their respective biosynthetic roles. In stark contrast to known fungal NRPSs, MpbA and MpcA contain bacterial-like dual epimerase/condensation domains allowing the racemization of enzyme-tetheredl-amino acids and the subsequent incorporation ofd-amino acids into the metabolites. Phylogenetic analyses of both NRPS genes indicate a bacterial origin and a horizontal gene transfer into the fungal genome. This is the first report of nonribosomal peptide biosynthesis in basal fungi which highlights this paraphylum as novel and underrated resource of natural products.IMPORTANCEFungal natural compounds are industrially produced with application in antibiotic treatment, cancer medications and crop plant protection. Traditionally, higher fungi have been intensively investigated concerning their metabolic potential, but re-identification of already known compounds is frequently observed. Hence, alternative strategies to acquire novel bioactive molecules are required. We present the genusMortierellaas representative of the early diverging fungi as an underestimated resource of natural products.Mortierella alpinaproduces two families of cyclopeptides, denoted malpicyclins and malpibaldins, respectively, via two pentamodular nonribosomal peptide synthetases (NRPSs). These enzymes are much closer related to bacterial than to other fungal NRPSs, suggesting a bacterial origin of these NRPS genes inMortierella. Both enzymes are the first biochemically characterized natural product biosynthesis enzymes of basal fungi. Hence, this report establishes early diverging fungi as prolific natural compound producers and sheds light on the origin of their biosynthetic capacity.
Impaired cytotoxic CD8+ T cell response in elderly COVID-19 patients
Authors: Westmeier Jaana , Paniskaki Krystallenia , Karaköse Zehra , Werner Tanja , Sutter Kathrin , Dolff Sebastian , Overbeck Marvin , Limmer Andreas , Liu Jia , Zheng Xin , Brenner Thorsten , Berger Marc M. , Witzke Oliver , Trilling Mirko , Lu Mengji , Yang Dongliang , Babel Nina , Westhoff Timm , Dittmer Ulf , Zelinskyy Gennadiy 
Published: August 2020

AbstractSARS-CoV-2 infection induces a T cell response that most likely contributes to virus control in COVID-19 patients, but may also induce immunopathology. Until now, the cytotoxic T cell response has not been very well characterized in COVID-19 patients.Here, we analyzed the differentiation and cytotoxic profile of T cells in 30 cases of mild COVID-19 during acute infection. SARS-CoV-2 infection induced a cytotoxic response of CD8+ T cells, but not CD4+ T cells, characterized by the simultaneous production of granzyme A and B, as well as perforin within different effector CD8+ T cell subsets. PD-1 expressing CD8+ T cells also produced cytotoxic molecules during acute infection indicating that they were not functionally exhausted. However, in COVID-19 patients over the age of 80 years the cytotoxic T cell potential was diminished, especially in effector memory and terminally differentiated effector CD8+ cells, showing that elderly patients have impaired cellular immunity against SARS-CoV-2.Our data provides valuable information about T cell responses in COVID-19 patients that may also have important implications for vaccine development.ImportanceCytotoxic T cells are responsible for the elimination of infected cells and are key players for the control of viruses. CD8+ T cells with an effector phenotype express cytotoxic molecules and are able to perform target cell killing. COVID-19 patients with a mild disease course were analyzed for the differentiation status and cytotoxic profile of CD8+ T cells. SARS-CoV-2 infection induced a vigorous cytotoxic CD8+ T cell response. However, this cytotoxic profile of T cells was not detected in COVID-19 patients over the age of 80 years. Thus, the absence of a cytotoxic response in elderly patients might be a possible reason for the more frequent severity of COVID-19 in this age group in comparison to younger patients.
Detection of SARS-CoV-2 using non-commercial RT-LAMP reagents and raw samples
Authors: Alekseenko Alisa , Barrett Donal , Pareja-Sanchez Yerma , J Howard Rebecca , Strandback Emilia , Ampah-Korsah Henry , Rovšnik Urška , Zuniga-Veliz Silvia , Klenov Alexander , Malloo Jayshna , Ye Shenglong , Liu Xiyang , Reinius Björn , Elsässer Simon , Nyman Tomas , Sandh Gustaf , Yin Xiushan , Pelechano Vicent 
Published: August 2020

AbstractAbstractRT-LAMP detection of SARS-CoV-2 has been shown as a valuable approach to scale up COVID-19 diagnostics and thus contribute to limiting the spread of the disease. Here we present the optimization of highly cost-effective in-house produced enzymes, and we benchmark their performance against commercial alternatives. We explore the compatibility between multiple DNA polymerases with high strand-displacement activity and thermostable reverse transcriptases required for RT-LAMP. We optimize reaction conditions and demonstrate their applicability using both synthetic RNA and clinical patient samples. Finally, we validated the optimized RT-LAMP assay for the detection of SARS-CoV-2 in raw nasopharyngeal samples from 184 patients. We anticipate that optimized and affordable reagents for RT-LAMP will facilitate the expansion of SARS-CoV-2 testing globally, especially in sites and settings with limited economic resources.
Adaptive learning under strategic and structural uncertainty: the case of auction games
Authors: Martinez-Saito Mario , Belianin Alexis , Shestakova Anna , Gutkin Boris , Klucharev Vasily 
Published: August 2020

AbstractIn games of incomplete information individual players make decisions facing a combination of structural uncertainty about the underlying parameters of the environment, and strategic uncertainty about the actions undertaken by their partners. How well are human actors able to cope with these uncertainties, and what models best describe their learning in such environments? We use a double auction task with different competitive and informational environments to characterize learning abilities of the single human participants (buyers) in a range of adaptive learning models covering reinforcement learning, directional learning and belief learning. Results show that real behaviour is best described using simple models of directional learning type with minimal knowledge assumptions about information efficiency of prices. This behavior is consistent with bounded rationality and risk aversion: human subjects try to maximize their chance for transaction, and do so using the simplest learning rule.
Oxidative stress inducing agents’ copper and alloxan accelerate cell cycle re-entering of somatic plant cells in the presence of suboptimal exogenous auxin
Authors: Pasternak Taras 
Published: August 2020

AbstractThe physiological status of differentiated somatic plant cells and kinetics of re-entering in cell cycle were investigated in the case of Medicago sativa leaf protoplasts after the application of oxidative stress-inducing agents. Excess copper (30μM) and alloxan (0.5 mM) accelerated cell cycle re-entry at an exogenous auxin concentration that alone was insufficient to induce cell activation. Application of stress-inducing agents accelerated changes in the nuclei landscape with further faster re-entry in DNA replication and cytokinesis. This acceleration was accompanied by a lower level of reactive oxygen species (ROS) accumulations. At later stages, stress-agents treated cells resemble stem cells in planta with a smaller size, higher cell viability, lower ROS level, and lower activities of major ROS scavenging enzymes. A similar cellular response could be achieved by increasing the exogenous auxin concentration. Based on these experimental results, it is suggested that sub-lethal stress treatments evoke a transient cell state that accelerates cellular reprogramming. We also speculate that this transient cell state serves as an effective mechanism for protection against oxidative stress.
A novel 3D atomistic-continuum cancer invasion model: In silico simulations of an in vitro organotypic invasion assay
Authors: Franssen Linnea C. , Sfakianakis Nikolaos , Chaplain Mark A.J. 
Published: August 2020

AbstractWe develop a three-dimensional genuinely hybrid atomistic-continuum model that describes the invasive growth dynamics of individual cancer cells in tissue. The framework explicitly accounts for phenotypic variation by distinguishing between cancer cells of an epithelial-like and a mesenchymal-like phenotype. It also describes mutations between these cell phenotypes in the form ofepithelial-mesenchymal transition(EMT) and its reverse processmesenchymal-epithelial transition(MET). The model consists of a hybrid system of partial and stochastic differential equations that describe the evolution of epithelial-like and mesenchymal-like cancer cells, respectively, under the consideration of matrix-degrading enzyme concentrations and the extracellular matrix density. With the help of inverse parameter estimation and a sensitivity analysis, this three-dimensional model is then calibrated to anin vitroorganotypic invasion assay experiment of oral squamous cell carcinoma cells.
A novel fluorescence and DNA combination for complex, long-term marking of mosquitoes
Authors: Faiman Roy , Krajacich Benjamin J. , Graber Leland , Dao Adama , Yaro Alpha Seydou , Yossi Ousmane , Sanogo Zana Lamissa , Diallo Moussa , Samaké Djibril , Sylla Daman , Coulibaly Modibo , Kone Salif , Goita Sekou , Coulibaly Mamadou B. , Muratova Olga , McCormack Ashley , Gonçalves Bronner P. , Hume Jennifer , Duffy Patrick , Lehmann Tovi 
Published: August 2020

AbstractBackgroundCurrent mark release recapture methodologies are limited in their ability to address complex problems in vector biology, such as studying multiple groups overlapping in space and time. Additionally, limited mark retention, reduced post-marking survival, and the large effort in marking, collection and recapture, all complicate effective insect tracking.MethodWe have developed and evaluated a marking method using a fluorescent dye (Smartwater®) combined with synthetic DNA tags to informatively and efficiently mark adult mosquitoes using an airbrush pump and nebulizer. Using handheld UV flashlights, the fluorescent marking enabled quick and simple initial detection of recaptures in a simple, field-ready, and non-destructive approach that when combined with a simple, extraction-free PCR on individual mosquito legs provides potentially unlimited marking information.ResultsThis marking, first tested in the laboratory withAnopheles gambiaes.l. mosquitoes, did not affect survival (median ages 24-28 days,p-adj> 0.25), oviposition (median eggs/female of 28.8, 32.5, 33.3 for water, green, red dyes, respectively,p-adj> 0.44), orPlasmodiumcompetence (mean oocysts 5.56 to 10.6,p-adj> 0.95). DNA and fluorescence had 100% retention up to 3 weeks (longest time point tested) with high intensity, indicating marks would persist longer.ConclusionsWe describe a novel, simple, no/low-impact, and long-lasting marking method that allows separation of multiple insect subpopulations by combining unlimited length and sequence variation in the synthetic DNA tags. This method can be readily deployed in the field for marking multiple groups of mosquitoes or other insects.