bluuebunny/crossref_metadata_2025_split huggingface dataset:
The invasion of de-differentiating cancer cells into hierarchical tissues
Authors: Zhou Da , Luo Yue , Dingli David , Traulsen Arne 
Published: March 2019

AbstractMany fast renewing tissues are characterized by a hierarchical cellular architecture, with tissue specific stem cells at the root of the cellular hierarchy and differentiating into a whole range of specialized cells. There is increasing evidence that tumors are structured in a very similar way, mirroring the hierarchical structure of the host tissue. In some tissues, differentiated cells can also revert to the stem cell phenotype, which increases the risk that cells that have already acquired mutations lead to long lasting clones in the tissue. Recently, the modelling community has paid special attention to the consequences of de-differentiation on cellular hierarchies. However, the adaptive significance of de-differentiation is still poorly understood and thus it is unclear under which circumstances de-differentiating cells will invade a tissue. To address this, we developed mathematical models to investigate how de-differentiation could be selected as an adaptive mechanism in the context of cellular hierarchies. We consider the cases of stepwise and jumpwise de-differentiation in this study. Our results show that the emergence of de-differentiation is driven by the combination of the properties of the cellular hierarchy and the de-differentiation pattern and derive thresholds for which de-differentiation is expected to emerge.
Karyotypic divergence confounds cellular phenotypes in large pharmacogenomic studies
Authors: Quevedo Rene , El-Hachem Nehme , Smirnov Petr , Safikhani Zhaleh , Pugh Trevor J. , Haibe-Kains Benjamin 
Published: March 2019

ABSTRACTBackgroundSomatic copy-number alterations that affect large genomic regions are a major source of genomic diversity in cancer and can impact cellular phenotypes. Clonal heterogeneity within cancer cell lines can affect phenotypic presentation, including drug response.MethodsWe aggregated and analyzed SNP and copy number profiles from six pharmacogenomic datasets encompassing 1,691 cell lines screened for 13 molecules. To look for sources of genotype and karyotype discordances, we compared SNP genotypes and segmental copy-ratios across 5 kb genomic bins. To assess the impact of genomic discordances on pharmacogenomic studies, we assessed gene expression and drug sensitivity data for compared discordant and concordant lines.ResultsWe found 6/1,378 (0.4%) cell lines profiled in two studies to be discordant in both genotypic and karyotypic identity, 51 (3.7%) discordant in genotype, 97 (7.0%) discordant in karyotype, and 125 (9.1%) potential misidentifications. We highlight cell lines REH, NCI-H23 and PSN1 as having drug response discordances that may hinge on divergent copy-number qConclusionsOur study highlights the low level of misidentification as evidence of effective cell line authentication standards in recent pharmacogenomic studies. However, the proclivity of cell lines to acquire somatic copy-number variants can alter the cellular phenotype, resulting in a biological and predictable effects on drug sensitivity. These findings highlight the need for verification of cell line copy number profiles to inform interpretation of drug sensitivity data in biomedical studies.
Analytical guidelines to increase the value of citizen science data: using eBird data to estimate species occurrence
Authors: Johnston A , Hochachka WM , Strimas-Mackey ME , Ruiz Gutierrez V , Robinson OJ , Miller ET , Auer T , Kelling ST , Fink D 
Published: March 2019

AbstractCitizen science data are valuable for addressing a wide range of ecological research questions, and there has been a rapid increase in the scope and volume of data available. However, data from large-scale citizen science projects typically present a number of challenges that can inhibit robust ecological inferences. These challenges include: species bias, spatial bias, and variation in effort.To demonstrate addressing key challenges in analysing citizen science data, we use the example of estimating species distributions with data from eBird, a large semi-structured citizen science project. We estimate two widely applied metrics of species distributions: encounter rate and occupancy probability. For each metric, we assess the impact of data processing steps that either degrade or refine the data used in the analyses. We also test whether differences in model performance are maintained at different sample sizes.Model performance improved when data processing and analytical methods addressed the challenges arising from citizen science data. The largest gains in model performance were achieved with: 1) the use of complete checklists (where observers report all the species they detect and identify); and 2) the use of covariates describing variation in effort and detectability for each checklist. Occupancy models were more robust to a lack of complete checklists and effort variables. Improvements in model performance with data refinement were more evident with larger sample sizes.Here, we describe processes to refine semi-structured citizen science data to estimate species distributions. We demonstrate the value of complete checklists, which can inform the design and adaptation of citizen science projects. We also demonstrate the value of information on effort. The methods we have outlined are also likely to improve other forms of inference, and will enable researchers to conduct robust analyses and harness the vast ecological knowledge that exists within citizen science data.
The Life History Of Human Foraging: Cross-Cultural And Individual Variation
Authors: Koster Jeremy , Mcelreath Richard , Hill Kim , Yu Douglas , Shepard Glenn , Vliet Nathalie Van , Gurven Michael , Kaplan Hillard , Trumble Benjamin , Bird Rebecca Bliege , Bird Douglas , Codding Brian , Coad Lauren , Pacheco-Cobos Luis , Winterhalder Bruce , Lupo Karen , Schmitt Dave , Sillitoe Paul , Franzen Margaret , Alvard Michael , Venkataraman Vivek , Kraft Thomas , Endicott Kirk , Beckerman Stephen , Marks Stuart A. , Headland Thomas , Pangau-Adam Margaretha , Siren Anders , Kramer Karen , Greaves Russell , Reyes-García Victoria , Guèze Maximilien , Duda Romain , Fernández-Llamazares Álvaro , Gallois Sandrine , Napitupulu Lucentezza , Ellen Roy , Ziker John , Nielsen Martin R. , Ready Elspeth , Healey Christopher , Ross Cody 
Published: March 2019

ABSTRACTHuman adaptation depends upon the integration of slow life history, complex production skills, and extensive sociality. Refining and testing models of the evolution of human life history and cultural learning will benefit from increasingly accurate measurement of knowledge, skills, and rates of production with age. We pursue this goal by inferring individual hunters’ of hunting skill gain and loss from approximately 23,000 hunting records generated by more than 1,800 individuals at 40 locations. The model provides an improved picture of ages of peak productivity as well as variation within and among ages. The data reveal an average age of peak productivity between 30 and 35 years of age, though high skill is maintained throughout much of adulthood. In addition, there is substantial variation both among individuals and sites. Within study sites, variation among individuals depends more upon heterogeneity in rates of decline than in rates of increase. This analysis sharpens questions about the co-evolution of human life history and cultural adaptation. It also demonstrates new statistical algorithms and models that expand the potential inferences drawn from detailed quantitative data collected in the field.
A comprehensive examination of Nanopore native RNA sequencing for characterization of complex transcriptomes
Authors: Soneson Charlotte , Yao Yao , Bratus-Neuenschwander Anna , Patrignani Andrea , Robinson Mark D. , Hussain Shobbir 
Published: March 2019

AbstractA platform for highly parallel direct sequencing of native RNA strands was recently described by Oxford Nanopore Technologies (ONT); in order to assess overall performance in transcript-level investigations, the technology was applied for sequencing sets of synthetic transcripts as well as a yeast transcriptome. However, despite initial efforts it remains crucial to further investigate characteristics of ONT native RNA sequencing when applied to much more complex transcriptomes. Here we thus undertook extensive native RNA sequencing of polyA+ RNA from two human cell lines, and thereby analysed ~5.2 million aligned native RNA reads which consisted of a total of ~4.6 billion bases. To enable informative comparisons, we also performed relevant ONT direct cDNA- and Illumina-sequencing. We find that while native RNA sequencing does enable some of the anticipated advantages, key unexpected aspects hamper its performance, most notably the quite frequent inability to obtain full-length transcripts from single reads, as well as difficulties to unambiguously infer their true transcript of origin. While characterising issues that need to be addressed when investigating more complex transcriptomes, our study highlights that with some defined improvements, native RNA sequencing could be an important addition to the mammalian transcriptomics toolbox.
A consensus set of genetic vulnerabilities to ATR inhibition
Authors: Hustedt Nicole , Álvarez-Quilón Alejandro , McEwan Andrea , Yuan Jing Yi , Cho Tiffany , Koob Lisa , Hart Traver , Durocher Daniel 
Published: March 2019

AbstractThe response to DNA replication stress in eukaryotes is under the control of the ataxia-telangiectasia and Rad3-related (ATR) kinase. ATR responds to single-stranded (ss) DNA to stabilize distressed DNA replication forks, modulate DNA replication firing and prevent cells with damaged DNA or incomplete DNA replication from entering into mitosis. Furthermore, inhibitors of ATR are currently in clinical development either as monotherapies or in combination with agents that perturb DNA replication. To gain a genetic view of the cellular pathways requiring ATR kinase function, we mapped genes whose mutation causes hypersensitivity to ATR inhibitors with genome-scale CRISPR/Cas9 screens. We delineate a consensus set of 117 genes enriched in DNA replication, DNA repair and cell cycle regulators that promote survival when ATR kinase activity is suppressed. We validate 14 genes from this set and report genes not previously described to modulate response to ATR inhibitors. In particular we found that the loss of the POLE3/POLE4 proteins, which are DNA polymerase e accessory subunits, results in marked hypersensitivity to ATR inhibition. We anticipate that this 117-gene set will be useful for the identification of genes involved in the regulation of genome integrity, the characterization of new biological processes involving ATR, and may reveal biomarkers of ATR inhibitor response in the clinic.
T Cell Receptor Immunotherapy Drives Human Immunodeficiency Virus Evolution in Humanized Mice
Authors: Joglekar Alok V. , Swift Margaret , Leonard Michael T. , Jeppson John D. , Sandoval Salemiz , Baltimore David 
Published: March 2019

SummaryT cell receptor mediated immunotherapy using engineered Hematopoietic Stem/Progenitor Cells leads to durable partial suppression of HIV in humanized mice. Sustained viral suppression is accompanied by viral evolution under selection pressure. This study highlights the potential for TCR immunotherapy and the need to target multiple epitopes.AbstractEffective CD8+ T cell responses targeted to the KK10 epitope of HIV presented by HLA-B*27:05, a protective HLA allele, correlate with the ability to control infection without antiretroviral therapy (ART). Here, we report an immunotherapy approach using two B*27:05-KK10-specific T Cell Receptors (TCRs) isolated from HIV controllers. Immunocompromised mice engrafted with human Hematopoietic Stem/Progenitor Cells (HSPCs) encoding for the TCRs showed differentiation into functionally active engineered T cells. Following infection with HIV, both TCRs showed sustained, albeit modest, viral suppression over 32 weeks, accompanied by a concomitant increase in CD4+ T cells. Sequencing of viral quasi-species from the plasma of infected mice demonstrated clear evidence for viral evolution under selection pressure from the TCRs. The most commonly observed mutation in the KK10 epitope was L6M, which preserved viral fitness but showed attenuated recognition by the TCRs. These studies show that TCR-immunotherapy was able to suppress HIV infection long-term while driving HIV evolution in humanized mice.
Genetic structure is stronger across human-impacted habitats than among islands in the coralPorites lobata
Authors: Tisthammer Kaho H. , Forsman Zac H. , Toonen Robert J. , Richmond Robert H. 
Published: March 2019

ABSTRACTWe examined genetic structure in the lobe coralPorites lobataamong pairs of highly variable and high-stress nearshore sites and adjacent less variable and less impacted offshore sites on the islands of Oʻahu and Maui, Hawai‘i. Using an analysis of molecular variance framework, we tested whether populations were more structured by geographic distance or environmental extremes. The genetic patterns we observed followed isolation by environment, where nearshore and adjacent offshore populations showed significant genetic structure at both locations (AMOVAFST= 0.04 ∼ 0.19,P< 0.001), but no significant isolation by distance between islands. In contrast, a third site with a less impacted nearshore site showed no significant structure. Strikingly, corals from the two impacted nearshore sites on different islands over 100km apart with similar environmentally stressful conditions were genetically closer (FST∼ 0, P = 0.733) than those within a single location less than 2 km apart (FST= 0.041∼0.079, P < 0.01). Our results suggest that ecological boundaries appear to play a strong role in forming genetic structure in the coastal environment, and that genetic divergence in the absence of geographical barriers to gene flow may be explained by disruptive selection across contrasting habitats.
Characterisation ofl(3)tbas a novel tumour suppressor allele ofDCP2inDrosophila melanogaster
Authors: Mishra Rakesh , Kunar Rohit , Mandal Lolitika , Alone Debasmita P , Chandrasekharan Shanti , Tiwari Anand Krishna , Mukherjee Ashim , Tapadia Madhu G , Roy Jagat Kumar 
Published: March 2019

AbstractMutants provide an excellent platform for the discovery and characterization of gene functions. The present communication is a pioneering treatise on a hitherto undescribed function of the gene coding for the mRNA decapping protein 2 (DCP2) inDrosophila melanogaster. DCP2, the gene coding for the mRNA decapping enzyme, has been studied in various model organisms in the light of maintenance of transcript abundance and stability but has never been implicated in tumourigenesis. Herein, we describe the mapping and characterization of a novel tumour suppressor allele ofDCP2(CG6169), which we named aslethal(3)tumorous brain[l(3)tb]. The homozygous mutant individuals show prolonged larval life, develop larval brain tumors and are lethal in the larval/pupal stages. The tumour is characterized by the presence of increased number of superficial neuroblasts, abnormal chromosomal condensation and causes overgrowth in the wing and the eye-antennal discs of the homozygous mutant larvae, all of which are rescued by the introduction of a functional copy ofDCP2in the mutant background, thereby establishing the causal role of the mutation and providing a genetic validation of the allelism. Our findings therefore ascribe a novel role of tumor suppression toDCP2besides its cognate function of mRNA decapping and thereby identify it as a potential candidate for future research on tumorigenesis.
Regional climate affects salmon lice dynamics, stage structure, and management
Authors: Hurford Amy , Wang Xiunan , Zhao Xiao-Qiang 
Published: March 2019

AbstractRegional variation in climate can generate differences in population dynamics and stage structure. Where regional differences exist, the best approach to pest management may be region specific. Salmon lice are a stage structured marine copepod that parasitizes salmonids at aquaculture sites worldwide, and have fecundity, development, and mortality rates that depend on temperature and salinity. We show that in Atlantic Canada and Norway, where the oceans are relatively cold, salmon lice abundance decreases during the winter months, but ultimately increases from year-to-year, while in Ireland and Chile, where the oceans are warmer, the population size grows monotonically without any seasonal declines. In colder regions, during the winter the stage structure is dominated by the adult stage, which is in contrast to warmer regions where all stages are abundant year round. These differences translate into region specific recommendations for management: regions with slower population growth have lower critical stocking densities, and regions with cold winters have a seasonal dependence in the timing of follow-up chemotherapeutic treatments. Predictions of our salmon lice model agree with empirical data, and our approach provides a method to understand the effects of regional differences in climate on salmon lice dynamics and management.
Modeling non-genetic dynamics of cancer cell states measured by single-cell analysis: Uncovering bifurcations that explain why treatment either kills a cancer cell or makes it resistant
Authors: Huang S. 
Published: March 2019

AbstractSingle-cell transcriptomics offers a new vista on non-genetic tumor cell plasticity, a neglected aspect of cancer. The gene expression state of each cell is governed by the gene regulatory network which represents a high-dimensional non-linear dynamical system that generates multiple stable attractor states and undergoes destabilizing bifurcations, manifest as critical transitions. Modeling clonal cell population as statistical ensembles of the same dynamical system, a index IC is derived for detecting destabilization towards critical transitions in single-cell molecular profiles. Therapy-induced bifurcation explains why treatment backfires: a drug-treated cell is imposed the binary choice to either apoptose or become a cancer-stem cell.
A novel, dynein-independent mechanism focuses the endoplasmic reticulum around spindle poles in dividingDrosophilaspermatocytes
Authors: Karabasheva Darya , Smyth Jeremy T. 
Published: March 2019

AbstractIn dividing animal cells the endoplasmic reticulum (ER) concentrates around the poles of the spindle apparatus by associating with astral microtubules (MTs), and this association is essential for proper ER partitioning to progeny cells. The mechanisms that associate the ER with astral MTs are unknown. Because astral MT minus-ends are anchored by centrosomes at spindle poles, we tested the hypothesis that the MT minus-end motor dynein mediates ER concentration around spindle poles. Livein vivoimaging ofDrosophilaspermatocytes undergoing the first meiotic division revealed that dynein is required for ER concentration around centrosomes during interphase. In marked contrast, however, dynein suppression had no effect on ER association with astral MTs and concentration around spindle poles in early M-phase. Importantly though, there was a sudden onset of ER-astral MT association inDhc64CRNAi cells, revealing activation of an M-phase specific mechanism. ER redistribution to spindle poles also did not require non-claret disjunctional (ncd), the other knownDrosophilaMT minus-end motor, nor Klp61F, a MT plus-end motor that generates spindle poleward forces. Collectively, our results suggest that a novel, M-phase specific mechanism of ER-MT association that is independent of MT minus-end motors is required for proper ER partitioning in dividing cells.
Multivariate pattern classification on BOLD activation pattern induced by deep brain stimulation in motor, associative, and limbic brain networks
Authors: Cho Shinho , Min Hoon-Ki , Gibson William S. , In Myung-Ho , Lee Kendall H. , Jo Hang Joon 
Published: March 2019

ABSTRACTFunctional magnetic resonance imaging (fMRI) concurrently conducted with the deep brain stimulation (DBS) has shown that diffuse BOLD activation occurred not only near stimulation locus, but in multiple brain networks, supporting that network-wide modulation would underlie its therapeutic effect. While the extent and pattern of activation varies depending on specific anatomical locus stimulated by DBS, some stimulation targets could induce similar activation pattern in cerebral cortex, albeit different therapeutic and adverse effects were yielded.In order to characterize the unique network-level activation effects of three DBS targets (subthalamic nucleus, the globus pallidus internus, and the nucleus accumbens), we trained the pattern classifier with DBS-fMRI data from three stimulation groups (21 healthy swine), wherein five six seconds of electrical stimulation was conducted while gradient-echo echo planar imaging was on going. Then whole brain regions were systematically grouped into different size of network-of-interest and the classification accuracy for individual target region was quantitatively assessed. We demonstrated that the pattern classifier could successfully differentiate BOLD activation pattern of cortical and subcortical brain regions originated from each individual stimulation target. Moreover, the success rate of classification indicated that some brain regions evoked indistinguishable BOLD pattern, suggesting the presence of commonly activated regions, which was influenced by stimulating different DBS targets.Our results provide an understanding of the biomarker of BOLD pattern that is associated with clinical effectiveness as well as an adverse effect associated to the stimulation. Further, we provide the proof-of-concept for multivariate pattern analysis that is capable of disentangling the complicated BOLD activation pattern, which cannot be readily achieved by a conventional univariate analysis.