bluuebunny/crossref_metadata_2025_split huggingface dataset:
DateLife: leveraging databases and analytical tools to reveal the dated Tree of Life
Authors: Reyes Luna L. Sánchez , McTavish Emily Jane , O’Meara Brian 
Published: October 2019

AbstractAchieving a high-quality reconstruction of a phylogenetic tree with branch lengths proportional to absolute time (chronogram) is a difficult and time-consuming task. But the increased availability of fossil and molecular data, and time-efficient analytical techniques has resulted in many recent publications of large chronograms for a large number and wide diversity of organisms. Knowledge of the evolutionary time frame of organisms is key for research in the natural sciences. It also represent valuable information for education, science communication, and policy decisions. When chronograms are shared in public and open databases, this wealth of expertly-curated and peer-reviewed data on evolutionary timeframe is exposed in a programatic and reusable way, as intensive and localized efforts have improved data sharing practices, as well as incentivizited open science in biology. Here we present DateLife, a service implemented as an R package and an R Shiny website application available at www.datelife.org, that provides functionalities for efficient and easy finding, summary, reuse, and reanalysis of expert, peer-reviewed, public data on time frame of evolution. The main DateLife workflow constructs a chronogram for any given combination of taxon names by searching a local chronogram database constructed and curated from the Open Tree of Life Phylesystem phylogenetic database, which incorporates phylogenetic data from the TreeBASE database as well. We implement and test methods for summarizing time data from multiple source chronograms using supertree and congruification algorithms, and using age data extracted from source chronograms as secondary calibration points to add branch lengths proportional to absolute time to a tree topology. DateLife will be useful to increase awareness of the existing variation in alternative hypothesis of evolutionary time for the same organisms, and can foster exploration of the effect of alternative evolutionary timing hypotheses on the results of downstream analyses, providing a framework for a more informed interpretation of evolutionary results.
Integration of Contours Defined by Second-Order Contrast-Modulation of Texture
Authors: Baldwin Alex S , Kenwood Madeleine , Hess Robert F 
Published: October 2019

ABSTRACTBoundaries in the visual world can be defined by changes in luminance and texture in the input image. A “contour integration” process joins together local changes into percepts of lines or edges. A previous study tested the integration of contours defined by second-order contrast-modulation. Their contours were placed in a background of random wavelets. Subjects performed near chance. We re-visited second-order contour integration with a different task. Subjects distinguished contours with “good continuation” from distractors. We measured thresholds in different amounts of external orientation or position noise. This gave two noise-masking functions. We also measured thresholds for contours with a baseline curvature to assess performance with more curvy targets. Our subjects were able to discriminate the good continuation of second-order contours. Thresholds were higher than for first-order contours. In our modelling, we found this was due to multiple factors. There was a doubling of equivalent internal noise between first- and second-order contour integration. There was also a reduction in efficiency. The efficiency difference was only significant in our orientation noise condition. For both first- and second-order stimuli, subjects were also able to perform our task with more curved contours. We conclude that humans can integrate second-order contours, even when they are curved. There is however reduced performance compared to first-order contours. We find both an impaired input to the integrating mechanism, and reduced efficiency seem responsible. Second-order contour integration may be more affected by the noise background used in the previous study. Difficulty segregating that background may explain their result.
Gouania willdenowi is a teleost fish without immunoglobulin genes
Authors: Mirete-Bachiller Serafin , Olivieri David N. , Gambón-Deza Francisco 
Published: October 2019

AbstractIn the study of immunoglobulin V genes in fish genomes, we found that the species Gouania willdenowi does not possess any such regions, neither for the heavy chain nor for the light chains. Also, genes that code for the immunoglobulin constant regions were also not found. A detailed analysis of the chromosomal region of these genes revealed a deletion in the entire locus for regions of the heavy and light chains. These studies provide evidence that this species does not possess genes coding for immunoglobulins. Additionally, we found the genes that code for CD79a and CD79b protein molecules have also been deleted. Regions for the Tα/β lymphocyte receptors are present but the T γ/δ receptors were not found. In transcripts of two other Gobiesocidae species, Acystus sp. and Tomicodon sp., no antibody sequences could be detected, possibly indicating the absence of immunoglobulins in all species of this family.
Dose-controlled tDCS reduces electric field intensity variability at a cortical target site
Authors: Evans Carys , Bachmann Clarissa , Lee Jenny , Gregoriou Evridiki , Ward Nick , Bestmann Sven 
Published: October 2019

AbstractBackgroundVariable effects limit the efficacy of transcranial direct current stimulation (tDCS) as a research and therapeutic tool. Conventional application of a fixed-dose of tDCS does not account for inter-individual differences in anatomy (e.g. skull thickness), which varies the amount of current reaching the brain. Individualised dose-control may reduce the variable effects of tDCS by reducing variability in electric field intensities at a cortical target site.ObjectiveTo characterise the variability in electric field intensity at a cortical site (left primary motor cortex; M1) and throughout the brain for conventional fixed-dose tDCS, and individualised dose-controlled tDCS.MethodsThe intensity and distribution of the electric field during tDCS was estimated using Realistic Volumetric Approach to Simulate Transcranial Electric Stimulation (ROAST) in 50 individual brain scans taken from the Human Connectome Project, for fixed-dose tDCS (1mA & 2mA) and individualised dose-controlled tDCS targeting left M1.ResultsWith a fixed-dose (1mA & 2mA), E-field intensity in left M1 varied by more than 100% across individuals, with substantial variation observed throughout the brain as well. Individualised dose-controlled ensured the same E-field intensity was delivered to left M1 in all individuals. Its variance in other regions of interest (right M1 and area underneath the electrodes) was comparable with fixed- and individualised-dose.ConclusionsIndividualized dose-control can eliminate the variance in electric field intensities at a cortical target site. Assuming that the current delivered to the brain directly determines its physiological and behavioural consequences, this approach may allow for reducing the known variability of tDCS effects.
Muscle-derived Myoglianin regulatesDrosophilaimaginal disc growth
Authors: Upadhyay Ambuj , Peterson Aidan J. , Kim Myung-Jun , O’Connor Michael B. 
Published: October 2019

ABSTRACTOrgan growth and size are finely tuned by intrinsic and extrinsic signaling molecules. InDrosophila, the BMP family member Dpp is produced in a limited set of imaginal disc cells and functions as a classic morphogen to regulate pattern and growth by diffusing throughout imaginal discs. However, the role of TGFβ/Activin-like ligands in disc growth control remains ill-defined. Here we demonstrate that Myoglianin (Myo), an Activin family member, and a close homolog of mammalian Myostatin (Mstn), is a muscle-derived extrinsic factor that uses canonical dSmad2 mediated signaling to regulate wing size. We propose that Myo is a myokine that helps mediate an allometric relationship between muscles and their associated appendages.
Diagnostic value of circulating tumor DNA as an effective biomarker in cervical cancer: a meta-analysis
Authors: Gu Yulan , Wan Chuandan , Qiu Jiaming , Cui Yanhong , Jiang Tingwang 
Published: October 2019

AbstractThe applications of liquid biopsy have attracted much attention in biomedical research in recent years. Circulating cell-free DNA (cfDNA) in the serum may serve as a unique tumor marker in various types of cancer. Circulating tumor DNA (ctDNA) is a type of serum cfDNA found in patients with cancer and contains abundant information regarding tumor characteristics, highlighting its potential diagnostic value in the clinical setting. However, the diagnostic value of cfDNA as a biomarker in cervical cancer remains unclear. Here, we performed a meta-analysis to evaluate the applications of ctDNA as a biomarker in cervical cancer. A systematic literature search was performed using PubMed, Embase, and WANFANG MED ONLINE databases up to March 18, 2019. All literature was analyzed using Meta Disc 1.4 and STATA 14.0 software. Diagnostic measures of accuracy of ctDNA in cervical cancer were pooled and investigated. Fifteen studies comprising 1109 patients with cervical cancer met our inclusion criteria and were subjected to analysis. The pooled sensitivity and specificity were 0.52 (95% confidence interval [CI], 0.33–0.71) and 0.97 (95% CI, 0.91–0.99), respectively. The pooled positive likelihood ratio and negative likelihood ratio were 16.0 (95% CI, 5.5–46.4) and 0.50 (95% CI, 0.33–0.75), respectively. The diagnostic odds ratio was 32 (95% CI, 10–108), and the area under the summary receiver operating characteristic curve was 0.92 (95% CI, 0.90– 0.94). There was no significant publication bias observed. In the included studies, ctDNA showed clear diagnostic value for diagnosing and monitoring cervical cancer. Our meta-analysis suggested that detection of human papilloma virus ctDNA in patients with cervical cancer could be used as a noninvasive early dynamic biomarker of tumors, with high specificity and moderate sensitivity. Further large-scale prospective studies are required to validate the factors that may influence the accuracy of cervical cancer diagnosis and monitoring.
Energy landscape steering mediates dynamic coupling in ATP-driven protein translocation by the bacterial Sec machinery
Authors: Crossley Joel A. , Allen William J. , Watkins Daniel W. , Sabir Tara , Radford Sheena E. , Tuma Roman , Collinson Ian , Fessl Tomas 
Published: October 2019

AbstractThe Sec translocon is a highly conserved membrane complex for transport of polypeptides across, or into, lipid bilayers. In bacteria, the core protein-channel SecYEG resides in the inner-membrane, through which secretion is powered by the cytosolic ATPase SecA. Here, we use single-molecule fluorescence to interrogate the dynamic state of SecYEG throughout the hydrolytic cycle of SecA. We show that the SecYEG channel fluctuates between open and closed states faster (∼20-fold during transport) than ATP turnover; while the nucleotide status of SecA modulates the rates of opening and closure. Interestingly, a SecY variant (PrlA4), exhibiting faster protein transport, but unaffected ATPase rates, increases the dwell time in the open state, facilitating pre-protein diffusion through the pore; thereby improving the efficiency of translocation. Thus, contrary to prevailing structure-based models, SecYEG plays an integral part in the translocation mechanism through dynamic allosteric coupling in which SecA ‘steers’ the energy landscape of the protein-channel.
Mitigating Temozolomide Resistance in Glioblastoma via DNA Damage-Repair Inhibition
Authors: Sorribes Inmaculada C. , Handelman Samuel K. , Jain Harsh V. 
Published: October 2019

AbstractGlioblastomas are among the most lethal cancers, with a five year survival rate below 25%. Temozolomide is typically used in glioblastoma treatment; however, the enzymes APNG and MGMT efficiently mediate the repair of DNA damage caused by temozolomide, reducing treatment efficacy. Consequently, APNG and MGMT inhibition has been proposed as a way of overcoming chemotherapy resistance. Here, we develop a mechanistic mathematical model that explicitly incorporates the effect of chemotherapy on tumor cells, including the processes of DNA damage induction, cell arrest and DNA repair. Our model is carefully parameterized and validated, and then used to virtually recreate the response of heteroclonal glioblastoma to dual treatment with TMZ and inhibitors of APNG/MGMT. Using our mechanistic model, we identify four combination treatment strategies optimized by tumor cell phenotype, and isolate the strategy most likely to succeed in a pre-clinical and clinical setting. If confirmed in clinical trials, these strategies have the potential to offset chemotherapy resistance in glioblastoma patients, and improve overall survival.
Imaging FCS Delineates Subtle Heterogeneity in Plasma Membranes of Resting Mast Cells
Authors: Bag Nirmalya , Holowka David A. , Baird Barbara A. 
Published: October 2019

ABSTRACTA myriad of transient, nanoscopic lipid- and protein-based interactions confer a steady-state organization of plasma membrane in resting cells that is poised to orchestrate assembly of key signaling components upon reception of an extracellular stimulus. Although difficult to observe directly in live cells, these subtle interactions can be discerned by their impact on the diffusion of membrane constituents. Herein, we quantified the diffusion properties of a panel of structurally distinct lipid-anchored and transmembrane (TM) probes in RBL mast cells by multiplexed Imaging Fluorescence Correlation Spectroscopy. We developed a statistical analysis of data combined from many pixels over multiple cells to characterize differences as small as 10% in diffusion coefficients, which reflect differences in underlying interactions. We found that the distinctive diffusion properties of lipid-anchored probes can be explained by their dynamic partitioning into ordered proteo-lipid nanodomains, which encompass a major fraction of the membrane and whose physical properties are influenced by actin polymerization. Effects on diffusion by functional protein modules in both lipid-anchored and TM probes reflect additional complexity in steady-state membrane organization. The contrast we observe between different probes diffusing through the same membrane milieu represent the dynamic resting steady-state, which serves as a baseline for monitoring plasma membrane remodeling that occurs upon stimulation.
Light activates the translational regulatory GCN2 kinase via reactive oxygen species emanating from the chloroplast
Authors: Lokdarshi Ansul , Guan Ju , Urquidi Camacho Ricardo A , Cho Sung Ki , Morgan Philip , Leonard Madison , Shimono Masaki , Day Brad , von Arnim Albrecht G 
Published: October 2019

ABSTRACTCytosolic mRNA translation is subject to global and mRNA-specific controls. Phosphorylation of translation initiation factor eIF2α anchors a reversible switch that represses translation globally. The stress-responsive GCN2 kinase is the only known kinase for eIF2α inArabidopsis. Here we show that conditions that generate reactive oxygen species (ROS) in the chloroplast, such as dark-light transitions, high light, and the herbicide methyl viologen all rapidly activated the GCN2 kinase, whereas mitochondrial and ER stress did not. In addition, GCN2 activation was light dependent and mitigated by photosynthesis inhibitors and ROS quenchers. Accordingly, seedling growth of multiplegcn2mutant alleles was retarded under conditions of excess light, implicating the GCN2-eIF2α pathway in responses to light and associated ROS. Once activated, the GCN2 kinase preferentially suppressed the ribosome loading of mRNAs for functions such as mitochondrial ATP synthesis, the chloroplast thylakoids, vesicle trafficking, and translation. The transcriptome ofgcn2mutants was sensitized to abiotic stress, including oxidative stress, as well as innate immune responses. Accordingly,gcn2displayed defects in immune priming by the fungal elicitor, chitin. In conclusion, we provide evidence that reactive oxygen species produced by the photosynthetic apparatus help to activate the highly conserved GCN2 kinase, leading to eIF2α phosphorylation and thus affecting the status of the cytosolic protein synthesis apparatus.
Multispectral Imaging Differentiates Unique Macrophage Profiles in Patients with Distinct Chronic Liver Diseases
Authors: Saldarriaga Omar A. , Booth Adam L. , Freiberg Benjamin , Burks Jared , Krishnan Santhoshi , Rao Arvind , Utay Netanya , Ferguson Monique , Yi Minkyung , Beretta Laura , Stevenson Heather L. 
Published: October 2019

ABSTRACTIntrahepatic macrophages influence the composition of the microenvironment, host immune response to liver injury, and development of fibrosis. Compared to stellate cells, the role of intrahepatic macrophages in the development of fibrosis remains ill defined. Multispectral imaging allows detection of multiple markersin situin human formalin-fixed, paraffin-embedded tissue. This cutting-edge technology is ideal for analyzing human liver tissues since it allows spectral unmixing of fluorophore signals, subtraction of auto-fluorescence, and preserves architecture and thein vivohepatic milieu. We analyzed resident Kupffer cells (CD68+), monocyte-derived macrophages (Mac387+), pro-fibrogenic macrophages (CD163+), and co-expression of pro-inflammatory (CD14) and anti-inflammatory (CD16) markers in liver biopsies from patients with hepatitis C virus (HCV) and different stages of fibrosis. Liver biopsies with advanced fibrosis showed increased accumulation of CD163+, MAC387+ and CD68+ macrophages in the portal tracts when compared to those with minimal fibrosis. Imaging software generated t-distributed stochastic neighbor embedding (t-SNE) plots and phenotype matrices that facilitated comparison of macrophage profiles. These included monocyte-derived (CD68+/Mac387+) and pro-fibrotic/anti-inflammatory (CD163+/CD16+) phenotypes. We established that the utility of this platform could be extended to liver biopsies from patients with other chronic liver diseases including nonalcoholic steatohepatitis and autoimmune hepatitis. Each disease exhibited a unique profile after spectral imaging analysis and this platform holds the potential to identify patients predisposed to progressive liver disease based on the macrophage composition. In summary, spectral imaging is a powerful tool that enables analysis of macrophage profiles in different types of chronic liver diseases and has potential to change the manner in which we evaluate liver biopsies leading to more personalized treatment strategies.
Novel functional insights revealed by distinct protein-protein interactions of the residual SWI/SNF complex in SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type
Authors: Raupach Elizabeth A. , Garcia-Mansfield Krystine , Sharma Ritin , Hegde Apurva M. , David-Dirgo Victoria , Wang Yemin , Shin Chae Young , Tao Lan V. , Facista Salvatore J. , Moore Rayvon , Lang Jessica D. , Zismann Victoria L. , Orlando Krystal A. , Spillman Monique , Karnezis Anthony N. , Bennett Lynda B. , Huntsman David G. , Trent Jeffrey M. , Hendricks William P. D. , Weissman Bernard E. , Pirrotte Patrick 
Published: October 2019

AbstractChromatin remodeling plays a critical role in tumor suppression as demonstrated by 20% of human cancers bearing inactivating mutations in SWI/SNF chromatin remodeling complex members. Mutations in different SWI/SNF subunits drive a variety of adult and pediatric tumor types, including non-small cell lung cancers, rhabdoid tumors, medulloblastomas, and ovarian cancers. Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is an aggressive subtype of ovarian cancer occurring in young women. Nearly all (>98%) SCCOHTs have inactivating mutations inSMARCA4, which encodes 1 of 2 mutually exclusive catalytic subunits of the SWI/SNF complex. Less than half of SCCOHT patients survive 5 years despite aggressive surgery and multimodal chemotherapy. Empirical support for effective SCCOHT treatments is scarce, in part because of the poor understanding of SCCOHT tumorigenesis. To gain insight into the functional consequences of SWI/SNF subunit loss, we defined SWI/SNF composition and its protein-protein interactions (PPIs) by immunoprecipitation and mass spectrometry (IP-MS) of SWI/SNF subunits in 3 SCCOHT cell lines. Comparing these results to a cell line containing a wild-type SWI/SNF complex, the interaction of most canonical core SWI/SNF subunits was observed in all SCCOHT cell lines at a lower abundance. The SCCOHT SWI/SNF also lacked ATPase module subunits and showed a drastic reduction in PBAF-specific subunit interactions. The wild-type and SCCOHT SWI/SNF subunits immunoprecipitated a shared set of 26 proteins, including core SWI/SNF subunits and RNA processing proteins. We observed 131 proteins exclusively interacting with the wild-type SWI/SNF complex including isoform-specific SWI/SNF subunits, members of the NuRD complex, and members of the MLL3/4 complex. We observed 60 PPIs exclusive to the SCCOHT residual SWI/SNF shared in at least 2 of the 3 SCCOHT cell lines, including many proteins involved in RNA processing. Differential interactions with the residual SWI/SNF complex in SCCOHT may further elucidate altered functional consequences of SMARCA4 mutations in these tumors as well as identify synthetic lethal targets that translate to other SWI/SNF-deficient tumors.
Range expansion shifts clonal interference patterns in evolving populations
Authors: Krishnan Nikhil , Fusco Diana , Scott Jacob G. 
Published: October 2019

ABSTRACTIncreasingly, predicting and even controlling evolutionary processes is a sought after goal in fields ranging from agriculture, artificial intelligence, astrobiology, oncology, and infectious diseases. However, our ability to predict evolution and plan such interventions in real populations is limited in part by our understanding of how spatial structure modulates evolutionary dynamics. Among current clinical assays applied to predict drug response in infectious diseases, for instance, many do not explicitly consider spatial structure and its influence on phenotypic heterogeneity, despite it being an inextricable characteristic of real populations. As spatially structured populations are subject to increased interference of beneficial mutants compared to their well-mixed counter-parts, among other effects, this population heterogeneity and structure may non-trivially impact drug response. In spatially-structured populations, the extent of this mutant interference is density dependent and thus varies with relative position within a meta-population in a manner modulated by mutant frequency, selection strength, migration speed, and habitat length, among other factors. In this study, we examine beneficial mutant fixation dynamics along the front of an asexual population expanding its range. We observe that multiple distinct evolutionary regimes of beneficial mutant origin-fixation dynamics are maintained at characteristic length scales along the front of the population expansion. Using an agent-based simulation of range expansion with mutation and selection in one dimension, we measure these length scales across a range of population sizes, selection strengths, and mutation rates. Furthermore, using simple scaling arguments to adapt theory from well-mixed populations, we find that the length scale at the tip of the front within which ‘local’ mutant fixation occurs in a successive mode decreases with increasing mutation rate, as well as population size in a manner predicted by our derived analytic expression. Finally, we discuss the relevance of our findings to real cellular populations, arguing that this conserved region of successive mutant fixation dynamics at the wave tip can be exploited by emerging evolutionary control strategies.