bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fibronectin receptor integrin α5β1 regulates assembly of PP2A complexes through PDE4D: modulation of vascular inflammation and atherosclerosis
Authors: Yun Sanguk , Hu Rui , Schwaemmle Melanie E. , Scherer Alexander N. , Zhuang Zhenwu , Koleske Anthony J. , Pallas David C. , Schwartz Martin A. 
Published: June 2019

AbstractFibronectin in the vascular wall promotes inflammatory activation of the endothelium during vascular remodeling and atherosclerosis. These effects are mediated in part by fibronectin binding to integrin α5, which recruits and activates phosphodiesterase 4D5 (PDE4D5) by inducing its dephosphorylation on an inhibitory site Ser651. Active PDE then hydrolyzes anti-inflammatory cAMP to facilitate inflammatory signaling. To test this model in vivo, we mutated the integrin binding site in PDE4D5 in mice. This mutation reduced endothelial inflammatory activation in athero-prone regions of arteries, and, in a hyperlipidemia model, reduced atherosclerotic plaque size while increasing markers of plaque stability. We then investigated the mechanism of PDE4D5 activation. Proteomics identified the PP2A regulatory subunit B55α as the factor recruiting PP2A to PDE4D5. The B55α-PP2A complex localized to adhesions and directly dephosphorylated PDE4D5. This interaction also unexpectedly stabilized the PP2A-B55α complex. The integrin-regulated, pro-atherosclerotic transcription factor Yap is also dephosphorylated and activated through this pathway. PDE4D5 therefore mediates matrix-specific regulation of EC phenotype via an unconventional adapter role, assembling and anchoring a multifunctional PP2A complex with other targets. These results are likely to have widespread consequences for control of cell function by integrins.
Impact of insertion sequences on convergent evolution ofShigellaspecies
Authors: Hawkey Jane , Monk Jonathan M. , Billman-Jacobe Helen , Palsson Bernhard , Holt Kathryn E. 
Published: June 2019

AbstractShigellaspecies are specialised lineages ofEscherichia colithat have converged to become human-adapted and cause dysentery by invading human gut epithelial cells. Most studies ofShigellaevolution have been restricted to comparisons of single representatives of each species; and population genomic studies of individualShigellaspecies have focused on genomic variation caused by single nucleotide variants and ignored the contribution of insertion sequences (IS) which are highly prevalent inShigellagenomes. Here, we investigate the distribution and evolutionary dynamics of IS within populations ofShigella dysenteriaeSd1,Shigella sonneiandShigella flexneri. We find that five IS (IS1, IS2, IS4, IS600and IS911) have undergone expansion in allShigellaspecies, creating substantial strain-to-strain variation within each population and contributing to convergent patterns of functional gene loss within and between species. We find that IS expansion and genome degradation are most advanced inS. dysenteriaeand least advanced inS. sonnei; and using genome-scale models of metabolism we show thatShigellaspecies display convergent loss of coreE. colimetabolic capabilities, withS. sonneiandS. flexnerifollowing a similar trajectory of metabolic streamlining to that ofS. dysenteriae. This study highlights the importance of IS to the evolution ofShigellaand provides a framework for the investigation of IS dynamics and metabolic reduction in other bacterial species.
Loss of SHMT2 mediates 5-FU chemoresistance by inducing autophagy in colorectal cancer
Authors: Chen Jian , Fan Guangjian , Xiao Chao , Wang Xiao , Wang Yupeng , Song Guohe , Liu Xueni , Chen Jiayi , Lu Huijun , Guo Weiping , Tang Huamei , Zhuang Guohong , Peng Zhihai 
Published: June 2019

AbstractSerine hydroxymethyltransferase 2 (SHMT2) plays a vital role in one-carbon metabolism and drives colorectal carcinogenesis. In our study, loss of SHMT2 induced 5-Fluorouracil (5-FU) chemoresistance and was associated with poor prognosis in colorectal cancer (CRC). To elucidate the possible mechanism and generate a strategy to sensitize CRC to 5-FU chemotherapy, we first identified the binding proteins of SHMT2 in cancer cells by mass spectrometry. We found that SHMT2 inhibited autophagy through binding cytoplasmic p53. In fact, SHMT2 prevented cytoplasmic p53 degradation by inhibiting the binding of p53 and HDM2. Under treatment with 5-FU, depletion of SHMT2 promoted autophagy and inhibited apoptosis. Autophagy inhibitors CQ decreased low SHMT2-induced 5-FU resistance in vitro and in vivo. Finally, we enhanced the lethality of 5-FU treatment to CRC cells through the autophagy inhibitor or knockdown of SHMT2 in patient-derived and CRC cell xenograft models. Our findings identified the low SHMT2-induced autophagy on 5-FU resistance in CRC. These results reveal SHMT2-p53 as a novel cancer therapeutic target to reduce chemotherapeutic drug resistance.
Adaptation to life on land at 21% O2via transition from ferredoxin- to NADH-dependent redox balance
Authors: Gould SB , Garg SG , Handrich M , Nelson-Sathi S , Gruenheit N , Tielens AGM , Martin WF 
Published: June 2019

AbstractPyruvate:ferredoxin oxidoreductase (PFO) and iron only hydrogenase ([Fe]-HYD) are common enzymes among eukaryotic microbes that inhabit anaerobic niches. Their function is to maintain redox balance by donating electrons from food oxidation via ferredoxin (Fd) to protons, generating H2as a waste product. Operating in series, they constitute a soluble electron transport chain of one-electron transfers between FeS clusters. They fulfill the same function — redox balance — served by two electron-transfers in the NADH- and O2-dependent respiratory chains of mitochondria. Although they possess O2-sensitive FeS clusters, PFO, Fd and [Fe]-HYD are also present among numerous algae that produce O2. The evolutionary persistence of these enzymes among eukaryotic aerobes is traditionally explained as enabling facultative anaerobic growth. Here we show that algae express enzymes of anaerobic energy metabolism at ambient O2levels (21% v/v),Chlamydomonas reinhardtiiexpresses them with diurnal regulation. High O2environments arose on Earth only some ∼450 million years ago. Gene presence absence and gene expression data indicate that during the transition to high O2environments and terrestrialization, diverse algal lineages retained enzymes of Fd-dependent one-electron based redox balance, while the land plant and land animal lineages underwent irreversible specialization to redox balance involving the O2-insensitive two-electron carrier NADH.Highlights- Algae express enzymes of anaerobic metabolism in 21% [v/v] O2atmosphere, independent of anaerobiosis- Retention of a plastid-encoded NADH dehydrogenase-like (NDH) was likely a prerequisite for the transition to life on land- Terrestrialization and adaption to high O2is accompanied by a shift to redox balance at higher midpoint potentials- Eukaryotes adapted to high O2life on land via specialization to two-electron based redox balance
Labelling effect in insects: cue associations influence perceived food value in ants
Authors: Wendt Stephanie , Czaczkes Tomer J. 
Published: June 2019

AbstractHumans usually assess things not in terms of absolute value, but relative to reference points. The framing of alternatives can strongly affect human decision-making, leading to different choices depending on the context within which options are presented. Similar reference-point effects have been recently reported in ants, in which foragers show a contrast effect: ants overvalue a medium-quality food source if they were expecting a poor one, and vice versa for expectations of good food. However, studies of human consumer psychology have demonstrated that expectations, for example from product labels, can drive value perception in the other direction via assimilation. For example, an expensive bottle of wine is perceived as more enjoyable compared to a cheaper bottle, even if the wine is the same. In this study, we demonstrate a similar labelling-association effect in an insect: ants showed assimilation effects by spending twice as long drinking at a medium quality food source if it was scented with an odour previously associated with high quality than if it was scented with a poor-quality label. The presence of odour cues in the food during consumption and evaluation is critical, as without them, odour-driven expectations of quality result in contrast, not assimilation effects. The addition of a quality label in the food thus reverses contrast effects and causes value to be aligned with expectations, rather than being contrasted against them. As value judgement is a key element in decision-making, relative value perception strongly influences which option is chosen, and ultimately how choices are made.
Estimation of Speciation Times Under the Multispecies Coalescent
Authors: Peng Jing , Swofford David L. , Kubatko Laura 
Published: June 2019

AbstractMotivationThe multispecies coalescent model is now widely accepted as an effective model for incorporating variation in the evolutionary histories of individual genes into methods for phylogenetic inference from genome-scale data. However, because model-based analysis under the coalescent can be computationally expensive for large data sets, a variety of inferential frameworks and corresponding algorithms have been proposed for estimation of species-level phylogenies and associated parameters, including speciation times and effective population sizes.ResultsWe consider the problem of estimating the timing of speciation events along a phylogeny in a coalescent framework. We propose a maximum a posteriori estimator based on composite likelihood (MAPCL) for inferring these speciation times under a model of DNA sequence evolution for which exact site pattern probabilities can be computed under the assumption of a constant θ throughout the species tree. We demonstrate that the MAPCL estimates are statistically consistent and asymptotically normally distributed, and we show how this result can be used to estimate their asymptotic variance. We also provide a more computationally efficient estimator of the asymptotic variance based on the nonparametric bootstrap. We evaluate the performance of our method using simulation and by application to an empirical dataset for gibbons.Availability and implementationThe method has been implemented in the PAUP* program, freely available at https://paup.phylosolutions.com for Macintosh, Windows, and Linux operating systems.Contactpeng.650@osu.eduSupplementary informationSupplementary data are available at Bioinformatics online.
LncRNA-dependent nuclear stress bodies promote intron retention through SR protein phosphorylation
Authors: Ninomiya Kensuke , Adachi Shungo , Natsume Tohru , Iwakiri Junichi , Terai Goro , Asai Kiyoshi , Hirose Tetsuro 
Published: June 2019

AbstractA number of long noncoding RNAs (lncRNAs) are induced in response to specific stresses to construct membrane-less nuclear bodies; however, their function remains poorly understood. Here, we report the role of nuclear stress bodies (nSBs) formed on highly repetitive satellite III (HSATIII) lncRNAs derived from primate-specific satellite III repeats upon thermal stress exposure. A transcriptomic analysis revealed that depletion of HSATIII lncRNAs, resulting in elimination of nSBs, promoted splicing of 533 retained introns during thermal stress recovery. A HSATIII-Comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS) analysis identified multiple splicing factors in nSBs, including serine and arginine-rich pre-mRNA splicing factors (SRSFs), the phosphorylation states of which affect splicing patterns. SRSFs are rapidly dephosphorylated upon thermal stress exposure. During stress recovery, CDC like kinase 1 (CLK1) was recruited to nSBs and accelerated the re-phosphorylation of SRSF9, thereby promoting target intron retention. Our findings suggest that HSATIII-dependent nSBs serve as a conditional platform for phosphorylation of SRSFs by CLK1 to promote the rapid adaptation of gene expression through intron retention following thermal stress exposure.
Genomic aberration based molecular signatures efficiently characterize homologous recombination deficiency in prostate cancer
Authors: Sztupinszki Zsofia , Diossy Miklos , Krzystanek Marcin , Borcsok Judit , Pomerantz Mark , Tisza Viktoria , Spisak Sandor , Rusz Orsolya , Csabai István , Freedman Matthew , Szallasi Zoltan 
Published: June 2019

AbstractBackgroundProstate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. It is not clear, however, whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, rendering them sensitive to HR-directed therapies.To identify a more comprehensive set of prostate cancer cases with homologous recombination deficiency (HRD) including those cases that do not harbor mutations in known HR genes.HRD levels can be estimated using various mutational signatures derived from next-generation sequencing data. We used this approach to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. Whole genome (n=311) and whole exome sequencing data (n=498) of both primary and metastatic prostate adenocarcinomas (PRAD) were analyzed.ResultsKnown BRCA-deficient samples showed robust signs of HR-deficiency associated mutational signatures. HRD-patterns were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR related genes. Patients with HRD signatures had a significantly worse prognosis than patients without signs of HRD.ConclusionsThese findings may expand the number of cases likely to respond to PARP-inhibitor treatment. Based on the HRD associated mutational signatures, 5-8 % of prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations).
Maturation of cortical microstructure and cognitive development in childhood and adolescence: a T1w/T2w ratio MRI study
Authors: Norbom Linn B. , Rokicki Jaroslav , Alnæs Dag , Kaufmann Tobias , Doan Nhat Trung , Andreassen Ole A. , Westlye Lars T. , Tamnes Christian K. 
Published: June 2019

AbstractThe restructuring and optimization of the cerebral cortex from early childhood and through adolescence is an essential feature of human brain development, underlying immense cognitive improvements. Beyond established morphometric cortical assessments, the T1w/T2w ratio quantifies partly separate biological processes, and might inform models of typical neurocognitive development and developmental psychopathology. In the present study, we computed vertex-wise T1w/T2w ratio across the cortical surface in 621 youths (3-21 years) sampled from the Pediatric Imaging, Neurocognition, and Genetics (PING) study and tested for associations with individual differences in age, sex, and both general and specific cognitive abilities. The results showed a near global linear age-related increase in T1w/T2w ratio across the brain surface, with a general posterior to anterior increasing gradient in association strength. Moreover, results indicated that boys in late adolescence had regionally higher T1w/T2w ratio as compared to girls. Across individuals, T1w/T2w ratio was negatively associated with general and several specific cognitive abilities mainly within anterior cortical regions. Our study indicates age-related differences in T1w/T2w ratio throughout childhood, adolescence and young adulthood, in line with the known protracted myelination of the cortex. Moreover, the study supports T1w/T2w ratio as a promising surrogate measure of individual differences in intracortical brain structure in neurodevelopment.
The Threshold Elemental Ratio of an ectotherm decreases then increases with rising temperature
Authors: Ruiz Thomas , Koussoroplis Apostolos-Manuel , Danger Michael , Aguer Jean-Pierre , Morel-Desrosiers Nicole , Bec Alexandre 
Published: June 2019

AbstractEarth is currently facing unprecedented global changes, hurrying scientists to provide predictive tools to explore the futures responses of ecosystems. Among those changes, temperature increase and alterations of nutrient availabilities largely drive consumer performances, yet their interactive effect remains poorly understood. Here we investigate how the dietary C:P ratio that optimizes consumer growth (TERC:P: Threshold Elemental Ratio) changes along temperature gradients by combining a TERC:P model and growth experiments on the model organism Daphnia magna. Both lines of evidence show that the TERC:P responds to temperature in an U-shaped fashion. This shape reconciles previous contradictive observations into a common framework, thereby improving our capacity to forecast the combined effects of nutrient cycle and climatic alterations on ectotherms.
Human caspase-1 autoproteolysis is required for ASC-dependent and -independent inflammasome activation
Authors: Ball Daniel P. , Taabazuing Cornelius Y. , Griswold Andrew R. , Orth Elizabeth L. , Rao Sahana D. , Kotliar Ilana B. , Johnson Darren C. , Bachovchin Daniel A. 
Published: June 2019

AbstractPathogen-related signals induce a number of cytosolic pattern-recognition receptors (PRRs) to form canonical inflammasomes, which activate pro-caspase-1 and trigger pyroptotic cell death. All well-studied PRRs oligomerize with the pro-caspase-1-adapter protein ASC to generate a single large structure in the cytosol, which induces the autoproteolysis and activation of the pro-caspase-1 zymogen. However, several PRRs can also directly interact with pro-caspase-1 without ASC, forming much smaller “ASC-independent” inflammasomes. It is currently thought that pro-caspase-1 autoproteolysis does not occur during, and is not required for, ASC-independent inflammasome activation. Here, we show that the related human PRRs NLRP1 and CARD8 exclusively form ASC-dependent and ASC-independent inflammasomes, respectively, identifying CARD8 as the first PRR that cannot form an ASC-containing signaling platform. Despite their different structures, we discovered that both the NLRP1 and CARD8 inflammasomes require pro-caspase-1 autoproteolysis between the small and large catalytic subunits to induce pyroptosis. Thus, pro-caspase-1 self-cleavage is an obligate regulatory step in the activation of human canonical inflammasomes.
Hydrological Extremes and their Association with ENSO Phases in Ethiopia
Authors: Gari Abu Tolcha 
Published: June 2019

AbstractEthiopia is a rain fed agriculture country, which is subjected to high climate variability in space and time, leading to hydrological extremes causing loss of life and property more frequently. Droughts are more common and sometime floods are experienced in various parts of the country. Being a tropical country, the inter-annual climate variability in Ethiopia is dominated by ENSO (ElNino and Southern Oscillation).In this study, an attempt has been made to determine the occurrence of droughts and floods on monthly basis, by calculating the monthly SPI (Standardized Precipitation Index) using the available rainfall data during (1975-2005) at selected 26 stations that spread across the country. Based on the monthly SPI values computed, the droughts and floods of different intensities; extreme, severe and dry have been determined for all stations. The frequencies of the droughts and floods on monthly scale during the two rainy seasons, Belg (Feb-May) and Kiremt (Jun-Sep) seasons have been determined. For instance, during Belg season, there were 11 extreme (SPI < −2.0) droughts at Nazreth, 10 severe (SPI between −1.99 and −1.50) droughts at Diredawa and 14 moderate (SPI between −1.49 and −1.00) droughts at Kulumsa. Total number of droughts of all intensities over the study period is also highest (22) at Kulumsa and lowest (8) at Mekelle. Moreover, at Kulumsa both the numbers of droughts (22) and floods (22) during Belg are more, which shows that the rainfall variability is the highest at this station.The association of the hydrological extremes during the two rainy seasons, belg and kiremt with the ENSO phases has also been examined, which forms a basis for the prediction of the occurrence of droughts (dry conditions) and floods (wet conditions) at individual stations using ENSO phases.
A novel imaging biomarker for survival prediction in EGFR-mutated NSCLC patients treated with TKI
Authors: Collin Annabelle , Groza Vladimir , Missenard Louise , Chomy François , Colin Thierry , Palussière Jean , Saut Olivier 
Published: June 2019

AbstractEGFR-mutated non-small cells lung carcinoma are treated with Tyrosine Kinase Inhibitors (TKI). Very often, the disease is only responding for a while before relapsing. TKI efficacy in the long run is therefore challenging to evaluate. Our objective is to derive a new imaging biomarker that could offer better insights on the disease response to treatment. This study includes 17 patients diagnosed as EGFR-mutated non-small cell lung cancer and exposed to an EGFR-targeting TKI. The early response to treatment is evaluated with 3 computed tomography (CT) scans of the primitive tumor (one before the TKI introduction and two after). Using our knowledge of the disease, an imaging biomarker based on the tumor heterogeneity evolution between the first and the third exams is defined and computed using a novel mathematical model calibrated on patient data. Defining the overall survival as the time between the introduction of the TKI treatment and the patient death, we obtain a statistically significant correlation between the overall survival and our imaging marker (p = 0.009). Using the ROC curve, the patients are separated into two populations hence the comparison of the survival curves is statistically significant (p = 0.025). Initial state of the tumor seems to have a role for the prognosis of the response to TKI treatment. More precisely, the imaging marker - defined using only the CT scan before the TKI introduction - allows us to determine a first classification of the population which is refined over time using the imaging marker as more CT scans become available. This exploratory study leads us to think that it is possible to obtain a survival assessment using only few CT scans of the primary tumor.
Antisense oligonucleotide therapy rescues aggresome formation in a novel Spinocerebellar Ataxia type 3 human embryonic stem cell line
Authors: Moore Lauren R. , Keller Laura , Bushart David D. , Delatorre Rodrigo , Li Duojia , McLoughlin Hayley S. , do Carmo Costa Maria , Shakkottai Vikram G. , Smith Gary D. , Paulson Henry L. 
Published: June 2019

AbstractSpinocerebellar ataxia type 3 (SCA3) is a fatal, late-onset neurodegenerative disorder characterized by selective neuropathology in the brainstem, cerebellum, spinal cord, and substantia nigra. Here, we characterize the first NIH-approved human embryonic stem cell (hESC) line derived from an embryo harboring the SCA3 mutation. Referred here as SCA3-hESC, this line is heterozygous for the mutant polyglutamine-encoding CAG repeat expansion in the ATXN3 gene within the pathogenic repeat range for SCA3. We observed relevant molecular hallmarks of the human disease at all differentiation stages from stem cells to cortical neurons, including robust ATXN3 aggregation and altered expression of key components of the protein quality control machinery. Finally, antisense oligonucleotide-mediated reduction of ATXN3 prevented the formation of p62-positive aggresomes in SCA3-hESCs. The SCA3-hESC line offers a unique and highly relevant human disease model that holds strong potential to advance understanding of SCA3 disease mechanisms and facilitate the evaluation of possible SCA3 therapies.HighlightsGenerated first NIH-approved SCA3 human embryonic stem cell line (SCA3-hESC)SCA3–hESC exhibit robust ATXN3 aggregation pathology and form p62+ aggresomesAnti-ATXN3 antisense oligonucleotides rescue aggresome formation in SCA3-hESCDerived SCA3 neurons form aggregates and exhibit impaired protein quality control