bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Detector Sampling on Noise Reduction in Clinical Photon-Counting Whole-Body Computed Tomography
Authors: Klein Laura , Dorn Sabrina , Amato Carlo , Heinze Sarah , Uhrig Monika , Schlemmer Heinz-Peter , Kachelrieß Marc , Sawall Stefan 
Published: November 2019

Objectives
Reconstructing images from measurements with small pixels below the system's resolution limit theoretically results in image noise reduction compared with measurements with larger pixels. We evaluate and quantify this effect using data acquired with the small pixels of a photon-counting (PC) computed tomography scanner that can be operated in different detector pixel binning modes and with a conventional energy-integrating (EI) detector.

Materials and Methods
An anthropomorphic abdominal phantom that can be extended to 3 sizes by adding fat extension rings, equipped with iodine inserts as well as human cadavers, was measured at tube voltages ranging from 80 to 140 kV. The images were acquired with the EI detector (0.6 mm pixel size at isocenter) and the PC detector operating in Macro mode (0.5 mm pixel size at iso) and ultrahigh-resolution (UHR) mode (0.25 mm pixel size at iso). Both detectors are components of the same dual-source prototype computed tomography system. During reconstruction, the modulation transfer functions were matched to the one of the EI detector. The dose-normalized contrast-to-noise ratio (CNRD) values are evaluated as a figure of merit.

Results
Images acquired in UHR mode achieve on average approximately 6% higher CNRD compared with Macro mode at the same spatial resolution for a quantitative D40f kernel. Using a sharper B70f kernel, the improvement increases to 21% on average. In addition, the better performance of PC detectors compared with EI detectors with regard to iodine imaging has been evaluated by comparing CNRD values for Macro and EI. Combining both of these effects, a CNRD improvement of up to 34%, corresponding to a potential dose reduction of up to 43%, can be achieved for D40f.

Conclusions
Reconstruction of UHR data with a modulation transfer function below the system's resolution limit reduces image noise for all patient sizes and tube voltages compared with standard acquisitions. Thus, a relevant dose reduction may be clinically possible while maintaining image quality.
Supporting Computational Apprenticeship through educational and software infrastructure. A case study in a mathematical oncology research lab
Authors: Madamanchi Aasakiran , Thomas Madison , Magana Alejandra , Heiland Randy , Macklin Paul 
Published: November 2019

AbstractThere is growing awareness of the need for mathematics and computing to quantitatively understand the complex dynamics and feedbacks in the life sciences. Although several institutions and research groups are conducting pioneering multidisciplinary research, communication and education across fields remains a bottleneck. The opportunity is ripe for using education research-supported mechanisms of cross-disciplinary training at the intersection of mathematics, computation and biology. This case study uses the computational apprenticeship theoretical framework to describe the efforts of a computational biology lab to rapidly prototype, test, and refine a mentorship infrastructure for undergraduate research experiences. We describe the challenges, benefits, and lessons learned, as well as the utility of the computational apprenticeship framework in supporting computational/math students learning and contributing to biology, and biologists in learning computational methods. We also explore implications for undergraduate classroom instruction, and cross-disciplinary scientific communication.
Idiosyncratic liver alterations of five frog species to land use changes in the Brazilian Cerrado
Authors: Franco-Belussi Lilian , Provete Diogo B. , Borges Rinneu Elias , de Oliveira Classius , de Souza Santos Lia Raquel 
Published: November 2019

AbstractChanges in land use trigger environmental changes that can lead to decreased biodiversity and species loss. The liver is an essential detoxification organ that reflects systemic physiological responses to environmental changes. Here, we tested whether land use changes influence the amount of substances from the hepatic cellular catabolism and melanomacrophages of five anuran species in the Brazilian Cerrado. We used routine histological and histochemical techniques. We then use recently developed ecological methods to relate functional traits to environmental variables. There was an increase in the amount of melanin in environments with high proportion of agriculture, as well as variation in the amount of lipofuscin and hemosiderin. Therefore, the area of melanomacrophages in the liver and the metabolic products in their cytoplasm can be used as biomarkers of environmental changes in regions with intense agricultural activities. Our results add a new perspective to the influence of land use changes on environmental health by highlighting the effect of environmental changes on internal morphological aspects of animals.
Tet2negatively regulates memory fidelity
Authors: Zengeler Kristine E. , Gettens Caroline P. , Smith Hannah C. , Caron Mallory M. , Zhang Xinyuan , Howard Alexandra H. , Boitnott Andrea R. , Gogliettino Alex R. , Reda Anas , Malachowsky Beth G. , Zhong Chun , Song Hongjun , Kaas Garrett A. , Kennedy Andrew J. 
Published: November 2019

SummaryDespite being fully differentiated, DNA methylation is dynamically regulated in post-mitotic glutamatergic neurons in the CA1 of the hippocampus through competing active DNA methylation and de-methylation, a process that regulates neuronal plasticity. Active DNA methylation after learning is necessary for long-term memory formation, and active DNA de-methylation by the TET enzymes has been implicated as a counter-regulator of that biochemical process. We demonstrate thatTet2functions in the CA1 as a negative regulator of long-term memory, whereby its knockdown across the CA1 or haploinsufficiency in glutamatergic neurons enhances the fidelity of hippocampal-dependent spatial and associative memory. Loci of altered DNA methylation were then determined using whole genome bisulfite sequencing from glutamatergicTet2haploinsufficient CA1 tissue, which revealed hypermethylation in the promoters of genes known to be transcriptionally regulated after experiential learning. This study demonstrates a link betweenTet2activity at genes important for memory formation in CA1 glutamatergic neurons and memory fidelity.
Inhibition of TXNRD or SOD1 overcomes NRF2-mediated resistance to β-lapachone
Authors: Torrente Laura , Prieto Nicolas , Falzone Aimee , Boothman David A. , Haura Eric B. , DeNicola Gina M. 
Published: November 2019

AbstractAlterations in the NRF2/KEAP1 pathway result in the constitutive activation of NRF2, leading to the aberrant induction of antioxidant and detoxification enzymes, including NQO1. The NQO1 bioactivatable agent β-lapachone can target cells with high NQO1 expression but relies in the generation of reactive oxygen species (ROS), which are actively scavenged in cells with NRF2/KEAP1 mutations. However, whether NRF2/KEAP1 mutations influence the response to β-lapachone treatment remains unknown. To address this question, we assessed the cytotoxicity of β-lapachone in a panel of NSCLC cell lines bearing either wild-type or mutant KEAP1. We found that, despite overexpression of NQO1, KEAP1 mutant cells were resistant to β-lapachone due to enhanced detoxification of ROS, which prevented DNA damage and cell death. To evaluate whether specific inhibition of the NRF2-regulated antioxidant enzymes could abrogate resistance to β-lapachone, we systematically inhibited the four major antioxidant cellular systems using genetic and/or pharmacologic approaches. We demonstrated that inhibition of the thioredoxin-dependent system or copper-zinc superoxide dismutase (SOD1) could abrogate NRF2-mediated resistance to β-lapachone, while depletion of catalase or glutathione was ineffective. Interestingly, inhibition of SOD1 selectively sensitized KEAP1 mutant cells to β-lapachone exposure. Our results suggest that NRF2/KEAP1 mutational status might serve as a predictive biomarker for response to NQO1-bioactivatable quinones in patients. Further, our results suggest SOD1 inhibition may have potential utility in combination with other ROS inducers in patients with KEAP1/NRF2 mutations.HighlightsAberrant activation of NRF2 in non-small cell lung cancer promotes resistance to β-lapachone via the antioxidant defense.Inhibition of the thioredoxin-dependent system and superoxide dismutase 1 increase sensitivity to β-lapachone treatment.Mutations in the NRF2/KEAP1 pathway might serve as predictive biomarker for response to β-lapachone in patients.
Dynamic evolution of cervical cancer mutations during chemoradiation using novel sampling approach
Authors: Chapman Bhavana V. , Karpinets Tatiana , Sims Travis T. , Biegert Greyson , Wu Xiaogang , Delgado Medrano Andrea Y. , Eifel Patricia J. , Jhingran Anuja , Lin Lilie L. , Ramondetta Lois M. , Futreal Andrew M. , Jazaeri Amir A. , Frumovitz Michael , Schmeler Kathleen M. , Yue Jingyan , Mitra Aparna , Yoshida-Court Kyoko , Solley Travis , Mathew Geena , Ahmed-Kaddar Mustapha , Zhang Jianhua , Klopp Ann H. , Colbert Lauren E. 
Published: November 2019

AbstractObjectiveThe aim of this study was to validate a whole exome sequencing approach to longitudinally characterize the tumor mutational profile of cervical cancer patients undergoing chemoradiation (CRT).Experimental DesignCervical cancer tumor specimens from twenty-seven patients undergoing chemoradiation were collected before and throughout CRT and whole exome sequencing (WES) was performed to characterize individual mutations and alterations in unique genes. WES data were analyzed from cervical cancer patients in The Cancer Genome Atlas (TCGA) as a comparison group.ResultsOver 93% of mutated genes detected at baseline were present in TCGA. Tumor purity from collected swabs correlated with MRI tumor volumes during the course of treatment (R2=0.969). CDK4/CDK6/cyclin D1-related gene mutations involved in the ERK1/2, p16INK4, and p53 pathway and G1/S checkpoint most commonly persisted at the end of CRT.ConclusionThis non-invasive swab technique to serially sample tumor during CRT will allow new discoveries of dynamic tumor mutational profile changes during chemoradiation for mucosal tumors. Mutations that survived or increased during the initial weeks of radiation treatment are potential drivers of radiation resistance including the CDL4/CDK6/cyclin D1-related pathway.Statement of Translational RelevanceThere are no established biomarkers to predict chemoradiation (CRT) response for cervical cancer patients. Serial biopsies cannot be performed due to risks of bleeding and fistula. We used a novel non-invasive swab-based biopsy technique to obtain serial samples from a cohort of twenty-seven patients through the course of treatment, and validated this approach to obtain whole exome sequencing data. We analyzed dynamic tumor mutation profiles during CRT. Results from this study show that mutations in CDK4/CDK6/cyclin D1-related genes increased at the end of CRT, suggesting this pathway as a potential driver of radiation resistance.
The identity and methylation status of the first transcribed nucleotide in eukaryotic mRNA 5’ cap modulates protein expression in living cells
Authors: Sikorski Pawel J. , Warminski Marcin , Kubacka Dorota , Ratajczak Tomasz , Nowis Dominika , Kowalska Joanna , Jemielity Jacek 
Published: November 2019

ABSTRACT7-Methylguanosine 5’-cap on mRNA is necessary for efficient protein expression in vitro and in vivo. Recent studies revealed structural diversity of endogenous mRNA caps, which carry different 5’-terminal nucleotides and additional methylations (2’-O-methylation and m6A). Currently available 5’-capping methods do not address this diversity. We report trinucleotide 5’-cap analogs (m7GpppN(m)pG), which are utilized by RNA polymerase T7 to initiate transcription from templates carrying Φ6.5 promoter and enable production of mRNAs differing in the identity of the first transcribed nucleotide (N = A, m6A, G, C, U) and its methylation status (± 2’-O-methylation). HPLC-purified mRNAs carrying these 5’ caps were used to study protein expression in three mammalian cell lines (3T3-L1, HeLa, and JAWS II). In all cases the highest expression was achieved for mRNAs carrying 5’-terminal A and m6A, whereas the lowest was observed for G and Gm. The 2’-O-methylation of the first transcribed nucleotide (cap 1) significantly increased expression compared to cap 0 only in JAWS II dendritic cells. Further experiments indicated that the mRNA expression characteristic does not correlate with affinity for translation initiation factor 4E or in vitro susceptibility to decapping, but instead depends on mRNA purity and the immune state of the cells.
An improved whole life cycle culture protocol for the hydrozoan genetic model Clytia hemisphaerica
Authors: Lechable Marion , Jan Alexandre , Weissbourd Brandon , Uveira Julie , Gissat Loann , Collet Sophie , Gilletta Laurent , Chevalier Sandra , Leclère Lucas , Peron Sophie , Barreau Carine , Lasbleiz Régis , Houliston Evelyn , Momose Tsuyoshi 
Published: November 2019

AbstractThe jellyfish species Clytia hemisphaerica (Cnidaria, Hydrozoa) has emerged as a new experimental model animal in the last decade. Favorable characters include a fully transparent body suitable for microscopy, daily gamete production and a relatively short life cycle. Furthermore, whole genome sequence assembly and efficient gene editing techniques using CRISPR/Cas9 have opened new possibilities for genetic studies. The quasi-immortal vegetatively-growing polyp colony stage provides a practical means to maintain mutant strains. In the context of developing Clytia as a genetic model, we report here an improved whole life cycle culture method including an aquarium tank system designed for culture of the tiny jellyfish form. We have compared different feeding regimes using Artemia larvae as the food and demonstrate that the stage-dependent feeding control is the key for rapid and reliable medusa and polyp rearing. Metamorphosis of the planula larvae into a polyp colony can be efficiently induced using a new synthetic peptide. The optimized procedures detailed here make it practical to generate new genetically modified Clytia strains and to safely maintain their whole life cycle in the laboratory.
The inhibition of cellular toxicity of amyloid-beta by dissociated transthyretin
Authors: Cao Qin , Anderson Daniel H. , Liang Wilson , Chou Joshua , Saelices Lorena 
Published: November 2019

AbstractThe protective effect of transthyretin (TTR) on cellular toxicity of amyloid-beta (Aβ) has been previously reported. TTR is a tetrameric carrier of thyroxine in blood and cerebrospinal fluid, whose pathogenic aggregation causes systemic amyloidosis. In contrast, many reports have shown that TTR binds amyloid-beta (Aβ), associated with Alzheimer’s disease, alters its aggregation, and inhibits its toxicity bothin vitroandin vivo. In this study, we question whether TTR amyloidogenic ability and its anti-amyloid inhibitory effect are associated. Our results indicate that the dissociation of the TTR tetramer, required for its amyloid pathogenesis, is also necessary to prevent cellular toxicity from Aβ oligomers. These findings suggest that the Aβ binding site of TTR may be hidden in its tetrameric form. Aided by computational docking and peptide screening, we identified a TTR segment that is capable of altering Aβ aggregation and toxicity, mimicking TTR cellular protection. This segment inhibits Aβ oligomer formation and also promotes the formation of non-toxic, non-amyloid, amorphous aggregates which are more sensitive to protease digestion. This segment also inhibits seeding of Aβ catalyzed by Aβ fibrils extracted from the brain of an Alzheimer’s patient. Our results suggest that mimicking the inhibitory effect of TTR with peptide-based therapeutics represents an additional avenue to explore for the treatment of Alzheimer’s disease.Significance statementThe pathological landmarks of Alzheimer’s disease are the formation of amyloid plaques and neurofibrillary tangles. Amyloid plaques contain fibrous structures made of aggregated amyloid-beta (Aβ). In 1982, Shirahama and colleagues observed the presence of transthyretin (TTR) in these plaques. TTR is a tetrameric protein whose aggregation causes transthyretin amyloidosis. However, TTR protects Aβ from aggregating and causing toxicity to neurons. In this study, we show that the dissociation of TTR tetramers is required to inhibit cellular toxicity caused by Aβ. In addition, we identified a minimum segment of TTR that inhibits Aβ aggregation and cellular toxicity by the formation of amorphous aggregates that are sensitive to proteases, similar to the natural effect of TTR found by others in vivo.
AGTR1 is overexpressed in neuroendocrine neoplasms, regulates secretion and may serve as a target for molecular imaging and therapy
Authors: Exner Samantha , Schuldt Claudia , Sachindra Sachindra , Du Jing , Heing-Becker Isabelle , Licha Kai , Wiedenmann Bertram , Grötzinger Carsten 
Published: November 2019

AbstractPeptide receptor targeting has proven to be a pivotal tool for diagnostic imaging and radioligand therapy of neuroendocrine neoplasms (NENs), which frequently express somatostatin receptors (SSTRs) on their cell surface. However, up to 30 % of NEN patients do not benefit from SSTR-based approaches, others develop a resistance. Consequently, alternative cell surface targets need to be identified. In this study, cell-based dynamic mass redistribution and calcium mobilization screening using a 998-compound library identified and confirmed angiotensin II (ATII) as a strong activator of cellular signaling in NEN cells. Expression analyses of the ATII receptor type 1 (AGTR1) revealed an upregulation of both mRNA levels (RT-qPCR) and radioligand binding (autoradiography) in pancreatic (n=42) and small-intestinal (n=71) NEN tissues compared to healthy controls (n=25). The two NEN cell lines BON (pancreas) and H727 (lung) with elevated AGTR1 expression exhibited concentration-dependent calcium mobilization and chromogranin A secretion upon stimulation with ATII, blocked by AGTR1 antagonism and Gαq inhibition. To assess the applicability of AGTR1 for optical in vivo imaging, the receptor ligand saralasin was coupled to the near-infrared dye indotricarbocyanine and tested for its biodistribution in a NMRI Foxn1nu/Foxn1nu mouse model bearing AGTR1-positive BON and negative QGP-1 xenograft tumors. Near-infrared fluorescent imaging showed a significantly higher uptake in BON tumors 3-6 hours after injection. This successful targeting in an NEN model establishes AGTR1 as an interesting target in this tumor entity, paving the way for the development of translational chelator-based probes for diagnostic PET imaging and peptide receptor radioligand therapy.
Host lipid alterations afterMacrophomina phaseolinainfection contribute to charcoal rot disease susceptibility in grain sorghum: Evidence from transcriptomic and lipidomic data
Authors: Bandara Ananda Y. , Weerasooriya Dilooshi K. , Liu Sanzhen , Little Christopher R. 
Published: November 2019

SUMMARYLipids are involved in central metabolic processes and confer basic configuration to cellular and subcellular membranes. Lipids also play a role in determining the outcome of plant-pathogen interactions. Lipid based links that delineate either host resistance or susceptibility against necrotrophic microorganisms are poorly investigated and described.Macrophomina phaseolina(MP) is an important necrotrophic fungus which causes diseases in over 500 plant species including charcoal rot in sorghum.We used RNA sequencing and automated direct infusion electrospray ionization-triple quadrupole mass spectrometry (ESI-MS/MS) to quantitatively profile the transcriptomes and lipidomes of a known charcoal rot resistant (SC599) and susceptible (Tx7000) sorghum genotype in response to MP inoculation.We found that MP is capable of significantly decreasing the phosphatidylserine, phytosterol, and ox-lipid contents in the susceptible genotype while significantly increasing its stigmasterol:sitosterol and monogalactosyldiacylglycerol: digalactosyldiacylglycerol ratios. None of the above was significantly affected in the resistant genotype, except for the significantly increased ox-lipid content.Our transcriptome and functional lipidome findings suggested the lethal impacts of MP inoculation on plastid- and cell- membrane integrity and the lipid based signaling capacity of the charcoal rot susceptible sorghum genotype, Tx7000. Findings also suggested the strong oxidative stress experienced by Tx7000 under MP inoculation and shed light on the potential lipid classes involved in induced charcoal rot disease susceptibility.
Lin28a/let-7Pathway Modulates theHoxCode viaPolycombRegulation during Axial Patterning in Vertebrates
Authors: Sato Tempei , Kataoka Kensuke , Ito Yoshiaki , Yokoyama Shigetoshi , Inui Masafumi , Mori Masaki , Takahashi Satoru , Akita Keiichi , Takada Shuji , Ueno-Kudoh Hiroe , Asahara Hiroshi 
Published: November 2019

AbstractThe body plan along the anteroposterior axis and regional identities are specified by the spatiotemporal expression ofHoxgenes. Multistep controls are required for their unique expression patterns; however, the molecular mechanisms behind the tight control ofHoxgenes are not fully understood. In this study, we demonstrated that theLin28a/let-7reciprocal regulatory pathway is critical for vertebral specification.Lin28a−/−mice exhibited homeotic transformations of vertebrae which were caused by the global dysregulation of posteriorHoxgenes. The accumulation oflet-7-family microRNAs inLin28a−/−mice resulted in the reduction of PRC1 occupancy at theHoxcluster loci by targetingCbx2. Consistently, Lin28a loss in embryonic stem-like cells led to aberrant induction of posteriorHoxgenes, which was rescued by the knockdown oflet-7-family microRNAs. These results suggest thatLin28/let-7pathway is possibly involved in the modulation of the “Hoxcode” viaPolycombregulation during axial patterning in vertebrates.
Paralogs and off-target sequences improve phylogenetic resolution in a densely-sampled study of the breadfruit genus (Artocarpus, Moraceae)
Authors: Gardner Elliot M. , Johnson Matthew G. , Pereira Joan T. , Ahmad Puad Aida Shafreena , Arifiani Deby , Sahromi  , Wickett Norman J. , Zerega Nyree J.C. 
Published: November 2019

AbstractWe present a 517-gene phylogenetic framework for the breadfruit genus Artocarpus (ca. 70 spp., Moraceae), making use of silica-dried leaves from recent fieldwork and herbarium specimens (some up to 106 years old) to achieve 96% taxon sampling. We explore issues relating to assembly, paralogous loci, partitions, and analysis method to reconstruct a phylogeny that is robust to variation in data and available tools. While codon partitioning did not result in any substantial topological differences, the inclusion of flanking non-coding sequence in analyses significantly increased the resolution of gene trees. We also found that increasing the size of datasets increased convergence between analysis methods but did not reduce gene tree conflict. We optimized the HybPiper targeted-enrichment sequence assembly pipeline for short sequences derived from degraded DNA extracted from museum specimens. While the subgenera of Artocarpus were monophyletic, revision is required at finer scales, particularly with respect to widespread species. We expect our results to provide a basis for further studies in Artocarpus and provide guidelines for future analyses of datasets based on target enrichment data, particularly those using sequences from both fresh and museum material, counseling careful attention to the potential of off-target sequences to improve resolution.