bluuebunny/crossref_metadata_2025_split huggingface dataset:
A model of Zebrafish Avatar for co-clinical trials
Authors: Usai Alice , Franco Gregorio Di , Colucci Patrizia , Pollina Luca Emanuele , Vasile Enrico , Funel Niccola , Palmeri Matteo , Dente Luciana , Falcone Alfredo , Morelli Luca , Raffa Vittoria 
Published: September 2019

ABSTRACTAnimal ‘‘Avatars’’ and co-clinical trials represent an emerging concept for implementing schemes of personalized medicine in oncology. In a co-clinical trial, the cancer cells of the patient tumor are xenotransplanted in the animal Avatar for drug efficacy studies and data collected in the animal trial are used to plan the best drug treatment in the patient trial. Recently, zebrafish has been proposed for implementing Avatar models but the lack of a general criterion for chemotherapy dose conversion from humans to fishes represents a limitation for conducting co-clinical trials.Here, we validate a simple, reliant and cost-effective Avatar model based on the use of zebrafish larvae; by crossing data from safety and efficacy studies, we found a basic formula for the estimation of the dose to be used for running co-clinical trials and we validate it in a clinical study enrolling 24 adult patients with solid cancers (XenoZ, NCT03668418).
Loss of Bacterial Cell Pole Stabilization inCaulobacter crescentusSensitizes to Outer Membrane Stress and Peptidoglycan-Directed Antibiotics
Authors: Vallet Simon-Ulysse , Hansen Lykke Haastrup , Bistrup Freja Cecillie , Chapalay Julien Bortoli , Chambon Marc , Turcatti Gerardo , Viollier Patrick H. , Kirkpatrick Clare L. 
Published: September 2019

AbstractRod-shaped bacteria frequently localise proteins to one or both cell poles in order to regulate processes such as chromosome replication or polar organelle development. However, the role of such polar factors in responses to extracellular stimuli has been generally unexplored. We employed chemical-genetic screening to probe the interaction between one such factor fromCaulobacter crescentus, TipN, and extracellular stress and found that TipN is required for normal tolerance of cell envelope-directed antibiotics, including vancomycin that does not normally inhibit growth of Gram-negative bacteria. Forward genetic screening for suppressors of vancomycin sensitivity in the absence of TipN revealed the TonB-dependent receptor ChvT as the mediator of vancomycin tolerance. Loss of ChvT improved resistance to vancomycin and cefixime in the otherwise sensitive ΔtipNstrain. The activity of the two-component system regulating ChvT (ChvIG) was increased in ΔtipNcells relative to wild type under some, but not all, cell wall stress conditions that this strain was sensitised to, in particular cefixime and detergent exposure. Together, these results indicate that the ChvIG two-component system has been co-opted as a sensor of cell wall stress and that TipN can influence cell envelope stability and ChvIG-mediated signaling in addition to its roles in intracellular development.Author summaryMaintenance of an intact cell envelope is essential for free-living bacteria to survive harsh conditions they may encounter in their environment. In the case of rod-shaped bacteria, the poles of the cell are potential weak points in the cell envelope due to the high curvature of the layers and the need to break and re-form parts of the cell envelope at the division plane in order to form new poles as the cells replicate and divide. We have found that TipN, a factor required for correct division and cell pole development in the rod-shaped bacterium,Caulobacter crescentus, is also needed for maintaining normal levels of resistance to cell wall-targeting antibiotics such as vancomycin and cefixime, which interfere with peptidoglycan synthesis. We also identified an outer membrane receptor, ChvT, that was responsible for allowing vancomycin access to the cells and found that the two-component system that negatively regulates ChvT production was activated by various kinds of cell wall stress. Presence or absence of TipN influenced how active this system was in the presence of cefixime or of the membrane-disrupting detergent sodium deoxycholate. Since TipN is normally located at the poles of the cell and at the division plane just before cells complete division, our results suggest that it is involved in stabilisation of these weak points of the cell envelope as well as its other roles inside the cell.
Spleen Transcriptome Analysis of C57BL/6 Mouse in Response to Hot Water Extract from Spent Mushroom Substrate ofGanoderma lucidumand Cyclophosphamide
Authors: Wang Zehui , Wang Annan , Li Jing , Liao Zhen , Sun Lianyue , Lin Zhanxi , Liu Yanling 
Published: September 2019

AbstractPreviously, we have indicated that Hot Water Extract (HWE) from Spent Mushroom Substrate (SMS) ofGanoderma lucidumenhanced immune function of normal mice, and improved antioxidant activity and enhanced immune function of immunosuppression mice induced by cyclophosphamide (Cy). Here we performed the high throughput RNA sequencing strategy using Illumina HiSeq™ 2000 to characterize the spleen transcriptome from normal (CK1), HWE-treated (CK2), Cy-treated (CY) and both high dose HWE and Cy-treated mice (CH). From the RNA Sequencing, total mapped reads of map to Gene in CK1, CK2, CY and CH was 54 759 942, 54 678 926, 44 728 132 and 54 006 596, respectively. And gene expression was significantly different among CK1 and CK2, CY and CH. Compared with CK1, the gene expression ofUgt1a6bwas down-regulated in CK2 after HWE treated. In addition, compared with CY, multiple tumor suppressor or tumorigenesis genes were down-regulated, such asCdkn1a,Cdkn1b,Mapk10,Vash1, andTncand other genes in CK2 and CH. Taken together, our study highlighted the spleen transcriptome profiles of C57BL/6 mouse in response to HWE from SMS ofG. lucidumand Cy, and indicated that HWE can improve the immune function of the mouse and accelerated the recovery of immunosuppression in Cy-treated mice.
3D Genome Structure Variation Across Cell Types Captured by Integrating Multi-omics
Authors: Xu Yang , Shen Tongye , McCord Rachel Patton 
Published: September 2019

AbstractBackground3D genome structure contributes to the establishment or maintenance of cell identity in part by organizing genes into spatial active or inactive compartments. Less is known about how compartment switching occurs across different cell types. Rather than analyze individual A/B compartment switches between pairs of cell types, here, we seek to identify coordinated changes in groups of compartment-scale interactions across a spectrum of cell types.ResultsTo characterize the impact of genome folding on cell identity, we integrated 35 Hi-C datasets with 125 DNase-seq, 244 RNA-seq, and 893 ChIP-seq datasets. We first find physical associations with the nuclear lamina inform the most dramatic changes in chromosome structure across cell types. By examining variations in chromosome structure, transcription, and chromatin accessibility, we further observe that certain sets of correlated chromosome structure contacts also co-vary in transcription and chromatin accessibility. Analyzing ChIP-seq signals, we find that sets of chromosome contacts that form and break in sync tend to share active or suppressive histone marks. Finally, we observe that similar principles appear to govern chromosome structure fluctuations across single cells as were found across cell types.ConclusionOur results suggest that cells adapt their chromosome structures, guided by variable associations with the lamina and histone marks, to allocate up-regulatory or down-regulatory resources to certain regions and achieve transcription and chromatin accessibility variation. Our study shows E-PCA can identify the major variable interaction sets within populations of single cells, across broad categories of normal cell types, and between cancer and non-cancerous cell types.
Structure and mechanism of a Type III CRISPR defence DNA nuclease activated by cyclic oligoadenylate
Authors: McMahon Stephen A , Zhu Wenlong , Graham Shirley , Rambo Robert , White Malcolm F , Gloster Tracey M 
Published: September 2019

AbstractThe CRISPR system provides adaptive immunity against mobile genetic elements in prokaryotes. On binding invading RNA species, Type III CRISPR systems generate cyclic oligoadenylate (cOA) molecules which act as a second messenger, signalling infection and potentiating a powerful immune response by activating a range of downstream effector proteins that can lead to viral clearance, cell dormancy or death. Only one type of effector enzyme has been studied – the Csm6/Csx1 ribonuclease domain, and the mechanism of cOA activation is not understood at a molecular level. Here we describe the structure and mechanism of a novel cOA-activated CRISPR defence DNA endonuclease, Can1 (“CRISPR ancillary nuclease 1”). Can1 has a unique monomeric structure with two CRISPR associated Rossman fold (CARF) CARF domains and two DNA nuclease-like domains. The crystal structure of the enzyme has been captured in the activated state, with a cyclic tetra-adenylate (cA4) molecule bound at the core of the protein. cA4 binding reorganises the structure to license a metal-dependent DNA nuclease activity specific for nicking of supercoiled DNA. DNA nicking by Can1 is predicted to slow down viral replication kinetics by leading to the collapse of DNA replication forks.
A quiescent state following mild sensory arousal inCaenorhabditis elegansis potentiated by stress
Authors: McClanahan Patrick D. , Dubuque Jessica M. , Kontogiorgos-Heintz Daphne , Habermeyer Ben F. , Xu Joyce H. , Ma Anthony M. , Raizen David M. , Fang-Yen Christopher 
Published: September 2019

AbstractAn animal’s behavioral and physiological response to stressors includes changes to its responses to stimuli. How such changes occur is not well understood. Here we describe aCaenorhabditis elegansquiescent behavior, post-response quiescence (PRQ), which is modulated by theC. elegansresponse to cellular stressors. Following an aversive mechanical or blue light stimulus, worms respond first by briefly moving, and then become more quiescent for a period lasting tens of seconds. PRQ occurs at low frequency in unstressed animals, but is more frequent in animals that have experienced cellular stress due to ultraviolet light exposure as well as in animals following overexpression of epidermal growth factor (EGF). PRQ requires the function of the carboxypeptidase EGL-21 and the calcium-activated protein for secretion (CAPS) UNC-31, suggesting it has a neuropeptidergic mechanism. Although PRQ requires the sleep-promoting neurons RIS and ALA, it is not accompanied by decreased arousability, and does not appear to be homeostatically regulated, suggesting that it is not a sleep state. PRQ represents a simple, tractable model for studying how neuromodulatory states like stress alter behavioral responses to stimuli.
Simultaneous and precise generation of Zebra3 and Wsl5 mutations in rice using CRISPR/Cas9-mediated adenine base editors
Authors: Molla Kutubuddin A. , Shih Justin , Yang Yinong 
Published: September 2019

AbstractThe CRISPR/Cas9-mediated base editing technology can efficiently generate point mutations in the genome without introducing double-strand break (DSB) or supplying a DNA donor template for homology-dependent repair (HDR). In this study, adenine base editors (ABEs) were used for rapid generation of precise point mutations in two distinct genes, OsWsl5, and OsZebra3 (Z3), in rice protoplasts and regenerated plants. The precisely engineered point mutations were stably inherited to subsequent generations. These single nucleotide alterations resulted in single amino acid changes and associated wsl5 and z3 phenotypes as evidenced by white stripe leaf and light green/dark green leaf pattern, respectively. Through selfing and segregation, transgene-free, base edited wsl5 and z3 mutants were readily obtained in a short period of time. We noticed a novel mutation (V540A) in Z3 locus could mimic the phenotype of Z3 mutation (S542P). Furthermore, we observed unexpected non-A/G or T/C mutations in the ABE editing window in a few of the edited plants. The ABE vectors and the method from in this study could be used to simultaneously generate point mutations in multiple genes in a single transformation and serve as a useful base editing tool for crop improvement as well as basic studies in plant biology.HighlightsAdenine base editors were adapted for plant base editing that can generate precise and heritable point mutations in rice genome without indel formation. The base editing approach allows rapid generation of transgene-free rice mutants with expected phenotypic changes.
Genotyping-by-sequencing illuminates high levels of divergence among sympatric forms of coregonines in the Laurentian Great Lakes
Authors: Ackiss Amanda S. , Larson Wesley A. , Stott Wendylee 
Published: September 2019

AbstractEffective resource management depends on our ability to partition diversity into biologically meaningful units. Recent evolutionary divergence, however, can often lead to ambiguity in morphological and genetic differentiation, complicating the delineation of valid conservation units. Such is the case with the “coregonine problem,” where recent post-glacial radiations of coregonines into lacustrine habitats resulted in the evolution of numerous species flocks, often with ambiguous taxonomy. The application of genomics methods is beginning to shed light on this problem and the evolutionary mechanisms underlying divergence in these ecologically and economically important fishes. Here, we used restriction site-associated DNA (RAD) sequencing to examine genetic diversity and differentiation among sympatric species in theCoregonus artedicomplex in the Apostle Islands of Lake Superior, the largest lake in the Laurentian Great Lakes. Using 29,068 SNPs, we were not only able to clearly distinguish the three most common forms for the first time, but putative hybrids and potentially mis-identified specimens as well. Assignment rates to form with our RAD data were 93-100% with the only mis-assignments arising from putative F1 hybrids, an improvement from 62-77% using microsatellites. Estimates of pairwise differentiation (FST: 0.045-0.056) were large given the detection of hybrids, suggesting that hybridization among forms may not be successful beyond the F1 state. We also used a newly builtC. artedilinkage map to look for islands of adaptive genetic divergence among forms and found widespread differentiation across the genome, a pattern indicative of long-term drift, suggesting that these forms have been reproductively isolated for a substantial amount of time. The results of this study provide valuable information that can be applied to develop well-informed management strategies and stress the importance of re-evaluating conservation units with genomic tools to ensure they accurately reflect species diversity.
Harmonization of large multi-site imaging datasets: Application to 10,232 MRIs for the analysis of imaging patterns of structural brain change throughout the lifespan
Authors: Pomponio Raymond , Erus Guray , Habes Mohamad , Doshi Jimit , Srinivasan Dhivya , Mamourian Elizabeth , Bashyam Vishnu , Fan Yong , Launer Lenore J. , Masters Colin L. , Maruff Paul , Zhuo Chuanjun , Nasrallah Ilya M. , Völzke Henry , Johnson Sterling C. , Fripp Jurgen , Koutsouleris Nikolaos , Satterthwaite Theodore D. , Wolf Daniel H. , Gur Raquel , Gur Ruben , Morris John , Albert Marilyn S. , Grabe Hans J. , Resnick Susan M. , Bryan R. Nick , Wolk David A. , Shinohara Russell T. , Shou Haochang , Davatzikos Christos 
Published: September 2019

AbstractAs medical imaging enters its information era and presents rapidly increasing needs for big data analytics, robust pooling and harmonization of imaging data across diverse cohorts with varying acquisition protocols have become critical. We describe a comprehensive effort that merges and harmonizes a large-scale dataset of 10,232 structural brain MRI scans from participants without known neuropsychiatric disorder from 18 different studies that represent geographic diversity. We use this dataset and multi-atlas-based image processing methods to obtain a hierarchical partition of the brain from larger anatomical regions to individual cortical and deep structures and derive normative age trends of brain structure through the lifespan (3 to 96 years old). Critically, we present and validate a methodology for harmonizing this pooled dataset in the presence of nonlinear age trends. We provide a web-based visualization interface to generate and present the resulting age trends, enabling future studies of brain structure to compare their data with this normative reference of brain development and aging, and to examine deviations from normative ranges, potentially related to disease.
Cytosolic Ca2+modulates Golgi structure through PKC-mediated GRASP55 phosphorylation
Authors: Ireland Stephen C. , Ramnarayanan Saiprasad , Fu Mingzhou , Zhang Xiaoyan , Emebo Dabel , Wang Yanzhuang 
Published: September 2019

ABSTRACTIt has been well documented that the endoplasmic reticulum (ER) responds to cellular stresses through the unfolded protein response (UPR), but it is unknown how the Golgi responds to similar stresses. In this study, we treated HeLa cells with ER stress inducers, thapsigargin (TG), tunicamycin (Tu) and Dithiothreitol (DTT), and found that only TG treatment caused Golgi fragmentation. TG induced Golgi fragmentation at a low dose and short time when UPR was undetectable, demonstrating that Golgi fragmentation occurs independently of ER stress. Further experiments demonstrated that TG induces Golgi fragmentation through elevated intracellular Ca2+and protein kinase Cα (PKCα) activity, which phosphorylates the Golgi stacking protein GRASP55. Significantly, activation of PKCα with other activating or inflammatory agents, including Phorbol 12-myristate 13-acetate (PMA) and histamine, modulates the Golgi structure in a similar fashion. Hence, our study revealed a novel mechanism through which increased cytosolic Ca2+modulates Golgi structure and function.
Quantitative Genomic Dissection of Soybean Yield Components
Authors: Xavier Alencar , Rainey Katy M 
Published: September 2019

AbstractSoybean is a crop of major economic importance with low rates of genetic gains for grain yield compared to other field crops. A deeper understanding of the genetic architecture of yield components may enable better ways to tackle the breeding challenges. Key yield components include the total number of pods, nodes and the ratio pods per node. We evaluated the SoyNAM population, containing approximately 5600 lines from 40 biparental families that share a common parent, in 6 environments distributed across 3 years. The study indicates that the yield components under evaluation have low heritability, a reasonable amount of epistatic control, and partially oligogenic architecture: 18 quantitative trait loci were identified across the three yield components using multi-approach signal detection. Genetic correlation between yield and yield components was highly variable from family-to-family, ranging from −0.2 to 0.5. The genotype-by-environment correlation of yield components ranged from −0.1 to 0.4 within families. The number of pods can be utilized for indirect selection of yield. The selection of soybean for enhanced yield components can be successfully performed via genomic prediction, but the challenging data collections necessary to recalibrate models over time makes the introgression of QTLs a potentially more feasible breeding strategy. The genomic prediction of yield components was relatively accurate across families, but less accurate predictions were obtained from within-family predictions and predicting families not observed included in the calibration set.
The motives for Japanese foreign direct investment in the Southeastern United States
Authors: Magnier-Watanabe Remy , Hoadley James 
Published: September 2019

Purpose
Whereas the USA is still the largest investment destination for Japanese companies, Japan also accounts as the second largest source of investment in the country. The purpose of this paper is to, empirically, examine the detailed motives of Japanese affiliates when investing in the Southeastern USA, adding to previous research at the national level.

Design/methodology/approach
This paper uses a qualitative approach based on the interviews of long-term Japanese investors in the manufacturing and wholesale trade industries in the Southeastern USA and applies text analysis to identify their motives.

Findings
The results show that Japanese firms engage in market- and efficiency-seeking foreign direct investment (FDI), and still apply a classic sequence of gradual and incremental market commitments. Market size and growth rate, reducing transaction or transportation costs, and integration within local value chains are the most important to them, whereas competition, creating an export base, lowering tax and accessing skilled labor are of little concern.

Practical implications
The goal of Japanese FDI in the USA is no longer to bypass tariffs but is still part of a complex industrial network of relations which drives further investment. This result can inform policy makers at the state level about the factors that can drive additional foreign investment, such as the establishment of industrial clusters.

Originality/value
This study offers current insights into the motives of Japanese FDI in two industries.
Corporate voluntary carbon disclosure strategy and carbon performance in the USA
Authors: Datt Ragini Rina , Luo Le , Tang Qingliang 
Published: September 2019

PurposeThis study aims to examine whether good carbon performers disclose more carbon information overall than poor performers, and if yes, how firms select different types of carbon information to signal their genuine superior carbon performance.Design/methodology/approachThe level of disclosure is measured based on content analysis of Carbon Disclosure Project (CDP) reports. The study sample consists of 487 US companies that voluntarily participated in the CDP survey from 2011 to 2012. The authors use thet-test and multiple regression models for analyses.FindingsThe results consistently indicate that firms with better carbon performance disclose a greater amount of overall carbon information, supporting the signalling theory. In addition, in contrast to previous studies that merely consider the overall disclosure level, the authors also investigate disclosure of each major aspect of carbon activities. The results show that good carbon performers disclose more key carbon items, such as goods and services that avoid greenhouse gas (GHG) emissions, external verification and carbon accounting, to signal their true type.Research limitations/implicationsThis study has some limitations. The authors rely on CDP reports for analysis and focus on the largest companies in the USA. Caution should be exercised when generalising the results to other countries, smaller firms or voluntary carbon information disclosed in other communications channels.Practical implicationsBecause carbon disclosure has already been moving from a voluntary to mandatory requirement in many jurisdictions, the format and content of CDP reports might be considered for a formal standalone GHG statement. Based on the results, the authors believe that there should be industry-specific disclosure guidelines, and more disclosure should be made at the project level.Originality/valueIn the context of climate change, this study provides support for the signalling theory by utilising the relationship between voluntary carbon disclosure and performance. The study also provides empirical evidence on how companies may use different types of carbon information to signal their underlying carbon performance.