bluuebunny/crossref_metadata_2025_split huggingface dataset:
Progression and Resolution of SARS-CoV-2 Infection in Golden Syrian Hamsters
Authors: Mulka Kathleen R. , Beck Sarah E. , Solis Clarisse V. , Johanson Andrew L. , Queen Suzanne E. , McCarron Megan E. , Richardson Morgan R. , Zhou Ruifeng , Marinho Paula , Jedlicka Anne , Guerrero-Martin Selena , Shirk Erin N. , Braxton Alicia , Brockhurst Jacqueline , Creisher Patrick S. , Dhakal Santosh , Brayton Cory F. , Veenhuis Rebecca T. , Metcalf Pate Kelly A. , Karakousis Petros C. , Klein Sabra L. , Jain Sanjay K. , Tarwater Patrick M. , Pekosz Andrew S. , Villano Jason S. , Mankowski Joseph L. ,   for the Johns Hopkins COVID-19 Hamster Study Group
Published: June 2021

AbstractTo catalyze SARS-CoV-2 research including development of novel interventive and preventive strategies, we characterized progression of disease in depth in a robust COVID-19 animal model. In this model, male and female golden Syrian hamsters were inoculated intranasally with SARS-CoV-2 USA-WA1/2020. Groups of inoculated and mock-inoculated uninfected control animals were euthanized at day 2, 4, 7, 14, and 28 days post-inoculation to track multiple clinical, pathology, virology, and immunology outcomes. SARS-CoV-2-inoculated animals consistently lost body weight during the first week of infection, had higher lung weights at terminal timepoints, and developed lung consolidation per histopathology and quantitative image analysis measurements. High levels of infectious virus and viral RNA were reliably present in the respiratory tract at days 2 and 4 post-inoculation, corresponding with widespread necrosis and inflammation. At day 7, when infectious virus was rare, interstitial and alveolar macrophage infiltrates and marked reparative epithelial responses (type II hyperplasia) dominated in the lung. These lesions resolved over time, with only residual epithelial repair evident by day 28 post-inoculation. The use of quantitative approaches to measure cellular and morphologic alterations in the lung provides valuable outcome measures for developing therapeutic and preventive interventions for COVID-19 using the hamster COVID-19 model.
Performance characteristics of next-generation sequencing for antimicrobial resistance gene detection in genomes and metagenomes
Authors: Rooney Ashley M. , Raphenya Amogelang R. , Melano Roberto G. , Seah Christine , Yee Noelle R. , MacFadden Derek R. , McArthur Andrew G. , Schneeberger Pierre H.H. , Coburn Bryan 
Published: June 2021

AbstractShort-read sequencing provides a culture-independent method for the detection of antimicrobial resistance (AMR) genes from single bacterial genomes and metagenomic samples. However, the performance characteristics of these approaches have not been systematically characterized. We compared assembly- and read-based approaches to determine sensitivity, positive predictive value, and sequencing limits of detection required for AMR gene detection in an Escherichia coli ST38 isolate spiked into a synthetic microbial community at varying abundances. Using an assembly-based method the limit of detection was 15X genome coverage. We are confident in AMR gene detection at target relative abundances of 100% to 1%, where a target abundance of 1% would require assembly of approximately 30 million reads to achieve 15X target coverage. Recent studies assessing AMR gene content in metagenomic samples may be inadequately sequenced to achieve high sensitivity. Our study informs future sequencing projects and analytical strategies for genomic and metagenomic AMR gene detection.
Hybrid assembly using ultra-long reads resolves repeats and completes the genome sequence of a laboratory strain of Staphylococcus aureus subsp. aureus RN4220
Authors: Panthee Suresh , Hamamoto Hiroshi , Paudel Atmika , Kaito Chikara , Suzuki Yutaka , Sekimizu Kazuhisa 
Published: June 2021

AbstractStaphylococcus aureus RN4220 has been extensively used by staphylococcal researchers as an intermediate strain for genetic manipulation due to its ability to accept foreign DNA. Despite its wide use in laboratories, its complete genome is not available. In this study, we used the hybrid genome assembly approach using the minION long reads and Illumina short reads to sequence the complete genome of S. aureus RN4220. The comparative analysis of the annotated complete genome showed the presence of 39 genes fragmented in the previous assembly, many of which were located near the repeat regions. Using RNA-Seq reads, we showed that a higher number of reads could be mapped to the complete genome than the draft genome and the gene expression profile obtained using the complete genome also differs from that obtained from the draft genome. Furthermore, by comparative transcriptomic analysis, we showed the correlation between expression levels of staphyloxanthin biosynthetic genes and the production of yellow pigment. This study highlighted the importance of long reads in completing the microbial genomes, especially those possessing repetitive elements.
Laminarin-triggered defence responses are geographically dependent for natural populations ofSolanum chilense
Authors: Kahlon Parvinderdeep S. , Förner Andrea , Muser Michael , Oubounyt Mhaned , Gigl Michael , Hammerl Richard , Baumbach Jan , Hückelhoven Ralph , Dawid Corinna , Stam Remco 
Published: June 2021

AbstractNatural plant populations are polymorphic and show intraspecific variation in resistance properties against pathogens. The activation of the underlying defence responses can depend on variation in perception of pathogen-associated molecular patterns or elicitors. To dissect such variation, we evaluated the responses induced by laminarin, (a glucan, representing an elicitor from oomycetes) in the wild tomato speciesSolanum chilenseand correlated this to observed infection frequencies ofPhytophthora infestans.We measured reactive oxygen species burst and levels of diverse phytohormones upon elicitation in 83 plants originating from nine populations. We found high diversity in basal and elicitor-induced levels of each component. Further we generated linear models to explain the observed infection frequency ofP. infestans. The effect of individual components differed dependent on the geographical origin of the plants. We found that the resistance in the southern coastal region, but not in the other regions is directly correlated to ethylene responses and confirmed this positive correlation using ethylene inhibition assays.Our findings reveal high diversity in the strength of defence responses within a species and the involvement of different components with a quantitatively different contribution of individual components to resistance in geographically separated populations of a wild plant species.HighlightLarge-scale screenings reveal geographically distinct intraspecific differences in the dominant physiological pathogen defence responses upon glucan elicitor treatment in a wild tomato species.
IFT20 is critical for early chondrogenesis during endochondral ossification
Authors: Yamaguchi Hiroyuki , Kitami Megumi , Uchima Koecklin Karin H. , He Li , Wang Jianbo , Perrien Daniel S. , Lagor William R. , Komatsu Yoshihiro 
Published: June 2021

AbstractCiliogenic components, such as the family of intraflagellar transport (IFT) proteins, are recognized to play key roles in endochondral ossification, a critical process to form most bones. However, it remains unclear how each IFT protein performs its unique function to regulate endochondral ossification. Here, we show that intraflagellar transport 20 (IFT20) is required for early chondrogenesis. Utilizing three osteo-chondrocyte lineage-specific Cre mice (Prx1-Cre, Col2-Cre and Aggrecan-CreERT2), we deleted Ift20 to examine its function. While chondrocyte-specific Ift20 deletion with Col2-Cre or Aggrecan-CreERT2 drivers did not cause overt skeletal defects, mesoderm-specific Ift20 deletion using Prx1-Cre (Ift20:Prx1-Cre) resulted in shortened limb outgrowth. Although primary cilia were not formed in Ift20:Prx1-Cre mice, ciliary Hedgehog signaling was only moderately affected. Interestingly, loss of Ift20 lead to upregulation of Fgf18 expression resulting in ERK1/2 activation and sustained Sox9 expression, thus preventing endochondral ossification. Inhibition of enhanced phospho-ERK1/2 activation partially rescued defective chondrogenesis in Ift20 mutant cells, supporting an important role for FGF signaling. Our findings demonstrate a novel mechanism of IFT20 in early chondrogenesis during endochondral ossification.
Developmental onset of a cerebellar-dependent forward model of movement in motor thalamus
Authors: Dooley James C. , Sokoloff Greta , Blumberg Mark S. 
Published: June 2021

SummaryTo execute complex behavior with temporal precision, adult animals use internal models to predict the sensory consequences of self-generated movement. Here, taking advantage of the unique kinematic features of twitches—the brief, discrete movements of active sleep—we captured the developmental onset of a cerebellar-dependent internal model. Using rats at postnatal days (P) 12, P16, and P20, we compared neural activity in two thalamic structures: the ventral posterior (VP) and ventral lateral (VL) nuclei, both of which receive somatosensory input but only the latter of which receives cerebellar input. At all ages, twitch-related activity in VP lagged behind movement, consistent with sensory processing; similar activity was observed in VL through P16. At P20, however, VL activity precisely mimicked the twitch itself, a pattern of activity that depended on cerebellar input. Altogether, these findings implicate twitches in the development and refinement of internal models of movement.
Revisiting the STRmix™likelihood ratio probability interval coverage considering multiple factors
Authors: Bright Jo-Anne , Lee Shan-I , Buckleton John , Taylor Duncan 
Published: June 2021

AbstractIn previously reported work a method for applying a lower bound to the variation induced by the Monte Carlo effect was trialled. This is implemented in the widely used probabilistic genotyping system, STRmix™. The approach did not give the desired 99% coverage.However, the method for assigning the lower bound to the MCMC variability is only one of a number of layers of conservativism applied in a typical application. We tested all but one of these sources of variability collectively and term the result the near global coverage. The near global coverage for all tested samples was greater than 99.5% for inclusionary averageLRs of known donors. This suggests that when included in the probability interval method the other layers of conservativism are more than adequate to compensate for the intermittent underperformance of the MCMC variability component. Running for extended MCMC accepts was also shown to result in improved precision.
DatumKB: A Database of Biological Experimental Results
Authors: Knapp Merrill , McCarthy Tim , Talcott Carolyn 
Published: June 2021

1.ABSTRACTDatumKB is a freely accessible database of experimental results involving the function and regulation of human proteins in cultured cells. The results are manually curated from biological research literature using a shorthand language and stored as datums. Datums were originally designed to be used as evidence for rules in a Pathway Logic model of intracellular signal transduction (STM8, http://pl.csl.sri.com/online.html) (1). They are independent units that can be understood by biologists, traced back to their source, and have enough structure to be interrogated computationally. The information is expressed using a controlled vocabulary with links to well known databases such as HUGO Gene Nomenclature Committee (HGNC), UniProt, PubChem, and Cellosaurus. DatumKB can be searched using a query interface and the results can be downloaded in the original datum format, a simplified text format, or a JSON file. Links to detailed documentation of datum structure and a tutorial for the search engine are provided.Database URLhttps://datum.csl.sri.com
The WZA: A window-based method for characterizing genotype-environment association
Authors: Booker Tom R. , Yeaman Sam , Whitlock Michael C. 
Published: June 2021

AbstractGenotype environment association (GEA) studies have the potential to elucidate the genetic basis of local adaptation in natural populations. Specifically, GEA approaches look for a correlation between allele frequencies and putatively selective features of the environment. Genetic markers with extreme evidence of correlation with the environment are presumed to be tagging the location of alleles that contribute to local adaptation. In this study, we propose a new method for GEA studies called the weighted-Z analysis (WZA) that combines information from closely linked sites into analysis windows in a way that was inspired by methods for calculating FST. We analyze simulations modelling local adaptation to heterogeneous environments either using a GEA method that controls for population structure or an uncorrected approach. In the majority of cases we tested, the WZA either outperformed single-SNP based approaches or performed similarly. The WZA outperformed individual SNP approaches when the measured environment is not perfectly correlated with the true selection pressure or when a small number of individuals or demes was sampled. We apply the WZA to previously published data from lodgepole pine and identified candidate loci that were not found in the original study.
Single Molecule Studies and Kinase Activity Measurements Reveal Regulatory Interactions between the Master Kinases Phosphoinositide-Dependent-Kinase-1 (PDK1), Protein Kinase B (AKT1/PKB) and Protein Kinase C (PKCα)
Authors: Gordon Moshe T. , Ziemba Brian P. , Falke Joseph J. 
Published: June 2021

ABSTRACTLeukocyte migration is controlled by a leading edge chemosensory pathway that generates the regulatory lipid PIP3, a growth signal, thereby driving leading edge expansion up attractant gradients toward sites of infection, inflammation, or tissue damage. PIP3 also serves as an important growth signal in growing cells and oncogenesis. The kinases PDK1, AKT1/PKB and PKCα are key components of a plasma membrane-based PIP3 and Ca2+ signaling circuit that regulates these processes. PDK1 and AKT1 are recruited to the membrane by PIP3, while PKCα is recruited to the membrane by Ca2+. All three of these master kinases phosphoregulate an array of protein targets. For example, PDK1 activates AKT1, PKCα and other AGC kinases by phosphorylation at key sites. PDK1 is known to form PDK1:AKT1 and PDK1:PKCα heterodimers stabilized by a PIF interaction between the PDK1 PIF pocket and the PIF motif of the AGC binding partner. Here we present the first, to our knowledge, single molecule studies of full length PDK1 and AKT1 on target membrane surfaces, as well as their interaction with full length PKCα. The findings show that membrane-bound PDK1:AKT1 and PDK1:PKCα heterodimers form under physiological conditions, and are stabilized by PIF interaction. PKCα exhibits 8-fold higher PDK1 affinity than AKT1, thus PKCα competitively displaces AKT1 from PDK1:AKT1 heterodimers. Ensemble activity measurements under matched conditions reveal that PDK1 activates AKT1 via a cis mechanism by phosphorylating an AKT1 molecule in the same PDK1:AKT1 heterodimer, while PKCα acts as a competitive inhibitor of this phosphoactivation reaction by displacing AKT1 from PDK1. Overall, the findings provide new insights into molecular and regulatory interactions of the three master kinases on their target membrane, and suggest that the recently described tumor suppressor activity of PKC may arise from its ability to downregulate PDK1-AKT1 phosphoactivation in the PIP3-PDK1-AKT1-mTOR pathway linked to cell growth and oncogenesis.STATEMENT OF SIGNIFICANCEThis work investigates three master kinases that play central roles in guiding white blood cell migration to sites of infection, inflammation or tissue damage. More broadly, the same kinases help regulate production of a cell growth signal, and may trigger cancer when dysregulated. Using powerful single molecule methods, the work detects and analyzes the interactions between the three purified kinases on their target membrane surface. The findings reveal functionally important differences between pairwise binding affinities of different binding partners. Additional studies reveal that the highest affinity kinase can disrupt and inhibit the activated complex formed by association of the other two kinases. Such inhibition is proposed to help prevent cancer by limiting growth signal production by the activated complex.
An acetyl-click screening platform identifies a small molecule inhibitor of Histone Acetyltransferase 1 (HAT1) with anti-tumor activity
Authors: Gruber Joshua J. , Rangarajan Amithvikram , Chou Tristan , Geller Benjamin S. , Banuelos Selene , Greenhouse Robert , Snyder Michael P. , Lipchik Andrew M. 
Published: June 2021

ABSTRACTHAT1 is a central regulator of chromatin synthesis that acetylates nascent histone H3:H4 tetramers in the cytoplasm. It may have a role in cancer metabolism by linking cytoplasmic production of acetyl-CoA to nuclear acetyl flux. This is because the HAT1 di-acetylation mark is not propagated in chromatin and instead is de-acetylated after nascent histone insertion into chromatin. Thus, HAT1 likely provides a nuclear source of free acetate that may be recycled to acetyl-CoA for nuclear acetylation reactions. Correspondingly, suppression of HAT1 protein expression impairs tumor growth. To ascertain whether targeting HAT1 is a viable anti-cancer treatment strategy we sought to identify small molecule inhibitors of HAT1. We developed a high-throughput HAT1 acetyl-click assay to facilitate drug discovery and enzymology. Screening of small molecules computationally predicted to bind the active site led to the discovery of multiple riboflavin analogs that inhibited HAT1 enzymatic activity by competing with acetyl-CoA binding. These hits were refined by synthesis and testing over 70 analogs, which yielded structure-activity relationships. The isoalloxazine core was required for enzymatic inhibition, whereas modifications of the ribityl sidechain improved enzymatic potency and cellular growth suppression. These efforts resulted in a lead compound (JG-2016) that suppressed growth of human cancer cells linesin vitroand impaired tumor growthin vivo. This is the first report of a small molecule inhibitor of the HAT1 enzyme complex and represents a step towards targeting this pathway for cancer therapy.
Work-related practices of local managers of live music events in Ostwestfalen-Lippe (OWL) and their impact on cultural participation
Authors: Flath Beate , Momen Pour Tafreshi Maryam 
Published: June 2021

PurposeThe purpose of this article is to illuminate the relations of work-related practices of local managers of live music events in Ostwestfalen-Lippe (OWL) and barriers and needs of vulnerable customers (VC) in order to explore possibilities to increase cultural participation of VC.Design/methodology/approachThis article explores work-related practices of managers of live music events in OWL and asks if and to what extent these practices have an influence on the cultural participation of “vulnerable customers” (VC). It combines the findings of two studies: a) an explorative investigation on the work-related self-conceptions of managers of live music events in OWL (Study 1), and b) a sub-project on cultural participation of VC, which is part of the research project “kulturPreis. Increasing cultural participation through innovative and economically sustainable pricing concepts”, funded by the German Federal Ministry of Education and Research (Study 2).FindingsIt can be stated that there is an imbalance of knowledge: while VC tend to have a clear understanding of which barriers are the responsibility of managers of live music events, managers tend to lack knowledge regarding the needs of VC, and regarding the interrelationships between financial and social barriers facing them. Whether this knowledge and understanding can be developed in the future depends on the possibilities of exchanges between managers of live music events, cultural institutions, welfare organisations, political institutions and not least VC.Originality/valueBased on these studies, this article combines different approaches by linking work-related practices of managers of live music events with cultural participation of VC.
The information content of managerial insider trading: evidence from analyst forecasts
Authors: Esqueda Omar , Ngo Thanh , Wang Daphne 
Published: June 2021

PurposeThis paper examines the effect of managerial insider trading on analyst forecast accuracy, dispersion and bias. Specifically, the authors test whether insider-trading information is positively associated with the precision of earnings forecasts. In addition, this relationship between Regulation Fair Disclosure (FD) and the Galleon insider trading case is examined.Design/methodology/approachPooled ordinary least squares (Pooled OLS) rregressions with year-fixed effects, firm-fixed effects, and firm-level clustered standard errors are used. Our proxies for forecast precision are regressed on alternative measures of insider trading activities and a vector of control variables.FindingsInsider-trading information is positively associated with the precision of earnings forecasts. Analysts provide better forecast accuracy, less forecast dispersion and lower forecast bias among firms with insider trading in the six months leading to the forecast issues. In addition, bullish (bearish) insider trades are associated with increased (decreased) forecast bias. Insider trading information complements analysts' independent opinion and increases the precision of their forecast.Practical implicationsRegulators may pursue rules that promote the rapid disclosure of managerial insider trades, particularly given the increasing availability of Internet tools. Securities regulators may attempt to increase transparency and enhance the reporting procedures of corporate insiders, for example, using Internet sources with direct release to the public to ensure more timely information dissemination.Originality/valueThe authors document a positive association between earnings forecast precision and managerial insider trading up to six months prior to the forecast issue. This relationship is stronger after the Securities and Exchange Commission (SEC) prohibited the selective disclosure of material nonpublic information through Regulation FD. In addition, the association between insider trading and forecast accuracy has weakened after the Galleon insider trading case.