bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vitro and in vivo co-infection and super-infection dynamics of Mayaro and Zika viruses in mosquito and vertebrate backgrounds
Authors: Brustolin Marco , Pujhari Sujit , Henderson Cory A. , Kim Donghun , Rasgon Jason L. 
Published: June 2021

AbstractFactors related to increasing globalization and climate change have contributed to the simultaneous increase and spread of arboviral diseases. Co-circulation of multiple arboviruses in the same geographic regions provides impetus to study the impacts of multiple arbovirus infections in a single vector. In the present study we describe co-infection and super-infection with Mayaro virus (Family Togaviridae, genus Alphavirus) and Zika virus (family Flaviviridae, genus Flavivirus) in vertebrate cells, mosquito cells, and Aedes aegypti mosquitoes to understand the interaction dynamics of these pathogens and effects on viral infection, dissemination and transmission. In Aedes aegypti mosquitoes, co-infection has a negative impact on infection and dissemination rates for Zika virus, but not Mayaro virus, when compared to single infection scenarios, and super-infection of Mayaro virus with a previous Zika virus infection resulted in increased Mayaro virus infection rates. We found that co-infection and super-infection negatively affected Zika viral replication in vertebrate cells (Vero and Huh), resulting in the complete blockage of Zika virus replication in some scenarios. At the cellular level, we demonstrate that single vertebrate and insect cells can be simultaneously infected with Zika and Mayaro viruses. This study highlights the dynamics of arboviral co- and super-infections and emphasizes the importance of considering these dynamics during risk assessment in epidemic areas.
Discovery and visualization of uncharacterized drug-protein adducts using mass spectrometry
Authors: Riffle Michael , Hoopmann Michael R. , Jaschob Daniel , Zhong Guo , Moritz Robert L. , MacCoss Michael J. , Davis Trisha N. , Isoherranen Nina , Zelter Alex 
Published: June 2021

AbstractDrugs are often metabolized to reactive intermediates that form protein adducts. Adducts can inhibit protein activity, elicit immune responses, and cause life threatening adverse drug reactions. The masses of reactive metabolites are frequently unknown, rendering traditional mass spectrometry-based proteomics incapable of adduct identification. Here, we present Magnum, an open-mass search algorithm optimized for adduct identification, and Limelight, a web-based data processing package for analysis and visualization of data from all existing algorithms. Limelight incorporates tools for sample comparisons and xenobiotic-adduct discovery. We validate our tools with two drug/protein combinations and apply our workflow to identify novel xenobiotic-protein adducts in CYP3A4. Our new methods and software enable accurate identification of xenobiotic-protein adducts with no prior knowledge of adduct masses or protein targets. Magnum outperforms existing tools in xenobiotic-protein adduct discovery, while Limelight fulfills a major need in the rapidly developing field of open-mass searching, which until now lacked comprehensive data visualization tools.
c-di-GMP inhibits early sporulation in Clostridioides difficile
Authors: Edwards Adrianne N. , Willams Caitlin L. , Pareek Nivedita , McBride Shonna M. , Tamayo Rita 
Published: June 2021

ABSTRACTThe formation of dormant spores is essential for the anaerobic pathogen Clostridioides difficile to survive outside of the host gastrointestinal tract. The regulatory pathways and environmental signals that initiate C. difficile spore formation within the host are not well understood. One bacterial second messenger signaling molecule, cyclic diguanylate (c-di-GMP), modulates several physiological processes important for C. difficile pathogenesis and colonization, but the impact of c-di-GMP on sporulation is unknown. In this study, we investigated the contribution of c-di-GMP to C. difficile sporulation. Overexpression of a gene encoding a diguanylate cyclase, dccA, decreased sporulation frequency and early sporulation gene transcription in both the epidemic R20291 and historical 630Δerm strains. Expression of a dccA allele encoding a catalytically inactive DccA that is unable to synthesize c-di-GMP no longer inhibited sporulation, indicating that the accumulation of intracellular c-di-GMP reduces C. difficile sporulation. A null mutation in dccA slightly increased sporulation in R20291 and slightly decreased sporulation in 630Δerm, suggesting that DccA may contribute to the intracellular pool of c-di-GMP in a strain-dependent manner. However, these data were highly variable, underscoring the complex regulation involved in modulating intracellular c-di-GMP concentrations. Finally, overexpression of dccA in known sporulation mutants revealed that c-di-GMP is likely signaling through an unidentified regulatory pathway to control early sporulation events in C. difficile. C-di-GMP-dependent regulation of C. difficile sporulation may represent an unexplored avenue of potential environmental and intracellular signaling that contributes to the complex regulation of sporulation initiation.IMPORTANCEMany bacterial organisms utilize the small signaling molecule cyclic diguanylate (c-di-GMP) to regulate important physiological processes, including motility, toxin production, biofilm formation, and colonization. C-di-GMP inhibits motility and toxin production and promotes biofilm formation and colonization in the anaerobic, gastrointestinal pathogen Clostridioides difficile. However, the impact of c-di-GMP on C. difficile spore formation, a critical step in this pathogen’s life cycle, is unknown. Here, we demonstrate that c-di-GMP negatively impacts sporulation in two clinically relevant C. difficile strains, the epidemic R20291 and the historical 630Δerm. The pathway through which c-di-GMP controls sporulation was investigated, and our results suggest that c-di-GMP is likely signaling through an unidentified regulatory pathway to control C. difficile sporulation. This work implicates c-di-GMP metabolism as a potential mechanism to integrate environmental and intracellular cues through c-di-GMP levels to influence C. difficile sporulation.
Genome-wide identification and characterization of DNA/RNA differences associated with Fusarium graminearum infection in wheat
Authors: Yang Guang , Pan Yan , Zhang Ruoyu , Huang Jiaqian , Pan Wenqiu , Cui Licao , Song Weining , Nie Xiaojun 
Published: June 2021

AbstractRNA editing (DNA/RNA differences) as a post-transcriptional modification approach to enrich genetic information, plays the crucial role in regulating diverse biological processes in eukaryotes. Although it has been extensively studied in plant chloroplast and mitochondria genome, RNA editing in plant nuclear genome, especially those associated with Fusarium head blight (FHB), is not well studied at present. Here, we investigated the DNA/RNA differences associated with FHB through a novel method by comparing the RNA-seq data from Fusarium-infected and control samples from 4 wheat genotypes. A total of 187 DNA/RNA differences were identified in 36 wheat genes, representing the first landscape of the FHB-responsive RNA editome in wheat. Furthermore, all of these 36 edited genes were located in the FHB related co-expression gene modules, which may involve in regulating FHB response. Finally, the effects of DNA/RNA differences were systematically investigated to show that they could cause the change of RNA structure and protein structure in edited genes. In particular, the G to C editing (chr3A_487854715) in TraesCS3A02G263900, which is the orthology of OsRACK1, resulted that it was targeted by tae-miR9664-3p to control its expression in different genotype through different editing efficiency, suggesting RNA editing could mediate miRNA to participate in the regulation network of FHB tolerance. This study reported the first wheat DNA/RNA differences associated with FHB, which not only contribute to better understand the molecular basis underlying FHB tolerance, but also shed light on improving FHB tolerance through epigenetic method in wheat and beyond.
A random priming amplification method for whole genome sequencing of SARS-CoV-2 and H1N1 influenza A virus
Authors: Chrzastek Klaudia , Tennakoon Chandana , Bialy Dagmara , Freimanis Graham , Flannery John , Shelton Holly 
Published: June 2021

AbstractBackgroundNon-targeted whole genome sequencing is a powerful tool to comprehensively identify constituents of microbial communities in a sample. There is no need to direct the analysis to any identification before sequencing which can decrease the introduction of bias and false negatives results. It also allows the assessment of genetic aberrations in the genome (e.g., single nucleotide variants, deletions, insertions and copy number variants) including in noncoding protein regions.MethodsThe performance of four different random priming amplification methods to recover RNA viral genetic material of SARS-CoV-2 were compared in this study. In method 1 (H-P) the reverse transcriptase (RT) step was performed with random hexamers whereas in methods 2-4 RT incorporating an octamer primer with a known tag. In methods 1 and 2 (K-P) sequencing was applied on material derived from the RT-PCR step, whereas in methods 3 (SISPA) and 4 (S-P) an additional amplification was incorporated before sequencing.ResultsThe SISPA method was the most effective and efficient method for non-targeted/random priming whole genome sequencing of COVID that we tested. The SISPA method described in this study allowed for whole genome assembly of SARS-CoV-2 and influenza A(H1N1)pdm09 in mixed samples. We determined the limit of detection and characterization of SARS-CoV-2 virus which was 103 pfu/ml (Ct, 22.4) for whole genome assembly and 101 pfu/ml (Ct, 30) for metagenomics detection.ConclusionsThe SISPA method is predominantly useful for obtaining genome sequences from RNA viruses or investigating complex clinical samples as no prior sequence information is needed. It might be applied to monitor genomic virus changes, virus evolution and can be used for fast metagenomics detection or to assess the general picture of different pathogens within the sample.
BayesDeBulk: A Flexible Bayesian Algorithm for the Deconvolution of Bulk Tumor Data
Authors: Petralia Francesca , Krek Azra , Calinawan Anna P. , Charytonowicz Daniel , Sebra Robert , Feng Song , Gosline Sara , Pugliese Pietro , Paulovich Amanda G. , Kennedy Jacob J. , Ceccarelli Michele , Wang Pei 
Published: June 2021

AbstractTo understand immune activation and evasion mechanisms in cancer, one crucial step is to characterize the composition of immune and stromal cells in the tumor microenvironment (TME). Deconvolution analysis based on bulk transcriptomic data has been used to estimate cell composition in TME. However, these algorithms are sub-optimal for proteomic data, which has hindered research in the rapidly growing field of proteogenomics. Moreover, with the increasing prevalence of multi-omics studies, there is an opportunity to enhance deconvolution analysis by utilizing paired proteomic and transcriptomic profiles of the same tissue samples. To bridge these gaps, we propose BayesDeBulk, a new method for estimating the immune/stromal cell composition based on bulk proteomic and gene expression data. BayesDeBulk utilizes the information of known cell-type-specific markers without requiring their absolute abundance levels as prior knowledge. We compared BayesDeBulk with existing tools on synthetic and real data examples, demonstrating its superior performance and versatility.AvailabilitySoftware available athttp://www.BayesDeBulk.com/ContactFor any information, please contactfrancesca.petralia@mssm.edu
Genomic miscellany and allelic frequencies of Plasmodium falciparum msp-1, msp-2 and glurp in parasite isolates
Authors: Ullah Ibrar , Afridi Sahib Gul , Ullah Asif , Israr Muhammad , Ali Anwar , Jabeen Hina , Rasool Akhtar , Akbar Fazal , Shah Muzafar 
Published: June 2021

AbstractThe genomic miscellany of malaria parasites can inform the intensity of transmission and identify potential deficiencies in malaria control programs. The aim of this study was to investigate the genomic miscellany, allele frequencies and multiplicity of infection (MOI) of P. falciparum.MethodsA total of 85 isolates from patients presenting to the local health centers with P. falciparum species were collected from 2017 to 2019. Parasite DNA was extracted from a total of 200 µl whole blood per patient using the Qiagen DNA extraction kit according to manufactures instructions. The polymorphic region of msp-1, msp-2 and glurp loci were genotyped by using nested polymerase chain reactions followed by gel electrophoresis for fragment analysis.ResultsGenetic diversity and allelic frequencies of msp-1, msp-2 and glurp were identified in 85 blood samples. A total of 62 msp alleles were detected in which 30 for msp-1 and 32 for msp-2. For msp-1 the successful amplification occurred in (75/85) 88.23% isolates for msp-1, 78.9% (67/85) for msp-2 and 70% (60/85) for glurp. For msp-1, the K1 allelic family was predominant at 66.66% (50/75), followed by RO33 and MAD20. The frequency of samples having only K1, MAD20 and RO33 were 21.34% (16/75), 8% (6/75) and 10.67% (8/75) respectively. In msp-2, the FC27 allelic family was the most abundant with 70.14% (47/67) compared to 3D7 with 67.16% (45/67). Nine glurp RII region genotypes were identified. The overall mean multiplicity of infection was 2.6 with1.8 and 1.4 for msp-1 and msp-2 respectively while for glurp RII genes (MOI=1.03). There was no significant association between multiplicity of infection and age group (Spearman’s rank coefficient = 0.050; P = 0.6). There was significant correlation between MOI and parasite density for msp-2 allelic family.ConclusionOur study showed high genetic diversity and allelic frequency with multiple clones of msp-1, msp-2 and glurp in P. falciparum isolates from malaria patients in Khyber Pakhtunkhwa Pakistan. In the present study the genotype data provided the valuable information which is essential for monitoring the impact of malaria eradication efforts in this region.
Essential role of translation factor eIF5a in cytokine production and cell cycle regulation in primary CD8 T lymphocytes
Authors: Tan Thomas CJ , Kelly Van , Zhou Xiaoyan , Ly Tony , Zamoyska Rose 
Published: June 2021

AbstractTranslational control adjusts protein production rapidly and facilitates local cellular responses to environmental conditions. Translation can be regulated through sequestration of mRNAs by regulatory proteins or RNAs, but also by the availability of ribosomes and translation factors which enable initiation and elongation of nascent polypeptides. Traditionally initiation of mRNA translation has been considered to be a major translational control point, however, control of peptide elongation can also play a role. Here we show that post-translational modification of the elongation factor, eIF5a, controls translation of subsets of proteins in naïve T-cells upon activation. Sequencing of nascent polypeptides indicated that functional eIF5a was required for the production of proteins which regulate T-cell proliferation and effector function. Control of translation in multiple immune cell lineages is required to co-ordinate immune responses and these data illustrate that translational elongation can contribute to post-transcriptional regulons important for the control of inflammation.
Precancer: Mutant clones in normal epithelium outcompete and eliminate esophageal micro-tumors
Authors: Colom B. , Herms A. , Hall M.W.J. , Dentro S.C. , King C. , Sood R.K. , Alcolea M.P. , Piedrafita G. , Fernandez-Antoran D. , Ong S.H. , Fowler J.C. , Mahbubani K.T. , Saeb-Parsy K. , Gerstung M. , Hall B.A. , Jones P.H. 
Published: June 2021

SummaryHuman epithelial tissues accumulate cancer-driver mutations with age1–7, yet tumor formation remains rare. The positive selection of these mutations argues they alter the behavior and fitness of proliferating cells8–10. Hence, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less-competitive neighbors9–12. However, little is known about how such dynamic competition in normal epithelia impacts early tumorigenesis. Here we show that the majority of newly formed esophageal tumors are eliminated through competition with mutant clones in the surrounding normal epithelium. We followed the fate of microscopic tumors in a mouse model of esophageal carcinogenesis. Most neoplasms are rapidly lost despite no indication of tumor cell death, decreased proliferation, or an anti-tumor immune response. Deep-sequencing of 10-day and 1-year-old tumors shows evidence of genetic selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased tumor removal, while pharmacologically inhibiting clonal competition reduced tumor loss. The results are consistent with a model where survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the adjacent normal tissue. We have identified an unexpected anti-tumorigenic role for mutant clones in normal epithelium by purging early neoplasms through cell competition, thereby preserving tissue integrity.
The Personalized Cancer Network Explorer (PeCaX) as a visual analytics tool to support molecular tumor boards
Authors: Figaschewski Mirjam , Sürün Bilge , Tiede Thorsten , Kohlbacher Oliver 
Published: June 2021

AbstractBackgroundPersonalized oncology represents a shift in cancer treatment from conventional methods to target specific therapies where the decisions are made based on the patient specific tumor profile. Selection of the optimal therapy relies on a complex interdisciplinary analysis and interpretation of these variants by experts in molecular tumor boards. With up to hundreds of somatic variants identified in a tumor, this process requires visual analytics tools to guide and accelerate the annotation process.ResultsThe Personal Cancer Network Explorer (PeCaX) is a visual analytics tool supporting the efficient annotation, navigation, and interpretation of somatic genomic variants through functional annotation, drug target annotation, and visual interpretation within the context of biological networks. Starting with somatic variants in a VCF file, PeCaX enables users to explore these variants through a web-based graphical user interface. The most protruding feature of PeCaX is the combination of clinical variant annotation and gene-drug networks with an interactive visualization. This reduces the time and effort the user needs to invest to get to a treatment suggestion and helps to generate new hypotheses. PeCaX is being provided as a platform-independent containerized software package for local or institution-wide deployment. PeCaX is available for download athttps://github.com/KohlbacherLab/PeCaX-docker.
Push recovery control for the underactuated lower extremity exoskeleton based on improved capture point concept
Authors: Zhang Jiaqi , Cong Ming , Liu Dong , Du Yu , Ma Hongjiang 
Published: June 2021

Purpose
The purpose of this paper is to use a simple method to enhance the ability of lower limb exoskeletons to restore balance under large interference conditions and to solve the problem that biped robot stability criterion cannot be fully applied to the underactuated lower limb exoskeletons.

Design/methodology/approach
The method used in this paper is to construct an underactuated lower extremity exoskeleton ankle joint with a torsion spring. Based on the constructed exoskeleton, the linear inverted torsion spring pendulum model is proposed, and the traditional capture point (CP) concept is optimized.

Findings
The underactuated exoskeleton ankle joint with torsion springs, combined with the improved CP concept, can effectively reduce the forward stepping distance under the same interference condition, which is equivalent to enhancing the balance ability of the lower extremity exoskeleton.

Originality/value
The contribution of this paper is to enhance the balance ability of the exoskeleton of the lower limbs under large interference conditions. The torsion spring is used as the exoskeleton ankle joint, and the traditional CP concept is optimized according to the constructed exoskeleton.
Integration effects of UAVs in non-segregated airspace
Authors: Savas Tamer , Usanmaz Oznur , Sahin Ozlem , Çınar Ertan , Karaderili Murat 
Published: June 2021

Purpose
The study aims to design a new route model for unmanned aerial vehicles (UAVs) to integrate them into non-segregated airspace.

Design/methodology/approach
The proposed route model was assessed and validated through real-time simulations.

Findings
The comparison results of baseline and proposed route model show that a reduction of 38% and 41% in the total flight time and total flight distance were obtained in favour of the proposed model, respectively.

Practical implications
The proposed route model can be applied by airspace designers and UAV users to perform safe and efficient landing in non-segregated airspace.

Originality/value
In this study, a new proposed route model is constructed for UAVs. Quantitative results, using a real-time simulation method, are achieved in terms of flight distance and flight time.
Do high-reputation companies pay more non-audit fees?
Authors: Huang Xuan , Kang Fei 
Published: June 2021

PurposeThe purpose of this study is to investigate the association between companies’ reputation and their purchase of non-audit services (NAS).Design/methodology/approachThis study measures company reputation using the reputation scores from Fortune’s “America’s Most Admired Companies” list. Multivariate analysis is performed to examine the association between public companies’ overall reputation and their decision of NAS purchase. Robustness checks are performed to control for self-selection bias and alternate measures are used to proxy for company reputation and NAS fees.FindingsThis study finds that high-reputation companies on average pay more NAS fees than their counterparts. The results suggest that due to less severe agency conflicts, high-reputation companies tend to purchase more NAS from their incumbent auditors to appreciate the potential benefits of the auditors’ knowledge spillovers.Originality/valueThe findings of this study on the association between company reputation and NAS fees contribute to the literature by providing additional insight on the factors influencing companies’ NAS purchases. The results of this study suggest that a unique company-level characteristic, company reputation, is significantly associated with companies’ NAS purchase, and therefore has both policy and practical implications for the demand of NAS. This study also adds to the growing literature on the influence of company reputation on corporate behavior by documenting the important role that company reputation plays in the managerial decision-making process.