bluuebunny/crossref_metadata_2025_split huggingface dataset:
Allosteric Inhibition of CRISPR-Cas9 by Bacteriophage-derived Peptides
Authors: Cui Yan-ru , Wang Shao-jie , Chen Jun , Li Jie , Chen Wenzhang , Wang Shuyue , Meng Bing , Zhu Wei , Zhang Zhuhong , Yang Bei , Jiang Biao , Yang Guang , Ma Peixiang , Liu Jia 
Published: May 2019

AbstractBackgroundCRISPR-Cas9 has been developed as a therapeutic agent for various infectious and genetic diseases. In many clinically relevant applications, constitutively active CRISPR-Cas9 is delivered into human cells without a temporal control system. Excessive and prolonged expression CRISPR-Cas9 can lead to elevated off-target cleavage. The need for modulating CRISPR-Cas9 activity over the dimensions of time and dose has created the demand of developing CRISPR-Cas off-switches. Protein and small molecule-based CRISPR-Cas inhibitors have been reported in previous studies.ResultsWe report the discovery of Cas9-inhibiting peptides from inoviridae bacteriophages. These peptides, derived from the periplasmic domain of phage major coat protein G8P (G8PPD), can inhibit the in vitro activity of Streptococcus pyogenes Cas9 (SpCas9) proteins in an allosteric manner. Importantly, the inhibitory activity of G8PPD on SpCas9 is dependent on the order of guide RNA addition. Ectopic expression of full-length G8P (G8PFL) or G8PPD in human cells can inactivate the genome-editing activity of SpCas9 with minimum alterations of the mutation patterns. Furthermore, unlike the anti-CRISPR protein AcrII4A that completely abolishes the cellular activity of CRISPR-Cas9, G8P co-transfection can reduce the off-target activity of co-transfected SpCas9 while retaining its on-target activity.ConclusionG8Ps discovered in the current study represent the first anti-CRISPR peptides that can allosterically inactivate CRISPR-Cas9. This finding may provide insights into developing next-generation CRISPR-Cas inhibitors for precision genome engineering.
Sequence Compression Benchmark (SCB) database — a comprehensive evaluation of reference-free compressors for FASTA-formatted sequences
Authors: Kryukov Kirill , Ueda Mahoko Takahashi , Nakagawa So , Imanishi Tadashi 
Published: May 2019

AbstractBackgroundNearly all molecular sequence databases currently use gzip for data compression. Ongoing rapid accumulation of stored data calls for more efficient compression tool. Although numerous compressors exist, both specialized and general-purpose, choosing one of them was difficult because no comprehensive analysis of their comparative advantages for sequence compression was available.FindingsWe systematically benchmarked 410 settings of 44 compressors (including 26 specialized sequence compressors and 18 general-purpose compressors) on representative FASTA-formatted datasets of DNA, RNA and protein sequences. Each compressor was evaluated on 17 performance measures, including compression strength, as well as time and memory required for compression and decompression. We used 25 test datasets including individual genomes of various sizes, DNA and RNA datasets, and standard protein datasets. We summarized the results as the Sequence Compression Benchmark database (SCB database, http://kirr.dyndns.org/sequence-compression-benchmark/) that allows building custom visualizations for selected subsets of benchmark results.ConclusionWe found that modern compressors offer large improvement in compactness and speed compared to gzip. Our benchmark allows comparing compressors and their settings using a variety of performance measures, offering the opportunity to select the optimal compressor based on the data type and usage scenario specific to particular application.
Decoupling of inter-regional functional connectivity and regional neural activity in Alzheimer Disease
Authors: Maleki-Balajoo Somayeh , Rahmani Farzaneh , Khosrowabadi Reza , Meng Chun , Grimmer Timo , Drzezga Alexander , Zarei Mojtaba , Sorg Christian , Tahmasian Masoud 
Published: May 2019

AbstractAlzheimer’s disease (AD) and mild cognitive impairment (MCI) are characterized by aberrant regional neural activity and disrupted inter-regional functional connectivity (FC). It is, however, poorly understood how changes in regional neural activity and inter-regional FC interact in AD and MCI. Here, we investigated the link between regional neural activity and nodal topological measures of FC through simultaneous PET/MR measurement in 20 patients with MCI, 33 patients with AD, and 26 healthy individuals. First, we assessed regional glucose metabolism identified through FDG-PET (rFDG) (as a proxy of regional neural activity), and regional FC topology through clustering coefficient (CC) and degree centrality (DC) (as surrogates of local segregation and global connectivity, respectively). Next, we examined the potential moderating effect of disease status (AD or MCI) on the link between rFDG and FC topology using hierarchical moderated multiple regression analysis. Alterations in rFDG, CC, and DC were widespread in patients, and AD alters physiological coupling between regional metabolism and functional connectivity particularly in the inferior temporal gyus and supplementary motor areas. While rFDG correlated with CC in healthy subjects, this correlation was lost in AD patients. We suggest that AD pathology decouples the normal association between regional neural activity and functional segregation.
Generation of strong casein kinase 1 inhibitor of Arabidopsis thaliana
Authors: Saito Ami N , Matsuo Hiromi , Kuwata Keiko , Ono Azusa , Kinoshita Toshinori , Yamaguchi Junichiro , Nakamichi Norihito 
Published: May 2019

AbstractCasein kinase 1 (CK1) is an evolutionarily conserved protein kinase among eukaryotes. Studies on yeast, fungi, and animals have revealed that CK1 plays roles in divergent biological processes. By contrast, the collective knowledge regarding the biological roles of plant CK1 lags was behind those of animal CK1. One of reasons for this is that plants have more multiple genes encoding CK1 than animals. To accelerate the research for plant CK1, a strong CK1 inhibitor that efficiently inhibits multiple members of CK1 proteins in vivo (in planta) is required. Here, we report a novel strong CK1 inhibitor of Arabidopsis (AMI-331). Using a circadian period-lengthening activity as estimation of the CK1 inhibitor effect in vivo, we performed a structure-activity relationship (SAR) study of PHA767491 (1,5,6,7-tetrahydro-2-(4-pyridinyl)-4H-pyrrolo[3,2-c]pyridin-4-one hydrochloride), a potent CK1 inhibitor of Arabidopsis, and found that PHA767491 analogues bearing a propargyl group at the pyrrole nitrogen atom (AMI-212) or a bromine atom at the pyrrole C3 position (AMI-23) enhance the period-lengthening activity. The period lengthening activity of a hybrid molecule of AMI-212 and AMI-23 (AMI-331) is about 100-fold stronger than that of PHA767491. An in vitro assay indicated a strong inhibitory activity of CK1 kinase by AMI-331. Also, affinity proteomics using an AMI-331 probe showed that targets of AMI-331 are mostly CK1 proteins. As such, AMI-331 is a strong potent CK1 inhibitor that shows promise in the research of CK1 in plants.
Overcoming Immunological Resistance Enhances the Efficacy of a Novel anti-tMUC1 CAR T Cell Treatment Against Pancreatic Ductal Adenocarcinoma
Authors: Yazdanifar Mahboubeh , Zhou Ru , Grover Priyanka , Williams Chandra , Bose Mukulika , Moore Laura Jeffords , Wu Shu-ta , Chi Richard , Maher John , Dreau Didier , Mukherjee Pinku 
Published: May 2019

AbstractChimeric antigen receptor engineered T cells (CAR T cells) have shown remarkable success in treating hematologic cancers. However, this efficacy has yet to translate to treatment in solid tumors. Pancreatic ductal adenocarcinoma (PDA) is a fatal malignancy with poor prognosis. Treatment options are limited and commonly associated with severe side effects. We have developed and characterized a second generation CAR engineered T cell using the light and heavy chain sequence derived from a novel monoclonal antibody, TAB004, that specifically binds the tumor associated antigen, tMUC1. tMUC1 is overexpressed in varying levels on ~85% of all human PDA. We present data showing that the TAB004 derived CAR T cells (tMUC1-CAR T cells) specifically bind to tMUC1 on PDA cells and is cytotoxic against the majority of the PDA cell lines. The tMUC1-CAR T cells do not bind or kill normal epithelial cells. We further demonstrate that the tMUC1-CAR T cells control the growth of orthotopic pancreatic tumorsin vivo.PDAs are generally cold tumors with resistance to many standard treatment modalities, thus, it was not surprising that some of the PDA cell lines were refractory to CAR T cell treatment. qPCR analysis of several genes known to be associated with immune resistance revealed overexpression of indoleamine 2, 3-dioxygenases-1 (IDO1), Cyclooxygenase 1 and 2 (COX1 and COX2), Adenosine deaminases acting on RNA (ADAR1) and galectin-9 (Gal-9). We treated resistant PDA cells with a combination of CAR T cells and biological inhibitors of IDO1, COX1/2, ADAR1, and Gal-9. Results showed a significant enhancement of CAR T cell cytotoxicity against PDA cells when inhibiting IDO1, COX1/2, and Gal-9 but not ADAR1 or COX2. Overcoming CAR T cell resistance in PDA is a significant advancement in the field and may lead to future combination therapies that are less toxic but more efficient against this deadly disease.
A general LC/MS-based RNA sequencing method for direct analysis of multiple-base modifications in RNA mixtures
Authors: Zhang Ning , Shi Shundi , Jia Tony Z. , Ziegler Ashley , Yoo Barney , Yuan Xiaohong , Li Wenjia , Zhang Shenglong 
Published: May 2019

ABSTRACTA complete understanding of the structural and functional potential of RNA requires understanding of chemical modifications and noncanonical bases; this in turn requires advances in current sequencing methods to be able to sequence not only canonical ribonucleotides, but at the same time directly sequence these nonstandard moieties. Here, we present the first direct and modification type-independent RNA sequencing method via integration of a hydrophobic end-labeling strategy with of 2-D mass-retention time LC/MS analysis to allow de novo sequencing of RNA mixtures and enhance sample usage efficiency. Our method can directly read out the complete sequence, while identifying, locating, and quantifying base modifications accurately in both single and mixed RNA samples containing multiple different modifications at single-base resolution. Our method can also quantify stoichiometry/percentage of modified RNA vs. its canonical counterpart RNA, simulating a real biological sample where modifications exist but may not be 100% at a particular site of the RNA. This method is a critical step towards fully sequencing real complex cellular RNA samples of any type and containing any modification types and can also be used in the quality control of modified therapeutic RNAs.
Jasmonate-regulated ERF109-MYB51-MYC3 ternary complexes control indolic glucosinolates biosynthesis
Authors: Zhang kaixuan , Meng Yu , Li Jinbo , Ding Mengqi , Khurshid Muhammad , Li Qiong , Lu Xiaoling , Zhou Meiliang 
Published: May 2019

SummaryJasmonates (JAs) are plant hormones which regulate biosynthesis of many secondary metabolites, such as glucosinolates (GLSs), through JAs-responsive transcription factors (TFs). The JAs-responsiveCYP83B1gene, has been shown to catalyze the conversion of indole-3-acetaldoxime (IAOx) to indolic glucosinolates (IGLSs). However, little is known about the regulatory mechanism ofCYP83B1gene expression by JAs. In yeast one-hybrid screens using theCYP83B1promoter as bait we isolated two JAs-responsive TFs ERF109 and MYB51 that are involved in JAs-regulated IGLS biosynthesis. Furthermore, using a yeast two-hybrid assay, we identified ERF109 as an interacting partner of MYB51, and Jasmonate ZIM-domain (JAZ) proteins as interactors of MYB51, and BTB/POZ-MATH (BPM) proteins as interactors of ERF109. Both JAZ and BPM proteins are necessary for the full repression of the ERF109-MYB51-MYC3 ternary complex activity onCYP83B1gene expression and JA-regulated IGLS biosynthesis. Biochemical analysis showed that the 26S proteasome-mediated degradation of ERF109 protein is mediated by a CRL3BPME3 ligase independently of JA signaling. Genetic and physiological evidence shows that MYB51 acts as an adaptor and activator to bridge the interaction with the co-activators MYC3 and ERF109, for synergistically activating theCYP83B1gene expression, and all three factors are essential and exert a coordinated control in JAs-induced IGLS biosynthesis. Overall, this study provides insights into the molecular mechanisms of JAs-responsive ERF109-MYB51-MYC3 ternary complexes in controlling JAs-regulated GLSs biosynthesis, which provides a better understanding of plant secondary metabolism.One-sentence summaryThe JA-responsive ERF109-MYB51-MYC3 ternary complex controls JAs-regulated GLSs biosynthesis.
AI’s path to the present and the painful transitions along the way
Authors: Garcia-Murillo Martha , MacInnes Ian 
Published: May 2019

Purpose
Artificial intelligence (AI) is likely to have a significant impact on work. It will enhance, but also displace, some professions. This paper aims to look retrospectively at the impact that previous revolutionary computing technologies have had and the institutional values that have shaped the way workers were affected.

Design/methodology/approach
This historical investigation relies on academic, government and trade publications of earlier periods in the development of computer technology. The analysis relies on the literature on institutional economics to understand societal outcomes. Within this framework, this paper explores both the ceremonial values associated with tradition and the instrumental values associated with the pursuit of knowledge.

Findings
The AI revolution, like previous technological evolutions, will go through stages. Initial implementations will suffer from failures that will, however, generate employment; but, as the technology improves, the AI revolution is likely to enhance productivity but displace workers. Up to this point, the US Government has not been able to respond adequately to the challenge. This paper attributes this to the ceremonial values that public officials and society entertain about personal responsibility and small government.

Practical implications
Given the differences in values, this study recommends fending off negative effects though education but also experimenting with other solutions at the local level.

Originality/value
Through the lens of history, this study provides a glimpse of what may happen. It also provides a framework that helps understand the outcomes of earlier technological revolutions.
On the theoretical basis of memory-free approaches for fractional differential equations
Authors: Liu Q.X. , Liu J.K. , Chen Y.M. 
Published: May 2019

PurposeA nonclassical method, usually called memory-free approach, has shown promising potential to release arithmetic complexity and meets high memory-storage requirements in solving fractional differential equations. Though many successful applications indicate the validity and effectiveness of memory-free methods, it has been much less understood in the rigorous theoretical basis. This study aims to focus on the theoretical basis of the memory-free Yuan–Agrawal (YA) method [Journal of Vibration and Acoustics 124 (2002), pp. 321-324].Design/methodology/approachMathematically, the YA method is based on the validity of two fundamental procedures. The first is to reverse the integration order of an improper quadrature deduced from the Caputo-type fractional derivative. And, the second concerns the passage to the limit under the integral sign of the improper quadrature.FindingsThough it suffices to verify the integration order reversibility, the uniform convergence of the improper integral is proved to be false. Alternatively, this paper proves that the integration order can still be reversed, as the target solution can be expanded as Taylor series on [0, ∞). Once the integration order is reversed, the paper presents a sufficient condition for the passage to the limit under the integral sign such that the target solution is continuous on [0, ∞). Both positive and counter examples are presented to illustrate and validate the theoretical analysis results.Originality/valueThis study presents some useful results for the real performance for the YA and some similar memory-free approaches. In addition, it opens a theoretical question on sufficient and necessary conditions, if any, for the validity of memory-free approaches.
Comparison of seven numerical methods for determining Weibull parameters of wind for sustainable energy in Douala, Cameroon
Authors: Kengne Signe Elie Bertrand , Kanmogne Abraham , Emmanuel Guemene D. , Meva’a Lucien 
Published: May 2019

Purpose
The purpose of this paper is contribution to estimate the potential of wind energy in Douala in Cameroon, by modeling and predicting the regime of wind. The paper deals with the analysis and comparison of seven numerical methods for the assessment of effectiveness in determining the parameters for the Weibull distribution, using wind speed data collected at Douala International Airport in Cameroon, in the period from September 2011 to May 2013, obtained by meteorological equipment belonging to the Laboratory of Energy Research of the Institute of Geological and Mining Research.

Design/methodology/approach
By using ANOVA, root mean square error and chi-square tests to compare the proposed methods, this study aims to determine which methods are effective in determining the parameters of the Weibull distribution for the available data, in an attempt to establish acceptable criteria for better usage of wind power in Douala, which is the economic capital and ought to have prominence in the use of renewable sources for electricity generation in Cameroon.

Findings
The study helps to determine that moment, empirical and energy pattern factor methods used to determine the shape parameter k and the scale parameter c of the Weibull distribution present a better curve fit with the histogram of the wind speed. This fact is clearly validated by means of the statistical tests. But, all the seven methods gave excellent performance. Then, k reaching levels ranging from 3.5 to 5.5 and c range from 1.7 to 2.4.

Originality/value
Then as far as we are concerned, for a significant contribution, it could be more effective to have a model for prediction of wind characteristics using wind data collected per hour, one at least three years. A comparison of results obtained from lots of other methods (seven in this case) is necessary before an efficient discussion. Standard deviations and errors between measured and predicted data must also be presented.
Improving pediatric experience of pain during vaccinations: a quality improvement project
Authors: MacDougall Terri , Cunningham Shawna , Whitney Leeann , Sawhney Monakshi 
Published: May 2019

Purpose
The purpose of this paper is to share lessons learned from a quality improvement (QI) project that studied pediatric pain assessment scores after implementing additional evidence-based pain mitigation strategies into practice. Most nurses will acknowledge they implement some practices to mitigate pain during injections. Addressing pain during vaccination is important to prevent needle fear, vaccine hesitancy and health care avoidance. The aim of this project was to reduce pain as evidenced by pain scores at the time of vaccination at the North Bay Nurse Practitioner-Led Clinic (NBNPLC).

Design/methodology/approach
The design for this study was quasi-experimental utilizing descriptive statistics and QI tools. The NBNPLC utilized the model for improvement to test change ideas. A validated observation tool to assess pain during vaccination with the pediatric population (revised Face Legs Activity Cry and Consolability) was used to test changes. The team deliberately planned improvements according to best practice guidelines to optimize use of strategies to mitigate pain during injections. QI tools and leadership skills were utilized to improve the pediatric experience of pain during vaccinations. Parents and clinicians provided qualitative and quantitative feedback to the project.

Findings
Nurses tested pain assessment tools and agreed to use a validated tool to assess pain during vaccinations. Parents agreed to use of topical anesthetic during vaccinations. Improved pain scores during vaccinations were demonstrated with the use of topical anesthetic. Parents agreed to use of standardized sucrose solution during vaccination. Reduced pain scores were observed with the use of standardized sucrose water. To sustain implementation of the guideline, a nursing documentation form was devised with nurses agreeing to ongoing use of the form.

Research limitations/implications
This is a QI project that examined the intricacies of moving clinical practice guidelines into clinical practice. The project validates guidelines for pain management during vaccinations. Leaders within clinics who want to improve pediatric pain during vaccinations will find this paper helpful as a guide.

Practical implications
Pain management in the pediatric population will be touched on in the context of parental expectations of pain. QI tools, lessons learned and suggestions for nurses will be outlined. Leadership plays an influential role in translating practice guidelines into practice.

Originality/value
This paper outlines how organizational supports were instrumental to give clinicians time to deliberately challenge practice to improve quality of care of children during vaccinations.