bluuebunny/crossref_metadata_2025_split huggingface dataset:
DECODER: A probabilistic approach to integrate big data reveals mitochondrial Complex I as a potential therapeutic target for Alzheimer’s disease
Authors: Celik Safiye , Russell Josh C. , Pestana Cezar R. , Lee Ting-I , Mukherjee Shubhabrata , Crane Paul K. , Keene C. Dirk , Bobb Jennifer F. , Kaeberlein Matt , Lee Su-In 
Published: April 2018

AbstractIdentifying gene expression markers for Alzheimer’s disease (AD) neuropathology through meta-analysis is a complex undertaking because available data are often from different studies and/or brain regions involving study-specific confounders and/or region-specific biological processes. Here we introduce a novel probabilistic model-based framework, DECODER, leveraging these discrepancies to identify robust biomarkers for complex phenotypes. Our experiments present: (1) DECODER’s potential as a general meta-analysis framework widely applicable to various diseases (e.g., AD and cancer) and phenotypes (e.g., Amyloid-β (Aβ) pathology, tau pathology, and survival), (2) our results from a meta-analysis using 1,746 human brain tissue samples from nine brain regions in three studies — the largest expression meta-analysis for AD, to our knowledge —, and (3)in vivovalidation of identified modifiers of Aβ toxicity in a transgenicCaenorhabditis elegansmodel expressing AD-associated Aβ, which pinpoints mitochondrial Complex I as a critical mediator of proteostasis and a promising pharmacological avenue toward treating AD.
Poly-Target Selection Identifies Broad-Spectrum RNA Aptamers
Authors: Alam Khalid K. , Chang Jonathan L. , Lange Margaret J. , Nguyen Phuong D.M. , Sawyer Andrew W. , Burke Donald H. 
Published: April 2018

ABSTRACTAptamer selections often yield distinct subpopulations, each with unique phenotypes that can be leveraged for specialized applications. RNA aptamers that bind HIV-1 reverse transcriptase (RT) exhibit potent RT inhibition and suppress viral replication when targeting the strain-specific RT that they were originally selected to bind, but some of these same aptamers fail against single-point mutant and phylogenetically-diverse RTs. We hypothesized that a subset of the total aptamer population in libraries pre-enriched against a single RT may exhibit broad-spectrum RT binding and inhibition, and we devised a multiplexed Poly-Target selection approach to elicit those phenotypes against a panel of diverse primate lentiviral RTs. High-throughput sequencing of starting, negative, and final libraries, followed by analysis of coenrichment and codepletion in parallel and duplicate selection trajectories, narrowed the list of candidate aptamers by orders of magnitude. Biochemical characterization of candidates identified a novel aptamer motif and several rare and unobserved variants of previously-known motifs that inhibited recombinant RTs from HIV-1, HIV-2 and SIV to varying degrees. These broad-spectrum aptamers also suppressed replication of viral constructs carrying phylogenetically-diverse RTs. The Poly-Target selection and coenrichment approach described herein is a generalizable strategy for identifying broad-spectrum behavior and cross-reactivity among related targets from combinatorial libraries.
Identification of a Novel Neutralizing and Two Non-Neutralizing Epitopes on Epstein-Barr Virus gp350 Protein
Authors: Mutsvunguma Lorraine Z , Barasa Anne , Warden Charles , Foley Joslyn , Muniraju Murali , Mulama David H , Ye Peng , Qin Hanjun , Wang Jinhui , Wu Xiwei , Mwangi Waithaka , Ogembo Javier Gordon 
Published: April 2018

AbstractPrevention of Epstein-Barr virus (EBV) primary infection has focused on generating neutralizing antibodies (nAbs) targeting the major envelope glycoprotein gp350/220 (gp350). To date, eight gp350 epitopes have been identified, but only one has elicited nAbs. In this study, we generated 23 hybridomas that produced anti-gp350 antibodies. We compared the candidate anti-gp350 antibodies to nAb-72A1 by: (1) testing their ability to detect gp350 using ELISA, flow cytometry, and immunoblot; (2) sequencing their heavy and light chain complementarity-determining regions (CDRs); (3) measuring the ability of each monoclonal antibody (mAb) to neutralize EBV infectionin vitro; and (4) mapping the gp350 amino acids bound by the mAbs using RepliTope peptide microarrays. Eight antibodies recognized both denatured and non-denatured gp350, whereas five failed to react with denatured gp350 but recognized native gp350, suggesting they recognized conformational epitope(s). Sequence analysis of the heavy and light chain variable regions of the hybridomas identified 15 as mAbs with novel CDR regions unique from those of nAb-72A1. Seven of the new mAbs neutralized EBVin vitro, with HB20 and HB17 reducing EBV infection by 40% and >60%, and >30% and 80%, at 10 μg/ml and 50 μg/ml, respectively. Epitope mapping identified nine epitopes and defined their core residues, including two unique immunodominant epitopes,253TPIPGTGYAYSLRLTPRPVSRFL253and875LLLLVMADCAFRRNLSTSHTYTTPPY899, and a novel nAb epitope381GAFASNRTFDIT392. This study provides comprehensivein vitromapping of the exact residues defining nine epitopes of EBV gp350. Our findings will inform novel strategies to design optimal EBV vaccines capable of conferring broader protection against the virus.ImportanceNeutralizing antibodies (nAbs) directed against Epstein-Barr virus envelope glycoprotein gp350/220 (gp350) are generated in humans upon infection or immunization, and are thought to prevent neonatal infection. However, clinical use of exogenous nAbs (passive immunization) is limited to a single study using the only well-characterized nAb, 72A1. The gp350 ectodomain contains at least eight unique B-cell binding epitopes; two of these epitopes are recognized by nAb-72A1. The exact amino acid residues of the other six epitopes and their role in generating nAbs has not been elucidated. We used our 15 newly generated and fully characterized monoclonal antibodies and a peptide-overlapping RepliTope array to provide a comprehensive map of the core amino acid residues that define epitopes of gp350 and to understand their role in generating nAbs. These results will inform design of better-targeted gp350 peptide vaccines that contain only protective epitopes, which will focus the B-cell response to produce predominantly nAbs.
Dogs as reservoirs ofEscherichia colistrains causing urinary tract infection in their owners
Authors: Damborg Peter , Gumpert Heidi , Johansson Laura , Jana Bimal , Frimodt-Møller Niels , Guardabassi Luca 
Published: April 2018

ABSTRACTIt is known that humans and pets living together can share the sameEscherichia colistrain. In this study we assessed the role played by household pets as reservoirs ofE. colistrains causing urinary tract infection (UTI) in their owners. Fecal swabs from 15 dogs and six cats living with 19 patients with community-acquiredE. coliUTI were screened by antimicrobial selective plating to detectE. colidisplaying the same susceptibility profile of the UTI-causing strain. Pet/patient pairs sharing strains with indistinguishable susceptibility and pulsed-field gel electrophoresis (PFGE) profiles were quantitatively screened for fecal carriage of the UTI-causing strain approximately 10 months later using bacterial counts on selective agar supplemented with the relevant antibiotics. Isolates from both time points were characterized by whole-genome single nucleotide polymorphism (SNP) analysis. PFGE revealed indistinguishableE. coliwithin two (11%) pet/patient pairs. In pair A, the UTI-causing strain was detected 10 months later in both the patient (108CFU/g) and her dog (104CFU/g). In pair B, only the dog was colonized with the UTI-causing strain upon re-sampling (105CFU/g), indicating dog-to-man transmission. For both pairs, less than 70 SNPs distinguished any isolate from the first and second sampling. The study shows regular co-carriership of UTI-causingE. colistrains between humans and their pets, and indicates that dogs can be a source of human infection. Although final evidence for transmission is lacking, hygiene precautions should be considered by people fraternizing pets. This may be particularly relevant for persons with a compromised immune system.
Development of an on-chip detection of Zika virus and antibodies simultaneously using array of nanowells
Authors: Semenova Touyana , Voigt Alexandria , Donelan William , Aranyos Alek , Yamamoto Janet , Rathore Mobeen R. , Nguyen Cuong Q. 
Published: April 2018

ABSTRACTZika virus (ZIKV) infections are an emerging health pandemic of significant medical importance. ZIKV appeared recently in the Americas from Africa via the South Pacific. The current outbreak has garnered attention by exhibiting unique characteristics of devastating neurodevelopmental defects in newborns of infected pregnant women. Current guidelines for ZIKV diagnostics developed by the Center of Diseases Control and Prevention (CDC) consist of nucleic acid testing, plaque reduction neutralization test (PRNT), and a serologic test for IgM detection. To better accommodate and comply with these guidelines, we developed a simultaneous on-chip detection of ZIKV and anti-ZIKV antibodies using an array of nanowells. Using on-chip microengraving, we were able to detect anti-ZIKV antibodies and their immunoglobulin isotypes. In parallel, applying on-chip real-time PCR with epifluorescence microscopy, we were able to quantify ZIKV viral load as low as one copy. To test clinical samples of patients at the postconvalescent stage, we analyzed samples from 8 patients. The on-chip nanowells could effectively identify antibodies that reacted against ZIKV envelope protein and their isotypes with high sensitivity and specificity. The small sample requirement with high specificity and sensitivity and combined molecular and serological tests could potentially be very advantageous and beneficial in accurate detection of Zika infection for better disease monitoring and management.
A novel sialylation site onNeisseria gonorrhoeaelipooligosaccharide links heptose II lactose expression with pathogenicity
Authors: Ram Sanjay , Gulati Sunita , Lewis Lisa A. , Chakraborti Srinjoy , Zheng Bo , DeOliveira Rosane B. , Reed George W. , Cox Andrew D. , Li Jianjun , St. Michael Frank , Stupak Jacek , Su Xia-Hong , Saha Sudeshna , Landig Corinna S. , Varki Ajit , Rice Peter A. 
Published: April 2018

AbstractSialylation of lacto-W-neotetraose (LNnT) extending from heptose I (HepI) of gonococcal lipooligosaccharide (LOS) contributes to pathogenesis. Previously, gonococcal LOS sialyltransterase (Lst) was shown to sialylate LOS in Triton X-100 extracts of strain 15253, which expresses lactose from both HepI and HepII, the minimal structure required for mAb 2C7 binding. Ongoing work has shown that growth of 15253 in cytidine monophospho-W-acetylneuraminic acid (CMP-Neu5Ac)-containing media enables binding to CD33/Siglec-3, a cell surface receptor that binds sialic acid, suggesting that lactose termini on LOS of intact gonococci can be sialylated. Neu5Ac was detected on LOSs of strains 15253 and a MS11 mutant with only lactose from HepI and HepII by mass spectrometry; deleting HepII lactose rendered Neu5Ac undetectable. Resistance of HepII lactose Neu5Ac to desialylation by α2-3-specific neuraminidase suggested an α2-6-linkage. Although not associated with increased factor H binding, HepII lactose sialylation inhibited complement C3 deposition on gonococci. 15253 mutants that lacked Lst or HepII lactose were significantly attenuated in mice, confirming the importance of HepII Neu5Ac in virulence. All 75 minimally passaged clinical isolates from Nanjing, China, expressed HepII lactose, evidenced by reactivity with mAb 2C7; mAb 2C7 was bactericidal against the first 62 (of 75) isolates that had been collected sequentially and were sialylated before testing. mAb 2C7 effectively attenuated 15253 vaginal colonization in mice. In conclusion, this novel sialylation site could explain the ubiquity of gonococcal HepII lactosein vivo. Our findings reiterate the candidacy of the 2C7 epitope as a vaccine antigen and mAb 2C7 as an immunotherapeutic antibody.
An optimized toolkit for precision base editing
Authors: Zafra Maria Paz , Schatoff Emma M , Katti Alyna , Foronda Miguel , Breinig Marco , Schweitzer Anabel Y. , Simon Amber , Han Teng , Goswami Sukanya , Montgomery Emma , Thibado Jordana , Sánchez-Rivera Francisco J. , Shi Junwei , Vakoc Christopher R , Lowe Scott W , Tschaharganeh Darjus F. , Dow Lukas E 
Published: April 2018

AbstractCRISPR base editing is a potentially powerful technology that enables the creation of genetic mutations with single base pair resolution. By re-engineering both DNA and protein sequences, we developed a collection of constitutive and inducible base editing vector systems that dramatically improve the ease and efficiency by which single nucleotide variants can be created. This new toolkit is effective in a wide range of model systems, and provides a means for efficientin vivosomatic base editing.
Machine learning based classification of cells into chronological stages using single-cell transcriptomics
Authors: Singh Sumeet Pal , Janjuha Sharan , Chaudhuri Samata , Reinhardt Susanne , Dietz Sevina , Eugster Anne , Bilgin Halil , Korkmaz Selçuk , Reid John E. , Zararsiz Gökmen , Ninov Nikolay 
Published: April 2018

ABSTRACTAge-associated deterioration of cellular physiology leads to pathological conditions. The ability to detect premature aging could provide a window for preventive therapies against age-related diseases. However, the techniques for determining cellular age are limited, as they rely on a limited set of histological markers and lack predictive power. Here, we implement GERAS (GEnetic Reference for Age of Single-cell), a machine learning based framework capable of assigning individual cells to chronological stages based on their trans criptomes. GERAS displays greater than 90% accuracy in classifying the chronological stage of zebrafish and human pancreatic cells. The framework demonstrates robustness against biological and technical noise, as evaluated by its performance on independent samplings of single-cells. Additionally, GERAS determines the impact of differences in calorie intake and BMI on the aging of zebrafish and human pancreatic cells, respectively. We further harness the predictive power of GERAS to identify genome-wide molecular factors that correlate with aging. We show that one of these factors, junb, is necessary to maintain the proliferative state of juvenile beta-cells. Our results showcase the applicability of a machine learning framework to classify the chronological stage of heterogeneous cell populations, while enabling to detect pro-aging factors and candidate genes associated with aging.
Changes in patterns of neural activity underlie a time-dependent transformation of memory in rats and humans
Authors: Sekeres Melanie J. , Winocur Gordon , Moscovitch Morris , Anderson John A.E. , Pishdadian Sara , Wojtowicz J. Martin , St-Laurent Marie , McAndrews Mary Pat , Grady Cheryl 
Published: April 2018

AbstractThe dynamic process of memory consolidation involves a reorganization of brain regions that support a memory trace over time, but exactly how the network reorganizes as the memory changes remains unclear. We present novel converging evidence from studies of animals (rats) and humans for the time-dependent reorganization and transformation of different types of memory as measured both by behavior and brain activation. We find that context-specific memories in rats, and naturalistic episodic memories in humans, lose precision over time and activity in the hippocampus decreases. If, however, the retrieved memories retain contextual or perceptual detail, the hippocampus is engaged similarly at recent and remote timepoints. As the interval between the timepoint increases, the medial prefrontal cortex is engaged increasingly during memory retrieval, regardless of the context or the amount of retrieved detail. Moreover, these hippocampal-frontal shifts are accompanied by corresponding changes in a network of cortical structures mediating perceptually-detailed as well as less precise, schematic memories. These findings provide cross-species evidence for the crucial interplay between hippocampus and neocortex that reflects changes in memory representation over time and underlies systems consolidation.
Systematic evaluation of isoform function in literature reports of alternative splicing
Authors: Bhuiyan Shamsuddin A. , Ly Sophia , Phan Minh , Huntington Brandon , Hogan Ellie , Liu Chao Chun , Liu James , Pavlidis Paul 
Published: April 2018

ABSTRACTAlthough most mammalian genes have multiple isoforms, an ongoing debate is whether these isoforms are all functional as well as the extent to which they increase the genome’s functional repertoire. To ground this debate in data, we established a curation framework for evaluating experimental evidence of functionally distinct splice isoforms (FDSIs) and analyzed splice isoform function for over 700 human and mouse genes. Despite our bias towards prominently studied genes, we found experimental evidence meeting the classical definition for functionally distinct isoforms for only ~5% of the curated genes. If we relax our criteria, the fraction of genes with support for FDSIs remains low (~13%). We provide evidence that this picture will not change substantially with further curation. Furthermore, many FDSIs did not trace to a specific isoform in Ensembl. Our work has implications for computational analyses of alternative splicing and should help shape research around the role of splicing on gene function from presuming large general effects to acknowledging the need for stronger experimental evidence.
Accountability and responsibility defined
Authors: McGrath Stephen Keith , Whitty Stephen Jonathan 
Published: April 2018

Purpose
The purpose of this paper is to remove confusion surrounding the terms responsibility and accountability from the general and project management arenas by creating “refined” (with unnecessary elements removed) definitions of these terms.

Design/methodology/approach
A method of deriving refined definitions for a group of terms by ensuring that there is no internal conflict or overlap is adopted and applied to resolve the confusion.

Findings
The confusion between responsibility and accountability can be characterised as a failure to separate the obligation to satisfactorily perform a task (responsibility) from the liability to ensure that it is satisfactorily done (accountability). Furthermore, clarity of application can be achieved if legislative and organisational accountabilities are differentiated and it is recognised that accountability and responsibility transition across organisational levels. A difficulty in applying accountability in RACI tables is also resolved.

Research limitations/implications
Clear definition of responsibility and accountability will facilitate future research endeavours by removing confusion surrounding the terms. Verification of the method used through its success in deriving these “refined” definitions suggests its suitability for application to other contested terms.

Practical implications
Projects and businesses alike can benefit from removal of confusion around the definitions of responsibility and accountability in the academic research they fund and attempt to apply. They can also achieve improvements in both efficiency and effectiveness in undertaking organisation-wide exercises to determine organisational responsibilities and accountabilities as well as in the application of governance models.

Social implications
Refined definitions of responsibility and accountability will facilitate building social and physical systems and infrastructure, benefitting organisations, whether public, charitable or private.

Originality/value
Clarity resulting in the avoidance of confusion and misunderstanding together with their consequent waste of time, resources and money.
Healthcare service failure: how dissatisfied patients respond to poor service quality
Authors: Um Ki Hyun , Lau Antonio K.W. 
Published: April 2018

Purpose
Few scholars have so far explored how healthcare service quality affects patient dissatisfaction, leading to negative behavior responses when a healthcare service fails. The purpose of this paper is to examine how different service quality attributes affect patient dissatisfaction leading to a variety of asymmetric negative behavior responses.

Design/methodology/approach
Following a survey of 453 dissatisfied outpatients in Korea, structural equation modeling with a series of post hoc analyses is used to test the research model. It consists of five hypotheses.

Findings
Outcome quality is found to be the most significant variable affecting patient dissatisfaction, followed by administrative quality, interactive quality, and environmental quality. Dissatisfied patients tend to engage more in active behaviors (e.g. negative word-of-mouth, switching, and complaining) than in remaining passive in a non-linear way. Also, the mediating role of dissatisfaction is found to be significant.

Research limitations/implications
This paper has empirically identified the most significant service quality attributes that lead to dissatisfied patients and negative behaviors on their part. These findings indicate that different quality attributes of service failure lead to different actions. However, this study has suffered from a few limitations as a result of its research context and scope.

Originality/value
This paper is one of the very few empirical studies examining the relationships among the output and process quality attributes, patient dissatisfaction, and actual behaviors in a healthcare service failure context.
Ecotourism as a path to sustainable development in an isolated Magic Town
Authors: Coronado Martínez Yasu , Rosas Baños Mara , Cerón Monroy Hazael 
Published: April 2018

Purpose
This study aims to reveal the potential for ecotourism of a locality with high marginalisation index in the municipality of Tlalpujahua, a Magic Town in the State of Michoacán, Mexico.

Design/methodology/approach
This case study was based on several methodologies. First, socioeconomic, environmental, sustainability, geographic and institutional variables were used in the evaluation of 62 localities of the municipality. Geographic information systems identified study areas and determined their potential for ecotourism. Second, participatory diagnosis was used to collect specific information about the locality regarding their organisational aspects, development strategies, current socioeconomic problems, land use and resources availability and interest in developing projects related to ecotourism. Finally, the authors adapted the FAS Model (factors, attractors and support systems) to include environmental and organisational variables contributing to a theoretical approach to ecotourism. To identify attractors, they applied a questionnaire to determine the profile of tourists visiting Magic Towns and their potential interest in ecotourism.

Findings
The authors conclude that ecotourism is a possible alternative to highly marginalised localities within Magic Town municipalities and would be able to expand the benefits engendered by the program. Ecotourism can therefore represent a new option for tourists visiting marginalised communities in Mexico.

Originality/value
A diverse methodology applied key elements to identify localities suitable for ecotourism, characteristics of marginalisation and endowment of natural heritage. The authors conclude that the benefits to localities included in the Magic Towns Program can be expanded to surrounding spaces through strategies such as ecotourism.