bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial domain analysis predicts risk of colorectal cancer recurrence and infers associated tumor microenvironment networks
Authors: Uttam Shikhar , Stern Andrew M. , Furman Samantha , Pullara Filippo , Spagnolo Daniel , Nguyen Luong , Gough Albert , Sevinsky Christopher J. , Ginty Fiona , Taylor D. Lansing , Chennubhotla S. Chakra 
Published: May 2019

AbstractAn unmet clinical need in solid tumor cancers is the ability to harness the intrinsic spatial information in primary tumors that can be exploited to optimize prognostics, diagnostics and therapeutic strategies for precision medicine. We have developed a transformational spatial analytics (SpAn) computational and systems biology platform that predicts clinical outcomes and captures emergent spatial biology that can potentially inform therapeutic strategies. Here we apply SpAn to primary tumor tissue samples from a cohort of 432 chemo-naïve colorectal cancer (CRC) patients iteratively labeled with a highly multiplexed (hyperplexed) panel of fifty-five fluorescently tagged antibodies. SpAn predicted the 5-year risk of CRC recurrence with a mean area under the ROC curve of 88.5% (SE of 0.1%), significantly better than current state-of-the-art methods. SpAn also inferred the emergent network biology of the tumor spatial domains revealing a synergistic role of known features from CRC consensus molecular subtypes that will enhance precision medicine.
Peptidoglycan associated cyclic lipopeptide disrupts viral infectivity
Authors: Johnson Bryan A. , Hage Adam , Kalveram Birte , Mears Megan , Plante Jessica A. , Rodriguez Sergio E. , Ding Zhixia , Luo Xuemei , Bente Dennis , Bradrick Shelton S. , Freiberg Alexander N. , Popov Vsevolod , Rajsbaum Ricardo , Rossi Shannan , Russell William K. , Menachery Vineet D. 
Published: May 2019

AbstractEnteric viruses exploit bacterial components including lipopolysaccharides (LPS) and peptidoglycan (PG) to facilitate infection in humans. With origins in the bat enteric system, we wondered if severe acute respiratory syndrome-coronavirus (SARS-CoV) or Middle East respiratory syndrome-CoV (MERS-CoV) also use bacterial components to modulate infectivity. To test this question, we incubated CoVs with LPS and PG and evaluated infectivity finding no change following LPS treatment. However, PG from B. subtilis reduced infection >10,000-fold while PG from other bacterial species failed to recapitulate this. Treatment with an alcohol solvent transferred inhibitory activity to the wash and mass spectrometry revealed surfactin, a cyclic lipopeptide antibiotic, as the inhibitory compound. This antibiotic had robust dose- and temperature-dependent inhibition of CoV infectivity. Mechanistic studies indicated that surfactin disrupts CoV virion integrity and surfactin treatment of the virus inoculum ablated infection in vivo. Finally, similar cyclic lipopeptides had no effect on CoV infectivity and the inhibitory effect of surfactin extended broadly to enveloped viruses including influenza, Ebola, Zika, Nipah, Chikungunya, Una, Mayaro, Dugbe, and Crimean-Congo hemorrhagic fever viruses. Overall, our results indicate that peptidoglycan-associated surfactin has broad virucidal activity and suggest bacteria byproducts may negatively modulate virus infection.ImportanceIn this manuscript, we considered a role for bacteria in shaping coronavirus infection. Taking cues from studies of enteric viruses, we initially investigated how bacterial surface components might improve CoV infection. Instead, we found that peptidoglycan-associated surfactin is a potent viricidal compound that disrupts virion integrity with broad activity against enveloped viruses. Our results indicate that interactions with commensal bacterial may improve or disrupt viral infections highlighting the importance of understanding these microbial interactions and their implications for viral pathogenesis and treatment.
Interspecific introgression mediates adaptation to whole genome duplication
Authors: Marburger Sarah , Monnahan Patrick , Seear Paul J. , Martin Simon H. , Koch Jordan , Paajanen Pirita , Bohutínská Magdalena , Higgins James D. , Schmickl Roswitha , Yant Levi 
Published: May 2019

AbstractAdaptive gene flow is a consequential evolutionary phenomenon across all kingdoms of life. While recognition of widespread gene flow is growing, examples lack of bidirectional gene flow mediating adaptations at specific loci that cooperatively manage core cellular processes. We previously described concerted molecular changes among physically interacting members of the meiotic machinery controlling crossover number and distribution upon adaptation to whole genome duplication (WGD) inArabidopsis arenosa. Here we conduct a population genomic study to test the hypothesis that escape from extinction following the trauma of WGD was mediated by adaptive gene flow betweenA. arenosaand its congenerArabidopsis lyrata. We show thatA. lyrataunderwent WGD more recently thanA. arenosa, indicating that specific pre-adapted alleles donated byA. arenosaunderwent selection and rescued the nascentA. lyratatetraploids from early extinction. At the same time, we detect specific signals of gene flow in the opposite direction at other functionally interacting gene coding loci that display dramatic signatures of selective sweep in both tetraploid species. Cytological analysis shows that A. lyrata tetraploids exhibit similar levels of meiotic stability asA. arenosatetraploids. Taken together, these data indicate that bidirectional gene flow allowed for an escape from extinction of the young autopolyploids, especially the rare tetraploidA. lyrata, and suggest that the merger of these species is greater than the sum of their parts.
A large-scale resource for tissue-specific CRISPR mutagenesis inDrosophila
Authors: Port Fillip , Strein Claudia , Stricker Mona , Rauscher Benedikt , Heigwer Florian , Zhou Jun , Beyersdörffer Celine , Frei Jana , Hess Amy , Kern Katharina , Malamud Roberta , Pavlovic Bojana , Rädecke Kristin , Schmitt Lukas , Voos Lukas , Valentini Erica , Boutros Michael 
Published: May 2019

SUMMARYGenetic screens are powerful tools for the functional annotation of genomes. In the context of multicellular organisms, interrogation of gene function is greatly facilitated by methods that allow spatial and temporal control of gene abrogation. Here, we describe a large-scale transgenic short guide (sg) RNA library for efficient CRISPR-based disruption of specific target genes in a constitutive or conditional manner. The library consists currently of more than 2600 plasmids and 1600 fly lines with a focus on targeting kinases, phosphatases and transcription factors, each expressing two sgRNAs under control of the Gal4/UAS system. We show that conditional CRISPR mutagenesis is robust across many target genes and can be efficiently employed in various somatic tissues, as well as the germline. In order to prevent artefacts commonly associated with excessive amounts of Cas9 protein, we have developed a series of novel UAS-Cas9 transgenes, which allow fine tuning of Cas9 expression to achieve high gene editing activity without detectable toxicity. Functional assays, as well as direct sequencing of genomic sgRNA target sites, indicates that the vast majority of transgenic sgRNA lines mediate efficient gene disruption. Furthermore, we conducted the so far largest fully transgenic CRISPR screen in any metazoan organism, which further supported the high efficiency and accuracy of our library and revealed many so far uncharacterized genes essential for development.
Structural state recognition facilitates tip tracking of EB1 at growing microtubule ends in cells
Authors: Reid Taylor A. , Coombes Courtney , Mukherjee Soumya , Goldblum Rebecca R. , White Kyle , Parmar Sneha , McClellan Mark , Zanic Marija , Courtemanche Naomi , Gardner Melissa K. 
Published: May 2019

AbstractThe microtubule binding protein EB1 specifically targets the growing ends of microtubules in cells, where EB1 facilitates the interactions of cellular proteins with microtubule plus-ends. Microtubule end targeting of EB1 has been attributed to high affinity binding of EB1 to GTP-tubulin that is present at growing microtubule ends. However, our 3D single-molecule diffusion simulations predicted a ∼6000% increase in EB1 arrivals to open, tapered microtubule tip structures relative to closed lattice conformations. Using quantitative fluorescence, single-molecule, and electron microscopy experiments, we found that the binding of EB1 onto opened, structurally disrupted microtubules was dramatically increased relative to closed, intact microtubules, regardless of hydrolysis state. Correspondingly, in cells, the conversion of growing microtubule ends from a tapered into a blunt configuration resulted in reduced EB1 targeting. Together, our results suggest that microtubule structural recognition, based on a fundamental diffusion-limited binding model, facilitates the tip tracking of EB1 at growing microtubule ends.
Parkin deficiency perturbs striatal circuit dynamics
Authors: Baaske Magdalena K. , Kramer Edgar R. , Meka Durga Praveen , Engler Gerhard , Engel Andreas K. , Moll Christian K.E. 
Published: May 2019

AbstractLoss-of-function mutations in the parkin-encoding PARK2 gene cause young-onset, autosomal recessive Parkinson’s disease (PD). Here, we investigated how parkin mutations affect cortico-basal ganglia circuit dynamics and cell-type-specific functional connectivity by recording simultaneously from motor cortex, striatum and globus pallidus (GP) in anesthetized parkin-mutant mice.While ongoing activity of presumed striatal spiny projection neurons and their downstream counterparts in the GP was not different from controls, parkin deficiency had a differential impact on striatal interneurons: In parkin-mutant mice, tonically active neurons displayed elevated activity levels. Baseline firing of transgenic striatal fast spiking interneurons (FSI), on the contrary, was reduced and the correlational structure of the FSI microcircuitry was disrupted. The entire transgenic striatal microcircuit showed enhanced and phase-shifted phase coupling to slow (1-3Hz) cortical population oscillations. Unexpectedly, local field potentials recorded from striatum and GP of parkin-mutant mice robustly displayed amplified beta oscillations (∼22Hz), phase-coupled to cortex. Moreover, parkin deficiency selectively increased spike-field coupling of FSIs to beta oscillations.Our findings suggest that loss of parkin function leads to amplifications of synchronized cortico-striatal oscillations and intrastriatal reconfiguration of interneuronal circuits. This presymptomatic disarrangement of dynamic functional connectivity may precede nigro-striatal neurodegeneration and predispose to imbalance of striatal outflow accompanying symptomatic PD.
PRAM: a novel pooling approach for discovering intergenic transcripts from large-scale RNA sequencing experiments
Authors: Liu Peng , Soukup Alexandra A. , Bresnick Emery H. , Dewey Colin N. , Keleş Sündüz 
Published: May 2019

AbstractPublicly available RNA-seq data is routinely used for retrospective analysis to elucidate new biology. Novel transcript discovery enabled by joint examination of large collections of RNA-seq datasets has emerged as one such analysis. Current methods for transcript discovery rely on a ‘2-Step’ approach where the first step encompasses building transcripts from individual datasets, followed by the second step that merges predicted transcripts across datasets. To increase the power of transcript discovery from large collections of RNA-seq datasets, we developed a novel ‘1-Step’ approach named Pooling RNA-seq and Assembling Models (PRAM) that builds transcript models from pooled RNA-seq datasets. We demonstrate in a computational benchmark that ‘1-Step’ outperforms ‘2-Step’ approaches in predicting overall transcript structures and individual splice junctions, while performing competitively in detecting exonic nucleotides. Applying PRAM to 30 human ENCODE RNA-seq datasets identified unannotated transcripts with epigenetic and RAMPAGE signatures similar to those of recently annotated transcripts. In a case study, we discovered and experimentally validated new transcripts through the application of PRAM to mouse hematopoietic RNA-seq datasets. Notably, we uncovered new transcripts that share a differential expression pattern with a neighboring genePik3cgimplicated in human hematopoietic phenotypes, and we provided evidence for the conservation of this relationship in human. PRAM is implemented as an R/Bioconductor package and is available athttps://bioconductor.org/packages/pram.
HA Nanocarriers Mediate HepG2 Vaccine Induction of hGM-CSF Gene Antitumor effect study
Authors: Robert Leah , Gupta David 
Published: May 2019

AbstractThis report developed a novel method to observe the anti-tumor effect of HA nanoparticle carrier-mediated HepG2 cell vaccine transfected with hGM-CSF gene in vitro, and provide evidence for the clinical application of hGM-CSF gene-modified HepG2 cell vaccine. HA nanoparticle-mediated hGM-CSF gene transfection of HepG2 cells was used to prepare HepG2 cell vaccine transfected with GMCSF gene. Human PBMC were isolated by density gradient centrifugation and human PBMC were induced in vitro. The proliferative activity of PBMC and the killing effect on HepG2 cells were determined by WST-1 method. The positive expression rates of CD4+ and CD8+ were analyzed by flow cytometry, and the secretion of INF-γ was determined by ELISA. WST-1 results showed that the transgenic HepG2 vaccine induced PBMC proliferation, and its proliferation rate was better than that of wild-type vaccine. The induced PBMC had a higher killing rate against HepG2 than the wild-type vaccine group and each blank. In the control group, FCM results showed that the positive expression rates of CD4+ and CD8+ in the transgenic HepG2 vaccine group were higher than those in the wild-type vaccine group and each blank control group. The ELISA results showed that the IFN-γ content in the transgenic PBMC culture supernatant was 1989.76. +/− 254.21 pg/ml, higher than the wild-type vaccine group and each blank control group.
Social foraging extends associative odor-food memory expression in an automated learning assay for Drosophila
Authors: Sehdev Aarti , Mohammed Yunusa G. , Tafrali Cansu , Szyszka Paul 
Published: May 2019

ABSTRACTAnimals socially interact during foraging and share information about the quality and location of food sources. The mechanisms of social information transfer during foraging have been mostly studied at the behavioral level, and its underlying neural mechanisms are largely unknown. The fruit fly Drosophila melanogaster has become a model for studying the neural bases of social information transfer, as fruit flies show a rich repertoire of social behaviors and provide a well-developed genetic toolbox to monitor and manipulate neuronal activity. Social information transfer has already been characterized for fruit flies’ egg laying, mate choice, foraging and aversive associative learning, however the role of social information transfer on associative odor-food learning during foraging are unknown. Here we present an automated learning and memory assay for walking flies that allows studying the effect of group size on social interactions and on the formation and expression of associative odor-food memories. We found that both inter-fly attraction and the duration of odor-food memory expression increase with group size. We discuss possible behavioral and neural mechanisms of this social effect on odor-food memory expression. This study opens up opportunities to investigate how social interactions are relayed in the neural circuitry of learning and memory expression.
In Silico Analysis of Ixodid Tick Aqauporin-1 Protein as a Candidate Anti-Tick Vaccine Antigen
Authors: Ndekezi Christian , Nkamwesiga Joseph , Ochwo Sylvester , Kimuda Magambo Phillip , Mwiine Frank Norbert , Tweyongyere Robert , Amanyire Wilson , Muhanguzi Dennis 
Published: May 2019

AbstractTicks are arthropod vectors of pathogens of both Veterinary and Public health importance. Ticks are largely controlled by acaricide application. However, acaricide efficacy is hampered by high cost, the need for regular application and selection of multi-acaricide resistant tick populations. In light of this, future tick control approaches are poised to rely on integration of rational acaricide application and other methods such as vaccination. To contribute to systematic research-guided efforts to produce anti-tick vaccines, we carried out an in silico tick Aquaporin-1 protein (AQP1) analysis to identify unique tick AQP1 peptide motifs that can be used in future peptide anti-tick vaccine development. We used multiple sequence alignment (MSA), motif analysis, homology modeling, and structural analysis to identify unique tick AQP1 peptide motifs. BepiPred, Chou & Fasman-Turn, Karplus & Schulz Flexibility and Parker-Hydrophilicity prediction models were used to asses these motifs’ abilities to induce antibody mediated immune responses. Tick AQP1 (MK334178) protein homology was largely similar to the bovine AQP1 (PDB:1J4N) (23% sequence similarity; Structural superimposition RMS=1.475). The highest similarities were observed in the transmembrane domains while differences were observed in the extra and intra cellular protein loops. Two unique tick AQP1 (MK334178) motifs, M7 (residues 106-125, p=5.4e-25) and M8 (residues 85-104, p=3.3e-24) were identified. These two motifs are located on the extra-cellular AQP1 domain and showed the highest Parker-Hydrophilicity prediction immunogenic scores of 1.153 and 2.612 respectively. The M7 and M8 motifs are a good starting point for the development of potential peptide-based anti-tick vaccine. Further analyses such as in vivo immunization assays are required to validate these findings.
Exploring family business decline with socioemotional wealth perspective
Authors: Llanos-Contreras Orlando Antonio , Jabri Muayyad 
Published: May 2019

PurposeThe purpose of this paper is to determine how family and business priorities influence organisational decline and turnaround in a family business.Design/methodology/approachFollowing critical realism as philosophical orientation, this research is based on an exploratory single case study.FindingsThis research identified specific socioemotional wealth priorities driving this organisation decline and turnaround. The study also determined how the family and business dynamic leads to decisions that first trigger the organisational decline and then explain the successful implementation of turnaround strategies.Research limitation/implicationsFindings of this research provide limited and contingent theoretical generalisation. Accordingly, replication and further quantitative research is required for a better understanding of this phenomenon.Practical implicationsManagers can benefit from this paper by noting which behaviour could lead to organisational decline and which factors could lead to a turnaround. Similarly, managers can learn about the importance of the alignment of socioemotional wealth priorities as a critical response factor to determine whether to follow exit strategies or turnaround (succession) actions.Originality valueThe study contributes to the organisational decline literature and family business literature. It advances the understanding of how family businesses should balance family and business priorities to avoid organisational decline and identify strategies successfully implemented for turning around.
Resilience in Talcahuano, Chile: appraising local disaster response
Authors: Engel Karen Elisabeth , Warner Jeroen Frank 
Published: May 2019

PurposeThe purpose of this paper is to present the findings of a qualitative and exploratory study aimed at learning more about the local forms of resilience that emerged in two localities (one rural and one urban locality) in Talcahuano, Chile, in response to the major earthquake and devastating tsunami that hit them on February 27, 2010.Design/methodology/approachTo ensure that people’s experiences remained leading throughout the study, data were collected in the field by the first author over a period of 13 months using a variety of qualitative methods. The primary methods were observation, participation and semi-structured interviews with a variety of actors, ranging from community members to local leaders and emergency professionals. For the analysis, a scheme was used that categorizes manifested resilience using two dimensions: damage and responsiveness. Since this scheme has been mostly used to evaluate tree populations, it was adapted to fit the appraisal of a social system.FindingsThe findings suggest that damage levels in the two communities were similar, but that the responsiveness was not. One locality revealed high levels of resilience, while the other exposed increased susceptibility to future similar events.Originality/valueThis research initiative was relevant because it exposed actual resilience. Also, the specificities of the findings enable insights about prevalent vulnerability, in particular the local capacity of response, and that can be used to elaborate concrete earthquake/tsunami disaster scenarios and design local disaster risk reduction interventions.
An exploratory temporal analysis of the lodging market and state economic recovery from Hurricane Sandy (The lodging market recovery from Hurricane Sandy)
Authors: Choi Danny Woosik , Lee Seoki , Singal Manisha 
Published: May 2019

PurposeThe purpose of this study is to examine how the lodging market and the state economy affected by Hurricane Sandy have recovered from the damages sustained. Specifically, this study examines and predicts the influence of revenue management key performance indicators (KPIs) on recovery and lodging revenue in the affected states and the states’ economies. These KPIs include average daily rate (ADR), occupancy and revenue per available room (RevPAR).Design/methodology/approachSecondary financial data were collected for the states most damaged by Hurricane Sandy. Subsequently, pooled Ordinary Least Square (OLS) regression was conducted combining time and non-time dependent variables based on the states and radius from the landfall.FindingsThe results indicate that although the lodging market and the state economies have recovered since the onslaught of Hurricane Sandy, certain KPIs still need to improve.Practical implicationsManagerial implications are suggested in terms of dynamic pricing, market-based recovery, the KPIs, federal aid and facility management.Originality/valueDespite its importance, research on the effects of climate change in the hospitality context has not actively progressed after Hurricane Katrina. Time and non-time dependent variables are combined in this analysis to gain a richer understanding of the impacts and recovery of KPIs on the revenue in the lodging market and the revenue on states’ economies. Additional analysis based on the radius from the landfall of the hurricane was performed to examine the impact and recovery based on geographical proximity.