bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic investigation reveals contaminated detergent as the source of an ESBL-producing Klebsiella michiganensis outbreak in a neonatal unit
Authors: Chapman Paul , Forde Brian M. , Roberts Leah W. , Bergh Haakon , Vesey Debra , Jennison Amy V. , Moss Susan , Paterson David L. , Beatson Scott A. , Harris Patrick N. A.
Published: March 2019

Background

Klebsiella species are problematic pathogens in neonatal units and may cause outbreaks, for which sources of transmission can be challenging to elucidate. We describe the use of whole genome sequencing (WGS) to investigate environmental sources of transmission during an outbreak of extended-spectrum-β-lactamase (ESBL)-producing Klebsiella michiganensis colonizing neonates.

Methods

Ceftriaxone-resistant Klebsiella spp. isolated from neonates (or their mothers) and the hospital environment were included. Short-read (Illumina) and long-read (MinION, Oxford Nanopore Technologies) sequencing was used to confirm species taxonomy, define antimicrobial resistance genes and determine phylogenetic relationships using single nucleotide polymorphism (SNP) profiling.

Results

A total of 21 organisms (10 patient-derived and 11 environmental isolates) were sequenced. Standard laboratory methods identified the outbreak strain as an ESBL-producing Klebsiella oxytoca, but taxonomic assignment from WGS data suggested closer identity to Klebsiella michiganensis. Strains isolated from baby bath drains and multiple detergent dispensing bottles were either identical or closely related by SNP comparison. Detergent bottles contaminated by K. michiganensis had been used for washing milk-expressing equipment. No new cases were identified once the detergent bottles were removed and the baby baths decommissioned.

Conclusions

Environmental reservoirs may be an important source in outbreaks of multi-drug resistant organisms. WGS, in conjunction with traditional epidemiological investigation, can be instrumental in revealing routes of transmission and guiding infection control responses.

Key points

K. michiganensis can be misidentified as K. oxytoca and is probably under-recognized as a nosocomial pathogen

Whole genome sequencing of neonatal and environmental isolates during an outbreak of ESBL-producing K. michiganensis confirmed contaminated detergent and sinks to be the source
Integrating deep and radiomics features in cancer bioimaging
Authors: Bizzego A. , Bussola N. , Salvalai D. , Chierici M. , Maggio V. , Jurman G. , Furlanello C.
Published: March 2019

Almost every clinical specialty will use artificial intelligence in the future. The first area of practical impact is expected to be the rapid and accurate interpretation of image streams such as radiology scans, histo-pathology slides, ophthalmic imaging, and any other bioimaging diagnostic systems, enriched by clinical phenotypes used as outcome labels or additional descriptors. In this study, we introduce a machine learning framework for automatic image interpretation that combines the current pattern recognition approach (“radiomics”) with Deep Learning (DL). As a first application in cancer bioimaging, we apply the framework for prognosis of locoregional recurrence in head and neck squamous cell carcinoma (N=298) from Computed Tomography (CT) and Positron Emission Tomography (PET) imaging. The DL architecture is composed of two parallel cascades of Convolutional Neural Network (CNN) layers merging in a softmax classification layer. The network is first pretrained on head and neck tumor stage diagnosis, then finetuned on the prognostic task by internal transfer learning. In parallel, radiomics features (e.g., shape of the tumor mass, texture and pixels intensity statistics) are derived by predefined feature extractors on the CT/PET pairs. We compare and mix deep learning and radiomics features into a unifying classification pipeline (RADLER), where model selection and evaluation are based on a data analysis plan developed in the MAQC initiative for reproducible biomarkers. On the multimodal CT/PET cancer dataset, the mixed deep learning/radiomics approach is more accurate than using only one feature type, or image mode. Further, RADLER significantly improves over published results on the same data.
RexAB is essential for the mutagenic repair ofStaphylococcus aureusDNA damage caused by co-trimoxazole
Authors: Clarke Rebecca S. , Bruderer Maya S. , Ha Kam Pou , Edwards Andrew M.
Published: March 2019

Co-trimoxazole (SXT) is a combination therapeutic that consists of sulfamethoxazole and trimethoprim that is increasingly used to treat skin and soft-tissue infections caused by methicillin-resistantStaphylococcus aureus(MRSA). However, the use of SXT is limited to the treatment of low-burden, superficialS. aureusinfections and its therapeutic value is compromised by the frequent emergence of resistance. As a first step towards the identification of approaches to enhance the efficacy of SXT, we examined the role of bacterial DNA repair in antibiotic susceptibility and mutagenesis. This revealed that SXT caused DNA damage inS. aureusvia both thymidine limitation and the generation of reactive oxygen species. Then, using mutants defective for DNA repair, it was found that repair of this damage required the RexAB nuclease/helicase complex, indicating that SXT causes DNA double-strand breaks. Furthermore, RexAB-mediated DNA repair led to induction of the SOS response, which resulted in an increased mutation rate and may explain the frequent emergence of resistant strains during SXT therapy. In summary, this work determined that SXT causes DNA damage inS. aureusvia both thymidine limitation and oxidative stress, which is repaired by the RexAB complex, leading to induction of the mutagenic SOS response. Small molecule inhibitors of RexAB could therefore have therapeutic value by increasing the efficacy of SXT and decreasing the emergence of drug-resistance during treatment of infections caused byS. aureus.
Effect of task and attention on neural tracking of speech
Authors: Vanthornhout Jonas , Decruy Lien , Francart Tom
Published: March 2019

EEG-based measures of neural tracking of natural running speech are becoming increasingly popular to investigate neural processing of speech and have applications in audiology. When the stimulus is a single speaker, it is usually assumed that the listener actively attends to and understands the stimulus. However, as the level of attention of the listener is inherently variable, we investigated how it affected neural envelope tracking. Using a movie as a distractor, we varied the level of attention while we estimated neural envelope tracking. We varied the intelligibility level by adding stationary noise. We found a significant difference in neural envelope tracking between the condition with maximal attention and the movie condition. This difference was most pronounced in the right-frontal region of the brain. The degree of neural envelope tracking was highly correlated with the stimulus signal-to-noise ratio, even in the movie condition. This could be due to residual neural resources to passively attend to the stimulus. When envelope tracking is used to objectively measure speech understanding this means that the procedure can be made more enjoyable and feasible by letting participants watch a movie during stimulus presentation.
Temperature accounts for the biodiversity of a hyperdiverse group of insects in urban Los Angeles
Authors: McGlynn Terrence P. , Meineke Emily K. , Bahlai Christie A. , Li Enjie , Hartop Emily A. , Adams Benjamin J. , Brown Brian V.
Published: March 2019

The urban heat island effect is a worldwide phenomenon that has been linked to species’ distributions and abundances in cities. However, effects of urban heat on biotic communities are nearly impossible to disentangle from effects of land cover in most cases because hotter urban sites also have less vegetation and more impervious surfaces than cooler sites within cities. We sampled phorid flies, one of the largest, most biologically diverse families of true flies (Insecta: Diptera: Phoridae), at 30 sites distributed within the central Los Angeles Basin, where we found that temperature and the density of urban land cover are decoupled. Abundance, richness, and community composition of phorids inside urban Los Angeles were most parsimoniously accounted for by mean air temperature in the week preceding sampling. Sites with intermediate mean temperatures had more phorid fly individuals and higher richness. Communities were more even at urban sites with lower minimum temperatures and sites located further away from natural areas, suggesting that communities separated from natural source populations may be more homogenized. Species composition was best explained by minimum temperature. Inasmuch as warmer areas within cities can predict future effects of climate change, phorid fly communities are likely to shift non-linearly under future climates in more natural areas. Exhaustive surveys of biotic communities within cities, such as the one we describe here, can provide baselines for determining the effects of urban and global climate warming as they intensify.
Content-based dissociation of hippocampal involvement in prediction
Authors: Kok Peter , Rait Lindsay I. , Turk-Browne Nicholas B.
Published: March 2019

It has recently become clear that one of the key functions of the hippocampus is to predict future inputs. In line with this, previous research has revealed prediction-related signals in the hippocampus for complex visual objects, such as fractals and abstract shapes. Based on this, it has been suggested that the hippocampus may generate perceptual expectations, especially when relying on rapidly learned predictive associations between arbitrary stimuli. However, it is currently unknown whether the hippocampus implements general-purpose computations that subserve all associative predictions, regardless of stimulus properties, or whether the involvement of the hippocampus is stimulus-dependent. To investigate this, we exposed male and female human participants to complex auditory cues predicting either the shape of a complex object (Experiment 1) or the orientation of a simple line grating (Experiment 2). We measured brain activity using high-resolution functional magnetic resonance imaging (fMRI), in combination with inverted encoding models to reconstruct shape and orientation representations in visual cortex and the hippocampus. Our results revealed that expectations about shape and orientation evoked distinct representations in the hippocampus. For complex shapes, the hippocampus represented which shape was expected, potentially serving as a source of top-down predictions. In contrast, for simple gratings, the hippocampus represented only unexpected orientations, more reminiscent of a prediction error. We discuss several potential explanations for this dissociation, concluding that the computational role of the hippocampus in predictive processing depends upon the nature and complexity of stimuli.

Significance Statement

To deal with the noisy and ambiguous sensory signals received by our brain, it is crucial to use prior knowledge of the world to guide perception. Previous research suggests that the hippocampus is involved in predicting upcoming visual stimuli based on prior knowledge. In the current study, we show that hippocampal prediction is specific to expectations of complex objects, whereas for simple features the hippocampus generates an opposite prediction error signal instead. These findings demonstrate that the computational role of the hippocampus can be content-sensitive and refine our understanding of the involvement of memory systems in predictive processing.
Synthetic lethality screening identifies FDA-approved drugs that overcome ATP7B-mediated tolerance of tumor cells to cisplatin
Authors: Mariniello Marta , Petruzzelli Raffaella , Wanderlingh Luca G. , La Montagna Raffaele , Carissimo Annamaria , Pane Francesca , Amoresano Angela , Medina Diego , Polishchuk Roman S.
Published: March 2019

Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease.

To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the resistant ovarian carcinoma cell line IGROV-CP20. Using a synthetic lethality approach we identified and validated three hits (Tranilast, Telmisartan and Amphotericin B) that could reduce cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these included key molecular players operating in the distribution of platinum to different intracellular compartments. In particular, Tranilast was found to suppress ATOX1 and, as a consequence, ATOX1-mediated trafficking of ATP7B in response to cisplatin.

Considering the well-known safety profiles of Tranilast, Telmisartan and Amphotericin B, these drugs emerge as potential candidates that might be used for the rapid development of new therapeutic strategies to overcome resistance of tumors to Pt-based chemotherapy.
Effect of time-series length and resolution on abundance- and trait-based early warning signals of population declines
Authors: Arkilanian A.A. , Clements C.F. , Ozgul A. , Baruah G.
Published: March 2019

Natural populations are increasingly threatened with collapse at the hands of anthropogenic effects. Predicting population collapse with the help of generic early warning signals (EWS) may provide a prospective tool for identifying species or populations at highest risk. However, pattern-to-process methods such as EWS have a multitude of challenges to overcome to be useful, including the low signal to noise ratio of ecological systems and the need for high quality time-series data. The inclusion of trait dynamics with EWS has been proposed as a more robust tool to predict population collapse. However, the length and resolution of available time series are highly variable from one system to another, especially when generation time is considered. As yet it remains unknown how this variability with regards to generation time will alter the efficacy of EWS. Here we take both a simulation- and experimental-based approach to assess the impacts of relative time-series length and resolution on the forecasting ability of EWS. We show that EWS’ performance decreases with decreasing length and resolution. Our simulations suggest a relative time-series length between ten and five generations and a resolution of half a generation are the minimum requirements for accurate forecasting by abundance-based EWS. However, when trait information is included alongside abundance-based EWS, we find positive signals at lengths and resolutions half of what was required without them. We suggest that, in systems where specific traits are known to affect demography, trait data should be monitored and included alongside abundance data to improve forecasting reliability.
Plant photoreceptors and their signaling components compete for binding to the ubiquitin ligase COP1 using their VP-peptide motifs
Authors: Lau Kelvin , Podolec Roman , Chappuis Richard , Ulm Roman , Hothorn Michael
Published: March 2019

Plants sense different parts of the sun’s light spectrum using specialized photoreceptors, many of which signal through the E3 ubiquitin ligase COP1. Photoreceptor binding modulates COP1’s ubiquitin ligase activity towards transcription factors. Here we analyze why many COP1-interacting transcription factors and photoreceptors harbor sequence-divergent Val-Pro (VP) peptide motifs. We demonstrate that VP motifs enable different light signaling components to bind to the WD40 domain of COP1 with various binding affinities. Crystal structures of the VP motifs of the UV-B photoreceptor UVR8 and the transcription factor HY5 in complex with COP1, quantitative binding assays and reverse genetic experiments together suggest that UVR8 and HY5 compete for the COP1 WD40 domain. Photoactivation of UVR8 leads to high-affinity cooperative binding of its VP domain and its photosensing core to COP1, interfering with the binding of COP1 to its substrate HY5. Functional UVR8 – VP motif chimeras suggest that UV-B signaling specificity resides in the UVR8 photoreceptor core, not its VP motif. Crystal structures of different COP1 – VP peptide complexes highlight sequence fingerprints required for COP1 targeting. The functionally distinct blue light receptors CRY1 and CRY2 also compete with downstream transcription factors for COP1 binding using similar VP-peptide motifs. Together, our work reveals that photoreceptors and their components compete for COP1 using a conserved displacement mechanism to control different light signaling cascades in plants.
What the odor is not: Estimation by elimination
Authors: Singh Vijay , Tchernookov Martin , Balasubramanian Vijay
Published: March 2019

Olfactory systems use a small number of broadly sensitive receptors to combinatorially encode a vast number of odors. We propose a method of decoding such distributed representations by exploiting a statistical fact: receptors that do not respond to an odor carry more information than receptors that do because they signal the absence of all odorants that bind to them. Thus, it is easier to identify what the odor is not, rather than what the odor is. For realistic numbers of receptors, response functions, and odor complexity, this method of elimination turns an underconstrained decoding problem into a solvable one, allowing accurate determination of odorants in a mixture and their concentrations. We construct a neural network realization of our algorithm based on the structure of the olfactory pathway.
Investigating the Inhibitory Aspects of Metformin/Curcumin Co-Treatment through Convergence of In-Silico and In-Vitro Approaches
Authors: Afzali Farzaneh , Nayeri Zahra , Minuchehr Zarrin , Gardaneh Mossa
Published: March 2019

Nearly 16% of people with breast cancer (BC) have Diabetes Mellitus type 2 (DM2) and are at a higher risk of death worldwide. Their common regulatory factors and functional mechanisms can be targeted applying multi-target drugs including Metformin (MTFN) and Curcumin (CURC). In this study, we used in-silico approaches to study the potential underlying mechanisms of this co-treatment strategy on BC and DM2 in order to introduce novel therapeutic targets.

The total number of 48 shared differentially expressed genes (17 up-regulated and 31 down-regulated) were identified through establishing diseases’ protein-protein network and BC RNA-sequencing expression data. The integration of functional clustering and pathway analyses revealed that the most involved cellular pathways and processes are regard to cells’ proliferation, death, migration, and response to external stimulus. Afterwards, the MTFN/CURC correlation and co-treatment optimization was probed through response surface methodology (RSM) based on MCF7 cell line and confirmed by MDA-MB-231. Combination index calculation by MTT viability assay proved supportive effects on both cell lines. The superior apoptotic potential of co-treatment compared to single treatments was shown on inhibition of MCF7 proliferation and induction of cell death demonstrated by cell body co-staining and flow cytometry as well as gene expression analysis via RT-PCR. Furthermore, wound-healing scratch assay showed that this co-treatment has a slightly higher effect on migration inhibition compared to single treatments.

In conclusion, our study used in-silico and in-vitro approaches and introduced a potential regulatory panel between BC and DM2. We also provided a linear model and equation that show the positive relation of drugs’ co-treatment. The proposed co-treatment strategy successfully controlled the biological processes under investigation.
Mapping the 3D genome through high speed single-molecule tracking of functional transcription factors in single living cells
Authors: Wollman Adam J. M. , Hedlund Erik G. , Shashkova Sviatlana , Leake Mark C.
Published: March 2019

How genomic DNA is organized within the cell nucleus is a long-standing question. We describe a single-molecule bioimaging method with super-resolution localization precision and very rapid millisecond temporal resolution, coupled to fully quantitative image analysis tools, to help to determine genome organization and dynamics using budding yeast Saccharomyces cerevisiae as a model eukaryotic organism. We utilize astigmatism imaging, a robust technique that enables extraction of 3D position data, on genomically encoded fluorescent protein reporters that bind to DNA. Our relatively straightforward method enables snapshot reconstructions of 3D architectures of single genome conformations directly in single functional living cells.
Evaluating genomic data for management of local adaptation in a changing climate: A lodgepole pine case study
Authors: Mahony Colin R. , MacLachlan Ian R. , Lind Brandon M. , Yoder Jeremy B. , Wang Tongli , Aitken Sally N.
Published: March 2019

The need for tools to cost-effectively identify adaptive variation within ecologically and economically important plant species is mounting as the detrimental effects of climate change become increasingly apparent. For crop and wild populations alike, mismatches between adaptive variation and climatic optima will reduce health, growth, survival, reproduction, and continued establishment. The ease with which land managers can quantify the relative importance of different climate factors or the spatial scale of local adaptation to climate will have direct implications for the potential of mitigating or resolving such risks. Using seed collected from 281 provenances of lodgepole pine (Pinus contorta) from across western Canada, we compare genomic data to phenotypic and climatic data to assess their effectiveness in characterizing the climatic drivers and spatial scale of local adaptation in this species. We find that genomic and climate data are nearly equivalent for describing local adaptation in seedling traits. We also find strong agreement between the climate variables associated with genomic variation and with 20-year heights from a long-term provenance trial, suggesting that genomic data may be a viable option for identifying climatic drivers of local adaptation where phenotypic data are unavailable. Genetic clines associated with cold injury occur at broad spatial scales, suggesting that standing variation of adaptive alleles for this and similar species does not require management at scales finer than are indicated by phenotypic data. This study demonstrates that genomic data are most useful when paired with phenotypic data, but can also fill some of the traditional roles of phenotypic data in management of species for which phenotypic trials are not feasible.
The caudate nucleus controls coordinated patterns of adaptive, context-dependent adjustments to complex decisions
Authors: Doi Takahiro , Fan Yunshu , Gold Joshua I. , Ding Long
Published: March 2019

Our decisions often need to balance what we observe and what we desire. However, our understanding of how and where in the brain such decisions are made remains limited. A prime candidate for integrating sensory observations and desired rewards, and a focus of many modeling studies, is the basal ganglia pathway, which is known to make separate contributions to perceptual decisions that require the interpretation of uncertain sensory evidence and value-based decisions that select among outcome options 1-16. Here we report direct evidence for a causal role for a major input station of the basal ganglia, the caudate nucleus, in incorporating reward context and uncertain visual evidence to guide adaptive decision-making. In monkeys making saccadic decisions based on visual motion evidence and asymmetric reward-choice associations 17, single caudate neurons encoded information about both the visual evidence and the asymmetric rewards. Electrical microstimulation at caudate sites with task-modulated activity during motion viewing affected how the visual and reward information was used to form the decision. The microstimulation effects included coordinated changes in multiple computational components of the decision process, mimicking the monkeys’ voluntary adjustments in response to the asymmetric reward contexts. These results imply that the caudate nucleus plays key roles in coordinating the deliberative decision process that balances external evidence and internal preferences to guide adaptive behavior.
Perturbation biology links temporal protein changes to drug responses in a melanoma cell line
Authors: Nyman Elin , Stein Richard R. , Jing Xiaohong , Wang Weiqing , Marks Benjamin , Zervantonakis Ioannis K. , Korkut Anil , Gauthier Nicholas P. , Sander Chris
Published: March 2019

Data-driven mathematical modeling of biological systems has enormous potential to understand and predict the interplay between molecular and phenotypic response to perturbation, and provides a rational approach to the nomination of therapies in complex diseases such as cancer. Melanoma is a particularly debilitating disease for which most therapies eventually fail as resistance to chemotherapy and targeted drugs develop. We have previously applied an iterative experimental-computational modeling approach, termed perturbation biology, to predict and test effective drug combinations in melanoma cell lines [1].

In this work, we extend our analysis framework to derive models of temporally-acquired perturbation data that do not require prior knowledge and explicit specification of the targets of individual drugs. Specifically, we characterize the response of the melanoma cell line A2058 to 54 cancer drug combinations at 8 logarithmically spaced time points from 10 minutes to 67 hours. At each time point, 124 antibodies of proteins and phospho-proteins with broad coverage of cancer-related pathways and two phenotypes (cell number and apoptosis) were measured. These data are used to infer interactions in ordinary differential equation-based models that capture temporal aspects of the drug perturbation data. This network representation of drug–protein, protein–protein, and protein–phenotype interactions can be used to identify new logical (not necessarily direct biochemical) interactions. The agreement between the predicted phenotypic response and corresponding data for unseen drug perturbations has a Pearson’s correlation coefficient of 0.79. We further use model predictions to nominate effective combination therapies and perform experimental validation of the highest ranked combinations.

This new data-driven modeling framework is a step forward in perturbation biology as it incorporates the temporal aspect of data. This work therefore opens the door to a new understanding of dynamic drug responses at a molecular level.
Effects of lipid composition on membrane distribution and permeability of natural quinones
Authors: Teixeira Murilo Hoias , Arantes Guilherme Menegon
Published: March 2019

Natural quinones are amphiphilic molecules that function as mobile charge carriers in biological energy transduction. Their distribution and permeation across membranes are important for binding to enzymatic complexes and for proton translocation. Here, we employ molecular dynamics simulations and free energy calculations with a carefully calibrated classical force-field to probe quinone distribution and permeation in a multicomponent bilayer trying to mimic the composition of membranes involved in bioenergetic processes. Ubiquinone, ubiquinol, plastoquinone and menaquinone molecules with short and long isoprenoid tails are simulated. We find that water penetration increases considerably in the less ordered and porous bilayer formed by di-linoleoyl (18:2) phospholipids, resulting in a lower free energy barrier for quinone permeation and faster transversal diffusion. In equilibrium, quinone and quinol heads localize preferentially near lipid glycerol groups, but do not perform specific contacts with lipid polar heads. Quinone distribution is not altered significantly by the quinone head, tail and lipid composition in comparison to a single-component bilayer. This study highlights the role of acyl chain unsaturation for molecular permeation and transversal diffusion across biological membranes.
Afferent-efferent connectivity between auditory brainstem and cortex accounts for poorer speech-in-noise comprehension in older adults
Authors: Bidelman Gavin M. , Price Caitlin N. , Shen Dawei , Arnott Stephen R. , Alain Claude
Published: March 2019

Age-related hearing loss leads to poorer speech comprehension, particularly in noise. Speech-in-noise (SIN) deficits among the elderly could result from weaker neural activity within, or poorer signal transmission between brainstem and auditory cortices. By recording neuroelectric responses from brainstem (BS) and primary auditory cortex (PAC), we show that beyond simply attenuating neural activity, hearing loss in older adults compromises the transmission of speech information between subcortical and cortical hubs of the auditory system. The strength of afferent BS→PAC neural signaling (but not the reverse efferent flow; PAC→BS) varied with mild declines in hearing acuity and this “bottom-up” functional connectivity robustly predicted older adults’ SIN perception. Our neuroimaging findings underscore the importance of brain connectivity, particularly afferent neural communication, in understanding the biological basis of age-related hearing deficits in real-world listening environments.
Functional metagenomics-guided discovery of potent Cas9 inhibitors in the human microbiome
Authors: Forsberg Kevin J. , Bhatt Ishan V. , Schmidtke Danica T. , Stoddard Barry L. , Kaiser Brett K. , Malik Harmit S.
Published: March 2019

CRISPR-Cas systems protect bacteria and archaea from phages and other mobile genetic elements, which use small anti-CRISPR (Acr) proteins to overcome CRISPR-Cas immunity. Because they are difficult to identify, the natural diversity and impact of Acrs on microbial ecosystems is underappreciated. To overcome this discovery bottleneck, we developed a high-throughput functional selection that isolatesacrgenes based on their ability to inhibit CRISPR-Cas function. Using this selection, we discovered ten DNA fragments from human oral and fecal metagenomes that antagonizeStreptococcus pyogenesCas9 (SpyCas9). The most potentacrdiscovered,acrIIA11, was recovered from aLachnospiraceaephage and is among the strongest known SpyCas9 inhibitors.AcrIIA11homologs are distributed across multiple bacterial phyla and many divergent homologs inhibit SpyCas9. We show that AcrIIA11 antagonizes SpyCas9 using a different mechanism than that of previously characterized inhibitors. Our study highlights the power of functional selections to uncover widespread Cas9 inhibitors within diverse microbiomes.
Geography Shapes the Population Genomics ofSalmonella entericaDublin
Authors: Fenske Gavin J. , Thachil Anil , McDonough Patrick L. , Glaser Amy , Scaria Joy
Published: March 2019

Salmonella enterica serotypeDublin (S.Dublin) is a bovine-adapted serotype that can cause serious systemic infections in humans. Despite the increasing prevalence of human infections and the negative impact on agricultural processes, little is known about the population structure of the serotype. To this end, we compiled a manually curated dataset comprising of 880S.Dublin genomes. Core genome phylogeny and ancestral state reconstruction revealed that region-specific clades dominate the global population structure ofS.Dublin. Strains ofS.Dublin in the UK are genomically distinct from US, Brazilian and African strains. The geographical partitioning impacts the composition of the core genome as well as the ancillary genome. Antibiotic resistance genes are almost exclusively found in US genomes and is mediated by an IncA/C2 plasmid. Phage content and theS.Dublin virulence plasmid were strongly conserved in the serotype. Comparison ofS.Dublin to a closely related serotype,Salmonella enterica serotypeEnteritidis, revealed thatS.Dublin contains 82 serotype specific genes that are not found inS. Enteritidis. Said genes encode metabolic functions involved in the uptake and catabolism of carbohydrates and virulence genes associated with type VI secretion systems and fimbria assembly respectively.

IMPORTANCE

S.Dublin is a bovine-adapted strain that can also cause human infections. TypicalS.Dublin human infections are characterized by invasion of tissue that ultimately traverses to the bloodstream causing life-threatening systemic cases. The preferred course of treatment for such infection is the administration of antibiotics. Thus, it is important to study the population structure of the serotype to monitor and identify which strains present the greatest threats to public health. Consequently, in this work, it was found thatS.Dublin genomic features are greatly influenced by the region in which they populate. Our analysis found that mostS.Dublin isolates from the US are distinct and have gained multidrug resistance through a new hybrid plasmid. Thus, it would be expected that infections in the US would respond less favorably to the first line of therapy and the region acts as the major source of a multidrug-resistantS.Dublin.
The splicing factor U2AF1 contributes to cancer progression through a noncanonical role in translation regulation
Authors: Palangat Murali , Anastasakis Dimitrios G. , Fei Dennis Liang , Lindblad Katherine E. , Bradley Robert , Hourigan Christopher S. , Hafner Markus , Larson Daniel R.
Published: March 2019

Somatic mutations in the genes encoding components of the spliceosome occur frequently in human neoplasms, including myeloid dysplasias and leukemias, and less often in solid tumors. One of the affected factors, U2AF1, is involved in splice site selection, and the most common change, S34F, alters a conserved nucleic acid-binding domain, recognition of the 3′ splice site, and alternative splicing of many mRNAs. However, the role that this mutation plays in oncogenesis is still unknown. Here, we uncovered a noncanonical function of U2AF1, showing that it directly binds mature mRNA in the cytoplasm and negatively regulates mRNA translation. This splicing-independent role of U2AF1 is altered by the S34F mutation, and polysome profiling indicates that the mutation affects translation of hundreds of mRNA. One functional consequence is increased synthesis of the secreted chemokine interleukin 8, which contributes to metastasis, inflammation, and cancer progression in mice and humans.
Wnt and Notch signaling govern self-renewal and differentiation in a subset of human glioblastoma stem cells
Authors: Rajakulendran Nishani , Rowland Katherine J. , Selvadurai Hayden J. , Ahmadi Moloud , Park Nicole I. , Naumenko Sergey , Dolma Sonam , Ward Ryan J. , So Milly , Lee Lilian , MacLeod Graham , Pasiliao Clarissa , Brandon Caroline , Clarke Ian D. , Cusimano Michael D. , Bernstein Mark , Batada Nizar , Angers Stephane , Dirks Peter B.
Published: March 2019

Developmental signal transduction pathways act diversely, with context-dependent roles across systems and disease types. Glioblastomas (GBMs), which are the poorest prognosis primary brain cancers, strongly resemble developmental systems, but these growth processes have not been exploited therapeutically, likely in part due to the extreme cellular and genetic heterogeneity observed in these tumors. The role of Wnt/βcatenin signaling in GBM stem cell (GSC) renewal and fate decisions remains controversial. Here, we report context-specific actions of Wnt/βcatenin signaling in directing cellular fate specification and renewal. A subset of primary GBM-derived stem cells requires Wnt proteins for self-renewal, and this subset specifically relies on Wnt/βcatenin signaling for enhanced tumor burden in xenograft models. In an orthotopic Wnt reporter model, Wnthi GBM cells (which exhibit high levels of βcatenin signaling) are a faster-cycling, highly self-renewing stem cell pool. In contrast, Wntlo cells (with low levels of signaling) are slower cycling and have decreased self-renewing potential. Dual inhibition of Wnt/βcatenin and Notch signaling in GSCs that express high levels of the proneural transcription factor ASCL1 leads to robust neuronal differentiation and inhibits clonogenic potential. Our work identifies new contexts for Wnt modulation for targeting stem cell differentiation and self-renewal in GBM heterogeneity, which deserve further exploration therapeutically.
Absorptive capacity as a confounder of the process of supply chain integration
Authors: Tarifa-Fernández Jorge , de-Burgos-Jimenez Jerónimo , Cespedes-Lorente José
Published: March 2019

Purpose

The purpose of this paper is to explore and advance on existing knowledge regarding supply chain integration (SCI) and absorptive capacity (AC). On the one hand, new elements, such as high-performance human resource practices (HPHRP) and internal integration (II) are proposed to foster AC within the supply chain. On the other hand, the study proposes a model and hypotheses to analyze the moderating effect of AC on the relationship between external SCI and supply chain performance.

Design/methodology/approach

Four hypotheses are formulated based on relevant literature. Data were collected from the horticultural marketing sector, using two different sources, a survey and archival data. A total of 99 responses were analyzed. Hierarchical multiple regressions were carried out to test the proposed hypotheses.

Findings

The results confirm that HPHRP are a crucial element when trying to increase the level of AC. In addition, the results show that AC has a moderating effect on the relationship between SCI and supply chain performance (both economic and financial). AC moderates the relationship between customer integration and economic performance.

Originality/value

This study examines the potential causes for the differences that exist in a firm’s ability to develop AC. Thus, on the one hand, HPHRP and II are proposed as triggers of AC, and on the other, AC is proposed as a moderator in the relationship between SCI and performance.
Reframing organizations through leadership communications: the four-frames of leadership viewed through motivating language
Authors: Holmes William T. , Scull W. Reed
Published: March 2019

Purpose

The purpose of this paper is to integrate the Bolman and Deal’s (2017) Four Frames of Reframing Organizations with the Mayfield and Mayfield (2018) Motivating Language Theory so that those who lead organizations can better do so and those who guide the improvement and development of organizations can better prepare organizational managers/leaders.

Design/methodology/approach

Through the fusion of the Four-Frames Assumptions and Motivating Language Categorical Forms into one integration table, linkages and connections between the two frameworks are identified.

Findings

The findings of this work provide a “voice” to the Four Frames of Reframing Organizations and extend the field Motivating Language Theory as the medium of leader praxis.

Research limitations/implications

The implications for researchers are new opportunities for research and teaching.

Practical implications

The implications for those in the field are new opportunities for leader development and training leading to improved outcomes for employees and organizations.

Originality/value

This is the first integration of the Four-Frames and Motivating Language Theory extending and enriching both fields.
Service gap in hotel website load performance
Authors: Stringam Betsy , Gerdes John
Published: March 2019

Purpose

The purpose of this paper is to investigate how well hotel website load time performance compared against customer expectation benchmarks. In a competitive market, service interactions are important. As customers move to mobile devices, the time to load a website is a critical part of the service delivery. Long load times can lead to poor service experiences, customer frustration and lost business. Hotel website load times on both mobile and desktop devices were examined and compared to service expectations.

Design/methodology/approach

The study used an online service to assess and compare website load performance using both desktop and mobile devices for 259 international hotel company and sub-brand websites.

Findings

The time to load hotel websites was significantly slower on mobile devices compared to desktops. Load times on both platforms exceeded 3 s, which is considered best practice. Long load times represent a service gap and can cause dissatisfaction resulting in a potential customer abandoning the website for a competitor’s site, thus affecting sales.

Research limitations/implications

While the population for the study was robust in size and contained most of the major hotel companies worldwide, it was not exhaustive. Data also represent a snapshot and will change over time. Load times vary based on test location, access device and network traffic. Additionally, web page load times and customer expectations will change as technology evolves.

Originality/value

Increased use of mobile devices for hotel reservations increases the importance of mobile service delivery. This is the first known study to measure hotel website load times for mobile devices, and to examine both mobile and desktop performance against best practice. The results of this study highlight a service gap, which can lead to loss of business. Given the consistency of the results, the authors suspect that this is an issue that has not been recognized within the industry. This study is valuable because it exposes an issue of website design not generally addressed in the hospitality industry, even though tools are available to monitor site performance.
Impact of test parameters on the water vapor permeability of textiles
Authors: Gidik Hayriye , Vololonirina Oly , Ghantous Rita Maria , Ankou Andreas
Published: March 2019

Purpose

Unlike other materials, textiles associate with aesthetic and mechanical properties such as flexibility and removability that allow them to be deployed or folded as required and which make them good candidates for clothing and furnishing but also, eventually, for other applications such as building. Actually, the clothing should ensure appropriate heat and mass transfers between the human body and its environment in order to maintain the thermo-physiological comfort. For that, it is important to determine water vapor permeability (WVP) of textile. Several normalized procedures with variants depending on the nature of the tested material exist to measure the WVP. One of the methods used is the “dish method” described by the British Standard (BS 7209). The purpose of this paper is to determine the influence of the test parameters on the WVP measurements.

Design/methodology/approach

Consequently, WVP of different textiles was measured while varying several parameters like: nature of fabrics, air layer thickness, vapor pressure gradient and air velocity.

Findings

A decrease in the WVP values was observed with an increase in the air layer thickness and the number of textile layers. On the other side, an increase in the water pressure gradient induces an increase in the WVP value. Finally, it was also observed that air velocity has an impact on the WVP measurements.

Originality/value

In addition to intrinsic properties of fabrics, i.e., nature of fiber, woven structure, the influence of the several extrinsic properties, i.e., the influence of the air layer thickness, the number of textile layers, the vapor pressure gradient and the air velocity, on the WVP were investigated. Some researchers have already investigated the impact of these parameters on the WVP measurement separately. However, this study presents a difference from other studies that it takes into account the influence of the both intrinsic and extrinsic properties on WVP. In addition to these, this work combine several extrinsic properties which are presented separately during other studies. The first time, in this study the influence of the air velocity on WVP was investigated. Results on both hydrophilic and hydrophobic fabrics showed a great variation in the results when varying the location of the cups inside the climatic chamber. This is the reason why future studies look at studying more deeply the effect of air velocity on the WVP properties on different types of fabrics by connecting WVP values with air velocity values. It is also planned to make tests with the rotation device and by fixing the value of the temperature and RH. The objective will be to obtain reliable values that do not take into account the effect of air velocity.
Selective industrial policies in China: investigating the choice of pillar industries
Authors: Barbieri Elisa , Di Tommaso Marco Rodolfo , Tassinari Mattia , Marozzi Marco
Published: March 2019

Purpose

China’s experience of industrial growth is noteworthy for several reasons, not least because it has made a massive use of selective industrial policies. The industrial development guidelines set by the Five-Year Plans are extensively based on the choice of “strategic” or “pillar” industries to be promoted and supported. What remains unclear is the way in which such industries are identified among many. The purpose of this paper is to propose a debate on how to improve the government choice of strategic sectors and suggests a methodology to make this choice more transparent and rigorous.

Design/methodology/approach

The methodology allows ranking the different industries according to their strategic importance in the Chinese economy. The authors employ an uncertainty analysis methodology to verify the robustness of the ranking.

Findings

The results point to a list of strategic sectors for China. Comparing the ranking of the strategic sectors to the list of strategic priorities described in the Twelfth Five-Year Plan, we find that, by and large, the ranking coincides with the list of strategic sectors of the Chinese government.

Social implications

The authors argue that improving the transparency and the rigor of the choice of pillar industries can be crucial for the Chinese government to maintain social legitimization in the transition to a “market” economy.

Originality/value

Very little is known about the choice of strategic sectors in China in the international literature. By addressing the debate on the choice of pillar industries in China, the paper discusses a topic scarcely studied offering a unique and original contribute.