bluuebunny/crossref_metadata_2025 huggingface dataset:
Mutant p63 affects epidermal cell identity through rewiring the enhancer landscape
Authors: Qu Jieqiong , Tanis Sabine , Smits Jos P.H. , Kouwenhoven Evelyn N. , Oti Martin , van den Bogaard Ellen H. , Logie Colin , Stunnenberg Hendrik G. , van Bokhoven Hans , Mulder Klaas , Zhou Huiqing
Published: August 2018

Transcription factor p63 is a key regulator of epidermal keratinocyte proliferation and differentiation. In humans mutations in p63 cause several developmental disorders with defects of ectoderm-derived structures including the epidermis. The underlying molecular mechanisms of these mutations however remain unclear. Here we characterized the transcriptome and epigenome from EEC syndrome patients carrying mutations in the p63 DNA-binding domain. The transcriptome of p63 mutant keratinocytes deviated from the normal epidermal cell identity. Epigenomic analyses showed that the deregulated gene expression in p63 mutant keratinocytes resulted from an altered enhancer landscape contributed by loss of p63-bound active enhancers and by unexpected gain of enhancers. The gained enhancers in mutant keratinocytes were frequently bound by deregulated transcription factors such as RUNX1. Reversing RUNX1 overexpression partially rescued deregulated gene expression as well as the enhancer distribution. Our findings support the pivotal role of p63 in controlling the enhancer landscape of epidermal keratinocytes and identify a novel mechanism whereby p63 DNA-binding mutations associated with EEC syndrome rewire the enhancer landscape and affect epidermal cell identity.
Correlates of cannabinoid concentrations, real-world driving, and driving-related skills
Authors: Johnson Mark B.
Published: August 2018

Research on the relationship between cannabis use and safe driving has produced mixed results. Most studies have focused exclusively on the presence or concentration of delta-9-tetrahydrocannabinol (THC), the primary psychoactive ingredient in the drug. However, cannabis is a complex substance, and both toxicological research and user experience suggests that some cannabis strains—often those with at least moderate levels of cannabidiol (CBD)— produce a different, more sedating “high” than cannabis strains with no or low levels of CBD. We hypothesize that the sedating properties of some high-CBD cannabis strains has potential to impair driving and driving-related skills above and beyond the effects of THC intoxication. Three studies—one instrumented vehicle driving study and two laboratory-style epidemiological studies—examined real driving and computerized task performance as a function THC and CBD concentrations (and their interactions). In all three studies, higher CBD levels predicted greater impairment. There was relatively little evidence of impairment when CBD was zero, even at high THC levels. The results suggest that THC concentrations alone are not sufficient to predict impairment due to cannabis use. Results are interpreted in the context of drug tolerance.
SyngenicDNA: stealth-based evasion of restriction-modification barriers during bacterial genetic engineering
Authors: Johnston Christopher D. , Cotton Sean , Rittling Susan R. , Starr Jacqueline R. , Borisy Gary , Dewhirst Floyd E. , Lemon Katherine P.
Published: August 2018

Restriction-modification (RM) systems hinder the use of genetic approaches in the vast majority of bacteria. Here, we describe a systematic approach to adapt genetic tools for use in bacteria that are genetically intractable or poorly tractable owing to active RM defenses. In this process, we determine the genome and methylome of a bacterial strain and use this information to define the bacterium’s RM target motifs. We then synonymously eliminate RM targets from the nucleotide sequence of a genetic toolin silico,synthesize an RM-silent ‘SyngenicDNA’ tool and propagate the tool as novel minicircle plasmids, termed SyMPL tools, before transformation. Using SyngenicDNA and SyMPL tools, we achieved a profound, >100,000- fold, improvement in the transformation of a clinically relevant USA300 strain ofStaphylococcus aureusdemonstrating the efficacy of these approaches for evading RM systems. The SyngenicDNA and SyMPL approaches are effective, flexible, and should be broadly applicable in microbial genetics. We expect these will facilitate a new era of microbial genetics free of the restraints of restriction-modification barriers.
Transcriptome analysis of mycorrhizal and non-mycorrhizal soybean plantlets upon infection withFusarium virguliforme, one causal agent of sudden death syndrome
Authors: Marquez N. , Giachero M. L. , Gallou A. , Debat H. J. , Declerck S. , Ducasse D. A.
Published: August 2018

Soilborne pathogens represent a threat to agriculture causing important yield losses. The “Sudden Death Syndrome” (SDS), a severe disease in soybean is caused by a complex ofFusariumspecies. This pathosystem has been widely investigated and several strategies were proposed to manage SDS. Although a decrease in symptoms and in the level of root tissue infection particularly byF. virguliformewas observed in presence of arbuscular mycorrhizal fungi (AMF), biological control based on AMF has received less attention. Here we report the results, under strictin vitroculture experimental conditions, a transcriptional analysis in mycorrhizal versus non-mycorrhizal soybean plantlets upon infection byF. virguliforme.An important transcriptional reprogramming was detected following infection by the pathogen. Results revealed 1768 and 967 differentially expressed genes in the AMF-colonized (+AMF+Fv) and non-colonized (−AMF+Fv) plants, respectively. Major transcriptional changes, corresponded to defence response related genes belonging to secondary metabolism, stress and signalling categories. The +AMF+Fv treatment showed the largest number of upregulated genes related to defence, as those encoding for disease resistance proteins, WRKY transcription factors, auxins, receptors kinases, and proteases. Only few genes had primed expression in +AMF+Fv treatment, as those coding for a thaumatin-like protein (TLP) and a pleiotropic drug resistance (PDR) protein. Moreover, +AMF+Fv showed a significant number of downregulated genes related to cell wall modification and peroxidases than – AMF+Fv treatment. This detailed insight increases our knowledge on the transcriptional changes and the potential metabolic pathways involved in the enhanced resistance/tolerance of mycorrhizal plants upon infection withF. virguliforme.
Measuring Illumina Size Bias Using REcount: A Novel Method for Highly Accurate Quantification of Engineered Genetic Constructs
Authors: Gohl Daryl M. , Becker Aaron , Johnson Darrell , Anderson Shea , Billstein Bradley , McDevitt Shana L. , Beckman Kenneth B.
Published: August 2018

Quantification of DNA sequence tags associated with engineered genetic constructs underlies many genomics measurements. Typically, such measurements are done using PCR to enrich sequence tags and add adapters, followed by next-generation sequencing (NGS). However, PCR amplification can introduce significant quantitative error into these measurements. Here we describe REcount, a novel PCR-free direct counting method for NGS-based quantification of engineered genetic constructs. By comparing measurements of defined plasmid pools to droplet digital PCR data, we demonstrate that this method is highly accurate and reproducible. We further demonstrate that the REcount approach is amenable to multiplexing through the use of orthogonal restriction enzymes. Finally, we use REcount to provide new insights into clustering biases due to molecule length across different Illumina sequencing platforms.
Virus-inclusive single cell RNA sequencing reveals molecular signature predictive of progression to severe dengue infection
Authors: Zanini Fabio , Robinson Makeda L. , Croote Derek , Sahoo Malaya Kumar , Sanz Ana Maria , Ortiz-Lasso Eliana , Albornoz Ludwig Luis , Suarez Fernando Rosso , Montoya Jose G. , Pinsky Benjamin A. , Quake Stephen R. , Einav Shirit
Published: August 2018

Dengue virus (DENV) infection can result in severe complications. Yet, the understanding of the molecular correlates of severity is limited, partly due to difficulties in defining the peripheral blood mononuclear cells (PBMCs) that are associated with DENV in vivo. Additionally, there are currently no biomarkers predictive of progression to severe dengue (SD). Bulk transcriptomics data are difficult to interpret because blood consists of multiple cell types that may react differently to infection. Here we applied virus-inclusive single cell RNA-seq approach (viscRNA-Seq) to profile transcriptomes of thousands of single PBMCs derived early in the course of disease from six dengue patients and four healthy controls, and to characterize distinct DENV-associated leukocytes. Multiple genes, particularly interferon response genes, were upregulated in a cell-specific manner prior to progression to SD. Expression of MX2 in naive B cells and CD163 in CD14+ CD16+ monocytes was predictive of SD. The majority of DENV-associated cells in the blood of two patients who progressed to SD were naive IgM B cells expressing the CD69 and CXCR4 receptors and antiviral genes, followed by monocytes. Bystander uninfected B cells also demonstrated immune activation, and plasmablasts from two patients exhibited antibody lineages with convergently hypermutated heavy chain sequences. Lastly, assembly of the DENV genome revealed diversity at unexpected genomic sites. This study presents a multi-faceted molecular elucidation of natural dengue infection in humans and proposes biomarkers for prediction of SD, with implications for profiling any tissue and viral infection, and for the development of a dengue prognostic assay.

Significance

A fraction of the 400 million people infected with dengue annually progresses to severe dengue (SD). Yet, there are currently no biomarkers to effectively predict disease progression. We profiled the landscape of host transcripts and viral RNA in thousands of single blood cells from dengue patients prior to progressing to SD. We discovered cell-type specific immune activation and candidate predictive biomarkers. We also revealed preferential virus association with specific cell populations, particularly naive B cells and monocytes. We then explored immune activation of bystander cells, clonality and somatic evolution of adaptive immune repertoires, and viral genomics. This multi-faceted approach could advance understanding of pathogenesis of any viral infection, map an atlas of infected cells and promote the development of prognostics.
The genetics and genome-wide screening of regrowth loci, a key component of perennialism in Zea diploperennis
Authors: Ma Anjun , Qiu Yinjie , Raihan Tajbir , Dahal Subha , Zhuang Yongbin , Galla Aravind , Auger Donald L. , Yen Yang
Published: August 2018

Perennialism is common among the higher plants, yet little is known about its inheritance. To address this, six hybrids were made by reciprocally crossing perennial Zea diploperennis Iltis, Doebley & R. Guzman with inbred lines B73 and Mo17 and Rhee Flint, a heirloom variety, of Z. mays L. ssp. mays. All the F1 plants demonstrated several cycles of growth, flowering, senescence and regrowth into normal flowering plants, indicating a dominant effect of the Z. diploperennis alleles. The regrowability (i.e. the plants' ability to regrow after senescence) was stably transmitted to progeny of the hybrids, so we focused on this trait. Segregation ratios in the F2 generations are consistent with the trait controlled by two dominant, complementary loci, but do not exclude the influence of other modifiers or environment. Genome-wide screening with genotyping-by-sequencing (GBS) indicated two major regrowth loci, regrowth 1 and regrowth 2, were on chromosomes 2 and 7, respectively. These findings lay the foundation for further exploration of the molecular mechanism of regrowth in Z. diploperennis.
Efficiency and precision of miRNA biogenesis modes in plants
Authors: Moro Belén , Chorostecki Uciel , Arikit Siwaret , Suarez Irina P. , Höbartner Claudia , Rasia Rodolfo M. , Meyers Blake C. , Palatnik Javier F.
Published: August 2018

Many evolutionary conserved microRNAs (miRNAs) in plants regulate transcription factors with key functions in development. Hence, mutations in the core components of the miRNA biogenesis machinery cause strong growth defects. An essential aspect of miRNA biogenesis is the precise excision of the small RNA from its precursor. In plants, miRNA precursors are largely variable in size and shape and can be processed by different modes. Here, we optimized an approach to detect intermediates during miRNA biogenesis. We characterized a miRNA whose processing is triggered by a terminal branched loop. Plant miRNA processing can be initiated by internal bubbles, small terminal loops or branched loops followed by dsRNA segments of 15-17 bp. Interestingly, precision and efficiency vary with the processing modes. Despite the various potential structural determinants present in a single a miRNA precursor, DCL1 is mostly guided by a predominant structural region in each precursor in wild-type plants. However, our studies in fiery1, hyl1 and se mutants revealed the existence of cleavage signatures consistent with the recognition of alternative processing determinants. The results provide a general view of the mechanisms underlying the specificity of miRNA biogenesis in plants.
bin3C : Exploiting Hi-C sequencing data to accurately resolve metagenome-assembled genomes (MAGs)
Authors: DeMaere Matthew Z. , Darling Aaron E.
Published: August 2018

Most microbes inhabiting the planet cannot be easily grown in the lab. Metagenomic techniques provide a means to study these organisms, and recent advances in the field have enabled the resolution of individual genomes from metagenomes, so-called Metagenome Assembled Genomes (MAGs). In addition to expanding the catalog of known microbial diversity, the systematic retrieval of MAGs stands as a tenable divide and conquer reduction of metagenome analysis to the simpler problem of single genome analysis. Many leading approaches to MAG retrieval depend upon time-series or transect data, whose effectiveness is a function of community complexity, target abundance and depth of sequencing. Without the need for time-series data, promising alternative methods are based upon the high-throughput sequencing technique called Hi-C.

The Hi-C technique produces read-pairs which capture in-vivo DNA-DNA proximity interactions (contacts). The physical structure of the community modulates the signal derived from these interactions and a hierarchy of interaction rates exists (īntra-chromosomal > Inter-chromosomal > Inter-cellular).

We describe an unsupervised method that exploits the hierarchical nature of Hi-C interaction rates to resolve MAGs from a single time-point. As a quantitative demonstration, next, we validate the method against the ground truth of a simulated human faecal microbiome. Lastly, we directly compare our method against a recently announced proprietary service ProxiMeta, which also performs MAG retrieval using Hi-C data.

bin3C has been implemented as a simple open-source pipeline and makes use of the unsupervised community detection algorithm Infomap (https://github.com/cerebis/bin3C).
Positive Selection and Adaptation of Novel Inner Ear Genes in the Mammalian Lineage
Authors: Pisciottano Francisco , Cinalli Alejandro R. , Stopiello Matías , Castagna Valeria C. , Belén Elgoyhen Ana , Rubinstein Marcelo , Gómez-Casati María Eugenia , Franchini Lucía F.
Published: August 2018

The mammalian inner ear possesses functional and morphological innovations that contribute to its unique hearing capacities. The genetic bases underlying the evolution of this mammalian landmark are poorly understood. We propose that the emergence of morphological and functional innovations in the mammalian inner ear could have been driven by adaptive molecular evolution.

In this work, we analyzed the complete inner ear transcriptome in order to identify genes that show signatures of adaptive evolution in this lineage. We analyzed approximately 1,300 inner ear expressed genes and found that 13 % show signatures of positive selection in the mammalian lineage. Several of these genes are known to play an important function in the inner ear. In addition, we identified that a significant proportion of genes showing signatures of adaptive evolution in mammals have not been previously reported to participate in inner ear development and/or physiology. We focused our analysis in two of these novel genes:STRIP2andABLIM2by generating null mutant mice and analyzed their auditory function. We found that mice lackingStrip2displayed a decrease in neural response amplitudes. In addition, we observed a reduction in the number of afferent synapses, suggesting a potential cochlear neuropathy.

Thus, this study shows the usefulness of pursuing a high-throughput evolutionary approach followed by functional studies to track down novel genes that are important for inner ear function. Moreover, this approach sheds light on the genetic basis underlying the evolution of the mammalian inner ear.
Focal cholesterol depletion during Fcγ receptor-mediated phagocytosis contributes to Lyn kinase regulation
Authors: Lu Stella M. , Volchuk Allen , Fairn Gregory D.
Published: August 2018

Cholesterol-rich nanodomains, historically referred to as lipid rafts, have previously been reported to be critical for proper Fcγ Receptor and Lyn kinase signaling during phagocytosis. Throughout the initial stages of phagocytosis, the nascent phagosome is actively remodeled by localized lipid metabolism and exocytosis. However, to date, little is known about the dynamics of cholesterol during this stage of particle engulfment. Using a genetically-encoded biosensor for cholesterol, we find that cholesterol is depleted from the nascent phagosome prior to sealing. Additionally, protein markers of both cholesterol-rich and cholesterol-poor nanodomains also clear from the site of phagocytosis arguing against the selective depletion of specific membrane domains. Consistent with previous studies we find that exocytosis contributes to the remodeling of the nascent phagosome. The displacement of cholesterol from the forming phagosome was paralleled by Lyn kinase helping to explain the reduction of phosphotyrosine signal in the nascent phagosome. This diminution of cholesterol and Lyn from the base of the cup may aid in the processivity of the phagocytic signal during pseudopod extension, and provide an unappreciated mechanism by which Lyn kinase signaling is regulated during phagocytosis.

Summary Statement: Localized exocytosis dilutes cholesterol from the phagocytic cup leading to the displacement of Lyn kinase and an attenuation of signaling.
Proton Conductivity of Glycosaminoglycans
Authors: Selberg John , Jia Manping , Rolandi Marco
Published: August 2018

Proton (H+) conductivity is important in many natural phenomena including oxidative phosphorylation in mitochondria and archea, uncoupling membrane potentials by the antibiotic Gramicidin, and proton actuated bioluminescence in dinoflagellate. In all of these phenomena, the conduction of H+ occurs along chains of hydrogen bonds between water and hydrophilic residues. These chains of hydrogen bonds are also present in many hydrated biopolymers and macromolecule including collagen, keratin, chitosan, and various proteins such as reflectin. All of these materials are also proton conductors. Recently, our group has discovered that the jelly found in the Ampullae of Lorenzini-shark’s electrosensing organs- is the highest naturally occurring proton conducting substance. The jelly has a complex composition, but we attributed the conductivity to the glycosaminoglycan keratan sulfate (KS). Here, we have measured the proton conductivity of hydrated keratan sulfate using PdHx contacts to be 0.50 ± 0.11 mS cm -1- consistent to that of Ampullae of Lorenzini jelly, 2 ± 1 mS cm -1. Proton conductivity, albeit with lower values, is also shared by other glycosaminoglycans with similar chemical structures including dermatan sulfate, chondroitin sulfate A, heparan sulfate, and hyaluronic acid. This observation confirms the structure property relationship between proton conductivity and the chemical structure of biopolymers.
Real time monitoring of transtibial elevated vacuum prostheses: a case series on socket air pressure
Authors: Schoepp Katherine R. , Schofield Jonathon S. , Home David , Dawson Michael R. , Lou Edmond , Keri McNiel , Marasco Paul D. , Hebert Jacqueline S.
Published: August 2018

Elevated vacuum is a prosthetic suspension method used to reduce slippage between the prosthetic socket and the residual limb. Evaluation of the effectiveness of these systems is limited due to a lack of correlation to actual socket air pressure, particularly during unconstrained movements. This may explain some of the variability in functional outcomes reported in the literature. We developed a light-weight portable socket measurement system to quantify internal socket air pressure, temperature, and acceleration. We implemented the system onto the sockets of three transtibial prosthesis users with mechanical elevated vacuum pumps. Participants completed five functional tasks with and without the vacuum pumps actively connected, including the 2-Minute Walk test, 5-Times Sit-to-Stand test, 4-Square Step test, L-Test, and Figure-8 test. Results demonstrated that the use of elevated vacuum pumps produced different gait profiles and pressure ranges for each user, with significant differences between pump conditions. Two of the participants demonstrated substantially lower air pressure (higher vacuum) over time while the pump was active compared to inactive. The minimum air pressure measured at the completion of the 2-Minute Walk test was −34.6 ± 7.7 kPa, which is not as low as pressures reported in literature during benchtop experiments. One participant did not show substantial changes in pressure over time for either pump condition. Functional task performance was not significantly different between pump conditions. Correlation with accelerometer readings allowed air pressure data to be aligned with the gait cycle; peak positive pressures occurred just following initial contact of the foot in early stance, and the most negative pressures (vacuum) were observed throughout swing. This study has demonstrated the use of a portable data logging tool that may serve the clinical and research communities to quantify the operation of elevated vacuum systems, and better understand the variability of mechanical pump operation and overall system performance.
Health-seeking behavior and associated factors among community in Southern Ethiopia:Community based cross-sectional study guided by Health belief model
Authors: Asfaw Likawunt Samuel , Ayanto Samuel Yohannes , Aweke Yitagessu Habtu
Published: August 2018

Background

Health-seeking behavior is a sequence of actions taken to promote health and prevent disease. Governments’ expenditure to health is being improved in Ethiopia. In contrast, high disease burden and low health service utilization is observed. The low health service utilization could be due to low health-seeking behavior of the community. Thus, this studywas aimed to determine the level of health-seeking behavior and associated factors in Hosanna town, Southern Ethiopia.

Methods

We used communitybased cross-sectional study design among community (n= 443) in Hosanna town. The overall health-seeking behavior of study participants was assessed using the mean score of each of the dimensions (health promotion and disease prevention activities) as a cut-off value. Having a score above the mean on each of the target dimensions was equated with having a high level of health seeking behaviour. STATA 12 soft-ware package (Stata Corporation, College Station, Texas, 77845, USA)was used for descriptive and logistic regression analysis.

Results

About eighty five percent of (85.4%) participants had low level of health-seeking behavior. Males were about two folds more likely to have low level of health-seeking behavior than females (AOR: 1.8; CI 1.03–3.42). Widowed participants were about five times more likely to have low health-seeking behavior (AOR: 4.8; CI 2.1–17.1) when compared to married participants. Those participants who are illiterate were about five times more likely to have low health-seeking behavior than who completed higher education (AOR: 4.5; CI 1.16–17.8).

Conclusion

The study revealed low health-seeking behavior among the study participants in the study area. This finding suggested the need forurgent interventions to the health literacy packages of Ethiopia to enhance the health seeking behavior of the country.
Individual-Based Network Model for Rift Valley Fever in Kabale District, Uganda, to Guide Mitigation Measures: A One Health Model
Authors: Sekamatte Musa , Riad Mahbubul H. , Tekleghiorghis Tesfaalem , Linthicum Kenneth J. , Britch Seth C. , Richt Juergen A. , Gonzalez J. P. , Scoglio Caterina M
Published: August 2018

Rift Valley fever (RVF) is a zoonotic disease which causes significant morbidity and mortality among ungulate livestock and humans in endemic regions. In the major RVF epizootic regions of East Africa, the causative agent of the disease, Rift Valley fever virus (RVFV), is primarily transmitted by multiple mosquito species in Aedes, Culex, and Mansonia genera during both epizootic and enzootic periods in a complex transmission cycle largely driven by the environment. However, recent RVFV activity in Uganda demonstrated that RVFV could also spread into new regions through livestock movements, and underscored the need to develop effective mitigation strategies to reduce transmission and prevent spread among cattle operations. We simulated RVFV transmission among cattle in different sub counties of Kabale District in Uganda using real world livestock data in a network-based model. This model considered livestock as spatially explicit factors in different sub-counties subjected to specific vector mosquito and environmental factors, and was configured to investigate and quantitatively evaluate the relative impacts of mosquito control, livestock movement regulations, and diversity in cattle populations on the spread of the RVF epizootic. We concluded that cattle movement should be restricted during periods of high vector mosquito abundance to control the epizootic spreading among sub-counties. On the other hand we found that mosquito control would only be sufficient to control the epizootic when mosquito abundance was low. Importantly, simulation results also showed that cattle populations with a higher diversity with regard to indigenous combined with exotic breeds led to reduced numbers of infected cattle compared to more homogenous cattle populations.
Monocyte depletion attenuates the development of posttraumatic hydrocephalus and preserves white matter integrity after traumatic brain injury
Authors: Makinde Hadijat M. , Just Talia B. , Cuda Carla M. , Bertolino Nicola , Procissi Daniele , Schwulst Steven J.
Published: August 2018

Monocytes are amongst the first cells recruited into the brain after traumatic brain injury (TBI). We have shown monocyte depletion 24 hours prior to TBI reduces brain edema, decreases neutrophil infiltration and improves behavioral outcomes. Additionally, both lesion and ventricle size correlate with poor neurologic outcome after TBI. Therefore, we aimed to determine the association between monocyte infiltration, lesion size, and ventricle volume. We hypothesized that monocyte depletion would attenuate lesion size, decrease ventricle enlargement, and preserve white matter in mice after TBI. C57BL/6 mice underwent pan monocyte depletion via intravenous injection of liposome-encapsulated clodronate. Control mice were injected with liposome-encapsulated PBS. TBI was induced via an open-head, controlled cortical impact. Mice were imaged using magnetic resonance imaging (MRI) at 1, 7, and 14 days post-injury to evaluate progression of lesion and to detect morphological changes associated with injury (3D T1- weighted MRI) including regional alterations in white matter patterns (multi-direction diffusion MRI). Lesion size and ventricle volume were measured using semi-automatic segmentation and active contour methods with the software program ITK-SNAP. Data was analyzed with the statistical software program PRISM. No significant effect of monocyte depletion on lesion size was detected using MRI following TBI (p=0.4). However, progressive ventricle enlargement following TBI was observed to be attenuated in the monocyte-depleted cohort (5.3 ± 0.9mm3) as compared to the sham-depleted cohort (13.2 ± 3.1mm3;p=0.02). Global white matter integrity and regional patterns were evaluated and quantified for each mouse after extracting fractional anisotropy maps from the multi-direction diffusion-MRI data using Siemens Syngo DTI analysis package. Fractional anisotropy values were preserved in the monocyte-depleted cohort (123.0 ± 4.4mm3) as compared to sham-depleted mice (94.9 ± 4.6mm3;p=0.025) by 14 days post-TBI. The MRI derived data suggests that monocyte depletion at the time of injury may be a novel therapeutic strategy in the treatment of TBI. Furthermore, non-invasive longitudinal imaging allows for the evaluation of both TBI progression as well as therapeutic response over the course of injury.
Understanding narwhal diving behaviour using Hidden Markov Models with dependent state distributions and long range dependence
Authors: Ngôe Manh Cuong , Heide-Jørgensen Mads Peter , Ditlevsen Susanne
Published: August 2018

Diving behaviour of narwhals is still largely unknown. We build three-state Hidden Markov models (HMM) to describe the diving behaviour of a narwhal and fit the models to a three-dimensional response vector of maximum dive depth, duration of dives and post-dive surface time of 8,609 dives measured in East Greenland over 83 days, an extraordinarily long and rich data set. In particular, diurnal patterns in diving behaviour for a marine mammal is being inferred, by using periodic B-splines with boundary knots in 0 and 24 hours. Several HMMs with covariates are used to characterize dive patterns. Narwhal diving patterns have not been analysed like this before, but in studies of other whale species, response variables have been assumed independent. We extend the existing models to allow for dependence between state distributions, and show that the dependence has an impact on the conclusions drawn about the diving behaviour. It is thus paramount to relax this strong and biologically unrealistic assumption to obtain trustworthy inferences.

Author summary

Narwhals live in pristine environments. However, the increase in average temperatures in the Arctic and the concomitant loss of summer sea ice, as well as increased human activities, such as ship traffic and mineral exploration leading to increased noise pollution, are changing the environment, and therefore probably also the behavior and well-being of the narwhal. Here, we use probabilistic models to unravel the diving and feeding behavior of a male narwhal, tagged in East Greenland in 2013, and followed for nearly two months. The goal is to gain knowledge of the whales’ normal behavior, to be able to later detect possible changes in behavior due to climatic changes and human influences. We find that the narwhal uses around two thirds of its time searching for food, it typically feeds during deep dives (more than 350 m), and it can have extended periods, up to 3 days, without feeding activity.
tudor-domain containing protein 5-primepromotes male sexual identity in theDrosophilagermline and is repressed in females bySex lethal
Authors: Primus Shekerah , Pozmanter Caitlin , Baxter Kelly , Van Doren Mark
Published: August 2018

For sexually reproducing organisms, production of male or female gametes depends on specifying the correct sexual identity in the germline. InD. melanogaster, Sex lethal(Sxl) is the key gene that controls sex determination in both the soma and the germline, but how it does so in the germline is unknown, other than that it is different than in the soma. We conducted an RNA expression profiling experiment to identify direct and indirect germline targets of Sxl specifically in the undifferentiated germline. We find that, in these cells,Sxlloss does not lead to a global masculinization observed at the whole-genome level. In contrast,Sxlappears to affect a discrete set of genes required in the male germline, such asPhf7. We also identifytudor domain containing protein 5-prime(tdrd5p) as a target for Sxl regulation that is important for male germline identity.tdrd5pis repressed by Sxl in female germ cells, but is highly expressed in male germ cells where it promotes proper male fertility and germline differentiation. Additionally, Tdrd5p localizes to cytoplasmic granules with some characteristics of RNA Processing (P-) Bodies, suggesting that it promotes male identity in the germline by regulating post-transcriptional gene expression.

Author summary

Like humans, all sexually reproducing organisms require gametes to reproduce. Gametes are made by specialized cells called germ cells, which must have the correct sexual identity information to properly make sperm or eggs. In fruit flies, germ cell sexual identity is controlled by the RNA-binding protein Sxl, which is expressed only in females. To better understand howSxlpromotes female identity, we conducted an RNA expression profiling experiment to identify genes whose expression changes in response to the loss ofSxlfrom germ cells. Here, we identifytudor domain containing protein 5-prime (tdrd5p), which is expressed 17-fold higher in ovaries lackingSxlcompared to control ovaries. Additionally,tdrd5pplays an important role in males as male flies that are mutant for this gene cannot make sperm properly and thus are less fertile. Moreover, we find thattdrd5ppromotes male identity in the germline, as several experiments show that it can shift the germ cell developmental program from female to male. This study tells us thatSxlpromotes female identity in germ cells by repressing genes, liketdrd5p, that promote male identity. Future studies into the function oftdrd5pwill provide mechanistic insight into how this gene promotes male identity.
Single-domain antibodies represent novel alternatives to monoclonal antibodies as targeting agents against the human papillomavirus 16 E6 protein
Authors: Togtema Melissa , Hussack Greg , Dayer Guillem , Teghtmeyer Megan , Raphael Shalini , Tanha Jamshid , Zehbe Ingeborg
Published: August 2018

Approximately one-fifth of all malignancies worldwide are etiologically-associated with a persistent viral or bacterial infection. Thus, there is particular interest in therapeutic molecules which utilize components of a natural immune response to specifically inhibit oncogenic microbial proteins, as it is anticipated they will elicit fewer off-target effects than conventional treatments. This concept has been explored in the context of human papillomavirus type 16 (HPV16)-related cancers, through the development of monoclonal antibodies and fragments thereof against the viral E6 oncoprotein. However, challenges related to the biology of E6 as well as the functional properties of the antibodies themselves appear to have precluded their clinical translation. In this study, we attempted to address these issues by exploring the utility of the variable domains of camelid heavy-chain-only antibodies (denoted as VHHs). Through the construction and panning of two llama immune VHH phage display libraries, a pool of potential VHHs was isolated. The interactions of these VHHs with recombinant E6 protein were further characterized using ELISA, Western blotting under both denaturing and native conditions, as well as surface plasmon resonance, and three antibodies were identified that bound recombinant E6 with affinities in the nanomolar range. Our results now lead the way for subsequent studies into the ability of these novel molecules to inhibit HPV16-infected cellsin vitroandin vivo.
Identification of Key Differentially Expressed MicroRNAs in Cancer Patients Through Pan-cancer Analysis
Authors: Hu Yu , Dingerdissen Hayley , Gupta Samir , Kahsay Robel , Shanker Vijay , Wan Quan , Yan Cheng , Mazumder Raja
Published: August 2018

A number of microRNAs (miRNAs) functioning in gene silencing have been associated with cancer progression. However, common expression patterns of abnormally expressed miRNAs and their potential roles in multiple cancer types have not yet been evaluated. To minimize the difference of patients, we collected miRNA sequencing data of 575 patients with tumor and adjacent non-tumorous tissues from 14 cancer types from The Cancer Genome Atlas (TCGA), and performed differential expression analysis using DESeq2 and edgeR. The results showed that cancer types can be grouped based on the distribution of miRNAs with different expression patterns. We found 81 significantly differentially expressed miRNAs (SDEmiRNAs) unique to one of the 14 cancers may affect patient survival rate, and 21 key SDEmiRNAs (nine overexpressed and 12 under-expressed) associated with at least eight cancers and enriched in more than 60% of patients per cancer, including four newly identified SDEmiRNAs (hsa-mir-4746, hsa-mir-3648, hsa-mir-3687, and hsa-mir-1269a). The downstream effect of these 21 SDEmiRNAs on cellular functions was evaluated through enrichment and pathway analysis of 7,186 protein-coding gene targets from literature mining with known differential expression profiles in cancers. It enables identification of their functional similarity in cell proliferation control across a wide range of cancers and to build common regulatory networks over cancer-related pathways. This is validated by construction of a regulatory network in PI3K pathway. This study provides evidence of the value of further analysis on SDEmiRNAs as potential biomarkers and therapeutic targets for cancer diagnosis and treatment.
Imperfect Linkage Disequilibrium Generates Phantom Epistasis (& Perils of Big Data)
Authors: de los Campos G. , Sorensen D. , Toro M. A.
Published: August 2018

The genetic architecture of complex human traits and diseases is affected by large number of possibly interacting genes, but detecting epistatic interactions can be challenging. In the last decade, several studies have alluded to problems that linkage disequilibrium can create when testing for epistatic interactions between DNA markers. However, these problems have not been formalized nor have their consequences been quantified in a precise manner. Here we use a conceptually simple three locus model involving a causal locus and two markers to show that imperfect LD can generate the illusion of epistasis, even when the underlying genetic architecture is purely additive. We describe necessary conditions for such “phantom epistasis” to emerge and quantify its relevance using simulations. Our empirical results demonstrate that phantom epistasis can be a very serious problem in GWAS studies (with rejection rates against the additive model greater than 0.2 for nominal p-values of 0.05, even when the model is purely additive). Some studies have sought to avoid this problem by only testing interactions between SNPs with R-sq. <0.1. We show that this threshold is not appropriate and demonstrate that the magnitude of the problem is even greater with large sample size. We conclude that caution must be exercised when interpreting GWAS results derived from very large data sets showing strong evidence in support of epistatic interactions between markers.
Powerful and interpretable behavioural features for quantitative phenotyping ofC. elegans
Authors: Javer Avelino , Ripoll-Sanchez Lidia , Brown André E.X.
Published: August 2018

Behaviour is a sensitive and integrative readout of nervous system function and therefore an attractive measure for assessing the effects of mutation or drug treatment on animals. Video data provides a rich but high-dimensional representation of behaviour and so the first step of analysis is often some form of tracking and feature extraction to reduce dimensionality while maintaining relevant information. Modern machine learning methods are powerful but notoriously difficult to interpret, while handcrafted features are interpretable but do not always perform as well. Here we report a new set of handcrafted features to compactly quantifyC. elegansbehaviour. The features are designed to be interpretable but to capture as much of the phenotypic differences between worms as possible. We show that the full feature set is more powerful than a previously defined feature set in classifying mutant strains. We then use a combination of automated and manual feature selection to define a core set of interpretable features that still provides sufficient power to detect behavioural differences between mutant strains and the wild type. Finally, we apply the new features to detect time-resolved behavioural differences in a series of optogenetic experiments targeting different neural subsets.
Aerodynamics of plunging airfoil in wind gust
Authors: Das Arpan , Tiwari Shaligram
Published: August 2018

Purpose

Growing application of micro aerial vehicle (MAV) sets in demand for accurate computations of low Reynolds number flows past their wings. The purpose of this study is to investigate the effect of unsteady freestream velocity or wind gust on a harmonically plunging symmetric NACA0012 airfoil at Re = 1,000. The influence of unsteady parameters, such as reduced frequency of plunging motion (0.25 < k < 1.5), non-dimensional plunging amplitude (ho = 0.2) and non-dimensional amplitude of wind gust (0.1 = λ = 0.4) has been studied.

Design/methodology/approach

Computations have been carried out using commercial software ANSYS Fluent 16.0. To incorporate the plunging motion, the entire reference frame is oscillating, and thereby, a source term is added in the Navier–Stokes equation.

Findings

The results have been presented in the form of streamlines, vorticity contours, lift and drag signals and their spectra. It is observed that the ratio of plunging frequency to gust frequency (f/fg) has strong influence on periodic characteristics of unsteady wake. It has also been observed that for a fixed plunging amplitude, an increase in value of k results into a change from positive drag to thrust.

Practical implications

The research has implications in the development of MAV.

Originality/value

This study is intended to get a better understanding of unsteady parameters associated with gusty flow in flapping wing applications and possible ways to alleviate its adverse effect on it.
Determinants of the knowledge of the total cost of consumer loans
Authors: Farías Pablo
Published: August 2018

Purpose

The purpose of this paper is to examine the influence of consumer-related and bank-related characteristics on the knowledge of the total cost of consumer loans paid by consumers and test the hypothesized relationships between them.

Design/methodology/approach

In order to identify the proportion of consumers who do not know the total cost of consumer loans and reasons for it in the Chilean consumer loans industry, an empirical study using a survey administered through personal in-home interviews was carried out.

Findings

Results show that knowledge of a consumer loans total cost is positively associated with product satisfaction as well as recent and infrequent purchases. This study also shows that a big market segment, comprising 37.2 percent of the probability sample, represents vulnerable consumers with high self-reported knowledge but low actual knowledge of the total costs of consumer loans. This study shows that this market segment has a higher use of the price-quality cue and a higher purchase frequency of consumer loans.

Originality/value

The present study contributes to the existing literature in the following ways. First, while previous research measured only self-reported knowledge for financial services, the present study examines actual knowledge of the total cost of consumer loans. Second, while previous research for financial services only examined the effects of the use of the price-quality cue and price advertising exposure, the present study also examines 11 other determinants, which are relevant for managers, regulators and researchers.
Development of switching performance evaluator and arc modelling tool for low-voltage switching devices
Authors: Shin Dongkyu , Golosnoy Igor , McBride John
Published: August 2018

Purpose

The purpose of this paper is to investigate a reliable evaluator of arc re-ignition and to develop a numerical tool for accurate prediction of arc behaviour of low-voltage switching devices (LVSDs) prior to empirical laboratory testing of real products.

Design/methodology/approach

Two types of interruption tests have been carried out in the investigation of re-ignition evaluators. Arc modelling tool coupled with the load circuit has been developed to predict arc characteristics based on conventional magnetohydrodynamics theory, with special attention given to Lorentz force acting on the arc column and surface phenomena on the splitter plate. The model assumptions have been validated by experimental observation of arc motion and current and voltage waveforms.

Findings

It is found that the exit-voltage across the switching device and the ratio of system to exit-voltage at the current zero point are reliable evaluators for prediction of re-ignition. Where the voltage ratio is positive, instantaneous re-ignition does not occur. Further, the probability of re-ignition is very low if the voltage ratio is in the rage of −1.3 to 0.

Originality/value

It is observed that the voltage ratio can be considered as a reliable global evaluator of re-ignition, which can be used for various types of LVSD test conditions. In addition, it is shown that arc modelling allows a good prediction of the current and voltage waveforms, arc motion as well as the exit-voltage, which can be used to obtain the evaluator of re-ignition.
Sharing risk experiences of polydrug use on YouTube
Authors: Kataja Kati , Hakkarainen Pekka , Koivula Petteri , Hautala Sanna
Published: August 2018

Purpose

The purpose of this paper is to discuss what kinds of messages about the risks of polydrug use are mediated in YouTube video blogs and on what kinds of norms and values do the vloggers base these messages.

Design/methodology/approach

The data consist of 12 YouTube videos where vloggers share their own experiences of the risks and harms of polydrug use. In the analysis, the actantial model of Greimas’ theory of structural semiotics was applied.

Findings

Two main types of videos were identified – sobriety and controlled use – where polydrug use has different meanings. In sobriety videos, polydrug use is presented as the heavy use of multiple substances. In the videos dealing with controlled use, polydrug use is taken as the combining of certain substances. Whereas the sobriety videos emphasized total abstinence from all substances due to their destructiveness, the videos about controlled use emphasized risk awareness when combining substances. Despite modern digital media and a new generation operating in this space, the messages of the risks of polydrug use mainly repeat those of familiar discourses.

Originality/value

This paper offers an analytical insight into the ways in which the risks of polydrug use are conceptualized in a YouTube context that is increasingly gaining a foothold among the youth. Greimas’ actantial model offers a fruitful tool to find semiotic meanings that hide under the surface. The model has not been applied in previous drug research.