bluuebunny/crossref_metadata_2025 huggingface dataset:
Combined behavioral and electrophysiological evidence for a direct cortical effect of prefrontal tDCS on disorders of consciousness
Authors: Hermann Bertrand , Raimondo Federico , Hirsch Lukas , Huang Yu , Denis-Valente Mélanie , Pérez Pauline , Engemann Denis , Faugeras Frédéric , Weiss Nicolas , Demeret Sophie , Rohaut Benjamin , Parra Lucas C. , Sitt Jacobo D. , Naccache Lionel
Published: April 2019

Severe brain injuries can lead to long-lasting disorders of consciousness (DoC) such as vegetative state/unresponsive wakefulness syndrome (VS/UWS) or minimally conscious state (MCS). While behavioral assessment remains the gold standard to determine conscious state, EEG has proven to be a promising complementary tool to monitor the effect of new therapeutics. Encouraging results have been obtained with invasive electrical stimulation of the brain, and recent studies identified transcranial direct current stimulation (tDCS) as an effective approach in randomized controlled trials. This non-invasive and inexpensive tool may turn out to be the preferred treatment option. However, its mechanisms of action and physiological effects on brain activity remain unclear and debated. Here, we stimulated 60 DoC patients with the anode placed over left-dorsolateral prefrontal cortex in a prospective open-label study. Clinical behavioral assessment improved in twelve patients (20%) and none deteriorated. This behavioral response after tDCS coincided with an enhancement of putative EEG markers of consciousness: in comparison with non-responders, responders showed increases of power and long-range cortico-cortical functional connectivity in the theta-alpha band, and a larger and more sustained P300 suggesting improved conscious access to auditory novelty. The EEG changes correlated with electric fields strengths in prefrontal cortices, and no correlation was found on the scalp. Taken together, this prospective intervention in a large cohort of DoC patients strengthens the validity of the proposed EEG signatures of consciousness, and is suggestive of a direct causal effect of tDCS on consciousness.
The self-organized learning of noisy environmental stimuli requires distinct phases of plasticity
Authors: Krüppel Steffen , Tetzlaff Christian
Published: April 2019

Along sensory pathways, representations of environmental stimuli become increasingly sparse and expanded. If additionally the feed-forward synaptic weights are structured according to the inherent organization of stimuli, the increase in sparseness and expansion leads to a reduction of sensory noise. However, it is unknown how the synapses in the brain form the required structure, especially given the omnipresent noise of environmental stimuli. Here, we employ a combination of synaptic plasticity and intrinsic plasticity - adapting the excitability of each neuron individually - and present stimuli with an inherent organization to a feed-forward network. We observe that intrinsic plasticity maintains the sparseness of the neural code and thereby enables synaptic plasticity to learn the organization of stimuli in low-noise environments. Nevertheless, even high levels of noise can be handled after a subsequent phase of readaptation of the neuronal excitabilities by intrinsic plasticity. Interestingly, during this phase the synaptic structure has to be maintained. These results demonstrate that learning in the presence of noise requires adaptation of the synaptic structure but also of the neuronal properties in two distinct phases of learning: an encoding phase, during which the inherent organization of the environmental stimuli is learned, followed by a readaptation phase to readapt the neuronal system according to the current level of noise. The necessity of these distinct phases of learning suggests a new role for synaptic consolidation.
Predictors of colony extinction vary by habitat type in social spiders
Authors: McEwen Brendan L. , Lichtenstein James L. L. , Fisher David N. , Wright Colin M. , Chism Greg T. , Pinter-Wollman Noa , Pruitt Jonathan N.
Published: April 2019

Many animal societies are susceptible to mass mortality events and collapse. Elucidating how environmental pressures determine patterns of collapse is key for our understanding of social evolution. Using the social spiderStegodyphus dumicolawe investigated the environmental drivers of colony extinction along two precipitation gradients across southern Africa, using the Namib and Kalahari deserts versus wetter savanna habitats to the north and east. We deployed experimental colonies (n = 242) along two 800km transects and returned to assess colony success in the field after two months. Specifically, we noted colony extinction events after the two-month duration and collected environmental data on the correlates of those extinction events (e.g., evidence of ant attacks, # prey captured). We found that colony extinction events at desert sites were more frequently associated with attacks by predatory ants as compared to savanna sites, while colony extinctions in wetter savannas sites were more tightly associated with fungal outbreaks. Our findings support the hypothesis that environments vary in the selection pressures that they impose on social organisms, which may explain why different social phenotypes are often favored in each habitat.
Comparative analysis of gene expression in virulent and attenuated strains of infectious bronchitis virus at sub-codon resolution
Authors: Dinan Adam M. , Keep Sarah , Bickerton Erica , Britton Paul , Firth Andrew E. , Brierley Ian
Published: April 2019

Infectious bronchitis virus (IBV) is a member of the genusGammacoronavirusand the causative agent of avian infectious bronchitis. IBV has a single-stranded, positive-sense RNA genome ~27 kb in length and, like all coronaviruses, produces a set of sub-genomic messenger RNAs (sgmRNAs) synthesised via the viral polymerase. Here, we used RNA sequencing (RNASeq) and ribosome profiling (RiboSeq) to delineate gene expression in the IBV M41-CK and Beau-CK strains at sub-codon resolution. Quantification of reads flanking the programmed ribosomal frameshifting (PRF) signal at the genomic RNA ORF1a/ORF1b junction revealed that PRF in IBV is highly efficient (33–40%), consistent within vitromeasurements. Triplet phasing of the profiling data allowed precise determination of reading frames and revealed the translation of two intergenic genes (4b and 4c on sgmRNA4), which are widely conserved across IBV isolates. RNASeq revealed two novel transcription junction sites in the attenuated Beau-CK strain, one of which would generate a sgmRNA encoding a ribosomally occupied ORF in the viral 3’ untranslated region (dORF). Within IBV transcripts, the nucleocapsid (N) protein was unexpectedly found to be inefficiently translated, despite being an abundant structural component of mature IBV virions. Finally, we demonstrate that the host cell response to IBV occurs primarily at the level of transcription, with a global up-regulation of immune-related mRNA transcripts following infection, and comparatively modest changes in the translation efficiencies of host genes.

IMPORTANCE

IBV is a major avian pathogen and presents a substantial economic burden to the poultry industry. Improved vaccination strategies are urgently needed to curb the global spread of this pathogen, and the development of suitable vaccine candidates will be aided by an improved understanding of IBV molecular biology. Our high-resolution data have enabled a precise study of transcription and translation in both pathogenic and attenuated forms of IBV, and expand our understanding of gammacoronaviral gene expression. We demonstrate that gene expression shows considerable intra-species variation, with single nucleotide polymorphisms associated with altered production of sgmRNA transcripts, and our RiboSeq data sets enabled us to uncover novel ribosomally occupied ORFs in both strains. We also identify numerous cellular genes and gene networks that are differentially expressed during virus infection, giving insights into the host cell reponse to IBV infection.
Induction of Rare Conformation of Oligosaccharide by Binding to Calcium-dependent Bacterial Lectin: X-ray Crystallography and Modelling Study
Authors: Lepsik Martin , Sommer Roman , Kuhaudomlarp Sakonwan , Lelimousin Mickaёl , Paci Emanuele , Varrot Annabelle , Titz Alexander , Imberty Anne
Published: April 2019

Pathogenic micro-organisms utilize protein receptors in adhesion to host tissues, a process that in some cases relies on the interaction between lectin and human glycoconjugates. Oligosaccharide epitopes are recognized through their three-dimensional structure and their flexibility is a key issue in specificity. In this paper, we analyse by X-ray crystallography the structures of the lectin LecB from two strains of Pseudomonas aeruginosa in complex with Lewis x oligosaccharide present on cell surfaces of human tissues. An unusual conformation of the glycan was observed in all binding sites with a non-canonical syn orientation of the N-acetyl group of N-acetyl-glucosamine. A PDB-wide search revealed that such an orientation occurs only in 2% of protein/carbohydrate complexes. Theoretical chemistry calculations showed that the observed conformation is unstable in solution but stabilised by the lectin. A reliable description of LecB/Lewis x complex by force field-based methods had proven as especially challenging due to the special feature of the binding site, two closely apposed Ca2+ ions which induce strong charge delocalisation. By comparing various force-field parametrisations, we design general protocols which will be useful in near future for designing carbohydrate-based ligands (glycodrugs) against other calcium-dependent protein receptors.
K-FIT: An accelerated kinetic parameterization algorithm using steady-state fluxomic data
Authors: Gopalakrishnan Saratram , Dash Satyakam , Maranas Costas
Published: April 2019

Kinetic models predict the metabolic flows by directly linking metabolite concentrations and enzyme levels to reaction fluxes. Robust parameterization of organism-level kinetic models that faithfully reproduce the effect of different genetic or environmental perturbations remains an open challenge due to the intractability of existing algorithms. This paper introduces K-FIT, an accelerated kinetic parameterization workflow that leverages a novel decomposition approach to identify steady-state fluxes in response to genetic perturbations followed by a gradient-based update of kinetic parameters until predictions simultaneously agree with the fluxomic data in all perturbed metabolic networks. The applicability of K-FIT to large-scale models is demonstrated by parameterizing an expanded kinetic model forE. coli(307 reactions and 258 metabolites) using fluxomic data from six mutants. The achieved thousand-fold speed-up afforded by K-FIT over meta-heuristic approaches is transformational enabling follow-up robustness of inference analyses and optimal design of experiments to inform metabolic engineering strategies.
Legofit: Estimating Population History from Genetic Data
Authors: Rogers Alan R.
Published: April 2019

Background

Our current understanding of archaic admixture in humans relies on statistical methods with large biases, whose magnitudes depend on the sizes and separation times of ancestral populations. To avoid these biases, it is necessary to estimate these parameters simultaneously with those describing admixture. Genetic estimates of population histories also confront problems of statistical identifiability: different models or different combinations of parameter values may fit the data equally well. To deal with this problem, we need methods of model selection and model averaging, which are lacking from most existing software.

Results

The Legofit software package allows simultaneous estimation of parameters describing admixture and other aspects of population history. It includes facilities for data manipulation, estimation, model selection, and model averaging. It outperforms several statistical methods that have been widely used to study archaic admixture in humans.
GABA-mediated tonic inhibition differentially modulates gain in functional subtypes of cortical interneurons
Authors: Bryson Alexander , Hatch Robert , Zandt Bas-Jan , Rossert Christian , Berkovic Samuel , Reid Christopher A , Grayden David B , Hill Sean , Petrou Steven
Published: April 2019

The binding of GABA to extra-synaptic GABAAreceptors generates tonic inhibition that acts as a powerful modulator of cortical network activity. Despite GABA being present at low levels throughout the extracellular space of the brain, previous work has shown that GABA may differentially modulate the excitability of neuron subtypes through variation in chloride gradient. Here, we introduce a distinct mechanism through which extracellular GABA can differentially modulate the excitability of neuron subtypes through variation in neuronal electrophysiological properties. Using biophysically-detailed computational models, we found that tonic inhibition enhanced the responsiveness (or gain) of models with electrophysiological features typically observed in somatostatin (Sst) interneurons and reduced gain in models with features typical for parvalbumin (Pv) interneurons. These predictions were experimentally verified using patch-clamp recordings. Further analysis revealed that differential gain modulation is also dependent upon the extent of outward rectification of the GABAAreceptor-mediated tonic current. Our detailed neuron models demonstrate two subcellular consequences of tonic inhibition. First, tonic inhibition enhances somatic action potential repolarisation by increasing current flow into the dendritic compartment. This enhanced repolarisation then reduces voltage-dependent potassium currents at the soma during the afterhyperpolarisation. Finally, we show that reductions of potassium current selectively increase gain within neurons exhibiting action potential dynamics typical for Sst interneurons. Potassium currents in Pv-type interneurons are not sensitive to this mechanism as they deactivate rapidly and are unavailable for further modulation. These findings introduce a neuromodulatory paradigm in which GABA can induce a state of differential interneuron excitability through differences in intrinsic electrophysiological properties.
Automated analysis of whole brain vasculature using machine learning
Authors: Todorov Mihail Ivilinov , Paetzold Johannes C. , Schoppe Oliver , Tetteh Giles , Efremov Velizar , Völgyi Katalin , Düring Marco , Dichgans Martin , Piraud Marie , Menze Bjoern , Ertürk Ali
Published: April 2019

Tissue clearing methods enable imaging of intact biological specimens without sectioning. However, reliable and scalable analysis of such large imaging data in 3D remains a challenge. Towards this goal, we developed a deep learning-based framework to quantify and analyze the brain vasculature, named Vessel Segmentation & Analysis Pipeline (VesSAP). Our pipeline uses a fully convolutional network with a transfer learning approach for segmentation. We systematically analyzed vascular features of the whole brains including their length, bifurcation points and radius at the micrometer scale by registering them to the Allen mouse brain atlas. We reported the first evidence of secondary intracranial collateral vascularization in CD1-Elite mice and found reduced vascularization in the brainstem as compared to the cerebrum. VesSAP thus enables unbiased and scalable quantifications for the angioarchitecture of the cleared intact mouse brain and yields new biological insights related to the vascular brain function.

GRAPHICAL ABSTRACT

Supporting material of VesSAP is available athttp://DISCOtechnologies.org/VesSAP
Power, positive predictive value, and sample size calculations for random field theory-based fMRI inference
Authors: Ostwald Dirk , Schneider Sebastian , Bruckner Rasmus , Horvath Lilla
Published: April 2019

Recent discussions on the reproducibility of task-related functional magnetic resonance imaging (fMRI) studies have emphasized the importance of power and sample size calculations in fMRI study planning. In general, statistical power and sample size calculations are dependent on the statistical inference framework that is used to test hypotheses. Bibliometric analyses suggest that random field theory (RFT)-based voxel- and cluster-level fMRI inference are the most commonly used approaches for the statistical evaluation of task-related fMRI data. However, general power and sample size calculations for these inference approaches remain elusive. Based on the mathematical theory of RFT-based inference, we here develop power and positive predictive value (PPV) functions for voxel- and cluster-level inference in both uncorrected single test and corrected multiple testing scenarios. Moreover, we apply the theoretical results to evaluate the sample size necessary to achieve desired power and PPV levels based on an fMRI pilot study.
Cross-modal integration of reward value during oculomotor planning
Authors: Cheng Felicia Pei-Hsin , Saglam Adem , André Selina , Pooresmaeili Arezoo
Published: April 2019

Reward value guides goal-directed behavior and modulates early sensory processing. Rewarding stimuli are often multisensory but it is not known how reward value is combined across sensory modalities. Here we show that the integration of reward value critically depends on whether the distinct sensory inputs are perceived to emanate from the same multisensory object. We systematically manipulated the congruency in monetary reward values and the relative spatial positions of co-occurring auditory and visual stimuli that served as bimodal distractors during an oculomotor task. The amount of interference induced by the distractors was used as an indicator of their perceptual salience. Our results across two experiments show that when reward value is linked to each modality separately, the value congruence between vision and audition determines the combined salience of the bimodal distractors. However, reward value of vision wins over the value of audition if visual and auditory stimuli have been experienced as belonging to the same audiovisual object prior to the learning of the reward values. The perceived spatial alignment of auditory and visual stimuli is a prerequisite for the integration of their reward values, as no effect of reward value was observed when the two modalities were perceived to be misaligned. These results show that in a task that highly relies on the processing of visual spatial information, the reward values from multiple sensory modalities are integrated with each other, each with their respective weights. This weighting depends on the congruency in reward values, exposure history, and spatial co-localization.
Use of latent class analysis to identify multimorbidity patterns and associated factors in Korean adults aged 50 years and older
Authors: Park Bomi , Lee Hye Ah , Park Hyesook
Published: April 2019

Introduction

Multimorbidity associated with significant disease and economic burdens is common among the aged. We identified chronic disease multimorbidity patterns in Koreans 50 years of age or older, and explored whether such patterns were associated with particular sociodemographic factors and health-related quality-of-life.

Methods

The multimorbidity patterns of 10 chronic diseases (hypertension, dyslipidemia, stroke, osteoarthritis, tuberculosis, asthma, allergic rhinitis, depression, diabetes mellitus, and thyroid disease) were identified via latent class analysis of data on 8,370 Korean adults aged 50+ years who participated in the sixth Korean National Health and Nutrition Examination Survey (2013-2015). The associations between multimorbidity patterns, and sociodemographic factors and health-related quality of life, were subjected to regression analysis.

Results

Three patterns of multimorbidity were identified: 1) a relatively healthy group (60.4% of the population); 2) a ‘cardiometabolic conditions’ group (27.8%); and, 3) an ‘arthritis, asthma, allergic rhinitis, depression, and thyroid disease’ group (11.8%). The female (compared to male) gender was associated with an increased likelihood of membership of thecardiometabolic conditionsgroup (odds ratio [OR]=1.32, 95% confidence interval [CI]=1.15-1.51) and (to a much greater extent) thearthritis, asthma, allergy, depression, and thyroid diseasegroup (OR=4.32, 95% CI=3.30-5.66). Low socioeconomic status was associated with membership of the two multimorbidity classes. Membership of thearthritis, asthma, allergy, depression, and thyroid diseasegroup was associated with a significantly poorer health-related quality-of-life than was membership of the other two groups.

Conclusion

The co-occurrence of chronic diseases was not attributable to chance. Multimorbidity patterns were associated with sociodemographic factors and quality-of-life. Our results suggest that targeted, integrated public health and clinical strategies dealing with chronic diseases should be based on an understanding of multimorbidity patterns; this would improve the quality-of-life of vulnerable multimorbid adults.
Determination of clinical risk factors associated with inflammation in hypertensive patients with type-2 diabetes mellitus
Authors: Ellulu Mohammed S.
Published: April 2019

Background

Obesity and chronic diseases associated with the development of inflammation have remained unclear if the observed inflammatory state in diabetic patients is due to excess adipose tissue mass and/or directly associated with the diabetic state. Therefore, this study determined the risk factors associated with inflammation in hypertensive patients with type-2 diabetes mellitus.

Methods

A total of 164 hypertensive diabetic patients aged 38 to 60 years were selected from seven primary health care centers in Gaza city, Palestine. Interview and questionnaire were employed to collect data related to age, gender, smoking habits, and physical activity pattern. Besides, the selection of patients depended on objective criteria.

Results

The study involved 118 (72%) women and 46 (28%) men. The mean of age for all patients was 53.7±0.46 years old. 76 patients (46.3%) were categorized as current smokers, 88 patients (53.7%) categorized as non-smokers. The baseline distribution of patients according to physical activity has displayed that 130 (79.3%) were low physically active patients, 28 (27.1%) were moderate, and 6 (3.7%) were highly physically active patients. A tertile of inflammation feature with high sensitivity C-reactive protein (hs-CRP) was developed. The highest tertile of hs-CRP was significantly associated with women, higher obesity indices, metabolic dysregulation involving lipid profile markers, fasting blood glucose (FBG) and blood pressure, higher interleukin 6 (IL-6), and lower adiponectin. Via ordinal logistic regression analysis, after adjusting for age, gender, smoking habits, and physical activity; the risk factors for hs-CRP were the increased body mass index [OR: 1.17, P=0.018], IL-6 [OR: 2.22, P=0.025] and FBG [OR: 1.01, P=0.007], as well as reduced adiponectin [OR: 0.81, P=0.002].

Conclusion

The inflammation state was affected by obesity and had been related to altered adipokines levels of IL-6 and adiponectin, as well as affected by the disease condition of diabetes, as evidenced by higher serum level of FBG.
The prevalence of vitamin D deficiency between Saudis and non-Saudis in Al-Madinah Al-Munawarah a cross-sectional study
Authors: Nasr Muhammed Hassan , Othman Noordin , Hassan Bassam Abdulrasol , Karoppannan Mahmathi , Abdulaziz Noorizan Binti , Alsarani Mohammed Ahmed , Eskembaji Mohammed Husain
Published: April 2019

Background

Vitamin D, or the “sunshine” hormone became an attractable topic that recently captivates many researchers. The increased prevalence of vitamin D deficiency became an alarming health concern despite the accumulative evidence exploring its crucial role not only in bone metabolism, but also in a variety of pleiotropic functions throughout the various body organs. The aim of this study is to compare the prevalence that might influence vitamin D deficiency among Saudi and non-Saudi nationalities in Almadinah Almunawarh, Saudi Arabia, and to study the different factors that may have an influence in the difference of this prevalence like the marital status, occupation, smoking, sunlight exposure, education, and dietary habits.

Methods

The study was a cross sectional study done in the medical care unit in Taiba University Almadina Almunawarah in which, 65 healthy male individuals from different nationalities (Saudis and non-Saudis), aged 18 - 65 years were divided into 2 groups, 33 Saudis and 32 non-Saudis. A sociodemographic questionnaire was filled by the study participants and 25-OH vitamin D3 (25(OH)D3) concentrations were detected by electrochemiluminescence immunoassay.

Results

Results showed a Significant percentage of the participants in the Saudi group (n = 30, 91%) suffered from deficiency in vitamin D levels [25 (OH) D < 20 ng/ml] 12.57 ± 4.82 (mean ± SD), compared to only 47% (n = 15) in the non-Saudi group [21.56 ± 6.82 (mean ± SD)]. Vitamin D deficiency was found to be significantly higher in the Saudi group than the non-Saudi group with P = 0.001.

Conclusion

Results showed a significant increase in vitamin D deficiency in Saudi population than the non-Saudis P = 0.001. The occupation status was found to be the only factor positively correlated with vitamin D deficiency.
Sex-dependent polygenic effects on the clinical progressions of Alzheimer’s disease
Authors: Fan Chun Chieh , Banks Sarah J. , Thompson Wesley K. , Chen Chi-Hua , McEvoy Linda K. , Tan Chin Hong , Kukull Walter , Bennett David A. , Farrer Lindsay A. , Mayeux Richard , Schellenberg Gerard D. , Andreassen Ole A. , Desikan Rahul , Dale Anders M.
Published: April 2019

Sex differences in the manifestations of Alzheimer’s disease (AD) are under intense investigations 1,2. Despite the emerging importance of polygenic predictions for AD 3–8, the sex-dependent polygenic effects have not been demonstrated. Here, using a sex crossover analysis, we show that sex-dependent autosomal genetic effects on AD can be revealed by characterizing disease progress via the hazard function. We first performed sex-stratified genome-wide associations, and then applied derived sex-dependent weights to two independent cohorts. Sex-matched polygenic hazard scores (PHS) have significantly stronger associations with age-at-disease-onset, clinical progressions, amyloid depositions, neurofibrillary tangles, and composite neuropathological scores, than sex-mismatched PHS, independent of apolipoprotein E. Models without using hazard weights, i.e. polygenic risk scores (PRS), have lower predictive power than PHS and show no evidence for sex differences. Our results indicate revealing sex-dependent genetic architecture requires the consideration of temporal processes of AD. This has strong implications not only for the genetic underpinning of AD but also for how we estimate sex-dependent polygenic effects for clinical use.
The role of diffusion and perivascular spaces in dynamic susceptibility contrast MRI
Authors: Doucette Jonathan , Kames Christian , Hernández-Torres Enedino , Traboulsee Anthony , Rauscher Alexander
Published: April 2019

We investigated the effects of brain tissue orientation, diffusion, and perivascular spaces on dynamic susceptibility contrast MRI. A 3D numerical model of a white matter voxel was created that consists of an isotropic capillary bed and anisotropic vessels that run in parallel with white matter tracts and are surrounded by perivascular spaces. The signal within the voxel was simulated by solving the Bloch-Torrey equation. Experimental perfusion data were acquired with a gradient echo dynamic susceptibility contrast scan. White matter fibre orientation was mapped with diffusion tensor imaging. Our numerical model of the contrast agent induced increase in R2*, as a function of tissue orientation, was fit to dynamic susceptibility contrast MRI data from thirteen subjects by minimizing the bias-corrected Akaike information criterion. White matter blood volume fraction in both the isotropic and the anisotropic vessels was determined as a free parameter, and results were analyzed as a function of diffusivity and perivascular space size. Total white matter blood volume was found to be 2.57%, with one third of the blood residing in blood vessels that run parallel with white matter tracts. Gradient echo dynamic susceptibility contrast MRI strongly depended on white matter tissue orientation and, according to the numerical simulations, this effect is amplified by diffusion and perivascular spaces.
Low Dose Ionizing Radiation Strongly Stimulates Insertional Mutagenesis in a γH2AX Dependent Manner
Authors: Zelensky Alex N. , Schoonakker Mascha , Brandsma Inger , Tijsterman Marcel , van Gent Dik C. , Essers Jeroen , Kanaar Roland
Published: April 2019

Extrachromosomal DNA can integrate into the genome with no sequence specificity producing an insertional mutation. This process, which is referred to as random integration (RI), requires a double stranded break (DSB) in the genome. Inducing DSBs by various means, including ionizing radiation, increases the frequency of integration. Here we report that non-lethal physiologically relevant doses of ionizing radiation (10-100 mGy), within the range produced by medical imaging equipment, stimulate RI of transfected and viral episomal DNA in human and mouse cells with an extremely high efficiency. Genetic analysis of stimulated RI (S-RI) revealed that it is distinct from the background RI, requires histone H2AX S139 phosphorylation (γH2AX) and is not reduced by DNA polymerase θ (Polq) inactivation. S-RI efficiency was unaffected by the main DSB repair pathway (homologous recombination and non-homologous end joining) disruptions, but double deficiency in MDC1 and 53BP1 phenocopies γH2AX inactivation. The robust responsiveness of S-RI to physiological amounts of DSBs has implications for radiation risk assessment and can be exploited for extremely sensitive, macroscopic and direct detection of DSB-induced mutations.
Investigation of betaine as a novel psychotherapeutic for schizophrenia
Authors: Ohnishi Tetsuo , Balan Shabeesh , Toyoshima Manabu , Maekawa Motoko , Ohba Hisako , Watanabe Akiko , Iwayama Yoshimi , Shimamoto-Mitsuyama Chie , Nozaki Yayoi , Hisano Yasuko , Esaki Kayoko , Nagaoka Atsuko , Matsumoto Junya , Hino Mizuki , Mataga Nobuko , Hayashi-Takagi Akiko , Kunii Yasuto , Kakita Akiyoshi , Yabe Hirooki , Yoshikawa Takeo
Published: April 2019

Betaine is known to act against various biological stresses and its levels were reported to be decreased in schizophrenia patients. Using Chdh (a gene for betaine synthesis)-deficient mice and betaine-supplemented inbred mice, we assessed the role of betaine in psychiatric pathophysiology, and its potential as a novel psychotherapeutic, by leveraging metabolomics, behavioral-, transcriptomics and DNA methylation analyses. The Chdh-deficient mice revealed remnants of psychiatric behaviors along with schizophrenia-related molecular perturbations. Betaine supplementation elicited genetic background-dependent improvement in cognitive performance, and suppressed methamphetamine (MAP)-induced behavioral sensitization. Furthermore, betaine rectified the altered antioxidative and proinflammatory responses induced by MAP and in vitro phencyclidine treatments. Notably, betaine levels were decreased in the postmortem brains from schizophrenia, and a coexisting elevated carbonyl stress, a form of oxidative stress, demarcated a subset of schizophrenia with “betaine deficit-oxidative stress pathology”. We revealed the decrease of betaine levels in glyoxylase 1 (GLO1)-defícient hiPSCs, which shows elevated carbonyl stress, and the efficacy of betaine in alleviating it, thus supporting a causal link between betaine and oxidative stress conditions. Furthermore, a CHDH variant, rs35518479, was identified as a cis-expression quantitative trait locus (QTL) for CHDH expression in postmortem brains from schizophrenia, allowing genotype-based stratification of schizophrenia patients for betaine efficacy. In conclusion, the present study underscores the potential benefit of betaine in a subset of schizophrenia.
Structural characterization of the PCV2d genotype at 3.3 Å resolution reveals differences to PCV2a and PCV2b genotypes, a tetranucleotide, and an N-terminus near the icosahedral 3-fold axes
Authors: Khayat Reza , Wen Ke , Alimova Aleksandra , Gavrilov Boris , Katz Al , Galarza Jose M. , Gottlieb J. Paul
Published: April 2019

Porcine circovirus 2 (PCV2) is a T=1 non-enveloped icosahedral virus that has a major impact on the swine industry as an agent of porcine circovirus associate disease. PCV2 capsid protein sequences have been employed by others to provide a temporal description of the emerging genotypes. PCV2a is believed to be the earliest genotype and responsible for giving rise to PCV2b, which gives rise to PCV2d. The underlying mechanism responsible for the emerging genotypes is not understood. To determine if a change in the PCV2d capsid accompanies the emergence of this genotype, we determined the cryo-electron microscopy image reconstruction of PCV2d VLP at 3.3 Å resolution and compared it to the previously reported PCV2a and PCV2b structures. Differences between the CD and GH loops identify structural changes that accompany the emergence of PCV2b from PCV2a, and PCV2d from PCV2b. We also model additional amino acids for the N-terminus near the icosahedral 3-fold axes of symmetry and a tetranucleotide between the 5- and 2-fold axes of symmetry. To interpret the sequence diversity that defines the PCV2 genotypes on a structural platform we have performed structure-based sequence comparison. Our analysis demonstrates that each genotype possesses a unique set of amino acids located on the surface of the capsid that experience a high degree of substitution. These substitutions may be a response to the PCV2 vaccination program. The structural difference between PCV2a, b and d genotypes indicate that it is important to determine the PCV2 capsid structure as the virus evolves into different genotypes.

Importance

PCV2 is a significant epidemic agricultural pathogen that is the causative agent of a variety of swine illnesses. PCV2 infections have significant economic impact in the swine industry and must be controlled by vaccination. Outbreaks in farms vaccinated for PCV2 suggest that improvements to the current vaccination programs are needed. Better understanding of the assembly, structure, replication and evolution of these viruses is necessary for production of improved vaccines. The ability of PCV2 to rapidly shift genotypes suggests that expression systems capable of rapidly producing large quantities of virus-like particles should be pursued. To these ends we have established a mammalian cell-based virus-like particle expression system and performed high resolution structural studies of a new PCV2 genotype. Differences between the structure of this genotype and earlier genotypes demonstrate that it is important to study the PCV2 structure as it shifts genotypes.
Age, Sex, and Genetics Influence the Abundance of Infiltrating Immune Cells in Human Tissues
Authors: Marderstein Andrew R. , Uppal Manik , Verma Akanksha , Bhinder Bhavneet , Mezey Jason , Clark Andrew G. , Elemento Olivier
Published: April 2019

Despite infiltrating immune cells playing an essential role in human disease and the patient response to treatment, the central mechanisms influencing variability in infiltration patterns are unclear. Using bulk RNA-seq data from 53 GTEx tissues, we applied cell-type deconvolution algorithms to evaluate the immune landscape across the healthy human body. We first performed a differential expression analysis of inflamed versus non-inflamed samples to identify essential pathways and regulators of infiltration. Next, we found 21 of 73 infiltration-related phenotypes to be associated with either age or sex (FDR< 0.1). Through our genetic analysis, we discovered 13 infiltration-related phenotypes have genome-wide significant associations (iQTLs) (P< 5.0 × 10−8), with a significant enrichment of tissue-specific expression quantitative trait loci in suggested iQTLs (P< 10−5). We highlight an association between neutrophil content in lung tissue and a variant near theCUX1transcription factor gene (P= 9.7 × 10−11), which has been previously linked to neutrophil infiltration, inflammatory mechanisms, and the regulation of several immune response genes. Together, our results identify key factors influencing inter-individual variability of specific tissue infiltration patterns, which could provide insights on therapeutic targets for shifting infiltration profiles to a more favorable one.
Engineered Retroviruses as Fluorescent Biological Reference Particles for Small Particle Flow Cytometry
Authors: Tang Vera A. , Fritzsche Anna K. , Renner Tyler M. , Burger Dylan , van der Pol Edwin , Lannigan Joanne A. , Brittain George C. , Welsh Joshua A. , Jones Jennifer C. , Langlois Marc-André
Published: April 2019

There has been renewed interest in the use of flow cytometry for single particle phenotypic analysis of particles in the nanometer size-range such as viruses, organelles, bacteria and extracellular vesicles (EVs). However, many of these particles are smaller than 200 nm in diameter, which places them at the limit of detection for many commercial flow cytometers. The use of reference particles of diameter, fluorescence, and light-scattering properties akin to those of the small biological particles being studied is therefore imperative for accurate and reproducible data acquisition and reporting across different instruments and analytical technologies. We show here that an engineered murine leukemia virus (MLV) can act as a fluorescence reference particle for other small particles such as retroviruses and EVs. More specifically, we show that engineered MLV is a highly monodisperse enveloped particle that can act as a surrogate to demonstrate the various effects of antibody labeling on the physical properties of small biological particles in a similar diameter range.
Laboratory validation of a clinical metagenomic sequencing assay for pathogen detection in cerebrospinal fluid
Authors: Miller Steve , Naccache Samia N. , Samayoa Erik , Messacar Kevin , Arevalo Shaun , Federman Scot , Stryke Doug , Pham Elizabeth , Fung Becky , Bolosky William J. , Ingebrigtsen Danielle , Lorizio Walter , Paff Sandra M. , Leake John A. , Pesano Rick , DeBiasi Roberta , Dominguez Samuel , Chiu Charles Y.
Published: April 2019

Metagenomic next-generation sequencing (mNGS) for pan-pathogen detection has been successfully tested in proof-of-concept case studies in patients with acute illness of unknown etiology but to date has been largely confined to research settings. Here, we developed and validated a clinical mNGS assay for diagnosis of infectious causes of meningitis and encephalitis from cerebrospinal fluid (CSF) in a licensed microbiology laboratory. A customized bioinformatics pipeline, SURPI+, was developed to rapidly analyze mNGS data, generate an automated summary of detected pathogens, and provide a graphical user interface for evaluating and interpreting results. We established quality metrics, threshold values, and limits of detection of 0.2–313 genomic copies or colony forming units per milliliter for each representative organism type. Gross hemolysis and excess host nucleic acid reduced assay sensitivity; however, spiked phages used as internal controls were reliable indicators of sensitivity loss. Diagnostic test accuracy was evaluated by blinded mNGS testing of 95 patient samples, revealing 73% sensitivity and 99% specificity compared to original clinical test results, and 81% positive percent agreement and 99% negative percent agreement after discrepancy analysis. Subsequent mNGS challenge testing of 20 positive CSF samples prospectively collected from a cohort of pediatric patients hospitalized with meningitis, encephalitis, and/or myelitis showed 92% sensitivity and 96% specificity relative to conventional microbiological testing of CSF in identifying the causative pathogen. These results demonstrate the analytic performance of a laboratory-validated mNGS assay for pan-pathogen detection, to be used clinically for diagnosis of neurological infections from CSF.
Pavlovian-to-instrumental transfer after human threat conditioning
Authors: Xia Yanfang , Gurkina Angelina , Bach Dominik R.
Published: April 2019

Threat conditioning is a common associative learning model with translational relevance. How threat-conditioned cues impact on formally unrelated instrumental behavior in humans is not well known. Such an effect is known as Pavlovian-to-instrumental transfer (PIT). While PIT with aversive primary Pavlovian reinforcers is established in nonhuman animals, this is less clear in humans, where secondary reinforcers or instructed instrumental responses are most often investigated. We modified an existing human PIT procedure to include primary reinforcers. Participants first learned to obtain (or avoid losing) appetitive instrumental reinforcement (chocolate) by appropriate approach or avoidance actions. They either had to act (Go) or to withhold an action (NoGo), and in the Go condition either to approach a reward target to collect it or to withdraw from the reward target to avoid losing it. Then they learned to associate screen color (CS) with aversive Pavlovian reinforcement (electric shock US). In the transfer phase, we conducted the instrumental task during the presence of Pavlovian CS. In a first experiment, we show that the aversive Pavlovian CS+, compared to CS−, increased response rate in Go-Withdraw trials, i.e., induce conditioned facilitation of avoidance responses. This finding was confirmed in a second and independent experiment with an increased number of Go-Withdraw trials. Notably, we observed no appreciable conditioned suppression of approach responses. Effect size to distinguish CS+/CS− in Go-Withdraw trials was d = 0.42 in the confirmation sample. This would require n = 37 participants to demonstrate threat learning with 80% power. Thus, the effect size is on a practically useful scale although smaller than for model-based analysis of autonomic measures. In summary, our results indicate conditioned facilitation of formally unrelated instrumental avoidance behavior in humans and provide a novel behavioral threat learning measure that requires only key presses.
Sukhpal Dairy Farm: considering customer engagement-based growth options
Authors: Srivastava Ritu , Mangla Akhil
Published: April 2019

Learning outcomes

The learning outcomes are as follows: understand the challenges and opportunities of an unorganized business/informal economy; compare and contrast the applications of customer engagement frameworks between small and big businesses; outline the steps in product design in a services context; discuss the services marketing mix as a part of the marketing strategy; and understand the need of scaling up the business operations in wake of new opportunity.

Case overview/synopsis

Sukhpal Dairy Farm (SDF) is a case of unorganized milk marketing in the Indian Emerging Market. Milk was sold as a commodity with a fragmented set of suppliers to only a small population. Changes in consumer demand, technology and supply chain presented huge opportunities to the small dairy farmer. But it was also a threat to him. The large corporater, players backed by strong logistics and supply chain operations support posed a big challenge to the small farmer who lacked scale and reach. Sukhpal, owner of SDF, struggled while considering the options to grow his business. He did not want to change the success factors of his existing business model that was based on word of mouth and customer engagement.

Complexity academic level

MBA students.

Supplementary materials

Teaching Notes are available for educators only. Please contact your library to gain login details or email support@emeraldinsight.com to request teaching notes.

Subject code

CSS: 8: Marketing.
Research on map matching algorithm based on priority rule for low sampling frequency vehicle navigation data
Authors: Liu Zhishuo , Dongxin Yao , Kuan Zhao , Fang Wang Chun
Published: April 2019

Purpose

There is a certain error in the satellite positioning of the vehicle. The error will cause the drift point of the positioning point, which makes the vehicle trajectory shift to the real road. This paper aims to solve this problem.

Design/methodology/approach

The key technology to solve the problem is map matching (MM). The low sampling frequency of the vehicle is far from the distance between adjacent points, which weakens the correlation between the points, making MM more difficult. In this paper, an MM algorithm based on priority rules is designed for vehicle trajectory characteristics at low sampling frequencies.

Findings

The experimental results show that the MM based on priority rule algorithm can effectively match the trajectory data of low sampling frequency with the actual road, and the matching accuracy is better than other similar algorithms, the processing speed reaches 73 per second.

Research limitations/implications

In the algorithm verification of this paper, although the algorithm design and experimental verification are considered considering the diversity of GPS data sampling frequency, the experimental data used are still a single source.

Originality/value

Based on the GPS trajectory data of the Ministry of Transport, the experimental results show that the accuracy of the priority-based weight-based algorithm is higher. The accuracy of this algorithm is over 98.1 per cent, which is better than other similar algorithms.
Perceived fairness of revenue management practices in casual and fine-dining restaurants
Authors: Tang Jason , Repetti Toni , Raab Carola
Published: April 2019

Purpose

Restaurants typically have small profit margins and with the pressure of increasing food and labor costs, management is looking to revenue as a way to maintain and drive profits. One technique to increase revenue is through revenue management practices, but management needs to be aware of their customers’ reactions to these practices prior to implementation. The paper aims to discuss this issue.

Design/methodology/approach

This study utilizes linear regression to determine the impact of select restaurant revenue management practices, customers’ familiarity with revenue management in general and in restaurants specifically, and customers’ demographics on perceived fairness of revenue management practices in casual and fine-dining restaurants.

Findings

Results indicate that customers find certain restaurant revenue management practices, such as charging premium prices on certain days of the week, fair in both casual and fine-dining restaurants, while others are not in either. Non-refundable reservation fees were found to be fair for fine-dining establishments only. Increased familiarity with restaurant revenue management was associated with higher perceptions of fairness for both casual and fine dining. Age was the only demographic studied that affected perceived fairness.

Originality/value

This study is the only known study to simultaneously evaluate the impact of price and duration restaurant revenue management techniques in combination with customer demographics and revenue management familiarity on consumer perceptions of fairness.