bluuebunny/crossref_metadata_2025 huggingface dataset:
OpenPathSampling: A Python framework for path sampling simulations. II. Building and customizing path ensembles and sample schemes
Authors: Swenson David W.H. , Prinz Jan-Hendrik , Noe Frank , Chodera John D. , Bolhuis Peter G.
Published: June 2018

The OpenPathSampling (OPS) package provides an easy-to-use framework to apply transition path sampling methodologies to complex molecular systems with a minimum of effort. Yet, the extensibility of OPS allows for the exploration of new path sampling algorithms by building on a variety of basic operations. In a companion paper [Swenson et al 2018] we introduced the basic concepts and the structure of the OPS package, and how it can be employed to perform standard transition path sampling and (replica exchange) transition interface sampling. In this paper, we elaborate on two theoretical developments that went into the design of OPS. The first development relates to the construction of path ensembles, the what is being sampled. We introduce a novel set-based notation forthepath ensemble, which provides an alternative paradigm for constructing path ensembles, and allows building arbitrarily complex path ensembles from fundamental ones. The second fundamental development is the structure for the customisation of Monte Carlo procedures; how path ensembles are being sampled. We describe in detail the OPS objects that implement this approach to customization, the MoveScheme and the PathMover, and provide tools to create and manipulate these objects. We illustrate both the path ensemble building and sampling scheme customization with several examples. OPS thus facilitates both standard path sampling application in complex systems as well as the development of new path sampling methodology, beyond the default.
Drug Interactions Between Dolutegravir and Artemether-Lumefantrine or Artesunate-Amodiaquine
Authors: Walimbwa Stephen I , Lamorde Mohammed , Waitt Catriona , Kaboggoza Julian , Else Laura , Byakika-Kibwika Pauline , Amara Alieu , Gini Joshua , Winterberg Markus , Chiong Justin , Tarning Joel , Khoo Saye H
Published: June 2018

Across sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need cotreatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artmether-lumefantrine (AL) or artesunate-amodiaquine (AS-AQ) given with 50mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artmether-lumefantrine or artesunate-amodiaquine and DTG. The DTG/artmether-lumefantrine interaction was evaluated in a two-way cross-over study and measured artemether (ARM), dihydroartemisinin (DHA), lumefantrine (LF), desbutyl-lumefantrine (DBL) over 264h. The DTG/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine (DEAQ) and measured artesunate (ARS), amodiaquine (AQ), DEAQ over 624h. Non-compartmental analysis was performed, and geometric mean ratios and 90% confidence intervals generated for evaluation of both interactions. Dolutegravir did not significantly change the maximum concentration in plasma, time to maximum concentration and area under the concentration-time curve (AUC) for ARM, DHA, LF and DBL nor significantly alter AUC for ARS, DHA, AQ and DEAQ. Co-administration of dolutegravir with AL resulted in a 37% decrease in DTG trough concentrations. Co-administration of dolutegravir with AS-AQ resulted in a decrease of approximately 42% and 24% in DTG trough concentrations and AUC respectively. Study drugs were well-tolerated with no serious adverse events. Standard doses of artmether-lumefantrine and artesunate-amodiaquine should be used in patients receiving DTG. The significant decreases in DTG trough concentrations with artemether-lumefantrine and artesunate-amodiaquine and DTG exposure with artesunate-amodiaquine are unlikely to be of clinical significance as DTG trough concentrations were above DTG target concentrations of 64ng/mL.
Comparison of the effects of metformin on MDA-MB-231 breast cancer cells in a monolayer culture and in tumour spheroids as a function of nutrient concentrations
Authors: Bizjak Maruša , Malavašič Petra , Pirkmajer Sergej , Pavlin Mojca
Published: June 2018

Metabolic pathways of cancer cells depend on the concentrations of nutrients in their micro-environment. However, they can vary also between monolayer cultures of cancer cells and tumour spheroids. Here we examined whether the absence of glucose, pyruvate and glutamine increases the sensitivity of MDA-MB-231 cells to metabolic drug metformin using twoin vitrocell models (monolayer culture and tumour spheroids). To evaluate the effects of nutrient depletion in more detail, we tested the effects of metformin in commonly used media (DMEM, MEM and RPMI-1640) that differ mainly in the concentrations of amino acids. We used MTS, Hoechst and propidium iodide assay to determine cell number, viability and survival, respectively. We evaluated the effects of metformin on the size of tumour spheroids and determined cell survival by calcein and propidium iodide staining. Finally, we observed the effects of metformin in nutrient depleted conditions on the phosphorylation of AMP-activated protein kinase using Western blotting. Our main finding is that the effects of metformin on MDA-MB-231 cells depend onin vitrocell model used (monolayer culture vs. tumour spheroids). While metformin did not have any major effect on proliferation of MDA-MB-231 cells grown in complete cell culture media in a monolayer culture, it disintegrated tumour spheroids in MEM and RPMI-1640 medium. The effects of metformin on tumour spheroids were most pronounced in MEM, which is deficient of several non-essential amino acids. Glutamine depletion had no effect on the sensitivity of MDA-MB-231 cells to metformin in all tested conditions, whereas pyruvate depletion sensitized MDA-MB-231 cells to metformin in a monolayer culture only in MEM. Taken together, our results show that media formulation as well asin vitrocell model (monolayer culture vs. tumour spheroids) must be considered, when we evaluate the effects of metformin on MDA-MB-231 cells as a function of nutrient availability.
Inferring Reaction Networks using Perturbation Data
Authors: Choi Kiri , Hellerstein Joesph , Wiley H. Steven , Sauro Herbert M.
Published: June 2018

In this paper we examine the use of perturbation data to infer the underlying mechanistic dynamic model. The approach uses an evolutionary strategy to evolve networks based on a fitness criterion that measures the difference between the experimentally determined set of perturbation data and proposed mechanistic models. At present we only deal with reaction networks that use mass-action kinetics employing uni-uni, bi-uni, uni-bi and bi-bi reactions. The key to our approach is to split the algorithm into two phases. The first phase focuses on evolving network topologies that are consistent with the perturbation data followed by a second phase that evolves the parameter values. This results in almost an exact match between the evolved network and the original network from which the perturbation data was generated from. We test the approach on four models that include linear chain, feed-forward loop, cyclic pathway and a branched pathway. Currently the algorithm is implemented using Python and libRoadRunner but could at a later date be rewritten in a compiled language to improve performance. Future studies will focus on the impact of noise in the perturbation data on convergence and variability in the evolved parameter values and topologies. In addition we will investigate the effect of nonlinear rate laws on generating unique solutions.
One size does not fit all: Caste and sex differences in the response of bumblebees (Bombus impatiens) to chronic oral neonicotinoid exposure
Authors: Mobley Melissa W. , Gegear Robert J.
Published: June 2018

Neonicotinoid insecticides have been implicated in the rapid global decline of bumblebees over recent years, particularly in agricultural and urban areas. While there is much known about neonicotinoid toxicity effects at the colony stage of the bumblebee annual cycle, far less is known about such effects at other stages critical for the maintenance of wild populations. In the present work, individual-based feeding assays were used to show that chronic consumption of the widely used neonicotinoid clothianidin at a field-realistic average rate of 3.6 and 4.0 ng/g·bee/day reduces survival of queen and male bumblebees, respectively, within a 7-day period whereas consumption at a similar rate of 3.9 ng/g·bee/day in workers had no effect on survival. To test the hypothesis that males have a lower tolerance for oral clothianidin exposure than workers due to their haploid genetic status, RNAseq analysis was used to compare the transcriptomic responses of workers and males to chronic intake of clothianidin at a sub-lethal dose of 0.37ng/day for 5 days. Surprisingly, only 25/100 clothianidin-induced putative detoxification genes had expression levels that differed in a sex-specific manner, with 17 genes showing increased expression in workers. Sub-lethal clothianidin intake also induced changes in genes associated with a variety of other major biological functions, including locomotion, reproduction, and immunity. Collectively, these results suggest that chronic oral toxicity effects of neonicotinoids are greatest during mating and nest establishment phases of the bumblebee life cycle. Chronic oral toxicity tests on males and queens are therefore required in order to fully assess the impact of neonicotinoids on wild bumblebee populations.
Hygroregulation, a key ability for eusocial insects: Native Western European bees as a case study
Authors: Eouzan Iris , Garnery Lionel , Pinto M. Alice , Delalande Damien , Neves Cátia J. , Fabre Francis , Lesobre Jérôme , Houte Sylvie , Estonba Andone , Montes Iratxe , Sime-Ngando Télesphore , Biron David G.
Published: June 2018

Sociality has brought many advantages to various hymenoptera species, including their ability of regulating physical factors in their nest (e.g., temperature). Although less studied, humidity is known to be important for egg, larval and pupal development. Two subspecies ofApis melliferaof the M branch, also called black bees, were used as models to test the “hygroregulation hypothesis”, by means of monitoring hygrometry in hives during one year in four conservation centers: two in France (A. m. mellifera) and two in Portugal (A. m. iberiensis). We investigated the ability of both subspecies to regulate the hygrometry daily, but also during the seasons and one complete year. Our data and statistical analysis probed the capacity of the bees to regulate humidity in their hive, regardless of the day, season or subspecies. Furthermore, the study showed that humidity in beehives is very stable even during winter, when brood is absent, and when temperature is known to be less stable in the beehives. These results would support that hygrometry could prevail over temperature in maintaining nest homeostasis, maybe because of a bigger importance of hygrometry for all the population during a year, or because of the ‘imprint’ of the evolutionary history of this hymenopteran lineage.
Sonic stimulation, and low power microwave radiation can modulate bacterial virulence towardsCaenorhabditis elegans
Authors: Patel Priya , Patel Hiteshi , Vekariya Dhara , Joshi Chinmayi , Patel Pooja , Muskal Steven , Kothari Vijay
Published: June 2018

Caenorhabditis elegansworms infected with different pathogenic bacteria were subjected to sonic treatment to investigate whether such sound treatment can exert any therapeutic effect on the infected worms. Sonic therapy corresponding to 400 Hz, and the divine sound ‘om’ were found to confer protective effect on this nematode worm in face of bacterial infection, particularly that caused bySerratia marcescensorStaphylococcus aureus. The observed effect seemed to occur due to influence of sound on bacteria, and not on the worm. In addition to this, effect of microwave exposure on bacterial virulence was also investigated, wherein microwave exposure was found to reduce virulence ofS. aureustowardsC. elegans.
Single cell expression analysis uncouples transdifferentiation and reprogramming
Authors: Francesconi Mirko , Stefano Bruno Di , Berenguer Clara , Andres Marisa de , Mendez Lago Maria , Guillaumet-Adkins Amy , Rodriguez-Esteban Gustavo , Gut Marta , Gut Ivo G. , Heyn Holger , Lehner Ben , Graf Thomas
Published: June 2018

Many somatic cell types are plastic, having the capacity to convert into other specialized cells (transdifferentiation)(1) or into induced pluripotent stem cells (iPSCs, reprogramming)(2) in response to transcription factor over-expression. To explore what makes a cell plastic and whether these different cell conversion processes are coupled, we exposed bone marrow derived pre-B cells to two different transcription factor overexpression protocols that efficiently convert them either into macrophages or iPSCs and monitored the two processes over time using single cell gene expression analysis. We found that even in these highly efficient cell fate conversion systems, cells differ in both their speed and path of transdifferentiation and reprogramming. This heterogeneity originatesin two starting pre-B cell subpopulations,large pre-BII and the small pre-BII cells they normally differentiate into. The large cells transdifferentiate slowly but exhibit a high efficiency of iPSC reprogramming. In contrast, the small cells transdifferentiate rapidly but are highly resistant to reprogramming. Moreover, the large B cells induce a stronger transient granulocyte/macrophage progenitor (GMP)-like state, while the small B cells undergo a more direct conversion to the macrophage fate. The large cells are cycling and exhibit high Myc activity whereas the small cells are Myc low and mostly quiescent. The observed heterogeneity of the two cell conversion processes can therefore be traced to two closely related cell types in the starting population that exhibit different types of plasticity. These data show that a somatic cell’s propensity for either transdifferentiation and reprogramming can be uncoupled.

One sentence summary

Single cell transcriptomics of cell conversions
An atomic-scale view at the composition of amyloid-beta fibrils by atom probe tomography
Authors: Rusitzka Kristiane A.K. , Stephenson Leigh T. , Szczepaniak Agnieszka , Gremer Lothar , Raabe Dierk , Willbold Dieter , Gault Baptiste
Published: June 2018

Amyloid-beta (Aβ) proteins play an important role in a number of neurodegenerative diseases. Aβ is found in senile plaques in brains of Alzeimer’s disease patients. The 42 residues of the monomer form dimers which stack to fibrils gaining several micrometers in length. Using Aβ fibrils with 13C and 15N marker substitution, we developed an innovative approach to obtain insights to structural and chemical information of the protein. We deposited the modified protein fibrils to pre-sharped aluminium needles with >100-nm apex diameters and, using the position-sensitive mass-to-charge spectrometry technique of atom probe tomography, we acquired the chemically-resolved three dimensional information for every detected ion evaporated in small fragments from the protein. We also discuss the influence of experimental parameters such as pulse energy and pulse frequency of the used Laser beam which lead to differences in the size of the gained fragments, developing the capability of localising metal atom within Aβ plaques.
Regulatory network controlling tumor-promoting inflammation in human cancers
Authors: Ji Zhe , He Lizhi , Regev Aviv , Struhl Kevin
Published: June 2018

Using an inducible, inflammatory model of breast cellular transformation, we describe the transcriptional regulatory network mediated by STAT3, NF-κB, and AP-1 factors on a genomic scale. These regulators form transcriptional complexes that directly regulate the expression of hundreds of genes in oncogenic pathways via a positive feedback loop. This inflammatory feedback loop, which functions to various extents in many types of cancer cells and patient tumors, is the basis for an “inflammation” index that defines cancer types by functional criteria. We identify a network of non-inflammatory genes whose expression is well correlated with the cancer inflammatory index. Conversely, the inflammation index is negatively correlated with expression of genes involved in DNA metabolism, and transformation is associated with genome instability. Inflammatory tumors are preferentially associated with infiltrating immune cells that might be recruited to the site of the tumor via inflammatory molecules produced by the cancer cells.
Inferring rates of metastatic dissemination using stochastic network models
Authors: Gerlee P. , Johansson M.
Published: June 2018

The formation of metastases is driven by the ability of cancer cells to disseminate from the site of the primary tumour to target organs. The process of dissemination is constrained by anatomical features such as the flow of blood and lymph in the circulatory system. We exploit this fact in a stochastic network model of metastasis formation, in which only anatomically feasible routes of dissemination are considered. By fitting this model to two different clinical datasets (tongue & ovarian cancer) we show that incidence data can be modelled using a small number of biologically meaningful parameters. The fitted models reveal site specific relative rates of dissemination and also allow for patient-specific predictions of metastatic involvement based on primary tumour location and stage. Applied to other data sets this type of model could yield insight about seed-soil effects, and could also be used in a clinical setting to provide personalised predictions about the extent of metastatic spread.

AUTHOR SUMMARY

For most cancer patients the occurrence of metastases equals incurable disease. Despite this fact our quantitative knowledge about the process of metastatic dissemination is limited. In this manuscript we improve on a previously published mathematical model by incorporating known biological facts about metastatic spread and also consider the temporal dimension of dissemination. The model is fit to two different cancer types with very different patterns of spread, which highlights the versatility of our framework. Properly parametrised this type of model can be used for making personalised predictions about metastatic burden.
Mutational load, inbreeding depression and heterosis in subdivided populations
Authors: Charlesworth Brian
Published: June 2018

This paper examines the extent to which empirical estimates of inbreeding depression and inter-population heterosis in subdivided populations, as well as the effects of local population size on mean fitness, can be explained in terms of estimates of mutation rates, and the distribution of selection coefficients against deleterious mutations provided by population genomics data. Using results from population genetics models, numerical predictions of the genetic load, inbreeding depression and heterosis were obtained for a broad range of selection coefficients and mutation rates. The models allowed for the possibility of very high mutation rates per nucleotide site, as is sometimes observed for epiallelic mutations. There was fairly good quantitative agreement between the theoretical predictions and empirical estimates of heterosis and the effects of population size on genetic load, on the assumption that the deleterious mutation rate per individual per generation is approximately one, but there was less good agreement for inbreeding depression. Weak selection, of the order of magnitude suggested by population genomic analyses, is required to explain the observed patterns. Possible caveats concerning the applicability of the models are discussed.
Longitudinally Mapping Childhood Socioeconomic Status Associations with Cortical and Subcortical Morphology
Authors: McDermott Cassidy L. , Seidlitz Jakob , Nadig Ajay , Liu Siyuan , Clasen Liv S. , Blumenthal Jonathan D. , Reardon Paul Kirkpatrick , Lalonde François , Patel Raihaan , Chakravarty Mallar M. , Lerch Jason P. , Raznahan Armin
Published: June 2018

Childhood socioeconomic status (SES) impacts cognitive development and mental health, but its association with structural brain development is not yet well-characterized. Here, we analyzed 1243 longitudinally-acquired structural MRI scans from 623 youth to investigate the relation between SES and cortical and subcortical morphology between ages 5 and 25 years. We found positive associations between SES and total volumes of the brain, cortical sheet, and four separate subcortical structures. These associations were developmentally fixed rather than age-dependent. Surface-based shape analysis revealed that higher SES is associated with areal expansion of (i) lateral prefrontal, anterior cingulate, lateral temporal, and superior parietal cortices and (ii) ventrolateral thalamic, and medial amygdalo-hippocampal sub-regions. Meta-analyses of functional imaging data indicate that cortical correlates of SES are centered on brain systems subserving sensorimotor functions, language, memory, and emotional processing. We further show that anatomical variation within a subset of these cortical regions partially mediates the positive association between SES and IQ. Finally, we identify neuroanatomical correlates of SES that exist above and beyond accompanying variation in IQ. Our findings clarify the spatiotemporal patterning of SES-related neuroanatomical variation and inform ongoing efforts to dissect the causal pathways underpinning observed associations between childhood SES and regional brain anatomy.
Turing patterns are common but not robust
Authors: Scholes Natalie S. , Schnoerr David , Isalan Mark , Stumpf Michael P. H.
Published: June 2018

Turing patterns (TPs) underlie many fundamental developmental processes, but they operate over narrow parameter ranges, raising the conundrum of how evolution can ever discover them. Here we explore TP design space to address this question and to distill design rules. We exhaustively analyze 2- and 3-node biological candidate Turing systems: crucially, network structure alone neither determines nor guarantees emergent TPs. A surprisingly large fraction (>60%) of network design space can produce TPs, but these are sensitive to even subtle changes in parameters, network structure and regulatory mechanisms. This implies that TP networks are more common than previously thought, and evolution might regularly encounter prototypic solutions. Importantly, we deduce compositional rules for TP systems that are almost necessary and sufficient (≈96% of TP networks contain them, and ≈95% of networks implementing them produce TPs). This comprehensive network atlas provides the blueprints for identifying natural TPs, and for engineering synthetic systems.
A theoretical analysis of single molecule protein sequencing via weak binding spectra
Authors: Rodriques Samuel , Marblestone Adam , Boyden Ed
Published: June 2018

We propose and theoretically study an approach to massively parallel single molecule peptide sequencing, based on single molecule measurement of the kinetics of probe binding [1] to the N-termini of immobilized peptides. Unlike previous proposals, this method is robust to both weak and non-specific probe-target affinities, which we demonstrate by applying the method to a range of randomized affinity matrices consisting of relatively low-quality binders. This suggests a novel principle for proteomic measurement whereby highly non-optimized sets of low-affinity binders could be applicable for protein sequencing, thus shifting the burden of amino acid identification from biomolecular design to readout. Measurement of probe occupancy times, or of time-averaged fluorescence, should allow high-accuracy determination of N-terminal amino acid identity for realistic probe sets. The time-averaged fluorescence method scales well to extremely weak-binding probes. We argue that this method could lead to an approach with single amino acid resolution and the ability to distinguish many canonical and modified amino acids, even using highly non-optimized probe sets. This readout method should expand the design space for single molecule peptide sequencing by removing constraints on the properties of the fluorescent binding probes.

Author summary

We simplify the problem of single molecule protein sequencing by proposing and analyzing an approach that makes use of low-affinity, low-specificity binding reagents. This decouples the problem of protein sequencing from the problem of generating a high-quality library of binding reagents against each of the amino acids.
Intestinal NF-κB and STAT signalling is important for uptake and clearance in a Drosophila-Herpetomonas interaction model
Authors: Wang Lihui , Sloan Megan A. , Ligoxygakis Petros
Published: June 2018

Dipteran insects transmit diseases to humans, often in the form of trypanosomatid parasites. To accelerate research in more difficult contexts of dipteran-parasite relationships, we studied the interaction of the model dipteran Drosophila melanogaster and its natural trypanosomatid Herpetomonas muscarum. Parasite infection reduced fecundity but not lifespan in NF-κB/Relish-deficient flies. Gene expression analysis implicated the two NF-κB pathways Toll and Imd as well as STAT signalling. Tissue specific knockdown of key components of these pathways in enterocytes (ECs) and intestinal progenitor cells influenced initial numbers, infection dynamics and time of clearance. Herpetomonas triggered STAT activation and proliferation of Intestinal Stem Cells (ISCs). Loss of Relish suppressed the latter, resulting in increased parasite numbers and delayed clearance. Finally, loss of Toll signalling decreased EC numbers and enabled parasite persistence. This network of signalling may represent a general mechanism of the dipteran early response to trypanosomatids, crucial for parasite establishment and therefore transmission.

AUTHOR SUMMARY

Neglected Tropical Diseases are the most common diseases of the world’s poorest people. Many are caused by parasites called trypanosomatids that are transmitted to humans via insects belonging to the order of Diptera (also known as true flies). These flies (including tsetse, sand flies and black flies) are difficult to study in the lab and so the prospect of rapid progress in the basic biology of fly-parasite interaction is bleak. However, a model dipteran species with an extensive “tool-box” is the fruit fly Drosophila melanogaster with its natural trypanosomatid Herpetomonas muscarum. Here we establish the framework of their early interaction with the view that part of this interaction will represent an evolutionary conserved component of the dipteran response to parasite infection and will inform more targeted studies into medically important but difficult to study Diptera.
Precise tuning of gene expression output levels in mammalian cells
Authors: Michaels Yale S. , Barnkob Mike B. , Barbosa Hector , Baeumler Toni A. , Thompson Mary K. , Andre Violaine , Colin-York Huw , Fritzsche Marco , Gileadi Uzi , Sheppard Hilary M. , Knapp David J.H.F. , Milne Thomas A. , Cerundolo Vincenzo , Fulga Tudor A.
Published: June 2018

Precise, analogue regulation of gene expression is critical for development, homeostasis and regeneration in mammals. In contrast, widely employed experimental and therapeutic approaches such as knock-in/out strategies are more suitable for binary control of gene activity, while RNA interference (RNAi) can lead to pervasive off-target effects and unpredictable levels of repression. Here we report on a method for the precise control of gene expression levels in mammalian cells based on engineered, synthetic microRNA response elements (MREs). To develop this system, we established a high-throughput sequencing approach for measuring the efficacy of thousands of miR-17 MRE variants. This allowed us to create a library of microRNA silencing-mediated fine-tuners (miSFITs) of varying strength that can be employed to control the expression of user specified genes. To demonstrate the value of this technology, we used a panel of miSFITs to tune the expression of a peptide antigen in a mouse melanoma model. This analysis revealed that antigen expression level is a key determinant of the anti-tumour immune response in vitro and in vivo. miSFITs are a powerful tool for modulating gene expression output levels with applications in research and cellular engineering.
Real Time Normalization of Fast Photochemical Oxidation of Proteins Experiments by Inline Adenine Radical Dosimetry
Authors: Sharp Joshua S. , Misra Sandeep K. , Persoff Jeffrey J. , Egan Robert W. , Weinberger Scot R.
Published: June 2018

Hydroxyl radical protein footprinting (HRPF) is a powerful method for measuring protein topography, allowing researchers to monitor events that alter the solvent accessible surface of a protein (e.g. ligand binding, aggregation, conformational changes, etc.) by measuring changes in the apparent rate of reaction of portions of the protein to hydroxyl radicals diffusing in solution. Fast Photochemical Oxidation of Proteins (FPOP) offers an ultra-fast benchtop method for performing HRPF, photolyzing hydrogen peroxide using a UV laser to generate high concentrations of hydroxyl radicals that are consumed on roughly a microsecond timescale. The broad reactivity of hydroxyl radicals means that almost anything added to the solution (e.g. ligands, buffers, excipients, etc.) will scavenge hydroxyl radicals, altering their half-life and changing the effective radical concentration experienced by the protein. Similarly, minute changes in peroxide concentration, laser fluence, and buffer composition can alter the effective radical concentration, making reproduction of data challenging. Here, we present a simple method for radical dosimetry that can be carried out as part of the FPOP workflow, allowing for measurement of effective radical concentration in real time. Additionally, by modulating the amount of radical generated, we demonstrate that FPOP HRPF experiments carried out in buffers with widely differing levels of hydroxyl radical scavenging capacity can be normalized on the fly, yielding statistically indistinguishable results for the same conformer. This method represents a major step in transforming FPOP into a robust and reproducible technology capable of probing protein structure in a wide variety of contexts.
Rod signaling in primate retina: range, routing and kinetics
Authors: Grimes William N , Baudin Jacob , Azevedo Anthony , Rieke Fred
Published: June 2018

Stimulus or context dependent routing of neural signals through parallel pathways can permit flexible processing of diverse inputs. For example, work in mouse shows that rod photoreceptor signals are routed through several retinal pathways, each specialized for different light levels. This light level-dependent routing of rod signals has been invoked to explain several human perceptual results, but it has not been tested in primate retina. Here we show, surprisingly, that rod signals traverse the primate retina almost exclusively through a single pathway, regardless of light level. Indeed, identical experiments in mouse and primate reveal large differences in how rod signals traverse the retina. These results require reevaluating human perceptual results in terms of flexible computation within this single pathway. This includes a prominent speeding of rod signals with light level – which we show is inherited directly from the rods photoreceptors themselves rather than from different pathways with different kinetics.
The Role of Location-Context Binding in Nonspatial Visual Working Memory
Authors: Cai Ying , Yu Qing , Sheldon Andrew D. , Postle Bradley R.
Published: June 2018

Successful retrieval of an item from visual working memory (VWM) often requires an associated representation of the trial-unique context in which that item was presented. We dissociated the effects on fMRI signal of memory load versus context binding by comparing nonspatial VWM for one oriented bar vs. three bars individuated by their location on the screen vs. three items drawn from different categories (orientation, color, and luminance), for which location context was superfluous. Delay-period fMRI signal in frontal and parietal cortex was sensitive to stimulus homogeneity rather than to memory load per se. Behavioral performance revealed a broad range in swap errors, an index of the efficacy of context binding, and subjects were classified as high swap error or low swap error. During the delay period, the strength of the representation of stimulus location in parietal cortex predicted individual differences in swap errors. During recall, activity in occipital cortex revealed two dissociable neural correlates of context binding: high swap-error subjects allocated less spatial attention to the location of the probed item and more spatial attention the location of non-probed items; high swap-error subjects also represented the orientation of the probed item more weakly and the orientation of nonprobed items more strongly. Our results suggest context binding is a computation that influences all stages of VWM processing.

Significance Statement

Although we often think of the contents of visual working memory (VWM) as representations of the items that need to be remembered, each item’s trial-unique context is also critical for successful performance. For example, if one observes a red, then a black, then a blue car passing through an intersection, vivid memory for the colors, alone, wouldn’t allow one to execute the instruction “Follow the first of the three cars that just drove by.” Although manipulating load is commonly assumed to isolate storage functions, requiring memory for multiple items drawn from the same category also increases demands on the context binding needed to individuate these items. This experiment tracked the influence of context binding on VWM stimulus processing.
Characterizing Building Blocks of Resource Constrained Biological Networks
Authors: Ren Yuanfang , Ay Ahmet , Dobra Alin , Kahveci Tamer
Published: June 2018

Identification of motifs-recurrent and statistically significant patterns-in biological networks is the key to understand the design principles, and to infer governing mechanisms of biological systems. This, however, is a computationally challenging task. This task is further complicated as biological interactions depend on limited resources, i.e., a reaction takes place if the reactant molecule concentrations are above a certain threshold level. This biochemical property implies that network edges can participate in a limited number of motifs simultaneously. Existing motif counting methods ignore this problem. This simplification often leads to inaccurate motif counts (over-or under-estimates), and thus, wrong biological interpretations. In this paper, we develop a novel motif counting algorithm, Partially Overlapping MOtif Counting (POMOC), that considers capacity levels for all interactions in counting motifs. Our experiments on real and synthetic networks demonstrate that motif count using the POMOC method significantly differs from the existing motif counting approaches, and our method extends to large-scale biological networks in practical time. Our results also show that our method makes it possible to characterize the impact of different stress factors on cell’s organization of network. In this regard, analysis of a S. cerevisiae transcriptional regulatory network using our method shows that oxidative stress is more disruptive to organization and abundance of motifs in this network than mutations of individual genes. Our analysis also suggests that by focusing on the edges that lead to variation in motif counts, our method can be used to find important genes, and to reveal subtle topological and functional differences of the biological networks under different cell states.
BioJupies: Automated Generation of Interactive Notebooks for RNA-seq Data Analysis in the Cloud
Authors: Torre Denis , Lachmann Alexander , Ma’ayan Avi
Published: June 2018

Interactive notebooks can make bioinformatics data analyses more transparent, accessible and reusable. However, creating notebooks requires computer programming expertise. Here we introduce BioJupies, a web server that enables automated creation, storage, and deployment of Jupyter Notebooks containing RNA-seq data analyses. Through an intuitive interface, novice users can rapidly generate tailored reports to analyze and visualize their own raw sequencing files, their gene expression tables, or fetch data from >5,500 published studies containing >250,000 preprocessed RNA-seq samples. Generated notebooks have executable code of the entire pipeline, rich narrative text, interactive data visualizations, and differential expression and enrichment analyses. The notebooks are permanently stored in the cloud and made available online through a persistent URL. The notebooks are downloadable, customizable, and can run within a Docker container. By providing an intuitive user interface for notebook generation for RNA-seq data analysis, starting from the raw reads, all the way to a complete interactive and reproducible report, BioJupies is a useful resource for experimental and computational biologists. BioJupies is freely available as a web-based application from:http://biojupies.cloudand as a Chrome extension from theChrome Web Store.
DoubletFinder: Doublet detection in single-cell RNA sequencing data using artificial nearest neighbors
Authors: McGinnis Christopher S. , Murrow Lyndsay M. , Gartner Zev J.
Published: June 2018

Single-cell RNA sequencing (scRNA-seq) using droplet microfluidics occasionally produces transcriptome data representing more than one cell. These technical artifacts are caused by cell doublets formed during cell capture and occur at a frequency proportional to the total number of sequenced cells. The presence of doublets can lead to spurious biological conclusions, which justifies the practice of sequencing fewer cells to limit doublet formation rates. Here, we present a computational doublet detection tool – DoubletFinder – that identifies doublets based solely on gene expression features. DoubletFinder infers the putative gene expression profile of real doublets by generating artificial doublets from existing scRNA-seq data. Neighborhood detection in gene expression space then identifies sequenced cells with increased probability of being doublets based on their proximity to artificial doublets. DoubletFinder robustly identifies doublets across scRNA-seq datasets with variable numbers of cells and sequencing depth, and predicts false-negative and false-positive doublets defined using conventional barcoding approaches. We anticipate that DoubletFinder will aid in scRNA-seq data analysis and will increase the throughput and accuracy of scRNA-seq experiments.
Persistence of cooperation in diffusive public goods games
Authors: Gerlee Philip , Altrock Philipp M.
Published: June 2018

Diffusive public goods (PG) games are difficult to analyze due to population assortment affecting growth rates of cooperators (producers) and free-riders. We study these growth rates using spectral decomposition of cellular densities, and derive a finite cell-size correction of the growth rate advantage, which exactly describes the dynamics of a randomly assorted population, and approximates the dynamics under limited dispersal. The resulting effective benefit to cost ratio relates the physical parameters of PG dynamics to the persistence of cooperation, and our findings provide a powerful tool for the analysis of diffusive PG games, explaining commonly observed patterns of cooperation.
Cancer stemness, intratumoral heterogeneity, and immune response across cancers
Authors: Miranda Alex , Hamilton Phineas T , Zhang Allen W , Becht Etienne , Mezheyeuski Artur , Bruun Jarle , Micke Patrick , De Reynies Aurélien , Nelson Brad H
Published: June 2018

Regulatory programs that control the function of stem cells are active in cancer and confer properties that promote progression and therapy resistance. However, the impact of a stem cell-like tumor phenotype (“sternness”) on the immunological properties of cancer has not been systematically explored. Using gene expression-based metrics, we evaluate the association of stemness with immune cell infiltration and genomic, transcriptomic, and clinical parameters across 21 solid cancers. We find pervasive negative associations between cancer stemness and anticancer immunity. This occurs despite high stemness cancers exhibiting increased mutation load, cancer-testis antigen expression, and intratumoral heterogeneity. Stemness was also strongly associated with cell-intrinsic suppression of endogenous retroviral expression and type I interferon signaling and increased expression of several therapeutically accessible signaling pathways. Thus, stemness is not only a fundamental process in cancer progression but may represent a unifying mechanism linking antigenicity, intratumoral heterogeneity, and immune suppression across cancers.
A comparative study and evaluation of ERP reference models in the context of ERP IT-driven implementation
Authors: Al-Sabri Hamdan Mohammed , Al-Mashari Majed , Chikh Azeddine
Published: June 2018

Purpose

The purpose of this paper is to consider the question of what is an appropriate enterprise resource planning (ERP) reference model for specifying areas of change in the context of IT-driven ERP implementation and through the model matching. There are other implicit goals to increasing the awareness of the reference models, as this highlights the principles embedded in ERP systems and explains the classification of reference models, which is useful in terms of the reuse of knowledge.

Design/methodology/approach

In this paper, a comparison between ERP reference models is conducted using a suitable decision-making technique and the final results are discussed. The comparison depends on nine criteria related to conceptual ERP reference models: scope, abstraction, granularity, views, purpose, simplicity, availability, ease of use for model matching, and target audience.

Findings

This study concludes that the business process reference model is best for specifying areas of change in the context of IT-driven ERP implementations. The final ranking of the alternatives based on all criteria places the system organizational model second, followed by the function and data/object reference models, in that order.

Originality/value

This paper is one of very few studies on the selection of appropriate ERP reference models according to the ERP implementation approach and model matching factors. This research also provides an in-depth analysis of various ERP reference model types.
MARISA “For you, a treat”
Authors: Lopez Carlos Eduardo
Published: June 2018

Subject area

Entrepreneurs, Strategic planning, Management, Family businesses.

Study level/applicability

Undergraduate and Graduate (as an introductory case study).

Case overview

Marisa® is a consolidated bakery in Guadalajara México, selling a wide variety of dessert products. It has achieved fast growth and has diversified with other brands, either by buying or developing them. Examples are Tía Lola® (economical cakes) and Dolce Natura® (artisanal ice creams). The company founder has maintained not only the growth and development of her brand but also the organizational values and culture. These she has transmitted to her over 400 employees. The company is currently facing expansion.

Expected learning outcomes

The expected learning outcomes are as follows: to distinguish the different expansion strategies; to discuss how to maintain culture and values in a firm despite time and growth; to analyze the current market and long-term objectives, as well as different competitors of the firm; and to make strategic decisions at the corporate level.

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: 3: Entrepreneurship.
Hepatitis caused by herpes viruses: A review
Authors: Noor Arish , Panwala Amruta , Forouhar Faripour , Wu George Y
Published: June 2018

Herpes virus hepatitis varies in presentation, ranging from asymptomatic to acute liver failure, in both immunocompetent and immunocompromised individuals. Hepatitis caused by the Herpesviridae family is uncommon and usually results in mild disease. It is also often self‐limiting, although in certain populations especially immunosuppressed patients, it can cause severe infections, leading to acute to fulminant hepatic failure. In addition, some isolated cases of fulminant disease in immunocompetent individuals have been reported. As the presentation is frequently non‐specific, it is important to maintain a high level of suspicion for these viral etiologies and start empiric therapy with antiviral agents as soon as possible. Liver transplantation is the last resort. Mortality remains high in fulminant hepatic failure caused by Herpesviridae without liver transplantation. Here we review the literatures on hepatitis caused by three members of the Herpesviridae family, cytomegalovirus, Epstein–Barr virus and herpes simplex virus to discuss the epidemiology, diagnostic methods, clinical features and current management, and also to determine which aspects need to be investigated in further detail. Herpesviridae‐mediated acute liver failure is rare but is associated with a poor prognosis, even after early treatment.
Incidence and prevalence of aphid‐borne viruses infecting strawberry in Argentina
Authors: Luciani C. , Celli M.G. , Torrico A.K. , Asinari F. , Pozzi E. , Peña Malavera A. , Kirschbaum D.S. , Perotto M.C. , Conci V.C.
Published: June 2018

The incidence and prevalence of strawberry viruses were determined in surveys of randomly selected strawberry plants grown in different regions of Argentina. In 2009 and 2010, 1034 plants from 28 fields and 1060 plants from 33 fields, respectively, were collected from Lules and Coronda. The samples were analysed by double‐antibody sandwich enzyme‐linked immunosorbent assay to detect Strawberry mild yellow edge virus (SMYEV). In 2014, 606 plants from 43 fields in Lules, Coronda and Mar del Plata were analysed by reverse transcription polymerase chain reaction with primers specific for SMYEV, Strawberry crinkle virus (SCV), Strawberry mottle virus (SMoV) and Strawberry polerovirus 1 (SPV1). The SMYEV incidence was 4–35%, while prevalence was 60–100%, depending on the year and region sampled. Meanwhile, SMoV and SPV1 incidences were 8–17%, and prevalences were 46–62%, depending on the virus and region sampled. SCV was observed relatively low (incidence was 0.5–8% and prevalence was 8–50%), although it was more abundant in Mar del Plata than in the other analysed regions. Spearman's correlation analysis indicated that SCV and SMYEV were correlated with disease symptoms (P < 0.005). A principal component analysis revealed a close relationship between SMYEV and SCV in Mar del Plata, in which the lowest temperatures were recorded. Interactions among viruses, regions and climatic conditions will need to be studied in greater detail. Accurately determining the incidence and prevalence of viruses in different regions will improve estimations of possible damages or yield decreases caused by viral infections during strawberry production.