bluuebunny/crossref_metadata_2025_split huggingface dataset:
Directional selection rather than functional constraints can shape the G matrix in rapidly adapting asexuals
Authors: Gomez Kevin , Bertram Jason , Masel Joanna 
Published: June 2018

ABSTRACTGenetic covariances represent a combination of pleiotropy and linkage disequilibrium, shaped by the population’s history. Observed genetic covariance is most often interpreted in pleiotropic terms. In particular, functional constraints restricting which phenotypes are physically possible can lead to a stableGmatrix with high genetic variance in fitness-associated traits and high pleiotropic negative covariance along the phenotypic curve of constraint. In contrast, population genetic models of relative fitness assume endless adaptation without constraint, through a series of selective sweeps that are well described by recent traveling wave models. We describe the implications of such population genetic models for theGmatrix when pleiotropy is excluded by design, such that all covariance comes from linkage disequilibrium. TheGmatrix is far less stable than has previously been found, fluctuating over the timescale of selective sweeps. However, its orientation is relatively stable, corresponding to high genetic variance in fitness-associated traits and strong negative covariance - the same pattern often interpreted in terms of pleiotropic constraints but caused instead by linkage disequilibrium. We find that different mechanisms drive the instabilities along versus perpendicular to the fitness gradient. The origin of linkage disequilibrium is not drift, but small amounts of linkage disequilibrium are instead introduced by mutation and then amplified during competing selective sweeps. This illustrates the need to integrate a broader range of population genetic phenomena into quantitative genetics.
Functional Analysis of TM6 MADS-box gene in the Octoploid Strawberry by CRISPR/Cas9 directed mutagenesis
Authors: Martín-Pizarro Carmen , Triviño Juan Carlos , Posé David 
Published: June 2018

AbstractThe B-class of MADS-box transcription factors has been studied in many plant species, but remain functionally uncharacterized in theRosaceaefamily. APETALA3 (AP3), a member of this class, controls the identity of petals and stamens inArabidopsis thaliana. In this work, we identified two members of the AP3 lineage in the cultivated strawberry (Fragaria×ananassa):FaAP3andFaTM6. Interestingly,FaTM6, and notFaAP3, shows an expression pattern equivalent to that ofAP3inArabidopsis. Genome editing using Cluster Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system is becoming a robust tool for targeted and stable mutagenesis of DNA. However, whether it can be efficiently used in an octoploid species such asF. ×ananassais not known. Here we report for the first time the application of CRISPR/Cas9 inF. ×ananassato characterize the function of FaTM6 in flower development. An exhaustive analysis by high-throughput sequencing of theFaTM6locus spanning the target sites showed a high efficiency genome editing already in the T0 generation. The phenotypic characterization of the mutant lines indicates that FaTM6 plays a key role in petal and especially in anther development in strawberry. in an octoploid species such asF. ×ananassa, and offer new opportunities for engineering strawberry to improve traits of interest in breeding programs.
Time preferences are reliable across time-horizons and verbal vs. experiential tasks
Authors: Lukinova Evgeniya , Wang Yuyue , Lehrer Steven F. , Erlich Jeffrey C. 
Published: June 2018

AbstractIndividual differences in delay-discounting correlate with important real world outcomes, e.g. education, income, drug use, & criminality. As such, delay-discounting has been extensively studied by economists, psychologists and neuroscientists to reveal its behavioral and biological mechanisms in both human and non-human animal models. However, two major methodological differences hinder comparing results across species. Human studies present long time-horizon options verbally, whereas animal studies employ experiential cues and short delays. To bridge these divides, we developed a novel language-free experiential task inspired by animal decision-making studies. We find that subjects’ time-preferences are reliable across both verbal/experiential differences and also second/day differences. When we examined whether discount factors shifted or scaled across the tasks, we found a surprisingly strong effect of temporal context. Taken together, this indicates that subjects have a stable, but context-dependent, time-preference that can be reliably assessed using different methods; thereby, providing a foundation to bridge studies of time-preferences across species.
Stable networks of water-mediated interactions are conserved in activation of diverse GPCRs
Authors: Venkatakrishnan A. J. , Ma Anthony K. , Fonseca Rasmus , Latorraca Naomi R. , Kelly Brendan , Betz Robin M. , Asawa Chaitanya , Kobilka Brian K. , Ron O. Dror 
Published: June 2018

AbstractG protein-coupled receptors (GPCRs) have evolved to recognize incredibly diverse extracellular ligands while sharing a common architecture and structurally conserved intracellular signaling partners. It remains unclear how binding of diverse ligands brings about GPCR activation, the common structural change that enables intracellular signaling. Here, we identify highly conserved networks of water-mediated interactions that play a central role in activation. Using atomic-level simulations of diverse GPCRs, we show that most of the water molecules in GPCR crystal structures are highly mobile. Several water molecules near the G protein-coupling interface, however, are stable. These water molecules form two kinds of polar networks that are conserved across diverse GPCRs: (i) a network that is maintained across the inactive and the active states and (ii) a network that rearranges upon activation. Comparative analysis of GPCR crystal structures independently confirms the striking conservation of water-mediated interaction networks. These conserved water-mediated interactions near the G protein-coupling region, along with diverse water-mediated interactions with extracellular ligands, have direct implications for structure-based drug design and GPCR engineering.
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

ABSTRACTAcross 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

AbstractMetabolic 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

AbstractIn 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

AbstractNeonicotinoid 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

AbstractSociality 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

AbstractCaenorhabditis 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

AbstractMany 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 summarySingle 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

ABSTRACTAmyloid-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

ABSTRACTUsing 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

AbstractThe 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 SUMMARYFor 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.