bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cyclin F-Chk1 synthetic lethality mediated by E2F1 degradation
Authors: Burdova Kamila , Yang Hongbin , Faedda Roberta , Hume Samuel , Ebner Daniel , Kessler Benedikt M , Vendrell Iolanda , Drewry David H , Wells Carrow I , Hatch Stephanie B , D’Angiolella Vincenzo 
Published: January 2019

SummaryCyclins are central engines of cell cycle progression when partnered with Cyclin Dependent Kinases (CDKs). Among the different cyclins controlling cell cycle progression, cyclin F does not partner with a CDK, but forms an E3 ubiquitin ligase, assembling through the F-box domain, an Skp1-Cul1-F-box (SCF) module. Although multiple substrates of cyclin F have been identified the vulnerabilities of cells lacking cyclin F are not known. Thus, we assessed viability of cells lacking cyclin F upon challenging cells with more than 200 kinase inhibitors. The screen revealed a striking synthetic lethality between Chk1 inhibition and cyclin F loss. Chk1 inhibition in cells lacking cyclin F leads to DNA replication catastrophe. The DNA replication catastrophe depends on the accumulation of E2F1 in cyclin F depleted cells. We observe that SCFcyclin F promotes E2F1 degradation after Chk1 inhibitors in a CDK dependent manner. Thus, Cyclin F restricts E2F1 activity during cell cycle and upon checkpoint inhibition to prevent DNA replication stress. Our findings pave the way for patient selection in the clinical use of checkpoint inhibitors.
A pseudo-meiotic centrosomal function of TEX12 in cancer
Authors: Sandhu S , Salmon LJ , Hunter JE , Wilson CL , Perkins ND , Hunter N , Davies OR , McClurg UL 
Published: January 2019

AbstractCell division by meiosis involves an extraordinary chromosome choreography including pairing, synapsis and crossing over between homologous chromosomes1, 2. The many meiosis-specific genes involved in these processes also constitute a latent toolbox of chromosome remodelling and recombination factors that may be exploited through aberrant expression in cancer3, 4. Here, we report that TEX12, a structural protein involved in meiotic chromosome synapsis5–7, is aberrantly expressed in human cancers, with high TEX12 levels correlating with poor prognosis. We find that TEX12 knock-down causes proliferative failure in multiple cancer cell lines, and confirm its role in the early stages of oncogenesis through murine cancer models. Remarkably, somatically expressed TEX12 localises to centrosomes, leading to altered centrosome number and structure, features associated with cancer development. Further, we identify TEX12 in meiotic centrin-rich bodies, likely precursors of the mitotic centrosome, suggesting that this may represent an additional cellular function of TEX12 in meiosis that has been previously overlooked. Thus, we propose that an otherwise meiotic function of TEX12 in centrosome duplication is responsible for promoting oncogenesis and cellular proliferation in cancer, which may be targeted for novel cancer therapeutics and diagnostics.
Modulation of tonotopic ventral MGB is behaviorally relevant for speech recognition
Authors: Mihai Paul Glad , Moerel Michelle , de Martino Federico , Trampel Robert , Kiebel Stefan , von Kriegstein Katharina 
Published: January 2019

AbstractSensory thalami are central sensory pathway stations for information processing. Their role for human cognition and perception, however, remains unclear. Recent evidence suggests a specific involvement of the sensory thalami in speech recognition. In particular, the auditory thalamus (medial geniculate body, MGB) response is modulated by speech recognition tasks and the amount of this task-dependent modulation is associated with speech recognition abilities. Here we tested the specific hypothesis that this behaviorally relevant modulation is present in the MGB subsection that corresponds to the primary auditory pathway (i.e., the ventral MGB [vMGB]). We used ultra-high field 7T fMRI to identify the vMGB, and found a significant positive correlation between the amount of task-dependent modulation and the speech recognition performance across participants within left vMGB, but not within the other MGB subsections. These results imply that modulation of thalamic driving input to the auditory cortex facilitates speech recognition.
Personalized Tumor Growth Prediction with Multiscale Tumor Modeling
Authors: Unsal Serbulent , Acar Aybar , Itik Mehmet , Kabatas Ayse , Gedikli Oznur , Ozdemir Feyyaz , Turhan Kemal 
Published: January 2019

AbstractBackgroundCancer is one of the most complex phenomena in biology and medicine. Extensive attempts have been made to work around this complexity. In this study, we try to take a selective approach; not modeling each particular facet in detail but rather only the pertinent and essential parts of the tumor system are simulated and followed by optimization, revealing specific traits. This leads us to a pellucid personalized model which is noteworthy as it closely approximates existing experimental results.MethodFor years, research has focused on modeling tumor growth but not many studies have put forward a framework for the personalization of models. In the present study, a hybrid modeling approach which consists of cellular automata for discrete cell state representation and diffusion equations to calculate distribution of relevant substances in the tumor micro-environment is favored. Moreover, naive Bayesian decision making with weighted stochastic equations and a Bayesian network to model the temporal order of mutations is presented. The model is personalized according to the evidence using Markov Chain Monte Carlo. Ultimately, this way of thinking about tumor modeling leads us to a vascular multi-scale model of tumor growth.ResultsTo validate the tumor model, a data set belonging to the A549 cell line is used. The data represents the growth of a tumor for 30 days. We optimize the coefficients of the stochastic decision making equations using first half of the timeline. Then we predict next 15 days of growth without any other supervision. Results are promising with their low error margin and simulated growth data is in line with laboratory results.ConclusionThere are many subsystems which have an effect in the growth of a tumor. A detailed model which includes all of them is currently virtually impossible to implement. We have therefore focused on a system that only includes fundamental components in this study, and have evaluated its predictions. We propose novel probability functions to obtain a personalized model and estimate the individual importance (weights) of each with parameter optimization. Our approach of using simulated annealing for parameter estimation and the subsequent validation of the prediction with in-vitro tumor growth data are, to our knowledge, unique in the literature.
Spatial single-cell profiling of intracellular metabolomesin situ
Authors: Rappez Luca , Stadler Mira , Triana Sergio , Phapale Prasad , Heikenwalder Mathias , Alexandrov Theodore 
Published: January 2019

SummaryThe recently unveiled extent of cellular heterogeneity demands for single-cell investigations of intracellular metabolomes to reveal their roles in intracellular processes, molecular microenvironment and cell-cell interactions. To address this, we developed SpaceM, a method forin situspatial single-cell metabolomics of cell monolayers which detects >100 metabolites in >10000 individual cells together with fluorescence and morpho-spatial cellular features. We discovered that the intracellular metabolomes of co-cultured human HeLa cells and mouse NIH3T3 fibroblasts predict the cell type with 90.4% accuracy and revealed a short-distance metabolic intermixing between HeLa and NIH3T3. We characterized lipid classes composing lipid droplets in steatotic differentiated human hepatocytes, and discovered a preferential accumulation of long-chain phospholipids, a co-regulation of oleic and linoleic acids, and an association of phosphatidylinositol monophosphate with high cell-cell contact. SpaceM provides single-cell metabolic, phenotypic, and spatial information and enables spatio-molecular investigations of intracellular metabolomes in a variety of cellular models.
Chemically-defined induction of a primitive endoderm and epiblast-like niche supports post-implantation progression from blastoids
Authors: Vrij Erik J. , Scholte op Reimer Yvonne S. , Frias Aldeguer Javier , Misteli Guerreiro Isabel , Kind Jop , Koo Bon-Kyoung , van Blitterswijk Clemens A. , Rivron Nicolas C. 
Published: January 2019

AbstractThe early mammalian conceptus (blastocyst) contains two supporting extraembryonic tissues - the trophectoderm and the primitive endoderm (PrE) - that encase and guide the epiblast (Epi) to eventually form the all body. Modifications of the conceptus exposed key genes regulating these tissues co-development. However, the combinations of signalling pathways underlying the interplay of PrE and Epi remains elusive. Stem cell-based models including embryoid bodies and blastoids can be generated in large numbers and subjected to high-content screens. Here, we use combinatorial screens of proteins, GPCR ligands and small molecules to rapidly (72 hours) and efficiently (80%) guide embryoid bodies to form a three-dimensional PrE-/Epiblast-like niche in chemically-defined conditions (gel-free, serum-free). This bipotent niche spontaneously progresses, without growth factors, to form a pro-amniotic cavity surrounded by a polarized Epi covered with parietal and visceral endoderm-like cells. In blastoids, these molecules enhance the ratio and number of Gata6+/Nanog+ cells and promote the survival, expansion and morphogenesis of a post-implantation-like Epiin vitro. Altogether, modelling early development in chemically-defined conditions delineates the pathways sufficient to form a functional PrE/Epiblast niche that fuels post-implantation development.
Variation inMelitaea cinxiagut microbiota is phylogenetically highly structured but only mildly driven by host plant microbiota, sex or parasitism
Authors: Minard G. , Tikhonov G , Ovaskainen O. , Saastamoinen M. 
Published: January 2019

Originality-Significance StatementThe factors contributing to the assembly of microbiota in animals are extremely complex, and thus a comprehensive understanding of the mechanisms shaping host-associated microbial communities in natural ecosystems requires extensive ecological studies and appropriate statistical methods. In this study, we investigated the bacterial microbiota associated with the caterpillars of the Glanville fritillary (Melitaea cinxia), which is a long-term-studied ecological model system. We assessed the structure of variation in both occurrence and abundance of gut microbial communities of individuals collected in the wild with joint-species modelling, with the aim to relate the microbial community structure with multiple potentially impacting covariates: host plant microbiota and metabolites, hosts’ sex, potential parasitoid infection, and family structure. These covariates exhibited substantial correlation with multiple microbial taxa’s occurrences, which correlations were consistent for phylogenetically related groups of taxa, but varied across the whole microbial community; on the contrary, only few correlations were found with taxa’s abundances. The dominating co-occurrence pattern of microbiota assembly, which effectively split caterpillar individuals into two distinct groups, was, however, unrelated to any of the considered covariates.SummaryUnderstanding of what ecological factors shape intraspecific variation of insect microbiota is still relatively poor. In Lepidopteran caterpillars, microbiota is assumed to be mainly composed of transient bacterial symbionts acquired from the host plant. We sampled Glanville fritillary (Melitaea cinxia) caterpillars from natural populations to describe the microbiome and to identify potential factors that determine the structure of the microbial community, including the sex of the host, the impact of parasitoid infection, and the possible link between host plant and caterpillar microbiota. Our results demonstrate high variability of microbiota composition even among caterpillars that shared the same host plant individual. The observed variation in microbiota composition is partially attributed to the measured properties of the host or its plant microbial and chemical composition, and is aligned with microbial phylogenetic structure, with related taxa exhibiting similar patterns. However, the prevailing part of the observed variation was not associated with any of the assessed characteristics, although it followed a pronounced segregation structure: in some caterpillars the microbial communities were dominated by several related Enterobacteriaceae taxa, while in others these taxa were absent. Our results challenge previous findings that the host plant properties are the major drivers of microbiota communities of insect herbivores.
BCR analysis of single-sorted, putative IgE+memory B cells in food allergy:an ephemeral existence?
Authors: Jiménez-Saiz Rodrigo , Ellenbogen Yosef , Bruton Kelly , Spill Paul , Sommer Doron D. , Lima Hermenio , Waserman Susan , Patil Sarita U. , Shreffler Wayne G. , Jordana Manel 
Published: January 2019

AbstractImmunoglobulin (Ig) E is the critical effector molecule in allergic reactions. Consequently, research efforts to understand the biology of IgE-expressing cells is of paramount importance. In particular, the role of IgE+memory B cells (MBCs) in the perpetuation of allergic reactivity has been the subject of intense research. Studies in mice have convincingly established that IgE+B cells are rare and transient and, therefore, an unlikely candidate to maintain allergic disease. In contrast, IgE+MBCs have been detected by flow cytometry in the sputum and peripheral blood of humans and have been proposed as a clinical marker of allergic disease. We established a method to genetically validate, at the single-cell level, the putative IgE+MBCs identified by flow cytometry from humans. We, then used this information to develop an enhanced flow cytometry protocol that more accurately identifiesbona fideIgE+MBCs. We found that IgE+MBCs were detected in some patients with atopic dermatitis, but at a frequency that was ~100 times lower than previously reported. We also found that IgE+MBCs were undetectable in PBMCs from peanut allergic patients. These findings provide tools to identifybona fideIgE+MBCs, demonstrate their extreme rarity in circulation and are consistent with the lack of a central role for IgE+MBCs in the maintenance of allergic sensitivity.One Sentence SummaryThe frequency of IgE+MBCs in the peripheral circulation of humans is orders of magnitude lower than previously reported and comparable between allergic and healthy donors, which cautions about the clinical utility of their assessment.
Oxidative Stress and Biomarker Responses in the Atlantic Halibut After Long Term Exposure to Elevated CO2and a Range of Temperatures
Authors: Carney Almroth B , Bresolin de Souza K , Jönsson E , Sturve J 
Published: January 2019

AbstractOceans are warming and pH levels are decreasing as a consequence of increasing levels of dissolved CO2concentrations. The CO2emissions are predicted to be produce in greater and faster changes in the ocean than any other event in geological and historical records over the past 300 million years. Marine organisms will need to respond to multiple stressors but the potential consequences of global change-related effects in fish are not fully understood. Since fish are affected by many biotic and abiotic environmental variables, including temperature and CO2fluctuations, it is critical to investigate how these variables may affect physiological and biochemical processes. We investigated the effects of elevated CO2levels (pH of 8.0, which served as a control, or 7.6, which is predicted for the year 2100) combined with exposure to different temperatures (5, 10, 12, 14, 16, and 18 °C) in the Atlantic halibut (Hippoglossus hippoglossus) during a three month experiment. We assessed effects on antioxidant and cholinesterase enzymes (AChE and BChE), and CYP1A enzyme activities (EROD). The treatments resulted in oxidative stress, and damage was evident in the form of protein carbonyls which were consistently higher in the elevated CO2-treated fish at all temperatures. Analyses of antioxidant enzymes did not show the same results, suggesting that the exposure to elevated CO2increased ROS formation but not defences. The antioxidant defence system was insufficient, and the resulting oxidative damage could impact physiological function of the halibut on a cellular level.
A free-running oscillator times and executes centriole biogenesis
Authors: Aydogan Mustafa G. , Steinacker Thomas L. , Mofatteh Mohammad , Gartenmann Lisa , Wainman Alan , Saurya Saroj , Conduit Paul T. , Zhou Felix Y. , Boemo Michael A. , Raff Jordan W. 
Published: January 2019

AbstractThe accurate timing of organelle biogenesis and the precise regulation of organelle size are crucial for cell physiology. Centriole biogenesis initiates exclusively in S-phase, when a daughter centriole emerges from the side of a pre-existing mother and grows until it reaches its mother’s size. This process is regulated by Polo-like kinase 4 (Plk4), which is recruited to centrioles in oscillatory waves in flies and human cells1,2. The nature and function of Plk4 oscillations is, however, unknown. Here we discover that Plk4 forms an adaptive oscillator at the base of the growing centriole, whose function is to time and set the duration of centriole biogenesis inDrosophilaembryos. We demonstrate that the Plk4 oscillator is free-running of, but is entrained and calibrated by, the core Cdk/Cyclin cell-cycle oscillator, explaining how centrioles can duplicate independently of the cell cycle3–5. Mathematical modelling and further experiments indicate that the Plk4 oscillator is generated by a time-delayed negative-feedback loop in which Plk4 recruitment to, and dissociation from, the centriole is monitored via changes in the affinity-state of its centriolar receptor, Asterless. We postulate that such organelle-specific autonomous oscillators could regulate the timing and execution of organelle biogenesis more generally.
Rigid Foot Soles Improve Balance in Beam Walking
Authors: Huber Meghan E. , Chiovetto Enrico , Giese Martin , Sternad Dagmar 
Published: January 2019

ABSTRACTMaintaining balance while walking on a narrow beam is a challenging motor task. This is presumably because the foot’s ability to exert torque on the support surface is limited by the beam width. Still, the feet serve as a critical interface between the body and the external environment, and it is unclear how the mechanical properties of the feet affect balance. Here we examined how restricting the degrees of freedom of the feet influenced balance behavior during beam walking. We recorded whole-body joint kinematics of subjects with varying skill levels as they walked on a narrow beam with and without wearing flat, rigid soles on their feet. We computed changes in whole-body motion and angular momentum across these conditions. Results showed that wearing rigid soles improved balance in the beam walking task, but that practice with rigid soles did not affect or transfer to task performance with bare feet. The absence of any after-effect suggested that the improved balance from constraining the foot was the result of a mechanical effect rather than a change in neural strategy. Though wearing rigid soles can be used to assist balance, there appear to be limited training or rehabilitation benefits from wearing rigid soles.
Sedentary behavior, physical inactivity and body composition in relation to idiopathic infertility among men and women
Authors: Aude-Marie Foucaut , Céline Faure , Chantal Julia , Sébastien Czernichow , Rachel Levy , Charlotte Dupont ,   the ALIFERT collaborative group
Published: January 2019

AbstractBackgroundPhysical activity and sedentary behavior has inconsistent effects on fertility. High body mass index is associated with infertility but to our knowledge, very few studies have explored body composition in association to fertility.ObjectiveTo assess the association between physical inactivity, sedentary behavior, body composition and idiopathic infertility in French men and women.DesignWe conducted a case-control multicentric observational study. 159 infertile (79 men and 80 women) and 143 fertile (72 men and 71 women) were recorded in four fertility centers.Main Outcome MeasuresParticipants completed self-administered questionnaires on sociodemographic and lifestyle characteristics, dietary intake, physical activity and sedentary behavior. Anthropometrics were measured, and bioelectrical impedance analysis was used to estimate body composition. Multivariable logistic regression was used to analyze the association of fertility with PA level and sedentary behavior.ResultsIn men, being physically inactive (Odd ratio [OR] 2.20; 95% confidence interval [CI], 1.06, 4.58) and having fat mass greater than the reference values for their age (OR 2.83; 95%CI, 1.31, 6.10) were positively associated with infertility. Sedentary behavior and fat-free mass were not related to infertility in men. In women, sedentary behavior (OR 3.61; 95%CI, 1.58, 8.24), high body fat (OR 3.16; 95%CI, 1.36, 7.37) and low fat-free mass (OR 2.65; 95%CI, 1.10, 6.37) were associated with infertility. PA level was not associated with fertility in women.ConclusionsThis study suggests that sedentary behavior and physical inactivity would represent two independent risk factors associated with fertility. The various elements that make up physical activity (frequency, intensity, time, and type of exercise) and the interrupting time spent sitting should be considered. Body composition variation should be explored further in relation to the biological pathways involved in idiopathic infertility. Moreover, the improvement of lifestyle factors should be considered in infertility treatment.
High innate preference for black substrate in the chive gnat,Bradysia odoriphaga(Diptera: Sciaridae)
Authors: An Lina , Fan Fan , Lunau Klaus , Li Mengyao , Yang Xiaofan , Wei Guoshu 
Published: January 2019

SummaryThe chive gnat,Bradysia odoriphaga, is a notorious pest ofAlliumspecies in China. Colour trapping is an established method for monitoring and controlling ofBradysiaspecies. In order to clarify the effect of colour preference ofB. odoriphagafor the egg-laying substrate, multiple-choice tests were employed to assess the spontaneous response of the chive gnat to different colour hues and brightness levels under different intensities of white illumination and two spectrally different illuminations. Given the choice among four colours differing in hue under different intensities of white illumination and two spectrally different illuminations, chive gnat adults visited preferably the black substrate, a lesser extent to brown and green substrates, and the least extent to orange substrate irrespective of illumination. Given the choice among four levels of brightness under the same illumination conditions as those in the previous experiment (different intensities of white illumination and two spectrally different illuminations), chive gnats preferred black substrate over dark grey, and these over light grey and white substrates. Meanwhile, both virgin and copulated adults significantly preferred black over other colour hues and brightness. Based on our results, we conclude that the chive gnat adults significantly prefer black substrates irrespective of colour hues and brightness. This behaviour does not alter due to ambient light condition changes. No difference observed between choices of female and male adults. Our results provide new insight for understanding the colour choice behaviour in chive gnat and pave a way to improve monitoring and control of chive gnats and management.Summary statementChive gnat (Bradysia odoriphaga) innately prefer to move to black substrate irrespective of colour hues and brightness. This behaviour maintained the ambient lights change.