bluuebunny/crossref_metadata_2025_split huggingface dataset:
Global analysis of the RpaB regulon based on the positional distribution of HLR1 sequences and comparative differential RNA-Seq data
Authors: Riediger Matthias , Kadowaki Taro , Nagayama Ryuta , Georg Jens , Hihara Yukako , Hess Wolfgang R. 
Published: October 2018

ABSTRACTThe transcription factor RpaB regulates the expression of genes encoding photosynthesis-associated proteins during light acclimation. The binding site of RpaB is the HLR1 motif, a pair of imperfect octameric direct repeats, separated by two random nucleotides. Here, we used high-resolution mapping data of transcriptional start sites (TSSs) in the modelSynechocystissp. PCC 6803 in conjunction with the positional distribution of HLR1 sites for the global prediction of the RpaB regulon. The results demonstrate that RpaB regulates the expression of more than 150 promoters, driving the transcription of protein-coding and non-coding genes and antisense transcripts under low light and upon the shift to high light when DNA binding activity is lost. Transcriptional activation by RpaB is achieved when the HLR1 motif is located 66 to 45 nt upstream, repression occurs when it is close to or overlapping the TSS. Selected examples were validated by multiple experimental approaches, including chromatin affinity purification, reporter gene, northern hybridization and electrophoretic mobility shift assays. We found that RpaB controlsssr2016/pgr5, which is involved in cyclic electron flow and state transitions; six out of nine ferredoxins; three of four FtsH proteases;gcvP/slr0293, encoding a crucial photorespiratory protein; andnirAandisiAfor which we suggest cross-regulation with the transcription factors NtcA or FurA, respectively. In addition to photosynthetic gene functions, RpaB contributes to the control of genes affiliated with nitrogen assimilation, cofactor biosyntheses, the CRISPR system and the circadian clock, making it one of the most versatile regulators in cyanobacteria.Significance StatementRpaB is a transcription factor in cyanobacteria and in the chloroplasts of several lineages of eukaryotic algae. Like other important transcription factors, the gene encoding RpaB cannot be deleted, making the study of deletion mutants impossible. Based on a bioinformatic approach, we increased the number of known genes controlled by RpaB by a factor of 5. Depending on the distance to the TSS, RpaB mediates transcriptional activation or repression. The high number and functional diversity among its target genes and co-regulation with other transcriptional regulators characterize RpaB as a regulatory hub.
Targeting MYC Overexpressing Leukemia with Cardiac Glycoside Proscillaridin Through Downregulation of Histone Acetyltransferases
Authors: Da Costa Elodie M. , Armaos Gregory , McInnes Gabrielle , Beaudry Annie , Moquin-Beaudry Gaël , Bertrand-Lehouillier Virginie , Caron Maxime , Richer Chantal , St-Onge Pascal , Johnson Jeffrey R. , Krogan Nevan , Sai Yuka , Downey Michael , Rafei Moutih , Boileau Meaghan , Eppert Kolja , Flores-Díaz Ema , Haman André , Hoang Trang , Sinnett Daniel , Beauséjour Christian , McGraw Serge , Raynal Noël J-M 
Published: October 2018

ABSTRACTTargeting MYC oncogene remains a major therapeutic goal in cancer chemotherapy. Here, we demonstrate that proscillaridin, a cardiac glycoside approved for heart failure treatment exhibit anticancer selectivity towards high MYC expressing leukemic cell lines and leukemia stem cells. At a clinically relevant concentration, proscillaridin induced a rapid downregulation of MYC protein level, due to a significant decrease in MYC protein half-life. Proscillaridin treatment induced a downregulation of gene sets involved in MYC pathway, and a concomitant upregulation of genes involved in hematopoietic differentiation. Proscillaridin induced a significant loss of lysine acetylation in histone H3 (K9, K14, K18 and K27) and in non-histone proteins such as MYC, MYC target proteins, and a series of histone acetylation regulators. Loss of lysine acetylation correlated with a rapid downregulation of histone acetyltransferase protein levels, involved in histone and MYC acetylation (CBP, P300, GCN5, TIP60, and MOZ), preferentially in MYC overexpressing leukemia as compared to other cancer cells. These results support the repurposing of proscillaridin in MYC overexpressing leukemia and propose a novel strategy to target MYC in cancer.
The influence of fluctuating population densities on evolutionary dynamics
Authors: Pisa Hanja , Hermisson Joachim , Polechova Jitka 
Published: October 2018

AbstractThe causes and consequences of fluctuating population densities are an important topic in ecological literature. Yet, the effects of such fluctuations on maintenance of variation in spatially structured populations have received little analytic treatment. We analyze what happens when two habitats coupled by migration not only differ in their trade-offs in selection but also in their demographic stability – and show that equilibrium allele frequencies can change significantly due to ecological feedback arising from locally fluctuating population sizes. When an ecological niche exhibits such fluctuations, these drive an asymmetry in the relative impact of gene flow, and therefore, the equilibrium frequency of the locally adapted type decreases. Our results extend the classic conditions on maintenance of diversity under selection and migration by including the effect of fluctuating population densities. We find simple analytic conditions in terms of the strength of selection, immigration, and the extent of fluctuations between generations in a continent-island model. Whereas weak fluctuations hardly affect coexistence, strong recurrent fluctuations lead to extinction of the type better adapted to the fluctuating niche – even if the invader is locally maladapted. There is a disadvantage to specialization to an unstable habitat, as it makes the population vulnerable to swamping from more stable habitats.
A simple approximation to bias in gene-environment interaction estimates when a case might not be the case
Authors: Lobach Iryna , Kim Inyoung , Alekseyenko Alexander , Lobach Siarhei , Zhang Li 
Published: October 2018

ABSTRACTCase-control genetic association studies are often used to examine the role of the genetic basis in complex diseases, such as cancer and neurodegenerative diseases. The role of the genetic basis might vary by non-genetic (environmental) measures, what is traditionally defined as gene-environment interactions (GxE). A commonly overlooked complication is that the set of clinically diagnosed cases might be contaminated by a subset with a nuisance pathologic state that presents with the same symptoms as the pathologic state of interest. The genetic basis of the pathologic state of interest might differ from that of the nuisance pathologic state. Often frequencies of the pathologically defined states within the clinically diagnosed set of cases vary by the environment. We derive a simple and general approximation to bias in GxE parameter estimates when presence of the nuisance pathologic state is ignored. We then perform extensive simulation studies to show that ignoring presence of the nuisance pathologic state can result in substantial bias in GxE estimates and that the approximation we derived is reasonably accurate in finite samples. We demonstrate the applicability of the proposed approximation in a study of Alzheimer’s disease.
ForestQC: quality control on genetic variants from next-generation sequencing data using random forest
Authors: Li Jiajin , Jew Brandon , Zhan Lingyu , Hwang Sungoo , Coppola Giovanni , Freimer Nelson B. , Sul Jae Hoon 
Published: October 2018

ABSTRACTNext-generation sequencing technology (NGS) enables discovery of nearly all genetic variants present in a genome. A subset of these variants, however, may have poor sequencing quality due to limitations in sequencing technology or in variant calling algorithms. In genetic studies that analyze a large number of sequenced individuals, it is critical to detect and remove those variants with poor quality as they may cause spurious findings. In this paper, we present a statistical approach for performing quality control on variants identified from NGS data by combining a traditional filtering approach and a machine learning approach. Our method uses information on sequencing quality such as sequencing depth, genotyping quality, and GC contents to predict whether a certain variant is likely to contain errors. To evaluate our method, we applied it to two whole-genome sequencing datasets where one dataset consists of related individuals from families while the other consists of unrelated individuals. Results indicate that our method outperforms widely used methods for performing quality control on variants such as VQSR of GATK by considerably improving the quality of variants to be included in the analysis. Our approach is also very efficient, and hence can be applied to large sequencing datasets. We conclude that combining a machine learning algorithm trained with sequencing quality information and the filtering approach is an effective approach to perform quality control on genetic variants from sequencing data.Author SummaryGenetic disorders can be caused by many types of genetic mutations, including common and rare single nucleotide variants, structural variants, insertions and deletions. Nowadays, next generation sequencing (NGS) technology allows us to identify various genetic variants that are associated with diseases. However, variants detected by NGS might have poor sequencing quality due to biases and errors in sequencing technologies and analysis tools. Therefore, it is critical to remove variants with low quality, which could cause spurious findings in follow-up analyses. Previously, people applied either hard filters or machine learning models for variant quality control (QC), which failed to filter out those variants accurately. Here, we developed a statistical tool, ForestQC, for variant QC by combining a filtering approach and a machine learning approach. We applied ForestQC to one family-based whole genome sequencing (WGS) dataset and one general case-control WGS dataset, to evaluate our method. Results show that ForestQC outperforms widely used methods for variant QC by considerably improving the quality of variants. Also, ForestQC is very efficient and scalable to large-scale sequencing datasets. Our study indicates that combining filtering approaches and machine learning approaches enables effective variant QC.
Pupillary dilations of mice performing a vibrotactile discrimination task reflect task engagement and response confidence
Authors: Ganea DA , Bexter A , Guenther M , Garderes PM , Kampa BM , Haiss F 
Published: October 2018

AbstractPupillometry, the measure of pupil size and reactivity, has been widely used to assess cognitive processes. As such, changes in pupil size have been shown to correlate with arousal, locomotion, cortical state and decision-making processes. In addition, pupillary responses have been linked to the activity of neuromodulatory systems that modulate attention and perception as the noradrenergic and cholinergic systems. Due to the extent of processes reflected by the pupil, we aimed at resolving pupillary responses in context of behavioral state and task performance while recording pupillary transients of mice performing a vibrotactile two-alternative forced choice task (2-AFC). We show that pre-stimulus pupil size differentiates between states of disengagement from task performance versus active engagement. In addition, when actively engaged, post-stimulus, pupillary dilations for correct responses are larger than for error responses with this difference reflecting response confidence. Importantly, in a delayed 2-AFC task version, we show that even though pupillary transients mainly reflect motor output or reward anticipation following the response of the animal, they also reflect animal decision confidence prior to its response. Finally, in a condition of passive engagement, when stimulus has no task relevance with reward provided automatically, pupillary dilations reflect stimulation and reward being reduced relative to a state of active engagement explained by shifts of attention from task variables. Our results provide further evidence for how pupillary dilations reflect cognitive processes in a task relevant context, showing that the pupil reflects response confidence and baseline pupil size encodes attentiveness rather than general arousal.Significance StatementFor the last 60 years, pupillometry has been used to study various cognitive processes. Among which are mental load, arousal and various decision related components, linking pupil dilations to underlying neuromodulatory systems. Our results provide extensive evidence that in addition to reflecting attentiveness under task performance, pupil dilations also reflect the confidence of the subject in his ensuing response. This confidence coding is overlaid within a more pronounced pupil dilation that reflects motor output or other post-decision components such that are related to the response itself but not to the decision. Our results also provide evidence how different behavioral states, imposed by task demands, modulate what the pupil is reflecting, presumably showing what the underlying cognitive network is coding for.
Abundance compensates kinetics: Similar effect of dopamine signals on D1 and D2 receptor populations
Authors: Hunger Lars , Kumar Arvind , Schmidt Robert 
Published: October 2018

AbstractThe neuromodulator dopamine plays a key role in motivation, reward-related learning and normal motor function. The different affinity of striatal D1 and D2 dopamine receptor types has been argued to constrain the D1 and D2 signalling pathways to phasic and tonic dopamine signals, respectively. However, this view assumes that dopamine receptor kinetics are instantaneous so that the time courses of changes in dopamine concentration and changes in receptor occupation are basically identical. Here we developed a neurochemical model of dopamine receptor binding taking into account the different kinetics and abundance of D1 and D2 receptors in the striatum. Testing a large range of behaviorally-relevant dopamine signals, we found that the D1 and D2 dopamine receptor populations responded very similarly to tonic and phasic dopamine signals. Furthermore, due to slow unbinding rates, both receptor populations integrated dopamine signals over a timescale of minutes. Our model provides a description of how physiological dopamine signals translate into changes in dopamine receptor occupation in the striatum, and explains why dopamine ramps are an effective signal to occupy dopamine receptors. Overall, our model points to the importance of taking into account receptor kinetics for functional considerations of dopamine signalling.Significance statementCurrent models of basal ganglia function are often based on a distinction of two types of dopamine receptors, D1 and D2, with low and high affinity, respectively. Thereby, phasic dopamine signals are believed to mostly affect striatal neurons with D1 receptors, and tonic dopamine signals are believed to mostly affect striatal neurons with D2 receptors. This view does not take into account the rates for the binding and unbinding of dopamine to D1 and D2 receptors. By incorporating these kinetics into a computational model we show that D1 and D2 receptors both respond to phasic and tonic dopamine signals. This has implications for the processing of reward-related and motivational signals in the basal ganglia.
Development of a robust automated tool for the annotation of embryo morphokinetic parameters
Authors: Feyeux M , Reignier A , Mocaer M , Lammers J , Meistermann D , Vandormael-Pournin S , Cohen-Tannoudji M , Barrière P , Barrière P , Paul-Gilloteaux P , David L , Fréour T 
Published: October 2018

AbstractStudy QuestionIs it possible to automatically annotate human embryo development in time-lapse devices, with results comparable to manual annotation?Summary AnswerWe developed an automated tool for the annotation of embryo morphokinetic parameters having a high concordance with expert manual annotation in a large scale-study.What is Known AlreadyMorphokinetic parameters obtained with time-lapse devices are increasingly used for human embryo quality assessment. However, their annotation is timeconsuming and can be operator-dependent, highlighting the need of developing automated approaches.Study Design, Size, DurationThis monocentric pilot study was conducted using 701 blastocysts originating from 584 couples undergoing IVF with embryo culture in a time-lapse device and on 4 mouse embryos.Participants/Materials, Setting, MethodsAn automated annotation tool was developed based on grey level coefficient of variation and detection of the thickness of the zona pellucida. The timings of cellular events obtained with the automated tool were compared with those obtained manually by 2 expert embryologists. The same procedure was applied on 4 mouse preimplantation embryos obtained with a different device in a different setting.Main Results and the Role of ChanceAlthough some differences were found when embryos were considered individually, we found an overall excellent concordance between automated and manual annotation of human embryo morphokinetics from fertilization to expanded blastocyst stage (r2=0.94). Moreover, the automated annotation tool gave promising results across species (human, mice).Limitations, Reasons for CautionThese results should undergo multi-centric external evaluation in order to test the overall performance of the annotation tool.Wider Implications of the FindingsOur system performs significantly better than the ones reported in the literature and on a bigger cohort, paving the way for high-throughput analysis of multicentric morphokinetic databases, providing new insights into the clinical value of morphokinetics as predictor of embryo quality and implantation.Study Funding/Competing Interest(s)This study was partly funded by Finox Forward Grant 2016.Trial Registration NumberNA
Connectional architecture of a mouse hypothalamic circuit node controlling social behavior
Authors: Lo Liching , Kim Dong-Wook , Yao Shenqin , Cetin Ali , Harris Julie , Zeng Hongkui , Anderson David J. , Weissbourd Brandon 
Published: October 2018

ABSTRACTType 1 Estrogen receptor-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvlEsr1) play a causal role in the control of social behaviors including aggression. Here we use six different viral-genetic tracing methods to map the connectional architecture of VMHvlEsr1 neurons. These data reveal a high level of input convergence and output divergence (“fan-in/fan-out”) from and to over 30 distinct brain regions, with a high degree (~90%) of recurrence. Unlike GABAergic populations in other hypothalamic nuclei controlling feeding and parenting behavior, VMHvlEsr1 glutamatergic neurons collateralize to multiple targets. However, we identify two anatomically distinct subpopulations with anterior vs. posterior biases in their collateralization patterns. Surprisingly, these two subpopulations receive indistinguishable inputs. These studies suggest an overall system architecture in which an anatomically feed-forward sensory-to-motor processing stream is integrated with a dense, highly recurrent central processing circuit. This architecture differs from the “brain-inspired” feed-forward circuits used in certain types of artificial intelligence networks.SIGNIFICANCEHow the cellular heterogeneity of brain nuclei maps onto circuit connectivity, the relationship of this anatomical mapping to behavioral function, and whether there are general principles underlying this relationship, remains poorly understood. Here we systematically map the connectivity of estrogen receptor-1-expressing neurons in the ventromedial hypothalamus (VMHvlEsr1), which control aggression and other social behaviors. We find that a relatively sparse, anatomically feed-forward sensory-to-motor processing stream is integrated with a dense, highly recurrent central processing circuit. Further, the VMHvl contains at least two subpopulations of Esr1+ neurons with different cell body characteristics and locations, with distinct patterns of collateralization to downstream targets. Nevertheless, these projection-defined subpopulations receive similar inputs. This input-output organization appears distinct from those described in other hypothalamic nuclei.
Probe Sensitivity to Cortical versus Intracellular Cytoskeletal Network Stiffness
Authors: Vahabakashi Amir , Young Park Chan , Perkumas Kristin , Zhang Zhiguo , Deurloo Emily K. , Wu Huayin , Weitz David A. , Stamer W Daniel , Goldman Robert D. , Fredberg Jeffrey J. , Johnson Mark 
Published: October 2018

ABSTRACTIn development, wound healing, and pathology, cell biomechanical properties are increasingly recognized as being of central importance. To measure these properties, experimental probes of various types have been developed, but how each probe reflects the properties of heterogeneous cell regions has remained obscure. To better understand differences attributable to the probe technology, as well as to define the relative sensitivity of each probe to different cellular structures, here we took a comprehensive approach. We studied two cell types --Schlemm’s canal (SC) endothelial cells and mouse embryonic fibroblasts (MEFs) – using four different probe technologies: 1) atomic force microscopy (AFM) with sharp-tip; 2) AFM with round-tip; 3) optical magnetic twisting cytometry (OMTC); and 4) traction microscopy (TM). Perturbation of SC cells with dexamethasone treatment, a-actinin overexpression, or Rho-A overexpression caused increases in traction reported by TM and stiffness reported by sharp-tip AFM, as compared to corresponding controls. By contrast, under these same experimental conditions, stiffness reported by round-tip AFM and by OMTC indicated little change. Knock out (KO) of vimentin in MEFs caused a diminution of traction reported by TM, as well as stiffness reported by sharp-tip and round-tip AFM. However, stiffness reported by OMTC in vimentin KO MEFs was greater than in wild-type. Finite element analysis demonstrated that this paradoxical OMTC result in vimentin KO MEFs could be attributed to reduced cell thickness. Our results also suggest that vimentin contributes not only to intracellular network stiffness but also cortex stiffness. Taken together, this evidence suggests that AFM sharp-tip and TM emphasize properties of the actin-rich shell of the cell whereas round-tip AFM and OMTC emphasize those of the non-cortical intracellular network.
What drives spectators’ experiential loyalty? A case study of the Olympic Football Tournament Rio 2016
Authors: Wu Hung-Che , Cheng Ching-Chan 
Published: October 2018

Purpose
The purpose of this paper is to examine the relationships among the experiential quality (EQ) dimensions, experiential satisfaction (ES), experiential involvement (EI), host city image (HCI), experiential equity (EE), spectator affection (SA) and experiential loyalty (EL) in the sport context.

Design/methodology/approach
The data used in this study were based on a sample of 674 spectators from the finals of the men’s and women’s football tournaments held at the Maracanã Stadium in Rio, indicating that the proposed model fitted the data.

Findings
Findings show that the six EQ dimensions physical environment quality, outcome quality, access quality (AQ), game quality, trip quality (TQ) and security quality (SQ), EI, EE, HCI and SA positively influence ES. Also, EI moderates the relationship between HCI and EL. Moreover, EL is influenced by EI, HCI, SA and ES.

Practical implications
Results will assist sport management in developing and implementing market-orientated service strategies to increase the EQ dimensions, ES, EI, EE, HCI and SA in order to increase EL.

Originality/value
This study provides data that result in a better understanding of the relationships among the EQ dimensions, ES, EI, HCI, EE, SA and EL in the sporting context.