bluuebunny/crossref_metadata_2025_split huggingface dataset:
A FOXO-dependent replication checkpoint restricts proliferation of damaged cells
Authors: Hornsveld Marten , Feringa Femke M , Krenning Lenno , van den Berg Jeroen , Smits Lydia MM , Nguyen Nguyen BT , Rodriguez-Colman Maria J , Dansen Tobias B , Medema Rene H , Burgering Boudewijn MT 
Published: January 2020

AbstractDNA replication is challenged by numerous exogenous and endogenous factors that can interfere with the progression of replication forks. Stalling or slowing of the replication fork as a result of replication stress leads to formation of aberrant single-stranded DNA (ssDNA) stretches and potentially DNA double-stranded-breaks (DSBs). Accumulation of ssDNA activates the ATR-dependent DNA replication stress checkpoint response that slows progression from S/G2- to M-phase to protect genomic integrity (1). However, whether mild replication stress restricts proliferation remains controversial (2–6). Here we identify a novel cell cycle exit mechanism, that prevents S/G2 phase arrested cells from undergoing mitosis after exposure to mild replication stress through premature activation of the CDH1 bound Anaphase Promoting Complex / Cyclosome (APC/CCDH1). We find that replication stress causes a gradual decrease of the levels of the APC/CCDH1inhibitor EMI1/FBXO5 through Forkhead Box O (FOXOs) mediated repression of its transcriptional regulator E2F1. By doing so, FOXOs limit the time during which the replication stress checkpoint is reversible, and thereby play an important role in maintaining genomic stability.
PPM-Decay: A Computational Model of Auditory Prediction with Memory Decay
Authors: Harrison Peter M. C. , Bianco Roberta , Chait Maria , Pearce Marcus T. 
Published: January 2020

AbstractStatistical learning and probabilistic prediction are fundamental processes in auditory cognition. A prominent computational model of these processes is Prediction by Partial Matching (PPM), a variable-order Markov model that learns by internalizingn-grams from training sequences. However, PPM has limitations as a cognitive model: in particular, it has a perfect memory that weights all historic observations equally, which is inconsistent with memory capacity constraints and recency effects observed in human cognition. We address these limitations with PPM-Decay, a new variant of PPM that introduces a customizable memory decay kernel. In three studies – one with artificially generated sequences, one with chord sequences from Western music, and one with new behavioral data from an auditory pattern detection experiment – we show how this decay kernel improves the model’s predictive performance for sequences whose underlying statistics change over time, and enables the model to capture effects of memory constraints on auditory pattern detection. The resulting model is available in our new open-source R package,ppm(https://github.com/pmcharrison/ppm).
Recently expanded clonal lineages of the rice blast fungus display distinct patterns of presence/absence of effector genes
Authors: Latorre Sergio M. , Reyes-Avila C. Sarai , Malmgren Angus , Win Joe , Kamoun Sophien , Burbano Hernán A. 
Published: January 2020

AbstractBackgroundUnderstanding the mechanisms and timescales of plant pathogen outbreaks requires a detailed genome-scale analysis of their population history. The fungusMagnaporthe(Syn.Pyricularia)oryzae—the causal agent of blast disease of cereals— is among the most destructive plant pathogens to world agriculture and a major threat to the production of rice, wheat and other cereals. AlthoughM. oryzaeis a multihost pathogen that infects more than 50 species of cereals and grasses, all rice-infecting isolates belong to a single genetically defined lineage. Here, we combined multiple genomics datasets to reconstruct the genetic history of the rice-infecting lineage ofM. oryzaebased on 131 isolates from 21 countries.ResultsThe global population of the rice blast fungus consists of a diverse set of individuals and three well-defined genetic groups. Multiple population genetic tests revealed that the rice-infecting lineage of the blast fungus probably originated from a recombining diverse group in South East Asia followed by three independent clonal expansions that took place over the last ∼200 years. Patterns of allele sharing identified a subpopulation from the recombining diverse group that introgressed with one of the clonal lineages before its global expansion. Remarkably, the four genetic lineages of the rice blast fungus vary in the number and patterns of presence/absence of candidate effector genes. In particular, clonal lineages carry a reduced repertoire of effector genes compared with the diverse group, and specific combinations of effector presence/absence define each of the pandemic clonal lineages.ConclusionsOur analyses reconstruct the genetic history of the rice-infecting lineage ofM. oryzaerevealing three clonal lineages associated with rice blast pandemics. Each of these lineages displays a specific pattern of presence/absence of effector genes that may have shaped their adaptation to the rice host and their evolutionary history.
A Simple and Robust Cell-Based Assay for the Discovery of Novel Cytokinesis Inhibitors
Authors: Radnai Laszlo , Stremel Rebecca F. , Vaissiere Thomas , Martin William H. , Rumbaugh Gavin , Kamenecka Theodore M. , Griffin Patrick R. , Miller Courtney A. 
Published: January 2020

AbstractCytokinesis is the last step of mitotic cell division that separates the cytoplasm of dividing cells. Small molecule inhibitors targeting either the elements of the regulatory pathways controlling cytokinesis, or the terminal effectors have been of interest as potential drug candidates for the treatment of various diseases. Here we have developed a cell-based assay for the discovery of novel cytokinesis inhibitors. The assay is performed in a 96-well plate format in 48 hours. Living cells, nuclei and nuclei of dead cells are revealed by a single staining step with three fluorescent dyes, followed by live cell imaging using an automated fluorescence microscope. The primary signal is the nuclei-to-cell ratio (NCR). In the presence of cytokinesis inhibitors, this ratio is expected to increase over time, as the ratio of multinucleated cells increases in the population. Cytotoxicity is quantified as the ratio of dead nuclei to total nuclei. A screening window coefficient (Z’) of 0.65 indicates that the assay is suitable for screening purposes, as the positive and negative controls are well-separated. EC50values for four compounds can be reliably determined in a single 96-well plate by using only six different compound concentrations. An excellent test-retest reliability (R2=0.998) was found for EC50values covering a ∼1500-fold range of potencies. The robustness, simplicity and flexibility of the assay is demonstrated here by using modulators of actin dynamics with different mechanisms of action (jasplakinolide, cytochalasin D and swinholide A) and derivatives of the nonmuscle myosin II inhibitor blebbistatin.
CB1receptor-mediated inhibitory LTD triggers presynaptic remodeling via protein synthesis and ubiquitination
Authors: Monday Hannah R. , Bourdenx Mathieu , Jordan Bryen A. , Castillo Pablo E. 
Published: January 2020

SummaryLong-lasting forms of postsynaptic plasticity commonly involve protein synthesis-dependent structural changes of dendritic spines. However, the relationship between protein synthesis and presynaptic structural plasticity remains unclear. Here, we investigated structural changes in cannabinoid-receptor 1 (CB1)-mediated long-term depression of inhibitory transmission (iLTD), a form of presynaptic plasticity that requires protein synthesis and involves a long-lasting reduction in GABA release. We found that CB1-iLTD in acute rat hippocampal slices was associated with protein synthesis-dependent presynaptic structural changes. Using proteomics, we determined that CB1activation in hippocampal neurons resulted in increased ribosomal proteins and initiation factors, but decreased levels of proteins involved in regulation of the actin cytoskeleton, such as Arp2/3, and presynaptic release. Moreover, while CB1-iLTD increased ubiquitin/proteasome activity, ubiquitination but not proteasomal degradation was critical for structural and functional presynaptic CB1-iLTD. Thus, CB1-iLTD relies on both protein synthesis and ubiquitination to elicit structural changes that underlie long-term reduction of GABA release.
EEG correlates of physical effort and reward processing during reinforcement learning
Authors: Palidis Dimitrios J. , Gribble Paul L. 
Published: January 2020

AbstractEffort-based decision making is often described by choices according to subjective value, a function of reward discounted by effort. We asked whether a neural reinforcement learning signal, the feedback related negativity (FRN), is modulated not only by reward outcomes but also physical effort. We recorded EEG from human participants while they performed a task in which they were required to accurately produce target levels of muscle activation to receive rewards. Participants performed isometric knee extensions while quadriceps muscle activation was recorded using EMG. Real-time feedback indicated muscle activation relative to a target. On a given trial, the target muscle activation required either low or high effort. The effort was determined probabilistically according to a binary choice, such that the responses were associated with 20% and 80% probability of high effort. This contingency could only be known by experience, and it reversed periodically. After each trial binary reinforcement feedback was provided to indicate whether participants were sufficiently accurate in producing the target muscle activity. Participants adaptively avoided effort by switching responses more frequently after choices that resulted in hard effort. Feedback after participants’ choices which revealed the resulting effort requirement for the subsequent knee extension did not elicit an FRN component. However, the neural response to reinforcement feedback after the knee extension was increased during and after the time period of the FRN by preceding physical effort. Thus, retrospective effort modulates reward processing which may underlie paradoxical behavioral findings whereby rewards requiring more effort to obtain can become more powerful reinforcers.Significance StatementWhen making decisions, we typically select more rewarding and less effortful options. Neural reinforcement learning signals reinforce rewarding actions and deter punishing actions. When participants received feedback that their choices would require easy or hard physical effort, we did not observe reinforcement learning signals that are typically observed in response to feedback predicting reward and punishment. Thus, the reinforcement learning system does not strictly treat effort as loss or punishment. However, when the effort was completed and participants received feedback indicating whether they successfully achieved a reward or not, reinforcement learning signals were amplified by preceding effort. Thus, retrospective effort can affect neural responses to reinforcement outcomes, which may explain how effort can enhance the motivational effect of reinforcers.
Circadian Rhythm Is Disrupted by ZNF704 in Breast Carcinogenesis
Authors: Yang Chao , Wu Jiajing , Liu Xinhua , Wang Yue , Liu Beibei , Chen Xing , Wu Xiaodi , Yan Dong , Han Lulu , Liu Shumeng , Shan Lin , Shang Yongfeng 
Published: January 2020

AbstractCopy number gain in chromosome 8q21 is considered as the prototype of genetic abnormalities associated with development of breast cancer, yet the oncogenic potential underlying this amplicon in breast carcinogenesis remains to be delineated. We report here thatZNF704, a gene mapped to 8q21, is recurrently amplified in various malignancies including breast cancer. We found that ZNF704 acts as transcription repressor and interacts with the transcription corepressor SIN3A complex. Genome-wide interrogation of the transcriptional targets identifies that the ZNF704/SIN3A complex represses a panel of genes includingPER2that are critically involved in the function of circadian clock. Indeed, ZNF704 overexpression prolongs the period and dampens the amplitude of circadian clock. We showed that ZNF704 promotes the proliferation and invasion of breast cancer cellsin vitroand accelerates the growth and metastasis of breast cancerin vivo. Consistently, the level of ZNF704 expression is inversely correlated with that of PER2 in breast carcinomas, and high level of ZNF704 correlates with advanced histological grades, lymph node positivity, and poor prognosis of breast cancer patients, especially those with HER2+and basal-like subtypes. These results indicate that ZNF704 is an important regulator of circadian clock and a potential driver for breast carcinogenesis.
Evolution of contribution timing in public goods games
Authors: Morsky Bryce , Smolla Marco , Akçay Erol 
Published: January 2020

AbstractLife history strategies are a crucial aspect of life, which are complicated in group-living species, where payoffs additionally depend on others’ behaviours. Previous theoretical models of public good games have generally focused on the amounts individuals contribute to the public good. Yet a much less studied strategic aspect of public good games, the timing of contributions, can also have dramatic consequences for individual and collective performance. Here, we develop game theoretical models to explore how the timing of contributions evolves. We show how contributing rapidly is not necessarily optimal, since delayers can act as “cheats,” avoiding contributing while reaping the benefits of the public good. However, delaying too long can put the delayers at a disadvantage as they can miss out on the benefits. These effects lead to bistability in a single group, and spatial diversity among multiple interacting groups.
Potent inhibitors of toxic alpha-synuclein oligomers identified via cellular time-resolved FRET biosensor
Authors: Braun Anthony R. , Liao Elly E. , Horvath Mian , Young Malaney C. , Lo Chih Hung , Brown Roland , Evans Michael D. , Luk Kelvin , Thomas David D. , Sachs Jonathan N. 
Published: January 2020

ABSTRACTPreventing or reversing the pathological misfolding and self-association of alpha-synuclein (aSyn) can rescue a broad spectrum of pathological cellular insults that manifest in Parkinson’s Disease (PD), Dementia with Lewy bodies (DLB), and other alpha-synucleinopathies. We have developed a high-throughput, FRET-based drug discovery platform that combines high-resolution protein structural detection in living cells with an array of functional and biophysical assays to identify novel lead compounds that protect SH-SY5Y cells from aSyn induced cytotoxicity as well as inhibiting seeded aSyn aggregation, even at nanomolar concentrations.Our combination of cellular and cell-free assays allow us to distinguish between direct aSyn binding or indirect mechanisms of action (MOA). We focus on targeting oligomers with the requisite sensitivity to detect subtle protein structural changes that may lead to effective therapeutic discoveries for PD, DLB, and other alpha-synucleinopathies. Pilot high-throughput screens (HTS) using our aSyn cellular FRET biosensors has led to the discovery of the first nanomolar-affinity small molecules that disrupt toxic aSyn oligomers in cells and inhibit cell death. Primary neuron assays of aSyn pathology (e.g. phosphorylation of mouse aSyn PFF) show rescue of pathology for two of our tested compounds. Subsequent seeded thioflavin-t (ThioT) aSyn aggregation assays demonstrate these compounds deter or block aSyn fibril assembly. Other hit compounds identified in our HTS are known to modulate oxidative stress, autophagy, and ER stress, providing validation that our biosensor is sensitive to indirect MOA as well.
Common and distinct brain activity associated with risky and ambiguous decision-making
Authors: Poudel Ranjita , Riedel Michael C. , Salo Taylor , Flannery Jessica S. , Hill-Bowen Lauren D. , Eickhoff Simon B. , Laird Angela R. , Sutherland Matthew T. 
Published: January 2020

ABSTRACTTwo often-studied forms of uncertain decision-making (DM) are risky-DM (outcome probabilities known) and ambiguous-DM (outcome probabilities unknown). While DM in general is associated with activation of several brain regions, previous neuroimaging efforts suggest a dissociation between activity linked with risky and ambiguous choices. However, the common and distinct neurobiological correlates associated with risky- and ambiguous-DM, as well as their specificity when compared to perceptual-DM (as a ‘control condition’), remains to be clarified. We conducted multiple meta-analyses on neuroimaging results from 151 studies to characterize common and domain-specific brain activity during risky-, ambiguous-, and perceptual-DM. When considering all DM tasks, convergent activity was observed in brain regions considered to be consituents of the canonical salience, valuation, and executive control networks. When considering subgroups of studies, risky-DM (vs. perceptual-DM) was linked with convergent activity in the striatum and anterior cingulate cortex (ACC), regions associated with reward-related processes (determined by objective functional decoding). When considering ambiguous-DM (vs. perceptual-DM), activity convergence was observed in the lateral prefrontal cortex and insula, regions implicated in affectively-neutral mental processes (e.g., cognitive control and behavioral responding; determined by functional decoding). An exploratory meta-analysis comparing brain activity between substance users and non-users during risky-DM identified reduced convergent activity among users in the striatum, cingulate, and thalamus. Taken together, these findings suggest a dissociation of brain regions linked with risky- and ambiguous-DM reflecting possible differential functionality and highlight brain alterations potentially contributing to poor decision-making in the context of substance use disorders.
The electrically conductive pili ofGeobacter soli
Authors: Zhuo Shiyan , Yang Guiqin , Zhuang Li 
Published: January 2020

AbstractElectrically conductive pili (e-pili) enable electron transport over multiple cell lengths to extracellular environments and play an important role in extracellular electron transfer (EET) ofGeobacterspecies. To date, the studies of e-pili have mainly focused onGeobacter sulfurreducensand the closely relatedGeobacter metallireducensbecause of their developed genetic manipulation systems. We investigated the role ofG. solipili in EET by directly deleting the pilin gene,pilA, which is predicted to encode e-pili. Deletion ofpilA, prevented the production of pili, resulting in poor Fe(III) oxide reduction and low current production, implying thatG. solipili is required for EET. To further evaluate the conductivity ofG. solipili compared withG. sulfurreducenspili, thepilAofG. soliwas heterologously expressed inG. sulfurreducens, yielding theG. sulfurreducensstrain GSP. This strain produced abundant pili with similar conductivity to the control strain that expressed nativeG. sulfurreducenspili, consistent withG. solias determined by direct measurement, which suggested thatG. solipili is electrically conductive. Surprisingly, strain GSP was deficient in Fe(III) oxide reduction and current production due to the impaired content of outer-surfacec-type cytochromes. These results demonstrated that heterologous pili ofG. sulfurreducensseverely reduces the content of outer-surfacec-type cytochromes and consequently eliminates the capacity for EET, which strongly suggests an attention should be paid to the content ofc-type cytochromes when employingG. sulfurreducensto heterologously express pili from other microorganisms.IMPORTANCEThe studies of electrically conductive pili (e-pili) ofGeobacterspecies are of interest because of its application prospects in electronic materials. e-Pili are considered a substitution for electronic materials due to its renewability, biodegradability and robustness. Continued exploration of additional e-pili ofGeobacter soliwill improve the understanding of their biological role in extracellular electron transfer and expand the range of available electronic materials. Heterologously expressing the pilin genes from phylogenetically diverse microorganisms has been proposed as an emerging approach to screen potential e-pili according to high current densities. However, our results indicated that aGeobacter sulfurreducensstrain heterologously expressing a pilin gene produced low current densities that resulted from a lack of content ofc-type cytochromes, which were likely to possess e-pili. These results provide referential significance to yield e-pili from diverse microorganisms.
Comprehensive benchmarking of computational deconvolution of transcriptomics data
Authors: Cobos Francisco Avila , Alquicira-Hernandez José , Powell Joseph , Mestdagh Pieter , De Preter Katleen 
Published: January 2020

AbstractMany computational methods to infer cell type proportions from bulk transcriptomics data have been developed. Attempts comparing these methods revealed that the choice of reference marker signatures is far more important than the method itself. However, a thorough evaluation of the combined impact of data transformation, pre-processing, marker selection, cell type composition and choice of methodology on the results is still lacking.Using different single-cell RNA-sequencing (scRNA-seq) datasets, we generated hundreds of pseudo-bulk mixtures to evaluate the combined impact of these factors on the deconvolution results. Along with methods to perform deconvolution of bulk RNA-seq data we also included five methods specifically designed to infer the cell type composition of bulk data using scRNA-seq data as reference.Both bulk and single-cell deconvolution methods perform best when applied to data in linear scale and the choice of normalization can have a dramatic impact on the performance of some, but not all methods. Overall, single-cell methods have comparable performance to the best performing bulk methods and bulk methods based on semi-supervised approaches showed higher error and lower correlation values between the computed and the expected proportions. Moreover, failure to include cell types in the reference that are present in a mixture always led to substantially worse results, regardless of any of the previous choices. Taken together, we provide a thorough evaluation of the combined impact of the different factors affecting the computational deconvolution task across different datasets and propose general guidelines to maximize its performance.