bluuebunny/crossref_metadata_2025_split huggingface dataset:
Content-based dissociation of hippocampal involvement in prediction
Authors: Kok Peter , Rait Lindsay I. , Turk-Browne Nicholas B. 
Published: March 2019

AbstractIt has recently become clear that one of the key functions of the hippocampus is to predict future inputs. In line with this, previous research has revealed prediction-related signals in the hippocampus for complex visual objects, such as fractals and abstract shapes. Based on this, it has been suggested that the hippocampus may generate perceptual expectations, especially when relying on rapidly learned predictive associations between arbitrary stimuli. However, it is currently unknown whether the hippocampus implements general-purpose computations that subserve all associative predictions, regardless of stimulus properties, or whether the involvement of the hippocampus is stimulus-dependent. To investigate this, we exposed male and female human participants to complex auditory cues predicting either the shape of a complex object (Experiment 1) or the orientation of a simple line grating (Experiment 2). We measured brain activity using high-resolution functional magnetic resonance imaging (fMRI), in combination with inverted encoding models to reconstruct shape and orientation representations in visual cortex and the hippocampus. Our results revealed that expectations about shape and orientation evoked distinct representations in the hippocampus. For complex shapes, the hippocampus represented which shape was expected, potentially serving as a source of top-down predictions. In contrast, for simple gratings, the hippocampus represented only unexpected orientations, more reminiscent of a prediction error. We discuss several potential explanations for this dissociation, concluding that the computational role of the hippocampus in predictive processing depends upon the nature and complexity of stimuli.Significance StatementTo deal with the noisy and ambiguous sensory signals received by our brain, it is crucial to use prior knowledge of the world to guide perception. Previous research suggests that the hippocampus is involved in predicting upcoming visual stimuli based on prior knowledge. In the current study, we show that hippocampal prediction is specific to expectations of complex objects, whereas for simple features the hippocampus generates an opposite prediction error signal instead. These findings demonstrate that the computational role of the hippocampus can be content-sensitive and refine our understanding of the involvement of memory systems in predictive processing.
Synthetic lethality screening identifies FDA-approved drugs that overcome ATP7B-mediated tolerance of tumor cells to cisplatin
Authors: Mariniello Marta , Petruzzelli Raffaella , Wanderlingh Luca G. , La Montagna Raffaele , Carissimo Annamaria , Pane Francesca , Amoresano Angela , Medina Diego , Polishchuk Roman S. 
Published: March 2019

ABSTRACTTumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease.To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the resistant ovarian carcinoma cell line IGROV-CP20. Using a synthetic lethality approach we identified and validated three hits (Tranilast, Telmisartan and Amphotericin B) that could reduce cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these included key molecular players operating in the distribution of platinum to different intracellular compartments. In particular, Tranilast was found to suppress ATOX1 and, as a consequence, ATOX1-mediated trafficking of ATP7B in response to cisplatin.Considering the well-known safety profiles of Tranilast, Telmisartan and Amphotericin B, these drugs emerge as potential candidates that might be used for the rapid development of new therapeutic strategies to overcome resistance of tumors to Pt-based chemotherapy.
Effect of time-series length and resolution on abundance- and trait-based early warning signals of population declines
Authors: Arkilanian A.A. , Clements C.F. , Ozgul A. , Baruah G. 
Published: March 2019

AbstractNatural populations are increasingly threatened with collapse at the hands of anthropogenic effects. Predicting population collapse with the help of generic early warning signals (EWS) may provide a prospective tool for identifying species or populations at highest risk. However, pattern-to-process methods such as EWS have a multitude of challenges to overcome to be useful, including the low signal to noise ratio of ecological systems and the need for high quality time-series data. The inclusion of trait dynamics with EWS has been proposed as a more robust tool to predict population collapse. However, the length and resolution of available time series are highly variable from one system to another, especially when generation time is considered. As yet it remains unknown how this variability with regards to generation time will alter the efficacy of EWS. Here we take both a simulation- and experimental-based approach to assess the impacts of relative time-series length and resolution on the forecasting ability of EWS. We show that EWS’ performance decreases with decreasing length and resolution. Our simulations suggest a relative time-series length between ten and five generations and a resolution of half a generation are the minimum requirements for accurate forecasting by abundance-based EWS. However, when trait information is included alongside abundance-based EWS, we find positive signals at lengths and resolutions half of what was required without them. We suggest that, in systems where specific traits are known to affect demography, trait data should be monitored and included alongside abundance data to improve forecasting reliability.
Plant photoreceptors and their signaling components compete for binding to the ubiquitin ligase COP1 using their VP-peptide motifs
Authors: Lau Kelvin , Podolec Roman , Chappuis Richard , Ulm Roman , Hothorn Michael 
Published: March 2019

SUMMARYPlants sense different parts of the sun’s light spectrum using specialized photoreceptors, many of which signal through the E3 ubiquitin ligase COP1. Photoreceptor binding modulates COP1’s ubiquitin ligase activity towards transcription factors. Here we analyze why many COP1-interacting transcription factors and photoreceptors harbor sequence-divergent Val-Pro (VP) peptide motifs. We demonstrate that VP motifs enable different light signaling components to bind to the WD40 domain of COP1 with various binding affinities. Crystal structures of the VP motifs of the UV-B photoreceptor UVR8 and the transcription factor HY5 in complex with COP1, quantitative binding assays and reverse genetic experiments together suggest that UVR8 and HY5 compete for the COP1 WD40 domain. Photoactivation of UVR8 leads to high-affinity cooperative binding of its VP domain and its photosensing core to COP1, interfering with the binding of COP1 to its substrate HY5. Functional UVR8 – VP motif chimeras suggest that UV-B signaling specificity resides in the UVR8 photoreceptor core, not its VP motif. Crystal structures of different COP1 – VP peptide complexes highlight sequence fingerprints required for COP1 targeting. The functionally distinct blue light receptors CRY1 and CRY2 also compete with downstream transcription factors for COP1 binding using similar VP-peptide motifs. Together, our work reveals that photoreceptors and their components compete for COP1 using a conserved displacement mechanism to control different light signaling cascades in plants.
Investigating the Inhibitory Aspects of Metformin/Curcumin Co-Treatment through Convergence of In-Silico and In-Vitro Approaches
Authors: Afzali Farzaneh , Nayeri Zahra , Minuchehr Zarrin , Gardaneh Mossa 
Published: March 2019

ABSTRACTNearly 16% of people with breast cancer (BC) have Diabetes Mellitus type 2 (DM2) and are at a higher risk of death worldwide. Their common regulatory factors and functional mechanisms can be targeted applying multi-target drugs including Metformin (MTFN) and Curcumin (CURC). In this study, we used in-silico approaches to study the potential underlying mechanisms of this co-treatment strategy on BC and DM2 in order to introduce novel therapeutic targets.The total number of 48 shared differentially expressed genes (17 up-regulated and 31 down-regulated) were identified through establishing diseases’ protein-protein network and BC RNA-sequencing expression data. The integration of functional clustering and pathway analyses revealed that the most involved cellular pathways and processes are regard to cells’ proliferation, death, migration, and response to external stimulus. Afterwards, the MTFN/CURC correlation and co-treatment optimization was probed through response surface methodology (RSM) based on MCF7 cell line and confirmed by MDA-MB-231. Combination index calculation by MTT viability assay proved supportive effects on both cell lines. The superior apoptotic potential of co-treatment compared to single treatments was shown on inhibition of MCF7 proliferation and induction of cell death demonstrated by cell body co-staining and flow cytometry as well as gene expression analysis via RT-PCR. Furthermore, wound-healing scratch assay showed that this co-treatment has a slightly higher effect on migration inhibition compared to single treatments.In conclusion, our study used in-silico and in-vitro approaches and introduced a potential regulatory panel between BC and DM2. We also provided a linear model and equation that show the positive relation of drugs’ co-treatment. The proposed co-treatment strategy successfully controlled the biological processes under investigation.
Mapping the 3D genome through high speed single-molecule tracking of functional transcription factors in single living cells
Authors: Wollman Adam J. M. , Hedlund Erik G. , Shashkova Sviatlana , Leake Mark C. 
Published: March 2019

AbstractHow genomic DNA is organized within the cell nucleus is a long-standing question. We describe a single-molecule bioimaging method with super-resolution localization precision and very rapid millisecond temporal resolution, coupled to fully quantitative image analysis tools, to help to determine genome organization and dynamics using budding yeast Saccharomyces cerevisiae as a model eukaryotic organism. We utilize astigmatism imaging, a robust technique that enables extraction of 3D position data, on genomically encoded fluorescent protein reporters that bind to DNA. Our relatively straightforward method enables snapshot reconstructions of 3D architectures of single genome conformations directly in single functional living cells.
Evaluating genomic data for management of local adaptation in a changing climate: A lodgepole pine case study
Authors: Mahony Colin R. , MacLachlan Ian R. , Lind Brandon M. , Yoder Jeremy B. , Wang Tongli , Aitken Sally N. 
Published: March 2019

AbstractThe need for tools to cost-effectively identify adaptive variation within ecologically and economically important plant species is mounting as the detrimental effects of climate change become increasingly apparent. For crop and wild populations alike, mismatches between adaptive variation and climatic optima will reduce health, growth, survival, reproduction, and continued establishment. The ease with which land managers can quantify the relative importance of different climate factors or the spatial scale of local adaptation to climate will have direct implications for the potential of mitigating or resolving such risks. Using seed collected from 281 provenances of lodgepole pine (Pinus contorta) from across western Canada, we compare genomic data to phenotypic and climatic data to assess their effectiveness in characterizing the climatic drivers and spatial scale of local adaptation in this species. We find that genomic and climate data are nearly equivalent for describing local adaptation in seedling traits. We also find strong agreement between the climate variables associated with genomic variation and with 20-year heights from a long-term provenance trial, suggesting that genomic data may be a viable option for identifying climatic drivers of local adaptation where phenotypic data are unavailable. Genetic clines associated with cold injury occur at broad spatial scales, suggesting that standing variation of adaptive alleles for this and similar species does not require management at scales finer than are indicated by phenotypic data. This study demonstrates that genomic data are most useful when paired with phenotypic data, but can also fill some of the traditional roles of phenotypic data in management of species for which phenotypic trials are not feasible.
The caudate nucleus controls coordinated patterns of adaptive, context-dependent adjustments to complex decisions
Authors: Doi Takahiro , Fan Yunshu , Gold Joshua I. , Ding Long 
Published: March 2019

AbstractOur decisions often need to balance what we observe and what we desire. However, our understanding of how and where in the brain such decisions are made remains limited. A prime candidate for integrating sensory observations and desired rewards, and a focus of many modeling studies, is the basal ganglia pathway, which is known to make separate contributions to perceptual decisions that require the interpretation of uncertain sensory evidence and value-based decisions that select among outcome options 1-16. Here we report direct evidence for a causal role for a major input station of the basal ganglia, the caudate nucleus, in incorporating reward context and uncertain visual evidence to guide adaptive decision-making. In monkeys making saccadic decisions based on visual motion evidence and asymmetric reward-choice associations 17, single caudate neurons encoded information about both the visual evidence and the asymmetric rewards. Electrical microstimulation at caudate sites with task-modulated activity during motion viewing affected how the visual and reward information was used to form the decision. The microstimulation effects included coordinated changes in multiple computational components of the decision process, mimicking the monkeys’ voluntary adjustments in response to the asymmetric reward contexts. These results imply that the caudate nucleus plays key roles in coordinating the deliberative decision process that balances external evidence and internal preferences to guide adaptive behavior.
Perturbation biology links temporal protein changes to drug responses in a melanoma cell line
Authors: Nyman Elin , Stein Richard R. , Jing Xiaohong , Wang Weiqing , Marks Benjamin , Zervantonakis Ioannis K. , Korkut Anil , Gauthier Nicholas P. , Sander Chris 
Published: March 2019

Data-driven mathematical modeling of biological systems has enormous potential to understand and predict the interplay between molecular and phenotypic response to perturbation, and provides a rational approach to the nomination of therapies in complex diseases such as cancer. Melanoma is a particularly debilitating disease for which most therapies eventually fail as resistance to chemotherapy and targeted drugs develop. We have previously applied an iterative experimental-computational modeling approach, termed perturbation biology, to predict and test effective drug combinations in melanoma cell lines [1].In this work, we extend our analysis framework to derive models of temporally-acquired perturbation data that do not require prior knowledge and explicit specification of the targets of individual drugs. Specifically, we characterize the response of the melanoma cell line A2058 to 54 cancer drug combinations at 8 logarithmically spaced time points from 10 minutes to 67 hours. At each time point, 124 antibodies of proteins and phospho-proteins with broad coverage of cancer-related pathways and two phenotypes (cell number and apoptosis) were measured. These data are used to infer interactions in ordinary differential equation-based models that capture temporal aspects of the drug perturbation data. This network representation of drug–protein, protein–protein, and protein–phenotype interactions can be used to identify new logical (not necessarily direct biochemical) interactions. The agreement between the predicted phenotypic response and corresponding data for unseen drug perturbations has a Pearson’s correlation coefficient of 0.79. We further use model predictions to nominate effective combination therapies and perform experimental validation of the highest ranked combinations.This new data-driven modeling framework is a step forward in perturbation biology as it incorporates the temporal aspect of data. This work therefore opens the door to a new understanding of dynamic drug responses at a molecular level.
Effects of lipid composition on membrane distribution and permeability of natural quinones
Authors: Teixeira Murilo Hoias , Arantes Guilherme Menegon 
Published: March 2019

ABSTRACTNatural quinones are amphiphilic molecules that function as mobile charge carriers in biological energy transduction. Their distribution and permeation across membranes are important for binding to enzymatic complexes and for proton translocation. Here, we employ molecular dynamics simulations and free energy calculations with a carefully calibrated classical force-field to probe quinone distribution and permeation in a multicomponent bilayer trying to mimic the composition of membranes involved in bioenergetic processes. Ubiquinone, ubiquinol, plastoquinone and menaquinone molecules with short and long isoprenoid tails are simulated. We find that water penetration increases considerably in the less ordered and porous bilayer formed by di-linoleoyl (18:2) phospholipids, resulting in a lower free energy barrier for quinone permeation and faster transversal diffusion. In equilibrium, quinone and quinol heads localize preferentially near lipid glycerol groups, but do not perform specific contacts with lipid polar heads. Quinone distribution is not altered significantly by the quinone head, tail and lipid composition in comparison to a single-component bilayer. This study highlights the role of acyl chain unsaturation for molecular permeation and transversal diffusion across biological membranes.
Afferent-efferent connectivity between auditory brainstem and cortex accounts for poorer speech-in-noise comprehension in older adults
Authors: Bidelman Gavin M. , Price Caitlin N. , Shen Dawei , Arnott Stephen R. , Alain Claude 
Published: March 2019

ABSTRACTAge-related hearing loss leads to poorer speech comprehension, particularly in noise. Speech-in-noise (SIN) deficits among the elderly could result from weaker neural activity within, or poorer signal transmission between brainstem and auditory cortices. By recording neuroelectric responses from brainstem (BS) and primary auditory cortex (PAC), we show that beyond simply attenuating neural activity, hearing loss in older adults compromises the transmission of speech information between subcortical and cortical hubs of the auditory system. The strength of afferent BS→PAC neural signaling (but not the reverse efferent flow; PAC→BS) varied with mild declines in hearing acuity and this “bottom-up” functional connectivity robustly predicted older adults’ SIN perception. Our neuroimaging findings underscore the importance of brain connectivity, particularly afferent neural communication, in understanding the biological basis of age-related hearing deficits in real-world listening environments.
Functional metagenomics-guided discovery of potent Cas9 inhibitors in the human microbiome
Authors: Forsberg Kevin J. , Bhatt Ishan V. , Schmidtke Danica T. , Stoddard Barry L. , Kaiser Brett K. , Malik Harmit S. 
Published: March 2019

AbstractCRISPR-Cas systems protect bacteria and archaea from phages and other mobile genetic elements, which use small anti-CRISPR (Acr) proteins to overcome CRISPR-Cas immunity. Because they are difficult to identify, the natural diversity and impact of Acrs on microbial ecosystems is underappreciated. To overcome this discovery bottleneck, we developed a high-throughput functional selection that isolatesacrgenes based on their ability to inhibit CRISPR-Cas function. Using this selection, we discovered ten DNA fragments from human oral and fecal metagenomes that antagonizeStreptococcus pyogenesCas9 (SpyCas9). The most potentacrdiscovered,acrIIA11, was recovered from aLachnospiraceaephage and is among the strongest known SpyCas9 inhibitors.AcrIIA11homologs are distributed across multiple bacterial phyla and many divergent homologs inhibit SpyCas9. We show that AcrIIA11 antagonizes SpyCas9 using a different mechanism than that of previously characterized inhibitors. Our study highlights the power of functional selections to uncover widespread Cas9 inhibitors within diverse microbiomes.
Geography Shapes the Population Genomics ofSalmonella entericaDublin
Authors: Fenske Gavin J. , Thachil Anil , McDonough Patrick L. , Glaser Amy , Scaria Joy 
Published: March 2019

ABSTRACTSalmonella enterica serotypeDublin (S.Dublin) is a bovine-adapted serotype that can cause serious systemic infections in humans. Despite the increasing prevalence of human infections and the negative impact on agricultural processes, little is known about the population structure of the serotype. To this end, we compiled a manually curated dataset comprising of 880S.Dublin genomes. Core genome phylogeny and ancestral state reconstruction revealed that region-specific clades dominate the global population structure ofS.Dublin. Strains ofS.Dublin in the UK are genomically distinct from US, Brazilian and African strains. The geographical partitioning impacts the composition of the core genome as well as the ancillary genome. Antibiotic resistance genes are almost exclusively found in US genomes and is mediated by an IncA/C2 plasmid. Phage content and theS.Dublin virulence plasmid were strongly conserved in the serotype. Comparison ofS.Dublin to a closely related serotype,Salmonella enterica serotypeEnteritidis, revealed thatS.Dublin contains 82 serotype specific genes that are not found inS. Enteritidis. Said genes encode metabolic functions involved in the uptake and catabolism of carbohydrates and virulence genes associated with type VI secretion systems and fimbria assembly respectively.IMPORTANCES.Dublin is a bovine-adapted strain that can also cause human infections. TypicalS.Dublin human infections are characterized by invasion of tissue that ultimately traverses to the bloodstream causing life-threatening systemic cases. The preferred course of treatment for such infection is the administration of antibiotics. Thus, it is important to study the population structure of the serotype to monitor and identify which strains present the greatest threats to public health. Consequently, in this work, it was found thatS.Dublin genomic features are greatly influenced by the region in which they populate. Our analysis found that mostS.Dublin isolates from the US are distinct and have gained multidrug resistance through a new hybrid plasmid. Thus, it would be expected that infections in the US would respond less favorably to the first line of therapy and the region acts as the major source of a multidrug-resistantS.Dublin.