bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reactivation of single-episode pain patterns in the hippocampus and decision making
Authors: Wimmer G. Elliott , Büchel Christian 
Published: May 2020

AbstractAversive and rewarding experiences can exert a strong influence on subsequent behavior. While decisions are often supported by the value of single past episodes, most research has focused on the role of well-learned value associations. Recent studies have begun to investigate the influence of reward-associated episodes, but it is unclear if these results generalize to negative experiences such as pain. To investigate whether and how the value of previous aversive experiences modulates behavior and brain activity, in our experiments female and male human participants experienced episodes of high or low pain in conjunction with incidental, trial-unique neutral pictures. In an incentive-compatible surprise test phase, we found that participants avoided pain-paired objects. In a separate fMRI experiment, at test, participants exhibited significant pain value memory. Neurally, when participants were re-exposed to pain-paired objects, we found no evidence for reactivation of pain-related patterns in pain-responsive regions such as the anterior insula. Critically, however, we found significant reactivation of pain-related patterns of activity in the hippocampus, such that activity significantly discriminated high versus low pain episodes. Further, stronger reactivation in the anterior hippocampus was related to improved pain value memory performance. Our results demonstrate that single incidental aversive experiences can build memories that affect decision making and that this influence may be supported by the hippocampus.Significance StatementAversive and rewarding experiences can exert a strong influence on our subsequent behavior. While decisions are often supported by single past negative or positive episodes, most research has focused on the role of well-learned value associations. In experiments using aversive heat pain in conjunction with incidental objects, we found that participant’s choices were biased by the level of pain associated with the objects. Further, when participants saw the objects again, pain-related neural patterns in the hippocampus were re-expressed and this was related to pain value memory performance. These results suggest a mechanism by which even single negative experiences can guide our later decisions.
Shape-centered representations of bounded regions of space mediate the transformation of retinotopic representations into conscious perception of objects
Authors: Vannuscorps G. , Galaburda A. , Caramazza A. 
Published: May 2020

AbstractThe primary visual cortex represents the retinotopic orientation of visual primitives (edges, blobs, bars), but our conscious perception is of orientated objects (e.g., dogs, forks) in the environment. How this transformation operates remains unknown. We report here the study of a young woman presenting with an extraordinarily clear and informative visual disorder that affects highly specific aspects of object perception allowing precise inferences about the type and properties of visual representations that mediate this transformation. Davida perceives sharp-edged 2D bounded regions of space of medium to high contrast as if they were plane-rotated by 90, 180 or 270 degrees around their center, mirrored across their own axes, or both. In contrast, her perception of strongly blurred or very low contrast shapes, and of compound shapes emerging from a collection of bounded elements, is intact. The nature of her errors implies that visual perception is mediated by a representation of each bounded region of space in a shape-centered coordinate system aligned on either the shape’s most elongated part or on the shape’s axis of symmetry and centered either at the midpoint of the shape’s most elongated part or at the shape’s centroid. The selectivity of her disorder to sharp-edged medium to high-contrast stimuli additionally suggests that duplicate shape-centered representations are computed in parallel from information derived from the parvocellular and magnocellular subcortical channels and integrated precisely at the level at which shape representations must be mapped onto a behaviorally relevant frame of reference.
Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-Inflammatory Effects Through SHIP1/STAT3 Complexes
Authors: Chamberlain Thomas C. , Cheung Sylvia T. , Yoon Jeff S.J. , Ming-Lum Andrew , Gardill Bernd R. , Shakibakho Soroush , Dzananovic Edis , Ban Fuqiang , Samiea Abrar , Jawanda Kamaldeep , Priatel John , Krystal Gerald , Ong Christopher J. , Cherkasov Artem , Andersen Raymond J. , McKenna Sean A. , Van Petegem Filip , Mui Alice L-F 
Published: May 2020

ABSTRACTThe anti-inflammatory actions of interleukin-10 (IL10) are thought to be mediated primarily by the STAT3 transcription factor, but pro-inflammatory cytokines such as interleukin-6 (IL6) also act through STAT3. We now report that IL10, but not IL6 signaling, induces formation of a complex between STAT3 and the inositol polyphosphate-5-phosphatase SHIP1 in macrophages. Both SHIP1 and STAT3 translocate to the nucleus in macrophages. Remarkably, sesquiterpenes of the Pelorol family we previously described as allosteric activators of SHIP1 phosphatase activity, could induce SHIP1/STAT3 complex formation in cells, and mimic the anti-inflammatory action of IL10 in a mouse model of colitis. Using crystallography and docking studies we identified a drug-binding pocket in SHIP1. Our studies reveal new mechanisms of action for both STAT3 and SHIP1, and provide a rationale for use of allosteric SHIP1-activating compounds which mimic the beneficial anti-inflammatory actions of IL10.
Two new immature and dysfunctional neutrophil cell subsets define a predictive signature of sepsis useable in clinical practice
Authors: Meghraoui-Kheddar Aïda , Chousterman Benjamin G. , Guillou Noëlline , Barone Sierra M. , Granjeaud Samuel , Vallet Helene , Corneau Aurélien , Guessous Karim , Boissonnas Alexandre , Irish Jonathan M. , Combadière Christophe 
Published: May 2020

AbstractSepsis is the leading cause of death in adult intensive care units. At present, sepsis diagnosis relies on non-specific clinical features. It could transform clinical care to have objective immune cell biomarkers that could predict sepsis diagnosis and guide treatment. For decades, neutrophil phenotypes have been studied in sepsis, but a diagnostic cell subset has yet to be identified. Here, high dimensional mass cytometry was used to reveal for the first time a specific neutrophil signature of sepsis severity that does not overlap with other inflammatory biomarkers, and that distinguishes patients with sepsis from those with non-infectious inflammatory syndrome. Unsupervised analysis of 42-dimesional mass cytometry data characterized previously unappreciated heterogeneity within the CD64+immature neutrophils and revealed two new subsets distinguished by CD123 and PD-L1 expression. These immature neutrophils exhibited diminished activation and phagocytosis functions. The proportion of CD123-expressing neutrophils also correlated with clinical severity. Critically, this study showed that these two new neutrophil subsets were specific to sepsis and detectable by routine flow cytometry using seven markers. The demonstration here that a simple blood test distinguishes sepsis from other inflammatory conditions represents a key biological milestone that can be immediately translated into improvements in patient care.One Sentence SummaryCD123+and/or PD-L1+immature and dysfunctional neutrophil subsets identified by mass cytometry, define an early human blood signature of sepsis
The mevalonate pathway contributes to monoterpene production in peppermint
Authors: Koley Somnath , Grafahrend-Belau Eva , Raorane Manish L. , Junker Björn H. 
Published: May 2020

ABSTRACTPeppermint produces monoterpenes which are of great commercial value in different traditional and modern pharmaceutical and cosmetic industries. In the classical view, monoterpenes are synthesized via the plastidic 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway, while the cytosolic mevalonate (MVA) pathway produces sesquiterpenes. Interactions between both pathways have been documented in several other plant species, however, a quantitative understanding of the metabolic network involved in monoterpene biosynthesis is still lacking. Isotopic tracer analysis, steady state13C metabolic flux analysis (MFA) and pathway inhibition studies were applied in this study to quantify metabolic fluxes of primary and isoprenoid metabolism of peppermint glandular trichomes (GT). Our results offer new insights into peppermint GT metabolism by confirming and quantifying the crosstalk between the two isoprenoid pathways towards monoterpene biosynthesis. In addition, a quantitative description of precursor pathways involved in isoprenoid metabolism is given. While glycolysis was shown to provide precursors for the MVA pathway, the oxidative bypass of glycolysis fueled the MEP pathway, indicating prominent roles for the oxidative branch of the pentose phosphate pathway and RuBisCO. This study reveals the potential of13C-MFA to ascertain previously unquantified metabolic routes of the trichomes and thus advancing insights on metabolic engineering of this organ.
Brachyury controlsCionanotochord fate as part of a feedforward network and not as a unitary master regulator
Authors: Reeves Wendy M. , Shimai Kotaro , Winkley Konner M. , Veeman Michael T. 
Published: May 2020

AbstractThe notochord is a defining feature of the chordates. The transcription factor Brachyury (Bra) is a key regulator of notochord fate but here we show that it is not a unitary master regulator in the model chordateCiona. Ectopic Bra expression only partially reprograms other cell types to a notochord-like transcriptional profile and a subset of notochord-enriched genes are unaffected by CRISPR Bra disruption. We identify Foxa.a and Mnx as potential co-regulators and find that combinatorial cocktails are more effective at reprograming other cell types than Bra alone. We reassess the network relationships between Bra, Foxa.a and other components of the notochord gene regulatory network and find that Foxa.a expression in the notochord is regulated by vegetal FGF signaling. It is a direct activator of Bra expression and has a binding motif that is significantly enriched in the regulatory regions of notochord-enriched genes. These and other results indicate that Bra and Foxa.a act together in a regulatory network dominated by positive feed-forward interactions, with neither being a classically-defined master regulator.
Pupil-linked arousal biases evidence accumulation towards desirable percepts during perceptual decision-making
Authors: Leong Yuan Chang , Dziembaj Roma , D’Esposito Mark 
Published: May 2020

AbstractPeople are biased towards seeing outcomes they are motivated to see. The arousal system coordinates the body’s response to motivationally significant events, and is well positioned to regulate motivational effects on sensory perception. However, it remains unclear whether arousal would enhance or reduce motivational biases. Here we measured pupil dilation as a measure of arousal while participants performed a visual categorization task. We used monetary bonuses to motivate participants to see one category over another. Even though the reward-maximizing strategy was to perform the task accurately, participants were more likely to report seeing the motivationally desirable category. Furthermore, higher arousal levels were associated with making motivationally biased responses. Analyses using computational models suggest that arousal enhanced motivational effects by biasing evidence accumulation in favor of motivationally desirable percepts. These results suggest heightened arousal biases people towards what they want to see and away from an objective representation of the environment.Statement of RelevanceWhen confronted with an event of motivational significance (e.g., an opportunity to earn a huge reward), people often experience a strong arousal response that includes increased sweating, faster heart-rate and larger pupils. Does this arousal response help individuals make more accurate decisions, or does it instead bias and impair decision-making? This work examines the effects of arousal on how people decide what they see when they are motivated to see a particular outcome. We found that heightened arousal, as measured by larger pupils, was associated with a bias in how participants accumulated sensory evidence to make their decisions. As a result, participants became more likely to report seeing an ambiguous visual image as the interpretation they were motivated to see. Our results suggest that arousal biases perceptual judgments towards desirable percepts, and that modulating arousal levels could be a promising approach in reducing motivational biases in decision-making.
NIMBus: a Negative Binomial Regression based Integrative Method for Mutation Burden Analysis
Authors: Zhang Jing , Liu Jason , McGillivray Patrick , Yi Caroline , Lochovsky Lucas , Lee Donghoon , Gerstein Mark 
Published: May 2020

ABSTRACTBackgroundIdentifying frequently mutated regions is a key approach to discover DNA elements influencing cancer progression. However, it is challenging to identify these burdened regions due to mutation rate heterogeneity across the genome and across different individuals. Moreover, it is known that this heterogeneity partially stems from genomic confounding factors, such as replication timing and chromatin organization. The increasing availability of cancer whole genome sequences and functional genomics data from the Encyclopedia of DNA Elements (ENCODE) may help address these issues.ResultsWe developed a Negative binomial regression-based Integrative Method for mutation Burden analysiS (NIMBus). Our approach addresses the over-dispersion of mutation count statistics by (1) using a Gamma-Poisson mixture model to capture the mutation-rate heterogeneity across different individuals and (2) estimating regional background mutation rates by regressing the varying local mutation counts against genomic features extracted from ENCODE.We applied NIMBus to whole-genome cancer sequences from the PanCancer Analysis of Whole Genomes project (PCAWG) and other cohorts. It successfully identified well-known coding and noncoding drivers, such as TP53 and the TERT promoter. To further characterize the burdening of non-coding regions, we used NIMBus to screen transcription factor binding sites in promoter regions that intersect DNase I hypersensitive sites (DHSs). This analysis identified mutational hotspots that potentially disrupt gene regulatory networks in cancer. We also compare this method to other mutation burden analysis methods.ConclusionNIMBus is a powerful tool to identify mutational hotspots. The NIMBus software and results are available as an online resource at github.gersteinlab.org/nimbus.
Lyn controls chemotaxis and motility of CLL cells via phosphorylation of ROR1
Authors: Dave Zankruti , Blanářová Olga Vondálová , Čada Štěpán , Janovská Pavlína , Zezula Nikodém , Běhal Martin , Hanáková Kateřina , Ganji Sri Ranjani , Krejci Pavel , Gömöryová Kristína , Peschelová Helena , Šmída Michael , Zdráhal Zbyněk , Pavlová Šárka , Kotašková Jana , Pospíšilová Šárka , Bryja Vítězslav 
Published: May 2020

AbstractChronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are malignancies characterized by the dependence on B-cell receptor (BCR) signaling and by the high expression of the cell surface receptor ROR1. Both, BCR and ROR1 are therapeutic targets in these diseases and the understanding of their mutual cross talk is thus of direct therapeutic relevance. In this study we analyzed the role of Lyn, a kinase from the Src family, as a mediator of the BCR-ROR1 crosstalk. We confirm the functional interaction between Lyn and ROR1 and demonstrate that Lyn kinase efficiently phosphorylates ROR1 in its kinase domain and aids the recruitment of an E3 ligase c-CBL. The absence of Lyn in Lyn KO Maver-1 cells produced by CRISPR-Cas9 resulted in the increased ROR1 cell surface levels and deregulated migratory properties. Similar correlations between ROR1 surface dynamics, levels of active Lyn and chemotactic properties were confirmed in primary CLL samples. Our data establish Lyn-mediated phosphorylation of ROR1 as a point of crosstalk between BCR and ROR1 signaling pathways.
Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver
Authors: Chembazhi Ullas V. , Bangru Sushant , Hernaez Mikel , Kalsotra Auinash 
Published: May 2020

ABSTRACTThe adult liver has exceptional ability to regenerate, but how it sustains normal metabolic activities during regeneration remains unclear. Here, we use partial hepatectomy (PHx) in tandem with single-cell transcriptomics to track cellular transitions and heterogeneities of ~22,000 liver cells through the initiation, progression, and termination phases of mouse liver regeneration. Our results reveal that following PHx, a subset of hepatocytes transiently reactivates an early-postnatal-like gene expression program to proliferate, while a distinct population of metabolically hyperactive cells appears to compensate for any temporary deficits in liver function. Importantly, through combined analysis of gene regulatory networks and cell-cell interaction maps, we find that regenerating hepatocytes redeploy key developmental gene regulons, which are guided by extensive ligand–receptor mediated signaling events between hepatocytes and non-parenchymal cells. Altogether, our study offers a detailed blueprint of the intercellular crosstalk and cellular reprogramming that balances the metabolic and proliferation requirements of a regenerating liver.
What is an adaptive pattern of brain network coupling for a child? It depends on their environment
Authors: Ellwood-Lowe Monica E. , Whitfield-Gabrieli Susan , Bunge Silvia A. 
Published: May 2020

AbstractPrior research indicates that lower resting-state functional coupling between two brain networks, lateral frontoparietal network (LFPN) and default mode network (DMN), relates to better cognitive test performance. However, most study samples skew towards wealthier individuals—and what is adaptive for one population may not be for another. In a pre-registered study, we analyzed resting-state fMRI from 6839 children ages 9-10 years. For children above poverty, we replicated the prior finding: better cognitive performance correlated with weaker LFPN-DMN coupling. For children in poverty, the slope of the relation was instead positive. This significant interaction related to several features of a child’s environment. Future research should investigate the possibility that leveraging internally guided cognition is a mechanism of resilience for children in poverty. In sum, “optimal” brain function depends in part on the external pressures children face, highlighting the need for more diverse samples in research on the human brain and behavior.
Distinct signalling routes mediates intercellular and intracellular rhizobial infection in Lotus japonicus
Authors: Montiel Jesús , Reid Dugald , Grønbæk Thomas H. , Benfeldt Caroline M. , James Euan K. , Ott Thomas , Ditengou Franck A. , Nadzieja Marcin , Kelly Simon , Stougaard Jens 
Published: May 2020

AbstractRhizobial infection of legume roots during development of nitrogen fixing root nodules occurs either intracellularly though plant derived infection threads traversing the epidermal and cortical cell layers to deliver the bacteria or intercellularly via bacterial entry between epidermal plant cells. Although, around 25% of all legume genera are postulated to be intercellularly infected, the pathways and mechanisms supporting this process has remained virtually unexplored due to lack of genetically amenable legumes that have this infection mode. In this study, we report that the model legume Lotus japonicus is infected intercellularly by Rhizobium sp. IRBG74 and demonstrate that the resources available in Lotus enable insight into the genetic requirements and the fine-tuning of the pathway governing intercellular infection. Inoculation of Lotus mutants shows that Ern1 and RinRK1 are dispensable for intercellular infection in contrast to intracellular infection. Other symbiotic genes, including Nfr5, SymRK, CCaMK, Epr3, Cyclops, Nin, Nsp1, Nsp2, Cbs and Vpy1 are equally important for both entry modes. Comparative RNAseq analysis of roots inoculated with IRBG74 revealed a distinctive transcriptome response compared to intracellular colonization. In particular, a number of cytokinin-related genes were differentially regulated. Corroborating this observation cyp735A and ipt4 cytokinin biosynthesis mutants were significantly affected in their nodulation with IRBG74 while lhk1 cytokinin receptor mutants did not form any nodules. These results indicate that a differential requirement for cytokinin signalling conditions intercellular rhizobial entry and highlight the distinct modalities of the inter- and intra-cellular infection mechanisms.
Elephant Genomes Elucidate Disease Defenses and Other Traits
Authors: Tollis Marc , Ferris Elliott , Campbell Michael S. , Harris Valerie K. , Rupp Shawn M. , Harrison Tara M. , Kiso Wendy K. , Schmitt Dennis L. , Garner Michael M. , Aktipis C. Athena , Maley Carlo C. , Boddy Amy M. , Yandell Mark , Gregg Christopher , Schiffman Joshua D. , Abegglen Lisa M. 
Published: May 2020

AbstractDisease susceptibility and resistance comprise important factors in conservation, particularly in elephants. To determine genetic mechanisms underlying disease resistance and other unique elephant traits, we estimated 862 and 1,017 potential regulatory elements in Asian and African elephants, respectively. These elements are significantly enriched in both species with differentially expressed genes involved in immunity pathways, including tumor-necrosis factor which plays a role in the response to elephant endotheliotropic herpesvirus (EEHV). Population genomics analyses indicate that amplifiedTP53retrogenes are maintained by purifying selection and may contribute to cancer resistance in elephants, including less malignancies in African vs. Asian elephants. Positive selection scans across elephant genomes revealed genes that may control iconic elephant traits such as tusk development, memory, and somatic maintenance. Our study supports the hypothesis that interspecies variation in gene regulation contributes to differential inflammatory responses leading to increased infectious disease and cancer susceptibility in Asian versus African elephants. Genomics can inform functional immunological studies which may improve both conservation for elephants and human therapies.
Adaptive Efficient Coding: A Variational Auto-encoder Approach
Authors: Aridor Guy , Grechi Francesco , Woodford Michael 
Published: May 2020

AbstractWe study a model of neural coding with the structure of a variational auto-encoder. The model posits that the encoding of individual stimulus values is optimally adjusted for a finite training sample of stimuli retained in memory. We demonstrate that this model can rationalize existing experimental evidence on both perceptual discrimination thresholds and neural tuning curve widths in multiple sensory domains. Finally, since our model implies that encoding is optimized for a sample from the environment, it also provides predictions about the adaptation of neural coding as the environmental frequency distribution changes.