bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bipartite functional fractionation within the default network supports disparate forms of internally oriented cognition
Authors: Chiou Rocco , Humphreys Gina F. , Lambon Ralph Matthew A. 
Published: December 2019

AbstractThe ‘default network’ (DN) becomes active when the mind is steered internally towards self-generated thoughts but turns dormant when the mind is directed externally towards the outside world. While hypotheses have been proposed to characterise the association and dissociation between different component areas of the DN, it remains unclear how they coalesce into a unitary network and fractionate into different sub-networks. Here we identified two distinct subsystems within the DN – while both subsystems show common disinterest in externally-oriented visuospatial tasks, their functional profiles differ strikingly according to the preferred contents of thoughts, preferred modes of task requirement, and causative neural dynamics among network nodes. Specifically, one subsystem comprises key nodes of the frontotemporal semantic regions. This network shows moderate dislike to visuospatial tasks, shows proclivity for task-contexts with restraints on thoughts and responses, and prefers thoughts that are focused on other people. By contrast, the other subsystem comprises the cortical midline structure and angular gyri. This network shows strong aversion to visuospatial tasks, favours task-contexts allowing free self-generated thoughts without constraints, and prefers thoughts that are focused on self. Furthermore, causative connectivity reveals that task-contexts systematically alter the dynamics within and between subsystems, suggesting flexible adaption to situational demands. This ‘self/inward vs. others/outward’ separation within the broad DN resembles recent discoveries regarding a dyadic structure within the frontoparietal network that comprises regions controlling memories/thoughts vs. regions controlling sensory-motoric processes, and echoes burgeoning views that the brain is organised with a spectrum-like architecture along gradational changes of ‘inward vs. outward’ preferences.SignificanceRather than construing the default network (DN) as ‘task-negative’ regions that passively react to off-task mind-wandering, researchers have begun to acknowledge the active role of the DN in supporting internally-directed cognition. Here we found a striking dichotomy within the DN in terms of the subsystems’ task-driven functional and connectivity profiles, extending beyond previous inferences using meta-analysis and resting-state fMRI. This dichotomy reflects a local manifestation of a macro-scale gradient representation spanning across the broad cerebral cortex. This cortical gradient increases its representational complexity, from primitive sensory and motoric processing, through lexical-semantic codes for language tasks, to abstract self-generated thoughts in task-free contexts. These findings enable a framework where the separate yet related literatures of semantic cognition and default-mode processes converge.
Ecophysiological traits of a clonal grass in its climate change response
Authors: Kosová Veronika , Hájek Tomáš , Hadincová Věroslava , Munzbergova Zuzana 
Published: December 2019

AbstractBackgroundUnderstanding the ability of species to respond to climate change is essential for prediction of their future distribution. When migration is not adequate, reaction via phenotypic plasticity or genetic adaptation is necessary. While many studies investigated the importance of plasticity and genetic differentiation (plant origin) in growth related traits, we know less about differentiation in ecophysiological traits. In addition, the existing studies looking at plant physiology usually do not estimate the consequences of these physiological changes for species performance.MethodsWe used a clonal grass Festuca rubra originating from localities representing factorially crossed gradients of temperatures and precipitations. We cultivated the plants in growth chambers set to simulate temperature and moisture regime in the four most extreme localities. We measured net photosynthetic rate, chlorophyll fluorescence, SLA, osmotic potential, stomatal density and stomatal length as range of ecophysiological traits and tested their relationship to plant fitness measured as ramet number and biomass.Key resultsWe found strong phenotypic plasticity in photosynthetic traits and genetic differentiation in stomatal traits. In most traits, the effects of temperature interacted with the effects of moisture. The relationship between the ecophysiological and fitness-related traits was significant but weak.ConclusionsEcophysiological response of Festuca rubra to climate change is driven by phenotypic plasticity as well as by genetic differentiation indicating potential ability of the populations to adapt to new climatic conditions. The changes in ecophysiological traits translate into plant fitness even though other unmeasured factors also play an important role in fitness determination. Inclusion of species ecophysiology into studies of species adaptation to climate can still increase our ability to understand how species may respond to novel conditions.
On deleterious mutations in perennials: inbreeding depression, mutation load and life-history evolution
Authors: Lesaffre Thomas , Billiard Sylvain 
Published: December 2019

ABSTRACTIn Angiosperms, perennials typically present much higher levels of inbreeding depression than annuals. One hypothesis to explain this pattern stems from the observation that inbreeding depression is expressed across multiple life stages in Angiosperms. It posits that increased inbreeding depression in more long-lived species could be explained by differences in the way mutations affect fitness in these species, through the life stages at which they are expressed. In this study, we investigate this hypothesis. We combine a physiological growth model and multilocus population genetics approaches to describe a full genotype-to-phenotype-to-fitness map. We study the behaviour of mutations affecting growth or survival, and explore their consequences in terms of inbreeding depression and mutation load. Although our results only agree with empirical data within a narrow range of conditions, we argue that they may point us towards the type of traits susceptible to underlie inbreeding depression in long-lived species, that is traits under sufficiently strong selection, on which selection decreases sharply as life expectancy increases. Then, we study the role deleterious mutations maintained at mutation-selection balance may play in the coevolution between growth and survival strategies.Description of the manuscriptThe main text of the manuscript, excluding captions and headers, is 5712 words long. There are 4 figures in the main text, numbered from 1 to 4. In the present file, pages 1 to 33 correspond to the main text (including title page, abstract and litterature cited), while the remaining pages (33 to 72) correspond to appendices. There are 5 sections in Appendices, which are all available at the end of the manuscript file. There are 12 figures in Appendices, numbered from S1 to S12.
Interdependent regulation of stereotyped and stochastic photoreceptor fates in the fly eye
Authors: Miller Adam C. , Urban Elizabeth , Lyons Eric L. , Herman Tory G. , Johnston Robert J. 
Published: December 2019

AbstractDiversification of neuronal subtypes often requires stochastic gene regulatory mechanisms. How stochastically expressed transcription factors interact with other regulators in gene networks to specify cell fates is poorly understood. The random mosaic of color-detecting R7 photoreceptor subtypes inDrosophilais controlled by the stochastic on/off expression of the transcription factor Spineless (Ss). In SsONR7s, Ss induces expression of Rhodopsin 4 (Rh4), whereas in SsOFFR7s, the absence of Ss allows expression of Rhodopsin 3 (Rh3). Here, we find that the transcription factor Runt, which is initially expressed in all R7s, activates expression of Spineless in a random subset of R7s. Later, as R7s develop, Ss negatively feeds back onto Runt to prevent repression of Rh4 and ensure proper fate specification. Together, stereotyped and stochastic regulatory inputs are integrated into feedforward and feedback mechanisms to control cell fate.
Widespread use of the “ascidian” mitochondrial genetic code in tunicates
Authors: Pichon Julien , Luscombe Nicholas M. , Plessy Charles 
Published: December 2019

AbstractBackgroundAscidians, a tunicate class, use a mitochondrial genetic code that is distinct from vertebrates and other invertebrates. Though it has been used to translate the coding sequences from other tunicate species on a case-by-case basis, it is has not been investigated whether this can be done systematically. This is an important because a) some tunicate mitochondrial sequences are currently translated with the invertebrate code by repositories such as NCBI’s GenBank, and b) uncertainties about the genetic code to use can complicate or introduce errors in phylogenetic studies based on translated mitochondrial protein sequences.MethodsWe collected publicly available nucleotide sequences for non-ascidian tunicates including appendicularians such asOikopleura dioica, translated them using the ascidian mitochondrial code, and built multiple sequence alignments covering all tunicate classes.ResultsAll tunicates studied here appear to translate AGR codons to glycine instead of serine (invertebrates) or as a stop codon (vertebrates), as initially described in ascidians. Among Oikopleuridae, we suggest further possible changes in the use of the ATA (Ile → Met) and TGA (Trp → Arg) codons.ConclusionsWe recommend using the ascidian mitochondrial code in automatic translation pipelines of mitochondrial sequences for all tunicates. Further investigation is required for additional species-specific differences.
Moxifloxacin efficacy againstMycobacterium abscessus in vivousing zebrafish model
Authors: Nie Wenjuan , Gao Shan , Teng Tianlu , Zhou Wenqiang , Shang Yuanyuan , Jing Wei , Shi Wenhui , Wang Qingfeng , Huang Xuerui , Cai Baoyun , Wang Jun , Wang Jing , Guo Ru , Ge Qiping , Nie Lihui , Han Xiqin , Du Yadong , Chu Naihui 
Published: December 2019

AbstractMoxifloxacin (MFX) showed good activityin vitroagainstMycobacterium abscessus(M. abscessus) and was suggested as one of the antibiotic regimens for adults withM. abscessusdisease. However, some other studies showed that MFX showed less or none activity againstM. abscessus. In our study we aim to evaluate MFX activity againstM. abscessususing zebrafish (ZF) modelin vivo. MIC of each drugs were determined by broth microdilution method.M. abscessuslabeled by CM-DiI, were micro-injected into ZF. Survival curves were determined by recording dead ZF every day. After 4 days of incubation ZF were lysed. Colony-forming unit (CFU) were enumerated and results are expressed as mean log10 CFU per ZF. Bacteria dissemination and fluorescence intensity in ZF were observed and analyzed. Inhibition rate was also calculated. In our study MFX showed good activityin vitro. Butin vivoMFX showed limited restriction toM. abscessus. The association between increased survival and high dose of MFX is not significant. Same results were observed in bacterial fluorescence intensity and inhibition rates, with no significant difference when compared with no drug group (P > 0.05). However, significant difference was observed in azithromycin (AZM) group. MFX showed limited efficacy onMycobacterium abscessus in vivousing ZF model. MFX’s activityin vivoneed to be confirmed.
Inference and visualization of phenome-wide causal relationships using genetic data: an application to dental caries and periodontitis
Authors: Haworth Simon , Kho Pik Fang , Holgerson Pernilla Lif , Hwang Liang-Dar , Timpson Nicholas J. , Rentería Miguel E. , Johansson Ingegerd , Cuellar-Partida Gabriel 
Published: December 2019

AbstractBackgroundHypothesis-free Mendelian randomization studies provide a way to assess the causal relevance of a trait across the human phenome but can be limited by statistical power or complicated by horizontal pleiotropy. The recently described latent causal variable (LCV) approach provides an alternative method for causal inference which might be useful in hypothesis-free experiments.MethodsWe developed an automated pipeline for phenome-wide tests using the LCV approach including steps to estimate partial genetic causality, filter to a meaningful set of estimates, apply correction for multiple testing and then present the findings in a graphical summary termed a causal architecture plot. We apply this process to body mass index and lipid traits as exemplars of traits where there is strong prior expectation for causal effects and dental caries and periodontitis as exemplars of traits where there is a need for causal inference.ResultsThe results for lipids and BMI suggest that these traits are best viewed as creating consequences on a multitude of traits and conditions, thus providing additional evidence that supports viewing these traits as targets for interventions to improve health. On the other hand, caries and periodontitis are best viewed as a downstream consequence of other traits and diseases rather than a cause of ill health.ConclusionsThe automated process is available as part of the MASSIVE pipeline from the Complex-Traits Genetics Virtual Lab (https://vl.genoma.io) and results are available in (https://view.genoma.io). We propose causal architecture plots based on phenome-wide partial genetic causality estimates as a way visualizing the overall causal map of the human phenome.Key messagesThe latent causal variable approach uses summary statistics from genome-wide association studies to estimate a parameter termedgenetic causality proportion.Systematic estimation of genetic causality proportion for many pairs of traits provides an alternative method for phenome-wide causal inference with some theoretical and practical advantages compared to phenome-wide Mendelian randomization.Using this approach, we confirm that lipid traits are an upstream risk factor for other traits and diseases, and we identify that dental diseases are predominantly a downstream consequence of other traits rather than a cause of poor systemic health.The method assumes no bidirectional causality and no confounding by environmental correlates of genotypes, so care is needed when these assumptions are not met.We developed an automated and accessible pipeline for estimating phenome-wide causal relationships and generating interactive visual summaries.
Biophysical analysis ofPlasmodium falciparumHsp70-Hsp90 organizing protein (PfHop) reveals a monomer that is characterised by folded segments connected by flexible linkers
Authors: Makumire Stanley , Zininga Tawanda , Vahokoski Juha , Kursula Inari , Shonhai Addmore 
Published: December 2019

AbstractPlasmodium falciparumcauses the most lethal form of malaria. The cooperation of heat shock protein (Hsp) 70 and 90 is important for folding of a select number of cellular proteins that are crucial for cyto-protection and development of the parasites. Hsp70 and Hsp90 are brought into a functional complex that allows substrate exchange by stress inducible protein 1 (STI1), also known as Hsp70-Hsp90 organizing protein (Hop).P. falciparumHop (PfHop) co-localises and occurs in complex with the parasite cytosolic chaperones, PfHsp70-1 and PfHsp90. Here, we characterised the structure of recombinant PfHop using synchrotron radiation circular dichroism (SRCD) and small-angle X-ray scattering. Structurally, PfHop is a monomeric, elongated but folded protein, in agreement with its predicted TPR domain structure. Using SRCD, we established that PfHop is unstable at temperatures higher than 40 °C. This suggests that PfHop is less stable at elevated temperatures compared to its functional partner, PfHsp70-1, that is reportedly stable at temperatures as high as 80 °C. These findings contribute towards our understanding of the role of the Hop-mediated functional partnership between Hsp70 and Hsp90.
A Homogeneous SIRPα-CD47 Cell-Based, Ligand-Binding Assay: Utility for Small Molecule Drug Development in Immuno-oncology
Authors: Burgess Teresa L. , Amason Joshua D. , Rubin Jeffrey S. , Duveau Damien Y. , Lamy Laurence , Roberts David D. , Farrell Catherine L. , Inglese James , Thomas Craig J. , Miller Thomas W. 
Published: December 2019

ABSTRACTCD47 is an immune checkpoint protein that downregulates both the innate and adaptive anti-tumor immune response via its counter receptor SIRPα. Biologics, including humanized CD47 monoclonal antibodies and decoy SIRPα receptors, that block the SIRPα-CD47 interaction, are currently being developed as cancer immunotherapy agents. However, adverse side effects and limited penetration of tumor tissue associated with their structure and large size may impede their clinical application. We recently developed a quantitative high throughput screening assay platform to identify small molecules that disrupt the binding of SIRPα and CD47 as an alternative approach to these protein-based therapeutics. Here, we report on the development and optimization of a cell-based binding assay to validate active small molecules from our biochemical screening effort. This assay has a low volume, high capacity homogenous format that relies on laser scanning cytometry (LSC) and associated techniques to enhance signal to noise measurement of cell surface binding. The LSC assay is specific, concentration dependent, and validated for the two major human SIRPα variants (V1 and V2), with results that parallel those of our biochemical data as well as published studies. The LSC assay also confirmed published studies, such as the inhibition of amino-terminal pyroglutamate formation in CD47 disrupts SIRPα binding. SIRPα-CD47 interaction could be quantitatively measured in live and fixed tumor cells. Use of fixed cells reduces the burden of cell maintenance and provides stable cell standards to control for inter- and intra-assay variations. We also demonstrate the utility of the assay to characterize the activity of the first reported small molecule antagonists of the SIRPα-CD47 interaction. This assay will support the screening of thousands of compounds to identify or validate active small molecules as hits, develop structure activity relationships and assist in the optimization of hits to leads by a typical iterative medicinal chemistry campaign.
An illustration of reproducibility in neuroscience research in the absence of selective reporting
Authors: Kong Xiang-Zhen ,   ENIGMA Laterality Working Group, Francks Clyde 
Published: December 2019

AbstractThe problem of poor reproducibility of scientific findings has received much attention over recent years, in a variety of fields including psychology and neuroscience. The problem has been partly attributed to publication bias and unwanted practices such as p-hacking. Low statistical power in individual studies is also understood to be an important factor. In a recent multi-site collaborative study, we mapped brain anatomical left-right asymmetries for regional measures of surface area and cortical thickness, in 99 MRI datasets from around the world, for a total of over 17,000 participants. In the present study, we re-visited these hemispheric effects from the perspective of reproducibility. Within each dataset, we considered that an effect had been reproduced when it matched the meta-analytic effect from the 98 other datasets, in terms of effect direction and uncorrected significance at p<0.05. In this sense, the results within each dataset were viewed as coming from separate studies in an ‘ideal publishing environment’, i.e. free from selective reporting and p hacking. We found an average reproducibility rate per dataset, over all effects, of 63.2% (SD = 22.9%, min = 22.2%, max = 97.0%). As expected, reproducibility was higher for larger effects and in larger datasets. There is clearly substantial room to improve reproducibility in brain MRI research through increasing statistical power. These findings constitute an empirical illustration of reproducibility in the absence of publication bias or p hacking, when assessing realistic biological effects in heterogeneous neuroscience data, and given typically-used sample sizes.
Vein Patterning by Tissue-Specific Auxin Transport
Authors: Govindaraju Priyanka , Verna Carla , Zhu Tongbo , Scarpella Enrico 
Published: December 2019

AbstractUnlike in animals, in plants vein patterning does not rely on direct cell-cell interaction and cell migration; instead, it depends on the transport of the plant signal auxin, which in turn depends on the activity of the PIN-FORMED1 (PIN1) auxin transporter. The current hypotheses of vein patterning by auxin transport propose that in the epidermis of the developing leaf PIN1-mediated auxin transport converges to peaks of auxin level. From those convergence points of epidermal PIN1 polarity, auxin would be transported in the inner tissues where it would give rise to major veins. Here we tested predictions of this hypothesis and found them unsupported: epidermal PIN1 expression is neither required nor sufficient for auxin-transport-dependent vein patterning, whereas inner-tissue PIN1 expression turns out to be both required and sufficient for auxin-transport-dependent vein patterning. Our results refute all vein patterning hypotheses based on auxin transport from the epidermis and suggest alternatives for future tests.
Rac1/ROCK-driven membrane dynamics promote Natural Killer cell cytotoxicity via necroptosis
Authors: Zhu Yanting , Xie Jun , Shi Jue 
Published: December 2019

AbstractNatural Killer (NK) cells play an important role in cancer immunosurveillance and therapy. However, the target selectivity of NK cell activity is still poorly understood. Here we used live-cell reporters to unravel differential epithelial cancer target killing by primary human NK cells. We found highly variable fraction of killing by distinct NK cell cytotoxic modes that was not determined by NK ligand expression. Rather, epithelial plasma membrane dynamics driven by ROCK-mediated blebs and/or Rac1-mediated lamellipodia promoted necrotic mode in preference to apoptotic mode of killing. Inhibition of granzyme and key necroptosis regulators RIP1, RIP3 and MLKL significantly attenuated necrotic killing, revealing a novel NK cytotoxic pathway by granzyme-induced necroptosis that conferred target selectivity. Our results not only elucidate a new NK cell effector mechanism but also suggest tissue microenvironment and oncogenic signaling pathways that promote membrane dynamics, e.g., Rac1 and Rho/ROCK, could be exploited to enhance proinflammatory NK cell killing.