bluuebunny/crossref_metadata_2025 huggingface dataset:
MINDFUL: A Method to Identify Novel and Diverse Signals with Fast, Unsupervised Learning
Authors: Parulekar Mallika , Narlikar Leelavati
Published: October 2019

With rapid advances in experimental methods that map transcription start sites (TSSs) at a high resolution, there is a need to characterize the sequence diversity of TSS neighborhoods. Most current techniques scan for previously discovered elements, such as the TATA box, the INR motif, CpG islands, etc. to categorize promoters into different classes. Reliance on such elements hinders the discovery of novel elements. On the other hand, methods that use standard motif discovery to discover de novo promoter elements are also limited by the fact that a motif is picked up only if it is over-represented in the dataset. An element that appears only in a small set of promoters can thus be missed. We previously developed a clustering-based approach that uses no prior knowledge of elements to solve this problem [1]. That method uses Gibbs sampling to learn the model parameters, but is untenable on large datasets. Here we propose a new, fast method called MINDFUL, that uses a greedy k-means-like approach to cluster promoters aligned by TSSs into diverse classes, while also learning the optimal value of k. It is general enough to be used for any data that has categorical variables, and is not restricted to DNA.
Prefrontal cortex exhibits multi-dimensional dynamic encoding during decision-making
Authors: Aoi Mikio C. , Mante Valerio , Pillow Jonathan W.
Published: October 2019

Recent work has suggested that prefrontal cortex (PFC) plays a key role in context-dependent perceptual decision-making. Here we investigate population-level coding of decision variables in monkey PFC using a new method for identifying task-relevant dimensions of neural activity. Our analyses reveal that, in contrast to one-dimensional attractor models, PFC has a multi-dimensional code for decisions, context, and relevant as well as irrelevant sensory information. Moreover, these representations evolve in time, with an early linear accumulation phase followed by a phase with rotational dynamics. We identify the dimensions of neural activity associated with these phases, and show that they are not the product of distinct populations, but of a single population with broad tuning characteristics. Finally, we use model-based decoding to show that the transition from linear to rotational dynamics coincides with a sustained plateau in decoding accuracy, revealing that rotational dynamics in PFC preserve sensory as well as choice information for the duration of the stimulus integration period.
Centromere scission drives chromosome shuffling and reproductive isolation
Authors: Yadav Vikas , Sun Sheng , Coelho Marco A. , Heitman Joseph
Published: October 2019

A fundamental characteristic of eukaryotic organisms is the generation of genetic variation via sexual reproduction. Conversely, significant large-scale genome structure variations could hamper sexual reproduction, causing reproductive isolation and promote speciation. The underlying processes behind large-scale genome rearrangements are not well understood and include chromosome translocations involving centromeres. Recent genomic studies in theCryptococcusspecies complex revealed that chromosome translocations generated via centromere recombination have reshaped the genomes of different species. In this study, multiple DNA double-strand breaks (DSBs) were generated via the CRISPR/Cas9 system at centromere-specific retrotransposons in the human fungal pathogenCryptococcus neoformans. The resulting DSBs were repaired in a complex manner, leading to the formation of multiple inter-chromosomal rearrangements and new telomeres, similar to chromothripsis-like events. The newly generated strains harboring chromosome translocations exhibited normal vegetative growth but failed to undergo successful sexual reproduction with the parental wild-type strain. One of these strains failed to produce any spores, while another produced ∼3% viable progeny. The germinated progeny exhibited aneuploidy for multiple chromosomes and showed improved fertility with both parents. All chromosome translocation events were accompanied without any detectable change in gene sequences and thus, suggest that chromosomal translocations alone may play an underappreciated role in the onset of reproductive isolation and speciation.
Decomposing Simon task BOLD activation using a drift-diffusion model framework
Authors: McIntosh James R , Sajda Paul
Published: October 2019

The Simon effect is observed in spatial conflict tasks where the response time of subjects is increased if stimuli are presented in a lateralized manner so that they are incongruous with the response information that they represent symbolically. Previous studies have used fMRI to investigate this phenomenon, and while some have been driven by considerations of an underlying model, none have attempted to directly tie model and BOLD response together. It is likely that this is due to Simon models having been predominantly descriptive of the phenomenon rather than capturing the full spectrum of behavior at the level of individual subjects. Sequential sampling models (SSM) which capture full response distributions for correct and incorrect responses have recently been extended to capture conflict tasks.

In this study we use our freely available framework for fitting and comparing non-standard SSM to fit the Simon effect SSM (SE-SSM) to behavioral data. This model extension includes specific estimates of automatic response bias and conflict monitoring based deployment of attention to individual subject behavioral data. We apply this approach in order to investigate whether our task specific model parameters have a correlate in BOLD response. Under the assumption that the SE-SSM reflects aspects of neural processing in this task, we go on to examine the BOLD correlates with the within trial expected decision-variable.

We find that the SE-SSM captures the behavioral data and that our two conflict specific model parameters have clear across subject BOLD correlates, while other model parameters, as well as more standard behavioral measures do not. We also find that examining BOLD in terms of the expected decision-variable leads to a specific pattern of activation that would not be otherwise possible to extract.
Network dynamics underlying OFF responses in the auditory cortex
Authors: Bondanelli Giulio , Deneux Thomas , Bathellier Brice , Ostojic Srdjan
Published: October 2019

Across sensory systems, complex spatio-temporal patterns of neural activity arise following the onset (ON) and offset (OFF) of stimuli. While ON responses have been widely studied, the mechanisms generating OFF responses in cortical areas have so far not been fully elucidated. We examine here the hypothesis that OFF responses are single-cell signatures of recurrent interactions at the network level. To test this hypothesis, we performed population analyses of two-photon calcium recordings in the auditory cortex of awake mice listening to auditory stimuli, and compared linear single-cell and network models. While the single-cell model explained some prominent features of the data, it could not capture the structure across stimuli and trials. In contrast, the network model accounted for the low-dimensional organisation of population responses and their global structure across stimuli, where distinct stimuli activated mostly orthogonal dimensions in the neural state-space.
Bayesian Evaluation of Temporal Signal in Measurably Evolving Populations
Authors: Duchene Sebastian , Lemey Philippe , Stadler Tanja , Ho Simon YW , Duchene David A , Dhanasekaran Vijaykrishna , Baele Guy
Published: October 2019

Phylogenetic methods can use the sampling times of molecular sequence data to calibrate the molecular clock, enabling the estimation of evolutionary rates and timescales for rapidly evolving pathogens and data sets containing ancient DNA samples. A key aspect of such calibrations is whether a sufficient amount of molecular evolution has occurred over the sampling time window, that is, whether the data can be treated as having come from a measurably evolving population. Here we investigate the performance of a fully Bayesian evaluation of temporal signal (BETS) in sequence data. The method involves comparing the fit to the data of two models: a model in which the data are accompanied by the actual (heterochronous) sampling times, and a model in which the samples are constrained to be contemporaneous (isochronous). We conducted simulations under a wide range of conditions to demonstrate that BETS accurately classifies data sets according to whether they contain temporal signal or not, even when there is substantial among-lineage rate variation. We explore the behaviour of this classification in analyses of five empirical data sets: modern samples ofA/H1N1 influenza virus, the bacteriumBordetella pertussis, coronaviruses from mammalian hosts, ancient DNA fromHepatitis B virusand mitochondrial genomes of dog species. Our results indicate that BETS is an effective alternative to other tests of temporal signal. In particular, this method has the key advantage of allowing a coherent assessment of the entire model, including the molecular clock and tree prior which are essential aspects of Bayesian phylodynamic analyses.
DNA methylation in the APOE gene: its link with Alzheimer’s and cardiovascular health
Authors: Mur Jure , McCartney Daniel L. , Walker Rosie M. , Campbell Archie , Bermingham Mairead L. , Morris Stewart W. , Porteous David J. , McIntosh Andrew M. , Deary Ian J. , Evans Kathryn L. , Marioni Riccardo E.
Published: October 2019

Genetic variation in the apolipoprotein E (APOE) gene is associated with Alzheimer’s disease (AD) and risk factors for cardiovascular disease (CVD). DNA methylation at APOE has been linked to altered cognition and AD. It is unclear if epigenetic marks could be used for predicting future disease. We assessed blood-based DNA methylation at 13 CpGs in the APOE gene in 5828 participants from the Generation Scotland (GS) cohort. Using linear regression, we examined the relationship between APOE methylation, cognition, cholesterol, and the risks for AD and CVD. DNA methylation at two CpGs was associated with the ratio of total-to-HDL cholesterol, but not with cognition, or the risks of AD or CVD. APOE methylation could be involved in the levels of blood cholesterol, but there is no evidence for the utility of APOE methylation as a biomarker for predicting AD or CVD.
Spontaneous Traveling Cortical Waves Gate Perception in Awake Behaving Primates
Authors: Davis Zachary W. , Muller Lyle , Trujillo Julio-Martinez , Sejnowski Terrence , Reynolds John H.
Published: October 2019

Perceptual sensitivity varies from moment to moment. One potential source of variability is spontaneous fluctuations in cortical activity that can travel as a wave. Spontaneous traveling waves have been reported during anesthesia, but questioned as to whether they are relevant to waking cortical function. Using newly developed analytic techniques, we find spontaneous waves of activity in extrastriate visual cortex of awake marmosets (Callithrix jacchus). In monkeys trained to detect faint visual targets, the timing and position of spontaneous traveling waves, prior to target onset, predict the magnitude of evoked activity and the likelihood of detection. In contrast, spatially disorganized fluctuations of neural activity are much less predictive. These results reveal an important role for spontaneous traveling waves in sensory processing through modulating neural and perceptual sensitivity.

One Sentence Summary

Fluctuations in cortical activity often travel as waves, shape incoming sensory information, and affect conscious perception.
Identifying robust strategies for assisted migration in a competitive stochastic metacommunity
Authors: Backus Gregory A. , Baskett Marissa L.
Published: October 2019

Assisted migration is the translocation of species beyond their historical range to locations that are expected to be more suitable under future climate change. However, a relocated population might fail to establish within its donor community if there is high uncertainty in decision making, climate, and interactions with the recipient ecological community. To quantify the benefit to persistence and risk of establishment failure of assisted migration under different management scenarios, we built a stochastic metacommunity model to simulate several species reproducing, dispersing, and competing on a temperature gradient as temperature increases over time. Without assisted migration, the species in our model were vulnerable to climate change if they had low population sizes, short dispersal, and strong poleword competition. When relocating species that exemplified these traits, assisted migration increased the long-term persistence of the species most when relocating a fraction of the donor population, even if the remaining population was very small or rapidly declining. This suggests that leaving behind a fraction of the population could be a robust approach, allowing managers to repeat assisted migration in case they move the species at the wrong place and wrong time, especially when it is difficult to identify a species’ optimal climate. We found that assisted migration was most beneficial to species with low dispersal ability and least beneficial to species with narrow thermal tolerances, for which assisted migration increased extinction risk on average. Lastly, while relocation did not affect the persistence of non-target species in our simple competitive model, researchers will need to consider a more complete set of community interactions to comprehensively understand invasion potential.
Physical activity improves sarcopenia in a murine model by enhancing the proliferative potential of muscle stem cells, oxidative capacity of mitochondrial enzymes and expression of Sestrins
Authors: Anwar Masroor , Mallick Saumya Ranjan , Paliwal Daizy , Sekhar Shashank , Panda S.K. , Dey Sharmistha , Dey A.B.
Published: October 2019

Sarcopenia is a major health issue in old age. Underlying molecular mechanisms in its genesis remain unclear and optimal animal models are yet to be established. A novel animal model was developed to identify structural and functional changes in skeletal muscles from sarcopenia. The influence of physical activity on animals of the sarcopenic model with respect to the expression of anti-oxidant proteins, mitochondrial oxidative capacity, and effect on muscle stem cells (MuSCs), were assessed. Male C57Bl/6 mice of different age groups were recruited: Y-Cntrl (young-control), A-Cntrl (aged-control), SAR-model and SAR-INT. SAR-model group was kept in a retrofitted confined cage and was fed with customized protein-restricted diet (14% protein), which is considered as a sarcopenic featured model. SAR-INT served as the intervention group. Three parameters, namely, muscle mass, grip strength, and physical endurance, were used to confirm the sarcopenic state. All physical parameters deteriorated most in SAR-model and it improved in the SAR-INT group. The impact of physical activity on the SAR-INT group was also evidenced by the improved proliferative potential of MuSCs determined by flow cytometric analysis. Compared with the SAR-model, the SAR-INT exhibited significant improvement in the oxidative capacity of mitochondrial enzymes and increased expression of anti-oxidant proteins, sestrins. In conclusion, physical activity improved physical parameters, MuSC proliferative potential, mitochondrial enzyme oxidative capacity and sestrin expression in sarcopenic animals. Hence, SAR-model in mice can serve as a novel sarcopenic model, physical activity provides scope for improvement in sarcopenic population and sestrin molecule can have a potential implication on sarcopenia.
Dual stochasticity in the cortex as a biologically plausible learning with the most efficient coding
Authors: Teramae Jun-nosuke
Published: October 2019

Neurons and synapses in the cerebral cortex behave stochastically. The advantages of such stochastic properties have been proposed in several works, but the relationship and synergy between the stochasticities of neurons and synapses remain largely unexplored. Here, we show that these stochastic features can be inseparably integrated into a simple framework that provides a practical and biologically plausible learning algorithm that consistently accounts for various experimental results, including the most efficient power-law coding of the cortex. The derived algorithm overcomes many of the limitations of conventional learning algorithms of neural networks. As an experimentally testable prediction, we derived the slow retrograde modulation of the excitability of neurons from this algorithm. Because of the simplicity and flexibility of this algorithm, we anticipate that it will be useful in the development of neuromorphic devices and scalable AI chips, and that it will help bridge the gap between neuroscience and machine learning.
Novel tau filament fold in corticobasal degeneration, a four-repeat tauopathy
Authors: Zhang Wenjuan , Tarutani Airi , Newell Kathy L. , Murzin Alexey G. , Matsubara Tomoyasu , Falcon Benjamin , Vidal Ruben , Garringer Holly J. , Shi Yang , Ikeuchi Takeshi , Murayama Shigeo , Ghetti Bernardino , Hasegawa Masato , Goedert Michel , Scheres Sjors H.W.
Published: October 2019

Corticobasal degeneration (CBD) is a neurodegenerative tauopathy that is characterised by motor and cognitive disturbances (1–3). A higher frequency of the H1 haplotype of MAPT, the tau gene, is present in cases of CBD than in controls (4, 5) and genome-wide association studies have identified additional risk factors (6). By histology, astrocytic plaques are diagnostic of CBD (7, 8), as are detergent-insoluble tau fragments of 37 kDa by SDS-PAGE (9). Like progressive supranuclear palsy (PSP), globular glial tauopathy (GGT) and argyrophilic grain disease (AGD) (10), CBD is characterised by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats (4R) (11–15). This distinguishes 4R tauopathies from Pick’s disease, filaments of which are made of three-repeat (3R) tau isoforms, and from Alzheimer’s disease and chronic traumatic encephalopathy (CTE), where both 3R and 4R tau isoforms are found in the filaments (16). Here we report the structures of tau filaments extracted from the brains of three individuals with CBD using electron cryo-microscopy (cryo-EM). They were identical between cases, but distinct from those of Alzheimer’s disease, Pick’s disease and CTE (17–19). The core of CBD filaments comprises residues K274-E380 of tau, spanning the last residue of R1, the whole of R2, R3 and R4, as well as 12 amino acids after R4. It adopts a novel four-layered fold, which encloses a large non-proteinaceous density. The latter is surrounded by the side chains of lysine residues 290 and 294 from R2 and 370 from the sequence after R4. CBD is the first 4R tauopathy with filaments of known structure.
Deconstructing the individual steps of vertebrate translation initiation
Authors: Giess Adam , Torres Cleuren Yamila N. , Tjeldnes Håkon , Krause Maximilian , Bizuayehu Teshome Tilahun , Hiensch Senna , Okon Aniekan , Wagner Carston R. , Valen Eivind
Published: October 2019

Translation initiation is often attributed as the rate determining step of eukaryotic protein synthesis and key to gene expression control1. Despite this centrality the series of steps involved in this process are poorly understood2,3. Here we capture the transcriptome-wide occupancy of ribosomes across all stages of translation initiation, enabling us to characterize the transcriptome-wide dynamics of ribosome recruitment to mRNAs, scanning across 5’ UTRs and stop codon recognition, in a higher eukaryote. We provide mechanistic evidence for ribosomes attaching to the mRNA by threading the mRNA through the small subunit. Moreover, we identify features regulating the recruitment and processivity of scanning ribosomes, redefine optimal initiation contexts and demonstrate endoplasmic reticulum specific regulation of initiation. Our approach enables deconvoluting translation initiation into separate stages and identifying the regulators at each step.
Evolutionary relationships amongMassosporaspp. (Entomophthorales), obligate pathogens of cicadas
Authors: Macias Angie M. , Geiser David M. , Stajich Jason E. , Łukasik Piotr , Veloso Claudio , Bublitz DeAnna C. , Berger Matthew C. , Boyce Greg R. , Hodge Kathie , Kasson Matt T.
Published: October 2019

The fungal genusMassospora(Zoopagomycota: Entomophthorales) includes more than a dozen obligate, sexually transmissible pathogenic species that infect cicadas (Hemiptera) worldwide. At least two species are known to produce psychoactive compounds during infection, which has garnered considerable interest for this enigmatic genus. As with many Entomophthorales, the evolutionary relationships and host associations ofMassosporaspp. are not well understood. The acquisition ofM. diceroproctaefrom Arizona,M. tettigatisfrom Chile, andM. platypediaefrom California and Colorado provided an opportunity to conduct molecular phylogenetic analyses and morphological studies to investigate if these fungi represent a monophyletic group and delimit species boundaries. In a three-locus phylogenetic analysis including the D1–D2 domains of the nuclear 28S rRNA gene (28S),elongation factor 1 alpha-like(EFL), andbeta-tubulin(BTUB),Massosporawas resolved in a strongly supported monophyletic group containing four well-supported genealogically exclusive lineages, based on two of three methods of phylogenetic inference. There was incongruence among the single-gene trees: two methods of phylogenetic inference recovered trees with either the same topology as the 3-gene concatenated tree (EFL), or a basal polytomy (28S, BTUB).Massospora levisporaandM. platypediaeisolates formed a single lineage in all analyses and are synonymized here asM. levispora.Massospora diceroproctaewas sister toM. cicadinain all three single-gene trees and on an extremely long branch relative to the otherMassospora, and even the outgroup taxa, which may reflect an accelerated rate of molecular evolution and/or incomplete taxa sampling. The results of the morphological study presented here indicate that spore measurements may not be phylogenetically or diagnostically informative. Despite recent advances in understanding the ecology ofMassospora, much about its host range and diversity remains unexplored. The emerging phylogenetic framework can provide a foundation for exploring co-evolutionary relationships with cicada hosts and the evolution of behavior-altering compounds.
Migraine aura, a predictor of near-death experiences in a crowdsourced study
Authors: Kondziella Daniel , Olsen Markus Harboe , Lemale Coline L. , Dreier Jens P.
Published: October 2019

Background

Near-death experiences (NDE) occur with imminent death and in situations of stress and danger but are poorly understood. Evidence suggests that NDE are associated with rapid eye movement (REM) sleep intrusion, a feature of narcolepsy. Previous studies further found REM abnormalities and an increased frequency of dream-enacting behavior in migraine patients, as well as an association between migraine with aura and narcolepsy. We therefore investigated if NDE are more common in people with migraine aura.

Methods

We recruited 1037 laypeople from 35 countries via a crowdsourcing platform. Reports were validated using the Greyson NDE Scale.

Results

Eighty-one of 1037 participants had NDE (7.8%; CI 6.3-9.7%). There were no significant associations between NDE and age (p>0.6, t-test independent samples) or gender (p>0.9, chi-square test). The only significant association was between NDE and migraine aura: Forty-eight (6.1%) of 783 subjects without migraine aura and 33 (13.0%) of 254 subjects with migraine aura had NDE (p<0.001, chi-square test, odds ratio (OR) = 2.29). In multiple logistic regression analysis, migraine aura remained significant after adjustment for age (p≤0.001, OR 2.31), gender (p<0.001, OR 2.33), or both (p<0.001, OR 2.33).

Conclusions

In our sample, migraine aura was a predictor of NDE. This indirectly supports the association between NDE and REM intrusion and might have implications for the understanding of NDE, because a variant of spreading depolarization (SD), terminal SD, occurs in humans at the end of life, while a short-lasting variant of SD is considered the pathophysiological correlate of migraine aura.
Towards an information theory of quantitative genetics
Authors: Galas David J. , Kunert-Graf James , Uechi Lisa , Sakhanenko Nikita A.
Published: October 2019

Quantitative genetics has evolved dramatically in the past century, and the proliferation of genetic data, in quantity as well as type, enables the characterization of complex interactions and mechanisms beyond the scope of its theoretical foundations. In this paper, we argue that revisiting the framework for analysis is important and we begin to lay the foundations of an alternative formulation of quantitative genetics based on information theory. Information theory can provide sensitive and unbiased measures of statistical dependencies among variables, and it provides a natural mathematical language for an alternative view of quantitative genetics. In previous work we examined the information content of discrete functions and applied this approach and methods to the analysis of genetic data. In this paper we present a framework built around a set of relationships that both unifies the information measures for the discrete functions and uses them to express key quantitative genetic relationships. Information theory measures of variable interdependency are used to identify significant interactions, and a general approach is described for inferring functional relationships within genotype and phenotype data. We present information-based measures of the genetic quantities: penetrance, heritability and degrees of statistical epistasis. Our scope here includes the consideration of both two- and three-variable dependencies and independently segregating variants, which captures additive effects, genetic interactions, and two phenotype pleiotropy. This formalism and the theoretical approach naturally applies to higher multi-variable interactions and complex dependencies, and can be adapted to account for population structure, linkage and non-randomly segregating markers. This paper thus focuses on presenting the initial groundwork for a full formulation of quantitative genetics based on information theory.
Linking influenza virus evolution within and between human hosts
Authors: Xue Katherine S. , Bloom Jesse D.
Published: October 2019

Influenza viruses rapidly diversify within individual human infections. Several recent studies have deep-sequenced clinical influenza infections to identify viral variation within hosts, but it remains unclear how within-host mutations fare in the global viral population. Here, we compare viral variation within and between hosts to link influenza’s evolutionary dynamics across scales. Synonymous sites evolve at similar rates at both scales, indicating that global evolution at these putatively neutral sites results from the accumulation of within-host variation. However, nonsynonymous mutations are depleted in global viral populations compared to within hosts, suggesting that selection purges many of the protein-altering changes that arise within hosts. The exception is at antigenic sites, where selection detectably favors nonsynonymous mutations at the global scale, but not within hosts. These results suggest that selection against deleterious mutations and selection for antigenic change are the main forces that transform influenza’s within-host genetic variation into global evolution.
Absolute quantification of transcription factors reveals principles of gene regulation in erythropoiesis
Authors: Gillespie Mark A. , Palii Carmen G. , Sanchez-Taltavull Daniel , Shannon Paul , Longabaugh William J.R. , Downes Damien J. , Sivaraman Karthi , Hughes Jim R. , Price Nathan D. , Perkins Theodore J. , Ranish Jeffrey A. , Brand Marjorie
Published: October 2019

Dynamic cellular processes such as differentiation are driven by changes in the abundances of transcription factors (TFs). Yet, despite years of studies we still do not know the protein copy number of TFs in the nucleus. Here, by determining the absolute abundances of 103 TFs and co-factors during the course of human erythropoiesis, we provide a dynamic and quantitative scale for TFs in the nucleus. Furthermore, we establish the first Gene Regulatory Network of cell fate commitment that integrates temporal protein stoichiometry data with mRNA measurements. The model revealed quantitative imbalances in TFs cross-antagonistic relationships that underlie lineage determination. Finally, we made the surprising discovery that in the nucleus, corepressors are dramatically more abundant than coactivators at the protein, but not at the RNA level, with profound implications for understanding transcriptional regulation. These analyses provide a unique quantitative framework to understand transcriptional regulation of cell differentiation in a dynamic context.
Cryopreservation impairs cytotoxicity and migration of NK cells in 3-D tissue: Implications for cancer immunotherapy
Authors: Mark Christoph , Czerwinski Tina , Roessner Susanne , Mainka Astrid , Hörsch Franziska , Heublein Lucas , Winterl Alexander , Sanokowski Sebastian , Richter Sebastian , Bauer Nina , Schuler Gerold , Fabry Ben , Voskens Caroline J.
Published: October 2019

Natural killer (NK) cells are important effector cells in the immune response to cancer. Clinical trials on adoptively transferred NK cells in patients with solid tumors, however, have thus far been unsuccessful. As NK cells need to pass stringent safety evaluation for clinical use, the cells are cryopreserved to bridge the necessary evaluation time. While a degranulation assay confirms the ability of cryopreserved NK cells to kill target cells, we find a significant decrease of cytotoxicity after cryopreservation in a chromium release assay. We complement these standard assays with measurements of NK cell motility and cytotoxicity in 3-dimensional (3-D) collagen gels that serve as a substitute for connective tissue. We find a 5.6 fold decrease of cytotoxicity after cryopreservation and establish that this is mainly caused by a 6-fold decrease in the fraction of motile NK cells. These findings may explain the persistent failure of NK cell therapy in patients with solid tumors and highlight the crucial role of a 3-D environment for testing NK cell function.

Synopsis

Cryopreservation of natural killer (NK) cells dramatically impairs their motility and cytotoxicity in tissue. This finding may explain the persistent failure of clinical trials in which NK cell therapy is used for treating solid tumors.
Model-based and model-free analyses of the neural correlates of tongue movements
Authors: Sörös Peter , Schäfer Sarah , Witt Karsten
Published: October 2019

The tongue performs movements in all directions to subserve its diverse functions in chewing, swallowing, and speech production. The aims of the present study were twofold: using task-based functional MRI in a group of 17 healthy young participants, we studied (1) potential differences in the cerebral control of frontal, horizontal, and vertical tongue movements and (2) potential inter-individual differences in tongue motor control. To investigate differences between different tongue movements, we performed voxel-wise multiple linear regressions. To investigate inter-individual differences, we applied a novel approach, spatio-temporal filtering of independent components. For this approach, individual functional data sets were decomposed into spatially independent components and corresponding time courses using ICA. A temporal filter (correlation with the expected brain response) was used to identify independent components time-locked to the tongue motor task. A spatial filter (cross-correlation with established neurofunctional systems) was used to identify brain activity not time-locked to the task. Our results confirm the importance of an extended bilateral cortical and subcortical network for the control of tongue movements, including the lateral primary sensorimotor cortex, supplementary motor cortex, anterior cingulate gyrus, insula, basal ganglia, thalamus, and cerebellum. Frontal tongue movements, highly overlearned movements related to speech production, showed less activity in parts of the frontal and parietal lobes compared to horizontal and vertical movements and greater activity in parts of the left frontal and temporal lobes compared to vertical movements. The investigation of inter-individual differences revealed a component representing the tongue primary sensorimotor cortex time-locked to the task in all participants. Using the spatial filter, we found the default mode network in 16 of 17 participants, the left fronto-parietal network in 16, the right fronto-parietal network in 8, and the executive control network in 4 participants. Further detailed analyses of speech-related tongue movements are warranted to increase our understanding of tongue motor control as a crucial part of articulation. Spatio-temporal filtering of independent components appears to be a powerful approach to study inter-individual differences in task-based functional MRI. This approach may be particularly useful for the assessment of individual patients and may be related to individual clinical, behavioral, and genetic information.
Drivers of plant traits and forest functional composition in coastal plant communities of the Atlantic Forest
Authors: Lourenço Jehová , Newman Erica A. , Ventura Jose A. , Milanez Camilla Rozindo Dias , Thomaz Luciana Dias , Wandekoken Douglas Tinoco , Enquist Brian J.
Published: October 2019

The severe deforestation of Brazil’s Atlantic Forest and increasing effects of climate change underscore the need to understand how tree species respond to climate and soil drivers. We studied 42 plots of coastal restinga forest, which is highly diverse and spans strong environmental gradients. We determined the forest physiognomy and functional composition, which are physical properties of a community that respond to climate and soil properties, to elucidate which factors drive community-level traits. To identify the most important environmental drivers of coastal Atlantic forest functional composition, we performed a forest inventory of all plants of diameter 5 cm and above. We collected wood samples and leaves from ∼85% of the most abundant plant species and estimated height, aboveground biomass (AGB), and basal area of individual plants, and the community-weighted specific leaf area (SLA). In addition to plant traits, we measured water table depth and 25 physicochemical soil parameters. We then parameterized several models for different hypotheses relating the roles of nutrients and soil to tropical forest diversity and functioning, as represented by plant traits. Hypotheses were formalized via generalized additive models and piecewise structural equation models. Water table depth, soil coarseness, potential acidity, sodium saturation index (SSI) and aluminum concentration were all components of the best models for AGB, height, basal area, and trait composition. Among the 25 environmental parameters measured, those related to water availability (water table depth and coarse sand), followed by potential acidity, SSI, and aluminum consistently emerged as the most important drivers of forest physiognomy and functional composition. Increases in water table depth, coarse sand, and soil concentration of aluminum negatively impacted all the measured functional traits, whereas SSI had a positive effect on AGB and plant height. These results suggest that sodium is not merely tolerated by Atlantic Forest restinga plant communities, but is important to their structure and functioning. Presence of aluminum in the soil had a complex relationship to overall basal area, possibly mediated by soil organic matter.
Combined Atomic Force Microscope and Volumetric Light Sheet System for Mechanobiology
Authors: Nelsen E. , Hobson C.M. , Kern M.E. , Hsiao J.P. , O’Brien E.T. , Watanabe T. , Condon B.M. , Boyce M. , Grinstein S. , Hahn K.M. , Falvo M.R. , Superfine R.
Published: October 2019

The central goals of mechanobiology are to understand how cells generate force and how they respond to environmental mechanical stimuli. A full picture of these processes requires high-resolution, volumetric imaging with time-correlated force measurements. Here we present an instrument that combines an open-top, single-objective light sheet fluorescence microscope with an atomic force microscope (AFM), providing simultaneous volumetric imaging with high spatiotemporal resolution and high dynamic range force capability (10 pN – 100 nN). With this system we have captured lysosome trafficking, vimentin nuclear caging, and actin dynamics on the order of one second per volume. To showcase the unique advantages of combining Line Bessel light sheet imaging with AFM, we measured the forces exerted by a macrophage during FcɣR-mediated phagocytosis while performing both sequential two-color, fixed plane and volumetric imaging of F-actin. This unique instrument allows for a myriad of novel studies investigating the coupling of cellular dynamics and mechanical forces.
Feature-based Molecular Networking in the GNPS Analysis Environment
Authors: Nothias Louis Felix , Petras Daniel , Schmid Robin , Dührkop Kai , Rainer Johannes , Sarvepalli Abinesh , Protsyuk Ivan , Ernst Madeleine , Tsugawa Hiroshi , Fleischauer Markus , Aicheler Fabian , Aksenov Alexander , Alka Oliver , Allard Pierre-Marie , Barsch Aiko , Cachet Xavier , Caraballo Mauricio , Da Silva Ricardo R. , Dang Tam , Garg Neha , Gauglitz Julia M. , Gurevich Alexey , Isaac Giorgis , Jarmusch Alan K. , Kameník Zdeněk , Kang Kyo Bin , Kessler Nikolas , Koester Irina , Korf Ansgar , Gouellec Audrey Le , Ludwig Marcus , Christian Martin H. , McCall Laura-Isobel , McSayles Jonathan , Meyer Sven W. , Mohimani Hosein , Morsy Mustafa , Moyne Oriane , Neumann Steffen , Neuweger Heiko , Nguyen Ngoc Hung , Nothias-Esposito Melissa , Paolini Julien , Phelan Vanessa V. , Pluskal Tomáš , Quinn Robert A. , Rogers Simon , Shrestha Bindesh , Tripathi Anupriya , van der Hooft Justin J.J. , Vargas Fernando , Weldon Kelly C. , Witting Michael , Yang Heejung , Zhang Zheng , Zubeil Florian , Kohlbacher Oliver , Böcker Sebastian , Alexandrov Theodore , Bandeira Nuno , Wang Mingxun , Dorrestein Pieter C.
Published: October 2019

Molecular networking has become a key method used to visualize and annotate the chemical space in non-targeted mass spectrometry-based experiments. However, distinguishing isomeric compounds and quantitative interpretation are currently limited. Therefore, we created Feature-based Molecular Networking (FBMN) as a new analysis method in the Global Natural Products Social Molecular Networking (GNPS) infrastructure. FBMN leverages feature detection and alignment tools to enhance quantitative analyses and isomer distinction, including from ion-mobility spectrometry experiments, in molecular networks.
Streptococcus equi subsp. zooepidemicus associated with sudden death of swine in North America
Authors: de Costa Matheus O. , Lage Brad
Published: October 2019

Historically described as a commensal of the swine upper-respiratory tract, Streptococcus equi subsp. zooepidemicus was only reported previously in Asia as an important swine pathogen. Here we report the isolation and whole genome characterization of Streptococcus equi subsp. zooepidemicus associated with a sudden death outbreak in pigs in North America.
Mapping Mesoscale Axonal Projections in the Mouse Brain Using A 3D Convolutional Network
Authors: Friedmann Drew , Pun Albert , Adams Eliza L , Lui Jan H , Kebschull Justus M , Grutzner Sophie M , Castagnola Caitlin , Tessier-Lavigne Marc , Luo Liqun
Published: October 2019

The projection targets of a neuronal population are a key feature of its anatomical characterization. Historically, tissue sectioning, confocal microscopy, and manual scoring of specific regions of interest have been used to generate coarse summaries of mesoscale projectomes. We present here TrailMap, a 3D convolutional network for extracting axonal projections from intact cleared mouse brains imaged by light-sheet microscopy. TrailMap allows region-based quantification of total axon content in large and complex 3D structures after registration to a standard reference atlas. The identification of axonal structures as thin as one voxel benefits from data augmentation but also requires a loss function that tolerates errors in annotation. A network trained with volumes of serotonergic axons in all major brain regions can be generalized to map and quantify axons from thalamocortical, deep cerebellar, and cortical projection neurons, validating transfer learning as a tool to adapt the model to novel categories of axonal morphology. Speed of training, ease of use, and accuracy improve over existing tools without a need for specialized computing hardware. Given the recent emphasis on genetically and functionally defining cell types in neural circuit analysis, TrailMap will facilitate automated extraction and quantification of axons from these specific cell types at the scale of the entire mouse brain, an essential component of deciphering their connectivity.
Some Statistical Consideration in Transcriptome-Wide Association Studies
Authors: Xue Haoran , Pan Wei ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: October 2019

Transcriptome-wide association study (TWAS) has become popular in integrating a reference eQTL dataset with an independent main GWAS dataset to identify (putatively) causal genes, shedding mechanistic insights to biological pathways from genetic variants to a GWAS trait mediated by gene expression. Statistically TWAS is a (two-sample) 2-stage least squares (2SLS) method in the framework of instrumental variables analysis for causal inference: in Stage 1 it uses the reference eQTL data to impute a gene’s expression for the main GWAS data, then in Stage 2 it tests for association between the imputed gene expression and the GWAS trait; if an association is detected in Stage 2, a (putatively) causal relationship between the gene and the GWAS trait is claimed. If a non-linear model or a generalized linear model (GLM) is fitted in Stage 2 (e.g. for a binary GWAS trait), it is known that using only imputed gene expression, as in standard TWAS, in general does not lead to a consistent (i.e. asymptotically unbiased) estimate for the causal effect; accordingly, a variation of 2SLS, called two-stage residual inclusion (2SRI), has been proposed to yield better estimates (e.g. being consistent under suitable conditions). Our main goal is to investigate whether it is necessary or even better to apply 2SRI, instead of the standard 2SLS. In addition, due to the use of imputed gene expression (i.e. with measurement errors), it is known that in general some correction to the standard error estimate of the causal effect estimate has to be applied, while in the standard TWAS no correction is applied. Is this an issue? We also compare one-sample 2SLS with two-sample 2SLS (i.e. the standard TWAS). We used the ADNI data and simulated data mimicking the ADNI data to address the above questions. At the end, we conclude that, in practice with the large sample sizes and small effect sizes of genetic variants, the standard TWAS performs well and is recommended.
The kinase inhibitor AT9283 selectively kills colorectal cancer cells with hyperactive NRF2
Authors: Torrente Laura , Maan Gunjit , Casares Laura , Jackson Angus , Honda Tadashi , Wells Geoff , Kulesskiy Evgeny , Saarela Jani , Dinkova-Kostova Albena T. , de la Vega Laureano
Published: October 2019

Aberrant hyperactivation of NRF2 is a common event in many tumour types and associates with resistance to therapy and poor patient prognosis. The identification of ways to overcome the protection provided by NRF2 and selectively kill cancer cells addicted to NRF2 is a desirable goal. Exploiting the CRISPR/Cas9 technology, we generated colorectal cancer cell lines with hyperactive NRF2, and used them to perform a drug screen. We identified AT9283, an Aurora kinase inhibitor, for its selectivity towards killing cancer cells with hyperactive NRF2 as a consequence to either genetic or pharmacological activation. Our results show that hyperactivation of NRF2 presents a potential vulnerability that could be therapeutically exploited, and further suggest that AT9283, a drug that is currently in clinical trials, holds promise for the treatment of tumours with hyperactive NRF2.

Highlights

We present a new model for NRF2 hyperactivation in colorectal cancer cells.

AT9283 selectively kills cancer cells with hyperactive NRF2

Both genetic and pharmacological activation of NRF2 sensitise cells to AT9283
Brain-wide electrical spatiotemporal dynamics encode reward anticipation
Authors: Vu Mai-Anh T. , David Lisa K. , Thomas Gwenaëlle E. , Vagwala Meghana , Burrus Caley , Gallagher Neil M. , Wang Joyce , Blount Cameron , Hughes Dalton N. , Adamson Elise , Ndubuizu Nkemdilim , Kim Il Hwan , Soderling Scott , Mague Stephen D. , Adcock R. Alison , Dzirasa Kafui
Published: October 2019

Anticipation of an upcoming stimulus induces neural activity across cortical and subcortical regions and influences subsequent behavior. Nevertheless, the network mechanism whereby the brain integrates this information to signal the anticipation of rewards remains relatively unexplored. Here we employ multi-circuit electrical recordings from six brain regions as mice perform a sample-to-match task in which reward anticipation is operationalized as their progress towards obtaining a potential reward. We then use machine learning to discover the naturally occurring network patterns that integrate this neural activity across timescales. Only one of the networks that we uncovered signals responses linked to reward anticipation, specifically relative proximity and reward magnitude. Activity in this Electome (electrical functional connectivity) network is dominated by theta oscillations leading from prelimbic cortex and striatum that converge on ventral tegmental area, and by beta oscillations leading from striatum that converge on prelimbic cortex. Network activity is also synchronized with brain-wide cellular firing. Critically, this network generalizes to new groups of healthy mice, as well as a mouse line that models aberrant neural circuitry observed in brain disorders that show altered reward anticipation. Thus, our findings reveal the network-level architecture whereby the brain integrates spatially distributed activity across timescales to signal reward anticipation.