bluuebunny/crossref_metadata_2025 huggingface dataset:
Poincaré Maps for Analyzing Complex Hierarchies in Single-Cell Data
Authors: Klimovskaia Anna , Lopez-Paz David , Bottou Léon , Nickel Maximilian
Published: July 2019

The need to understand cell developmental processes spawned a plethora of computational methods for discovering hierarchies from scRNAseq data. However, existing techniques are based on Euclidean geometry, a suboptimal choice for modeling complex cell trajectories with multiple branches. To overcome this fundamental representation issue we propose Poincaré maps, a method that harness the power of hyperbolic geometry into the realm of single-cell data analysis. Often understood as a continuous extension of trees, hyperbolic geometry enables the embedding of complex hierarchical data in only two dimensions while preserving the pairwise distances between points in the hierarchy. This enables direct exploratory analysis and the use of our embeddings in a wide variety of downstream data analysis tasks, such as visualization, clustering, lineage detection and pseudo-time inference. When compared to existing methods —unable to address all these important tasks using a single embedding— Poincaré maps produce state-of-the-art two-dimensional representations of cell trajectories on multiple scRNAseq datasets. More specifically, we demonstrate that Poincaré maps allow in a straightforward manner to formulate new hypotheses about biological processes unbeknown to prior methods.

Significance statement

The discovery of hierarchies in biological processes is central to developmental biology. We propose Poincaré maps, a new method based on hyperbolic geometry to discover continuous hierarchies from pairwise similarities. We demonstrate the efficacy of our method on multiple single-cell datasets on tasks such as visualization, clustering, lineage identification, and pseudo-time inference.
Large-scale hyperparameter search for predicting human brain responses in the Algonauts challenge
Authors: Jozwik Kamila M. , Lee Michael , Marques Tiago , Schrimpf Martin , Bashivan Pouya
Published: July 2019

Image features computed by specific convolutional artificial neural networks (ANNs) can be used to make state-of-the-art predictions of primate ventral stream responses to visual stimuli.

However, in addition to selecting the specific ANN and layer that is used, the modeler makes other choices in preprocessing the stimulus image and generating brain predictions from ANN features. The effect of these choices on brain predictivity is currently underexplored.

Here, we directly evaluated many of these choices by performing a grid search over network architectures, layers, image preprocessing strategies, feature pooling mechanisms, and the use of dimensionality reduction. Our goal was to identify model configurations that produce responses to visual stimuli that are most similar to the human neural representations, as measured by human fMRI and MEG responses. In total, we evaluated more than 140,338 model configurations. We found that specific configurations of CORnet-S best predicted fMRI responses in early visual cortex, and CORnet-R and SqueezeNet models best predicted fMRI responses in inferior temporal cortex. We found specific configurations of VGG-16 and CORnet-S models that best predicted the MEG responses.

We also observed that downsizing input images to ~50-75% of the input tensor size lead to better performing models compared to no downsizing (the default choice in most brain models for vision). Taken together, we present evidence that brain predictivity is sensitive not only to which ANN architecture and layer is used, but choices in image preprocessing and feature postprocessing, and these choices should be further explored.
Observing changes in human functioning during induced sleep deficiency and recovery periods
Authors: Ochab Jeremi K. , Szwed Jerzy , Oleś Katarzyna , Bereś Anna , Chialvo Dante R. , Domagalik Aleksandra , Fafrowicz Magdalena , Gudowska-Nowak Ewa , Marek Tadeusz , Nowak Maciej A. , Ogińska Halszka
Published: July 2019

The duration of sleep, wakefulness and dynamic changes in human performance are determined by neural and genetic mechanisms. Sleep deprivation and chronic restriction of sleep cause perturbations of circadian rhythmicity and degradation of waking alertness as reflected in attention, cognitive efficiency and memory. In this work we report on multiple neurobehavioral correlates of sleep loss in healthy adults in an unprecedented study comprising 21 consecutive days divided into periods of 4 days of regular life (a baseline), 10 days of chronic partial sleep restriction and 7 days of recovery. Throughout the whole experiment we continuously measured the spontaneous locomotor activity by means of actigraphy with 1-minute resolution in two acquisition modes (frequency and intensity of movement). Moreover, on daily basis the subjects were undergoing EEG measurements (64-electrodes with 500 Hz sampling frequency): resting state with eyes open and closed (RS; 8 minutes long each) followed by Stroop task (ST; 22 minutes). Altogether we analyzed actigraphy (distributions of rest and activity durations), behavioral measures (accuracy and reaction times from Stroop task) and EEG (amplitudes, latencies and scalp maps of event-related potentials from Stroop task and power spectra from resting states). The actigraphy measures clearly indicate rapid changes after sleep restriction onset, confirming our former investigations — the novel insight is a slow and incomplete relaxation to the original locomotor behavior. The pattern of partial recovery appears also in accuracy (in ST) and power of delta rhythm (in RS). The impact of sleep loss is also evident in reaction times (in ST), yet followed by complete recovery, and finally in ERP amplitudes and latencies, which however did not return to the baseline at all. The results indicate that short periods (a few days) of recovery sleep subsequent to prolonged periods of sleep restriction are overall insufficient to recover fully.
Phylogenomic analysis reveals the basis of adaptation of Pseudorhizobium species to extreme environments
Authors: Lassalle Florent , Dastgheib Seyed M. M. , Zhao Fang-Jie , Zhang Jun , Verbarg Susanne , Frühling Anja , Brinkmann Henner , Osborne Thomas H. , Sikorski Johannes , Balloux Francois , Didelot Xavier , Santini Joanne M. , Petersen Jörn
Published: July 2019

The family Rhizobiaceae includes many genera of soil bacteria, often isolated for their association with plants. Herein, we investigate the genomic diversity of a group of Rhizobium species and unclassified strains isolated from atypical environments, including seawater, rock matrix or polluted soil. Based on whole-genome similarity and core genome phylogeny, we show that this group corresponds to the genus Pseudorhizobium. We thus reclassify Rhizobium halotolerans, R. marinum, R. flavum and R. endolithicum as P. halotolerans comb. nov., P. marinum comb. nov., P. flavum comb. nov. and R. endolithicum comb. nov., respectively, and show that P. pelagicum is a synonym of P. marinum. We also delineate a new chemolithoautotroph species, P. banfieldiae sp. nov., whose type strain is NT-26T (= DSM 106348T = CFBP 8663T). This genome-based classification was supported by a chemotaxonomic comparison, with gradual taxonomic resolution provided by fatty acid, protein and metabolic profiles. In addition, we used a phylogenetic approach to infer scenarios of duplication, horizontal transfer and loss for all genes in the Pseudorhizobium pangenome. We thus identify the key functions associated with the diversification of each species and higher clades, shedding light on the mechanisms of adaptation to their respective ecological niches. Respiratory proteins acquired at the origin of Pseudorhizobium are combined with clade-specific genes to encode different strategies for detoxification and nutrition in harsh, nutrient-poor environments. Finally, we predict diagnostic phenotypes for the distinction of P. banfieldiae from other Pseudorhizobium species, including autotrophy and sensitivity to the azo dye Congo Red, which we experimentally validated.
TheDrosophilafertility factorkl-3is linked to the Y-chromosome of the vector of Chagas’ diseaseTriatoma infestans(Hemiptera: Reduviidae) and is essential for male fertility
Authors: Martins Carlos H. , da Silva Rodrigo S. V. P , Ferreira Thalia K. , Paim Rafaela , Pessoa Grasielle C. D. , Sant’Anna Mauricio V. , Gontijo Nelder F. , Araujo Ricardo N. , Pereira Marcos H. , Carvalho A. Bernardo , Koerich Leonardo B.
Published: July 2019

In many insects, the Y chromosome plays a key role in sexual determination and male fertility. The Chagas disease vectorTriatoma infestanshas 22 autosomal chromosomes and a pair of XY sex chromosomes. However, the knowledge on the Y chromosome of this species, its genetic content or its biological function, is very poor. Due to repetitive DNA, Y chromosome sequences are poorly assembled in genome projects, hindering structural and functional studies on Y-linked genes. Our group has developed many of the bioinformatic tools to identify Y-linked sequences in assembled genomes. Here, we describe the identification of a γ-dynein heavy chain linked to the Y-chromosome ofT. infestans. This protein is orthologous to theDrosophila melanogasterY-linked genekl-3. InD. melanogaster, dyneins of the Y chromosome are known as male fertility factors and their deletion causes male infertility. We performed knockdown of thekl-3expression to ascertain its function inT. infestans. Our results showed that injection of dsKL3 reduced, significantly, the fertility ofT. infestansmales (p<0.01). The mean number of eggs laid by the control group was 35.64 eggs/couple while the kl-3 knockdown group was of 11.82 eggs/couple (five couples did not lay any eggs). Differences in eclosion rate was even more significant, with a hatching mean rate of 16.85±10.03 and 1.69±3.58 (p<0.001) for the control and the silenced groups respectively. Our results suggest thatkl-3maintains its functional role as essential for male fertility inT. infestans. Hence, it seems that the Y-chromosome ofT. infestanshas a key role in male fertility. This is the first report of akl-3orthologue linked to the Y chromosome of an insect species outside the diptera clade. In addition to the first report of a Y-linked gene inT. infestanswith a role for male fertility, this finding is of great relevance for the study of the evolution of Y chromosomes and further studies that could lead to novel approaches in insect control.
uap: Reproducible and Robust HTS Data Analysis
Authors: Kämpf Christoph , Specht Michael , Scholz Alexander , Puppel Sven-Holger , Doose Gero , Reiche Kristin , Schor Jana , Hackermüller Jörg
Published: July 2019

Background

A lack of reproducibility has been repeatedly criticized in computational research. High throughput sequencing (HTS) data analysis is a complex multi-step process. For most of the steps a range of bioinformatic tools is available and for most tools manifold parameters need to be set. Due to this complexity, HTS data analysis is particularly prone to reproducibility and consistency issues. We have defined four criteria that in our opinion ensure a minimal degree of reproducible research for HTS data analysis. A series of workflow management systems is available for assisting complex multi-step data analyses. However, to the best of our knowledge, none of the currently available work flow management systems satisfies all four criteria for reproducible HTS analysis.

Results

Here we present uap, a workflow management system dedicated to robust, consistent, and reproducible HTS data analysis. uap is optimized for the application to omics data, but can be easily extended to other complex analyses. It is available under the GNU GPL v3 license at https://github.com/yigbt/uap.

Conclusions

uap is a freely available tool that enables researchers to easily adhere to reproducible research principles for HTS data analyses.
A missense variant in CREBRF is associated with taller stature in Samoans
Authors: Carlson Jenna C. , Rosenthal Samantha L. , Russell Emily M. , Hawley Nicola L. , Sun Guangyun , Cheng Hong , Naseri Take , Reupena Muagututi‘a Sefuiva , Tuitele John , Deka Ranjan , McGarvey Stephen T. , Weeks Daniel E. , Minster Ryan L.
Published: July 2019

Objectives

Studies have demonstrated that rs373863828, a missense mutation in CREBRF, is associated with a number of anthropometric traits including body mass index (BMI), obesity, percent body fat, hip circumference, and abdominal circumference. Given the biological relationship between height and adiposity, we hypothesized that the effect of this variant on BMI might be due in part to a previously untested association of this variant with height.

Methods

We tested the hypothesis that minor allele of rs373863828 is associated with height in a Samoan population in two adult cohorts and in a separate cohort of children (age 5 - 18 years old) using linear mixed modeling.

Results

We found evidence of a strong relationship between rs373863828 and greater mean height in Samoan adults (0.77 cm greater average height for each copy of the minor allele) with the same direction of effect in Samoan children.

Conclusions

These results suggest that the missense variant rs373863828 in CREBRF, first identified through an association with larger BMI, may be related to an underlying biological mechanism affecting overall body size including stature.
Air-interfaced colonization model suggests a commensal-like interaction ofNeisseria meningitidiswith the epithelium, which benefit from colonization byStreptococcus mitis
Authors: Audry Mathilde , Robbe-Masselot Catherine , Barnier Jean-Philippe , Gachet Benoit , Saubaméa Bruno , Schmitt Alain , Schönherr-Hellec Sophia , Léonard Renaud , Nassif Xavier , Coureuil Mathieu
Published: July 2019

Neisseria meningitidisis an inhabitant of the nasopharynx, from which it is transmitted from person to person or disseminates in the blood and becomes a harmful pathogen. In this work, we addressed the colonization of the nasopharyngeal niche by focusing on the interplay between meningococci and the mucus that lines the mucosa of the host. Using Calu-3 cells grown in air-interfaced culture, we studied the meningococcal colonization of the mucus and the host response. Our results suggested thatN. meningitidisbehaved like commensal bacteria in mucus, without interacting with human cells or actively transmigrating through the cell layer. As such, meningococci did not trigger a strong innate immune response from the Calu-3 cells. Finally, we have shown that this model is suitable for studying interaction ofN. meningitidiswith other bacteria living in the nasopharynx, and thatStreptococcus mitisbut notMoraxella catarrhaliscan promote meningococcal growth in this model.
Common neurodegeneration-associated proteins are physiologically expressed by antigen-presenting cells and are interconnected via the inflammation/autophagy-related proteins TRAF6 and SQSTM1
Authors: Nataf Serge , Guillen Marine , Pays Laurent
Published: July 2019

There is circumstantial evidence that, under neurodegenerative conditions, peptides deriving from aggregated or misfolded specific proteins elicit adaptive immune responses. On another hand, several genes involved in familial forms of neurodegenerative diseases were found to exert key innate immune functions. However, whether or not such observations are causally linked remains unknown. To start addressing this issue, we followed a systems biology strategy based on the mining of large proteomics and immunopeptidomics databases. First, we retrieved the expression patterns of common neurodegeneration-associated proteins in two professional antigen-presenting cells, namely B-cells and dendritic cells. Surprisingly, we found that under physiological conditions, numerous neurodegeneration-associated proteins are abundantly expressed by human B-cells. A survey of the human proteome allowed us to map a unique protein-protein interaction network linking common neurodegeneration-associated proteins and their first shell interactors in human B-cells. Surprisingly, network connectivity analysis identified two major hubs that both relate with inflammation and autophagy, namely TRAF6 (TNF Receptor Associated Factor 6) and SQSTM1 (Sequestosome-1). Moreover, the mapped network in B-cells also comprised two other hub proteins involved in both inflammation and autoimmunity: HSPA8 (Heat Shock Protein Family A Member 8 also known as HSC70) and HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1). Based on these results, we then explored the Immune Epitope Database “IEDB-AR” and actually found that a large share of neurodegeneration-associated proteins were previously reported to provide endogenous MHC class II-binding peptides in human B-cells. Of note, peptides deriving from amyloid beta A4 protein, sequestosome-1 or profilin-1 were reported to bind multiple allele-specific MHC class II molecules. In contrast, peptides deriving from microtubule-associated protein tau, presenilin 2 and serine/threonine-protein kinase TBK1 were exclusively reported to bind MHC molecules encoded by the HLA-DRB1 1501 allele, a recently-identified susceptibility gene for late onset Alzheimer’s disease. Finally, we observed that the whole list of proteins reported to provide endogenous MHC class II-binding peptides in human B-cells is specifically enriched in neurodegeneration-associated proteins. Overall, our work indicates that immunization against neurodegeneration-associated proteins might be a physiological process which is shaped, at least in part, by B-cells.
Abundance, fatty acid composition and saturation index of neutral lipids are significantly different between isogenic primary and metastatic colon cancer cell lines
Authors: Munir Rimsha , Lisec Jan , Jaeger Carsten , Zaidi Nousheen
Published: July 2019

Lipid droplets, the dynamic organelles that store triglycerides (TG) and cholesterol esters (CE), are highly accumulated in colon cancer cells. This work studies the TG and CE subspecies profile in colon carcinoma cells lines, SW480 derived from primary tumor, and SW620 derived from a metastasis of the same tumor. It was previously reported that the total TG and CE content is dramatically higher in SW620 cells; however, TG and CE subspecies profile has not been investigated in detail. The presented work confirms that total TG and CE content is significantly higher in SW620 cells. Moreover, the FA-composition of TGs is significantly altered in SW620 cells, with significant decrease in the abundance of saturated triglycerides. This resulted in significantly decreased TG saturation index in SW620 cells. The saturation index of CEs was also significantly decreased in SW620 cells. The saturation indices of some other major lipid classes were either similar or only moderately different between SW480 and SW620 cells. We also compared the expression of metabolic genes that may regulate these changes in the lipidomic profiles.
An HSP90-regulated reduced-eye phenotype in Tribolium shows fitness benefits and thus provides evidence for evolutionary capacitance
Authors: Aboelsoud Rasha , Kurtz Joachim
Published: July 2019

Evolution relies on genetic variation as the raw material for adaptation. The release of cryptic genetic variation (CGV), which can be regulated by the evolutionary capacitor heat shock protein 90 (HSP90), may thus be important for rapid adaptation. However, the fitness benefits of HSP90-regulated phenotypes are still under debate. Here, we show in the important model insect Tribolium castaneum that HSP90 impairment by two independent methods, RNA interference and chemical inhibition, revealed the same reduced-eye phenotype, which was stably inherited without further HSP90 inhibition. The penetrance and fitness of this trait increased under ambient light stress. This is the first demonstration that a phenotype released through HSP90 inhibition can be adaptive.
A novel multidimensional reinforcement task in mice elucidates sex-specific behavioral strategies
Authors: Kutlu Munir Gunes , Zachry Jennifer E , Brady Lillian J , Melugin Patrick R , Sanders Christina , Tat Jennifer , Johnson Amy R , Thibeault Kimberly , Lopez Alberto J. , Calipari Erin S.
Published: July 2019

Background

Sex is a critical biological variable in the neuropathology of psychiatric disease, and in many cases, women represent a vulnerable population. It has been hypothesized that sex differences in neuropsychiatric disorders are manifestations of differences in basic reward processing. However, preclinical models often present rewards in isolation, ignoring that ethologically, reward seeking requires the consideration of potential aversive outcomes.

Methods

We developed a Multidimensional Cue Outcome Action Task (MCOAT) to dissociate motivated action from cue learning and valence. Mice are trained in a series of operant tasks. In phase 1, mice acquire positive and negative reinforcement in the presence of discrete discriminative stimuli. In phase 2, both discriminative stimuli are presented concurrently allowing us to parse innate behavioral strategies based on reward seeking and shock avoidance. Phase 3 is punished responding where a discriminative stimulus predicts that nose-poking for sucrose occurs concurrently with footshock, allowing for the assessment of how positive and negative outcomes are relatively valued.

Results

Females prioritize avoidance of negative outcomes over seeking positive, while males have the opposite strategy. In cases where rules are uncertain, males and females employ different strategies, with females demonstrating bias for shock avoidance.

Conclusions

The MCOAT has broad utility for neuroscience research where pairing this task with recording and manipulation techniques will allow for the definition of the discrete information encoded within cellular populations. Ultimately, we show that making conclusions from unidimensional data leads to inaccurate generalizations about sex-specific behaviors that do not accurately represent ground truth.
Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine: Anin vivo1H-magnetic resonance spectroscopy study at 14 T
Authors: Cherix Antoine , Larrieu Thomas , Grosse Jocelyn , Rodrigues João , McEwen Bruce , Nasca Carla , Gruetter Rolf , Sandi Carmen
Published: July 2019

Background

Emerging evidence suggests that hierarchical status may provide vulnerability to develop stress-induced depression. Energy metabolism in the nucleus accumbens (NAc) was recently related to hierarchical status and vulnerability to develop depression-like behavior. Acetyl-L-carnitine (LAC), a mitochondria-boosting supplement, has shown promising antidepressant-like effects opening promising therapeutic strategies for restoring energy balance in depressed patients. Here, we investigated the metabolic impact in the NAc of antidepressant LAC treatment in chronically stressed mice.

Method

Mice were characterized for emotional behaviors and social rank. They were then exposed to chronic restraint stress (CRS) for 21 days and subsequently tested in a social behavior (SB) test. A group of mice was also given LAC supplementation during the 7 last CRS days. Mice were then tested in the SB and forced swim tests (FST) and scannedin vivousing1H-magnetic resonance spectroscopy (1H-MRS) to quantitatively assess the NAc neurochemical profile.

Results

Dominant, but not subordinate, mice showed behavioral vulnerability to CRS. In the NAc, dominant mice showed reduced levels of several energy-related metabolites. LAC treatment counteracted stress-induced behavioral changes in dominant mice, and normalized levels of taurine, phosphocreatine, glutamine and phosphocholine in the NAc. No major accumbal metabolic changes were observed in subordinate mice.

Conclusion

High social rank is confirmed as a vulnerability factor to develop chronic stress-induced depressive-like behaviors. We reveal a metabolic signature in the NAc for the antidepressant-like effects of LAC in vulnerable mice, characterized by restoration of stress-induced alterations in neuroenergetics and lipid function.
Isolation of muscle stem cells from rat skeletal muscles
Authors: Sesillo Francesca Boscolo , Wong Michelle , Cortez Amy , Alperin Marianna
Published: July 2019

Background

Muscle stem cells (MuSCs) are involved in homeostatic maintenance of skeletal muscles and play a central role in muscle regeneration in response to injury. Thus, understanding MuSC autonomous properties is of fundamental importance for studies of muscle degenerative diseases and muscle plasticity. Rat, as an animal model, has been widely used in the skeletal muscle field, however an efficient approach for MuSC isolation through fluorescence-activated cell sorting from rat muscles has never been described. This work aims to develop and validate an effective protocol for MuSC isolation from rat skeletal muscles.

Methods

Tibialis anterior, gastrocnemius, diaphragm, and the individual components of the pelvic floor muscle complex (coccygeus, iliocaudalis, and pubocaudalis) were harvested from female rats and digested for isolation of MuSCs. Three protocols, employing different cell surface markers (CD106, CD56, and CD29), were compared for their ability to isolate a pure MuSC population.

Results

Cells obtained using the protocol that relies only on VCAM-1 (CD106) as a positive marker showed high expression of Pax7 upon isolation, ability to progress through myogenic lineage while in culture, and complete differentiation in serum deprived conditions. The protocol was further validated in other skeletal muscles proving to be reproducible.

Conclusions

CD106 is an efficient marker for reliable isolation of MuSCs from a variety of rat skeletal muscles.
Temporal and spatiotemporal perturbations in paced finger tapping point to a common mechanism for the processing of time errors
Authors: López Sabrina L. , Laje Rodrigo
Published: July 2019

Paced finger tapping is a sensorimotor synchronization task where a subject is instructed to keep pace with an external metronome, as when following along with the beat of music, and the time differences (asynchronies) between each stimulus and its response are recorded. The usual way to study the underlying error correction mechanism is to make unexpected temporal perturbations to the stimuli sequence and then let the subject recover average synchronization. A critical but overlooked issue in traditional temporal perturbations, however, is that at the moment of perturbation two things change: both the stimuli period (a parameter) and the asynchrony (a variable). In terms of experimental manipulation, it would be desirable to have separate, independent control of parameter and variable values. In this work we perform paced finger tapping experiments combining simple temporal perturbations (tempo step change) and spatial perturbations with temporal effect (raised or lowered point of contact). In this way we decouple the parameter-and-variable confounding of traditional temporal perturbations and perform novel perturbations where either the parameter only changes or the variable only changes. Our results show nonlinear features like asymmetry and are compatible with the idea of a common mechanism for the correction of all types of asynchronies. We suggest taking this confounding into account when analyzing perturbations of any kind in finger tapping tasks but also in other areas of sensorimotor synchronization, like music performance experiments and paced walking in gait coordination studies.
Identification of activators of human fumarate hydratase by quantitative high-throughput screening
Authors: Zhu Hu , Lee Olivia W. , Shah Pranav , Jadhav Ajit , Xu Xin , Patnaik Samarjit , Shen Min , Hall Matthew D.
Published: July 2019

Fumarate hydratase (FH) is a metabolic enzyme that is part of the Krebs-cycle, and reversibly catalyzes the hydration of fumarate to malate. Mutations of the FH gene have been associated with fumarate hydratase deficiency (FHD), hereditary leiomyomatosis, renal cell cancer (HLRCC), and other diseases. Currently there are no high-quality small molecule probes for studying human fumarate hydratase. To address this, we developed a quantitative high throughput screening (qHTS) FH assay and screened a total of 57,037 compounds from in-house libraries in dose-response. While no inhibitors of FH were confirmed, a series of phenyl-pyrrolo-pyrimidine-diones were identified as activators of human fumarate hydratase. These compounds were not substrates of fumarate hydratase, were inactive in a malate dehydrogenase counter screen, and showed no detectable reduction–oxidation activity. The binding of two compounds from the series to human fumarate hydratase was confirmed by microscale thermophoresis. The low hit rate in this screening campaign confirmed that FH is a ‘tough target’ to modulate, and the small molecule activators of human fumarate hydratase reported here may serve as a starting point for further optimization and development into cellular probes of human FH and potential drug candidates.
A general approach to engineer positive-going eFRET voltage indicators
Authors: Abdelfattah Ahmed S. , Valenti Rosario , Wong Allan , Koyama Minoru , Kim Douglas S. , Schreiter Eric R.
Published: July 2019

We engineered electrochromic fluorescence resonance energy transfer (eFRET) genetically encoded voltage indicators (GEVIs) with “positive-going” fluorescence response to membrane depolarization through rational manipulation of the native proton transport pathway in microbial rhodopsins. We transformed the state-of-the-art eFRET GEVI Voltron into Positron, with kinetics and sensitivity equivalent to Voltron but flipped fluorescence signal polarity. We further applied this general approach to GEVIs containing different voltage sensitive rhodopsin domains and various fluorescent dye and fluorescent protein reporters.
Drosophila menthol sensitivity and the Precambrian origins of TRP-dependent chemosensation
Authors: Himmel Nathaniel J. , Letcher Jamin M. , Sakurai Akira , Gray Thomas R. , Benson Maggie N. , Cox Daniel N.
Published: July 2019

Transient receptor potential (TRP) cation channels are highly conserved, polymodal sensors which respond to a wide variety of stimuli. Perhaps most notably, TRP channels serve critical functions in nociception and pain. A growing body of evidence suggests that TRPM (Melastatin) and TRPA (Ankyrin) thermal and electrophile sensitivities predate the protostome-deuterostome split (>550 million years ago). However, TRPM and TRPA channels are also thought to detect modified terpenes (e.g., menthol). Although terpenoids like menthol are thought to be aversive and/or harmful to insects, mechanistic sensitivity studies have been largely restricted to chordates. Furthermore, it is unknown if TRP-menthol sensing is as ancient as thermal and/or electrophile sensitivity. Combining genetic, optical, electrophysiological, behavioural, and phylogenetic approaches, we tested the hypothesis that insect TRP channels play a conserved role in menthol sensing. We found that topical application of menthol to Drosophila melanogaster larvae elicits a Trpm- and TrpA1-dependent nocifensive rolling behaviour, which requires activation of Class IV nociceptor neurons. Further, in characterizing the evolution of TRP channels, we put forth the hypotheses that 3 previously undescribed TRPM channel clades (basal, αTRPM, and βTRPM), as well as TRPs with residues critical for menthol sensing, were present in ancestral bilaterians.
Evaluating three different adaptive decomposition methods for EEG signal seizure detection and classification
Authors: Carvalho Vinícius R. , Moraes Márcio F.D. , Braga Antônio P. , Mendes Eduardo M.A.M.
Published: July 2019

Signal processing and machine learning methods are valuable tools in epilepsy research, potentially assisting in diagnosis, seizure detection, prediction and real-time event detection during long term monitoring. Recent approaches involve the decomposition of these signals in different modes or functions in a data-dependent and adaptive way. These approaches may provide advantages over commonly used Fourier based methods due to their ability to work with nonlinear and non-stationary data. In this work, three adaptive decomposition methods (Empirical Mode Decomposition, Empirical Wavelet Transform and Variational Mode Decomposition) are evaluated for the classification of normal, ictal and inter-ictal EEG signals using a freely available database. We provide a previously unavailable common methodology for comparing the performance of these methods for EEG seizure detection, with the use of the same classifiers, parameters and spectral and time domain features. It is shown that the outcomes using the three methods are quite similar, with maximum accuracies of 97.5% for Empirical Mode Decomposition, 96.7% for Empirical Wavelet Transform and 98.2% for Variational Mode Decomposition. Features were also extracted from the original non-decomposed signals, yielding inferior, but still fairly accurate (95.3%) results. The evaluated decomposition methods are promising approaches for seizure detection, but their use should be judiciously analysed, especially in situations that require real-time processing and computational power is an issue. An additional methodological contribution of this work is the development of two python packages, already available at the PyPI repository: One for the Empirical Wavelet Transform (ewtpy) and another for Variational Mode Decomposition (vmdpy).
The Role of Evolving Interfacial Substrate Properties on Heterogeneous Cellulose Hydrolysis Kinetics
Authors: Nill Jennifer , Jeoh Tina
Published: July 2019

Interfacial enzyme reactions require formation of an enzyme-substrate complex at the surface of a heterogeneous substrate, but often multiple modes of enzyme binding and types of binding sites complicate analysis of their kinetics. Excess of heterogeneous substrate is often used as a justification to model the substrate as unchanging; but using the study of the enzymatic hydrolysis of insoluble cellulose as an example, we argue that reaction rates are dependent on evolving substrate interfacial properties. We hypothesize that the relative abundance of binding sites on cellulose where hydrolysis can occur (productive binding sites) and binding sites where hydrolysis cannot be initiated or is inhibited (non-productive binding sites) contribute to rate limitations. We show that the initial total number of productive binding sites (the productive binding capacity) determines the magnitude of the initial burst phase of cellulose hydrolysis, while productive binding site depletion explains overall hydrolysis kinetics. Furthermore, we show that irreversibly bound surface enzymes contribute to the depletion of productive binding sites. Our model shows that increasing the ratio of productive- to non-productive binding sites promotes hydrolysis, while maintaining an elevated productive binding capacity throughout conversion is key to preventing hydrolysis slowdown.
Maternal effects and environmental filtering shape seed fungal communities in oak trees
Authors: Fort Tania , Pauvert Charlie , Zanne Amy E. , Ovaskainen Otso , Caignard Thomas , Barret Matthieu , Compant Stéphane , Hampe Arndt , Delzon Sylvain , Vacher Corinne
Published: July 2019

Trees, as foundation species, play a pivotal role in the species interaction networks that constitute forest ecosystems. From the seed stage, they interact with microbial communities that affect their growth, health and fitness. Despite their eco-evolutionary importance, the processes shaping seed microbial communities in natural forests have received little attention.

To unravel these processes, we analyzed the microbial communities of seeds collected in populations of sessile oak (Quercus petraea) growing along elevation gradients. We focused on the fungal communities as this group includes seed pathogens. Ecological processes shaping the communities were quantified using joint species distribution models.

Fungi were present in all seed tissues, including the embryo. Fungal communities differed significantly among oak populations along the elevation gradients, and among mother trees within the same population. These maternal effects remained significant after seed fall, despite colonization by fungal species on the ground. Associations between tree pathogens and their antagonists were detected in the seeds.

Our results demonstrate that both maternal effects and environmental filtering shape seed microbial communities of sessile oak. They provide a starting point for future research aimed at identifying the seed extended phenotypic traits that influence seed dispersal and germination, and seedling survival and growth across environments.
Interictal discharges spread along local recurrent networks between tubers and surrounding cortex
Authors: Tumpa S , Thornton R , Tisdall M , Baldeweg T , Friston KJ , Rosch RE
Published: July 2019

The presence of interictal epileptiform discharges on electroencephalography (EEG) may indicate increased epileptic seizure risk and on invasive EEG are the signature of the irritative zone. In highly epileptogenic lesions – such as cortical tubers in tuberous sclerosis – these discharges can be recorded with intracranial stereotactic EEG as part of the evaluation for epilepsy surgery. Yet the network mechanisms that underwrite the generation and spread of these discharges remain poorly understood, limiting their current diagnostic use.

Here, we investigate the dynamics of interictal epileptiform discharges using a combination of quantitative analysis of invasive EEG recordings and mesoscale neural mass modelling of cortical dynamics. We first characterise spatially organised local dynamics of discharges recorded from 36 separate tubers in 8 patients with tuberous sclerosis. We characterise these dynamics with a set of competing explanatory network models using dynamic causal modelling. Bayesian model comparison of plausible network architectures suggests that the recurrent coupling between neuronal populations within – and adjacent to – the tuber core explains the travelling wave dynamics observed in these patient recordings.

Our results – based on interictal activity – unify competing theories about the pathological organisation of epileptic foci and surrounding cortex in patients with tuberous sclerosis. Coupled oscillator dynamics have previously been used to describe ictal activity, where fast travelling ictal discharges are commonly observed within the recruited seizure network. The interictal data analysed here add the insight that this functional architecture is already established in the interictal state. This links observations of interictal EEG abnormalities directly to pathological network coupling in epilepsy, with possible implications for epilepsy surgery approaches in tuberous sclerosis.

Significance Statement

Interictal epileptiform discharges (IEDs) are clinically important markers of an epileptic brain. Here we link local IED spread to network coupling through a combination of clinical recordings in paediatric patients with tuberous sclerosis complex, quantitative EEG analysis of interictal discharges spread, and Bayesian inference on coupled neural mass model parameters. We show that the kinds of interictal discharges seen in our patients require recurrent local network coupling extending beyond the putative seizure focus and that in fact only those recurrent coupled networks can support seizure-like and interictal dynamics when run in simulation. Our findings provide a novel integrated perspective on emergent epileptic dynamics in human patients.
A common polymorphism in the druggable ion channel PIEZO1 is associated with protection from severe malaria
Authors: Nguetse Christian N. , Purington Natasha , Shakya Bikash , Ebel Emily R. , Kremsner Peter G. , Velavan Thirumalaisamy P. , Egan Elizabeth S.
Published: July 2019

Malaria caused by the Apicomplexan parasite Plasmodium falciparum has served as a strong evolutionary force throughout human history, selecting for red blood cell polymorphisms that confer innate protection against severe disease. Recently, gain-of-function mutations in the mechanosensitive ion channel PIEZO1 were shown to ameliorate Plasmodium parasite growth, blood-brain barrier dysfunction, and mortality in a mouse model of malaria. In humans, the gain-of-function allele PIEZO1 E756del is highly prevalent and enriched in Africans, raising the possibility that it is under positive selection due to malaria. Here we used a case-control study design to test for an association between PIEZO1 E756del and malaria severity among children in Gabon. We found that the E756del variant is strongly associated with protection against severe malaria in heterozygotes, independent of the protection conferred by the sickle cell trait (hemoglobin AS). In vitro experiments using donor red blood cells failed to find an effect of E756del on parasite growth, suggesting this variant confers a mild channel defect and/or that its protective effect may be mediated by other tissue types in vivo. Nonetheless, we show that Yoda1, a small molecule agonist of PIEZO1, has potent antimalarial activity in both E756del and wild-type red blood cells. Our findings demonstrate that PIEZO1 is an important innate determinant of malaria susceptibility in humans and holds potential as druggable host target for malaria control.
IDR2D identifies reproducible genomic interactions
Authors: Krismer Konstantin , Guo Yuchun , Gifford David K.
Published: July 2019

Chromatin interaction data from protocols such as ChIA-PET, HiChIP, and HiC provide valuable insights into genome organization and gene regulation, but can include spurious interactions that do not reflect underlying genome biology. We introduce a generalization of the Irreproducible Discovery Rate (IDR) method called IDR2D that identifies replicable interactions shared by chromatin interaction experiments. IDR2D provides a principled set of interactions and eliminates artifacts from single experiments. The method is available as a Bioconductor package for the R community, as well as an online service at https://idr2d.mit.edu.
LKB1 negatively regulates AKT1 signaling via DBC1 and TRB3
Authors: Sarwar Zarka , Bhat Sameer , Gillani Qaaifah , Reshi Irfana , Nisa Misbah Un , Adelmant Guillaume , Marto Jarrod , Andrabi Shaida
Published: July 2019

DBC1 plays a critical role in various cellular functions notably cell proliferation, transcription, histone modification and adipogenesis. Current reports about the role of DBC1 in tumorigenesis are paradoxical and designate DBC1 both as a tumor suppressor or an oncogene. Here, using small T antigen of polyoma virus (PyST) as a tool, we have delineated a signaling mechanism that connects LKB1 to AKT1 via DBC1. We report that PyST associates with DBC1 and leads to its down-regulation. Our results also show that PyST expression promotes LKB1 activation which in turn leads to in the downregulation of DBC1 protein. Absence of DBC1 results in transcriptional upregulation and consequently enhanced protein levels of TRB3. TRB3 sequesters AKT1, and consequently the phosphorylation and activity of AKT1 is compromised. This ultimately results in inactivation of pro-survival pathways triggered via AKT1 signaling. Our studies thus provide an insight into a signaling pathway that connects LKB1, DBC1, TRB3 and AKT1.
Plasticity in aDrosophilawing circuit supports an adaptive sleep function
Authors: Melnattur K. , Zhang B. , Shaw P.J.
Published: July 2019

Sleep is a near universal phenomenon whose function remains controversial. An influential theory of sleep function posits that ecological factors that place animals in harm’s way increase sleep as a state of adaptive inactivity. Here we find that manipulations that impair flight inDrosophilaincrease sleep. Further, we identify a novel neural pathway from peripheral wing sensory neurons to the central brain that mediates the change in sleep. Moreover, we show that flight impairments activate and induce structural plasticity in specific projection neurons to support increases in sleep over days. Thus, chemosensory neurons do not only signal sensory cues but also appear to provide information on wing-integrity to support behavioural adaptability. Together, these data provide mechanistic support of adaptive increases in sleep and highlight the importance of behavioural flexibility for fitness and survival.
The naive T-cell receptor repertoire has an extremely broad distribution of clone sizes
Authors: de Greef Peter C. , Oakes Theres , Gerritsen Bram , Ismail Mazlina , Heather James M. , Hermsen Rutger , Chain Benjamin , de Boer Rob J.
Published: July 2019

The human naive T-cell receptor (TCR) repertoire is extremely diverse and accurately estimating its distribution is challenging. We address this challenge by combining a quantitative sequencing protocol of TCRA and TCRB sequences with computational modelling. We observed the vast majority of TCR chains only once in our samples, confirming the enormous diversity of the naive repertoire. However, a substantial number of sequences were observed multiple times within samples, and we demonstrated that this is due to expression by many cells in the naive pool. We reason that α and β chains are frequently observed due to a combination of selective processes and summation over multiple clones expressing these chains. We test the contribution of both mechanisms by predicting samples from phenomenological and mechanistically modelled repertoire distributions. By comparing these with sequencing data, we show that frequently observed chains are likely to be derived from multiple clones. Still, a neutral model of T-cell homeostasis cannot account for the observed distributions. We conclude that the data are only compatible with distributions of many small clones in combination with a sufficient number of very large naive T-cell clones, the latter most likely as a result of peripheral selection.