title: Global transcriptional regulation by cell-free supernatant of Salmonella Typhimurium peptide transporter mutant leads to inhibition of intra-species biofilm initiation

abstract:
Salmonella is a genus of widely spread Gram negative, facultative anaerobic bacteria, which is known to cause [1/4]th of diarrheal morbidity and mortality globally. It causes typhoid fever and gastroenteritis by gaining access to the host gut through contaminated food and water. Salmonella utilizes its biofilm lifestyle to strongly resist antibiotics and persist in the host. Although biofilm removal or dispersal has been studied widely, the inhibition of the initiation of Salmonella biofilm remains elusive. This study was conducted to determine the anti-biofilm property of the cell-free supernatant obtained from a carbon-starvation inducible proline peptide transporter mutant ({Delta}yjiY) strain. Our study shows that Salmonella {Delta}yjiY culture supernatant primarily inhibits biofilm initiation by regulating biofilm-associated transcriptional network. This work demonstrates that highly abundant proteases such as HslV and GrpE cleave the protein aggregates, whereas global transcription regulators H-NS, FlgM regulate expression of SPIs and flagellar genes. Relatively low abundances of flavoredoxin, glutaredoxin, thiol peroxidase etc. leads to accumulation of ROS within the biofilm, and subsequent toxicity. This work further suggests that targeting these oxidative stress relieving proteins might be a good druggable choice to reduce Salmonella biofilm.

ImportanceThe enteric pathogen Salmonella forms biofilm in the internal organs of asymptomatic carriers, and on abiotic surfaces that leads to contamination of food and water. Biofilms are highly drug-resistant life forms that also helps in host immune evasion. Therefore, recent insurgence of drug tolerant strains necessitates development of biofilm inhibitory strategies, and finding novel druggable targets. In this study we investigated the bioactive molecules present in the cell-free supernatant of a biofilm deficient strain of Salmonella Typhimurium that inhibit biofilm initiation by the wildtype strain. Further we showed that the supernatant treatment leads to virulence defect in vivo. Collectively, our results suggest a comprehensive view of virulence regulation in Salmonella by the cell-free supernatant of the biofilm deficient strain.


title: Global organization of neuronal activity only requires unstructured local connectivity

abstract: Modern electrophysiological recordings simultaneously capture single-unit spiking activities of hundreds of neurons spread across large cortical distances. Yet this massively parallel activity is often confined to relatively low-dimensional manifolds. This implies strong coordination also among neurons that are most likely not even connected. Here, we combine in vivo recordings with network models and theory to characterize the nature of mesoscopic coordination patterns in macaque motor cortex and to expose their origin: We find that heterogeneity in local connectivity supports network states with complex long-range cooperation between neurons that arises from multi-synaptic, short-range connections. Our theory explains the experimentally observed spatial organization of covariances in resting state recordings as well as the behaviorally related modulation of covariance patterns during a reach-to-grasp task. The ubiquity of heterogeneity in local cortical circuits suggests that the brain uses the described mechanism to flexibly adapt neuronal coordination to momentary demands.

category: neuroscience


title: The planning horizon for movement sequences

abstract:
When performing a long chain of actions in rapid sequence, future movements need to be planned concurrently with ongoing action. However, how far ahead we plan, and whether this ability improves with practice, is currently unknown. Here we designed an experiment in which healthy volunteers produced sequences of 14 finger presses quickly and accurately on a keyboard in response to numerical stimuli. On every trial, participants were only shown a fixed number of stimuli ahead of the current keypress. The size of this viewing window varied between 1 (next digit revealed with the pressing of the current key) and 14 (full view of the sequence). Participants practiced the task for five days and their performance was continuously assessed on random sequences. Our results indicate that participants used the available visual information to plan multiple actions into the future, but that the planning horizon was limited: receiving information about more than 3 movements ahead did not result in faster sequence production. Over the course of practice, we found larger performance improvements for larger viewing windows and an expansion of the planning horizon. These findings suggest that the ability to plan future responses during ongoing movement constitutes an important aspect of skillful movement. Based on the results, we propose a framework to investigate the neuronal processes underlying simultaneous planning and execution.

Significance StatementAlthough skill learning has typically focused on the training of specific movement sequences, practice improves performance even for random sequences. Here we hypothesize that a fundamental aspect of skilled sequential behavior is the ability to plan multiple actions into the future, both before and during execution. By controlling the amount of visual information available for motor planning, we show that people plan at least three movements beyond current action and that this planning horizon expands with practice. Our findings suggest that coordinating ongoing movement and planning of future actions is an essential component of skilled sequential behavior and offer testable predictions for the neural implementation of online motor planning.


title: Variability in infants functional brain network connectivity is associated with differences in affect and behavior

abstract: Variability in functional brain network connectivity has been linked to individual differences in cognitive, affective, and behavioral traits in adults. However, little is known about the developmental origins of such brain-behavior correlations. The current study examined functional brain network connectivity and its link to behavioral temperament in newborn and 1-month-old infants (M [age] = 25 days; N = 75) using functional near-infrared spectroscopy (fNIRS). Specifically, we measured long-range connectivity between cortical regions approximating fronto-parietal, default mode, and homologous-interhemispheric networks. Our results show that connectivity in these functional brain networks varies across infants and maps onto individual differences in behavioral temperament. Specifically, connectivity in the fronto-parietal network was positively associated with regulation and orienting behaviors, whereas connectivity in the default mode network showed the opposite effect on these behaviors. Our analysis also revealed a significant positive association between the homologous-interhemispheric network and infants negative affect. The current results suggest that variability in long-range intra-hemispheric and cross-hemispheric functional connectivity between frontal, parietal and temporal cortex is associated with individual differences in affect and behavior. These findings shed new light on the brain origins of individual differences in early-emerging behavioral traits and thus represent a viable novel approach for investigating developmental trajectories in typical and atypical neurodevelopment.


title: CLAMP and Zelda function together as pioneer transcription factors to promote Drosophila zygotic genome activation

abstract: During the essential and conserved process of zygotic genome activation (ZGA), chromatin accessibility must increase to promote transcription. Drosophila is a well-established model for defining mechanisms that drive ZGA. Zelda (ZLD) is a key pioneer transcription factor (TF) that promotes ZGA in the Drosophila embryo. However, many genomic loci that contain GA-rich motifs become accessible during ZGA independent of ZLD. Therefore, we hypothesized that other early TFs that function with ZLD have not yet been identified, especially those that are capable of binding to GA-rich motifs such as CLAMP. Here, we demonstrate that Drosophila embryonic development requires maternal CLAMP to: 1) activate zygotic transcription; 2) increase chromatin accessibility at promoters of specific genes that often encode other essential TFs; 3) enhance chromatin accessibility to facilitate ZLD occupancy at a subset of key embryonic promoters. Thus, maternal CLAMP functions with ZLD in a pioneer-like role to drive zygotic genome activation.

category: genomics


title: CLAMP and Zelda function together to promote Drosophila zygotic genome activation


title: Re-exposure to a sensorimotor perturbation produces opposite effects on explicit and implicit learning processes

abstract: The motor system demonstrates an exquisite ability to adapt to changes in the environment, and to quickly reset when these changes prove transient. If similar environmental changes are encountered in the future, learning may be faster, a phenomenon known as savings. In studies of sensorimotor learning, a central component of savings is attributed to the explicit recall of the task structure and appropriate compensatory strategies. Whether implicit adaptation also contributes to savings remains subject to debate (Leow et al., 2020; Yin and Wei, 2020). We tackled this question by measuring, in parallel, explicit and implicit adaptive responses in a visuomotor rotation task, employing a protocol that typically elicits savings. While the initial rate of learning was faster in the second exposure to the perturbation, an analysis decomposing the two processes showed the benefit to be solely associated with explicit re-aiming. Surprisingly, we found a significant decrease after relearning in aftereffect magnitudes during no-feedback trials, a direct measure of implicit adaptation. In a second experiment, we isolated implicit adaptation using clamped visual feedback, a method known to eliminate the contribution of explicit learning processes. Consistent with the results of the first experiment, participants exhibited a marked reduction in the adaptation function, as well as an attenuated aftereffect when re-learning from the clamped feedback. Motivated by these results, we re-analyzed data from prior studies and observed a consistent, yet unappreciated pattern of attenuation of implicit adaptation during relearning. These results indicate that explicit and implicit sensorimotor processes exhibit opposite effects upon relearning: Explicit learning shows savings, while implicit adaptation becomes attenuated.


title: Cas9 fusions for precision in vivo editing

abstract: Cas9 targets genomic loci with high specificity. When used for knockin, however, Cas9 often leads to unintended on-target knockout rather than intended edits. This imprecision is a barrier for direct in vivo editing where clonal selection is not feasible. Here we demonstrate a high-throughput workflow to ratiometrically assess on-target efficiency and precision of editing outcomes. Using this workflow, we screened combinations of donor DNA and Cas9 variants, as well as fusions to DNA repair proteins. This yielded novel high-performance double-strand break repair editing agents and combinatorial optimizations with orders-of-magnitude increases in knockin precision. Cas9-RC, a novel Cas9 fusion to eRad18 and CtIP, increased knockin performance over 3-fold in vitro and in vivo in the developing mouse brain. Continued comparative assessment of existing and novel editing agents with this ratiometric framework of efficiency and precision will further the development of direct in vivo knockin and future genetic therapies.

category: synthetic biology


title: Mitochondria-dependent phase separation of disease-relevant proteins drives pathological features of age-related macular degeneration

abstract: Age-related macular degeneration (AMD) damages the retinal pigment epithelium (RPE), the tissue that safeguards photoreceptor health, leading to irreversible vision loss. Polymorphisms in cholesterol and complement genes are implicated in AMD, yet mechanisms linking risk variants to RPE injury remain unclear. We sought to determine how allelic variants in the apolipoprotein E cholesterol transporter modulate RPE homeostasis and function. Using live-cell imaging, we show that inefficient cholesterol transport by the AMD risk-associated ApoE2 increases RPE ceramide, leading to autophagic defects and complement-mediated mitochondrial damage. Mitochondrial injury drives redox state-sensitive cysteine-mediated phase separation of ApoE2, forming biomolecular condensates that could nucleate drusen. The protective ApoE4 isoform lacks these cysteines and is resistant to phase separation and condensate formation. In Abca4-/- Stargardt macular degeneration mice, mitochondrial dysfunction induces liquid-liquid phase separation of p62/SQSTM1, a multifunctional protein that regulates autophagy. Drugs that decrease RPE cholesterol or ceramide prevent mitochondrial injury and phase separation in vitro and in vivo. In AMD donor RPE, mitochondrial fragmentation correlates with ApoE and p62 condensates. Our studies demonstrate that major AMD genetic and biological risk pathways converge upon RPE mitochondria, and identify mitochondrial stress-mediated protein phase separation as an important pathogenic mechanism and promising therapeutic target in AMD.


title: Long-read-sequenced reference genomes of the seven major lineages of enterotoxigenic Escherichia coli (ETEC) circulating in modern time

abstract:
BackgroundEnterotoxigenic Escherichia coli (ETEC) is an enteric pathogen responsible for the majority of diarrheal cases worldwide. ETEC infections are estimated to cause 80,000 fatalities per year, with the highest rates of burden, ca 75 million cases per year, amongst children under five years of age in resource-poor countries. It is also the leading cause of diarrhoea in travellers. Previous large-scale sequencing studies have found seven major ETEC lineages currently in circulation worldwide.

ResultsWe used PacBio long-read sequencing combined with Illumina sequencing to create high-quality complete reference genomes for each of the major lineages with manually curated chromosomes and plasmids. The plasmids carrying ETEC virulence genes were compared to other available long-read sequenced ETEC strains using blastn. The ETEC reference strains harbour between two and five plasmids, including virulence, antibiotic resistance and phage-plasmids. The virulence plasmids carrying the colonisation factors are highly conserved as shown by comparison with plasmids with other ETEC strains and confirm that the plasmids and chromosomes of ETEC are both crucial for ETEC virulence and success as pathogens.

ConclusionWe confirm that the major ETEC lineages all harbour conserved plasmids that have been associated with their respective background genomes for decades. The in-depth analysis of gene content, synteny and correct annotations of plasmids will elucidate other plasmids with and without virulence factors in related bacterial species. These reference genomes allow for fast and accurate comparison between different ETEC strains, and these data will form the foundation of ETEC genomics research for years to come.


title: Retinoic acid fluctuation activates an uneven, direction-dependent network-wide robustness response in early embryogenesis

abstract: Robustness is a feature of regulatory pathways to ensure signal consistency in light of environmental changes or genetic polymorphisms. The retinoic acid (RA) pathway, is a central developmental and tissue homeostasis regulatory signal, strongly dependent on nutritional sources of retinoids and affected by environmental chemicals. This pathway is characterized by multiple proteins or enzymes capable of performing each step and their integration into a self-regulating network. We studied RA network robustness by transient physiological RA signaling disturbances followed by kinetic transcriptomic analysis of the recovery during embryogenesis. The RA metabolic network was identified as the main regulated module to achieve signaling robustness using an unbiased pattern analysis. We describe the network-wide responses to RA signal manipulation and found the feedback autoregulation to be sensitive to the direction of the RA perturbation: RA knockdown exhibited an upper response limit, whereas RA addition had a minimal feedback-activation threshold. Surprisingly, our robustness response analysis suggests that the RA metabolic network regulation exhibits a multi-objective optimization, known as Pareto optimization, characterized by trade-offs between competing functionalities. We observe that efficient robustness to increasing RA is accompanied by worsening robustness to reduced RA levels and vice versa. This direction-dependent trade-off in the network-wide feedback response, results in an uneven robustness capacity of the RA network during early embryogenesis, likely a significant contributor to the manifestation of developmental defects.

category: developmental biology


title: Sense the Moment: a highly sensitive antimicrobial activity predictor based on hydrophobic moment

abstract:
BackgroundComputer-aided identification and design tools are indispensable for developing antimicrobial agents for controlling antibiotic-resistant bacteria. Antimicrobial peptides (AMPs) have aroused intense interest, since they have a broad spectrum of activity, and therefore, several systems for predicting antimicrobial peptides have been developed, using scalar physicochemical properties; however, regardless of the machine learning algorithm, these systems often fail in discriminating AMPs from their shuffled versions, leading to the need for new training methods to overcome this bias. Aiming to solve this bias, here we present "Sense the Moment", a prediction system capable of discriminating AMPs and shuffled versions.

MethodsThe system was trained using 776 entries: 388 from known AMPs and another 388 based on shuffled versions of known AMPs. Each entry contained the geometric average of three hydrophobic moments measured with different scales.

ResultsThe model showed good accuracy (>80 %) and excellent sensitivity (>90 %) for AMP prediction, exceeding deep-learning-based methods.

ConclusionOur results demonstrate the systems applicability, aiding in identifying and discarding non-AMPs, since the number of false negatives is lower than false positives. General Significance: The application of this model in virtual screening protocols for identifying and/or creating antimicrobial agents could aid in the identification of potential drugs to control pathogenic microorganisms and in solving the antibiotic resistance crisis.

AvailabilityThe system was implemented as a web application, available at <http://portoreports.com/stm/>.

category: bioinformatics


title: Pathogen-driven coevolution across CBP60 plant immune regulator subfamilies confers resilience on the regulator module

abstract: Among eight Arabidopsis CaM-Binding Protein (CBP) 60 family members, AtCBP60g and AtSARD1 are partially functionally redundant, major positive immune regulators while AtCBP60a is a negative immune regulator. Phylogenetic analysis of CBP60 protein sequences of 247 diverse land plant species indicated that the CBP60a, CBP60g, and SARD1 immune regulator subfamilies diversified around the time of Angiosperm divergence. The immune regulator subfamilies, especially the CBP60g subfamily, have been evolving very fast, suggesting strong selection pressure from CBP60-targeting pathogen effectors. We closely examined this fast evolution of the immune regulator subfamilies using the subfamily protein sequences from 12 diverse Core Eudicot species. The fast evolution was caused by both high proportions of polymorphic sites and high evolution rates per polymorphic site, compared to the genomic norm. We developed an analytical platform for physical-chemical characteristics of amino acids, called Protein Evolution Analysis in Euclidean Space (PEAES). Using the pairwise distance rank on PEAES (PEAES-PDR), we detected signatures of significant coevolutionary interactions across the immune regulator subfamilies within the CBP60-conserved domain. The patterns of detected coevolutionary interactions were consistent with hypothetical coevolutionary mechanisms that protect the positive immune regulator function from targeting by pathogen effectors. The coevolutionary interactions across the subfamilies were largely specific to each species lineage, suggesting that the coevolution occurred through species lineage-specific histories of variable pathogen pressure. Thus, fast coevolution of the subfamilies with overlapping or opposing functions appears crucial to maintain resilience of the CBP60 immune regulator module against fast-evolving pathogen effectors.

category: evolutionary biology


title: Trade-off between reducing mutational accumulation and increasing commitment to differentiation determines tissue organization

abstract: Species-specific differences control cancer risk across orders of magnitude variation in body size and lifespan, e.g., by varying the copy numbers of tumor suppressor genes. It is unclear, however, how different tissues within an organism can control somatic evolution despite being subject to markedly different constraints, but sharing the same genome. Hierarchical differentiation, characteristic of self-renewing tissues, can restrain somatic evolution both by limiting divisional load, thereby reducing mutation accumulation, and by increasing cells commitment to differentiation, which can "wash out" mutants. Here, we explore the organization of hierarchical tissues that have evolved to limit their lifetime incidence of cancer. Estimating the likelihood of cancer in the presence of mutations that enhance self-proliferation, we demonstrate that a trade-off exists between mutation accumulation and the strength of washing out. Our results explain differences in the organization of widely different hierarchical tissues, such as colon and blood.


title: Interleukin-10 suppression enhances T-cell antitumor immunity and responses to checkpoint blockade in chronic lymphocytic leukemia

abstract: T-cell dysfunction is a hallmark of B-cell Chronic Lymphocytic Leukemia (CLL), where CLL cells downregulate T-cell responses through regulatory molecules including programmed death ligand-1 (PD-L1) and Interleukin-10 (IL-10). Immune checkpoint blockade (ICB) aims to restore T-cell function by preventing the ligation of inhibitory receptors like PD-1. However, most CLL patients do not respond well to this therapy. Thus, we investigated whether IL-10 suppression could enhance antitumor T-cell activity and responses to ICB. Since CLL IL-10 expression depends on Sp1, we utilized a novel, better tolerated analogue of the Sp1 inhibitor mithramycin (MTMox32E) to suppress CLL IL-10. MTMox32E treatment inhibited mouse and human CLL IL-10 production and maintained T-cell effector function in vitro. In the E-Tcl1 mouse model, treatment reduced plasma IL-10 and CLL burden and increased CD8+ T-cell proliferation, effector and memory cell prevalence, and interferon-{gamma} production. When combined with ICB, suppression of IL-10 improved responses to anti-PD-L1 as shown by a 4.5-fold decrease in CLL cell burden compared to anti-PD-L1 alone. Combination therapy also produced more interferon-{gamma}+, cytotoxic effector KLRG1+, and memory CD8+ T-cells, and fewer exhausted T-cells. Since current therapies for CLL do not target IL-10, this provides a novel strategy to improve immunotherapies.

category: immunology


title: Targeted intragenic demethylation initiates chromatin rewiring for gene activation

abstract:
Aberrant DNA methylation in the region surrounding the transcription start site is a hallmark of gene silencing in cancer. Currently approved demethylating agents lack specificity and exhibit high toxicity. Herein we show, using the p16 gene as an example, that targeted demethylation of the promoter-exon 1-intron 1 (PrExI) region initiates an epigenetic wave of local chromatin remodeling and distal long-range interactions, culminating in gene-locus specific activation. Through development of CRISPR-DiR (DNMT1-interacting RNA), in which ad hoc edited guides block methyltransferase activity in a locus-specific fashion, we demonstrate that demethylation is coupled to epigenetic and topological changes. These results suggest the existence of a specialized "demethylation firing center (DFC)" which can be switched on by an adaptable and selective RNA-mediated approach for locus-specific transcriptional activation.

One Sentence SummaryLocus demethylation via CRISPR-DiR reshapes chromatin structure and specifically reactivates its cognate gene.

category: genetics


title: Nef enhances HIV-1 replication and infectivity independently of SERINC3 and SERINC5 in CEM T cells

abstract: The authors have withdrawn their manuscript whilst they perform additional experiments to test some of their conclusions further. They found upon resequencing DNA from the cell lines used in their study that non-CRISPR edited genomes dominated the cultures. They believed they had confirmed complete editing in single-cell clones at the outset. Therefore, they are not confident based on their current experiments that the virologic effect of HIV-1 Nef is independent of SERINC3 and SERINC5 in T cells of the leukemic CEM line as they originally claimed. They are reengineering the cells to resolve this and apologize for any inconvenience that this has caused. Therefore, the authors do not wish this work to be cited as a reference for the project. If you have any questions, please contact the corresponding author.

category: microbiology


title: Parametric tests for Leave-One-Out Inter-Subject Correlations in fMRI provide adequate Type I error control while providing high sensitivity

abstract: The inter-subject correlation (ISC) of fMRI data of different subjects performing the same task is a powerful way to localize and differentiate neural processes caused by a stimulus from those that spontaneously or idiosyncratically take place in each subject. The wider adoption of this method has however been impeded by the lack of widely available tools to assess the significance of the observed correlations. Several non-parametric approaches have been proposed, but these approaches are computationally intensive, challenging to implement, and sensitive methods to correct for multiple comparison across voxels are not yet well established. More widely available, and computationally simple, parametric methods have been criticized theoretically on the basis that dependencies in the data could inflate false positives. Here, we therefore endeavored to assess the actual performance of parametric tests on leave-one-out ISC values in two ways. First, we assess whether parametric tests protect against Type I error by assessing how often they find significant clusters of synchronized activity in publicly available datasets, in which such synchronization should not occur. This includes three resting state datasets, and one dataset in which participants did view movies, but where we randomly select segments that were not taken at the same time in the same movie. Contrary to what has been suspected, we find that parametric tests with corrections for multiple comparisons do protect appropriately against Type I error in that data. This was true for FDR correction at the voxel level at q < 0.05, with a minimum cluster-size of k = 20 voxels, FWE correction at the voxel level at  < 0.05, with a minimum cluster-size of k = 5, and for correction at the cluster-level with punc < 0.001 with k = max(20, FWEc). Second, we assessed how these parametric tests compare with non-parametric methods when it comes to detecting ISC when participants actually did watch the same movies. We used a dataset including 150 participants viewing two movies, and used a bootstrapping thresholding of the ISC in the entire dataset to outline our best guess of the network of brain regions that truly synchronize while viewing the movies. We then drew subsamples of between 10 and 50 participants from the entire dataset, calculated the ISC, and thresholded it using our candidate methods. We find that FDR thresholding with k = 20 in particular, was substantially more sensitive than bootstrapping methods in detecting this network even in smallish samples of N = 20 participants typical of cognitive neuroscience studies, while at the same time retaining appropriate specificity. Because the parametric tests we show to perform well are more readily available to the neuroscience community than the non-parametric tests previously championed, we trust that this finding paves the way to a wider adoption of ISC, and empowers a wider range of neuroimagers to use ISC to tackle the challenges of naturalistic neuroscience. In particular in the context of often limited sample sizes and modest effect sizes in cognitive neuroscience, we trust that using FDR correction in particular will help neuroimagers identify the contribution of higher brain regions that process stimuli in more loosely timed fashions, more effectively than non-parametric alternatives.


title: Tau in the brain interstitial fluid is fragmented and seeding-competent

abstract:
In Alzheimer disease, Tau pathology is thought to propagate from cell to cell throughout interconnected brain areas. However, the forms of Tau released into the brain interstitial fluid (ISF) in vivo during the development of Tauopathy and their pathological relevance remain unclear. Combining in vivo microdialysis and biochemical analysis, we find that in Tau transgenic mice, human Tau (hTau) present in brain ISF is truncated and comprises at least 10 distinct fragments spanning the entire Tau protein. The fragmentation pattern is similar across different Tau transgenic models, pathological stages and brain areas. ISF hTau concentration decreases during Tauopathy progression, while its phosphorylation increases. ISF from mice with established Tauopathy induces Tau aggregation in HEK293-Tau biosensor cells. Notably, immunodepletion of ISF phosphorylated Tau, but not Tau fragments, significantly reduces its ability to seed Tau aggregation and only a fraction of Tau, separated by ultracentrifugation, is seeding competent. These results indicate that ISF seeding competence is driven by a small subset of Tau, which potentially contribute to the propagation of Tau pathology.

HighlightsO_LIIn interstitial fluid (ISF) of transgenic mice, Tau comprises >10 distinct fragments
C_LIO_LIISF Tau decreases with Tauopathy progression, while its phosphorylation increases
C_LIO_LIOnly ISF from mice with established Tauopathy is seeding competent in vitro
C_LIO_LIRemoval of phospho-Tau reduces ISF seeding competence
C_LIO_LIISF seeding competence is driven by less soluble, aggregated and phosphorylated Tau
C_LI

Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY


title: Mechanical overstimulation causes acute injury and synapse loss followed by fast recovery in lateral-line neuromasts of larval zebrafish

abstract: Excess noise damages sensory hair cells, resulting in loss of synaptic connections with auditory nerves and, in some cases, hair-cell death. The cellular mechanisms underlying mechanically induced hair-cell damage and subsequent repair are not completely understood. Hair cells in neuromasts of larval zebrafish are structurally and functionally comparable to mammalian hair cells but undergo robust regeneration following ototoxic damage. We therefore developed a model for mechanically induced hair-cell damage in this highly tractable system. Free swimming larvae exposed to strong water wave stimulus for 2 hours displayed mechanical injury to neuromasts, including afferent neurite retraction, damaged hair bundles, and reduced mechanotransduction. Synapse loss was observed in apparently intact exposed neuromasts, and this loss was exacerbated by inhibiting glutamate uptake. Mechanical damage also elicited an inflammatory response and macrophage recruitment. Remarkably, neuromast hair-cell morphology and mechanotransduction recovered within hours following exposure, suggesting severely damaged neuromasts undergo repair. Our results indicate functional changes and synapse loss in mechanically damaged lateral-line neuromasts that share key features of damage observed in noise-exposed mammalian ear. Yet, unlike the mammalian ear, mechanical damage to neuromasts is rapidly reversible.


title: Incorporating genome-based phylogeny and functional similarity into diversity assessments helps to resolve a global collection of human gut metagenomes

abstract:
Tree-based diversity measures incorporate phylogenetic or functional relatedness into comparisons of microbial communities. This can improve the identification of explanatory factors compared to tree-agnostic diversity measures. However, applying tree-based diversity measures to metagenome data is more challenging than for single-locus sequencing (e.g., 16S rRNA gene). The Genome Taxonomy Database (GTDB) provides a genome-based reference database that can be used for species-level metagenome profiling, and a multi-locus phylogeny of all genomes that can be employed for diversity calculations. This approach also allows for functional diversity measures based on genomic content or traits inferred from it. Still, it is unclear how metagenome-based assessments of microbiome diversity benefit from incorporating phylogeny or function into measures of diversity. We assessed this by measuring phylogeny-based, function-based, and tree-agnostic diversity measures from a large, global collection of human gut metagenomes composed of 33 studies and 3348 samples. We found tree-based measures to explain phenotypic variation (e.g., westernization, disease status, and gender) better or on par with tree-agnostic measures. Ecophylogenetic and functional diversity measures provided unique insight into how microbiome diversity was partitioned by phenotype. Tree-based measures greatly improved machine learning model performance for predicting westernization, disease status, and gender, relative to models trained solely on tree-agnostic measures. Notably, ecophylogenetic and functional diversity measures were generally the most important features for predictive performance. Our findings illustrate the usefulness of tree- and function-based measures for metagenomic assessments of microbial diversity - a fundamental component of microbiome science.

ImportanceEstimations of microbiome diversity are fundamental to understanding spatiotemporal changes of microbial communities and identifying which factors mediate such changes. Tree-based measures of diversity, which consider species relatedness, are widespread for amplicon-based microbiome studies due to their utility relative to tree-agnostic measures. However, tree-based measures are seldomly applied to shotgun metagenomics data. We evaluated the utility of phylogeny, functional relatedness, and tree-agnostic diversity measures on a large scale human gut metagenome dataset to help guide researchers with the complex task of evaluating microbiome diversity via metagenomics.


title: Localized nanoscale induction by single domain magnetic particles

abstract:
Single domain magnetic nanoparticles are increasingly investigated as actuators of biological and chemical processes that respond to externally applied magnetic fields. Although their localized effects are frequently attributed to nanoscale heating, recent experimental evidence casts doubt on the existence of nanoscale temperature gradients in these systems. Here, using the stochastic Landau-Lifshitz-Gilbert equation and finite element modelling, we critically examine an alternative hypothesis that localized effects may be mediated by the induced electric fields arising from the detailed dynamical behavior of individual single domain magnetic particles. We apply our model to two significant case studies of magnetic nanoparticles in alternating magnetic fields: 1) magnetogenetic stimulation of channel proteins associated with ferritin and 2) catalytic enhancement of electrochemical hydrolysis. For the first case, while the local electric fields that ferritin generates are shown to be insufficient to perturb the transmembrane potential, fields on the surface of its mineral core on the order of 102 to 103 V/m may play a role in mass transport or release of iron ions that indirectly lead to stimulation. For the second case, our model indicates electric fields of approximately 300 V/m on the surface of the catalytic particles, with the highest interfacial electric field strengths expected during reversal events. This suggests that the nanoparticles best suited for hysteresis heating would also act as intermittent sources of localized induced electric fields in response to an alternating applied field. Finally, we put the magnitude and timescale of these electric fields in the context of technologically relevant phenomena, showing that they are generally weaker and faster.

Popular SummaryThe possibility of using magnetic fields to exert wireless control over biological or chemical processes has stimulated vigorous research efforts across disciplines. Magnetic nanoparticles exposed to alternating magnetic fields have repeatedly been found to exert an influence at the nanoscale, for instance triggering biological responses or regulating chemical catalysis. While these effects have been attributed to nanoscale heating, recent experiments have shown that the temperature in the vicinity of magnetic nanoparticles may not differ appreciably from their surroundings. Could another nanoscale phenomenon be at work?

Here, we critically examined the idea that electric fields induced in the immediate vicinity of magnetic nanoparticles might help explain nanoscale effects. The fact that magnetic nanoparticles thermally fluctuate is widely appreciated, but the process that dominates the generation of electric fields is the rapid (typically > 1 GHz) precession that the magnetic moment undergoes during reversal events. Combining a model of the detailed motion of a single magnetic moment with numerical calculation of the induced electric field, we consider the possible role of induced electric fields in two technologically important cases. The first is stimulation of neurons with weakly magnetic ferritin and the second is enhancement of hydrogen production by catalytic magnetic nanoparticles.

Understanding the mechanism by which magnetic nanoparticles act on their surroundings is crucial to designing more optimal materials for triggering chemical and biological processes. The role of electric fields explored here also suggests the possibility of pairing magnetic nanoparticles with resonant stimuli to directly drive precession.


title: Demography, education, and research trends in the interdisciplinary field of disease ecology

abstract: Micro- and macroparasites are a leading cause of mortality for humans, animals, and plants, and there is great need to understand their origins, transmission dynamics, and impacts. Disease ecology formed as an interdisciplinary field in the 1970s to fill this need and has recently rapidly grown in size and influence. Because interdisciplinary fields integrate diverse scientific expertise and training experiences, understanding their composition and research priorities is often difficult. Here, for the first time, we quantify the composition and educational experiences of a subset of disease ecology practitioners and identify topical trends in published research. We combined a large survey of self-declared disease ecologists with a literature synthesis involving machine-learning topic detection of over 18,500 disease ecology research articles. The number of graduate degrees earned by disease ecology practitioners has grown dramatically since the early 2000s. Similar to other science fields, we show that practitioners in disease ecology have diversified in the last decade in terms of gender identity and institution, with weaker diversification in race and ethnicity. Topic detection analysis revealed how the frequency of publications on certain topics have declined (e.g., HIV, serology), increased (e.g., the dilution effect, infectious disease in bats), remained relatively common (e.g., malaria ecology, influenza, vaccine research and development), or have consistently remained relatively infrequent (e.g., theoretical models, field experiments). Other topics, such as climate change, superspreading, emerging infectious diseases, and network analyses, have recently come to prominence. This study helps identify the major themes of disease ecology and demonstrates how publication frequency corresponds to emergent health and environmental threats. More broadly, our approach provides a framework to examine the composition and publication trends of other major research fields that cross traditional disciplinary boundaries.

category: ecology


title: A Self-Replicating Radiation-Shield for Human Deep-Space Exploration: Radiotrophic Fungi can Attenuate Ionizing Radiation aboard the International Space Station

abstract:
The greatest hazard for humans on deep-space exploration missions is radiation. To protect astronauts venturing out beyond Earths protective magnetosphere, advanced passive radiation protection is highly sought after. In search of innovative radiation-shields, biotechnology appeals with suitability for in-situ resource utilization (ISRU), self-regeneration, and adaptability.

Certain fungi thrive in high-radiation environments on Earth, such as the contamination radius of the Chernobyl Nuclear Power Plant. Analogous to photosynthesis, these organisms appear to perform radiosynthesis, utilizing ionizing radiation to generate chemical energy. It has been postulated that the absorption of radiation is attributable to the pigment melanin. It is further hypothesized that this phenomenon translates to radiation-shielding properties.

Here, growth of Cladosporium sphaerospermum and its capability to attenuate ionizing radiation, was studied aboard the International Space Station (ISS) over a period of 26 days, as an analog to habitation on the surface of Mars. At full maturity, radiation beneath a {approx} 1.7 mm thick lawn of the dematiaceous radiotrophic fungus was approx. 0.84% lower as compared to the negative-control. In addition, a growth advantage in Space of [~] 21% was observed, substantiating the thesis that the fungus radiotropism is extendable to Space radiation.


title: Growth of the Radiotrophic Fungus Cladosporium sphaerospermum aboard the International SpaceStation and Effects of Ionizing Radiation


title: A neuromechanical model for Drosophila larval crawling based on physical measurements

abstract: Animal locomotion requires dynamic interactions between neural circuits, muscles, and surrounding environments. In contrast to intensive studies on neural circuits, the neuromechanical basis for animal behaviour remains unclear due to the lack of information on the physical properties of animals. Here, we proposed an integrated neuromechanical model based on physical measurements by taking Drosophila larvae as a model of soft- bodied animals. The biomechanical parameters of fly larvae were measured by the stress- relaxation test. By optimizing parameters in the neural circuit, our neuromechanical model succeeded in quantitatively reproducing the kinematics of larval locomotion that were obtained experimentally. This model could reproduce the observation of optogenetic studies reported previously. The model predicted that peristaltic locomotion could be exhibited in a low friction condition. Analysis of floating larvae provided results consistent with this prediction. Furthermore, the model predicted a significant contribution of intersegmental connections in the central nervous system, which contrasts with a previous study. This hypothesis allowed us to make a testable prediction for the variability in intersegmental connection in sister species of the genus Drosophila. Our model based on physical measurement provides a new foundation to study locomotion in soft-bodied animals and soft robot engineering.


title: Time-dependent inhibition of covert shift of attention

abstract: Visual transients can interrupt overt orienting by abolishing the execution of a planned eye movement due about 90 ms later, a phenomenon known as saccadic inhibition (SI). It is not known if the same inhibitory process might influence covert orienting in the absence of saccades, and consequently alter visual perception. In Experiment 1 (n=14), we measured orientation discrimination during a covert orienting task in which an uninformative exogenous visual cue preceded the onset of an oriented probe by 140 to 290 ms. In half of the trials the onset of the probe was accompanied by a brief irrelevant flash, a visual transient that would normally induce SI. We report a time-dependent inhibition of covert orienting in which the irrelevant flash impaired orientation discrimination accuracy when the probe followed the cue by 190 and 240 ms. The interference was more pronounced when the cue was incongruent with the probe location, suggesting an impact on the reorienting component of the attentional shift. In Experiment 2 (n=12), we tested whether the inhibitory effect of the flash could occur within an earlier time range, or only within the later, reorienting range. We presented probes at congruent cue locations in a time window between 50 to 200 ms. Similarly to Experiment 1, discrimination performance was altered at 200 ms after the cue. We suggest that covert attention may be susceptible to similar inhibitory mechanisms that generate SI, especially in later stages of attentional shifting (> 200ms after a cue), typically associated with reorienting.


title: The long non-coding RNA Pax6os1/PAX6-AS1 modulates pancreatic beta cell identity and function.

abstract: Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of {beta}-cell development and function. Here, we investigate roles for an antisense lncRNA expressed from the Pax6 locus (annotated as Pax6os1 in mice and PAX6-AS1 in humans) in {beta}-cell function. Pax6os1/PAX6-AS1 expression was increased in islets from mice fed a high fat diet and in those from patients with type 2 diabetes. Silencing or deletion of Pax6os1/PAX6-AS1 in MIN6 and EndoC-{beta}H1cells, respectively, upregulated {beta}-cell signature genes, including Insulin. Moreover, shRNA-mediated silencing of PAX6-AS1 in human islets increased insulin mRNA, enhanced glucose-stimulated insulin secretion and calcium dynamics, while overexpressing the lncRNA reduced insulin expression and secretion. Together, our results suggest that increased expression of PAX6-AS1 at high glucose levels may contribute to {beta}-cell dedifferentiation and failure in some forms of type 2 diabetes. Thus, targeting PAX6-AS1 may provide a promising strategy to enhance insulin secretion and improve glucose homeostasis in this disease.

category: cell biology


title: The regulatory landscape of Arabidopsis thaliana roots at single-cell resolution

abstract: In plants, chromatin accessibility - the primary mark of regulatory DNA - is relatively static across tissues and conditions. This scarcity of accessible sites that are dynamic or tissue-specific may be due in part to tissue heterogeneity in previous bulk studies. To assess the effects of tissue heterogeneity, we apply single-cell ATAC-seq to A. thaliana roots and identify thousands of differentially accessible sites, sufficient to resolve all major cell types of the root. However, even this vast increase relative to bulk studies in the number of dynamic sites does not resolve the poor correlation at individual loci between accessibility and expression. Instead, we find that the entirety of a cells regulatory landscape and its transcriptome each capture cell type identity independently. We leverage this shared information on cell identity to integrate accessibility and transcriptome data in order to characterize developmental progression, endoreduplication and cell division in the root. We further use the combined data to characterize cell type-specific motif enrichments of large transcription factor families and to link the expression of individual family members to changing accessibility at specific loci, taking the first steps toward resolving the direct and indirect effects that shape gene expression. Our approach provides an analytical framework to infer the gene regulatory networks that execute plant development.


title: Y705 and S727 are required for mitochondrial import and transcriptional activities of STAT3 and regulate proliferation of embryonic and tissue stem cells

abstract: The STAT3 transcription factor, acting both in the nucleus and mitochondria, maintains embryonic stem cell pluripotency and promotes their proliferation. In this work, using zebrafish, we determined in vivo that mitochondrial STAT3 regulates mtDNA transcription in embryonic and larval stem cell niches and that this activity affects their proliferation rates. As a result, we demonstrated that STAT3 import inside mitochondria requires Y705 phosphorylation by Jak2, while its mitochondrial transcriptional activity, as well as its effect on proliferation, depends on the MAPK target S727. These data were confirmed using mouse embryonic stem cells: Y705 mutated STAT3 cannot enter the mitochondrion while the S727 mutation does not affect mitochondrial import of the protein. Surprisingly, STAT3-dependent increase of mitochondrial transcription seems independent from STAT3 binding to STAT3 responsive elements. Finally, loss of function experiments, with chemical inhibition of JAK/STAT3 pathway or genetic ablation of stat3 gene, demonstrated that STAT3 is also required for cell proliferation in the intestine of zebrafish.


title: Free-fatty acid receptor 4 inhibitory signaling in delta cells regulates islet hormone secretion in mice

abstract:
ObjectiveMaintenance of glucose homeostasis requires the precise regulation of hormone secretion from the endocrine pancreas. Free fatty-acid receptor 4 (FFAR4/GPR120) is a G protein-coupled receptor whose activation in islets of Langerhans promotes insulin and glucagon secretion and inhibits somatostatin secretion. However, the contribution of individual islet cell types (, {beta}, and {delta} cells) to the insulinotropic and glucagonotropic effects of GPR120 remains unclear. As gpr120 mRNA is enriched in somatostatin-secreting {delta} cells, we hypothesized that GPR120 activation stimulates insulin and glucagon secretion via inhibition of somatostatin release.

MethodsGlucose tolerance tests were performed in mice after administration of the selective GPR120 agonist Compound A. Insulin, glucagon and somatostatin secretion were measured in static incubations of isolated mouse islets in response to endogenous ({omega}-3 polyunsaturated fatty acids) and/or pharmacological (Compound A and AZ-13581837) GPR120 agonists. The effect of Compound A on hormone secretion was tested further in islets isolated from mice with global or somatostatin cell-specific knockout of gpr120. Gpr120 expression was assessed in pancreatic sections by RNA in situ hybridization. Cyclic AMP (cAMP) and calcium dynamics in response to pharmacological GPR120 agonists were measured specifically in , {beta} and {delta} cells in intact islets using cAMPER and GCaMP6 reporter mice, respectively.

ResultsAcute exposure to Compound A increased glucose tolerance and circulating insulin and glucagon levels in vivo. Endogenous and/or pharmacological and GPR120 agonists reduced somatostatin secretion in isolated islets and concomitantly demonstrated dose-dependent potentiation of glucose-stimulated insulin secretion and arginine-stimulated glucagon secretion. Gpr120 was enriched in {delta} cells. Pharmacological GPR120 agonists reduced cAMP and calcium levels in {delta} cells but increased these signals in  and {beta} cells. Compound A-mediated inhibition of somatostatin secretion was insensitive to pertussis toxin. The effect of Compound A on hormone secretion was completely absent in islets from mice with either global or somatostatin cell-specific deletion of gpr120 and was partially reduced upon blockade of somatostatin receptor signaling by cyclosomatostatin.

ConclusionsInhibitory GPR120 signaling in {delta} cells contributes to both insulin and glucagon secretion in part via mitigating somatostatin release.


title: A genomic link in China roses: and they all lived prickly but water deficient ever after?

abstract: Prickles act against herbivores, pathogens or mechanical injury, while also prevent water loss. However, whether prickles have new function and the molecular genetics of prickle patterning remains poorly explored. Here, we generated a high-quality reference genome assembly for  Basyes Thornless (BT), a prickle-free cultivar of Rosa wichuraiana, to identify genetic elements related to stem prickle development. The BT genome harbors a high level of sequence diversity in itself and between cultivar  Old Blush (R. chinensis), a founder genotype in rose domestication. Inheritance of stem prickle density was determined and two QTL were identified. Differentially expressed genes in QTL were involved in water-related functions, suggesting that prickle density may hitchhike with adaptations to moist environments. While the prickle-related gene-regulatory-network (GRN) was highly conserved, the expression variation of key candidate genes was associated with prickle density. Our study provides fundamental resources and insights for genome evolution in the Rosaceae. Ongoing efforts on identification of the molecular bases for key rose traits may lead to the improvement of horticultural markets.

category: plant biology


title: Sequential 3D OrbiSIMS and LESA-MS/MS-based metabolomics for prediction of brain tumor relapse from sample-limited primary tissue archives

abstract:
We present here a novel surface mass spectrometry strategy to perform untargeted metabolite profiling of formalin-fixed paraffin-embedded (FFPE) pediatric ependymoma archives. Sequential Orbitrap secondary ion mass spectrometry (3D OrbiSIMS) and liquid extraction surface analysis-tandem MS (LESA-MS/MS) permitted the detection of 887 metabolites (163 chemical classes) from pediatric ependymoma tumor tissue microarrays (diameter <1 mm; thickness: 4 m). From these 163 classes, 60 classes were detected with both techniques, whilst LESA-MS/MS and 3D OrbiSIMS individually allowed the detection of another 83 and 20 unique metabolite classes, respectively. Through data fusion and multivariate analysis, we were able to identify key metabolites and corresponding pathways predictive of tumor relapse which were retrospectively confirmed using gene expression analysis with publicly available data. Altogether, this sequential mass spectrometry strategy has shown to be a versatile tool to perform high throughput metabolite profiling on sample-limited tissue archives.

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category: cancer biology


title: Biased orientation representations can be explained by experience with non-uniform training set statistics

abstract: Visual acuity is better for vertical and horizontal compared to other orientations. This cross-species phenomenon is often explained by "efficient coding", whereby more neurons show sharper tuning for the orientations most common in natural vision. However, it is unclear if experience alone can account for such biases. Here, we measured orientation representations in a convolutional neural network, VGG-16, trained on modified versions of ImageNet (rotated by 0{degrees}, 22.5{degrees}, or 45{degrees} counter-clockwise of upright). Discriminability for each model was highest near the orientations that were most common in the networks training set. Furthermore, there was an over-representation of narrowly tuned units selective for the most common orientations. These effects emerged in middle layers and increased with depth in the network. Biases emerged early in training, consistent with the possibility that non-uniform representations may play a functional role in the networks task performance. Together, our results suggest that biased orientation representations can emerge through experience with a non-uniform distribution of orientations, supporting the efficient coding hypothesis.


title: Landscape management for grassland multifunctionality

abstract:
Land-use intensification has contrasting effects on different ecosystem services, often leading to land-use conflicts. While multiple studies have demonstrated how landscape-scale strategies can minimise the trade-off between agricultural production and biodiversity conservation, little is known about which land-use strategies maximise the landscape-level supply of multiple ecosystem services (landscape multifunctionality), a common goal of stakeholder communities.

We combine comprehensive data collected from 150 German grassland sites with a simulation approach to identify landscape compositions, with differing proportions of low-, medium-, and high-intensity grasslands, that minimise trade-offs between the six main grassland ecosystem services prioritised by local stakeholders: biodiversity conservation, aesthetic value, productivity, carbon storage, foraging, and regional identity. Results are made accessible through an online tool that provides information on which compositions best meet any combination of user-defined priorities (https://neyret.shinyapps.io/landscape_composition_for_multifunctionality/).

Results show that an optimal landscape composition can be identified for any pattern of ecosystem service priorities. However, multifunctionality was similar and low for all landscape compositions in cases where there are strong trade-offs between services (e.g. aesthetic value and fodder production), where many services were prioritised, and where drivers other than land use played an important role. We also found that if moderate service levels are deemed acceptable, then strategies in which both high and low intensity grasslands are present can deliver landscape multifunctionality. The tool presented can aid informed decision-making by predicting the impact of future changes in landscape composition, and by allowing for the relative roles of stakeholder priorities and biophysical trade-offs to be understood by scientists and practitioners alike.

HighlightsO_LIAn online tool identifies optimal landscape compositions for desired ecosystem services
C_LIO_LIWhen the desired services are synergic, the optimum is their common best landscape composition
C_LIO_LIWhen the desired services trade-off, a mix of grassland intensity is most multifunctional
C_LIO_LISuch tools could support decision-making processes and aid conflict resolution
C_LI

Graphical abstract

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title: Assessing the impact of grassland management on landscape multifunctionality


title: A novel approach for assessing hypoperfusion in stroke using spatial independent component analysis of resting-state fMRI data

abstract: Individualized treatment of acute stroke depends on the timely detection of ischemia and potentially salvageable tissue in the brain. Using functional MRI (fMRI), it is possible to characterize cerebral blood flow from blood-oxygen-level-dependent (BOLD) signals without the administration of exogenous contrast agents. In this study, we applied spatial independent component analysis to resting-state fMRI data of 37 stroke patients scanned within 24 hours of symptom onset, 17 of whom received follow-up scans the next day. Our analysis revealed "Hypoperfusion spatially-Independent Components" (HICs) whose spatial patterns of BOLD signal resembled regions of delayed perfusion depicted by dynamic susceptibility contrast MRI. These HICs were detected even in the presence of excessive patient motion, and disappeared following successful tissue reperfusion. The unique spatial and temporal features of HICs allowed them to be distinguished with high accuracy from other components in a user-independent manner (AUC = 0.95, accuracy = 0.96, sensitivity = 1.00, specificity = 0.96). Our study therefore presents a new, non-invasive method for assessing blood flow in acute stroke that minimizes interpretative subjectivity and is robust to severe patient motion.


title: Functional differentiation in the language network revealed by lesion-symptom mapping

abstract: Theories of language organization in the brain commonly posit that different regions underlie distinct linguistic mechanisms. However, such theories have been criticized on the grounds that many neuroimaging studies of language processing find similar effects across regions. Moreover, condition by region interaction effects, which provide the strongest evidence of functional differentiation between regions, have rarely been offered in support of these theories. Here we address this by using lesion-symptom mapping in three large, partially-overlapping groups of aphasia patients with left hemisphere brain damage due to stroke (N=121, N=92, N= 218). We identified multiple measure by region interaction effects, associating damage to the posterior middle temporal gyrus with syntactic comprehension deficits, damage to posterior inferior frontal gyrus with expressive agrammatism, and damage to inferior angular gyrus with semantic category word fluency deficits. Our results are inconsistent with recent hypotheses that regions of the language network are undifferentiated with respect to high-level linguistic processing.


title: Protein homeostasis imprinting across evolution

abstract: Protein homeostasis (a.k.a. proteostasis) is associated with the primary functions of life, and therefore with evolution. However, it is unclear how the cellular proteostasis machines have evolved to adjust the protein biogenesis needs to environmental constraints. Herein, we describe a novel computational approach, based on semantic network analysis, to evaluate proteostasis during evolution. We show that the molecular components of the proteostasis network (PN) are reliable metrics to deconvolute the life forms into Archaea, Bacteria and Eukaryotes and to assess the evolution rates among species. Semantic graphs were used as a new criterion to evaluate PN complexity of 94 Eukaryotes, 250 Bacteria and 93 Archaea, thus representing a novel strategy for taxonomic classification. This functional analysis provided information about species divergence and pointed towards taxonomic clades that evolved faster than others. Kingdom-specific PN were identified, suggesting that PN complexity correlates evolution. Through the analysis of gene conservation, we found that the gains or losses that occurred throughout PN evolution revealed a dichotomy within both the PN conserved modules and within species-specific modules. Since the PN is implicated in cell fitness, aging and disease onset, it could be used as a new metric to tackle mechanisms underlying  gain-of-functions, and their biological ramifications.


title: Theoretical analysis predicts an optimal therapeutic strategy in distinct parkinsonian landscapes of the striatum

abstract: Parkinsons disease (PD) results from a loss of dopaminergic neurons. The age of disease onset, its progression and symptoms vary significantly between patients, pointing to a complex relationship between neuron loss and PD etiology. Yet, our understanding of the clinical variability remains incomplete. Here, we use biophysical modelling to characterize the dopaminergic landscape in the healthy and denervated striatum. Based on currently proposed mechanisms causing PD, we model three distinct denervation patterns, and show notable differences in the dopaminergic network as denervation progresses. We find local and global differences in the activity of two types of striatal neurons depending on the denervation pattern. Finally, we identify an optimal cellular strategy for maintaining normal dopamine signaling when neurons degenerate stochastically within our model. Our results derive a conceptual framework in which the clinical variability of PD is rooted in distinct denervation patterns and forms testable predictions for future PD research.

category: biophysics


title: Modelling cortical laminar connectivity in the macaque brain

abstract: In 1991, Felleman and Van Essen published their seminal study regarding hierarchical processing in the primate cerebral cortex. Their work encompassed a widescale analysis of connections reported through tracing between 35 regions in the macaque visual cortex, extending from cortical regions to the laminar level. In this work, we revisit laminar-level connectivity in the macaque brain using a whole-brain MRI-based approach. We use multi-modal ex-vivo MRI imaging of the macaque brain in both white and grey matter, which are then integrated via a simple model of laminar connectivity. This model uses a granularity-based approach to define a set of rules that expands cortical connections to the laminar level. Different fiber tracking routines are then examined in order to explore the ability of our model to infer laminar connectivity. The network of macaque cortical laminar connectivity resulting from the chosen routine is then validated in the visual cortex by comparison to findings from Felleman and Van Essen with an 83% accuracy level. By using a more comprehensive definition of the cortex that addresses its heterogenous laminar composition, we can explore a new avenue of structural connectivity on the laminar level.


title: Confirmation of interpersonal expectations is intrinsically rewarding

abstract: People want to interact successfully with other individuals, and they invest significant efforts in attempting to do so. Decades of research have demonstrated that to simplify the dauntingly complex task of interpersonal communication, perceivers use stereotypes and other sources of prior knowledge to predict the responses of individuals in their environment. Here, we show that these top-down expectations can also shape the subjective value of expectation-consistent and expectation-violating targets. Specifically, in two neuroimaging experiments (n = 58), we observed increased activation in brain regions associated with reward processing--including the nucleus accumbens--when perceivers observed information consistent with their social expectations. In two additional behavioral experiments (n = 704), we observed that perceivers were willing to forgo money to encounter an expectation-consistent target and avoid an expectation-violating target. Together, these findings suggest that perceivers value having their social expectations confirmed, much like food or monetary rewards.


title: Genetic Analysis of Human RNA Binding Motif Protein 48 (RBM48) Reveals an Essential Role in U12-Type Intron Splicing

abstract: U12-type or minor introns are found in most multicellular eukaryotes and constitute [~]0.5% of all introns in species with a minor spliceosome. Although the biological significance for evolutionary conservation of U12-type introns is debated, mutations disrupting U12 splicing cause developmental defects in both plants and animals. In human hematopoietic stem cells, U12 splicing defects disrupt proper differentiation of myeloid lineages and are associated with myelodysplastic syndrome (MDS), predisposing individuals to acute myeloid leukemia. Mutants in the maize ortholog of RNA Binding Motif Protein48 (RBM48) have aberrant U12-type intron splicing. Human RBM48 was recently purified biochemically as part of the minor spliceosome and shown to recognize the 5 end of the U6atac snRNA. In this report, we use CRISPR/Cas9-mediated ablation of RBM48 in human K-562 cells to show the genetic function of RBM48. RNA-seq analysis comparing wild-type and mutant K-562 genotypes found that 48% of minor intron containing genes (MIGs) have significant U12-type intron retention in RBM48 mutants. Comparing these results to maize rbm48 mutants defined a subset of MIGs disrupted in both species. Mutations in the majority of these orthologous MIGs have been reported to cause developmental defects in both plants and animals. Our results provide genetic evidence that the primary defect of human RBM48 mutants is aberrant U12-type intron splicing, while a comparison of human and maize RNA-seq data identifies candidate genes likely to mediate mutant phenotypes of U12-type splicing defects.


title: Phenotypic plasticity explains apparent reverse evolution of fat synthesis in parasitoid insects

abstract: Over the last few decades, numerous examples have been described where a trait that was once lost during the course of evolution had been regained. Here, we argue that such reverse evolution can also become apparent when trait expression is plastic in response to the environment. We tested this hypothesis for the loss and regain of fat synthesis in parasitic wasps. Wasps from lineages that supposedly regained lipogenic ability ~80 million years ago were grown under a fat-poor or fat-rich environment. In line with our hypothesis, it turned out that fat synthesis had not been lost and regained, but was only switched on in low-fat environments. Functional protein domains of key lipogenesis genes were also found in other parasitoid species, suggesting that plasticity of fat synthesis may be more widespread in parasitoids. Individual-based simulations then revealed that a switch for plastic expression can remain functional in the genome for thousands of generations, even if it is only used sporadically. The evolution of plasticity may thus also explain other examples of apparent reverse evolution.


title: Dynamic regulatory module networks for inference of cell type-specific transcriptional networks

abstract: Multi-omic datasets with parallel transcriptomic and epigenomic measurements across time or cell types are becoming increasingly common. However, integrating these data to infer regulatory network dynamics is a major challenge. We present Dynamic Regulatory Module Networks (DRMNs), a novel approach that uses multi-task learning to infer cell type-specific cis-regulatory networks dynamics. Compared to existing approaches, DRMN integrates expression, chromatin state and accessibility, accurately predicts cis-regulators of context-specific expression and models network dynamics across linearly and hierarchically related contexts. We apply DRMN to three dynamic processes of different experimental designs and predict known and novel regulators driving cell type-specific expression patterns.


title: Genome scans of diverse dog behaviors implicate a neurodevelopmental gene network in mammalian adaptation and psychopathology

abstract:
Genetic studies show a general factor associated with all human psychopathology and strongly correlated with personality and intelligence, but its basis is unknown. We performed genome scans of 17 normal and problem behaviors in three multi-breed dog cohorts. 21 of 90 mapped loci were supported for the same, or a related, trait in a second cohort. Several of those loci were also associated with brain structure differences across breeds; and six of the respective top-candidate genes are also associated with human brain structure and function. More broadly, the geneset of canine behavioral scans is supported by enrichment for genes mapped for human behavior, personality, cognition, psychopathology and brain structure. The biology implicated includes, neurogenesis, axon guidance, angiogenesis, brain structure, alternative splicing, disease association, Hox-family transcription factors, and subiculum expression. Because body size and behavior are correlated in dogs, we isolated the effect of body size in the dog mapping and in the comparative human UK Biobank analyses. Our dog findings are consistent with pleiotropy of diverse brain traits with energy metabolism and growth, and suggest behavioral variations often affect neurogenesis. There is support for such pleiotropy in humans and well-powered genetic studies of human psychiatric traits consistently implicate neurogenesis. We propose a genetic network which underlies neuron birth and development throughout life is associated with evolutionary adaptation of behavior and the general psychopathology factor. This understanding has implications for genetic and environmental contributions to psychiatric disease. We discuss how canine translational models can further accelerate the study of psychopathology.

Author summaryWe genetically mapped diverse normal and problem behaviors in dogs. The well-established approach we used is ideally suited for finding variation that is common across dog breeds and for pin-pointing the most likely gene candidates. Our analysis of the genes implicated at 90 genome regions shows they are enriched for i) genes mapped for diverse brain functions and pathologies in humans; ii) genes involved in brain development throughout life; and iii) footprints of evolution in dogs, humans and other animals. We propose that is consistent with evolutionary conservation of the general genetic factor of mental health in humans, which is correlated with personality and intelligence. The implications are that this super-network of genes is preferentially targeted by evolutionary adaptation for behavior and that its dysregulation increases risk of mental health disorders.


title: Musicianship can be decoded from magnetic resonance images

abstract: Learning induces structural changes in the brain. Especially repeated, long-term behaviors, such as extensive training of playing a musical instrument, are likely to produce characteristic features to brain structure. However, it is not clear to what extent such structural features can be extracted from magnetic resonance images of the brain. Here we show that it is possible to predict whether a person is a musician or a non-musician based on the thickness of the cerebral cortex measured at 148 brain regions en-compassing the whole cortex. Using a supervised machine-learning technique, we achieved a significant ({kappa} = 0.321, p < 0.001) agreement between the actual and predicted participant groups of 30 musicians and 85 non-musicians. The areas contributing to the prediction were mostly in the frontal, parietal, and occipital lobes of the left hemisphere. Our results suggest that decoding musicianship from magnetic resonance images of brain structure is feasible. Further, the distribution of the areas that were informative in the classification, which mostly, but not entirely, overlapped with earlier findings on areas relevant for musical skills, implies that decoding-based analyses of structural properties of the brain can reveal novel aspects of musical aptitude. In particular, our results highlight differences in visual areas in addition to the already more established differences located in motor networks and networks of higher-order cognitive function.


title: Phylogenetic diversity analysis of shotgun metagenomic reads describes gut microbiome development and treatment effects in the post-weaned pig

abstract:
BackgroundIntensive farming practices can increase exposure of animals to infectious agents against which antibiotics are used. Besides leading to antimicrobial resistance (AMR), orally administered antibiotics are well known to cause dysbiosis. To counteract dysbiotic effects, numerous studies in the past two decades sought to understand whether probiotics are a valid tool to help re-establish a healthy gut microbial community after antibiotic treatment. However, although dysbiotic effects of antibiotics are well investigated, little is known about the effects of intramuscular antibiotic treatment on the gut microbiome and a few studies attempted to study treatment effects using phylogenetic diversity analysis techniques. In this study we sought to determine the effects of two probiotic- and one intramuscularly administered antibiotic treatment on the developing gut microbiome of post-weaning piglets between their 3rd and 9th week of life.

MethodsShotgun metagenomic sequences from over 800 faecal time-series samples derived from 126 piglets and 42 sows were analysed in a phylogenetic framework to characterise the developing gut microbial community composition of post-weaning piglets. We assessed the effects of intramuscular antibiotic treatment and probiotic oral treatment on the diversity of these gut microbial communities using alpha and beta diversity measures.

ResultsDifferences between individual hosts such as breed, litter, and age, were found to be important contributors to variation in the community composition. Host age was the dominant factor in shaping the gut microbiota of piglets after weaning. The post-weaning pig gut microbiome appeared to follow a highly structured developmental program with characteristic post-weaning changes that can distinguish hosts that were born as little as two days apart in the second month of life. Treatment effects of the antibiotic and probiotic treatments were found but were subtle and included a higher representation of Mollicutes associated with intramuscular antibiotic treatment, and an increase of Lactobacillus associated with probiotic treatment.

DiscussionThe discovery of correlations between experimental factors and microbial community composition is more commonly addressed with OTU-based methods and rarely analysed via phylogenetic diversity measures. The latter method, although less intuitive than the former, suffers less from library size normalization biases, and it proved to be instrumental in this study for the discovery of correlations between microbiome composition and host-, and treatment factors.


title: Power analysis of transcriptome-wide association study: implications for practical protocol choice

abstract:
The transcriptome-wide association study (TWAS) has emerged as one of several promising techniques for integrating multi-scale  omics data into traditional genome-wide association studies (GWAS). Unlike GWAS, which associates phenotypic variance directly with genetic variants, TWAS uses a reference dataset to train a predictive model for gene expressions, which allows it to associate phenotype with variants through the mediating effect of expressions. Although effective, this core innovation of TWAS is poorly understood, since the predictive accuracy of the genotype-expression model is generally low and further bounded by expression heritability. This raises the question: to what degree does the accuracy of the expression model affect the power of TWAS? Furthermore, would replacing predictions with actual, experimentally determined expressions improve power? To answer these questions, we compared the power of GWAS, TWAS, and a hypothetical protocol utilizing real expression data. We derived non-centrality parameters (NCPs) for linear mixed models (LMMs) to enable closed-form calculations of statistical power that do not rely on specific protocol implementations. We examined two representative scenarios: causality (genotype contributes to phenotype through expression) and pleiotropy (genotype contributes directly to both phenotype and expression), and also tested the effects of various properties including expression heritability. Our analysis reveals two main outcomes: (1) Under pleiotropy, the use of predicted expressions in TWAS is superior to actual expressions. This explains why TWAS can function with weak expression models, and shows that TWAS remains relevant even when real expressions are available. (2) GWAS outperforms TWAS when expression heritability is below a threshold of 0.04 under causality, or 0.06 under pleiotropy. Analysis of existing publications suggests that TWAS has been misapplied in place of GWAS, in situations where expression heritability is low.

Author SummaryWe compared the effectiveness of three methods for finding genetic effects on disease in order to quantify their strengths and help researchers choose the best protocol for their data. The genome-wide association study (GWAS) is the standard method for identifying how the genetic differences between individuals relate to disease. Recently, the transcriptome-wide association study (TWAS) has improved GWAS by also estimating the effect of each genetic variant on the activity level (or expression) of genes related to disease. The effectiveness of TWAS is surprising because its estimates of gene expressions are very inaccurate, so we ask if a method using real expression data instead of estimates would perform better. Unlike past studies, which only use simulation to compare these methods, we incorporate novel statistical calculations to make our comparisons more accurate and universally applicable. We discover that depending on the type of relationship between genetics, gene expression, and disease, the estimates used by TWAS could be actually more relevant than real gene expressions. We also find that TWAS is not always better than GWAS when the relationship between genetics and expression is weak and identify specific turning points where past studies have incorrectly used TWAS instead of GWAS.


title: Nutrient supplementation experiments with saltern microbial communities implicate utilization of DNA as a source of phosphorus

abstract: All environments including hypersaline ones harbor measurable concentrations of dissolved extracellular DNA (eDNA) that can be utilized by microbes as a nutrient. However, it remains poorly understood which eDNA components are used, and who in a community utilizes it. For this study, we incubated a saltern microbial community with combinations of carbon, nitrogen, phosphorus, and DNA, and tracked the community response in each microcosm treatment via 16S rRNA and rpoB gene sequencing. We show that microbial communities used DNA only as a phosphorus source, and provision of other sources of carbon and nitrogen was needed to exhibit a substantial growth. The taxonomic composition of eDNA in the water column changed with the availability of inorganic phosphorus or supplied DNA, hinting at preferential uptake of eDNA from specific organismal sources. Especially favored for growth was eDNA from the most abundant taxa, suggesting some haloarchaea prefer eDNA from closely related taxa. Additionally, microcosms composition shifted substantially depending on the provided nutrient combinations. These shifts allowed us to predict supplemented nutrients from microbial composition with high accuracy, suggesting that nutrient availability in an environment could be assessed from a taxonomic survey of its microbial community.


title: Optimising passive surveillance of a neglected tropical disease in the era of elimination: A modelling study

abstract:
BackgroundSurveillance is an essential component of global programs to eliminate infectious diseases and avert epidemics of (re-)emerging diseases. As the numbers of cases decline, costs of treatment and control diminish but those for surveillance remain high even after the  last case. Reducing surveillance may risk missing persistent or (re-)emerging foci of disease. Here, we use a simulation-based approach to determine the minimal number of passive surveillance sites required to ensure maximum coverage of a population at-risk (PAR) of an infectious disease.

Methodology and Principal FindingsFor this study, we use Gambian human African trypanosomiasis (g-HAT) in north-western Uganda, a neglected tropical disease (NTD) which has been reduced to historically low levels (<1000 cases/year globally), as an example. To quantify travel time to diagnostic facilities, a proxy for surveillance coverage, we produced a high spatial-resolution resistance surface and performed cost-distance analyses. We simulated travel time for the PAR with different numbers (1-170) and locations (170,000 total placement combinations) of diagnostic facilities, quantifying the percentage of the PAR within 1h and 5h travel of the facilities, as per in-country targets. Our simulations indicate that a 70% reduction (51/170) in diagnostic centres still exceeded minimal targets of coverage even for remote populations, with >95% of a total PAR of ~3million individuals living [≤]1h from a diagnostic centre, and we demonstrate an approach to best place these facilities, informing a minimal impact scale back.

ConclusionsOur results highlight that surveillance of g-HAT in north-western Uganda can be scaled back without substantially reducing coverage of the PAR. The methodology described can contribute to cost-effective and equable strategies for the surveillance of NTDs and other infectious diseases approaching elimination or (re-)emergence.

Author SummaryDisease surveillance systems are an essential component of public health practice and are often considered the first line in averting epidemics for (re-)emerging diseases. Regular evaluation of surveillance systems ensures that they remain operating at maximum efficiency; systems that survey diseases of low incidence, such as those within elimination settings, should be simplified to reduce the reporting burden. A lack of guidance on how to optimise disease surveillance in an elimination setting may result in added expense, and/or the underreporting of disease. Here, we propose a framework methodology to determine systematically the optimal number and placement of surveillance sites for the surveillance of infectious diseases approaching elimination. By utilising estimates of geographic accessibility, through the construction of a resistance surface and a simulation approach, we identify that the number of operational diagnostic facilities for Gambian human African trypanosomiasis in north-western Uganda can be reduced by 70% with a minimal reduction in existing coverage, and identify the minimum number of facilities required to meet coverage targets. Our analysis can be used to inform the number and positioning of surveillance sites for diseases within an elimination setting. Passive surveillance becomes increasingly important as cases decline and active surveillance becomes less cost-effective; methods to evaluate how best to engage this passive surveillance capacity given facility capacity and geographic distribution are pertinent for several NTDs where diagnosis is complex. Not only is this a complicated research area for diseases approaching elimination, a well-designed surveillance system is essential for the detection of emerging diseases, with this work being topical in a climate where emerging pathogens are becoming more commonplace.

category: pathology


title: Sex-specific speed-accuracy tradeoffs shape neural processing of acoustic signals in a grasshopper

abstract: Speed-accuracy tradeoffs - being fast at the risk of being wrong - are fundamental to many decisions and natural selection is expected to resolve these tradeoffs according to the costs and benefits of behavior. We here test the prediction that females and males should integrate information from courtship signals differently because they experience different payoffs along the speed-accuracy continuum. We fitted a neural model of decision making (a drift-diffusion model of integration to threshold) to behavioral data from the grasshopper Chorthippus biguttulus to determine the parameters of temporal integration of acoustic directional information used by male grasshoppers to locate receptive females. The model revealed that males had a low threshold for initiating a turning response, yet a large integration time constant enabled them to continue to gather information when cues were weak. This contrasts with parameters estimated for females of the same species when evaluating potential mates, in which response thresholds were much higher and behavior was strongly influenced by unattractive stimuli. Our results reveal differences in neural integration consistent with the sex-specific costs of mate search: Males often face competition and need to be fast, while females often pay high error costs and need to be deliberate.


title: Light-powered reactivation of flagella and contraction of microtubules network: towards building an artificial cell

abstract:
Artificial systems capable of self-sustained movement with self-sufficient energy are of high interest with respect to the development of many challenging applications including medical treatments but also technical applications. The bottom-up assembly of such systems in the context of synthetic biology is still a challenging task. In this work, we demonstrate the biocompatibility and efficiency of an artificial light-driven energy module and a motility functional unit by integrating light-switchable photosynthetic vesicles with demembranated flagella that provide ATP for dynein molecular motors upon illumination. The flagellar propulsion is coupled to the beating frequency and dynamic ATP synthesis in response to illumination allows us to control beating frequency of flagella in a light-dependent manner. In addition, we verified the functionality of light-powered synthetic vesicles in in vitro motility assays by encapsulating microtubules assembled with force-generating kinesin-1 motors and the energy module to investigate the dynamics of a contractile filamentous network in cell-like compartments by optical stimulation. Integration of this photosynthetic system with various biological building blocks such as cytoskeletal filaments and molecular motors may contribute to the bottom-up synthesis of artificial cells that are able to undergo motor-driven morphological deformations and exhibit directional motion in a light-controllable fashion.

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title: Antifeedant activities of L-arabinose to caterpillars of the cotton bollworm Helicoverpa armigera (H&uumlbner)

abstract: Exploring botanical biopesticide is one of the eco-friendly approaches for pest control in current crop protection. L-arabinose, a plant-specific and less absorptive pentose, is known for its selective inhibitory effect on the sucrose digestion in mammals. In this study, we investigated the effects of L-arabinose on the feeding preference, the peripheral gustatory perception, the larval development, as well as the activity of intestinal sucrase of an insect pest species, the cotton bollworm Helicoverpa armigera (Hubner) (Lepidoptera: Noctuidae), in an attempt to explore the antifeedant activities of this pentose. The results showed that L-arabinose deterred the feeding preferences of H. armigera caterpillars for its two host plants and two phagostimulants, the tobacco, the pepper, the sucrose and the fructose. Gustatory receptor neurons (GRNs) sensitive to L-arabinose were not found in the peripheral maxillary sensilla of H. armigera caterpillars, but the sensitivities of GRNs sensitive to sucrose, fructose and tobacco saps were suppressed by the additions of L-arabinose. Exposure of H. armigera caterpillars to dietary L-arabinose resulted in a prolonged larval developmental duration, a suppressed activity of intestinal sucrase and a reduced glucose level in midgut. In vitro, L-arabinose inhibited activities of the intestinal sucrase of H. armigera caterpillars in an uncompetitive manner. Taken together, these findings demonstrate that L-arabinose is a behavioral, gustatory and physiological inhibitor to caterpillars of the extremely generalist pest species H. armigera, suggesting the great potential of L-arabinose to be an effective antifeedant.

category: animal behavior and cognition


title: Dentate spikes and external control of hippocampal function

abstract: Mouse hippocampus CA1 place-cell discharge typically encodes current location but during slow gamma dominance (SGdom), when slow gamma oscillations (30-50 Hz) dominate mid-frequency gamma oscillations (70-90 Hz) in CA1 local field potentials, CA1 discharge switches to represent distant recollected locations. We report that dentate spike type 2 (DSM) events initiated by MECII[->]DG inputs promote SGdom and change excitation-inhibition coordinated discharge in DG, CA3, and CA1, whereas type 1 (DSL) events initiated by LECII[->]DG inputs do not. Just before SGdom, LECII-originating slow gamma oscillations in dentate gyrus and CA3-originating slow gamma oscillations in CA1 phase and frequency synchronize at the DSM peak when discharge within DG and CA3 increases to promote excitation-inhibition cofiring within and across the DG[->]CA3[->]CA1 pathway. This optimizes discharge for the 5-10 ms DG-to-CA1 neuro-transmission that coincides with SGdom. DSM properties identify extrahippocampal control of SGdom, and a cortico-hippocampal mechanism that switches between memory-related modes of information processing.


title: Accel-Align: A Fast Sequence Mapper and Aligner based on the Seed-Embed-Extend Method

abstract:
BackgroundImprovements in sequencing technology continue to drive sequencing cost towards $100 per genome. However, mapping sequenced data to a reference genome remains a computationally-intensive task due to the dependence on edit distance for dealing with indels and mismatches introduced by sequencing. All modern aligners use seed-filter-extend (SFE) methodology and rely on filtration heuristics to reduce the overhead of edit distance computation. However, filtering has inherent performance-accuracy trade-offs that limits its effectiveness.

ResultsMotivated by algorithmic advances in randomized low-distortion embedding, we introduce seed- embed-extend (SEE), a new methodology for developing sequence mappers and aligners. While SFE focuses on eliminating sub-optimal candidates, SEE focuses instead on identifying optimal candidates. To do so, SEE transforms the read and reference strings from edit distance regime to the Hamming regime by embedding them using a randomized algorithm, and uses Hamming distance over the embedded set to identify optimal candidates. To show that SEE performs well in practice, we present Accel-Align, an SEE-based short-read sequence mapper and aligner that is 3-12x faster than state-of-the-art aligners on commodity CPUs, without any special-purpose hardware, while providing comparable accuracy.

ConclusionsAs sequencing technologies continue to increase read length while improving throughput and accuracy, we believe that randomized embeddings open up new avenues for optimization that cannot be achieved by using edit distance. Thus, the techniques presented in this paper have a much broader scope as they can be used for other applications like graph alignment, multiple sequence alignment, and sequence assembly.

Availabilityhttps://github.com/raja-appuswamy/accel-align-release


title: Automated phenotyping of mosquito larvae enables high-throughput screening for novel larvicides and offers potential for smartphone-based detection of larval insecticide resistance

abstract:
Pyrethroid-impregnated nets have contributed significantly to halving the burden of malaria but resistance threatens their future efficacy and the pipeline of new insecticides is short. Here we report that an invertebrate automated phenotyping platform (INVAPP), combined with the algorithm Paragon, provides a robust system for measuring larval motility in Anopheles gambiae (and An. coluzzi) as well as Aedes aegypti with the capacity for high-throughput screening for new larvicides. By this means, we reliably quantified both time- and concentration-dependent actions of chemical insecticides faster than using the WHO standard larval assay. We illustrate the effectiveness of the system using an established larvicide (temephos) and demonstrate its capacity for library-scale chemical screening using the Medicines for Malaria Venture (MMV) Pathogen Box library. As a proof-of-principle, this library screen identified a compound, subsequently confirmed to be tolfenpyrad, as an effective larvicide. We have also used the INVAPP / Paragon system to compare responses in larvae derived from WHO classified deltamethrin resistant and sensitive mosquitoes. We show how this approach to monitoring larval response to insecticides can be adapted for use with a smartphone camera application and therefore has potential for further development as a simple portable field-assay with associated real-time, geo-located information to identify hotspots.

Author summaryWe have developed an automated platform for recording the motility of mosquito larvae and applied it to larvae of a mosquito vector of malaria and a mosquito vector of dengue, Zika, yellow fever and other human diseases. The platform facilitates high-throughput, chemical screening for new compounds to control mosquito larvae and also detects differences in response in larval progeny from pryethroid resistant adult mosquitoes. Pyrethroid-impregnated bednets have helped to halve the deaths from malaria in recent years but pyrethroid resistance is an important threat to this progress. Our approach assays insecticide actions faster than the current WHO standard test and we show that it can be adapted for use with a smartphone, which offers the prospect of a future field assay to monitor developing resistance associated with behavioural response with the added benefit of precise satellite-based location.

category: pharmacology and toxicology