Tailoring r-index for Document Listing Towards Metagenomics Applications

A basic problem in metagenomics is to assign a sequenced read to the correct species in the reference collection. In typical applications in genomic epidemiology and viral metagenomics the reference collection consists of a set of species with each species represented by its highly similar strains. It has been recently shown that accurate read assignment can be achieved with k-mer hashing-based pseudoalignment: a read is assigned to species A if each of its k-mer hits to a reference collection is located only on strains of A. We study the underlying primitives required in pseudoalignment and related tasks. We propose three space-efficient solutions building upon the document listing with frequencies problem. All the solutions use an r-index (Gagie et al., SODA 2018) as an underlying index structure for the text obtained as concatenation of the set of species, as well as for each species. Given t species whose concatenation length is n, and whose Burrows-Wheeler transform contains r runs, our first solution, based on a grammar-compressed document array with precomputed queries at non terminal symbols, reports the frequencies for the distinct documents in which the pattern of length m occurs in time. Our second solution is also based on a grammar-compressed document array, but enhanced with bitvectors and reports the frequencies in time, over a machine with wordsize w. Our third solution, based on the interleaved LCP array, answers the same query in time. We implemented our solutions and tested them on real-world and synthetic datasets. The results show that all the solutions are fast on highly-repetitive data, and the size overhead introduced by the indexes are comparable with the size of the r-index.Peer reviewe

Self-Organization of Muscle Cell Structure and Function

The organization of muscle is the product of functional adaptation over several length scales spanning from the sarcomere to the muscle bundle. One possible strategy for solving this multiscale coupling problem is to physically constrain the muscle cells in microenvironments that potentiate the organization of their intracellular space. We hypothesized that boundary conditions in the extracellular space potentiate the organization of cytoskeletal scaffolds for directed sarcomeregenesis. We developed a quantitative model of how the cytoskeleton of neonatal rat ventricular myocytes organizes with respect to geometric cues in the extracellular matrix. Numerical results and in vitro assays to control myocyte shape indicated that distinct cytoskeletal architectures arise from two temporally-ordered, organizational processes: the interaction between actin fibers, premyofibrils and focal adhesions, as well as cooperative alignment and parallel bundling of nascent myofibrils. Our results suggest that a hierarchy of mechanisms regulate the self-organization of the contractile cytoskeleton and that a positive feedback loop is responsible for initiating the break in symmetry, potentiated by extracellular boundary conditions, is required to polarize the contractile cytoskeleton

Individual biases, cultural evolution, and the statistical nature of language universals: the case of colour naming systems

Language universals have long been attributed to an innate Universal Grammar. An alternative explanation states that linguistic universals emerged independently in every language in response to shared cognitive or perceptual biases. A computational model has recently shown how this could be the case, focusing on the paradigmatic example of the universal properties of colour naming patterns, and producing results in quantitative agreement with the experimental data. Here we investigate the role of an individual perceptual bias in the framework of the model. We study how, and to what extent, the structure of the bias influences the corresponding linguistic universal patterns. We show that the cultural history of a group of speakers introduces population-specific constraints that act against the pressure for uniformity arising from the individual bias, and we clarify the interplay between these two forces

Active dendrites enhance neuronal dynamic range

Since the first experimental evidences of active conductances in dendrites, most neurons have been shown to exhibit dendritic excitability through the expression of a variety of voltage-gated ion channels. However, despite experimental and theoretical efforts undertaken in the last decades, the role of this excitability for some kind of dendritic computation has remained elusive. Here we show that, owing to very general properties of excitable media, the average output of a model of active dendritic trees is a highly non-linear function of their afferent rate, attaining extremely large dynamic ranges (above 50 dB). Moreover, the model yields double-sigmoid response functions as experimentally observed in retinal ganglion cells. We claim that enhancement of dynamic range is the primary functional role of active dendritic conductances. We predict that neurons with larger dendritic trees should have larger dynamic range and that blocking of active conductances should lead to a decrease of dynamic range.Comment: 20 pages, 6 figure

Differential analysis of RNA-seq incorporating quantification uncertainty

We describe sleuth (http://pachterlab.github.io/sleuth), a method for the differential analysis of gene expression data that utilizes bootstrapping in conjunction with response error linear modeling to decouple biological variance from inferential variance. sleuth is implemented in an interactive shiny app that utilizes kallisto quantifications and bootstraps for fast and accurate analysis of data from RNA-seq experiments

Individual Attachment Style Modulates Human Amygdala and Striatum Activation during Social Appraisal

Adult attachment style refers to individual personality traits that strongly influence emotional bonds and reactions to social partners. Behavioral research has shown that adult attachment style reflects profound differences in sensitivity to social signals of support or conflict, but the neural substrates underlying such differences remain unsettled. Using functional magnetic resonance imaging (fMRI), we examined how the three classic prototypes of attachment style (secure, avoidant, anxious) modulate brain responses to facial expressions conveying either positive or negative feedback about task performance (either supportive or hostile) in a social game context. Activation of striatum and ventral tegmental area was enhanced to positive feedback signaled by a smiling face, but this was reduced in participants with avoidant attachment, indicating relative impassiveness to social reward. Conversely, a left amygdala response was evoked by angry faces associated with negative feedback, and correlated positively with anxious attachment, suggesting an increased sensitivity to social punishment. Secure attachment showed mirror effects in striatum and amygdala, but no other specific correlate. These results reveal a critical role for brain systems implicated in reward and threat processing in the biological underpinnings of adult attachment style, and provide new support to psychological models that have postulated two separate affective dimensions to explain these individual differences, centered on the ventral striatum and amygdala circuits, respectively. These findings also demonstrate that brain responses to face expressions are not driven by facial features alone but determined by the personal significance of expressions in current social context. By linking fundamental psychosocial dimensions of adult attachment with brain function, our results do not only corroborate their biological bases but also help understand their impact on behavior

Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis.

Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass cytometry demonstrates a 3-fold expansion of memory CD8 T cells in the joints of PsA patients compared to peripheral blood. Meanwhile, droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show pronounced CD8 T cell clonal expansions within the joints. Transcriptome analyses find these expanded synovial CD8 T cells to express cycling, activation, tissue-homing and tissue residency markers. T cell receptor sequence comparison between patients identifies clonal convergence. Finally, chemokine receptor CXCR3 is upregulated in the expanded synovial CD8 T cells, while two CXCR3 ligands, CXCL9 and CXCL10, are elevated in PsA synovial fluid. Our data thus provide a quantitative molecular insight into the cellular immune landscape of psoriatic arthritis

SUPPA2:fast, accurate, and uncertainty-aware differential splicing analysis across multiple conditions

Supplementary methods. (PDF 315 kb