Faster algorithms for 1-mappability of a sequence

In the k-mappability problem, we are given a string x of length n and integers m and k, and we are asked to count, for each length-m factor y of x, the number of other factors of length m of x that are at Hamming distance at most k from y. We focus here on the version of the problem where k = 1. The fastest known algorithm for k = 1 requires time O(mn log n/ log log n) and space O(n). We present two algorithms that require worst-case time O(mn) and O(n log^2 n), respectively, and space O(n), thus greatly improving the state of the art. Moreover, we present an algorithm that requires average-case time and space O(n) for integer alphabets if m = {\Omega}(log n/ log {\sigma}), where {\sigma} is the alphabet size

Shedding light on the african enigma: In vitro testing of homo sapiens-helicobacter pylori coevolution

The continuous characterization of genome-wide diversity in population and case- cohort samples, allied to the development of new algorithms, are shedding light on host ancestry impact and selection events on various infectious diseases. Especially interesting are the longstanding associations between humans and certain bacteria, such as the case of Helicobacter pylori, which could have been strong drivers of adaptation leading to coevolution. Some evidence on admixed gastric cancer cohorts have been suggested as supporting Homo-Helicobacter coevolution, but reliable experimental data that control both the bacterium and the host ancestries are lacking. Here, we conducted the first in vitro coinfection assays with dual humanand bacterium-matched and -mismatched ancestries, in African and European backgrounds, to evaluate the genome wide gene expression host response to H. pylori. Our results showed that: (1) the host response to H. pylori infection was greatly shaped by the human ancestry, with variability on innate immune system and metabolism; (2) African human ancestry showed signs of coevolution with H. pylori while European ancestry appeared to be maladapted; and (3) mismatched ancestry did not seem to be an important differentiator of gene expression at the initial stages of infection as assayed here.Funds were guaranteed by the project “Advancing cancer research: from basic knowledge to application”; NORTE-01-0145-FEDER-000029; Projetos Estruturados de I & D & I, funded by Norte 2020-Programa Operacional Regional do Norte. i3S is financed by FEDER-Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020-Competitiveness and Internationalization Operational Programme (POCI), Portugal 2020, and by Portuguese funds through FCT/Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274)

Gene Classification Based on Amino Acid Motifs and Residues: The DLX (distal-less) Test Case

BACKGROUND:Comparative studies using hundreds of sequences can give a detailed picture of the evolution of a given gene family. Nevertheless, retrieving only the sequences of interest from public databases can be difficult, in particular, when working with highly divergent sequences. The difficulty increases substantially when one wants to include in the study sequences from many (or less well studied) species whose genomes are non-annotated or incompletely annotated. METHODOLOGY/PRINCIPAL FINDINGS:In this work we evaluate the usefulness of different approaches of gene retrieval and classification, using the distal-less (DLX) gene family as a test case. Furthermore, we evaluate whether the use of a large number of gene sequences from a wide range of animal species, the use of multiple alternative alignments, and the use of amino acids aligned with high confidence only, is enough to recover the accepted DLX evolutionary history. CONCLUSIONS/SIGNIFICANCE:The canonical DLX homeobox gene sequence here derived, together with the characteristic amino acid variants here identified in the DLX homeodomain region, can be used to retrieve and classify DLX genes in a simple and efficient way. A program is made available that allows the easy retrieval of synteny information that can be used to classify gene sequences. Maximum likelihood trees using hundreds of sequences can be used for gene identification. Nevertheless, for the DLX case, the proposed DLX evolutionary is not recovered even when multiple alignment algorithms are used

An RNA-seq Based Machine Learning Approach Identifies Latent Tuberculosis Patients With an Active Tuberculosis Profile.

A better understanding of the response against Tuberculosis (TB) infection is required to accurately identify the individuals with an active or a latent TB infection (LTBI) and also those LTBI patients at higher risk of developing active TB. In this work, we have used the information obtained from studying the gene expression profile of active TB patients and their infected -LTBI- or uninfected -NoTBI- contacts, recruited in Spain and Mozambique, to build a class-prediction model that identifies individuals with a TB infection profile. Following this approach, we have identified several genes and metabolic pathways that provide important information of the immune mechanisms triggered against TB infection. As a novelty of our work, a combination of this class-prediction model and the direct measurement of different immunological parameters, was used to identify a subset of LTBI contacts (called TB-like) whose transcriptional and immunological profiles are suggestive of infection with a higher probability of developing active TB. Validation of this novel approach to identifying LTBI individuals with the highest risk of active TB disease merits further longitudinal studies on larger cohorts in TB endemic areas

Piperidinols that show anti-tubercular activity as inhibitors of arylamine N-acetyltransferase: an essential enzyme for mycobacterial survival inside macrophages

Latent M. tuberculosis infection presents one of the major obstacles in the global eradication of tuberculosis (TB). Cholesterol plays a critical role in the persistence of M. tuberculosis within the macrophage during latent infection. Catabolism of cholesterol contributes to the pool of propionyl-CoA, a precursor that is incorporated into cell-wall lipids. Arylamine N-acetyltransferase (NAT) is encoded within a gene cluster that is involved in the cholesterol sterol-ring degradation and is essential for intracellular survival. The ability of the NAT from M. tuberculosis (TBNAT) to utilise propionyl-CoA links it to the cholesterol-catabolism pathway. Deleting the nat gene or inhibiting the NAT enzyme prevents intracellular survival and results in depletion of cell-wall lipids. TBNAT has been investigated as a potential target for TB therapies. From a previous high-throughput screen, 3-benzoyl-4-phenyl-1-methylpiperidinol was identified as a selective inhibitor of prokaryotic NAT that exhibited antimycobacterial activity. The compound resulted in time-dependent irreversible inhibition of the NAT activity when tested against NAT from M. marinum (MMNAT). To further evaluate the antimycobacterial activity and the NAT inhibition of this compound, four piperidinol analogues were tested. All five compounds exert potent antimycobacterial activity against M. tuberculosis with MIC values of 2.3-16.9 µM. Treatment of the MMNAT enzyme with this set of inhibitors resulted in an irreversible time-dependent inhibition of NAT activity. Here we investigate the mechanism of NAT inhibition by studying protein-ligand interactions using mass spectrometry in combination with enzyme analysis and structure determination. We propose a covalent mechanism of NAT inhibition that involves the formation of a reactive intermediate and selective cysteine residue modification. These piperidinols present a unique class of antimycobacterial compounds that have a novel mode of action different from known anti-tubercular drugs

Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors

Delta-9-tetrahydrocannabinol (THC), the main psychoactive compound of marijuana, induces numerous undesirable effects, including memory impairments, anxiety, and dependence. Conversely, THC also has potentially therapeutic effects, including analgesia, muscle relaxation, and neuroprotection. However, the mechanisms that dissociate these responses are still not known. Using mice lacking the serotonin receptor 5-HT2A, we revealed that the analgesic and amnesic effects of THC are independent of each other: while amnesia induced by THC disappears in the mutant mice, THC can still promote analgesia in these animals. In subsequent molecular studies, we showed that in specific brain regions involved in memory formation, the receptors for THC and the 5-HT2A receptors work together by physically interacting with each other. Experimentally interfering with this interaction prevented the memory deficits induced by THC, but not its analgesic properties. Our results highlight a novel mechanism by which the beneficial analgesic properties of THC can be dissociated from its cognitive side effects

Methods to study splicing from high-throughput RNA Sequencing data

The development of novel high-throughput sequencing (HTS) methods for RNA (RNA-Seq) has provided a very powerful mean to study splicing under multiple conditions at unprecedented depth. However, the complexity of the information to be analyzed has turned this into a challenging task. In the last few years, a plethora of tools have been developed, allowing researchers to process RNA-Seq data to study the expression of isoforms and splicing events, and their relative changes under different conditions. We provide an overview of the methods available to study splicing from short RNA-Seq data. We group the methods according to the different questions they address: 1) Assignment of the sequencing reads to their likely gene of origin. This is addressed by methods that map reads to the genome and/or to the available gene annotations. 2) Recovering the sequence of splicing events and isoforms. This is addressed by transcript reconstruction and de novo assembly methods. 3) Quantification of events and isoforms. Either after reconstructing transcripts or using an annotation, many methods estimate the expression level or the relative usage of isoforms and/or events. 4) Providing an isoform or event view of differential splicing or expression. These include methods that compare relative event/isoform abundance or isoform expression across two or more conditions. 5) Visualizing splicing regulation. Various tools facilitate the visualization of the RNA-Seq data in the context of alternative splicing. In this review, we do not describe the specific mathematical models behind each method. Our aim is rather to provide an overview that could serve as an entry point for users who need to decide on a suitable tool for a specific analysis. We also attempt to propose a classification of the tools according to the operations they do, to facilitate the comparison and choice of methods.Comment: 31 pages, 1 figure, 9 tables. Small corrections adde

MAGIC detection of short-term variability of the high-peaked BL Lac object 1ES 0806+524

The high-frequency-peaked BL Lac (HBL) 1ES 0806+524 (z = 0.138) was discovered in VHE $\gamma$ rays in 2008. Until now, the broad-band spectrum of 1ES 0806+524 has been only poorly characterized, in particular at high energies. We analysed multiwavelength observations from $\gamma$ rays to radio performed from 2011 January to March, which were triggered by the high activity detected at optical frequencies. These observations constitute the most precise determination of the broad-band emission of 1ES 0806+524 to date. The stereoscopic MAGIC observations yielded a $\gamma$-ray signal above 250 GeV of $(3.7 \pm 0.7)$ per cent of the Crab Nebula flux with a statistical significance of 9.9 $\sigma$. The multiwavelength observations showed significant variability in essentially all energy bands, including a VHE $\gamma$-ray flare that lasted less than one night, which provided unprecedented evidence for short-term variability in 1ES 0806+524. The spectrum of this flare is well described by a power law with a photon index of $2.97 \pm 0.29$ between $\sim$150 GeV and 1 TeV and an integral flux of $(9.3 \pm 1.9)$ per cent of the Crab Nebula flux above 250 GeV. The spectrum during the non-flaring VHE activity is compatible with the only available VHE observation performed in 2008 with VERITAS when the source was in a low optical state. The broad-band spectral energy distribution can be described with a one-zone Synchrotron Self Compton model with parameters typical for HBLs, indicating that 1ES 0806+524 is not substantially different from the HBLs previously detected.Comment: 12 pages, 8 figures, 3 tables, accepted 2015 April 20 for publication in Monthly Notices of the Royal Astronomical Society Main Journa