Fast motif recognition via application of statistical thresholds

Background: Improving the accuracy and efficiency of motif recognition is an important computational challenge that has application to detecting transcription factor binding sites in genomic data. Closely related to motif recognition is the Consensus String decision problem that asks, given a parameter d and a set of ℓ-length strings S = {s1,...,sn}, whether there exists a consensus string that has Hamming distance at most d from any string in S. A set of strings S is pairwise bounded if the Hamming distance between any pair of strings in S is at most 2d. It is trivial to determine whether a set is pairwise bounded, and a set cannot have a consensus string unless it is pairwise bounded. We use Consensus String to determine whether or not a pairwise bounded set has a consensus. Unfortunately, Consensus String is NP-complete. The lack of an efficient method to solve the Consensus String problem has caused it to become a computational bottleneck in MCL-WMR, a motif recognition program capable of solving difficult motif recognition problem instances. Results: We focus on the development of a method for solving Consensus String quickly with a small probability of error. We apply this heuristic to develop a new motif recognition program, sMCL-WMR, which has impressive accuracy and efficiency. We demonstrate the performance of sMCL-WMR in detecting weak motifs in large data sets and in real genomic data sets, and compare the performance to other leading motif recognitio

Identification of Giardia lamblia DHHC Proteins and the Role of Protein S-palmitoylation in the Encystation Process

Protein S-palmitoylation, a hydrophobic post-translational modification, is performed by protein acyltransferases that have a common DHHC Cys-rich domain (DHHC proteins), and provides a regulatory switch for protein membrane association. In this work, we analyzed the presence of DHHC proteins in the protozoa parasite Giardia lamblia and the function of the reversible S-palmitoylation of proteins during parasite differentiation into cyst. Two specific events were observed: encysting cells displayed a larger amount of palmitoylated proteins, and parasites treated with palmitoylation inhibitors produced a reduced number of mature cysts. With bioinformatics tools, we found nine DHHC proteins, potential protein acyltransferases, in the Giardia proteome. These proteins displayed a conserved structure when compared to different organisms and are distributed in different monophyletic clades. Although all Giardia DHHC proteins were found to be present in trophozoites and encysting cells, these proteins showed a different intracellular localization in trophozoites and seemed to be differently involved in the encystation process when they were overexpressed. dhhc transgenic parasites showed a different pattern of cyst wall protein expression and yielded different amounts of mature cysts when they were induced to encyst. Our findings disclosed some important issues regarding the role of DHHC proteins and palmitoylation during Giardia encystation.Fil: Merino, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Zamponi, Nahuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Vranych, Cecilia Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Touz, Maria Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Ropolo, Andrea Silvana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentin

The Absolute of Advaita and the Spirit of Hegel: Situating Vedānta on the Horizons of British Idealisms

$\textit{Purpose}$ A significant volume of philosophical literature produced by Indian academic philosophers in the first half of the twentieth century can be placed under the rubric of ‘Śaṁkara and X’, where X is Hegel, or a German or a British philosopher who had commented on, elaborated or critiqued the Hegelian system. We will explore in this essay the philosophical significance of Hegel-influenced systems as an intellectual conduit for these Indo-European conceptual encounters, and highlight how for some Indian philosophers the British variations on Hegelian systems were both a point of entry into debates over ‘idealism’ and ‘realism’ in contemporary European philosophy and an occasion for defending Advaita against the charge of propounding a doctrine of world illusionism. $\textit{Methodology}$ Our study of the philosophical enquiries of A.C. Mukerji, P.T. Raju, and S.N.L. Shrivastava indicates that they developed distinctive styles of engaging with Hegelian idealisms as they reconfigured certain aspects of the classical Advaita of Śaṁkara through contemporary vocabulary. $\textit{Result and Conclusion}$ These appropriations of Hegelian idioms can be placed under three overlapping styles: (a) Mukerji was partly involved in locating Advaita in an intermediate conceptual space between, on the one hand, Kantian agnosticism and, on the other hand, Hegelian absolutism; (b) Raju and Shrivastava presented Advaitic thought as the fulfilment of certain insights of Hegel and F.H. Bradley; and (c) the interrogations of Hegel’s ‘idealism’ provided several Indian academic philosophers with a hermeneutic opportunity to revisit the vexed question of whether the ‘idealism’ of Śaṁkara reduces the phenomenal world, structured by $\textit{māyā}$, to a bundle of ideas

Alcohol affects neuronal substrates of response inhibition but not of perceptual processing of stimuli signalling a stop response

Alcohol impairs inhibitory control, including the ability to terminate an initiated action. While there is increasing knowledge about neural mechanisms involved in response inhibition, the level at which alcohol impairs such mechanisms remains poorly understood. Thirty-nine healthy social drinkers received either 0.4g/kg or 0.8g/kg of alcohol, or placebo, and performed two variants of a Visual Stop-signal task during acquisition of functional magnetic resonance imaging (fMRI) data. The two task variants differed only in their instructions: in the classic variant (VSST), participants inhibited their response to a “Go-stimulus” when it was followed by a “Stop-stimulus”. In the control variant (VSST_C), participants responded to the “Go-stimulus” even if it was followed by a “Stop-stimulus”. Comparison of successful Stop-trials (Sstop)>Go, and unsuccessful Stop-trials (Ustop)>Sstop between the three beverage groups enabled the identification of alcohol effects on functional neural circuits supporting inhibitory behaviour and error processing. Alcohol impaired inhibitory control as measured by the Stop-signal reaction time, but did not affect other aspects of VSST performance, nor performance on the VSST_C. The low alcohol dose evoked changes in neural activity within prefrontal, temporal, occipital and motor cortices. The high alcohol dose evoked changes in activity in areas affected by the low dose but importantly induced changes in activity within subcortical centres including the globus pallidus and thalamus. Alcohol did not affect neural correlates of perceptual processing of infrequent cues, as revealed by conjunction analyses of VSST and VSST_C tasks. Alcohol ingestion compromises the inhibitory control of action by modulating cortical regions supporting attentional, sensorimotor and action-planning processes. At higher doses the impact of alcohol also extends to affect subcortical nodes of fronto-basal ganglia- thalamo-cortical motor circuits. In contrast, alcohol appears to have little impact on the early visual processing of infrequent perceptual cues. These observations clarify clinically-important effects of alcohol on behaviour

Could a defective epithelial sodium channel lead to bronchiectasis

<p>Abstract</p> <p>Background</p> <p>Bronchiectasis is defined as a permanent dilation of the airways arising from chronic bronchial inflammation/infection. In 50% of cases, no etiology can be identified. Recently, the role of the epithelial sodium channel ENaC has been pointed out in the pathophysiology of cystic fibrosis, a disease due to mutations in the <it>CFTR </it>gene and causing bronchiectasis in the airways. Moreover, it was found that transgenic mice overexpressing <it>ENaCβ </it>present cystic fibrosis-like lung disease symptoms. Our aim was to evaluate if a defective ENaC protein could be involved in the development of bronchiectasis.</p> <p>Methods</p> <p>We extensively analysed <it>ENaCβ </it>and <it>γ </it>genes in 55 patients with idiopathic bronchiectasis and without two mutations in the coding regions of <it>CFTR</it>. Thirty-eight patients presented functional abnormalities suggesting impaired sodium transport (abnormal sweat chloride concentration or nasal potential difference measurement), and 17 had no such evidence.</p> <p>Results</p> <p>Sequencing of the exons and flanking introns of the <it>ENaCβ </it>and <it>γ </it>gene identified five different amino-acid changes (p.Ser82Cys, p.Pro369Thr, p.Asn288Ser in <it>ENaCβ </it>; and p.Gly183Ser, p.Glu197Lys in <it>ENaCγ</it>) in heterozygous state in 8 patients. The p.Ser82Cys amino-acid change was found in 3 unrelated patients who were also heterozygous for a <it>CFTR </it>mutation or variant (1 p.F508del, 1 IVS8-5T, and 1 IVS8-5T:1716G>A (p.E528E)). The other mutations were found in patients without <it>CFTR </it>mutation, the p.Glu197Lys mutation in 2 patients and the other variants in single patients. Among the 8 patients bearing an <it>ENaC </it>mutation, 5 had functional abnormalities suggesting impaired sodium transport.</p> <p>Conclusion</p> <p>Our results suggest that several variants in <it>ENaCβ </it>and <it>γ </it>genes might be deleterious for ENaC function and lead to bronchiectasis, especially in patients who are trans-heterozygotes for <it>ENaCβ/CFTR </it>mutations or variants.</p

MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

Mast Cell-Derived Histamine Mediates Cystitis Pain

Background: Mast cells trigger inflammation that is associated with local pain, but the mechanisms mediating pain are unclear. Interstitial cystitis (IC) is a bladder disease that causes debilitating pelvic pain of unknown origin and without consistent inflammation, but IC symptoms correlate with elevated bladder lamina propria mast cell counts. We hypothesized that mast cells mediate pelvic pain directly and examined pain behavior using a murine model that recapitulates key aspects of IC. Methods and Findings: Infection of mice with pseudorabies virus (PRV) induces a neurogenic cystitis associated with lamina propria mast cell accumulation dependent upon tumor necrosis factor alpha (TNF), TNF-mediated bladder barrier dysfunction, and pelvic pain behavior, but the molecular basis for pelvic pain is unknown. In this study, both PRV-induced pelvic pain and bladder pathophysiology were abrogated in mast cell-deficient mice but were restored by reconstitution with wild type bone marrow. Pelvic pain developed normally in TNF- and TNF receptor-deficient mice, while bladder pathophysiology was abrogated. Conversely, genetic or pharmacologic disruption of histamine receptor H1R or H2R attenuated pelvic pain without altering pathophysiology. Conclusions: These data demonstrate that mast cells promote cystitis pain and bladder pathophysiology through the separable actions of histamine and TNF, respectively. Therefore, pain is independent of pathology and inflammation, an

The co-development of a linguistic and culturally tailored tele-retinopathy screening intervention for immigrants living with diabetes from China and African-Caribbean countries in Ottawa, Canada

Background: Diabetic retinopathy is a sight-threatening ocular complication of diabetes. Screening is an effective way to reduce severe complications, but screening attendance rates are often low, particularly for newcomers and immigrants to Canada and people from cultural and linguistic minority groups. Building on previous work, in partnership with patient and health system stakeholders, we co-developed a linguistically and culturally tailored tele-retinopathy screening intervention for people living with diabetes who recently immigrated to Canada from either China or African-Caribbean countries. Methods: Following an environmental scan of diabetes eye care pathways in Ottawa, we conducted co-development workshops using a nominal group technique to create and prioritize personas of individuals requiring screening and identify barriers to screening that each persona may face. Next, we used the Theoretical Domains Framework to categorize the barriers/enablers and then mapped these categories to potential evidence-informed behaviour change techniques. Finally with these techniques in mind, participants prioritized strategies and channels of delivery, developed intervention content, and clarified actions required by different actors to overcome anticipated intervention delivery barriers. Results: We carried out iterative co-development workshops with Mandarin and French-speaking individuals living with diabetes (i.e., patients in the community) who immigrated to Canada from China and African-Caribbean countries (n = 13), patient partners (n = 7), and health system partners (n = 6) recruited from community health centres in Ottawa. Patients in the community co-development workshops were conducted in Mandarin or French. Together, we prioritized five barriers to attending diabetic retinopathy screening: language (TDF Domains: skills, social influences), retinopathy familiarity (knowledge, beliefs about consequences), physician barriers regarding communication for screening (social influences), lack of publicity about screening (knowledge, environmental context and resources), and fitting screening around other activities (environmental context and resources). The resulting intervention included the following behaviour change techniques to address prioritized local barriers: information about health consequence, providing instructions on how to attend screening, prompts/cues, adding objects to the environment, social support, and restructuring the social environment. Operationalized delivery channels incorporated language support, pre-booking screening and sending reminders, social support via social media and community champions, and providing using flyers and videos as delivery channels. Conclusion: Working with intervention users and stakeholders, we co-developed a culturally and linguistically relevant tele-retinopathy intervention to address barriers to attending diabetic retinopathy screening and increase uptake among two under-served groups