A two-base encoded DNA sequence alignment problem in computational biology

The recent introduction of instruments capable of producing millions of DNA sequence reads in a single run is rapidly changing the landscape of genetics. The primary objective of the "sequence alignment" problem is to search for a new algorithm that facilitates the use of two-base encoded data for large-scale re-sequencing projects. This algorithm should be able to perform local sequence alignment as well as error detection and correction in a reliable and systematic manner, enabling the direct comparison of encoded DNA sequence reads to a candidate reference DNA sequence. We will first briefly review two well-known sequence alignment approaches and provide a rudimentary improvement for implementation on parallel systems. Then, we carefully examin a unique sequencing technique known as the SOLiDTM System that can be implemented, and follow by the results from the global and local sequence alignment. In this report, the team presents an explanation of the algorithms for color space sequence data from the high-throughput re-sequencing technology and a theoretical parallel approach to the dynamic programming method for global and local alignment. The combination of the di-base approach and dynamic programming provides a possible viewpoint for large-scale re-sequencing projects. We anticipate the use of distributed computing to be the next-generation engine for large-scale problems like such

Prospective, historically controlled study to evaluate the efficacy and safety of a new paediatric formulation of nifurtimox in children aged 0 to 17 years with chagas disease one year after treatment (Chico)

Nifurtimox is a recommended treatment for Chagas disease, but data from treated children are limited. We investigated the efficacy, safety and tolerability of nifurtimox administered as divisible, dispersible 30 mg and 120 mg tablets in children with Chagas disease. In this blinded, controlled study conducted January 2016–July 2018, 330 patients aged <18 years from 25 medical centres across three South American countries were randomised 2:1 to nifurtimox 10–20 mg/kg/day (aged <12 years) or 8–10 mg/kg/day (aged ≥12 years) for 60 days (n = 219), or for 30 days plus placebo for 30 days (n = 111) (ClinicalTrials.gov NCT02625974). The primary outcome was anti-Trypanosoma cruzi serological response (negative seroconversion or seroreduction ≥20% in mean optical density from baseline determined by two conventional enzyme-linked immunosorbent assays) at 12 months in the 60-day treatment group versus historical placebo controls. Nifurtimox for 60 days achieved negative seroconversion (n = 10) and seroreduction (n = 62) in 72 patients (serological response 32.9%; 95% confidence interval [CI] 26.4%, 39.3%, of all treated patients), confirming superiority relative to the upper 95% CI of 16% for controls. In patients aged <8 months, 10/12 treated for 60 days (83.3%) and 5/7 treated for 30 days (71.4%) achieved negative seroconversion. Overall serological response was lower for 30-day than for 60-day nifurtimox (between-treatment difference 14.0% [95% CI 3.7%, 24.2%]). The frequency of T. cruzi-positive quantitative polymerase chain reactions decreased substantially from baseline levels (60-day regimen 53.4% versus 1.4%; 30-day regimen 51.4% versus 4.5%). Study drug-related treatment-emergent adverse events (TEAEs), which were observed in 62 patients (28.3%) treated for 60 days and 29 patients (26.1%) treated for 30 days, were generally mild or moderate and resolved without sequelae; 4.2% of all TEAEs led to nifurti-mox discontinuation. Age-and weight-adjusted nifurtimox for 60 days achieved a serological response at 12 months post-treatment that was superior to historical placebo, was well tolerated and had a favourable safety profile in children with Chagas disease. Although, at 1 year serological follow-up, efficacy of the shorter nifurtimox treatment was not comparable to the 60-day treatment regimen for the overall study population, further long-term follow-up of the patients will provide important information about the progress of serological conversion in children treated with nifurtimox, as well as the potential efficacy difference between the two regimens over time.Fil: Altcheh, Jaime Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; ArgentinaFil: Castro, Luis. Centro de Atención E Investigación Médica; ColombiaFil: Dib, Juan C.. Universidad del Norte; ColombiaFil: Grossmann, Ulrike. No especifíca;Fil: Huang, Erya. No especifíca;Fil: Moscatelli, Guillermo. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; ArgentinaFil: Pinto Rocha, Jimy José. Fundación Ceades; BoliviaFil: Ramírez, Teresa Estela. Centro de Enfermedad de Chagas y Patologias Regionales; Argentin

Integrated micro/messenger RNA regulatory networks in essential thrombocytosis

<div><p>Essential thrombocytosis (ET) is a chronic myeloproliferative disorder with an unregulated surplus of platelets. Complications of ET include stroke, heart attack, and formation of blood clots. Although platelet-enhancing mutations have been identified in ET cohorts, genetic networks causally implicated in thrombotic risk remain unestablished. In this study, we aim to identify novel ET-related miRNA-mRNA regulatory networks through comparisons of transcriptomes between healthy controls and ET patients. Four network discovery algorithms have been employed, including (a) Pearson correlation network, (b) sparse supervised canonical correlation analysis (sSCCA), (c) sparse partial correlation network analysis (SPACE), and, (d) (sparse) Bayesian network analysis–all through a combined data-driven and knowledge-based analysis. The result predicts a close relationship between an 8-miRNA set (miR-9, miR-490-5p, miR-490-3p, miR-182, miR-34a, miR-196b, miR-34b*, miR-181a-2*) and a 9-mRNA set (CAV2, LAPTM4B, TIMP1, PKIG, WASF1, MMP1, ERVH-4, NME4, HSD17B12). The majority of the identified variables have been linked to hematologic functions by a number of studies. Furthermore, it is observed that the selected mRNAs are highly relevant to ET disease, and provide an initial framework for dissecting both platelet-enhancing and functional consequences of dysregulated platelet production.</p></div

Bipartite plot of the SPACE result.

<p>Red circles represent miRNAs that have direct connection with the mRNAs, while the red squares denote the mRNAs that have direct link with the miRNAs. In addition, red and green lines represent positive or negative partial correlations between the pairs.</p

Bipartite plot of the sSCCA result.

<p>Red or green node represents positive or negative weight in vector <i>u</i> and <i>v</i>. The node size represents the absolute value of weight.</p

Integrated network analysis results.

<p>(A) is the integrated result between sSCCA and SPACE. (B) is the integrated result between sSCCA and A* Lasso method. The arrow is added back on figure (B). The red represents positive values (either weight or correlation coefficient) and green means negative values.</p

Effect of neladenoson bialanate on exercise capacity among patients with heart failure with preserved ejection fraction: a randomized clinical trial

Importance: Heart failure with preserved ejection fraction (HFpEF) lacks effective treatments. Based on preclinical studies, neladenoson bialanate, a first-in-class partial adenosine A1 receptor agonist, has the potential to improve several heart failure–related cardiac and noncardiac abnormalities but has not been evaluated to treat HFpEF. Objectives: To determine whether neladenoson improves exercise capacity, physical activity, cardiac biomarkers, and quality of life in patients with HFpEF and to find the optimal dose. Design, Setting, and Participants: Phase 2b randomized clinical trial conducted at 76 centers in the United States, Europe, and Japan. Patients (N = 305) with New York Heart Association class II or III HFpEF with elevated natriuretic peptide levels were enrolled between May 10, 2017, and December 7, 2017 (date of final follow-up: June 20, 2018). Interventions: Participants were randomized (1:2:2:2:2:3) to neladenoson (n = 27 [5 mg], n = 50 [10 mg], n = 51 [20 mg], n = 50 [30 mg], and n = 51 [40 mg]) or matching placebo (n = 76) for 20 weeks of treatment. Main Outcomes and Measures: The primary end point was change in 6-minute walk test distance from baseline to 20 weeks (minimal clinically important difference, 40 m). Key safety measures included bradyarrhythmias and adverse events. To evaluate the effects of varying doses of neladenoson, a multiple comparison procedure with 5 modeling techniques (linear, Emax, 2 variations of sigmoidal Emax, and quadratic) was used to evaluate diverse dose-response profiles. Results: Among 305 patients who were randomized (mean age, 74 years; 160 [53%] women; mean 6-minute walk test distance, 321.5 m), 261 (86%) completed the trial and were included in the primary analysis. After 20 weeks of treatment, the mean absolute changes from baseline in 6-minute walk test distance were 0.2 m (95% CI, −12.1 to 12.4 m) for the placebo group; 19.4 m (95% CI, −10.8 to 49.7 m) for the 5 mg of neladenoson group; 29.4 m (95% CI, 3.0 to 55.8 m) for 10 mg of neladenoson group; 13.8 m (95% CI, −2.3 to 29.8 m) for 20 mg of neladenoson group; 16.3 m (95% CI, −1.1 to 33.6 m) for 30 mg of neladenoson group; and 13.0 m (95% CI, −5.9 to 31.9 m) for 40 mg of neladenoson group. Because none of the neladenoson groups achieved the clinically relevant 40-m increase in 6-minute walk test distance from baseline, an optimal dose of neladenoson was not identified. There was no significant dose-response relationship for the change in 6-minute walk test distance among the 5 different dose-response models (P = .05 for Emax; P = .18 for quadratic; P = .21 for sigmoidal Emax 1; P = .39 for linear; and P = .52 for sigmoidal Emax 2). Serious adverse events were similar among the neladenoson groups (61/229 [26.6%]) and the placebo group (21/76 [27.6%]). Conclusions and Relevance: Among patients with HFpEF, there was no significant dose-response relationship detected for neladenoson with regard to the change in exercise capacity from baseline to 20 weeks. In light of these findings, novel approaches will be needed if further development of neladenoson for the treatment of patients with HFpEF is pursued