Multivariate Hawkes process models of the occurrence of regulatory elements

<p>Abstract</p> <p>Background</p> <p>A central question in molecular biology is how transcriptional regulatory elements (TREs) act in combination. Recent high-throughput data provide us with the location of multiple regulatory regions for multiple regulators, and thus with the possibility of analyzing the multivariate distribution of the occurrences of these TREs along the genome.</p> <p>Results</p> <p>We present a model of TRE occurrences known as the Hawkes process. We illustrate the use of this model by analyzing two different publically available data sets. We are able to model, in detail, how the occurrence of one TRE is affected by the occurrences of others, and we can test a range of natural hypotheses about the dependencies among the TRE occurrences. In contrast to earlier efforts, pre-processing steps such as clustering or binning are not needed, and we thus retain information about the dependencies among the TREs that is otherwise lost. For each of the two data sets we provide two results: first, a qualitative description of the dependencies among the occurrences of the TREs, and second, quantitative results on the favored or avoided distances between the different TREs.</p> <p>Conclusions</p> <p>The Hawkes process is a novel way of modeling the joint occurrences of multiple TREs along the genome that is capable of providing new insights into dependencies among elements involved in transcriptional regulation. The method is available as an R package from <url>http://www.math.ku.dk/~richard/ppstat/</url>.</p

Experimental investigation of cut-off phenomena in non-linear photonic crystal fibers

The modal cut-off is investigated experimentally in a series of high quality non-linear photonic crystal fibers. We demonstrate a suitable measurement technique to determine the cut-off wavelength and verify it by inspecting the near field of the modes that may be excited below and above the cut-off. We observe a double peak structure in the cut-off spectra, which is attributed to a splitting of the higher order modes. The cut-off is measured for seven different fiber geometries with different pitches and relative hole size, and a very good agreement with recent theoretical work is found.Comment: 3 pages including 1 table and 4 figures. Accepted for Optics Letter

Antimicrobial Activity of α-Peptide/β-Peptoid Lysine-Based Peptidomimetics Against Colistin-Resistant Pseudomonas aeruginosa Isolated From Cystic Fibrosis Patients

Pseudomonas aeruginosa infection is a predominant cause of morbidity and mortality in patients with cystic fibrosis infection and with a compromised immune system. Emergence of bacterial resistance renders existing antibiotics inefficient, and therefore discovery of new antimicrobial agents is highly warranted. In recent years, numerous studies have demonstrated that antimicrobial peptides (AMPs) constitute potent agents against a range of pathogenic bacteria. However, AMPs possess a number of drawbacks such as susceptibility to proteolytic degradation with ensuing low bioavailability. To circumvent these undesired properties of AMPs unnatural amino acids or altered backbones have been incorporated to provide stable peptidomimetics with retained antibacterial activity. Here, we report on antimicrobial α-peptide/β-peptoid lysine-based peptidomimetics that exhibit high potency against clinical drug-resistant P. aeruginosa strains obtained from cystic fibrosis patients. These clinical strains possess phoQ and/or pmrB mutations that confer high resistance to colistin, the last-resort antibiotic for treatment of infections caused by P. aeruginosa. The lead peptidomimetic LBP-2 demonstrated a 12-fold improved anti-pseudomonal activity as compared to colistin sulfate as well as favorable killing kinetics, similar antibiofilm activity, and moderate cytotoxicity

Teamwork and Adherence to Guideline on Newborn Resuscitation-Video Review of Neonatal Interdisciplinary Teams

BACKGROUND: Little is known about the importance of non-technical skills for the adherence to guidelines, when teams of midwives, obstetricians, anesthesiologists, and pediatricians resuscitate and support the transition of newborns. Non-technical skills are competences underpinning successful teamwork in healthcare. These are usually referred to as leadership, situational awareness, communication, teamwork, decision making, and coping with stress and fatigue. OBJECTIVE: By review of videos of teams managing newborns with difficult transition, we aimed to investigate whether the level of the teams' non-technical skills was associated with the degree of adherence to guidelines for newborn resuscitation and transitional support at birth. METHODS: Four expert raters independently assessed 43 real-life videos of teams managing newborns with transitional difficulties, two assessed the non-technical score and two assessed the clinical performance. Exposure was the non-technical score, obtained by the Global Assessment Of Team Performance checklist (GAOTP). GAOTP was rated on a Likert Scale 1–5 (1 = poor, 3 = average and 5 = excellent). The outcome was the clinical performance score of the team assessed according to adherence of the European Resuscitation Counsel (ERC) guideline for neonatal resuscitation and transitional support. The ERC guideline was adapted into the checklist TeamOBS-Newborn to facilitate a structured and simple performance assessment (low score 0–60, average 60–84, high 85–100). Interrater agreement was analyzed by intraclass correlation (ICC), Bland-Altman analysis, and Cohen's kappa weighted. The risk of high and low clinical performance was analyzed on the logit scale to meet the assumptions of normality and constant standard deviation. RESULTS: Teams with an excellent non-technical score had a relative risk 5.5 [95% confidence interval (CI) 2.4–22.5] of high clinical performance score compared to teams with average non-technical score. In addition, we found a dose response like association. The specific non-technical skills associated with the highest degree of adherence to guidelines were leadership and teamwork, coping with stress and fatigue, and communication with parents. Inter-rater agreement was high; raters assessing non-technical skills had an interclass coefficient (ICC) 0.88 (95% CI 0.79–0.94); the neonatologists assessing clinical performance had an ICC of 0.81 (95% CI 0.66–0.89). CONCLUSION: Teams with an excellent non-technical score had five times the chance of high clinical performance compared to teams with average non-technical skills. High performance teams were characterized by good leadership and teamwork, coping with stress, and fatigue and communication with parents

NT-proBNP levels, atherosclerosis and vascular function in asymptomatic type 2 diabetic patients with microalbuminuria: peripheral reactive hyperaemia index but not NT-proBNP is an independent predictor of coronary atherosclerosis

Intensive multifactorial treatment aimed at cardiovascular (CV) risk factor reduction in type 2 diabetic patients with microalbuminuria can diminish fatal and non-fatal CV. Plasma N-terminal (NT)-proBNP predicts CV mortality in diabetic patients but the utility of P-NT-proBNP in screening for atherosclerosis is unclear. We examined the interrelationship between P-NT-proBNP, presence of atherosclerosis and/or vascular dysfunction in the coronary, carotid and peripheral arteries in asymptomatic type 2 diabetic patients with microalbuminuria that received intensive multifactorial treatment

NT-proBNP, echocardiographic abnormalities and subclinical coronary artery disease in high risk type 2 diabetic patients

<p>Abstract</p> <p>Background</p> <p>Intensive multifactorial treatment aimed at prevention of cardiovascular (CV) disease may reduce left ventricular (LV) echocardiographic abnormalities in diabetic subjects. Plasma N-terminal (NT)-proBNP predicts CV mortality in diabetic patients but the association between P-NT-proBNP and the putative residual abnormalities in such patients are not well described. This study examined echocardiographic measurements of LV hypertrophy, atrial dilatation and LV dysfunction and their relation to P-NT-proBNP levels or subclinical coronary artery disease (CAD) in type 2 diabetic patients with microalbuminuria receiving intensive multifactorial treatment.</p> <p>Methods</p> <p>Echocardiography including tissue Doppler imaging and P-NT-proBNP measurements were performed in 200 patients without prior CAD. Patients with P-NT-proBNP > 45.2 ng/L and/or coronary calcium score ≥ 400 were stratified as high risk patients for CAD(n = 133) and examined for significant CAD by myocardial perfusion imaging and/or CT-angiography and/or coronary angiography.</p> <p>Results</p> <p>LV mass index was 41.2 ± 10.9 g/m^2.7and 48 (24%) patients had LV hypertrophy. LA and RA dilatation were found in 54(27%) and 45(23%) patients, respectively, and LV diastolic dysfunction was found in 109(55%) patients. Patients with increased P-NT-proBNP levels did not have more major echocardiographic abnormalities. In 70(53%) of 133 high risk patients significant CAD was demonstrated and patients with LV hypertrophy had increased risk of significant CAD(adjusted odd ratio[CI] was 4.53[1.14-18.06]).</p> <p>Conclusion</p> <p>Among asymptomatic type 2 diabetic patients with microalbuminuria that received intensive multifactorial treatment, P-NT-proBNP levels is not associated with echocardiographic abnormalities. LV diastolic dysfunction was frequently observed, whereas LV hypertrophy was less frequent but associated with significant CAD.</p

Gill transcriptomic responses to toxin-producing alga Prymnesium parvum in rainbow trout

This work was supported by the BBSRC EastBio PhD studentship awarded to MC, the Danish Strategic Research Council grant No 060300449B HABFISH, and the European Maritime and Fisheries Fund and the Danish Fisheries Agency joint grant “Sundt Dambrug”. Molecular work at University of Aberdeen was funded by Scottish Aquaculture Innovation grant SL 2017 08. EK was supported by BBSRC grant BB/R018812/1.The gill of teleost fish is a multifunctional organ involved in many physiological processes, including protection of the mucosal gill surface against pathogens and other environmental antigens by the gill-associated lymphoid tissue (GIALT). Climate change associated phenomena, such as increasing frequency and magnitude of harmful algal blooms (HABs) put extra strain on gill function, contributing to enhanced fish mortality and fish kills. However, the molecular basis of the HAB-induced gill injury remains largely unknown due to the lack of high-throughput transcriptomic studies performed on teleost fish in laboratory conditions. We used juvenile rainbow trout (Oncorhynchus mykiss) to investigate the transcriptomic responses of the gill tissue to two (high and low) sublethal densities of the toxin-producing alga Prymnesium parvum, in relation to non-exposed control fish. The exposure time to P. parvum (4–5 h) was sufficient to identify three different phenotypic responses among the exposed fish, enabling us to focus on the common gill transcriptomic responses to P. parvum that were independent of dose and phenotype. The inspection of common differentially expressed genes (DEGs), canonical pathways, upstream regulators and downstream effects pointed towards P. parvum-induced inflammatory response and gill inflammation driven by alterations of Acute Phase Response Signalling, IL-6 Signalling, IL-10 Signalling, Role of PKR in Interferon Induction and Antiviral Response, IL-8 Signalling and IL-17 Signalling pathways. While we could not determine if the inferred gill inflammation was progressing or resolving, our study clearly suggests that P. parvum blooms may contribute to the serious gill disorders in fish. By providing insights into the gill transcriptomic responses to toxin-producing P. parvum in teleost fish, our research opens new avenues for investigating how to monitor and mitigate toxicity of HABs before they become lethal.Publisher PDFPeer reviewe