C1D family proteins in coordinating RNA processing,chromosome condensation and DNA damage response

Research on the involvement of C1D and its yeast homologues Rrp47 (S. cerevisiae) and Cti1 (S. pombe) in DNA damage repair and RNA processing has remained mutually exclusive, with most studies predominantly concentrating on Rrp47. This review will look to reconcile the functions of these proteins in their involvement with the RNA exosome, in the regulation of chromatin architecture, and in the repair of DNA double-strand breaks, focusing on non-homologous end joining and homologous recombination. We propose that C1D is situated in a central position to maintain genomic stability at highly transcribed gene loci by coordinating these processes through the timely recruitment of relevant regulatory factors. In the event that the damage is beyond repair, C1D induces apoptosis in a p53-dependent manner.     

The use of dynamic elastomeric fabric orthosis suits as an orthotic intervention in the management of children with neuropathic onset scoliosis: A retrospective audit of routine clinical case notes

Background

To date the main treatment approach for neuropathic onset scoliosis has utilised thoracic lumbar sacral orthoses (TLSO) to stabilize the spine and enable stable sitting. Dynamic elastomeric fabric orthoses (DEFOs) may achieve both of these aims if used as an early intervention. Due to a lack of evidence in this area, a retrospective audit of case notes was undertaken to understand current orthotic practice investigating the usage, outcomes and clinical characteristics of treated children with neuropathic onset scoliosis. Clinical notes of 180 children at risk for, or identified with, scoliosis were audited using a search matrix to identify diagnostic group, spinal muscle tone, Gross Motor Functional Classification Scale (GMFCS) level, orthotic treatment modalities, scoliosis specific data, surgical interventions, adaptive technologies used, and outcome measurements reported.

Results

Of the 180 notes examined, 85 were male; mean age nine years one month [SD four years seven months]. Spinal muscle tone was reported in 137 cases: 122/137 presented as low tone, 4/137 high tone, 6/137 fluctuating tone and 5/137 typical tone. Scoliosis was confirmed in (77/180) of whom (39/77) used a DEFO. Another (43/180) had a spinal curve developing, of whom (22/43) used a DEFO. The remaining (60/180) had no report of spinal curvature, but used a DEFO as a preventative measure. GMFCS scores were reported for 49 children of whom 14/49 were graded as level 4 and 17/49 level 5. Of the children with scoliosis who had spinal curve shapes reported, 48/60 had a C-shape presentation and 12/60 had an S-shape.

Conclusions

The findings confirm previously reported papers in children with neuropathic onset scoliosis in relation to curve shape and GMFCS levels. It provides some evidence of the role DEFOs may have in the management of these children, and highlights the need for further research in this area due to the lack of peer-reviewed publications.

     

BiC2PAM: constraint-guided biclustering for biological data analysis with domain knowledge

Background

Biclustering has been largely used in biological data analysis, enabling the discovery of putative functional modules from omic and network data. Despite the recognized importance of incorporating domain knowledge to guide biclustering and guarantee a focus on relevant and non-trivial biclusters, this possibility has not yet been comprehensively addressed. This results from the fact that the majority of existing algorithms are only able to deliver sub-optimal solutions with restrictive assumptions on the structure, coherency and quality of biclustering solutions, thus preventing the up-front satisfaction of knowledge-driven constraints. Interestingly, in recent years, a clearer understanding of the synergies between pattern mining and biclustering gave rise to a new class of algorithms, termed as pattern-based biclustering algorithms. These algorithms, able to efficiently discover flexible biclustering solutions with optimality guarantees, are thus positioned as good candidates for knowledge incorporation. In this context, this work aims to bridge the current lack of solid views on the use of background knowledge to guide (pattern-based) biclustering tasks.

Methods

This work extends (pattern-based) biclustering algorithms to guarantee the satisfiability of constraints derived from background knowledge and to effectively explore efficiency gains from their incorporation. In this context, we first show the relevance of constraints with succinct, (anti-)monotone and convertible properties for the analysis of expression data and biological networks. We further show how pattern-based biclustering algorithms can be adapted to effectively prune of the search space in the presence of such constraints, as well as be guided in the presence of biological annotations. Relying on these contributions, we propose BiClustering with Constraints using PAttern Mining (BiC2PAM), an extension of BicPAM and BicNET biclustering algorithms.

Results

Experimental results on biological data demonstrate the importance of incorporating knowledge within biclustering to foster efficiency and enable the discovery of non-trivial biclusters with heightened biological relevance.

Conclusions

This work provides the first comprehensive view and sound algorithm for biclustering biological data with constraints derived from user expectations, knowledge repositories and/or literature.

     

A representation of a compressed de Bruijn graph for pan-genome analysis that enables search

Background

Recently, Marcus et al. (Bioinformatics 30:3476–83, 2014) proposed to use a compressed de Bruijn graph to describe the relationship between the genomes of many individuals/strains of the same or closely related species. They devised an \(O(n\log g)\) time algorithm called splitMEM that constructs this graph directly (i.e., without using the uncompressed de Bruijn graph) based on a suffix tree, where n is the total length of the genomes and g is the length of the longest genome. Baier et al. (Bioinformatics 32:497–504, 2016) improved their result.

Results

In this paper, we propose a new space-efficient representation of the compressed de Bruijn graph that adds the possibility to search for a pattern (e.g. an allele—a variant form of a gene) within the pan-genome. The ability to search within the pan-genome graph is of utmost importance and is a design goal of pan-genome data structures.

     

Serial Change in Cervical Length for the Prediction of Emergency Cesarean Section in Placenta Previa

Purpose

To evaluate whether serial change in cervical length (CL) over time can be a predictor for emergency cesarean section (CS) in patients with placenta previa.

Methods

This was a retrospective cohort study of patients with placenta previa between January 2010 and November 2014. All women were offered serial measurement of CL by transvaginal ultrasound at 19 to 23 weeks (CL1), 24 to 28 weeks (CL2), 29 to 31 weeks (CL3), and 32 to 34 weeks (CL4). We compared clinical characteristics, serial change in CL, and outcomes between the emergency CS group (case group) and elective CS group (control group). The predictive value of change in CL for emergency CS was evaluated.

Results

A total of 93 women were evaluated; 31 had emergency CS due to massive vaginal bleeding. CL tended to decrease with advancing gestational age in each group. Until 29–31 weeks, CL showed no significant differences between the two groups, but after that, CL in the emergency CS group decreased abruptly, even though CL in the elective CS group continued to gradually decrease. On multivariate analysis to determine risk factors, only admissions for bleeding (odds ratio, 34.710; 95% CI, 5.239–229.973) and change in CL (odds ratio, 3.522; 95% CI, 1.210–10.253) were significantly associated with emergency CS. Analysis of the receiver operating characteristic curve showed that change in CL could be the predictor of emergency CS (area under the curve 0.734, p < 0.001), with optimal cutoff for predicting emergency cesarean delivery of 6.0 mm.

Conclusions

Previous admission for vaginal bleeding and change in CL are independent predictors of emergency CS in placenta previa. Women with change in CL more than 6 mm between the second and third trimester are at high risk of emergency CS in placenta previa. Single measurements of short CL at the second or third trimester do not seem to predict emergency CS.     

Identification of Human Islet Amyloid Polypeptide as a BACE2 Substrate

Pancreatic amyloid formation by islet amyloid polypeptide (IAPP) is a hallmark pathological feature of type 2 diabetes. IAPP is stored in the secretory granules of pancreatic beta-cells and co-secreted with insulin to maintain glucose homeostasis. IAPP is innocuous under homeostatic conditions but imbalances in production or processing of IAPP may result in homodimer formation leading to the rapid production of cytotoxic oligomers and amyloid fibrils. The consequence is beta-cell dysfunction and the accumulation of proteinaceous plaques in and around pancreatic islets. Beta-site APP-cleaving enzyme 2, BACE2, is an aspartyl protease commonly associated with BACE1, a related homolog responsible for amyloid processing in the brain and strongly implicated in Alzheimer’s disease. Herein, we identify two distinct sites of the mature human IAPP sequence that are susceptible to BACE2-mediated proteolytic activity. The result of proteolysis is modulation of human IAPP fibrillation and human IAPP protein degradation. These results suggest a potential therapeutic role for BACE2 in type 2 diabetes-associated hyperamylinaemia.     

Left Atrial Structure and Function in Heart Failure with Preserved Ejection Fraction: A RELAX Substudy

Given the emerging recognition of left atrial structure and function as an important marker of disease in heart failure with preserved ejection fraction (HF-pEF), we investigated the association between left atrial volume and function with markers of disease severity and cardiac structure in HF-pEF. We studied 100 patients enrolled in the PhosphdiesteRasE-5 Inhibition to Improve CLinical Status and EXercise Capacity in Diastolic Heart Failure (RELAX) trial who underwent cardiac magnetic resonance (CMR), cardiopulmonary exercise testing, and blood collection before randomization. Maximal left atrial volume index (LAVi; N = 100), left atrial emptying fraction (LAEF; N = 99; including passive and active components (LAEF_P, LAEF_A; N = 80, 79, respectively) were quantified by CMR. After adjustment for multiple testing, maximal LAVi was only associated with age (ρ = 0.39), transmitral filling patterns (medial E/e’ ρ = 0.43), and N-terminal pro-BNP (NT-proBNP; ρ = 0.65; all p<0.05). Lower LAEF was associated with older age, higher transmitral E/A ratio and higher NT-proBNP. Peak VO₂ and V_E/VCO₂ slope were not associated with left atrial structure or function. After adjustment for age, sex, transmitral E/A ratio, CMR LV mass, LV ejection fraction, and creatinine clearance, NT-proBNP remained associated with maximal LAVi (β = 0.028, p = 0.0007) and total LAEF (β = -0.033, p = 0.001). Passive and active LAEF were most strongly associated with age and NT-proBNP, but not gas exchange or other markers of ventricular structure or filling properties. Left atrial volume and emptying function are associated most strongly with NT-proBNP and diastolic filling properties, but not significantly with gas exchange, in HFpEF. Further research to explore the relevance of left atrial structure and function in HF-pEF is warranted.     

Molecular dynamics simulations of the orientation properties of cytochrome <Emphasis Type="Italic">c</Emphasis> on the surface of single-walled carbon nanotubes

Electron transfer between cytochrome c (Cytc) and electrodes can be influenced greatly by the orientation of protein on the surface of the electrodes. In the present study, different initial orientations of Cytc on the surface of five types of single-walled carbon nanotubes (SWNTs), with different diameters and chirality, were constructed. Properties of the orientations of proteins on the surface of these tubes were first investigated through molecular dynamics simulations. It was shown that variations in SWNT diameter do not significantly affect the orientation; however, the chirality of the SWNTs is crucial to the orientation of the heme embedded in Cytc, and the orientation of the protein can consequently be influenced by the heme orientation. A new electron pathway between Cytc and SWNT, which hopefully benefits electron transfer efficiency, has also been proposed. This study promises to provide theoretical guidance for the rational design of bio-sensors or bio-fuel cells by using Cytc-decorated carbon nanotube electrodes.