Genome-wide detection of segmental duplications and potential assembly errors in the human genome sequence

BACKGROUND: Previous studies have suggested that recent segmental duplications, which are often involved in chromosome rearrangements underlying genomic disease, account for some 5% of the human genome. We have developed rapid computational heuristics based on BLAST analysis to detect segmental duplications, as well as regions containing potential sequence misassignments in the human genome assemblies. RESULTS: Our analysis of the June 2002 public human genome assembly revealed that 107.4 of 3,043.1 megabases (Mb) (3.53%) of sequence contained segmental duplications, each with size equal or more than 5 kb and 90% identity. We have also detected that 38.9 Mb (1.28%) of sequence within this assembly is likely to be involved in sequence misassignment errors. Furthermore, we have identified a significant subset (199,965 of 2,327,473 or 8.6%) of single-nucleotide polymorphisms (SNPs) in the public databases that are not true SNPs but are potential paralogous sequence variants. CONCLUSION: Using two distinct computational approaches, we have identified most of the sequences in the human genome that have undergone recent segmental duplications. Near-identical segmental duplications present a major challenge to the completion of the human genome sequence. Potential sequence misassignments detected in this study would require additional efforts to resolve

Synthesis and a study of the 13C NMR spectroscopic properties of positional isomers of some C18 acetylenic thia fatty esters

The carbon magnetic resonance spectra of four positional acetylenic thia fatty acid methyl ester isomers have been recorded to investigate the effect of the sulfur atom on the chemical shifts of the carbon nuclei adjacent to it.published_or_final_versio

Network analysis of differential Ras isoform mutation effects on intestinal epithelial responses to TNF-α

Tumor necrosis factor alpha (TNF-α) is an inflammatory cytokine that can elicit distinct cellular behaviors under different molecular contexts. Mitogen activated protein kinase (MAPK) pathways, especially the extracellular signal-regulated kinase (Erk) pathway, help to integrate influences from the environmental context, and therefore modulate the phenotypic effect of TNF-α exposure. To test how variations in flux through the Erk pathway modulate TNF-α-elicited phenotypes in a complex physiological environment, we exposed mice with different Ras mutations (K-Ras activation, N-Ras activation, and N-Ras ablation) to TNF-α and observed phenotypic and signaling changes in the intestinal epithelium. Hyperactivation of Mek1, an Erk kinase, was observed in the intestine of mice with K-Ras activation and, surprisingly, in N-Ras null mice. Nevertheless, these similar Mek1 outputs did not give rise to the same phenotype, as N-Ras null intestine was hypersensitive to TNF-α-induced intestinal cell death while K-Ras mutant intestine was not. A systems biology approach applied to sample the network state revealed that the signaling contexts presented by these two Ras isoform mutations were different. Consistent with our experimental data, N-Ras ablation induced a signaling network state that was mathematically predicted to be pro-death, while K-Ras activation did not. Further modeling by constrained Fuzzy Logic (cFL) revealed that N-Ras and K-Ras activate the signaling network with different downstream distributions and dynamics, with N-Ras effects being more transient and diverted more towards PI3K-Akt signaling and K-Ras effects being more sustained and broadly activating many pathways. Our study highlights the necessity to consider both environmental and genomic contexts of signaling pathway activation in dictating phenotypic responses, and demonstrates how modeling can provide insight into complex in vivo biological mechanisms, such as the complex interplay between K-Ras and N-Ras in their downstream effects.National Institute of General Medical Sciences (U.S.) (Grant R01-GM088827)National Cancer Institute (U.S.) (U54-CA112967)United States. Army Research Office (Institute for Collaborative Biotechnologies Grant W911NF-09-D-000

In Vivo Systems Analysis Identifies Spatial and Temporal Aspects of the Modulation of TNF-α-Induced Apoptosis and Proliferation by MAPKs

Cellular responses to external stimuli depend on dynamic features of multipathway network signaling; thus, cell behavior is influenced in a complex manner by the environment and by intrinsic properties. Methods of multivariate systems analysis have provided an understanding of these convoluted effects, but only for relatively simplified examples in vitro. To determine whether such approaches could be successfully used in vivo, we analyzed the signaling network that determines the response of intestinal epithelial cells to tumor necrosis factor–α (TNF-α). We built data-driven, partial least-squares discriminant analysis (PLSDA) models based on signaling, apoptotic, and proliferative responses in the mouse small intestinal epithelium after systemic exposure to TNF-α. The extracellular signal–regulated kinase (ERK) signaling axis was a critical modulator of the temporal variation in apoptosis at different doses of TNF-α and of the spatial variation in proliferation in distinct intestinal regions. Inhibition of MEK, a mitogen-activated protein kinase kinase upstream of ERK, altered the signaling network and changed the temporal and spatial phenotypes consistent with model predictions. Our results demonstrate the dynamic, adaptive nature of in vivo signaling networks and identify natural, tissue-level variation in responses that can be deconvoluted only with quantitative, multivariate computational modeling. This study lays a foundation for the use of systems-based approaches to understand how dysregulation of the cellular network state underlies complex diseases.National Institute of General Medical Sciences (U.S.) (Grant R01-GM088827)National Cancer Institute (U.S.) (Grant U54-CA112967

The aetiology and incidence of infective endocarditis in people living with rheumatic heart disease in tropical Australia

Purpose: To define the incidence and microbiological aetiology of infective endocarditis (IE) in patients with rheumatic heart disease (RHD) in tropical Australia. Methods: A retrospective study that examined all episodes of IE between January 1998 and June 2021 among individuals on the RHD register in Far North Queensland, Australia. Results: There were 1135 individuals with a diagnosis of RHD on the register during the study period, representing 10962 patient-years at risk. Overall, there were 18 episodes of definite IE occurring in 16 individuals, although only 7 episodes occurred in native valves (11 occurred in prosthetic valves) equating to 0.7 episodes of native valve IE/1000 patient-years. No patient with mild RHD - and only one child with RHD - developed IE during the study period. Despite the study’s tropical location, the causative organism was usually typical skin or oral flora. Among individuals with an indication for benzathine penicillin G (BPG) prophylaxis, only 1/6 episodes of IE due to a penicillin-susceptible organism received BPG in the month before presentation. Conclusion: Although RHD predisposes individuals to IE, the absolute risk of IE in native valve disease in tropical Australia is low and might be reduced further by improved adherence to secondary BPG prophylaxis

Multi-Scale In Vivo Systems Analysis Reveals the Influence of Immune Cells on TNF-α-Induced Apoptosis in the Intestinal Epithelium

Intestinal epithelial cells exist within a complex environment that affects how they interpret and respond to stimuli. We have applied a multi-scale in vivo systems approach to understand how intestinal immune cells communicate with epithelial cells to regulate responses to inflammatory signals. Multivariate modeling analysis of a large dataset composed of phospho-signals, cytokines, and immune cell populations within the intestine revealed an intimate relationship between immune cells and the epithelial response to TNF-α. Ablation of lymphocytes in the intestine prompted a decrease in the expression of MCP-1, which in turn increased the steady state number of intestinal plasmacytoid dendritic cells (pDCs). This change in the immune compartment affected the intestinal cytokine milieu and subsequent epithelial cell signaling network, with cells becoming hypersensitive to TNF-α-induced apoptosis in a way that could be predicted by mathematical modeling. In summary, we have uncovered a novel cellular network that regulates the response of intestinal epithelial cells to inflammatory stimuli in an in vivo setting

Age composition and survival of public housing stock in Hong Kong

Emerging notably in more developed regions, building stock ageing which is characterised by shrinking new completions and falling “mortality” has been posing challenges to various stakeholders in built environment. To find way out of this transition, we need to know how long buildings will last these days and the factors leading to their “mortality”. By using data from 1950s till to date, a comprehensive investigation is conducted to analyse the age composition and life expectancy of public housing stock in Hong Kong. What comes after are survival analysis and empirical analysis of those demolished to identify the key factors leading to demolition. Presented in this paper are the preliminary findings as well as the research agenda on the theme to model age composition and survival of both private and public building stocks in Hong Kong and other similar cities in Asia Pacific Rim such as Adelaide and Singapore, together with research activities to formulate policies for sustainable urban management

Acute Haemodynamic Changes During Haemodialysis Do Not Exacerbate Gut Hyperpermeability

© 2019 The Author(s)Introduction: The gastrointestinal tract is a potential source of inflammation in dialysis patients. In-vitro studies suggest breakdown of the gut barrier in uraemia leading to increased intestinal permeability and it is hypothesised that haemodialysis exacerbates this problem due to mesenteric ischemia induced by blood volume changes during treatment. Method: The effect of haemodialysis on intestinal permeability was studied in ten haemodialysis patients and compared with five controls. Intestinal permeability was assessed by measuring the differential absorption of four orally administered sugar probes which provides an index of small and whole bowel permeability. A multi-sugar solution (containing lactulose, rhamnose, sucralose and erythritol) was orally administered after an overnight fast. Plasma levels of all sugar probes were measured hourly for 10hrs post-administration. In haemodialysis patients, the procedure was carried out twice – once on a non-dialysis day and once immediately after haemodialysis. Results: Area under curve (AUC) for lactulose: rhamnose (L:R) ratio and sucralose: erythritol (S:E) ratio was similar post-dialysis and on non-dialysis days. AUC for L:R was higher in haemodialysis patients compared to controls (0.071 vs. 0.034,p=0.001), AUC for S:E ratio was not significantly different. Levels of lactulose, sucralose and erythritol were elevated and retained for longer in haemodialysis patients compared to controls due to dependence of sugars on kidney function for clearance. Conclusion: We found no significant acute changes in intestinal permeability in relation to the haemodialysis procedure. Valid comparison of intestinal permeability between controls and haemodialysis patients was not possible due to the strong influence of kidney function on sugar levels.Peer reviewedFinal Published versio