A new computational method to split large biochemical networks into coherent subnets

<p>Abstract</p> <p>Background</p> <p>Compared to more general networks, biochemical networks have some special features: while generally sparse, there are a small number of highly connected metabolite nodes; and metabolite nodes can also be divided into two classes: internal nodes with associated mass balance constraints and external ones without. Based on these features, reclassifying selected internal nodes (separators) to external ones can be used to divide a large complex metabolic network into simpler subnetworks. Selection of separators based on node connectivity is commonly used but affords little detailed control and tends to produce excessive fragmentation.</p> <p>The method proposed here (Netsplitter) allows the user to control separator selection. It combines local connection degree partitioning with global connectivity derived from random walks on the network, to produce a more even distribution of subnetwork sizes. Partitioning is performed progressively and the interactive visual matrix presentation used allows the user considerable control over the process, while incorporating special strategies to maintain the network integrity and minimise the information loss due to partitioning.</p> <p>Results</p> <p>Partitioning of a genome scale network of 1348 metabolites and 1468 reactions for <it>Arabidopsis thaliana </it>encapsulates 66% of the network into 10 medium sized subnets. Applied to the flavonoid subnetwork extracted in this way, it is shown that Netsplitter separates this naturally into four subnets with recognisable functionality, namely synthesis of lignin precursors, flavonoids, coumarin and benzenoids. A quantitative quality measure called <it>efficacy </it>is constructed and shows that the new method gives improved partitioning for several metabolic networks, including bacterial, plant and mammal species.</p> <p>Conclusions</p> <p>For the examples studied the Netsplitter method is a considerable improvement on the performance of connection degree partitioning, giving a better balance of subnet sizes with the removal of fewer mass balance constraints. In addition, the user can interactively control which metabolite nodes are selected for cutting and when to stop further partitioning as the desired granularity has been reached. Finally, the blocking transformation at the heart of the procedure provides a powerful visual display of network structure that may be useful for its exploration independent of whether partitioning is required.</p

One question might be capable of replacing the Shoulder Pain and Disability Index (SPADI) when measuring disability: a prospective cohort study

Questions: Is it possible to replace the Shoulder Pain and Disability Index (SPADI) with a single substitute question for people with shoulder pain, when measuring disability and how well does this substitute question perform as a predictor for recovery. Design: A prospective cohort study. Participants: A total of 356 patients with shoulder pain in primary care. Analyses: Convergent, divergent, and “known” groups validity were assessed by using hypotheses testing. Responsiveness was assessed using the Receiver Operating Curve and hypothesis testing. In addition, we performed multivariate regression to assess if the substitute question showed similar properties as the SPADI and if it affected the model itself, using recovery as an outcome. Results: The Spearman correlation coefficient between the total SPADI score and the substitute question was high, and moderate with the Shoulder Disability Questionnaire. The correlation between the substitute question and the EQ-5D-3L was low and the responsiveness was acceptable. The substitute question did not significantly contribute to both prognostic prediction models as opposed to the SPADI. Regardless all models showed poor to fair discrimination. Conclusion: The single question is a reasonable substitute for the SPADI and can be used as a screening instrument for shoulder disability in primary clinical practice. It has slightly poorer predictive power and should therefore not be used for prognosis

The morphology and morphogenesis of jaagsiekte retrovirus (JSRV)

Jaagsiekte retrovirus (JSRV) was recently shown to be the aetiological agent of jaagsiekte (ovine pulmonary adenomatosis). The morphogenesis of JSRV was studied in jaagsiekte tumour tissue. Intracytoplasmic particles, often associated with centrioles, were found in tumour cells. JSRV budded from tumour cells with a complete core which appeared to mature during the budding process. Extracellular particles were found in the alveolar lumen. Immature extracellular particles were rare. Mature extracellular JSRV was membrane-bound and had a slightly eccentric nucleoid with an electron-dense perinucleoidal space. In negatively stained preparations of JSRV the envelope was covered with spikes. JSRV is morphologically distinct from all known retroviruses.The articles have been scanned in colour with a HP Scanjet 5590; 600dpi. Adobe Acrobat XI Pro was used to OCR the text and also for the merging and conversion to the final presentation PDF-format

New first trimester crown-rump length's equations optimized by structured data collection from a French general population

--- Objectives --- Prior to foetal karyotyping, the likelihood of Down's syndrome is often determined combining maternal age, serum free beta-HCG, PAPP-A levels and embryonic measurements of crown-rump length and nuchal translucency for gestational ages between 11 and 13 weeks. It appeared important to get a precise knowledge of these scan parameters' normal values during the first trimester. This paper focused on crown-rump length. --- METHODS --- 402 pregnancies from in-vitro fertilization allowing a precise estimation of foetal ages (FA) were used to determine the best model that describes crown-rump length (CRL) as a function of FA. Scan measures by a single operator from 3846 spontaneous pregnancies representative of the general population from Northern France were used to build a mathematical model linking FA and CRL in a context as close as possible to normal scan screening used in Down's syndrome likelihood determination. We modeled both CRL as a function of FA and FA as a function of CRL. For this, we used a clear methodology and performed regressions with heteroskedastic corrections and robust regressions. The results were compared by cross-validation to retain the equations with the best predictive power. We also studied the errors between observed and predicted values. --- Results --- Data from 513 spontaneous pregnancies allowed to model CRL as a function of age of foetal age. The best model was a polynomial of degree 2. Datation with our equation that models spontaneous pregnancies from a general population was in quite agreement with objective datations obtained from 402 IVF pregnancies and thus support the validity of our model. The most precise measure of CRL was when the SD was minimal (1.83mm), for a CRL of 23.6 mm where our model predicted a 49.4 days of foetal age. Our study allowed to model the SD from 30 to 90 days of foetal age and offers the opportunity of using Zscores in the future to detect growth abnormalities. --- Conclusion --- With powerful statistical tools we report a good modeling of the first trimester embryonic growth in the general population allowing a better knowledge of the date of fertilization useful in the ultrasound screening of Down's syndrome. The optimal period to measure CRL and predict foetal age was 49.4 days (9 weeks of gestational age). Our results open the way to the detection of foetal growth abnormalities using CRL Zscores throughout the first trimester

There are no non-zero Stable Fixed Points for dense networks in the homogeneous Kuramoto model

This paper is concerned with the existence of multiple stable fixed point solutions of the homogeneous Kuramoto model. We develop a necessary condition for the existence of stable fixed points for the general network Kuramoto model. This condition is applied to show that for sufficiently dense n-node networks, with node degrees at least 0.9395(n-1), the homogeneous (equal frequencies) model has no non-zero stable fixed point solution over the full space of phase angles in the range -Pi to Pi. This result together with existing research proves a conjecture of Verwoerd and Mason (2007) that for the complete network and homogeneous model the zero fixed point has a basin of attraction consisting of the entire space minus a set of measure zero. The necessary conditions are also tested to see how close to sufficiency they might be by applying them to a class of regular degree networks studied by Wiley, Strogatz and Girvan (2006).Comment: 15 pages 8 figures. arXiv admin note: text overlap with arXiv:1010.076

A glue for heterochromatin maintenance: stable SUV39H1 binding to heterochromatin is reinforced by the SET domain

Trimethylation of histone H3 lysine 9 and the subsequent binding of heterochromatin protein 1 (HP1) mediate the formation and maintenance of pericentromeric heterochromatin. Trimethylation of H3K9 is governed by the histone methyltransferase SUV39H1. Recent studies of HP1 dynamics revealed that HP1 is not a stable component of heterochromatin but is highly mobile (Cheutin, T., A.J. McNairn, T. Jenuwein, D.M. Gilbert, P.B. Singh, and T. Misteli. 2003. Science. 299:721–725; Festenstein, R., S.N. Pagakis, K. Hiragami, D. Lyon, A. Verreault, B. Sekkali, and D. Kioussis. 2003. Science. 299:719–721). Because the mechanism by which SUV39H1 is recruited to and interacts with heterochromatin is unknown, we studied the dynamic properties of SUV39H1 in living cells by using fluorescence recovery after photobleaching and fluorescence resonance energy transfer. Our results show that a substantial population of SUV39H1 is immobile at pericentromeric heterochromatin, suggesting that, in addition to its catalytic activity, SUV39H1 may also play a structural role at pericentromeric regions. Analysis of SUV39H1 deletion mutants indicated that the SET domain mediates this stable binding. Furthermore, our data suggest that the recruitment of SUV39H1 to heterochromatin is at least partly independent from that of HP1 and that HP1 transiently interacts with SUV39H1 at heterochromatin

Oesophageal Perforation: A diagnostic and therapeutic challenge in a resource limited setting. A report of three cases

Oesophageal perforation is a condition associated with a high mortality. Its management is still controversial with operative treatment being favoured but a shift to conservative management is occurring. Very little exists in medical literature about its management in Sub-Saharan Africa, where the paucity of thoracic surgeons is compounded by limited diagnostic and therapeutic facilities. We report three cases of oesophageal perforation which were all treated conservatively with tube thoracostomy, nil by mouth with feeding gastrostomy, intravenous antibiotics and chest physiotherapy. Two patients achieved oesophageal healing but one died due to severe septicaemia. In a resource restricted setting, conservative management which includes enteral nutrition by feeding gastrostomy, tube thoracostomy to drain inter pleural contaminants, intravenous antibiotics and chest physiotherapy is a safe and effective treatment for oesophageal perforations

Lung adenocarcinoma originates from retrovirus infection of proliferating type 2 pneumocytes during pulmonary post-natal development or tissue repair

Jaagsiekte sheep retrovirus (JSRV) is a unique oncogenic virus with distinctive biological properties. JSRV is the only virus causing a naturally occurring lung cancer (ovine pulmonary adenocarcinoma, OPA) and possessing a major structural protein that functions as a dominant oncoprotein. Lung cancer is the major cause of death among cancer patients. OPA can be an extremely useful animal model in order to identify the cells originating lung adenocarcinoma and to study the early events of pulmonary carcinogenesis. In this study, we demonstrated that lung adenocarcinoma in sheep originates from infection and transformation of proliferating type 2 pneumocytes (termed here lung alveolar proliferating cells, LAPCs). We excluded that OPA originates from a bronchioalveolar stem cell, or from mature post-mitotic type 2 pneumocytes or from either proliferating or non-proliferating Clara cells. We show that young animals possess abundant LAPCs and are highly susceptible to JSRV infection and transformation. On the contrary, healthy adult sheep, which are normally resistant to experimental OPA induction, exhibit a relatively low number of LAPCs and are resistant to JSRV infection of the respiratory epithelium. Importantly, induction of lung injury increased dramatically the number of LAPCs in adult sheep and rendered these animals fully susceptible to JSRV infection and transformation. Furthermore, we show that JSRV preferentially infects actively dividing cell in vitro. Overall, our study provides unique insights into pulmonary biology and carcinogenesis and suggests that JSRV and its host have reached an evolutionary equilibrium in which productive infection (and transformation) can occur only in cells that are scarce for most of the lifespan of the sheep. Our data also indicate that, at least in this model, inflammation can predispose to retroviral infection and cancer