Global parameter identification of stochastic reaction networks from single trajectories

We consider the problem of inferring the unknown parameters of a stochastic biochemical network model from a single measured time-course of the concentration of some of the involved species. Such measurements are available, e.g., from live-cell fluorescence microscopy in image-based systems biology. In addition, fluctuation time-courses from, e.g., fluorescence correlation spectroscopy provide additional information about the system dynamics that can be used to more robustly infer parameters than when considering only mean concentrations. Estimating model parameters from a single experimental trajectory enables single-cell measurements and quantification of cell--cell variability. We propose a novel combination of an adaptive Monte Carlo sampler, called Gaussian Adaptation, and efficient exact stochastic simulation algorithms that allows parameter identification from single stochastic trajectories. We benchmark the proposed method on a linear and a non-linear reaction network at steady state and during transient phases. In addition, we demonstrate that the present method also provides an ellipsoidal volume estimate of the viable part of parameter space and is able to estimate the physical volume of the compartment in which the observed reactions take place.Comment: Article in print as a book chapter in Springer's "Advances in Systems Biology

An organelle-specific protein landscape identifies novel diseases and molecular mechanisms

Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine

Serum VEGF levels are related to the presence of pulmonary arterial hypertension in systemic sclerosis

<p>Abstract</p> <p>Background</p> <p>The association between systemic sclerosis and pulmonary arterial hypertension (PAH) is well recognized. Vascular endothelial growth factor (VEGF) has been reported to play an important role in pulmonary hypertension. The aim of the present study was to examine the relationship between systolic pulmonary artery pressure, clinical and functional manifestations of the disease and serum VEGF levels in systemic sclerosis.</p> <p>Methods</p> <p>Serum VEGF levels were measured in 40 patients with systemic sclerosis and 13 control subjects. All patients underwent clinical examination, pulmonary function tests and echocardiography.</p> <p>Results</p> <p>Serum VEGF levels were higher in systemic sclerosis patients with sPAP ≥ 35 mmHg than in those with sPAP < 35 mmHg (352 (266, 462 pg/ml)) vs (240 (201, 275 pg/ml)) (p < 0.01), while they did not differ between systemic sclerosis patients with sPAP < 35 mmHg and controls. Serum VEGF levels correlated to systolic pulmonary artery pressure, to diffusing capacity for carbon monoxide and to MRC dyspnea score. In multiple linear regression analysis, serum VEGF levels, MRC dyspnea score, and D_LCOwere independent predictors of systolic pulmonary artery pressure.</p> <p>Conclusion</p> <p>Serum VEGF levels are increased in systemic sclerosis patients with sPAP ≥ 35 mmHg. The correlation between VEGF levels and systolic pulmonary artery pressure may suggest a possible role of VEGF in the pathogenesis of PAH in systemic sclerosis.</p

Hand osteoarthritis: clinical phenotypes, molecular mechanisms and disease management

Osteoarthritis (OA) is a highly prevalent condition and the hand is the most commonly affected site. Patients with hand OA frequently report symptoms of pain, functional limitations, and frustration in undertaking everyday activities. The condition presents clinically with changes to the bone, ligaments, cartilage and synovial tissue, which can be observed using radiography, ultrasonography or MRI. Hand OA is a heterogeneous disorder and is considered to be multifactorial in aetiology. This review provides an overview of the epidemiology, presentation and burden of hand OA, including an update on hand OA imaging (including the development of novel techniques), disease mechanisms and management. In particular, areas for which new evidence has substantially changed the way we understand, consider and treat hand OA are highlighted. For example, genetic studies, clinical trials and careful prospective imaging studies from the past 5 years are beginning to provide insights into the pathogenesis of hand OA that might uncover new therapeutic targets in disease

Ultrasonographic evidence of inflammation is frequent in hands of patients with erosive osteoarthritis

Objective: Erosive osteoarthritis (OA) (EOA) is considered an aggressive form of primary OA that is defined radiographically by intra-articular erosions of the inter-phalangeal joints of the hand and characteristic deformities. The aim of the present study was the sonographic investigation of hand small joints in patients with EOA and comparison of the imaging findings with conventional radiography (CR). Method Twenty-two patients (20 women, mean age 62.5 years) with clinical and radiographic diagnosis of EOA formed our study group. A total of 660 joints were assessed by both radiographs and ultrasound (US). US and plain films were evaluated by two different physicians on a blinded fashion. Erosions, osteophytes and deformities were evaluated by both US and plain films. Synovial thickening, effusion, and power Doppler signal indicative of abnormal vascularity were recorded in each joint during US scanning. Results: Erosions were detected in 231/660 (35%) small joints by US and in 115/660 (17.4%) small joints by conventional radiographs (P < 0.05). Osteophytes were detected in 360/660 (54.5%) small joints by US, and in 310/660 (47.0%) small joints by conventional radiographs (P < 0.05). Thickened synovium was detected in 19 of 22 patients and increased intra-articular power Doppler signal, indicative of active inflammation, was detected in 18 of 22 patients. Thickened synovium was found in 159/660 (24.1%), effusion in 119/660 (18%) and increased power Doppler in 148/660 (22.4%) small joints. Intra-observer kappa value for agreement regarding US was 0.81 and plain films 0.86. In 31 instances extensive finger tenosynovitis was also evident. Conclusion: In patients with EOA, US is a reliable and a more sensitive imaging modality than CR in detecting erosions and osteophytes. US detects inflammatory changes in small hand joints in the vast majority of patients with EOA and suggests that current treatment modalities are inadequate treatment for this disease. (c) 2009 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved