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

The prevalence of rheumatic diseases in central Greece: a population survey

<p>Abstract</p> <p>Background</p> <p>Rheumatic diseases are a major health and financial burden for societies. The prevalence of rheumatic diseases may change over time, and therefore, we sought to estimate the prevalence of rheumatic diseases in an adult population of central Greece.</p> <p>Methods</p> <p>In this prospective cross-sectional population survey, a random sample of adult population was drawn from poll catalogues of a region in central Greece. A postal questionnaire was sent to 3,528 people for the presence of any rheumatic disease. All positive cases were further confirmed by clinical examination using the American College of Rheumatoloy criteria. Multiple regression analysis was used to assess risk factors for rheumatic diseases.</p> <p>Results</p> <p>The response rate was 48.3% (1,705 answers). Four hundred and twenty individuals (24.6%) had a rheumatic disease. The prevalence of rheumatoid arthritis was 0.58% (95% confidence interval [CI], 0.32-0.87), of psoriatic arthritis was 0.35% (95% CI, 0.33-1.13), of ankylosing spondylitis was 0.29% (95% CI, 0.28-0.94), of primary Sjögren's syndrome was 0.23% (95% CI, 0.22-0.75) and of systemic lupus erythematosus was 0.11% (95% CI, 0.11-0.37). One individual had systemic sclerosis (prevalence, 0.058%), 1 individual had dermatomyositis (prevalence, 0.058%; 95% CI, 0.05-0.18), 2 individuals had vasculitis (prevalence 0.11%; 95% CI, 0.11-0.37), 81 individuals had gout (prevalence, 4.75%; 95% CI, 4.41-5.13), and 304 individuals had osteoarthritis (OA) (prevalence 17.82%; 95% CI, 16.50-19.34). Gout was associated with male gender, diabetes mellitus, and hypertension, and OA was associated with age, female gender, and hypertension.</p> <p>Conclusions</p> <p>Rheumatic diseases are common in central Greece, affecting nearly a quarter of adult population. OA and gout are the most common joint disorders.</p

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

Contains fulltext : 158967.pdf (publisher's version ) (Open Access)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

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

The pharmacological treatment of osteoarthritis

The pharmacological treatment of Osteoarthritis (OA) has three goals: to relieve pain, to improve function and quality of life and to modify the course of the disease. Drugs targeting pain are analgesics, including opioid and non-opioid analgesics, oral or topical classical non-steroidal anti-inflammatory drugs, and selective cyclo-oxygenase-2 inhibitors (lumiracoxib, valdecoxib, etoricoxib, celecoxib). Chondroitin sulfate, glucosamine and diacerein showed efficacy in relieving pain and improving function in randomised trials, but meta-analyses showed conflicting results. Intra-articular corticosteroids and hyaluronans gave a variable relief from pain. The effect of medications on structural damage and course of the disease is questionable. Doxycycline, diacerein, chondroitin sulfate and glucozamine showed a beneficial effect on disease progression in randomised controlled trials (RCTs), but this effect is not invariably shown in meta-analyses. Cardiovascular safety concerns for NSAIDs have led to development of a cyclo-oxygenase-inhibiting, nitric oxide donator drugs (naproxcinod) that improved symptoms of OA, without adversely affecting blood pressure in RCTs. A dual cyclo-oxygenase and 5-lipoxygenase inhibitor (licofelone), that decreases the production of pro-inflammatory prostaglandins and leukotrienes showed a symptomatic and chondroprotective effect, along with a favorable gastrointestinal safety profile. Disease-modifying antirheumatic drugs for rheumatoid arthritis are being studied in OA. These include methotrexate, hydroxychloroquine, and drugs targeting cytokines, such as interleukin-1 (anakinra, canakinumab) and tumor necrosis factor-α (infliximab, adalimumab). Biphosphonates, drugs that suppress osteoclasts and bone turnover, (risendronate and clodronate) showed contradictory effects on symptoms and radiographic progression in OA, while a bradykinin-receptor antagonist, icatibant, did not show any clear effect on pain. A novel, oral inhibitor of type-4 phosphodiesterase, apremilast, that has anti-inflammatory effects through downregulation of tumor necrosis factor-α, is being investigated in OA. Botulinum toxin type A is also under study as a pain relief medication for OA. © 2012 by Nova Science Publishers, Inc. All rights reserved

Investigation on the apple proliferation epidemics in the orchards of the Pelion Mountain and preliminary observations on possible phytoplasma vectors

The apple producing region in the Pelion Mountain (Magnesia prefecture, Thessaly, Greece) is suffering for more than 10 years from the apple proliferation disease. The orchards are basically planted with cv 'Starking Delicious', are grafted on seedling rootstocks and are older than 40 years. The presence of the 'Candidams Phytoplasma mali' was proven by PCR/RFLP analyses as well as by sequencing. 'Ca. P. pyri' was also detected in at least three different orchards. First attempts to identify the vectors were carried out by monitoring the insect populations in 8 different orchards, one species of psyllids morphologically identified as Cacopsylla pulchella (Low) was the most present insect in the orchards all along the two-month monitoring (May/June). Cacopsylla mali (Schmidberger) was also present in the orchards but in lower numbers. The monitoring is continued and still in progress