Functional models for large-scale gene regulation networks: realism and fiction

High-throughput experiments are shedding light on the topology of large regulatory networks and at the same time their functional states, namely the states of activation of the nodes (for example transcript or protein levels) in different conditions, times, environments. We now possess a certain amount of information about these two levels of description, stored in libraries, databases and ontologies. A current challenge is to bridge the gap between topology and function, i.e. developing quantitative models aimed at characterizing the expression patterns of large sets of genes. However, approaches that work well for small networks become impossible to master at large scales, mainly because parameters proliferate. In this review we discuss the state of the art of large-scale functional network models, addressing the issue of what can be considered as realistic and what the main limitations may be. We also show some directions for future work, trying to set the goals that future models should try to achieve. Finally, we will emphasize the possible benefits in the understanding of biological mechanisms underlying complex multifactorial diseases, and in the development of novel strategies for the description and the treatment of such pathologies.Comment: to appear on Mol. BioSyst. 200

Universal Features in the Genome-level Evolution of Protein Domains

Protein domains are found on genomes with notable statistical distributions, which bear a high degree of similarity. Previous work has shown how these distributions can be accounted for by simple models, where the main ingredients are probabilities of duplication, innovation, and loss of domains. However, no one so far has addressed the issue that these distributions follow definite trends depending on protein-coding genome size only. We present a stochastic duplication/innovation model, falling in the class of so-called Chinese Restaurant Processes, able to explain this feature of the data. Using only two universal parameters, related to a minimal number of domains and to the relative weight of innovation to duplication, the model reproduces two important aspects: (a) the populations of domain classes (the sets, related to homology classes, containing realizations of the same domain in different proteins) follow common power-laws whose cutoff is dictated by genome size, and (b) the number of domain families is universal and markedly sublinear in genome size. An important ingredient of the model is that the innovation probability decreases with genome size. We propose the possibility to interpret this as a global constraint given by the cost of expanding an increasingly complex interactome. Finally, we introduce a variant of the model where the choice of a new domain relates to its occurrence in genomic data, and thus accounts for fold specificity. Both models have general quantitative agreement with data from hundreds of genomes, which indicates the coexistence of the well-known specificity of proteomes with robust self-organizing phenomena related to the basic evolutionary ``moves'' of duplication and innovation

How much money can be saved by applying intravenous antibiotics once instead of several times a day?

Background: The preparation, administration and monitoring of intravenous (IV) applications are time consuming and require human resources. We estimated the potential time and cost savings by replacing antibiotics given 3-4 times daily with antibiotics with similar spectrum and efficacy given once daily. Methods: The savings of indirect costs were estimated based on the antibiotic consumption data of a two-year period (i.e. 2007 and 2008), a nurse's mean workload per application and the average nurse's salary in Switzerland. Results: The consumption of IV antibiotics in 2007 and 2008 at the University Hospital of Basel was 29.0 and 32.2 defined daily doses (DDD) per 100 patient days, respectively. Nurses spent an estimated 13,786h on the application of the estimated 82,715 does of IV antibiotics. A total of 56,404 applications or nursing staff time costs of 338,436 Swiss Francs (CHF; 236,669 €), equal to 16% of the overall costs spent on purchasing antibiotics in the year 2008, may have been saved by switching multiple-dose antibiotics to a hypothetical once-daily antibiotic. Including disposable materials, 21% or 456,884 CHF (319,499 €) could be saved annually (purchase costs not taken into account). Conclusion: We found a potential cost saving of 21% of the purchase costs in a 750-bed institution. Hence, indirect costs should be included in the calculation of the total cost for the application of broad-spectrum IV antibiotics. Switching from a 3-4 times daily application to a once-daily antibiotic should be considered if a once-daily antibiotic is deemed equally effective and has a similar spectru

Kinetic models with randomly perturbed binary collisions

We introduce a class of Kac-like kinetic equations on the real line, with general random collisional rules, which include as particular cases models for wealth redistribution in an agent-based market or models for granular gases with a background heat bath. Conditions on these collisional rules which guarantee both the existence and uniqueness of equilibrium profiles and their main properties are found. We show that the characterization of these stationary solutions is of independent interest, since the same profiles are shown to be solutions of different evolution problems, both in the econophysics context and in the kinetic theory of rarefied gases

Central periodic breathing during sleep in 74 patients with acute ischemic stroke - Neurogenic and cardiogenic factors

Objectives : The aims of our study were 1) to better characterize central periodic breathing during sleep (CPBS) and its clinical relevance in acute stroke, 2) to better define the role of brain damage in its pathogenesis. Methods : We included 74 consecutive patients admitted within 96 hours after stroke onset. Stroke severity at admission, stroke outcome at discharge and stroke topography were assessed. ECG and transesophageal echocardiography were performed. Nocturnal breathing was assessed with an ambulatory device the first night after admission. CPBS severity was represented as absolute time and percentage of recording time. Results : Age was 63 ± 13 (25-82), 49 (66 %) were male. Thirty (41 %) patients showed CPBS during ≥ 10 % and 7 (9 %) during ≥ 50 % of recording time. CPBS severity was associated with age (p = 0.017), stroke severity (p = 0.008), ECG abnormalities (p = 0.005) and lower left ventricular ejection fraction (p < 0.0001). CPBS severity was higher in patients with extensive hemispheric strokes (n = 6, p < 0.0001), and lower in patients with partial strokes involving the left insula (n = 5, p < 0.0001) and the mesencephalon (n = 5, p = 0.002). Conclusions : CPBS is frequent in acute ischemic stroke and is associated with older age, stroke severity/extension, and lower left ventricular function. The lower occurrence of CPBS in left insular and mesencephalic stroke suggests a major role of distinct brain areas in the modulation of respiratory phenomena accompanying acute strok

Morphological differences in Parkinson's disease with and without rest tremor

Background : Rest tremor is a hallmark of Parkinson's disease (PD), but its pathogenesis remains incompletely understood. Nigro-striatal dopamine deficiency correlates best with bradykinesia, but not with tremor. Oscillating neurons in one or multiple localizations within the basal gangliathalamo-cortical loop may cause rest tremor, and an active contribution of the cerebellum and the cerebello-thalamo-cortical projections has been postulated. Objective : To compare the pattern of grey matter volume in PD patients with and without tremor to identify structural correlates of rest tremor. Methods : Voxel-based morphometry (VBM) of a high-resolution 3 Tesla, T1-weighted MR images, pre-processed according to an optimized protocol using SPM2, was performed in 24 patients with mild to moderate PD comparing local grey matter volume in patients with (n = 14) and without rest tremor (n = 10). Results : Grey matter volume is decreased in the right quadrangular lobe and declive of the cerebellum in PD with tremor compared to those without (PFDR < 0.05). Conclusions : These results demonstrate for the first time morphological changes in the cerebellum in PD patients with rest tremor and highlight the involvement of the cerebellum and cerebello- thalamo-cortical circuit in the pathogenesis of parkinsonian rest tremo

Spritzenabszesse bei intravenös Drogenabhängigen: Häufigkeit assoziierter Komplikationen in Abhängigkeit der Lokalisation

Zusammenfassung: Hintergrund: Haut- und Weichteilabszesse sind bei intravenös Drogenabhängigen der häufigste Hospitalisationsgrund. Zu den mit Spritzenabszessen assoziierten Komplikationen gehören septische Arthritiden, septische Thrombosen und Embolien, lokale Schädigung von umliegenden Strukturen, periphere Ischämie durch intraarterielle Injektion, Pseudoaneurysmata von Venen und Arterien und die nekrotisierende Fasziitis. Material und Methode: Wir führten eine retrospektive Studie von 108Hospitalisationen bei 85Patienten mit insgesamt 130Abszessen in Hinblick auf die aufgetretenen Komplikationen durch. Ergebnisse: Fünfundfünfzig Prozent der Abszesse waren an der unteren Extremität lokalisiert. Die Komplikationsrate an dieser Lokalisation war mit 12/71 (16,9%) signifikant höher (p=0,0005) als an der oberen Extremität mit 0/55. Abszesse an der unteren Extremität führten zu einer signifikant längeren Hospitalisationsdauer als solche an der oberen Extremität (8,5 vs. 4,2Tage, p=0,005) und damit zu höheren Kosten. Schlussfolgerung: Bei der Behandlung von Spritzenabszessen der unteren Extremität muss an das erhöhte Risiko assoziierter Komplikationen gedacht werden. In den Beratungsstellen durchzuführende präventive Maßnahmen könnten durch Vermeiden von Injektionen an den unteren Extremitäten zu einer Verminderung der durch den Drogenkonsum verursachten Kosten führe