A novel methodology to estimate metabolic flux distributions in constraint-based models

Quite generally, constraint-based metabolic flux analysis describes the space of viable flux configurations for a metabolic network as a high-dimensional polytope defined by the linear constraints that enforce the balancing of production and consumption fluxes for each chemical species in the system. In some cases, the complexity of the solution space can be reduced by performing an additional optimization, while in other cases, knowing the range of variability of fluxes over the polytope provides a sufficient characterization of the allowed configurations. There are cases, however, in which the thorough information encoded in the individual distributions of viable fluxes over the polytope is required. Obtaining such distributions is known to be a highly challenging computational task when the dimensionality of the polytope is sufficiently large, and the problem of developing cost-effective ad hoc algorithms has recently seen a major surge of interest. Here, we propose a method that allows us to perform the required computation heuristically in a time scaling linearly with the number of reactions in the network, overcoming some limitations of similar techniques employed in recent years. As a case study, we apply it to the analysis of the human red blood cell metabolic network, whose solution space can be sampled by different exact techniques, like Hit-and-Run Monte Carlo (scaling roughly like the third power of the system size). Remarkably accurate estimates for the true distributions of viable reaction fluxes are obtained, suggesting that, although further improvements are desirable, our method enhances our ability to analyze the space of allowed configurations for large biochemical reaction networks. © 2013 by the authors; licensee MDPI, Basel, Switzerland

Energy metabolism and glutamate-glutamine cycle in the brain: a stoichiometric modeling perspective

Background: The energetics of cerebral activity critically relies on the functional and metabolic interactions between neurons and astrocytes. Important open questions include the relation between neuronal versus astrocytic energy demand, glucose uptake and intercellular lactate transfer, as well as their dependence on the level of activity. Results: We have developed a large-scale, constraint-based network model of the metabolic partnership between astrocytes and glutamatergic neurons that allows for a quantitative appraisal of the extent to which stoichiometry alone drives the energetics of the system. We find that the velocity of the glutamate-glutamine cycle (Vcyc) explains part of the uncoupling between glucose and oxygen utilization at increasing Vcyc levels. Thus, we are able to characterize different activation states in terms of the tissue oxygen-glucose index (OGI). Calculations show that glucose is taken up and metabolized according to cellular energy requirements, and that partitioning of the sugar between different cell types is not significantly affected by Vcyc. Furthermore, both the direction and magnitude of the lactate shuttle between neurons and astrocytes turn out to depend on the relative cell glucose uptake while being roughly independent of Vcyc. Conclusions: These findings suggest that, in absence of ad hoc activity-related constraints on neuronal and astrocytic metabolism, the glutamate-glutamine cycle does not control the relative energy demand of neurons and astrocytes, and hence their glucose uptake and lactate exchange. © 2013 Massucci et al.; licensee BioMed Central Ltd

CEA and CYFRA 21-1 as prognostic biomarker and as a tool for treatment monitoring in advanced NSCLC treated with immune checkpoint inhibitors

Aims: To assess prognostic value of pre-therapy carcinoembryonic antigen (CEA) and cytokeratin-19 fragments (CYFRA 21-1) blood levels in non-small cell lung cancer (NSCLC) patients treated with immune-checkpoint inhibitors (ICIs) and their early change as predictor of benefit. Materials and methods: This is a retrospective cohort study including patients with stage IIIB–IV NSCLC who received anti PD-1/PD-L1 in first or advanced lines of therapy in two institutions. A control cohort of patients treated only with chemotherapy has been enrolled as well. Results: A total of 133 patients treated with nivolumab or atezolizumab were included in the test set, 74 treated with pembrolizumab first line in the validation set and 89 in the chemotherapy only cohort. CYFRA 21-1 >8 ng/mL was correlated with overall survival (OS) in the test set, validation set and in univariate and multivariate analysis (pooled cohort hazard ratio (HR) 1.90, 95% confidence interval (CI) 1.24–2.93, p 0.003). Early 20% reduction after the third cycle was correlated with OS for CEA (HR 0.12; 95% CI 0.04–0.33; p < 0.001), and for CYFRA 21-1 (HR 0.19; 95% CI 0.07–0.55; p 0.002) Conclusions: CYFRA 21-1 pre-therapy assessment provides clinicians with relevant prognostic information about patients treated with ICI. CEA and CYFRA 21-1 repeated measures could be useful as an early marker of benefit

Interseismic Active Deformation in the central-southern Apennine

The GPS results are of utmost relevance for the study of the complex plate boundary geodynamics. The lithosphere strain partitioning is part of the seismic cycle. We present the first GPS kinematic pattern obtained during the interseismic phase by a dense episodic GPS network, the Southern Apennine Geodetic Network - SAGNet (Sepe et al., 2009), in the time span 2002-2013. This network is located across the transition zone between central and southern Apennine, including Meta-Mainarde-Venafro and AltoMolise-Sannio-Matese mounts. This region is characterized by seismogenic fault systems responsible, in the past, for several destructive earthquakes of intensity I ≥ IX MCS and, in more recent years, characterised mainly by some moderate magnitude seismic sequences (max magnitude Mw 5.0, December 29 2013) and single small events (Ml < 2.5).SAGNet GPS data were processed by BERNESE sw v.5.0 and the resulting velocities were least-squares combined with the permanent stations velocity field and with the velocity solution of Giuliani et al. 2009. The combined GPS velocity field, shows a perpendicular maximum extension with respect to the Apennine chain of about 2.0 mm/y.The Matese area was hit on December 29, 2013 by a Mw=5.0 (Convertito et al., 2016) earthquake. It was followed by an intense seismic activity until the beginning of February 2014. After the mainshock a GPS survey was carried out on the SAGnet stations. We collected data from 2013, 30 December to 2014, 4 April. The time series of 17 stations are affect by an offsets on the linear drift. The map of horizontal coseismic displacements (Figure 3) shows a sub-radial displacement shape with respect to the epicentre. Larger displacements are observed in correspondence of NE portion of the Matese massif. Considering the Matese Lake Fault as the probable source of the mainshock (dip 65°, strike 116, rake 270 – MLF, Ferranti et al, 2015), we found that the Okada modelling does not fit the observed displacements and only a small fraction of displacements are resolved with a simple slip.Figure 4 resembles the results of previous studies compared with our GPS analysis. We considered seismological analyses, tomographic models, degassing of CO2 data and conceptual model of processes recognized in South Apennine (L. Bisio, et al., 2004; Chiarabba and Chiodini, 2013; Improta et al., 2014; Ventura et al., 2007, R. Di Stefano and M.G. Ciaccio, 2014; Ferranti et al., 2015; Convertito et al., 2016;). The GPS results indicate that the relative motion between Eurasia and Adria plates is responsible of the active deformation in the Apennines. The most important outcomes of this study are: (i) During the interseismic phase the differential motion between Adriatic and Tyrrhenian domains seems to be accommodated in a narrow belt bordering the westward flank of the Sannio Mts, showing a 2 mm/y extension. (ii) The maximum extension does not follow the topographic high of the chain but is shifted toward the eastern outer belt. (iii) No significant GPS deformation is highlighted in correspondence of major and known fault systems where the GPS velocities appear almost steady. We propose that the observed coseismic displacements are only marginally explained by a slip on the MLF fault. The vertical directivity and depth distribution of the seismic sequence (Convertito et al., 2016), the vertical and horizontal heterogeneity of lower crust and upper mantle (Bisio et al., 2004; Di Stefano and Ciaccio, 2014), the high flux of CO2 degassing (Ventura et al., 2007, Chiarabba e Chiodini, 2013 ), the probable presence of pressurized CO2 bodies fed by fluids uprising from the mantle wedge (Improta et al.,2014 ), suggest instead that the seismic sequence could be caused by sub-vertical cracks that originate at the Moho interface and reach the bottom of the seismogenic layer (10km depth).DPCUnpublishedSan Francisco (USA)2T. Tettonica attivaope

The CXCR1/CXCR2 Inhibitor Reparixin Alters the Development of Myelofibrosis in the Gata1 low Mice

A major role for human (h)CXCL8 (interleukin-8) in the pathobiology of myelofibrosis (MF) has been suggested by observations indicating that MF megakaryocytes express increased levels of hCXCL8 and that plasma levels of this cytokine in MF patients are predictive of poor patient outcomes. Here, we demonstrate that, in addition to high levels of TGF-β, the megakaryocytes from the bone marrow of the Gata1low mouse model of myelofibrosis express high levels of murine (m)CXCL1, the murine equivalent of hCXCL8, and its receptors CXCR1 and CXCR2. Treatment with the CXCR1/R2 inhibitor, Reparixin in aged-matched Gata1low mice demonstrated reductions in bone marrow and splenic fibrosis. Of note, the levels of fibrosis detected using two independent methods (Gomori and reticulin staining) were inversely correlated with plasma levels of Reparixin. Immunostaining of marrow sections indicated that the bone marrow from the Reparixin-treated group expressed lower levels of TGF-β1 than those expressed by the bone marrow from vehicle-treated mice while the levels of mCXCL1, and expression of CXCR1 and CXCR2, were similar to that of vehicle-treated mice. Moreover, immunofluorescence analyses performed on bone marrow sections from Gata1low mice indicated that treatment with Reparixin induced expression of GATA1 while reducing expression of collagen III in megakaryocytes. These data suggest that in Gata1low mice, Reparixin reduces fibrosis by reducing TGF-β1 and collagen III expression while increasing GATA1 in megakaryocytes. Our results provide a preclinical rationale for further evaluation of this drug alone and in combination with current JAK inhibitor therapy for the treatment of patients with myelofibrosis

Replica theory for learning curves for Gaussian processes on random graphs

Statistical physics approaches can be used to derive accurate predictions for the performance of inference methods learning from potentially noisy data, as quantified by the learning curve defined as the average error versus number of training examples. We analyse a challenging problem in the area of non-parametric inference where an effectively infinite number of parameters has to be learned, specifically Gaussian process regression. When the inputs are vertices on a random graph and the outputs noisy function values, we show that replica techniques can be used to obtain exact performance predictions in the limit of large graphs. The covariance of the Gaussian process prior is defined by a random walk kernel, the discrete analogue of squared exponential kernels on continuous spaces. Conventionally this kernel is normalised only globally, so that the prior variance can differ between vertices; as a more principled alternative we consider local normalisation, where the prior variance is uniform

GPS observations of coseismic deformation following the May 20 and 29, 2012, Emilia seismic events (northern Italy): data, analysis and preliminary models

In May-July 2012, a seismic sequence struck a broad area of the Po Plain Region in northern Italy. The sequence in- cluded two ML >5.5 mainshocks. The first one (ML 5.9) oc- curred near the city of Finale Emilia (ca. 30 km west of Ferrara) on May 20 at 02:03:53 (UTC), and the second (ML 5.8) occurred on May 29 at 7:00:03 (UTC), about 12 km south- west of the May 20 mainshock (Figure 1), near the city of Mirandola. The seismic sequence involved an area that ex- tended in an E-W direction for more than 50 km, and in- cluded seven ML ≥5.0 events and more than 2,300 ML >1.5 events (http://iside.rm.ingv.it). The focal mechanisms of the main events [Pondrelli et al. 2012, Scognamiglio et al. 2012, this volume] consistently showed compressional kinematics with E-W oriented reverse nodal planes. This sector of the Po Plain is known as a region charac- terized by slow deformation rates due to the northwards mo- tion of the northern Apennines fold-and-thrust belt, which is buried beneath the sedimentary cover of the Po Plain [Pi- cotti and Pazzaglia 2008, Toscani et al. 2009]. Early global po- sitioning system (GPS) measurements [Serpelloni et al. 2006] and the most recent updates [Devoti et al. 2011, Bennett et al. 2012] recognized that less than 2 mm/yr of SW-NE short- ening are accommodated across this sector of the Po Plain, in agreement with other present-day stress indicators [Mon- tone et al. 2012] and known active faults [Basili et al. 2008]. In the present study, we describe the GPS data used to study the coseismic deformation related to the May 20 and 29 mainshocks, and provide preliminary models of the two seismic sources, as inverted from consensus GPS coseismic deformation fields

L’indagine macrosismica: metodologia, parametri del terremoto, questioni aperte

Subito dopo l’evento del 6 aprile 2009, come di consueto è stata realizzata una lunga e complessa indagine macrosismica, promossa dal gruppo operativo QUEST, che ha avuto inizialmente l’obiettivo di delimitare l’area di danneggiamento, a supporto delle attività di pronto intervento della Protezione Civile, e successivamente quello di classificare nel modo più accurato e capillare possibile, gli effetti prodotti dall’evento, particolarmente nelle aree danneggiate. A questo scopo è stata prodotta una stima utilizzando la scala MCS (Sieberg, 1930); in un secondo momento è stata rifinita l’indagine per una cinquantina di località dell’area maggiormente danneggiata (Is MCS>VII), raccogliendo ed elaborando i dati in termini di scala macrosismica EMS98 (Grünthal, 1998). Per la complessità e la dimensione dei problemi affrontati, questo terremoto ha costituito un banco di prova di grande importanza per la macrosismologia italiana. In questo testo viene descritto il lavoro realizzato, discutendo in particolare alcuni aspetti che hanno messo alla prova le metodologie di indagine tradizionali (sistematiche irregolarità degli insediamenti monitorati, forti divergenze degli scenari di danno rispetto a quelli previsti dalle scale, difficile comparabilità con scenari storici, ecc.) e presentandone i risultati, in relazione ai parametri epicentrali che ne risultano e il loro contributo più diretto alla comprensione complessiva della sismicità dell’area

L’indagine macrosismica: metodologia, parametri del terremoto, questioni aperte

Subito dopo l’evento del 6 aprile 2009, come di consueto è stata realizzata una lunga e complessa indagine macrosismica, promossa dal gruppo operativo QUEST, che ha avuto inizialmente l’obiettivo di delimitare l’area di danneggiamento, a supporto delle attività di pronto intervento della Protezione Civile, e successivamente quello di classificare nel modo più accurato e capillare possibile, gli effetti prodotti dall’evento, particolarmente nelle aree danneggiate. A questo scopo è stata prodotta una stima utilizzando la scala MCS (Sieberg, 1930); in un secondo momento è stata rifinita l’indagine per una cinquantina di località dell’area maggiormente danneggiata (Is MCS>VII), raccogliendo ed elaborando i dati in termini di scala macrosismica EMS98 (Grünthal, 1998). Per la complessità e la dimensione dei problemi affrontati, questo terremoto ha costituito un banco di prova di grande importanza per la macrosismologia italiana. In questo testo viene descritto il lavoro realizzato, discutendo in particolare alcuni aspetti che hanno messo alla prova le metodologie di indagine tradizionali (sistematiche irregolarità degli insediamenti monitorati, forti divergenze degli scenari di danno rispetto a quelli previsti dalle scale, difficile comparabilità con scenari storici, ecc.) e presentandone i risultati, in relazione ai parametri epicentrali che ne risultano e il loro contributo più diretto alla comprensione complessiva della sismicità dell’area.Published49-551.11. TTC - Osservazioni e monitoraggio macrosismico del territorio nazionaleN/A or not JCRope

Detecting interdisciplinarity in top-class research using topic modeling

The paper applies topic modeling to the collection of ERC-funded proposals, interim reports and relative publications, with the aim of measuring in a novel way the degree of interdisciplinarity and addressing several open research questions which broadly aim at understanding how environmental conditions can favour the blossoming of interdisciplinarity. Without venturing into potential interpretations and explanations, we present a series of quantitative results linked with the above questions, while deliberately maintaining a descriptive attitude