Model-Free Reconstruction of Excitatory Neuronal Connectivity from Calcium Imaging Signals

A systematic assessment of global neural network connectivity through direct electrophysiological assays has remained technically infeasible, even in simpler systems like dissociated neuronal cultures. We introduce an improved algorithmic approach based on Transfer Entropy to reconstruct structural connectivity from network activity monitored through calcium imaging. We focus in this study on the inference of excitatory synaptic links. Based on information theory, our method requires no prior assumptions on the statistics of neuronal firing and neuronal connections. The performance of our algorithm is benchmarked on surrogate time series of calcium fluorescence generated by the simulated dynamics of a network with known ground-truth topology. We find that the functional network topology revealed by Transfer Entropy depends qualitatively on the time-dependent dynamic state of the network (bursting or non-bursting). Thus by conditioning with respect to the global mean activity, we improve the performance of our method. This allows us to focus the analysis to specific dynamical regimes of the network in which the inferred functional connectivity is shaped by monosynaptic excitatory connections, rather than by collective synchrony. Our method can discriminate between actual causal influences between neurons and spurious non-causal correlations due to light scattering artifacts, which inherently affect the quality of fluorescence imaging. Compared to other reconstruction strategies such as cross-correlation or Granger Causality methods, our method based on improved Transfer Entropy is remarkably more accurate. In particular, it provides a good estimation of the excitatory network clustering coefficient, allowing for discrimination between weakly and strongly clustered topologies. Finally, we demonstrate the applicability of our method to analyses of real recordings of in vitro disinhibited cortical cultures where we suggest that excitatory connections are characterized by an elevated level of clustering compared to a random graph (although not extreme) and can be markedly non-local.

How to improve flow during cardiopulmonary bypass in an acardia experimental model.

OBJECTIVES In extreme scenarios, such as hyperacute rejection of heart transplant, an urgent heart explantation might be necessary. The aim of this experimental study was to determine the feasibility and to improve the haemodynamics of a venoarterial cardiopulmonary bypass after cardiectomy. METHODS A venoarterial cardiopulmonary bypass was established in seven calves (56.4 ± 7 kg) by the transjugular insertion to the caval axis of a self-expanding cannula, with a carotid artery return. After baseline measurements (A), ventricular fibrillation was induced (B), great arteries were clamped (C), the heart was excised and the right and left atria remnants, containing the pulmonary veins, were sutured together leaving an atrial septal defect over the cannula in the caval axis (D). Measurements were taken with the pulmonary artery clamped and declamped. RESULTS Initial pump flow was 4.16 ± 0.75 l/min dropping to 2.9 ± 0.63 l/min (P(AB )< 0.001) 10 min after induction of ventricular fibrillation. After cardiectomy with the pulmonary artery clamped, the pump flow increased non-significantly to 3.20 ± 0.78 l/min. After declamping, the flow significantly increased close to baseline levels (3.61 ± 0.73 l/min, P(DB )= 0.009, P(DC )= 0.017), supporting the notion that full cardiopulmonary bypass in acardia is feasible only if adequate drainage of pulmonary circulation is assured to avoid pulmonary congestion and loss of volume from the left-to-right shunt of bronchial vessels.

Flow targeted 3D steady-state free-precession coronary MR angiography: comparison of three different imaging approaches.

PURPOSE: To compare 3 different flow targeted magnetization preparation strategies for coronary MR angiography (cMRA), which allow selective visualization of the vessel lumen. MATERIAL AND METHODS: The right coronary artery of 10 healthy subjects was investigated on a 1.5 Tesla MR system (Gyroscan ACS-NT, Philips Healthcare, Best, NL). A navigator-gated and ECG-triggered 3D radial steady-state free-precession (SSFP) cMRA sequence with 3 different magnetization preparation schemes was performed referred to as projection SSFP (selective labeling of the aorta, subtraction of 2 data sets), LoReIn SSFP (double-inversion preparation, selective labeling of the aorta, 1 data set), and inflow SSFP (inversion preparation, selective labeling of the coronary artery, 1 data set). Signal-to-noise ratio (SNR) of the coronary artery and aorta, contrast-to-noise ratio (CNR) between the coronary artery and epicardial fat, vessel length and vessel sharpness were analyzed. RESULTS: All cMRA sequences were successfully obtained in all subjects. Both projection SSFP and LoReIn SSFP allowed for selective visualization of the coronary arteries with excellent background suppression. Scan time was doubled in projection SSFP because of the need for subtraction of 2 data sets. In inflow SSFP, background suppression was limited to the tissue included in the inversion volume. Projection SSFP (SNR(coro): 25.6 +/- 12.1; SNR(ao): 26.1 +/- 16.8; CNR(coro-fat): 22.0 +/- 11.7) and inflow SSFP (SNR(coro): 27.9 +/- 5.4; SNR(ao): 37.4 +/- 9.2; CNR(coro-fat): 24.9 +/- 4.8) yielded significantly increased SNR and CNR compared with LoReIn SSFP (SNR(coro): 12.3 +/- 5.4; SNR(ao): 11.8 +/- 5.8; CNR(coro-fat): 9.8 +/- 5.5; P &lt; 0.05 for both). Longest visible vessel length was found with projection SSFP (79.5 mm +/- 18.9; P &lt; 0.05 vs. LoReIn) whereas vessel sharpness was best in inflow SSFP (68.2% +/- 4.5%; P &lt; 0.05 vs. LoReIn). Consistently good image quality was achieved using inflow SSFP likely because of the simple planning procedure and short scanning time. CONCLUSION: Three flow targeted cMRA approaches are presented, which provide selective visualization of the coronary vessel lumen and in addition blood flow information without the need of contrast agent administration. Inflow SSFP yielded highest SNR, CNR and vessel sharpness and may prove useful as a fast and efficient approach for assessing proximal and mid vessel coronary blood flow, whereas requiring less planning skills than projection SSFP or LoReIn SSFP.

Distribution of free and liposomal doxorubicin after isolated lung perfusion in a sarcoma model.

BACKGROUND: Isolated lung perfusion (ILP) with free and a novel liposomal-encapsulated doxorubicin (Liporubicin, CT Sciences SA, Lausanne, Switzerland) was compared with respect to drug uptake and distribution in rat lungs bearing a sarcomatous tumor. METHODS: A single sarcomatous tumor was generated in the left lung of 39 Fischer rats, followed 10 days later by left-sided ILP (n = 36) with free and equimolar-dosed liposomal doxorubicin at doses of 100 microg (n = 9) and 400 microg (n = 9) for each doxorubicin formulation. In each perfused lung, the drug concentration and distribution were assessed in the tumor and in three areas of normal lung parenchyma by high-performance liquid chromatography (n = 6) and fluorescence microscopy (n = 3). Histologic assessment and immunostaining with von Willebrand factor was performed in 3 animals with untreated tumors. RESULTS: The sarcomatous tumors in controls were well vascularized with fine branching capillaries present throughout the tumors. Isolated lung perfusion resulted in a heterogeneous drug distribution within the perfused lung and a consistently lower drug uptake in tumors than in lung parenchyma for both doxorubicin formulations and both drug doses applied. Isolated lung perfusion with free doxorubicin resulted in a significantly higher drug uptake than Liporubicin in both the tumor and lung tissue for both drug doses applied (p < 0.01). However, the tumor/normal tissue drug ratio was lower for free than for liposomal doxorubicin at a drug dose of 100 microg (0.27 +/- 0.1 vs 0.53 +/- 0.5; p = 0.225) and similar for both doxorubicin formulations at a drug dose of 400 microg (0.67 +/- 0.2 vs 0.54 +/- 0.2; p = 0.335). Both doxorubicin formulations resulted in fluorescence signaling emerging from all tissue compartments of normal lung parenchyma but only in weak and sporadic signaling from the tumors confined to the tumor periphery and vessels situated within the tumor for both drug doses assessed. CONCLUSIONS: Isolated lung perfusion with free and liposomal doxorubicin resulted in a heterogeneous drug distribution within the perfused lung and in a lower drug uptake in tumors than in lung tissue for both doxorubicin formulations and drug doses applied.

Navigator-gated free-breathing 3D balanced FFE projection renal MRA: Comparison with contrast-enhanced breath-hold 3D MRA in a swine model.

A cardiac-triggered, free-breathing, 3D balanced FFE projection renal MR angiography (MRA) technique with a 2D pencil beam aortic labeling pulse for selective aortic spin tagging was developed. For respiratory motion artifact suppression during free breathing, a prospective real-time navigator was implemented for renal MRA. Images obtained with the new approach were compared with standard contrast-enhanced (CE) 3D breath-hold MRA in seven swine. Signal properties and vessel visualization were analyzed. With the presented technique, high-resolution, high-contrast renal projection MRA with superior vessel length visualization (including a greater visible number of distal branches of the renal arteries) compared to standard breath-hold CE-MRA was obtained. The present results warrant clinical studies in patients with renal artery disease.

Premsa gratuïta, un model de comunicació local = Free press, a local communication model

The relationship between non-institutional free press and local communication is quite particular since this type of press forms a very characteristic model of local communication, showing that advertising suffices to finance an information product addressed to a fairly well-defined readership as long as this product has a good advertising sales department and an effective distribution in its operating area. This paper discusses the present situation of the free press in Catalonia, where this phenomenon has been quite prominent. It points out the main features of this type of press and makes a review of its history, which runs from the euphoria of its early years and its expansion and consolidation, to the current crisis

Gas-liquid mass transfer in bubbly flow: Estimation of mass transfer, bubble size and reactor performance in various applications

Gas-liquid mass transfer is an important issue in the design and operation of many chemical unit operations. Despite its importance, the evaluation of gas-liquid mass transfer is not straightforward due to the complex nature of the phenomena involved. In this thesis gas-liquid mass transfer was evaluated in three different gas-liquid reactors in a traditional way by measuring the volumetric mass transfer coefficient (kLa). The studied reactors were a bubble column with a T-junction two-phase nozzle for gas dispersion, an industrial scale bubble column reactor for the oxidation of tetrahydroanthrahydroquinone and a concurrent downflow structured bed.The main drawback of this approach is that the obtained correlations give only the average volumetric mass transfer coefficient, which is dependent on average conditions. Moreover, the obtained correlations are valid only for the studied geometry and for the chemical system used in the measurements. In principle, a more fundamental approach is to estimate the interfacial area available for mass transfer from bubble size distributions obtained by solution of population balance equations. This approach has been used in this thesis by developing a population balance model for a bubble column together with phenomenological models for bubble breakage and coalescence. The parameters of the bubble breakage rate and coalescence rate models were estimated by comparing the measured and calculated bubble sizes. The coalescence models always have at least one experimental parameter. This is because the bubble coalescence depends on liquid composition in a way which is difficult to evaluate using known physical properties. The coalescence properties of some model solutions were evaluated by measuring the time that a bubble rests at the free liquid-gas interface before coalescing (the so-calledpersistence time or rest time). The measured persistence times range from 10 msup to 15 s depending on the solution. The coalescence was never found to be instantaneous. The bubble oscillates up and down at the interface at least a coupleof times before coalescence takes place. The measured persistence times were compared to coalescence times obtained by parameter fitting using measured bubble size distributions in a bubble column and a bubble column population balance model. For short persistence times, the persistence and coalescence times are in good agreement. For longer persistence times, however, the persistence times are at least an order of magnitude longer than the corresponding coalescence times from parameter fitting. This discrepancy may be attributed to the uncertainties concerning the estimation of energy dissipation rates, collision rates and mechanisms and contact times of the bubbles.

Calculations of Boiling Two-Phase Flow Using a Porous Media Model

Boiling two-phase flow and the equations governing the motion of fluid in two-phase flows are discussed in this thesis. Disposition of the governing equations in three-dimensional complex geometries is considered from the perspective of the porous medium concept. The equations governing motion in two-phase flows were formulated, discretized and implemented in a subroutine for pressure-velocity solution utilizing the SIMPLE algorithm modified for two-phase flow. The subroutine was included in PORFLO, which is a three-dimensional 5-equation porous media model developed at VTT by Jaakko Miettinen. The development of two-phase flow and the resulting void fraction distribution was predicted in a geometry resembling a section of BWR fuel bundle in a couple of test cases using PORFLO.

Machine Learning and Clinical Text. Supporting Health Information Flow

Fluent health information flow is critical for clinical decision-making. However, a considerable part of this information is free-form text and inabilities to utilize it create risks to patient safety and cost-­effective hospital administration. Methods for automated processing of clinical text are emerging. The aim in this doctoral dissertation is to study machine learning and clinical text in order to support health information flow.First, by analyzing the content of authentic patient records, the aim is to specify clinical needs in order to guide the development of machine learning applications.The contributions are a model of the ideal information flow,a model of the problems and challenges in reality, and a road map for the technology development. Second, by developing applications for practical cases,the aim is to concretize ways to support health information flow. Altogether five machine learning applications for three practical cases are described: The first two applications are binary classification and regression related to the practical case of topic labeling and relevance ranking.The third and fourth application are supervised and unsupervised multi-class classification for the practical case of topic segmentation and labeling.These four applications are tested with Finnish intensive care patient records.The fifth application is multi-label classification for the practical task of diagnosis coding. It is tested with English radiology reports.The performance of all these applications is promising. Third, the aim is to study how the quality of machine learning applications can be reliably evaluated.The associations between performance evaluation measures and methods are addressed,and a new hold-out method is introduced.This method contributes not only to processing time but also to the evaluation diversity and quality. The main conclusion is that developing machine learning applications for text requires interdisciplinary, international collaboration. Practical cases are very different, and hence the development must begin from genuine user needs and domain expertise. The technological expertise must cover linguistics,machine learning, and information systems. Finally, the methods must be evaluated both statistically and through authentic user-feedback.

Separation of Gas Bubbles from Circulation Waters and Pulp Suspensions in Open Channel Flow

The objective of this thesis was to study the removal of gases from paper mill circulation waters experimentally and to provide data for CFD modeling. Flow and bubble size measurements were carried out in a laboratory scale open gas separation channel. Particle Image Velocimetry (PIV) technique was used to measure the gas and liquid flow fields, while bubble size measurements were conducted using digital imaging technique with back light illumination. Samples of paper machine waters as well as a model solution were used for the experiments. The PIV results show that the gas bubbles near the feed position have the tendency to escape from the circulation channel at a faster rate than those bubbles which are further away from the feed position. This was due to an increased rate of bubble coalescence as a result of the relatively larger bubbles near the feed position. Moreover, a close similarity between the measured slip velocities of the paper mill waters and that of literature values was obtained. It was found that due to dilution of paper mill waters, the observed average bubble size was considerably large as compared to the average bubble sizes in real industrial pulp suspension and circulation waters. Among the studied solutions, the model solution has the highest average drag coefficient value due to its relatively high viscosity. The results were compared to a 2D steady sate CFD simulation model. A standard Euler-Euler k-ε turbulence model was used in the simulations. The channel free surface was modeled as a degassing boundary. From the drag models used in the simulations, the Grace drag model gave velocity fields closest to the experimental values. In general, the results obtained from experiments and CFD simulations are in good qualitative agreement.

Model for subchannel friction factors and flow redistribution in wire-wrapped rod bundles

The fuel element of LMFBR consists of a bundle of rods wrapped with an helical wire as spacer, surrounded by an hexagonal duct. In the present work, a semi-empirical model is developed to calculate bundle average and subchannel based friction factors and flow redistribution. The obtained results were compared to experimental data and they were considered satisfactory for wide range of geometrical parameters.

Detection of Horizontal Two-Phase Flow Patterns Through a Neural Network Model

One of the main problems related to the transport and manipulation of multiphase fluids concerns the existence of characteristic flow patterns and its strong influence on important operation parameters. A good example of this occurs in gas-liquid chemical reactors in which maximum efficiencies can be achieved by maintaining a finely dispersed bubbly flow to maximize the total interfacial area. Thus, the ability to automatically detect flow patterns is of crucial importance, especially for the adequate operation of multiphase systems. This work describes the application of a neural model to process the signals delivered by a direct imaging probe to produce a diagnostic of the corresponding flow pattern. The neural model is constituted of six independent neural modules, each of which trained to detect one of the main horizontal flow patterns, and a last winner-take-all layer responsible for resolving when two or more patterns are simultaneously detected. Experimental signals representing different bubbly, intermittent, annular and stratified flow patterns were used to validate the neural model.

Comparison of Model-Based Flow Rate Estimation Methods in Frequency-Converter-Driven Pumps and Fans

Fluid handling systems such as pump and fan systems are found to have a significant potential for energy efficiency improvements. To deliver the energy saving potential, there is a need for easily implementable methods to monitor the system output. This is because information is needed to identify inefficient operation of the fluid handling system and to control the output of the pumping system according to process needs. Model-based pump or fan monitoring methods implemented in variable speed drives have proven to be able to give information on the system output without additional metering; however, the current model-based methods may not be usable or sufficiently accurate in the whole operation range of the fluid handling device. To apply model-based system monitoring in a wider selection of systems and to improve the accuracy of the monitoring, this paper proposes a new method for pump and fan output monitoring with variable-speed drives. The method uses a combination of already known operating point estimation methods. Laboratory measurements are used to verify the benefits and applicability of the improved estimation method, and the new method is compared with five previously introduced model-based estimation methods. According to the laboratory measurements, the new estimation method is the most accurate and reliable of the model-based estimation methods.

Effect of whey protein concentrate on texture of fat-free desserts: sensory and instrumental measurements

It is important to understand how changes in the product formulation can modify its characteristics. Thus, the objective of this study was to investigate the effect of whey protein concentrate (WPC) on the texture of fat-free dairy desserts. The correlation between instrumental and sensory measurements was also investigated. Four formulations were prepared with different WPC concentrations (0, 1.5, 3.0, and 4.5 wt. (%)) and were evaluated using the texture profile analysis (TPA) and rheology. Thickness was evaluated by nine trained panelists. Formulations containing WPC showed higher firmness, elasticity, chewiness, and gumminess and clearly differed from the control as indicated by principal component analysis (PCA). Flow behavior was characterized as time-dependent and pseudoplastic. Formulation with 4.5% WPC at 10 °C showed the highest thixotropic behavior. Experimental data were fitted to Herschel-Bulkley model. The addition of WPC contributed to the texture of the fat-free dairy dessert. The yield stress, apparent viscosity, and perceived thickness in the dairy desserts increased with WPC concentration. The presence of WPC promotes the formation of a stronger gel structure as a result of protein-protein interactions. The correlation between instrumental parameters and thickness provided practical results for food industries.