Personalized modeling for drug concentration prediction using Support Vector Machine

Building a personalized model to describe the drug concentration inside the human body for each patient is highly important to the clinical practice and demanding to the modeling tools. Instead of using traditional explicit methods, in this paper we propose a machine learning approach to describe the relation between the drug concentration and patients' features. Machine learning has been largely applied to analyze data in various domains, but it is still new to personalized medicine, especially dose individualization. We focus mainly on the prediction of the drug concentrations as well as the analysis of different features' influence. Models are built based on Support Vector Machine and the prediction results are compared with the traditional analytical models.

Student modeling based on fuzzy inference mechanisms

The paper presents a competence-based instructional design system and a way to provide a personalization of navigation in the course content. The navigation aid tool builds on the competence graph and the student model, which includes the elements of uncertainty in the assessment of students. An individualized navigation graph is constructed for each student, suggesting the competences the student is more prepared to study. We use fuzzy set theory for dealing with uncertainty. The marks of the assessment tests are transformed into linguistic terms and used for assigning values to linguistic variables. For each competence, the level of difficulty and the level of knowing its prerequisites are calculated based on the assessment marks. Using these linguistic variables and approximate reasoning (fuzzy IF-THEN rules), a crisp category is assigned to each competence regarding its level of recommendation.

The history and role of long duration stimulation in fMRI.

During the past 20 years, BOLD fMRI has developed towards a central and fundamental tool in neuroscience. It has been shown that the BOLD response provides an indicator of neuronal activity in the brain. Consequently, for an accurate interpretation of findings in BOLD MRI experiments and to draw meaningful conclusions about the temporal evolution of neural events, a deep understanding of the nature of the BOLD contrast has become of essential importance. Since the dynamics of the major direct determinants of the BOLD signal (CBF, CBV and CMRO(2)) range between seconds and minutes, long duration stimulation was an early key strategy needed to study and understand the BOLD characteristics. This paper summarizes and discusses the thoughts and rationales of the long duration stimulation studies.

Echo-time independent signal modulations for strongly coupled systems in triple echo localization schemes: an extension of S-PRESS editing.

The double spin-echo point resolved spectroscopy sequence (PRESS) is a widely used method and standard in clinical MR spectroscopy. Existence of important J-modulations at constant echo times, depending on the temporal delays between the rf-pulses, have been demonstrated recently for strongly coupled spin systems and were exploited for difference editing, removing singlets from the spectrum (strong-coupling PRESS, S-PRESS). A drawback of this method for in vivo applications is that large signal modulations needed for difference editing occur only at relatively long echo times. In this work we demonstrate that, by simply adding a third refocusing pulse (3S-PRESS), difference editing becomes possible at substantially shorter echo times while, as applied to citrate, more favorable lineshapes can be obtained. For the example of an AB system an analytical description of the MR signal, obtained with this triple refocusing sequence (3S-PRESS), is provided.

Prediction of infant drug exposure through breastfeeding: population PK modeling and simulation of fluoxetine

BACKGROUND: Risks of significant infant drug exposurethrough breastmilk are poorly defined for many drugs, and largescalepopulation data are lacking. We used population pharmacokinetics(PK) modeling to predict fluoxetine exposure levels ofinfants via mother's milk in a simulated population of 1000 motherinfantpairs.METHODS: Using our original data on fluoxetine PK of 25breastfeeding women, a population PK model was developed withNONMEM and parameters, including milk concentrations, wereestimated. An exponential distribution model was used to account forindividual variation. Simulation random and distribution-constrainedassignment of doses, dosing time, feeding intervals and milk volumewas conducted to generate 1000 mother-infant pairs with characteristicssuch as the steady-state serum concentrations (Css) and infantdose relative to the maternal weight-adjusted dose (relative infantdose: RID). Full bioavailability and a conservative point estimate of1-month-old infant CYP2D6 activity to be 20% of the adult value(adjusted by weigth) according to a recent study, were assumed forinfant Css calculations.RESULTS: A linear 2-compartment model was selected as thebest model. Derived parameters, including milk-to-plasma ratios(mean: 0.66; SD: 0.34; range, 0 - 1.1) were consistent with the valuesreported in the literature. The estimated RID was below 10% in >95%of infants. The model predicted median infant-mother Css ratio was0.096 (range 0.035 - 0.25); literature reported mean was 0.07 (range0-0.59). Moreover, the predicted incidence of infant-mother Css ratioof >0.2 was less than 1%.CONCLUSION: Our in silico model prediction is consistent withclinical observations, suggesting that substantial systemic fluoxetineexposure in infants through human milk is rare, but further analysisshould include active metabolites. Our approach may be valid forother drugs. [supported by CIHR and Swiss National Science Foundation(SNSF)]

Development of neuronal markers in aggregating fetal rat telencephalon cells cultured in the presence of triiodothyronine.

The concentrations of the general neuronal markers D2-protein (N-CAM), D3-protein and neuron specific enolase (NSE) in reaggregating cultures of fetal rat telencephalon cells were affected by the presence of 30 nM triiodothyronine in the defined culture medium. The extent of normal developmental changes were enhanced by triiodothyronine, as demonstrated by crossed immunoelectrophoresis. From 13 to 19 days in culture, the concentration of D2-protein decreased, and the concentrations of both D3-protein and NSE increased. Nerve growth factor (NGF) was without effect on the development of these general neuronal markers. However, as shown previously both triiodothyronine and NGF increased the activity of choline acetyltransferase, a marker for cholinergic neurons. The results suggest an enhanced overall differentiation of several types of telencephalon neurons in the presence of triiodothyronine, and a specific stimulation of cholinergic telencephalon neurons by NGF.

Relatedness influences signal reliability in evolving robots.

Communication is an indispensable component of animal societies, yet many open questions remain regarding the factors affecting the evolution and reliability of signalling systems. A potentially important factor is the level of genetic relatedness between signallers and receivers. To quantitatively explore the role of relatedness in the evolution of reliable signals, we conducted artificial evolution over 500 generations in a system of foraging robots that can emit and perceive light signals. By devising a quantitative measure of signal reliability, and comparing independently evolving populations differing in within-group relatedness, we show a strong positive correlation between relatedness and reliability. Unrelated robots produced unreliable signals, whereas highly related robots produced signals that reliably indicated the location of the food source and thereby increased performance. Comparisons across populations also revealed that the frequency for signal production-which is often used as a proxy of signal reliability in empirical studies on animal communication-is a poor predictor of signal reliability and, accordingly, is not consistently correlated with group performance. This has important implications for our understanding of signal evolution and the empirical tools that are used to investigate communication.

Aerodynamic drag modeling of alpine skiers performing giant slalom turns.

PURPOSE: Aerodynamic drag plays an important role in performance for athletes practicing sports that involve high-velocity motions. In giant slalom, the skier is continuously changing his/her body posture, and this affects the energy dissipated in aerodynamic drag. It is therefore important to quantify this energy to understand the dynamic behavior of the skier. The aims of this study were to model the aerodynamic drag of alpine skiers in giant slalom simulated conditions and to apply these models in a field experiment to estimate energy dissipated through aerodynamic drag. METHODS: The aerodynamic characteristics of 15 recreational male and female skiers were measured in a wind tunnel while holding nine different skiing-specific postures. The drag and the frontal area were recorded simultaneously for each posture. Four generalized and two individualized models of the drag coefficient were built, using different sets of parameters. These models were subsequently applied in a field study designed to compare the aerodynamic energy losses between a dynamic and a compact skiing technique. RESULTS: The generalized models estimated aerodynamic drag with an accuracy of between 11.00% and 14.28%, and the individualized models estimated aerodynamic drag with an accuracy between 4.52% and 5.30%. The individualized model used for the field study showed that using a dynamic technique led to 10% more aerodynamic drag energy loss than using a compact technique. DISCUSSION: The individualized models were capable of discriminating different techniques performed by advanced skiers and seemed more accurate than the generalized models. The models presented here offer a simple yet accurate method to estimate the aerodynamic drag acting upon alpine skiers while rapidly moving through the range of positions typical to turning technique.

Determination of Transmembrane Water Fluxes in Neurons Elicited by Glutamate Ionotropic Receptors and by the Cotransporters KCC2 and NKCC1: A Digital Holographic Microscopy Study.

Digital holographic microscopy (DHM) is a noninvasive optical imaging technique that provides quantitative phase images of living cells. In a recent study, we showed that the quantitative monitoring of the phase signal by DHM was a simple label-free method to study the effects of glutamate on neuronal optical responses (Pavillon et al., 2010). Here, we refine these observations and show that glutamate produces the following three distinct optical responses in mouse primary cortical neurons in culture, predominantly mediated by NMDA receptors: biphasic, reversible decrease (RD) and irreversible decrease (ID) responses. The shape and amplitude of the optical signal were not associated with a particular cellular phenotype but reflected the physiopathological status of neurons linked to the degree of NMDA activity. Thus, the biphasic, RD, and ID responses indicated, respectively, a low-level, a high-level, and an "excitotoxic" level of NMDA activation. Moreover, furosemide and bumetanide, two inhibitors of sodium-coupled and/or potassium-coupled chloride movement strongly modified the phase shift, suggesting an involvement of two neuronal cotransporters, NKCC1 (Na-K-Cl) and KCC2 (K-Cl) in the genesis of the optical signal. This observation is of particular interest since it shows that DHM is the first imaging technique able to monitor dynamically and in situ the activity of these cotransporters during physiological and/or pathological neuronal conditions.

New Trends in Public Facility Location Modeling

The past four decades have witnessed an explosive growth in the field of networkbased facility location modeling. This is not at all surprising since location policy is one of the most profitable areas of applied systems analysis in regional science and ample theoretical and applied challenges are offered. Location-allocation models seek the location of facilities and/or services (e.g., schools, hospitals, and warehouses) so as to optimize one or several objectives generally related to the efficiency of the system or to the allocation of resources. This paper concerns the location of facilities or services in discrete space or networks, that are related to the public sector, such as emergency services (ambulances, fire stations, and police units), school systems and postal facilities. The paper is structured as follows: first, we will focus on public facility location models that use some type of coverage criterion, with special emphasis in emergency services. The second section will examine models based on the P-Median problem and some of the issues faced by planners when implementing this formulation in real world locational decisions. Finally, the last section will examine new trends in public sector facility location modeling.

Distribution of neuronal and metabolic markers in the human auditory cortex

SUMMARY The human auditory cortex, located on the supratemporal plane of the temporal lobe, is divided in a primary auditory area and several non-primary areas surrounding it. These different areas show anatomical and functional differences. Many studies have focussed on auditory areas in non-human primates, using investigation techniques such as electrophysiological recordings, tracing of neural connections, or immunohistochemical and histochemical staining. Some of these studies have suggested parallel and hierarchical organization of the cortical auditory areas as well as subcortical auditory relays. In humans, only few studies have investigated these regions immunohistochemically, but activation and lesion studies speak in favour of parallel and hierarchical organization, very similar to that of non-human primates. Calcium-binding proteins and metabolic markers were used to investigate possible correlates of hierarchical and parallel organization in man. Calcium-binding proteins, parvalbumin, calretinin and calbindin, modulate the concentration of intracellular free calcium ions and were found in distinct subpopulations of GABAergic neurons in non-human primates species. In our study, their distribution showed several differences between auditory areas: the primary auditory area was darkly stained for both parvalbumin and calbindin, and their expression rapidly decreased while moving away from the primary area. This staining pattern suggests a hierarchical organization of the areas, in which the more darkly stained areas could correspond to an earlier integration level and the areas showing light staining may correspond to higher level integration areas. Parallel organization of primary and non-primary auditory areas was suggested by the complementarity, within a given area, between parvalbumin and calbindin expression across layers. To investigate the possible differences in the energetic metabolism of the cortical auditory areas, several metabolic markers were used: cytochrome oxidase and LDH1 were used as oxidative metabolism markers and LDH5 was used as glycolytic metabolism marker. The results obtained show a difference in the expression of enzymes involved in oxidative metabolism between areas. In the primary auditory area the oxidative metabolism markers were maximally expressed in layer IV. In contrast, higher order areas showed maximal staining in supragranular layers. The expression of LDH5 varied in patches, but did not differ between the different hierarchical auditory areas. The distribution of the two LDH enzymes isoforms also provides information about cellular aspects of metabolic organization, since neurons expressed the LDH1 isoform whereas astrocytes express primarily LDH5, but some astrocytes also contained the LDH1 isoform. This cellular distribution pattern supports the hypothesis of the existence of an astrocyte-neuron lactate shuttle, previously suggested in rodent studies, and in particular of lactate transfer from astrocytes, which produce lactate from the glucose obtained from the circulation, to neurons that use lactate as energy substrate. In conclusion, the hypothesis of parallel and hierarchical organization of the auditory areas can be supported by CaBPs, cytochrome oxidase and LDH1 distribution. Moreover, the two LDHs cellular distribution pattern support the hypothesis of an astrocyte-neuron lactate shuttle in human cortex.

Neuronal autophagy as a mediator of life and death: contrasting roles in chronic neurodegenerative and acute neural disorders.

Autophagy is a cellular mechanism for degrading proteins and organelles. It was first described as a physiological process essential for cellular health and survival, and this is its role in most cells. However, it can also be a mediator of cell death, either by the triggering of apoptosis or by an independent "autophagic" cell death mechanism. This duality is important in the central nervous system, where the activation of autophagy has recently been shown to be protective in certain chronic neurodegenerative diseases but deleterious in acute neural disorders such as stroke and hypoxic/ischemic injury. The authors here discuss these distinct roles of autophagy in the nervous system with a focus on the role of autophagy in mediating neuronal death. The development of new therapeutic strategies based on the manipulation of autophagy will need to take into account these opposing roles of autophagy.

Effects of phylogenetic signal on ancestral state reconstruction.

One of the standard tools used to understand the processes shaping trait evolution along the branches of a phylogenetic tree is the reconstruction of ancestral states (Pagel 1999). The purpose is to estimate the values of the trait of interest for every internal node of a phylogenetic tree based on the trait values of the extant species, a topology and, depending on the method used, branch lengths and a model of trait evolution (Ronquist 2004). This approach has been used in a variety of contexts such as biogeography (e.g., Nepokroeff et al. 2003, Blackburn 2008), ecological niche evolution (e.g., Smith and Beaulieu 2009, Evans et al. 2009) and metabolic pathway evolution (e.g., Gabaldón 2003, Christin et al. 2008). Investigations of the factors affecting the accuracy with which ancestral character states can be reconstructed have focused in particular on the choice of statistical framework (Ekman et al. 2008) and the selection of the best model of evolution (Cunningham et al. 1998, Mooers et al. 1999). However, other potential biases affecting these methods, such as the effect of tree shape (Mooers 2004), taxon sampling (Salisbury and Kim 2001) as well as reconstructing traits involved in species diversification (Goldberg and Igić 2008), have also received specific attention. Most of these studies conclude that ancestral character states reconstruction is still not perfect, and that further developments are necessary to improve its accuracy (e.g., Christin et al. 2010). Here, we examine how different estimations of branch lengths affect the accuracy of ancestral character state reconstruction. In particular, we tested the effect of using time-calibrated versus molecular branch lengths and provide guidelines to select the most appropriate branch lengths to reconstruct the ancestral state of a trait.

Sequence determinants of a microtubule tip localization signal (MtLS).

Microtubule plus-end-tracking proteins (+TIPs) specifically localize to the growing plus-ends of microtubules to regulate microtubule dynamics and functions. A large group of +TIPs contain a short linear motif, SXIP, which is essential for them to bind to end-binding proteins (EBs) and target microtubule ends. The SXIP sequence site thus acts as a widespread microtubule tip localization signal (MtLS). Here we have analyzed the sequence-function relationship of a canonical MtLS. Using synthetic peptide arrays on membrane supports, we identified the residue preferences at each amino acid position of the SXIP motif and its surrounding sequence with respect to EB binding. We further developed an assay based on fluorescence polarization to assess the mechanism of the EB-SXIP interaction and to correlate EB binding and microtubule tip tracking of MtLS sequences from different +TIPs. Finally, we investigated the role of phosphorylation in regulating the EB-SXIP interaction. Together, our results define the sequence determinants of a canonical MtLS and provide the experimental data for bioinformatics approaches to carry out genome-wide predictions of novel +TIPs in multiple organisms.

Selective changes in the neurofilament and microtubule cytoskeleton of NF-H/LacZ mice.

This study focused mainly on changes in the microtubule cytoskeleton in a transgenic mouse where beta-galactosidase fused to a truncated neurofilament subunit led to a decrease in neurofilament triplet protein expression and a loss in neurofilament assembly and abolished transport into neuronal processes in spinal cord and brain. Although all neurofilament subunits accumulated in neuronal cell bodies, our data suggest an increased solubility of all three subunits, rather than increased precipitation, and point to a perturbed filament assembly. In addition, reduced neurofilament phosphorylation may favor an increased filament degradation. The function of microtubules seemed largely unaffected, in that tubulin and microtubule-associated proteins (MAP) expression and their distribution were largely unchanged in transgenic animals. MAP1A was the only MAP with a reduced signal in spinal cord tissue, and differences in immunostaining in various brain regions corroborate a relationship between MAP1A and neurofilaments.