How Can Network-Pharmacology Contribute to Antiepileptic Drug Development?

Network-pharmacology is a field of pharmacology emerging from the observation that most clinical drugs have multiple targets, contrasting with the previously dominant magic bullet paradigm which proposed the search of exquisitely selective drugs. What is more, drug targets are often involved in multiple diseases and frequently present co-expression patterns. Therefore, useful therapeutic information can be drawn from network representations of drug targets. Here, we discuss potential applications of drug-target networks in the field of antiepileptic drug development.Fil: Di Ianni, Mauricio Emiliano. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Talevi, Alan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; Argentin

Aging under Shear: Structural Relaxation of a Non-Newtonian Fluid

The influence of an applied shear field on the dynamics of an aging colloidal suspension has been investigated by the dynamic light scattering determination of the density autocorrelation function. Though a stationary state is never observed, the slow dynamics crosses between two different non-equilibrium regimes as soon as the structural relaxation time approaches the inverse shear rate. In the shear dominated regime (at high shear rate values) the structural relaxation time is found to be strongly sensitive to shear rate while aging proceeds at a very slow rate. The effect of shear on the detailed shape of the density autocorrelation function is quantitatively described assuming that the structural relaxation process arises from the heterogeneous superposition of many relaxing units each one independently coupled to shear with a parallel composition rule for timescales.Comment: 5 pages, 5 figure

Colloidal attraction induced by a temperature gradient

Colloidal crystals are of extreme importance for applied research, such as photonic crystals technology, and for fundamental studies in statistical mechanics. Long range attractive interactions, such as capillary forces, can drive the spontaneous assembly of such mesoscopic ordered structures. However long range attractive forces are very rare in the colloidal realm. Here we report a novel strong and long ranged attraction induced by a thermal gradient in the presence of a wall. Switching on and off the thermal gradient we can rapidly and reversibly form stable hexagonal 2D crystals. We show that the observed attraction is hydrodynamic in nature and arises from thermal induced slip flow on particle surfaces. We used optical tweezers to directly measure the force law and compare it to an analytic prediction based on Stokes flow driven by Marangoni forces.Comment: 4 pages, 4 figure

Portable Ultrasound Imaging

This PhD project investigates hardware strategies and imaging methods for hand-held ultrasound systems. The overall idea is to use a wireless ultrasound probe linked to general-purpose mobile devices for the processing and visualization. The approach has the potential to reduce the upfront costs of the ultrasound system and, consequently, to allow for a wide-scale utilization of diagnostic ultrasound in any medical specialties and out of the radiology department. The first part of the contribution deals with the study of hardware solutions for the reduction of the system complexity. Analog and digital beamforming strategies are simulated from a system-level perspective. The quality of the B-mode image is evaluated and the minimum specifications are derived for the design of a portable probe with integrated electronics in-handle. The system is based on a synthetic aperture sequential beamforming approach that allows to significantly reduce the data rate between the probe and processing unit. The second part investigates the feasibility of vector flow imaging in a hand-held ultrasound system. Vector flow imaging overcomes the limitations of conventional imaging methods in terms of flow angle compensation. Furthermore, high frame rate can be obtained by using synthetic aperture focusing techniques. A method is developed combining synthetic aperture sequential beamforming and directional transverse oscillation to achieve the wireless transmission of the data along with a relatively inexpensive 2-D velocity estimation. The performance of the method is thoroughly assessed through simulations and measurements, and in vivo investigations are carried out to show its potential in presence of complex flow dynamics. A sufficient frame rate is achieved to allow for the visualization of vortices in the carotid bifurcation. Furthermore, the method is implemented on a commercially available tablet to evaluate the real-time processing performance in the built-in GPU with concurrent wireless transmission of the data. Based on the demonstrations in this thesis, a flexible framework can be implemented with performance that can be scaled to the needs of the user and according to the computing resources available. The integration of high-frame-rate vector flow imaging in a hand-held ultrasound scanner, in addition, has the potential to improve the operator’s workflow and opens the way to new possibilities in the clinical practice

Exploring the role of LDH in cancer cells through the use of small-molecule inhibitors.

Metabolic reprogramming represents a potential therapeutic target in cancer. The studies of this thesis work lead to assume the enzyme lactate dehydrogenase (LDH) as key element coordinating neoplastic proliferation and invasive growth, suggesting for LDH inhibitor compounds a wider potential in anticancer treatment. The increased LDH-A expression has been observed in many tumor forms. In neoplastic cells, LDH commonly reduce pyruvate to lactate even in the presence of adequate oxygen supply (aerobic glycolysis). The rationale for targeting LDH activity in anticancer strategies is because LDH activity is not needed for pyruvate metabolism through the TCA cycle, thus, LDH inhibitors should spare glucose metabolism of normal cells. The objective of this work, simultaneously with the ongoing search for new LDH inhibitors, is the study of the role of LDH in cancer cells by pharmaceutical approach, through the use of inhibitors in different cell lines and conditions, and by genetic approach consisting in the depletion of LDH genes by the innovative CRISPR/Cas9 technology. By the use of two LDH inhibitors, oxamate and galloflavin, we demonstrated that LDH inhibition can impact on chemo-sensitivity, inflammation and heat shock response in cancer cell lines. The genetic knock-out of LDH enzyme evidenced that some cells are able to survive by switching their metabolism from glycolysis to OXPHOS, showing limited ability to grow and proliferate. Importantly, this genetic knock-out, used as control, allowed us to confirm the specificity of GNE-140 (LDH inhibitor) for the target, representing an important help in the search of LDH inhibitors suitable for clinical use, proved to be, in our studies, an important goal in the anti-cancer treatments

Latency-bounded target set selection in signed networks

It is well-documented that social networks play a considerable role in information spreading. The dynamic processes governing the diffusion of information have been studied in many fields, including epidemiology, sociology, economics, and computer science. A widely studied problem in the area of viral marketing is the target set selection: in order to market a new product, hoping it will be adopted by a large fraction of individuals in the network, which set of individuals should we “target” (for instance, by offering them free samples of the product)? In this paper, we introduce a diffusion model in which some of the neighbors of a node have a negative influence on that node, namely, they induce the node to reject the feature that is supposed to be spread. We study the target set selection problem within this model, first proving a strong inapproximability result holding also when the diffusion process is required to reach all the nodes in a couple of rounds. Then, we consider a set of restrictions under which the problem is approximable to some extent

How Can Network-Pharmacology Contribute to Antiepileptic Drug Development?

Network-pharmacology is a field of pharmacology emerging from the observation that most clinical drugs have multiple targets, contrasting with the previously dominant magic bullet paradigm which proposed the search of exquisitely selective drugs. What is more, drug targets are often involved in multiple diseases and frequently present co-expression patterns. Therefore, useful therapeutic information can be drawn from network representations of drug targets. Here, we discuss potential applications of drug-target networks in the field of antiepileptic drug development.Facultad de Ciencias Exacta

Aging after shear rejuvenation in a soft glassy colloidal suspension: evidence for two different regimes

The aging dynamics after shear rejuvenation in a glassy, charged clay suspension have been investigated through dynamic light scattering (DLS). Two different aging regimes are observed: one is attained if the sample is rejuvenated before its gelation and one after the rejuvenation of the gelled sample. In the first regime, the application of shear fully rejuvenates the sample, as the system dynamics soon after shear cessation follow the same aging evolution characteristic of normal aging. In the second regime, aging proceeds very fast after shear rejuvenation, and classical DLS cannot be used. An original protocol to measure an ensemble averaged intensity correlation function is proposed and its consistency with classical DLS is verified. The fast aging dynamics of rejuvenated gelled samples exhibit a power law dependence of the slow relaxation time on the waiting time.Comment: 7 pages, 6 figure