Analysis of co-isogenic prion protein deficient mice reveals behavioral deficits, learning impairment, and enhanced hippocampal excitability.

BACKGROUND: Cellular prion protein (PrPC) is a cell surface GPI-anchored protein, usually known for its role in the pathogenesis of human and animal prionopathies. However, increasing knowledge about the participation of PrPC in prion pathogenesis contrasts with puzzling data regarding its natural physiological role. PrPC is expressed in a number of tissues, including at high levels in the nervous system, especially in neurons and glial cells, and while previous studies have established a neuroprotective role, conflicting evidence for a synaptic function has revealed both reduced and enhanced long-term potentiation, and variable observations on memory, learning, and behavior. Such evidence has been confounded by the absence of an appropriate knock-out mouse model to dissect the biological relevance of PrPC, with some functions recently shown to be misattributed to PrPC due to the presence of genetic artifacts in mouse models. Here we elucidate the role of PrPC in the hippocampal circuitry and its related functions, such as learning and memory, using a recently available strictly co-isogenic Prnp0/0 mouse model (PrnpZH3/ZH3). RESULTS: We performed behavioral and operant conditioning tests to evaluate memory and learning capabilities, with results showing decreased motility, impaired operant conditioning learning, and anxiety-related behavior in PrnpZH3/ZH3 animals. We also carried in vivo electrophysiological recordings on CA3-CA1 synapses in living behaving mice and monitored spontaneous neuronal firing and network formation in primary neuronal cultures of PrnpZH3/ZH3 vs wildtype mice. PrPC absence enhanced susceptibility to high-intensity stimulations and kainate-induced seizures. However, long-term potentiation (LTP) was not enhanced in the PrnpZH3/ZH3 hippocampus. In addition, we observed a delay in neuronal maturation and network formation in PrnpZH3/ZH3 cultures. CONCLUSION: Our results demonstrate that PrPC promotes neuronal network formation and connectivity. PrPC mediates synaptic function and protects the synapse from excitotoxic insults. Its deletion may underlie an epileptogenic-susceptible brain that fails to perform highly cognitive-demanding tasks such as associative learning and anxiety-like behaviors.

Optical and thermal properties of edible coatings for application in solar drying.

Solar drying is a sustainable process that may impact the quality of dried food. This is because, pigments contained in food are sensitive to sunlight, and exposure to ultraviolet radiation can affect them. We applied biopolymer-based coatings on strawberry, from hydro-colloidal solutions of Opuntia ficus indica-mucilage, fenugreek, xanthan gum, gum Arabic, and guar gum to evaluate their potential use as UV filters for solar drying of food. Thermal properties and the optical transmittance, absorbance and reflectance of the coatings were measured to assess their influence on food-sunlight interaction. During the drying experiments, the moisture content, total anthocyanins (TA), and total phenolic compounds (TPC) were measured. Optical and thermal properties are influenced by the biopolymer-based coatings. Also, the optical properties are influenced by the coating thickness. The differences in optical and thermal properties influence the drying process. Differences exist in the drying rate for strawberry slices with coating, compared with those without the coatings. In general, the TA and TPC content in the product are better preserved under solar drying than in control experiments done in a drying oven. A partial transmittance of solar UV radiation is recommended to obtain increased TA and TPC contents in the dried product.

Optical and thermal performance of a toroidal compound parabolic concentrator.

The design, construction, and ray simulation of a new compound parabolic concentrator based on a toroidal shape (toroidal compound parabolic concentrator, TCPC) are addressed. Such analysis indicates that the amount of concentrated radiation is independent of the Sun trajectory. Thus, the TCPC has the advantage of concentrating Sun rays in a spot, and if positioned with an inclination corresponding to the latitude, a solar tracker would not be needed. Experimental measurements with a prototype model are shown to be in good agreement with the simulation results. The possibility of a variety of applications, as natural illumination for this TCPC device, is also pointed out. The simple design, fabrication, and implementation of the TCPC make it an excellent alternative for low concentration in a spot. We present the analysis of the TCPC in natural illumination as one of these applications.

Stochastic optimization of broadband reflecting photonic structures.

Photonic crystals (PCs) are built to control the propagation of light within their structure. These can be used for an assortment of applications where custom designed devices are of interest. Among them, one-dimensional PCs can be produced to achieve the reflection of specific and broad wavelength ranges. However, their design and fabrication are challenging due to the diversity of periodic arrangement and layer configuration that each different PC needs. In this study, we present a framework to design high reflecting PCs for any desired wavelength range. Our method combines three stochastic optimization algorithms (Random Search, Particle Swarm Optimization and Simulated Annealing) along with a reduced space-search methodology to obtain a custom and optimized PC configuration. The optimization procedure is evaluated through theoretical reflectance spectra calculated by using the Equispaced Thickness Method, which improves the simulations due to the consideration of incoherent light transmission. We prove the viability of our procedure by fabricating different reflecting PCs made of porous silicon and obtain good agreement between experiment and theory using a merit function. With this methodology, diverse reflecting PCs can be designed for any applications and fabricated with different materials.

Diffusion of Charged Species in Liquids.

In this study the laws of mechanics for multi-component systems are used to develop a theory for the diffusion of ions in the presence of an electrostatic field. The analysis begins with the governing equation for the species velocity and it leads to the governing equation for the species diffusion velocity. Simplification of this latter result provides a momentum equation containing three dominant forces: (a) the gradient of the partial pressure, (b) the electrostatic force, and (c) the diffusive drag force that is a central feature of the Maxwell-Stefan equations. For ideal gas mixtures we derive the classic Nernst-Planck equation. For liquid-phase diffusion we encounter a situation in which the Nernst-Planck contribution to diffusion differs by several orders of magnitude from that obtained for ideal gases.

Social defeat leads to changes in the endocannabinoid system: An overexpression of calreticulin and motor impairment in mice.

Prolonged and sustained stimulation of the hypothalamo-pituitary-adrenal axis have adverse effects on numerous brain regions, including the cerebellum. Motor coordination and motor learning are essential for animal and require the regulation of cerebellar neurons. The G-protein-coupled cannabinoid CB1 receptor coordinates synaptic transmission throughout the CNS and is of highest abundance in the cerebellum. Accordingly, the aim of this study was to investigate the long-lasting effects of chronic psychosocial stress on motor coordination and motor learning, CB1 receptor expression, endogenous cannabinoid ligands and gene expression in the cerebellum. After chronic psychosocial stress, motor coordination and motor learning were impaired as indicated the righting reflex and the rota-rod. The amount of the endocannabinoid 2-AG increased while CB1 mRNA and protein expression were downregulated after chronic stress. Transcriptome analysis revealed 319 genes differentially expressed by chronic psychosocial stress in the cerebellum; mainly involved in synaptic transmission, transmission of nerve impulse, and cell-cell signaling. Calreticulin was validated as a stress candidate gene. The present study provides evidence that chronic stress activates calreticulin and might be one of the pathological mechanisms underlying the motor coordination and motor learning dysfunctions seen in social defeat mice.

Role of PrP(C) Expression in Tau Protein Levels and Phosphorylation in Alzheimer's Disease Evolution.

Alzheimer's disease (AD) is characterized by the presence of amyloid plaques mainly consisting of hydrophobic ß-amyloid peptide (Aß) aggregates and neurofibrillary tangles (NFTs) composed principally of hyperphosphorylated tau. Aß oligomers have been described as the earliest effectors to negatively affect synaptic structure and plasticity in the affected brains, and cellular prion protein (PrP(C)) has been proposed as receptor for these oligomers. The most widely accepted theory holds that the toxic effects of Aß are upstream of change in tau, a neuronal microtubule-associated protein that promotes the polymerization and stabilization of microtubules. However, tau is considered decisive for the progression of neurodegeneration, and, indeed, tau pathology correlates well with clinical symptoms such as dementia. Different pathways can lead to abnormal phosphorylation, and, as a consequence, tau aggregates into paired helical filaments (PHF) and later on into NFTs. Reported data suggest a regulatory tendency of PrP(C) expression in the development of AD, and a putative relationship between PrP(C) and tau processing is emerging. However, the role of tau/PrP(C) interaction in AD is poorly understood. In this study, we show increased susceptibility to Aß-derived diffusible ligands (ADDLs) in neuronal primary cultures from PrP(C) knockout mice, compared to wild-type, which correlates with increased tau expression. Moreover, we found increased PrP(C) expression that paralleled with tau at early ages in an AD murine model and in early Braak stages of AD in affected individuals. Taken together, these results suggest a protective role for PrP(C) in AD by downregulating tau expression, and they point to this protein as being crucial in the molecular events that lead to neurodegeneration in AD.

The bifoil photodyne: a photonic crystal oscillator.

Optical tweezers is an example how to use light to generate a physical force. They have been used to levitate viruses, bacteria, cells, and sub cellular organisms. Nonetheless it would be beneficial to use such force to develop a new kind of applications. However the radiation pressure usually is small to think in moving larger objects. Currently, there is some research investigating novel photonic working principles to generate a higher force. Here, we studied theoretically and experimentally the induction of electromagnetic forces in one-dimensional photonic crystals when light impinges on the off-axis direction. The photonic structure consists of a micro-cavity like structure formed of two one-dimensional photonic crystals made of free-standing porous silicon, separated by a variable air gap and the working wavelength is 633 nm. We show experimental evidence of this force when the photonic structure is capable of making auto-oscillations and forced-oscillations. We measured peak displacements and velocities ranging from 2 up to 35 microns and 0.4 up to 2.1 mm/s with a power of 13 mW. Recent evidence showed that giant resonant light forces could induce average velocity values of 0.45 mm/s in microspheres embedded in water with 43 mW light power.

A role for the tyrosine kinase ACK1 in neurotrophin signaling and neuronal extension and branching.

Neurotrophins are involved in many crucial cellular functions, including neurite outgrowth, synapse formation, and plasticity. Although these events have long been known, the molecular determinants underlying neuritogenesis have not been fully characterized. Ack1 (activated Cdc42-associated tyrosine kinase) is a non-receptor tyrosine kinase that is highly expressed in the brain. Here, we demonstrate that Ack1 is a molecular constituent of neurotrophin signaling cascades in neurons and PC12 cells. We report that Ack1 interacts with Trk receptors and becomes tyrosine phosphorylated and its kinase activity is increased in response to neurotrophins. Moreover, our data indicate that Ack1 acts upstream of the Akt and MAPK pathways. We show that Ack1 overexpression induces neuritic outgrowth and promotes branching in neurotrophin-treated neuronal cells, whereas the expression of Ack1 dominant negatives or short-hairpin RNAs counteract neurotrophin-stimulated differentiation. Our results identify Ack1 as a novel regulator of neurotrophin-mediated events in primary neurons and in PC12 cells.

Anomalous patterned scattering spectra of one-dimensional porous silicon photonic crystals.

Far-field secondary emission spectra of one-dimensional periodic photonic structures based on porous silicon show characteristic co-focal rings centered close to the structure plane normal. The rings appear when the frequency of picosecond excitation laser pulses is tuned to the edges of the fourth photonic band gap. They can be clearly distinguished from the typical reflected and transmitted light in the oblique incidence geometry. The rings number is dependent on the excitation frequency and the incidence angle. We explain these anomalous spectral features of porous silicon structures by the spectral filtering of light elastically scattered inside the photonic structure by the narrow photonic bands. The elastic scattering of light due to the photonic disorder in the structure causes the appearance of secondary waves propagating in any direction. But only those waves which fall into the allowed photonic bands penetrate through the whole structure and move through its front or back surfaces. The observed patterned secondary emission is an example of efficient photonic engineering by simple means of multilayer porous silicon structures.

A plausible explanation for heart rates in mammals.

We consider a simple model to give a plausible mechanical explanation of what are the actual resting heart rates of mammals optimized for. We study what is the optimal frequency for a viscoelastic fluid circulating in a pulsatile way through a network of tubes and conclude that the heart rate is not optimized to transport blood through the whole net. Rather, actual resting heart rates of mammals happen at frequencies that optimize flow in vessels of radii that correspond to large arteries, which bring oxygenated blood rapidly far away from the heart, towards head and limbs. Our results for the optimal frequencies, obtained using observed radii of femoral arteries in mammals, agree best with the heart rates observed. We find a theoretical allometric relation between optimal flow frequency and radius: nu approximately R(-1). This one, agrees with the exponent obtained when plotting observed heart rates versus radii of both, femoral arteries and carotids in mammals of different sizes, from mice to horses.

Involvement of Dab1 in APP processing and beta-amyloid deposition in sporadic Creutzfeldt-Jakob patients.

Alzheimer's disease and prion pathologies (e.g., Creutzfeldt-Jakob disease (CJD)) display profound neural lesions associated with aberrant protein processing and extracellular amyloid deposits. Dab1 has been implicated in the regulation of amyloid precursor protein (APP), but a direct link between human prion diseases and Dab1/APP interactions has not been published. Here we examined this putative relationship in 17 cases of sporadic CJD (sCJD) post-mortem. Biochemical analyses of brain tissue revealed two groups, which also correlated with PrP(sc) types 1 and 2. One group with PrP(sc) type 1 showed increased Dab1 phosphorylation and lower betaCTF production with an absence of Abeta deposition. The second sCJD group, which carried PrP(sc) type 2, showed lower levels of Dab1 phosphorylation and betaCTF production, and Abeta deposition. Thus, the present observations suggest a correlation between Dab1 phosphorylation, Abeta deposition and PrP(sc) type in sCJD.

Perfect light transmission in Fibonacci arrays of dielectric multilayers.

In this paper we study the propagation of light through an asymmetric array of dielectric multilayers built by joining two porous silicon substructures in a Fibonacci sequence. Each Fibonacci substructure follows the well-known recursive rule but in the second substructure dielectric layers A and B are exchanged. Even without mirror symmetry, this array gives rise to multiple transparent states, which follow the scaling properties and self-similar spectra of a single Fibonacci multilayer. We apply the transfer matrix formalism to calculate the transmittance. By setting the transfer matrix of the array equal to ± I, the identity matrix, frequencies of perfect light transmission are reproduced in our theoretical calculations. Although the light absorption of porous silicon in the optical range limits our experimental study to low Fibonacci generations, the positions of the transparent states are well predicted by the above-mentioned condition. We conclude that mirror symmetry in arrays of Fibonacci multilayers is sufficient but not necessary to generate multiple transparent states, opening broader applications of quasiperiodic systems as filters and microcavities of multiple frequencies.

Instabilities in the oscillatory flow of a complex fluid.

The dynamics of a fluid in a vertical tube, subjected to an oscillatory pressure gradient, is studied experimentally for both a Newtonian and a viscoelastic shear-thinning fluid. Particle image velocimetry is used to determine the two-dimensional velocity fields in the vertical plane of the tube axis, in a range of driving amplitudes from 0.8 to 2.5 mm and of driving frequencies from 2.0 to 11.5 Hz. The Newtonian fluid exhibits a laminar flow regime, independent of the axial position, in the whole range of drivings. For the complex fluid, instead, the parallel shear flow regime exhibited at low amplitudes [Torralba, Phys. Rev. E 72, 016308 (2005)] becomes unstable at higher drivings against the formation of symmetric vortices, equally spaced along the tube. At even higher drivings the vortex structure itself becomes unstable, and complex nonsymmetric structures develop. Given that inertial effects remain negligible even at the hardest drivings (Re < 10(-1)), it is the complex rheology of the fluid that is responsible for the instabilities observed. The system studied represents an interesting example of the development of shear-induced instabilities in nonlinear complex fluids in purely parallel shear flow.

Overcoming chondroitin sulphate proteoglycan inhibition of axon growth in the injured brain: lessons from chondroitinase ABC.

The presence of numerous axon-inhibitory molecules limits the capacity of injured neurons in the adult mammalian central nervous system (CNS) to regenerate damaged axons. Among others, chondroitin sulphate proteoglycans (CSPGs) enriched in glycosaminoglycan (GAG) chains, acting intracellularly via Rho GTPase activation and cytoskeletal modification, prevent axon re-growth after injury. However, axon regeneration can be induced by modulating the extrinsic environment or the intrinsic neural response to axon extension. Among other strategies, the use of chondroitinase ABC (ChABC) to degrade GAGs and decrease CSPG-associated inhibition has been analyzed. Recent reports have extended the use of this enzyme, in combination with cell transplantation or pharmacological treatment. The steady advances made in these combinations offer promising perspectives for the development of new therapies to repair the injured nervous system.

Beneficial action of Citrus flavonoids on multiple cancer-related biological pathways.

Attempts to control cancer involve a variety of means, including the use of suppressing, blocking and transforming agents. Suppressing agents prevent the formation of new cancers from pro-carcinogens, blocking agents prevent carcinogenic compounds from reaching critical initiation sites, while transformation agents act to facilitate the metabolism of carcinogenic components into less toxic materials or to prevent their biological actions. Flavonoids can act as all three types of agent. Epidemiological and animal studies suggest that flavonoids have a protective effect against cardiovascular diseases and some types of cancer. Although flavonoids have been studied for about 50 years, the cellular mechanisms involved in their biological action are still not completely understood. In recent years, experimental studies have provided growing evidence supporting the beneficial action of flavonoids on multiple cancer-related biological pathways (carcinogen bio-activation, cell-signaling, cell cycle regulation, angiogenesis and inflammation). Within the last decade, reports on flavonoid activity have largely associated with enzyme inhibition and anti-proliferative activity. Many of these studies have pointed to a structural-functional relationship, in that the antioxidant, enzyme-inhibition or antiproliferative activities of flavonoids are dependent on particular structural motifs. Our own studies have shown that structural factors would explain the antioxidant, antiproliferative and antimetastatic properties of some citrus flavonoids. In this paper we discuss the relation between each structural factor and the anticancer activity of Citrus flavonoids.

Expression of discoidin domain receptor 1 during mouse brain development follows the progress of myelination.

Discoidin domain receptor 1 is a tyrosine kinase receptor expressed in a variety of tissues including the brain. This study describes mRNA and protein expression of discoidin domain receptor 1 in mouse brain during development and provides new insights into its role during gliogenesis and neurogenesis. We performed in situ hybridization for discoidin domain receptor 1 in mouse brains at embryonic day 18, postnatal days 5, 9, 15, 21 and adulthood and observed a diffuse pattern in the proliferative areas during embryogenesis. From postnatal day 5 onwards, a defined cellular expression pattern of discoidin domain receptor 1 was observed, mainly located in white matter tracts and following a spatio-temporal pattern that overlapped the progress of myelination. Next, we performed double-labeling reactions (in situ hybridization followed by immunohistochemistry) that confirmed that discoidin domain receptor 1 was expressed by mature oligodendrocytes. We observed that cells positive for discoidin domain receptor 1 also expressed carnosine and anti-adenomatous polyposis coli, two mature oligodendrocyte markers. Based on the localization of discoidin domain receptor 1 specifically in the white matter fiber tracts during postnatal development, we suggest that discoidin domain receptor 1 participates in the development and maintenance of the myelin sheath.

Control of neuronal branching by the death receptor CD95 (Fas/Apo-1).

The CD95 (Apo-1/Fas)/CD95 ligand (CD95L) system is best characterized as a trigger of apoptosis. Nevertheless, despite broad expression of CD95L and CD95 in the developing brain, absence of functional CD95 (lpr mice) or CD95L (gld mice) does not alter neuronal numbers. Here, we report that in embryonic hippocampal and cortical neurons in vivo and in vitro CD95L does not induce apoptosis. Triggering of CD95 in cultured immature neurons substantially increases neurite branches by promoting their formation. The branching increase occurs in a caspase-independent and death domain-dependent manner and is paralleled by an increase in the nonphosphorylated form of Tau. Most importantly, lpr and gld mutants exhibit a reduced number of dendritic branches in vivo at the time when synapse formation takes place. These data reveal a novel function for the CD95 system and add to the picture of guidance molecules in the developing brain.

Measurements of the bulk and interfacial velocity profiles in oscillating Newtonian and Maxwellian fluids.

We present the dynamic velocity profiles of a Newtonian fluid (glycerol) and a viscoelastic Maxwell fluid (CPyCl-NaSal in water) driven by an oscillating pressure gradient in a vertical cylindrical pipe. The frequency range explored has been chosen to include the first three resonance peaks of the dynamic permeability of the viscoelastic-fluid--pipe system. Three different optical measurement techniques have been employed. Laser Doppler anemometry has been used to measure the magnitude of the velocity at the center of the liquid column. Particle image velocimetry and optical deflectometry are used to determine the velocity profiles at the bulk of the liquid column and at the liquid-air interface respectively. The velocity measurements in the bulk are in good agreement with the theoretical predictions of a linear theory. The results, however, show dramatic differences in the dynamic behavior of Newtonian and viscoelastic fluids, and demonstrate the importance of resonance phenomena in viscoelastic fluid flows, biofluids in particular, in confined geometries.

Optimal behavior of viscoelastic flow at resonant frequencies.

The global entropy generation rate in the zero-mean oscillatory flow of a Maxwell fluid in a pipe is analyzed with the aim of determining its behavior at resonant flow conditions. This quantity is calculated explicitly using the analytic expression for the velocity field and assuming isothermal conditions. The global entropy generation rate shows well-defined peaks at the resonant frequencies where the flow displays maximum velocities. It was found that resonant frequencies can be considered optimal in the sense that they maximize the power transmitted to the pulsating flow at the expense of maximum dissipation.