Computational Modeling of Channelrhodopsin-2 Photocurrent Characteristics in Relation to Neural Signaling

Channelrhodopsins-2 (ChR2) are a class of light sensitive proteins that offer the ability to use light stimulation to regulate neural activity with millisecond precision. In order to address the limitations in the efficacy of the wild-type ChR2 (ChRwt) to achieve this objective, new variants of ChR2 that exhibit fast mono-exponential photocurrent decay characteristics have been recently developed and validated. In this paper, we investigate whether the framework of transition rate model with 4 states, primarily developed to mimic the bi-exponential photocurrent decay kinetics of ChRwt, as opposed to the low complexity 3 state model, is warranted to mimic the mono-exponential photocurrent decay kinetics of the newly developed fast ChR2 variants: ChETA (Gunaydin et al., Nature Neurosci, 13:387-392, 2010) and ChRET/TC (Berndt et al., PNAS, 108:7595-7600, 2011). We begin by estimating the parameters for the 3-state and 4-state models from experimental data on the photocurrent kinetics of ChRwt, ChETA and ChRET/TC. We then incorporate these models into a fast-spiking interneuron model (Wang and Buzsaki., J Neurosci, 16:6402-6413,1996) and a hippocampal pyramidal cell model (Golomb et al., J Neurophysiol, 96:1912-1926, 2006) and investigate the extent to which the experimentally observed neural response to various optostimulation protocols can be captured by these models. We demonstrate that for all ChR2 variants investigated, the 4 state model implementation is better able to capture neural response consistent with experiments across wide range of optostimulation protocol. We conclude by analytically investigating the conditions under which the characteristic specific to the 3-state model, namely the mono-exponential photocurrent decay of the newly developed variants of ChR2, can occurs in the framework of the 4-state model.Comment: 10 figure

Experimental Performance of a Micromachined Heat Flux Sensor

Steady-state and frequency response calibration of a microfabricated heat-flux sensor have been completed. This sensor is batch fabricated using standard, micromachining techniques, allowing both miniaturization and the ability to create arrays of sensors and their corresponding interconnects. Both high-frequency and spatial response is desired, so the sensors are both thin and of small cross-sectional area. Thin-film, temperature-sensitive resistors are used as the active gauge elements. Two sensor configurations are investigated: (1) a Wheatstone-bridge using four resistors; and (2) a simple, two-resistor design. In each design, one resistor (or pair) is covered by a thin layer (5000 A) thermal barrier; the other resistor (or pair) is covered by a thick (5 microns) thermal barrier. The active area of a single resistor is 360 microns by 360 microns; the total gauge area is 1.5 mm square. The resistors are made of 2000 A-thick metal; and the entire gauge is fabricated on a 25 microns-thick flexible, polyimide substrate. Heat flux through the surface changes the temperature of the resistors and produces a corresponding change in resistance. Sensors were calibrated using two radiation heat sources: (1) a furnace for steady-state, and (2) a light and chopper for frequency response

The Catalan butterfly monitoring scheme has the capacity to detect effects of modifying agricultural practices

Impacts of agricultural management practices on the receiving environment are seldom suitably assessed because environmental monitoring is costly. In this regard, data generated by already existing environmental survey networks (ESNs) may have sufficient capacity to detect effects. Here, we study the capacity of the Catalan butterfly monitoring scheme (CBMS) to detect differences in butterfly abundance due to changes in agricultural practices. As a model, we compared butterfly abundance across two landscape types according to agricultural intensification. A 2 km diameter buffer area was centered on the CBMS transect, the control group were transects located in areas where intensive agriculture represented <20% of the area; a treated group was simulated by selecting transects located in areas where intensive agriculture occupied an area over 40%. The Welch t‐test (α = 0.05 and 80% power) was used to compare butterfly abundance per section across landscape types. The capacity of the t‐test to detect changes in mean butterfly abundance, of 12 butterfly indicators relevant to farmland, was calculated annually and for 5‐, 10‐, and 15‐yr periods. Detection capacity of the t‐test depended mainly on butterfly data sample size and variability; difference in butterfly abundance was less important. The t‐test would be capable of detecting acceptably small population changes across years and sites. For instance, considering a 15‐yr period, it would be possible to detect a change in abundance below 10% of the multispecies indicators (all butterfly species, open habitat species, mobile species, and grassland indicators) and two single species (Lasiommata megera and Lycaena phlaeas). When comparisons were carried out within each year, the t‐test would only be capable of detecting a change below 30% for all butterfly species, mobile species, and L. megera. However, detection capacity rapidly improved with the addition of further years, and with 5 yr of monitoring, all indicators but Thymelicus acteon had a detection capacity below 30%. We therefore conclude that, from a statistical point of view, the CBMS data “as is” are sensitive enough for monitoring effects of changes in agricultural practices. It could be used, for instance, for the general surveillance of genetically modified crops.This work was partially supported by the Spanish Government‐funded project AGL2011‐23996 and a FI‐DGR scholarship to M. Lee from the Catalan Government

Very fast optical flaring from a possible new Galactic magnetar

Highly luminous rapid flares are characteristic of processes around compact objects like white dwarfs, neutron stars or black holes. In the high energy regime of X- and gamma-rays, outbursts with variability time-scales of seconds and faster are routinely observed, e.g. in gamma-ray bursts or Soft Gamma Repeaters. In the optical, flaring activity on such time-scales has never been observed outside the prompt phase of GRBs. This is mostly due to the fact that outbursts with strong, fast flaring usually are discovered in the high-energy regime. Most optical follow-up observations of such transients employ instruments with integration times exceeding tens of seconds, which are therefore unable to resolve fast variability. Here we show the observation of extremely bright and rapid optical flaring in the galactic transient SWIFT J195509.6+261406. Flaring of this kind has never previously been reported. Our optical light-curves are phenomenologically similar to high energy light-curves of Soft Gamma Repeaters and Anomalous X-ray Pulsars, which are thought to be neutron stars with extremely high magnetic fields (magnetars). This suggests similar emission processes may be at work, but in contrast to the other known magnetars with strong emission in the optical.Comment: 8 pages, 3 figures. A substantially revised version of this manuscript was published in Nature. Due to license issues, the accepted manuscript will only be put on astro-ph as v2 6 months after this versio

Elasticity and safety of alkoxyethyl cyanoacrylate tissue adhesives

Cyanoacrylate glues are easily applied to wounds with good cosmetic results. However, they tend to be brittle and can induce local tissue toxicity. A series of cyanoacrylate monomers with a flexible ether linkage and varying side-chain lengths was synthesized and characterized for potential use as tissue adhesives. The effect of side-chain length on synthesis yield, physical and mechanical properties, formaldehyde generation, cytotoxicity in vitro and biocompatibility in vivo were examined. The incorporation of etheric oxygen allowed the production of flexible monomers with good adhesive strength. Monomers with longer side-chains were found to have less toxicity both in vitro and in vivo. Polymerized hexoxyethyl cyanoacrylate was more elastic than its commercially available and widely used alkyl analog 2-octyl cyanoacrylate, without compromising biocompatibility.DuPont MIT Allianc

Evolutionary dynamics of cancer cell populations under immune selection pressure and optimal control of chemotherapy

Increasing experimental evidence suggests that epigenetic and microenvironmental factors play a key role in cancer progression. In this respect, it is now generally recognized that the immune system can act as an additional selective pressure, which modulates tumor development and leads, through cancer immunoediting, to the selection for resistance to immune effector mechanisms. This may have serious implications for the design of effective anti-cancer protocols. Motivated by these considerations, we present a mathematical model for the dynamics of cancer and immune cells under the effects of chemotherapy and immunity-boosters. Tumor cells are modeled as a population structured by a continuous phenotypic trait, that is related to the level of resistance to receptor-induced cell death triggered by effector lymphocytes. The level of resistance can vary over time due to the effects of epigenetic modifications. In the asymptotic regime of small epimutations, we highlight the ability of the model to reproduce cancer immunoediting. In an optimal control framework, we tackle the problem of designing effective anti-cancer protocols. The results obtained suggest that chemotherapeutic drugs characterized by high cytotoxic effects can be useful for treating tumors of large size. On the other hand, less cytotoxic chemotherapy in combination with immunity-boosters can be effective against tumors of smaller size. Taken together, these results support the development of therapeutic protocols relying on combinations of less cytotoxic agents and immune-boosters to fight cancer in the early stages. © EDP Sciences, 2014

A strong optical flare before the rising afterglow of GRB 080129

We report on GROND observations of a 40 sec duration (rest-frame) optical flare from GRB 080129 at redshift 4.349. The rise- and decay time follow a power law with indices +12 and -8, respectively, inconsistent with a reverse shock and a factor 10$^5$ faster than variability caused by ISM interaction. While optical flares have been seen in the past (e.g. GRB 990123, 041219B, 060111B and 080319B), for the first time, our observations not only resolve the optical flare into sub-components, but also provide a spectral energy distribution from the optical to the near-infrared once every minute. The delay of the flare relative to the GRB, its spectral energy distribution as well as the ratio of pulse widths suggest it to arise from residual collisions in GRB outflows \cite{liw08}.If this interpretation is correct and can be supported by more detailed modelling or observation in further GRBs, the delay measurement provides an independent, determination of the Lorentz factor of the outflow.Comment: accepted for publ. in ApJ, 5 Fig

Nature of yrast excitations near N=40: Level structure of Ni-67

Excited states in Ni-67 were populated in deep-inelastic reactions of a Ni-64 beam at 430 MeV on a thick U-238 target. A level scheme built on the previously known 13 micro-s isomer has been delineated up to an excitation energy of ~5.3 MeV and a tentative spin and parity of (21/2-). Shell model calculations have been carried out using two effective interactions in the f5/2pg9/2 model space with a Ni-56 core. Satisfactory agreement between experiment and theory is achieved for the measured transition energies and branching ratios. The calculations indicate that the yrast states are associated with rather complex configurations, herewith demonstrating the relative weakness of the N=40 subshell gap and the importance of multi particle-hole excitations involving the g9/2 neutron orbital.Comment: Accepted by Physical Review