Transcranial magnetic stimulation (TMS) is a technique used to treat different neurological disorders non-invasively. A pulsed current to a coil generates a magnetic field (<inline-formula> <tex-math ...notation="LaTeX">B </tex-math></inline-formula>-field) which induces an electric field (<inline-formula> <tex-math notation="LaTeX">E </tex-math></inline-formula>-field). Underlying biophysical effects of TMS are unclear. Therefore, animal experiments are needed; however, making small TMS coils suitable for mice is difficult and their field strengths are typically much lower than for human sized coils. Objectives/Hypothesis . We aimed to design and demonstrate a mouse-specific coil that can generate high and focused <inline-formula> <tex-math notation="LaTeX">E </tex-math></inline-formula>-field. Methods . We designed a tapered TMS coil of 50 turns of 0.2 mm diameter copper wire around a 5 mm diameter tapered powdered iron core and discharged a <inline-formula> <tex-math notation="LaTeX">220~\mu \text{F} </tex-math></inline-formula> capacitor at 50 V through it. We measured <inline-formula> <tex-math notation="LaTeX">B </tex-math></inline-formula>-field with a Hall probe and induced <inline-formula> <tex-math notation="LaTeX">E </tex-math></inline-formula>-field with a wire loop. We measured temperature rise with a thermocouple. We applied 1200 pulses of continuous theta burst stimulation (cTBS) and intermittent theta burst stimulation (iTBS) to mouse brain slices and analyzed how spontaneous electrical activity changed. Results . The coil gave maximum <inline-formula> <tex-math notation="LaTeX">B </tex-math></inline-formula>-field of 685 mT at the base of the coil and 340 mT at 2 mm below the coil, and maximum <inline-formula> <tex-math notation="LaTeX">E </tex-math></inline-formula>-field 2 mm below the coil of approximately 10 V/m, at 50 V power supply, with a temperature increase of 20 °C after 1200 pulses of cTBS. We observed no changes in <inline-formula> <tex-math notation="LaTeX">B </tex-math></inline-formula>-field with heating. cTBS reduced frequency of spontaneous population events in mouse brain slices up to 20 min after stimulation and iTBS increased frequency up to 20 min after stimulation. No frequency changes occurred after 20 min. No changes in amplitude of spontaneous events were found. Conclusion . The design generated fields strong enough to modulate brain activity in vitro .
To investigate the impact of experimental interventions on living biological tissue, ex vivo rodent brain slices are often used as a more controllable alternative to a live animal model. However, for ...meaningful results, the biological sample must be known to be healthy and viable. One of the gold-standard approaches to identifying tissue viability status is to measure the rate of tissue oxygen consumption under specific controlled conditions. Here, we work with thin (400 μm) slices of mouse cortical brain tissue which are sustained by a steady flow of oxygenated artificial cerebralspinal fluid (aCSF) at room temperature. To quantify tissue oxygen consumption (
), we measure oxygen partial pressure (pO2) as a function of probe depth. The curvature of the obtained parabolic (or parabola-like) pO2 profiles can be used to extract
, providing one knows the Krogh coefficient Kt, for the tissue. The oxygen trends are well described by a Fick's law diffusion-consumption model developed by Ivanova and Simeonov, and expressed in terms of ratio (Q/K), being the rate of oxygen consumption in tissue divided by the Krogh coefficient (oxygen diffusivity × oxygen solubility) for tissue. If the fluid immediately adjacent to the tissue can be assumed to be stationary (i.e., nonflowing), one may invoke conservation of oxygen flux K·(∂P/∂x) across the interface to deduce (Kt/Kf), the ratio of Krogh coefficients for tissue and fluid. Using published interpolation formulas for the effect of salt content and temperature on oxygen diffusivity and solubility for pure water, we estimate Kf, the Krogh coefficient for aCSF, and hence deduce the Kt coefficient for tissue. We distinguish experimental uncertainty from natural biological variability by using pairs of repeated profiles at the same tissue location. We report a dimensionless Krogh ratio (Kt/Kf)=0.562±0.088 (mean ± SD), corresponding to a Krogh coefficient Kt=(1.29±0.21)×10-14 mol/(m·s·Pa) for mouse cortical tissue at room temperature, but acknowledge the experimental limitation of being unable to verify that the fluid boundary layer is truly stationary. We compare our results with those reported in the literature, and comment on the challenges and ambiguities caused by the extensive use of 'biologically convenient' non-SI units for tissue Krogh coefficient.
SCASA is a patented technique commercialized as a surge protector device (SPD) that adheres to UL-1449 test standards. Apart from the novel use of supercapacitors, SCASA design incorporates a ...coupled-inductor wound to a specially selected magnetic material of powdered-iron. In this study, we investigate the limitations of the present design under transient operation and elucidate ways to eliminate them with the use of air-gapped ferrite cores. In modelling the operation under 50 Hz AC and transient conditions, a permeance-based approach is used; in addition, non-ideal characteristics of the transformer core are emphasized and discussed with empirical validations. The experimental work was facilitated using a lightning surge simulator coupled with the 230 V AC utility mains; combinational surge-waveforms (6 kV/3 kA) defined by IEEE C62.41 standards were continuously injected into SPD prototypes during destructive testing. Such procedures substantiate the overall surge-endurance capabilities of the different core types under testing. With regard to optimizations, we validated a 95% depletion of a negative-surge effect that would otherwise pass to the load-end, and another 13–16% reduction of the clamping voltage verified the effectiveness of the methods undertaken. In conclusion, SCASA prototypes that utilized air-gapped cores revealed a greater surge endurance with improved load-end characteristics.
State-of-the-art microprocessors require very low DC-voltages at sub-1 V levels. Many processors draw high-current at low voltages and require low-noise DC-power rails. Switched-mode power supply ...(SMPS) topologies are the common approach to design voltage regulator modules (VRMs). Fast operations of switches in SMPSs allow the use of smaller inductors but ultimately result in radio frequency and electromagnetic interference issues. Compared to SMPSs, linear regulators have lower noise, high quality DC output, and faster response to the load high-current slew rates; however, with the serious disadvantage of low efficiency. Supercapacitor assisted low-dropout (SCALDO) regulator is a technique to achieve high end-to-end efficiency (ETEE) for linear regulator-based converters. Though, the switch-operation frequency is extremely low, number of switches required for SCALDO configuration is three times larger than that of supercapacitors. Reduced-switch SCALDO (RS-SCALDO) is a topological variation of SCALDO that requires fewer switches. By designing an alternately operated high-current LDO pair, RS-SCALDO can handle high load currents, allowing development of a linear VRM. This study presents a proof of concept prototype of 3.5-to-1.5 V RS-SCALDO for a maximum 5 A load with digitally adjustable output voltages. The prototype achieved an ETEE better than 80%, and required half the switch count of an equivalent SCALDO circuit.
Growth of critical fluctuations prior to catastrophic state transition is generally regarded as a universal phenomenon, providing a valuable early warning signal in dynamical systems. Using an ...ecological fisheries model of three populations (juvenile prey J, adult prey A and predator P), a recent study has reported silent early warning signals obtained from P and A populations prior to saddle-node (SN) bifurcation, and thus concluded that early warning signals are not universal. By performing a full eigenvalue analysis of the same system we demonstrate that while J and P populations undergo SN bifurcation, A does not jump to a new state, so it is not expected to carry early warning signs. In contrast with the previous study, we capture a significant increase in the noise-induced fluctuations in the P population, but only on close approach to the bifurcation point; it is not clear why the P variance initially shows a decaying trend. Here we resolve this puzzle using observability measures from control theory. By computing the observability coefficient for the system from the recordings of each population considered one at a time, we are able to quantify their ability to describe changing internal dynamics. We demonstrate that precursor fluctuations are best observed using only the J variable, and also P variable if close to transition. Using observability analysis we are able to describe why a poorly observable variable (P) has poor forecasting capabilities although a full eigenvalue analysis shows that this variable undergoes a bifurcation. We conclude that observability analysis provides complementary information to identify the variables carrying early-warning signs about impending state transition.
Summary
Purpose: The role of gap junctions in seizures is an area of intense research. Many groups have reported anticonvulsant effects of gap junction blockade, strengthening the case for a role ...for gap junctions in ictogenesis. The cerebral cortex is underrepresented in this body of research. We have investigated the effect of gap junction blockade on seizure‐like activity in rat and mouse cerebral cortex slices.
Methods: Seizure‐like activity was induced by perfusing with low‐magnesium artificial cerebrospinal fluid. The effect of three gap junction blockers was investigated in rat cortical slices; quinine (200 and 400 μm), quinidine (100 and 200 μm), and carbenoxolone (100 and 200 μm). In addition, the effect of mefloquine was investigated in wild‐type mice and connexin36 knockout mice. The data were analyzed for the effect on frequency and amplitude of seizure‐like events.
Results: Paradoxical excitatory effects on seizure‐like activity were observed for all three agents in rat cortical slices. Quinine (200 μm) and carbenoxolone (100 μm) increased both the frequency and amplitude of seizure‐like events. Quinidine (100 μm) increased the frequency of events. Higher doses of quinine (400 μm) and carbenoxolone (200 μm) had biphasic excitatory–inhibitory effects. Similar excitatory effects were observed in adult wild‐type mouse cortical slices perfused with mefloquine (5 μm or 10 μm), but were absent in slices from connexin36‐deficient mice.
Discussion: In conclusion, we have shown a paradoxical proseizure effect of pharmacologic gap junction blockade in a cortical model of seizure‐like activity. We suggest that this effect is probably due to a disruption of inhibitory interneuron coupling secondary to connexin36 blockade.
Working class groups have historically been excluded from participation in higher education. Past decades have seen an expansion of the system towards a more inclusive higher education, but ...participation among people from working class groups has remained persistently low. Is higher education unattractive for these groups or are the institutions acting to exclude them? This thought-provoking and revealing book examines the many factors and reasons why working class groups are under-represented in higher education. In particular, the book addresses issues around differential access to information about university, the value of higher education to working class groups, the costs of participating and the propensity to participate. Issues of gender and ethnicity are also explored and questions are raised for those who are currently involved in 'widening participation' projects and initiatives. A unique feature of the book is that its findings are drawn from an innovative study where the views of both working class participants and non-participants in higher education were explored. This book will be of interest to students of social policy, educational studies and sociology of education at undergraduate and postgraduate level. Academics, researchers and policy makers nationally and internationally will also find it valuable.
Cancer cells are thought to use actin rich invadopodia to facilitate matrix degradation. Formation and maturation of invadopodia requires the co-ordained activity of Rho-GTPases, however the ...molecular mechanisms that underlie the invadopodia lifecycle are not fully elucidated. Previous work has suggested a formation and disassembly role for Rho family effector p-21 activated kinase 1 (PAK1) however, related family member PAK4 has not been explored. Systematic analysis of isoform specific depletion using in vitro and in vivo invasion assays revealed there are differential invadopodia-associated functions. We consolidated a role for PAK1 in the invadopodia formation phase and identified PAK4 as a novel invadopodia protein that is required for successful maturation. Furthermore, we find that PAK4 (but not PAK1) mediates invadopodia maturation likely via inhibition of PDZ-RhoGEF. Our work points to an essential role for both PAKs during melanoma invasion but provides a significant advance in our understanding of differential PAK function.
General anaesthetics have been hypothesised to ablate consciousness by decoupling intracortical neural connectivity. We explored this by investigating the effect of etomidate and ketamine on coupling ...of neural population activity using the low magnesium neocortical slice model. Four extracellular electrodes (50μm) were positioned in mouse neocortical slices (400μm thick) with varying separation. The effect of etomidate (24μM) and ketamine (16μM) on the timing of population activity recorded between channels was analysed. No decoupling was observed at the closest electrode separation of 0.2mm. At 4mm separation, decoupling was observed in 50% and 42% of slices during etomidate and ketamine delivery, respectively (P<0.0001 and P=0.002, compared to 0.2mm separation). A lower rate of decoupling was observed with 1mm separation (21% and 8%, respectively, P<0.03 for etomidate compared to 0.2mm separation). The data support the hypothesis that mechanistically diverse general anaesthetics disrupt neuronal connectivity across widely distributed intracortical networks.
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