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The pre-Botzinger complex (pBC) is a vital subcircuit of the respiratory central pattern generator. Although the existence of neurons with pacemaker-like bursting properties in this network is not questioned, their role in network rhythmogenesis is unresolved. Modeling is ideally suited to address this debate because of the ease with which biophysical parameters of individual cells and network architecture can be manipulated. We modeled the parameter variability of experimental data from pBC bursting pacemaker and nonpacemaker neurons using a modified version of our previously developed pBC neuron and network models. To investigate the role of pacemakers in networkwide rhythmogenesis, we simulated networks of these neurons and varied the fraction of the population made up of pacemakers. For each number of pacemaker neurons, we varied the amount of tonic drive to the network and measured the frequency of synchronous networkwide bursting produced. Both excitatory networks with all-to-all coupling and sparsely connected networks were explored for several levels of synaptic coupling strength. Networks containing only nonpacemakers were able to produce networkwide bursting, but with a low probability of bursting and low input and output ranges. Our results indicate that inclusion of pacemakers in an excitatory network increases robustness of the network by more than tripling the input and output ranges compared with networks containing no pacemakers. The largest increase in dynamic range occurs when the number of pacemakers in the network is greater than 20% of the population. Experimental tests of our model predictions are proposed.
Networks of neurons that generate rhythmic networkwide bursts of action potentials are found in many areas of the nervous system. One such network is the pre-Botzinger complex (pBC), a population of neurons that is critical for generating the respiratory rhythm (Gray et al. 2001; Smith et al. 1991). Despite extensive research to date, the details of the mechanisms of rhythmogenesis in the pBC are still not completely resolved. Many experiments have established that the pBC both in vitro and in more intact states contains intrinsic bursters or "pacemaker" neurons—cells that are capable of rhythmic bursting in the absence of synaptic input (Del Negro et al. 2002a, 2005; Johnson et al. 1994; Koshiya and Smith 1999; Pagliardini et al. 2005; Paton et al. 2006; Pena et al. 2004; Smith et al. 1991; Thoby-Brisson and Ramirez 2001; Tryba et al. 2006). Two types of pacemaker neurons are found in the pBC: one is dependent on a persistent sodium current (NaP dependent, also cadmium insensitive; Del Negro et al. 2002a,b, 2005; Paton et al. 2006; Pena et al. 2004; Thoby-Brisson and Ramirez 2001; Tryba et al. 2006) and the other uses a calcium-dependent mechanism (CaN dependent, also cadmium sensitive; Del Negro et al. 2005; Pena et al. 2004; Thoby-Brisson and Ramirez 2001; Tryba et al. 2006). Furthermore, these and other pBC neurons are coupled by excitatory synaptic connections (Funk et al. 1993; Koshiya and Smith 1999) and the pBC excitatory network itself exhibits autorhythmic properties (Johnson et al. 2001). Recent literature raises questions about the significance and the abundance of pacemaker cells within the pBC network (Del Negro et al. 2002a,b, 2005; Pagliardini et al. 2005; Paton et al. 2006; Pena et al. 2004; Tryba et al. 2006). In the intact respiratory network, the pBC is part of a much larger circuit (Feldman and Del Negro 2006; Smith et al. 2000) and pBC cells are responsive to modulation that controls inspiratory frequency (Johnson et al. 1996; Schwarzacher et al. 2002; Solomon et al. 2000, 2002). It was also established that the number of pacemakers in the pBC can be dynamically varied by neuromodulators acting on the network (Pena and Ramirez 2002, 2004; Ramirez et al. 2004). Here we use modeling studies to investigate how the fraction of the network population that is composed of intrinsic bursters affects measures of rhythmogenic capacity or "robustness" of network activity. Robustness is quantified in terms of both the input range and output range of the network. The input range is the size of parameter space where networkwide synchronous rhythmic bursting occurs and the output range is the range of bursting frequencies that the network produces across this input range. Thus a network is considered robust if it bursts at many levels of tonic excitation and over a wide range of frequencies. In general, the question of the contributions of pacemaker neurons to the dynamic performance of excitatory networks was not previously addressed quantitatively.
We ran network simulations to investigate this problem using a modified version of our previously developed pBC neuron and network models (Butera et al. 1999a,b). We simulated a heterogeneous excitatory network consisting of 50 pBC neurons—the smallest number of neurons that captures the dynamics of larger networks (Butera et al. 1999b)—and we varied the fraction of the population made up of pacemakers from 0 to 100%. While varying the fraction of pacemakers, we also varied the amount of excitatory drive supplied to the network at several different levels of excitatory synaptic coupling strength. Simulations with no pacemakers in the network were able to produce synchronous networkwide rhythmic activity; however, the input and output ranges were substantially reduced. Our simulations suggest that the inclusion of pacemaker neurons in a bursting network allows for greater controllability of the frequency range produced by that network. We conclude by proposing experimental tests of our model predictions.
Experimental data
Experimental data obtained from neonatal rat pBC inspiratory neurons in vitro shows from voltage-clamp recording analysis that a primary difference between pacemakers (PMs) and nonpacemakers (NPMs) in the pBC is the ratio of the persistent sodium conductance to the leak conductance (gNaP/gLeak): to date all pBC inspiratory neurons analyzed in vitro exhibit NaP and K+-dominated leak currents, although the gNaP/gLeak ratio is typically larger in PMs than in NPMs (Del Negro et al. 2002a; Koizumi and Smith 2004). When viewing the recent data of Koizumi and Smith (2004) as a scatterplot in gNaP and gLeak space (Fig. 1 A), there is a clear distinction between the PMs and NPMs (dashed line). Because the hand-drawn dashed line in Fig. 1A has a nonzero y-intercept, the gNaP/gLeak ratio is not a perfect indicator of the single-cell dynamics (i.e., whether the cell is a PM or NPM). To accurately compare the experimental data to the model (see following text) in terms of conductance densities, the data for individual neurons (n = 50) were normalized by the measured capacitance and then multiplied by the nominal whole cell capacitance used in the model (21 pF). PMs used for this analysis were differentiated from NPMs after pharmacological block of glutamatergic excitatory synaptic currents as previously described (Del Negro et al. 2002a; Koshiya and Smith 1999) and the dependency of intrinsic rhythmic bursting on gNaP was confirmed pharmacologically for identified PMs. All gNaP and gLeak data used in this study are from the set of PMs and NPMs obtained by Koizumi and Smith (2004) and are reproduced here for data parameter space mapping, model parameter adjustments, and data-model comparisons.
Neuron model
This study uses our previous pBC neuron model (see appendix) and heterogeneous excitatory network models of these cells (Butera et al. 1999a,b). The neuron model (Model 1 of Butera et al. 1999a) is a Hodgkin–Huxley (Hodgkin and Huxley 1952) style, electrophysiological model of a bursting pBC cell. The model consists of three voltage-gated ionic currents and a K+-dominated ohmic leak current. The voltage-gated currents are 1) a fast Na+ current, 2) a delayed-rectifier K+ current, and 3) a slowly inactivating persistent Na+ current (NaP). NaP is responsible for the intrinsic voltage-dependent, rhythmic bursting behavior displayed by these neurons (i.e., this is a model of the NaP-dependent or cadmium-insensitive bursters; Butera et al. 1999a). This is the biophysically minimal set of currents required to describe the main features (below) of pBC neuron properties. Other currents include a tonic excitatory drive current and an excitatory synaptic current. The excitatory drive, modeled as gtonic, models input from a tonic spiking population, which is proposed to function for pBC network burst frequency control (e.g., see Butera et al. 1999b; Smith et al. 2000). The excitatory synaptic current models the excitatory amino acid–mediated coupling between individual bursting neurons in all simulations using the conductance gsyn (Butera et al. 1999b).
Some parameters of the original Model 1 neurons were adjusted to more closely match recent experimental data. Specifically, more accurate values for NaP half-activation (V1/2max = −45 mV) and slope factor (k = 5) are used (Koizumi and Smith 2004). Because the NaP half-activation value was hyperpolarized by 5 mV, we also hyperpolarized the NaP half-inactivation by 5 mV. These adjustments are also consistent with other measurements of NaP properties of neurons isolated from the pBC region in vitro (Ptak et al. 2005; Rybak et al. 2004). NaP inactivation kinetics was not previously quantified experimentally for pBC neurons, so the original Model 1 kinetics was used. Simulations with these adjusted models provide behavior very similar to that of the original Model 1 neurons including voltage-dependent rhythmic bursting with a similar range of oscillation frequencies, controllable by applied current or tonic excitatory synaptic input (see Fig. 6 in Butera et al. 1999a). Figure 2 illustrates the pacemaker and nonpacemaker behaviors exhibited by the model for two different values of gNaP. NPMs make the transition from silence directly to beating as excitatory drive is increased (Fig. 2A, gNaP = 1.5 nS), whereas PMs make the transition from silence to bursting to beating (Fig. 2B, gNaP = 2.5 nS). This model also captured prominent properties of the recorded data neurons, justifying our parameter sets, including 1) silent, rhythmic bursting, and tonic spiking regimes determined by baseline membrane potential as controlled by an applied current; 2) bursting frequencies tunable over an order of magnitude range of frequencies by applied current (see also Koshiya and Smith 1999); 3) subthreshold current–voltage relations obtained during slow voltage-clamp ramps (30 mV/s used to obtain the data) that are separable into gNaP and gLeak as the two main conductance components (see also Butera et al. 2005); and 4) rhythmic bursting controllable as seen experimentally by gNaP and gLeak (i.e., by gNaP/gLeak ratios). Detailed comparisons of the data-model gNaP–gLeak parameter spaces (Fig. 3) also indicate that our simplified model is consistent with the differentiation between data PMs and NPMs in the majority of cases.
The network simulations required a mixed population of models of PMs and NPMs. Although previous modeling results classified the activity modes of the model (beating, bursting, silence; see Fig. 7 of Butera et al., 1999a) at rest (i.e., with no externally applied current), the PM and NPM classification of Fig. 1A was experimentally determined by testing for bursting at any level of applied current under current-clamp recording. Therefore a similar process was applied to the model using the interactive differential equation simulation package XPP (Ermentrout 2002) for model simulations along with Perl scripts and MATLAB (The MathWorks, Natick, MA) for data analysis. Both gNaP and gLeak were swept from 0 to 6 nS, which covers the full range of experimentally measured values. For each set of parameters represented in Fig. 1B, the stimulus current was swept from −30 to +30 pA. The stimulus current was started at −30 pA to ensure that the cell is at rest. If the values of gNaP and gLeak are such that the model is a nonpacemaker, then the modes of activity as the stimulus current is increased will progress from silence directly to beating (Fig. 2A). If rhythmic bursting occurs during part of this range (Fig. 2B), the neuron is classified as a pacemaker with this parameter set. The results of these simulations are given in Fig. 1B. Figure 1, A and B shares a clear boundary between the PM and the NPM regions. When creating a population of PMs and NPMs for the network simulations, the parameters must be chosen based on the modes of activity defined in Fig. 1B.
Modeling intrinsic parameter variability
The heterogeneous network simulations use parameters chosen from a two-dimensional parameter space (only gNaP and gLeak are varied). For these simulations, we created two heterogeneous populations of PMs and NPMs whose variability reflects the variability that exists in the experimental data (Table 1). That is, we constructed population distributions reflecting not only the ranges of NaP and leak conductance densities but also the experimentally determined variability of these parameters (Table 1). Accomplishing this requires completing three tasks: 1) correcting experimental conductance data for measurement errors, 2) determining the model's acceptable operating range for PMs and NPMs, and 3) defining parameter distributions inside the model's acceptable operating range that provide mean and SD values consistent with the corrected experimental data.
It is known that experimental measurements of gNaP depend on the rate of voltage-clamp ramps (Del Negro et al. 2002a) used to estimate values of gNaP, which is consistent with our model kinetics for NaP inactivation. We simulated the ramp protocol used to determine the gNaP values of the experimental data we are attempting to model to produce an estimate of the underestimation resulting from the ramp rate. The simulation suggests an underestimation arising from the ramp rate of roughly 20% and we conservatively estimated an additional 5% error from other potential measurement errors (e.g., space-clamp). Therefore we corrected the gNaP data by multiplying by the expected underestimation of 25%. The value of gLeak was not found experimentally to be affected by ramp rates as predicted by the model and was therefore left unchanged. After correcting the data, 86% of the data points are on the appropriate side of the model's PM/NPM boundary (Fig. 3A).
To completely describe an allowable parameter space of the model for network simulations, both the PM/NPM boundary and the boundary that defines the operating range of the model must be defined. An accurate description of this space is necessary to reliably separate PM and NPM model neurons; parameter sets outside of the model's operating range will produce spurious results (e.g., plateau potentials) or nonphysiological models (e.g., negative conductances). The boundary between PMs and NPMs was chosen by fitting a diagonal line to the boundary previously computed (Figs. 1B and 3A). A model whose parameters lie on the PM/NPM boundary will produce doublet or triplet bursts of spikes. Therefore the y-intercept of the line was increased by 0.2 for PMs and decreased by 0.2 for NPMs (see white space between PM and NPM regions in Fig. 3C), to provide a conservative separation between PMs and NPMs and definitively determine that a model in that region is a PM or NPM. The minimum value for gNaP for all simulations was chosen to be 0.5 nS. The other diagonal boundary at the upper edge of the PM space was set to keep the model inside its operating range. Figure 3B displays these conservative model boundaries plotted with the experimental data of Fig. 1A. Seventy-four percent of the data points are inside the conservative boundaries allowed for the model parameters.
As stated earlier, the network simulations will use values from a two-dimensional normal distribution in gNaP and gLeak for PMs and NPMs. When randomly choosing parameters to generate a PM model, the parameters must be verified to ensure that the model actually is a PM (likewise for NPMs). The parameters must also be tested to ensure that they are not outside the operating range of the model. Thus some of the values that are randomly chosen from the two-dimensional distribution must be discarded because they fall outside these boundaries. Therefore the values for mean and SD of the experimental data listed in Table 1 cannot be used for the random-number generator because the act of discarding and repicking from the normal distribution will result in a different mean and SD for the population. C++ simulations were run that selected 10,000 random sets of parameters to determine the actual mean and SD values after bounding the allowable parameter space. The simulation was then repeated for various nominal means and SDs until the actual mean and SD after discarding/repicking was similar to the mean and SD of the corrected data (Table 1). These trials were repeated 100,000 times and the best parameter distributions were determined by taking the minimum of the summed percentage error between the computed mean/SD and the data mean/SD. Table 1 provides the optimal means and SDs for gNaP and gLeak whole distribution statistics that best match the experimental data.
Once initial mean/SD values for the normal distribution were chosen such that the calculated mean/SD after discarding/repicking closely matched the experimental data, we used these distributions to choose model parameters of PMs and NPMs for the network simulations. For example, Fig. 3C provides a sample parameter distribution to be used for model simulations that includes 30 PMs and 20 NPMs. Although this data-mapping scheme is not perfect (26% of the corrected experimental data falls outside the model's allowable range; Fig. 3B), it does provide a model approximation of the variability of the experimental data.
Network simulations
The network simulations consist of a population of 50 cells, of which there are 1K PMs and 50K NPMs. It is important to note that the total number of cells in the network remains constant at 50 while K is varied from 0 to 50 in increments of one (i.e., only the percentage of the population that are PMs or NPMs changes). For each K, the amount of excitatory drive, or gtonic, is varied in 0.1-nS increments from 0 to 1.5 nS. Varying the amount of drive allows us to explore this voltage-dependent frequency control, as exhibited by the isolated pBC in slice preparations (Del Negro et al. 2001; Smith et al. 1991). Also, because the exact amount of excitatory synaptic coupling is unknown, the level of excitatory coupling is varied over physiological ranges for each simulation. Physiological range was determined by examining the synaptic current for various values of gsyn (see, e.g., Fig. 13 of Butera et al. 1999b) and comparing it to values measured experimentally (see, e.g., Fig. 1 of Del Negro et al. 2002a). The model of fast excitatory synaptic dynamics used is as previously specified in Butera et al. (1999b). The results presented are from networks with all-to-all excitatory coupling. Similar results were obtained with sparsely connected networks (see following text).
Network simulations were run on Linux and Unix workstations using C code (Butera et al. 1999b) and the results were analyzed using Perl scripts and MATLAB. Network simulations were run for 2 min of simulation time with the first 30 s being ignored to allow start-up transients to decay.
Data analysis
An automated burst-detection technique was implemented by generating a combined histogram of spike times from every cell in the network (Fig. 4). The maximum and minimum amplitude of the histogram was calculated and the difference between those values was compared with a threshold. If the threshold was met and if the amplitude of the histogram remained <10% of the maximum amplitude for some minimum amount of time, then the output was defined as a burst. The values for amplitude threshold and minimum time <10% of maximum amplitude were chosen by visual inspection of the histogram data. This method classifies the results illustrated in Fig. 4, A and C as bursting, although the network producing the pattern illustrated in Fig. 4B is classified as a nonbursting network. For the results reported herein, only "regular" bursting patterns were considered; therefore the bursting patterns in Fig. 4, A and C were further analyzed. To determine whether regular bursting patterns were present, the burst period (BP), burst duration (BD), and burst amplitude were measured. Before measuring these values, the data were smoothed using a 20-point moving average. After smoothing, the start of a burst was calculated using a rising phase threshold of 30% of the maximum amplitude and the end of the burst was calculated using a falling phase threshold of 10% of the maximum amplitude. The BD is the time between these two thresholds, the BP is the time between the rising phase of two subsequent bursts, and the burst amplitude is the maximum amplitude measured during the BD. If each of these values had a coefficient of variation among all bursts in a trace <20% and if more than two bursts were found in the 90-s time window, then the bursting was defined as regular and is hereafter referred to as networkwide bursting. Thus the automated burst detection would define the bursts in Fig. 4C as irregular because the BP has a coefficient of variation >20%. The bursting pattern in Fig. 4A meets all requirements for regular networkwide bursting. This analysis scheme was verified in preliminary simulations studies by inspection of raster plots of the 50 cell-activity patterns to confirm the degree of cell synchrony between successive cycles. The values reported for the frequency of networkwide bursting were calculated using the inverse of the mean BP.
Once the existence of networkwide bursting has been established, input and output ranges are computed. Input range is defined as the size of parameter space where networkwide bursting occurs. The simulation data for input and output ranges are analyzed in some cases by grouping the number of PMs into bins where bin 0 is the special case when the network contains no PMs, bin 1 contains 1–5 PMs, bin 2 contains 6–10 PMs, and so forth. Input range is then defined as the percentage of the maximum number of simulations inside a bin that produce networkwide bursting, i.e., the fraction of the range of gtonic where networkwide bursting occurs. For example, bin 1 contains five values of PMs (from 1 to 5 PMs) and 16 values of gtonic (from 0 to 1.5 nS in 0.1-nS increments) for each number of PMs, giving 80 total simulations inside that bin. If networkwide bursting is found in only four of the 80 simulations (as is the case for bin 1 where gsyn = 0.2 nS; see following text), then the input range would be 4/80 or 5%. Output range is computed by subtracting the maximum frequency of networkwide bursting for a given number of PMs from the minimum frequency of networkwide bursting for the same number of PMs (as gtonic is varied) and averaging this range across all PMs in that bin. Therefore for a given number of PMs, if the network bursts with a maximum frequency of 0.75 Hz when gtonic = 0.9 nS and the network bursts with a minimum frequency of 0.25 Hz when gtonic = 0.1 nS, the output range is defined as 0.50 Hz for that number of PMs.
Figure 5 illustrates the existence and frequency of networkwide bursting as the number of PMs and excitatory drive (gtonic) are varied for five values of excitatory synaptic coupling (gsyn). The color indicates the frequency of networkwide bursting; black regions indicate the absence of networkwide bursting. The simulations in the black region could produce a network containing neurons that are all or mostly silent, a network containing neurons that are all or mostly tonically firing, or a network that produces an irregular bursting pattern. Each point in Fig. 5 is the result of a single simulation with a new randomly generated set of parameters. It is this independent parameter selection for each simulation that causes the "noise," or variability among adjacent points. Figures 6–8 further quantify the results shown in Fig. 5; Figs. 9 and 10 illustrate the averaged results of multiple simulations using a single value for gsyn. Figure 11 provides a method of displaying our results that will allow a straightforward comparison to future experimental data.
Networkwide bursting
At lower levels of synaptic conductance (Fig. 5, top), more PMs are required to generate networkwide bursting. At higher levels of synaptic conductance (Fig. 5, bottom right), networkwide bursting is seen with fewer PMs, but the range of frequencies produced by the network is dramatically reduced. Other levels of synaptic conductance (>0.3 and <0.075 nS) were explored, but did not result in significant amounts of networkwide bursting. Also, increased excitatory drive (gtonic >1.5 nS) did not produce networkwide bursting at any level of synaptic conductance or for any fraction of PMs. At these high levels of excitatory drive, only tonically firing activity within the network was seen. The results of Fig. 5 also suggest that, for a fixed level of synaptic conductance and gtonic, reducing the number of PMs, in general, reduces the frequency of networkwide bursting until the rhythm is eventually abolished.
Input range and output range
Figure 6 is a plot of the input range for all values of gsyn as a function of K and levels of excitatory coupling. For the lower values of gsyn (0.075, 0.1, and 0.15 nS), the input range displays a generally increasing trend as the percentage of PMs increases from 0 to 100% of the population, with the lowest levels of synaptic conductance failing to produce any networkwide bursting until >20 or 25 PMs are in the population (bin 5, gsyn = 0.1 nS; bin 6, gsyn = 0.075 nS). For the larger values of gsyn (0.2 and 0.3 nS), the input range increases as the number of PMs is initially increased and then decreases slightly for higher percentages of PMs. Networks with gsyn values of 0.15 and 0.2 nS span the greatest range of input ranges (Fig. 6).
Table 2 quantifies the input and output ranges for three cases: a network containing no PMs, a network where less than (or equal to) half of the population is made up of PMs, and a network where more than half of the population is made up of PMs. Only two of the five synaptic conductances explored produced networkwide bursting when no PMs are present in the network (Fig. 6, bin zero). At gsyn values of 0.2 and 0.3 nS, networkwide bursting occurs with no PMs >13% of the input range. The average input range for a network with 1–25 PMs at gsyn values of 0.2 and 0.3 nS is 25 and 41%, respectively. The average input range for a network with more than half of its population made up of PMs at gsyn values of 0.2 and 0.3 nS is 52 and 39%, respectively (Table 2). Thus for a given level of synaptic conductance, increasing the number of PMs in the network can more than triple the input range compared with a network containing no PMs.
Figure 7 illustrates the output range of the network for each level of synaptic conductance. The maximum and minimum frequencies for each number of PMs in a bin are given by solid and open circles, respectively. The frequencies measured in our simulations (from about 0.04 to 1.0 Hz) are similar to those measured by Del Negro et al. (2001; from about 0.05 to 0.8 Hz). For most cases, the output range increases as the number of PMs is increased (Fig. 7). Networks containing no PMs were able to burst (bottom center and right panels of Fig. 7); however, the output range in this case is considerably reduced compared with simulations with larger percentages of PMs. At gsyn values of 0.2 and 0.3 nS, the output range with no PMs is 0.20 and 0.04 Hz, respectively. The average output range when gsyn = 0.2 nS with 1–25 PMs and with 26–50 PMs is 0.19 and 0.43 Hz, respectively. When gsyn = 0.3 nS, the average output range with 1–25 PMs and with 26–50 PMs is 0.13 and 0.12 Hz, respectively (Table 2). The largest attainable output ranges for a given number of PMs with gsyn values of 0.15 and 0.2 nS are 0.88 Hz (with 46 PMs) and 0.71 Hz (with 41 PMs), respectively. These values are more than triple the largest output range obtained with no PMs in the network.
Input–output range trade-offs
For a given level of gsyn, input range (Fig. 6) and output range (Fig. 7) were quantified and averaged across a range of K. Figure 8 plots the input range and the output range versus each other as K and gsyn are varied, allowing a compact visualization of how varying K and gsyn affect these metrics. Figure 8A is a plot of the input range versus output range for different numbers of PMs. The plot of Fig. 8A displays a clockwise trend as the level of synaptic conductance is increased for each number of PMs. In general, the input and output ranges increase as the number of PMs is increased. There is an optimal value of gsyn for a given number of PMs that maximizes the input and output ranges. Figure 8B is a plot of the input range versus output range for different levels of synaptic conductance. Here, the number of PMs increases as the trace progresses from left to right. Figure 8B emphasizes the depressing effect on output range of increasing synaptic strength. Weaker coupling produces a smaller input range and coupling also strongly produces a smaller output range. The moderate levels of synaptic conductance that provide the largest input and output ranges are found with gsyn values of 0.15 and 0.2 nS. At these moderate levels of synaptic conductance, the largest gain (or largest rate of change) in input and output ranges occurs when the number of PMs increases to >20–40% of the population (see, for example, the large increase between the second and third points where gsyn = 0.2 nS in Fig. 8B; see also Fig. 5).
Multiple simulations
Because the optimal synaptic conductance level was found to be between gsyn = 0.15 nS and gsyn = 0.2 nS, four additional simulations were run at both levels of synaptic conductance. This was to validate general trends just described and average over the variability of individually randomly generated simulations. The input and output ranges for each simulation are given in Fig. 9 and the average of all five simulations is plotted as a bold line. The input range is fairly consistent among all simulations for gsyn values of 0.15 and 0.2 nS (Fig. 9, A and B). The output range for gsyn = 0.2 nS is more variable (Fig. 9D) but both display a clear upward trend as the number of PMs is increased (Fig. 9, C and D). Previously, the largest output range obtained for a network with no PMs was 0.20 Hz when gsyn = 0.2 nS. However, none of the four additional simulations at gsyn = 0.2 nS produced networkwide bursting at more than a single value of gtonic with no PMs in the network. This reduces the average output range with no PMs in the network to 0.04 Hz.
Figure 10, A and B displays the average results of varying gtonic and number of PMs for all simulations with gsyn values of 0.15 and 0.2 nS. When computing the average, simulations that did not produce networkwide bursting were ignored (rather than including a zero frequency in this average). Averaging multiple runs removes much of the variability among adjacent points seen in the results from a single run (compare Fig. 10, A and B to bottom left and center panels of Fig. 5). Figure 10, C and D reveals the likelihood of choosing a random set of parameters that can produce networkwide bursting with a certain number of PMs in the population for a given level of excitatory drive. In Fig. 10, C and D, the (black and white) color bar indicates in how many of the five simulations networkwide bursting was measured. The white regions are where bursting occurs for all five simulations and the black regions are where no networkwide bursting is recorded. Figure 10, B and D illustrates that the network is able to burst with fewer numbers of PMs and is also capable of producing a large range of frequencies with fewer PMs. However, the likelihood of producing networkwide bursting in this region is minimal (Fig. 10D, top left). The network does produce bursting when few PMs are present, but it does not consistently produce bursting at the same points in parameter space. This is the cause of the variability seen in Fig. 9D.
Sparsely connected networks
The simulations were repeated using a sparsely connected population and the results were compared with the all-to-all coupling simulations given earlier. For these simulations, the probability of connection was reduced to 10% (as an example of very sparse connectivity) and the level of synaptic conductance was increased so that the mean level of synaptic current provided to each cell remained roughly the same. For the sparsely connected networks, we explored three values of synaptic conductance, gsyn values of 1.0, 1.5, and 2.0 nS, that roughly correspond to gsyn values of 0.1, 0.15, and 0.2 nS using the all-to-all connectivity presented earlier. The results of the simulations using the sparsely connected networks (not shown) are completely consistent with all results using all-to-all connectivity. Both input and output ranges of the sparsely connected networks increased as the number of PMs increased in a similar fashion to the corresponding levels of synaptic conductance with all-to-all coupling. Also, the magnitudes of the ranges of frequencies measured were similar.
These simulations were performed to investigate the functional significance of PM cells in the pBC excitatory network. The simulations use two types of heterogeneity: cell-type heterogeneity (PMs and NPMs) and parameter heterogeneity within a given cell type that is based on experimental data. Before running the data-based simulations presented here, we performed several simulations (not shown) using less heterogeneous parameter distributions: a semihomogeneous parameter space (gLeak was kept constant for all cells; gNaP was constant within each subpopulation of PMs or NPMs) and a one-dimensional heterogeneous parameter space (gLeak was kept constant for all cells whether PM or NPM; mean gNaP was different for PMs and NPMs and varied with SD of ±10%, and then ±30%). The semihomogeneous simulations produced networks with reduced input and output ranges compared with networks with more heterogeneous parameter distributions, which might be expected based on previous studies examining the role of heterogeneity in this network (Butera et al. 1999b). Although there were minor quantitative differences, both the simulations using less heterogeneous and less data-based parameter distributions and the simulations using sparsely connected networks provide results that are qualitatively similar to the results of the data-based simulations presented here. The major conclusion of this study was reiterated in every simulation performed, that is, pacemakers can increase the input and output ranges of a bursting network.
The absolute values for input range are not meaningful because the percentages calculated are a function of the size of parameter space chosen (gtonic varies from 0 to 1.5 nS in 0.1-nS increments). If gtonic were allowed to increase to ≤2.0 nS, then all calculated percentages would be reduced. However, the relative differences between the input ranges for different numbers of PMs and for different levels of gsyn are important. The input ranges given in Fig. 6 and Table 2 reveal that networkwide bursting is easier to obtain when the fraction of the network population made up of PMs is increased. Like input range, output range shows a generally increasing trend as the number of PMs is increased. This highlights an important difference between the controllability potential of synaptic conductance versus the number of PMs in a network. Increasing gsyn can increase input range but at the cost of output range. Alternatively, increasing the number of PMs in the network can increase both input range and output range.
Comparing both the input range and the output range for several values of gsyn reveals an optimal synaptic conductance near gsyn values of 0.15 and 0.2 nS. Therefore we ran multiple simulations at these levels of synaptic conductance. Examining the results of these simulations revealed that large output ranges were possible with few PMs at gsyn = 0.2 nS, but the output range in this region was highly variable because of the inability to unfailingly generate networks capable of producing networkwide bursting. In general, the network input–output range increased as the percentage of PMs increased under these optimal synaptic coupling conditions.
The reported estimates for the number of PMs in the pBC vary from 5 to roughly 50% for different in vitro slice preparations and recording conditions (Del Negro et al. 2002a, 2005; Koshiya and Smith 1999; Pagliardini et al. 2005; Pena et al. 2004). Because the PM or NPM state of a pBC cell is modulatable (Pena and Ramirez 2002, 2004), it is possible that the number of PMs in this network is modulated to meet particular dynamic range requirements. Indeed, our current and original model analyses indicate that any neuromodulatory conditions that change the gNaP/gLeak ratios within the network can potentially change the relative numbers of PMs and NPMs and thus the network's dynamic performance. Thus the varying estimates for the number of PMs in the pBC under different recording conditions may in part reflect the modulated state of the pBC. With optimal values of gsyn in our simulations, the largest increase in dynamic range occurs when the number of PMs increases to ≳20% of the population (see Figs. 8–10). We are currently using reduced-order models to investigate the mechanism and significance of this threshold-like effect of the number of PMs on network dynamics.
Limitations of the model
These simulations use a minimal model of pBC cells that lack some voltage-gated ionic currents known to exist in these cells, such as the low-voltage–activated or high-voltage–activated calcium channels (Elsen and Ramirez 2005). This minimality undoubtedly plays a role in the inability of the model to perfectly match the experimental data. In constructing our network models, we sought to rigorously incorporate conductance density distributions, their variability, and voltage dependencies that are consistent with the experimental data. An important model parameter that has not yet been directly verified by measurements, however, is the kinetics for the voltage-dependent slow inactivation of NaP incorporated in the model. This parameter controls the dynamics of the single-neuron rhythmic bursting cycle and synchronized rhythmic bursting at the population level.
Because model parameters were chosen from a two-dimensional heterogeneous parameter space, ideally, multiple simulations should be run so that any variability among simulations can be averaged out. This is computationally time consuming. Figure 5 contains almost 4,000 simulations, where each simulation is a network of 50 cells. However, our results indicate that more simulations are not necessary. When multiple simulations were run for a single value of synaptic conductance, all simulations displayed similar trends. Also, as previously stated, all simulations using less heterogeneous parameter distributions and sparsely connected networks provided results consistent with the results presented in this study.
The simulations that produced networkwide bursting with few or no PMs typically provided minimal output ranges. Although some simulations with few PMs were able to produce large output ranges (Fig. 9D), the likelihood of producing networkwide bursting here was low (Fig. 10D). Attempts were made to choose data-based parameters for the simulations. However, the limitations of the minimal model and of the parameter selection technique could be the source of the inability to unfailingly produce robust networkwide bursting with fewer numbers of PMs in the population.
We should note that, although PMs are not required to produce networkwide bursting in our model (Butera et al. 1999b), the NaP current is required. If this slowly inactivating inward current were completely removed from our model, there would be no slow process in the network to terminate networkwide bursting activity once it has begun. Thus we emphasize that NaP provides not only a mechanism for rhythmic bursting of individual PMs (when isolated from synaptic input), but also a mechanism for synchronized rhythmic bursting and its termination at the population level. This mechanism results from the voltage dependency and kinetics of NaP inactivation and the dynamic interaction of NaP current with phasic excitatory synaptic drive currents in the coupled population of cells (see Fig. 10 of Butera et al. 1999b).
Whether the NaP current provides the primary mechanism for burst termination and regenerative reactivation of the network in in vitro slice preparations remains to be clearly resolved. Published investigations of this mechanism appear to appreciably depend on the experimental preparation (i.e., thin vs. thick slices in vitro vs. the more intact network in situ) (Del Negro et al. 2005; Paton et al. 2006; Pena et al. 2004; Rybak et al. 2003; Tryba et al. 2006). Our results (Fig. 5) suggest that at least for preparations with a relatively isolated pBC network (e.g., thin in vitro slice preparations) and for a fixed level of synaptic conductance, reducing gNaP and thus the number of PMs, in general, reduces the frequency of networkwide bursting until the rhythm is eventually abolished. This agrees with some experimental results where gNaP was reduced pharmacologically by riluzole or low concentrations of tetrodotoxin (TTX), presumably reducing gNaP/gLeak ratios to parameter space regions with few PMs (Koizumi and Smith 2004; Rybak et al. 2003). Our model does not include the cadmium-sensitive bursters found in the pBC of slice preparations from mice (Del Negro et al. 2005; Pena et al. 2004; Thoby-Brisson and Ramirez 2001; Tryba et al. 2006), but not rats (Del Negro et al. 2005). Further modeling and simulations are required to determine the effects of adding these pacemakers to our network models. At present, little is known about the biophysical parameters of the CaN current and these cells may (Thoby-Brisson and Ramirez 2001) or may not (Del Negro et al. 2005) provide voltage-dependent control of PM oscillation frequency, which would impart a very different contribution to the input–output range of the network. Indeed, a unique property of NaP-dependent mechanisms may be the enabling of a broad range of tunable network oscillation frequencies, which is inherent in the voltage-dependent properties of this conductance mechanism. In considering the functional significance of any type of PM mechanism, the issue of frequency control may be fundamental. That is, it is not simply the capability of a particular cellular pacemaker mechanism when coupled with excitatory synaptic interactions to organize a networkwide rhythm in the pBC, but it is the inherent ability of any mechanism to allow functionally for frequency control over a wide dynamic range. This control is a prominent feature of experimental data, at least for the isolated pBC in slices in vitro under conditions where tonic drive is varied (e.g., Del Negro et al. 2001).
Rhythmic networks
Although we have analyzed dynamics of excitatory networks incorporating bursting cells to investigate rhythm generation mechanisms in the pBC, our results would pertain to rhythmogenesis in the isolated pBC as in slice preparations in vitro, or under hypoxic conditions in perfused brain stem preparations in situ (Paton et al. 2006), where there is evidence for NaP-dependent mechanisms. As we originally pointed out (Smith et al. 2000), when the pBC is embedded in the brain stem respiratory network in more intact states of the system, as in vivo, phasic (and possibly tonic) inhibitory inputs to the pBC become important for dynamically regulating the evolution/termination of pBC inspiratory activity (Tryba et al. 2003). We proposed (Smith et al. 2000), for example, that network-based phasic inhibition contributes importantly to the termination of pBC networkwide bursting in the intact system, as opposed to termination solely by the slow inactivation kinetics of NaP and interactions of NaP and leak currents. Thus it remains an important theoretical and experimental problem to understand rhythm generation when inhibitory network mechanisms are overlaid on the excitatory network interactions that we have analyzed here.
Although our model is based on intrinsic bursting cells in the pBC, this study is representative of a particular class of rhythmic bursting networks—those where the connectivity is predominantly mediated by excitatory synapses. Examples include rhythmic bursting in transverse brain stem slices (Koshiya and Smith 1999; Smith et al. 1991), rhythmic activity in disinhibited embryonic spinal cords (O'Donovan 1989; Streit 1993), rhythmic activity in disinhibited medial septum and diagonal band complex (Manseau et al. 2005), and 7- to 14-Hz oscillations in motor cortex (Castro-Alamancos et al. 2006). In such networks, the synaptic excitation is responsible for the coordination and spread of activity through the network at the start of an episode of activity; in other cases such excitation may play a key role in the initiation of a burst of activity as well. In all these cases, burst episode initiation is attributed to some combination of intrinsic cellular properties and/or recurrent excitatory coupling. Burst termination can be explained by the slower kinetics of ionic currents intrinsic to the component neurons (e.g., this manuscript) or the slower kinetics associated with synaptic depression (Tabak et al. 2000).
Model predictions
To date, we are unaware of any experimental studies that quantify dynamic range under conditions that putatively alter the number of PMs. Based on the simulation results, we expect both the input range and the output range of the network would be reduced as the fraction of PMs in the network is reduced. Likewise, if the conductance density of NaP channels is augmented, then we predict that neurons that were previously NPMs would become PMs and would produce an increased dynamic range. Some have claimed (Del Negro et al. 2002b, 2005) and our modeling studies have shown that networkwide bursting is possible after sufficiently reducing NaP such that no PM activity is seen in the network (Butera et al. 1999b). When PMs are blocked experimentally, an increased level of depolarization is required to restore rhythmic activity (Del Negro et al. 2005). Our simulations confirm these results. If no (or few) PMs are present in the network, increased levels of gtonic are required to produce networkwide bursting (Figs. 5 and 10B). However, our simulations suggest that under these conditions the dynamic range of the network is greatly reduced. Substance P was previously shown to reactivate networkwide bursting after ostensibly blocking all PMs (Del Negro et al. 2005; Tryba et al. 2006). Even if this reactivation is caused by the apparent ability of substance P to temporarily restore PM activity to some cells where PM activity was previously abolished (Tryba et al. 2006), based on our simulation results, we would still expect the dynamic range of the network to be reduced under these conditions. Experiments to test the model predictions would involve measuring the range of frequencies produced by the network while varying, for example, the level of tonic activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors or tonic excitation with extracellular potassium concentration under control conditions and when gNaP and thus PM activity have been attenuated by application of riluzole or small amounts of TTX. Our model analog to the experimental figure this would produce is given in Fig. 11, where we plot frequency versus gtonic for different numbers of PMs. Experimentally varying the level of AMPA receptor activation or extracellular potassium within the pBC is qualitatively equivalent to varying EK (Del Negro et al. 2001; Rybak et al. 2003), EL (Butera et al. 1999a), or gtonic (Butera et al. 1999b) in the model. Figure 11 can be compared with future experimental tests of these model predictions. In Fig. 11, the nonmonotonic increase in frequency as gtonic is increased is caused by heterogeneity among simulations. This variability is reduced when averaging the results of multiple simulations (see bold lines in Fig. 9).
Hypoxia increases NaP conductance density (Hammarstrom and Gage 1998, 2002; Horn and Waldrop 2000) and recent studies showed the importance of NaP-dependent bursting cells during hypoxia (Paton et al. 2006; Tryba et al. 2006). If hypoxia increases the number of PMs in the network, this would cause a shift in parameter space to a region capable of producing higher-frequency rhythms. This is a potential mechanism for obtaining the initial increase in burst frequency seen during hypoxia (Solomon et al. 2000; Telgkamp and Ramirez 1999; Tryba et al. 2006). Again, the dynamic range of the network could be examined at different levels of pBC hypoxia. In general such comparisons under any experimental conditions that are found to either selectively augment gNaP or augment gNaP/gLeak ratios to increase the number of PMs would be instructive.
In conclusion, although the significance and abundance of PMs in the pBC are not completely understood, the existence of these cells is not questioned. We used modeling studies to quantitatively explore the role that one of the main types of PMs (i.e., NaP-dependent) found in the pBC plays in this bursting network. Networks containing no PMs were able to produce regular, synchronous networkwide bursting (albeit with a low probability of bursting, as well as low input and output ranges), demonstrating that PMs are not critical for rhythm generation, provided that excitatory synaptic coupling strength is high. Thus the NaP current can provide not only a mechanism for rhythmic bursting of individual PMs, but also a mechanism for synchronized rhythmic bursting and its termination at the network level. However, our modeling studies suggest that including PMs in the network allows the input and output ranges to more than triple compared with networks with no PMs. Indeed, the fraction of PMs profoundly affects the controllability of the rhythm. Unlike synaptic coupling that requires a trade-off between input range and output range, increasing the number of PMs can increase both the input range and the output range of the network. Additional experimental tests as suggested by our results will be required to either confirm or refute our model prediction that PMs increase the robustness of rhythm generation.
The model used for all simulations is a modified version of Model 1 of Butera et al. (1999a) and is based on a single-compartment Hodgkin–Huxley (HH) formalism. The membrane potential is found using the differential equation where V is the membrane potential (mV), Cm is the whole cell capacitance (21 pF), t is time (ms), Itonic is the excitatory drive current (nA), Isyn is the synaptic current (nA) from other pBC cells in the network, and Iionic are the ionic currents listed below and have the form where Eionic is the equilibrium reversal potential for the ionic species carried by the current and where ḡ is the maximum conductance of each current, and x is the product of one or more gating variables raised to integer powers, as subsequently described.
The dynamics of the conductances of the ionic currents regulated by voltage-dependent activation or inactivation variables are described according to where x∞(V) is the steady-state voltage-dependent (in)activation function of x and τx(V) is the voltage-dependent time constant. x∞(V) is a sigmoid with a half-(in)activation at V = θx and a slope factor σx. τx(V) is a bell-shaped curve that has a maximal value τ̄x at V = θx and a half-width determined by σx. Thus each gating variable is described by only three parameters.
Action potentials in the model are generated by a fast Na+ current (INa) and a delayed-rectifier K+ current (IK). The equations for these currents are inspired by the HH formulation, but the gating variables satisfy a reduced voltage-dependent description where the parameters of INa are ḡNa = 28 nS, ENa = 50 mV, θm = −34 mV, and σm = −5 mV; the parameters of IK are ḡK = 11.2 nS, EK = −85 mV, θn = −29 mV, σn = −4 mV, and τ̄n = 10 ms.
The persistent sodium current is described by the following equation where ENa = 50 mV, θm = −45.1 mV, σm = −5 mV, θh = −53 mV, σh = 6 mV, and τ̄h = 10,000 ms. ḡNaP is varied in each simulation as described earlier.
The model has a passive leak current defined as This current is K+ dominated. EL is set to −70 mV and ḡLeak is varied in each simulation as previously described. The reader is referred to Butera et al. (1999a,b) for a more detailed description of the model.
This work was supported by National Institute of Mental Health Grant R01-MH-62057 and, in part, by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Copyright © 2007 by the American Physiological Society


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If the R 1200 R LC or the RS LC are redesigned with our tail fairing (item no.: 44810-000), you can upgrade the tail section even further with these subtle indicators. The cube-shaped Cube LED indicators fit very discreetly into the tail section's sporty line. This indicator set includes both brackets with which the indicators simply screw onto the bottom of the tail section.
The facts:
- Powerful, fail-proof LED lights
- Extremely compact and discreet
- Simple assembly on the original points
- Incl. complete bracket set
Note:Cannot be combined with case carrier
In principle, use of the original BMW case with this blinker set can impair the legally required beam angle of 30°. This not apply for more slimly designed soft cases such as our Street or Royster soft case set.

subset: commoncrawl


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WRIGHT Centres
WHO Research Into Global Hazards of Travel
Group I: Epidemiological studies
Participating centre - Leiden University Medical Center, Leiden, and Academic Medical Center, Amsterdam, the Netherlands
Venous thrombosis occurs in 1-3 per 1000 people per year. Air travel has been associated with venous thrombosis in many case reports, but the few controlled studies are contradictory. Elucidation of the magnitude of the risk has direct public health relevance in helping to decide which prophylactic measures may have a net beneficial effect, and which might be ill-advised. Since hundreds of millions of people travel by air each year, even a risk increase that is small in absolute terms may have major public health impact. These studies focus on clinical endpoints to estimate the magnitude of the risk and contributing risk factors. The results will be useful for studying the effect of interventions.
Group II: Pathophysiological and coagulation studies
Participating centre - Leiden University Medical Center, Leiden, and Academic Medical Center, Amsterdam, the Netherlands
Airliners provide a safe and effective means of rapid transportation. Each year more passengers travel over increasing distances. Physicians working close to major airports have observed patients presenting with thromboembolic problems following air travel and published these as case reports. The purpose of this study is to establish the overall incidence of deep vein thrombosis in long haul airline passengers and to assess the factors associated with the risk of thrombosis. The studies in this group aim to establish the incidence of deep vein thrombosis following airline travel in passengers employing a series of measures of DVT prevention. The rates of symptomatic and asymptomatic DVTs will be investigated including an assessment of the proportion of distal and proximal deep vein thrombosis.
Group III: Pathophysiological study on hypobaric hypoxia
Participating centres - Leiden University Medical Center, Leiden, and Academic Medical Center, Amsterdam, the Netherlands, the University of Leicester, Leicester, United Kingdom
It is generally accepted that prolonged immobility predisposes to venous thromboembolism (VTE) and that this may be an important factor in the causation of travellers' thrombosis. It is not clear, however, whether the risk associated with long-haul air travel is qualitatively different from any other form of transport or from prolonged sitting in other circumstances. The aim of the study is to determine whether exposure to hypobaric hypoxia, at levels comparable to those that might be encountered during commercial air travel, promotes a hypercoagulable state that could predispose to VTE. The effect of prolonged sitting in the coach position under normal atmospheric conditions will be evaluated as a control condition and this may provide useful insights into the risk associated with immobility alone.


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Luke Graham: Steamboat hockey starting to play well
February 5, 2012
Steamboat Springs — It very well could come down to mid-February to decide the Steamboat Springs High School hockey team's playoff fate.
The team sits just one spot out of the last playoff position and when looking at the schedule ahead, Steamboat plays three of its last four games against teams ahead of it in the standings.
So win, and the team is in.
But just getting to this point has been quite the accomplishment. The Sailors are 5-0-1 in their last six games.
After an ugly 6-3 loss Jan. 7 to Summit, Steamboat found itself in the basement of the standings with little chance to make the playoffs.
In that game against Summit, everything that was wrong with the team came out.
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They took undisciplined penalties. They turned the puck over at an alarming rate in their own zone. The neutral zone belonged to Summit.
In the third period of that game, and down just one goal, Steamboat spent 12 of the 17 minutes of the period in the penalty box.
That is no way to win.
From that point, the season was ratcheted up a notch.
It became a playoff-like scenario. With a roster full of sophomores and just three seniors, the pressure-packed situation would tell what type of team the Sailors were. They could have packed it in and called the season a wash, blamed it on the youths at every level and for most who were focused on lacrosse in the spring.
But something happened after Summit. Steamboat started to play its systems. Sophomore goalie Trent Trask finally grasped the No. 1 position.
The top line of John Wharton, Matt Hale and Lance Ostrom started to go on a tear. The three have scored 20 goals in the last six games, spurring Steamboat back into the race. Junior defenseman Christian Ramirez has been as good as he has in his high school career.
Steamboat getting back into the race proves how far along this team actually has come.
They've gone from a poor defensive and occasionally OK offensive team, to one that actually looks like a playoff contender.
Keep in mind that five of the last six games have come against teams behind the Sailors in the standings.
But the team has to start somewhere.
With three crucial games this week and one to follow, Steamboat has a chance to be evidence of a team growing up.
Going from pre-holiday play that made people shutter to how it is playing now no doubt has been one of the most telling developments of this high school season.
Now it's a matter of finishing it off. By my account, Steamboat needs to win at least three of its last four to ensure the playoffs. Win four in a row and it's guaranteed. Go 2-2 and start getting ready for lacrosse season.
But one thing this group can take solace in, no matter how the next two weeks work out, is that they've battled.
They've gone from the playoffs being a distant dot way on the horizon, to controlling their own destiny.
Now all they have to do is keep winning.
To reach Luke Graham, call 970-871-4229 or email firstname.lastname@example.com


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EY's positive verdict on the investment climate in sub-Saharan Africa, and Ghana particularly, is gratifying news, but says more of the past than of what's to come.
The results of the fourth annual Africa Attractiveness Survey, a report by the global advisory and accounting firm EY that measures collective confidence in Africa as an investment destination, may have come as a surprise to Ghanaians and foreigners doing business here.
Any local discussion of Ghana's economy in the last several months seems to inevitably take a turn for the dreary – the concern over the country's fiscal deficit, manifesting itself in development-funding anxiety and ratings agency scoldings; the skyrocketing costs of necessities like fuel and power; the constant interruptions in electricity supply that are clearly beginning to wear on even well-established businesses; and, most pertinently, the 20% drop in foreign direct investment (FDI) recorded in Ghana last year.
But EY's survey, titled 'Executing Growth', reminds us that another, longer view exists: It reports that FDI in Ghana has been climbing since 2007, and gives no clear sign that that trend will change despite the gloom of the present day.
And despite the 20% drop in total FDI value last year, as stated by the Ghana Investment Promotion Centre (GIPC), EY says that the number of foreign-funded projectsin Ghana actually grew by more than 48% between 2012 and 2013. Among all African countries, Ghana ranked eighth in number of FDI projects from 2007 to 2013, above Uganda and Rwanda, which are frequently cited as attracting a great deal of foreign interest.
What remains less clear is whether the enthusiasm for Ghana will be sustained going forward, a subject EY addresses only indirectly in this report. There is some reason to be hopeful that it will, but this is an optimism that must be anchored by the same long-term perspective that infuses the document's look back at the last seven years.
For instance, EY finds that FDI is often concentrated in urban areas, which in Africa are growing rapidly. Accra is a prime example of the fast-expanding African metropolis with a rising middle class, whose buying power and interest in consumer goods are rising along with it.
Moreover, it is relatively close to a few other major urban centres in Nigeria, making it part of what EY calls the Greater Ibadan-Lagos-Accra (GILA) corridor. This urban cluster, whose points lie in different countries but are connected by transport and trade routes, could serve to draw – in fact, already is drawing – investors who want to enter several markets in West Africa but aren't prepared to tackle the whole region at once.
Global perceptions are also changing, for the better, about the feasibility of conducting business in Africa as a whole. EY notes that of companies that have already established a presence in Africa, a majority find Africa to be a more attractive investment destination than any other region. Businesses that have not yet entered the region, on the other hand, are more inclined to consider it less attractive. It's rather cheering to think this means that mythology, not reality, is the main driver of any skepticism surrounding Africa.
Ghana is still beset by challenges. In Doing Business 2014, a report by the World Bank and International Finance Corporation(IFC) that scores 189 economies on the ease of setting up shop there – getting electricity, paying taxes, lining up credit and so forth – Ghana ranked 67th overall, representing a backslide from its 2013 ranking of 62nd. Securing construction permits, starting a business and resolving insolvency were found to be some of the biggest headaches for entrepreneurs here relative to the rest of the world. Regionally, however, Ghana fared quite well on theDoing Business report, ranking fifth out of all countries in Africa, and in certain areas it even outperformed developed nations.
It's best kept in mind that the World Bank's report does not include several factors, some unique to Ghana and some not, that consistently pose problems for businesses already in operation, like the absence of reliable market data and, of course, the power cuts that continue unabated. Nor do its results take into account macroeconomic stability or infrastructure in a given country. Finally, and importantly, it covers only the regulations and requirements that apply to domestic businesses. Those can be extrapolated in some cases to relate to foreign companies as well (especially those setting up partnerships with indigenous firms), but undoubtedly the upshot is that certain processes will be even more time-consuming and costly for outsiders.
Perhaps more than anything else, EY's Africa Attractiveness survey shows that foreign investors are a mercurial lot, whose priorities and tastes can change rapidly based on trends of the day, bad or good PR, and their own level of experience with a region like Africa. Strengthening local institutions and underlying economic conditions must be a far more reliable path to prosperity, creating opportunities for both indigenous and foreign companies without fostering overdependence on the latter.
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FEDERAL WAY, Wash., Oct. 29 (UPI) -- A Washington state man accused of beating a Sikh cabbie while shouting anti-Muslim slurs is facing a hate crime charge, police said.
Jamie W. Larson, 48, of Federal Way, 15 miles north of Tacoma, allegedly attacked the cab driver Oct. 17 after commenting on his turban, SeattlePI.com reported. Larson is accused of pulling out a portion of the man's beard and hitting him in the mouth, loosening one of his teeth. When police arrived, Larson allegedly continued on his anti-Muslim tirade, the online newspaper said.
Larson had been placed in the cab by Auburn police about 4:30 p.m. He allegedly had been too drunk to drive or walk home after being picked up by police and taken back to the station during an unrelated incident.
Larson was charged with malicious harassment under Washington's hate crime statute, court records show.


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Note: Riverton finished with a 6-5 overall record in 2012 and was third in Region 4 with a 3-2 record. It lost to Alta 27-14 in the first round of the 5A playoffs.
RIVERTON — The Riverton High football team is not made up of heavyweights. Rather, the players on head coach Mike Miller's team gravitate more to the longer, leaner, faster side.
"We just have tall, thin, hard-working kids," the coach said, surveying his team. "We're not real big, but we've got very good team speed."
Miller said that team makeup is more and more typical of his rosters, catering to the tempo he prefers.
"I've always believed in speed over size," he said, "and it's why we run the type of offense we run."
The Silverwolves run the wing-T, an offense that involves run and pass fakes.
"If I tried to line up and go smash-mouth with my size of kids, it wouldn't be that successful," Miller said. "We have to use deception and speed in our offense to be successful. And it carries over to our defense, which is pretty aggressive."
In addition to speed, Miller says this year's squad is at an advantage because so many players want to be leaders, and have figured out how to do so cohesively.
"It's really hard this year to point out just a few leaders," he said. "With this group, what age group or class you're in doesn't matter. All of them feel comfortable enough to speak up and try to be leaders. I think, for the most part, they enjoy each other's friendship and like to spread the wealth."
Miller said there are a couple of exceptional kids who rise to the top of the pack, and Connor Henderson is one of them.
"He's just an extremely competitive young man," the coach said of his senior, who fills a dual role of quarterback and one of the team's top defensive backs. "He's a very good athlete because he's so competitive."
Henderson will direct his team behind the protection of linemen McKay Clarke, a two-year starter Miller described as the "best leader on the offensive line", along with Preston Crapo, Wyatt Pickering and Presley Timothy.
"He's a stud," Miller said of the 6-foot Timothy. "He's a kid that's just worked hard and plays hard. If he had a 6-foot-5 body, he would play in the NFL."
The Silverwolves are also anticipating big things from seniors LeGrand Toiaivao and Dallin Munger and juniors Cam Christiansen and junior Keaton Kimball — all four strong, athletic running backs.
"LeGrand is one of the great surprises of the program," Miller said of the player who had 375 total yards along with 61 tackles and two sacks last season.
"When we got him, he was just a real little guy and he's hit a big growth spurt," said the coach. "He's now about 6-1, but because he was a small guy early on, he had to learn his work ethic. Now that he's gotten big, all that is helping him out. But he's really tough and really football smart — has a good feel for the game."
Brady Slack and Yuri Yassin are both talented special teams players but too athletic for Miller to keep off the field, so both will step into the receiver rotation with Trent Denos and tight ends Ethan Cutler, Tevita Loamanu and Tanner Anderson.
"We got a great group of kids who are really unified and play together well," the coach said. "We don't have a lot of egos; they like to play together. I feel like we're well-rounded and they know it, so they're not counting on one kid to do everything."
Riverton Silverwolves at a glance
Coach: Mike Miller is entering his 10th season as Riverton's head coach, where he has led the Silverwolves to a 54-44 record. He was accumulated a 102-64 record in 16 years as a head coach. Miller is a graduate of Kearns High.
(7 returning starters; wing-T)
Connor Henderson returns to run the speedy Silverwolves' offense, which averaged 23.2 points per game a season ago. The offense is loaded with athletic players who each provide the team with ability in multiple positions, like LeGrand Toiaivao, who was a great surprise for the team, totaling 374 yards on offense last season.
(6 returning starters)
Riverton runs an aggressive defense to take advantage of the length and athleticism on the roster. The Silverwolves ranked seventh in 5A in points allowed in 2012, giving up 22.4 ppg, a number they will work to improve upon with kids like Trent Denos and Keaton Kimball working in the secondary.
Coaches preseason Region 4 straw poll: Third
Deseret News Region 4 prediction: Fourth2 comments on this story
Bottom line: As usual, the Silverwolves will rely on team speed and an up-tempo game. It is a strategy that, along with the fact that numerous players return, has earned Riverton a No. 16 preseason ranking without even playing a down. As long as the team stays healthy and unified behind its senior leadership, the group should be successful in the new Region 4.
Riverton coaching history
2004-present — Mike Miller (54-44)
1999-2003 — Rick Bojak (13-38)
Deseret News First Team all-staters the past 10 years
2010 — Landon Fisher TE
2010 — Skyler Fullmer LB
2008 — Zach Spencer, RB
2002 — Todd Jensen, DB
To view second team and honorable mention all-staters through the years, check out the Deseret News All-State Archives.


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GTA: Vice City Map Cleaner
Posted 28 December 2007 - 01:52 AM
I have been looking for a map cleaner for vice city but i can't find one.
I know that one existed as i used it about 3 years ago.
<SK> | Aussie Adam
Posted 28 December 2007 - 02:37 PM
Put it in your Root folder (Same place as vicecity.exe)...Uncheck all read only attributes for that folder.Then Run it..Then you just rebuild the IMG..
Posted 29 December 2007 - 06:07 AM
|QUOTE (l3mmy @ Dec 28 2007, 14:37)
| You want IDE Killer 2...
Put it in your Root folder (Same place as vicecity.exe)...Uncheck all read only attributes for that folder.Then Run it..Then you just rebuild the IMG..
Thanks for the fast response.
will it delete all the dff and txd files that are not needed, or does it just remove the ide files?
<SK> | Aussie Adam
Posted 07 January 2008 - 02:15 AM
Posted 27 June 2009 - 05:15 PM
Posted 25 August 2009 - 08:16 PM
I took the liberty of making a few changes to it since I couldn't believe the amount of duplicate .dff and .txd files in the both of the .bat files, there were a total of 9310 entries!
I managed to narrow the list down to 4948, so that was 4362 unneeded entries!
Since the optimised script is now half that of the original two, this means you only need to use 1 bat file to clean you gta3.img
The updated .bat file can be downloaded from the following link: http://www.bttfhillv...dMapCleaner.bat
I am also working on a NSIS installer which will allow me to run the map cleaner without moving my gta3.img to a different directory, if this would be of use to other people, just let me know and I will upload it.
Posted 03 February 2013 - 07:17 PM
|QUOTE (GTARandom @ Saturday, Jun 27 2009, 18:15)
|You can find the real working map cleaner for VC here : http://files.filefro...;/fileinfo.html
So bad that the link won't work anymore. I can't understand why these retards can't upload it on GTAGarage or somewhere else, where no one retared delete it. I need that tool, anyone have working link?
Posted 04 February 2013 - 05:43 AM Edited by Swoorup, 04 February 2013 - 05:47 AM.
EDIT: Still Mike's fast clean version is better.
Posted 05 February 2013 - 12:02 PM
1 user(s) are reading this topic
0 members, 1 guests, 0 anonymous users


text: I'm putting this in miscellaneous 'cause it's a darkroom related question, but a mod may move it if they think it fits better elsewhere. I have a regular light in my darkroom that just blew the other day. It was a 100W one and I don't have any more and can't get one. Of the brighter replacements out there, which ones turn off the fastest and how long do they take? The boxes only mention if they turn on instantly. I don't really want to stand around for 10 minutes to wait for the light to be completely off. I tried using a 60W, but it isn't really bright enough 'cause it has to cover the whole room.


text:
The society model who's stolen Harry's heart
IS SHE merely the latest in a parade of identikit upper-crust blondes? Or is she The One who will do a Grace Kelly and win the heart of a prince?
It is tempting to bet on the latter, especially as bookmakers Paddy Power are offering odds of 8/1 on Prince Harry announcing his engagement to Cressida Bonas before the year is out – odds which are likely to shorten when Harry meets Cressida's family, as he is due to do in a fortnight's time.
The pair are enjoying – in the broadest sense – each other's company on a skiing holiday in Verbier. Whether on the slopes or in the après-ski bars, the comely Miss Bonas, 24, and the party-loving Prince, 28, have been stuck together like limpets, oblivious to the stares of onlookers.
At dinner the other night in The Pot Luck restaurant they were kissing so ardently that others at the table, including Harry's uncle Prince Andrew and his ex-wife Sarah, had to turn away to spare their blushes.
As the party moved on to the Casbah nightclub Harry and Cressida retreated into a private booth where they "could barely keep their hands off each other" according to other revellers.
For a man who must necessarily demand discretion from his female companions Harry's has gone out of the window.
Since splitting up for good with Chelsy Davy, his last significant blonde, in 2011, Harry has hardly lived like a monk.
But this is perhaps the first time that he has behaved like a man head over heels in love.
So who is the girl who has turned Harry's head? As the willowy blonde daughter of old Harrovian entrepreneur Jeffrey Bonas and Lady Mary-Gaye Curzon, daughter of the 6th Earl Howe, Cressida has the right breeding and physical accountrements.
Like Chelsy Davy and another of Harry's old flames Florence Brudenell-Bruce, Cressida was educated at Stowe (fees: £10,000 a term) and like Chelsy she went on to Leeds university.
She has modelled for Burberry, worked as a ski instructor and is now studying dance. So far, so typical posh girl's CV.
But Cressida has something else: the allure of the unconventional, for which she can thank her mother.
But Cressida has something else: the allure of the unconventional, for which she can thank her mother.
Mary-Gaye Curzon – MG to her friends – is a four-times divorcee who so dazzled London society as a Sixties pin-up that Claridge's invented the Curzon cocktail in her honour.
She also posed semi-nude and covered in oil for a glossy coffee table book entitled Birds Of Britain (well it was the Sixties).
The oil was a reference to her grandfather Francis, the 5th Earl Howe, who was a racing driver with his own stable of cars as well as serving in the Navy and in Parliament.
The photographer John D Green recalled: "She was absolutely great fun and loved a party. We shot the pictures in my London studio and we made it look like she was topless."
Mary-Gaye's first husband was Kevin Esmond Cooper-Key, son of the then Tory MP for Hastings.
They married in 1971 when MG was 23 and divorced five years later after having a daughter Pandora, now 38.
A year after the divorce MG married property tycoon John Anstruther-Gough-Calthorpe and had three more children: Georgiana, now 34, Isabella, now 32 and an actress, and son Jacobi, 29 – before they divorced in 1986 after nine years.
She then began an affair with the married Jeffrey Bonas which led to a messy and costly divorce for him. In a court case over money the judge called Bonas "unreliable" and accused him of not being honest about his wealth.
Jeffrey and MG married in 1988 and Cressida, their only child, was born the following year.
Five years later the marriage was over as MG moved in with old Etonian financier and former Grenadier Guards officer Christopher Shaw, marrying him in 1996.
Cressida's childhood was split between her father's home in Norfolk and Hinton Ampner, a National Trust stately home with views over the South Downs where her mother lived with Cressida's new stepfather. As well as Stowe she spent three years at the Royal Ballet School.
Life with the Shaws was glamorous with parties at Claridge's, picnics at Royal Ascot with silver service and summers in St Tropez.
One of the Claridge's bashes Christopher Shaw hosted in the late Nineties had a Venetian theme and featured stilt-walkers and a performing dwarf.
Among the 350 guests was the Earl of Lichfield, who carried a white cane and said he had come as a Venetian blind.
Like her other forays into matrimony, MG's fourth marriage ended in divorce in 2000 when her husband left her for another woman.
She now lives in Chelsea and despite all those pregnancies, at 66 (her birthday was on Thursday) she remains a beautiful and elegant woman with undimmed joie de vivre.
Questions about Cressida's romance are met with laughter and not a hint of the anxiety that would beset a less confident woman. And she has passed this self-assurance to her daughter.
Princess Eugenie – cousin of Harry and close friend of Cressida – is credited with playing Cupid by getting them together at The Valley music festival last May.
Friends say Harry was instantly smitten. They also note Cressida was not remotely fazed by his status. Since they move in the same circles – Prince William used to have a crush on Cressida's half-sister Isabella who is due to marry their pal Sam Branson (son of Sir Richard) in two weeks – their romance was able to develop over the summer without too much comment.
They even enjoyed a holiday on Necker, the Bransons' Caribbean island. Harry then headed off on that ill-fated lads' outing to Las Vegas which resulted in naked pictures of him going global.
Was Cressida upset at her boyfriend being caught naked with other women? Not a bit. What really worried her was the enormous attention it received.
For Cressida is not interested in being a party girl.During the week she focuses on her studies at the Trinity Laban Conservatoire of Music and Dance in Greenwich and rarely goes out.
At weekends her social life revolves around dancing and a coterie which includes her siblings. Not for her the all-night benders.
It is this aloofness which has so beguiled Harry. During his five months in Afghanistan he phoned Cressida more often than he called his father.
However for Cressida the Las Vegas episode was a disturbing insight into the sort of scrutiny she could expect if she gets serious with Harry.
Nonetheless things have moved up a notch as the reports from Verbier show.
Soon Harry will meet Cressida's clan when her sister Isabella marries Sam Branson in South Africa.
For now the question is not is she The One for Prince Harry but is he The One for Cressida?


text:
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February 2012
The Pro-Flo Display Stand lets dealers showcase a designer or contemporary RO faucet along with a color kit featuring the nine finishes available for either faucet style. Each sample piece in the color kit is engraved with the finish name. The display stand base measures 10 in. wide and 5.5 in. deep and contains non-skid feet to hold it firmly in place.


text:
Ham Lake fire intensifies, weather not helping
ALONG THE GUNFLINT TRAIL - The Ham Lake fire spotted Thursday night across Gunflint Lake to the lake's south side, home to dozens of cabins, homes and the historic Gunflint Lodge.
Officials weren't able to say exactly where the fire was burning because conditions changed minute by minute.
The fire's size had grown to 30,000 acres, or 46 square miles, and was active on both sides of the border.
The worst scenario happened earlier Thursday when flames from the fire jumped a safety line and toward the Gunflint Lake area, forcing mandatory evacuations.
By Thursday night, that evacuation had been extended to north and west of the Poplar Lake Fire Hall, according to Cook County Sheriff Mark Falk. The sheriff's department maintained a cautionary roadblock at Trail Center Lodge. About the last third of the Gunflint Trail was closed to all outside traffic.
Northwest winds gusting to 25 mph, along with hot sun and temperatures around 80 degrees, pushed the fire toward developed areas of the Gunflint Trail. The heavily developed South Gunflint Lake Road and Loon Lake Road areas were evacuated just before 2 p.m.
It appears flames from the intentionally lit fire Wednesday night may have unexpectedly rekindled and moved back across fire lines.
Fire experts had hoped the intentional fires lit just northwest of Gunflint Lake would burn out fuel, slowing the wildfire as the northwest winds hit Thursday. But the intentional fire continued to burn all night and may have sent flames in the unexpected direction Thursday.
The National Weather Service says the Gunflint Trail area should see highs in the 50s and northeast winds. A red flag warning was in effect through Thursday night, a signal to the public and fire experts that dry, windy conditions could quickly push small fires into problem blazes. The best chance of rain isn't forecast until Sunday.
"We're back to the conditions we had in the first two days of the fire," Daria Day, an interagency fire center information officer, said Thursday.
A ban on all outdoor fires is in effect across St. Louis, Lake and Cook Counties, and a similar ban is in effect across Wisconsin's northern tier of counties.
Almost 600 firefighters from across the country were on the scene Thursday, with more expected. They are being supported by several helicopters and fixed-wing aircraft.
Ardis David, 81, was eating at the Gunflint Lodge when the winds brought the fire within sight and the smoke rolled in overhead. "I've never seen a sky quite like that," she said after she had evacuated. "Flames were coming off the ridge."
Gloria Johnson, 59, watched the sky darken while she was working at the Trail Center Lodge and Black Bear Bar and Restaurant, about midway down the Gunflint Trail. She and her colleagues took several nervous glances out the window.
"It's scary -- not just for myself, but this is Cook County's livelihood," she said. "We depend on the tourists in the summer."
After looking at the ominous sky, Johnson said she was going to prepare to evacuate even though her house was still miles away.
"We're nervous," she said, then began crying. "I'm emotional because I just lost my husband and so the thought of losing my house too is just too much."


text:
BROOKLYN'S 7th ANNUAL SENIOR IDOL FINALISTS ANNOUNCED
Senator Golden, "…a night of laughter, of tears and true fun in our neighborhood…"
Brooklyn- State Senator Martin J. Golden (R-C-I, Brooklyn) today is announcing that ten finalists have been selected to compete in Brooklyn's 7th Annual Senior Idol to be held on Saturday, October 5, 2013, at 7:00 p.m. at Our Lady of Angels Auditorium, located at 347 74th Street. The show begins at 7:00PM. Auditions were held with over 30 contestants participating.
Senator Marty Golden stated, "This week we are hosting what is now a very popular Brooklyn tradition, Senior Idol. This year, we have another list of performers who have great talent and will be sure to entertain the crowd. If you are looking for a night of laughter, tears, and true fun right in our neighborhood, don't miss the show."
The finalists, who auditioned for the show in September, and the songs they will sing, are as follows:
Victoria Keller "Cabaret"
Louis Keith "Georgia On My Mind"
Stephanie Spathakis "Today I Met The Boy I'm Gonna Marry"
Wei Rong Chu "Our Country"
Sherry Kayser "You Belong To Me"
Andy Gandolfo "Peggy Sue"
Gagz Danzo "Ain't That A Kick In The Head"
Nick Thomas "Can't Buy Me Love"
Daniel Onzo "Being Alive"
Florence Irving "Don't Cry Out Loud"
Larry Morrish will serve as the contest Master of Ceremonies, and a panel of judges, including Charles Otey, Joseph Loposky, and Karen Chalif will help choose Brooklyn's 7th Senior Idol. The winner will be selected through the votes of the audience and the judges.
Tickets for the event are $10.00 and can only be purchased at the door, with all proceeds to benefit the Xaverian High School Music Scholarship Fund and to purchase new instruments to support the Xaverian High School music program.


text:
I JUST got a new Lenovo SL510 (2847D2U) yesterday; my first. So far I am pleased with it. I do have a couple of issues. The first is the position of the CTRL key.
Looking through the Lenovo site, this forum, and using Google, I see that this is a common problem users have. I came from a Dell Latitude 6410. Apparently Lenovo has responded and provided a BIOS setting for this. However, in the initial BIOS of this system (1.40) and now 1.44 there is no such setting.
Is there anyway I can swap the FN and CTRL keys?
Solved! Go to Solution.
Hello mate,
I don't think it's possible for the SL series
I hope you are mistaken. So far I am impressed with this laptop; however, the placement of the CTRL key is important to me and may force me to return it. Even if I can train my finger to find the second key in, I already sense that it will cause significant pain as it forces the finger to curl under.
There is a version 1.37 of the BIOS which purports to switch the keys. There is also someone else who has hacked a more recent BIOS versions. I would much prefer to have an official solution, especially in light of the fact that Lenovo produced a solution in Oct-Nov of 2009. I hope Lenovo folks prowl these forums and may have a more positive message.
Thanks and regards,
04-01-2011 06:46 AM - edited 04-01-2011 06:47 AM
Vince69 is right. The BIOS option to swap Fn/Ctrl does not exist on SL series.
OK - Not being able to switch the CTRL and FN keys is a big deal to me. If you use Emacs you'd immediately know why. I have turned the CapsLk key into a CTRL key which helps; however, that is not as good as I'd like. I think overall the ThinkPad is an AWESOME laptop. This keyboard, stupid key positioning aside, is AWESOME! The construction just feels good.
If I upgraded to the L512 or Z560 ThinkPads would I be able to swap the CTRL and FN keys in the BIOS?
Personally I don't have a problem with the key positioning. I use visual studio where ctrl-key combos are used everywhere and it's no problem for me. I think it's just what you get used to, and you're used to something different, which is completely understandable. God forbid if I had to use a Dell, I'm sure I would complain about the same thing!
The L410/412/510/512 series does not have the option you want.
If you wanted to wait for the upcoming L420/L520 series, they will have it. In fact I *think* all of the upcoming 2011 thinkpad products will have that feature.
As for the Z560, that's not a thinkpad (it's an ideapad) so you would need to ask on that forum. I'm sorry that I don't have one to check.
**bleep**... I am constrained in that I am trying to buy a replacement laptop after losing my job. I do not have a lot of time to wait for new models. (What!? You didn't start producing this year's models last year like they do with cars? Shocking!)
I am starting to hate Lenovo for making me make tough choices. You guys should be ashamed of yourselves!
As a problem solver I have even considered re-wiriing the keyboard. However, I would screw up the warranty regardless of success so I won't... for another two years.
Thank you for your quick response.


text:
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text: I stumbled upon this photographer quite by accident. My father happened to take a trip to the north shore of Massachusetts a couple weeks ago and struck up a conversation with a woman who turned out to be Vassilev's wife. Knowing my interest in photography, my father passed along his name to me. Anyhow, he is originally from Bulgaria and the people of that country are the central theme in most of his work. I, generally, do not do much in the way of photographing people in their envrionment. I think this mostly stems from a lingering fear of confrontation that I have. As a result, I am fascinated by photographers who are comfortable doing this sort of thing - as Vassilev obviously is. Anyhow, I visited his site (http://www.jackovassilevphotography.com) and came away very impressed at his obvious talent for what HCB would have called "the decisive moment" and I think it stems from a thorough understanding of his subjects. I'm curious as to what others think. It's quite striking to note that he began his career as a technical photographer at an electrical supply company! Don't worry; he appears to be strictly analog. Curiously, the prints he has for sale are on an old communist-era paper brand known as "Fohar". I wonder if anybody has heard of it.


text:
Who's The Best Movie Sidekick?
The sidekick in film is the character who is latched onto the main character and will bend over backward to do anything the hero needs. The sidekick is the loyal servant, the one in the motorcycle's sidecar who isn't embarrassed to be there. While many have graced the big screen, we can only have one favorite, and will put it to a vote. Here are the finalists. Did we miss any? Name them in the comments and call us retards for forgetting them.
Though Azamat fights (naked) with Borat and abandons him, he redeems himself in the end and gets Borat what he wants: Pamela Anderson.
It's John Candy in a Mel Brooks movie!
Forget Jenny – she did nothing but hurt Forrest. This shrimp-lover pulls through, plants an idea in Forrest's head and makes him a millionaire. Bubba is the real hero of Forrest Gump.
This man stays loyal to Ricky Bobby even after stealing his wife and taking his home.
A guy like Ferris Bueller needs a guy like Cameron, who just so happens to be sick on the same day that Bueller takes a day off. Oh yeah, "Ed, this is George Peterson."
One of the most loyal sidekicks ever, Chewbacca is trusted by Han Solo, a man who trusts very few.
If it weren't for the voice of Eddie Murphy, this character would be left off the list like all Disney sidekicks.
It's Marty Feldman in a Mel Brooks movie!
As an actor, Dana Carvey wants to be front and center, but instead takes a demotion while working with Mike Myers' Wayne Campbell. Myers has two sidekicks on this list, including Shrek.
He doesn't get much screen time but he's a legend and the loyal sidekick to Don Vito Corleone. Read Gunaxin's Tribute to Luca Brasi.
This time, the sidekick gets to be president!
Sam isn't the most memorable character but he pulls through for Frodo and ultimately saves Middle Earth.
My No. 1 pick, Short Round is the classic sidekick – an Asian pickpocket. Also read Gunaxin's Tribute to Short Round.
When Sloth meets Chunk, it's not clear who's the master and who's the sidekick, but toward the end, Sloth abandons his family (as if that was really an ordeal for him) and joins up with Chunk and the Goonies. Don't forget to read Gunaxin's Tribute to Sloth, and Tribute to Chunk.
Walter isn't your ordinary sidekick because he pretty much does what he wants and doesn't really let The Dude lead the way. But after The Dude's ordeal, Walter steps in like any good buddy would. And Walter has his own sidekick – Donnie.
Note: Some people, like Doc Brown from Back to the Future or Mr. Miyagi from The Karate Kid, were purposely left out because they aren't really sidekicks, but teachers who weren't latched onto the main character in typical sidekick fashion. Also, side characters such as R2-D2 and C-3PO, and those two buffoons from Pirates of the Caribbean, were left off because they are comedic duos, who feed off each other instead of the main character.
For a similar list, check out Gunaxin's Film's Greatest Slacker Duos.
One last thing… Robin sucks.
[poll id="57″]


text:
Rules that sell the market short
That morning, the veteran market maker has been interviewing for a couple of juniors. Twenty grand a year and, if they're any good, a shot at the Big Time at one of the City's best firms.
No degree needed, but do try to make a passable stab at the killer question he's been firing at would-be market makers for years: what are 25,000 ha'pennies? No calculators. No pencil and paper. Think on your feet, don't stare at them.
An hour later and he's perched on barstool, girding against the cold snap with an agreeable Burgundy and railing against the latest dopey rule changes threatening to pour sugar into his industry's petrol tank.
It's Europe again. In the name of greater financial stability — read: propping up…


text:
Dayshon Smith has mid-major coaches facing one of their biggest fears: one of their main targets playing their way into the high-major field.
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