High leverage interventions: three cases of defensive action and their lessons for OR/MS today.

This paper has two aims. First, to present cases in which scientists developed a defensive system for their homeland: Blackett and the air defense of Britain in WWII, Forrester and the SAGE system for North America in the Cold War, and Archimedes’ work defending Syracuse during the Second Punic War. In each case the historical context and the individual’s other achievements are outlined, and a description of the contribution’s relationship to OR/MS is given. The second aim is to consider some of the features the cases share and examine them in terms of contemporary OR/MS methodology. Particular reference is made to a recent analysis of the field’s strengths and weaknesses. This allows both a critical appraisal of the field and a set of potential responses for strengthening it. Although a mixed set of lessons arise, the overall conclusion is that the cases are examples to build on and that OR/MS retains the ability to do high stakes work.

Effect of pH, temperature and surface contact on the elaboration of fimbriae and flagella by Salmonella serotype Enteritidis

Survival of enteric pathogens exposed to various environmental stresses depends upon a number of protective responses, some of which are associated with induction of virulence determinants. Flagella and fimbriae are putative virulence determinants of Salmonella spp, and ELISAs specific for the detection of flagella and SEF21, SEF14 and SEF17 fimbriae were used to assess the effect of temperature and pH upon their elaboration by isolates of Salmonella serotype Enteritidis in planktonic growth and on the surface of two-dimensional gradient agar plates, For three phage type 4 isolates of Enteritidis of comparative clinical provenance, similar phenotypes for the elaboration of these surface antigens were observed. SEF14 fimbriae were elaborated in planktonic growth at 37 degrees C, but not 20 degrees C, at pH 4.77 and above but not at pH 4.04; whereas on agar gradient plates SEF14 fimbriae were elaborated poorly but with best yields at pH 4.04, SEF17 fimbriae were elaborated in planktonic growth at 20 degrees C, but not at 37 degrees C, at pH 6.18 and above but not at pH 5.09 or below; whereas on agar gradient plates SEF17 fimbriae were elaborated well even at pH 4.65, SEF21 fimbriae were expressed very poorly under all conditions tested, Planktonic growth at 37 degrees C induced least flagella whereas growth at 20 degrees C, and particularly surface growth at lower pH values, induced a 'hyper-flagellate' phenotype, Single colonies allowed to form on gradient agar plates were shown to generate different colonial morphologies which were dependent on initial pH. These results demonstrate that the physicochemical environment is an important determinant of bacterial response, especially the induction of putative virulence factors.

c-Cbl mediates ubiquitination, degradation, and down-regulation of human protease-activated receptor 2

Mechanisms that arrest G-protein-coupled receptor (GPCR) signaling prevent uncontrolled stimulation that could cause disease. Although uncoupling from heterotrimeric G-proteins, which transiently arrests signaling, is well described, little is known about the mechanisms that permanently arrest signaling. Here we reported on the mechanisms that terminate signaling by protease-activated receptor 2 (PAR(2)), which mediated the proinflammatory and nociceptive actions of proteases. Given its irreversible mechanism of proteolytic activation, PAR(2) is a model to study the permanent arrest of GPCR signaling. By immunoprecipitation and immunoblotting, we observed that activated PAR(2) was mono-ubiquitinated. Immunofluorescence indicated that activated PAR(2) translocated from the plasma membrane to early endosomes and lysosomes where it was degraded, as determined by immunoblotting. Mutant PAR(2) lacking intracellular lysine residues (PAR(2)Delta14K/R) was expressed at the plasma membrane and signaled normally but was not ubiquitinated. Activated PAR(2) Delta14K/R internalized but was retained in early endosomes and avoided lysosomal degradation. Activation of wild type PAR(2) stimulated tyrosine phosphorylation of the ubiquitin-protein isopeptide ligase c-Cbl and promoted its interaction with PAR(2) at the plasma membrane and in endosomes in an Src-dependent manner. Dominant negative c-Cbl lacking the ring finger domain inhibited PAR(2) ubiquitination and induced retention in early endosomes, thereby impeding lysosomal degradation. Although wild type PAR(2) was degraded, and recovery of agonist responses required synthesis of new receptors, lysine mutation and dominant negative c-Cbl impeded receptor ubiquitination and degradation and allowed PAR(2) to recycle and continue to signal. Thus, c-Cbl mediated ubiquitination and lysosomal degradation of PAR(2) to irrevocably terminate signaling by this and perhaps other GPCRs.

Modulation of potassium ion channel proteins utilising antibodies

The application of antibodies to living cells has the potential to modulate the function of specific proteins by virtue of their high specificity. This specificity has proven effective in determining the involvement of many proteins in neuronal function where specific agonists and antagonists do not exist, e.g. ion channel subunits. We discuss a way to utilise subunit specific antibodies to target individual channel subunits in electrophysiological experiments to determine functional roles within native neurones. Utilising this approach, we have investigated the role of the voltage-gated potassium channel Kv3.1b subunit within a region of the brainstem important in the regulation of autonomic function. We provide some useful control experiments in order to help validate this method. We conclude that antibodies can be extremely valuable in determining the functions of specific proteins in living neurones in neuroscience research.

Multivariate analysis of the dielectric response of materials modeled using networks of resistors and capacitors

We discuss the modeling of dielectric responses of electromagnetically excited networks which are composed of a mixture of capacitors and resistors. Such networks can be employed as lumped-parameter circuits to model the response of composite materials containing conductive and insulating grains. The dynamics of the excited network systems are studied using a state space model derived from a randomized incidence matrix. Time and frequency domain responses from synthetic data sets generated from state space models are analyzed for the purpose of estimating the fraction of capacitors in the network. Good results were obtained by using either the time-domain response to a pulse excitation or impedance data at selected frequencies. A chemometric framework based on a Successive Projections Algorithm (SPA) enables the construction of multiple linear regression (MLR) models which can efficiently determine the ratio of conductive to insulating components in composite material samples. The proposed method avoids restrictions commonly associated with Archie’s law, the application of percolation theory or Kohlrausch-Williams-Watts models and is applicable to experimental results generated by either time domain transient spectrometers or continuous-wave instruments. Furthermore, it is quite generic and applicable to tomography, acoustics as well as other spectroscopies such as nuclear magnetic resonance, electron paramagnetic resonance and, therefore, should be of general interest across the dielectrics community.

Evaluation of climate models using palaeoclimatic data.

There is large uncertainty about the magnitude of warming and how rainfall patterns will change in response to any given scenario of future changes in atmospheric composition and land use. The models used for future climate projections were developed and calibrated using climate observations from the past 40 years. The geologic record of environmental responses to climate changes provides a unique opportunity to test model performance outside this limited climate range. Evaluation of model simulations against palaeodata shows that models reproduce the direction and large-scale patterns of past changes in climate, but tend to underestimate the magnitude of regional changes. As part of the effort to reduce model-related uncertainty and produce more reliable estimates of twenty-first century climate, the Palaeoclimate Modelling Intercomparison Project is systematically applying palaeoevaluation techniques to simulations of the past run with the models used to make future projections. This evaluation will provide assessments of model performance, including whether a model is sufficiently sensitive to changes in atmospheric composition, as well as providing estimates of the strength of biosphere and other feedbacks that could amplify the model response to these changes and modify the characteristics of climate variability.

Classification of cortical microcircuits based on micro-electrode-array data from slices of rat barrel cortex

The bewildering complexity of cortical microcircuits at the single cell level gives rise to surprisingly robust emergent activity patterns at the level of laminar and columnar local field potentials (LFPs) in response to targeted local stimuli. Here we report the results of our multivariate data-analytic approach based on simultaneous multi-site recordings using micro-electrode-array chips for investigation of the microcircuitary of rat somatosensory (barrel) cortex. We find high repeatability of stimulus-induced responses, and typical spatial distributions of LFP responses to stimuli in supragranular, granular, and infragranular layers, where the last form a particularly distinct class. Population spikes appear to travel with about 33 cm/s from granular to infragranular layers. Responses within barrel related columns have different profiles than those in neighbouring columns to the left or interchangeably to the right. Variations between slices occur, but can be minimized by strictly obeying controlled experimental protocols. Cluster analysis on normalized recordings indicates specific spatial distributions of time series reflecting the location of sources and sinks independent of the stimulus layer. Although the precise correspondences between single cell activity and LFPs are still far from clear, a sophisticated neuroinformatics approach in combination with multi-site LFP recordings in the standardized slice preparation is suitable for comparing normal conditions to genetically or pharmacologically altered situations based on real cortical microcircuitry.

The evolutionary basis for differences between the immune systems of man, mouse, pig and ruminants

Studying the pathogenesis of an infectious disease like colibacillosis requires an understanding of the responses of target hosts to the organism both as a pathogen and as a commensal. The mucosal immune system constitutes the primary line of defence against luminal micro-organisms. The immunoglobulin-superfamily-based adaptive immune system evolved in the earliest jawed vertebrates, and the adaptive and innate immune system of humans, mice, pigs and ruminants co-evolved in common ancestors for approximately 300 million years. The divergence occurred only 100 mya and, as a consequence, most of the fundamental immunological mechanisms are very similar. However, since pressure on the immune system comes from rapidly evolving pathogens, immune systems must also evolve rapidly to maintain the ability of the host to survive and reproduce. As a consequence, there are a number of areas of detail where mammalian immune systems have diverged markedly from each other, such that results obtained in one species are not always immediately transferable to another. Thus, animal models of specific diseases need to be selected carefully, and the results interpreted with caution. Selection is made simpler where specific host species like cattle and pigs can be both target species and reservoirs for human disease, as in infections with Escherichia coli.

Temporal coupling between stimulus-evoked neural activity and hemodynamic responses from individual cortical columns

Using previously published data from the whisker barrel cortex of anesthetized rodents (Berwick et al 2008 J. Neurophysiol. 99 787–98) we investigated whether highly spatially localized stimulus-evoked cortical hemodynamics responses displayed a linear time-invariant (LTI) relationship with neural activity. Presentation of stimuli to individual whiskers of 2 s and 16 s durations produced hemodynamics and neural activity spatially localized to individual cortical columns. Two-dimensional optical imaging spectroscopy (2D-OIS) measured hemoglobin responses, while multi-laminar electrophysiology recorded neural activity. Hemoglobin responses to 2 s stimuli were deconvolved with underlying evoked neural activity to estimate impulse response functions which were then convolved with neural activity evoked by 16 s stimuli to generate predictions of hemodynamic responses. An LTI system more adequately described the temporal neuro-hemodynamics coupling relationship for these spatially localized sensory stimuli than in previous studies that activated the entire whisker cortex. An inability to predict the magnitude of an initial 'peak' in the total and oxy- hemoglobin responses was alleviated when excluding responses influenced by overlying arterial components. However, this did not improve estimation of the hemodynamic responses return to baseline post-stimulus cessation.

Does neural input or processing play a greater role in the magnitude of neuroimaging signals?

An important constraint on how hemodynamic neuroimaging signals such as fMRI can be interpreted in terms of the underlying evoked activity is an understanding of neurovascular coupling mechanisms that actually generate hemodynamic responses. The predominant view at present is that the hemodynamic response is most correlated with synaptic input and subsequent neural processing rather than spiking output. It is still not clear whether input or processing is more important in the generation of hemodynamics responses. In order to investigate this we measured the hemodynamic and neural responses to electrical whisker pad stimuli in rat whisker barrel somatosensory cortex both before and after the local cortical injections of the GABAA agonist muscimol. Muscimol would not be expected to affect the thalamocortical input into the cortex but would inhibit subsequent intra-cortical processing. Pre-muscimol infusion whisker stimuli elicited the expected neural and accompanying hemodynamic responses to that reported previously. Following infusion of muscimol, although the temporal profile of neural responses to each pulse of the stimulus train was similar, the average response was reduced in magnitude by ∼79% compared to that elicited pre-infusion. The whisker-evoked hemodynamic responses were reduced by a commensurate magnitude suggesting that, although the neurovascular coupling relationships were similar for synaptic input as well as for cortical processing, the magnitude of the overall response is dominated by processing rather than from that produced from the thalamocortical input alone.

Improving assessment and modelling of climate change impacts on global terrestrial biodiversity.

Understanding how species and ecosystems respond to climate change has become a major focus of ecology and conservation biology. Modelling approaches provide important tools for making future projections, but current models of the climate-biosphere interface remain overly simplistic, undermining the credibility of projections. We identify five ways in which substantial advances could be made in the next few years: (i) improving the accessibility and efficiency of biodiversity monitoring data, (ii) quantifying the main determinants of the sensitivity of species to climate change, (iii) incorporating community dynamics into projections of biodiversity responses, (iv) accounting for the influence of evolutionary processes on the response of species to climate change, and (v) improving the biophysical rule sets that define functional groupings of species in global models.

The next generation of scenarios for climate change research and assessment

Advances in the science and observation of climate change are providing a clearer understanding of the inherent variability of Earth’s climate system and its likely response to human and natural influences. The implications of climate change for the environment and society will depend not only on the response of the Earth system to changes in radiative forcings, but also on how humankind responds through changes in technology, economies, lifestyle and policy. Extensive uncertainties exist in future forcings of and responses to climate change, necessitating the use of scenarios of the future to explore the potential consequences of different response options. To date, such scenarios have not adequately examined crucial possibilities, such as climate change mitigation and adaptation, and have relied on research processes that slowed the exchange of information among physical, biological and social scientists. Here we describe a new process for creating plausible scenarios to investigate some of the most challenging and important questions about climate change confronting the global community

The effects of distraction on metacognition and metacognition on distraction: evidence from recognition memory

The effects of auditory distraction in memory tasks have been examined to date with procedures that minimize participants’ control over their own memory processes. Surprisingly little attention has been paid to metacognitive control factors which might affect memory performance. In this study, we investigate the effects of auditory distraction on metacognitive control of memory, examining the effects of auditory distraction in recognition tasks utilizing the metacognitive framework of Koriat and Goldsmith (1996), to determine whether strategic regulation of memory accuracy is impacted by auditory distraction. Results replicated previous findings in showing that auditory distraction impairs memory performance in tasks minimizing participants’ metacognitive control (forced-report test). However, the results revealed also that when metacognitive control is allowed (free-report tests), auditory distraction impacts upon a range of metacognitive indices. In the present study, auditory distraction undermined accuracy of metacognitive monitoring (resolution), reduced confidence in responses provided and, correspondingly, increased participants’ propensity to withhold responses in free-report recognition. Crucially, changes in metacognitive processes were related to impairment in free-report recognition performance, as the use of the ‘don’t know’ option under distraction led to a reduction in the number of correct responses volunteered in free-report tests. Overall, the present results show how auditory distraction exerts its influence on memory performance via both memory and metamemory processes.

Effects of the 5-HT(1A) agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on cocaine choice in cynomolgus monkeys

Drugs that alter brain serotonin (5-HT) function can modulate the behavioral effects of cocaine, but the underlying receptor mechanisms are poorly understood. The present study examined the effects of the selective 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.01-0.1 mg/kg, i.v.) on cocaine self-administration in the context of a choice procedure. Five adult male cynomolgus monkeys self-administered cocaine (saline, 0.003-0.03 mg/kg per injection) under a concurrent fixed-ratio 50 schedule of food (1-g banana-flavored pellets) and cocaine presentation. Allocation of responses to the cocaine-associated lever (cocaine choice) increased in a dose-related manner from < or =20% of total responses when saline or 0.003 mg/kg per injection cocaine was the alternative to food to > or =75% when 0.03 mg/kg per injection cocaine was available. In four of five monkeys, when choice was between a low cocaine dose and food, 0.01 mg/kg 8-OH-DPAT increased injection-lever responding. At cocaine doses which occasioned > or =75% cocaine choice, 8-OH-DPAT did not alter response allocation. In the fifth monkey, 8-OH-DPAT only decreased injection-lever responding. When choice was between saline and food, 8-OH-DPAT did not reliably shift responding to the injection lever, except at doses that disrupted operant performance. These results suggest that a 5-HT1A receptor agonist can increase the reinforcing strength of a low cocaine dose relative to a concurrently available non-drug reinforcer.

Ionospheric and geomagnetic responses to changes in IMF B_Z: a superposed epoch study

Superposed epoch studies have been carried out in order to determine the ionospheric response at mid-latitudes to southward turnings of the interplanetary magnetic field (IMF). This is compared with the geomagnetic response, as seen in the indices K p, AE and Dst. The solar wind, IMF and geomagnetic data used were hourly averages from the years 1967–1989 and thus cover a full 22-year cycle in the solar magnetic field. These data were divided into subsets, determined by the magnitudes of the southward turnings and the concomitant increase in solar wind pressure. The superposed epoch studies were carried out using the time of the southward turning as time zero. The response of the mid-latitude ionosphere is studied by looking at the F-layer critical frequencies, f o F2, from hourly soundings by the Slough ionosonde and their deviation from the monthly median values, δf o F2. For the southward turnings with a change in B z of δB z > 11.5 nT accompanied by a solar wind dynamic pressure P exceeding 5 nPa, the F region critical frequency, f o F2, shows a marked decrease, reaching a minimum value about 20 h after the southward turning. This recovers to pre-event values over the subsequent 24 h, on average. The Dst index shows the classic storm-time decrease to about −60 nT. Four days later, the index has still to fully recover and is at about −25 nT. Both the K p and AE indices show rises before the southward turnings, when the IMF is strongly northward but the solar wind dynamic pressure is enhanced. The average AE index does register a clear isolated pulse (averaging 650 nT for 2 h, compared with a background peak level of near 450 nT at these times) showing enhanced energy deposition at high latitudes in substorms but, like K p, remains somewhat enhanced for several days, even after the average IMF has returned to zero after 1 day. This AE background decays away over several days as the Dst index recovers, indicating that there is some contamination of the currents observed at the AE stations by the continuing enhanced equatorial ring current. For data averaged over all seasons, the critical frequencies are depressed at Slough by 1.3 MHz, which is close to the lower decile of the overall distribution of δf o Fl values. Taking 30-day periods around summer and winter solstice, the largest depression is 1.6 and 1.2 MHz, respectively. This seasonal dependence is confirmed by a similar study for a Southern Hemisphere station, Argentine Island, giving peak depressions of 1.8 MHz and 0.5 MHz for summer and winter. For the subset of turnings where δB z > 11.5 nT and P ≤ 5 nPa, the response of the geomagnetic indices is similar but smaller, while the change in δf o F2 has all but disappeared. This confirms that the energy deposited at high latitudes, which leads to the geomagnetic and ionospheric disturbances following a southward turning of the IMF, increases with the energy density (dynamic pressure) of the solar wind flow. The magnitude of all responses are shown to depend on δB z . At Slough, the peak depression always occurs when Slough rotates into the noon sector. The largest ionospheric response is for southward turnings seen between 15–21 UT.