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The solution of the KdV equation with single‐minimum initial data has a zero‐dispersion limit characterized by Lax and Levermore as the solution of an infinite‐dimensional constrained quadratic minimization problem. An adaptive numerical method for computing the weak limit from this characterization is constructed and validated. The method is then used to study the weak limit. Initial simple experiments confirm theoretical predictions, while experiments with more complicated data display multiphase behavior considerably beyond the scope of current theoretical analyses. The method computes accurate weak limits with multiphase structures sufficiently complex to provide useful test cases for the calibration of numerical averaging algorithms. © 1994 John Wiley & Sons, Inc. Copyright © 1994 Wiley Periodicals, Inc., A Wiley Company

The causal connectivity of a network is often inferred to understand network function. It is arguably acknowledged that the inferred causal connectivity relies on the causality measure one applies, and it may differ from the network's underlying structural connectivity. However, the interpretation of causal connectivity remains to be fully clarified, in particular, how causal connectivity depends on causality measures and how causal connectivity relates to structural connectivity. Here, we focus on nonlinear networks with pulse signals as measured output, e.g., neural networks with spike output, and address the above issues based on four commonly utilized causality measures, i.e., time-delayed correlation coefficient, time-delayed mutual information, Granger causality, and transfer entropy. We theoretically show how these causality measures are related to one another when applied to pulse signals. Taking a simulated Hodgkin-Huxley network and a real mouse brain network as two illustrative examples, we further verify the quantitative relations among the four causality measures and demonstrate that the causal connectivity inferred by any of the four well coincides with the underlying network structural connectivity, therefore illustrating a direct link between the causal and structural connectivity. We stress that the structural connectivity of pulse-output networks can be reconstructed pairwise without conditioning on the global information of all other nodes in a network, thus circumventing the curse of dimensionality. Our framework provides a practical and effective approach for pulse-output network reconstruction., Competing Interests: Competing interests statement:The authors declare no competing interest.

Synaptic plasticity [long-term potentiation/depression (LTP/D)], is a cellular mechanism underlying learning. Two distinct types of early LTP/D (E-LTP/D), acting on very different time scales, have been observed experimentally-spike timing dependent plasticity (STDP), on time scales of tens of ms; and behavioral time scale synaptic plasticity (BTSP), on time scales of seconds. BTSP is a candidate for a mechanism underlying rapid learning of spatial location by place cells. Here, a computational model of the induction of E-LTP/D at a spine head of a synapse of a hippocampal pyramidal neuron is developed. The single-compartment model represents two interacting biochemical pathways for the activation (phosphorylation) of the kinase (CaMKII) with a phosphatase, with ion inflow through channels (NMDAR, CaV1,Na). The biochemical reactions are represented by a deterministic system of differential equations, with a detailed description of the activation of CaMKII that includes the opening of the compact state of CaMKII. This single model captures realistic responses (temporal profiles with the differing timescales) of STDP and BTSP and their asymmetries. The simulations distinguish several mechanisms underlying STDP vs. BTSP, including i) the flow of [Formula: see text] through NMDAR vs. CaV1 channels, and ii) the origin of several time scales in the activation of CaMKII. The model also realizes a priming mechanism for E-LTP that is induced by [Formula: see text] flow through CaV1.3 channels. Once in the spine head, this small additional [Formula: see text] opens the compact state of CaMKII, placing CaMKII ready for subsequent induction of LTP., Competing Interests: Competing interests statement:The authors declare no competing interest.

Recent experiments in the developing mammalian visual cortex have revealed that gap junctions couple excitatory cells and potentially influence the formation of chemical synapses. In particular, cells that were coupled by a gap junction during development tend to share an orientation preference and are preferentially coupled by a chemical synapse in the adult cortex, a property that is diminished when gap junctions are blocked. In this work, we construct a simplified model of the developing mouse visual cortex including spike-timing-dependent plasticity of both the feedforward synaptic inputs and recurrent cortical synapses. We use this model to show that synchrony among gap-junction-coupled cells underlies their preference to form strong recurrent synapses and develop similar orientation preference; this effect decreases with an increase in coupling density. Additionally, we demonstrate that gap-junction coupling works, together with the relative timing of synaptic development of the feedforward and recurrent synapses, to determine the resulting cortical map of orientation preference., Competing Interests: The authors have declared that no competing interests exist.

Cortical networks are complex systems of a great many interconnected neurons that operate from collective dynamical states. To understand how cortical neural networks function, it is important to identify their common dynamical operating states from the probabilistic viewpoint. Probabilistic characteristics of these operating states often underlie network functions. Here, using multi-electrode data from three separate experiments, we identify and characterize a cortical operating state (the "probability polling" or "p-polling" state), common across mouse and monkey with different behaviors. If the interaction among neurons is weak, the p-polling state provides a quantitative understanding of how the high dimensional probability distribution of firing patterns can be obtained by the low-order maximum entropy formulation, effectively utilizing a low dimensional stimulus-coding structure. These results show evidence for generality of the p-polling state and in certain situations its advantage of providing a mathematical validation for the low-order maximum entropy principle as a coding strategy., (© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

When similar visual stimuli are presented binocularly to both eyes, one perceives a fused single image. However, when the two stimuli are distinct, one does not perceive a single image; instead, one perceives binocular rivalry. That is, one perceives one of the stimulated patterns for a few seconds, then the other for few seconds, and so on - with random transitions between the two percepts. Most theoretical studies focus on rivalry, with few considering the coexistence of fusion and rivalry. Here we develop three distinct computational neuronal network models which capture binocular rivalry with realistic stochastic properties, fusion, and the hysteretic transition between. Each is a conductance-based point neuron model, which is multi-layer with two ocular dominance columns (L & R) and with an idealized "ring" architecture where the orientation preference of each neuron labels its location on a ring. In each model, the primary mechanism initiating binocular rivalry is cross-column inhibition, with firing rate adaptation governing the temporal properties of the transitions between percepts. Under stimulation by similar visual patterns, each of three models uses its own mechanism to overcome cross-column inhibition, and thus to prevent rivalry and allow the fusion of similar images: The first model uses cross-column feedforward inhibition from the opposite eye to "shut off" the cross-column feedback inhibition; the second model "turns on" a second layer of monocular neurons as a parallel pathway to the binocular neurons, rivaling out of phase with the first layer, and together these two pathways represent fusion; and the third model uses cross-column excitation to overcome the cross-column inhibition and enable fusion. Thus, each of the idealized ring models depends upon a different mechanism for fusion that might emerge as an underlying mechanism present in real visual cortex.

Complex dendrites in general present formidable challenges to understanding neuronal information processing. To circumvent the difficulty, a prevalent viewpoint simplifies the neuronal morphology as a point representing the soma, and the excitatory and inhibitory synaptic currents originated from the dendrites are treated as linearly summed at the soma. Despite its extensive applications, the validity of the synaptic current description remains unclear, and the existing point neuron framework fails to characterize the spatiotemporal aspects of dendritic integration supporting specific computations. Using electrophysiological experiments, realistic neuronal simulations, and theoretical analyses, we demonstrate that the traditional assumption of linear summation of synaptic currents is oversimplified and underestimates the inhibition effect. We then derive a form of synaptic integration current within the point neuron framework to capture dendritic effects. In the derived form, the interaction between each pair of synaptic inputs on the dendrites can be reliably parameterized by a single coefficient, suggesting the inherent low-dimensional structure of dendritic integration. We further generalize the form of synaptic integration current to capture the spatiotemporal interactions among multiple synaptic inputs and show that a point neuron model with the synaptic integration current incorporated possesses the computational ability of a spatial neuron with dendrites, including direction selectivity, coincidence detection, logical operation, and a bilinear dendritic integration rule discovered in experiment. Our work amends the modeling of synaptic inputs and improves the computational power of a modeling neuron within the point neuron framework., (Copyright © 2019 the Author(s). Published by PNAS.)

Recent experiments have shown that mouse primary visual cortex (V1) is very different from that of cat or monkey, including response properties-one of which is that contrast invariance in the orientation selectivity (OS) of the neurons' firing rates is replaced in mouse with contrast-dependent sharpening (broadening) of OS in excitatory (inhibitory) neurons. These differences indicate a different circuit design for mouse V1 than that of cat or monkey. Here we develop a large-scale computational model of an effective input layer of mouse V1. Constrained by experiment data, the model successfully reproduces experimentally observed response properties-for example, distributions of firing rates, orientation tuning widths, and response modulations of simple and complex neurons, including the contrast dependence of orientation tuning curves. Analysis of the model shows that strong feedback inhibition and strong orientation-preferential cortical excitation to the excitatory population are the predominant mechanisms underlying the contrast-sharpening of OS in excitatory neurons, while the contrast-broadening of OS in inhibitory neurons results from a strong but nonpreferential cortical excitation to these inhibitory neurons, with the resulting contrast-broadened inhibition producing a secondary enhancement on the contrast-sharpened OS of excitatory neurons. Finally, based on these mechanisms, we show that adjusting the detailed balances between the predominant mechanisms can lead to contrast invariance-providing insights for future studies on contrast dependence (invariance)., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

One of the fundamental questions in system neuroscience is how the brain encodes external stimuli in the early sensory cortex. It has been found in experiments that even some simple sensory stimuli can activate large populations of neurons. It is believed that information can be encoded in the spatiotemporal profile of these collective neuronal responses. Here, we use a large-scale computational model of the primary visual cortex (V1) to study the population responses in V1 as observed in experiments in which monkeys performed visual detection tasks. We show that our model can capture very well spatiotemporal activities measured by voltage-sensitive-dye-based optical imaging in V1 of the awake state. In our model, the properties of horizontal long-range connections with NMDA conductance play an important role in the correlated population responses and have strong implications for spatiotemporal coding of neuronal populations. Our computational modeling approach allows us to reveal intrinsic cortical dynamics, separating them from those statistical effects arising from averaging procedures in experiment. For example, in experiments, it was shown that there was a spatially antagonistic center-surround structure in optimal weights in signal detection theory, which was believed to underlie the efficiency of population coding. However, our study shows that this feature is an artifact of data processing.

Aneurysms of the hepatic artery are rare, but are associated with significant mortality because of their lack of symptoms at presentation and risk of rupture. We report a case of an enlarging 4-cm hepatic artery aneurysm involving the proximal common hepatic artery to the bifurcation of the right and left hepatic arteries which was found incidentally on ultrasound examination. Endovascular treatment with a stent was considered, but because of the location of the aneurysm as well as the presence of significant thrombosis involving the right and left hepatic arteries, aneurysmectomy and revascularization using saphenous vein was performed. Doppler ultrasound measurements demonstrated good flow through the graft postoperatively and at 1-month follow-up. Although a variety of endovascular techniques exist to treat hepatic artery aneurysms, our results indicate that open excision and revascularization may be required and can have a good outcome., (Copyright © 2011 Annals of Vascular Surgery Inc. Published by Elsevier Inc. All rights reserved.)

Animals process information about many stimulus features simultaneously, swiftly (in a few 100 ms), and robustly (even when individual neurons do not themselves respond reliably). When the brain carries, codes, and certainly when it decodes information, it must do so through some coarse-grained projection mechanism. How can a projection retain information about network dynamics that covers multiple features, swiftly and robustly? Here, by a coarse-grained projection to event trees and to the event chains that comprise these trees, we propose a method of characterizing dynamic information of neuronal networks by using a statistical collection of spatial-temporal sequences of relevant physiological observables (such as sequences of spiking multiple neurons). We demonstrate, through idealized point neuron simulations in small networks, that this event tree analysis can reveal, with high reliability, information about multiple stimulus features within short realistic observation times. Then, with a large-scale realistic computational model of V1, we show that coarse-grained event trees contain sufficient information, again over short observation times, for fine discrimination of orientation, with results consistent with recent experimental observation.

Within a large-scale neuronal network model of macaque primary visual cortex, we examined how intrinsic dynamic fluctuations in synaptic currents modify the effect of strong recurrent excitation on orientation selectivity. Previously, we showed that, using a strong network inhibition countered by feedforward and recurrent excitation, the cortical model reproduced many observed properties of simple and complex cells. However, that network's complex cells were poorly selective for orientation, and increasing cortical self-excitation led to network instabilities and unrealistically high firing rates. Here, we show that a sparsity of connections in the network produces large, intrinsic fluctuations in the cortico-cortical conductances that can stabilize the network and that there is a critical level of fluctuations (controllable by sparsity) that allows strong cortical gain and the emergence of orientation-selective complex cells. The resultant sparse network also shows near contrast invariance in its selectivity and, in agreement with recent experiments, has extracellular tuning properties that are similar in pinwheel center and iso-orientation regions, whereas intracellular conductances show positional dependencies. Varying the strength of synaptic fluctuations by adjusting the sparsity of network connectivity, we identified a transition between the dynamics of bistability and without bistability. In a network with strong recurrent excitation, this transition is characterized by a near hysteretic behavior and a rapid rise of network firing rates as the synaptic drive or stimulus input is increased. We discuss the connection between this transition and orientation selectivity in our model of primary visual cortex.

In order to identify and understand mechanistically the cortical circuitry of sensory information processing estimates are needed of synaptic input fields that drive neurons. From intracellular in vivo recordings one would like to estimate net synaptic conductance time courses for excitation and inhibition, g(E)(t) and g(I)(t), during time-varying stimulus presentations. However, the intrinsic conductance transients associated with neuronal spiking can confound such estimates, and thereby jeopardize functional interpretations. Here, using a conductance-based pyramidal neuron model we illustrate errors in estimates when the influence of spike-generating conductances are not reduced or avoided. A typical estimation procedure involves approximating the current-voltage relation at each time point during repeated stimuli. The repeated presentations are done in a few sets, each with a different steady bias current. From the trial-averaged smoothed membrane potential one estimates total membrane conductance and then dissects out estimates for g(E)(t) and g(I)(t). Simulations show that estimates obtained during phases without spikes are good but those obtained from phases with spiking should be viewed with skeptism. For the simulations, we consider two different synaptic input scenarios, each corresponding to computational network models of orientation tuning in visual cortex. One input scenario mimics a push-pull arrangement for g(E)(t) and g(I)(t) and idealized as specified smooth time courses. The other is taken directly from a large-scale network simulation of stochastically spiking neurons in a slab of cortex with recurrent excitation and inhibition. For both, we show that spike-generating conductances cause serious errors in the estimates of g(E) and g(I). In some phases for the push-pull examples even the polarity of g(I) is mis-estimated, indicating significant increase when g(I) is actually decreased. Our primary message is to be cautious about forming interpretations based on estimates developed during spiking phases.

Our large-scale computational model of the primary visual cortex that incorporates orientation-specific, long-range couplings with slow NMDA conductances operates in a fluctuating dynamic state of intermittent desuppression (IDS), which captures the behavior of coherent spontaneous cortical activity, as revealed by in vivo optical imaging based on voltage-sensitive dyes. Here, we address the functional significance of the IDS cortical operating points by investigating our model cortex response to the Hikosaka line-motion illusion (LMI) stimulus-a cue of a quickly flashed stationary square followed a few milliseconds later by a stationary bar. As revealed by voltage-sensitive dye imaging, there is an intriguing similarity between the cortical spatiotemporal activity in response to (i) the Hikosaka LMI stimulus and (ii) a small moving square. This similarity is believed to be associated with the preattentive illusory motion perception. Our numerical cortex produces similar spatiotemporal patterns in response to the two stimuli above, which are both in very good agreement with experimental results. The essential network mechanisms underpinning the LMI phenomenon in our model are (i) the spatiotemporal structure of the LMI input as sculpted by the lateral geniculate nucleus, (ii) a priming effect of the long-range NMDA-type cortical coupling, and (iii) the NMDA conductance-voltage correlation manifested in the IDS state. This mechanism in our model cortex, in turn, suggests a physiological underpinning for the LMI-associated patterns in the visual cortex of anaesthetized cat.

Hydrogels are frequently employed as medical device biomaterials due to their advantageous biological properties, e.g. resistance to infection and encrustation, biocompatibility; however, their poor mechanical properties generally limit the scope of application to coatings of medical devices. To address this limitation, this study described the formulation of sequential interpenetrating polymer networks (IPN) of poly(-caprolactone) (PCL) and poly(hydroxyethylmethacrylate) (p(HEMA)). IPN containing 20% w/w PCL, p(HEMA), both in the presence or absence of ethyleneglycol dimethacrylate (EGDMA 1% w/w), were prepared by free radical polymerisation. Following preparation the degradation and the mechanical and surface properties of the biomaterials and, in addition, the resistances to microbial adherence and encrustation in vitro were examined. In comparison to p(HEMA) the various IPN exhibited substantially greater tensile properties (ultimate tensile strength, % elongation, Young's modulus) that were accredited to the discrete distribution of PCL within the hydrogel network. The IPN exhibited two glass transition temperatures that were statistically similar to those of the individual components, thereby providing evidence of the immiscible nature of the two polymers. The IPN possessed higher receding contact angles and lower equilibrium water contents in comparison to p(HEMA), whereas the limited degradation of the IPN at both pH 7 and 9 was deemed suitable for clinical usage for periods of at least 4 weeks. The resistances of the various IPN to bacterial adherence and urinary encrustation were examined using in vitro models. Importantly the resistance of the IPN to encrustation was, in general, similar to that of p(HEMA) but greater than that of PCL whereas, the resistance of the IPN to bacterial adherence was frequently greater than that of p(HEMA) and PCL. Therefore, this study has shown that the mechanical properties of p(HEMA) may be substantially increased by the formation of IPN with PCL whilst maintaining other appropriate physicochemical properties and resistances to urinary encrustation and bacterial adherence. It is suggested that these IPN may be suitable for device fabrication thereby expanding the manufacturing application of hydrogels without compromising their potential clinical efficacy.

To investigate the existence and the characteristics of possible cortical operating points of the primary visual cortex, as manifested by the coherent spontaneous ongoing activity revealed by real-time optical imaging based on voltage-sensitive dyes, we studied numerically a very large-scale ( approximately 5 x 10(5)) conductance-based, integrate-and-fire neuronal network model of an approximately 16-mm(2) patch of 64 orientation hypercolumns, which incorporates both isotropic local couplings and lateral orientation-specific long-range connections with a slow NMDA component. A dynamic scenario of an intermittent desuppressed state (IDS) is identified in the computational model, which is a dynamic state of (i) high conductance, (ii) strong inhibition, and (iii) large fluctuations that arise from intermittent spiking events that are strongly correlated in time as well as in orientation domains, with the correlation time of the fluctuations controlled by the NMDA decay time scale. Our simulation results demonstrate that the IDS state captures numerically many aspects of experimental observation related to spontaneous ongoing activity, and the specific network mechanism of the IDS may suggest cortical mechanisms and the cortical operating point underlying observed spontaneous activity.

To address computational "scale-up" issues in modeling large regions of the cortex, many coarse-graining procedures have been invoked to obtain effective descriptions of neuronal network dynamics. However, because of local averaging in space and time, these methods do not contain detailed spike information and, thus, cannot be used to investigate, e.g., cortical mechanisms that are encoded through detailed spike-timing statistics. To retain high-order statistical information of spikes, we develop a hybrid theoretical framework that embeds a subnetwork of point neurons within, and fully interacting with, a coarse-grained network of dynamical background. We use a newly developed kinetic theory for the description of the coarse-grained background, in combination with a Poisson spike reconstruction procedure to ensure that our method applies to the fluctuation-driven regime as well as to the mean-driven regime. This embedded-network approach is verified to be dynamically accurate and numerically efficient. As an example, we use this embedded representation to construct "reverse-time correlations" as spiked-triggered averages in a ring model of orientation-tuning dynamics.

A coarse-grained representation of neuronal network dynamics is developed in terms of kinetic equations, which are derived by a moment closure, directly from the original large-scale integrate-and-fire (I&F) network. This powerful kinetic theory captures the full dynamic range of neuronal networks, from the mean-driven limit (a limit such as the number of neurons N --> infinity, in which the fluctuations vanish) to the fluctuation-dominated limit (such as in small N networks). Comparison with full numerical simulations of the original I&F network establishes that the reduced dynamics is very accurate and numerically efficient over all dynamic ranges. Both analytical insights and scale-up of numerical representation can be achieved by this kinetic approach. Here, the theory is illustrated by a study of the dynamical properties of networks of various architectures, including excitatory and inhibitory neurons of both simple and complex type, which exhibit rich dynamic phenomena, such as, transitions to bistability and hysteresis, even in the presence of large fluctuations. The implication for possible connections between the structure of the bifurcations and the behavior of complex cells is discussed. Finally, I&F networks and kinetic theory are used to discuss orientation selectivity of complex cells for "ring-model" architectures that characterize changes in the response of neurons located from near "orientation pinwheel centers" to far from them.

Potential mechanisms of the developmental toxicities of ethanol, acetaldehyde, and thioacetamide were evaluated using frog embryo teratogenesis assay-Xenopus (FETAX). Early X. laevis embryos were exposed to ethanol and thioacetamide in two separate definitive concentration-response tests with and without differentially induced exogenous metabolic activation systems (MAS) or selectively inhibited MAS. Two concentration-response tests were also performed with ethanol metabolites, acetaldehyde and acetic acid. The MAS was treated with 3,4-amino-1,2,4-triazole to modulate CYP2E1 activity, and heat to inactivate flavin containing monooxygenases (FMO) activity. Results from these studies suggested that thioacetamide may be bioactivated by both CYP2E1 and the FMO systems. Ethanol also appeared to be bioactivated by CYP2E1. Acetaldehyde was markedly more potent as a developmental toxicant than ethanol or acetic acid. Binary joint mixture studies conducted with ethanol and acetaldehyde indicated that the parent compound and metabolite acetaldehyde acted in a response additive manner. These results warrant the continued use of FETAX as a means of evaluating mechanisms of developmental toxicity in vitro.

The toxicity of boron has been understood for many years. However, limited data currently exist concerning the nutritional essentiality of B in chordates. Results from an ongoing research program evaluating the nutritional essentiality of B in the South African clawed frog, Xenopus laevis, found that X. laevis fed a low-B diet in a low-B culture media produced a substantially higher number of necrotic eggs and fertilized embryos than frogs fed a boron-sufficient diet. Markedly decreased embryo cell counts at mid-blastula transition and an increased frequency of abnormal gastrulation were also noted in embryos from adult frogs fed the B-deficient diet. By 96 h of development, none of the larvae collected from the B-deficient adults and maintained in low-boron culture media developed normally. Reproductive effects associated with B deficiency in female Xenopus included ovary atrophy, oocyte necrosis, and incomplete oocyte maturation. In males, a decrease in testis weight and sperm count was noted. These studies suggest that these adverse effects resulting from B deficiency could be found during gametogenesis, gamete maturation, embryonic development, and larval maturation. The studies also confirmed that B deficiency was capable of interrupting the X. laevis life cycle. Additional studies evaluating the role of B in the thyroid axis and the oocyte plasma membrane progesterone receptor provide the first line of direct evidence for a biochemical role of boron in X. laevis. Combined together, this research program provides firm evidence that B is nutritionally essential in X. laevis.

Currently, no standardized and well-validated alternative models exist for screening for progesterone-responsive endocrine disrupting chemicals (EDCs). Because of this, a rapid assay for evaluating progestin/antiprogestin activity using Xenopus oocyte germinal vesicle breakdown (GVBD) as a model was evaluated. Five compounds, including progesterone (P), ethinyl estradiol (EE), ethylene glycol monomethyl ether (EGME), cadmium (Cd), and boric acid (B) were used to validate the model on a preliminary basis. Each test material was tested for progestin/anti-progestin activity. The binding affinity of each test material to the oocyte plasma membrane receptor (OPMR) relative to progesterone was then determined. Results from the present studies suggested that both EE and EGME were capable of inhibiting GVBD in a concentration-dependent manner. Cd had a subtle inhibitory effect at high concentrations. B had no effect on GVBD even at concentrations of 100 mg B/L, and thus appears to have no EDC activity in this model. The binding capacity of the test substances to the OMPR relative to progesterone was low. Thus, the relative inhibitory potential of the test materials study was EE > EGME >> Cd > B. However, the relative binding affinity of the toxicants to the OMPR can be expressed as P >> EGME > EE > Cd > B. Although EE was more effective in inhibiting GVBD, EGME appeared to bind more tightly to the OMPR.

A commercial latex agglutination assay (LA) and a sandwich enzyme immunoassay (SEIA) (Sanofi Diagnostics Pasteur, Marnes-la-Coquette, France) were compared with a competitive binding inhibition assay (enzyme immunoassay [EIA]) to determine the potential uses and limitations of these antigen detection tests for the sensitive, specific, and rapid diagnosis of invasive aspergillosis (IA). Toward this end, well-characterized serum and urine specimens were obtained by using a rabbit model of IA. Serially collected serum or urine specimens were obtained daily from control rabbits or from rabbits immunosuppressed and infected systemically with Aspergillus fumigatus. By 4 days after infection, EIA, LA, and SEIA detected antigen in the sera of 93, 93, and 100% of A. fumigatus-infected rabbits, respectively, whereas antigen was detected in the urine of 93, 100, and 100% of the rabbits, respectively. False-positive results for non-A. fumigatus-infected rabbits for EIA, LA, and SEIA were as follows: for serum, 14, 11, and 23%, respectively; for urine, 14, 84, and 90%, respectively. Therefore, although the sensitivities of all three tests were similar, the specificity was generally greater for EIA than for LA or SEIA. Infection was also detected earlier by EIA, by which the serum of 53% of A. fumigatus-infected rabbits was positive as early as 1 day after infection, whereas the serum of only 27% of the rabbits tested by LA was positive. Although the serum of 92% of A. fumigatus-infected rabbits was positive by SEIA as early as 1 day after infection, the serum of a high percentage (50%) was false positive before infection. The urine of 21% of A. fumigatus-infected rabbits was positive by EIA as early as 1 day after infection, and the urine of none of the rabbits was false positive before infection. When EIA results for urine specimens were combined with those for serum, sensitivity was improved (i.e., 67% of rabbits were positive by 1 day after infection and only one rabbit gave a false-positive result). A total of 93% of A. fumigatus-infected rabbits were positive for antigen in urine as early as 1 day after infection and the urine of 100% of the rabbits was positive by SEIA. However, before infection, 79% of A. fumigatus-infected rabbits were false positive for antigen in urine by LA and 90% were false positive for antigen in urine by SEIA. These data indicate that the EIA has the potential to be used to diagnose IA with both serum and urine specimens and to detect a greater number of infections earlier with greater specificity than the specificities achieved with the commercial tests.

Dispersive wave turbulence is studied numerically for a class of one-dimensional nonlinear wave equations. Both deterministic and random (white noise in time) forcings are studied. Four distinct stable spectra are observed-the direct and inverse cascades of weak turbulence (WT) theory, thermal equilibrium, and a fourth spectrum (MMT; Majda, McLaughlin, Tabak). Each spectrum can describe long-time behavior, and each can be only metastable (with quite diverse lifetimes)-depending on details of nonlinearity, forcing, and dissipation. Cases of a long-live MMT transient state dcaying to a state with WT spectra, and vice-versa, are displayed. In the case of freely decaying turbulence, without forcing, both cascades of weak turbulence are observed. These WT states constitute the clearest and most striking numerical observations of WT spectra to date-over four decades of energy, and three decades of spatial, scales. Numerical experiments that study details of the composition, coexistence, and transition between spectra are then discussed, including: (i) for deterministic forcing, sharp distinctions between focusing and defocusing nonlinearities, including the role of long wavelength instabilities, localized coherent structures, and chaotic behavior; (ii) the role of energy growth in time to monitor the selection of MMT or WT spectra; (iii) a second manifestation of the MMT spectrum as it describes a self-similar evolution of the wave, without temporal averaging; (iv) coherent structures and the evolution of the direct and inverse cascades; and (v) nonlocality (in k-space) in the transferral process.

Aspartyl proteinase (AP) is an extracellular enzyme of Candida albicans implicated as a pathogenic factor. Previous reports on the purification and characterization of AP suggested that a single DEAE-Sephadex chromatographic step was sufficient for the removal of extraneous proteins and that the final product was glycosylated. We purified AP using a chromatographic series consisting of DEAE-Sephadex A25, Sephadex G75 and rechromatography on DEAE-Sephadex A25. Use of DEAE-Sephadex alone did not remove extraneous proteins and removed little contaminating mannoprotein (MP). The addition of a Sephadex G75 column to the purification scheme removed the majority of contaminating MP and proteins. The final DEAE-Sephadex A25 chromatographic step resulted in (a) removal of detectable extraneous proteins, (b) removal of immunologically detectable MP by dot blot and Western blot enzyme immunoassay, (c) loss of periodic acid-silver stain positivity, and (d) a high AP yield (1295 U l-1) and specific activity (1749 U mg-1). We conclude that a single DEAE-Sephadex A25 purification step is insufficient to remove extraneous proteins and MP, which could interfere with the production of AP-specific antibodies and the dissection of moieties responsible for immune reactivity. Reports of periodic acid-Schiff or anthrone positivity of AP preparations may reflect the presence of extraneous MP, which can be removed by the chromatographic series we describe.

Antigen-rich mycelial extract (ME) and fractions of Aspergillus fumigatus were compared with culture filtrates of A. fumigatus. A. flavus, and A. niger for their abilities to detect antibody in serums from patients with confirmed aspergillosis caused by these fungi. In double immunodiffusion tests, homologous antigen preparations were more effective than heterologous preparations in detecting precipitins. Mycelial extract of A. fumigatus was more effective than A. fumigatus culture filtrate in detecting antibody in serums from patients with disease caused by A. flavus and A. niger. It did not, however, detect antibody in the serums from approximately half of the patients with heterologous infections.

A 2-h indirect enzyme-linked immunosorbent assay (ELISA) using homogenate antigens of Rhizopus arrhizus and Rhizomucor pusillus was developed and compared with the existing immunodiffusion (ID) test for zygomycosis, using homogenate antigens of R. arrhizus. Utilizing 1:400 as a minimally positive ELISA titer, 33 of 43 proven cases of zygomycosis were diagnosed. The sensitivity of the ELISA was 81%. The ID test, in contrast, detected only 21 cases and demonstrated a sensitivity of 66%. The specificity of the ELISA was 94%, whereas that of the ID test was 91%. Nonspecific ELISA reactivity was particularly evident with sera from patients with aspergillosis and candidiasis. With the antigens now available, the ELISA was unable to generically or specifically identify the etiologic agents.

A newly developed latex agglutination (LA) test and a modified immunodiffusion (ID) test were evaluated. The antigen used was a homogenate of Candida albicans. A total of 167 antisera were employed in the evaluation. They included 36 sera from clinically well persons; 78 from patients with various clinical forms of candidiasis; 52 from patients with proven cases of aspergillosis, blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, nocardiosis, paracoccidioidomycosis, sporotrichosis, and tuberculosis; and one serum from a patient with toruloposis. Use of the LA test in conjunction with the ID test permitted the detection of more than 90% of 43 proven candidiasis cases. Of all the heterologous cases and normal human sera tested, LA reactions were noted with 3 of 10 cryptococcosis case specimens, 1 of 9 tuberculosis case specimens, and with the torulopsemia case serum. In contrast, the only heterologous serum reactive in the ID test was that from the patient with torulopsemia. Torulopsis glabrata and C. albicans antisera gave identical reactions in LA and ID tests with T. glabrata or C. albicans antigens. ID tests with selected antigens, however, permitted differentiation of rabbit and human T. glabrata antibody from that of C. albicans antibody. Six different precipitins were recognized with the C. albicans antigens. The occurrence of multiple precipitin lines and high LA titers was suggestive of severe candidiasis. The LA test, in contrast to the ID test, appeared to have prognostic value. Together, the LA and ID tests provided a simple, rapid, and accurate means of detecting and monitoring infections by species of Candida.

The diagnosis of sporotrichosis can be time consuming. Serological procedures could facilitate the rapid and accurate diagnosis of this disease. A slide latex agglutination (SLA) test for sporotrichosis was developed and compared with the tube agglutination (TA), complement fixation (CF), and immunodiffusion (ID) tests in the serological study of 80 proven human cases of sporotrichosis representing the cutaneous, subcutaneous, and extracutaneous forms of the disease. In addition, the indirect fluorescent antibody (IFA) technique was applied to 61 case sera. In the SLA test, latex particles sensitized with culture filtrate antigens from the yeast form of Sporothrix schenckii (B 959) detected 94% of the cases, as compared to 96% of the cases detected by the TA test, 68% by the CF test, and 56% by the ID test. The IFA test detected 90% of the 61 cases. The SLA and ID tests were specific, showing no reactions with sera from 86 persons with no disease or with diseases other than sporotrichosis. Because of its sensitivity, specificity, ease of performance, and ability to provide results in 5 min, the SLA test is highly recommended for routine use in the clinical laboratory.

A specific immunodiffusion test for blastomycosis has been developed. The test permitted the detection of approximately 80% of 113 proven cases of blastomycosis. Two diagnostically important precipitins designated A and B were frequently recognized in patients with blastomycosis. Routine use of reference sera containing the A and B precipitins in immunodiffusion tests would permit the specific diagnosis of blastomycosis without the need for parallel tests with coccidioidin and histoplasmin.