Biomedical subjects

James Theiler

Publications and source records attributed to James Theiler.

9 recordsLinked to original sources

PubMed2006

Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants.

HIV-1/AIDS vaccines must address the extreme diversity of HIV-1. We have designed new polyvalent vaccine antigens comprised of sets of 'mosaic' proteins, assembled from fragments of natural sequences via a computational optimization method. Mosaic proteins resemble natural proteins, and a mosaic set maximizes the coverage of potential T-cell epitopes (peptides of nine amino acids) for a viral population. We found that coverage of viral diversity using mosaics was greatly increased compared to coverage by natural-sequence vaccine candidates, for both variable and conserved proteins; for conserved HIV-1 proteins, global coverage may be feasible. For example, four mosaic proteins perfectly matched 74% of 9-amino-acid potential epitopes in global Gag sequences; 87% of potential epitopes matched at least 8 of 9 positions. In contrast, a single natural Gag protein covered only 37% (9 of 9) and 67% (8 of 9). Mosaics provide diversity coverage comparable to that afforded by thousands of separate peptides, but, because the fragments of natural proteins are compressed into a small number of native-like proteins, they are tractable for vaccines.

AIDS Vaccines↗

PubMed2006

Cross-subtype T-cell immune responses induced by a human immunodeficiency virus type 1 group m consensus env immunogen.

The genetic diversity among globally circulating human immunodeficiency virus type 1 (HIV-1) strains is a serious challenge for HIV-1 vaccine design. We have generated a synthetic group M consensus env gene (CON6) for induction of cross-subtype immune responses and report here a comparative study of T-cell responses to this and natural strain env immunogens in a murine model. Three different strains of mice were immunized with CON6 as well as subtype A, B, or C env immunogens, using a DNA prime-recombinant vaccinia virus boost strategy. T-cell epitopes were mapped by gamma interferon enzyme-linked immunospot analysis using five overlapping Env peptide sets from heterologous subtype A, B, and C viruses. The CON6-derived vaccine was immunogenic and induced a greater number of T-cell epitope responses than any single wild-type subtype A, B, and C env immunogen and similar T-cell responses to a polyvalent vaccine. The responses were comparable to within-clade responses but significantly more than between-clade responses. The magnitude of the T-cell responses induced by CON6 (measured by individual epitope peptides) was also greater than the magnitude of responses induced by individual wild-type env immunogens. Though the limited major histocompatibility complex repertoire in inbred mice does not necessarily predict responses in nonhuman primates and humans, these results suggest that synthetic centralized env immunogens represent a promising approach for HIV-1 vaccine design that merits further characterization.

AIDS Vaccines↗

PubMed2004

Stimulus-specific oscillations in a retinal model.

High-frequency oscillatory potentials (HFOPs) in the vertebrate retina are stimulus specific. The phases of HFOPs recorded at any given retinal location drift randomly over time, but regions activated by the same stimulus tend to remain phase locked with approximately zero lag, whereas regions activated by spatially separate stimuli are typically uncorrelated. Based on retinal anatomy, we previously postulated that HFOPs are mediated by feedback from a class of axon-bearing amacrine cells that receive excitation from neighboring ganglion cells-via gap junctions-and make inhibitory synapses back onto the surrounding ganglion cells. Using a computer model, we show here that such circuitry can account for the stimulus specificity of HFOPs in response to both high- and low-contrast features. Phase locking between pairs of model ganglion cells did not depend critically on their separation distance, but on whether the applied stimulus created a continuous path between them. The degree of phase locking between spatially separate stimuli was reduced by lateral inhibition, which created a buffer zone around strongly activated regions. Stimulating the inhibited region between spatially separate stimuli increased their degree of phase locking proportionately. Our results suggest several experimental strategies for testing the hypothesis that stimulus-specific HFOPs arise from axon-mediated feedback in the inner retina.

Action Potentials↗

PubMed2004

Correlated firing improves stimulus discrimination in a retinal model.

Synchronous firing limits the amount of information that can be extracted by averaging the firing rates of similarly tuned neurons. Here, we show that the loss of such rate-coded information due to synchronous oscillations between retinal ganglion cells can be overcome by exploiting the information encoded by the correlations themselves. Two very different models, one based on axon-mediated inhibitory feedback and the other on oscillatory common input, were used to generate artificial spike trains whose synchronous oscillations were similar to those measured experimentally. Pooled spike trains were summed into a threshold detector whose output was classified using Bayesian discrimination. For a threshold detector with short summation times, realistic oscillatory input yielded superior discrimination of stimulus intensity compared to rate-matched Poisson controls. Even for summation times too long to resolve synchronous inputs, gamma band oscillations still contributed to improved discrimination by reducing the total spike count variability, or Fano factor. In separate experiments in which neurons were synchronized in a stimulus-dependent manner without attendant oscillations, the Fano factor increased markedly with stimulus intensity, implying that stimulus-dependent oscillations can offset the increased variability due to synchrony alone.

Algorithms↗

PubMed2003

Advantage of rare HLA supertype in HIV disease progression.

The highly polymorphic human leukocyte antigen (HLA) class I molecules help to determine the specificity and repertoire of the immune response. The great diversity of these antigen-binding molecules confers differential advantages in responding to pathogens, but presents a major obstacle to distinguishing HLA allele-specific effects. HLA class I supertypes provide a functional classification for the many different HLA alleles that overlap in their peptide-binding specificities. We analyzed the association of these discrete HLA supertypes with HIV disease progression rates in a population of HIV-infected men. We found that HLA supertypes alone and in combination conferred a strong differential advantage in responding to HIV infection, independent of the contribution of single HLA alleles that associate with progression of the disease. The correlation of the frequency of the HLA supertypes with viral load suggests that HIV adapts to the most frequent alleles in the population, providing a selective advantage for those individuals who express rare alleles.

Amino Acid Motifs↗

PubMed2003

Accurate on-line support vector regression.

Batch implementations of support vector regression (SVR) are inefficient when used in an on-line setting because they must be retrained from scratch every time the training set is modified. Following an incremental support vector classification algorithm introduced by Cauwenberghs and Poggio (2001), we have developed an accurate on-line support vector regression (AOSVR) that efficiently updates a trained SVR function whenever a sample is added to or removed from the training set. The updated SVR function is identical to that produced by a batch algorithm. Applications of AOSVR in both on-line and cross-validation scenarios are presented. In both scenarios, numerical experiments indicate that AOSVR is faster than batch SVR algorithms with both cold and warm start.

Algorithms↗

PubMed1993

Don't bleach chaotic data.

A common first step in time series signal analysis involves digitally filtering the data to remove linear correlations. The residual data is spectrally white (it is "bleached"), but in principle retains the nonlinear structure of the original time series. It is well known that simple linear autocorrelation can give rise to spurious results in algorithms for estimating nonlinear invariants, such as fractal dimension and Lyapunov exponents. In theory, bleached data avoids these pitfalls. But in practice, bleaching obscures the underlying deterministic structure of a low-dimensional chaotic process. This appears to be a property of the chaos itself, since nonchaotic data are not similarly affected. The adverse effects of bleaching are demonstrated in a series of numerical experiments on known chaotic data. Some theoretical aspects are also discussed.

Journal Article↗

PubMedDate not supplied

A theory of the Benham Top based on center-surround interactions in the parvocellular pathway.

A model color-opponent neuron was used to investigate the subjective colors evoked by the Benham Top (BT). Color-opponent inputs from cone-selective parvocellular (P) pathway neurons with center-surround receptive fields were subtracted with a short relative delay, yielding a small transient input in response to a white spot. This transient input was amplified by BT-like stimuli, modeled as a thin dark bar followed by full-field illumination. The narrow bar produced maximal activation of the P-pathway surrounds but only partial activation of the P-pathway centers. Due to saturation, subsequent removal of the bar had little effect on the P-pathway surrounds, whereas the transient input from the P-pathway centers was amplified via disinhibition. Responses to BT-like stimuli became weaker as surround sensitivity recovered, producing an effect analogous to the progression of perceived BT colors. Our results suggest that the BT-illusion arises because cone-selective neurons convey information about both color and luminance contrast, allowing the two signals become confounded.

Animals↗

PubMedDate not supplied

A model of high-frequency oscillatory potentials in retinal ganglion cells.

High-frequency oscillatory potentials (HFOPs) have been recorded from ganglion cells in cat, rabbit, frog, and mudpuppy retina and in electroretinograms (ERGs) from humans and other primates. However, the origin of HFOPs is unknown. Based on patterns of tracer coupling, we hypothesized that HFOPs could be generated, in part, by negative feedback from axon-bearing amacrine cells excited via electrical synapses with neighboring ganglion cells. Computer simulations were used to determine whether such axon-mediated feedback was consistent with the experimentally observed properties of HFOPs. (1) Periodic signals are typically absent from ganglion cell PSTHs, in part because the phases of retinal HFOPs vary randomly over time and are only weakly stimulus locked. In the retinal model, this phase variability resulted from the nonlinear properties of axon-mediated feedback in combination with synaptic noise. (2) HFOPs increase as a function of stimulus size up to several times the receptive-field center diameter. In the model, axon-mediated feedback pooled signals over a large retinal area, producing HFOPs that were similarly size dependent. (3) HFOPs are stimulus specific. In the model, gap junctions between neighboring neurons caused contiguous regions to become phase locked, but did not synchronize separate regions. Model-generated HFOPs were consistent with the receptive-field center dynamics and spatial organization of cat alpha cells. HFOPs did not depend qualitatively on the exact value of any model parameter or on the numerical precision of the integration method. We conclude that HFOPs could be mediated, in part, by circuitry consistent with known retinal anatomy.

Action Potentials↗