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PubMed2005

A hybrid machine-learning approach for segmentation of protein localization data.

MOTIVATION: Subcellular protein localization data are critical to the quantitative understanding of cellular function and regulation. Such data are acquired via observation and quantitative analysis of fluorescently labeled proteins in living cells. Differentiation of labeled protein from cellular artifacts remains an obstacle to accurate quantification. We have developed a novel hybrid machine-learning-based method to differentiate signal from artifact in membrane protein localization data by deriving positional information via surface fitting and combining this with fluorescence-intensity-based data to generate input for a support vector machine. RESULTS: We have employed this classifier to analyze signaling protein localization in T-cell activation. Our classifier displayed increased performance over previously available techniques, exhibiting both flexibility and adaptability: training on heterogeneous data yielded a general classifier with good overall performance; training on more specific data yielded an extremely high-performance specific classifier. We also demonstrate accurate automated learning utilizing additional experimental data.

Animals↗
PubMed2004

Certain 1,4-disubstituted aromatic piperidines and piperazines with extreme selectivity for the dopamine D4 receptor interact with a common receptor microdomain.

We previously demonstrated that, in the D4 dopamine receptor, the aromatic microdomain that spans the interface of the second and third transmembrane segments influences the high-affinity interactions with the D4-selective ligand L750,667 [3-[[4-(4-iodophenyl) piperazin-1-yl]methyl]-1H-pyrrolo[2,3-b]pyridine] and the D2-selective ligands methylspiperone, aripiprazole, and its congener OPC4392 [7-[3-(4-(2,3-dimethylphenyl) piperazinyl) propoxy] 2-(1H)-quinolinone] (Schetz et al., 2000). Here we tested a variety of 1,4-disubstituted aromatic piperidines/piperazines (1,4-DAPs) with different subtype selectivities and functional properties against a panel of D4 receptor mutations in the aromatic microdomain to ascertain whether these ligands recognize this common site. Mutant D4 receptors were constructed by substituting the nonconserved amino acid(s) from the corresponding locations in the D2 receptor. The D4-L2.60W, D4-F2.61V, and D4-LM3.28-3.29FV substitutions result in alterations of the relative position of members of the aromatic microdomain. From these results and molecular models of the ligand-receptor complexes, we conclude that 9 of the 11 D4-selective 1,4-DAPs, including L750,667, have a common pattern of ligand-receptor recognition that depends upon favorable interactions with the phenylalanine at position 2.61 (D4-F2.61V, 20-96-fold decrease). Like methylspiperone, aripiprazole, and OPC4392, the two D4-selective 1,4-DAPs that are insensitive to the D4-F2.61V mutation are sensitive to aromatics at position 2.60 (D4-L2.60W, 7-20-fold increase), and they all have longer spacer arms that permit their tethered aromatics to adopt alternative orientations in the binding-site crevice. All 11 of the D4-selective 1,4-DAPs were sensitive to the D4-LM3.28-3.29FV mutation (13-494-fold decrease) but not the moderately D2-selective methylspiperone. The inferences suggest that subtype selectivity involves two different modes of interaction with the microdomain for the D4-selective 1,4-DAPs and a third mode for D2-selective 1,4-DAPs.

Animals↗
PubMed2002

Redistribution of synaptic efficacy supports stable pattern learning in neural networks.

Markram and Tsodyks, by showing that the elevated synaptic efficacy observed with single-pulse long-term potentiation (LTP) measurements disappears with higher-frequency test pulses, have critically challenged the conventional assumption that LTP reflects a general gain increase. This observed change in frequency dependence during synaptic potentiation is called redistribution of synaptic efficacy (RSE). RSE is here seen as the local realization of a global design principle in a neural network for pattern coding. The underlying computational model posits an adaptive threshold rather than a multiplicative weight as the elementary unit of long-term memory. A distributed instar learning law allows thresholds to increase only monotonically, but adaptation has a bidirectional effect on the model postsynaptic potential. At each synapse, threshold increases implement pattern selectivity via a frequency-dependent signal component, while a complementary frequency-independent component nonspecifically strengthens the path. This synaptic balance produces changes in frequency dependence that are robustly similar to those observed by Markram and Tsodyks. The network design therefore suggests a functional purpose for RSE, which, by helping to bound total memory change, supports a distributed coding scheme that is stable with fast as well as slow learning. Multiplicative weights have served as a cornerstone for models of physiological data and neural systems for decades. Although the model discussed here does not implement detailed physiology of synaptic transmission, its new learning laws operate in a network architecture that suggests how recently discovered synaptic computations such as RSE may help produce new network capabilities such as learning that is fast, stable, and distributed.

Algorithms↗
PubMed1999

On the role of biophysical properties of cortical neurons in binding and segmentation of visual scenes.

Neuroscience is progressing vigorously, and knowledge at different levels of description is rapidly accumulating. To establish relationships between results found at these different levels is one of the central challenges. In this simulation study, we demonstrate how microscopic cellular properties, taking the example of the action of modulatory substances onto the membrane leakage current, can provide the basis for the perceptual functions reflected in the macroscopic behavior of a cortical network. In the first part, the action of the modulatory system on cortical dynamics is investigated. First, it is demonstrated that the inclusion of these biophysical properties in a model of the primary visual cortex leads to the dynamic formation of synchronously active neuronal assemblies reflecting a context-dependent binding and segmentation of image components. Second, it is shown that the differential regulation of the leakage current can be used to bias the interactions of multiple cortical modules. This allows the flexible use of different feature domains for scene segmentation. Third, we demonstrate how, within the proposed architecture, the mapping of a moving stimulus onto the spatial dimension of the network results in an increased speed of synchronization. In the second part, we demonstrate how the differential regulation of neuromodulatory activity can be achieved in a self-consistent system. Three different mechanisms are described and investigated. This study thus demonstrates how a modulatory system, affecting the biophysical properties of single cells, can be used to achieve context-dependent processing at the system level.

Animals↗
PubMed2002

Pattern storage and processing in attractor networks with short-time synaptic dynamics.

Neurophysiological experiments show that the strength of synaptic connections can undergo substantial changes on a short time scale. These changes depend on the history of the presynaptic input. Using mean-field techniques, we study how short-time dynamics of synaptic connections influence the performance of attractor neural networks in terms of their memory capacity and capability to process external signals. For binary discrete-time as well as for firing rate continuous-time neural networks, the fixed points of the network dynamics are shown to be unaffected by synaptic dynamics. However, the stability of patterns changes considerably. Synaptic depression turns out to reduce the storage capacity. On the other hand, synaptic depression is shown to be advantageous for processing of pattern sequences. The analytical results on stability, size of the basins of attraction and on the switching between patterns are complemented by numerical simulations.

Algorithms↗
PubMed2004

Pathogen recognition or homeostasis? APC receptor functions in innate immunity.

Myeloid cells (macrophages, neutrophils, dendritic cells) express a repertoire of plasma membrane receptors able to recognize all classes of macromolecules. The concept of pattern recognition has emphasized microbial ligands and host defence. However, these receptors play a broader role in tissue homeostasis within multicellular hosts, clearing the extracellular environment of potential undesirable ligands arising endogenously as well as from without. This article will evaluate one of the paradigms that underlie innate immunity.

Animals↗
PubMed2006

Characterization and functional investigation of single nucleotide polymorphisms (SNPs) in the human TLR5 gene.

Toll-like receptors recognize pathogen-associated molecular patterns (PAMPs) and TLR5 is the pathogen recognition receptor (PRR) for bacterial flagellin. Patients carrying a R392 stop polymorphism display an inflammatory phenotype and increased susceptibility to pneumonia caused by the flagellated bacteria Legionella pneumophila. While this suggests that TLR5 mutations may be clinically relevant, functional data are not available for the majority of the other TLR5 polymorphisms. We have characterized all known single nucleotide polymorphisms (SNPs) of TLR5 for their functional relevance upon stimulation in transiently transfected CHO-K1 cells. Among the 13 missense SNPs of TLR5 reported in the human genetic databases, three SNPs (c.1174C>T, p.R392X; c.2081A>G, p.D694G; and c.2464C>T, p.L822F) were found to be functionally relevant in transiently transfected CHO-K1 cells. The prevalences of these functionally relevant SNPs in our investigation were 11.9 %, 0 %, and 0 %, in healthy donors. The p.D694G and p.L822F SNPs are of low frequency in the Caucasian population though further investigations of the common p.R392X variant alone or of functional relevant TLR5 SNPs in combination with other TLR SNPs will elucidate their possible role on disease susceptibility in humans and may facilitate clinical diagnosis.

Alleles↗
PubMedDate not supplied

Human splenic dendritic cells react differently to bacterial and allogeneic antigens.

We investigated the ability of bacterial (cells, LPS, and DNA) or allogeneic antigens to stimulate splenic dendritic cells (DCs) and expression of Toll-like receptors (TLRs), CD14 (co-functional molecule to TLR), CD83 (activation molecule on migrating DCs), CD123 (IL-3R specific for myeloid DC), Hsp60 and Hsp90 (heat shock proteins) involved in recognizing pathogen-associated molecular patterns (PAMP) and other pathogen recognition receptors (PRR) ligands. Allogeneic stimulation of DC TLRs was weak compared with that of bacterial products. This suggests that the highly conserved TLRs destined to react to bacterial products do not recognize donor products differing at the major histocompatibility complex (MHC) locus, at least using in vitro culture conditions.

Antigens, Bacterial↗
PubMed2006

CD14: chaperone or matchmaker?

In this issue of Immunity, describe a physical and functional relationship between Toll-like receptor 3 (TLR3) and the pattern recognition protein CD14. In the presence of CD14, TLR3-mediated signal transduction events are amplified.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Species-specific restriction of cell surface expression of mouse MARCO glycoprotein in murine cell lines.

The MARCO (macrophage receptor with collagenous structure) glycoprotein belongs to the scavenger receptor type family of pattern-recognition molecules produced by a subset of marginal zone macrophages in the spleen. Stimulation with LPS leads to its appearance on macrophages located at other tissue compartments. In the present work, we report its in vitro expression by various cell lines using transient and stable (lentiviral) gene delivery aimed at investigating the signaling properties of this receptor and its analysis using a novel rat monoclonal antibody against the SRCR-domain of mouse MARCO. When trying to establish stable mouse MARCO-transfectants using lentiviral transduction and other methods, we consistently found that MARCO accumulated intracellularly in various murine host cells. In contrast, such a phenomenon was not observed in non-murine cell lines. Our observations indicate the presence of an unexpected limitation of the in vitro expression of mouse MARCO glycoprotein in murine cell lines. We believe that the failure to express MARCO on the cell surface of the many murine cell lines is likely due to the absence of endoplasmic reticulum molecular chaperones needed for the correct folding and assembly of the trimeric MARCO molecule.

Animals↗
PubMed2006

Allelic variation of the ovine Toll-like receptor 4 gene.

The family of Toll-like receptors (TLRs) is responsible for recognition of pathogen-associated molecular patterns (PAMPs), and Toll-like receptor 4 (TLR4) recognizes not only exogenous ligands such as the lipopolysaccharide (LPS) of Gram-negative bacteria, but also a number of endogenous ligands. Variation in the nucleotide sequence of the ovine TLR4 gene was investigated by amplification of a fragment containing a putative ligand-binding region using polymerase chain reaction (PCR), followed by single-strand conformational polymorphism (PCR-SSCP) analysis and DNA sequencing. Four novel SSCP patterns, representing four different sequences, were identified. Either one or two different sequences were detected in individual sheep and all the sequences identified shared high homology to the TLR4 sequences from a variety of species, suggesting that these sequences represent allelic variants of the ovine TLR4 gene. Fourteen single nucleotide polymorphisms (SNPs) were detected, and 79% (11 of 14) of SNPs were non-synonymous substitutions that would result in amino acid changes. Variation detected here might have an impact on pattern recognition and hence affect the immune response to pathogens.

Alleles↗
PubMedDate not supplied

Chiral recognition in adrenergic receptor binding mimics prepared by molecular imprinting.

Molecularly imprinted polymers were prepared against the adrenomimetic agents ephedrine and pseudoephedrine. These compounds each incorporate two chiral centres. The polymers were evaluated with respect to enantiodiscrimination of various adrenergic ligands. The selectivity of the polymeric binding sites for the imprinted molecules was very high, and it was found that binding of both the enantiomeric and diastereomeric isomers of the imprint species were effectively obstructed, it was found that these polymers could selectively recognize the enantiomers of the endogenous adrenergic ligand epinephrine as well as several beta-adrenergic blockers. These observations suggest that these polymers effectively mimic the recognition patterns exhibited by natural adrenergic receptors.

Adrenergic Agents↗
PubMed2005

Mammalian Toll-like receptors: to immunity and beyond.

Toll-like receptors (TLRs) constitute an archetypal pattern recognition system. Their sophisticated biology underpins the ability of innate immunity to discriminate between highly diverse microbial pathogens and self. However, the remarkable progress made in describing this biology has also revealed new immunological systems and processes previously hidden to investigators. In particular, TLRs appear to have a fundamental role in the generation of clonal adaptive immune responses, non-infectious disease pathogenesis and even in the maintenance of normal mammalian homeostasis. Although an understanding of TLRs has answered some fundamental questions at the host-pathogen interface, further issues, particularly regarding therapeutic modulation of these receptors, have yet to be resolved.

Animals↗
PubMed1994

In vitro inhibition of the actions of basic FGF by a novel 16 amino acid peptide.

A composite procedure involving molecular modelling and a property-pattern algorithm, the Resonant Recognition Model (RRM), has been applied to structure-function studies with basic fibroblast growth factor (bFGF). Property-pattern characteristics for biological activity and receptor recognition for a group of FGF-related proteins were defined and then used to aid the design of a set of peptides which can act as bFGF antagonists. Molecular modelling techniques were then employed to identify the peptide within this set with the greatest conformational similarity to the putative receptor domain of bFGF. This 16 amino acid residue peptide (16mer), which exhibits no sequence homology to bFGF, antagonised the stimulatory effect of bFGF on fibroblast [3H]thymidine incorporation and cell proliferation, but exerted no effect itself in these in vitro bioassays.

Algorithms↗
PubMed1996

The glycine/NMDA receptor antagonist HA-966 impairs visual recognition memory in rhesus monkeys.

Recent studies have shown that strychnine-insensitive glycine binding sites positively modulate the N-methyl-D-asparate (NMDA) subclass of glutamate receptors, which are important in neural pathways involved in cognitive function. We examined the effect of (+/-)-3-amino-1-hydroxy-2-pyrrolidone (HA-966), a highly specific antagonist of this glycine modulatory site on the NMDA receptor, on visual recognition memory in four rhesus monkeys performing a computer-automated version of delayed nonmatching-to-sample (DNMS) with a list length of 20 trial-unique graphic symbols. In addition, the effect of HA-966 was compared with that of (+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine (dizocilpine; MK-801), a noncompetitive NMDA channel blocker. Administration of HA-966 (0.1-10 mg/kg, i.m.) 30 min before testing impaired DNMS performance dose-dependently, starting at doses of 3.2 mg/kg; the memory deficity following the highest dose (10 mg/kg) was associated with prolonged response latencies. Similar impairments in recognition memory were observed following treatment with MK-801, though at much lower doses (3.2-32 micrograms/kg) than those at which HA-966 was effective. Administration of low doses of HA-966 (1 mg/kg) and MK-801 (10 micrograms/kg), each of which had no significant effect on performance when given alone, also failed to impair performance when given concurrently. Combined administration of both drugs, each at amnesia-producing doses (3.2 mg/kg of HA-966 plus 32 micrograms/kg of MK-801), markedly impaired performance in an additive, not a synergistic, manner. From these results, we propose that the recognition memory impairment observed in our monkeys following HA-966 administration is via an action on the glycine modulatory site of the NMDA receptor complex.

Animals↗
PubMed1998

A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts.

Recognition of antigen by T cells requires the formation of a specialized junction between the T cell and the antigen-presenting cell. This junction is generated by the recruitment and the exclusion of specific proteins from the contact area. The mechanisms that regulate these events are unknown. Here we demonstrate that ligand engagement of the adhesion molecule, CD2, initiates a process of protein segregation, CD2 clustering, and cytoskeletal polarization. Although protein segregation was not dependent on the cytoplasmic domain of CD2, CD2 clustering and cytoskeletal polarization required an interaction of the CD2 cytoplasmic domain with a novel SH3-containing protein. This novel protein, called CD2AP, is likely to facilitate receptor patterning in the contact area by linking specific adhesion receptors to the cytoskeleton.

Adaptor Proteins, Signal Transducing↗
PubMed2006

When T cells recognize a pattern, they might cause trouble.

The mechanisms of self and non-self discrimination by T cells remain a fascinating topic for immunologists. How the immune system achieves protection of the host against an ever-changing realm of pathogens using a rather limited repertoire of T-cell receptors and at the same time avoids inflicting damage against its own tissues is equally puzzling. Although a better understanding of these questions has come from studies of the extent of cross reactivity of T-cell clones specific for foreign or self antigens, and also from examination of the different antigen avidities by which they recognize either type of antigen, many details are still lacking. Recently, there has been investigation into how T cells of the adaptive immune system can recognize functional protein domains or amino acid patterns. This type of T-cell reactivity is reminiscent of the pattern recognition that is firmly established as an important function of innate immune receptors such as Toll-like receptors. Many functional protein domains are conserved in evolution and are shared by a wide spectrum of pathogens, as well as by proteins of animals and humans. Hence, pattern recognition by adaptive immune cells might represent an efficient mechanism for host protection by the above-mentioned limited number of T-cell receptors. However, the fact that such functional domains occur so frequently in nature also implies that pattern recognition by T cells might cause autoimmunity, and recent data support this hypothesis.

Amino Acids↗