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PubMed1979

Gastric pacemaker rhythm in conscious dog.

The pacemaker rhythm in the stomach of six healthy conscious dogs was studied by means of the measurement of sequential electrical control activity (ECA) intervals. Only the rhythm originating in the normal pacemake area was studied. An electrical response activity (ERA) score was used to assess contractile activity. Whereas substantial shortening of nonectopic ECA intervals did not occur, contraction-related interval lengthening was a characteristic phenomenon. The temporal relations between ERA scores and interval durations were found to be dependent on the gastric level at which the signals were derived. The activity front of the interdigestive myoelectric complex (IDMEC) appeared to be correlated with the periodic occurrence of considerably prolonged intervals; this sign could be used for recognition of the IDMEC. The motor quiescence phase of the IDMEC was correlated with small interval-to-interval variation, as was the early postprandial phase.

Action Potentials↗
PubMed2005

The etiopathogenesis of autoimmunity.

Acquisition by mammals of an adaptive immune system was an evolutionary leap, but occurred at the cost of autoimmunity. The necessity for self-recognition was appreciated in 1900, but autoimmune disease did not become a clinical reality until the 1950s-still the perimeters are indistinct. Autoimmune responses recapitulate the complex events of normal immune responses but cannot shut down. Immune tolerance is established during repertoire development centrally in thymus or bone marrow by deletion of self-reactive immunocytes, and is supplemented peripherally by regulatory T cells (Tregs). A startling discovery is the autoimmune regulator AIRE gene that enables expression of organ-specific autoantigens for intrathymic deletional tolerance of T cells. The origins, activities, and markers of Tregs are under intensive investigation. Of genes implicated in autoimmune, only few are characterized; contributions of environment are similarly uncertain. Time-latency considerations implicate stochastic factors or chance in the etiopathogenesis of autoimmunity, whether they are somatic mutations or successive random gene-environment interactions. Solutions to etiopathogenesis require novel experimental models and finely designed gene-environment studies on human populations. Perhaps immunomodulatory therapies will effect cures before causes are fully understood.

Animals↗
PubMed1996

Detection and localization of individual antibody-antigen recognition events by atomic force microscopy.

A methodology has been developed for the study of molecular recognition at the level of single events and for the localization of sites on biosurfaces, in combining force microscopy with molecular recognition by specific ligands. For this goal, a sensor was designed by covalently linking an antibody (anti-human serum albumin, polyclonal) via a flexible spacer to the tip of a force microscope. This sensor permitted detection of single antibody-antigen recognition events by force signals of unique shape with an unbinding force of 244 +/- 22 pN. Analysis revealed that observed unbinding forces originate from the dissociation of individual Fab fragments from a human serum albumin molecule. The two Fab fragments of the antibody were found to bind independently and with equal probability. The flexible linkage provided the antibody with a 6-nm dynamical reach for binding, rendering binding probability high, 0.5 for encounter times of 60 ms. This permitted fast and reliable detection of antigenic sites during lateral scans with a positional accuracy of 1.5 nm. It is indicated that this methodology has promise for characterizing rate constants and kinetics of molecular recognition complexes and for molecular mapping of biosurfaces such as membranes.

Animals↗
PubMed1989

Preferential binding of simian virus 40 T-antigen dimers to origin region I.

The sequence components that direct high-affinity binding of simian virus 40 (SV40) T antigen to SV40 origin region I are composed of two recognition pentanucleotides separated by a spacer. This region has binding sites for two T-antigen monomeric units. We extended the tripartite region I sequence by one and two sets of spacers and pentanucleotides and also shortened the region by one pentanucleotide. Our T-antigen-binding studies with these constructs show that the protein has a strong preference for binding to an even rather than an odd number of pentanucleotides separated by spacer sequences. Gel retardation assays reveal that the size of the complex formed between the 17-base-pair region I sequence and T antigen did not increase when the sequence was extended with one spacer-pentanucleotide sequence but did increase with two such units. DNase I footprinting and fragment assay experiments indicate that the protein did not protect a pentanucleotide that was not paired with another pentanucleotide. The unpaired pentanucleotide resumed its binding activity when it was paired with a spacer and another pentanucleotide sequence. We propose that T antigen binds to region I as a preformed dimer.

Animals↗
PubMed1999

Homeobox genes, fossils, and the origin of species.

Ever since Darwin there has been a history of debate on the tempo and mode of evolution. Is speciation a gradual process involving the accumulation of minute variations extant within a species, or is it rapid, the result of major organismal reorganization? Does one define a species on the basis of genes, morphology, or geographic or reproductive isolation? In this communication I present a model of evolutionary change that is based on the Mendelian inheritance of mutations in regulatory genes and the fact that most nonlethal mutations arise in the recessive state. Since the new recessive allele will spread through many generations without expression until there is a critical mass of heterozygotes capable of producing homozygotes for the mutation, the novel feature thus produced will appear abruptly in the population and in more than one individual. This picture of punctuation is consistent with the fossil record, which typically fails to provide evidence of smoothly transitional states of morphological change. Given that the first of their kind in the fossil record are organisms in which their novel characteristics are often more fully expressed or complex than in their descendants, it would seem that, after the mutation involving a regulatory gene is introduced, the general tendency is for its effects to become diminished. Among the implications for speciation is that this process does not depend on either reproductive isolation or genetic incompatibility. Rather, barring effects on reproductive organs or behavior, homozygotes for a novelty should be able to breed with heterozygotes and homozygotes for the wild state of the original population. This, in turn, suggests that the species barrier between individuals is probably a matter of mate recognition.

Adaptation, Physiological↗
PubMed1998

The DNA recognition subunit of the type IB restriction-modification enzyme EcoAI tolerates circular permutions of its polypeptide chain.

The DNA specificity subunit (HsdS) of type I restriction-modification enzymes is composed of two independent target recognition domains and several regions whose amino acid sequence is conserved within an enzyme family. The conserved regions participate in intersubunit interactions with two modification subunits (HsdM) and two restriction subunits (HsdR) to form the complete endonuclease. It has been proposed that the domains of the HsdS subunit have a circular organisation providing the required symmetry for their interaction with the other subunits and with the bipartite DNA target. To test this model, we circularly permuted the HsdS subunit of the type IB R-M enzyme EcoAI at the DNA level by direct linkage of codons for original termini and introduction of new termini elsewhere along the N-terminal and central conserved regions. By analysing the activity of mutant enzymes, two circularly permuted variants of HsdS that had termini located at equivalent positions in the N-terminal and central repeats, respectively, were found to fold into a functional DNA recognition subunit with wild-type specificity, suggesting a close proximity of the N and C termini in the native protein. The wild-type HsdS subunit was purified to homogeneity and shown to form a stable trimeric complex with HsdM, M2S1, which was fully active as a DNA methyltransferase. Gel electrophoretic mobility shift assays revealed that the HsdS protein alone was not able to form a specific complex with a 30-mer oligoduplex containing a single EcoAI recognition site. However, addition of stoichiometric amounts of HsdM to HsdS led to efficient specific DNA binding. Our data provide evidence for the circular organisation of domains of the HsdS subunit. In addition, they suggest a possible role of HsdM subunits in the formation of this structure.

Amino Acid Sequence↗
PubMed2000

Identification of the novel allele HLA-A*6813 in two members of a family of Syrian origin: implications for bone marrow transplantation.

The identification of the new allele HLA-A*6813, which was found in a woman of Syrian origin and her son, is described. In the sequence analysis the new allele differs from A*68011 by positions 259 (A>G) and 261 (C>G) in exon 2. As the structure is thus identical to the HLA-A consensus sequence it is likely that the new allele originated by gene conversion. At the protein level, the new allele has one amino acid difference from A*6801 (Asn63Glu), which results in a distinct banding pattern in one dimensional-isoelectric focusing. Amino acid residue 63 contributes to the formation of pocket A and B and is thus important for peptide binding. A*6813 was serologically detectable only by two of six polyclonal, but by three monoclonal antisera. The restricted serological A68 activity may be explained by altered peptide binding as presented peptides can affect the serological recognition of major histocompatibility complex (MHC) class I molecules. Moreover, our findings suggest that a possible mismatch with the other known A*68 variants may impair clinical outcome of bone marrow transplantation.

Alleles↗
PubMed1990

Recycling of glucosylceramide and sphingosine for the biosynthesis of gangliosides and sphingomyelin in rat liver.

It was previously shown that sphingomyelin and gangliosides can be biosynthesized starting from sphingosine or sphingosine-containing fragments which originated in the course of GM1 ganglioside catabolism. In the present paper we investigated which fragments were specifically re-used for sphingomyelin and ganglioside biosynthesis in rat liver. At 30 h after intravenous injection of GM1 labelled at the level of the fatty acid ([stearoyl-14C]GM1) or of the sphingosine ([Sph-3H]) moiety, it was observed that radioactive sphingomyelin was formed almost exclusively after the sphingosine-labelled-GM1 administration. This permitted the recognition of sphingosine as the metabolite re-used for sphingomyelin biosynthesis. Conversely, gangliosides more complex than GM1 were similarly radiolabelled after the two treatments, thus ruling out sphingosine re-utilization for ganglioside biosynthesis. For the identification of the lipid fragment re-used for ganglioside biosynthesis, we administered to rats neutral glycosphingolipids (galactosylceramide, glucosylceramide and lactosylceramide) each radiolabelled in the sphingosine moiety or in the terminal sugar residue. Thereafter we compared the formation of radiolabelled gangliosides in the liver with respect to the species administered and the label location. After galactosylceramide was injected, no radiolabelled gangliosides were formed. After the administration of differently labelled glucosylceramide, radiolabelled gangliosides were formed, regardless of the position of the label. After lactosylceramide administration, the ganglioside fraction became more radioactive when the long-chain-base-labelled precursors were used. These results suggest that glucosylceramide, derived from glycosphingolipid and ganglioside catabolism, is recycled for ganglioside biosynthesis.

Animals↗
PubMed2004

Comparative ITS and AFLP analysis of diploid Cardamine (Brassicaceae) taxa from closely related polyploid complexes.

BACKGROUND AND AIMS: Diploid representatives from the related polyploid complexes of Cardamine amara, C. pratensis and C. raphanifolia (Brassicaceae), were studied to elucidate phylogenetic relationships among the complexes and among the individual taxa included. METHODS: Two independent molecular data sets were used: nucleotide sequences from the internal transcribed spacers (ITS) of nrDNA, and amplified fragment length polymorphism (AFLP) markers. Seventeen diploid taxa from the studied groups were sampled. KEY RESULTS: Both ITS and AFLP analyses provided congruent results in inferred relationships, and revealed two main lineages. While the C. amara group, consisting of C. wiedemanniana and four subspecies of C. amara, was resolved as a well-supported monophyletic group, taxa from the C. pratensis and C. tenera groups (the latter representing diploid taxa of the complex of C. raphanifolia) all appeared together in a single clade/cluster with no support for the recognition of either of the groups. Intra-individual polymorphisms and patterns of nucleotide variation in the ITS region in C. uliginosa and C. tenera, together with the distribution of AFLP bands, indicate ancient hybridization and introgression among these Caucasian diploids. CONCLUSIONS: The lack of supported hierarchical structure suggests that extensive reticulate evolution between these groups, even at the diploid level, has occurred (although an alternative explanation, namely ancestral polymorphism in ITS data, cannot be completely excluded). Several implications for the investigation of the polyploid complexes of concern are drawn. When tracing origins of polyploid taxa, a much more complex scenario should be expected, taking into account all relatives as potential parents, irrespective of the group in which they are classified.

Base Sequence↗
PubMed2001

Human NKT cells mediate antitumor cytotoxicity directly by recognizing target cell CD1d with bound ligand or indirectly by producing IL-2 to activate NK cells.

alpha-Galactosylceramide (alphaGalCer) stimulates NKT cells and has antitumor activity in mice. Murine NKT cells may directly kill tumor cells and induce NK cell cytotoxicity, but the mechanisms are not well defined. Newly developed human CD1d/alphaGalCer tetrameric complexes were used to obtain highly purified human alphaGalCer-reactive NKT cell lines (>99%), and the mechanisms of NKT cell cytotoxicity and activation of NK cells were investigated. Human NKT cells were cytotoxic against CD1d(-) neuroblastoma cells only when they were rendered CD1d(+) by transfection and pulsed with alphaGalCer. Four other CD1d(-) tumor cell lines of diverse origin were resistant to NKT cells, whereas Jurkat and U937 leukemia cell lines, which are constitutively CD1d(+), were killed. Killing of the latter was greatly augmented in the presence of alphaGalCer. Upon human CD1d/alphaGalCer recognition, NKT cells induced potent cytotoxicity of NK cells against CD1d(-) neuroblastoma cell lines that were not killed directly by NKT cells. NK cell activation depended upon NKT cell production of IL-2, and was enhanced by secretion of IFN-gamma. These data demonstrate that cytotoxicity of human NKT cells can be CD1d and ligand dependent, and that TCR-stimulated NKT cells produce IL-2 that is required to induce NK cell cytotoxicity. Thus, NKT cells can mediate potent antitumor activity both directly by targeting CD1d and indirectly by activating NK cells.

Adjuvants, Immunologic↗
PubMed1993

The importance of dominant negative effects of amino acid side chain substitution in peptide-MHC molecule interactions and T cell recognition.

Previous studies on the role of specific residues of the peptide or MHC molecule in Ag presentation have revealed the sensitivity of this complex system to even small changes in structure. In our study, we have analyzed the effect of amino acid substitution in a major CD4+ T cell determinant (T1) of HIV-1 gp160 on binding and recognition in the context of various E alpha E beta MHC class II molecules. Individual alanine substitutions at all but three positions had little or no negative effect on either MHC binding or recognition by a specific T hybridoma, whereas substitutions with larger side chains often diminished reactivity. A poly-alanine peptide containing only four of the original residues was an effective MHC class II binder and in vivo immunogen, although lacking the ability to stimulate the hybridoma. Replacement of a glutamic acid in T1 with alanine or a size-conservative, uncharged glutamine, but not a negatively charged aspartic acid produced a peptide at least 100-fold more potent than the parent peptide, indicating an inhibitory effect of the negative charge. Conversely, substitution of a glutamic acid for valine at position 29 in the floor of the peptide binding site of the E alpha E beta molecule decreased functional presentation of this peptide by more than 2 logs. However, these two effects of glutamic acid were not complementary and were mediated by distinct mechanisms, as the change in the peptide altered the extent of binding to class II, but the change in the MHC molecule decreased recognition without inhibiting peptide binding. Taken together, the data all suggest the conclusion that changes in side-chains of peptides and MHC molecules affect Ag presentation and T cell stimulation most often by introducing dominant negative or interfering groups that prevent or alter the pattern of binding events primarily mediated by a very limited number of other residues in the Ag or presenting molecule. These results have important implications for understanding the biochemistry of peptide-MHC-TCR interactions and for the possible design of vaccines both more potent and less subject to allele-specific limitations on immunogenicity.

Amino Acid Sequence↗
PubMed2006

Generalized core vector machines.

Kernel methods, such as the support vector machine (SVM), are often formulated as quadratic programming (QP) problems. However, given m training patterns, a naive implementation of the QP solver takes O(m3) training time and at least O(m2) space. Hence, scaling up these QPs is a major stumbling block in applying kernel methods on very large data sets, and a replacement of the naive method for finding the QP solutions is highly desirable. Recently, by using approximation algorithms for the minimum enclosing ball (MEB) problem, we proposed the core vector machine (CVM) algorithm that is much faster and can handle much larger data sets than existing SVM implementations. However, the CVM can only be used with certain kernel functions and kernel methods. For example, the very popular support vector regression (SVR) cannot be used with the CVM. In this paper, we introduce the center-constrained MEB problem and subsequently extend the CVM algorithm. The generalized CVM algorithm can now be used with any linear/nonlinear kernel and can also be applied to kernel methods such as SVR and the ranking SVM. Moreover, like the original CVM, its asymptotic time complexity is again linear in m and its space complexity is independent of m. Experiments show that the generalized CVM has comparable performance with state-of-the-art SVM and SVR implementations, but is faster and produces fewer support vectors on very large data sets.

Algorithms↗
PubMed1991

Recognition by class II alloreactive T cells of processed determinants from human serum proteins.

Alloreactive T cells recognize a complex composed of an allogeneic major histocompatibility complex (MHC) molecule and a peptide derived from the processing of nonpolymorphic proteins. A sizable fraction of MHC class II alloreactive T cells is shown to recognize peptides derived from constitutive processing of human serum proteins. One such epitope is a fragment of human serum albumin. This epitope bound selectively to the human class II molecule DRw11 and was constitutively present on antigen-presenting cells in vivo. These data indicate that, in the case of MHC class II, peptides involved in allorecognition may originate from exogenous proteins.

Antigen-Presenting Cells↗
PubMed2005

Evolution of the tRNA(Tyr)/TyrRS aminoacylation systems.

The tRNA identity rules ensuring fidelity of translation are globally conserved throughout evolution except for tyrosyl-tRNA synthetases (TyrRSs) that display species-specific tRNA recognition. This discrimination originates from the presence of a conserved identity pair, G1-C72, located at the top of the acceptor stem of tRNA(Tyr) from eubacteria that is invariably replaced by an unusual C1-G72 pair in archaeal and eubacterial tRNA(Tyr). In addition to the key role of pair 1-72 in tyrosylation, discriminator base A73, the anticodon triplet and the large variable region (present in eubacterial tRNA(Tyr) but not found in eukaryal tRNA(Tyr)) contribute to tyrosylation with variable strengths. Crystallographic structures of two tRNA(Tyr)/TyrRS complexes revealed different interaction modes in accordance with the phylum-specificity. Recent functional studies on the human mitochondrial tRNA(Tyr)/TyrRS system indicates strong deviations from the canonical tyrosylation rules. These differences are discussed in the light of the present knowledge on TyrRSs.

Alanine-tRNA Ligase↗
PubMed2000

Transcription factor BACH1 is recruited to the nucleus by its novel alternative spliced isoform.

The transcription factor Bach1 is a member of a novel family of broad complex, tramtrack, bric-a-brac/poxvirus and zinc finger (BTB/POZ) basic region leucine zipper factors. Bach1 forms a heterodimer with MafK, a member of the small Maf protein family (MafF, MafG, and MafK), which recognizes the NF-E2/Maf recognition element, a cis-regulatory motif containing a 12-O-tetradecanoylphorbol-13-acetate-responsive element. Here we describe the gene structure of human BACH1, including a newly identified promoter and an alternatively RNA-spliced truncated form of BACH1, designated BACH1t, abundantly transcribed in human testis. The alternate splicing originated from the usage of a novel exon located 5.6 kilobase pairs downstream of the exon encoding the leucine zipper domain, and produced a protein that contained the conserved BTB/POZ, Cap'n collar, and basic region domains, but lacked the leucine zipper domain essential for NF-E2/Maf recognition element binding. Subcellular localization studies using green fluorescent protein as a reporter showed that full-length BACH1 localized to the cytoplasm, whereas BACH1t accumulated in the nucleus. Interestingly, coexpression of BACH1 and BACH1t demonstrated interaction between the molecules and the induction of nuclear import of BACH1. These results suggested that BACH1t recruits BACH1 to the nucleus through BTB domain-mediated interaction.

Alternative Splicing↗
PubMed1987

Intraneural microstimulation in man. Its relation to specificity of tactile sensations.

Recent advances in knowledge, and controversy, concerning cutaneous mechanoreception are reviewed. In particular, the question of perceptive specificity is discussed in the light of new experimental approaches, namely microneurography and microstimulation of identified tactile units from the glabrous skin of the human hand. Additional data are also presented. It is concluded that the human brain has an exquisite capacity to detect, localize, delineate, and classify sensations from the input of individual tactile units in the glabrous skin of the hand. The physiological specificity of low-threshold mechanoreceptors in the hand, which has been well documented in previous studies, can now be linked to distinct attributes of very simple tactile sensations which subjects report when a single afferent is stimulated electrically through an intraneural microelectrode. This conclusion does not conflict with the concept that the brain normally makes use of temporal and spatial patterns of impulses from a large number of receptors of various types to form more complex tactile percepts, such as in the recognition of texture, but the microstimulation data demonstrate that particular patterns of nerve impulses are not a necessary determinant of the subjective quality attribute of a simple tactile sensation. On the contrary, the sensations elicited by a train of impulses in a single afferent unit are remarkably distinct and well characterized in a number of respects. A further conclusion is that the afferent inputs are processed differently in tactile subsystems. This observation warrants caution in generalizing results from one system into a common theory of the origin of sensory modality.

Electric Stimulation↗
PubMed1997

Synthesis and evaluation of eight aminodeoxy trisaccharide inhibitors for N-acetylglucosaminyltransferase-V.

N-Acetylglucosaminyltransferase-V is an important enzyme controlling the branching pattern of N-linked oligosaccharides. This enzyme recognizes the trisaccharide octyl 2-acetamido-2-deoxy-beta-D-glucopyranosyl-(1-->2)-alpha-D-mannopyranosyl -(1-->6)-beta-D-glucopyranoside (5) as a substrate and adds a beta-linked GlcNAc residue to OH-6 of the central alpha-Man unit. Eight analogs of 5 were chemically synthesized where C-6 of the alpha-Man residue in 5 was deoxygenated, and structurally diverse modifications were introduced at C-4 of the same residue. The key intermediate prepared for this purpose was octyl 2-acetamido-2-deoxy-beta-D- glucopyranosyl-(1-->2)-4-amino-4,6-dideoxy-alpha-D-mannopyranosyl- (1-->6)-beta-D-glucopyranoside (7a) where the original 4'-amino group was readily derivatized on the unprotected sugar. The eight analogs 7a-7h were evaluated as inhibitors for GlcNAcT-V, both isolated (from hamster kidney) and cloned (from rat kidney). All of the compounds were found to be competitive inhibitors with Ki in the range of 3-106 microM. The conclusion of this work is that recognition of acceptor 5 does not involve contact of the C-6--C-4 end of the alpha-Man residue with the protein in the E-I (or E-S) complex.

Amino Sugars↗
PubMed1997

Identification of sequence similarity between 60 kDa and 70 kDa molecular chaperones: evidence for a common evolutionary background?

Recent findings support the premise that chaperonins (60 kDa stress-proteins) and alpha-subunits of F-type ATPases (alpha-ATPase) are evolutionary related protein families. Two-dimensional gel patterns of synthesized proteins in unstressed and heat-shocked embryonic Drosophila melanogaster SL2 cells revealed that antibodies raised against the alpha-subunit of the F1-ATPase complex from rat liver recognize an inducible p71 member of the 70 kDa stress-responsive protein family. Molecular recognition of this stress-responsive 70 kDa protein by antibodies raised against the F1-ATPase alpha-subunit suggests the possibility of partial sequence similarity within these ATP-binding protein families. A multiple sequence alignment between alpha-ATPases and 60 kDa and 70 kDa molecular chaperones is presented. Statistical evaluation of sequence similarity reveals a significant degree of sequence conservation within the three protein families. The finding suggests a common evolutionary origin for the ATPases and molecular chaperone protein families of 60 kDa and 70 kDa, despite the lack of obvious structural resemblance between them.

Amino Acid Sequence↗