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PubMed2004

Distribution of Listeria monocytogenes molecular subtypes among human and food isolates from New York State shows persistence of human disease--associated Listeria monocytogenes strains in retail environments.

While there is considerable information available regarding Listeria monocytogenes contamination patterns in food processing plants, our understanding of L. monocytogenes contamination and transmission in retail operations is limited. We characterized 125 food, 40 environmental, and 342 human clinical L. monocytogenes isolates collected in New York State from 1997 to 2002 using automated ribotyping and hly allelic variation. All environmental isolates were obtained from retail establishments and the majority of food isolates (98 isolates) were obtained from foods that were prepared or handled at retail. Overall, food and/or environmental isolates from 50 different retail establishments were characterized. The 125 food and 40 environmental isolates were differentiated into 29 and 10 ribotypes, respectively. For 16 retail establishments, we found evidence for persistence of one or more specific L. monocytogenes strains as indicated by isolation of the same EcoRI ribotype from food or environmental samples collected in a given establishment on different days. The human isolates were differentiated into 48 ribotypes. Statistical analyses showed that two ribotypes were significantly (P < 0.0001) more common among food isolates as compared with human isolates. However, a total of 17 ribotypes found among the human clinical isolates were also found among the food and environmental isolates. We conclude that L. monocytogenes, including subtypes that have been linked to human disease, can persist in retail environments. Implementation of Listeria control procedures in retail operations, which process and handle products that permit the growth of L. monocytogenes, are thus a critical component of a farm-to-table L. monocytogenes control program.

Animals↗
PubMed2001

Molecular subtyping of Shigella flexneri 3a isolates by plasmid profile analysis and pulsed-field gel electrophoresis.

Twenty-two clinical isolates of Shigella flexneri 3a that were obtained from stool specimens from seven outbreaks of infection in northern Taiwan were subtyped and compared using plasmid profile analysis and pulsed-field gel electrophoresis (PFGE). Among 32 isolates, three distinct patterns were found by plasmid profile analysis and six by PFGE, with three different restriction enzymes, XbaI, SfiI, or NotI. Seven PFGE patterns were observed in a comparative analysis using a combination of these three enzymes. Isolates collected from the same outbreaks had the same PFGE combination patterns and were distinguishable from those obtained during other outbreaks. These findings suggest that PFGE may be the most powerful method of genotyping S. flexneri 3a in epidemiological studies.

Electrophoresis, Gel, Pulsed-Field↗
PubMedDate not supplied

Molecular subtyping of group A streptococcal strains based on virulence regulon polymorphism.

A total of 64 Streptococcus pyogenes isolates included in a previous study (Shundi et al., 2000) were further analyzed by Vir typing. Vir typing is based on restriction fragment length polymorphism (RFLP) analysis of a 4- to 8-kb pathogenicity island (vir regulon) encoding emm and other virulence genes. As all our isolates contained a single vir regulon, the stoichiometric yield of restriction fragments avoided ambiguities in interpretation of results. By using both HaeIII and HinfI restriction endonucleases to generate RFLP profiles, the 64 GAS isolates were distributed among 22 Hae- and 26 Hinf-Vir types respectively.

Bacterial Proteins↗
PubMed1995

Molecular subtyping of clinical isolates of Escherichia coli from patients with lower urinary tract infections in Japan.

Crossed-field gel electrophoresis was used to analyse the chromosomal genomic DNA from 41 clinical isolates of Escherichia coli serotypes O-2, O-4, O-6 and O-75 from patients with lower urinary tract infections after digestion of the DNA with Not I and Xba I, respectively. Not I generated 28 distinctly different genomic profiles after crossed-field gel electrophoresis (CFGE) from 34 strains and Xba I generated 35 distinctly different genomic profiles from 41 strains. Not I failed to cleave the genomic DNA from one strain of E. coli serotype O-6 and from all of six strains of serotype O-75. Both enzymes were shown to have equal potential utility for detection of variability in CFGE profiles among 34 strains because both classified 34 of the 41 strains into 28 profiles in a similar manner. No examples of essentially identical restriction profiles among strains of different serotypes were obtained.

Bacterial Typing Techniques↗
PubMed1998

[HLA-B27 molecular subtypes and spondylarthropathies].

The close association between HLA-B27 and spondyloarthropathies remains unexplained. Twelve HLA-B27 subtypes designated B*2701 to B*2712 have been described in various populations. Variations in the ability of these alleles to carry susceptibility to spondyloarthropathies may exist, and may be ascribable to differences in endogenous peptide presentation. This hypothesis was evaluated by a study of peptide-binding motifs of endogenous peptides extracted from various HLA-B27 alleles. A peptide motif with a tyrosine residue at the C-terminus was not characteristic of HLA-B27 subtypes carrying susceptibility, consistent with the known lack of association of B*2707 with spondyloarthropathies. However, at the level of the individual, differences may exist between endogenous peptides presented by subtypes that do and do not confer susceptibility.

Alleles↗
PubMed1995

p53 gene inactivation in acute lymphoblastic leukemia of B cell lineage associates with chromosomal breakpoints at 11q23 and 8q24.

The clinical heterogeneity of acute lymphoblastic leukemia (ALL) of B cell lineage reflects the presence of distinct molecular pathways leading to well-defined ALL molecular subtypes. These molecular pathways include the formation of the fusion transcripts BCR/ABL and E2A/PBX1, due to t(9;22) and t(1;19), respectively, as well as rearrangements of the MLL gene at 11q23 and of c-MYC at 8q24. Hyperdiploid ALL in the absence of chromosomal structural abnormalities is an additional ALL molecular subtype. Mutations of the RAS family genes and of the p53 tumor suppressor gene represent additional genetic lesions detected in a fraction (10-20%) of ALL cases. RAS activation in ALL may be detected in all molecular subtypes of ALL and denotes poor prognosis. Conversely, little is known regarding the clinical and biological features of ALL cases carrying p53 mutations. In order to help clarify the role of p53 inactivation in ALL development, we have determined the frequency of p53 mutations throughout the molecular spectrum of B cell lineage ALL. We report that p53 inactivation in ALL of B cell lineage is restricted to cases carrying a rearrangement of MLL or c-MYC, whereas it is consistently negative in other molecular subgroups. These data underline the molecular heterogeneity of ALL of B cell lineage and indicate that at least some of the molecular pathways involved in ALL pathogenesis require more than one genetic lesion.

Base Sequence↗
PubMed2004

Comparative study of adaptive molecular evolution in different human immunodeficiency virus groups and subtypes.

Molecular adaptation, as characterized by the detection of positive selection, was quantified in a number of genes from different human immunodeficiency virus type 1 (HIV-1) group M subtypes, group O, and an HIV-2 subtype using the codon-based maximum-likelihood method of Yang and coworkers (Z. H. Yang, R. Nielsen, N. Goldman, and A. M. K. Pedersen, Genetics 155:431-449, 2000). The env gene was investigated further since it exhibited the strongest signal for positive selection compared to those of the other two major HIV genes (gag and pol). In order to investigate the pattern of adaptive evolution across env, the location and strength of positive selection in different HIV-1 sequence alignments was compared. The number of sites having a significant probability of being positively selected varied among these different alignment data sets, ranging from 25 in HIV-1 group M subtype A to 40 in HIV-1 group O. Strikingly, there was a significant tendency for positively selected sites to be located at the same position in different HIV-1 alignments, ranging from 10 to 16 shared sites for the group M intersubtype comparisons and from 6 to 8 for the group O to M comparisons, suggesting that all HIV-1 variants are subject to similar selective forces. As the host immune response is believed to be the dominant driving force of adaptive evolution in HIV, this result would suggest that the same sites are contributing to viral persistence in diverse HIV infections. Thus, the positions of the positively selected sites were investigated in reference to the inferred locations of different epitope types (antibody, T helper, and cytotoxic T lymphocytes) and the positions of N and O glycosylation sites. We found a significant tendency for positively selected sites to fall outside T-helper epitopes and for positively selected sites to be strongly associated with N glycosylation sites.

Adaptation, Physiological↗
PubMed2006

Attributing risk to Listeria monocytogenes subgroups: dose response in relation to genetic lineages.

The objective of this study was to evaluate the hypothesis that the dose-response relationship for Listeria monocytogenes in humans varies with genotypic lineage or subtype. The linkages between molecular subtyping data and enumeration data for L. monocytogenes subtypes in foods consumed by the at-risk population were examined to test this hypothesis. We applied a conditional probability model to conduct a subtype-specific dose-response analysis, with the focus on invasive listeriosis. L. monocytogenes differed not only in the molecular subtype and lineage but also in the contamination level when isolates of the pathogen occurred in retail samples of ready-to-eat foods. Using the exponential model parameter r-value as a measure (essentially the probability of a single cell causing illness), we found that the virulence varied among L. monocytogenes lineages by several orders of magnitude. Under the assumptions made, for L. monocytogenes lineages I and II the consumption of a single cell would result in listeriosis with log average probabilities of -7.88 (equivalent to once in 10(7.78) times) and -10.3, respectively, as compared with -9.72 for L. monocytogenes independent of subtype. A greater difference in r-values was found for selected ribotypes. The uncertainty about the r-value estimates was small compared with the large differences in the virulence parameters themselves. Thus, for L. monocytogenes both subtype and the number of cells consumed matter, highlighting the usefulness of considering both exposure concentration and subtype prevalence in dose-response analysis. As advances are made in molecular subtyping and quantitative tools for dose-response analysis, further studies integrating genomic data into quantitative risk assessments will enable better attribution of disease risk to L. monocytogenes subtypes.

Animals↗
PubMed1997

Alpha 1-adrenoceptor subtype selectivity: molecular modelling and theoretical quantitative structure-affinity relationships.

This study constitutes a preliminary rationalization, at the molecular level, of antagonist selectivity towards the three cloned alpha 1-adrenergic receptor (alpha 1-AR) subtypes. Molecular dynamics simulations allowed a structural/dynamics analysis of the seven alpha-helix-bundle models of the bovine alpha 1a-, hamster alpha 1b-, and rat alpha 1d-AR subtypes. The results showed that the transmembrane domains of these subtypes have different dynamic behaviours and different topographies of the binding sites, which are mainly constituted by conserved residues. In particular, the alpha 1a-AR binding site is more flexible and topographically different with respect to the other two subtypes. The results of the theoretical structural/dynamics analysis of the isolated receptors are consistent with the binding affinities of the 16 antagonists tested towards the three cloned alpha 1-AR subtypes. Moreover, the theoretical quantitative structure-affinity relationships obtained from the antagonist-receptor interaction models further corroborates the hypothesis that selectivity towards one preferential subtype is mainly modulated by receptor and/or ligand distortion energies. In other words, subtype selectivity seems to be mainly guided by the dynamic complementarity (induced fit) between ligand and receptor. On the basis of the quantitative models presented it is possible to predict both affinities and selectivities of putative alpha 1-AR ligands as well as to estimate the theoretical alpha 1-AR subtype affinities and selectivities of existing antagonists.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1994

The alpha 1-adrenergic receptor that mediates smooth muscle contraction in human prostate has the pharmacological properties of the cloned human alpha 1c subtype.

Molecular cloning studies have revealed the existence of three subtypes of alpha 1-adrenergic receptors. However, the link between any individual subtype and its functional role in the body has remained elusive. In an effort to bridge the gap between molecular biology and pathophysiology, we have chosen a model smooth muscle system, the human prostate, and investigated the role of alpha 1 subtypes in this tissue. To determine which alpha 1-adrenergic receptor subtype mediates the contractile response of the human prostate, we first studied the pharmacological properties of three cloned human alpha 1 subtypes (alpha 1a/d, alpha 1b, and alpha 1c). Prazosin, terazosin, doxazosin, alfuzosin, and abanoquil showed no selectivity for the human alpha 1 subtypes. WB-4101 and 5-methylurapidil showed a rank order of potency of alpha 1c > alpha 1a/d >> alpha 1b. Indoramin and (+)-niguldipine were selective for the alpha 1c-adrenergic receptor, with at least 10-fold lower affinity at either alpha 1a/d or alpha 1b subtypes. SK&F104856 was found to be 6-fold more potent at the alpha 1a/d receptor subtype than at alpha 1b- or alpha 1c-adrenergic receptors. We next determined the potency of these antagonists to inhibit the phenylephrine-induced contraction of human prostatic tissue in vitro. The potencies of indoramin, 5-methylurapidil, and SK&F104856 to inhibit the contractile response and to displace [3H]prazosin from the cloned human alpha 1c subtype were similar. Our data suggest that the alpha 1 receptor that mediates the contraction of human prostate smooth muscle has the pharmacological properties of the cloned human alpha 1c-adrenergic receptor. The findings of the present study suggest that selective alpha 1c-adrenergic receptor antagonists may be clinically more efficacious and better tolerated agents for the treatment of symptomatic benign prostatic hyperplasia.

Animals↗
PubMedDate not supplied

Rapid molecular genetic subtyping of serotype M1 group A Streptococcus strains.

Serotype M1 group A Streptococcus, the most common cause of invasive disease in many case series, generally have resisted extensive molecular subtyping by standard techniques (e.g., multilocus enzyme electrophoresis, pulsed-field gel electrophoresis). We used automated sequencing of the sic gene encoding streptococcal inhibitor of complement and of a region of the chromosome with direct repeat sequences to unambiguously differentiate 30 M1 isolates recovered from 28 patients in Texas with invasive disease episodes temporally clustered and thought to represent an outbreak. Sequencing of the emm gene was less useful for M1 strain differentiation, and restriction fragment length polymorphism analysis with IS1548 or IS1562 as Southern hybridization probes did not provide epidemiologically useful subtyping information. Sequence polymorphism in the direct repeat region of the chromosome and IS1548 profiling data support the hypothesis that M1 organisms have two main evolutionary lineages marked by the presence or absence of the speA2 allele encoding streptococcal pyrogenic exotoxin A2.

Amino Acid Sequence↗
PubMed2005

Microbiological aspects of the investigation that traced the 1998 outbreak of listeriosis in the United States to contaminated hot dogs and establishment of molecular subtyping-based surveillance for Listeria monocytogenes in the PulseNet network.

A multistate outbreak of listeriosis occurred in the United States in 1998 with illness onset dates between August and December. The outbreak caused illness in 108 persons residing in 24 states and caused 14 deaths and four miscarriages or stillbirths. This outbreak was detected by public health officials in Tennessee and New York who observed significant increases over expected listeriosis cases in their states. Subsequently, the Centers for Disease Control and Prevention (CDC) began laboratory characterization of clinical isolates of Listeria monocytogenes by serotyping and restriction fragment length polymorphism analysis using pulsed-field gel electrophoresis (PFGE). For the purpose of this investigation, outbreak-related isolates were defined as those that had a specific AscI-PFGE pattern and indistinguishable or highly similar (no more than 2 band difference in 26 bands) ApaI-PFGE patterns when their DNA was restricted by AscI and ApaI restriction enzymes. Timely availability of molecular subtyping results enabled epidemiologists to separate outbreak cases from temporally associated sporadic cases in the same geographic areas and facilitated the identification of contaminated hot dogs manufactured at a single commercial facility as the source of the outbreak. During the investigation of this outbreak, a standardized protocol for subtyping L. monocytogenes by PFGE was developed and disseminated to public health laboratories participating with CDC's PulseNet network; these laboratories were requested to begin routine PFGE subtyping of L. monocytogenes.

Animals↗
PubMed1999

Molecular heterogeneity in medulloblastoma with implications for differing tumor biology.

Medulloblastomas and related primitive neuroectodermal tumors are the second most common malignant tumors of childhood. In spite of improvements in cancer therapy, these tumors are still associated with significant morbidity and mortality. Although these tumors share similar histologic features, recent molecular studies suggest that they could represent a genetically mixed group of tumors. The genetic events that might play a role in the biology of these tumors also could allow a molecular subtyping of medulloblastomas. Such molecular subtyping of medulloblastomas could allow for the use of newer therapeutic techniques, such as gene therapy, for selective targeting of critical genetic events in subsets of medulloblastomas. It is becoming increasingly clear that in medulloblastomas, the morphologic similarity of "small blue" cells does not imply similar or shared molecular characteristics, with implications for differing tumor biology.

Cell Cycle↗
PubMedDate not supplied

The structural and functional interrelationships of muscarinic acetylcholine receptor subtypes.

Molecular cloning of the genes encoding the muscarinic acetylcholine receptors has shown that receptor subtypes classified on the basis of pharmacological properties are related polypeptides encoded by distinct genes. These studies have also revealed the existence of novel muscarinic receptor subtypes. Functional analysis of each of the subtypes expressed in mammalian cells indicates that the different subtypes activate distinct biochemical pathways, a finding that explains the tissue-specific physiological response elicited by the neurotransmitter, acetylcholine.

Amino Acid Sequence↗
PubMed2003

Gene expression profiling in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) presents a difficult medical problem. T-ALL's clinical features and the biological properties of the leukemia cells are not predictive of prognosis, and thus have not been useful for risk-specific adjustments in therapeutic intensity. Microarray gene expression analyses of T-cell leukemic lymphoblasts have not only improved our understanding of the biological heterogeneity of this disease but have revealed clinically relevant molecular subtypes. Five different multistep molecular pathways have been identified that lead to T-ALL, involving activation of different T-ALL oncogenes: (1) HOX11, (2) HOX11L2, (3) TAL1 plus LMO1/2, (4) LYL1 plus LMO2, and (5) MLL-ENL. Gene expression studies indicate activation of a subset of these genes-HOX11, TAL1, LYL1, LMO1, and LMO2-in a much larger fraction of T-ALL cases than those harboring activating chromosomal translocations. In many such cases, the abnormal expression of one or more of these oncogenes is biallelic, implicating upstream regulatory mechanisms. Among these molecular subtypes, overexpression of the HOX11 orphan homeobox gene occurs in approximately 5% to 10% of childhood and 30% of adult T-ALL cases. Patients with HOX11-positive lymphoblasts have an excellent prognosis when treated with modern combination chemotherapy, while cases at high risk of early failure are included largely in the TAL1- and LYL1-positive groups. Supervised learning approaches applied to microarray data have identified a group of genes whose expression is able to distinguish high-risk cases. Further analyses of gene expression signatures of T-ALL lymphoblasts are especially needed for patients treated on modern combination chemotherapy trials to clearly distinguish the 10% to 15% of patients who fail induction or relapse in the first year of treatment. These high-risk patients would be ideal candidates for more intensive therapies in first remission, such as myeloablative regimens with stem cell rescue. Based on the rapid pace of research in T-ALL, made possible in large part through microarray technology, deep analysis of molecular pathways should lead to new and much more specific targeted therapies.

Cell Differentiation↗
PubMed2004

Allele-dependent similarity between viral and self-peptide presentation by HLA-B27 subtypes.

Molecular mimicry is discussed as a possible mechanism that may contribute to the development of autoimmune diseases. It could also be involved in the differential association of the human major histocompatibility subtypes HLA-B(*)2705 and HLA-B(*)2709 with ankylosing spondylitis. These two subtypes differ only in residue 116 of the heavy chain (Asp in B(*)2705 and His in B(*)2709), but the reason for the differential disease association is not understood. Using x-ray crystallography, we show here that the viral peptide pLMP2 (RRRWRRLTV, derived from latent membrane protein 2 (residues 236-244) of Epstein-Barr virus) is presented by the B(*)2705 and B(*)2709 molecules in two drastically deviating conformations. Extensive structural similarity between pLMP2 and the self-peptide pVIPR (RRKWRRWHL, derived from vasoactive intestinal peptide type 1 receptor (residues 400-408)) is observed only when the peptides are presented by B(*)2705 because of a salt bridge between Arg(5) of both peptides and the subtype-specific heavy chain residue Asp(116). Combined with functional studies using pLMP2/pVIPR-cross-reactive cytotoxic T cell lines and clones, together with target cells presenting these peptides or a modified peptide analogue, our results reveal that a pathogen-derived peptide can exhibit major histocompatibility complex class I subtype-dependent, drastically distinct binding modes. Furthermore, the results demonstrate that molecular mimicry between pLMP2 and pVIPR in the HLA-B27 context is an allele-dependent property.

Alleles↗
PubMed1995

Resolution and in vitro and initial in vivo evaluation of isomers of iodine-125-labeled 1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate: a high-affinity ligand for the muscarinic receptor.

1-Azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)- alpha-phenylacetate (IQNP, 1), is a highly selective ligand for the muscarinic acetylcholinergic receptor (mAChR). There are eight stereoisomers in the racemic mixture. The optical isomers of alpha-hydroxy-alpha-phenyl-alpha-(1-propyn-3-yl)acetic acid were resolved as the alpha-methylbenzylamine salts, and the optical isomers of 3-quinuclidinol were resolved as the tartrate salts. The E and Z isomers were prepared by varying the reaction conditions for the stannylation of the triple bond followed by purification utilizing flash column chromatography. In vitro binding assay of the four stereoisomers containing the (R)-(-)-3-quinuclidinyl ester demonstrated that each isomer of 1 bound to mAChR with high affinity. In addition, (E)-(-)-(-)-IQNP demonstrated the highest receptor subtype specificity between the m1 molecular subtype (KD, nM, 0.383 +/- 0.102) and the m2 molecular subtype (29.6 +/- 9.70). In vivo biodistribution studies demonstrated that iodine-125-labeled (E)-(-)-(+)-1 cleared rapidly from the brain and heart. In contrast, iodine-125-labeled (E)-(-)-(-)-, (Z)-(-)-(-)-, and (Z)-(-)-(+)-1 have high uptake and retention in mAChR rich areas of the brain. It was also observed that (E)-(-)-(-)-IQNP demonstrated an apparent subtype selectivity in vivo with retention in M1 (m1, m4) mAChR areas of the rain. In addition, (Z)-(-)-(-)-IQNP also demonstrated significant uptake in tissues containing the M2 (m2) mAChR subtype. These results demonstrate that the iodine-123-labeled analogues of the (E)-(-)-(-)- and (Z)-(-)-(-)-IQNP isomers are attractive candidates for single-photon emission-computed tomographic imaging of cerebral and cardiac mAChR receptor densities.

Animals↗