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PubMed1996

Allogeneic class I MHC requirement for alloantigen-reactive helper T-lymphocyte responses in vivo. Evidence for indirect presentation of alloantigen.

The mechanisms by which host T cells recognize transplant-associated alloantigens in vivo have not been established. Two alloantigen presentation pathways may be used: (1) allogeneic class I and class II MHC molecules may be recognized directly by host CD8+ and CD4+ cells, respectively, or (2) allogeneic MHC molecules may be processed as foreign peptide and presented by host antigen-presenting cells to CD4+ cells in the context of self class II proteins. In this study, the sponge matrix allograft model was used to examine the relative contributions of these alloantigen presentation pathways to CD4+ T-cell activation in vivo. Limiting dilution analysis was used to quantify the localization of interleukin-2-producing helper T lymphocytes (HTL) following implantation of sponge allografts. Allografts either were disparate at both class I and class 11, or were derived from beta2-microglobulin knockout (beta2M-/-) mice, which express class II but are deficient in class I. Two measures of in vivo HTL function were monitored: (1) the accumulation of HTL within the allograft (a process that is dependent upon antigen-driven cytokine production), and (2) the development of cytolytic alloantibodies. After implantation of sponge allografts expressing both class I and class II, HTL were readily detectable in the allograft, and cytolytic alloantibodies were present in the serum. When mice were implanted with beta2M-/- sponge allografts, HTL failed to infiltrate these class I-deficient allografts, and alloantibodies were not detectable in the sera of recipients of beta2M-/- sponge allografts. This in vivo requirement for class I expression was not reflected by traditional in vitro measures of HTL function; cells obtained from lymphoid tissues mounted a mixed lymphocyte response and produced interleukin-2 when stimulated with beta2M-/- splenocytes in vitro. One possible interpretation of these data is that in vivo HTL functions are dependent upon the presence of class I-reactive CD8+ T cells. However, HTL readily infiltrated grafts expressing both class I and class II when recipients depleted of CD8+ T cells, and alloantibodies were produced. These observations support the idea that indirect presentation of allogeneic class I molecules plays a critical role in regulating CD4+ HTL functions associated with allograft rejection in vivo.

Animals↗

PubMed1994

Lytic susceptibility of target cells to cytotoxic T cells is determined by their constitutive major histocompatibility complex class I antigen expression and cytokine-induced activation status.

Cytotoxic T-cell lines (TCL) were raised in vitro using stimulator cells with a defined major histocompatibility complex (MHC) mismatch and tested in a cytotoxic chromium-release assay against haemopoietic and non-haemopoietic target cells from the original stimulator. Monoclonal antibody (mAb)-blocking experiments and simultaneous determination of MHC class I, class II, lymphocyte function-associated antigen-1 (LFA-1) and intracellular adhesion molecule-1 (ICAM-1) density by quantitative radioimmunometric methods and flow cytometry on target cells demonstrated that lysis was restricted by MHC class I and dependent upon the constitutive MHC class I antigen expression. Measurements showed a high constitutive expression of class I MHC antigens on peripheral blood mononuclear cells (PBMC), but a low one on keratinocytes (K). Also, PBMC were more susceptible to lysis by TCL than K. Interferon-gamma (IFN-gamma) treatment of K resulted in increased MHC class I antigen expression and enhanced lytic susceptibility to TCL. IFN-alpha and tumour necrosis factor-alpha (TNF-alpha) treatment, which did not modulate MHC class I antigen expression on K, did not influence the amount of K lysis either. None of the cytokines tested in this analysis, however, increased the expression of MHC class I, class II, ICAM-1 and LFA-1 on PBMC. Only IFN-gamma pretreatment showed a minimal, statistically significant increase in MHC class I antigen expression. In spite of the minimal effect of IFN-gamma and no effect of IFN-alpha on class I MHC expression, pretreatment of target cells with both cytokines considerably increased their lytic susceptibility. The mechanism of cytokine-induced enhanced lytic susceptibility to TCL was not explained by increased MHC class I, LFA-1 or ICAM-1 expression, since no correlation was found between surface expression of these molecules and lytic susceptibility to TCL. These data demonstrate that: (1) the constitutive density of MHC class I antigens determines the extent of TCL lysis; (2) IFN-gamma, and not IFN-alpha or TNF-alpha controls the amount of K target cell lysis by increasing their MHC class I antigen expression; and (3) IFN-gamma and IFN-alpha control the amount of PBMC target cell lysis by a mechanism independent of MHC class I, ICAM-1 or LFA-1 expression.

Cell Adhesion Molecules↗

PubMed1999

The role of familial values in understanding the impact of social class on weight concern.

OBJECTIVE: To examine the role of social class on aspects of weight concern and to assess the possible impact of values on mediating this association. METHOD: Two hundred fifty-seven girls ranging in age from 13 to 16, from either a fee paying inner city independent girls school (higher class school, n = 135) or a state comprehensive, inner city girls school (lower class school, n = 122) completed a questionnaire concerning their profile characteristics (age, social class), aspects of their weight concern, and their own and their perceptions of their significant others' values (achievement, family life, and physical appearance). RESULTS: The results showed consistent effects of class on weight concern, with the higher class subjects reporting higher levels of restrained eating, greater body dissatisfaction, and body distortion than their lower class counterparts. The results also showed an effect of class on values, with the lower class subjects placing more importance on family life from both their own perspective and that of their parents and friends, and rating their friends as valuing achievement and physical appearance more than the higher class subjects. In terms of the best predictors of weight concern, the results showed that higher levels of restrained eating were related to being from a higher class, placing greater importance upon physical appearance, preferring a thinner ideal female body, and placing less importance upon family life; greater body dissatisfaction was related to being from a higher social class, placing greater importance upon physical appearance and a lower importance upon achievement, and greater body distortion was related to being from a higher social class and a high value placed upon physical appearance. CONCLUSION: The results indicate both a direct social class/weight concern link and a relationship which is mediated by values. The results are discussed in terms of developing an improved measure of class values and the relatively stable nature of class boundaries.

Adolescent↗

PubMed1993

The relationship between severe asthma and social class.

Asthma is one of the few diseases which has been reported to be common in the higher social classes. In order to assess the relationship between severe asthma and social class we analysed a national study of disabled adults undertaken by the Office of Population Censuses and Surveys (OPCS). The study estimated that there were 5.8 million people over 16 years with some degree of disability living in private households in England and Wales. Thirteen percent of disabilities were due to respiratory disease: 6% chronic bronchitis and emphysema, 3% asthma and allergy, and 4% other respiratory diseases. Among 10,000 individuals interviewed, 338 disabled adults reported asthma as a contributing cause of their disability. Of 291 cases with social class recorded, 41 (14%) were in social classes 1 and 2, 128 (44%) in social class 3, and 122 (42%) in social classes 4 and 5. An estimate of the relationship between social class and adult asthma in the general population was derived by calculating a morbidity ratio for the different social classes. The morbidity ratio for all social classes combined equals 100: for social classes 1 and 2 it was 63 (95% confidence intervals 48, 91); 93 (95% confidence intervals 77, 109) for social class 3; and 131 (95% confidence intervals 108, 153) for social classes 4 and 5. Adults in social classes 4 and 5 were approximately twice as likely to have severe asthma as those in social classes 1 and 2. This could be as a result of differences in the prevalence or treatment of asthma among the social classes.

Adolescent↗

PubMed1993

Intracellular distribution of the MHC class II molecules and the associated invariant chain (Ii) in different cell lines.

Intracellular localization and routing of MHC class II molecules and the associated invariant chain (Ii) were studied using rat-2 cells and HeLa cells stably transfected with the murine class II genes A alpha kA beta k (Ak) alone or supertransfected with human Ii or a truncated delta 20Ii lacking the endosomal sorting signal within Ii. We show that Ii and delta 20Ii are able to bind the class II molecules and replace the highly homologous murine Ii in class II sorting. Expression of transfected Ii or delta 20Ii also result in more efficient transport of class II molecules from the ER. There are, however, cell type specific differences in the intracellular routing of the class II molecules. The endosomal sorting signal within Ii is required to target class II molecules to endosomes in HeLa cells, whereas class II molecules alone enter endosomes in rat-2 cells. Class II molecules cannot direct the associated delta 20Ii to endosomes, suggesting that they follow a direct route to the cell surface and the majority of class II may enter endosomes by internalization. This is also supported by the long lived presence of class II molecules in endosomes after arresting protein transport with cycloheximide or brefeldin A. Class II molecules expressed alone or together with Ii are located in the whole endosomal pathway in rat-2 cells. However, full length Ii is required to target the class II molecules to vesicles that are more chloroquine sensitive than vesicles containing class II molecules alone. Our results thus indicate that Ii is responsible for endosomal sorting of class II molecules in HeLa cells, whereas in rat-2 cells the presence of Ii leads to an altered endosomal distribution.

Animals↗

PubMed2005

Social class and access to specialist palliative care services.

OBJECTIVE: To determine any social class differences in place of death of cancer patients in South Bristol; to explore the experience of carers; and to identify inequalities in access to palliative care. DESIGN: Two-part study: (1) A cross-sectional survey of all 960 cancer deaths in South Bristol between September 1999 and December 2002. (2) A qualitative in-depth interview study of 18 carers of patients who died of cancer during the same period in South Bristol. Fourteen of those who died were from social class IIIM (manual), IV and V (i.e. lower social classes). MAIN OUTCOMES: Place of death of patients according to social class and geographical distance from the hospice. Carers' accounts of the way in which illness and death were conducted, and their response to the management of death and dying. RESULTS: The cross sectional survey showed that patients from social class V were less likely to die in the hospice. This finding was independent of geographical proximity. In the qualitative study, no class specific beliefs about death and dying were identified. Attitudes to the way dying should be conducted were common across the classes. Families expected to be present and centre stage at the time of death and for it to be conducted in a dignified and personal manner. Health care staff in all settings supported them in this aim. No one in this study died without a family member present. Some elderly carers were less open than younger carers in the way they talked about death and did not wish to be present at the death. Some carers from social class IV and V were less active in seeking information or asking for hospice admission than carers from other classes. Unrealistic expectations about the availability of hospice beds were common to all carers. Anxiety was common among carers. It was reduced by the provision of reliable and consistent healthcare support, by information provided in a timely and sensitive way, and by open and shared decision making between carer and patient. Most important in reducing anxiety was the support of a second carer who lived locally and was reliable. Carers from social classes IIIM (manual), IV and V were more likely to have this kind of support than carers from social classes I, II and IIIN (non-manual). CONCLUSION: Although cancer patients from social class V were less likely than others to die in the hospice, social inequality in access to or utilisation of healthcare in terminal illness was not prominent in carers' accounts. When it did arise, it was associated with passivity in seeking information and support on the part of some carers from social classes IV and V. Carers from social classes IIIM-V received more regular and reliable support from their families than those from social classes I-IIIN.

Aged↗

PubMed1999

H-2M molecules, like MHC class II molecules, are targeted to parasitophorous vacuoles of Leishmania-infected macrophages and internalized by amastigotes of L. amazonensis and L. mexicana.

In their amastigote stage, Leishmania are obligatory intracellular parasites of mammalian macrophages, residing and multiplying within phagolysosomal compartments called parasitophorous vacuoles (PV). These organelles have properties similar to those described for the MHC class II compartments of antigen-presenting cells, sites where peptide-class II molecule complexes are formed before their expression at the cell surface. After infection with Leishmania amazonensis or L. mexicana, endocytosis and degradation of class II molecules by intracellular amastigotes have also been described, suggesting that these parasites have evolved mechanisms to escape the potentially hazardous antigen-presentation process. To determine whether these events extend to other molecules of the antigen-presentation machinery, we have now studied the fate of the MHC molecule H-2M in mouse macrophages infected with Leishmania amastigotes. At least for certain class II alleles, H-2M is an essential cofactor, which catalyses the release of the invariant chain-derived CLIP peptide from the peptide-binding groove of class II molecules and facilitates the binding of antigenic peptides. H-2M was detected in PV of mouse macrophages infected with various Leishmania species including L. amazonensis, L. mexicana, L. major and L. donovani. PV thus contain all the molecules required for the formation of peptide-class II molecule complexes and especially of complexes with parasite peptides. The present data indicate, however, that if this process occurs, it does not lead to a clear increase of SDS-stable compact (alpha)(beta) dimers of class II. In PV that contained L. amazonensis or L. mexicana, both class II and H-2M molecules often colocalized at the level where amastigotes bind to the PV membrane, suggesting that these molecules are physically associated, directly or indirectly, and possibly interact with parasite components. Furthermore, as class II molecules, H-2M molecules were internalized by amastigotes of these Leishmania species and reached parasite compartments that also contained class II molecules. Immunostaining of H-2M within parasites was increased by treatment of infected macrophages with the cysteine protease inhibitors Z-Phe-AlaCHN2 or Z-Phe-PheCHN2 or by incubation of the parasites with the same inhibitors before infection. These data thus support the idea that amastigotes of certain Leishmania species capture and degrade some of the molecules required for antigen presentation. To examine whether endocytosis of class II molecules by the parasites occurs through interactions with parasite components involving their peptide-binding groove, we made use of the fact that a large fraction of the class II molecules of H-2M(alpha) knock-out H-2(b) mice are occupied by the peptide CLIP and are unable to bind other peptides. We found that, in Leishmania-infected macrophages of these mutant mice, class II-CLIP complexes reached PV and were internalized by amastigotes. These results thus prove that endocytosis of class II molecules by amastigotes (1) is H-2M-independent and (2) does not necessarily involve the peptide-binding pocket of these molecules. Altogether, these data are compatible with an endocytic mechanism based on general properties shared by classical and non-classical class II molecules.

Animals↗

PubMed2005

Bias measuring mortality gradients by occupational class in New Zealand.

BACKGROUND: Socioeconomic differences in mortality in New Zealand have traditionally been measured using occupational class from mortality data (based on usual or last occupation) as the numerator, and class from census data (current occupation on census night) as the denominator. Such analyses are prone to numerator-denominator bias. Record linkage of census and mortality data in the New Zealand Census-Mortality Study (NZCMS) allows analyses of 'linked' data that will avoid numerator-denominator bias, but may be prone to other biases. OBJECTIVES: To determine differences in the assignment of occupational class between census and mortality data; to investigate biases in the observed association of class with mortality using linked census-mortality data; and to compare the class-mortality association using unlinked versus linked census-mortality data. METHODS: Census records for males aged 25-64 years on census night 1991 were anonymously and probabilistically linked to 5,844 out of 8,145 eligible deaths occurring in the second and third years following census night. RESULTS: (by objective) Only 47% of linked deaths had an occupation recorded on census data, compared to 84% on mortality data - a census to mortality ratio of 0.56. Relatively fewer deaths were identified as class 4 on census data (census to mortality ratio of 0.45) compared to other classes (ratios 0.55 to 0.64). Linkage bias: A lower likelihood of 25-44 year old deaths (but not 45-64 year olds) from lower socioeconomic classes being successfully linked to a census record meant that analyses using linked census-mortality data underestimated the class-mortality association. Bias due to exclusion of economically inactive: Analyses on linked-census data (using current occupational class) considerably underestimated the estimated association of usual occupational class with mortality. The strength of the association of class with mortality according to linked census-mortality data (and adjusted for the above two biases) and unlinked data were roughly comparable. CONCLUSION: Differences in the recording of occupational class on census and mortality data in New Zealand mean measuring mortality differences by class is thwart with difficulty. If one assumes that biases for any particular method of analysis are similar over time, or one carefully adjusts where possible for bias, using occupational class to monitor trends in socioeconomic mortality gradients may be valid.

Adult↗

PubMed1992

The class II MHC-restricted presentation of endogenously synthesized ovalbumin displays clonal variation, requires endosomal/lysosomal processing, and is up-regulated by heat shock.

LB27.4 cells (a B lymphoblastoid APC) were transfected with a plasmid containing an OVA cDNA. Functional analysis of six independent clones yielded three patterns of MHC-restricted presentation of the endogenously synthesized OVA. A clone displayed either: 1) strong class I and class II-restricted presentation, 2) strong class I but little or no class II-restricted presentation or, 3) only a modest class I-restricted presentation. There was no clonal variation in class II-restricted presentation of exogenous Ag or in the amount of surface class I or II molecules. Heat shock increased the presentation of endogenous but not exogenous Ag with class II. These results indicate that an endogenously synthesized Ag both constitutively and during heat shock can gain access to the class II, MHC-restricted, presentation pathway. The amount of OVA synthesized by a cell correlated with whether OVA-class II complexes were detected. However, the amount of OVA secreted into the extracellular fluid was not sufficient to sensitize APC, which suggests that endogenously synthesized OVA enters the class II pathway of Ag presentation by an intracellular route rather than by an extracellular/reuptake route. Also, the functional and quantitative analysis of the clones suggests that endogenously synthesized OVA was presented more efficiently with class I as compared to class II-MHC molecules. Leupeptin and chloroquine inhibited the class II-restricted presentation of endogenously synthesized OVA. Together these results indicate that endogenously synthesized OVA can gain access to an endosomal/lysosomal compartment via an intracellular route and be processed and presented in association with class II-MHC molecules.

Animals↗

PubMed1985

Participation of class II alloantigens in in vivo regulation of K/D region disparate thyroid graft rejection in mice.

Class I and II molecules preferentially activate cytotoxic T cells and helper T cells, respectively, in primary in vitro alloactivation of T lymphocytes. Collaboration between these subpopulations leads to an efficient anti-class I specific cytotoxic response. We tested whether the presence of class II, in addition to class I, alloantigens on thyroid allografts in vivo induces augmentation of anti-class I antigen immune response and leads to rejection of K/D region disparate grafts which otherwise would have been accepted. Different pairs of K or D region disparate mouse strains were selected in which transplantation across a class I antigen disparity alone resulted in long-term graft acceptance. In some pairs of mouse strains, co-transplantation of recipient mice with a second thyroid graft sharing the K/D region of the first, but additionally expressing an allo class II molecule, led to accelerated K/D region disparate thyroid graft rejection. Transplantation of thyroid allografts expressing both class II and I alloantigens did not induce increased host anti-class I antigen cytotoxic response, or affect the frequency of specific precursor cytotoxic T cells. In one pair of congenic mouse strains, acute rejection of K/D region disparate thyroid grafts occurred in the absence of class II alloantigen stimulation; in other strains, co-transplantation of class I and II alloantigen disparate thyroid allografts was not sufficient to induce K/D region disparate graft rejection. The results thus demonstrate that a class II alloantigen on a thyroid graft may augment the rejection response directed against the graft class I alloantigens. The class II alloantigen stimulation was not always essential or sufficient for induction of class I antigen disparate thyroid graft rejection, and was dependent on the specific I region and/or K/D region gene allele.

Animals↗

PubMed2001

European Epidemiologic Registry of Cystic Fibrosis (ERCF): comparison of major disease manifestations between patients with different classes of mutations.

SUMMARY. By August 1997, 11,749 patients with cystic fibrosis had been enrolled in the European Epidemiologic Registry of Cystic Fibrosis (ERCF). Genotype analysis had been performed on 8,963 (76%) of these patients, and the majority had one or two identifiable mutations. Patients with known mutations were classified according to the type of mutation (Classes I-V), and were grouped according to the class of mutation on both chromosomes. This resulted in six subgroups, including all patients homozygous for Class I (I/I, n = 72), for Class II (II/II, n = 5,020), and for Class III mutations, (III/III, n = 23). Since there were only 23 patients homozygous for Class III mutations, a fourth group was made up of patients who were compound heterozygous for a Class II and III mutation (II/III, n = 265). There were only five patients homozygous for Class IV mutations, and consequently a fifth group was made up of all patients carrying at least one Class IV mutation, regardless of the nature of the mutation on the other chromosome (IV/any, n = 187). None were homozygous for Class V mutations; consequently, a sixth group consisted of patients carrying at least one Class V mutation (V/any, n = 22). Mean age was highest in groups III/III, IV/any, and V/any (15.6, 16, and 17 years, respectively) as opposed to 12.4 years in group II/II and 13.4 in group II/III, but both group III/III and V/any were small, and the confidence interval of the mean was large. The percentage of patients receiving pancreatic enzymes was lower in groups IV/any and V/any than in any of the other groups, i.e., approximately 50% of patients 18 years or older in both groups as opposed to between 90-100% of all other patients regardless of age. The prevalence of diabetes mellitus increased with age from 2.6% in patients < 18 years to 22.1% in patients 18 years or older in the large group II/II, but was only 1.5% in patients 18 years or older in group IV/any. Disregarding the small group III/III, abnormally elevated liver enzymes and/or bilirubin (1.5 x upper normal limit) was much less frequent in group IV/any than in any of the other groups, both overall and in patients aged 18 years or more. The course of lung disease appeared to be less dependent on genotype than pancreatic function, with only minor differences between groups; however, the mean values of both FVC % and FEV(1) % were slightly higher in group IV/any than all other groups in both younger and older patients. The same was found for the prevalence of some major clinical signs of severe lung disease, such as clubbing, hyperinflation, and crepitations. Overall mean weight expressed as an age percentile was markedly higher in group IV/any than in any other group, which may be related to the finding of a much lower prevalence of chronic P. aeruginosa infection in patients 18 years or older belonging to group IV/any (and V/any) than in any other group. In conclusion, the presence of a class IV mutation appears to offer some degree of protection against pancreatic insufficiency, diabetes mellitus, and liver disease. We confirmed that lung disease follows a milder clinical course in patients with a class IV mutation and that the presence of a class IV mutation (and possibly class V) is associated with a delay in the onset of P. aeruginosa infection.

Adolescent↗

PubMed2006

To mind the mind: an event-related potential study of word class and semantic ambiguity.

The goal of this study was to jointly examine the effects of word class, word class ambiguity, and semantic ambiguity on the brain response to words in syntactically specified contexts. Four types of words were used: (1) word class ambiguous words with a high degree of semantic ambiguity (e.g., 'duck'); (2) word class ambiguous words with little or no semantic ambiguity (e.g., 'vote'); (3) word class unambiguous nouns (e.g., 'sofa'); and (4) word class unambiguous verbs (e.g., 'eat'). These words were embedded in minimal phrases that explicitly specified their word class: "the" for nouns (and ambiguous words used as nouns) and "to" for verbs (and ambiguous words used as verbs). Our results replicate the basic word class effects found in prior work (Federmeier, K.D., Segal, J.B., Lombrozo, T., Kutas, M., 2000. Brain responses to nouns, verbs and class ambiguous words in context. Brain, 123 (12), 2552-2566), including an enhanced N400 (250-450 ms) to nouns compared with verbs and an enhanced frontal positivity (300-700 ms) to unambiguous verbs in relation to unambiguous nouns. A sustained frontal negativity (250-900 ms) that was previously linked to word class ambiguity also appeared in this study but was specific to word class ambiguous items that also had a high level of semantic ambiguity; word class ambiguous items without semantic ambiguity, in contrast, were more positive than class unambiguous words in the early part of this time window (250-500 ms). Thus, this frontal negative effect seems to be driven by the need to resolve the semantic ambiguity that is sometimes associated with different grammatical uses of a word class ambiguous homograph rather than by the class ambiguity per se.

Adolescent↗

PubMedDate not supplied

Data mining the NCI cancer cell line compound GI(50) values: identifying quinone subtypes effective against melanoma and leukemia cell classes.

Using data mining techniques, we have studied a subset (1400) of compounds from the large public National Cancer Institute (NCI) compounds data repository. We first carried out a functional class identity assignment for the 60 NCI cancer testing cell lines via hierarchical clustering of gene expression data. Comprised of nine clinical tissue types, the 60 cell lines were placed into six classes-melanoma, leukemia, renal, lung, and colorectal, and the sixth class was comprised of mixed tissue cell lines not found in any of the other five classes. We then carried out supervised machine learning, using the GI(50) values tested on a panel of 60 NCI cancer cell lines. For separate 3-class and 2-class problem clustering, we successfully carried out clear cell line class separation at high stringency, p < 0.01 (Bonferroni corrected t-statistic), using feature reduction clustering algorithms embedded in RadViz, an integrated high dimensional analytic and visualization tool. We started with the 1400 compound GI(50) values as input and selected only those compounds, or features, significant in carrying out the classification. With this approach, we identified two small sets of compounds that were most effective in carrying out complete class separation of the melanoma, non-melanoma classes and leukemia, non-leukemia classes. To validate these results, we showed that these two compound sets' GI(50) values were highly accurate classifiers using five standard analytical algorithms. One compound set was most effective against the melanoma class cell lines (14 compounds), and the other set was most effective against the leukemia class cell lines (30 compounds). The two compound classes were both significantly enriched in two different types of substituted p-quinones. The melanoma cell line class of 14 compounds was comprised of 11 compounds that were internal substituted p-quinones, and the leukemia cell line class of 30 compounds was comprised of 6 compounds that were external substituted p-quinones. Attempts to subclassify melanoma or leukemia cell lines based upon their clinical cancer subtype met with limited success. For example, using GI(50) values for the 30 compounds we identified as effective against all leukemia cell lines, we could subclassify acute lymphoblastic leukemia (ALL) origin cell lines from non-ALL leukemia origin cell lines without significant overlap from non-leukemia cell lines. Based upon clustering using GI(50) values for the 60 cancer cell lines laid out by the RadViz algorithm, these two compound subsets did not overlap with clusters containing any of the NCI's 92 compounds of known mechanism of action, a few of which are quinones. Given their structural patterns, the two p-quinone subtypes we identified would clearly be expected to possess different redox potentials/substrate specificities for enzymatic reduction in vivo. These two p-quinone subtypes represent valuable information that may be used in the elucidation of pharmacophores for the design of compounds to treat these two cancer tissue types in the clinic.

Algorithms↗

PubMed1990

Differentiation between two biologically distinct classes of group A streptococci by limited substitutions of amino acids within the shared region of M protein-like molecules.

Group A streptococci can be categorized into two classes (I and II) based on immunodeterminants contained within a surface-exposed, conserved region (C repeat domain) of the major virulence factor, M protein. Previous studies have shown that several biological properties correlate strongly with streptococcal class, and thus, there is a strong impetus to precisely define the antigenic epitopes unique to class I and II M proteins. Using synthetic peptides, the binding sites of two class I-specific mAbs were mapped to distinct epitopes within the C repeat region of type 6 M protein (class I). A class II M protein-like gene (type 2) was cloned and sequenced, and the predicted amino acid sequence was compared for homology to class I and II molecules, whose sequences were previously reported. For a given C repeat block 35 amino acid residues in length, 20 residue positions were conserved among all sequences analyzed. Of the 15 variable amino acid positions, only four were class specific, and three of the four positions were localized in the area to which the class I-specific mAbs bound. The predicted secondary structures of class I and II C repeat blocks reveals that they are alpha-helical, except for a single area of disruption. In the class I molecules, the area of disruption corresponds to the class I-specific mAb binding sites. Importantly, the predicted conformational characteristics of this disruption differs for class I and II molecules. The data suggest that only limited changes in amino acid residues differentiate between class I and II molecules in the C repeat region. Therefore, selective (biological) pressures may have contributed to the evolution of these two classes of molecules.

Amino Acid Sequence↗

PubMed2001

Latent class analysis of ADHD and comorbid symptoms in a population sample of adolescent female twins.

Attention-deficit/hyperactivity disorder (ADHD) is a phenotypically heterogeneous and highly heritable syndrome. which commonly co-occurs with other psychiatry disorders. To assess the role of genetic influences in ADHD, we used latent class analysis (LCA) to identify subtypes of ADHD taking into account its comorbidity with separation anxiety, oppositional defiant disorder (ODD), and three major depression symptoms. A structured interview was used to collect diagnostic data from a population sample of 2,904 adolescent female twins and their parents. LCA was applied to ADHD. separation anxiety. ODD symptom profiles obtained from the twins' parents, and major depression symptom profiles obtained from the twins' self-report. Odds ratios were used to test for familiality of class membership by examining the effect of zygosity on twin concordance within and between latent classes. Structural equation modeling was used to compute heritabilities for latent class membership. LCA revealed three ADHD categories of clinical interest: an inattentive subtype without comorbidity, a second inattentive subtype with increased number of ODD symptoms. and a combined inattentive/hyperactive-impulsive type with elevated levels of ODD, separation anxiety, and depressive symptoms. LCA also distinguished an ODD class and a separation anxiety class, each without increased levels of other comorbid symptoms; a second ODD class co-occurring with increased separation anxiety and depression symptoms; and a pure depression class. Odds ratios for MZ contrasted with DZ twin concordance for individual latent class membership ranged from 2.5 to 19.4. Overall, 66% of MZ pairs, but only 36% of DZ pairs, were assigned to the same latent class, consistent with a genetic hypothesis for latent class membership. Individual class membership was shown to have high heritability ranging from .34-.85. The pattern of latent classes suggested that in the general female adolescent population, there are three highly heritable ADHD subtypes, two of which are comorbid with other disorders. These classes were consistent with a genetic hypothesis for ADHD, with each class potentially reflecting a unique genetic subtype.

Adolescent↗

PubMed2007

A latent class analysis of illicit drug abuse/dependence: results from the National Epidemiological Survey on Alcohol and Related Conditions.

AIMS: We examine the co-occurrence of abuse/dependence across different illicit drugs and test associations between these classes and major psychiatric disorders. METHOD: Latent class analyses were used to characterize polysubstance abuse/dependence (AB/D) in 43 093 individuals who participated in the National Epidemiological Survey on Alcohol and Related Conditions. Multinomial logistic regression was performed to examine the association between the classes of life-time illicit drug AB/D and gender, age and race, as well as life-time Diagnostic and Statistical Manual version IV (DSM-IV) alcohol abuse/dependence, nicotine dependence, major depressive disorder, generalized anxiety disorder, panic disorder, social phobia and antisocial personality disorder. RESULTS: Five latent classes were identified: no AB/D (class 1: 92.5%), cannabis AB/D only (class 2: 5.8%), stimulants + hallucinogen AB/D (class 3: 0.6%), prescription drug AB/D (class 4: 0.6%) and polysubstance AB/D (class 5: 0.5%). Major depressive disorder and nicotine dependence were associated most strongly with class 5. Anxiety disorders were associated strongly with the prescription drug AB/D class while alcohol AB/D and ASPD were associated with classes 2, 3, 4 and 5 when compared to the reference class (class 1). CONCLUSIONS: Significant heterogeneity exists in this US population for polysubstance AB/D patterns with evidence for a subgroup with high rates of sedative, tranquilizer and opiate AB/D and a history of anxiety disorders, a stimulant/hallucinogens group, a high-risk group with elevated rates of all psychiatric disorders and a milder cannabis AB/D only group. Replication of such classes across other samples has significant implications, such as characterizing risk groups that may be etiologically diverse.

Adolescent↗

PubMed1988

Rat liver alcohol dehydrogenase of class III. Primary structure, functional consequences and relationships to other alcohol dehydrogenases.

The amino acid sequence of alcohol dehydrogenase of class III from rat liver (the enzyme ADH-2) has been determined. This type of structure is quite different from those of both the class I and the class II alcohol dehydrogenases. The rat class III structure differs from the rat and human class I structures by 133-138 residues (exact value depending on species and isozyme type); and from that of human class II by 132 residues. In contrast, the rat/human species difference within the class III enzymes is only 21 residues. The protein was carboxymethylated with iodo[2(14)C]acetate, and cleaved with CNBr and proteolytic enzymes. Peptides purified by exclusion chromatography and reverse-phase high-performance liquid chromatography were analyzed by degradation with a gas-phase sequencer and with the manual 4-N,N-dimethylaminoazobenzene-4'-isothiocyanate double-coupling method. The protein chain has 373 residues with a blocked N terminus. No evidence was obtained for heterogeneity. The rat ADH-2 enzyme of class III contains an insertion of Cys at position 60 in relation to the class I enzymes, while the latter alcohol dehydrogenase in rat (ADH-3) has another Cys insertion (at position 111) relative to ADH-2. The structure deduced explains the characteristic differences of the class III alcohol dehydrogenase in relation to the other classes of alcohol dehydrogenase, including a high absorbance, an anodic electrophoretic mobility and special kinetic properties. The main amino acid substitutions are found in the catalytic domain and in the subunit interacting segments of the coenzyme-binding domain, the latter explaining the lack of hybrid dimers between subunits of different classes. Several substitutions provide an enlarged and more hydrophilic substrate-binding pocket, which appears compatible with a higher water content in the pocket and hence could possibly explain the higher Km for all substrates as compared with the corresponding values for the class I enzymes. Finally the class III structure supports evolutionary relationships suggesting that the three classes constitute clearly separate enzymes within the group of mammalian zinc-containing alcohol dehydrogenases.

Alcohol Oxidoreductases↗

PubMed1990

Comparison of three classes of human liver alcohol dehydrogenase. Emphasis on different substrate binding pockets.

Conformational models of the three characterized classes of mammalian liver alcohol dehydrogenase were constructed using computer graphics based on the known three-dimensional structure of the E subunit of the horse enzyme (class I) and the primary structures of the three human enzyme classes. This correlates the substrate-binding pockets of the class I subunits (alpha, beta and gamma in the human enzyme) with those of the class II and III subunits (pi and chi, respectively) for three enzymes that differ in substrate specificity, inhibition pattern and many other properties. The substrate-binding sites exhibit pronounced differences in both shape and properties. Comparing human class I subunits with those of class II and III subunits there are no less than 8 and 10 replacements, respectively, out of 11 residues in the substrate pocket, while in the human class I isozyme variants, only 1-3 of these 11 positions differ. A single residue, Val294, is conserved throughout. The liver alcohol dehydrogenases, with different substrate-specificity pockets, resemble the patterns of other enzyme families such as the pancreatic serine proteases. The inner part of the substrate cleft in the class II and III enzymes is smaller than in the horse class I enzyme, because both Ser48 and Phe93 are replaced by larger residues, Thr and Tyr, respectively. In class II, the residues in the substrate pocket are larger in about half of the positions. It is rich in aromatic residues, four Phe and one Tyr, making the substrate site distinctly smaller than in the class I subunits. In class III, the inner part of the substrate cleft is narrow but the outer part considerably wider and more polar than in the class I and II enzymes. In addition, Ser (or Thr) and Tyr in class II and III instead of His51 may influence proton abstraction/donation at the active site.

Alcohol Dehydrogenase↗