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PubMed2002

A perspective on clonal phenotypic (antigenic) variation in protozoan parasites.

Intra-clonal phenotypic (antigenic) variation is used by many pathogens to evade the consequences of immune-mediated killing by mammalian hosts. In this substantially theoretical article, I emphasise that antigenic variation (sensu stricto) involves no change in genotype; its importance as a mechanism for promoting pathogen transmission and its polyphyletic origin. From a functional perspective, antigenic variation is constrained by the requirement to meet five conditions. These are: capability to express several antigens against which functional immunity predominates; capability to interact with the environment; mutually exclusive expression of variable antigens in each cell within an infection; mutually exclusive expression in the within-host pathogen population and the capability for population growth within a host. Meeting these conditions leads to chronicity of infection and high rates of hierarchical and reversible switching of expression between variable antigens. The organisation of hierarchical expression is discussed in some detail.

Animals↗
PubMed2006

Evolution of exon-intron structure and alternative splicing in fruit flies and malarial mosquito genomes.

Comparative analysis of alternative splicing of orthologous genes from fruit flies (Drosophila melanogaster and Drosophila pseudoobscura) and mosquito (Anopheles gambiae) demonstrated that both in the fruit fly genes and in fruit fly-mosquito comparisons, constitutive exons and splicing sites are more conserved than alternative ones. While >97% of constitutive D. melanogaster exons are conserved in D. pseudoobscura, only approximately 80% of alternative exons are conserved. Similarly, 77% of constitutive fruit fly exons are conserved in the mosquito genes, compared with <50% of alternative exons. Internal alternatives are more conserved than terminal ones. Retained introns are the least conserved, alternative acceptor sites are slightly more conserved than donor sites, and mutually exclusive exons are almost as conserved as constitutive exons. Cassette and mutually exclusive exons experience almost no intron insertions. We also observed cases of interconversion of various elementary alternatives, e.g., transformation of cassette exons into alternative sites. These results agree with the observations made earlier in human-mouse comparisons and demonstrate that the phenomenon of relatively low conservation of alternatively spliced regions may be universal, as it has been observed in different taxonomic groups (mammals and insects) and at various evolutionary distances.

Alternative Splicing↗
PubMed1983

The comparative kinetics of soluble and heparin-Sepharose-immobilized bovine lipoprotein lipase.

While lipoprotein lipase (LPL) acts in vivo as an immobilized enzyme, its kinetics are commonly studied with soluble LPL (S-LPL). Hence kinetic parameters of S-LPL and heparin-Sepharose-immobilized LPL (B-LPL) were compared. A modified purification procedure for bovine milk, LPL gave a 56% yield of S-LPL, purified 7250-fold, and a specific activity of 27,000 mumol fatty acid/mg LPL/h when assayed with triolein (TG) emulsions in the presence of serum. The purified LPL also showed low but detectable esterase activity with p-nitrophenylacetate and p-nitrophenylbutyrate as substrates. Apolipoprotein C-II (C-II) had no effect on the esterase activity of LPL. Dixon plots of experiments with S-LPL indicated that heparin is a competitive inhibitor against both C-II and TG, and that the binding of either C-II or heparin to the enzyme is a mutually exclusive event. Similarly, the binding of TG and heparin to the enzyme is mutually exclusive. From the Dixon plots, the dissociation constant Ki for the LPL:heparin binary complex was determined to be 5.0 X 10(-8) M. In contrast to the heparin inhibitory effect on LPL activity against triolein, heparin had no effect on the esterase activity of LPL against p-nitrophenylacetate or p-nitrophenylbutyrate. Comparative studies with B-LPL and S-LPL, using triolein as substrate and apolipoprotein C-II or serum as activator, indicated that S-LPL has a higher apparent Km and lower apparent Vmax than B-LPL. It is concluded that most of the LPL bound to heparin-Sepharose is probably inaccessible to substrate, hence a low Vmax. However, Km (C-II) and Km (TG) were higher for B-LPL due to the competitive inhibitory effect of heparin on LPL. Consistent with these kinetic analyses and with the use of human very low density lipoproteins (VLDL) as substrate, S-LPL, even in the presence of heparin, was found to have an apparent rate of lipolysis of VLDL approximately ninefold greater than B-LPL.

Animals↗
PubMed1994

Structure and expression of the human gene for the alpha subunit of prolyl 4-hydroxylase. The two alternatively spliced types of mRNA correspond to two homologous exons the sequences of which are expressed in a variety of tissues.

Prolyl 4-hydroxylase, an alpha 2 beta 2 tetramer, plays a central role in collagen synthesis as it catalyzes the formation of 4-hydroxyproline residues by the hydroxylation of proline in X-Pro-Gly sequences. We report here that the human gene for the catalytically important alpha subunit is more than 69 kilobase pairs and consists of 16 exons. The exons that encode solely protein sequences vary from 54 to 240 base pairs (bp), and the introns vary from 750 to more than 16,000 bp. The 133 bp of 5'-untranslated sequences of the mRNA are coded by two exons, and these sequences contain inverted repeats with a potential for stem-loop formation, which may be involved in translational control of the expression of this gene. The 5'-flanking region contains a TATa motif at -29 relative to the major transcription site but no CCAAT motif. The 5'-flanking region and the downstream sequences contain several motifs that may act as binding sites for various transcription factors. Evidence has previously been reported for a mutually exclusive alternative splicing of RNA transcripts of this gene. The present data indicate that the mutually exclusive sequences found in the mRNAs are coded by two consecutive, homologous 71-bp exons 9 and 10. These exons are identical in their first 5 bp and the overall identity between them is 61% at the nucleotide level and 58% at the level of the coded amino acids. Both types of mRNA were found to be expressed in all of the tissues studied, but in some tissues the type coding for exon 9 or 10 sequences was more abundant than the other type.

Alternative Splicing↗
PubMed1997

BCL-6 protein expression in AIDS-related non-Hodgkin's lymphomas: inverse relationship with Epstein-Barr virus-encoded latent membrane protein-1 expression.

This study aimed at investigating the expression of the BCL-6 protein in acquired immune deficiency syndrome (AIDS)-related non-Hodgkin's lymphomas (AIDS-NHLs) and at comparing the expression pattern with the presence of Epstein-Barr virus (EBV) infection of the tumor clone. A total of 34 AIDS-NHL biopsies, including 16 AIDS-related diffuse large-cell lymphomas (AIDS-DLCLs) and 18 AIDS-related small-noncleaved-cell lymphomas (AIDS-SNCCLs) as well as 7 AIDS-SNCCL cell lines were immunostained with a BCL-6-specific monoclonal antibody. Expression of BCL-6 protein was detected in 9 of 16 AIDS-DLCLs, 18 of 18 AIDS-SNCCLs, and 3 of 7 AIDS-SNCCL cell lines. Expression of BCL-6 among AIDS-NHLs occurred independently of the presence of molecular lesions of the bcl-6 gene. Notably, among EBV-positive AIDS-NHL biopsies and cell lines, expression of BCL-6 was mutually exclusive with the expression of EBV-encoded transforming antigen latent membrane protein-1. The mutual exclusion between BCL-6 and latent membrane protein-1 expression was further confirmed by in vitro superinfection experiments of an AIDS-SNCCL cell line originally devoid of EBV sequences. Overall, the frequent association between AIDS-NHLs and expression of BCL-6, a protein selectively expressed by germinal center B cells, suggests that these lymphomas may originate from the germinal center.

Acquired Immunodeficiency Syndrome↗
PubMed1997

The effect of perceptual similarity and linguistic input on children's acquisition of object labels.

This study investigated whether and when children establish various semantic relations between old and new words. Fifty two-year-olds were taught labels for objects previously referred to by an overextended term. We found that children were more likely to learn a new label when (a) it referred to a new object that was perceptually dissimilar, rather than similar, to a known one, and (b) when linguistic information indicated it had an inclusion, rather than a mutually exclusive, relation to a known label. Children were more likely to interpret a new label as mutually exclusive to a known one when their referents were perceptually dissimilar. These findings are discussed in light of theories of lexical development, particularly with regard to conceptualizations of constraints on the acquisition of word meaning.

Child Language↗
PubMed1997

Word learning in a special population: do individuals with Williams syndrome obey lexical constraints?

Williams syndrome (WS), a rare neurodevelopmental disorder, is of special interest to developmental psycholinguists because of its uneven linguistico-cognitive profile of abilities and deficits. One proficiency manifest in WS adolescents and adults is an unusually large vocabulary despite serious deficits in other domains. In this paper, rather than focus on vocabulary size, we explore the processes underlying vocabulary acquisition, i.e. how new words are learned. A WS group was compared to groups of normal MA-matched controls in the range 3-9 years in four different experiments testing for constraints on word learning. We show that in construing the meaning of new words, normal children at all ages display fast mapping and abide by the constraints tested: mutual exclusivity, whole object and taxonomic. By contrast, while the WS group showed fast mapping and the mutual exclusivity constraint, they did not abide by the whole object or taxonomic constraints. This suggests that measuring only the size of WS vocabulary can distort conclusions about the normalcy of WS language. Our study shows that despite equivalent behaviour (i.e. vocabulary test age), the processes underlying how vocabulary is acquired in WS follow a somewhat different path from that of normal children and that the atypically developing brain is not necessarily a window on normal development.

Age Factors↗
PubMed1987

Interactions of inhibitors on anion transporter of human erythrocyte.

Chloride tracer efflux was measured from intact human erythrocytes into media containing different chloride concentrations and different concentrations of the inhibitors 4,4'-dinitrostilbene-2-2'-disulfonate (DNDS), N-(4-azido-2-nitrophenyl)-2-aminoethylsulfonate (NAP-taurine), phloretin, and sulfate. The data were analyzed to test whether these inhibitors were mutually exclusive with each other or whether they could bind at the same time. Under the assumption that mutual exclusiveness is due to steric interference, the data can be used to map out the protein surface near the outward-facing anion binding-transport site. It is concluded that there are separate domains for NAP taurine and phloretin that do not overlap with each other or with the chloride binding site. These two domains do, however, overlap with the binding domain for DNDS that, in addition, excludes the binding of chloride and sulfate.

Anions↗
PubMed2006

Phantom ROC: Recollection rejection in a hybrid conjoint recognition signal detection model.

The present experiments test predictions of dual process models with regards to recollection rejection using a model called phantom ROC. Participants studied pictures and then took a recognition test in which they were presented with targets (i.e., the exact picture presented), related lures (i.e., the same object but from a different angle), and unrelated lures (i.e., objects that had not been shown). For each item, participants answered both standard recognition and meaning recognition questions. In Experiment 1 participants studied pictures under either full attention or divided attention. In Experiment 2 some participants were told that no object was shown twice (i.e., mutual exclusivity instructions), while others were told that both camera angles might have been shown for some objects (no mutual exclusivity instructions). The present experiments provide three converging measures, all of which are consistent with dual process models that propose a recollection rejection mechanism.

Attention↗
PubMed2003

The development of a word-learning strategy.

Two studies investigated young infants' use of the word-learning principle Mutual Exclusivity. In Experiment 1, a linear relationship between age and performance was discovered. Seventeen-month-old infants successfully used Mutual Exclusivity to map novel labels to novel objects in a preferential looking paradigm. That is, when presented a familiar and a novel object (e.g. car and phototube) and asked to "look at the dax", 17-month-olds increased looking to the novel object (i.e. phototube) above baseline preference. On these trials, 16-month-olds were at chance. And, 14-month-olds systematically increased looking to the familiar object (i.e. car) in response to hearing the novel label "dax". Experiment 2 established that this increase in looking to the car was due solely to hearing the novel label "dax". Several possible interpretations of the surprising form of failure at 14 months are discussed.

Fixation, Ocular↗
PubMed1971

A model for choice in simple concurrent and concurrent-chains schedules.

Pigeons' responses in the presence of two concurrently available (initial-link) stimuli produced one of two different (terminal-link) stimuli. Entrance into the mutually exclusive terminal links was arranged by different and independent variable-interval schedules for each key, while responses during the mutually exclusive terminal-link stimuli produced a single food reinforcement according to indentical and independent variable-interval schedules. The pigeons emitted more initial-link responses on the key with the shorter average interreinforcement interval in the initial link. This difference in initial-link response rates varied directly with the difference between the average inter-reinforcement intervals of the initial-link schedules and decreased when the initial-link schedule with the longer average interreinforcement interval was followed by several consecutive food reinforcements on the variable-interval schedule in the terminal link on that key. These results are incompatible with previous formulations of choice behavior with the concurrent-chains procedure. A modified formulation with a multiplier for the overall rate of primary reinforcement obtained on each key provides a better description of choice. In addition, the new formulation applies to behavior in simple (concurrent) choice situations, an advantage not achieved by previous formulations.

Journal Article↗
PubMed1996

Distinct sub-populations of carcinoma-associated MUC1 mucins as detected by the monoclonal antibody 9H8 and antibodies against the sialyl-Lewis a and sialyl-Lewis x epitopes in the circulation of breast-cancer patients.

The cancer-associated epitope defined by the monoclonal antibody (MAb) 9H8 was shown to be closely related to the T antigen (Thomsen-Friedenreich antigen) by its sensitivity to 0-glycanase treatment of a mucin glycopeptide known to express this epitope. The reactivity with this glycopeptide increased upon neuraminiclase treatment, and among several MAbs tested for ability to block binding of the 9H8 antibody, the one specific for the T antigen was the most efficient. Out of 41 serum samples from breast-cancer patients, 11 showed elevated levels of the 9H8 epitope, and several sera also showed elevated levels of the cancer-associated carbohydrate epitopes sialyl-Lewis a and sialyl-Lewis x. By the use of antibodies specific for the MUC1 apoprotein (Ma552 and HMFG-2) it could be shown that these epitopes were attached to the MUC1 apoprotein in at least 4 of the cases. By combining antibodies specific to 9H8, sialyl-Lewis a and sialyl-Lewis x in catcher and tracer positions in several types of immunofluorometric assays, it was shown that the 9H8 epitope was rarely co-expressed with sialyl-Lewis a or sialyl-Lewis x epitopes an the same molecule, though all were expressed on MUC1 mucins. In fact, they can be considered as mutually exclusive epitopes, suggesting that these sera contained different populations of MUC1 mucins distinguishable by different sets of oligosaccharides. The existence of mutually exclusive carbohydrate epitopes on different MUC1 mucins in one and the same patient should be taken into account when designing immunoassays exploiting MUC1-reactive antibodies.

Antibodies↗
PubMed2003

Expression of cyclin D3 and cyclin E and identification of distinct clusters of proliferation and apoptosis in diffuse large B-cell lymphomas.

In the present study 79 cases of de novo Diffuse Large B-cell Lymphomas (DLBCL) were studied in order: a) to analyse the expression of cyclin D3, cyclin E and cyclin D1 in relation to other proliferative features (expression of Ki67, cyclin A and cyclin B1), the apoptosis status and the expression of p53, Rb, p16 and p27; and b) to determine whether distinct clusters of proliferation and apoptosis could be identified in DLBCL. Overexpression of cyclin D3 and cyclin E was found in 35/79 (43%) and 18/79 (22%) cases, respectively, whereas overexpression of cyclin D1 was not detected in any case. In most cases (39/46) overexpression of cyclin D3 and cyclin E was mutually exclusive possibly reflecting different underlying pathways inducing deregulated expression of these cyclins. In most cases (29/35) overexpression of cyclin D3 was mutually exclusive with Rb/p16 aberrant expression status supporting an oncogenic role for cyclin D3 and suggesting that the pathogenetic effect of cyclin D3 overexpression occurs through perturbation of the Rb1 pathway. Combined alterations of the P53 and the Rb/p16/cyclin D3 expression status were significantly associated with higher mean values of cyclin A (p=0.023) and cyclin B1 (p=0.033) indicating that concurrent impairment of the p53 and Rb1 pathways induces increased tumour cell proliferation in DLBCL. Cluster analysis of the apoptosis and the proliferation status permitted separation of DLBCL into distinct groups with low (44 cases) and high (18 cases) apoptotic activity and into distinct groups with low (32 cases), intermediate (36 cases) and high (11 cases) proliferative activity. The identification of distinct clusters with respect to the proliferation and the apoptosis status indicates that groups with distinct cellular kinetic properties can be defined in the histological group of DLBCL.

Apoptosis↗
PubMed1999

Correlations in palmitoylation and multiple phosphorylation of rat bradykinin B2 receptor in Chinese hamster ovary cells.

Rat bradykinin B2 receptor from unstimulated Chinese hamster ovary cells transfected with the corresponding cDNA has been isolated, and subsequent mass spectrometric analysis of multiple phosphorylated species and of the palmitoylation attachment site is described. Bradykinin B2 receptor was isolated on oligo(dT)-cellulose using N-(epsilon-maleimidocaproyloxy)succinimide-Met-Lys-bradykinin coupled to a protected (dA)30-mer. This allowed a one-step isolation of the receptor on an oligo(dT)-cellulose column via variation solely of salt concentration. After enzymatic in-gel digestion, matrix-assisted laser desorption ionization and electrospray ion trap mass spectrometric analysis of the isolated rat bradykinin B2 receptor showed phosphorylation at Ser365, Ser371, Ser378, Ser380, and Thr374. Further phosphorylation at Tyr352 and Tyr161 was observed. Rat bradykinin receptor B2 receptor is also palmitoylated at Cys356. All of the phosphorylation sites except for Tyr161 cluster at the carboxyl-terminal domain of the receptor located on the cytoplasmic face of the cell membrane. Surprisingly, many of the post-translational modifications were shown by MSn mass spectroscopic analysis to be correlated pairwise, e.g. diphosphorylation at Ser365 and Ser371, at Ser378 and Ser380, and at Thr374 and Ser380 as well as mutually exclusive phosphorylation at Tyr352 and palmitoylation at Cys356. The last correlation may be involved in a receptor internalization motif. Pairwise correlations and mutual exclusion of phosphorylation and palmitoylation suggest critical roles of multiple post-translational modifications for the regulation of activity, coupling to intracelluar signaling pathways, and/or sequestration of the bradykinin receptor.

Acylation↗
PubMed2001

Management of erectile dysfunction in diabetic subjects: results from a survey of 400 diabetes centres in Italy.

We report the results of a survey on erectile dysfunction (ED) conducted in 400 Italian Diabetes Centres in 1998. A questionnaire consisting of 10 items was sent to the Centres recorded by the Italian Association of Diabetologists and the Italian Society of Diabetology; 400 Centres returned the completed questionnaire (58%). Forty-nine percent of the Centres declared that they investigated ED systematically but less than half of them (46%) had done it autonomously. The percentage of Centres performing intracavernous injection (ICI) was 84%. This maneuvre was most commonly performed by diabetologists (61%), followed by urologists (29%) and andrologists (18%) (categories are not mutually exclusive). ICI was also the most common type of treatment (85%), followed by oral (32%) and topic (7%) therapies (categories are not mutually exclusive). Slightly more than half of the interviewed Centres (51%) did not investigate ED routinely, attributing this to structural problems, lack of specific training and the availability of more specialised Centres as the main reasons for this. However, the majority of Centres expressed interest in managing ED. Among the available tests for ED, ICI was the most frequently employed. While most Centres seek the collaboration of external specialists to diagnose ED, the diabetologist is the physician who most frequently performs ICI. We conclude that Italian diabetologists need specific training to reach a greater degree of autonomy in the management of ED in their patients.

Community Health Centers↗
PubMed1991

Alternative splicing is an efficient mechanism for the generation of protein diversity: contractile protein genes as a model system.

Alternative splicing has emerged in recent years as a widespread device for regulating gene expression and generating protein diversity. Its analysis has provided some mechanistic understanding of this form of gene regulation and, in addition, has provided new insights into some fundamental aspects of splicing. This mode of regulation is particularly prevalent in muscle cells, where genes such as troponin T are able to generate up to 64 different isoforms from a single transcriptional unit. Alternative splicing has the potential to raise the coding capacity of the small multigene families that code for the contractile proteins so that several million structurally different sarcomeres can be generated. The mammalian alpha-tropomyosin gene has proved particularly useful for the analysis of the mechanisms involved in this type of regulation. In particular, the mutually exclusive splicing of exons 2 and 3 has provided answers about the processes involved in the three main regulatory steps: (a) establishment of mutually exclusive behavior; (b) the elements involved in setting up the default pattern of splicing, and (c) the switch from the default to the regulated splicing pattern in some cell types.

Animals↗
PubMed1982

The classification of anxiety and hysterical states. Part I. Historical review and empirical delineation.

The history of the classification of anxiety, hysterical, and hypochondriacal disorders is reviewed. Problems in the ability of current classification schemes to predict, control, and describe the relationship between the symptoms and other phenomena are outlined. Existing classification schemes failed the first test of a good classification model--that of providing categories that are mutually exclusive. The independence of these diagnostic categories from each other does not appear to hold up on empirical testing. In the absence of inherently mutually exclusive categories, further empirical investigation of these classes is obstructed since statistically valid analysis of the nominal data and any useful multivariate analysis would be difficult if not impossible. It is concluded that the existing classifications are unsatisfactory and require some fundamental reconceptualization.

Agoraphobia↗
PubMed1994

New aspects of the kinetics of inhibition by lincomycin of peptide bond formation.

We have investigated the inhibition of peptide bond formation by the antibiotic lincomycin, at 150 mM NH4Cl. We have used an in vitro system in which a ribosomal ternary complex, the acetyl[3H] phenylalanine-tRNA-70 S ribosome-poly(U) complex (complex C), reacts with puromycin, forming peptide bonds. Complex C can be considered an analog of the elongating ribosomal complex and puromycin an analog of aminoacyl-tRNA. In a previous study we reported on the kinetics of inhibition by lincomycin at 100 mM NH4Cl. In the present investigation, we find that an increase of the ammonium ion concentration to 150 mM causes profound changes in the kinetic behavior of the system, which can be summarized as follows. First, the association rate for complex C and lincomycin is increased. At a lincomycin concentration of 10 microM the apparent equilibration rate constant is 4.3 min-1 at 100 mM NH4Cl, whereas it becomes 6.7 min-1 at 150 mM. Second, at 150 mM NH4Cl, with increasing concentrations of lincomycin, there is a transition from competitive to mixed-noncompetitive inhibition. The prevailing notion is that lincomycin acts at the ribosomal A-site, a mechanism that agrees only with competitive kinetics (mutually exclusive binding between puromycin and lincomycin). At the molecular level, the change in the kinetics of inhibition that we observe may mean that the mutually exclusive binding between aminoacyl-tRNA and lincomycin is converted to simultaneous binding, as a result of conformational changes occurring in the elongating ribosomal complex.

Binding, Competitive↗