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PubMed1995

Structural analysis of invariant chain subsets as a function of their association with MHC class II chains.

Respective subsets of human invariant chain (Ii), as identified with antibodies to two different epitopes, were characterized as a function of their associations with major histocompatibility complex (MHC) class II alpha,beta chains and intracellular processing. E1 antiserum to Ii(183-193) and VIC-Y1 monoclonal antibody to an N-terminal determinant identified Ii(E1) and Ii(VIC) populations, respectively. Ii proteins comprise several species which have been defined with either genomic or post-translational processes: Ii itself; IpN and IpO, which represent the glycosylated forms on asparagine or threonine/serine, respectively; gamma 2 and gamma 3, which originate from an alternative initiation site for transcription; and p41, which has a 64-amino-acid insert which originated from an additional exon placed after the sixth exon of Ii. Immunoprecipitates of detergent-solubilized protein complexes from [35S]methionine-labeled Raji cells showed that Ii(E1) consisted of Ii, p41, IpN, and immature alpha chain, while Ii(VIC) consisted of Ii, processed Ii with N- and O-linked glycosylation (IpN,IpO), p41, and associated MHC class II alpha,beta chains. In the MHC class II-deficient P3HR-1 cells, Ii(E1) and Ii(VIC) were virtually identical. Ii(E1) was resistant to cathepsin B digestion while Ii(VIC) was sensitive. In pulse-chase radiolabeling experiments with brefeldin A (BFA)-treated cells, Ii(VIC) progressively became resistant to endoglycosidase H (endo H) and had a longer half-life than that in cells not treated with BFA, but Ii(E1) remained susceptible to endo H and its half-life was unaffected by BFA. Since BFA redistributes Golgi enzymes to the endoplasmic reticulum, this observation suggests that Ii(E1) is protected from processing enzymes while Ii(VIC) is not. These studies define association of Ii with MHC class II molecules when certain epitopes on Ii are exposed or not. These differences relate to intracellular transport of Ii and to its release for the binding of antigenic peptides.

Antibodies, Monoclonal↗

PubMed1996

AltFGF-2, a novel ER-associated FGF-2 protein isoform: its embryonic distribution and functional analysis during neural tube development.

A novel fibroblast growth factor-2 (FGF-2) protein isoform, called altFGF-2, is expressed abundantly during chicken embryogenesis. The amino-terminal domain of the 21.5-kDa altFGF-2 protein diverges completely from the other three FGF-2 proteins due to alternative splicing of their first coding exons. Furthermore, the altFGF-2 protein, in contrast to FGF-2 proteins, is targeted predominantly to the endoplasmic reticulum. In chicken embryos, altFGF-2 and FGF-2 proteins are differentially distributed in several mesodermal structures including developing limbs and kidneys. All four FGF-2 protein isoforms are also expressed in the developing neural tube from early neural plate stages onward. In contrast to FGF-2 proteins, the altFGF-2 isoform is distributed in a dynamic, spatially restricted pattern in notochord and ventral neural tube (floor plate and motor neurons) during specification of neuronal populations. To study the possible shared or differential signaling functions of chicken altFGF-2 and FGF-2 gene products, they were ectopically expressed in the dorsal neural tube aspect of transgenic mouse embryos. Dorsal expression of altFGF-2, but not FGF-2 gene products, induced alteration of neural tube morphology in a significant fraction of mouse embryos (25%). However, no alterations of dorsoventral (d/v) neural tube polarity were detected, indicating that altFGF-2 and FGF-2 gene products either function as permissive cofactors or regulate neural tube growth without affecting establishment of its primary d/v polarity.

Alternative Splicing↗

PubMed1988

Structure and function of Y chromosomal DNA. II. Analysis of lampbrush loop associated transcripts in nuclei of primary spermatocytes of Drosophila hydei by in situ hybridization using asymmetric RNA probes of four different families of repetitive DNA.

pSP64/65 subclones of four different families of repetitive sequences on the Y chromosome of Drosophila hydei were used for in vitro synthesis of labelled RNA. Pairs of RNA probes of opposite strand polarity were employed to analyse RNAs transcribed on, or associated with, various Y chromosomal lampbrush loops in nuclei of primary spermatocytes of D. hydei. The results of RNA filter analysis and in situ hybridization experiments can be generalized as follows: (1) Y-specific transcripts are heterogeneous in length and are synthesized on lampbrush loops. (2) Transcription of tandemly repeated sequences is usually strand specific. (3) Members of the same sequence family can be found in transcripts from different lampbrush loops. (4) Transcripts not coded by the Y chromosome are accumulated on different subregions of Y chromosomal lampbrush loops.

Animals↗

PubMed1994

Analysis of the functional effects of a mutation in SOD1 associated with familial amyotrophic lateral sclerosis.

Mutations in the Cu, Zn superoxide dismutase (SOD1) gene have been reported in some pedigrees with Familial Amyotrophic Lateral Sclerosis (FALS). We have investigated the functional and structural effects of a Gly-->Ser mutation at codon 41 of SOD1 in a pedigree with FALS and the topography of SOD1 expression in the mammalian CNS. These analyses show that the 41Gly-->Ser mutation causes a 27% reduction in Cu, Zn SOD activity. SOD1 is transcribed at high levels in rat motoneurons and four other types of neurons homologous to upper motoneurons that degenerate in human ALS. However, SOD1 is transcribed at lower levels in other types of neurons, such as cerebellar Purkinje cells, which are not usually involved significantly in human ALS. On the other hand, immunocytochemical studies indicate that most types of rat neurons contain similar levels of Cu, Zn SOD immunoreactive protein. Nevertheless, these results suggest that the essential feature causing this subtype of ALS is either a reduction in Cu, Zn SOD activity in cell types that presumably critically require Cu, Zn SOD for protection against oxidative damage or the fact that the mutation in SOD1 associated with FALS results in a novel gain of function that is particularly deleterious to those cell types expressing SOD1 at high levels.

Amino Acid Sequence↗

PubMed2002

Systematic identification of novel protein domain families associated with nuclear functions.

A systematic computational analysis of protein sequences containing known nuclear domains led to the identification of 28 novel domain families. This represents a 26% increase in the starting set of 107 known nuclear domain families used for the analysis. Most of the novel domains are present in all major eukaryotic lineages, but 3 are species specific. For about 500 of the 1200 proteins that contain these new domains, nuclear localization could be inferred, and for 700, additional features could be predicted. For example, we identified a new domain, likely to have a role downstream of the unfolded protein response; a nematode-specific signalling domain; and a widespread domain, likely to be a noncatalytic homolog of ubiquitin-conjugating enzymes.

Amidohydrolases↗

PubMed1999

Prediction of gene function by genome-scale expression analysis: prostate cancer-associated genes.

We wish to identify genes associated with disease. To do so, we look for novel genes whose expression patterns mimic those of known disease-associated genes, using a method we call Guilt-by-Association (GBA), on the basis of a combinatoric measure of association. Using GBA, we have examined the expression of 40,000 human genes in 522 cDNA libraries, and have discovered several hundred previously unidentified genes associated with cancer, inflammation, steroid-synthesis, insulin-synthesis, neurotransmitter processing, matrix remodeling, and other disease processes. The majority of the genes thus discovered show no sequence similarity to known genes, and thus could not have been identified by homology searches. We present here an example of the discovery of eight genes associated with prostate cancer. Of the 40,000 most-abundant human genes, these 8 are the most closely linked to the known diagnostic genes, and thus are prime targets for pharmaceutical research.

Gene Expression Profiling↗

PubMed1991

Expression of the CD2 activation epitope T11-3 (CD2R) on T cells in rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and Lyme disease: phenotypic and functional analysis.

CD2R is an activation-associated epitope unmasked by a conformational change of the CD2 cell-surface glycoprotein. In spite of elaborate studies on the role of CD2 and CD2R in adhesion and stimulation of T cells in vitro, no instances of CD2R expression in vivo were known to date. We report high levels of CD2R observed on blood and synovial fluid T cells in rheumatoid arthritis and on peripheral blood T cells in juvenile rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and Lyme disease. In vivo, expression of CD2R was restricted to T cells, not limited to a particular T-cell subset and not correlated with the expression of p55 interleukin 2R (IL-2R) (CD25) or major histocompatibility complex (MHC) class II molecules. When stimulated to proliferation via CD2 or CD3, ex vivo CD2R+ T cells showed the same basic activation requirements as CD2R-T cells.

Antigens, Differentiation, T-Lymphocyte↗

PubMed1993

Analysis of the function of the 70-kilodalton cyclase-associated protein (CAP) by using mutants of yeast adenylyl cyclase defective in CAP binding.

In Saccharomyces cerevisiae, adenylyl cyclase forms a complex with the 70-kDa cyclase-associated protein (CAP). By in vitro mutagenesis, we assigned a CAP-binding site of adenylyl cyclase to a small segment near its C terminus and created mutants which lost the ability to bind CAP. CAP binding was assessed first by observing the ability of the overproduced C-terminal 150 residues of adenylyl cyclase to sequester CAP, thereby suppressing the heat shock sensitivity of yeast cells bearing the activated RAS2 gene (RAS2Val-19), and then by immunoprecipitability of adenylyl cyclase activity with anti-CAP antibody and by direct measurement of the amount of CAP bound. Yeast cells whose chromosomal adenylyl cyclase genes were replaced by the CAP-nonbinding mutants possessed adenylyl cyclase activity fully responsive to RAS2 protein in vitro. However, they did not exhibit sensitivity to heat shock in the RAS2Val-19 background. When glucose-induced accumulation of cyclic AMP (cAMP) was measured in these mutants carrying RAS2Val-19, a rapid transient rise indistinguishable from that of wild-type cells was observed and a high peak level and following persistent elevation of the cAMP concentration characteristic of RAS2Val-19 were abolished. In contrast, in the wild-type RAS2 background, similar cyclase gene replacement did not affect the glucose-induced cAMP response. These results suggest that the association with CAP, although not involved in the in vivo response to the wild-type RAS2 protein, is somehow required for the exaggerated response of adenylyl cyclase to activated RAS2.

Adaptor Proteins, Signal Transducing↗

PubMed2005

[An analysis of induced expression and function of telomerase-regulation associated hALP gene on genotoxic agents].

OBJECTIVE: To confirm the responses and function of hALP, a telomerase-regulation associated gene, in DNA damage. METHODS: HeLa and Hep2 cells were treated by genotoxic agents H2O2 and cisplatin, and the induced expression of hALP was measured by quantitative RT-PCR and immunofluorescent histochemistry. The alterations in transcriptional activity of hALP promoter were estimated by luciferase reporter assays. The effects of genotoxic agents on cells in different status of hALP expression were analyzed by MTT method. RESULTS: The level of hALP mRNA could be increased when treated by 0.2 - 1.6 mmol/L H2O2 and reach a peak in concentration of 0.4 mmol/L. The induction could be observed after 6 h in the treatment of 0.4 mmol/L H2O2 and the higher level can be retained for 36 h. Similarly, cisplatin induced hALP mRNA expression is also dose and time dependent. The immunofluorescent staining showed that the treatment of 0.2 or 0.4 mmol/L H2O2, 0.2 or 0.5 micromol/L cisplatin increased the intensity of hALP protein in cellular nuclei. The luciferase assays demonstrated that both H2O2 and cisplatin could up-regulate hALP promoter activity through its upstream - 705 - +20 nt region. In cell survivor assay, the HeLa cells expressing sense hALP gene could grow continuously in the presence of 0.4 mmol/L H2O2 or 0. 5 micromol/L cisplatin while cells with antisense hALP or control cells were slower in growth. CONCLUSIONS: The expression of hALP gene could be up-regulated by DNA damage through activating transcription of its promoter, and increase cellular resistance to genotoxic agents.

Antineoplastic Agents↗

PubMed1997

Reduced incidence of rectal cancer, compared to gastric and colonic cancer, in a population of 73,076 men and women chronically immunosuppressed.

The incidence of gastric, colonic, and rectal cancers was determined in a cohort of 73,076 men and women chronically immunosuppressed after heart or renal transplantation, to test the hypothesis that there would be a reduced incidence of gastric cancer by dampening chronic gastritis secondary to infection caused by Helicobacter pylori. Follow-up was from 1-13 years. No change in the incidence of gastric cancer was found (32 cases observed, 32.86 expected). An increase in colon cancer was found (75 cases observed, 62.27 expected). A significant reduction in the incidence of rectal cancer was found (15 cases observed, 41.5 expected). This led to a chi2 of 16.92 with 1 degree of freedom, significant at the 0.1% level. The effect was greater in men than women and more marked in heart recipients than in those receiving renal transplants. This unexpected finding led to a review of experiments in mice and rats that present evidence for immune promotion of large-bowel cancers induced by carcinogens by gut-associated lymphoid tissue. We conclude that an analysis of immune function in gut-associated lymphoid tissue in the stomach, colon, and rectum in healthy and immunosuppressed patients may lead to a better understanding of immunosurveillance in the colon and immune promotion of rectal cancers.

Animals↗

PubMed1987

Radiation inactivation analysis of assimilatory NADH:nitrate reductase. Apparent functional sizes of partial activities associated with intact and proteolytically modified enzyme.

Recently we demonstrated that target sizes for the partial activities of nitrate reductase were considerably smaller than the 100-kDa subunit which corresponded to the target size of the full (physiologic) activity NADH:nitrate reductase. These results suggested that the partial activities resided on functionally independent domains and that radiation inactivation may be due to localized rather than extensive damage to protein structure. The present study extends these observations and addresses several associated questions. Monophasic plots were observed over a wide range of radiation doses, suggesting a single activity component in each case. No apparent differences were observed over a 10-fold range of concentration for each substrate, suggesting that the observed slopes were not due to marked changes in Km values. Apparent target sizes estimated for partial activities associated with native enzyme and with limited proteolysis products of native enzyme suggested that the functional size obtained by radiation inactivation analysis is independent of the size of the polypeptide chain. The presence of free radical scavengers during irradiation reduced the apparent target size of both the physiologic and partial activities by an amount ranging from 24 to 43%, suggesting that a free radical mechanism is at least partially responsible for the inactivation. Immunoblot analysis of nitrate reductase irradiated in the presence of free radical scavengers revealed formation of distinct bands at 90, 75, and 40 kDa with increasing doses of irradiation rather than complete destruction of the polypeptide chain.

Chlorella↗

PubMed2006

Trail making test errors and executive function in schizophrenia and depression.

The Trail Making Test (TMT) frequently is used as a measure of executive cognitive function. However, traditional use of test completion time as the primary outcome score does not give the more detailed information on cognitive processes that analysis of test-taking errors may provide. The present study compared TMT performance of three groups: patients with schizophrenia, patients with major depression, and healthy control participants (n = 30 for each group). Three operationally defined error types were examined: (a) tracking, (b) perseverative, and (c) proximity. Although both patient groups were slower than the healthy control group, only the schizophrenia group made significantly more errors, particularly tracking errors, suggesting a greater degree of cognitive disorganization. Within-group analysis of a larger group of schizophrenia patients (n = 84) revealed that TMT time was most strongly associated with the Withdrawal-Retardation factor of the Brief Psychiatric Rating scale. In contrast, TMT errors were most strongly associated with the Conceptual Disorganization factor. Comparisons of TMT scores and other cognitive tests showed moderate to high associations with tests of working memory, psychomotor speed, and executive function. Stepwise regression analysis revealed an independent association between Digit Cancellation and Part B Time, indicating a unique contribution of visuomotor scanning to performance. In contrast, Part B errors were uniquely associated with the Verbal Series Attention Test and the Token Test, tests of mental tracking and executive-mediated working memory, respectively. These findings demonstrate the utility of TMT error analysis in revealing cognitive deficits not traditionally captured using completion time as the sole outcome variable.

Adult↗

PubMed1997

Impact of activated protein C resistance on general vascular surgical patients.

PURPOSE: The prevalence of activated protein C resistance (APCR) and associated thrombotic morbidity among patients who undergo arterial reconstruction were investigated. METHODS: Preoperative assays for functional APCR and factor V (Leiden) mutation were performed on 262 patients who underwent arterial reconstructions that consisted of cerebrovascular surgery (109), aortic or iliofemoral procedures (76), or infrainguinal bypass procedures (77). Patients were monitored for thrombotic complications during the postoperative period. RESULTS: Depending on the stringency of the definition used, functional APCR was detected in 10.6% to 22.0% of patients tested. Factor V (Leiden) was found in 5.3% of patients. Thrombotic morbidity consisting of myocardial infarction, cerebrovascular event, or graft thrombosis occurred in 9.9% of patients, who were followed-up for a mean of 4.8 months. No significant overall correlations were found between APCR and thrombotic morbidity. Subgroup analysis revealed significant associations between functional APCR and total early postoperative thrombotic complications and early graft failure, and between factor V (Leiden) and early cerebrovascular events and late graft thrombosis (p < 0.03). CONCLUSIONS: Functional APCR is somewhat more prevalent among general vascular surgical patients than in the general population, but factor V (Leiden) is no more prevalent. APCR is not a prominent cause of thrombotic morbidity in contemporary vascular surgery. Nonetheless, it is a sufficiently important potential contributor to morbidity among some subgroups to warrant selective testing and directed therapy pending further study.

Factor V↗

PubMed1998

Vesicle-associated brain myosin-V can be activated to catalyze actin-based transport.

Myosin-V has been linked to actin-based organelle transport by a variety of genetic, biochemical and localization studies. However, it has yet to be determined whether myosin-V functions as an organelle motor. To further investigate this possibility, we conducted a biochemical and functional analysis of organelle-associated brain myosin-V. Using the initial fractionation steps of an established protocol for the purification of brain myosin-V, we isolated a population of brain microsomes that is approx. fivefold enriched for myosin-V, and is similarly enriched for synaptic vesicle proteins. As demonstrated by immunoelectron microscopy, myosin-V associates with 30-40% of the vesicles in this population. Although a majority of myosin-V-associated vesicles also label with the synaptic vesicle marker protein, SV2, less than half of the total SV2-positive vesicles label with myosin-V. The average size of myosin-V/SV2 double-labeled vesicles (90+/-45 nm) is larger than vesicles that label only with SV2 antibodies (60+/-30 nm). To determine if these vesicles are capable of actin-based transport, we used an in vitro actin filament motility assay in which vesicles were adsorbed to motility assay substrates. As isolated, the myosin-V-associated vesicle fraction was nonmotile. However, vesicles pre-treated with ice-cold 0.1% Triton X-100 supported actin filament motility at rates comparable to those on purified myosin-V. This dilute detergent treatment did not disrupt vesicle integrity. Furthermore, while this treatment removed over 80% of the total vesicle proteins, myosin-V remained tightly vesicle-associated. Finally, function-blocking antibodies against the myosin-V motor domain completely inhibited motility on these substrates. These studies provide direct evidence that vesicle-associated myosin-V is capable of actin transport, and suggest that the activity of myosin-V may be regulated by proteins or lipids on the vesicle surface.

Actins↗

PubMed2003

Analysis of genetic variation in the GenomEUtwin project.

Multiallelic short tandem repeat polymorphisms, or microsatellites, are useful markers in genome wide scans to identify chromosomal regions containing genes underlying disease loci. The biallelic single nucleotide polymorphism (SNP) can be used to fine map previously identified large candidate regions or to test functional candidate genes by association analysis. In the GenomEUtwin project the population based impact of susceptibility genes for six multifactorial traits will be studied. A genome wide panel of informative human microsatellite markers will be analyzed by fluorescent capillary electrophoresis in well characterized twin and population samples. Contrary to microsatellites, selection of the most informative panels of SNPs is hampered by imperfect data on the allele frequencies and population distribution of SNPs markers in the databases. Therefore, selection of SNPs requires a substantial amount of bioinformatics, and, the SNPs need to be validated experimentally in the relevant populations prior to genotyping large sample sets. In the GenomEUtwin project, large scale genotyping of SNPs will be performed using the SNPstreamUHT and MassARRAY genotyping systems that are based on the primer extension reaction principle combined with fluorescent and mass spectrometric detection, respectively. Production of the genotyping data will be a joint effort by GenomEUtwin partners at the University of Helsinki, the National Public Health Institute in Helsinki, Finland and Uppsala University, Sweden. All genotyping data will be stored in a common database established specifically for the GenomEUtwin project, from where it can be accessed by the twin research centres that provided the samples for genotyping.

Databases, Genetic↗

PubMed1989

The CaaX motif of lamin A functions in conjunction with the nuclear localization signal to target assembly to the nuclear envelope.

While the nuclear lamin proteins (A, B, and C) assemble specifically at the surface of the nuclear membrane, their sequences do not reveal stretches of hydrophobic amino acids that might explain their association with the nuclear membranes. However, the A and B lamin proteins possess Ras-like C-terminal CaaX sequence motifs, which in Ras proteins are sites of hydrophobic modifications required for membrane association and function. From the analysis of single and double lamin A mutants affecting the CaaX motif, the nuclear localization signal, and higher-order assembly properties, we propose that the CaaX motif functions as a nonspecific, low affinity membrane probe for proteins ultimately segregated to specific cellular membrane systems. Committed association with specific membranes requires additional interactions with membrane-resident factors.

Amino Acid Sequence↗

PubMed1998

Management of glass intraocular foreign bodies.

PURPOSE: To describe the results of management of glass intraocular foreign bodies (IOFBs). METHODS: A total of 51 eyes of 43 patients that sustained penetrating injury with glass IOFB were studied retrospectively. A total of 23.5% had IOFB only in the anterior segment; the rest had IOFB in the posterior segment alone or in both the anterior and posterior segments. Six eyes were followed conservatively despite IOFB in a functional eye. Removal of IOFB was combined with repair of retinal detachment (where present) using internal tamponade with gas or silicone oil or buckle. RESULTS: After a mean follow-up of 16.8 months, 66.7% of eyes recovered better than 6/60 (20/200) vision and 75.6% had attached retina. On univariate analysis, scleral entry wound, posterior segment IOFB, larger size of IOFB, and retinal damage were found to be associated with poor anatomic outcome. Lower presenting visual acuity, hyphema, retinal damage, subretinal hemorrhage, detached retina, and larger IOFB were associated with a poor functional result. Multivariate analysis identified retinal damage caused by the foreign body as the only factor significantly associated with poor anatomic as well as functional outcome. CONCLUSIONS: Glass IOFBs are caused in a majority of cases by blast injury. Bilaterality is not uncommon. Presence of retinal damage is predictive of poor functional and anatomic results. Overall results are modest with modern vitreoretinal surgical techniques.

Adult↗

PubMed2000

Prognostic value of neurohormonal activation and cardiopulmonary exercise testing in patients with chronic heart failure.

We compared the value of plasma neurohormones and cardiopulmonary exercise testing for predicting long-term prognosis in patients with moderate congestive heart failure (CHF). We studied 264 consecutive patients with CHF due to left ventricular systolic dysfunction. Plasma atrial natriuretic peptide (ANP), norepinephrine, and endothelin-1 were measured at rest in all patients, who also underwent a symptom-limited maximal exercise with oxygen consumption (VO(2)) determination. After a median follow-up of 789 days, 52 deaths and 31 heart transplantations occurred, of which 4 were urgent. In an univariate analysis, New York Heart Association functional class, systolic blood pressure at rest, left ventricular end-diastolic diameter, left ventricular ejection fraction, peak VO(2), percent of predicted peak VO(2), plasma ANP, plasma norepinephrine, and plasma endothelin-1 were associated with survival without urgent heart transplantation. In a multivariate stepwise regression analysis, only plasma ANP (p = 0.0001), left ventricular ejection fraction (p = 0.007), and plasma norepinephrine (p = 0.035), but neither peak VO(2) nor percentage of predicted peak VO(2), were independent predictors of death or urgent heart transplantation. Determination of plasma ANP and norepinephrine provides additional independent information for long-term prognostic determination compared with exercise testing alone. Measurement of plasma neurohormones should therefore be considered routinely as a complementary or alternative tool for identifying high-risk patients with moderate CHF.

Atrial Natriuretic Factor↗