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PubMedDate not supplied

Expression of HLA class I antigens in human tumors and their involvement in tumor growth.

A decreased expression of major histocompatibility complex (MHC) class I antigens is a common feature of many experimental and human tumors and can often be correlated with malignancy grade. In fact, reduction of class I antigens is associated in most tumors with an enhanced ability to elude immune surveillance. Loss of HLA-A,B,C antigens ranges from a decrease in the percentage of A,B,C-positive cells to selective loss of particular antigens and total loss of class I molecule expression. In man, this has been documented in melanomas, carcinomas, lymphomas, neuroblastoma and acute leukemias. The reduction in membrane antigens is generally associated with a parallel fall in immunoprecipitable intracellular proteins and the corresponding mRNAs in the absence of structural changes in the coding genes. The literature concerning the above mentioned topics is reviewed and discussed.

Genes, MHC Class I↗
PubMed2004

Phenotypic variability in Hey2 -/- mice and absence of HEY2 mutations in patients with congenital heart defects or Alagille syndrome.

The genetic alterations leading to congenital heart defects (CHD) are still poorly understood. We and others have recently shown that in mice loss of Hey2 results in a high incidence of fatal ventricular and atrial septal defects, combined with tricuspid stenosis or atresia in some cases. The phenotype has been postulated to resemble human tetralogy of Fallot. Our analysis of CD1 outbred mice suggests that phenotypic consequences of Hey2 loss can be quite variable and dependent on modifier genes as we detected only isolated VSDs with lower prevalence and a significantly reduced mortality rate in this strain. Since Hey2 is one of the few Notch target genes, it is also conceivable that HEY2 mutations may account for cases of Alagille syndrome (AGS: variable combinations of heart, skeleton, eye, and facial malformations and cholestasis), in which the typical mutations of the Notch ligand JAG1 cannot be found. To clarify the role of HEY2 in human CHD and AGS, we screened by direct sequencing 23 children with CHD and 38 patients diagnosed with AGS, which lack mutations in the JAG1 gene. We found two types of silent changes in the coding region: a CTT-->CTG transition in exon 3 and a CTG-->CTC polymorphism in exon 5. Furthermore, a heterozygous SNP in the splice donor site of exon 4 was detected that is unlikely to disrupt splicing. Although the high incidence and variability of human congenital heart defects implies a multifactorial genetic basis, our results suggest that mutation of HEY2 is not a major contributing factor.

Adolescent↗
PubMed2000

A new spontaneous mouse mutation in the Kcne1 gene.

A new mouse mutant, punk rocker (allele symbol Kcne1(pkr)), arose spontaneously on a C57BL/10J inbred strain background and is characterized by a distinctive head-tossing, circling, and ataxic phenotype. It is also profoundly and bilaterally deaf. The mutation resides in the Kcne1 gene on Chromosome (Chr) 16 and has been identified as a single base change within the coding region of the third exon. The C to T nucleotide substitution causes an arginine to be altered to a termination codon at amino acid position 67, and predictably this will result in a significantly truncated protein product. The Kcne1(pkr) mutant represents the first spontaneous mouse model for the human disorder, Jervell and Lange-Nielsen syndrome, associated with mutations in the homologous KCNE1 gene on human Chr 21.

Amino Acid Sequence↗
PubMed2003

Tyrosinase gene mutations in oculocutaneous albinism 1 (OCA1): definition of the phenotype.

Oculocutaneous albinism (OCA) is a common human genetic condition resulting from mutations in at least twelve different genes. OCA1 results from mutations of the tyrosinase gene and presents with the life-long absence of melanin pigment after birth (OCA1A) or with the development of minimal-to-moderate amounts of cutaneous and ocular pigment (OCA1B). Other types of OCA have variable amounts of cutaneous and ocular pigment. We hypothesized that white hair at birth indicates OCA1 and tested this in a sample of 120 probands with OCA and white hair at birth. We found that 102 (85%) of the probands had OCA1 with one or two identifiable tyrosinase gene mutations, with 169 (83%) of the 204 OCA1 tyrosinase gene alleles having identifiable mutations and 35 (17%) having no identifiable change in the coding, splice junction, or proximal promoter regions of the gene. The inability to identify the mutation was more common with OCA1B (24/35, 69%) than with OCA1A (11/35, 31%) alleles. Seven probands with no tyrosinase gene mutations were found to have OCA2 with one or two P gene mutations, and in eleven, no mutations were detected in either gene. We conclude that (1) the presence of white hair at birth is a useful clinical tool suggesting OCA1 in a child or adult with OCA, although OCA2 may also have this presentation; (2) the molecular analysis of the tyrosinase and P genes are necessary for precise diagnosis; and (3) the presence of alleles without identifiable mutations of the tyrosinase gene, particularly in OCA1B, suggests that more complex mutation mechanisms of this gene are common in OCA.

Adolescent↗
PubMed2006

Mutational targets in colorectal cancer cells with microsatellite instability.

Cancers arise from the sequential acquisition of genetic alterations in specific genes. The high number of mutations in cancer cells led to the hypothesis that an early step in tumor progression is the generation of a genetic instability. The potent role of genetic instability in initiation and progression of colorectal cancers has been well defined in hereditary nonpolyposis colon cancer (HNPCC) syndrome. HNPCC is a common hereditary disorder caused by germline mutations of DNA mismatch repair (MMR) genes. Somatic loss of the normal allele of the predisposition gene leads to a strong "mutator phenotype", characterized by a high rate of mutations in repetitive sequences. Nevertheless, the observation of frequent alterations of key growth regulatory genes in MMR-deficient cells such as NF1, APC, p53, K-Ras, with no significant excess of frameshift mutations and changes at short coding repeats, suggest that even in the presence of an inherited tendency to genomic instability, tumor progression is mainly driven by a process of natural selection.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Evolutionary studies on an alpha-amylase gene segment in bats and other mammals.

Comparative studies of salivary glands showed that they maybe related to the adaptive radiation of bats, especially in the family Phylostomidae. In this study we have been searching for a likely relationship between different feeding habits found in bats and possible adaptive changes in a coding segment of the alpha-amylase enzyme. We have also tested some hypothesis about the phylogenetic relationship of bats and other mammals. A 663 bp segment of the alpha-amylase gene, corresponding to the exon 4 and part of the intron c, was sequenced in nine bat species. The exon 4 was also sequenced in further ten mammalian species. The phylogenetic trees generated with different methods produced the same results. When the intron c and the exon 4 were independently analyzed, they showed distinct topologies involving the bat species Sturnira lilium, different from the traditional bat phylogeny. Phylogenetic analysis of bats, primates and rodents supports the Euarchontoglires-Laurasiatheria hypothesis about the relationship among these groups. Selection tests showed that the alpha-amylase exon 4 is under strong purifying selection, probably caused by functional constraints. The conflicting bat phylogenies could not be explained by evolutionary convergence due to adaptive forces, and the different topologies may be likely due to the retention of plesiomorphic characters or the independent acquisition by evolutionary parallelism.

Amino Acid Sequence↗
PubMed1976

The divergence between human and baboon globin genes.

Complementary DNA (cDNA) was prepared with viral RNA-directed DNA polymerase from purified baboon globin messenger RNA (mRNA). Homologous and heterologous hybrids between human and baboon mRNAs and cDNAs were compared for extent of hybridisation and thermal stability. Higher mRNA inputs to the hybridizations were required to reach saturation in the heterologous cases. The melting temperature of the heterologous hybrid was 5 degrees C lower than the homologous hybrid. Between these two primates, divergence has occurred in the globin gene to a smaller extent than that possible from third position changes in the coding sequences of the divergence of total DNA. Globin cDNA prepared from baboon will not in general be useful as a probe for human globin mRNA or human globin gene sequences.

Animals↗
PubMed1989

Protein changes during anterograde-to-retrograde conversion of axonally transported vesicles.

In the axon tip, cell biological mechanisms convert anterogradely transported membranous elements. To study the effects of these anterograde-to-retrograde (A-R) converting mechanisms on the electrophoretic behaviour of vesicle proteins, we compared the proteins of anterograde vesicles (before A-R conversion at the axon tip) with those of retrograde vesicles (after A-R conversion at the axon tip). The proteins in transported vesicles were pulse-labeled with [35S]methionine, and the radiolabeled vesicles were concentrated by ligating the axons-anterograde vesicles accumulate selectively on the proximal side of the ligature and retrograde vesicles accumulate on the distal side of the ligature. Analyses of vesicle proteins by polyacrylamide gel electrophoresis (SDS-PAGE) show that most of the anterograde proteins were also present in the retrograde vesicles. In addition to the conservation of these anterograde proteins in the retrograde vesicles, there were also many differences: some anterograde proteins were diminished in the retrograde vesicles, other anterograde proteins were absent from the retrograde vesicles, and the retrograde vesicles contained some new protein bands that were not present in the anterograde vesicles. These results indicate that A-R converting mechanisms modify membranous vesicle proteins in the axon tip. We propose that some of these post-translational protein modifications change the directional code on the vesicle surfaces, thereby converting anterograde membranous elements into retrograde membranous elements.

Animals↗
PubMed1994

Repetition blindness between visually different items: the case of pictures and words.

Repetition blindness (RB) is the failure to see or recall the second of two visually similar or identical items in rapid serial visual presentation. It was initially demonstrated by Kanwisher (1987), who proposed that a second token of a given word or object type cannot be established when the two items occur close in time. Bavelier and Potter (1992) showed that RB also occurs between visually different items that are phonologically similar. They proposed that RB may occur not only when the targets are physically similar, but also when they have to be registered or encoded in short-term memory (STM) along dimensions on which they are similar. This hypothesis predicts that RB between visually different items should not be restricted to words, but should occur with any stimuli, as long as the task requires these stimuli to be encoded along dimensions on which they are similar. Moreover, it also implies that a task that changes the preferred code of targets will affect the size of RB. The first prediction was confirmed by establishing RB between phonologically similar pictures and words, whether semantically related (the picture of a cat and the word "cat") or not (the picture of a sun and the word "son"), when using a task that requires phonological encoding (Experiments 1 and 2). The second prediction was also supported: the magnitude of RB depended on whether the task required similar or different codes for pictures and words (Experiments 3 and 4). These experiments confirm that RB between visually different items is due to the similarity of the codes initially used in STM. The results suggest that RB can occur at any step during the instantiation of a token, arising not only from a failure to create a new token, but also from a failure to stabilize an opened token. In this view, tokens are to be seen as dynamical entities, built over time as a function of type activation and task requirements, and varying in stability as a function of the information that is entered into them.

Adult↗
PubMed1991

Induced color blindness in goldfish: a behavioral and electrophysiological study.

To answer the question whether, like man, ethambutol treated fish would become color-blind, wavelength discrimination was measured behaviorally in goldfish, preceding, during and after ethambutol treatment. The results are that of the three high discrimination abilities at around 400, 500 and 600 nm, ethambutol affected the latter one. Red-green discrimination is lost reversibly leaving the discriminations in the blue-green and violet range unaffected. This red-green discrimination deficiency cannot be accounted for by a loss of long wavelength cones since the ERG and luminosity functions remain unaffected. Intracellular horizontal cell recordings in goldfish show that ethambutol hyperpolarizes all three types of cone driven horizontal cells and changes their color coding such that their spectral characteristics become cone-like as is the case in dark adapted retina. So, the initial effect induced by ethambutol seems to be an adaptation deficiency in color vision related tasks. Human wavelength discrimination and increment threshold spectral sensitivity functions obtained at low luminance levels are compared to behavioral functions in ethambutol treated goldfish. The high similarity between the ethambutol effects in man and goldfish, and the effects observed in the horizontal cell responses in goldfish are highly indicative that horizontal cells play a key role in color vision. So far their function has been puzzling.

Animals↗
PubMed1994

Temporal integration at equiluminance and chromatic adaptation.

The present study showed that at equiluminance the critical duration of temporal integration became shorter as the chromatic saturation of an adaptation field was increased. These results suggest that the chromatic coding system (which is assumed to posses poorer temporal resolution or larger temporal integration time than the luminance coding system) can change its temporal integrating organization with its own adaptation level, independently of the luminance system.

Adaptation, Ocular↗
PubMed1991

Changes in expression of peptides in rat facial motoneurons after facial nerve crushing and resection.

In situ hybridization histochemistry was used to study changes in mRNAs coding neuropeptides such as alpha-calcitonin gene-related peptide (CGRP), beta-CGRP, cholecystokinin (CCK) and galanin, in rat facial motoneurons following axotomy of the facial nerve. In control rats, 38%, 55% and 7% of the facial motoneurons expressed alpha-CGRP, beta-CGRP and CCK mRNAs, respectively. No galanin mRNA-containing motoneurons were observed in these animals. The levels of mRNA for alpha-CGRP, CCK and galanin were increased while the beta-CGRP mRNA level was decreased after axotomy. The levels of mRNAs for these peptides returned to the control values by 2-4 weeks after nerve crush, whereas nerve resection had more prolonged effects. Within 3-4 weeks after injury, nerve resection had greater effects on beta-CGRP, CCK and galanin mRNAs than did nerve crush. Thus, there appear to be differences in the regulation of mRNA expression of these peptides in axotomized motoneurons.

Animals↗
PubMed1995

Combinatorial expression of immediate early genes in single neurons.

To address the question how relatively small numbers of immediate early gene (IEG) could specifically couple a wide range of stimulus-response cascades, we examined the possibility that IEG could be expressed heterogeneously in individual neurons. Analysis of multiple IEG in single neurons revealed that many individual DRG neurons express several IEGs. The combinatorial expression of IEGs by individual DRG displays substantial heterogeneity. Analysis of mRNA species encoding AP-1 composition in single cells also revealed coordinated change of mRNAs coding for AP-1 factors after membrane depolarization. Our results indicate that differential expression of IEG in individual cells, and the possible interaction among them may represent a mechanism by which the specificity in stimulation-response coupling may be achieved by IEGs.

Animals↗
PubMed1990

Cloning and sequence analysis of the cDNA for the pituitary glycoprotein hormone alpha-subunit of the European eel.

A cDNA library constructed using mRNAs isolated from pituitary glands of estradiol-treated eels was screened with a cDNA fragment for the rat glycoprotein hormone alpha-subunit. Three out of 10,000 cDNA clones were revealed and subcloned in pUC13 for characterization and sequencing. All three had the same nucleotide sequence except for a single, silent change in the coding sequence for one of them, and for the location of the poly(A) tail. Analysis of the deduced amino acid sequence strongly suggests that these cDNA clones encode the precursor for the eel common glycoprotein hormone alpha-subunit. This precursor would therefore consist of a 93 amino acid apoprotein preceded by a 24 amino acid long signal peptide. Alignment with glycoprotein hormone alpha-subunits from fish and mammals reveals high homology, ranging from 60 to 90%. Particularly, the ten cysteines and the two putative N-linked glycosylation sites were at the same position. Comparison between fish and mammals shows also that two regions are highly conserved, comprising about half of the protein length. This high conservation rate through evolution argues for the importance of these regions in the conservation of biological properties of the alpha-subunits. In contrast, other regions are highly variable and could be responsible for the immunological specificity. Northern blot analysis of pituitary RNA from control and estradiol-treated eels showed that estradiol treatment strongly increases the pituitary content of mRNA encoding the glycoprotein hormone alpha-subunit.

Amino Acid Sequence↗
PubMed1990

Complete amino acid sequence of human cartilage link protein (CRTL1) deduced from cDNA clones and chromosomal assignment of the gene.

Little is known about the primary amino acid structure of human cartilage link protein (CRTL1). We screened a human genomic library with a cDNA encoding the 3' untranslated region and the adjoining B1 domain of chicken link protein. One clone was isolated and characterized. A 3.5-kb EcoRI-KpnI fragment from this genomic clone that contains the human B1 exon was used to map the gene to chromosome 5q13----q14.1. The same fragment was used to screen a cDNA library prepared from mRNA of Caco-2, a human colon tumor cell line. Two overlapping clones were isolated and shown to encode all of CRTL1. The deduced amino acid sequence is 354 residues long. The amino acid sequence shows a striking degree of identity to the porcine (96%), rat (96%), and chicken (85%) link protein sequences. Furthermore, there is greater than 86% homology between the 3' untranslated region of the genes encoding human and porcine link proteins. These results indicate that there has been strong evolutionary pressure against changes in the coding and 3' untranslated regions of the gene encoding cartilage link protein.

Amino Acid Sequence↗
PubMed2004

Mitochondrial genome mutations in hypertensive individuals.

Human essential hypertension (HTN), a polygenic, multifactorial, and highly heterogeneous disorder of unknown etiology, has been shown to have excess maternal transmission in several studies, suggesting a possible mitochondrial involvement. In an effort to assess the contribution of the mitochondrial genome to HTN we initiated a systematic, extended screening of hypertensive individuals to identify potentially pathogenic mtDNA mutations. We applied our newly developed novel class of tests for the detection of mitochondrial mutation involvement in complex diseases to the hypertension data set from 350 pedigrees of white ethnicity and 98 of African American ethnicity ascertained at HTN clinics associated with Boston Medical Center, and we identified families with a likely mitochondrial involvement. We analyzed the sequence of the entire mitochondrial genome in probands from 20 such pedigrees, consisting of 10 African American and 10 white families. Comparison with the reference "Cambridge" sequence revealed a total of 297 base changes, including 24 in the ribosomal RNA (rRNA) genes, 15 in the transfer RNA (tRNA) genes, and 46 amino acid substitutions, with the remainder involving the noncoding regions or synonymous changes. Among the coding region mutations, 30 are novel, with 13 hypertensive probands carrying at least one novel variant, usually in combination with the previously described common polymorphisms, several of which are associated with cardiovascular and renal pathologies. These data will serve as a starting point for large-scale case-control association studies.

Black People↗
PubMed2006

Solution for underflow problem in linkage and segregation analysis.

Finding genes for complex traits is one of the major challenges of modern human genetics. Current developments of molecular techniques facilitated use of large pedigrees and marker sets of thousands of single-nucleotide polymorphisms (SNPs). However, one of the problems occurring in statistical analysis of such large data sets is that the likelihood is very low and underflow may easily occur. In this work we describe a method permitting to avoid underflow during computation of a likelihood function, using different algorithms. Our method makes practically possible analysis of thousands of individuals and thousands of SNPs. The method is easy to implement without major change of the code of existing programs. It also helps to reduce the amount of computer memory used in analysis without noticeable alteration of the program running time. The algorithm was implemented in the software packages for segregation and linkage analysis, which are available from http://mga.bionet.nsc.ru/.

Algorithms↗
PubMed2006

Time trends in the registration of Hodgkin and non-Hodgkin lymphomas in Europe.

Lymphoma incidence is reported to be increasing globally. If real, these trends can only be explained by an increasing exposure to risk(s) as yet unknown. There have been numerous coding and classification changes over time and greater access to ever more sensitive diagnostic tests. It is important to understand the consequences that these changes, coupled with general improvements in cancer registration, have had on observed temporal trends. Trends in the registration rates of both non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) in Europe are presented. Age-adjusted and age-specific rates are described in men and women in 13 European countries according to both period of diagnosis and year of birth. Age, period and cohort effects are modelled. Overall, there are increases in the numbers of NHL registrations made with a corresponding decrease in HL. In recent history, however, there is a suggestion that the rate of increase is less and stable.

Adolescent↗