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PubMed1995

Spinocerebellar ataxia type 1.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant progressive neurodegenerative disorder characterized by ataxia, dysarthria, ophthalmoparesis, and variable degrees of amyotrophy and neuropathy. Symptoms usually develop in the third or fourth decade but anticipation has been noted in juvenile onset cases. Neuropathologic findings include severe neuronal loss in the cerebellum and brainstem as well as degeneration of spinocerebellar tracts. The SCA1 gene which maps to the short arm of human chromosome 6 was identified using a positional cloning approach. The disease causing mutation is an expansion of a CAG trinucleotide repeat which lies within the coding region of a novel protein, ataxin-1, and encodes a polyglutamine tract. The number of CAG repeats varies from 6-39 repeats on normal alleles and 40-81 repeats on SCA1 alleles. The repeat has a perfect CAG configuration on expanded alleles whereas it is interrupted by 1-3 CAT units on normal alleles. Both wild type and expanded alleles are transcribed, ruling out impairment of transcriptional efficiency in SCA1. A pathogenetic model is proposed based on the findings in SCA1 and other neurodegenerative diseases caused by expansion of polyglutamine tracts. The expanded polyglutamine tract in ataxin-1 may lead to neurodegeneration through a gain of function mechanism involving aberrant interactions with other molecules in the involved neurons.

Base Sequence↗
PubMed1990

Tissue plasminogen activator as an alternative to vena cava interruption in recurrent pulmonary thromboembolism.

We have described a woman with pulmonary thromboembolism (PTE) who had acute dyspnea, chest pain, and hypotension during adequate heparin therapy. Pulmonary angiography was consistent with recurrent PTE. The patient was given intravenous TPA and showed significant improvement. Repeat angiography showed resolution of the thrombus in the right main pulmonary artery. The patient did not require vena cava interruption.

Acute Disease↗
PubMed1990

Analysis of large deletions in the Mauriceville and Varkud mitochondrial plasmids of Neurospora.

The Mauriceville and Varkud mitochondrial plasmids are closely related, closed-circular DNAs (3.6 and 3.7 kb, respectively) that have characteristics of mtDNA introns and retroid elements. Both plasmids contain a 710 amino acid open reading frame (ORF) that encodes an 81 kDa protein having reverse transcriptase activity. Here, we analyzed two mutant plasmids, V5-36 and M3-24, that have undergone relatively large deletions (approximately 0.35 and 0.5 kb, respectively). Both deletions occur downstream of the long ORF in a non-coding region of the plasmids that contains a direct repeat of 160 bp and a cluster of five PstI-palindromes, a repetitive sequence element in Neurospora mtDNA. In V5-36, the deletion end points are at the bases of two hairpin structures that are centered around PstI-palindromes and flank the deleted region. In M3-24, the deletion junction contains an extra T-residue that is not encoded in the plasmid. In both plasmids, the deletion end points do not correspond to homologous or directly repeated sequences of more than one nucleotide, whose pairing could account for the deletion junction. The characteristics of the deletion end points can be accounted for either by illegitimate recombination, possibly following double strand breaks at cruciform structures, or by interruption of reverse transcription followed by reinitiation downstream. The finding that the deletions encompass the 160 bp direct repeat and all five PstI-palindromes indicates that neither are required for propagation of the plasmids and supports the hypothesis that PstI-palindromes are selfish DNA elements that inserted into a nonessential region of the plasmid.

Amino Acid Sequence↗
PubMed1995

Vascular interventions for impotence: lessons learned.

PURPOSE: The purpose of this study was to analyze the results of vascular interventions for impotence in men with this complaint. METHODS: Between September 1983 and March 1993, 1094 men with the chief complaint of impotence (average age 54.5 years) were screened by use of penile plethysmography and penile brachial indexes: 635 were considered to have normal flow, and 459 were considered to have abnormal arterial flow, 12.2% of whom were found to have aortoiliac disease. Based on negative neural screening results, absence of erectile responses on increasing doses of intracavernously injected papaverine or prostaglandin E1 (ICI), surgical candidates for microvascular procedures were referred for dynamic infusion cavernosography (DICC) and pudendal arteriography. Operations for men discovered to have aortoiliac disease were based on conventional indications including aneurysm size or limb ischemia. None of the subjects had diabetes. Only those patients without diabetes and those not requiring blood pressure medications were selected for microvascular procedures. We report our experience and surgical outcomes at average follow-ups of 33 to 48 months. Four types of operations were performed on 67 men (age 18 to 79 years). These included 17 aortoiliac reconstructions, 11 dorsal penile artery bypasses, 12 dorsal vein arterializations, and 27 venous interruptions. Follow-up data were obtained by direct examination and noninvasive Doppler examinations; repeat arteriography (4 of 11); repeat DICC after venous ablation procedures (18 of 27) and postoperative ICI response. Mail questionnaires completed postoperative surveillance. RESULTS: Among 17 men undergoing aortoiliac intervention for aneurysms in eight and occlusive disease in nine, 58% functioned spontaneously after operation and 18% used ICI or vacuum constrictor devices at an average follow-up time of 38 months. Among 11 men with dorsal penile artery bypasses, 27% functioned spontaneously and 45% used ICI at an average follow-up time of 34.5 months. Among 12 men with dorsal vein arterialization, 33% functioned spontaneously, and 47% used ICI at an average follow-up time of 48 months. Among 27 with venous interruption, 33% functioned spontaneously and 44% used ICI. In seven of eight aneurysms of 4.5 to 6.0 cm in size, impotence workup led to discovery; probable embolic mechanisms existed in three. Venous interruption efficacy correlated with postoperative DICC results when flow to maintain erection was 40 ml or less. Apart from two cases of glans hyperemia, no surgical complications occurred in the microvascular procedures. There was one episode of bleeding caused by DICC after aortic reconstruction. There were no deaths. CONCLUSIONS: With prospective screening criteria, 6% to 7% of impotent men became candidates for vascular intervention. Including those functioning with ICI or vacuum constriction devices, about 70% of these men were functional after operation. Men undergoing aortoiliac reconstruction has a significantly higher rate (58%) of spontaneous function as compared with those undergoing microvascular procedures.

Adolescent↗
PubMedDate not supplied

The Urine Stream Interruption Test and pelvic muscle function.

The Urine Stream Interruption Test (UST) was developed to assess the effectiveness of the pelvic floor muscles in impeding urine flow. In the present study, the repeatability of the UST and its relationship to other measures of pelvic muscle strength were tested. Seventy-five women (25 each nulliparous, primiparous, and secundiparous) were enrolled. Repeatability of the UST was demonstrated by a correlation of r = .83. Stronger pelvic muscle strength, as assessed by the Digital Measure, was correlated with more rapid interruption of the stream of urine, r = -.55 to -.59. Greater parity was associated with decreased ability to stop the flow, F = 10.2 [2, 72], p less than .001), with the UST scores longest in secundiparas (M = 4.4 seconds), next longest in primiparas (M = 3.6 seconds), and shortest in nulliparas (M = 1.96 seconds).

Adult↗
PubMed2000

Genes involved in the determination of the rate of inversions at short inverted repeats.

BACKGROUND: Not all of the enzymatic pathways involved in genetic rearrangements have been elucidated. While some rearrangements occur by recombination at areas of high homology, others are mediated by short, often interrupted homologies. We have previously constructed an Escherichia coli strain that allows us to examine inversions at microhomologies, and have shown that inversions can occur at short inverted repeats in a recB,C-dependent fashion. RESULTS: Here, we report on the use of this strain to define genetic loci involved in limiting rearrangements on an F' plasmid carrying the lac genes. Employing mini-Tn10 derivatives to generate insertions near or into genes of interest, we detected three loci (rmuA,B,C) that, when mutated, increase inversions. We have mapped, cloned and sequenced these mutator loci. In one case, inactivation of the sbcC gene leads to an increase in rearrangements, and in another, insertions near the recE gene lead to an even larger increase. The third gene involved in limiting inversions, rmuC, has been mapped at 86 min on the E. coli chromosome and encodes a protein of unknown function with a limited homology to myosins, and some of the SMC (structural maintenance of chromosomes) proteins. CONCLUSIONS: This work presents the first example of an anti-mutator role of the sbcC,D genes, and defines a new gene (rmuC) involved in DNA recombination.

Chromosome Inversion↗
PubMed1996

Origin and evolution of homologous repeated sequences in the mitochondrial DNA control region of shrews.

The complete mitochondrial DNA (mtDNA) control region was amplified and directly sequenced in two species of shrew, Crocidura russula and Sorex araneus (Insectivora, Mammalia). The general organization is similar to that found in other mammals: a central conserved region surrounded by two more variable domains. However, we have found in shrews the simultaneous presence of arrays of tandem repeats in potential locations where repeats tend to occur separately in other mammalian species. These locations correspond to regions which are associated with a possible interruption of the replication processes, either at the end of the three-stranded D-loop structure or toward the end of the heavy-strand replication. In the left domain the repeated sequences (R1 repeats) are 78 bp long, whereas in the right domain the repeats are 12 bp long in C. russula and 14 bp long in S. araneus (R2 repeats). Variation in the copy number of these repeated sequences results in mtDNA control region length differences. Southern blot analysis indicates that level of heteroplasmy (more than one mtDNA form within an individual) differs between species. A comparative study of the R2 repeats in 12 additional species representing three shrew subfamilies provides useful indications for the understanding of the origin and the evolution of these homologous tandemly repeated sequences. An asymmetry in the distribution of variants within the arrays, as well as the constant occurrence of shorter repeated sequences flanking only one side of the R2 arrays, could be related to asymmetry in the replication of each strand of the mtDNA molecule. The pattern of sequence and length variation within and between species, together with the capability of the arrays to form stable secondary structures, suggests that the dominant mechanism involved in the evolution of these arrays in unidirectional replication slippage.

Animals↗
PubMed2006

Structure of a signaling-competent reelin fragment revealed by X-ray crystallography and electron tomography.

The large extracellular glycoprotein reelin directs neuronal migration during brain development and plays a fundamental role in layer formation. It is composed of eight tandem repeats of an approximately 380-residue unit, termed the reelin repeat, which has a central epidermal growth factor (EGF) module flanked by two homologous subrepeats with no obvious sequence similarity to proteins of known structure. The 2.05 A crystal structure of the mouse reelin repeat 3 reveals that the subrepeat assumes a beta-jelly-roll fold with unexpected structural similarity to carbohydrate-binding domains. Despite the interruption by the EGF module, the two subdomains make direct contact, resulting in a compact overall structure. Electron micrographs of a four-domain fragment encompassing repeats 3-6, which is capable of inducing Disabled-1 phosphorylation in neurons, show a rod-like shape. Furthermore, a three-dimensional molecular envelope of the fragment obtained by single-particle tomography can be fitted with four concatenated repeat 3 atomic structures, providing the first glimpse of the structural unit for this important signaling molecule.

Amino Acid Sequence↗
PubMed1990

Role of repeated doses of oral activated charcoal in the treatment of acute intoxications.

While single dose activated charcoal is effective in preventing drug absorption, repeated doses not only prevent absorption but also can increase systemic drug clearance. The mechanism for the latter effect may involve interruption of enterohepatic recycling and/or promotion of drug exsorption from the systemic circulation into the gut lumen. A comprehensive review of reported studies in volunteer subjects and overdose patients showed that repeated dose activated charcoal markedly decreased the half-life and/or increased the clearance of a wide range of drugs. Side-effects of the treatment were infrequent, but included aspiration pneumonia, diarrhoea and constipation. The addition of laxatives to repeated dose charcoal treatment did not offer any significant increase in drug clearance and is not recommended. It is suggested that the optimal regimen for the use of repeat dose activated charcoal in acute drug intoxications is an initial dose of 75-100 g, followed by 50 g every 4 hours until the risks of systemic drug toxicity are reduced to an acceptable level.

Acute Disease↗
PubMed1993

Characterization of rat pseudogenes for enhancer factor I subunit A: ripping provides clues to the evolution of the EFIA/dbpB/YB-1 multigene family.

Genomic Southern blot analysis of rat EFIA (gene encoding enhancer factor I subunit A) reveals a complex band pattern when cDNA subfragment probes are used. Screening a rat genomic library with a rat EFIA cDNA probe yields two different processed EFIA pseudogenes, designated rat psi EFIA#(2/3) and #(4/7), in addition to two other different, but less extensively characterized clones. psi EFIA#(4/7) has no open reading frame (ORF) sequences. psi EFIA#(2/3) contains two ORFs (83 and 178 codons), the products of which (if expressed) might be negative-acting EFIA transcription factors. Located nearly 0.6 kb upstream from psi EFIA#(2/3) is a perfect 69-bp dinucleotide (CT) tandem repeat, a sequence element associated with other isolated pseudogenes. Additionally, the 3' end of this processed gene is interrupted by an unusual retroposon, an inverted dimeric B1-like short interspersed repetitive element (SINE). The isolation of several independent clones of the same EFIA processed pseudogenes indicates that they comprise a significant component of the rat EFIA copy multiplicity. The phenomenon of repeat induced point mutagenesis (ripping) at rat EFIA pseudogene CpG doublets occurs at a frequency at least 6.5 times higher than predicted from random mutagenesis. This is consonant with the proposal that ripping may be the mechanism which inactivates the ectopic recombination potential of the rat EFIA pseudogenes.

Amino Acid Sequence↗
PubMed1977

Cloned segment of Drosophila melanogaster rDNA containing new types of sequence insertion.

A cloned 14.3-kbase segment of Drosophila melanogaster rDNA (Dm207) is described in which only a 4-kbase region is homologous to a cloned 17-kbase rDNA repeating unit, Dm103; this 4-kbase region consists of part of the 28S rRNA gene and most but not all of the adjacent transcribed spacer that normally connects the 18S and 28S genes. The transcribed spacer in Dm207 is interrupted by a 2.2-kbase stretch of DNA that does not contain any 18S gene sequences. At the other end of the 4-kbase homology, the 28S gene is interrupted by an 8.1-kbase stretch of DNA at a position equivalent to the site of the 28S insertion found in the 17-kbase units. The question of whether the 2.2-kbase and 8.1-kbase interrupter segments in Dm207 derive from longer insertions into the transcribed spacer and 28S genes of a very long repeating unit (greater than or equal to 22 kbases) or represent a region of the chromosomal DNA into which a 4-kbase fragment of rDNA has been inserted is discussed.

Base Sequence↗
PubMed1998

Cloning and characterization of a symbiosis-related gene from an ectomycorrhizal fungus Laccaria bicolor.

An in vitro system for a Laccaria bicolorxPinus resinosa interaction was used to identify and clone a symbiosis-regulated gene from L. bicolor employing the mRNA differential display technique (DDRT-PCR). The DDRT-PCR identified several cDNAs that are differentially expressed as early as 6h into the interaction. One such cDNA was used to screen a L. bicolor cDNA library enriched for mRNAs expressed during early interaction with red pine seedlings. Characterization of a cDNA clone, PF6.2, showed that it contained a 1551 bp insert coding for a protein of 433 amino acids. Sequence analysis of the PF6.2 cDNA revealed the presence of several evolving repeats in the protein. To confirm this, the gene corresponding to PF6.2 was isolated and sequenced. The PF6.2 gene consisted of seven exons interrupted by six relatively small introns. Although the amino-acid sequence of the PF6.2 did not show significant overall similarity to any previously characterized proteins, of several direct repeats it contained a feature similar to other proteins involved in signal transduction through protein-protein interaction. Northern analysis showed that the PF6.2 mRNA was detectable in the fungus 6h after interaction and continued to be expressed in established ectomycorrhizas, suggesting that it plays an important role in the formation and maintenance of the symbiosis.

Agaricales↗
PubMed1989

Rapid growth of regenerating axons across the segments of sciatic nerve devoid of Schwann cells.

The characteristic response of Schwann cells (SC) accompanies peripheral nerve injury and regeneration. To elucidate their role, the question of whether or not regenerating axons can elongate across the segments of a peripheral nerve devoid of SC was investigated. Rat sciatic nerve was crushed so that the continuity of SC basal laminae was not interrupted. A segment about 15 mm long distal to the crush was either repeatedly frozen/thawed to eliminate SC or scalded by moist heat which, in addition, denatured the proteins in the SC basal laminae, too. Both sensory and motor axons grew rapidly across the frozen/thawed segment of the nerve. Their rate of elongation was reduced by only 30% in comparison to control crushed nerves. SC were not present along the path of growing axons adhering tightly to the bare SC basal laminae. The rate of elongation of regenerating sensory and motor axons in scalded nerve segments was eight times lower than in control crushed nerves. SC were present in that part of the scalded region that had been invaded by the regenerating axons but no further distally. These results suggest that acellular basal laminae of SC provide very good, although not optimal, conditions for elongation of regenerating sensory and motor axons. If biochemical integrity of the basal lamina is destroyed, the regenerating axons must be accompanied or preceded by viable SC. and axon elongation rate is significantly reduced.

Animals↗
PubMed1989

Postprandial disruption of migrating myoelectric complex in dogs. Hormonal versus extrinsic nervous factors.

Our aim was to determine the mechanism whereby the jejunoileum regulates postprandial gastroduodenal motility. Five dogs were prepared with a proximal jejunal infusion catheter and with gastric manometry catheters and serosal intestinal electrodes for recording gastric and intestinal motility. After two weeks, fasted dogs were studied during jejunal infusion of either isosmolar NaCl (154 mM) or isosmolar mixed nutrient solution (50% Meritene) on four separate days each. After completion of these baseline studies, the dogs underwent a model of autotransplantation of the entire jejunoileum (extrinsic denervation, disruption of intrinsic neural continuity with proximal duodenum). Two weeks later, identical studies as before were repeated with the now "autotransplanted" jejunoileum. Before transplantation, infusion of NaCl did not interrupt the characteristic interdigestive migrating motor complex either in the gastroduodenum or in the jejunoileum. However, infusion of nutrients interrupted the migrating motor complex both in the gastroduodenum and jejunoileum for the duration of the infusion (5 hr). After autotransplantation of the jejunoileum, the migrating motor complex continued to occur in the gastroduodenum and in the jejunoileum during infusion of NaCl, but the migrating motor complex cycled independently in each region without any temporal coordination. Jejunal infusion of nutrients interrupted the MMC in both regions for the duration of infusion (5 hr). Because inhibition of the gastroduodenal and jejunoileal migrating motor complex continued to occur during infusion of nutrients into the transplanted jejunum, we concluded that jejunoileal regulation of postprandial inhibition of interdigestive motility in the stomach and duodenum is mediated by hormonal factors and does not require intrinsic neural continuity.

Animals↗
PubMed2005

Two different transposable elements inserted in flavonoid 3',5'-hydroxylase gene contribute to pink flower coloration in Gentiana scabra.

Pink-flowered gentian plants (Gentiana scabra) have been bred from spontaneous mutations of blue-flowered gentian plants, but the formation mechanism(s) is unknown so far. To investigate the process, two independent pink-flowered gentian plant lines were analyzed by a molecular biological approach. HPLC analysis showed that petals of the blue-flowered cultivar contained a small amount of cyanidin derivatives and major delphinidin derivatives, whereas pink petals had only a small amount of cyanidin derivatives. To find the causal factor(s) of this change, we focused on flavonoid 3',5'-hydroxylase (F3',5'H), which is a key enzyme for delphinidin biosynthesis in the flavonoid biosynthetic pathway. Molecular analyses confirmed that the loss of delphinidin synthesis could be attributed to the insertions of different transposable elements in the F3',5'H gene in each independent pink-flowered gentian plant. Sequence analysis showed that these transposable elements were classified into an hAT superfamily and terminal-repeat retrotransposon in miniature (TRIM), by which normal F3',5'H transcripts were interrupted. Southern blot analysis indicated that they belong to high copy number elements and are also found in a related gentian species (G. triflora). These results suggest that the transposable elements inserted in F3',5'H are the source of the mutations and may also play a substantial role in the genomic evolution of the genus Gentiana.

Amino Acid Sequence↗
PubMed1989

The full-length nucleotide sequences of the virulent Trinidad donkey strain of Venezuelan equine encephalitis virus and its attenuated vaccine derivative, strain TC-83.

Nucleotide sequence analysis of cDNA clones covering the entire genomes of Trinidad donkey (TRD) Venezuelan equine encephalitis (VEE) virus and its vaccine derivative, TC-83, has revealed 11 differences between the genomes of TC-83 virus and its parent. One nucleotide substitution and a single nucleotide deletion occurred in the 5'- and 3'-noncoding regions of the TC-83 genome, respectively. The deduced amino acid sequences of the nonstructural polypeptides of the two viruses differed only in a conservative Ser(TRD) to Thr(TC-83) substitution in nonstructural protein (nsP) three at amino acid position 260. The two silent mutations (one each in E1 and E2), one amino acid substitution in the E1 glycoprotein, and five substitutions in the E2 envelope glycoprotein of TC-83 virus were reported previously (B.J.B. Johnson, R.M. Kinney, C.L. Kost, and D.W. Trent, 1986, J. Gen. Virol. 67, 1951-1960). The genome of TRD virus was 11,444 nucleotides long with a 5'-noncoding region of 44 nucleotides. The carboxyl terminal portion of VEE nsP3 contained two peptide segments (7 and 34 amino acids long) that were repeated with high fidelity. The open reading frame of the nonstructural polyprotein was interrupted by an in-frame opal termination codon between nsP3 and nsP4, as has been reported for Sindbis, Ross River, and Middelburg viruses. The deduced amino acid sequences of the VEE TRD nsP1, nsP2, nsP3, and nsP4 polypeptides showed 60-66%, 57-58%, 35-44%, and 73-71% identity with the aligned sequences of the cognate polypeptides of Sindbis and Semliki Forest viruses, respectively. The lack of homology in the nsP3 of the viruses is due to sequence variation in the carboxyl terminal half of this polypeptide.

Amino Acid Sequence↗
PubMed1992

Structure of the human TNF receptor 1 (p60) gene (TNFR1) and localization to chromosome 12p13 [corrected].

Clones encoding the entire coding and 3' untranslated region of the human type I tumor necrosis factor receptor (p60) gene (TNFR1) were isolated by hybridization using probes derived from TNFR-1 cDNA. The gene was characterized by restriction mapping. DNA blot analysis and sequence analysis. The coding region and the 3' untranslated region are distributed over 10 exons. Each of the four repeats, comprising the extracellular ligand binding domain and characterizing a receptor superfamily, is interrupted by an intron. However, the intron-exon structure is not conserved in the nerve growth factor receptor gene, another member of this superfamily. By PCR analysis of human-mouse somatic cell hybrids and in situ hybridization using biotinylated genomic TNFR1 DNA, we localized the gene to human chromosomal band 12p13. This corresponds to the homologous murine gene localized at the distal region of mouse chromosome 6.

Amino Acid Sequence↗
PubMed2000

Implicit and explicit learning of event sequences: evidence for distinct coding of perceptual and motor representations.

Event-related brain potentials (ERPs) of 21 subjects were recorded in a choice reaction time task with a repeating eight-element long stimulus sequence. The regular event sequence was sometimes interrupted by 'perceptual' or by 'motor deviants' which both replaced an expected stimulus but either preserved or violated the sequence of motor responses. Response times confirmed that all subjects had acquired some knowledge of the sequential dependencies. By means of a post-experimental free recall and recognition test, subjects were classified as having either explicit or implicit knowledge of the event sequence. The ERPs showed different effects for different types of stimuli and the two groups. In the group of explicit learners, a larger N200 component was evoked by both types of deviants and a larger P300 by motor deviants only. In the group of implicit learners these 'perceptual components' remained unaffected. In contrast, in both groups of subjects the lateralized readiness potential (LRP) which accompanied motor deviants revealed a partial activation of the to be expected but incorrect response, i.e. motor learning. These results suggest that explicit learners acquire knowledge about both, stimulus and response dependencies while implicit learners acquire knowledge about response dependencies only.

Adult↗