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PubMed2000

Fragile X CGG repeat structures among African-Americans: identification of a novel factor responsible for repeat instability.

The cryptic CGG repeat responsible for the fragile X syndrome, located in the 5'-UTR of FMR1, is unique compared with the many other triplet repeat-causing diseases, making it ideal for identifying factors involved in repeat expansion that may be common to other triplet repeat diseases. To date, a number of factors have been identified which may influence repeat instability, including the number and position of interspersed AGGs, length of the 3' pure CGG repeat and haplotype background. However, nearly all such data were derived from studies of Caucasians. Using a large African-American population, we present the only comprehensive examination of factors associated with CGG repeat instability in a non-Caucasian population. Among Caucasians, susceptible alleles were thought to come from those in the intermediate repeat range (41-60 repeats); however, we find that susceptible alleles may come from a larger repeat pool (35-60 repeats) and are better defined by their pure CGG repeat and/or -presence of only one AGG interruption. These results demonstrate the existence of different susceptible alleles among world populations and may account for the similar prevalence of the fragile X syndrome in African-Americans compared with Caucasians despite the lower frequency of inter-mediate sized alleles in the African-American population. Finally, we show that repeat structures among unaffected African-Americans with the most frequent fragile X haplotype background are either pure or contain a single distal interruption. We propose that the lack of a proximal most interruption is a novel factor involved in CGG repeat instability.

5' Untranslated Regions↗
PubMed1993

Structure and organization of the gene encoding a mouse mitochondrial stress-70 protein.

We have previously found that an antigenic protein specific for C3H strain mouse (C3H strain-specific antigen, CSA) is identical to peptide-binding protein 74 (PBP74). PBP74/CSA is a novel member of the stress-70 protein family in mitochondria. In this study, mouse genomic clones encoding PBP74/CSA, including the 5'- and 3'-flanking regions of the gene, have been isolated and sequenced. The PBP74/CSA gene contained 17 exons interrupted by 16 introns. Two dimeric repeats of the consensus sequence of the heat-shock element are present in the 5'-flanking region of the PBP74/CSA gene. Moreover, the first intron is interrupted within the amino-terminal leader sequence, the pattern of which is similar to that of cytochrome c1 located in the mitochondria.

Amino Acid Sequence↗
PubMed1995

DNA CTG triplet repeats involved in dynamic mutations of neurologically related gene sequences form stable duplexes.

DNA triplet repeats, 5'-d(CTG)n and 5'-d(CAG)n, are present in genes which have been implicated in several neurodegenerative disorders. To investigate possible stable structures formed by these repeating sequences, we have examined d(CTG)n, d(CAG)n and d(CTG).d(CAG)n (n = 2 and 3) using NMR and UV optical spectroscopy. These studies reveal that single stranded (CTG)n (n > 2) forms stable, antiparallel helical duplexes, while the single stranded (CAG)n requires at least three repeating units to form a duplex. NMR and UV melting experiments show that the Tm increases in the order of [(CAG)3]2 < [(CTG)3]2 << (CAG)3.(CTG)3. The (CTG)3 duplex is stable and exhibits similar NMR spectra in solutions containing 0.1-4 M NaCl and at a pH range from 4.6 to 8.8. The (CTG)3 duplex, which contains multiple-T.T mismatches, displays many NMR spectral characteristics similar to those of B-form DNA. However, unique NOE and 1H-31P coupling patterns associated with the repetitive T.T mismatches in the CTG repeats are discerned. These results, in conjunction with recent in vitro studies suggest that longer CTG repeats may form hairpin structures, which can potentially cause interruption in replication, leading to dynamic expansion or deletion of triplet repeats.

Base Composition↗
PubMed1996

Genetic variation and evolutionary stability of the FMR1 CGG repeat in six closed human populations.

In an attempt to understand the allelic diversity and mutability of the human FMR1 CGG repeat, we have analyzed the AGG substructure of this locus within six genetically-closed populations (Mbuti pygmy, Baka pygmy, R. surui, Karitiana, Mayan, and Hutterite). Most alleles (61/92 or 66%) possessed two AGG interspersions occurring with a periodicity of one AGG every nine or ten CGG repeats, indicating that this pattern is highly conserved in all human populations. significant differences in allele distribution were observed among the populations for rare variants possessing fewer or more AGG interruptions than the canonical FMR1 CGG repeat sequence. Comparisons of expected heterozygosity of the FMR1 CGG repeat locus with 30 other microsatellite loci, demonstrated remarkably similar levels of polymorphism within each population, suggesting that most FMR1 CGG repeat alleles mutate at rates indistinguishable from other microsatellite loci. A single allele (1 out of 92) was identified with a large uninterrupted tract of pure repeats (42 pure CGG triplets). Retrospective pedigree analysis indicated that this allele had been transmitted unstably. Although such alleles mutate rapidly and likely represent evolving premutations, our analysis suggests that in spite of the estimated frequency of their occurrence, these unstable alleles do not significantly alter the expected heterozygosity of the FMR1 CGG repeat in the human population.

Biological Evolution↗
PubMed1998

Spider minor ampullate silk proteins contain new repetitive sequences and highly conserved non-silk-like "spacer regions".

Spider minor ampullate silk is a strong non-elastic deformably stretchable silk used in web formation. This silk from Nephila clavipes is composed of two proteins, MiSp 1 and 2, whose transcripts are 9.5 and 7.5 kb, respectively, as determined by Northern blots. Both MiSp proteins are organized into a predominantly repetitive region and a small nonrepetitive carboxy terminal region. These highly repetitive regions are composed mainly of glycine and alanine, but also contain tyrosine, glutamine, and arginine. The sequences are mainly GGX and GA repeats. The repetitive regions are interrupted by nonrepetitive serine-rich spacer regions. Although the sequences of the spacer regions differ from the repetitive regions, sequences of the spacers from different regions of the proteins are nearly identical. The sequence differences between major and minor ampullate silks may explain the differing mechanical properties of the fibers.

Amino Acid Sequence↗
PubMed2000

Characterization of Ngef, a novel member of the Dbl family of genes expressed predominantly in the caudate nucleus.

We have identified Ngef as a novel member of the family of Dbl genes. Many members of this family have been shown to function as guanine nucleotide exchange factors for the Rho-type GTPases. Ngef is predominantly expressed in brain, with the strongest signal in the caudate nucleus, a region associated with the control of movement. Ngef contains a translated trinucleotide repeat, a polyglutamic acid stretch interrupted by a glycine. We have localized the Ngef gene to mouse chromosome 1 and the human homologue of Ngef to human chromosome 2q37. We have shown in preliminary experiments that Ngef has transforming potential in cell culture and is able to induce tumors in nude mice.

3T3 Cells↗
PubMed1995

Adaptational and learning processes during human split-belt locomotion: interaction between central mechanisms and afferent input.

Split-belt locomotion (i.e., walking with unequal leg speeds) requires a rapid adaptation of biomechanical parameters and therefore of leg muscle electromyographic (EMG) activity. This adaptational process during the first strides of asymmetric gait as well as learning effects induced by repetition were studied in 11 healthy volunteers. Subjects were switched from slow (0.5 m/s) symmetric gait to split-belt locomotion with speeds of 0.5 m/s and 1.5 m/s, respectively. All subjects were observed to adapt in a similar way: (1) during the first trial, adaptation required about 12-15 strides. This was achieved by an increase in stride cycle duration, i.e., an increase in swing duration on the fast side and an increase in support duration on the slow side. (2) Adaptation of leg extensor and flexor EMG activity paralleled the changes of biomechanical parameters. During the first strides, muscle activity was enhanced with no increase in coactivity of antagonistic leg muscles. (3) A motor learning effect was seen when the same paradigm was repeated a few minutes later--interrupted by symmetric locomotion--as adaptation to the split-belt speeds was achieved within 1-3 strides. (4) This short-time learning effect did not occur in the "mirror" condition when the slow and fast sides were inverted. In this case adaptation again required 12-15 strides. A close link between central and proprioceptive mechanisms of interlimb coordination is suggested to underlie the adaptational processes during split-belt conditions. It can be assumed that, as in quadrupedal locomotion of the cat, human bipedal locomotion involves separate locomotor generators to provide the flexibility demanded. The present results suggest that side-specific proprioceptive information regarding the dynamics of the movement is necessary to adjust the centrally generated locomotor activity for both legs to the actual needs for controlled locomotion. Although the required pattern is quickly learned, this learning effect cannot be transferred to the contralateral side.

Adaptation, Physiological↗
PubMedDate not supplied

Biochemical and ultrastructural studies of the C-type lectin bovine conglutinin.

The aim of this study was to correlate the supramolecular organization of conglutinin (BK) with its primary and tertiary structure and to gain more knowledge of functionally important regions of the molecule. BK analyzed by SDS-PAGE under standard reducing conditions (40 mM DTT) showed a major band at 43 kDa and weaker bands at 86 and 180 kDa. In contrast, reduction with 6-50 mM L-cysteine resulted in 37-kDa subunits indicating the presence of intrachain disulfide bonds within this subunit. Hydroxylamine treatment indicated presence of ester bonds in the 86- and 180-kDa subunits. Collagenase digestion and SDS-PAGE under reducing and nonreducing conditions resulted in bands of 20 and 15 kDa, respectively, indicating the presence of intrachain, rather than interchain, disulfide bonds in the carboxy terminus. Deglycosylation and glycan differentiation analysis of BK revealed the presence of O-linked glycans of GalNAc and alpha (2-3) linked sialic acid type, whereas no N-linked glycans were demonstrated. Binding experiments with GlcNAc-gold suggested that multivalency is required for carbohydrate binding to BK. Electron microscopy showed mostly tetramers, 96 nm in diameter, but also mono-, di-, and trimers were seen. The tetramers consisted of 40-nm strands, each with a peripheral globular head composed of subunits and connected to a common central lobe built from four ring-formed structures. The strands occasionally showed two bends, one close to the central lobe and another 25 nm from the lobe. These bends most likely correspond to the interrupted Gly-Xaa-Yaa repeats at residues 38 and 123.

Amino Acid Sequence↗
PubMed2000

Large exons encoding multiple ectodomains are a characteristic feature of protocadherin genes.

Recent studies revealed a striking difference in the genomic organization of classic cadherin genes and one family of "nonclassic cadherin" genes designated protocadherins. Specifically, the DNA sequences encoding the ectodomain repeats of classic cadherins are interrupted by multiple introns. By contrast, all of the encoded ectodomains of each member of the protocadherin gene clusters are present in one large exon. To determine whether large ectodomain exons are a general feature of protocadherin genes we have investigated the genomic organization of several additional human protocadherin genes by using DNA sequence information in GenBank. These genes include protocadherin 12 (Pcdh12), an ortholog of the mouse vascular endothelial cadherin-2 gene; hFmi1 and hFmi2, homologs of the Drosophila planar cell polarity gene, flamingo; hFat2, a homolog of the Drosophila tumor suppressor gene fat; and the Drosophila DN-cadherin and DE-cadherin genes. Each of these genes was found to be a member of the protocadherin subfamily, based on amino acid sequence comparisons of their ectodomains. Remarkably, all of these protocadherin genes share a common feature: most of the genomic DNA sequences encoding their ectodomains are not interrupted by an intron. We conclude that the presence of unusually large exons is a characteristic feature of protocadherin genes.

Amino Acid Sequence↗
PubMed2006

Removal of pattern-breaking sequences in microtubule binding repeats produces instantaneous tau aggregation and toxicity.

Aggregated and highly phosphorylated tau protein is a pathological hallmark of Alzheimer's disease (AD) and other tauopathies. We identified motifs of alternating polar and apolar amino acids within the microtubule-binding repeats of tau which were interrupted by small breaking stretches. Minimal mutation of these breaking sequences yielded a unique instantly aggregating tau mutant containing longer stretches of polar/apolar amino acids without losing its microtubule-binding capacity. These modifications produced rapid aggregation and cytotoxicity with accompanying occurrence of pathologic tau phosphoepitopes (AT8, AT180, AT270, AT100, Ser(422), and PHF-1) and conformational epitopes (MC-1 and Alz50) in cells. Similar to pathological tau in the pretangle state, toxicity appeared to occur early without the requirement for extensive fibril formation. Thus, our mutant protein provides a novel platform for the investigation of the molecular mechanisms for toxicity and cellular behavior of pathologically aggregated tau proteins and the identification of its interaction partners.

Amino Acid Sequence↗
PubMed1993

In-frame deletion of von Willebrand factor A domains in a dominant type of von Willebrand disease.

von Willebrand disease (vWD), the most common inherited bleeding disorder in humans, is very heterogeneous and has been classified into several subtypes. Missense mutations have been found to be responsible for the dominant type II vWD, characterized by qualitative abnormalities affecting von Willebrand factor (vWF) function. The breakpoints of a heterozygous vWF gene deletion (31 Kb), occurring 'de novo' in a patient with a variant of type II vWD, were localized to introns 25 and 34 and sequenced. An Alu repeat in intron 25 was interrupted between the transcriptional boxes A and B. The new junction present in the abnormal von Willebrand factor mRNA was sequenced after reverse transcription of platelet RNA. The codon 1104 (Cys) is followed in frame by the mutated codon 1926 (Cys to Arg), thus removing the complete A domains, found in a wide variety of genes and characterized by independent assembly 'in vitro'. We propose that the abnormal vWF, which carries intact protein domains responsible for vWF dimer and multimer formation, makes ineffective interactions with the normal molecules in the biosynthetic process, causing the dominant type II phenotype through a novel mechanism.

Base Sequence↗
PubMed1978

Isolation and characterization of Hfr strains of Erwinia amylovora.

Hfr strains (Hfr 159 and its derivatives, Hfr 160 and Hfr 161) were constructed from Erwinia amylovora ICPB EA178 by introducing an Escherichia coli F'his+ plasmid and then selecting for integration of F'his+ after treatment with acridine orange. The Hfr strains were relatively stable upon repeated transfers on nonselective media. Interrupted mating experiments and analyses of inheritance of unselected markers showed that his+ is transferred by Hfr 159 as the proximal marker at a relatively high frequency (about 5 x 10(-4) recombinants per input donor cell), followed by ilv+, orn+, arg+, pro+, rbs+, met+, trp+, leu+, ser+, and thr+ (not necessarily in that precise order). The donor strains, previously constructed in E. amylovora by integration of F'lac+ from E. coli transfer cys+ as the proximal marker followed by ser+. Further analysis of one of those earlier donor strains, Hfr99, showed that ser+ is followed by arg+, orn+, met+, pro+, leu+, ilv+, rbs+, his+, trp+, and thr+ (not necessarily in that precise order). Thus, the Hfr strains constructed by integration of F'his+ are different, in terms of origin and direction of transfer, from those derived from integration of F'lac+. The applicability of these Hfr strains to mapping the genes on the E. amylovora chromosome is indicated.

Acridines↗
PubMed1992

Effects of anoxia and aglycemia on the adult and immature hippocampus.

Brief anoxic episodes induce a loss of consciousness due to an interruption of synaptic responses and repeated on more sustained episodes induce a selective neuronal loss in vulnerable regions notably in the CA1-H1 region of the hippocampus. The use of brain slices kept in vitro has considerably improved our understanding of the mechanisms underlying anoxia and ischemia and the strategies of development of protective drugs or manipulations. This report reviews our present understanding of the effects of anoxia-ischemia on neuronal activity in particular concerning the abrupt and major changes in vulnerability which occur with maturation of the brain.

Aging↗
PubMed1989

Duration of ischemia is vital for collateral development: repeated brief coronary artery occlusions in conscious dogs.

The effects of two types of repeated transient coronary artery occlusions on collateral development were examined in chronically instrumented, conscious dogs. A 2-minute coronary occlusion at 32-minute intervals (group 1, n = 11) or a 15-second occlusion at 4-minute intervals (group 2, n = 7) were repeated day and night without interruption. In both groups, the total duration of coronary occlusions each day was the same (90 minutes). Before and after repetitive occlusions of either group, effects of transient 2-minute coronary occlusion on regional segment shortening in the ischemic area were examined to assess the functional state of the collateral vessels. In group 1, systolic segment shortening in the area rendered ischemic was reduced to -97.8 +/- 17.7% of the preocclusive control value during 2 minutes of coronary occlusion. After 125-478 repetitive occlusions (3-11 days), the degree of hypokinesia during the 2-minute occlusion was significantly improved to -0.6 +/- 4.6% of the preocclusive value (p less than 0.001 vs. before the repetition). In group 2, it remained unchanged even after 3,500-5,450 repetitive occlusions (11-16 days): -111.8 +/- 8.2% before and -111.4 +/- 13.8% after the repetition of 15-second occlusions (NS). The ratio of peripheral coronary arterial pressure to aortic pressure during transient-coronary occlusion, measured by selective catheterization, was significantly higher in group 1 than in group 2 (64.4 +/- 5.3% vs. 20.7 +/- 1.3%, p less than 0.001). These findings suggest that myocardial ischemia of 2 minutes but not 15 seconds is vital to provide effective stimuli for angiogenesis.

Angiography↗
PubMedDate not supplied

Intermittent treatment with streptokinase in arterial disease of the limbs.

Sixty-two patients with arterial disease of the lower limbs were treated with streptokinase by intermittent administration. All patients had experienced recent aggravation of their arterial disease, and 22 had thrombolysis confirmed by arteriography. In 20 cases clinical study showed repermeation--in 8 cases during the first perfusion and in 8 cases during the third perfusion. During the first perfusion the fall in fibrinogen was significantly greater in the 8 patients with thrombolysis. Further, the third perfusion corresponded to a new phase of fibrinogenolysis. These results support the possibility of the relationship between plasminemia and thrombolysis, and emphasize the limits of the classic theory of Sherry, Fletcher, and Alkjaersig. Permitting phases of repeated but limited plasminemia, the interruption method used here is a compromise between the risk of hemorrhage and the efficacy of treatment at low dosage.

Angiography↗
PubMed2002

Nocturnal microhabitat distribution of adult Culex tarsalis (Diptera: Culicidae) impacts control effectiveness.

Suction traps (30 cm diameter) were more effective for non-attractant sampling of flying adult Culex tarsalis Coquillett than were smaller CDC (5.5 cm diameter), Malaise or ramp traps. Comparative catch in suction traps operated in a variety of vegetation types indicated that females congregated along elevated ecotones and were significantly less abundant flying over low vegetation or under and over elevated vegetation. Most females taken at upland orchards or Tamarisk tree lines were unfed (97%, n = 5,278) and similar in reproductive condition to host-seeking females. Blood fed and gravid females and males were only abundant near emergence sites. Pyrocide 7396 (Pyrethrin 5%, PBO 25%) was applied at the label rate of 5 oz/min by truck mounted Pro-Mist ultra low volume (ULV) equipment and particle drift measured by bioassay. ULV particles dispersed well downwind over low vegetation, between citrus orchard rows, and under date orchard canopy, but did not penetrate citrus orchards or vineyards when rows were perpendicular to wind direction. Particles did move up and over vegetation contacting sentinel mosquitoes placed above the canopy. The congregation of adult mosquitoes at vegetative ecotones and within orchard vegetation may afford protection from ground applied ULV particles, negatively impacting control. These data may explain why repeated applications often fail to interrupt encephalitis virus transmission.

Animals↗
PubMed2002

[Epidemiologic effectivness of poludane in preventing influenza and other acute respiratory diseases in troops].

The epidemiological effectiveness of interferon inductor "Poludanum" produced by "LENS Pharm" (Russia) for prevention of acute respiratory viral infections was tested. The drug was administered among the students of Military Medical Academy (101 students) according to scheme 1: in a nose, 3 drops in each nasal passage two times per week during 4 weeks, with 2 week interruption then the scheme was repeated. The scheme 2 included 3 drops in each nasal passage once a week during 10 weeks (95 students). The placebo group (96 students) received the distilled water. In the students receiving "Poludanum" according to scheme 1 the incidence of acute respiratory diseases (ARD) was significantly lower than in the control group (p = 0.058). The coefficient of effectiveness was 50%, i.e. the incidence has decreased in two times. The use of poludanum according to scheme 2 caused no decrease in ARD incidence.

Acute Disease↗
PubMed2003

[Monitoring of irrigating fluid absorption in transvesical resection of the myometrium].

INTRODUCTION: Monitoring of the absorption of irrigating fluid during transcervical resection of the myometrium was studied. Irrigating fluid under pressure was used. Absorption can give symptoms as seen in transurethral resection syndrome. MATERIAL AND METHODS: A method using ethanol labelled irrigation fluid measuring ethanol in expired air was used. Serum natrium and absorbed irrigation fluid estimated by weight was measured. A total of 100 women were included. The investigation was part of the daily routine with varying anaesthetists and nurses. RESULTS: Four patients with an absorption of more than 1200 ml were identified. The end-tidal ethanol and serum natrium deficit were equally accurate in determination of this. In absorption of less than 1200 ml, the serum natrium deficit and end-tidal ethanol were not correlated to absorbed irrigation fluid judged by weighing. CONCLUSION: Determination of the end-tidal ethanol during transcervical resection is recommended as a supplement. The method is non-invasive and simple and can be repeated at any time without interruption of surgery.

Breath Tests↗