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PubMed2001

Crystallization and preliminary X-ray analysis of dmpFG-encoded 4-hydroxy-2-ketovalerate aldolase--aldehyde dehydrogenase (acylating) from Pseudomonas sp. strain CF600.

The final two steps of the meta-cleavage pathway for catechol degradation in Pseudomonas sp. strain CF600 involve the conversion of 4-hydroxy-2-ketovalerate to pyruvate and acetyl coenzyme A by the enzymes 4-hydroxy-2-ketovalerate aldolase and NAD(+)-dependent acylating aldehyde dehydrogenase. Biochemical studies indicate that these two enzymes comprise a bifunctional heterodimer (DmpFG, molecular mass 71 kDa) and suggest that the product of the aldolase reaction is transferred to the dehydrogenase active site via a channeling mechanism. Crystals of the DmpFG complex grow in multiple fan-like clusters of thin plates by the hanging-drop method and are improved by streak-seeding. The crystals belong to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 102.0, b = 140.7, c = 191.3 A, and diffract to 2.1 A resolution. The asymmetric unit contains four DmpFG heterodimers. Heavy-atom derivative screening identified three isomorphous derivatives.

Aldehyde Oxidoreductases↗
PubMed2004

Synchronization phenomena in pulse-coupled networks driven by spike-train inputs.

We present a pulse-coupled network (PCN) of spiking oscillators (SOCs) which can be implemented as a simple electrical circuit. The SOC has a periodic reset level that can realize rich dynamics represented by chaotic spike-trains. Applying a spike-train input, the PCN can exhibit the following interesting phenomena. 1) Each SOC synchronizes with a part of the input without overlapping, i.e., the input is decomposed. 2) Some SOCs synchronize with a part of the input with overlapping, i.e., the input is decomposed and the SOCs are clustered. The PCN has multiple synchronization phenomena and exhibits one of them depending on the initial state. We clarify the numbers of the synchronization phenomena and the parameter regions in which these phenomena can be observed. Also stability of the synchronization phenomena is clarified. Presenting a simple test circuit, typical phenomena are confirmed experimentally.

Action Potentials↗
PubMed1997

Identification, prevalence and aspects of molecular biology of hepatitis G virus.

Hepatitis G virus (HGV) is a newly identified member of the Flaviviridae family. The positive-sense RNA genome of the virus contains a single open reading frame that encodes the viral polyprotein. Its genomic organization is similar to that of the hepatitis C virus (HCV) with which it has only 25% homology at the nucleotide level. Nucleotide sequences from the NS-3 helicase region of HCV varied by 10-30%. HGV is therefore much less variable than HCV. Construction of phylogenetic trees, and calculation of mean distances between possible subtypes, indicated one level of variation in NS-3 sequences: the degree of variation between isolates was similar to that observed between HCV subtypes. Thus no evidence for clustering of sequences into multiple genotypes was found. The virus is transmissible through blood transfusion and by exposure to blood products or intravenous drug use, and may result in acute or chronic hepatitis. A causative role of HGV in acute and chronic hepatitis is not yet established. Concurrent infection with hepatitis B virus (HBV) and HCV is common and persistent viraemia has been documented for many years, in many cases, in the absence of transaminase elevations.

Antiviral Agents↗
PubMed1990

Structural characterization of the human DNA topoisomerase I gene promoter.

We have isolated a genomic DNA fragment from HeLa cells containing the promoter region and the first two exons of the human gene encoding DNA topoisomerase I (hTOP1). Transcription of hTOP1 mRNA initiates at multiple sites which are clustered 247 nucleotides and 210 nucleotides upstream of the translation-initiation site of the protein coding region. The nucleotide sequence of the region preceding the transcription-initiation sites is G/C rich and contains sequence motifs which are known binding sites of the transcription factors Oct1 (octameric transcription factor 1), Sp1 and AP2 (activator protein 2). Furthermore, one cAMP-responsive element is present 50 nucleotides upstream of the transcription-initiation site nearest the 5' end. Neither TATA nor CAAT boxes were found in the promoter region of the hTOP1 gene. A 918-bp fragment containing the sequence elements described above drives the transient expression of a chloramphenicol acetyl transferase (CAT) gene sequence in transfected HeLa and 293 cells. In addition we analyzed a 10-kb fragment containing the promoter and exons 1 and 2 for regions of DNase I hypersensitivity. We detected one prominent DNase-I-hypersensitive region in the promoter close to the putative transcription-factor-binding sites and several weaker regions in intron 2.

Autoradiography↗
PubMed2006

Behaviour during attacks and assessment of intensity in primary headaches of children and adolescents.

Assessment of attack intensity in primary headaches of paediatric age has not received great attention in the literature to date and in the international classification the criteria to define pain intensity are also not specified. The purpose of this research was to evaluate whether behaviour during attacks, reported by the child or a parent, can be used as a measure of attack disability, and so as an indirect measure of attack intensity in primary headaches of children and adolescents. The subjects were 320 patients aged between 3 and 14 years (mean age 9.9 years, SD 2.6 years) affected by primary recurrent headaches and first seen at a headache clinic. Twelve variables taken from their history were considered and sequentially analysed with multiple correspondence analysis and cluster analysis. Five types of behaviour during attacks were identified: (i) the child (or the parent) is unable to answer the questions or the child has no limitation in activities; (ii) the child may have some activity limitation, but only in lively games; (iii) the child has limitations in daily life with regard also to quiet activities; (iv) at least during some attacks the child lies down with closed eyes or in the dark; (v) during each attack the child lies down with closed eyes or in the dark. The least important variables for the identification of the five behaviour types were studying at school and absence from school. There are some limitations in considering child's behaviour as a measure of attack intensity/disability; one of these is the fact that it was found to be related to the educational level of the mother. However, behaviour during attacks, reported by the child or the parent, provides useful information independently of child's age and, together with the score of pain, when this is given, it can be used as measure of attack intensity.

Adolescent↗
PubMed2006

Assessment of fecal pollution sources in a small northern-plains watershed using PCR and phylogenetic analyses of Bacteroidetes 16S rRNA gene.

We evaluated the efficacy, sensitivity, host-specificity, and spatial/temporal dynamics of human- and ruminant-specific 16S rRNA gene Bacteroidetes markers used to assess the sources of fecal pollution in a fecally impacted watershed. Phylogenetic analyses of 1271 fecal and environmental 16S rRNA gene clones were also performed to study the diversity of Bacteroidetes in this watershed. The host-specific assays indicated that ruminant feces were present in 28-54% of the water samples and in all sampling seasons, with increasing frequency in downstream sites. The human-targeted assays indicated that only 3-5% of the water samples were positive for human fecal signals, although a higher percentage of human-associated signals (19-24%) were detected in sediment samples. Phylogenetic analysis indicated that 57% of all water clones clustered with yet-to-be-cultured Bacteroidetes species associated with sequences obtained from ruminant feces, further supporting the prevalence of ruminant contamination in this watershed. However, since several clusters contained sequences from multiple sources, future studies need to consider the potential cosmopolitan nature of these bacterial populations when assessing fecal pollution sources using Bacteroidetes markers. Moreover, additional data is needed in order to understand the distribution of Bacteroidetes host-specific markers and their relationship to water quality regulatory standards.

Animals↗
PubMed2005

Mass screening for antimicrobial resistant Escherichia coli in dairy cows in northern New South Wales.

OBJECTIVE: To describe aspects of the epidemiology of antimicrobial resistance in Escherichia coli shed in the faeces of milking cows in a dairying region of New South Wales. DESIGN: A survey based on multi-stage sampling with repeated measures made within herds for estimating within-herd correlation of resistance status, and with repeated measures made on identical specimens for estimating test-retest reliability. PROCEDURE: From a population of 110 dairy herds, 30 were selected at random and from each herd between 5 and 10 faecal specimens were obtained from fresh manure pats. E coli from faecal specimens were grown on hydrophobic grid membrane filters (HGMF) and replicated onto chromogenic agar and agar containing antimicrobials (gentamicin, ampicillin, tetracycline and sulfamethoxazole). Image analysis was used to assess colony growth. Data were analysed descriptively, by generalised linear mixed models and by Taylor series linearisation to account for attributes of the survey design. RESULTS: Of the 10,279 E coli isolates assessed, 91% expressed no resistance, 7.3% were resistant to sulfamethoxazole, 3.6% to tetracycline, 2.2% to ampicillin and 0.09% to gentamicin. The most common multiple resistance phenotype was ampicillin-tetracycline-sulfamethoxazole (1.8% of isolates). Most multiple resistant isolates appeared clustered within particular herds but were too rare to obtain valid estimates of variance, confidence intervals or intra-herd correlation. The estimated proportion of isolates in the population that were susceptible to all four antimicrobials was 97% (95% CI: 91% to 100%) and 55% of cows had no resistance detected in faecal E coli (95% CI: 27% to 83%). Within-herd correlation of shedding status (any resistance pattern) was absent and test-retest reliability of the measurement system was estimated to be at the lower end of good (0.40) but increased to excellent (0.89) after excluding sulfamethoxazole resistance, which had a greater measurement error. CONCLUSION: Antimicrobial resistance was uncommon in E coli in the population of dairy cows studied. HGMF and image analysis is an effective tool for detecting rare forms of resistant E coli that are not uniformly distributed in livestock populations.

Animals↗
PubMed1990

The activation of calcium and calcium-activated potassium channels in mammalian colonic smooth muscle by substance P.

1. The regulation of Ca2(+)-activated K+ channels by the agonist substance P in freshly dissociated smooth muscle cells from the rabbit longitudinal colonic muscle was characterized using the patch clamp technique. 2. In the cell-attached recording mode, when pipette and bath solutions contained equal [K+] (126 mM), the Ca2(+)-activated K+ channels showed a linear current-voltage relationship (between -50 mV and 50 mV) with a slope conductance of 210 +/- 35 pS (n = 12). Reversal potential measurements indicated that the channel was highly selective for K+ over Na+ (PK/PNa = 110). 3. Channels were activated by depolarizing membrane voltages and cytosolic Ca2+, and in inside-out patches channel activation depended sigmoidally on voltage and [Ca2+]. The potential for half-activation at a cytosolic [Ca2+] of 5 x 10(-6) M was 0 mV. A tenfold increase in cytosolic Ca2+ resulted in a 60 mV shift of the sigmoidal voltage activation curve to more negative potentials. 4. Threshold concentrations of substance P (10(-12) M), which did not result in cell contraction, caused a prolonged activation of K+ channels. The K+ channels were observed to open in clusters: simultaneous opening of multiple channels was interrupted by complete, prolonged channel closure. 5. Lowering bath [Ca2+] to submicromolar concentrations abolished the effect of substance P. The activation of K+ channels by substance P (10(-12) M) was also inhibited by the dihydropyridine nifedipine (10(-6) M), a blocker of L-type Ca2+ channels. 6. In the whole-cell recording mode, with the pipette solution containing 126 mM-KCl, 0.77 mM-EGTA and 1 mM-ATP, depolarization from a holding potential of -70 mV elicited outward currents which increased to steady-state values. These were K+ currents as they were blocked by TEA (tetraethylammonium, 30 mM) and Ba2+ (1 mM) and were abolished when pipette K+ was replaced by Cs+. 7. The depolarization-activated outward current was not affected by lowering extracellular [Ca2+] or by the Ca2+ channel antagonists Cd2+ (200 microM), nifedipine (10(-6)-10(-5) M) or verapamil (10(-6) M). The current was greatly reduced when the EGTA concentration in the pipette solution was increased from 0.77 to 10 mM. 8. When the pipette solution contained CsCl, membrane depolarization activated inward currents. The peak inward current was identified as current through L-type Ca2+ channels based on its voltage- and time-dependent kinetics, and its modulation by dihydropyridines.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2006

Frictional afterslip following the 2005 Nias-Simeulue earthquake, Sumatra.

Continuously recording Global Positioning System stations near the 28 March 2005 rupture of the Sunda megathrust [moment magnitude (Mw) 8.7] show that the earthquake triggered aseismic frictional afterslip on the subduction megathrust, with a major fraction of this slip in the up-dip direction from the main rupture. Eleven months after the main shock, afterslip continues at rates several times the average interseismic rate, resulting in deformation equivalent to at least a M(w) 8.2 earthquake. In general, along-strike variations in frictional behavior appear to persist over multiple earthquake cycles. Aftershocks cluster along the boundary between the region of coseismic slip and the up-dip creeping zone. We observe that the cumulative number of aftershocks increases linearly with postseismic displacements; this finding suggests that the temporal evolution of aftershocks is governed by afterslip.

Journal Article↗
PubMed2006

GliZ, a transcriptional regulator of gliotoxin biosynthesis, contributes to Aspergillus fumigatus virulence.

Gliotoxin is a nonribosomal peptide produced by Aspergillus fumigatus. This compound has been proposed as an A. fumigatus virulence factor due to its cytotoxic, genotoxic, and apoptotic properties. Recent identification of the gliotoxin gene cluster identified several genes (gli genes) likely involved in gliotoxin production, including gliZ, encoding a putative Zn(2)Cys(6) binuclear transcription factor. Replacement of gliZ with a marker gene (DeltagliZ) resulted in no detectable gliotoxin production and loss of gene expression of other gli cluster genes. Placement of multiple copies of gliZ in the genome increased gliotoxin production. Using endpoint survival data, the DeltagliZ and a multiple-copy gliZ strain were not statistically different from the wild type in a murine pulmonary model; however, both the wild-type and the multiple-copy gliZ strain were more virulent than DeltalaeA (a mutant reduced in production of gliotoxin and other toxins). A flow-cytometric analysis of polymorphonuclear leukocytes (PMNs) exposed to supernatants from wild-type, DeltagliZ, complemented DeltagliZ, and DeltalaeA strains supported a role for gliotoxin in apoptotic but not necrotic PMN cell death. This may indicate that several secondary metabolites are involved in A. fumigatus virulence.

Animals↗
PubMed1998

Characterization of unusual escape variants of hepatitis B virus isolated from a hepatitis B surface antigen-negative subject.

Hepatitis B virus DNA was extracted from serial serum samples of a hepatitis B surface antigen-negative patient with antibodies to the core protein as the only marker of an infection with hepatitis B virus. This patient showed no symptoms of hepatic injury. Sequencing of the amplified viral DNA demonstrated multiple amino acid changes clustering in surface-exposed regions of the surface protein. Synthesis and association of the middle (M) and small (S) surface proteins could be shown in vitro. The variant surface antigens were recognized neither by monoclonal antibodies to the surface antigen nor by the vaccinee's sera. Consequences for hepatitis B surface antigen testing and vaccine development are discussed.

Amino Acid Sequence↗
PubMed1997

Expressed var genes are found in Plasmodium falciparum subtelomeric regions.

The antigenic variation and cytoadherence of Plasmodium falciparum-infected erythrocytes are modulated by a family of variant surface proteins encoded by the var multigene family. The var genes occur on multiple chromosomes, often in clusters, and 50 to 150 genes are estimated to be present in the haploid parasite genome. Transcripts from var genes have been previously mapped to internal chromosome positions, but the generality of such assignments and the expression sites and mechanisms that control switches of var gene expression are still in early stages of investigation. Here we describe investigations of closely related var genes that occur in association with repetitive elements near the telomeres of P. falciparum chromosomes. DNA sequence analysis of one of these genes (FCR3-varT11-1) shows the characteristic two-exon structure encoding expected var features, including three variable Duffy binding-like (DBL) domains, a transmembrane sequence, and a carboxy-terminal segment thought to anchor the protein product in knobs at the surface of the parasitized erythrocyte. FCR3-varT11-1 cross-hybridizes with var genes located close to the telomeres of many other P. falciparum chromosomes, including a transcribed gene (FCR3-varT3-1) in chromosome 3 of the P. falciparum FCR3 line. The relatively high level transcription from this gene shows that the polymorphic chromosome ends of P. falciparum, which have been proposed to be transcriptionally silent, can be active expression sites for var genes. The pattern of the FCR3-varT11-1 and FCR3-varT3-1 genes are variable between different P. falciparum lines, presumably due to DNA rearrangements. Thus, recombination events in subtelomeric DNA may have a role in the expression of novel var forms.

Amino Acid Sequence↗
PubMed2005

Analysis of somatic molecular changes, clinicopathological features, family history, and germline mutations in colorectal cancer families: evidence for efficient diagnosis of HNPCC and for the existence of distinct groups of non-HNPCC families.

OBJECTIVE: To analyse somatic molecular changes, clinicopathological features, family history, and germline mutations in families with colorectal cancer (CRC). METHODS: Molecular changes (K-ras and beta-catenin mutations, chromosome 18q allele loss (LOH), APC LOH, microsatellite instability (MSI), and expression of beta-catenin and p53) were examined in four series of CRC patients with proven or probable hereditary disease: hereditary non-polyposis colon cancer (HNPCC); MYH associated polyposis (MAP); multiple (>5) colorectal adenomas without familial adenomatous polyposis (FAP); and other families/cases referred to family cancer clinics (FCC series). HNPCC was diagnosed using a combination of germline mutation screening and tumour studies. A series of unselected CRC patients was also studied. RESULTS: There was overlap between genetic pathways followed by each type of CRC, but significant differences included: increased frequency of K-ras mutation and reduced frequency of APC LOH in cancers from MAP, but not from multiple adenoma patients; reduced frequency of LOH in HNPCC CRCs; and increased MSI in CRCs from HNPCC, but not from FCC or multiple adenoma patients. HNPCC was apparently detected efficiently by combined germline and somatic analysis. Cancers from the FCC, unselected, and multiple adenoma series shared similar molecular characteristics. In the FCC and multiple adenoma series, hierarchical cluster analysis using the molecular features of the cancers consistently identified two distinct groups, distinguished by presence or absence of K-ras mutation. CONCLUSIONS: While K-ras mutation status is known to differentiate hereditary bowel cancer syndromes such as MAP and FAP, it may also distinguish groups of non-HNPCC, FCC patients whose disease has different, as yet unknown, genetic origins.

Adult↗
PubMed1995

Antihypertensive therapy in dyslipidemic men. Effects on coronary heart disease incidence and total mortality.

To investigate the influence of antihypertensive therapy and the success of blood pressure control on coronary heart disease incidence and total mortality, we studied dyslipidemic middle-aged men participating in the placebo arm of the Helsinki Heart Study, a randomized coronary primary prevention trial with gemfibrozil. Based on blood pressure level and the presence of antihypertensive therapy at study entry, the participants were classified into four categories. Relative risks of coronary heart disease (nonfatal myocardial infarction or cardiac death) and total mortality during the 5-year trial period were calculated using Cox proportional hazards models. With subjects who were not using antihypertensive drugs and who had normal blood pressure (category I) as reference, the relative risks of coronary heart disease during the trial period were 2.1 (95% confidence interval [CI], 1.3 to 3.3) in untreated hypertensive subjects (category II), 0.9 (95% CI, 0.2 to 3.8) in subjects with successful antihypertensive therapy (category III), and 2.0 (95% CI, 1.0 to 4.1) in subjects who remained hypertensive despite drug therapy (category IV). The relative risks of death were 1.9 (95% CI, 0.9 to 3.9) in category II and 1.0 (95% CI, 0.1 to 7.3) in category III; in category IV subjects, those with unsuccessful antihypertensive therapy, the relative risk was 4.4 (95% CI, 2.0 to 9.6). The excess mortality in this category was due to cardiovascular causes and was clustered in subjects with multiple drug therapy for hypertension control. We conclude that successful antihypertensive therapy in dyslipidemic men reduced coronary heart disease incidence despite its adverse effects on high-density lipoprotein cholesterol and triglycerides.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive Agents↗
PubMed2006

White matter alterations in cerebral amyloid angiopathy measured by diffusion tensor imaging.

BACKGROUND AND PURPOSE: Cerebral amyloid angiopathy (CAA) represents beta-amyloid deposition in the small- and medium-sized vessels of the brain and meninges. CAA contributes to altered vessel function and is associated with white matter damage, cognitive impairment, and most salient, hemorrhagic stroke. We used diffusion tensor imaging to evaluate the anatomic distribution of white matter degeneration in participants diagnosed with advanced CAA. METHODS: Diffusion tensor imaging was obtained from 11 participants diagnosed with CAA-related intracerebral hemorrhage and 13 matched healthy control participants. Fractional anisotropy (FA) and diffusivity maps were compared using voxel based t test and region-of-interest analyses. RESULTS: FA was reduced in CAA in temporal white matter and in the splenium of the corpus callosum (P<0.001 with approximately 17% reduction in temporal white matter and 15% reduction in the splenium). FA was marginally increased in CAA in the posterior limb of the internal capsule and subthalamic gray matter regions (approximately 7% increase in subthalamic gray). FA changes were bilateral, remained significant in cluster analysis controlling for multiple comparisons, and did not depend on the hemisphere of the cerebral hemorrhage. Diffusivity was not substantially altered. CONCLUSIONS: These findings suggest that a pattern of regional brain tissue degeneration is a characteristic feature of advanced CAA.

Aged↗
PubMed2006

Induction of myasthenia by immunization against muscle-specific kinase.

Muscle-specific kinase (MuSK) is critical for the synaptic clustering of nicotinic acetylcholine receptors (AChRs) and plays multiple roles in the organization and maintenance of neuromuscular junctions (NMJs). MuSK is activated by agrin, which is released from motoneurons, and induces AChR clustering at the postsynaptic membrane. Although autoantibodies against the ectodomain of MuSK have been found in a proportion of patients with generalized myasthenia gravis (MG), it is unclear whether MuSK autoantibodies are the causative agent of generalized MG. In the present study, rabbits immunized with MuSK ectodomain protein manifested MG-like muscle weakness with a reduction of AChR clustering at the NMJs. The autoantibodies activated MuSK and blocked AChR clustering induced by agrin or by mediators that do not activate MuSK. Thus MuSK autoantibodies rigorously inhibit AChR clustering mediated by multiple pathways, an outcome that broadens our general comprehension of the pathogenesis of MG.

Agrin↗
PubMed1994

Health consciousness in relation to education in Korea--focusing on seven preventable health risk factors.

This research was carried out to investigate the relationships of a set of several selected sociodemographic variables with a group of health-related practices with special emphasis on educational attainment. The sample consisted of 5,245 adults aged 20-59 selected through stratified cluster random sampling. Univariate, multiple logistic regression and canonical correlation procedures were employed for analyses. It was found that educational attainment was independently associated with at-risk health behavior; the less educated had less desirable health habits than the more educated. Pattern of at-risk health behavior varied with educational level; the significant health-related practice variables among the seven factors were cigarette smoking, heavy alcohol drinking, physical inactivity, being overweight, and inadequate sleeping. These findings suggested that the less educated should be given higher priority in health education programs for the identified health risk behavior and in the formulation of related health policies.

Adult↗
PubMed2004

Identification of endogenous retroviral reading frames in the human genome.

BACKGROUND: Human endogenous retroviruses (HERVs) comprise a large class of repetitive retroelements. Most HERVs are ancient and invaded our genome at least 25 million years ago, except for the evolutionary young HERV-K group. The far majority of the encoded genes are degenerate due to mutational decay and only a few non-HERV-K loci are known to retain intact reading frames. Additional intact HERV genes may exist, since retroviral reading frames have not been systematically annotated on a genome-wide scale. RESULTS: By clustering of hits from multiple BLAST searches using known retroviral sequences we have mapped 1.1% of the human genome as retrovirus related. The coding potential of all identified HERV regions were analyzed by annotating viral open reading frames (vORFs) and we report 7836 loci as verified by protein homology criteria. Among 59 intact or almost-intact viral polyproteins scattered around the human genome we have found 29 envelope genes including two novel gammaretroviral types. One encodes a protein similar to a recently discovered zebrafish retrovirus (ZFERV) while another shows partial, C-terminal, homology to Syncytin (HERV-W/FRD). CONCLUSIONS: This compilation of HERV sequences and their coding potential provide a useful tool for pursuing functional analysis such as RNA expression profiling and effects of viral proteins, which may, in turn, reveal a role for HERVs in human health and disease. All data are publicly available through a database at http://www.retrosearch.dk.

Codon↗