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PubMed2002

Hand preference and hand skill in families with schizophrenia.

Direction and degree of handedness in humans are variable between individuals and thought to be in part inherited. Several studies have shown an increase in non-right handedness among patients with schizophrenia, and some have included unaffected relatives. The present study was designed to determine whether reduced right handedness is more frequent among individuals with schizophrenia as compared with their well relatives and whether it clusters within families having multiple ill members. A total of 259 families comprising 418 individuals diagnosed with schizophrenia or schizoaffective disorder, 54 individuals with other psychoses, 145 family members with depression and other minor diagnoses, and 288 unaffected individuals were included. Hand preference was assessed by the Annett Scale and right relative to left hand skill measured using the Tapley-Bryden test. For all assessments of hand preference and hand skill, females were significantly more lateralised towards the right than males. Those individuals with schizophrenia or schizoaffective disorder had significantly less right hand preference than their unaffected relatives when measured as a quantitative index of items from the Annett Scale (p = .019), but not categorically (right, left or mixed). In contrast, there was no difference in hand skill between diagnostic groups. Hand preference was significantly correlated among male-male affected sibling pairs (p = .01) and similar results were found for hand skill among the total group of affected pairs (p = .001). Although these results only partially support a relationship between handedness and schizophrenia, they nevertheless draw attention to sex differences in hand preference and the familial aspects of hand preference in this disorder. More direct approaches to the genetics of cerebral dominance and psychosis are required.

Journal Article↗
PubMed1999

Peopling of Sahul: mtDNA variation in aboriginal Australian and Papua New Guinean populations.

We examined genetic affinities of Aboriginal Australian and New Guinean populations by using nucleotide variation in the two hypervariable segments of the mtDNA control region (CR). A total of 318 individuals from highland Papua New Guinea (PNG), coastal PNG, and Aboriginal Australian populations were typed with a panel of 29 sequence-specific oligonucleotide (SSO) probes. The SSO-probe panel included five new probes that were used to type an additional 1,037 individuals from several Asian populations. The SSO-type data guided the selection of 78 individuals from Australia and east Indonesia for CR sequencing. A gene tree of these CR sequences, combined with published sequences from worldwide populations, contains two previously identified highland PNG clusters that do not include any Aboriginal Australians; the highland PNG clusters have coalescent time estimates of approximately 80,000 and 122,000 years ago, suggesting ancient isolation and genetic drift. SSO-type data indicate that 84% of the sample of PNG highlander mtDNA belong to these two clusters. In contrast, the Aboriginal Australian sequences are intermingled throughout the tree and cluster with sequences from multiple populations. Phylogenetic and multidimensional-scaling analyses of CR sequences and SSO types split PNG highland and Aboriginal Australian populations and link Aboriginal Australian populations with populations from the subcontinent of India. These mtDNA results do not support a close relationship between Aboriginal Australian and PNG populations but instead suggest multiple migrations in the peopling of Sahul.

Africa↗
PubMed2002

Epidemiologic and molecular trends of "Norwalk-like viruses" associated with outbreaks of gastroenteritis in the United States.

Between July 1997 and June 2000, fecal specimens from 284 outbreaks of nonbacterial gastroenteritis were submitted to the Centers for Disease Control and Prevention for testing for "Norwalk-like viruses" (NLVs). Specimens were examined by reverse-transcription polymerase chain reaction and direct electron microscopy for the presence of NLVs. Adequate descriptive data were available from 233 of the outbreaks, and, of these, 217 (93%) were positive for NLVs. Restaurants and events with catered food were the most common settings, and contaminated food was the most common mode of transmission. Genogroup II (GII) strains were the predominant type (73%), with genogroup I strains causing 26% of all NLV-positive outbreaks. Certain GII clusters (GII/1,4,j) were more commonly associated with outbreaks in nursing home settings than with outbreaks in other settings. Strain diversity was great: one potential new sequence cluster was implicated in multiple outbreaks, and strains belonging to a tentative new genogroup were identified.

Adolescent↗
PubMed2004

Predicting allergenic proteins using wavelet transform.

MOTIVATION: With many transgenic proteins introduced today, the ability to predict their potential allergenicity has become an important issue. Previous studies were based on either sequence similarity or the protein motifs identified from known allergen databases. The similarity-based approaches, although being able to produce high recalls, usually have low prediction precisions. Previous motif-based approaches have been shown to be able to improve the precisions on cross-validation experiments. In this study, a system that combines the advantages of similarity-based and motif-based prediction is described. RESULTS: The new prediction system uses a clustering algorithm that groups the known allergenic proteins into clusters. Proteins within each cluster are assumed to carry one or more common motifs. After a multiple sequence alignment, proteins in each cluster go through a wavelet analysis program whereby conserved motifs will be identified. A hidden Markov model (HMM) profile will then be prepared for each identified motif. The allergens that do not appear to carry detectable allergen motifs will be saved in a small database. The allergenicity of an unknown protein may be predicted by comparing it against the HMM profiles, and, if no matching profiles are found, against the small allergen database by BLASTP. Over 70% of recall and over 90% of precision were observed using cross-validation experiments. Using the entire Swiss-Prot as the query, we predicted about 2000 potential allergens. AVAILABILITY: The software is available upon request from the authors.

Algorithms↗
PubMed2005

A comprehensive and non-redundant database of protein domain movements.

MOTIVATION: The current DynDom database of protein domain motions is a user-created database that suffers from selectivity and redundancy. The aim of the analysis presented here was to overcome both these limitations and to produce both a comprehensive and a non-redundant description of domain movements from structures stored in the current protein data bank. RESULTS: A multi-step procedure is applied that starts with grouping proteins in the structural databank into families based on sequence similarity. Multiple sequence alignment, conformational clustering and a dimensional clustering method based on the Gram-Schmidt algorithm are applied to members of each family to remove dynamic redundancy in their domain movements. Representative domain movements are described in terms of domains, hinge axes and hinge-bending residues using the DynDom program. The results show that within an average family of 11.5 members, there are on average only 1.31 different domain movements indicating a high redundancy in the movements these structures represent. This verifies earlier findings that domain movements are usually highly controlled. Despite the removal of this considerable redundancy, the process has resulted in double the number of domain movements stored in the user-created database. The data are organized in a relational database with a web-interface. AVAILABILITY: The database can be browsed and searched at http://www.cmp.uea.ac.uk/dyndom CONTACT: sjh@cmp.uea.ac.uk.

Algorithms↗
PubMed1993

Methicillin-sensitive and -resistant homologues of Staphylococcus aureus occur together among clinical isolates.

Clinical isolates of Staphylococcus aureus collected from hospitals in Australia were analyzed for genetic similarities using restriction fragment length polymorphisms. Methicillin-resistant (Mcr) isolates from Melbourne (1982) and from Hobart (1986) were closely related to a methicillin-multiresistant S. aureus (MRSA) strain, ANS46, originally isolated in Melbourne in 1982 and studied extensively since. Methicillin-sensitive (Mcs) isolates were isolated concurrently with the Melbourne and Hobart Mcr isolates. These were found to be similar to induced Mcs variants of ANS46; these laboratory variants have lost approximately 40-70 kb of DNA carrying multiple resistance (R) determinants clustered around the mec gene. The Melbourne and Hobart Mcs isolates appear to be natural variants lacking this region of their chromosome. A clinical Mcr and Mcs pair of isolates differing only in the presence of an R-cluster near the mec gene were also isolated in Melbourne in 1990; these are not of the same clonal line as the earlier types from Melbourne and Hobart. These data suggest that insertion or deletion (or both) similar to that produced by known mutagens occurs in the mec region of the chromosome of MRSA in clinical populations under natural selective pressures; such processes may be important in the balance of resistant and sensitive staphylococci in hospitals and other clinical environments.

Australia↗
PubMed2000

Discovering regulatory elements in non-coding sequences by analysis of spaced dyads.

The application of microarray and related technologies is currently generating a systematic catalog of the transcriptional response of any single gene to a multiplicity of experimental conditions. Clustering genes according to the similarity of their transcriptional response provides a direct hint to the regulons of the different transcription factors, many of which have still not been characterized. We have developed a new method for deciphering the mechanism underlying the common transcriptional response of a set of genes, i.e. discovering cis -acting regulatory elements from a set of unaligned upstream sequences. This method, called dyad analysis, is based on the observation that many regulatory sites consist of a pair of highly conserved trinucleotides, spaced by a non-conserved region of fixed width. The approach is to count the number of occurrences of each possible spaced pair of trinucleotides, and to assess its statistical significance. The method is highly efficient in the detection of sites bound by C(6)Zn(2)binuclear cluster proteins, as well as other transcription factors. In addition, we show that the dyad and single-word analyses are efficient for the detection of regulatory patterns in gene clusters from DNA chip experiments. In combination, these programs should provide a fast and efficient way to discover new regulatory sites for as yet unknown transcription factors.

Base Sequence↗
PubMed2002

Distinct proteins encoded by alternative transcripts of the PURG gene, located contrapodal to WRN on chromosome 8, determined by differential termination/polyadenylation.

A gene encoding a new member of the Pur protein family, Purgamma, has been detected upstream of, and contrapodal to, the gene encoding the Werner syndrome helicase, Wrn, at human chromosome band 8p11-12. Both the PURG and WRN genes initiate transcription at multiple sites, the major clusters of which are approximately 90 bp apart. A segment containing this region strongly promotes transcription of a reporter gene in both directions. Both promoters are TATA-less and CAAT-less and both are positively regulated by Sp1 elements. While promoter elements for the two genes are interleaved, in the contrapodal direction, certain elements critical for each gene are distinct. Sequencing of cDNAs for Purgamma mRNA reveals that two alternative coding sequences are generated from a single gene, resulting in different Purgamma C-termini. PURG-A mRNA consists of a single intronless transcript of approximately 3 kb. PURG-B mRNA results from transcription through the PURG-A polyadenylation site and splicing out of an intron of >30 kb. In this unique example of a switch, splicing of a single intron either occurs or does not occur depending upon differential termination/polyadenylation. PURG-B is the primary PURG transcript detected in testis, but it is undetectable in all members of a normal adult tissue cDNA panel. PURG-A levels are low or undetectable in the normal tissue panel, but they are greatly elevated in all members of a tumor tissue panel. PURG-B is detected in several tumor panel members.

5' Untranslated Regions↗
PubMed2006

The fidelity of DNA synthesis by yeast DNA polymerase zeta alone and with accessory proteins.

DNA polymerase zeta (pol zeta) participates in several DNA transactions in eukaryotic cells that increase spontaneous and damage-induced mutagenesis. To better understand this central role in mutagenesis in vivo, here we report the fidelity of DNA synthesis in vitro by yeast pol zeta alone and with RFC, PCNA and RPA. Overall, the accessory proteins have little effect on the fidelity of pol zeta. Pol zeta is relatively accurate for single base insertion/deletion errors. However, the average base substitution fidelity of pol zeta is substantially lower than that of homologous B family pols alpha, delta and epsilon. Pol zeta is particularly error prone for substitutions in specific sequence contexts and generates multiple single base errors clustered in short patches at a rate that is unprecedented in comparison with other polymerases. The unique error specificity of pol zeta in vitro is consistent with Pol zeta-dependent mutagenic specificity reported in vivo. This fact, combined with the high rate of single base substitution errors and complex mutations observed here, indicates that pol zeta contributes to mutagenesis in vivo not only by extending mismatches made by other polymerases, but also by directly generating its own mismatches and then extending them.

Base Sequence↗
PubMed1998

Dysfunctions in multiple interrelated systems as the neurobiological bases of schizophrenic symptom clusters.

The absence of an animal model that accurately approximates schizophrenia limits current research into the pathophysiology of this disorder. Obviously, the cognitive disturbances associated with schizophrenia are difficult to evaluate in laboratory animals. Nonetheless, animal studies have provided insight into the anatomy and physiology of the brain systems that have been implicated in schizophrenia. These studies also suggest how brain systems may be involved in information processing in normal and pathological conditions. Thus, a careful assessment of the properties and functions of the brain regions suggested to be involved in schizophrenic symptoms has been a primary objective in several laboratories. In this review, we discuss the interactions among the brain regions implicated in schizophrenia--the ventral striatum, prefrontal cortex, hippocampus, and dopamine systems--and provide an integrative model linking altered function in these regions with specific clusters of symptoms of schizophrenia.

Animals↗
PubMed2000

On the spatial disposition of the fifth transmembrane helix and the structural integrity of the transmembrane binding site in the opioid and ORL1 G protein-coupled receptor family.

Evidence from statistical cluster analyses of a multiple sequence alignment of G protein-coupled receptor seven-helix folds supports the existence of structurally conserved transmembrane (TM) ligand binding sites in the opioid/opioid receptor-like (ORL1) and amine receptor families. Based on the expectation that functionally conserved regions in homologous proteins will display locally higher levels of sequence identity compared with global sequence similarities that pertain to the overall fold, this approach may have wider applications in functional genomics to annotate sequence data. Binding sites in models of the kappa-opioid receptor seven-helix bundle built from the rhodopsin templates of Baldwin et al. (1997) [J. Mol. Biol., 272, 144-164] and Herzyk and Hubbard (1998) [J. Mol. Biol., 281, 742-751] are compared. The Herzyk and Hubbard template is found to be in better accord with experimental studies of amine, opioid and rhodopsin receptors owing to the reduced physical separation of the extracellular parts of TM helices V and VI and differences in the rotational orientation of the N-terminal of helix V that reveal side chain accessibilities in the Baldwin et al. structure to be out of phase with relative alkylation rates of engineered cysteine residues in the TM binding site of the alpha(2A)-adrenergic receptor. TM helix V in the Baldwin et al. template has been remodelled with a different proline kink to satisfy experimental constraints. A recent proposal that rotation of helix V is associated with receptor activation is critically discussed.

Binding Sites↗
PubMed1992

Classification of nonspecific low back pain. I. Psychological involvement in low back pain. A clinical, descriptive approach.

An unselected sample of outpatient subjects (n = 330) with localized nonspecific low back pain (LBP) was studied. Investigation consisted of clinical assessment, physical examination, and psychiatric interview based on the DSM-III classification. A psychiatric disorder, according to the DSM-III criteria (axis I) was found in 41% of the subjects. Multiple correspondence analysis and cluster analysis were used to objectively identify clinical subtypes without preconceived theoretical models. Correspondence analyses suggested the existence of a 'psychological pain' syndrome consisting of several of the following symptoms: diffuse back pain, impossibility to assess intensity of pain on a pain scale, aggravation of pain by changing climate, by domestic activities or by psychological factors and dysesthesias in the back. Cluster analysis provided support for a four-group classification of low back pain, which may be interpreted through the relationships between psychological disturbances and the LBP clinical features. The results call for further investigation of the complex relationship between psychological disturbances and back pain. However, clinicians must be aware of the interest of a minimal psychiatric assessment in low back pain patients: psychiatric disorders frequently appear in these patients and an appropriate treatment of the psychiatric syndrome may reduce back pain.

Adolescent↗
PubMed2004

Association of GABRG3 with alcohol dependence.

BACKGROUND: Evidence from human, animal, and in vitro cell models suggests that gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the human central nervous system, is involved in many of the neurochemical pathways that affect alcohol use, abuse, and dependence. Both linkage and association to the region on chromosome 15q that contains a cluster of GABAA receptor genes have previously been reported, but the role of these genes in alcoholism remains inconclusive. METHODS: We conducted family-based association analyses by using a large sample of multiplex alcoholic families collected as part of the Collaborative Study on the Genetics of Alcoholism, to test for an association between alcohol dependence and the GABAA receptor genes clustered on chromosome 15q. Multiple single-nucleotide polymorphisms were tested in each of the three chromosome 15q GABAA receptor genes: GABRA5, GABRB3, and GABRG3. RESULTS: Using both classic trio-based analyses and extended-family analyses, we found consistent evidence of association between alcohol dependence and GABRG3. Nearly all single-nucleotide polymorphisms across the gene yielded evidence of association, and haplotype analyses were highly significant. No consistent evidence of association was observed with either GABRA5 or GABRB3, nor was there evidence for parent-of-origin effects with any of the genes. CONCLUSIONS: These analyses suggest that GABRG3 may be involved in the risk for alcohol dependence. These findings support the theory that the predisposition to alcoholism may be inherited as a general state of central nervous system disinhibition/hyperexcitability that results from an altered responsiveness to GABA.

Alcoholism↗
PubMed2006

Rapid atrophy of the lumbar multifidus follows experimental disc or nerve root injury.

STUDY DESIGN: Experimental study of muscle changes after lumbar spinal injury. OBJECTIVES: To investigate effects of intervertebral disc and nerve root lesions on cross-sectional area, histology and chemistry of porcine lumbar multifidus. SUMMARY OF BACKGROUND DATA: The multifidus cross-sectional area is reduced in acute and chronic low back pain. Although chronic changes are widespread, acute changes at 1 segment are identified within days of injury. It is uncertain whether changes precede or follow injury, or what is the mechanism. METHODS: The multifidus cross-sectional area was measured in 21 pigs from L1 to S1 with ultrasound before and 3 or 6 days after lesions: incision into L3-L4 disc, medial branch transection of the L3 dorsal ramus, and a sham procedure. Samples from L3 to L5 were studied histologically and chemically. RESULTS: The multifidus cross-sectional area was reduced at L4 ipsilateral to disc lesion but at L4-L6 after nerve lesion. There was no change after sham or on the opposite side. Water and lactate were reduced bilaterally after disc lesion and ipsilateral to nerve lesion. Histology revealed enlargement of adipocytes and clustering of myofibers at multiple levels after disc and nerve lesions. CONCLUSIONS: These data resolve the controversy that the multifidus cross-sectional area reduces rapidly after lumbar injury. Changes after disc lesion affect 1 level with a different distribution to denervation. Such changes may be due to disuse following reflex inhibitory mechanisms.

Animals↗
PubMed1997

Genetic diversity between hepatitis G virus isolates: analysis of nucleotide variation in the NS-3 and putative 'core' peptide genes.

Significant variation was found, between 46 isolates of hepatitis G virus (HGV), following direct sequencing of subgenomic PCR fragments from either or both the NS-3 and putative 'core' peptide. Nucleotide sequences of most HGV NS-3 fragments varied by 10-30% and of most putative 'core' peptide fragments by 2-20%. HGV was therefore shown to be much less variable than hepatitis C virus (HCV) and pairwise comparisons of HGV sequences demonstrated a single distinct distribution of evolutionary distances. Construction of phylogenetic trees, bootstrap analysis and calculation of mean distances between possible subtypes also indicated one level of variation between HGV NS-3 and putative 'core' peptide sequences, and the suggested degree of variation between isolates was similar to that between HCV subtypes. No evidence for clustering of sequences into multiple subtypes or genotypes was found. Although very small subgenomic fragments of HCV are indicative of the viral genotype it seems that the assignment of genetic groups is not possible for HGV using such small subgenomic fragments. The relatively limited genetic variation observed in HGV may reflect a relatively low level of host selection pressure stemming from the low level of host immunity stimulated by this virus.

DNA Primers↗
PubMed2004

A multisubunit membrane-bound [NiFe] hydrogenase and an NADH-dependent Fe-only hydrogenase in the fermenting bacterium Thermoanaerobacter tengcongensis.

Thermoanaerobacter tengcongensis is a thermophilic Gram-positive bacterium able to dispose of the reducing equivalents generated during the fermentation of glucose to acetate and CO(2) by reducing H(+) to H(2). A unique combination of hydrogenases, a ferredoxin-dependent [NiFe] hydrogenase and an NADH-dependent Fe-only hydrogenase, were found to be responsible for H(2) formation in this organism. Both enzymes were purified and characterized. The tightly membrane-bound [NiFe] hydrogenase belongs to a small group of complex-I-related [NiFe] hydrogenases and has highest sequence similarity to energy-converting [NiFe] hydrogenase (Ech) from Methanosarcina barkeri. A ferredoxin isolated from Ta. tengcongensis was identified as the physiological substrate of this enzyme. The heterotetrameric Fe-only hydrogenase was isolated from the soluble fraction. It contained FMN and multiple iron-sulfur clusters, and exhibited a typical H-cluster EPR signal after autooxidation. Sequence analysis predicted and kinetic studies confirmed that the enzyme is an NAD(H)-dependent Fe-only hydrogenase. When H(2) was allowed to accumulate in the culture, the fermentation was partially shifted to ethanol production. In cells grown at high hydrogen partial pressure [p(H(2))] the NADH-dependent hydrogenase activity was fourfold lower than in cells grown at low p(H(2)), whereas aldehyde dehydrogenase and alcohol dehydrogenase activities were higher in cells grown at elevated p(H(2)). These results indicate a regulation in response to the p(H(2)).

Amino Acid Sequence↗
PubMed1998

Analysis of EST-driven gene annotation in human genomic sequence.

We have performed a systematic analysis of gene identification in genomic sequence by similarity search against expressed sequence tags (ESTs) to assess the suitability of this method for automated annotation of the human genome. A BLAST-based strategy was constructed to examine the potential of this approach, and was applied to test sets containing all human genomic sequences longer than 5 kb in public databases, plus 300 kb of exhaustively characterized benchmark sequence. At high stringency, 70%-90% of all annotated genes are detected by near-identity to EST sequence; >95% of ESTs aligning with well-annotated sequences overlap a gene. These ESTs provide immediate access to the corresponding cDNA clones for follow-up laboratory verification and subsequent biologic analysis. At lower stringency, up to 97% of annotated genes were identified by similarity to ESTs. The apparent false-positive rate rose to 55% of ESTs among all sequences and 20% among benchmark sequences at the lowest stringency, indicating that many genes in public database entries are unannotated. Approximately half of the alignments span multiple exons, and thus aid in the construction of gene predictions and elucidation of alternative splicing. In addition, ESTs from multiple cDNA libraries frequently cluster over genes, providing a starting point for crude expression profiles. Clone IDs may be used to form EST pairs, and particularly to extend models by associating alignments of lower stringency with high-quality alignments. These results demonstrate that EST similarity search is a practical general-purpose annotation technique that complements pattern recognition methods as a tool for gene characterization.

Base Sequence↗
PubMed2004

Are Brazil nuts attractive?

We present event-driven simulation results for single and multiple intruders in a vertically vibrated granular bed. Under our vibratory conditions, the mean vertical position of a single intruder is governed primarily by a buoyancylike effect. Multiple intruders also exhibit buoyancy governed behavior; however, multiple neutrally buoyant intruders cluster spontaneously and undergo horizontal segregation. These effects can be understood by considering the dynamics of two neutrally buoyant intruders. We have measured an attractive force between such intruders which has a range of five intruder diameters, and we provide a mechanistic explanation for the origins of this force.

Journal Article↗