A comparison of the Celera and Ensembl predicted gene sets reveals little overlap in novel genes.
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Computational Biology↗
Biomedical subjects
J R Walker
Publications and source records attributed to J R Walker.
Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair.
The Ku heterodimer (Ku70 and Ku80 subunits) contributes to genomic integrity through its ability to bind DNA double-strand breaks and facilitate repair by the non-homologous end-joining pathway. The crystal structure of the human Ku heterodimer was determined both alone and bound to a 55-nucleotide DNA element at 2.7 and 2.5 A resolution, respectively. Ku70 and Ku80 share a common topology and form a dyad-symmetrical molecule with a preformed ring that encircles duplex DNA. The binding site can cradle two full turns of DNA while encircling only the central 3-4 base pairs (bp). Ku makes no contacts with DNA bases and few with the sugar-phosphate backbone, but it fits sterically to major and minor groove contours so as to position the DNA helix in a defined path through the protein ring. These features seem well designed to structurally support broken DNA ends and to bring the DNA helix into phase across the junction during end processing and ligation.
Amino Acid Sequence↗
Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia.
Neuropathological and brain imaging studies suggest that schizophrenia may result from neurodevelopmental defects. Cytoarchitectural studies indicate cellular abnormalities suggestive of a disruption in neuronal connectivity in schizophrenia, particularly in the dorsolateral prefrontal cortex. Yet, the molecular mechanisms underlying these findings remain unclear. To identify molecular substrates associated with schizophrenia, DNA microarray analysis was used to assay gene expression levels in postmortem dorsolateral prefrontal cortex of schizophrenic and control patients. Genes determined to have altered expression levels in schizophrenics relative to controls are involved in a number of biological processes, including synaptic plasticity, neuronal development, neurotransmission, and signal transduction. Most notable was the differential expression of myelination-related genes suggesting a disruption in oligodendrocyte function in schizophrenia.
Chronic Disease↗
The physiological effects and metabolic alterations caused by the expression of Rhizobium etli pyruvate carboxylase in Escherichia coli.
Oxaloacetate (OAA) plays an important role in the tricarboxylic acid cycle and for the biosynthesis of a variety of cellular compounds. Some microorganisms, such as Rhizobium etli and Corynebacterium glutamicum, are able to synthesize OAA during growth on glucose via either of the enzymes pyruvate carboxylase (PYC) or phosphoenolpyruvate carboxylase (PPC). Other microorganisms, including Escherichia coli, synthesize OAA during growth on glucose only via PPC because they lack PYC. In this study we have examined the effect that the R. etli PYC has on the physiology of E. coli. The expressed R. etli PYC was biotinylated by the native biotin holoenzyme synthase of E. coli and displayed kinetic properties similar to those reported for alpha4 PYC enzymes from other sources. R. etli PYC was able to restore the growth of an E. coli ppc null mutant in minimal glucose medium, and PYC expression caused increased carbon flow towards OAA in wild-type E. coli cells without affecting the glucose uptake rate or the growth rate. During aerobic glucose metabolism, expression of PYC resulted in a 56% increase in biomass yield and a 43% decrease in acetate yield. During anaerobic glucose metabolism, expression of PYC caused a 2.7-fold increase in succinate concentration, making it the major product by mass. The increase in succinate came mainly at the expense of lactate formation. However, in a mutant lacking lactate dehydrogenase activity, expression of PYC resulted in only a 1.7-fold increase in succinate concentration. The decreased enhancement of succinate formation in the /dh mutant was hypothesized to be due to accumulation of pyruvate and NADH, metabolites that affect the interconversion of the active and inactive form of the enzyme pyruvate formate-lyase.
Acetates↗
Psychological vulnerabilities in patients with major depression vs panic disorder.
The tripartite model (Clark & Watson, 1991: Clark, L. A., & Watson, D. (1991). Tripartite model of anxiety and depression: Psychometric evidence and taxonomic implications. Journal of Abnormal Psychology, 100, 316-336) posits that anxiety and depression share nonspecific features of neuroticism but that somatic arousal appears unique to anxiety, and low positive affect appears unique to depression. The present study controlled for these higher-order effects and evaluated the relative contributions of four, specific lower-order vulnerabilities (anxiety sensitivity, rumination, self-criticism, self-oriented perfectionism). Participants were 38 depressed patients and 38 patients with panic disorder matched as closely as possible for age and gender, and all were diagnosed using the same structured interview by an experienced clinician. Results from hierarchical logistic regression analysis were consistent with predictions from the tripartite model in that only the unique features of arousal and positive affectivity differentiated the two diagnostic groups. At a lower-order level, only anxiety sensitivity (and its facet of fear of physical symptoms) and a ruminative response style demonstrated incremental predictive ability. The discussion focuses on the relationships among these higher-order and lower-order variables, and their potential importance for understanding specific manifestations of psychopathology.
Adult↗
Anxiety sensitivity and major depression: examination of affective state dependence.
An emerging body of research suggests that anxiety sensitivity (AS), and particularly a facet of AS labelled fear of cognitive dyscontrol, is elevated in depressed individuals and is associated with severity of depressed mood. The current prospective study extended previous work by investigating the extent of affective state dependency in the AS-depression relationship in 51 patients who had major depressive episode (MDE) at baseline assessment (Time 1) and did not have MDE 1 year later at follow-up (Time 2). Despite considerable reduction in severity of depressed mood, scores on the Anxiety Sensitivity Index (M=27) remained elevated. Hierarchical regression analysis indicated that, after controlling for both Time 1 and Time 2 depression severity, Time 1 AS continued to predict residual Time 2 AS and increased prediction of variance from approximately 25% to 50%. Time 1 fear of cognitive dyscontrol AS continued to significantly predict Time 2 fear of cognitive dyscontrol AS when Time 2 fear of physical symptoms AS was statistically controlled. A subsample of recovered patients who displayed only minimal depression symptoms was compared to a matched sample of community controls. While the two groups did not significantly differ on level of depressed mood, the formerly depressed patients had significantly higher levels of AS. Implications for a proposed "depression sensitivity" are discussed.
Adult↗
Defective initiation in an Escherichia coli dnaA(Cs,Sx) mutant.
Mutations in the Escherichia coli gene for initiation of DNA replication, dnaA, which suppress the polymerization defect and growth inhibition caused by temperature-sensitive (Ts) mutations in the polymerization gene, dnaX, are called Cs,Sx. We show here that these mutations, on their own, also cause defects in initiation, including inhibition of initiation at both low (20 degrees C) and high (44 degrees C) temperatures and asynchronous initiation at both the permissive (34 degrees C) and suppression (39 degrees C) temperatures. These findings suggests a relationship between partially defective initiation and suppression of the polymerization defect, both of which occur at 39 degrees C.
Bacterial Proteins↗
Social phobia and potential childhood risk factors in a community sample.
BACKGROUND: This study examined the relationship between potential childhood risk factors and social phobia in an epidemiological sample. Identifying risk factors such as childhood adversities can often uncover important clues as to the aetiology of a disorder. This information also enables health care providers to predict which individuals are most likely to develop the disorder. METHODS: Data came from the Mental Health Supplement to the Ontario Health Survey of a survey of 8116 Canadian respondents, aged 15-64. Social phobia was diagnosed using the Composite International Diagnostic Interview (CIDI). Childhood risk factors were assessed by a series of standardized questions. RESULTS: A positive relationship was observed between social phobia and lack of close relationship with an adult, not being first born (in males only), marital conflict in the family of origin, parental history of mental disorder, moving more than three times as a child, juvenile justice and child welfare involvement, running away from home, childhood physical and sexual abuse, failing a grade, requirement of special education before age 9 and dropping out of high school. Many of these variables remained significant after controlling for phobias, major depressive disorder and alcohol abuse. The data also suggest that some childhood risk factors may interact with gender to influence the development of social phobia. CONCLUSIONS: Although an association was detected between social phobia and childhood risk factors, naturalistic prospective studies are needed to clarify the aetiological importance of these and other potential risk factors for the disorder.
Adolescent↗
Sertraline treatment of generalized social phobia: a 20-week, double-blind, placebo-controlled study.
OBJECTIVE: The authors evaluated the efficacy, safety, and tolerability of sertraline, a selective serotonin reuptake inhibitor, in the treatment of generalized social phobia. METHOD: Adult outpatients with generalized social phobia (N=204) from 10 Canadian centers were randomly assigned to receive sertraline or placebo in a 2:1 ratio for a 20-week double-blind study following a 1-week, single-blind, placebo run-in. The initial dose of sertraline was 50 mg/day with increases of 50 mg/day every 3 weeks permitted after the fourth week of treatment (dosing was flexible up to a maximum of 200 mg/day). Primary efficacy assessments were the percentage of patients rated much or very much improved on the Clinical Global Impression (CGI) improvement item and the mean changes from baseline to study endpoint in total score on the social phobia subscale of the Marks Fear Questionnaire and total score on the Brief Social Phobia Scale. RESULTS: In intent-to-treat endpoint analyses of 203 of the patients, significantly more of the 134 patients given sertraline (N=71 [53%]) than of the 69 patients receiving placebo (N=20 [29%]) were considered responders according to their CGI improvement scores at the end of treatment. The mean reductions in the social phobia subscale of the Marks Fear Questionnaire and in the total score on the Brief Social Phobia Scale were 32.6% and 34.3% in the sertraline group and 10.8% and 18.6% in the placebo group, respectively. Analysis of covariance showed superiority of sertraline over placebo on all primary and secondary efficacy measures. Sertraline was well tolerated: 103 (76%) of the 135 sertraline-treated patients and 54 (78%) of the 69 placebo-treated patients completed the study. CONCLUSIONS: Sertraline is an effective treatment for patients with generalized social phobia.
Adult↗
Do selective serotonin re-uptake inhibitors enhance the efficacy of very brief cognitive behavioral therapy for panic disorder? A pilot study.
Selective serotonin re-uptake inhibitors (SSRIs) and cognitive behavioral therapies (CBTs) are both considered as first-line treatments for panic disorder, but the advantages of a combined therapy have yet to be definitively demonstrated. We evaluated in this pilot study the effects of combining SSRIs (vs. a placebo) with a very brief form of cognitive-behavioral therapy provided to all participants. Thirty-three subjects with DSM-IV panic disorder, with or without agoraphobia, were randomized to receive either paroxetine or a placebo with flexible dosing (10-50 mg/day). Medication visits were brief (15 min), infrequent (6 in total) and non-directive. An expert cognitive-behavior therapist administered one initial 45-min session and one subsequent 30-min session of very brief CBT (vbCBT) at weeks 5 and 7, respectively. Sessions were supplemented with educational and directive reading materials. Patients in both groups (i.e. vbCBT+paroxetine; vbCBT+placebo) improved similarly and substantially on most measures during the 10 weeks of acute treatment. At week 10, the proportion of panic-free patients was significantly higher in the paroxetine-treated group than in the placebo group (80 vs. 25%; P<0.007), as was the proportion of subjects who rated themselves as 'very much improved' at week 10 (60 vs. 13%; P<0.017). These findings point to the need for additional studies to confirm the effectiveness of very brief forms of CBT, and to document the circumstances in which combined treatment with an SSRI would be warranted.
Adolescent↗
Microinjections of an opiate receptor antagonist into the bed nucleus of the stria terminalis suppress heroin self-administration in dependent rats.
Recent anatomical evidence suggests that the shell of the nucleus accumbens, the bed nucleus of the stria terminalis, and the central nucleus of the amygdala, together referred to as the extended amygdala, may play a role in opiate dependence. The bed nucleus of the stria terminalis and the shell of the nucleus accumbens have a moderately high density of opiate receptors, which allows for manipulation of opiate neurotransmission with receptor antagonists. The goal of this study was to determine the role these regions play in opiate reinforcement, and whether dependence alters the reinforcing effects of opiates by examining the effect of local administration of the opiate receptor antagonist methylnaloxonium on heroin self-administration in dependent and nondependent rats. Previous studies revealed that blockade of the reinforcing effects of opiates with systemic administration of opiate receptor antagonists results in an increase in heroin self-administration in nondependent rats, and a greater increase in dependent rats. In the present study, methylnaloxonium dose-dependently suppressed heroin intake when injected into the bed nucleus of the stria terminalis and shell of the nucleus accumbens of dependent rats, and had no effect in nondependent rats. These results demonstrate that opiate receptors in parts of the extended amygdala may be responsible for the reinforcing effects of opiates in dependent animals and suggest that activity in this system may be recruited during the development of dependence.
Animals↗
Social phobia symptoms, subtypes, and severity: findings from a community survey.
OBJECTIVES: Our goals were (1) to ascertain the range of functional impairment attributable to social phobia in a community sample, and (2) to verify the existence of social phobia subtypes in the community, and report on their relative prevalence, severity, and levels of impairment. METHODS: Community surveys were conducted contemporaneously in Winnipeg, Manitoba, and in Alberta, with a total of 1956 respondents. Instruments included the Comprehensive International Diagnostic Interview-Version 2.1 module for DSM-IV social phobia, enhanced with 6 additional (for a total of 12) social phobic situational probes to provide a more comprehensive assessment of possible subtypes, and additional questions about specific functional impairment due to social phobia. RESULTS: Of those persons in the community surveyed, most had no (60.4%) or few (ie, 1-3) (27.8%) social fears; few persons (3.4%) had many (ie, >/=7). Among those with DSM-IV social phobia (7.2%), classification based on number (normally distributed with median of 3, mode of 5) or content (eg, speaking-only vs other fears; performance-only vs interactional fears) of social fears failed to yield a defensible subtyping solution. Impairment increased linearly as the number of social fears was increased, with no clear threshold evident. CONCLUSIONS: Social phobia is associated with substantial impairment in multiple functional domains. Support for subtyping based on the extent or pattern of social fears was not provided. Rather, social phobia in the community seems to exist on a continuum of severity, with a greater number of feared situations associated with greater disability.
Adult↗
Construction and characterization of a highly regulable expression vector, pLAC11, and its multipurpose derivatives, pLAC22 and pLAC33.
A number of different expression vectors have been developed to facilitate the regulated overproduction of proteins in Escherichia coli and related bacteria. Some of the more popular ones include pKK223-3, pKK233-2, pTrc99A, and the pET family of expression vectors. These vectors were designed to be regulable and can be grown under conditions that repress protein production or under conditions that induce protein production. Unfortunately, however, numerous researchers have found that these vectors produce significant amounts of protein even when grown under repressed conditions. We describe here a new expression vector, pLAC11, which was designed to be more regulable and thus more tightly repressible when grown under repressed conditions. The tight regulation of pLAC11 was achieved by utilizing the O3 auxiliary operator, CAP binding site, promoter, and O1 operator that occur in the wild-type lac control region. The pLAC11 vector can be used to conduct physiologically relevant studies in which the cloned gene is expressed at levels comparable to that obtainable from the chromosomal copy of the gene in question. In experiments in which a bacterial cell contained both a null allele in the chromosome and a second copy of the wild-type allele on pLAC11, we observed that cells grown under repressed conditions exhibited the null phenotype while cells grown under induced conditions exhibited the wild-type phenotype. Two multipurpose derivatives of pLAC11, pLAC22, and pLAC33 have also been constructed to fulfill different experimental needs.
Base Sequence↗
Gender differences in susceptibility to posttraumatic stress disorder.
We examined data from a community survey of trauma exposure and DSM-IV PTSD in Winnipeg, Canada to explore factors associated with the higher rate of PTSD in women than men. Women were found to be at significantly increased risk for PTSD following exposure to serious trauma (odds ratio approximately 5), even when sexual trauma--which predominates in women--was excluded (odds ratio approximately 3). Adjusting for gender differences in the number of lifetime traumata, or in the likelihood of the trauma being associated with particular reactions to or consequences of the event (i.e. thinking that one would be killed or seriously injured; sustaining a serious physical injury; seeing someone else seriously injured or killed) did not result in a lessening of the PTSD risk in women. Women were found to be at increased risk for PTSD following nonsexual assaultive violence (e.g. mugging or other physical attack) but not following non-assaultive trauma (e.g. fire, witnessing injury to others). Understanding the basis of (and parameters for) this increased susceptibility to PTSD in women compared to men following trauma exposure should be a priority for future traumatic stress research.
Adolescent↗
Perfectionism and chronic insomnia.
The relationship between chronic insomnia and perfectionism was investigated using a sample of 32 adults with chronic insomnia and 26 healthy controls. Different aspects of perfectionism were measured using two Multi-Dimensional Perfectionism Scales [Frost RO, Marten P, Lahart C, Rosenblate R. The dimensions of perfectionism. Cognit Ther Res 1990;14(5):449-468; Hewitt PL, Flett GL. The Multidimensional Perfectionism Scale: development and validation. Can Psychol 1989;30:339; Hewitt PL, Flett GL. Perfectionism in the self and social contexts: conceptualization, assessment, and association with psychopathology. J Pers Soc Psychol 1991;60:456-470.]. Using a univariate approach, results indicated that those with chronic insomnia were more likely to endorse features of "maladaptive" perfectionism relative to healthy controls. Further, those with chronic insomnia were more likely to report doubts about action, frequent parental criticism, and concern over mistakes. Although those with chronic insomnia were found to be more perfectionistic in these areas, only perception of heightened parental criticism was associated with the reporting of delayed sleep-onset latency. No other aspect of perfectionism was associated with sleep-onset latency, total sleep time, or sleep quality. Implications for theories of the development of insomnia are discussed.
Adaptation, Psychological↗
A program evaluation study of a nursing home operated as a modified therapeutic community for chemically dependent persons with AIDS. Project Samaritan AIDS Services, Inc.'s Residential Health Care Facility, Highbridge Section, Bronx, NY.
An interagency evaluation of the treatment effectiveness of a speciality nursing home (NH) run as a therapeutic community (TC) for residents diagnosed with acquired immunodeficiency syndrome (AIDS) and substance abuse/dependence (SA/D) was conducted. A total of 79 chemically dependent men and women with AIDS were: (a) administered the Tennessee Self-Concept Scale (TSCS; Roid & Fitts, 1991) at initial testing (T(1)) and 8 months after their initial testing (T(2)); and (b) assessed on specific physical health indicators (i.e. , weight, CD-4 count, and viral load) and other treatment outcomes (e.g., abstinence) over the same two time periods. The TSCS results identified a valid and invalid TSCS test group and further distinguished among three subgroups of invalid responders. Significant improvements were observed from T(1) testing to T(2) testing on the TSCS, on the physical health indicators, and on other treatment outcomes. The need for additional and continued mental health services for this population was noted.
Acquired Immunodeficiency Syndrome↗
Persistent increase in the motivation to take heroin in rats with a history of drug escalation.
The transition from stable to escalated levels of cocaine self-administration has been shown to depend upon drug availability. The generality of this phenomenon is assessed here by studying the effects of availability on heroin self-administration. Two groups of rats were trained on a 1-h continuous schedule of self-administration, after which, access to heroin (40 microg/injection) was increased to 11 h in one group (long access or LgA rats) or kept to 1 h in the other group (short access or ShA rats). After 18 sessions on this regimen, both ShA and LgA rats were tested for extinction and stress-induced reinstatement of heroin-seeking behavior. In LgA rats, both total and first hour intake gradually escalated over time. After escalation, LgA rats were slower to extinguish heroin-seeking behavior and responded more to the reinstating effect of stress after extinction. These findings show that: (1) the escalation process in drug consumption is common to both opiate and stimulant self-administration; (2) escalation in heroin consumption is associated with a persistent increase in the motivation for taking heroin.
Animals↗
Bioweapons protocol update.
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Biological Warfare↗