Faulty Processing Research Articles

Evidence that yeast SGS1, DNA2, SRS2, and FOB1 interact to maintain rDNA stability

We and others have proposed that faulty processing of arrested replication forks leads to increases in recombination and chromosome instability in Saccharomyces cerevisiae. Now we use the ribosomal DNA locus, which is a good model for all stages of DNA replication, to test this hypothesis. We showed previously that DNA replication pausing at the ribosomal DNA replication fork barrier (RFB) is accompanied by the occurrence of double-strand breaks near the RFB. Both pausing and breakage are elevated in the hypomorphic dna2-2 helicase mutant. Deletion of FOB1 suppresses the elevated pausing and DSB formation. Our current work shows that mutation inactivating Sgs1, the yeast RecQ helicase ortholog, also causes accumulation of stalled replication forks and DSBs at the rDNA RFB. Either deletion of FOB1, which suppresses fork blocking and certain types of rDNA recombination, or an increase in SIR2 gene dosage, which suppresses rDNA recombination, reduces the number of forks persisting at the RFB. Although dna2-2 sgs1Δ double mutants are conditionally lethal, they do not show enhanced rDNA defects compared to sgs1Δ alone. However, surprisingly, the dna2-2 sgs1Δ lethality is suppressed by deletion of FOB1. On the other hand, the dna2-2 sgs1Δ lethality is only partially suppressed by deletion of rad51Δ. We propose that the replication-associated defects that we document in the rDNA are characteristic of similar events occurring either stochastically throughout the genome or at other regions where replication forks move slowly or stall, such as telomeres, centromeres, or replication slow zones.

Mutations in Yeast Replication Proteins That Increase CAG/CTG Expansions Also Increase Repeat Fragility

Expansion of trinucleotide repeats (TNRs) is the causative mutation in several human genetic diseases. Expanded TNR tracts are both unstable (changing in length) and fragile (displaying an increased propensity to break). We have investigated the relationship between fidelity of lagging-strand replication and both stability and fragility of TNRs. We devised a new yeast artificial chromomosme (YAC)-based assay for chromosome breakage to analyze fragility of CAG/CTG tracts in mutants deficient for proteins involved in lagging-strand replication: Fen1/Rad27, an endo/exonuclease involved in Okazaki fragment maturation, the nuclease/helicase Dna2, RNase HI, DNA ligase, polymerase delta, and primase. We found that deletion of RAD27 caused a large increase in breakage of short and long CAG/CTG tracts, and defects in DNA ligase and primase increased breakage of long tracts. We also found a correlation between mutations that increase CAG/CTG tract breakage and those that increase repeat expansion. These results suggest that processes that generate strand breaks, such as faulty Okazaki fragment processing or DNA repair, are an important source of TNR expansions.

Base Station Fears

This article discusses a central paradox behind mobile geography – mobile phones are ubiquitous and bodily intimate technologies, yet the public seems particularly fearful of any spatial proximity to mobile phone masts. Such fears are generally understood in terms of ‘risk perception’, an irrational consequence of media hype, faulty cognitive processing, or communication failure. This merely psychologises what is a deeply spatial paradox. Tbe routine ‘nomadic intimacy’ of mobile phone use establishes place as a mere backdrop to being always ‘on-call’, too absorbed In the ‘busy-ness’ of everyday life to notice what is close at hand. In contrast, what we term ‘place intimacy’ becomes evident when public protest over the unwanted intrusion of phone masts helps refashion familiar places as meaningful, safe and worth protecting.

Nuclease-deficient FEN-1 blocks Rad51/BRCA1-mediated repair and causes trinucleotide repeat instability.

Previous studies have shown that expansion-prone repeats form structures that inhibit human flap endonuclease (FEN-1). We report here that faulty processing by FEN-1 initiates repeat instability in mammalian cells. Disease-length CAG tracts in Huntington's disease mice heterozygous for FEN-1 display a tendency toward expansions over contractions during intergenerational inheritance compared to those in homozygous wild-type mice. Further, with regard to human cells expressing a nuclease-defective FEN-1, we provide direct evidence that an unprocessed FEN-1 substrate is a precursor to instability. In cells with no endogenous defects in DNA repair, exogenous nuclease-defective FEN-1 causes repeat instability and aberrant DNA repair. Inefficient flap processing blocks the formation of Rad51/BRCA1 complexes but invokes repair by other pathways.

Detailed glycan analysis of serum glycoproteins of patients with congenital disorders of glycosylation indicates the specific defective glycan processing step and provides an insight into pathogenesis.

The fundamental importance of correct protein glycosylation is abundantly clear in a group of diseases known as congenital disorders of glycosylation (CDGs). In these diseases, many biological functions are compromised, giving rise to a wide range of severe clinical conditions. By performing detailed analyses of the total serum glycoproteins as well as isolated transferrin and IgG, we have directly correlated aberrant glycosylation with a faulty glycosylation processing step. In one patient the complete absence of complex type sugars was consistent with ablation of GlcNAcTase II activity. In another CDG type II patient, the identification of specific hybrid sugars suggested that the defective processing step was cell type-specific and involved the mannosidase III pathway. In each case, complementary serum proteome analyses revealed significant changes in some 31 glycoproteins, including components of the complement system. This biochemical approach to charting diseases that involve alterations in glycan processing provides a rapid indicator of the nature, severity, and cell type specificity of the suboptimal glycan processing steps; allows links to genetic mutations; indicates the expression levels of proteins; and gives insight into the pathways affected in the disease process.

Dna2 Helicase/Nuclease Causes Replicative Fork Stalling and Double-strand Breaks in the Ribosomal DNA of Saccharomyces cerevisiae

We have proposed that faulty processing of arrested replication forks leads to increases in recombination and chromosome instability in Saccharomyces cerevisiae and contributes to the shortened lifespan of dna2 mutants. Now we use the ribosomal DNA locus, which is a good model for all stages of DNA replication, to test this hypothesis. We show directly that DNA replication pausing at the ribosomal DNA replication fork barrier (RFB) is accompanied by the occurrence of double-strand breaks near the RFB. Both pausing and breakage are elevated in the early aging, hypomorphic dna2-2 helicase mutant. Deletion of FOB1, encoding the fork barrier protein, suppresses the elevated pausing and DSB formation, and represses initiation at rDNA ARSs. The dna2-2 mutation is synthetically lethal with deltarrm3, encoding another DNA helicase involved in rDNA replication. It does not appear to be the case that the rDNA is the only determinant of genome stability during the yeast lifespan however since strains carrying deletion of all chromosomal rDNA but with all rDNA supplied on a plasmid, have decreased rather than increased lifespan. We conclude that the replication-associated defects that we can measure in the rDNA are symbolic of similar events occurring either stochastically throughout the genome or at other regions where replication forks move slowly or stall, such as telomeres, centromeres, or replication slow zones.

Reality monitoring and visual hallucinations in Parkinson’s disease

Between 8 and 40% of Parkinson disease (PD) patients will have visual hallucinations (VHs) during the course of their illness. Although cognitive impairment has been identified as a risk factor for hallucinations, more specific neuropsychological deficits underlying such phenomena have not been established. Research in psychopathology has converged to suggest that hallucinations are associated with confusion between internal representations of events and real events (i.e. impaired-source monitoring). We evaluated three groups: 17 Parkinson’s patients with visual hallucinations, 20 Parkinson’s patients without hallucinations and 20 age-matched controls, using tests of visual imagery, visual perception and memory, including tests of source monitoring and recollective experience. The study revealed that Parkinson’s patients with hallucinations appear to have intact visual imagery processes and spatial perception. However, there were impairments in object perception and recognition memory, and poor recollection of the encoding episode in comparison to both non-hallucinating Parkinson’s patients and healthy controls. Errors were especially likely to occur when encoding and retrieval cues were in different modalities. The findings raise the possibility that visual hallucinations in Parkinson’s patients could stem from a combination of faulty perceptual processing of environmental stimuli, and less detailed recollection of experience combined with intact image generation.

Representations of health risks: What social psychology can offer health promotion

This paper proposes that health promotion may benefit from a social psychological theory that maps the contents and evolution of lay `logic'. Social representations theory forms the focus, since it facilitates entry into people's meaning systems regarding risks, as well as into the functions served by such meanings. The theory is assessed once the assumptions of the more commonly used, contrasting perspective of risk perception is examined. Cognitive theories of risk perception tend to focus on an ideal of rational information processing and assume that people are averse to harm. They are unified in their centre of attention being the intrapersonal level. Having looked at studies of lay responses to childhood vaccination, diabetes and smoking, the paper demonstrates that such assumptions can be challenged. Social representations theory is summoned as a unifying rubric in which to conduct studies that operate from wholly different assumptions: the history and symbols held dear within particular social networks fashion their representations of the health issues they face. These are difficult to change because they serve an identity protective function, rather than being products of faulty information processing which can be rectified by way of a dose of'reality'. However, at least by mapping the evolution and contents of such representations one can help health promoters in starting with where audiences are located, rather than operating from models of behaviour change that are underpinned by assumptions that have limited validity.

Psychological Correlates of Perception of Sexual Intent in Women

In a sample of 183 men and 186 women, the authors assessed (a) the relative contributions of gender and level of nonverbal social cues to the perception of a female actor's sexual intent during a videotaped social interaction with a man and (b) the association between those variables and personality traits implicated in faulty sexual-information processing. The authors assessed those variables while the participants viewed 1 of 3 film segments depicting a female-male interaction. The authors experimentally manipulated eye contact, touch, physical proximity, and female clothing. At all levels of those nonverbal cues, the men perceived more sexual intent in the female actor than did the women. The perception of the female actor's sexual intent increased as the nonverbal cues in the film segments were magnified: Both actors displayed more eye contact, touch, and physical proximity, and the female actor wore more revealing clothing. Relative to the women, the men demonstrated greater sexual preoccupation and reduced sociosexual effectiveness, variables associated with inferring greater sexual intent in the female actor.

Schizotypy and leadership: a contrasting model for deficit symptoms, and a possible therapeutic role for sex hormones

Associational loosening, slow and faulty information processing, poor gating of irrelevant stimuli, poor ability to shift attention, poor working memory, passivity, ambivalence, anhedonia, and impaired motor coordination are cardinal features of schizophrenia but, unlike delusions and hallucinations, they are related more to negative/deficit symptoms. As summarized by Bass, numerous studies have correlated leadership with ‘ambition, initiative and persistence’ (opposite of passivity), ‘speed and accuracy of thought’, ‘finality of decision,’ or decisiveness (the opposite of ambivalence), ‘mood control, optimism and sense of humor’ (opposite of anhedonia), etc. Andreasen et al postulate that a disruption in the circuitry among nodes located in the prefrontal regions, the thalamic nuclei, and the cerebellum produces ‘cognitive dysmetria’, meaning difficulty in prioritizing, coordinating, and responding to information, and that it can account for the broad diversity of symptoms of schizophrenia. A relationship between cognitive processes and cerebellar and basal ganglia functions, and a role of neocerebellum in rapidly shifting attention, have been demonstrated. The cognitive styles, including a proficiency to quickly shift attention, of several famous leaders are used as examples of this contrasting model. Julius Caesar and Napoleon, for instance, could dictate to up to six secretaries simultaneously, using their exceptional working memories, and proficiency in quickly and effortlessly shifting attention while flawlessly gating irrelevant external and internal stimuli. It is suggested that specific brain imaging studies could illustrate this contrast. Gray et al noted positive correlations between ‘dominance’, an important leadership trait, and serum levels of dehydroepiandrosterone (DHEA) and testosterone (T), but not of more potent dihydrotestosterone (DHT), in over 1700 older men. Though not scientifically rigorous, the author noted positive correlations (P = 0.0162) between the self-rated ratings of voice depth (promoted by T) and of leadership, but none between those of body hair (DHT dependent) and of leadership in 47 male US National Academy of Sciences members. And 43 male US Senators had deeper voices than 36 male House members (P< 0.01) who, in turn, had deeper voices than either of two groups (numbers 102 and 72) of male scientists (P< 0.01). Therapeutically, before chlorpromazine, DHEA had been used in young schizophrenics with modest success in improving deficit symptoms. DHEA, or other sex hormones, or some of their natural and synthetic derivatives may prove to be valuable to treat deficit symptoms of schizophrenia in both sexes.

Loss of visual acuity under dopamine substitution therapy

Visual dysfunction is a well-known feature of Parkinson’s disease. Dopamine has been shown to be a functional modulator at many levels of the visual system. We report on a parkinsonian patient, suffering concurrently from various ophthalmological conditions including glaucoma and cataracts and displaying objectively measurable loss of visual acuity and blurring of vision while under medication with an MAO-B inhibitor and multiple ergolene-derived dopamine agonists. Various studies have investigated the effects of different D1- and D2-agonists and -antagonists on visual function and found that the presynaptic dopaminergic autoreceptor involved in the modulation of dopamine release in the retina displays characteristics of D2-receptors. We conclude that the observed phenomenon represents either an inhibition of dopamine release due to excessive stimulation of presynaptic D2-autoreceptors, leading to an insufficient stimulation of postsynaptic dopaminergic receptors and thus impeding retinal signal conduction, or a heretofore unclear interaction between the patient’s ophthalmological pathologies and dopaminergic therapy, possibly due to excessive stimulation of postsynaptic dopamine receptors, leading to faulty retinal information processing.

Fault-tolerant rank order filtering for image enhancement

This paper presents an approach for the fault-tolerant computation of the rank order filtering on a SIMD (single instruction multiple data) mesh processor. The proposed approach improves over a previous approach in two respects: by changing the data dependency in the execution of the rank order filtering, a new algorithm with constant execution time complexity can be designed; and by introducing a dependency for the rank values of faulty processing elements (PEs) as computed by neighboring (fault free) PEs, a lower distortion can be achieved for the image enhancement. An algorithm is presented; this algorithm is based on a two-phase technique in which the rank corresponding to each faulty PE is computed by a selected fault free PE. The effect of the rank computation for a faulty PE is restricted within a window of the image, such that no significant overhead is accounted for in execution complexity. This results in a considerable improvement in speed-up ratio, fault-tolerance as well as a lower distortion in the reconstructed image. The proposed approach is also evaluated using experimental results. As the proposed algorithm is directly compatible with a SIMD mesh execution, a discussion of the communication constructs and switching architecture to support array processing is also presented.

Prospects for gene therapy in cystic fibrosis.

Since the discovery of the gene encoding cystic fibrosis (CF), there has been much excitement about the possibility of gene therapy, which has now reached the stage of phase I clinical trials in adults. The baby born with CF has normal lungs at birth, but evidence of inflammation and lung changes are present as early as 4 weeks of age. Ideally, future novel treatments such as gene therapy should begin before the onset of airway damage. We review the pathophysiology of CF, including current molecular understanding, and set out the issues involved in gene therapy for children with CF. CF is the commonest lethal inherited disease in white people in the UK, with an incidence of ∼ 1/2000 live births. The median estimated life expectancy of children born in the 1990s is 40 years, which represents a doubling in the past 20 years. It is estimated that in the next millennium half of all patients will be adults. In 1989, the gene responsible for CF was localised to the long arm of chromosome 7. This gene encodes a protein called the CF transmembrane conductance regulator (CFTR), which is situated in the apical membrane of epithelial cells and functions as a chloride channel regulated by a cAMP dependent protein kinase. It also modulates the activity of other ion channels including the downregulation of the amiloride sensitive sodium channel. More than 800 mutations of the gene have been identified and they are categorised into five classes on the basis of CFTR protein alterations. Class I mutations result in either unstable mRNA or an abnormal protein that is rapidly degraded. Class II mutations result in faulty processing of the protein and failure of the protein to traffic to the apical membrane. This class includes the ΔF508 mutation, which is a codon deletion resulting in …

Abnormal Information Processing Systems in PTSD

Patients with posttraumatic stress disorder (PTSD) have problems in learning and in retrieving nontraumatic memories and with over-learned traumatic memories. These imaging studies comparing veterans with and without combat-related PTSD suggest that faulty information processing, possibly related to an imbalance between arousal systems and other stress-response systems, may underlie the symptoms. In the first study, 20 Vietnam combat veterans …

DIFFERENT KINDS AND ROLES OF ENVIRONMENTAL UNCERTAINTY

In environmental psychology different roles appears to be ascribed to the concept of environmental uncertainty: in environmental aesthetics optimization of environmental uncertainty is assumed to explain preferences, in environmental-stress research minimization of environmental uncertainty is assumed to reduce stress, and in research on resource dilemmas environmental uncertainty is assumed to be accurately monitored. An analysis of the different definitions in each area of research reveals that environmental uncertainty refers to both event–event and response–consequence covariation, that it is not assumed to be inherent but to relate to ignorance or faulty information processing, and that it is multifacet subsuming the concepts of probability, vagueness and ambiguity. Although the different research areas do not seem to differ importantly in their definitions of environmental uncertainty, there are differences in emphasis. A possible reconciliation rests on: (1) that in research on resource dilemmas it is incorrect that people accurately monitor environmental uncertainty but, in fact, are susceptible to a desirability bias; (2) that sensation seeking plays a role for risk taking in resource dilemmas; and (3) that in environmental-stress research conditions of high environmental uncertainty have primarily been investigated, thus leaving out conditions when an increase of uncertainty would be desirable. It may be concluded then that basically people are optimizers of environmental uncertainty. However, this does not rule out that they, under most of the prevailing conditions, want to reduce environmental uncertainty. To help them do that seems, therefore, more appropriate than to do the reverse.@ 1998 Academic Press

Catastrophic faults in reconfigurable systolic linear arrays

In regular architectures of identical processing elements, a widely used technique to improve the reconfigurability of the system consists of providing redundant processing elements and connections together with mechanisms of reconfiguration. In this paper we consider linear arrays of processing elements, with unidirectional bypass links of length g. We study those sets of faulty processing elements, called catastrophic, which prevent the reconfiguration. We show that the number of catastrophic faults of g elements is equal to the ( g − 1)th Catalan number. We also provide algorithms to rank and unrank all catastrophic sets of g faults. Finally, we describe a linear-time algorithm that generates all such sets of faults. Our results are useful to provide reliability estimates of linear arrays and for testing the behavior of reconfiguration strategies in the presence of catastrophic faults.

Asymmetric performances in binaural localization of sound in space

Twenty right-handers and 20 left-handers were tested on a sound localization task. Broadband noise was presented from either the left or right hemifield. Localization accuracy was significantly greater ( P = 0.002) when sounds emanated from the left hemifield thereby suggesting a paramount role played by the right hemisphere. Correcting for front-rear reversals, attributable to impoverished spectral cues and/or faulty processing of such cues, rendered differences in error scores linked to hemifield nonsignificant. The data were interpreted to mean that the special contribution of the right hemisphere to this task was its greater fidelity in processing spectral cues. No differences in localization proficiency between right- and left-handers were observed.

A nuclear function for RNase MRP.

A nuclear function for RNase MRP.

Probabilistic diagnosis of multiprocessor systems

This paper critically surveys methods for the automated probabilistic diagnosis of large multiprocessor systems. In recent years, much of the work on system-level diagnosis has focused on probabilistic methods, which can diagnose intermittently faulty processing nodes and can be applied in general situations on general interconnection networks. The theory behind the probabilistic diagnosis methods is explained, and the various diagnosis algorithms are described in simple terms with the aid of a running example. The diagnosis methods are compared and analyzed, and a chart is produced, showing the comparative advantages of the various diagnosis algorithms on the basis of several factors important to the probabilistic diagnosis.

Diagnosis by signature analysis of test responses

Proposes a new approach for identification of faulty processing elements based on an analysis of the compressed test response of the system. The test response is compressed first in space and then in time, and faulty processing elements are identified by hard decision decoding of the corresponding space-time signature. The approach results in considerable savings in hardware required for diagnostics.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>