Utilization of a deoxynucleoside diphosphate substrate by HIV reverse transcriptase

Background: Deoxynucleoside triphosphates (dNTPs) are the normal substrates for DNA sysnthesis is catalyzed by polymerases such as HIV-1 reverse transcriptase (RT). However, substantial amounts of deoxynucleoside diphosphates (dNDPs) are also present in the cell. Use of dNDPs in HIV-1 DNA sysnthesis could have significant implications for the efficacy of nucleoside RT inhibitors such as AZT which are first line therapeutics fro treatment of HIV infection. Our earlier work on HIV-1 reverse transcriptase (RT) suggested that the interaction between the γ phosphate of the incoming dNTP and RT residue K65 in the active site is not essential for dNTP insertion, implying that this polymerase may be able to insert dNPs in addition to dNTPs. Methodology/Principal Findings: We examined the ability of recombinant wild type (wt) and mutant RTs with substitutions at residue K65 to utilize a dNDP substrate in primer extension reactions. We found that wild type HIV-1 RT indeed catalyzes incorporation of dNDP substrates whereas RT with mutations of residue K645 were unable to catalyze this reaction. Wild type HIV-1 RT also catalyzed the reverse reaction, inorganic phosphate-dependent phosphorolysis. Nucleotide-mediated phosphorolytic removal of chain-terminating 3′-terminal nucleoside inhibitors such as AZT forms the basis of HIV-1 resistance to such drugs, and this removal is enhanced by thymidine analog mutations (TAMs). We found that both wt and TAM-containing RTs were able to catalyze Pi-mediated phosphorolysis of 3′-terminal AZT at physiological levels of Pi with an efficacy similar to that for ATP-dependent AZT-excision. Conclusion: We have identified two new catalytic function of HIV-1 RT, the use of dNDPs as substrates for DNA synthesis, and the use of Pi as substrate for phosphorolytic removal of primer 3′-terminal nucleotides. The ability to insert dNDPs has been documented for only one other DNA polymerase The RB69 DNA polymerase and the reverse reaction employing inorganic phosphate has not been documented for any DNA polymerase. Importantly, our results show that Pi-mediated phosphorolysis can contribute to AZT resistance and indicates that factors that influence HIV resistance to AZT are more complex than previously appreciated. © 2008 Garforth et al

Effects of gestational age at birth on cognitive performance : a function of cognitive workload demands

Objective: Cognitive deficits have been inconsistently described for late or moderately preterm children but are consistently found in very preterm children. This study investigates the association between cognitive workload demands of tasks and cognitive performance in relation to gestational age at birth. Methods: Data were collected as part of a prospective geographically defined whole-population study of neonatal at-risk children in Southern Bavaria. At 8;5 years, n = 1326 children (gestation range: 23–41 weeks) were assessed with the K-ABC and a Mathematics Test. Results: Cognitive scores of preterm children decreased as cognitive workload demands of tasks increased. The relationship between gestation and task workload was curvilinear and more pronounced the higher the cognitive workload: GA2 (quadratic term) on low cognitive workload: R2 = .02, p<0.001; moderate cognitive workload: R2 = .09, p<0.001; and high cognitive workload tasks: R2 = .14, p<0.001. Specifically, disproportionally lower scores were found for very (<32 weeks gestation) and moderately (32–33 weeks gestation) preterm children the higher the cognitive workload of the tasks. Early biological factors such as gestation and neonatal complications explained more of the variance in high (12.5%) compared with moderate (8.1%) and low cognitive workload tasks (1.7%). Conclusions: The cognitive workload model may help to explain variations of findings on the relationship of gestational age with cognitive performance in the literature. The findings have implications for routine cognitive follow-up, educational intervention, and basic research into neuro-plasticity and brain reorganization after preterm birth

Cerebral Accumulation of Dietary Derivable Plant Sterols does not Interfere with Memory and Anxiety Related Behavior in Abcg5−/− Mice

Plant sterols such as sitosterol and campesterol are frequently applied as functional food in the prevention of atherosclerosis. Recently, it became clear that plasma derived plant sterols accumulate in murine brains. We questioned whether plant sterols in the brain are associated with alterations in brain cholesterol homeostasis and subsequently with brain functions. ATP binding cassette (Abc)g5−/− mice, a phytosterolemia model, were compared to Abcg5+/+ mice for serum and brain plant sterol accumulation and behavioral and cognitive performance. Serum and brain plant sterol concentrations were respectively 35–70-fold and 5–12-fold increased in Abcg5−/− mice (P < 0.001). Plant sterol accumulation resulted in decreased levels of desmosterol (P < 0.01) and 24(S)-hydroxycholesterol (P < 0.01) in the hippocampus, the brain region important for learning and memory functions, and increased lanosterol levels (P < 0.01) in the cortex. However, Abcg5−/− and Abcg5+/+ displayed no differences in memory functions or in anxiety and mood related behavior. The swimming speed of the Abcg5−/− mice was slightly higher compared to Abcg5+/+ mice (P < 0.001). In conclusion, plant sterols in the brains of Abcg5−/− mice did have consequences for brain cholesterol metabolism, but did not lead to an overt phenotype of memory or anxiety related behavior. Thus, our data provide no contra-indication for nutritional intake of plant sterol enriched nutrition

myKaryoView: A Light-Weight Client for Visualization of Genomic Data

The Distributed Annotation System (DAS) is a protocol for easy sharing and integration of biological annotations. In order to visualize feature annotations in a genomic context a client is required. Here we present myKaryoView, a simple light-weight DAS tool for visualization of genomic annotation. myKaryoView has been specifically configured to help analyse data derived from personal genomics, although it can also be used as a generic genome browser visualization. Several well-known data sources are provided to facilitate comparison of known genes and normal variation regions. The navigation experience is enhanced by simultaneous rendering of different levels of detail across chromosomes. A simple interface is provided to allow searches for any SNP, gene or chromosomal region. User-defined DAS data sources may also be added when querying the system. We demonstrate myKaryoView capabilities for adding user-defined sources with a set of genetic profiles of family-related individuals downloaded directly from 23andMe. myKaryoView is a web tool for visualization of genomic data specifically designed for direct-to-consumer genomic data that uses publicly available data distributed throughout the Internet. It does not require data to be held locally and it is capable of rendering any feature as long as it conforms to DAS specifications. Configuration and addition of sources to myKaryoView can be done through the interface. Here we show a proof of principle of myKaryoView's ability to display personal genomics data with 23andMe genome data sources. The tool is available at: http://mykaryoview.com

Functioning styles of personality disorders and five-factor normal personality traits: a correlation study in Chinese students

BACKGROUND: Previous studies show that both the categorical and dimensional descriptors of personality disorders are correlated with normal personality traits. Recently, a 92-item inventory, the Parker Personality Measure (PERM) was designed as a more efficient and precise first-level assessment of personality disorders. Whether the PERM constructs are correlated with those of the five-factor models of personality needs to be clarified. METHODS: We therefore invited 913 students from poly-technical schools and colleges in China to answer the PERM, the Five-Factor Nonverbal Personality Questionnaire (FFNPQ), and the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ). RESULTS: Most personality constructs had satisfactory internal alphas. PERM constructs were loaded with FFNPQ and ZKPQ traits clearly on four factors, which can be labelled as Dissocial, Emotional Dysregulation, Inhibition and Compulsivity, as reported previously. FFNPQ Openness to Experience, Conscientiousness and Extraversion formed another Factor, named Experience Hunting, which was not clearly covered by PERM or ZKPQ. CONCLUSION: The PERM constructs were loaded in a predictable way on the disordered super-traits, suggesting the PERM might offer assistance measuring personality function in clinical practice

Cold gas accretion in galaxies

Evidence for the accretion of cold gas in galaxies has been rapidly accumulating in the past years. HI observations of galaxies and their environment have brought to light new facts and phenomena which are evidence of ongoing or recent accretion: 1) A large number of galaxies are accompanied by gas-rich dwarfs or are surrounded by HI cloud complexes, tails and filaments. It may be regarded as direct evidence of cold gas accretion in the local universe. It is probably the same kind of phenomenon of material infall as the stellar streams observed in the halos of our galaxy and M31. 2) Considerable amounts of extra-planar HI have been found in nearby spiral galaxies. While a large fraction of this gas is produced by galactic fountains, it is likely that a part of it is of extragalactic origin. 3) Spirals are known to have extended and warped outer layers of HI. It is not clear how these have formed, and how and for how long the warps can be sustained. Gas infall has been proposed as the origin. 4) The majority of galactic disks are lopsided in their morphology as well as in their kinematics. Also here recent accretion has been advocated as a possible cause. In our view, accretion takes place both through the arrival and merging of gas-rich satellites and through gas infall from the intergalactic medium (IGM). The infall may have observable effects on the disk such as bursts of star formation and lopsidedness. We infer a mean ``visible'' accretion rate of cold gas in galaxies of at least 0.2 Msol/yr. In order to reach the accretion rates needed to sustain the observed star formation (~1 Msol/yr), additional infall of large amounts of gas from the IGM seems to be required.Comment: To appear in Astronomy & Astrophysics Reviews. 34 pages. Full-resolution version available at http://www.astron.nl/~oosterlo/accretionRevie

Effect of simulated dawn on quality of sleep – a community-based trial

BACKGROUND: Morning light exposure administered as simulated dawn looks a promising method to treat Seasonal Affective Disorder, but it may moreover help with resetting the inaccurate organisation of body clock functions relative to sleep occurring in winter among people in general. Disturbances in sleep patterns are common and may compromise wellbeing even in the short term. Our hypothesis was that simulated dawn could improve the subjective quality of sleep during winter. METHODS: A community-based trial with 100 volunteer subjects provided with dawn simulators. Study period lasted for eight weeks, and subjects used the dawn simulators for two weeks at a time, each subject acting as his own control (ABAB-design). Main outcome measure was subjective quality of sleep recorded each morning with Groningen Sleep Quality Scale. RESULTS: 77 subjects completed the trial. Quality of sleep improved while subjects were using dawn simulator-devices (p = 0.001). The treatment became beneficial after six days' use of dawn simulator, but the effect did not last after the use was ceased. CONCLUSION: Dawn simulation may help to improve the subjective quality of sleep, but the benefits are modest. Further research is needed to verify these findings and to elucidate the mechanism by which dawn simulation acts on the sleep-wake pattern

Quantitative Characterization of the Filiform Mechanosensory Hair Array on the Cricket Cercus

Crickets and other orthopteran insects sense air currents with a pair of abdominal appendages resembling antennae, called cerci. Each cercus in the common house cricket Acheta domesticus is approximately 1 cm long, and is covered with 500 to 750 filiform mechanosensory hairs. The distribution of the hairs on the cerci, as well as the global patterns of their movement vectors, have been characterized semi-quantitatively in studies over the last 40 years, and have been shown to be very stereotypical across different animals in this species. Although the cercal sensory system has been the focus of many studies in the areas of neuroethology, development, biomechanics, sensory function and neural coding, there has not yet been a quantitative study of the functional morphology of the receptor array of this important model system.We present a quantitative characterization of the structural characteristics and functional morphology of the cercal filiform hair array. We demonstrate that the excitatory direction along each hair's movement plane can be identified by features of its socket that are visible at the light-microscopic level, and that the length of the hair associated with each socket can also be estimated accurately from a structural parameter of the socket. We characterize the length and directionality of all hairs on the basal half of a sample of three cerci, and present statistical analyses of the distributions.The inter-animal variation of several global organizational features is low, consistent with constraints imposed by functional effectiveness and/or developmental processes. Contrary to previous reports, however, we show that the filiform hairs are not re-identifiable in the strict sense

A new measure for functional similarity of gene products based on Gene Ontology

BACKGROUND: Gene Ontology (GO) is a standard vocabulary of functional terms and allows for coherent annotation of gene products. These annotations provide a basis for new methods that compare gene products regarding their molecular function and biological role. RESULTS: We present a new method for comparing sets of GO terms and for assessing the functional similarity of gene products. The method relies on two semantic similarity measures; sim(Rel )and funSim. One measure (sim(Rel)) is applied in the comparison of the biological processes found in different groups of organisms. The other measure (funSim) is used to find functionally related gene products within the same or between different genomes. Results indicate that the method, in addition to being in good agreement with established sequence similarity approaches, also provides a means for the identification of functionally related proteins independent of evolutionary relationships. The method is also applied to estimating functional similarity between all proteins in Saccharomyces cerevisiae and to visualizing the molecular function space of yeast in a map of the functional space. A similar approach is used to visualize the functional relationships between protein families. CONCLUSION: The approach enables the comparison of the underlying molecular biology of different taxonomic groups and provides a new comparative genomics tool identifying functionally related gene products independent of homology. The proposed map of the functional space provides a new global view on the functional relationships between gene products or protein families

The emergence of inequality in social groups: network structure and institutions affect the distribution of earnings in cooperation games

From small communities to entire nations and society at large, inequality in wealth, social status, and power is one of the most pervasive and tenacious features of the social world. What causes inequality to emerge and persist? In this study, we investigate how the structure and rules of our interactions can increase inequality in social groups. Specifically, we look into the effects of four structural conditions—network structure, network fluidity, reputation tracking, and punishment institutions—on the distribution of earnings in network cooperation games. We analyze 33 experiments comprising 96 experimental conditions altogether. We find that there is more inequality in clustered networks compared to random networks, in fixed networks compared to randomly rewired and strategically updated networks, and in groups with punishment institutions compared to groups without. Secondary analyses suggest that the reasons inequality emerges under these conditions may have to do with the fact that fixed networks allow exploitation of the poor by the wealthy and clustered networks foster segregation between the poor and the wealthy, while the burden of costly punishment falls onto the poor, leaving them poorer. Surprisingly, we do not find evidence that inequality is affected by reputation in a systematic way but this could be because reputation needs to play out in a particular network environment in order to have an effect. Overall, our findings suggest possible strategies and interventions to decrease inequality and mitigate its negative impact, particularly in the context of mid- and large-sized organizations and online communities