1,256 research outputs found
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 Ξ³ 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 3β²-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 3β²-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 3β²-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. Β© 2008 Garforth et al
Focus on vulnerable populations and promoting equity in health service utilization ββan analysis of visitor characteristics and service utilization of the Chinese community health service
Background Community health service in China is designed to provide a convenient and affordable primary health service for the city residents, and to promote health equity. Based on data from a large national study of 35 cities across China, we examined the characteristics of the patients and the utilization of community health institutions (CHIs), and assessed the role of community health service in promoting equity in health service utilization for community residents. Methods Multistage sampling method was applied to select 35 cities in China. Four CHIs were randomly chosen in every district of the 35 cities. A total of 88,482 visitors to the selected CHIs were investigated by using intercept survey method at the exit of the CHIs in 2008, 2009, 2010, and 2011. Descriptive analyses were used to analyze the main characteristics (gender, age, and income) of the CHI visitors, and the results were compared with that from the National Health Services Survey (NHSS, including CHIs and higher levels of hospitals). We also analyzed the service utilization and the satisfactions of the CHI visitors. Results The proportions of the children (2.4%) and the elderly (about 22.7%) were lower in our survey than those in NHSS (9.8% and 38.8% respectively). The proportion of the low-income group (26.4%) was apparently higher than that in NHSS (12.5%). The children group had the lowest satisfaction with the CHIs than other age groups. The satisfaction of the low-income visitors was slightly higher than that of the higher-income visitors. The utilization rate of public health services was low in CHIs. Conclusions The CHIs in China appears to fulfill the public health target of uptake by vulnerable populations, and may play an important role in promoting equity in health service utilization. However, services for children and the elderly should be strengthened
Impact of periodic health examination on surgical treatment for uterine fibroids in Beijing: a case-control study
<p>Abstract</p> <p>Background</p> <p>During the past 2 decades, there has been a rapid proliferation of "health examination center (HEC)" across China. The effects of their services on public's health have not been systemically investigated. This study aimed to assess the impact of periodic health examination (PHE) at HEC on surgical treatment for uterine fibroids in Beijing residents.</p> <p>Methods</p> <p>We identified 224 patients with a primary diagnosis of uterine fibroids who had surgical treatment at four Level-1 general hospitals in Beijing, from June 1, 2009 to October 20, 2009. Controls were women who did not have surgery for uterine fibroids, matched (1:1 ratio) for age (within 2 years). A standard questionnaire was used to inquire about whether participants had PHE at HEC during the previous 2 years.</p> <p>Results</p> <p>PHE at HEC within 2 years were associated with surgical treatment for uterine fibroids. Odds ratios was 4.05 (95% CI, 2.61-6.29 P < 0.001), after adjustment for marital status, whether have children, annual family income, health insurance, education level and self-rated uterine fibroids-related symptom severity.</p> <p>Conclusions</p> <p>Our study showed PHE currently provided at HEC in China were associated with significantly increased use of surgical treatment for uterine fibroids in women. Further studies are needed to assess the effects of PHE on clinical as well as on broad societal outcomes in Chinese in contemporary medical settings.</p
A population of luminous accreting black holes with hidden mergers
Major galaxy mergers are thought to play an important part in fuelling the
growth of supermassive black holes. However, observational support for this
hypothesis is mixed, with some studies showing a correlation between merging
galaxies and luminous quasars and others showing no such association. Recent
observations have shown that a black hole is likely to become heavily obscured
behind merger-driven gas and dust, even in the early stages of the merger, when
the galaxies are well separated (5 to 40 kiloparsecs). Merger simulations
further suggest that such obscuration and black-hole accretion peaks in the
final merger stage, when the two galactic nuclei are closely separated (less
than 3 kiloparsecs). Resolving this final stage requires a combination of
high-spatial-resolution infrared imaging and high-sensitivity hard-X-ray
observations to detect highly obscured sources. However, large numbers of
obscured luminous accreting supermassive black holes have been recently
detected nearby (distances below 250 megaparsecs) in X-ray observations. Here
we report high-resolution infrared observations of hard-X-ray-selected black
holes and the discovery of obscured nuclear mergers, the parent populations of
supermassive-black-hole mergers. We find that obscured luminous black holes
(bolometric luminosity higher than 2x10^44 ergs per second) show a significant
(P<0.001) excess of late-stage nuclear mergers (17.6 per cent) compared to a
sample of inactive galaxies with matching stellar masses and star formation
rates (1.1 per cent), in agreement with theoretical predictions. Using
hydrodynamic simulations, we confirm that the excess of nuclear mergers is
indeed strongest for gas-rich major-merger hosts of obscured luminous black
holes in this final stage.Comment: To appear in the 8 November 2018 issue of Nature. This is the
authors' version of the wor
Wide-Scale Analysis of Human Functional Transcription Factor Binding Reveals a Strong Bias towards the Transcription Start Site
We introduce a novel method to screen the promoters of a set of genes with
shared biological function, against a precompiled library of motifs, and find
those motifs which are statistically over-represented in the gene set. The gene
sets were obtained from the functional Gene Ontology (GO) classification; for
each set and motif we optimized the sequence similarity score threshold,
independently for every location window (measured with respect to the TSS),
taking into account the location dependent nucleotide heterogeneity along the
promoters of the target genes. We performed a high throughput analysis,
searching the promoters (from 200bp downstream to 1000bp upstream the TSS), of
more than 8000 human and 23,000 mouse genes, for 134 functional Gene Ontology
classes and for 412 known DNA motifs. When combined with binding site and
location conservation between human and mouse, the method identifies with high
probability functional binding sites that regulate groups of biologically
related genes. We found many location-sensitive functional binding events and
showed that they clustered close to the TSS. Our method and findings were put
to several experimental tests. By allowing a "flexible" threshold and combining
our functional class and location specific search method with conservation
between human and mouse, we are able to identify reliably functional TF binding
sites. This is an essential step towards constructing regulatory networks and
elucidating the design principles that govern transcriptional regulation of
expression. The promoter region proximal to the TSS appears to be of central
importance for regulation of transcription in human and mouse, just as it is in
bacteria and yeast.Comment: 31 pages, including Supplementary Information and figure
Removal of phenol using sulphate radicals activated by natural zeolite-supported cobalt catalysts
Two Co oxide catalysts supported on natural zeolites from Indonesia (INZ) and Australia (ANZ) were prepared and used to activate peroxymonosulphate for degradation of aqueous phenol. The two catalysts were characterized by several techniques such as X-ray diffraction, scanning electron microscopy, energy dispersive X-ray spectroscopy (EDS) and N2 adsorption. It was found that Co/INZ and Co/ANZ are effective in activation of peroxymonosulphate to produce sulphate radicals for phenol degradation. Co/INZ and Co/ANZ could remove phenol up to 100 and 70 %, respectively, at the conditions of 25 ppm phenol (500 mL), 0.2 g catalyst, 1 g oxone and 25 Β°C. Several parameters such as amount of catalyst loading, phenol concentration, oxidant concentration and temperature were found to be the key factors influencing phenol degradation. A pseudo first order would fit to phenol degradation kinetics, and the activation energies on Co/INZ and Co/ANZ were obtained as 52.4 and 61.3 kJ/mol,respectively
Down-Regulation of ZnT8 Expression in INS-1 Rat Pancreatic Beta Cells Reduces Insulin Content and Glucose-Inducible Insulin Secretion
The SLC30A8 gene codes for a pancreatic beta-cell-expressed zinc transporter, ZnT8. A polymorphism in the SLC30A8 gene is associated with susceptibility to type 2 diabetes, although the molecular mechanism through which this phenotype is manifest is incompletely understood. Such polymorphisms may exert their effect via impacting expression level of the gene product. We used an shRNA-mediated approach to reproducibly downregulate ZnT8 mRNA expression by >90% in the INS-1 pancreatic beta cell line. The ZnT8-downregulated cells exhibited diminished uptake of exogenous zinc, as determined using the zinc-sensitive reporter dye, zinquin. ZnT8-downregulated cells showed reduced insulin content and decreased insulin secretion (expressed as percent of total insulin content) in response to hyperglycemic stimulus, as determined by insulin immunoassay. ZnT8-depleted cells also showed fewer dense-core vesicles via electron microscopy. These data indicate that reduced ZnT8 expression in cultured pancreatic beta cells gives rise to a reduced insulin response to hyperglycemia. In addition, although we provide no direct evidence, these data suggest that an SLC30A8 expression-level polymorphism could affect insulin secretion and the glycemic response in vivo
Context and culture associated with alcohol use amongst youth in major urban cities: A cross-country population based survey
Background: Alcohol consumption patterns are dependent upon culture and context. The aim of this study was to interview people aged 18β34 year old living in four cities in different regions of the world to explore differences in a range of alcohol measures to assist in determining culturally appropriate alcohol initiatives for this age group. Method: Multistage random sampling was consistent across the four cities (Ilorin (Nigeria), Wuhan (China), Montevideo (Uruguay) and Moscow (Russia)). The questionnaire was forward and back translated into relevant languages and face-to-face interviewing undertaken. The data were weighted to the population of each city. Uni-variable analysis (ever consumed, first time consumed, age when drunk for first time, number of days consumed, type consumed) and logistic regression modeling were undertaken. The final model for each city was adjusted for age, sex, marital status, highest education and employment status. In total 6235 interviews were undertaken (1391 in Ilorin, 1600 in Montevideo, 1604 in Moscow and 1640 in Wuhan). Results: Alcohol was consumed by 96.4% in Montevideo, 86.1% in Moscow, 53.4% in Wuhan and 33.3% in Ilorin. There was very little difference by gender except Ilorin males were more likely to consume alcohol than females. Alcohol was consumed on more days for Ilorin males; Wuhan females consumed alcohol on the least number of days; Ilorin had the most abstainers; Montevideo and Moscow the highest proportion of light drinkers; Ilorin and Montevideo the highest proportion of heavy drinkers. Differences by type of alcohol were also apparent. The final logistic regression model provided different models including higher alcohol consumption rates for males, 25β34 years of age, divorced/separated marital status and employed part time for Ilorin respondents; males and higher educated for Montevideo; males, 25 to 29 years of age and higher educated for Moscow; and 25β29 years of age, non-married and vocationally trained for those in Wuhan. Conclusion: Alcohol consumption in these four cities does not increase with age as found in most high income countries. The alcohol consumption patterns during this stage of the life cycle are important to assess so that high level, as well as country-specific, planning and interventions can be implemented
Incremental grouping of image elements in vision
One important task for the visual system is to group image elements that belong to an object and to segregate them from other objects and the background. We here present an incremental grouping theory (IGT) that addresses the role of object-based attention in perceptual grouping at a psychological level and, at the same time, outlines the mechanisms for grouping at the neurophysiological level. The IGT proposes that there are two processes for perceptual grouping. The first process is base grouping and relies on neurons that are tuned to feature conjunctions. Base grouping is fast and occurs in parallel across the visual scene, but not all possible feature conjunctions can be coded as base groupings. If there are no neurons tuned to the relevant feature conjunctions, a second process called incremental grouping comes into play. Incremental grouping is a time-consuming and capacity-limited process that requires the gradual spread of enhanced neuronal activity across the representation of an object in the visual cortex. The spread of enhanced neuronal activity corresponds to the labeling of image elements with object-based attention
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