All organisms have elaborate mechanisms to control rates of protein production. However, protein production is also subject to stochastic fluctuations, or "noise." Several recent studies in ...Saccharomyces cerevisiae and Escherichia coli have investigated the relationship between transcription and translation rates and stochastic fluctuations in protein levels, or more generally, how such randomness is a function of intrinsic and extrinsic factors. However, the fundamental question of whether stochasticity in protein expression is generally biologically relevant has not been addressed, and it remains unknown whether random noise in the protein production rate of most genes significantly affects the fitness of any organism. We propose that organisms should be particularly sensitive to variation in the protein levels of two classes of genes: genes whose deletion is lethal to the organism and genes that encode subunits of multiprotein complexes. Using an experimentally verified model of stochastic gene expression in S. cerevisiae, we estimate the noise in protein production for nearly every yeast gene, and confirm our prediction that the production of essential and complex-forming proteins involves lower levels of noise than does the production of most other genes. Our results support the hypothesis that noise in gene expression is a biologically important variable, is generally detrimental to organismal fitness, and is subject to natural selection.
Physically interacting proteins or parts of proteins are expected to evolve in a coordinated manner that preserves proper interactions. Such coevolution at the amino acid-sequence level is well ...documented and has been used to predict interacting proteins, domains, and amino acids. Interacting proteins are also often precisely coexpressed with one another, presumably to maintain proper stoichiometry among interacting components. Here, we show that the expression levels of physically interacting proteins coevolve. We estimate average expression levels of genes from four closely related fungi of the genus Saccharomyces using the codon adaptation index and show that expression levels of interacting proteins exhibit coordinated changes in these different species. We find that this coevolution of expression is a more powerful predictor of physical interaction than is coevolution of amino acid sequence. These results demonstrate that gene expression levels can coevolve, adding another dimension to the study of the coevolution of interacting proteins and underscoring the importance of maintaining coexpression of interacting proteins over evolutionary time. Our results also suggest that expression coevolution can be used for computational prediction of protein-protein interactions.
To evaluate the efficacy and upper gastrointestinal (UGI) safety of celecoxib, compared with nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs), among patients with osteoarthritis.
A total of ...13
274 osteoarthritis patients from 39 countries were randomly assigned to double-blind treatment with either celecoxib 100 mg twice daily (BID), celecoxib 200 mg BID, or nonselective NSAID therapy (diclofenac 50 mg BID or naproxen 500 mg BID) for 12 weeks. Standard validated measures were used to assess osteoarthritis efficacy. Serious UGI events were evaluated by 2 blinded, independent, gastrointestinal events committees.
Results from all primary efficacy assessments showed that both dosages of celecoxib were as effective as NSAIDs in treating osteoarthritis. Significantly more ulcer complications occurred within the nonselective NSAID group (0.8/100 patient-years) compared with the celecoxib group (0.1/100 patient-years) (odds ratio = 7.02; 95% confidence interval CI, 1.46 to 33.80;
P =.008). There were fewer ulcer complications in the celecoxib group compared with the NSAID group, both in patients taking concomitant aspirin and those not taking aspirin, but the difference reached statistical significance only in the latter comparison. The number of cardiovascular thromboembolic events was low and not statistically different between the groups (eg, myocardial infarction rates: celecoxib 10 events 0.55/100 patient-years vs NSAIDs 1 event 0.11/100 patient-years, (
P =.11), but the study was not powered to detect such differences.
In the treatment of osteoarthritis, celecoxib is as effective as the nonspecific NSAIDs naproxen and diclofenac, but has significantly fewer serious upper gastrointestinal events.
The addition of breast magnetic resonance imaging (MRI) to screening mammography for women with BRCA mutations significantly increases sensitivity, but there is little data on clinical outcomes. We ...report screening performance, cancer stage, distant recurrence rate, and breast cancer-specific mortality in our screening study.
From 1997 to 2009, 496 women aged 25 to 65 years with a known BRCA1/2 mutation, of whom 380 had no previous cancer history, were enrolled in a prospective screening trial that included annual MRI and mammography.
In 1847 screening rounds, 57 cancers were identified (53 screen-detected, 1 interval, and 3 incidental at prophylactic mastectomy), of which 37 (65%) were invasive. Sensitivity of MRI vs mammography was 86% vs 19% over the entire study period (P<0.0001), but was 74% vs 35% from 1997 to 2002 (P=0.02) and 94% vs 9% from 2003 to 2009 (P<0.0001), respectively. The relative sensitivities of MRI and mammography did not differ by mutation, age, or invasive vs non-invasive disease. Of the incident cancers, 97% were Stage 0 or 1. Of 28 previously unaffected women diagnosed with invasive cancer, 1 BRCA1 mutation carrier died following relapse of a 3 cm, node-positive breast cancer diagnosed on her first screen at age 48 (annual breast cancer mortality rate=0.5%). Three patients died of other causes. None of the 24 survivors has had a distant recurrence at a median follow-up of 8.4 years since diagnosis.
Magnetic resonance imaging surveillance of women with BRCA1/2 mutations will detect the majority of breast cancers at a very early stage. The absence of distant recurrences of incident cancers to date is encouraging. However, longer follow-up is needed to confirm the safety of breast surveillance.
Summary
Background
Evidence suggests that exposure to polycyclic aromatic hydrocarbons (PAHs) increases atopy; it is unclear how PAH exposure is linked to increased severity of atopic diseases.
...Objective
We hypothesized that ambient PAH exposure is linked to impairment of immunity in atopic children (defined as children with asthma and/or allergic rhinitis) from Fresno, California, an area with elevated ambient PAHs.
Methods
We recruited 256 subjects from Fresno, CA. Ambient PAH concentrations (ng/m3) were measured using a spatial‐temporal regression model over multiple time periods. Asthma diagnosis was determined by current NHLBI criteria. Phenotyping and functional immune measurements were performed from isolated cells. For epigenetic measurements, DNA was isolated and pyrosequenced.
Results
We show that higher average PAH exposure was significantly associated with impaired Treg function and increased methylation in the forkhead box protein 3 (FOXP3) locus (P < 0.05), conditional on atopic status. These epigenetic modifications were significantly linked to differential protein expression of FOXP3 (P < 0.001). Methylation was associated with cellular functional changes, specifically Treg dysfunction, and an increase in total plasma IgE levels. Protein expression of IL‐10 decreased and IFN‐γ increased as the extent of PAH exposure increased. The strength of the associations generally increased as the time window for average PAH exposure increased from 24 hr to 1 year, suggesting more of a chronic response. Significant associations with chronic PAH exposure and immune outcomes were also observed in subjects with allergic rhinitis.
Conclusions and Clinical Relevance
Collectively, these results demonstrate that increased ambient PAH exposure is associated with impaired systemic immunity and epigenetic modifications in a key locus involved in atopy: FOXP3, with a higher impact on atopic children. The results suggest that increased atopic clinical symptoms in children could be linked to increased PAH exposure in air pollution.
We used cDNA microarrays to assess gene expression profiles in 60 human cancer cell lines used in a drug discovery screen by the National Cancer Institute. Using these data, we linked bioinformatics ...and chemoinformatics by correlating gene expression and drug activity patterns in the NCI60 lines. Clustering the cell lines on the basis of gene expression yielded relationships very different from those obtained by clustering the cell lines on the basis of their response to drugs. Gene-drug relationships for the clinical agents 5-fluorouracil and L-asparaginase exemplify how variations in the transcript levels of particular genes relate to mechanisms of drug sensitivity and resistance. This is the first study to integrate large databases on gene expression and molecular pharmacology.
Objectives Most studies of carpal tunnel syndrome (CTS) incidence and prevalence among workers have been limited by small sample sizes or restricted to a small subset of jobs. We established a common ...CTS case definition and then pooled CTS prevalence and incidence data across six prospective studies of musculoskeletal outcomes to measure CTS frequency and allow better studies of etiology. Methods Six research groups collected prospective data at >50 workplaces including symptoms characteristic of CTS and electrodiagnostic studies (EDS) of the median and ulnar nerves across the dominant wrist. While study designs and the timing of data collection varied across groups, we were able to create a common CTS case definition incorporating both symptoms and EDS results from data that were collected in all studies. Results At the time of enrollment, 7.8% of 4321 subjects met our case definition and were considered prevalent cases of CTS. During 8833 person-years of follow-up, an additional 204 subjects met the CTS case definition for an overall incidence rate of 2.3 CTS cases per 100 person-years. Conclusions Both prevalent and incident CTS were common in data pooled across multiple studies and sites. The large number of incident cases in this prospective study provides adequate power for future exposure— response analyses to identify work- and non-work-related risk factors for CTS. The prospective nature allows determination of the temporal relations necessary for causal inference.
The complete sequence of the 1,267,782 bp genome of Wolbachia pipientis wMel, an obligate intracellular bacteria of Drosophila melanogaster, has been determined. Wolbachia, which are found in a ...variety of invertebrate species, are of great interest due to their diverse interactions with different hosts, which range from many forms of reproductive parasitism to mutualistic symbioses. Analysis of the wMel genome, in particular phylogenomic comparisons with other intracellular bacteria, has revealed many insights into the biology and evolution of wMel and Wolbachia in general. For example, the wMel genome is unique among sequenced obligate intracellular species in both being highly streamlined and containing very high levels of repetitive DNA and mobile DNA elements. This observation, coupled with multiple evolutionary reconstructions, suggests that natural selection is somewhat inefficient in wMel, most likely owing to the occurrence of repeated population bottlenecks. Genome analysis predicts many metabolic differences with the closely related Rickettsia species, including the presence of intact glycolysis and purine synthesis, which may compensate for an inability to obtain ATP directly from its host, as Rickettsia can. Other discoveries include the apparent inability of wMel to synthesize lipopolysaccharide and the presence of the most genes encoding proteins with ankyrin repeat domains of any prokaryotic genome yet sequenced. Despite the ability of wMel to infect the germline of its host, we find no evidence for either recent lateral gene transfer between wMel and D. melanogaster or older transfers between Wolbachia and any host. Evolutionary analysis further supports the hypothesis that mitochondria share a common ancestor with the alpha-Proteobacteria, but shows little support for the grouping of mitochondria with species in the order Rickettsiales. With the availability of the complete genomes of both species and excellent genetic tools for the host, the wMel-D. melanogaster symbiosis is now an ideal system for studying the biology and evolution of Wolbachia infections.
Individuals appraise events as a consequence of their own actions (i.e. internal locus of control, LoC) or as the outcome of chance or others' will (i.e. external LoC). We hypothesized that having a ...more external LoC would be associated with higher risk of tobacco and alcohol use. Few studies have examined this association using large prospective data. We evaluated within the Avon Longitudinal Study of Parents and Children (ALSPAC) the associations between LoC at 16 and tobacco and alcohol consumption at 17 and 21 years using logistic regression. A more external LoC at age 16 (
= 4656) was associated with higher odds of being a weekly smoker at age 17 (OR 1.18, 95% CI 1.10-1.25) and 21 (OR 1.14, 95% CI 1.07-1.21) and with dependence measured using the Fagerström Test of Nicotine Dependence at age 17 (OR 1.26, 95% CI 1.05-1.51) and 21 (OR 1.25, 95% CI 1.05-1.49). Individuals with external LoC at age 16 were more likely to be hazardous drinkers according to the Alcohol Use Disorders Identification Test at age 17 (OR 1.09, 95% CI 1.04-1.15) but not at 21 (OR 1.01, 95% CI 0.96-1.06). Having a more external LoC at age 16 is associated with increased tobacco consumption at age 17 and 21 and alcohol consumption at 17 years. LoC may represent an intervention target for preventing substance use and dependence.
Air pollution causes several adverse cardiovascular and respiratory effects. In occupational studies, where levels of particulate matter and polycyclic aromatic hydrocarbons (PAHs) are higher, the ...evidence is inconsistent. The effects of acute and chronic PAH exposure on cardiopulmonary mortality were examined within a Kitimat, Canada, aluminum smelter cohort (n = 7,026) linked to a national mortality database (1957–1999). No standardized mortality ratio was significantly elevated compared with the province's population. Smoking-adjusted internal comparisons were conducted using Cox regression for male subjects (n = 6,423). Ischemic heart disease (IHD) mortality (n = 281) was associated with cumulative benzoapyrene (B(a)P) exposure (hazard ratio = 1.62, 95% confidence interval: 1.06, 2.46) in the highest category. A monotonic but nonsignificant trend was observed with chronic B(a)P exposure and acute myocardial infarction (n = 184). When follow-up was restricted to active employment, the hazard ratio for IHD was 2.39 (95% confidence interval: 0.95, 6.05) in the highest cumulative B(a)P category. The stronger associations observed during employment suggest that risk may not persist after exposure cessation. No associations with recent or current exposure were observed. IHD was associated with chronic (but not current) PAH exposure in a high-exposure occupational setting. Given the widespread workplace exposure to PAHs and heart disease's high prevalence, even modest associations produce a high burden.
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