Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase.

BACKGROUND: Insulin resistance and arterial hypertension are related, but the underlying mechanism is unknown. Endothelial nitric oxide synthase (eNOS) is expressed in skeletal muscle, where it may govern metabolic processes, and in the vascular endothelium, where it regulates arterial pressure. METHODS AND RESULTS: To study the role of eNOS in the control of the metabolic action of insulin, we assessed insulin sensitivity in conscious mice with disruption of the gene encoding for eNOS. eNOS(-/-) mice were hypertensive and had fasting hyperinsulinemia, hyperlipidemia, and a 40% lower insulin-stimulated glucose uptake than control mice. Insulin resistance in eNOS(-/-) mice was related specifically to impaired NO synthesis, because in equally hypertensive 1-kidney/1-clip mice (a model of renovascular hypertension), insulin-stimulated glucose uptake was normal. CONCLUSIONS: These results indicate that eNOS is important for the control not only of arterial pressure but also of glucose and lipid homeostasis. A single gene defect, eNOS deficiency, may represent the link between metabolic and cardiovascular disease.

Experimentally increased group diversity improves disease resistance in an ant species.

A leading hypothesis linking parasites to social evolution is that more genetically diverse social groups better resist parasites. Moreover, group diversity can encompass factors other than genetic variation that may also influence disease resistance. Here, we tested whether group diversity improved disease resistance in an ant species with natural variation in colony queen number. We formed experimental groups of workers and challenged them with the fungal parasite Metarhizium anisopliae. Workers originating from monogynous colonies (headed by a single queen and with low genetic diversity) had higher survival than workers originating from polygynous ones, both in uninfected groups and in groups challenged with M. anisopliae. However, an experimental increase of group diversity by mixing workers originating from monogynous colonies strongly increased the survival of workers challenged with M. anisopliae, whereas it tended to decrease their survival in absence of infection. This experiment suggests that group diversity, be it genetic or environmental, improves the mean resistance of group members to the fungal infection, probably through the sharing of physiological or behavioural defences.

Pressure to change and resistance against it: consumer perceptions and acceptance of nutritionally modified foods

Selostus: Muutospaineet ja muutosvastarinta: kuluttajien suhtautuminen ravitsemuksellisesti muunnettuihin elintarvikkeisiin

The ATP-binding cassette transporter-encoding gene CgSNQ2 is contributing to the CgPDR1-dependent azole resistance of Candida glabrata.

Our previous investigation on Candida glabrata azole-resistant isolates identified two isolates with unaltered expression of CgCDR1/CgCDR2, but with upregulation of another ATP-binding cassette transporter, CgSNQ2, which is a gene highly similar to ScSNQ2 from Saccharomyces cerevisiae. One of the two isolates (BPY55) was used here to elucidate this phenomenon. Disruption of CgSNQ2 in BPY55 decreased azole resistance, whereas reintroduction of the gene in a CgSNQ2 deletion mutant fully reversed this effect. Expression of CgSNQ2 in a S. cerevisiae strain lacking PDR5 mediated not only resistance to azoles but also to 4-nitroquinoline N-oxide, which is a ScSNQ2-specific substrate. A putative gain-of-function mutation, P822L, was identified in CgPDR1 from BPY55. Disruption of CgPDR1 in BPY55 conferred enhanced azole susceptibility and eliminated CgSNQ2 expression, whereas introduction of the mutated allele in a susceptible strain where CgPDR1 had been disrupted conferred azole resistance and CgSNQ2 upregulation, indicating that CgSNQ2 was controlled by CgPDR1. Finally, CgSNQ2 was shown to be involved in the in vivo response to fluconazole. Together, our data first demonstrate that CgSNQ2 contributes to the development of CgPDR1-dependent azole resistance in C. glabrata. The overlapping in function and regulation between CgSNQ2 and ScSNQ2 further highlight the relationship between S. cerevisiae and C. glabrata.

Fecundity and survival in relation to resistance to oxidative stress in a free-living bird.

Major life history traits, such as fecundity and survival, have been consistently demonstrated to covary positively in nature, some individuals having more resources than others to allocate to all aspects of their life history. Yet, little is known about which resources (or state variables) may account for such covariation. Reactive oxygen species (ROS) are natural by-products of metabolism and, when ROS production exceeds antioxidant defenses, organisms are exposed to oxidative stress that can have deleterious effects on their fecundity and survival. Using a wild, long-lived bird, the Alpine Swift (Apus melba), we examined whether individual red cell resistance to oxidative stress covaried with fecundity and survival. We found that males that survived to the next breeding season tended to be more resistant to oxidative stress, and females with higher resistance to oxidative stress laid larger clutches. Furthermore, the eggs of females with low resistance to oxidative stress were less likely to hatch than those of females with high resistance to oxidative stress. By swapping entire clutches at clutch completion, we then demonstrated that hatching failure was related to the production of low-quality eggs by females with low resistance to oxidative stress, rather than to inadequate parental care during incubation. Although male and female resistance to oxidative stress covaried with age, the relationships among oxidative stress, survival, and fecundity occurred independently of chronological age. Overall, our study suggests that oxidative stress may play a significant role in shaping fecundity and survival in the wild. It further suggests that the nature of the covariation between resistance to oxidative stress and life history traits is sex specific, high resistance to oxidative stress covarying primarily with fecundity in females and with survival in males.

Differences in low-grade chronic inflammation and insulin resistance in women with previous gestational diabetes mellitus and women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) and gestational diabetes mellitus (GDM) are both characterized by an increase in insulin resistance. Our goal in the present study was to measure insulin resistance (as estimated by homeostasis model assessment, sex hormone-binding globulin (SHBG) and adiponectin concentrations) and parameters of low-grade inflammation in non-diabetic, non-hyperandrogenic ovulatory women with previous GDM (pGDM) and in non-diabetic women with classic PCOS, characterized by hyperandrogenism and oligo/anovulation. PATIENTS AND DESIGN: We evaluated 20 women with PCOS, 18 women with pGDM and 19 controls, all matched according to body mass index (BMI). Fasting blood samples were drawn in all women 3-6 days after spontaneous or dydrogesterone-induced withdrawal bleeding. Body fat distribution was assessed using dual-energy X-ray absorptiometry in all women. RESULTS: After adjusting for age and percent body fat, measures of insulin resistance such as SHBG and adiponectin concentrations were decreased and central obesity was increased in women with PCOS and pGDM compared with controls (all p < 0.05). Parameters of low-grade inflammation such as serum tumor necrosis factor-alpha and highly sensitive C-reactive protein concentrations, white blood cell and neutrophil count were increased only in women with PCOS compared with BMI-matched controls (all p < 0.05). CONCLUSIONS: Certain markers of insulin resistance are increased in both women with PCOS and women with pGDM, while low-grade inflammation is increased only in PCOS. PCOS and GDM might represent specific phenotypes of one disease entity with an increased risk of cardiovascular disease, whereby women with PCOS demonstrate an augmented cardiovascular risk profile.

Natural malaria infection reduces starvation resistance of nutritionally stressed mosquitoes.

In disease ecology, there is growing evidence that environmental quality interacts with parasite and host to determine host susceptibility to an infection. Most studies of malaria parasites have focused on the infection costs incurred by the hosts, and few have investigated the costs on mosquito vectors. The interplay between the environment, the vector and the parasite has therefore mostly been ignored and often relied on unnatural or allopatric Plasmodium/vector associations. Here, we investigated the effects of natural avian malaria infection on both fecundity and survival of field-caught female Culex pipiens mosquitoes, individually maintained in laboratory conditions. We manipulated environmental quality by providing mosquitoes with different concentrations of glucose-feeding solution prior to submitting them to a starvation challenge. We used molecular-based methods to assess mosquitoes' infection status. We found that mosquitoes infected with Plasmodium had lower starvation resistance than uninfected ones only under low nutritional conditions. The effect of nutritional stress varied with time, with the difference of starvation resistance between optimally and suboptimally fed mosquitoes increasing from spring to summer, as shown by a significant interaction between diet treatment and months of capture. Infected and uninfected mosquitoes had similar clutch size, indicating no effect of infection on fecundity. Overall, this study suggests that avian malaria vectors may suffer Plasmodium infection costs in their natural habitat, under certain environmental conditions. This may have major implications for disease transmission in the wild.

Detection of HIV drug resistance during antiretroviral treatment and clinical progression in a large European cohort study.

OBJECTIVE(S): To investigate the relationship between detection of HIV drug resistance by 2 years from starting antiretroviral therapy and the subsequent risk of progression to AIDS and death. DESIGN: Virological failure was defined as experiencing two consecutive viral loads of more than 400 copies/ml in the time window between 0.5 and 2 years from starting antiretroviral therapy (baseline). Patients were grouped according to evidence of virological failure and whether there was detection of the International AIDS Society resistance mutations to one, two or three drug classes in the time window. METHODS: Standard survival analysis using Kaplan-Meier curves and Cox proportional hazards regression model with time-fixed covariates defined at baseline was employed. RESULTS: We studied 8229 patients in EuroSIDA who started antiretroviral therapy and who had at least 2 years of clinical follow-up. We observed 829 AIDS events and 571 deaths during 38,814 person-years of follow-up resulting in an overall incidence of new AIDS and death of 3.6 per 100 person-years of follow-up [95% confidence interval (CI):3.4-3.8]. By 96 months from baseline, the proportion of patients with a new AIDS diagnosis or death was 20.3% (95% CI:17.7-22.9) in patients with no evidence of virological failure and 53% (39.3-66.7) in those with virological failure and mutations to three drug classes (P = 0.0001). An almost two-fold difference in risk was confirmed in the multivariable analysis (adjusted relative hazard = 1.8, 95% CI:1.2-2.7, P = 0.005). CONCLUSION: Although this study shows an association between the detection of resistance at failure and risk of clinical progression, further research is needed to clarify whether resistance reflects poor adherence or directly increases the risk of clinical events via exhaustion of drug options.

Antifungal drug resistance mechanisms in fungal pathogens from the perspective of transcriptional gene regulation.

Fungi are primitive eukaryotes and have adapted to a variety of niches during evolution. Some fungal species may interact with other life forms (plants, insects, mammals), but are considered as pathogens when they cause mild to severe diseases. Chemical control strategies have emerged with the development of several drugs with antifungal activity against pathogenic fungi. Antifungal agents have demonstrated their efficacy by improving patient health in medicine. However, fungi have counteracted antifungal agents in several cases by developing resistance mechanisms. These mechanisms rely on drug resistance genes including multidrug transporters and drug targets. Their regulation is crucial for the development of antifungal drug resistance and therefore transcriptional factors critical for their regulation are being characterized. Recent genome-wide studies have revealed complex regulatory circuits involving these genetic and transcriptional regulators. Here, we review the current understanding of the transcriptional regulation of drug resistance genes from several fungal pathogens including Candida and Aspergillus species.

Perception and Interpretation of Advance Warning Signs on County Roads, HR-256, 1984

This research consisted of five laboratory experiments designed to address the following two objectives in an integrated analysis: (1) To discriminate between the symbol Stop Ahead warning sign and a small set of other signs (which included the word-legend Stop Ahead sign); and (2) To analyze sign detection, recognizability, and processing characteristics by drivers. A set of 16 signs was used in each of three experiments. A tachistoscope was used to display each sign image to a respondent for a brief interval in a controlled viewing experiment. The first experiment was designed to test detection of a sign in the driver's visual field; the second experiment was designed to test the driver's ability to recognize a given sign in the visual field; and the third experiment was designed to test the speed and accuracy of a driver's response to each sign as a command to perform a driving action. A fourth experiment tested the meanings drivers associated with an eight-sign subset of the 16 signs used in the first three experiments. A fifth experiment required all persons to select which (if any) signs they considered to be appropriate for use on two scale model county road intersections. The conclusions are that word-legend Stop Ahead signs are more effective driver communication devices than symbol stop-ahead signs; that it is helpful to drivers to have a word plate supplementing the symbol sign if a symbol sign is used; and that the guidance in the Manual on Uniform Traffic Control Devices on the placement of advance warning signs should not supplant engineering judgment in providing proper sign communication at an intersection.

Lateral Load Resistance of Diaphragms in Prestressed Concrete Girder Bridges, HR-319, 1991

Each year several prestressed concrete girder bridges in Iowa and other states are struck and damaged by vehicles with loads too high to pass under the bridge. Whether or not intermediate diaphragms play a significant role in reducing the effect of these unusual loading conditions has often been a topic of discussion. A study of the effects of the type and location of intermediate diaphragms in prestressed concrete girder bridges when the bridge girder flanges were subjected to various levels of vertical and horizontal loading was undertaken. The purpose of the research was to determine whether steel diaphragms of any conventional configuration can provide adequate protection to minimize the damage to prestressed concrete girders caused by lateral loads, similar to the protection provided by the reinforced concrete intermediate diaphragms presently being used by the Iowa Department of Transportation. The research program conducted and described in this report included the following: A comprehensive literature search and survey questionnaire were undertaken to define the state-of-the-art in the use of intermediate diaphragms in prestressed concrete girder bridges. A full scale, simple span, restressed concrete girder bridge model, containing three beams was constructed and tested with several types of intermediate diaphragms located at the one-third points of the span or at the mid-span. Analytical studies involving a three-dimensional finite element analysis model were used to provide additional information on the behavior of the experimental bridge. The performance of the bridge with no intermediate diaphragms was quite different than that with intermediate diaphragms in place. All intermediate diaphragms tested had some effect in distributing the loads to the slab and other girders, although some diaphragm types performed better than others. The research conducted has indicated that the replacement of the reinforced concrete intermediate diaphragms currently being used in Iowa with structural steel diaphragms may be possible.

Development of a Conductometric Test for Frost Resistance of Concrete, HR-272, 1988

Research is described that was aimed at developing a test method which can be reasonably and rapidly performed in the laboratory and in the field to predict, with a high degree of certainty, the behavior of concrete subjected to the action of alternate freezing and thawing. The conductometric evaluation of concrete durability was explored with 3 different test methods: conductometric evaluation of the resistance of concrete to rapid freezing and thawing; conductomtric evaluation of the resistance of concrete to natural freezing and thawing, and conductometric evaluation of the pore size distribution of concrete and its correlation to concrete durability. The study showed that conductance could be used as a viable method for determining the durability of portland cement concrete. This would also allow the continuous monitoring of concrete durability without the removal twice per week from the freeze/thaw chamber. Recommendations for the continued development of these test methods are also included.

Resistance to extreme strategies, rather than prosocial preferences, can explain human cooperation in public goods games.

The results of numerous economic games suggest that humans behave more cooperatively than would be expected if they were maximizing selfish interests. It has been argued that this is because individuals gain satisfaction from the success of others, and that such prosocial preferences require a novel evolutionary explanation. However, in previous games, imperfect behavior would automatically lead to an increase in cooperation, making it impossible to decouple any form of mistake or error from prosocial cooperative decisions. Here we empirically test between these alternatives by decoupling imperfect behavior from prosocial preferences in modified versions of the public goods game, in which individuals would maximize their selfish gain by completely (100%) cooperating. We found that, although this led to higher levels of cooperation, it did not lead to full cooperation, and individuals still perceived their group mates as competitors. This is inconsistent with either selfish or prosocial preferences, suggesting that the most parsimonious explanation is imperfect behavior triggered by psychological drives that can prevent both complete defection and complete cooperation. More generally, our results illustrate the caution that must be exercised when interpreting the evolutionary implications of economic experiments, especially the absolute level of cooperation in a particular treatment.