The fate of redundant cues: Further analysis of the redundancy effect

Pearce, Dopson, Haselgrove, and Esber (Journal of Experimental Psychology: Animal Behavior Processes, 38, 167–179, 2012) conducted a series of experiments with rats and pigeons in which the conditioned responding elicited by two types of redundant cue was compared. One of these redundant cues was a blocked cue X from A+ AX+ training, whereas the other was cue Y from a simple discrimination BY+ CY–. Greater conditioned responding was elicited by X than by Y; we refer to this difference as the redundancy effect. To test an explanation of this effect in terms of comparator theory (Denniston, Savastano, & Miller, 2001), a single group of rats in Experiment 1 received training of the form A+ AX+ BY+ CY–, followed by an A– Y+ discrimination. Responding to the individual cues was tested both before and after the latter discrimination. In addition to a replication of the redundancy effect during the earlier test, we observed stronger responding to B than to X, both during the earlier test and, in contradiction of the theory, after the A– Y+ discrimination. In Experiment 2, a blocking group received A+ AX+, a continuous group received AX+ BX–, and a partial group received AX± BX± training. Subsequent tests with X again demonstrated the redundancy effect, but also revealed a stronger response in the partial than in the continuous group. This pattern of results is difficult to explain with error-correction theories that assume that stimuli compete for associative strength during conditioning. We suggest, instead, that the influence of a redundant cue is determined by its relationship with the event with which it is paired, and by the attention it is paid

Patterns of Reproductive Isolation in Toads

Understanding the general features of speciation is an important goal in evolutionary biology, and despite significant progress, several unresolved questions remain. We analyzed an extensive comparative dataset consisting of more than 1900 crosses between 92 species of toads to infer patterns of reproductive isolation. This unique dataset provides an opportunity to examine the strength of reproductive isolation, the development and sex ratios of hybrid offspring, patterns of fertility and infertility, and polyploidization in hybrids all in the context of genetic divergence between parental species. We found that the strength of intrinsic postzygotic isolation increases with genetic divergence, but relatively high levels of divergence are necessary before reproductive isolation is complete in toads. Fertilization rates were not correlated to genetic divergence, but hatching success, the number of larvae produced, and the percentage of tadpoles reaching metamorphosis were all inversely related with genetic divergence. Hybrids between species with lower levels of divergence developed to metamorphosis, while hybrids with higher levels of divergence stopped developing in gastrula and larval stages. Sex ratios of hybrid offspring were biased towards males in 70% of crosses and biased towards females in 30% of crosses. Hybrid females from crosses between closely related species were completely fertile, while approximately half (53%) of hybrid males were sterile, with sterility predicted by genetic divergence. The degree of abnormal ploidy in hybrids was positively related to genetic divergence between parental species, but surprisingly, polyploidization had no effect on patterns of asymmetrical inviability. We discuss explanations for these patterns, including the role of Haldane's rule in toads and anurans in general, and suggest mechanisms generating patterns of reproductive isolation in anurans

Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing:a population-based study

Background<p></p> Familial hypercholesterolaemia (FH) is a common Mendelian condition which, untreated, results in premature coronary heart disease. An estimated 88% of FH cases are undiagnosed in the UK. We previously validated a method for FH mutation detection in a lipid clinic population using next generation sequencing (NGS), but this did not address the challenge of identifying index cases in primary care where most undiagnosed patients receive healthcare. Here, we evaluate the targeted use of NGS as a potential route to diagnosis of FH in a primary care population subset selected for hypercholesterolaemia.<p></p> Methods<p></p> We used microfluidics-based PCR amplification coupled with NGS and multiplex ligation-dependent probe amplification (MLPA) to detect mutations in LDLR, APOB and PCSK9 in three phenotypic groups within the Generation Scotland: Scottish Family Health Study including 193 individuals with high total cholesterol, 232 with moderately high total cholesterol despite cholesterol-lowering therapy, and 192 normocholesterolaemic controls.<p></p> Results<p></p> Pathogenic mutations were found in 2.1% of hypercholesterolaemic individuals, in 2.2% of subjects on cholesterol-lowering therapy and in 42% of their available first-degree relatives. In addition, variants of uncertain clinical significance (VUCS) were detected in 1.4% of the hypercholesterolaemic and cholesterol-lowering therapy groups. No pathogenic variants or VUCS were detected in controls.<p></p> Conclusions<p></p> We demonstrated that population-based genetic testing using these protocols is able to deliver definitive molecular diagnoses of FH in individuals with high cholesterol or on cholesterol-lowering therapy. The lower cost and labour associated with NGS-based testing may increase the attractiveness of a population-based approach to FH detection compared to genetic testing with conventional sequencing. This could provide one route to increasing the present low percentage of FH cases with a genetic diagnosis

Clustering of Unhealthy Behaviors in the Aerobics Center Longitudinal Study

Background Clustering of unhealthy behaviors has been reported in previous studies; however the link with all-cause mortality and differences between those with and without chronic disease requires further investigation. Objectives To observe the clustering effects of unhealthy diet, fitness, smoking, and excessive alcohol consumption in adults with and without chronic disease and to assess all-cause mortality risk according to the clustering of unhealthy behaviors. Methods Participants were 13,621 adults (aged 20–84) from the Aerobics Center Longitudinal Study. Four health behaviors were observed (diet, fitness, smoking, and drinking). Baseline characteristics of the study population and bivariate relations between pairs of the health behaviors were evaluated separately for those with and without chronic disease using cross-tabulation and a chi-square test. The odds of partaking in unhealthy behaviors were also calculated. Latent class analysis (LCA) was used to assess clustering. Cox regression was used to assess the relationship between the behaviors and mortality. Results The four health behaviors were related to each other. LCA results suggested that two classes existed. Participants in class 1 had a higher probability of partaking in each of the four unhealthy behaviors than participants in class 2. No differences in health behavior clustering were found between participants with and without chronic disease. Mortality risk increased relative to the number of unhealthy behaviors participants engaged in. Conclusion Unhealthy behaviors cluster together irrespective of chronic disease status. Such findings suggest that multi-behavioral intervention strategies can be similar in those with and without chronic disease

Physical activity, exercise and self-rated health: a population-based study from Sweden

<p>Abstract</p> <p>Background</p> <p>In order to screen for the most inactive individuals in the population and target health-related interventions where they are most needed it is important to assess different forms of physical activity in population-based studies. The aims were (1) to identify the most inactive individuals in the population by assessing two dimensions of physical activity, (2) to investigate the correlation between exercise and total physical activity and (3) to investigate the association between exercise, total physical activity and good self-rated health.</p> <p>Methods</p> <p>A simple random sample of the Swedish population aged 25–64 years were interviewed about their living conditions, health and lifestyle in a survey performed by Statitics Sweden. In total 1876 women and 1880 men completed the survey during 1999 (response rate 76.6%) when two different questions about physical activity assessed exercise and total physical activity in all domains (e.g. transportation, exercise, and at work). Logistic regression models were used to estimate odds ratios.</p> <p>Results</p> <p>The most inactive individuals (no exercise and total physical activity ≤ 2 hours per week) constituted 4.3% of the sample. The correlation between exercise and total physical activity was low (gamma = 0.4, <it>p = </it>0.02). There were significant associations between higher levels of exercise, total physical activity and good self-rated health after adjustment for age, gender, country of birth, education, employment, marital status, housing tenure, smoking and BMI.</p> <p>Conclusion</p> <p>Both exercise and total physical activity were independently associated with good self-rated health. It seems to be advantageous to use more than one question in population based surveys in order to evaluate several dimensions of physical activity and identify the most inactive individuals.</p

Trends over 5 Decades in U.S. Occupation-Related Physical Activity and Their Associations with Obesity

BACKGROUND: The true causes of the obesity epidemic are not well understood and there are few longitudinal population-based data published examining this issue. The objective of this analysis was to examine trends in occupational physical activity during the past 5 decades and explore how these trends relate to concurrent changes in body weight in the U.S. METHODOLOGY/PRINCIPAL FINDINGS: Analysis of energy expenditure for occupations in U.S. private industry since 1960 using data from the U.S. Bureau of Labor Statistics. Mean body weight was derived from the U.S. National Health and Nutrition Examination Surveys (NHANES). In the early 1960's almost half the jobs in private industry in the U.S. required at least moderate intensity physical activity whereas now less than 20% demand this level of energy expenditure. Since 1960 the estimated mean daily energy expenditure due to work related physical activity has dropped by more than 100 calories in both women and men. Energy balance model predicted weights based on change in occupation-related daily energy expenditure since 1960 for each NHANES examination period closely matched the actual change in weight for 40-50 year old men and women. For example from 1960-62 to 2003-06 we estimated that the occupation-related daily energy expenditure decreased by 142 calories in men. Given a baseline weight of 76.9 kg in 1960-02, we estimated that a 142 calories reduction would result in an increase in mean weight to 89.7 kg, which closely matched the mean NHANES weight of 91.8 kg in 2003-06. The results were similar for women. CONCLUSION: Over the last 50 years in the U.S. we estimate that daily occupation-related energy expenditure has decreased by more than 100 calories, and this reduction in energy expenditure accounts for a significant portion of the increase in mean U.S. body weights for women and men

Aerobic exercise in adolescents with obesity: preliminary evaluation of a modular training program and the modified shuttle test

BACKGROUND: Increasing activity levels in adolescents with obesity requires the development of exercise programs that are both attractive to adolescents and easily reproducible. The aim of this study was to develop a modular aerobic training program for adolescents with severe obesity, with a focus on variety, individual targets and acquiring physical skills. We report here the effects on aerobic fitness from a pilot study. Furthermore, we examined the feasibility of the modified shuttle test (MST) as an outcome parameter for aerobic fitness in adolescents with severe obesity. METHODS: Fifteen adolescents from an inpatient body weight management program participated in the aerobic training study (age 14.7 ± 2.1 yrs, body mass index 37.4 ± 3.5). The subjects trained three days per week for 12 weeks, with each session lasting 30–60 minutes. The modular training program consisted of indoor, outdoor and swimming activities. Feasibility of the MST was studied by assessing construct validity, test-retest reliability and sensitivity to change. RESULTS: Comparing pretraining and end of training period showed large clinically relevant and significant improvements for all aerobic indices: e.g. VO(2 peak )17.5%, effect size (ES) 2.4; W(max )8%, ES 0.8. In addition, a significant improvement was found for the efficiency of the cardiovascular system as assessed by the oxygen pulse (15.8%, ES 1.6). Construct validity, test-retest reliability and sensitivity to change of the MST were very good. MST was significantly correlated with VO(2 peak )(r = 0.79) and W(max )(r = 0.84) but not with anthropometric measures. The MST walking distance improved significantly by 32.5%, ES 2.5. The attendance rate at the exercise sessions was excellent. CONCLUSION: This modular, varied aerobic training program has clinically relevant effects on aerobic performance in adolescents with severe obesity. The added value of our aerobic training program for body weight management programs for adolescents with severe obesity should be studied with a randomized trial. This study further demonstrated that the MST is a reliable, sensitive and easy to administer outcome measure for aerobic fitness in adolescent body weight management trials

Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding

Data availability: All data generated during this study that support the findings are included in the manuscript or in the Supplementary Information.Copyright © 2022, Furniss et al. Antimicrobial resistance in Gram-negative bacteria is one of the greatest threats to global health. New antibacterial strategies are urgently needed, and the development of antibiotic adjuvants that either neutralize resistance proteins or compromise the integrity of the cell envelope is of ever-growing interest. Most available adjuvants are only effective against specific resistance proteins. Here we demonstrate that disruption of cell envelope protein homeostasis simultaneously compromises several classes of resistance determinants. In particular, we find that impairing DsbA-mediated disulfide bond formation incapacitates diverse β-lactamases and destabilizes mobile colistin resistance enzymes. Furthermore, we show that chemical inhibition of DsbA sensitizes multidrug-resistant clinical isolates to existing antibiotics and that the absence of DsbA, in combination with antibiotic treatment, substantially increases the survival of Galleria mellonella larvae infected with multidrug-resistant Pseudomonas aeruginosa. This work lays the foundation for the development of novel antibiotic adjuvants that function as broad-acting resistance breakers.MRC Career Development Award MR/M009505/1 (to D.A.I.M.); the institutional BBSRC-DTP studentships BB/M011178/1 (to N.K.) and BB/M01116X/1 (to H.L.P.); the BBSRC David Philips Fellowship BB/M02623X/1 (to J.M.A.B.); the ISSF Wellcome Trust grant 105603/Z/14/Z (to G.L.-M.); the Brunel Research Innovation and Enterprise Fund, Innovate UK and British Society for Antimicrobial Chemotherapy grants 2018-11143, 37800 and BSAC-2018-0095, respectively (to R.R.MC); the Swiss National Science Foundation Postdoc Mobility and Ambizione Fellowships P300PA_167703 and PZ00P3_180142, respectively (to D.G.)