Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes

Drug resistant infections represent one of the most challenging medical problems of our time. D-cycloserine is an antibiotic used for six decades without significant appearance and dissemination of antibiotic resistant strains, making it an ideal model compound to understand what drives resistance evasion. We therefore investigated why Mycobacterium tuberculosis fails to become resistant to D-cycloserine. To address this question, we employed a combination of bacterial genetics, genomics, biochemistry and fitness analysis in vitro, in macrophages and in mice. Altogether, our results suggest that the ultra-low rate of emergence of D-cycloserine resistance mutations is the dominant biological factor delaying the appearance of clinical resistance to this antibiotic. Furthermore, we also identified potential compensatory mechanisms able to minimize the severe fitness costs of primary D-cycloserine resistance conferring mutations

Thermoelectric properties of Ca0.8Dy0.2MnO3 synthesized by solution combustion process

High-quality Ca0.8Dy0.2MnO3 nano-powders were synthesized by the solution combustion process. The size of the synthesized Ca0.8Dy0.2MnO3 powders was approximately 23 nm. The green pellets were sintered at 1150-1300°C at a step size of 50°C. Sintered Ca0.8Dy0.2MnO3 bodies crystallized in the perovskite structure with an orthorhombic symmetry. The sintering temperature did not affect the Seebeck coefficient, but significantly affected the electrical conductivity. The electrical conductivity of Ca0.8Dy0.2MnO3 increased with increasing temperature, indicating a semiconducting behavior. The absolute value of the Seebeck coefficient gradually increased with an increase in temperature. The highest power factor (3.7 × 10-5 Wm-1 K-2 at 800°C) was obtained for Ca0.8Dy0.2MnO3 sintered at 1,250°C. In this study, we investigated the microstructure and thermoelectric properties of Ca0.8Dy0.2MnO3, depending on sintering temperature

Stratification of Patients With Sjögren’s Syndrome and Patients With Systemic Lupus Erythematosus According to Two Shared Immune Cell Signatures, With Potential Therapeutic Implications

OBJECTIVE: Similarities in the clinical and laboratory features of patients with primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE) have led to attempts to treat pSS and SLE patients with similar biologic therapeutics. However, the results of many clinical trials are disappointing, and no biologic treatments are licensed in pSS, while few are available for SLE patients with refractory disease. Identifying shared immunological features between pSS and SLE could lead to better treatment selection using a stratification approach. METHODS: Immune-phenotyping of 29 immune-cell subsets in peripheral blood from patients with pSS (n=45), SLE (n=29) and secondary SS associated with SLE (SLE/SS) (n=14) with low disease activity or in clinical remission, and sex-matched healthy controls (n=31), was performed using flow cytometry. Data were analysed using supervised machine learning (balanced random forest, sparse partial least squares discriminant analysis), logistic regression and multiple t-tests. Patients were stratified by k-means clustering, and clinical trajectory analysis. RESULTS: Patients with pSS and SLE had a similar immunological architecture despite having different clinical presentations and prognosis. K-means cluster analysis of the combined pSS, SLE and SLE/SS patient cohorts identified two endotypes characterized by distinct immune-cell profiles which spanned patient diagnoses. Logistic regression and machine learning models identified a signature of eight T-cell subsets that differentiated between the two endotypes with high accuracy (AUC=0.9979). Baseline and five-year clinical trajectory analysis identified differential damage scores and disease activity between the two endotypes. CONCLUSION: An immune-cell toolkit could differentiate patients across diseases with high accuracy for targeted therapeutic approaches

Diet and lupus: what do the patients think?

OBJECTIVES: Cardiovascular disease is the leading cause of mortality in patients with systemic lupus erythematosus. Therefore, using diet to control blood lipid levels and modify cardiovascular disease risk could be a promising therapeutic strategy to control disease symptoms. The primary objective of this study was to learn about systemic lupus erythematosus patient experiences with diet, including their opinion on considering diet as a therapeutic option. The secondary objective was to obtain this information in a cost- and time-effective manner. METHODS: A lay summary and a 15-question diet-based online survey were publicly available for 3 weeks. Social media was used to promote the survey through relevant charities, hospitals and research groups. RESULTS: A total of 300 responses were received, 284 from patients with systemic lupus erythematosus. Patients reported that there was a lack of clinical counselling regarding diet, with only 24% stating their doctor had spoken to them about diet. Despite this, 100% of patients stated they would change their diet if they knew it would help their symptoms and 83% would take part in a future diet-based clinical trial. Text analysis of patient research suggestions identified a particular interest in using diet to treat fatigue and manage disease flares. CONCLUSIONS: This project successfully gathered patient information regarding diet and systemic lupus erythematosus over a short timeframe using an anonymous social media platform. The survey provided evidence that patients support further research and potential diet intervention studies investigating the effect of diet on the symptoms of systemic lupus erythematosus

Racial/Ethnic Disparities in Exercise and Dietary Behaviors of Middle-Aged and Older Adults

BackgroundDifferences in health behaviors may be important contributors to racial/ethnic disparities in the health status of adults. Studies to date have not compared whether there are health behavior differences in exercise and dietary behaviors among middle-age and older adults in the four largest racial/ethnic categories.ObjectiveTo investigate racial/ethnic differences in exercise and dietary behaviors of middle-aged and older adults.DesignWe used data from the 2007 California Health Interview Survey. Multivariable logistic regression was used to examine interactions between age and race/ethnicity in predicting two categories of health behaviors. Analyses were conducted adjusting for sociodemographic characteristics, health insurance status, and healthcare utilization.ParticipantsA population-based sample of 33,189 California adults 45 years old and older: 26,522 non-Hispanic whites, 1,686 African American/blacks, 2,565 Asian/Pacific Islanders (1,741 English-proficient; 824 limited English-proficient), and 2,416 Latinos (1,538 English-proficient; 878 limited English-proficient).Main measuresSelf-report leisure-time physical activity (moderate and vigorous) and daily consumption of fruits and vegetables.Key resultsRacial/ethnic minorities generally engaged in less healthy exercise and dietary behaviors than whites, with differences more pronounced in middle adulthood. The disparities were the greatest among English-proficient minorities. Specifically, among middle-aged respondents, all racial/ethnic minorities engaged in less vigorous physical activity than whites (ORs range = 0.28 to 0.73; 95% CI range = 0.16-1.00). Additionally, middle-aged, English-proficient minorities engaged in less moderate physical activity compared to whites (ORs range =0.57 to 0.67; 95% CI range = 0.45-0.79). Furthermore, middle-aged, English-proficient Latinos had a poorer diet than whites (OR = 0.54; 0.39-0.75). Few significant racial/ethnic differences emerged in the exercise and dietary behaviors of older adults.ConclusionsRacial/ethnic disparities in exercise and dietary behaviors are most notable among middle-aged, acculturated minorities. Results highlight the need to promote positive exercise and dietary behaviors during critical preventive ages, when racial/ethnic disparities are large and the potential to prevent chronic disease is great

Methods to estimate aboveground wood productivity from long-term forest inventory plots

Forest inventory plots are widely used to estimate biomass carbon storage and its change over time. While there has been much debate and exploration of the analytical methods for calculating biomass, the methods used to determine rates of wood production have not been evaluated to the same degree. This affects assessment of ecosystem fluxes and may have wider implications if inventory data are used to parameterise biospheric models, or scaled to large areas in assessments of carbon sequestration. Here we use a dataset of 35 long-term Amazonian forest inventory plots to test different methods of calculating wood production rates. These address potential biases associated with three issues that routinely impact the interpretation of tree measurement data: (1) changes in the point of measurement (POM) of stem diameter as trees grow over time; (2) unequal length of time between censuses; and (3) the treatment of trees that pass the minimum diameter threshold (“recruits”). We derive corrections that control for changing POM height, that account for the unobserved growth of trees that die within census intervals, and that explore different assumptions regarding the growth of recruits during the previous census interval. For our dataset we find that annual aboveground coarse wood production (AGWP; in Mg ha−1 year−1 of dry matter) is underestimated on average by 9.2% if corrections are not made to control for changes in POM height. Failure to control for the length of sampling intervals results in a mean underestimation of 2.7% in annual AGWP in our plots for a mean interval length of 3.6 years. Different methods for treating recruits result in mean differences of up to 8.1% in AGWP. In general, the greater the length of time a plot is sampled for and the greater the time elapsed between censuses, the greater the tendency to underestimate wood production. We recommend that POM changes, census interval length, and the contribution of recruits should all be accounted for when estimating productivity rates, and suggest methods for doing this.European UnionUK Natural Environment Research CouncilGordon and Betty Moore FoundationCASE sponsorship from UNEP-WCMCRoyal Society University Research FellowshipERC Advanced Grant “Tropical Forests in the Changing Earth System”Royal Society Wolfson Research Merit Awar

Mapping quantitative trait loci (QTL) in sheep. I. A new male framework linkage map and QTL for growth rate and body weight

A male sheep linkage map comprising 191 microsatellites was generated from a single family of 510 Awassi-Merino backcross progeny. Except for ovine chromosomes 1, 2, 10 and 17, all other chromosomes yielded a LOD score difference greater than 3.0 between the best and second-best map order. The map is on average 11% longer than the Sheep Linkage Map v4.7 male-specific map. This map was employed in quantitative trait loci (QTL) analyses on body-weight and growth-rate traits between birth and 98 weeks of age. A custom maximum likelihood program was developed to map QTL in half-sib families for non-inbred strains (QTL-MLE) and is freely available on request. The new analysis package offers the advantage of enabling QTL × fixed effect interactions to be included in the model. Fifty-four putative QTL were identified on nine chromosomes. Significant QTL with sex-specific effects (i.e. QTL × sex interaction) in the range of 0.4 to 0.7 SD were found on ovine chromosomes 1, 3, 6, 11, 21, 23, 24 and 26