Search

FK506 is a potential antifungal compound that inhibits calcineurin, but it also has immunosuppressive activity. Here, Juvvadi et al. report the structure of FK506 in complex with the FK506-binding protein FKPB12 and calcineurin, and design a less immunosuppresive FK506 analog with antifungal activity in mice.

Detecting and explaining differences between palaeoclimates can provide valuable insights for Earth scientists investigating processes that are affected by climate change over geologic time. In this study, we describe and explain spatiotemporal patterns in palaeoclimate change that are relevant to Earth surface scientists. We apply a combination of multivariate cluster and discriminant analysis techniques to a set of high-resolution palaeoclimate simulations. The simulations were conducted with the ECHAM5 climate model and consistent setup. A pre-industrial (PI) climate simulation serves as the control experiment, which is compared to a suite of simulations of Late Cenozoic climates, namely a Mid-Holocene (MH, approximately 6.5 ka), Last Glacial Maximum (LGM, approximately 21 ka) and Pliocene (PLIO, approximately 3 Ma) climate. For each of the study regions (western South America, Europe, South Asia and southern Alaska), differences in climate are subjected to geographical clustering to identify dominant modes of climate change and their spatial extent for each time slice comparison (PI–MH, PI–LGM and PI–PLIO). The selection of climate variables for the cluster analysis is made on the basis of their relevance to Earth surface processes and includes 2 m air temperature, 2 m air temperature amplitude, consecutive freezing days, freeze–thaw days, maximum precipitation, consecutive wet days, consecutive dry days, zonal wind speed and meridional wind speed. We then apply a two-class multivariate discriminant analysis to simulation pairs PI–MH, PI–LGM and PI–PLIO to evaluate and explain the discriminability between climates within each of the anomaly clusters. Changes in ice cover create the most distinct and stable patterns of climate change, and create the best discriminability between climates in western Patagonia. The distinct nature of European palaeoclimates is statistically explained mostly by changes in 2 m air temperature (MH, LGM, PLIO), consecutive freezing days (LGM) and consecutive wet days (PLIO). These factors typically contribute 30 %–50 %, 10 %–40 % and 10 %–30 %, respectively, to climate discriminability. Finally, our results identify regions particularly prone to changes in precipitation-induced erosion and temperature-dependent physical weathering.

Objective: The present study investigates the relationship between night-time screen-based media devices (SBMD) use, which refers to use within 1 h before sleep, in both lit and dark rooms, and sleep outcomes and health-related quality of life (HRQoL) among 11 to 12-year-olds. Methods: We analysed baseline data from a large cohort of 6616 adolescents from 39 schools in and around London, United Kingdom, participating in the Study of Cognition Adolescents and Mobile Phone (SCAMP). Adolescents self-reported their use of any SBMD (mobile phone, tablet, laptop, television etc.). Sleep variables were derived from self-reported weekday and/or weekend bedtime, sleep onset latency (SOL) and wake time. Sleep quality was assessed using four standardised dimensions from the Swiss Health Survey. HRQoL was estimated using the KIDSCREEN-10 questionnaire. Results: Over two-thirds (71.5%) of adolescents reported using at least one SBMD at night-time, and about a third (32.2%) reported using mobile phones at night-time in darkness. Night-time mobile phone and television use was associated with higher odds of insufficient sleep duration on weekdays (Odds Ratio, OR = 1.82, 95% Confidence Interval, CI [1.59, 2.07] and OR = 1.40, 95% CI [1.23, 1.60], respectively). Adolescents who used mobile phones in a room with light were more likely to have insufficient sleep (OR = 1.32, 95% CI [1.10, 1.60]) and later sleep midpoint (OR = 1.64, 95% CI [1.37, 1.95]) on weekends compared to non-users. The magnitude of these associations was even stronger for those who used mobile phones in darkness for insufficient sleep duration on weekdays (OR = 2.13, 95% CI [1.79, 2.54]) and for later sleep midpoint on weekdays (OR = 3.88, 95% CI [3.25, 4.62]) compared to non-users. Night-time use of mobile phones was associated with lower HRQoL and use in a dark room was associated with even lower KIDSCREEN-10 score (β = –1.18, 95% CI [–1.85, –0.52]) compared to no use. Conclusions: We found consistent associations between night-time SBMD use and poor sleep outcomes and worse HRQoL in adolescents. The magnitude of these associations was stronger when SBMD use occurred in a dark room versus a lit room. Keywords: Screen-based media, Mobile phone, Television, Children, Sleep, Quality of life

Bacteriophages play key roles in the dynamics of the human microbiome. By far the most abundant components of the human gut virome are tailed bacteriophages of the realm Duplodnaviria, in particular, crAss-like phages. However, apart from duplodnaviruses, the gut virome has not been dissected in detail. Here we report a comprehensive census of a minor component of the gut virome, the tailless bacteriophages of the realm Varidnaviria. Tailless phages are primarily represented in the gut by prophages, that are mostly integrated in genomes of Alphaproteobacteria and Verrucomicrobia and belong to the order Vinavirales, which currently consists of the families Corticoviridae and Autolykiviridae. Phylogenetic analysis of the major capsid proteins (MCP) suggests that at least three new families should be established within Vinavirales to accommodate the diversity of prophages from the human gut virome. Previously, only the MCP and packaging ATPase genes were reported as conserved core genes of Vinavirales. Here we report an extended core set of 12 proteins, including MCP, packaging ATPase, and previously undetected lysis enzymes, that are shared by most of these viruses. We further demonstrate that replication system components are frequently replaced in the genomes of Vinavirales, suggestive of selective pressure for escape from yet unknown host defenses or avoidance of incompatibility with coinfecting related viruses. The results of this analysis show that, in a sharp contrast to marine viromes, varidnaviruses are a minor component of the human gut virome. Moreover, they are primarily represented by prophages, as indicated by the analysis of the flanking genes, suggesting that there are few, if any, lytic varidnavirus infections in the gut at any given time. These findings complement the existing knowledge of the human gut virome by exploring a group of viruses that has been virtually overlooked in previous work.

The aim of the present study was to evaluate the sensory acceptability limit of refrigerated fish through a multivariate approach, involving classic physicochemical and bacteriological indicators and considering different consumer profiles. The results of the survival analysis demonstrated that, in general, consumers still considered the fish to be suitable for purchase (4.128 days of storage), despite being microbiologically unsuitable for consumption. However, the subsequent division of consumers into clusters indicated that women and individuals with high income and education levels tend to reject fish with few days of storage (3.650 days), mainly due to discoloration, despite still being microbiologically suitable for consumption. Thus, these segments present a safer behavior regarding the purchase of fresh fish. The influence of different frequencies of fish consumption and age of consumers on the assessment of fish freshness was not clarified. The responsibility for ensuring safe and healthy products at the point of sale must lie with the producers and distributors. However, improving consumers’ ability to make good choices when buying fresh fish would bring social and economic benefits related to public health and to the seafood industry, because it would enable them to make relevant claims and demand their rights.

Introduction Individuals with mental disorders, on average, die prematurely and may experience accelerated biological ageing. Objectives We examined sex-specific associations between age and physiological measures in individuals with lifetime depression and healthy controls. Methods UK Biobank recruited >500,000 participants, aged 37-73, between 2006–2010. Generalised additive models (GAMs) were used to examine associations between age and multiple cardiovascular, body composition, grip strength and lung function measures. Analyses were conducted separately in males and females with lifetime depression compared to healthy controls. Results Analytical samples included up to 342,393 adults (mean age = 55.87 years, SD = 8.09; 52.61% females). We found statistically significant differences between individuals with lifetime depression and healthy controls for most physiological measures, with standardised mean differences between -0.145 and 0.156. There was some evidence that age-related changes in body composition, cardiovascular measures, lung function and heel bone mineral density followed different trajectories in individuals with lifetime depression. However, these differences did not uniformly narrow or widen with age. For example, BMI in females with lifetime depression was approximately 1.1 kg/m2 higher at age 40 and this difference narrowed to about 0.4 kg/m2 at age 70. In males, systolic blood pressure was approximately 1 mmHg lower in individuals with lifetime depression at age 45 and this difference widened to about 2.5 mmHg at age 65. Conclusions Evidence of differences in ageing trajectories between individuals with lifetime depression and healthy controls was not uniform across physiological measures and differed by sex. Disclosure JM receives studentship funding from the Biotechnology and Biological Sciences Research Council (BBSRC) and Eli Lilly and Company Limited. CML is a member of the Scientific Advisory Board of Myriad Neuroscience.

This study uses experimental methods to assess the causal effect of media presentations on viewer's emotions, national identification, and nation-related values. In three experiments covering marginal sports disciplines, viewers watched broadcasts of compatriots winning an Olympic gold medal, either featuring emotional and partisan reporting styles or a neutral audio commentary. Findings show that those exposed to the partisan commentary experienced heightened emotions; identified more strongly with their nation; exhibited more patriotism and nationalism; and ascribed positive values (e.g., achievement, diligence) more strongly to their home country than did viewers in the control group. These results suggest that the broadcasting styles influence viewers' emotions, attitudes, and collective identifications beyond the effects of the sporting competition itself. [ABSTRACT FROM AUTHOR]

The effects of previous Salmonella Typhimurium habituation to an Italian-style salami concerning pathogen resistance against ultraviolet-C light (UV-C) treatment were modeled in order to establish treatment feasibility for the decontamination of dry-fermented sausage. S. Typhimurium following 24 h habituation in fermented sausage (habituated cells) or non-habituation (non-habituated cells) were exposed to increasing UV-C radiation treatment times. The Weibull model was the best fit for describing S. Typhimurium UV-C inactivation. Heterogeneity in UV-C treatment susceptibilities within the S. Typhimurium population was observed, revealing intrinsic persistence in a sub-population. UV-C radiation up to 1.50 J/cm2 was a feasible treatment for dry-fermented sausage decontamination, as the matrices retained instrumental color and lipid oxidation physiochemical characteristics. However, habituation in the sausage matrix led to a 14-fold increase in the UV-C dose required to achieve the first logarithm reduction (δ value) in S. Typhimurium population. The results indicate that, although UV-C radiation might be considered an efficient method for dry-fermented sausage decontamination, effective doses should be reconsidered in order to reach desirable food safety parameters while preserving matrix quality.