Molecular basis of RNA guanine-7 methyltransferase (RNMT) activation by RAM

Maturation and translation of mRNA in eukaryotes requires the addition of the 7-methylguanosine cap. In vertebrates, the cap methyltransferase, RNA guanine-7 methyltransferase (RNMT), has an activating subunit, RNMT-Activating Miniprotein (RAM). Here we report the first crystal structure of the human RNMT in complex with the activation domain of RAM. A relatively unstructured and negatively charged RAM binds to a positively charged surface groove on RNMT, distal to the active site. This results in stabilisation of a RNMT lobe structure which co-evolved with RAM and is required for RAM binding. Structure-guided mutagenesis and molecular dynamics simulations reveal that RAM stabilises the structure and positioning of the RNMT lobe and the adjacent α-helix hinge, resulting in optimal positioning of helix A which contacts substrates in the active site. Using biophysical and biochemical approaches, we observe that RAM increases the recruitment of the methyl donor, AdoMet (S-adenosyl methionine), to RNMT. Thus we report the mechanism by which RAM allosterically activates RNMT, allowing it to function as a molecular rheostat for mRNA cap methylation

Genetic Variants in Platelet Factor 4 Modulate Inflammatory and Platelet Activation Biomarkers

African Americans suffer from higher prevalence and severity of atherosclerosis compared to Whites, highlighting racial and ethnic disparities in cardiovascular disease. Previous studies have pointed to the role of vascular inflammation and platelet activation in the formation of atherosclerotic lesions

Immunological Outcomes of New Tuberculosis Vaccine Trials: WHO Panel Recommendations

Willem Hanekom and colleagues make recommendations on assay harmonization for novel tuberculosis vaccine trials

Good physicians from the perspective of their patients

BACKGROUND: It is not currently known what is the patient's viewpoint of a "good" physician. We set out to define patient's priorities regarding different physician's attributes in 3 domains important in medical care. METHODS: Patients hospitalized or attending clinics at a large teaching hospital selected the 4 attributes that they considered most important out of 21 listed arbitrarily in a questionnaire. The questionnaire included 7 items each in the domains of patient autonomy, professional expertise and humanism. RESULTS: Participating patients (n = 445, mean age 57.5 ± 16 years) selected professional expertise (50%), physician's patience and attentiveness (38% and 30%, respectively), and informing the patient, representing the patient's interests, being truthful and respecting patient's preferences (25–36% each) as the most essential attributes. Patient's selections were not significantly influenced by different demographic or clinical background. Selections of attributes in the domain of patient's autonomy were significantly more frequent and this was the preferred domain for 31% and as important as another domain for 16% – significantly more than the domain of professional expertise (P = 0.008), and much more than the domain of humanism and support (P < 0.0005). CONCLUSIONS: Patients studied want their physicians to be highly professional and expert clinicians and show humaneness and support, but their first priority is for the physician to respect their autonomy

The impact of xylem geometry on olive cultivar resistance to Xylella fastidiosa: an image‐based study

Xylella fastidiosa is a xylem-limited plant pathogen infecting many crops globally and is the cause of the recent olive disease epidemic in Italy. One strategy proposed to mitigate losses is to replant susceptible crops with resistant varieties. Several genetic, biochemical and biophysical traits are associated to X. fastidiosa disease resistance. However, mechanisms underpinning resistance are poorly understood. We hypothesize that the susceptibility of olive cultivars to infection will correlate to xylem vessel diameters, with narrower vessels being resistant to air embolisms and having slower flow rates limiting pathogen spread. To test this, we scanned stems from four olive cultivars of varying susceptibility to X. fastidiosa using X-ray computed tomography. Scans were processed by a bespoke methodology that segmented vessels, facilitating diameter measurements. Though significant differences were not found comparing stem-average vessel section diameters among cultivars, they were found when comparing diameter distributions. Moreover, the measurements indicated that although vessel diameter distributions may play a role regarding the resistance of Leccino, it is unlikely they do for FS17. Considering Young–Laplace and Hagen–Poiseuille equations, we inferred differences in embolism susceptibility and hydraulic conductivity of the vasculature. Our results suggest susceptible cultivars, having a greater proportion of larger vessels, are more vulnerable to air embolisms. In addition, results suggest that under certain pressure conditions, functional vasculature in susceptible cultivars could be subject to greater stresses than in resistant cultivars. These results support investigation into xylem morphological screening to help inform olive replanting. Furthermore, our framework could test the relevance of xylem geometry to disease resistance in other crops

Coronary Atherosclerotic Plaque Activity and Future Coronary Events

This study was funded by a Wellcome Trust Senior Investigator Award (WT103782AIA). Image analysis was supported by National Institutes for Health (R34HL161195 and 1R01HL135557). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Wellcome Trust or the National Institutes of Health. The British Heart Foundation supports DEN (CH/09/002, RG/16/10/32375, RE/18/5/34216), MRD (FS/SCRF/21/32010), NLM (CH/F/21/90010, RG/20/10/34966, RE/18/5/34216) AJM (AA/18/3/34220) and MCW (FS/ICRF/20/26002) and DD (FS/RTF/20/30009, NH/19/1/34595, PG/18/35/33786, PG/15/88/31780, PG/17/64/33205). MRD is the recipient of the Sir Jules Thorn Award for Biomedical Research 2015 (15/JTA). PJS is supported by outstanding investigator award National Institutes for Health (R35HL161195). JK is supported by the National Science Centre 2021/41/B/NZ5/02630. EvB is supported by SINAPSE (www.sinapse.ac.uk). AB is supported by a Clinical Research Training Fellowships (MR/V007254/1). DD is supported by Chest Heart and Stroke Scotland (19/53), Tenovus Scotland (G.18.01), and Friends of Anchor and Grampian NHS-Endowments. The Edinburgh Clinical Research Facilities, Edinburgh Imaging facility and Edinburgh Clinical Trials Unit are supported by the National Health Service Research Scotland through National Health Service Lothian Health Board. The Leeds Clinical Research Facilities are supported by the UK National Institute for Health Research (NIHR) via its Clinical Research Facility programme. The work at Cedars-Sinai Medical Center (the Los Angeles site) was supported in part by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission. The Chief Investigator and Edinburgh Clinical Trials Unit had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Peer reviewedPostprin

A Strategy for the Proliferation of Ulva prolifera, Main Causative Species of Green Tides, with Formation of Sporangia by Fragmentation

Ulva prolifera, a common green seaweed, is one of the causative species of green tides that occurred frequently along the shores of Qingdao in 2008 and had detrimental effects on the preparations for the 2008 Beijing Olympic Games sailing competition, since more than 30 percent of the area of the games was invaded. In view of the rapid accumulation of the vast biomass of floating U. prolifera in green tides, we investigated the formation of sporangia in disks of different diameters excised from U. prolifera, changes of the photosynthetic properties of cells during sporangia formation, and development of spores. The results suggested that disks less than 1.00 mm in diameter were optimal for the formation of sporangia, but there was a small amount of spore release in these. The highest percentage of area of spore release occurred in disks that were 2.50 mm in diameter. In contrast, sporangia were formed only at the cut edges of larger disks (3.00 mm, 3.50 mm, and 4.00 mm in diameter). Additionally, the majority of spores liberated from the disks appeared vigorous and developed successfully into new individuals. These results implied that fragments of the appropriate size from the U. prolifera thalli broken by a variety of factors via producing spores gave rise to the rapid proliferation of the seaweed under field conditions, which may be one of the most important factors to the rapid accumulation of the vast biomass of U. prolifera in the green tide that occurred in Qingdao, 2008

Atypical development of white matter microstructure of the corpus callosum in males with autism: a longitudinal investigation

Background: The corpus callosum is the largest white matter structure in the brain, and it is the most consistently reported to be atypical in diffusion tensor imaging studies of autism spectrum disorder. In individuals with typical development, the corpus callosum is known to undergo a protracted development from childhood through young adulthood. However, no study has longitudinally examined the developmental trajectory of corpus callosum in autism past early childhood. Methods: The present study used a cohort sequential design over 9 years to examine age-related changes of the corpus callosum in 100 males with autism and 56 age-matched males with typical development from early childhood (when autism can first be reliably diagnosed) to mid-adulthood (after development of the corpus callosum has been completed) (3 to 41 years of age). Results: The group with autism demonstrated a different developmental trajectory of white matter microstructure in the anterior corpus callosum’s (genu and body) fractional anisotropy, which suggests atypical brain maturation in these regions in autism. When analyses were broken down by age group, atypical developmental trajectories were present only in the youngest participants (10 years of age and younger). Significant main effects for group were found in terms of decreased fractional anisotropy across all three subregions of the corpus callosum (genu, body, and splenium) and increased mean diffusivity, radial diffusivity, and axial diffusivity in the posterior corpus callosum. Conclusions: These longitudinal results suggest atypical early childhood development of the corpus callosum microstructure in autism that transitions into sustained group differences in adolescence and adulthood. This pattern of results provides longitudinal evidence consistent with a growing number of published studies and hypotheses regarding abnormal brain connectivity across the life span in autism. Electronic supplementary material The online version of this article (doi:10.1186/s13229-015-0001-8) contains supplementary material, which is available to authorized users

Tourism and Economic Globalization: An Emerging Research Agenda

Globalization characterizes the economic, social, political, and cultural spheres of the modern world. Tourism has long been claimed as a crucial force shaping globalization, while in turn the developments of the tourism sector are under the influences of growing interdependence across the world. As globalization proceeds, destination countries have become more and more susceptible to local and global events. By linking the existing literature coherently, this study explores a number of themes on economic globalization in tourism. It attempts to identify the forces underpinning globalization and assess the implications on both the supply side and the demand side of the tourism sector. In view of a lack of quantitative evidence, future directions for empirical research have been suggested to investigate the interdependence of tourism demand, the convergence of tourism productivity, and the impact of global events

Locomotion disorders and skin and claw lesions in gestating sows housed in dynamic versus static groups

Lameness and lesions to the skin and claws of sows in group housing are commonly occurring indicators of reduced welfare. Typically, these problems are more common in group housing than in individual housing systems. Group management type (dynamic versus static) and stage of gestation influence the behavior of the animals, which in turn influences the occurrence of these problems. The present study compared prevalence, incidence and mean scores of lameness and skin and claw lesions in static versus dynamic group housed sows at different stages of gestation during three consecutive reproductive cycles. A total of 10 Belgian sow herds were monitored; 5 in which dynamic groups and 5 in which static groups were utilized. All sows were visually assessed for lameness and skin lesions three times per cycle and the claws of the hind limbs were assessed once per cycle. Lameness and claw lesions were assessed using visual analogue scales. Static groups, in comparison with dynamic groups, demonstrated lower lameness scores (P<0.05) and decreased skin lesion prevalence (24.9 vs. 47.3%, P<0.05) at the end of gestation. There was no difference between treatment group regarding claw lesion prevalence with 75.5% of sows demonstrating claw lesions regardless of group management. Prevalences of lameness (22.4 vs. 8.9%, P<0.05) and skin lesions (46.6 vs. 4.4%, P<0.05) were highest during the group-housed phase compared to the individually housed phases. Although the prevalence of lameness and skin lesions did not differ three days after grouping versus at the end of the group-housing phase, their incidence peaked during the first three days after moving from the insemination stalls to the group. In conclusion, the first three days after grouping was the most risky period for lameness incidence, but there was no significant difference between static or dynamic group management