What do we visually focus on in a World Heritage Site? A case study in the Historic Centre of Prague

Since socio-economic development is associated with artificial construction, heritage environments must be protected and renewed while adapting to such development. Many World Heritage Sites’ visual integrity is endangered by new construction. The paper aims to explore people’s visual focus patterns concerning the integrity of heritage to ensure that traditional culture is not endangered by the construction and development of modern life, and to protect Outstanding Universal Values. In this study, visual heatmaps are generated to investigate people’s visual integrity in the Historic Centre of Prague from micro to macro viewpoints using an eye tracker. We found that humans’ perspectives are unobstructed or concentrated, and the view of main attractions is generally maintained by a buffer zone. However, newly constructed high-rise buildings can result in major visual concerns. Therefore, new buildings with large heights and strong contrasting colours should be restricted to World Heritage Sites. Moreover, complex artistic effects (facade midline, domes, mural painting, faces of sculptures) will likely attract people’s attention. In contrast, visual focus is not concentrated on greenery, roofs and floors. Accordingly, greenery could become a flexible space to serve as a background for buildings and landscape nodes. Furthermore, visual focal factors are associated with two significant aspects: people and the environment. Since people and transportation could pose visual concerns, tourism managers should optimise for characteristics such as controlling the density of pedestrian flow and planning parking spaces. The visual patterns identified could be useful for the design, conservation, and management of visual integrity in cultural heritage sites to avoid the spread of artificial constructions within the boundaries of heritage sites, which may lead to their being endangered or delisted

On the definition of noise

Urbanization has exposed people to extreme sound levels. Although researchers have investigated the ability of people to listen, analyze, and distinguish sound, the concept of noise has not been clearly articulated from a human perspective. The lack of knowledge on how people perceive noise limits our capacity to control it in a targeted manner. This study aimed to interpret the definition of noise from the public perspective based on a grounded theory approach. Seventy-eight participants were interviewed about noise, and four categories of perceived understanding of noise were identified: challenges, definitions of noise, opportunities, and action. As one of the challenges, urbanization is associated with increased noise levels around the human environment. In terms of definition, perceiving sound as noise is considered to be a result of the complex and dynamic process that includes sound, the environment, and humans. Sound and humans interact with the environment. In terms of opportunities, noise may have positive roles on certain occasions, dispelling the misconception that noise is exclusively negative. In addition, we found that noise perception has gradually shifted from noise control to noise utilization. In terms of action, noise can be controlled at the sound sources, susceptible target groups, susceptible behaviors and states, locations, and times where noise is perceived with high frequency. In this study, we investigated several aspects of noise, ranging from noise control, soundscape definition, and ‘soundscape indices’ (SSID) integration and application. Our findings provide an additional basis for developing better definitions, control, and utilization strategies of noise in the future, thereby improving the quality of the sound environment

Hydrogen-rich water treatment improves fresh-cut Gastrodia elata quality by regulating reactive oxygen species metabolism and energy metabolism during low temperature storage

The application of hydrogen-rich water (HRW) can extend the shelf life of fruits and vegetables. This study aims to investigate the effects of HRW on the quality of fresh-cut Gastrodia elata during low-temperature (4°C) storage. The results indicate that HRW treatment inhibited the decrease in weight loss and the increase in respiration rate, and also slowed down the decrease in total acidity and total soluble solids. HRW treatment could reduce the generation of superoxide anions and hydrogen peroxide, enhance the activity and expression of antioxidant-related enzymes such as superoxide dismutase, catalase, ascorbate peroxidase, glutathione reductase, monodehydroascorbate reductase, and dehydroascorbate reductase, and increase the content of non-enzymatic antioxidant substances, ascorbic acid and glutathione, while decreasing the activity and expression of peroxidase and polyphenol oxidase. Furthermore, HRW treatment not only inhibited the reduction in ADP and ATP content and energy charge but also attenuated the increase in AMP content. It also slowed down the decrease in the activities of H+-ATPase, succinate dehydrogenase, Ca2+-ATPase, and cytochrome C oxidase. In conclusion, these results demonstrate that HRW treatment enhances the energy levels and effectively mitigates oxidative damage, thereby preserving postharvest quality of fresh-cut G. elata

RNF216 Regulates the Migration of Immortalized GnRH Neurons by Suppressing Beclin1-Mediated Autophagy

RNF216, encoding an E3 ubiquitin ligase, has been identified as a causative gene for Gordon Holmes syndrome, characterized by ataxia, dementia, and hypogonadotropic hypogonadism. However, it is still elusive how deficiency in RNF216 leads to hypogonadotropic hypogonadism. In this study, by using GN11 immature GnRH neuronal cell line, we demonstrated an important role of RNF216 in the GnRH neuron migration. RNA interference of RNF216 inhibited GN11 cell migration, but had no effect on the proliferation of GN11 cells or GnRH expression. Knockdown of RNF216 increased the protein levels of its targets, Arc and Beclin1. RNAi of Beclin1, but not Arc, normalized the suppressive effect caused by RNF216 knockdown. As Beclin1 plays a critical role in the autophagy regulation, we further demonstrated that RNAi of RNF216 led to increase in autophagy, and autophagy inhibitor CQ and 3-MA rescued the GN11 cell migration deficit caused by RNF216 knockdown. We further demonstrated that pharmacological increase autophagy by rapamycin could suppress the GN11 cell migration. We thus have identified that RNF216 regulates the migration of GnRH neuron by suppressing Beclin1 mediated autophagy, and indicated a potential contribution of autophagy to the hypogonadotropic hypogonadism

Base-assisted synthesis of 4-pyridinate gold(I) metallaligands: a study of their use in self-assembly reactions

The synthesis of di- and tritopic gold(I) metallaligands of the type [(Au4-py)2(μ2-diphosphane)] (diphosphane = bis(diphenylphosphanyl)isopropane or dppip (1), 1,2-bis(diphenylphosphanyl)ethane or dppe (2), 1,3-bis(diphenylphosphanyl)propane or dppp (3) and 1,4-bis(diphenylphosphanyl)butane or dppb (4)) and [(Au4-py)3(μ3-triphosphane)] (triphosphane = 1,1,1-tris(diphenylphosphanylmethyl)ethane or triphos (5) and 1,3,5-tris(diphenylphosphanyl)benzene or triphosph (6)) from [(AuCl)2(μ2-diphosphane)] or [(AuCl)3(μ3-triphosphane)] and 4-pyridylboronic acid in the presence of Cs2CO3 has been conducted. Interestingly, when [(AuCl)2(μ2-dppm)] (dppm = bis(diphenylphosphanyl)methane) was used as a starting material, the cyclic tetranuclear gold(I) compound [(Au4-py)2(CH)2{μ2-Au(PPh2)2}2] (I) was obtained instead. All the products have been characterized by IR and multinuclear NMR spectroscopy, mass spectrometry and elemental analysis and in the case of 1, 3, 5 and I by X-ray crystallography, which showed the presence of aurophilic interactions in all of them. The obtained metallaligands have been used as building blocks in self-assembly reactions with cis-blocked palladium or platinum acceptor moieties producing [2 + 2] metallamacrocycles or trigonal bipyramidal (TBP) [2 + 3] metallacages in good yields. The photophysical properties of both the metallaligands and the corresponding assemblies have been investigated

Spatiotemporal pattern analysis of scarlet fever incidence in Beijing, China, 2005–2014

Objective: To probe the spatiotemporal patterns of the incidence of scarlet fever in Beijing, China, from 2005 to 2014. Methods: A spatiotemporal analysis was conducted at the district/county level in the Beijing region based on the reported cases of scarlet fever during the study period. Moran’s autocorrelation coefficient was used to examine the spatial autocorrelation of scarlet fever, whereas the Getis-Ord Gi* statistic was used to determine the hotspot incidence of scarlet fever. Likewise, the space-time scan statistic was used to detect the space-time clusters, including the relative risk of scarlet fever incidence across all settings. Results: A total of 26,860 scarlet fever cases were reported in Beijing during the study period (2005–2014). The average annual incidence of scarlet fever was 14.25 per 100,000 population (range, 6.76 to 32.03 per 100,000). The incidence among males was higher than that among females, and more than two-thirds of scarlet fever cases (83.8%) were among children 3–8 years old. The seasonal incidence peaks occurred from March to July. A higher relative risk area was mainly in the city and urban districts of Beijing. The most likely space-time clusters and secondary clusters were detected to be diversely distributed in every study year. Conclusions: The spatiotemporal patterns of scarlet fever were relatively unsteady in Beijing from 2005 to 2014. The at-risk population was mainly scattered in urban settings and dense districts with high population, indicating a positive relationship between population density and increased risk of scarlet fever exposure. Children under 15 years of age were the most susceptible to scarlet fever. © 2016 by the authors; licensee MDPI, Basel, Switzerland

Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: A pooled analysis of 1018 population-based measurement studies with 88.6 million participants

© The Author(s) 2018. Background: Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure. Methods: We pooled 1018 population-based studies with blood pressure measurements on 88.6 million participants from 1985 to 2016. We first calculated mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP) and prevalence of raised blood pressure by sex and 10-year age group from 20-29 years to 70-79 years in each study, taking into account complex survey design and survey sample weights, where relevant. We used a linear mixed effect model to quantify the association between (probittransformed) prevalence of raised blood pressure and age-group- and sex-specific mean blood pressure. We calculated the contributions of change in mean SBP and DBP, and of change in the prevalence-mean association, to the change in prevalence of raised blood pressure. Results: In 2005-16, at the same level of population mean SBP and DBP, men and women in South Asia and in Central Asia, the Middle East and North Africa would have the highest prevalence of raised blood pressure, and men and women in the highincome Asia Pacific and high-income Western regions would have the lowest. In most region-sex-age groups where the prevalence of raised blood pressure declined, one half or more of the decline was due to the decline in mean blood pressure. Where prevalence of raised blood pressure has increased, the change was entirely driven by increasing mean blood pressure, offset partly by the change in the prevalence-mean association. Conclusions: Change in mean blood pressure is the main driver of the worldwide change in the prevalence of raised blood pressure, but change in the high-blood-pressure tail of the distribution has also contributed to the change in prevalence, especially in older age groups

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe

sFlt Multivalent Conjugates Inhibit Angiogenesis and Improve Half-Life In Vivo

We would like to thank Jonathan Winger and Xiao Zhu for guidance with the insect cell protein expression system and providing reagents. We would like to acknowledge Ann Fischer for help with expressing the sFlt protein in the Tissue Culture Facility at UC Berkeley and Dawn Spelke and Anusuya Ramasubramanian for help optimizing protein purification from insect cells. We are also grateful for the help from Leah Byrne and John Flannery at in the Helen Wills Neuroscience Institute at UC Berkeley for aiding us in the development of the rat intravitreal residence time model and for allowing us to use their facilities.Current anti-VEGF drugs for patients with diabetic retinopathy suffer from short residence time in the vitreous of the eye. In order to maintain biologically effective doses of drug for inhibiting retinal neovascularization, patients are required to receive regular monthly injections of drug, which often results in low patient compliance and progression of the disease. To improve the intravitreal residence time of anti-VEGF drugs, we have synthesized multivalent bioconjugates of an anti-VEGF protein, soluble fms-like tyrosine kinase-1 (sFlt) that is covalently grafted to chains of hyaluronic acid (HyA), conjugates that are termed mvsFlt. Using a mouse corneal angiogenesis assay, we demonstrate that covalent conjugation to HyA chains does not decrease the bioactivity of sFlt and that mvsFlt is equivalent to sFlt at inhibiting corneal angiogenesis. In a rat vitreous model, we observed that mvsFlt had significantly increased intravitreal residence time compared to the unconjugated sFlt after 2 days. The calculated intravitreal half-lives for sFlt and mvsFlt were 3.3 and 35 hours, respectively. Furthermore, we show that mvsFlt is more effective than the unconjugated form at inhibiting retinal neovascularization in an oxygen-induced retinopathy model, an effect that is most likely due to the longer half-life of mvsFlt in the vitreous. Taken together, our results indicate that conjugation of sFlt to HyA does not affect its affinity for VEGF and this conjugation significantly improves drug half-life. These in vivo results suggest that our strategy of multivalent conjugation could substantially improve upon drug half-life, and thus the efficacy of currently available drugs that are used in diseases such as diabetic retinopathy, thereby improving patient quality of life.Yeshttp://www.plosone.org/static/editorial#pee