The saturated fatty acids acylated on Lipid A of lipopolysaccharide (LPS) or bacterial lipoproteins play critical roles in ligand recognition and receptor activation for Toll-like Receptor 4 (TLR4) ...and TLR2. The results from our previous studies demonstrated that saturated and polyunsaturated fatty acids reciprocally modulate the activation of TLR4. However, the underlying mechanism has not been understood. Here, we report for the first time that the saturated fatty acid lauric acid induced dimerization and recruitment of TLR4 into lipid rafts, however, dimerization was not observed in non-lipid raft fractions. Similarly, LPS and lauric acid enhanced the association of TLR4 with MD-2 and downstream adaptor molecules, TRIF and MyD88, into lipid rafts leading to the activation of downstream signaling pathways and target gene expression. However, docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, inhibited LPS- or lauric acid-induced dimerization and recruitment of TLR4 into lipid raft fractions. Together, these results demonstrate that lauric acid and DHA reciprocally modulate TLR4 activation by regulation of the dimerization and recruitment of TLR4 into lipid rafts. In addition, we showed that TLR4 recruitment to lipid rafts and dimerization were coupled events mediated at least in part by NADPH oxidase-dependent reactive oxygen species generation. These results provide a new insight in understanding the mechanism by which fatty acids differentially modulate TLR4-mediated signaling pathway and consequent inflammatory responses which are implicated in the development and progression of many chronic diseases.
Serine phosphorylation is a key post-translational modification that regulates diverse biological processes. Powerful analytical methods have identified thousands of phosphorylation sites, but many ...of their functions remain to be deciphered. A key to understanding the function of protein phosphorylation is access to phosphorylated proteins, but this is often challenging or impossible. Here we evolve an orthogonal aminoacyl-tRNA synthetase/tRNACUA pair that directs the efficient incorporation of phosphoserine (pSer (1)) into recombinant proteins in Escherichia coli. Moreover, combining the orthogonal pair with a metabolically engineered E. coli enables the site-specific incorporation of a nonhydrolyzable analog of pSer. Our approach enables quantitative decoding of the amber stop codon as pSer, and we purify, with yields of several milligrams per liter of culture, proteins bearing biologically relevant phosphorylations that were previously challenging or impossible to access--including phosphorylated ubiquitin and the kinase Nek7, which is synthetically activated by a genetically encoded phosphorylation in its activation loop.
Summary Background In 2010, overweight and obesity were estimated to cause 3·4 million deaths, 3·9% of years of life lost, and 3·8% of disability-adjusted life-years (DALYs) worldwide. The rise in ...obesity has led to widespread calls for regular monitoring of changes in overweight and obesity prevalence in all populations. Comparable, up-to-date information about levels and trends is essential to quantify population health effects and to prompt decision makers to prioritise action. We estimate the global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013. Methods We systematically identified surveys, reports, and published studies (n=1769) that included data for height and weight, both through physical measurements and self-reports. We used mixed effects linear regression to correct for bias in self-reports. We obtained data for prevalence of obesity and overweight by age, sex, country, and year (n=19 244) with a spatiotemporal Gaussian process regression model to estimate prevalence with 95% uncertainty intervals (UIs). Findings Worldwide, the proportion of adults with a body-mass index (BMI) of 25 kg/m2 or greater increased between 1980 and 2013 from 28·8% (95% UI 28·4–29·3) to 36·9% (36·3–37·4) in men, and from 29·8% (29·3–30·2) to 38·0% (37·5–38·5) in women. Prevalence has increased substantially in children and adolescents in developed countries; 23·8% (22·9–24·7) of boys and 22·6% (21·7–23·6) of girls were overweight or obese in 2013. The prevalence of overweight and obesity has also increased in children and adolescents in developing countries, from 8·1% (7·7–8·6) to 12·9% (12·3–13·5) in 2013 for boys and from 8·4% (8·1–8·8) to 13·4% (13·0–13·9) in girls. In adults, estimated prevalence of obesity exceeded 50% in men in Tonga and in women in Kuwait, Kiribati, Federated States of Micronesia, Libya, Qatar, Tonga, and Samoa. Since 2006, the increase in adult obesity in developed countries has slowed down. Interpretation Because of the established health risks and substantial increases in prevalence, obesity has become a major global health challenge. Not only is obesity increasing, but no national success stories have been reported in the past 33 years. Urgent global action and leadership is needed to help countries to more effectively intervene. Funding Bill & Melinda Gates Foundation.
Hydrogen is recognized as one of the cleanest energy carriers, which can be produced from renewable biomass as a promising feedstock to achieve sustainable bioeconomy. Thermochemical technologies ...(e.g., gasification and pyrolysis) are the main routes for hydrogen production from biomass. Although biomass gasification, including steam gasification and supercritical water gasification, shows a high potential in field-scale applications, the selectivity and efficiency of hydrogen production need improvement to secure cost-effective industrial applications with high atom economy. This article reviews the two main-stream biomass-to-hydrogen technologies and discusses the significance of operating conditions and considerations in the catalytic system design. Challenges and prospects of hydrogen production via biomass gasification are explored to advise on the critical information gaps that require future investigations.
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•Comparison of thermochemical method with other techniques for hydrogen production.•Significance of individual parameter on hydrogen production from biomass gasification.•Advances in mineral and hybrid catalysts for biomass gasification.•Challenges and prospects of hydrogen production from biomass gasification.
Cultural ecosystem services are a function of people and place, so may change as a location transitions from rural to urban. Singapore has undergone rapid urbanization after its independence in 1965, ...with a concomitant decline in natural habitat extent and accessibility. Using coastal mangrove forests as a case study habitat, changing cultural values were explored with a novel array of techniques, including qualitative archival analysis (photographs, oral histories), current sources (publically uploaded social media photographs), and surveys of (a) the general public and (b) visitors to publically accessible mangroves. Cultural value changed through time, with a significant transition from intrinsic, intrapersonal values (spiritual, cultural heritage) to instrumental, interpersonal values (recreation, education). Additionally, cultural value varied between different mangroves depending on their public accessibility, and the evolving degree of human interaction with the ecosystem as urban development occured. Cultural values change as development transitions, though mangroves still play an important cultural role in a heavily urbanized environment.
The ability to interact with others has gained recognition as part of the L2 speaking construct in the assessment literature and in high- and low-stakes speaking assessments. This paper first ...presents a review of the literature on interactional competence (IC) in L2 learning and assessment. It then discusses a particular feature – producing responses contingent on previous speakers’ contributions – that emerged as a de facto construct feature of IC, oriented to both candidates and examiners within the school-based group speaking assessment in the Hong Kong Diploma of Secondary Education (HKDSE) English Language Examination. Previous studies have, similarly, argued for the importance of responding to or linking one’s own talk to previous speakers’ contributions as a way of demonstrating comprehension of co-participants’ talk. However, what counts as such a response has yet to be explored systematically. This paper presents a conversation analytic study of the candidate discourse in the assessed group interactions, identifying three conversational actions through which student-candidates construct contingent responses to co-participants. The thick description about the nature of contingent responses lays the groundwork for further empirical investigations on the relevance of this IC feature and its proficiency implications.
Background. School-aged children suffer high rates of influenza virus infections and associated illnesses each year, and are a major source of transmission in the community. However, information on ...the cumulative incidence of infection in specific epidemics is scarce, and there are limited studies with sufficient follow-up to identify the strength and duration of protection against reinfection. Methods. We randomly allocated children 5–17 years of age to receive trivalent inactivated influenza vaccine (TIV) or placebo from September 2009 through January 2010, and then conducted follow-up for 3 years including regular collection of sera, symptom diaries, and collection of nose and throat swabs during illness episodes in participants or their household members. Results. Of 796 children initially randomized, 484 continued to participate for all 3 years. In unvaccinated children, cumulative incidence of infection was estimated to be 59% in the first wave of H1N1pdm09 in 2009–2010, and 7%, 14%, 20%, and 31% in subsequent epidemics of H3N2 (2010), H1N1pdm09 (2011), B (2012), and H3N2 (2012), respectively. Infection with H1N1pdm09 in 2009–2010 and H3N2 in 2010 was associated with protection against infection with subsequent epidemics of the same subtype in 2011 and 2012, respectively, but we found no evidence of heterotypic or heterosubtypic protection against infection. Conclusions. We identified substantial incidence of influenza virus infections in children in Hong Kong in 5 major epidemics over a 3-year period, and evidence of homosubtypic but not heterosubtypic protection following infection. Clinical Trials Registration. NCT00792051.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to ...chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6. We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid. Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. These data provide a direct molecular link between mitochondria and the pathogenesis of PD.
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