RASL11B (RAS-like, family 11, member B)

Review on RASL11B (RAS-like, family 11, member B), with data on DNA, on the protein encoded, and where the gene is implicated

Recent Change—North Sea

This chapter discusses past and ongoing change in the following physical variables within the North Sea: temperature, salinity and stratification; currents and circulation; mean sea level; and extreme sea levels. Also considered are carbon dioxide; pH and nutrients; oxygen; suspended particulate matter and turbidity; coastal erosion, sedimentation and morphology; and sea ice. The distinctive character of the Wadden Sea is addressed, with a particular focus on nutrients and sediments. This chapter covers the past 200 years and focuses on the historical development of evidence (measurements, process understanding and models), the form, duration and accuracy of the evidence available, and what the evidence shows in terms of the state and trends in the respective variables. Much work has focused on detecting long-term change in the North Sea region, either from measurements or with models. Attempts to attribute such changes to, for example, anthropogenic forcing are still missing for the North Sea. Studies are urgently needed to assess consistency between observed changes and current expectations, in order to increase the level of confidence in projections of expected future conditions

Exploration of Long-Chain Vitamin E Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation.

Endogenous long-chain metabolites of vitamin E (LCMs) mediate immune functions by targeting 5-lipoxygenase (5-LOX) and increasing the systemic concentrations of resolvin E3, a specialized proresolving lipid mediator. SAR studies on semisynthesized analogues highlight α-amplexichromanol (27a), which allosterically inhibits 5-LOX, being considerably more potent than endogenous LCMs in human primary immune cells and blood. Other enzymes within lipid mediator biosynthesis were not substantially inhibited, except for microsomal prostaglandin E2 synthase-1. Compound 27a is metabolized by sulfation and β-oxidation in human liver-on-chips and exhibits superior metabolic stability in mice over LCMs. Pharmacokinetic studies show distribution of 27a from plasma to the inflamed peritoneal cavity and lung. In parallel, 5-LOX-derived leukotriene levels decrease, and the inflammatory reaction is suppressed in reconstructed human epidermis, murine peritonitis, and experimental asthma in mice. Our study highlights 27a as an orally active, LCM-inspired drug candidate that limits inflammation with superior potency and metabolic stability to the endogenous lead

Semisynthetic and Natural Garcinoic Acid Isoforms as New mPGES-1 Inhibitors

Over the last twenty years, tocotrienol analogues raised great interest because of their higher level and larger domain of biological activities when compared with tocopherols. Amongst the most promising therapeutic application, anti-inflammatory potency has been evaluated through the inhibition of various mediators of inflammation. Here, we worked on the isolation of two natural isoforms of garcinoic acid (i.e., δ and γ) from two different sources, respectively, Garcinia kola seeds and Garcinia amplexicaulis bark. We also developed semisynthetic strategies to access the other two non-natural α- and β-garcinoic acid isoforms. In the next stage of our work, microsomal prostaglandin E2 synthase was defined as a target to evaluate the anti-inflammatory potential of the four garcinoic acid isomers. Both dimethylated isoforms, β- and γ-garcinoic acid, exhibited the lowest IC50, 2.8 µM and 2.0 µM, respectively. These results showed that the affinity of tocotrienol analogues to microsomal prostaglandin E2 synthase-1 most probably contributes to the anti-inflammatory potential of this class of derivatives

Dietary protein intake and health-related outcomes: a methodological protocol for the evidence evaluation and the outline of an evidence to decision framework underlying the evidence-based guideline of the German Nutrition Society

PURPOSE: The present work aimed to delineate (i) a revised protocol according to recent methodological developments in evidence generation, to (ii) describe its interpretation, the assessment of the overall certainty of evidence and to (iii) outline an Evidence to Decision framework for deriving an evidence-based guideline on quantitative and qualitative aspects of dietary protein intake. METHODS: A methodological protocol to systematically investigate the association between dietary protein intake and several health outcomes and for deriving dietary protein intake recommendations for the primary prevention of various non-communicable diseases in the general adult population was developed. RESULTS: The developed methodological protocol relies on umbrella reviews including systematic reviews with or without meta-analyses. Systematic literature searches in three databases will be performed for each health-related outcome. The methodological quality of all selected systematic reviews will be evaluated using a modified version of AMSTAR 2, and the outcome-specific certainty of evidence for systematic reviews with or without meta-analysis will be assessed with NutriGrade. The general outline of the Evidence to Decision framework foresees that recommendations in the derived guideline will be given based on the overall certainty of evidence as well as on additional criteria such as sustainability. CONCLUSION: The methodological protocol permits a systematic evaluation of published systematic reviews on dietary protein intake and its association with selected health-related outcomes. An Evidence to Decision framework will be the basis for the overall conclusions and the resulting recommendations for dietary protein intake

The main actors involved in parasitization of Heliothis virescens larva

At the moment of parasitization by another insect, the host Heliothis larva is able to defend itself by the activation of humoral and cellular defenses characterized by unusual reactions of hemocytes in response to external stimuli. Here, we have combined light and electron microscopy, staining reactions, and immunocytochemical characterization to analyze the activation and deactivation of one of the most important immune responses involved in invertebrates defense, i.e., melanin production and deposition. The insect host/parasitoid system is a good model to study these events. The activated granulocytes of the host insect are a major repository of amyloid fibrils forming a lattice in the cell. Subsequently, the exocytosed amyloid lattice constitutes the template for melanin deposition in the hemocel. Furthermore, cross-talk between immune and neuroendocrine systems mediated by hormones, cytokines, and neuromodulators with the activation of stress-sensoring circuits to produce and release molecules such as adrenocorticotropin hormone, alpha melanocyte-stimulating hormone, and neutral endopeptidase occurs. Thus, parasitization promotes massive morphological and physiological modifications in the host insect hemocytes and mimics general stress conditions in which phenomena such as amyloid fibril formation, melanin polymerization, pro-inflammatory cytokine production, and activation of the adrenocorticotropin hormone system occur. These events observed in invertebrates are also reported in the literature for vertebrates, suggesting that this network of mechanisms and responses is maintained throughout evolution

Rupture of the atherosclerotic plaque: does a good animal model exist?

By its very nature, rupture of the atherosclerotic plaque is difficult to study directly in humans. A good animal model would help us not only to understand how rupture occurs but also to design and test treatments to prevent it from happening. However, several difficulties surround existing models of plaque rupture, including the need for radical interventions to produce the rupture, lack of direct evidence of rupture per se, and absence of convincing evidence of platelet- and fibrin-rich thrombus at the rupture site. At the present time, attention should therefore focus on the processes of plaque breakdown and thrombus formation in humans, whereas the use of animal models should probably be reserved for studying the function of particular genes and for investigating isolated features of plaques, such as the relationship between cap thickness and plaque stability

Global burden of peripheral artery disease and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: Peripheral artery disease is a growing public health problem. We aimed to estimate the global disease burden of peripheral artery disease, its risk factors, and temporospatial trends to inform policy and public measures. Methods: Data on peripheral artery disease were modelled using the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2019 database. Prevalence, disability-adjusted life years (DALYs), and mortality estimates of peripheral artery disease were extracted from GBD 2019. Total DALYs and age-standardised DALY rate of peripheral artery disease attributed to modifiable risk factors were also assessed. Findings: In 2019, the number of people aged 40 years and older with peripheral artery disease was 113 million (95% uncertainty interval [UI] 99·2–128·4), with a global prevalence of 1·52% (95% UI 1·33–1·72), of which 42·6% was in countries with low to middle Socio-demographic Index (SDI). The global prevalence of peripheral artery disease was higher in older people, (14·91% [12·41–17·87] in those aged 80–84 years), and was generally higher in females than in males. Globally, the total number of DALYs attributable to modifiable risk factors in 2019 accounted for 69·4% (64·2–74·3) of total peripheral artery disease DALYs. The prevalence of peripheral artery disease was highest in countries with high SDI and lowest in countries with low SDI, whereas DALY and mortality rates showed U-shaped curves, with the highest burden in the high and low SDI quintiles. Interpretation: The total number of people with peripheral artery disease has increased globally from 1990 to 2019. Despite the lower prevalence of peripheral artery disease in males and low-income countries, these groups showed similar DALY rates to females and higher-income countries, highlighting disproportionate burden in these groups. Modifiable risk factors were responsible for around 70% of the global peripheral artery disease burden. Public measures could mitigate the burden of peripheral artery disease by modifying risk factors. Funding: Bill & Melinda Gates Foundation

Burden of non-communicable diseases among adolescents aged 10–24 years in the EU, 1990–2019: a systematic analysis of the Global Burden of Diseases Study 2019

Background: Disability and mortality burden of non-communicable diseases (NCDs) have risen worldwide; however, the NCD burden among adolescents remains poorly described in the EU. Methods: Estimates were retrieved from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. Causes of NCDs were analysed at three different levels of the GBD 2019 hierarchy, for which mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) were extracted. Estimates, with the 95% uncertainty intervals (UI), were retrieved for EU Member States from 1990 to 2019, three age subgroups (10–14 years, 15–19 years, and 20–24 years), and by sex. Spearman's correlation was conducted between DALY rates for NCDs and the Socio-demographic Index (SDI) of each EU Member State. Findings: In 2019, NCDs accounted for 86·4% (95% uncertainty interval 83·5–88·8) of all YLDs and 38·8% (37·4–39·8) of total deaths in adolescents aged 10–24 years. For NCDs in this age group, neoplasms were the leading causes of both mortality (4·01 [95% uncertainty interval 3·62–4·25] per 100 000 population) and YLLs (281·78 [254·25–298·92] per 100 000 population), whereas mental disorders were the leading cause for YLDs (2039·36 [1432·56–2773·47] per 100 000 population) and DALYs (2040·59 [1433·96–2774·62] per 100 000 population) in all EU Member States, and in all studied age groups. In 2019, among adolescents aged 10–24 years, males had a higher mortality rate per 100 000 population due to NCDs than females (11·66 [11·04–12·28] vs 7·89 [7·53–8·23]), whereas females presented a higher DALY rate per 100 000 population due to NCDs (8003·25 [5812·78–10 701·59] vs 6083·91 [4576·63–7857·92]). From 1990 to 2019, mortality rate due to NCDs in adolescents aged 10–24 years substantially decreased (–40·41% [–43·00 to –37·61), and also the YLL rate considerably decreased (–40·56% [–43·16 to –37·74]), except for mental disorders (which increased by 32·18% [1·67 to 66·49]), whereas the YLD rate increased slightly (1·44% [0·09 to 2·79]). Positive correlations were observed between DALY rates and SDIs for substance use disorders (rs=0·58, p=0·0012) and skin and subcutaneous diseases (rs=0·45, p=0·017), whereas negative correlations were found between DALY rates and SDIs for cardiovascular diseases (rs=–0·46, p=0·015), neoplasms (rs=–0·57, p=0·0015), and sense organ diseases (rs=–0·61, p=0·0005). Interpretation: NCD-related mortality has substantially declined among adolescents in the EU between 1990 and 2019, but the rising trend of YLL attributed to mental disorders and their YLD burden are concerning. Differences by sex, age group, and across EU Member States highlight the importance of preventive interventions and scaling up adolescent-responsive health-care systems, which should prioritise specific needs by sex, age, and location. Funding: Bill & Melinda Gates Foundation

Search for effective Lorentz and CPT violation using ZEUS data

Lorentz and CPT symmetry in the quark sector of the Standard Model are studied in the context of an effective field theory using ZEUS e±p data. Symmetry-violating effects can lead to time-dependent oscillations of otherwise time-independent observables, including scattering cross sections. An analysis using five years of inclusive neutral-current deep inelastic scattering events corresponding to an integrated HERA luminosity of 372 pb-1 at s=318 GeV has been performed. No evidence for oscillations in sidereal time has been observed within statistical and systematic uncertainties. Constraints, most for the first time, are placed on 42 coefficients parametrizing dominant CPT-even dimension-four and CPT-odd dimension-five spin-independent modifications to the propagation and interaction of light quarks