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Accordingly, interleukin-2 treatment improved the Treg-like compartment and survival.The risk of cardiovascular disease is increased in patients with rheumatoid arthritis compared with the general population owing to the influence of traditional and non-traditional risk factors. Inflammation has a pivotal contribution and can accelerate the atherosclerotic process. Although dampening inflammation with DMARDs should theoretically abrogate this process, evidence suggests that these drugs can also promote atherosclerosis directly and indirectly, hence adding to an increased cardiovascular burden. However, the extent and direction of the effects largely differ across drugs. Understanding how these drugs influence endothelial damage and vascular repair mechanisms is key to understanding these outcomes. NSAIDs and glucocorticoids can increase the cardiovascular risk. Conversely, conventional, biologic and targeted DMARDs control inflammation and reduce this risk, although some of these drugs can also aggravate traditional factors or thrombotic events. Given these data, the fundamental objective for clinicians should be disease control, in an individualized approach that considers the most appropriate drug for each patient, taking into account joint and cardiovascular outcomes. This Review provides a comprehensive analysis of the effects of DMARDs and other approved drugs on cardiovascular involvement in rheumatoid arthritis, from a clinical and mechanistic perspective, with a roadmap to inform the research agenda.Immune checkpoint inhibitors have revolutionized medical oncology, although currently only a subset of patients has a response to such treatment. GW788388 A compelling body of evidence indicates that anti-angiogenic therapy has the capacity to ameliorate antitumour immunity owing to the inhibition of various immunosuppressive features of angiogenesis. Hence, combinations of anti-angiogenic agents and immunotherapy are currently being tested in >90 clinical trials and 5 such combinations have been approved by the FDA in the past few years. In this Perspective, we describe how the angiogenesis-induced endothelial immune cell barrier hampers antitumour immunity and the role of endothelial cell anergy as the vascular counterpart of immune checkpoints. We review the antitumour immunity-promoting effects of anti-angiogenic agents and provide an update on the current clinical successes achieved when these agents are combined with immune checkpoint inhibitors. Finally, we propose that anti-angiogenic agents are immunotherapies - and vice versa - and discuss future research priorities.Biomolecular condensates (biocondensates) formed via liquid-liquid phase-separation of soluble proteins have been studied extensively. However, neither the phase-separation of endoplasmic reticulum (ER) transmembrane protein nor a biocondensate with organized membranous structures has been reported. Here, we have discovered a spherical ER membranous biocondensate with puzzle-like structures caused by condensation of the ER-resident stimulator of interferon genes (STING) in DNA virus-infected or 2'3'-cGAMP (cyclic GMP-AMP)-treated cells, which required STING transmembrane domains, an intrinsically disordered region (IDR) and a dimerization domain. Intracellular 2'3'-cGAMP concentrations determined STING translocation or condensation. STING biocondensates constrained STING and TBK1 (TANK binding protein 1) to prevent innate immunity from overactivation, presumably acting like a 'STING-TBK1-cGAMP sponge'. Cells expressing STING-E336G/E337G showed notably enhanced innate immune responses due to impaired STING condensation after viral infection at later stages. Microtubule inhibitors impeded the STING condensate gel-like transition and augmented type I-interferon production in DNA virus-infected cells. This membranous biocondensate was therefore named the STING phase-separator.Mobile transposable elements (TEs) not only participate in genome evolution but also threaten genome integrity. In healthy cells, TEs that encode all of the components that are necessary for their mobility are specifically silenced, yet the precise mechanism remains unknown. Here, we characterize the mechanism used by a conserved class of chromatin remodelers that prevent TE mobility. In the Arabidopsis chromatin remodeler DECREASE IN DNA METHYLATION 1 (DDM1), we identify two conserved binding domains for the histone variant H2A.W, which marks plant heterochromatin. DDM1 is necessary and sufficient for the deposition of H2A.W onto potentially mobile TEs, yet does not act on TE fragments or host protein-coding genes. DDM1-mediated H2A.W deposition changes the properties of chromatin, resulting in the silencing of TEs and, therefore, prevents their mobility. This distinct mechanism provides insights into the interplay between TEs and their host in the contexts of evolution and disease, and potentiates innovative strategies for targeted gene silencing.Online reviews promise to provide people with immediate access to the wisdom of the crowds. Yet, half of all reviews on Amazon and Yelp provide the most positive rating possible, despite human behaviour being substantially more varied in nature. We term the challenge of discerning success within this sea of positive ratings the 'positivity problem'. Positivity, however, is only one facet of individuals' opinions. We propose that one solution to the positivity problem lies with the emotionality of people's opinions. Using computational linguistics, we predict the box office revenue of nearly 2,400 movies, sales of 1.6 million books, new brand followers across two years of Super Bowl commercials, and real-world reservations at over 1,000 restaurants. Whereas star ratings are an unreliable predictor of success, emotionality from the very same reviews offers a consistent diagnostic signal. More emotional language was associated with more subsequent success.The development and dispersal of agropastoralism transformed the cultural and ecological landscapes of the Old World, but little is known about when or how this process first impacted Central Asia. Here, we present archaeological and biomolecular evidence from Obishir V in southern Kyrgyzstan, establishing the presence of domesticated sheep by ca. 6,000 BCE. Zooarchaeological and collagen peptide mass fingerprinting show exploitation of Ovis and Capra, while cementum analysis of intact teeth implicates possible pastoral slaughter during the fall season. Most significantly, ancient DNA reveals these directly dated specimens as the domestic O. aries, within the genetic diversity of domesticated sheep lineages. Together, these results provide the earliest evidence for the use of livestock in the mountains of the Ferghana Valley, predating previous evidence by 3,000 years and suggesting that domestic animal economies reached the mountains of interior Central Asia far earlier than previously recognized.Since 1989, China has established a system of powerful laws and regulations aimed to preserve its rich natural flora and fauna. However, this legislative framework still has shortcomings, in terms of sentencing standards across related crimes and the extent of scientific basis for sentences. Here, we review Chinese biodiversity protection laws and some example cases with the goal of suggesting ways to increase law compliance and thus better protect biodiversity. In particular, our suggestions involve regular updates of threat assessments based on scientific evidence including herbaceous plants, fungi and algae; considering ecological differences among the species groups and ensuing ecological damage and financial profit gained; and a differentiation of punishment between organized and individual crimes, with a preference for custodial sentences for the former and monetary fines for the latter, to comply better with international standards and to minimize the incentive to engage in such conduct.The Convention on Biological Diversity's post-2020 Global Biodiversity Framework will probably include a goal to stabilize and restore the status of species. Its delivery would be facilitated by making the actions required to halt and reverse species loss spatially explicit. Here, we develop a species threat abatement and restoration (STAR) metric that is scalable across species, threats and geographies. STAR quantifies the contributions that abating threats and restoring habitats in specific places offer towards reducing extinction risk. While every nation can contribute towards halting biodiversity loss, Indonesia, Colombia, Mexico, Madagascar and Brazil combined have stewardship over 31% of total STAR values for terrestrial amphibians, birds and mammals. Among actions, sustainable crop production and forestry dominate, contributing 41% of total STAR values for these taxonomic groups. Key Biodiversity Areas cover 9% of the terrestrial surface but capture 47% of STAR values. STAR could support governmental and non-state actors in quantifying their contributions to meeting science-based species targets within the framework.To explore the role of chronic inflammation inherent to autoimmune diseases in the development of subclinical atherosclerosis and arterial stiffness, this study recruited two population-based samples of individuals with and without autoimmune disease (ratio 15) matched by age, sex, and education level and with a longstanding (≥6 years) diagnosis of autoimmune disease. Common carotid intima-media thickness (IMT) and arterial distensibility and compliance were assessed with carotid ultrasound. Multivariable linear and logistic regression models were adjusted for 10-year cardiovascular risk. In total, 546 individuals with and without autoimmune diseases (91 and 455, respectively) were included. The mean age was 66 years (standard deviation 12), and 240 (43.9%) were women. Arterial stiffness did not differ according to the presence of autoimmune diseases. In men, the diagnosis of autoimmune diseases significantly increased common carotid IMT [beta-coefficient (95% confidence interval) 0.058 (0.009; 0.108); p value = 0.022] and the percentage with IMT ≥ 75th percentile [1.012 (0.145; 1.880); p value = 0.022]. Women without autoimmune disease were more likely to have IMT ≥ the 75th percentile [-2.181 (-4.214; -0.149); p value = 0.035], but the analysis of IMT as a continuous variable did not yield significant results. In conclusion, subclinical carotid atherosclerosis, but not arterial stiffness, was more common in men with autoimmune diseases. Women did not show significant differences in any of these carotid features. Sex was an effect modifier in the association between common carotid IMT values and the diagnosis of autoimmune diseases.While the advent of GWAS more than a decade ago has ushered in remarkable advances in our understanding of complex traits, the limitations of single-SNP analysis have also led to the development of several other approaches. Simulation studies have shown that the regional heritability mapping (RHM) method, which makes use of multiple adjacent SNPs jointly to estimate the genetic effect of a given region of the genome, generally has higher detection power than single-SNP GWAS. However, thus far its use has been mostly limited to agricultural settings, and its potential for the discovery of new genes in human diseases is yet to be fully exploited. In this study, by applying the RHM method to primary biliary cholangitis (PBC) in the Japanese population, we identified three novel loci (STAT4, ULK4, and KCNH5) at the genome-wide significance level, two of which (ULK4 and KCNH5) have not been found associated with PBC in any population previously. Notably, these genes could not be detected by using conventional single-SNP GWAS, highlighting the potential of the RHM method for the detection of new susceptibility loci in human diseases.