Variants in ALDH1A2 reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis

More than 40% of individuals will develop osteoarthritis (OA) during their lifetime, yet there are currently no licensed disease-modifying treatments for this disabling condition. Common polymorphic variants in ALDH1A2, which encodes the key enzyme for synthesis of all-trans retinoic acid (atRA), are associated with severe hand OA. Here, we sought to elucidate the biological significance of this association. We first confirmed that ALDH1A2 risk variants were associated with hand OA in the U.K. Biobank. Articular cartilage was acquired from 33 individuals with hand OA at the time of routine hand OA surgery. After stratification by genotype, RNA sequencing was performed. A reciprocal relationship between ALDH1A2 mRNA and inflammatory genes was observed. Articular cartilage injury up-regulated similar inflammatory genes by a process that we have previously termed mechanoflammation, which we believe is a primary driver of OA. Cartilage injury was also associated with a concomitant drop in atRA-inducible genes, which were used as a surrogate measure of cellular atRA concentration. Both responses to injury were reversed using talarozole, a retinoic acid metabolism blocking agent (RAMBA). Suppression of mechanoflammation by talarozole was mediated by a peroxisome proliferator–activated receptor gamma (PPARγ)–dependent mechanism. Talarozole was able to suppress mechano-inflammatory genes in articular cartilage in vivo 6 hours after mouse knee joint destabilization and reduced cartilage degradation and osteophyte formation after 26 days. These data show that boosting atRA suppresses mechanoflammation in the articular cartilage in vitro and in vivo and identifies RAMBAs as potential disease-modifying drugs for OA

Policy mixes for incumbency: the destructive recreation of renewable energy, shale gas 'fracking,' and nuclear power in the United Kingdom

The notion of a ‘policy mix’ can describe interactions across a wide range of innovation policies, including ‘motors for creation’ as well as for ‘destruction’. This paper focuses on the United Kingdom’s (UK) ‘new policy direction’ that has weakened support for renewables and energy efficiency schemes while strengthening promotion of nuclear power and hydraulic fracturing for natural gas (‘fracking’). The paper argues that a ‘policy apparatus for incumbency’ is emerging which strengthens key regimebased technologies while arguably damaging emerging niche innovations. Basing the discussion around the three technology-based cases of renewable energy and efficiency, fracking, and nuclear power, this paper refers to this process as “destructive recreation”. Our study raises questions over the extent to which policymaking in the energy field is not so much driven by stated aims around sustainability transitions, as by other policy drivers. It investigates different ‘strategies of incumbency’ including ‘securitization’, ‘masking’, ‘reinvention’, and ‘capture.’ It suggests that analytical frameworks should extend beyond the particular sectors in focus, with notions of what counts as a relevant ‘policy maker’ correspondingly also expanded, in order to explore a wider range of nodes and critical junctures as entry points for understanding how relations of incumbency are forged and reproduced

Learners’ and teachers’ beliefs about learning tones and pinyin

This paper reports a study of the perceptions of English-speaking learners and teachers about the challenges and difficulties of Chinese as a Second Language (CSL) learning in England. The study involved a Likert-scale questionnaire and follow-up interviews with 37 university student learners, 443 school students and the 42 teachers of both groups. The questionnaires and interviews explored beliefs about language learning, about Chinese language learning and about language learning strategies. This paper focuses on the findings concerning the perceived challenges of speaking Chinese and of tones in learning Chinese. The findings of this study present a picture of teachers who are keen for their students to learn to speak and communicate in Chinese, and of students who are keen to take risks in speaking. However, in contrast to earlier findings about learners’ views about learning Chinese, the learners in this study claimed to be very tone aware and reported that they found listening and understanding Chinese more difficult than production. This is explored in relation to the pupils’ views about learning tones and pinyin and raises questions about the ways they address tones and pinyin learning in the context of their expressed aim of communicating and taking risks in speaking. The discussion raises issues about the possible effects of communicative teaching of languages in English schools. We ask whether an emphasis on communicative approaches may affect how learners address difficulties of the Chinese pronunciation system and the use of pinyin

Cystic Fibrosis

Cystic fibrosis was first recognized as a new disease in 1938 when autopsies of children who died from malnourishment revealed similar findings. Currently, there are approximately 30,000 people living in the U.S. who are affected by this rare genetic disease. Cystic fibrosis is a congenital progressive disorder caused by a mutation in the gene encoding cystic fibrosis transmembrane conductance regulator (CTFR). Mutations in the CTFR gene cause the mucus in the body to become thick and glue-like, blocking ducts and tubes distributed within the body. Buildup in mucus can cause a multitude of problems, eventually leading to death. Treatment of an individual with cystic fibrosis depends on the severity of symptoms. Antibiotics can prevent and treat chest infections. Other medications can also treat thick mucus in the lungs by thinning and hydrating the mucus, allowing it to clear and also widening the airways to make breathing easier. Lung transplant may be needed in the case of lung damage. The FDA recently approved Trikafta, the first triple combination therapy available to treat CF. Here, we explore the manner in which this trifecta of drugs helps the protein encoded by the CTFR gene mutation function more effectively