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Background: Pulmonary arterial hypertension (PAH) is a rare disease characterized by remodeling of the pulmonary arteries, increased vascular resistance, and right-sided heart failure. Genome-wide association studies of idiopathic/heritable PAH established novel genetic risk variants, including conserved enhancers upstream of transcription factor (TF) SOX17 containing 2 independent signals. SOX17 is an important TF in embryonic development and in the homeostasis of pulmonary artery endothelial cells (hPAEC) in the adult. Rare pathogenic mutations in SOX17 cause heritable PAH. We hypothesized that PAH risk alleles in an enhancer region impair TF-binding upstream of SOX17 , which in turn reduces SOX17 expression and contributes to disturbed endothelial cell function and PAH development. Methods: CRISPR manipulation and siRNA were used to modulate SOX17 expression. Electromobility shift assays were used to confirm in silico – predicted TF differential binding to the SOX17 variants. Functional assays in hPAECs were used to establish the biological consequences of SOX17 loss. In silico analysis with the connectivity map was used to predict compounds that rescue disturbed SOX17 signaling. Mice with deletion of the SOX17 -signal 1 enhancer region ( SOX17 -4593/enhKO) were phenotyped in response to chronic hypoxia and SU5416/hypoxia. Results: CRISPR inhibition of SOX17 -signal 2 and deletion of SOX17 -signal 1 specifically decreased SOX17 expression. Electromobility shift assays demonstrated differential binding of hPAEC nuclear proteins to the risk and nonrisk alleles from both SOX17 signals. Candidate TFs HOXA5 and ROR-α were identified through in silico analysis and antibody electromobility shift assays. Analysis of the hPAEC transcriptomes revealed alteration of PAH-relevant pathways on SOX17 silencing, including extracellular matrix regulation. SOX17 silencing in hPAECs resulted in increased apoptosis, proliferation, and disturbance of barrier function. With the use of the connectivity map, compounds were identified that reversed the SOX17-dysfunction transcriptomic signatures in hPAECs. SOX17 enhancer knockout in mice reduced lung SOX17 expression, resulting in more severe pulmonary vascular leak and hypoxia or SU5416/hypoxia-induced pulmonary hypertension. Conclusions: Common PAH risk variants upstream of the SOX17 promoter reduce endothelial SOX17 expression, at least in part, through differential binding of HOXA5 and ROR-α. Reduced SOX17 expression results in disturbed hPAEC function and PAH. Existing drug compounds can reverse the disturbed SOX17 pulmonary endothelial transcriptomic signature.

Suicide notes and poetry have been used in text analysis to identify emotional states and mental illness, although there have been no corpus linguistics studies examining the lyrics of musicians who have died by suicide. The present study aimed to fill a gap in the research on understanding the suicidal mind and the development of protocols for using language to predict suicide risk and to prevent suicide. Linguistic Inquiry and Word Count, a computerized method for text analysis, is often used to examine suicide writings. In the current study, lyrics written by Kurt Cobain and a reference corpus of late 1980s/early 1990s grunge were analyzed to explore different linguistic categories in the lyrics of authors with suicidal intent and those without. For the four broad psycholinguistic variables three (clout, authenticity, and tone) all had a |14| point difference in percentile rank. For linguistic, and psychological variables, multiple were found to differ significantly (first-person plural pronouns, third-person singular pronouns, and anxiety). None of the four broad psycholinguistic variables were found to have significant difference in Cobain’s writing over time. Reasons for the obtained results as well as implications for research and for practice are discussed.

Suicidology has a rich history of looking at the relationship between language and suicide via the review of suicide notes, memoirs, and other writings. This research has identified differences in the language of persons with suicidal intent and without suicidal intent. No prior research has been done regarding the relationship between lyrics and suicide. The current study aimed to identify differences in the lyrics written by artists with suicidal intent and without suicidal intent. A keyword analysis was used to compare a corpus of lyrics written by Kurt Cobain to that of similar late 1980s/early 1990s grunge music. The three words with the strongest keyness were “gimme”, “daddy’s”, and “stay”. The first and second most frequent words (“yeah” and “girl”) were identified as well as the collocations for these words as well as the collocations for of the words stems “depress*”, and “gun*” and the word “death”. A discussion of the results and implications for practice and future research will be reviewed.

COVID-19 has affected the research studies of undergraduate students and has caused projects to go in directions or face obstacles that are not expected. Our research group took part in a public sociology class and worked with partners from Nepal to study teacher’s perspectives of the Nepali education system during COVID-19. During this research experience, we navigated obstacles with communication, cultural sensitivity, time constraints, COVID-19, and research methodology. In this article, we share how we overcame these obstacles. We illustrate the benefits we found from this research project experience, the lessons we have learned, and the future advice we have for both ourselves and for other undergraduate students that are conducting research during COVID-19.

Pulmonary arterial hypertension (PAH) is a progressive disease predominantly targeting pre-capillary blood vessels. Adverse structural remodelling and increased pulmonary vascular resistance result in cardiac hypertrophy and ultimately failure of the right ventricle. Recent whole-genome and whole-exome sequencing studies have identifiedSOX17as a novel risk gene in PAH, with a dominant mode of inheritance and incomplete penetrance. Rare deleterious variants in the gene and more common variants in upstream enhancer sites have both been associated with the disease, and a deficiency ofSOX17expression may predispose to PAH. This review aims to consolidate the evidence linking genetic variants inSOX17to PAH, and explores the numerous targets and effects of the transcription factor, focusing on the pulmonary vasculature and the pathobiology of PAH.

Pulmonary arterial hypertension (PAH) is a progressive disease predominantly targeting pre-capillary blood vessels. Adverse structural remodelling and increased pulmonary vascular resistance result in cardiac hypertrophy and ultimately failure of the right ventricle. Recent whole-genome and whole-exome sequencing studies have identified

Interventions targeting mitochondrial dysfunction have the potential to extend survival in preclinical models of amyotrophic lateral sclerosis. The aim of this systematic review was to assess the efficacy of targeting mitochondria as a potential therapeutic target in amyotrophic lateral sclerosis. Preclinical studies written in the English language were identified with no restrictions on publication date from PubMed, Medline and EMBASE databases. All studies adopting interventions targeting mitochondria to treat amyotrophic lateral sclerosis in genetic or drug-induced organism models were considered for inclusion. A total of 76 studies were included in the analysis. Survival data were extracted, and the meta-analysis was completed in RevMan 5 software. We show that targeting mitochondrial dysfunction in amyotrophic lateral sclerosis results in a statistically significant improvement in survival (Z = 5.31; P

Motor Neuron Disease (MND) typically affects patients during the later stages of life, and thus, MND is having an increasingly devastating impact on diagnosed individuals, their families and society. The umbrella term MND refers to diseases which cause the progressive loss of upper and/or lower motor neurons and a subsequent decrease in motor ability such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). The study of these diseases is complex and has recently involved the use of genome-wide association studies (GWAS). However, in the case of MND, it has been difficult to identify the complex genetics involved in subtypes, and functional investigation of new candidate disease genes is warranted. Drosophila is a powerful model for addressing these complex diseases. The UAS/Gal4/Gal80 system allows for the upregulation of Drosophila genes, the “knockdown” of genes and the ectopic expression of human genes or mutations in a tissue-specific manner; often resulting in Drosophila models which exhibit typical MND disease pathologies. These can then be further interrogated to identify disease-modifying genes or mutations and disease pathways. This review will discuss two common MNDs and the current Drosophila models which are being used to research their genetic basis and the different pathologies of MND.

Aims There is an increased drive towards healthcare integration in the UK (UK) to adapt to new health care needs. In response to this, new ways of delivering care have been developed such as the provision of integrated respiratory specialists. This project set out to describe these roles, the key skills needed and how junior staff can aspire to these roles. Methods Semi-structured telephone interviews with 12 integrated care specialists or those currently working with integrated respiratory care teams were undertaken to explore and discuss the role of integrated respiratory specialists. Results Nine integrated specialists were interviewed (6 physicians, 2 nurses, 1 physiotherapist). One Specialist Trainee (StR), a general practitioner (GP) and a pharmacist were also interviewed. The integrated role was variable for participants; most were involved in MDTs, education for staff and developing guidance, with some involved in community or virtual clinics. Physicians were more likely to be involved in Acute Medical Unit reviews. Five interviewees had two joint leads with either two physicians, or a physician and a nurse. Key skills identified by the interviewees included respiratory specialist knowledge, prior primary care experience as well as knowledge of the NHS, commissioning and social services processes. Specific training included conflict management, advanced communication and research and evaluation skills (health economics and service evaluation). Three areas were highlighted to support the establishment of new posts: clear details about the posts and standards of care; embedding integrated care into training; increasing visibility of this new area and gaining support from appropriate organisations. Conclusions Interviewees highlighted that existing posts should be used as exemplars to provide junior staff with more information about these roles. Greater collaboration with professional societies such as the BTS, ERS and PCRS for education as well as to promote and advance these new potential career pathways should be undertaken. Funded by the British Thoracic Society.

Aim The way we deliver healthcare in the UK is changing, joining up care between the different health sectors has created a new field of “integrated care”. Recent publications from the Kings Fund, Nuffield Trust and National Voices has shown that it is difficult to define “integrated care”. This project surveyed health professionals on their views about integrated care and the value of integrated respiratory specialists. Method A questionnaire was sent to all BTS members in Oct 2013 on the role of integrated care specialists, 216 responses were received. Results Most respondents (82.5%, 178/216) included integration of primary and secondary care in their definition of integrated care, only 36.5% (65/178) included community, and a smaller number included social care as part of the definition. In the free-text there was also emphasis on the bridging role of the post, and providing “seamless care” across sectors. 62% (86/139) agreed that integrated respiratory specialists had added value (compared to respiratory specialist roles); providing continuity of care for a defined population (87%, [121/139), and 77% (106/138) agreed that they improve outcomes for patients with a long term condition. Eighty-nine percent (124/140) also agreed that integrated specialists improve relationships between primary and secondary care. When asked the most important role that an integrated respiratory specialist should undertake (98 comments), the provision of specialist leadership, clinical decision-making and supervision (20 comments) were highly rated. Teaching (10 comments) and providing liaison support for the whole pathway were also important (9 comments). Conclusion 82% of respondents (178/216) included integration of primary and secondary care in their definition of integrated care. However 14.4% were unsure of what integrated care was. Considerable more work is needed to promote this new way of working and potential career pathway. However of those who did know about these roles, a large majority agreed that these roles had added value compared to traditional specialist roles. Funded by the BTS. Abstracts M35 to M43 can be found on pages A208–A211.