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Animal African Trypanosomiasis (AAT) is a debilitating livestock disease prevalent across sub-Saharan Africa, a main cause of which is the protozoan parasite Trypanosoma congolense . In comparison to the well-studied T . brucei , there is a major paucity of knowledge regarding the biology of T . congolense . Here, we use a combination of omics technologies and novel genetic tools to characterise core metabolism in T . congolense mammalian-infective bloodstream-form parasites, and test whether metabolic differences compared to T . brucei impact upon sensitivity to metabolic inhibition. Like the bloodstream stage of T . brucei , glycolysis plays a major part in T . congolense energy metabolism. However, the rate of glucose uptake is significantly lower in bloodstream stage T . congolense , with cells remaining viable when cultured in concentrations as low as 2 mM. Instead of pyruvate, the primary glycolytic endpoints are succinate, malate and acetate. Transcriptomics analysis showed higher levels of transcripts associated with the mitochondrial pyruvate dehydrogenase complex, acetate generation, and the glycosomal succinate shunt in T . congolense , compared to T . brucei . Stable-isotope labelling of glucose enabled the comparison of carbon usage between T . brucei and T . congolense , highlighting differences in nucleotide and saturated fatty acid metabolism. To validate the metabolic similarities and differences, both species were treated with metabolic inhibitors, confirming that electron transport chain activity is not essential in T . congolense . However, the parasite exhibits increased sensitivity to inhibition of mitochondrial pyruvate import, compared to T . brucei . Strikingly, T . congolense exhibited significant resistance to inhibitors of fatty acid synthesis, including a 780-fold higher EC 50 for the lipase and fatty acid synthase inhibitor Orlistat, compared to T . brucei . These data highlight that bloodstream form T . congolense diverges from T . brucei in key areas of metabolism, with several features that are intermediate between bloodstream- and insect-stage T . brucei . These results have implications for drug development, mechanisms of drug resistance and host-pathogen interactions.

Pulmonary arterial hypertension (PAH) is a rare but fatal disease. Current treatments increase life expectancy but have limited impact on the progressive pulmonary vascular remodelling that drives PAH. Osteoprotegerin (OPG) is increased within serum and lesions of patients with idiopathic PAH and is a mitogen and migratory stimulus for pulmonary artery smooth muscle cells (PASMCs). Here, we report that the pro-proliferative and migratory phenotype in PASMCs stimulated with OPG is mediated via the Fas receptor and that treatment with a human antibody targeting OPG can attenuate pulmonary vascular remodelling associated with PAH in multiple rodent models of early and late treatment. We also demonstrate that the therapeutic efficacy of the anti-OPG antibody approach in the presence of standard of care vasodilator therapy is mediated by a reduction in pulmonary vascular remodelling. Targeting OPG with a therapeutic antibody is a potential treatment strategy in PAH. Pulmonary arterial hypertension (PAH) is characterised by progressive pulmonary vascular remodelling. Here, Arnold et al. develop a therapeutic antibody targeting osteoprotegerin and find it attenuates pulmonary vascular remodelling in multiple rodent models of PAH, alone or in combination with standard of care vasodilator therapy.

Bone morphogenetic protein receptor type 2 (BMPR2) mutations are present in patients with heritable and idiopathic pulmonary arterial hypertension (PAH). Circulating levels of interleukin-1 (IL-1) are raised in patients and animal models. Whether interplay between BMP and IL-1 signaling can explain the local manifestation of PAH in the lung remains unclear. Cell culture, siRNA, and mRNA microarray analysis of RNA isolated from human pulmonary artery (PASMC) and aortic (AoSMC) smooth muscle cells were used. R899X+/– BMPR2 transgenic mice fed a Western diet for six weeks were given daily injections of IL-1ß prior to assessment for PAH and tissue collection. PASMC have reduced inflammatory activation in response to IL-1ß compared with AoSMCs; however, PASMC with reduced BMPR2 demonstrated an exaggerated response. Mice treated with IL-1ß had higher white blood cell counts and significantly raised serum protein levels of IL-6 and osteoprotegerin (OPG) plasma levels recapitulating in vitro data. Phenotypically, IL-1ß treated mice demonstrated increased pulmonary vascular remodeling. IL-1ß induces an exaggerated pulmonary artery specific transcriptomic inflammatory response when BMPR2 signaling is reduced.

Loss of the growth-suppressive effects of bone morphogenetic protein (BMP) signaling has been demonstrated to promote pulmonary arterial endothelial cell dysfunction and induce pulmonary arterial smooth muscle cell (PASMC) proliferation, leading to the development of pulmonary arterial hypertension (PAH). MicroRNAs (miRs) mediate higher order regulation of cellular function through coordinated modulation of mRNA targets; however, miR expression is altered by disease development and drug therapy. Here, we examined treatment-naive patients and experimental models of PAH and identified a reduction in the levels of miR-140-5p. Inhibition of miR-140-5p promoted PASMC proliferation and migration in vitro. In rat models of PAH, nebulized delivery of miR-140-5p mimic prevented the development of PAH and attenuated the progression of established PAH. Network and pathway analysis identified SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) as a key miR-140-5p target and regulator of BMP signaling. Evaluation of human tissue revealed that SMURF1 is increased in patients with PAH. miR-140-5p mimic or SMURF1 knockdown in PASMCs altered BMP signaling, further supporting these factors as regulators of BMP signaling. Finally, Smurf1 deletion protected mice from PAH, demonstrating a critical role in disease development. Together, these studies identify both miR-140-5p and SMURF1 as key regulators of disease pathology and as potential therapeutic targets for the treatment of PAH.

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG , and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH. Idiopathic pulmonary arterial hypertension is a rare and fatal disease with a heterogeneous treatment response. Here the authors show that unsupervised machine learning of whole blood transcriptomes from 359 patients with idiopathic pulmonary arterial hypertension identifies 3 subgroups (endophenotypes) that improve risk stratification and provide new molecular insights.

Background Engaging influential stakeholders in meaningful exchange is essential for pharmaceutical companies aiming to improve care. At a time where opportunities for face-to-face engagement are limited, the ability to interact, learn and generate actionable insights through digital channels such as Twitter, is of considerable value. Aim The aim of this study was to evaluate digital engagement among global diabetes mellitus researchers. Materials and Methods We identified every global tweet (20,614,515) and scientific publication (44,135) regarding diabetes mellitus from 1 August 2018 to 1 August 2020. Through author matching we combined datasets, resulting in a list of digitally active scientific authors. Generalised linear modelling identified factors predicting their digital engagement. Findings Globally, 2686 diabetes researchers used Twitter to discuss the management of diabetes mellitus, posting 110,346 diabetes-related tweets. As Twitter followers increased, so did tweet frequency ( p  < 0.001), retweets ( p  < 0.001) and replies ( p  < 0.001) to their content. Publication count (overall/per month) and proportion of first/last authorships were unrelated to tweet frequency and the likelihood of being retweeted or replied to ( p  > 0.05). Those with the most  academic co-authors were significantly less likely to tweet than those with smaller networks (< 50; p  = 0.001). Finally, those publishing most frequently on specific themes, including insulin ( p  = 0.041) and paediatrics ( p  < 0.001), were significantly more likely to tweet about these themes. Conclusion Academic expertise and seniority cannot be assumed as proxies for digital influence. Those aiming to promote science and obtain digital insights regarding condition management should consider looking beyond well-known ‘key opinion leaders’ to perhaps lesser known ‘digital opinion leaders’ with smaller academic networks, who are likely to specialise in the delivery of highly specific content to captive audiences. Plain Language Summary Traditionally, research scientists and clinical experts in any field make their opinions and expertise known by writing academic journal papers. After successful peer review, they are accepted and made publicly available. However, during the coronavirus disease 2019 (COVID-19) pandemic, more scientific information has been shared and discussed using digital platforms such as Twitter than ever before, setting the stage for their greater role in scientific discussions in the future. It is important that the pharmaceutical industry is aware of this shift as it may offer up new insights and opportunities. Using diabetes as a test case, we compared researchers’ publishing activity with their Twitter activity over a 2-year period. We found that less established researchers who are less well-known in their fields, and with less publications to their name, are far more likely to be active in sharing valuable scientific content to large Twitter audiences. This makes them ‘opinion leaders’ even if they would not be thought of as such in a traditional, academic sense, suggesting that those who look only to high-ranking academic journals, and those who publish within them, may be missing an important and ever-increasing part of the conversation. This is the first ever study to compare digital and traditional publishing activities and highlights the potential of this approach to gain novel and valuable knowledge about specific topics.

Introduction Pulmonary arterial hypertension (PAH) is a devastating disease with a high mortality and prognosis worse than many cancers. Pathologically, PAH is characterised by progressive arteriole remodelling driven by pulmonary artery smooth muscle cell (PASMC) proliferation and migration. Although current treatments alleviate symptoms, they do not reverse the underlying progressive pulmonary vascular proliferation. We have previously shown that the secreted glycoprotein osteoprotegerin (OPG, TNFRSF11B) is increased within pulmonary vascular lesions and serum from patients with idiopathic PAH, and promotes the proliferation and migration of PASMCs in vitro . Recent experiments have shown that administration of an anti-OPG antibody can prevent and reverse PAH in rodent models of disease. However, how OPG signals to mediate PASMC phenotype remains unknown. We hypothesise that OPG mediates these effects through a previously undescribed cell surface receptor. We aim to identify this receptor on PASMC and characterise the OPG signalling cascade leading to the proliferative phenotype. Methods Quiesced PASMCs (Lonza, Basel, Switzerland) were stimulated with 0.2% FCS (negative), and OPG (50 ng/ml) for 10 and 60 min. Phosphorylation targets were identified from protein lysates by Kinex antibody microarray (Kinexus, Canada). Selected targets were verified by western blotting. Transcriptomic analysis of PASMCs stimulated with OPG for 6 h was performed using an RNA expression microarray (Agilent) and confirmed by TaqMan RT-PCR. Novel OPG binding proteins were identified following reverse transfection of HEK293 cells with 2054 human membrane proteins (Retrogenix, Sheffield, UK) and confirmed in PASMC by co-immunoprecipitation. To assess the effect of Fas blockade, proliferation was assessed in PASMCs pre-incubated with Fas neutralising antibody (500 ng/ml) 30 min before 72h stimulation with OPG. Results OPG stimulation of PASMC resulted in significant activation of CDK4 and 5, HSP27 and ERK1/2, and significant decrease in phospho-mTOR. OPG increased TRAIL, PDGFRA, TNC, Cav-1 and reduced VIP receptor gene expression. Four novel OPG interactions with IL1RAP, Fas, TMPRSS11D and GAP43 were identified by the Retrogenix cell microarray. We have confirmed OPG interaction with IL1RAP and Fas in PASMC by co-immunoprecipitation. Fas protein expression is elevated in the pulmonary artery and right ventricle of IPAH patients. Fas RNA expression is increased in PASMCs from IPAH patient lungs. Furthermore, blocking Fas with a neutralising antibody reduces OPG-induced proliferation, PDGFRA and TNC RNA expression. Conclusions These data highlight novel binding partners for OPG. In particular the OPG-FAS interaction regulates a diverse and important intracellular signalling cascade by which OPG regulates proliferation, apoptosis and autophagy proteins, and PAH associated genes in PASMC. These data further highlight therapeutic potential of targeting OPG in PAH.