Proteomic profiling of the large-vessel vasculitis spectrum identifies shared signatures of innate immune activation and stromal remodelling

Background: Takayasu arteritis (TAK) and giant cell arteritis (GCA), the most common forms of large-vessel vasculitis (LVV), can result in serious morbidity. Understanding the molecular basis of LVV should aid in developing better biomarkers and treatments. Methods: Plasma proteomic profiling of 184 proteins was performed in two cohorts. Cohort 1 included patients with established TAK (n=96) and large-vessel GCA (LV-GCA, n=35) in addition to healthy control participants (HCs, n=35). Cohort 2 comprised patients presenting acutely with possible cranial-GCA in whom the diagnosis was subsequently confirmed (C-GCA, n=150) or excluded (Not C-GCA, n=89). Proteomic findings were compared to published transcriptomic data from LVV-affected arteries. Results: In Cohort 1, comparison to HCs revealed 52 differentially abundant proteins (DAPs) in TAK and 72 in LV-GCA. Within-case analyses identified 16 and 18 disease activity-associated proteins in TAK and LV-GCA, respectively. In Cohort 2, comparing C-GCA versus Not C-GCA revealed 31 DAPs. Analysis within C-GCA cases suggested the presence of distinct endotypes, with more pronounced proteomic changes in the biopsy-proven subgroup. Cross-comparison of TAK, LV-GCA and biopsy-proven C-GCA revealed highly similar plasma proteomic profiles, with 26 shared DAPs including IL6, monocyte/macrophage related proteins (CCL7, CSF1), tissue remodelling proteins (TIMP1, TNC) and novel associations (TNFSF14, IL7R). Plasma proteomic findings reflected LVV arterial phenotype; for 42% of DAPs, the corresponding gene was differentially expressed in tissue. Conclusions: These findings suggest shared pathobiology across the LVV spectrum involving innate immunity, lymphocyte homeostasis and tissue remodelling. Network-based analyses highlighted immune-stromal crosstalk and identified novel therapeutic targets (e.g. TNFSF14)

Dilated cardiomyopathy in the young: a patient-scientist informed review of unmet needs

Dilated Cardiomyopathy (DCM) is a leading cause of heart failure and the most common indication for a heart transplant. Guidelines are regularly based on studies of adults and applied to the young. Children and adolescents diagnosed with DCM face different lifestyle challenges from individuals diagnosed in adulthood that include medical trauma and are influenced by maturity levels and confidence with advocacy to adults. Using a UK patient-scientist’s perspective (ERJ), we reviewed the age-specific challenges faced by the young with DCM, evaluated current guidelines and evidence, and identified areas requiring further recommendations and research. We highlight the importance of i) the transition clinic from paediatric to adult services, ii) repeated signposting to mental health services, iii) standardised guidance on physical activity, iv) caution surrounding alcohol and smoking, v) the dangers of illegal drugs, and vi) reproductive options and health. Further research is needed to address the many uncertainties in these areas with respect to young age, particularly for physical activity, and such guidance would be welcomed by the young with DCM who must come to terms with being different and more limited amongst healthy peers

Design and behaviour of moment resisting precast concrete connections with cast-in shear fasteners

The paper proposes a novel design procedure for an innovative connector that provides flexural continuity between ribbed precast concrete flooring units. The innovation was driven by the goal of rapid onsite assembly which precluded the use of structural toppings, complex in-situ stitching of projecting bars or onsite welding. Assembly on site is a simple process of bringing the precast elements together on temporary supports and grouting the prefabricated steel connectors into well-voids cast into the member ends. The benefits of the developed connection have been successfully demonstrated within a number of full-scale prototypes. Due to the novel and unconventional form of the proposed connector, physical testing was crucial to provide an in-depth understanding of its response characteristics under serviceability and ultimate loading conditions. Towards this end, three full size specimens were tested to failure under four-point bending. The outcomes of these experiments are used to validate 3-D high-fidelity nonlinear finite element analysis models. These are finally used in a wide-ranging study to demonstrate the applicability of the proposed design procedure for this novel precast concrete connection system

The influence of phosphoinositide lipids in the molecular biology of membrane proteins: recent insights from simulations

The phosphoinositide family of membrane lipids play diverse and critical roles in eukaryotic molecular biology. Much of this biological activity derives from interactions of phosphoinositide lipids with integral and peripheral membrane proteins, leading to modulation of protein structure, function, and cellular distribution. Since the discovery of phosphoinositides in the 1940s, combined molecular biology, biophysical, and structural approaches have made enormous progress in untangling this vast and diverse cellular network of interactions. More recently, in silico approaches such as molecular dynamics simulations have proven to be an asset in prospectively identifying, characterising, explaining the structural basis of these interactions, and in the best cases providing atomic level testable hypotheses on how such interactions control the function of a given membrane protein. This review details a number of recent seminal discoveries in phosphoinositide biology, enabled by advanced biomolecular simulation, and its integration with molecular biology, biophysical, and structural biology approaches. The results of the simulation studies agree well with experimental work, and in a number of notable cases have arrived at the key conclusion several years in advance of the experimental structures

Building the capacity of young professionals in family planning to publish: insights from the ICFP2022 WHO Scientific Writing, Mentoring and Coaching course

We describe the development, delivery, and evaluation of a program to support junior professionals to publish their work in a scientific journal. Study design Conference delegates with an accepted abstract at the International Conference on Family Planning (ICFP), self-identifying as junior professionals and from a low- or middle-income country (LMIC) or working predominantly in LMIC settings, were eligible for the program. The program involved: (i) Four face-to-face workshops at ICFP from the 14th to 17th of November 2022; (ii) mentoring meetings at ICFP; (iii) a six-month post-conference online coaching program; and (iv) post-conference learning webinars from December 2022 to May 2023. We used online surveys to assess the participants' reactions, learning, and behavior changes to the workshops and the online coaching program. We present participants' self-reported progress towards achieving a scientific publication. Results Sixty-seven participants from 29 countries participated in the workshops, and 40 attended the post-conference program. Workshops were rated positively, though the in-conference mentoring program faced challenges, including low attendance. The post-conference program was highly rated, with most participants engaging well with coaching and the webinars. At the end of the six-month program, 31 (46%) participants reported some progress in manuscript writing, with five completed manuscripts submitted. Conclusions Scientific writing is a complex skill, and whilst our program had several positive elements, our participants faced many challenges completing their manuscripts within six months. The post-conference coaching and webinar program was rated highly, emphasizing the need for ongoing support. Future programs should address this and other difficulties we highlight

Argumentative review aggregation and dialogical explanations

The aggregation of online reviews is one of the dominant methods of quality control for users in various domains, from retail to entertainment. Consequently, explainable aggregation of reviews is increasingly sought-after. We introduce quantitative argumentation technology to this setting, towards automatically generating reasoned review aggregations equipped with dialogical explanations. To this end, we define a novel form of argumentative dialogical agent (ADA), using ontologies to harbour information from reviews into argumentation frameworks. These agents may then be evaluated with a quantitative argumentation semantics and used to mediate the generation of dialogical explanations for item recommendations based on the reviews. We show how to deploy ADAs in three different contexts in which argumentation frameworks are mined from text, guided by ontologies. First, for hotel recommendations, we use a human-authored ontology and exemplify the potential range of dialogical explanations afforded by ADAs. Second, for movie recommendations, we empirically evaluate an ADA based on a bespoke ontology (extracted semi-automatically, by natural language processing), by demonstrating that its quantitative evaluations, which are shown to satisfy desirable theoretical properties, are comparable with those on a well-known movie review aggregation website. Finally, for product recommendation in e-commerce, we use another bespoke ontology (extracted fully automatically, by natural language processing, from a website’s reviews) to construct an ADA which is then empirically evaluated favourably against review aggregations from the website

A cell-based model to study mechanisms of endothelial dependent thrombin generation in response to inflammation and its modulation by hydroxychloroquine

Background Inflammation is a driver of thrombosis but the phenomenon of thromboinflammation has been defined only recently, bringing together the multiple pathways involved. In vitro models can support the development of new therapeutics targeting the endothelium also assess the existing immunomodulatory drugs such as hydroxychloroquine in modulating the inflammation driven endothelial prothrombotic phenotype. Objectives Developing a model for thrombin generation (TG) on the surface of human endothelial cells to assess pro/antithrombotic properties in response to inflammation. Furthermore, to elucidate the mechanisms of TG regulation and its modulation by immunomodulatory therapies. Methods Cytokine-induced (TNF-α, IL-1β, IFN-γ) effects on endothelial cells isolated from umbilical vein or human aortic tissue were assessed using calibrated automated thrombography in platelet-poor plasma. Expression of key coagulant and inflammatory regulators was measured at mRNA level. Tissue factor (TF) protein levels were further assessed by flow cytometry. Results Endothelial stimulation with TNF-α or IL-1β caused EC to trigger TG without addition of exogenous TF, with higher TG observed after 6hrs stimulation compared to 24 hrs. IL-1β induced higher peak thrombin (170±5.9nM vs 115±4.9nM), endogenous thrombin potential (1632±35nM*min vs 1370±23nM*min), and TF expression (∼2.8-fold higher), compared to TNF-α at 6hrs. IFN-γ stimulation failed to induce TG and TF expression. The immunomodulatory hydroxychloroquine reduced cytokine-induced TG and downregulated TF expression. Conclusions We provide a detailed optimisation of a robust in vitro model to assess induction of an inflammation-driven endothelial prothrombotic phenotype that is also sensitive to immunomodulatory therapies, providing a tool for investigating mechanisms of disease and new drugs