111 research outputs found
The integration of on-line monitoring and reconfiguration functions using IEEE1149.4 into a safety critical automotive electronic control unit.
This paper presents an innovative application of IEEE 1149.4 and the integrated diagnostic reconfiguration (IDR) as tools for the implementation of an embedded test solution for an automotive electronic control unit, implemented as a fully integrated mixed signal system. The paper describes how the test architecture can be used for fault avoidance with results from a hardware prototype presented. The paper concludes that fault avoidance can be integrated into mixed signal electronic systems to handle key failure modes
Defining the miRnome of Saphenous Vein Smooth Muscle Cells from Patients with Type 2 Diabetes Mellitus
Citation: Hussain, A.; Asare-Amankwah, Y.; Qureshi, S.; Thornton, M.J.; Palmer, T.M.; Bolanle, I.O.; Wood, I.C.; Turner, N.A.; Porter, K.E.; Tedder, A.; et al. Defining the miRnome of Saphenous Vein Smooth Muscle Cells from Patients with Type 2 Diabetes Mellitus. Diabetology 2024, 5, 178-189. https://doi. Abstract: Type 2 diabetes mellitus (T2DM) patients suffer premature development of cardiovascular disease and commonly require cardiac revascularization using the autologous saphenous vein (SV). Smooth muscle cells (SMCs) are the principal cell type within the vascular wall and are dysfunctional in T2DM SV-SMCs, yet the mechanisms underpinning this are incompletely understood. The purpose of this study was to interrogate differential microRNA (miRNA) expression in SV-SMCs to enhance our understanding of T2DM SV-SMC phenotypic change. miRNA expression in primary human SV-SMCs from T2DM and non-diabetic (ND) donors was determined using an array (n = 6 each of ND and T2DM SV-SMCs). Differentially expressed miRNAs were ranked, and functional annotation of the 30 most differentially expressed miRNAs using DAVID and KEGG analysis revealed pathways related to SMC phenotype, including proliferation, migration, cytokine production and cell signaling. After selecting miRNAs known to be involved in SMC phenotypic regulation, miR-17, miR-29b-2, miR-31, miR-130b and miR-491 were further validated using qRT-PCR (n = 5 each of ND and T2DM SV-SMC), with miR-29b-2 subsequently being removed from further investigation. Potential mRNA targets were identified using mirDIP. Predicted target analysis highlighted likely dysregulation in transcription, epigenetic regulation, cell survival, intracellular signaling and cytoskeletal regulation, all of which are known to be dysfunctional in T2DM SV-SMCs. In conclusion, this paper identified four miRNAs that are dysregulated in T2DM SV-SMCs and are implicated in functional changes in the behavior of these cells. This provides a step forward in our understanding of the molecular and epigenetic regulation of vascular dysfunction in T2DM
Contested space: The contradictory political dynamics of food banking in the UK
This paper offers a critical reappraisal of the politics of food banking in the UK. Existing work has raised concerns about the institutionalisation of food banks, with charitable assistance apparently â even if inadvertently â undermining collectivist welfare and deflecting attention from fundamental injustices in the food system. This paper presents original ethnographic work that examines the neglected politics articulated within food banks themselves. Conceptualising food banks as potential spaces of encounter where predominantly middle-class volunteers come into contact with âpoor othersâ (Lawson and Elwood, 2013), we illustrate the ways food banks may both reinforce but also rework and generate new, ethical and political attitudes, beliefs and identities. We also draw attention to the limits of these progressive possibilities and examine the ways in which some food banks continue to operate within a set of highly restrictive, and stigmatising, welfare technologies. By highlighting the contradictory dynamics at work in food bank organisations, and among food bank volunteers and clients, we suggest the political role of food banks warrants neither uncritical celebration nor outright dismissal. Rather, food banks represent a highly ambiguous political space still in the making and open to contestatio
The geographies of food banks in the meantime
The authors gratefully acknowledge the support
given by the British Academy for this research (grant
no. SG131950). The âEmergency Food Provision in
the UKâ research includes: over eighteen months of
ethnographic research in a Trussell Trust Foodbank;
a national survey of the Trussell Trust Network and
Independent food banks (and other food aid providers);
and in-depth interviews with food bank managers,
volunteers and service-users in London,
Bristol, Leicestershire, South Wales, Devon, and
Cornwall
Case Reports1.âA Late Presentation of Loeys-Dietz Syndrome: Beware of TGFÎČ Receptor Mutations in Benign Joint Hypermobility
Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFÎČ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFÎČ receptor, paradoxical activation of TGFÎČ signalling is seen, suggesting that TGFÎČ antagonism may confer disease modifying effects similar to those observed in MFS. TGFÎČ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes
Whole-genome sequencing reveals host factors underlying critical COVID-19
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2â4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genesâincluding reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)âin critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
Genetic mechanisms of critical illness in COVID-19.
Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, PÂ =Â 1.65Â ĂÂ 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, PÂ =Â 2.3Â ĂÂ 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, PÂ =Â 3.98Â ĂÂ Â 10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, PÂ =Â 4.99Â ĂÂ 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice
AI is a viable alternative to high throughput screening: a 318-target study
: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNetÂź convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNetÂź model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery
Whole-genome sequencing reveals host factors underlying critical COVID-19
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genesâincluding reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)âin critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
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