Mesangial cells are key contributors to the fibrotic damage seen in the lupus nephritis glomerulus.

Background: Lupus nephritis (LN) affects up to 80% of juvenile-onset systemic lupus erythematosus patients. Mesangial cells (MCs) comprise a third of the glomerular cells and are key contributors to fibrotic changes within the kidney. This project aims to identify the roles of MCs in an in vitro model of LN. Methods: Conditionally immortalised MCs were treated with pro-inflammatory cytokines or with patient sera in an in vitro model of LN and assessed for their roles in inflammation and fibrosis. Results: MCs were shown to produce pro-inflammatory cytokines in response to a model of the inflammatory environment in LN. Further the cells expressed increased levels of mRNA for extracellular matrix (ECM) proteins (COL1A1, COL1A2, COL4A1 and LAMB1), matrix metalloproteinase enzymes (MMP9) and tissue inhibitors of matrix metalloproteinases (TIMP1). Treatment of MCs with serum from patients with active LN was able to induce a similar, albeit milder phenotype. Treatment of MCs with cytokines or patient sera was able to induce secretion of TGF-β1, a known inducer of fibrotic changes. Inhibition of TGF-β1 actions through SB-431542 (an activin A receptor type II-like kinase (ALK5) inhibitor) was able to reduce these responses suggesting that the release of TGF-β1 plays a role in these changes. Conclusions: MCs contribute to the inflammatory environment in LN by producing cytokines involved in leukocyte recruitment, activation and maturation. Further the cells remodel the ECM via protein deposition and enzymatic degradation. This occurs through the actions of TGF-β1 on its receptor, ALK5. This may represent a potential therapeutic target for treatment of LN-associated fibrosis

The human glomerular endothelial cells are potent pro-inflammatory contributors in an in vitro model of lupus nephritis

Juvenile-onset lupus nephritis (LN) affects up to 80% of juvenile-onset systemic lupus erythematosus patients (JSLE). As the exact role of human renal glomerular endothelial cells (GEnCs) in LN has not been fully elucidated, the aim of this study was to investigate their involvement in LN. Conditionally immortalised human GEnCs (ciGEnCs) were treated with pro-inflammatory cytokines known to be involved in LN pathogenesis and also with LPS. Secretion and surface expression of pro-inflammatory proteins was quantified via ELISA and flow cytometry. NF-κΒ and STAT-1 activation was investigated via immunofluorescence. Serum samples from JSLE patients and from healthy controls were used to treat ciGEnCs to determine via qRT-PCR potential changes in the mRNA levels of pro-inflammatory genes. Our results identified TNF-α, IL-1β, IL-13, IFN-γ and LPS as robust in vitro stimuli of ciGEnCs. Each of them led to significantly increased production of different pro-inflammatory proteins, including; IL-6, IL-10, MCP-1, sVCAM-1, MIP-1α, IP-10, GM-CSF, M-CSF, TNF-α, IFN-γ, VCAM-1, ICAM-1, PD-L1 and ICOS-L. TNF-α and IL-1β were shown to activate NF-κB, whilst IFN-γ activated STAT-1. JSLE patient serum promoted IL-6 and IL-1β mRNA expression. In conclusion, our in vitro model provides evidence that human GEnCs play a pivotal role in LN-associated inflammatory process

Apparent absence of Batrachochytrium salamandrivorans in wild urodeles in the United Kingdom

This is the final version. Available from the publisher via the DOI in this record.Whether an infectious disease threat to wildlife arises from pathogen introduction or the increased incidence of an already-present agent informs mitigation policy and actions. The prior absence of a pathogen can be difcult to establish, particularly in free-living wildlife. Subsequent to the epidemic emergence of the fungus, Batrachochytrium salamandrivorans (Bsal), in mainland Europe in 2010 and prior to its detection in captive amphibians in the United Kingdom (UK), we tested archived skin swabs using a Bsal-specifc qPCR. These samples had been collected in 2011 from 2409 wild newts from ponds across the UK. All swabs were negative for Bsal. Bayesian hierarchical modelling suggests that Bsal was absent from, or present at very low levels in, these ponds at the time of sampling. Additionally, surveillance of newt mortality incidents, 2013–2017, failed to detect Bsal. As this pathogen has been shown to be widespread in British captive amphibian collections, there is an urgent need to raise awareness of the importance of efective biosecurity measures, especially amongst people with captive amphibians, to help minimise the risk of Bsal spreading to the wild. Continued and heightened wild amphibian disease surveillance is a priority to provide an early warning system for potential incursion eventsDepartment for Environment, Food and Rural Affairs (DEFRA)Animal & Plant Health Agency (APHA

Towards a quantum representation of the ampere using single electron pumps

Electron pumps generate a macroscopic electric current by controlled manipulation of single electrons. Despite intensive research towards a quantum current standard over the last 25 years, making a fast and accurate quantised electron pump has proved extremely difficult. Here we demonstrate that the accuracy of a semiconductor quantum dot pump can be dramatically improved by using specially designed gate drive waveforms. Our pump can generate a current of up to 150 pA, corresponding to almost a billion electrons per second, with an experimentally demonstrated current accuracy better than 1.2 parts per million (ppm) and strong evidence, based on fitting data to a model, that the true accuracy is approaching 0.01 ppm. This type of pump is a promising candidate for further development as a realisation of the SI base unit ampere, following a re-definition of the ampere in terms of a fixed value of the elementary charge.Comment: 8 pages, 7 figure

Rheumatoid nodule of the thyrohyoid membrane: a case report

BACKGROUND: Rheumatoid nodules are common extra-articular findings occurring in 20% of rheumatoid arthritis patients. They develop most commonly subcutaneously in pressure areas (elbows and finger joints) and may occasionally affect internal organs including pleura, lungs, meninges, larynx, and in other connective tissues elsewhere in the body CASE PRESENTATION: We present the case of a 62-year-old male who presented with a midline neck mass. Clinically it moved on swallowing and tongue protrusion-suggesting attachment to the thyrohyoid membrane. Ultrasound examination revealed a cystic lesion in the absence of cervical lymphadenopathy in a non-smoker. The neck was explored and histological examination of the excised lesion which was attached to the thyrohyoid membrane revealed a rheumatoid nodule. CONCLUSION: A rheumatoid nodule of the thyrohyoid membrane is very rare. The triple diagnostic scheme of clinical examination supplemented with ultrasound and guided fine needle aspiration for neck lumps remains valid in most cases. If excision is indicated we feel it should be performed in such a manner that the scar tract could easily be encompassed in a neck dissection excision should definitive histological examination be adverse. We suggest that when dealing with patients with established rheumatoid arthritis one should consider a rheumatoid nodule as a differential diagnosis for any swelling on the patient whether it be subcutaneous or deep

Duration of shedding of respiratory syncytial virus in a community study of Kenyan children

Background: Our understanding of the transmission dynamics of respiratory syncytial virus (RSV) infection will be better informed with improved data on the patterns of shedding in cases not limited only to hospital admissions. Methods: In a household study, children testing RSV positive by direct immunofluorescent antibody test (DFA) were enrolled. Nasal washings were scheduled right away, then every three days until day 14, every 7 days until day 28 and every 2 weeks until a maximum of 16 weeks, or until the first DFA negative RSV specimen. The relationship between host factors, illness severity and viral shedding was investigated using Cox regression methods. Results: From 151 families a total of 193 children were enrolled with a median age of 21 months (range 1-164 months), 10% infants and 46% male. The rate of recovery from infection was 0.22/person/day (95% CI 0.19-0.25) equivalent to a mean duration of shedding of 4.5 days (95%CI 4.0-5.3), with a median duration of shedding of 4 days (IQR 2-6, range 1-14). Children with a history of RSV infection had a 40% increased rate of recovery i.e. shorter duration of viral shedding (hazard ratio 1.4, 95% CI 1.01-1.86). The rate of cessation of shedding did not differ significantly between males and females, by severity of infection or by age. Conclusion: We provide evidence of a relationship between the duration of shedding and history of infection, which may have a bearing on the relative role of primary versus re-infections in RSV transmission in the community

Ebookness

Since the mid-2000s, the ebook has stabilized into an ontologically distinct form, separate from PDFs and other representations of the book on the screen. The current article delineates the ebook from other emerging digital genres with recourse to the methodologies of platform studies and book history. The ebook is modelled as three concentric circles representing its technological, textual and service infrastructure innovations. This analysis reveals two distinct properties of the ebook: a simulation of the services of the book trade and an emphasis on user textual manipulation. The proposed model is tested with reference to comparative studies of several ebooks published since 2007 and defended against common claims of ebookness about other digital textual genres

Update of the human and mouse SERPIN gene superfamily

The serpin family comprises a structurally similar, yet functionally diverse, set of proteins. Named originally for their function as serine proteinase inhibitors, many of its members are not inhibitors but rather chaperones, involved in storage, transport, and other roles. Serpins are found in genomes of all kingdoms, with 36 human protein-coding genes and five pseudogenes. The mouse has 60 Serpin functional genes, many of which are orthologous to human SERPIN genes and some of which have expanded into multiple paralogous genes. Serpins are found in tissues throughout the body; whereas most are extracellular, there is a class of intracellular serpins. Serpins appear to have roles in inflammation, immune function, tumorigenesis, blood clotting, dementia, and cancer metastasis. Further characterization of these proteins will likely reveal potential biomarkers and therapeutic targets for disease. © 2013 Heit et al

The N-terminal intrinsically disordered domain of mgm101p is localized to the mitochondrial nucleoid.

The mitochondrial genome maintenance gene, MGM101, is essential for yeasts that depend on mitochondrial DNA replication. Previously, in Saccharomyces cerevisiae, it has been found that the carboxy-terminal two-thirds of Mgm101p has a functional core. Furthermore, there is a high level of amino acid sequence conservation in this region from widely diverse species. By contrast, the amino-terminal region, that is also essential for function, does not have recognizable conservation. Using a bioinformatic approach we find that the functional core from yeast and a corresponding region of Mgm101p from the coral Acropora millepora have an ordered structure, while the N-terminal domains of sequences from yeast and coral are predicted to be disordered. To examine whether ordered and disordered domains of Mgm101p have specific or general functions we made chimeric proteins from yeast and coral by swapping the two regions. We find, by an in vivo assay in S.cerevisiae, that the ordered domain of A.millepora can functionally replace the yeast core region but the disordered domain of the coral protein cannot substitute for its yeast counterpart. Mgm101p is found in the mitochondrial nucleoid along with enzymes and proteins involved in mtDNA replication. By attaching green fluorescent protein to the N-terminal disordered domain of yeast Mgm101p we find that GFP is still directed to the mitochondrial nucleoid where full-length Mgm101p-GFP is targeted