Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson's disease mouse model.

Mutations in SNCA, the gene encoding α-synuclein (αSyn), cause familial Parkinson's disease (PD) and aberrant αSyn is a key pathological hallmark of idiopathic PD. This α-synucleinopathy leads to mitochondrial dysfunction, which may drive dopaminergic neurodegeneration. PARKIN and PINK1, mutated in autosomal recessive PD, regulate the preferential autophagic clearance of dysfunctional mitochondria ("mitophagy") by inducing ubiquitylation of mitochondrial proteins, a process counteracted by deubiquitylation via USP30.

Impact of COVID-19 on Ethnically Minoritised Carers in UK's Care Home Settings: a Systematic Scoping Review.

COVID-19 has impacted disproportionately two groups in the UK: healthcare workers and people from ethnically minoritised groups. However, there is a lack of evidence on how COVID-19 affected ethnically minoritised carers in care homes. Therefore, the present study aimed to explore the available evidence regarding the impact of COVID-19 on ethnically minoritised carers in UK.

Developing new treatments in partnership for primary mitochondrial disease: What does industry need from academics, and what do academics need from industry?

Developing novel therapeutics for primary mitochondrial disease is likely to require significant academia-industry collaboration. Translational assessments, a tool often used in industry at target validation stage, can highlight disease specific development challenges which requires focused collaborative effort. For PMD, definition of pivotal trial populations and primary endpoints is challenging given lack of clinical precedence, high numbers of subgroups with overlapping symptoms despite common genetics.

Anti-IL-7 receptor α monoclonal antibody (GSK2618960) in healthy subjects - a randomized, double-blind, placebo-controlled study.

Aim: Interleukin (IL)-7 signalling modulates T cell activity and is implicated in numerous autoimmune diseases. The present study investigated the safety, pharmacokinetics, target engagement, pharmacodynamics and immunogenicity of GSK2618960, an IL-7 receptor-α subunit (CD127) monoclonal antibody.

Methods: A double-blind (sponsor-unblind) study of a single intravenous infusion of either GSK2618960 (0.

Interaction of the amyloid imaging tracer FDDNP with hallmark Alzheimer's disease pathologies.

The distinctive cortical uptake of the tracer (18)F-FDDNP (2-(1-{6-[(2-fluoroethyl(methyl)amino]-2-naphthyl}ethylidene)malononitrile) in Alzheimer's disease (AD) is believed to be because of its binding to both neurofibrillary tangles (NFTs) and highly fibrillar senile plaques. We therefore investigated the binding of a tracer concentration of (3)H-FDDNP to brain sections containing AD hallmark pathologies. Semi-adjacent sections were labelled with (3)H-PIB (Pittsburgh compound-B, 2-[4'-(methylamino)phenyl]-6-hydroxybenzothiazole) and (14)C-SB13 (4-N-methylamino-4'-hydroxystilbene) for comparison.

Monitoring the amyloid beta-peptide in vivo--caveat emptor.

As a wave of 'disease modifying' (DM) therapies for Alzheimer's disease (AD) progresses towards the later stages of clinical development, an evaluation of our ability to measure relevant pharmacodynamic effects of such therapies is warranted. Reducing accumulation of amyloid beta (Abeta)-peptide in the brain parenchyma is the primary objective of most current DM approaches. Although a number of methods are available to measure Abeta in blood, cerebrospinal fluid (CSF) and the cerebrum, putative DM-induced changes in the levels of the peptides may not be fully captured, and the reasons for any such changes are not fully understood.

Atorvastatin and uptake of ultrasmall superparamagnetic iron oxide nanoparticles (Ferumoxtran-10) in human monocyte-macrophages: implications for magnetic resonance imaging.

Ferumoxtran-10 is an ultrasmall superparamagnetic iron oxide nanoparticle potentially useful as a contrast material in magnetic resonance imaging for the diagnosis of inflammatory and degenerative disorders associated with high macrophage activity. In clinical trials, it is currently applied to monitor the effect of atorvastatin therapy on macrophage activity in human carotid plaques. A recent study reported the inhibition of iron oxide nanoparticle uptake in macrophages by lovastatin, an effect which could compromise the suitability of Ferumoxtran-10 as an MRI contrast material in patients on statin therapy.

Interleukin-10 is upregulated by nanomolar rosiglitazone treatment of mature dendritic cells and human CD4+ T cells.

Activators of peroxisome proliferator-activated receptor (PPAR)-gamma are anti-inflammatory and have been proposed as therapeutic agents for the treatment of Th1-type inflammatory diseases. We report that nanomolar concentrations of rosiglitazone enhance the production of IL-10 from activated human mature monocyte-derived dendritic cells. Also, rosiglitazone specifically induces the production of IL-10 from TCR-activated human CD4+ T cells and that this effect is PPAR-gamma-dependent.

Rosiglitazone suppresses cyclosporin-induced chronic transplant dysfunction and prolongs survival of rat cardiac allografts.

Background: The lack of effective treatment for chronic transplant dysfunction restricts the long-term survival of solid organ allografts. Peroxisome proliferator-activated receptor ligands can suppress vascular inflammation. The aim of this study was to analyze the effects of rosiglitazone on chronic transplant dysfunction in a rat cardiac transplant model.

Effect of ultrasmall superparamagnetic iron oxide nanoparticles (Ferumoxtran-10) on human monocyte-macrophages in vitro.

Ferumoxtran-10, a dextran-coated ultrasmall superparamagnetic iron oxide particle, has the potential to reveal macrophages in vivo using magnetic resonance imaging potentially acting as a marker of inflammatory status. Pending clinical trials, we examined the interactions of Ferumoxtran-10 with human monocyte-macrophages (HMMs) in vitro to assess its safety and lack of pro-inflammatory activity. After 72 h, Ferumoxtran-10 was not toxic at 1 mg/ml and may be only mildly toxic at 10 mg/ml.

Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes.

The bulk of glucose that is filtered by the renal glomerulus is reabsorbed by the glucose transporters of the proximal convoluted tubular epithelium. However, it has been difficult to investigate this in diseases such as type 2 diabetes because of the inability to isolate primary renal cells from patients without a renal biopsy. We report here a method for the immunomagnetic isolation and novel primary culture of human exfoliated proximal tubular epithelial cells (HEPTECs) from fresh urine.

The annual incidence and seasonal variation of fractures of the distal radius in men and women over 25 years in Dorset, UK.

Adults who suffer fractures of the distal radius are at increased risk of further osteoporosis related fractures and represent a high-risk group in whom therapies are available to reduce the risk. We have undertaken a prospective study of distal radius fracture patients over the age of 25 years to establish the extent of the problem in Dorset. All patients presenting with any forearm fracture to hospitals serving Dorset residents during 1 year were identified.

Intercellular adhesion molecule (ICAM)-1, but not ICAM-2, activates RhoA and stimulates c-fos and rhoA transcription in endothelial cells.

ICAM-1 and -2 are integrin-binding Ig superfamily adhesion molecules that are important for leukocyte transmigration across endothelial monolayers. ICAM-1 cross-linking is known to activate the small GTPase RhoA and induce stress fiber formation in endothelial cells, but ICAM-2 signaling has not been investigated. In this study, we compare ICAM-1 and ICAM-2 signaling and localization in HUVECs.