Role of the ubiquitin-like protein Urm1 as a noncanonical lysine-directed protein modifier

The ubiquitin (Ub)-related modifier Urm1 functions as a sulfur carrier in tRNA thiolation by means of a mechanism that requires the formation of a thiocarboxylate at the C-terminal glycine residue of Urm1. However, whether Urm1 plays an additional role as a Ub-like protein modifier remains unclear. Here, we show that Urm1 is conjugated to lysine residues of target proteins and that oxidative stress enhances protein urmylation in both Saccharomyces cerevisiae and mammalian cells. Similar to ubiquitylation, urmylation involves a thioester intermediate and results in the formation of a covalent peptide bond between Urm1 and its substrates. In contrast to modification by canonical Ub-like modifiers, however, conjugation of Urm1 involves a C-terminal thiocarboxylate of the modifier. We have confirmed that the peroxiredoxin Ahp1 is such a substrate in S. cerevisiae and found that Urm1 targets a specific lysine residue of Ahp1 in vivo. In addition, we have identified several unique substrates in mammalian cells and show that Urm1 targets at least two pathways on oxidant treatment. First, Urm1 is appended to lysine residues of three components that function in its own pathway (i.e., MOCS3, ATPBD3, and CTU2). Second, Urm1 is conjugated to the nucleocytoplasmic shuttling factor cellular apoptosis susceptibility protein. Thus, Urm1 has a conserved dual role by integrating the functions of prokaryotic sulfur carriers with those of eukaryotic protein modifiers of the Ub family.     

Psychosine induces the dephosphorylation of neurofilaments by deregulation of PP1 and PP2A phosphatases

Patients with Krabbe disease, a genetic demyelinating syndrome caused by deficiency of galactosyl-ceramidase and the resulting accumulation of galactosyl-sphingolipids, develop signs of a dying-back axonopathy compounded by a deficiency of large-caliber axons. Here, we show that axonal caliber in Twitcher mice, an animal model for Krabbe disease, is impaired in peripheral axons and is accompanied by a progressive reduction in the abundance and phosphorylation of the three neurofilament (NF) subunits. These changes correlate with an increase in the density of NFs per cross-sectional area in numerous mutant peripheral axons and abnormal increases in the activity of two serine/threonine phosphatases (PP1 and PP2A) in mutant tissue. Similarly, acutely isolated mutant cortical neurons show abnormal phosphorylation of NFs. Psychosine, the neurotoxin accumulated in Krabbe disease, was sufficient to induce abnormal dephosphorylation of NF subunits in a normal motor neuron cell line as well as in acutely isolated normal cortical neurons. This in vitro effect was mediated by PP1 and PP2A, which specifically dephosphorylated NFs. These results demonstrate that the reduced caliber observed in some axons in Krabbe disease involves abnormal dephosphorylation of NFs. We propose that a psychosine-driven pathogenic mechanism through deregulated phosphotransferase activities may be involved in this process.     

Atherosclerotic pattern of coronary myocardial bridging assessed with CT coronary angiography

The aim of our study was to evaluate the atherosclerotic pattern of patients with coronary myocardial bridging (MB) by means of CT Coronary Angiography (CT-CA). 254 consecutive patients (166 male, mean age 58.6 ± 10.3) who underwent 64-slice CT-CA according to current clinical indications were reviewed for the presence of MB and concomitant segmental atherosclerotic pattern. Coronary plaques were assessed in all patients enrolled. 73 patients (29%) presented single (90%) or multiple (10%) MB, frequently (93%) localized in the mid-distal left anterior descending artery. The MB segment was always free of atherosclerosis. Segments proximal to the MB presented: no atherosclerotic disease (n = 37), positive remodeling (n = 23), <50% (n = 14), or >50% stenoses (n = 7). Distal segments presented a different atherosclerosis pattern (P < 0.0001): absence of disease (n = 73), no significant lesions (n = 8). No significant differences were found between segments proximal to MB and proximal coronary segments apart from left main trunk. Pattern of atherosclerotic lesions located in segments 6 and 7 significantly differs between patients with MB and patients without MB (P < 0.05). CT-CA is a reliable method to non-invasively demonstrate MB and related atherosclerotic pattern. CT-CA provides new insight regarding atherosclerosis distribution in segments close to MB.     

Brain structure and joint hypermobility: relevance to the expression of psychiatric symptoms

Joint hypermobility is overrepresented among people with anxiety and can be associated with abnormal autonomic reactivity. We tested for associations between regional cerebral grey matter and hypermobility in 72 healthy volunteers using voxel-based morphometry of structural brain scans. Strikingly, bilateral amygdala volume distinguished those with from those without hypermobility. The hypermobility group scored higher for interoceptive sensitivity yet were not significantly more anxious. Our findings specifically link hypermobility to the structural integrity of a brain centre implicated in normal and abnormal emotions and physiological responses. Our observations endorse hypermobility as a multisystem phenotype and suggest potential mechanisms mediating clinical vulnerability to neuropsychiatric symptoms.     

Neuropathic diabetic foot ulcers treated with cerium dioxide nanoparticles: A case report

Wound healing in diabetes is frequently impaired and its treatment remains a challenge. The ability of topical application of cerium (Ce) dioxide nanoparticles (CNPs) to accelerate wound healing in an animal model provides a rationale to develop this technology for use in humans affected by traumatic injury, diabetes and burns. We first described a case report of successful topical treatment of neuropathic diabetic foot ulcers with novel gel containing CNPs. The CNPs has bacteriostatic activity, anti-inflammatory properties and can penetrated into the wound tissue and reduced oxidative damage therefore protect regenerative tissue, suggesting a therapeutic potential for topical treatment of diabetic foot ulcers.     

Correction to: Impact of smoking habit on adult-onset Still’s disease prognosis,findings from a multicentre observational study

Clinical Rheumatology -     

Impact of the metabolic syndrome on the evolution of neurodegenerative diseases

正Metabo lic syndro me(MetS) might be defined as the simultaneous accumulation of several functional changes that frequently occur in adults over 60 years of age(Gomez et al., 2018). The diagnosis of MetS requires the presence of three or more factors such as high body mass, type-2 diabetes mellitus(T2DM), dyslipidemia,     

Radioembolisation in patients with hepatocellular carcinoma that have previously received liver-directed therapies

Purpose

Radioembolisation is part of the multimodal treatment of hepatocellular carcinoma (HCC) at specialist liver centres. This study analysed the impact of prior treatment on tolerability and survival following radioembolisation.

Methods

This was a retrospective analysis of 325 consecutive patients with a confirmed diagnosis of HCC, who received radioembolisation with yttrium-90 resin microspheres at eight European centres between September 2003 and December 2009. The decision to treat was based on the clinical judgement of multidisciplinary teams. Patients were followed from the date of radioembolisation to last contact or death and the nature and severity of all adverse events (AEs) recorded from medical records.

Results

Most radioembolisation candidates were Child-Pugh class A (82.5%) with multinodular HCC (75.9%) invading both lobes (53.1%); 56.3% were advanced stage. Radioembolisation was used first-line in 57.5% of patients and second-line in 34.2%. Common prior procedures were transarterial (chemo)embolisation therapies (27.1%), surgical resection/transplantation (17.2%) and ablation (8.6%). There was no difference in AE incidence and severity between prior treatment subgroups. Median (95% confidence interval [CI]) survival following radioembolisation was similar between procedure-naive and prior treatment groups for Barcelona Clinic Liver Cancer (BCLC) stage A: 22.1 months (15.1–45.9) versus 30.9 months (19.6–46.8); p?= 0.243); stage B: 18.4 months (11.2–19.4) versus 22.8 months (10.9–34.2); p?= 0.815; and stage C: 8.8 months (7.1–10.8) versus 10.8 months (7.7–12.6); p?= 0.976.

Conclusions

Radioembolisation is a valuable treatment option for patients who relapse following surgical, ablative or vascular procedures and remain suitable candidates for this treatment.