Anti-protein C antibodies and acquired protein C resistance in SLE: novel markers for thromboembolic events and disease activity?

OBJECTIVES: Risk factors for thromboembolism in SLE are poorly understood. We hypothesized a possible role for protein C, based on its dual activity in inflammation and haemostasis and on the evidence of an association between acquired activated protein C (APC) resistance (APCR) and high-avidity anti-protein C antibodies (anti-PC) with a severe thrombotic phenotype in venous thrombosis APS patients. METHODS: In a cross-sectional study of 156 SLE patients, the presence and avidity of IgG anti-PC was established by in house-ELISA, and APCR to exogenous recombinant human APC (rhAPC) and Protac (which activates endogenous protein C) was assessed by thrombin generation-based assays. Associations with aPL profile, thrombotic history and disease activity (BILAG and SLEDAI-2K) were also established. RESULTS: Anti-PC were detected in 54.5% of patients and APCR in 59%. Anti-PC positivity was associated with APCR to both rhAPC (P <0.0001) and Protac (P =0.0001). High-avidity anti-PC, detected in 26.3% of SLE patients, were associated with APCR in patients with thrombosis only (P <0.05), and with the development of thrombosis over time (range: 0-52 years; P =0.014). High-avidity anti-PC levels correlated with SLEDAI-2K (P =0.033) and total BILAG (P =0.019); SLEDAI-2K correlated inversely with APCR to Protac (P =0.004). CONCLUSION: Anti-PC occur in patients with SLE, independently of aPL profile, and are associated with APCR. High-avidity anti-PC are associated with thrombosis and with active disease and might prove a novel marker to monitor the risk of thrombosis and disease progression in SLE

Properties of Intra-group Stars and Galaxies in Galaxy Groups: "Normal" versus "Fossil" Groups

Cosmological LCDM simulations of 12 M_vir~10^14 Msun galaxy groups have been performed, invoking star formation, chemical evolution with non-instantaneous recycling, metallicity dependent radiative cooling, strong star-burst driven galactic super-winds and effects of a meta-galactic UV field. At z=0, intra-group light (IGL) fractions are found to be 12-45%. Low values refer to groups with only a small difference between the R-band magnitudes of the first and second ranked group galaxy, large are typical of "fossil" groups (FGs). The IG stars in the 4 FGs are 0.3-0.5 Gyr older than in the 8 nonFGs. For the IGL, B-R=~1.4, in good agreement with observations. For FGs/nonFGs the iron abundance of the IG stars is slightly sub-solar in the central parts (r~100 kpc) decreasing to about 40% solar at about 0.5 r_vir The IG stars are alpha-element enhanced with [O/Fe] increasing with r, and an overall [O/Fe]~0.45, indicating predominant SNII enrichment. The velocity distributions of the IG stars and group galaxies are, at r>~30 kpc, significantly more radially anisotropic for FGs than for nonFGs. So a characteristic of FG formation, apart from formation time (D'Onghia et al.), may be the "initial" velocity distribution of the group galaxies. For FGs one can dynamically infer the (dark matter dominated) mass distribution of the groups all the way to r_vir, from the kinematics of the IG stars or group galaxies. For the nonFGs this method overestimates the group mass at r>~200 kpc, by up to a factor of two at r_vir. This is interpreted as FGs being, in general, more relaxed than nonFGs. Finally, FGs of the above M_vir should host ~500 planetary nebulae at projected distances between 100 and 1000 kpc from the first ranked galaxy. All results appear consistent with the FG formation scenario of D'Onghia et al.Comment: 12 pages, 15 figures, Accepted for MNRAS, Printing in colour recommende

ImPACT: a multifaceted implementation for conversation partner training in aphasia in Dutch rehabilitation settings.

Purpose: Exploration of the clinical uptake of a novel conversation partner training (CPT) programme in aphasia in ten Dutch rehabilitation facilities and identification of its perceived facilitators and barriers in service providers, and the evaluation of the implementation methods used. Method: Ten rehabilitation centres took part in a multifaceted implementation of conversation partner training over thirteen months. Each centre selected two speech and language therapists to act as knowledge brokers whose role it was to raise awareness of CPT in the team and to facilitate getting partners of people with aphasia into the programme. The implementation was evaluated using analysis of recruitment data and questionnaires, supplemented by consensus data and scrutiny of implementation plans. Results: Successful implementation was described as 1) four dyads included during the intervention period, 2) two more dyads included after the intervention period, before the end of the study and 3) inclusion of Partners of Aphasic Clients Conversation Training (PACT) in a description of the logistics of local stroke care (stroke care pathway). Seven centres were successful in reaching the target inclusion of 6 dyads in total. Only one centre had care pathways in place. From a recruitment pool of 504 dyads, 41 dyads were recruited and 34 partners completed the implementation of PACT study (ImPACT). Observed facilitators included the motivation to engage partners in the rehabilitation process and the perceived added value of PACT. The perceived barriers focused on time limitations within current systems to discuss the consequences of PACT with relevant professionals and to establish allocated time for PACT within existing care routines. Conclusions: The motivation of professionals to involve partners in the rehabilitation process assisted with the introduction of PACT in practice. The main barrier was time, linked to the requirement to think through integration of this innovation within existing care. Longer term evaluation would ascertain how centres sustain uptake without support

Polymyalgia Rheumatica (PMR) Special Interest Group at OMERACT 11: outcomes of importance for patients with PMR

We worked toward developing a core outcome set for clinical research studies in polymyalgia rheumatica (PMR) by conducting (1) patient consultations using modified nominal group technique; (2) a systematic literature review of outcome measures in PMR; (3) a pilot observational study of patients presenting with untreated PMR, and further discussion with patient research partners; and (4) a qualitative focus group study of patients with PMR on the meaning of stiffness, using thematic analysis. (1) Consultations included 104 patients at 4 centers. Symptoms of PMR included pain, stiffness, fatigue, and sleep disturbance. Function, anxiety, and depression were also often mentioned. Participants expressed concerns about diagnostic delay, adverse effects of glucocorticoids, and fear of relapse. (2) In the systematic review, outcome measures previously used for PMR include pain visual analog scores (VAS), morning stiffness, blood markers, function, and quality of life; standardized effect sizes posttreatment were large. (3) Findings from the observational study indicated that asking about symptom severity at 7 AM, or "on waking," appeared more relevant to disease activity than asking about symptom severity "now" (which depended on the time of assessment). (4) Preliminary results were presented from the focus group qualitative study, encompassing broad themes of stiffness, pain, and the effect of PMR on patients' lives. It was concluded that further validation work is required before a core outcome set in PMR can be recommended. Nevertheless, the large standardized effect sizes suggest that pain VAS is likely to be satisfactory as a primary outcome measure for assessing response to initial therapy of PMR. Dissection of between-patient heterogeneity in the subsequent treatment course may require attention to comorbidity as a potential confounding factor

Structural insight into the Scribble PDZ domains interaction with the oncogenic Human T-cell lymphotrophic virus-1 (HTLV-1) Tax1 PBM

First published: 27 August 2022. OnlinePublScribble (Scrib) is a highly conserved cell polarity regulator that harbours potent tumour suppressor activity and plays an important role in cell migration. Dysregulation of polarity is associated with poor prognosis during viral infections. Human T-cell lymphotrophic virus-1 (HTLV-1) encodes for the oncogenic Tax1 protein, a modulator of the transcription of viral and human proteins that can cause cell cycle dysregulation as well as a loss of genomic integrity. Previous studies established that Scribble interacts with Tax1 via its C-terminal PDZ binding motif (PBM), leading to aggregation of polarity regulators and subsequent perturbation of host cell adhesion, proliferation, and signalling. Using isothermal titration calorimetry (ITC) we now show that all four PDZ domains of Scribble bind to Tax1 PBM. We then determined crystal structures of Scribble PDZ1, PDZ2 and PDZ3 domains bound to Tax1 PBM. Our findings establish a structural basis for Tax1 mediated subversion of Scribble mediated cell polarity signalling and provide the platform for mechanistic studies to examine Tax1 induced mislocalisation of Scribble and the associated changes in cellular architecture and subsequent tumorigenesis.Airah Javorsky, Janesha C. Maddumage, Emily R. R. Mackie, Tatiana P. Soares da Costa, Patrick O. Humbert and Marc Kvansaku

A dual-target herbicidal inhibitor of lysine biosynthesis

Herbicides with novel modes of action are urgently needed to safeguard global agricultural industries against the damaging effects of herbicide-resistant weeds. We recently developed the first herbicidal inhibitors of lysine biosynthesis, which provided proof-of- concept for a promising novel herbicide target. In this study, we expanded upon our understanding of the mode of action of herbicidal lysine biosynthesis inhibitors. We previously postulated that these inhibitors may act as proherbicides. Here, we show this is not the case. We report an additional mode of action of these inhibitors, through their inhibition of a second lysine biosynthesis enzyme, and investigate the molecular determinants of inhibition. Furthermore, we extend our herbicidal activity analyses to include a weed species of global significance.Emily RR Mackie, Andrew S Barrow, Rebecca M Christoff, Belinda M Abbott, Anthony R Gendall, Tatiana P Soares da Cost

Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial.

BACKGROUND: Rivaroxaban is established for the treatment and secondary prevention of venous thromboembolism, but whether it is useful in patients with antiphospholipid syndrome is uncertain. METHODS: This randomised, controlled, open-label, phase 2/3, non-inferiority trial, done in two UK hospitals, included patients with antiphospholipid syndrome who were taking warfarin for previous venous thromboembolism, with a target international normalised ratio of 2·5. Patients were randomly assigned 1:1 to continue with warfarin or receive 20 mg oral rivaroxaban daily. Randomisation was done centrally, stratified by centre and patient type (with vs without systemic lupus erythematosus). The primary outcome was percentage change in endogenous thrombin potential (ETP) from randomisation to day 42, with non-inferiority set at less than 20% difference from warfarin in mean percentage change. Analysis was by modified intention to treat. Other thrombin generation parameters, thrombosis, and bleeding were also assessed. Treatment effect was measured as the ratio of rivaroxaban to warfarin for thrombin generation. This trial is registered with the ISRCTN registry, number ISRCTN68222801. FINDINGS: Of 116 patients randomised between June 5, 2013, and Nov 11, 2014, 54 who received rivaroxaban and 56 who received warfarin were assessed. At day 42, ETP was higher in the rivaroxaban than in the warfarin group (geometric mean 1086 nmol/L per min, 95% CI 957-1233 vs 548, 484-621, treatment effect 2·0, 95% CI 1·7-2·4, p<0·0001). Peak thrombin generation was lower in the rivaroxaban group (56 nmol/L, 95% CI 47-66 vs 86 nmol/L, 72-102, treatment effect 0·6, 95% CI 0·5-0·8, p=0·0006). No thrombosis or major bleeding were seen. Serious adverse events occurred in four patients in each group. INTERPRETATION: ETP for rivaroxaban did not reach the non-inferiority threshold, but as there was no increase in thrombotic risk compared with standard-intensity warfarin, this drug could be an effective and safe alternative in patients with antiphospholipid syndrome and previous venous thromboembolism

Study of the impact of perilipin polymorphisms in a French population

BACKGROUND: Perilipins are proteins localized at the surface of the lipid droplet in adipocytes, steroid-producing cells and ruptured atherosclerotic plaques playing a role in the regulation of triglyceride deposition and mobilization. We investigated whether perilipin gene polymorphisms were associated with obesity, type 2 diabetes, and their related variables (anthropometric variables, plasma leptin, lipids, glucose and insulin concentrations) in a cross-sectional random sample of 1120 French men and women aged 35 to 65 years old, including 227 obese (BMI ≥ 30 kg/m(2)) and 275 type 2 diabetes subjects. RESULTS: Among 7 perilipin polymorphisms tested, only 2 (rs4578621 and rs894160) of them were frequent enough to be fully investigated and we genotyped the sample using the PCR-RFLP method. No significant associations could be found between any of these polymorphisms and the studied phenotypes. CONCLUSION: The rs4578621 and rs894160 polymorphisms of the perilipin gene are not major genetic determinants of obesity and type 2 diabetes-related phenotypes in a random sample of French men and women

Structural characterisation of a MAPR-related archaeal cytochrome b(5M) protein

First published: 09 August 2022We recently reported that the membrane-associated progesterone receptor(MAPR) protein family (mammalian members: PGRMC1, PGRMC2,NEUFC and NENF) originated from a new class of prokaryotic cytochromeb5(cytb5) domain proteins, called cytb5M(MAPR-like). Relative to classicalcytb5proteins, MAPR and ctyb5Mproteins shared unique sequence elementsand a distinct heme-binding orientation at an approximately 90°rotation rel-ative to classical cytb5, as demonstrated in the archetypal crystal structure ofa cytb5Mprotein (PDB accession number6NZX). Here, we present the crys-tal structure of an archaeal cytb5Mdomain (Methanococcoides burtoniiWP_011499504.1, PDB:6VZ6). It exhibits similar heme binding to the 6NZXcytb5M, supporting the deduction that MAPR-like heme orientation wasinherited from the prokaryotic ancestor of the original eukaryotic MAPRgene.Sarah Teakel, Michealla Marama, David Aragao, Sofiya Tsimbalyuk, Emily R. R. Mackie, Tatiana P. Soares da Costa, Jade K. Forwood and Michael A. Cahil

Polymyalgia Rheumatica (PMR) Special Interest Group at OMERACT 11: outcomes of importance for patients with PMR

We worked toward developing a core outcome set for clinical research studies in polymyalgia rheumatica (PMR) by conducting (1) patient consultations using modified nominal group technique; (2) a systematic literature review of outcome measures in PMR; (3) a pilot observational study of patients presenting with untreated PMR, and further discussion with patient research partners; and (4) a qualitative focus group study of patients with PMR on the meaning of stiffness, using thematic analysis. (1) Consultations included 104 patients at 4 centers. Symptoms of PMR included pain, stiffness, fatigue, and sleep disturbance. Function, anxiety, and depression were also often mentioned. Participants expressed concerns about diagnostic delay, adverse effects of glucocorticoids, and fear of relapse. (2) In the systematic review, outcome measures previously used for PMR include pain visual analog scores (VAS), morning stiffness, blood markers, function, and quality of life; standardized effect sizes posttreatment were large. (3) Findings from the observational study indicated that asking about symptom severity at 7 AM, or "on waking," appeared more relevant to disease activity than asking about symptom severity "now" (which depended on the time of assessment). (4) Preliminary results were presented from the focus group qualitative study, encompassing broad themes of stiffness, pain, and the effect of PMR on patients' lives. It was concluded that further validation work is required before a core outcome set in PMR can be recommended. Nevertheless, the large standardized effect sizes suggest that pain VAS is likely to be satisfactory as a primary outcome measure for assessing response to initial therapy of PMR. Dissection of between-patient heterogeneity in the subsequent treatment course may require attention to comorbidity as a potential confounding factor