The effect of variations in the magnetic field direction from turbulence on kinetic-scale instabilities

At kinetic scales in the solar wind, instabilities transfer energy from particles to fluctuations in the electromagnetic fields while restoring plasma conditions towards thermodynamic equilibrium. We investigate the interplay between background turbulent fluctuations at the small-scale end of the inertial range and kinetic instabilities acting to reduce proton temperature anisotropy. We analyse in situ solar wind observations from the Solar Orbiter mission to develop a measure for variability in the magnetic field direction. We find that non-equilibrium conditions sufficient to cause micro-instabilities in the plasma coincide with elevated levels of variability. We show that our measure for the fluctuations in the magnetic field is non-ergodic in regions unstable to the growth of temperature anisotropy-driven instabilities. We conclude that the competition between the action of the turbulence and the instabilities plays a significant role in the regulation of the proton-scale energetics of the solar wind. This competition depends not only on the variability of the magnetic field but also on the spatial persistence of the plasma in non-equilibrium conditions

Efficacy and Safety of Atacicept in Patients With Systemic Lupus Erythematosus: Results of a Twenty‐Four–Week, Multicenter, Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Arm, Phase IIb Study

OBJECTIVE: To evaluate the efficacy and safety of atacicept, an antagonist of BLyS/APRIL-mediated B cell activation, in patients with systemic lupus erythematosus (SLE). METHODS: ADDRESS II was a phase IIb, multicentre study (NCT01972568). Patients with active, autoantibody-positive SLE receiving standard therapy were randomized (1:1:1) to atacicept (75 or 150 mg) or placebo for 24 weeks. The primary endpoint was the SLE responder index (SRI)-4 at Week 24. RESULTS: The ITT population included 306 patients. There was a trend towards improved SRI-4 response rate with atacicept 75 mg (57.8% [adjusted OR 1.78], P = 0.045) and 150 mg (53.8% [adjusted OR 1.56], P = 0.121) versus placebo (44.0%) at Week 24 (primary analysis; screening visit as baseline). In a pre-specified sensitivity analysis using study Day 1 as baseline, a significantly larger proportion of patients receiving atacicept 75 mg (55.9% [adjusted OR 1.88], P = 0.029) and 150 mg (55.8% [adjusted OR 1.96], P = 0.020) achieved SRI-4 response at Week 24 versus placebo (41%). In pre-defined subpopulations with baseline high disease activity (HDA), serologically active disease (SA), or both, statistically significant improvements in SRI-4 and SRI-6 response rates were seen with atacicept versus placebo. Severe flare risk was reduced with atacicept in both the ITT and HDA populations. The risks of serious adverse events and serious or severe infection were not increased with atacicept versus placebo. CONCLUSION: Atacicept showed evidence of efficacy in SLE, particularly in HDA and SA patients. Reductions in disease activity and severe flare were observed with atacicept treatment, along with an acceptable safety profile

The role of thrombospondins in wound healing, ischemia, and the foreign body reaction

Thrombospondin (TSP) 1 and TSP2 have been implicated in the regulation of several processes during tissue repair. Due to their matricellular nature, these proteins are thought to modulate cell-matrix interactions through a variety of mechanisms specific to the spatio-temporal context of their expression. Most notably, TSP1 and TSP2 appear to play distinct, non-overlapping roles in the healing of skin wounds. In contrast, both proteins have been implicated as regulators of ischemia-induced angiogenesis. Moreover, TSP2 has been shown to be a critical regulator of angiogenesis in the foreign body response (FBR). In this review, we discuss the role of TSPs in tissue repair and examine the mechanistic data regarding the ability of the thrombospondins to modulate cell-matrix interactions in this context

CapZ-lipid membrane interactions: a computer analysis

BACKGROUND: CapZ is a calcium-insensitive and lipid-dependent actin filament capping protein, the main function of which is to regulate the assembly of the actin cytoskeleton. CapZ is associated with membranes in cells and it is generally assumed that this interaction is mediated by polyphosphoinositides (PPI) particularly PIP(2), which has been characterized in vitro. RESULTS: We propose that non-PPI lipids also bind CapZ. Data from computer-aided sequence and structure analyses further suggest that CapZ could become partially buried in the lipid bilayer probably under mildly acidic conditions, in a manner that is not only dependent on the presence of PPIs. We show that lipid binding could involve a number of sites that are spread throughout the CapZ molecule i.e., alpha- and beta-subunits. However, a beta-subunit segment between residues 134–151 is most likely to be involved in interacting with and inserting into lipid membrane due to a slighly higher ratio of positively to negatively charged residues and also due to the presence of a small hydrophobic helix. CONCLUSION: CapZ may therefore play an essential role in providing a stable membrane anchor for actin filaments

[Plasma 2020 Decadal] Disentangling the Spatiotemporal Structure of Turbulence Using Multi-Spacecraft Data

This white paper submitted for 2020 Decadal Assessment of Plasma Science concerns the importance of multi-spacecraft missions to address fundamental questions concerning plasma turbulence. Plasma turbulence is ubiquitous in the universe, and it is responsible for the transport of mass, momentum, and energy in such diverse systems as the solar corona and wind, accretion discs, planet formation, and laboratory fusion devices. Turbulence is an inherently multi-scale and multi-process phenomenon, coupling the largest scales of a system to sub-electron scales via a cascade of energy, while simultaneously generating reconnecting current layers, shocks, and a myriad of instabilities and waves. The solar wind is humankind's best resource for studying the naturally occurring turbulent plasmas that permeate the universe. Since launching our first major scientific spacecraft mission, Explorer 1, in 1958, we have made significant progress characterizing solar wind turbulence. Yet, due to the severe limitations imposed by single point measurements, we are unable to characterize sufficiently the spatial and temporal properties of the solar wind, leaving many fundamental questions about plasma turbulence unanswered. Therefore, the time has now come wherein making significant additional progress to determine the dynamical nature of solar wind turbulence requires multi-spacecraft missions spanning a wide range of scales simultaneously. A dedicated multi-spacecraft mission concurrently covering a wide range of scales in the solar wind would not only allow us to directly determine the spatial and temporal structure of plasma turbulence, but it would also mitigate the limitations that current multi-spacecraft missions face, such as non-ideal orbits for observing solar wind turbulence. Some of the fundamentally important questions that can only be addressed by in situ multipoint measurements are discussed

Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis.

OBJECTIVES: To develop recommendations for the management of adult and paediatric lupus nephritis (LN). METHODS: The available evidence was systematically reviewed using the PubMed database. A modified Delphi method was used to compile questions, elicit expert opinions and reach consensus. RESULTS: Immunosuppressive treatment should be guided by renal biopsy, and aiming for complete renal response (proteinuria <0.5 g/24 h with normal or near-normal renal function). Hydroxychloroquine is recommended for all patients with LN. Because of a more favourable efficacy/toxicity ratio, as initial treatment for patients with class III-IV(A) or (A/C) (±V) LN according to the International Society of Nephrology/Renal Pathology Society 2003 classification, mycophenolic acid (MPA) or low-dose intravenous cyclophosphamide (CY) in combination with glucocorticoids is recommended. In patients with adverse clinical or histological features, CY can be prescribed at higher doses, while azathioprine is an alternative for milder cases. For pure class V LN with nephrotic-range proteinuria, MPA in combination with oral glucocorticoids is recommended as initial treatment. In patients improving after initial treatment, subsequent immunosuppression with MPA or azathioprine is recommended for at least 3 years; in such cases, initial treatment with MPA should be followed by MPA. For MPA or CY failures, switching to the other agent, or to rituximab, is the suggested course of action. In anticipation of pregnancy, patients should be switched to appropriate medications without reducing the intensity of treatment. There is no evidence to suggest that management of LN should differ in children versus adults. CONCLUSIONS: Recommendations for the management of LN were developed using an evidence-based approach followed by expert consensus

Improved monitoring of clinical response in Systemic Lupus Erythematosus by longitudinal trend in soluble vascular cell adhesion molecule-1

This work was funded by Arthritis Research UK. MJL holds an Arthritis Research UK Clinician Scientist Fellowship (19631), and was previously supported by the St Thomas’ Lupus Trust. The study received support from the National Institute for Health Research (NIHR)-funded Flow Cytometry Core Facility and the Biomedical Research Centre based at Guy’s & St. Thomas’ National Health Service (NHS) Foundation Trust, in partnership with King’s College London

Cross-Platform Array Screening Identifies COL1A2, THBS1, TNFRSF10D and UCHL1 as Genes Frequently Silenced by Methylation in Melanoma

Epigenetic regulation of tumor suppressor genes (TSGs) has been shown to play a central role in melanomagenesis. By integrating gene expression and methylation array analysis we identified novel candidate genes frequently methylated in melanoma. We validated the methylation status of the most promising genes using highly sensitive Sequenom Epityper assays in a large panel of melanoma cell lines and resected melanomas, and compared the findings with those from cultured melanocytes. We found transcript levels of UCHL1, COL1A2, THBS1 and TNFRSF10D were inversely correlated with promoter methylation. For THBS1 and UCHL1 the effect of this methylation on expression was confirmed at the protein level. Identification of these candidate TSGs and future research designed to understand how their silencing is related to melanoma development will increase our understanding of the etiology of this cancer and may provide tools for its early diagnosis