Hsp70 Binding to the N-terminal Domain of Hsp104 Regulates [] Curing by Hsp104 Overexpression.

Hsp104 propagates the yeast prion [], the infectious form of Sup35, by severing the prion seeds, but when Hsp104 is overexpressed, it cures [] in a process that is not yet understood but may be caused by trimming, which removes monomers from the ends of the amyloid fibers. This curing was shown to depend on both the N-terminal domain of Hsp104 and the expression level of various members of the Hsp70 family, which raises the question as to whether these effects of Hsp70 are due to it binding to the Hsp70 binding site that was identified in the N-terminal domain of Hsp104, a site not involved in prion propagation. Investigating this question, we now find, first, that mutating this site prevents both the curing of [] by Hsp104 overexpression and the trimming activity of Hsp104.

New-Onset Hyperreligiosity, Demonic Hallucinations, and Apocalyptic Delusions following COVID-19 Infection.

Background: Neuropsychiatric sequelae of COVID-19 have been documented, including delusions, hallucinations, agitation, and disorganized behavior. Although the mechanisms for these symptoms remain unclear, there has been an increasing body of literature suggesting a correlation between COVID-19 infection and psychosis. Here, we illustrate the case of a 34-year-old female with no previous psychiatric history who contracted COVID-19 and subsequently developed severe symptoms of psychosis.

Cell-bound complement activation products associate with lupus severity in SLE.

Objectives: To evaluate the association between lupus severity and cell-bound complement activation products (CB-CAPs) or low complement proteins C3 and C4.

Methods: All subjects (n=495) fulfilled the American College of Rheumatology (ACR) classification criteria for SLE. Abnormal CB-CAPs (erythrocyte-bound C4d or B-lymphocyte-bound C4d levels >99th percentile of healthy) and complement proteins C3 and C4 were determined using flow cytometry and turbidimetry, respectively.

3D MicroCT spatial and temporal characterization of thoracic aorta perivascular adipose tissue and plaque volumes in the ApoE-/- mouse model.

Perivascular adipose tissue (PVAT) influences vascular function and pathology. We present a protocol using micro-computed tomography (microCT), a novel imaging technique typically used for hard biological tissue, to characterize the temporal and spatial development of aorta PVAT and luminal plaque soft tissue. Apolipoprotein E deficient (ApoE) and C57Bl/6J (control) mice were fed a high fat western diet up to 30 weeks.

Study rationale, design, and pretransplantation alloantibody status: A first report of Clinical Trials in Organ Transplantation in Children-04 (CTOTC-04) in pediatric heart transplantation.

Anti-HLA donor-specific antibodies are associated with worse outcomes after organ transplantation. Among sensitized pediatric heart candidates, requirement for negative donor-specific cytotoxicity crossmatch increases wait times and mortality. However, transplantation with positive crossmatch may increase posttransplantation morbidity and mortality.

Real-time imaging of yeast cells reveals several distinct mechanisms of curing of the [URE3] prion.

The [URE3] yeast prion is the self-propagating amyloid form of the Ure2 protein. [URE3] is cured by overexpression of several yeast proteins, including Ydj1, Btn2, Cur1, Hsp42, and human DnaJB6. To better understand [URE3] curing, we used real-time imaging with a yeast strain expressing a GFP-labeled full-length Ure2 construct to monitor the curing of [URE3] over time.

Cell-bound complement activation products as lupus biomarkers: diagnosis, monitoring and stratification.

Cell-bound complement activation products (CB-CAPs) were first reported in 2004, since which time multiple laboratories have demonstrated their value as biomarkers for diagnosis, monitoring, and stratification of patients with systemic lupus erythematosus. Areas covered: This review summarizes the highlights of these 14 years of CB-CAPs discovery and validation, concluding with a view toward their future potential for precision medicine. Expert commentary: The practice of medicine is both art and science and each physician can be considered both artist and scientist with a variable blend of the two skill sets.

Potential Roles of Antiphospholipid Antibodies in Generating Platelet-C4d in Systemic Lupus Erythematosus.

Premature, accelerated onset of atherothrombotic disease is prevalent in patients with systemic lupus erythematosus (SLE). Most, if not all, atherothrombotic diseases are likely to involve platelets and complement. Previously, we discovered that platelets bearing complement activation product C4d (P-C4d) are present in SLE patients, and are significantly associated with antiphospholipid (aPL) antibody positivity and stroke in SLE patients.

Association of aortic perivascular adipose tissue density with aortic calcification in women with systemic lupus erythematosus.

Background And Aims: Women with systemic lupus erythematosus (SLE) have an increased risk of cardiovascular disease (CVD). Perivascular adipose tissue (PVAT) surrounds the vascular wall, is associated with CVD risk factors, and may contribute to premature CVD in SLE. We previously found greater volumes of aortic PVAT associated with aortic calcification (AC) in female SLE patients.

Heat shock protein 104 (Hsp104)-mediated curing of [] yeast prions depends on both [] conformation and the properties of the Hsp104 homologs.

Prions arise from proteins that have two possible conformations: properly folded and non-infectious or misfolded and infectious. The [] yeast prion, which is the misfolded and self-propagating form of the translation termination factor eRF3 (Sup35), can be cured of its infectious conformation by overexpression of Hsp104, which helps dissolve the prion seeds. This dissolution depends on the trimming activity of Hsp104, which reduces the size of the prion seeds without increasing their number.

Plasma complement and vascular complement deposition in patients with coronary artery disease with and without inflammatory rheumatic diseases.

Purpose: Inflammatory rheumatic diseases (IRD) are associated with accelerated coronary artery disease (CAD), which may result from both systemic and vascular wall inflammation. There are indications that complement may be involved in the pathogenesis of CAD in Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA). This study aimed to evaluate the associations between circulating complement and complement activation products with mononuclear cell infiltrates (MCI, surrogate marker of vascular inflammation) in the aortic media and adventitia in IRDCAD and non-IRDCAD patients undergoing coronary artery bypass grafting (CABG).

Cardiovascular disease biomarkers across autoimmune diseases.

Cardiovascular disease is increasingly recognized as a major cause of premature mortality among those with autoimmune disorders. There is an urgent need to identify those patients with autoimmune disease who are at risk for CVD so as to optimize therapeutic intervention and ultimately prevention. Accurate identification, monitoring and stratification of such patients will depend upon a panel of biomarkers of cardiovascular disease.

Cell-bound complement activation products in systemic lupus erythematosus: comparison with anti-double-stranded DNA and standard complement measurements.

Objective: To compare the performance characteristics of cell-bound complement (C4d) activation products (CBCAPS) on erythrocyte (EC4d) and B cells (BC4d) with antibodies to double-stranded DNA (anti-dsDNA) and complement C3 and C4 in systemic lupus erythematosus (SLE).

Methods: The study enrolled 794 subjects consisting of 304 SLE and a control group consisting of 285 patients with other rheumatic diseases and 205 normal individuals. Anti-dsDNA and other autoantibodies were measured using solid-phase immunoassays while EC4d and BC4d were determined using flow cytometry.

Antilymphocyte autoantibodies generate T cell-C4d signatures in systemic lupus erythematosus.

T cells bearing C4d, a complement activation product (CAP), have been shown to be highly sensitive and specific as diagnostic biomarkers for systemic lupus erythematosus (SLE). T cells bearing C4d are also functionally abnormal, suggesting a role for cell-bound CAPs in lupus pathogenesis. However, the mechanism responsible for generation of T-C4d has not been determined.

The lupus biomarker odyssey: one experience.

The last decade has witnessed an explosion in efforts to discover and validate lupus biomarkers. The currently steep trajectory of this progress is unprecedented. However, advances in the lupus biomarker field remain fewer and slower than physicians, patients, and pharmaceutical companies have hoped for.

Relation of platelet C4d with all-cause mortality and ischemic stroke in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease associated with significant morbidity, including premature cardiovascular disease, and mortality. Platelets bearing complement protein C4d (P-C4d) were initially determined to be specific for diagnosis of SLE and were later found to be associated with acute ischemic stroke in non-SLE patients. P-C4d may identify a subset of SLE patients with a worse clinical prognosis.

Biomarkers in systemic lupus erythematosus: challenges and prospects for the future.

The search for lupus biomarkers to diagnose, monitor, stratify, and predict individual response to therapy is currently more intense than ever before. This effort is essential for several reasons. First, epidemic overdiagnosis and underdiagnosis of lupus, even by certified rheumatologists, leads to errors in therapy with concomitant side effects which may be more serious than the disease itself.

Cardiovascular disease in autoimmune rheumatic diseases.

Various autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis, spondyloarthritis, vasculitis and systemic lupus erythematosus, are associated with premature atherosclerosis. However, premature atherosclerosis has not been uniformly observed in systemic sclerosis. Furthermore, although experimental models of atherosclerosis support the role of antiphospholipid antibodies in atherosclerosis, there is no clear evidence of premature atherosclerosis in antiphospholipid syndrome (APA).

Biomarkers for systemic lupus erythematosus.

The urgent need for lupus biomarkers was demonstrated in September 2011 during a Workshop sponsored by the Food and Drug Administration: Potential Biomarkers Predictive of Disease Flare. After 2 days of discussion and more than 2 dozen presentations from thought leaders in both industry and academia, it became apparent that highly sought biomarkers to predict lupus flare have not yet been identified. Even short of the elusive biomarker of flare, few biomarkers for systemic lupus erythematosus (SLE) diagnosis, monitoring, and stratification have been validated and employed for making clinical decisions.

Complement proteins C3 and C4 bind to collagen and elastin in the vascular wall: a potential role in vascular stiffness and atherosclerosis.

Circulating inflammatory mediators including complement activation products participate in the pathogenesis of cardiovascular diseases. As such, previous reports demonstrating the presence of complement proteins within atherosclerotic plaque and on the luminal surface would be anticipated. In contrast, we have recently made the unexpected observation that complement proteins also deposit along the external elastic lamina of mouse aortas in the absence of luminal deposition or plaque development.

Cell-bound complement biomarkers for systemic lupus erythematosus: from benchtop to bedside.

Systemic lupus erythematosus is arguably the most clinically and serologically diverse autoimmune disease. This article highlights the biomarkers helpful in diagnosing this disease. The authors' own research is presented.

Erythrocyte C3d and C4d for monitoring disease activity in systemic lupus erythematosus.

Objective: Disease activity in systemic lupus erythematosus (SLE) is typically monitored by measuring serum C3 and C4. However, these proteins have limited utility as lupus biomarkers, because they are substrates rather than products of complement activation. The aim of this study was to evaluate the utility of measuring the erythrocyte-bound complement activation products, erythrocyte-bound C3d (E-C3d) and E-C4d, compared with that of serum C3 and C4 for monitoring disease activity in patients with SLE.

Lymphocyte-bound complement activation products as biomarkers for diagnosis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is frequently misdiagnosed due to the lack of definitive diagnostic tests. The purpose of this study was to determine specifically whether complement activation products (CAP) are deposited on lymphocytes of SLE patients and whether lymphocyte-bound CAP (LB-CAP) may serve as novel biomarkers for the diagnosis of SLE. We conducted a cross-sectional study of 224 patients with SLE, 179 patients with other diseases, and 114 healthy controls.

Increased erythrocyte C4D is associated with known alloantibody and autoantibody markers of antibody-mediated rejection in human lung transplant recipients.

Background: Immune responses to mismatched donor human leukocyte antigens (HLA) are important in the pathogenesis of chronic rejection. This study evaluated whether erythrocyte-bound C4d (E-C4d) is associated with known alloimmune and autoimmune markers of antibody-mediated rejection after human lung transplantation (LTx).

Methods: Flow cytometry was used to analyze 22 LTx recipients and 15 healthy individuals for E-C4d.

The search for lupus biomarkers.

Few biomarkers for systemic lupus erythematosus (SLE) have been validated and employed for making clinical decisions. The lack of reliable, specific biomarkers for SLE hampers the proper clinical management of patients with SLE and impedes the development of new lupus therapeutics. This void has led to renewed enthusiasm for identifying biomarkers that precisely and specifically reflect the pathophysiological and clinical changes of SLE.