scholarly journals Circulating Proteasomes Are Functional and Have a Subtype Pattern Distinct from 20S Proteasomes in Major Blood Cells

2006 ◽  
Vol 52 (11) ◽  
pp. 2079-2086 ◽  
Author(s):  
Annette Zoeger ◽  
Michael Blau ◽  
Karl Egerer ◽  
Eugen Feist ◽  
Burkhardt Dahlmann
Keyword(s):  
Autoimmune Disease ◽  
Human Plasma ◽  
Lupus Erythematosus ◽  
Blood Cells ◽  
Healthy Donor ◽  
Intracellular Protein ◽  
Disease Markers ◽  
Apparent Homogeneity ◽  
Healthy Donors ◽  
Donor Plasma

Abstract Background: 20S proteasomes, the proteolytic core particles of the major intracellular protein degradative pathway, are potential disease markers because they are detectable in human plasma as circulating proteasomes and their concentrations are increased in patients suffering from various diseases. To investigate the origin of circulating proteasomes, we compared some of their features with those of proteasomes isolated from major blood cells. Methods: We isolated circulating proteasomes from the plasma of 2 patients with rheumatoid arthritis and 2 with systemic lupus erythematosus and from human plasma from healthy donors. We purified the proteasomes to apparent homogeneity and then used electron microscopy for imaging and chromatography for subtype spectrum analysis. We compared subtype results with those from 20S proteasomes purified from 4 major blood cell populations. We also tested proteasomes for enzymatic activity and immunosubunit content. Results: Circulating proteasomes from plasma of healthy donors and from patients with autoimmune disease were found to have the same size and shape as erythrocyte proteasomes, be proteolytically active, and contain standard- and immunosubunits. Chromatography revealed 6 circulating proteasome subtype peaks in healthy donor plasma and 7 in patient donor plasma. Proteasomes from erythrocytes had 3 subtype peaks and those of monocytes, T-lymphocytes, and thrombocytes each had 5 different subtype peaks. Conclusion: Circulating proteasomes were intact and enzymatically active in plasma from healthy donors and from patients with autoimmune disease. Because the subtype patterns of circulating proteasomes clearly differ from those of proteasomes from blood cells, these cells cannot be regarded as a major source of circulating proteasomes.

scholarly journals Natalizumab Blocks VLA-4 Mediated Red Blood Cell Adhesion and Is a Potential Therapy for Sickle Cell Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 221-221 ◽  
Author(s):  
Patrick C. Hines ◽  
Sriram Krishnamoorthy ◽  
Jennell White ◽  
Dipti Gupta ◽  
Arjan van der Flier ◽  
...  
Keyword(s):  
Whole Blood ◽  
Blood Cells ◽  
Research Funding ◽  
Healthy Donor ◽  
Cell Disease ◽  
Flow Conditions ◽  
Employment Equity ◽  
Healthy Donors ◽  
Equity Ownership ◽  
Adhesive Interactions

Abstract Sickle cell disease (SCD) is caused by a point mutation in the beta-chain of hemoglobin, which triggers a complex pathophysiology resulting in recurrent, painful vaso-occlusive events (VOCs) and chronic hemolytic anemia. Among other abnormalities, sickle red blood cells (RBCs) are more adhesive than normal RBCs. Sickle RBC adhesion is an important pathway leading to both VOC and hemolysis: adhesive interactions promote the formation of blood flow-obstructing heterocellular aggregates that induce ischemic tissue damage and slow the transit of RBCs through the vasculature, promoting sickle hemoglobin polymerization and hemolysis. The capacity of sickle RBCs to adhere to endothelium positively correlates with disease severity. Interventions that reduce sickle RBC adhesion, in particular that of reticulocytes, by blocking specific molecular targets may limit or prevent disease sequelae. Very Late Antigen – 4 (VLA-4 or α4β1 integrin) is an important integrin on reticulocytes that mediates adhesive interactions to endothelial and plasma vascular cell adhesion molecule - 1 (VCAM-1), plasma fibrinogen, and other ligands. VLA-4 is expressed on the surface of sickle reticulocytes, with levels decreasing during maturation such that mature RBCs do not express surface VLA-4. Natalizumab is a recombinant humanized antibody that binds to the α4 subunit of VLA-4 and is used to treat multiple sclerosis (MS) and Crohn’s Disease (CD) by preventing leukocyte trafficking into tissues at sites of inflammation. We investigated the ability of natalizumab to block VLA-4 in the context of sickle whole blood, and evaluated the effect on sickle reticulocyte, mature erythrocyte, and leukocyte adhesion during physiologic flow conditions. Whole blood samples obtained from SCD donors were analyzed for saturation binding of natalizumab to surface VLA-4 on leukocytes and reticulocytes using flow cytometry. Up to 20% of reticulocytes from SCD donors (n=13) were positive for VLA-4 surface staining, whereas VLA-4 was undetectable on the surface of reticulocytes from healthy donors (n=4). VLA-4 on SCD reticulocytes and mononuclear leukocytes was saturated by natalizumab concentrations lower than known plasma trough concentrations achieved in MS and CD patients after natalizumab treatment, with SCD reticulocyte EC50 = 0.11 ± 0.01 μg/mL and SCD leukocyte EC50 = 0.16 ± 0.01 μg/mL (n=6). This translates to a binding affinity of 0.7 to 1.3 nM, similar to that found for healthy donor leukocytes. Both whole blood cells and isolated leukocytes from SCD donors adhered to immobilized VCAM-1 during physiologic flow conditions simulating post-capillary venules (shear stress =1 dynes/cm2) using a microfluidic flow-based adhesion system. Leukocytes from SCD donors adhered more to VCAM-1 (Mean = 20.7 + 10.0 from n=7) than leukocytes from healthy donors (Mean = 5.0 + 1.4 from n=5). The adhesion of leukocytes and reticulocytes to VCAM-1 was blocked by natalizumab in a dose-dependent manner and as a function of natalizumab saturation of cell surface VLA-4. Therapeutic IgG4 antibodies, including natalizumab, undergo chain shuffling in vivo with endogenous IgG4, leading to mono-specific IgG4 molecules, with one Fab arm specific to the antigen it was raised against. Compared to divalent natalizumab, monovalent chain-shuffled natalizumab bound to SCD reticulocytes at a7-fold higher EC50 and inhibited SCD reticulocyte adhesion to VCAM-1 at higher antibody concentrations (10 and 1 µg/mL). While increased, these values are still below trough natalizumab levels achieved in natalizumab-treated patients. In summary, natalizumab bound VLA-4 on the surface of SCD reticulocytes and leukocytes similarly to healthy donor leukocytes and blocked adhesion of SCD reticulocytes and leukocytes to immobilized VCAM-1 under shear conditions. Natalizumab binding and adhesion inhibition occurred at plasma concentrations similar to those seen in natalizumab treated MS and CD patients. Based on these findings, natalizumab may have potential as an anti-adhesive therapy for SCD. Further clinical studies are needed to evaluate the safety and efficacy of natalizumab in SCD. Disclosures Hines: Biogen Idec: Research Funding. Krishnamoorthy:Biogen Idec: Employment, Equity Ownership. White:Biogen Idec: Research Funding. Gupta:Biogen Idec: Employment, Equity Ownership. van der Flier:Biogen Idec: Employment, Equity Ownership. Peters:Biogen Idec: Employment, Equity Ownership. Jiang:Biogen Idec: Employment, Equity Ownership. Hobbs:Biogen Idec: Employment, Equity Ownership. Light:Biogen Idec: Employment, Equity Ownership.

Haptoglobin polymorphisms and fucosylation change: possible influence of variation on the identified lung cancer-relevant biomarkers

2020 ◽  
Vol 17 ◽  
Author(s):  
Kongsak Boonyapranai ◽  
Sakaewan Ounjaijean ◽  
Kanokwan Kulprachakarn ◽  
Laddawan Potpromanee ◽  
Miles Chih-Ming Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Healthy Donor ◽  
Blood Donors ◽  
Acute Phase Protein ◽  
Biological Properties ◽  
Diagnostic Biomarker ◽  
Lung Cancer Patients ◽  
Healthy Donors ◽  
Phase Protein ◽  
Blotting Technique

Background: Haptoglobin (Hp), an acute-phase protein, is known as a potential diagnostic biomarker in human diseases. Two alleles of Hp (Hp1 and Hp2) exist in humans allowing three phenotypes (Hp1-1, Hp2-1, and Hp2-2), which influence the biophysical and biological properties of Hp. Objective: This work aimed to investigate the variation of serum level and fucosylation change among Hp phenotypes in pa-tients with lung cancer compared to healthy donors. Method: 44 patients with lung cancer and 26 healthy blood donors who lived in the Northern-Thailand region were investi-gated by glycoproteomic procedure. Results: The phenotypic distribution of the Hp (Hp1-1:Hp2-1:Hp2-2) in healthy donors were 0.04:0.38:0.58, while the pa-tient group were 0.09:0.52:0.39. The Hp1 allele frequency of the patients with lung cancer (0.34) was higher than the healthy donor (0.23). Glycoprotein blotting technique represented that the level of serum Hp and its fucosylation were sig-nificantly higher among lung cancer patients compared to those of the healthy donors. However, a downward trend in the fucosylation level from Hp1-1 to Hp2-1, Hp2-2, was seen in the patient group, but varying in the serum Hp level. An N-linked glycan was enzymatically released from discrete Hp multimers of Hp2-1 and Hp2-2 samples. Analysis of glycan pro-filing by MALDI-TOF-MS showed that reduction of the fucosylated glycan was associated with the size of Hp multimers, resulting in the lower level of fucosylation in Hp2-1 and Hp2-2, respectively. Conclusion: Our finding demonstrates that the Hp phenotype is a dependent risk factor for lung cancer and should be incor-porated into further clinical and biochemical investigations of diseases, including lung cancer.

scholarly journals Atypical and Rare Forms of Cutaneous Lupus Erythematosus: The Importance of the Diagnosis for the Best Management of Patients

Dermatology ◽  
2021 ◽  
pp. 1-10
Author(s):  
Astrid Herzum ◽  
Giulia Gasparini ◽  
Emanuele Cozzani ◽  
Martina Burlando ◽  
Aurora Parodi
Keyword(s):  
General Practitioner ◽  
Autoimmune Disease ◽  
Lupus Erythematosus ◽  
Cutaneous Lupus Erythematosus ◽  
Cutaneous Manifestations ◽  
Skin Manifestation ◽  
Systemic Involvement ◽  
Best Management ◽  
Wide Range ◽  
Cutaneous Lupus

Lupus erythematosus (LE) is an autoimmune disease with a wide range of clinical and cutaneous manifestations. Along with the well-known typical cutaneous manifestations of LE, some cutaneous manifestations are rarer, but still characteristic, enabling the dermatologist and the general practitioner who know them to suspect cutaneous LE (CLE) and investigate a possible underlying systemic involvement. Indeed, not infrequently a skin manifestation is the first presentation of systemic LE (SLE), and >75% of SLE patients show signs of skin disease during the course of the illness. Especially, SLE involvement occurs in cases of acute CLE, while it is uncommon in subacute CLE and rare in chronic CLE. This review aims to concentrate especially on atypical cutaneous manifestations of LE to enable the clinician to diagnose even the rarest forms of CLE.

scholarly journals AB0009 ASSOCIATION OF STAT4 RS7574865, RUNX1 RS9979383, IL6 RS1800795, IL6R RS2228145, IL6R RS4845618 WITH SYSTEMIC LUPUS ERYTHEMATOSUS SUSCEPTIBILITY AND SOME LUPUS MANIFESTATIONS IN BELARUSIAN POPULATION

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1039.2-1040
Author(s):  
N. Dostanko ◽  
V. Yagur ◽  
R. Goncharova ◽  
E. Siniauskaya ◽  
T. Zybalova
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Diagnostic Odds Ratio ◽  
Protective Role ◽  
Fisher Exact Test ◽  
Systemic Lupus ◽  
Exact Test ◽  
American College Of Rheumatology ◽  
Healthy Donors ◽  
Significant Difference

Background:Systemic lupus erythematosus (SLE) has a significant genetic predisposition. Many genetic variants of susceptibility to SLE have been published and analyzed, but the clinical and functional significance of the various genotypes has not yet been clearly defined [1].Objectives:To estimate the association between some of non-HLA gene polymorphisms such as STAT4 rs7574865, RUNX1 rs9979383, IL6 rs1800795, IL6R rs2228145, IL6R rs4845618 and susceptibility to SLE in Belarusian population as well as some disease manifestations.Methods:We examined 383 healthy blood donors and 54 SLE patients (18-72 years old, median age 35) classified according to the 1997 American College of Rheumatology (ACR) revised classification criteria [2]. Deoxyribonucleic acid was extracted from peripheral blood samples by phenol-chloroform method. Genotyping was performed by real-time PCR with fluorescent probes. Differences of distribution of all the single nucleotide polymorphism (SNP) genotypes and their associations with secondary antiphospholipid syndrom (APS) and lupus arthritis were analyzed using Pearson χ2 (χ2) and two-way Fisher exact test (F, p2-t). Diagnostic odds ratio (dOR), likelihood ratio of positive (LR +) and negative (LR –) tests and corresponding 95% confidence intervals (CI) were also calculated.Results:We revealed significant difference in STAT4 rs7574865 genotypes in SLE patients and healthy donors (χ2=8,27, р=0,016) with significant increase of ТТ genotype frequency in SLE patients vs healthy donors (χ2=6.83 p=0.009; p2-t =0.020; dOR=3.78 (CI95% 1.36-10.55); LR+ =3.44 (CI95% 1.35-8.71); LR– =0.91 (CI95% 0.83-0.98)). Lupus arthritis was more common in risk TT-genotype SLE carriers than in other SLE patients (χ2=5.902 p=0.015; p2-t =0.027).We revealed significant increase of СТ genotype (RUNX1 rs9979383) in healthy donors vs SLE patients (χ2=4.14; p=0.042; dOR=0.53 (CI95% 0.29-0.98); LR+ =0.69 (CI95% 0.45-0.99); LR– =1.3 (CI95% 1.01-1,56)). Lupus arthritis was more common in SLE СТ-genotype carriers than in other SLE patients (χ2=4.66 p=0.031; p2-t =0.058).Significant differences in IL6 rs1800795, IL6R rs2228145 and IL6R rs4845618 genotypes distribution between studied groups were not found (χ2, p=0.427, p=0.559 and p=0.407, correspondingly) but GG-genotype (IL6 rs1800795) carriership in SLE patients was associated with increased APS frequency (χ2=4.45, p=0.035; dOR=0.19 (CI95% 0.04-0.9); LR+ =0.28 (CI95% 0.07-0.93); LR– =1.41 (CI95% 1.03-1.64).Conclusion:Our data suggest the susceptibility to SLE in ТТ genotype of STAT4 rs7574865 polymorphism, protective role of СТ genotype of RUNX1 rs9979383 for SLE and association between GG-genotype of IL6 rs1800795 and APS in SLE patients in Belarusian population. Lupus arthritis was associated with ТТ genotype of STAT4 rs7574865 and СТ genotype of RUNX1 rs9979383.References:[1]Chen L, Morris DL, Vyse TJ. Genetic advances in systemic lupus erythematosus: an update. Curr Opin Rheumatol 2017;29:423–33.[2]Hochberg MC. Updating the American College of Rheumatology Revised Criteria for the classification of Systemic Lupus Erythematosus. Arthritis Rheum 1997;40:1725.Disclosure of Interests:None declared

Modulation of cardiometabolic disease markers by type I interferon inhibition in systemic lupus erythematosus

2020 ◽  
Author(s):  
Kerry A Casey ◽  
Michael A Smith ◽  
Dominic Sinibaldi ◽  
Nickie L Seto ◽  
Martin P Playford ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Type I Interferon ◽  
Cardiometabolic Disease ◽  
Type I ◽  
Systemic Lupus ◽  
Disease Markers

The Association Between Immunodeficiency and the Development of Autoimmune Disease

1996 ◽  
Vol 10 (1) ◽  
pp. 57-61 ◽  
Author(s):  
J.W. Sleasman
Keyword(s):  
Immune System ◽  
Autoimmune Disease ◽  
Lupus Erythematosus ◽  
Iga Deficiency ◽  
Selective Iga Deficiency ◽  
Increased Risk ◽  
High Incidence ◽  
Autoimmune Cytopenias ◽  
The Complement System ◽  
Common Variable

There is a paradoxical relationship between immunodeficiency diseases and autoimmunity. While not all individuals with immunodeficiency develop autoimmunity, nor are all individuals with autoimmunity immunodeficient, defects within certain components of the immune system carry a high risk for the development of autoimmune disease. Inherited deficiencies of the complement system have a high incidence of systemic lupus erythematosus (SLE), glomerulonephritis, and vasculitis. Carrier mothers of children with chronic granulomatous disease, an X-linked defect of phagocytosis, often develop discoid lupus. Several antibody deficiencies are associated with autoimmune disease. Autoimmune cytopenias are commonly observed in individuals with selective IgA deficiency and common variable immune deficiency. Polyarticular arthritis can be seen in children with X-linked agammaglobulinemia. Combined cellular and antibody deficiencies, such as Wiskott-Aldrich syndrome, carry an increased risk for juvenile rheumatoid arthritis and autoimmune hemolytic anemia. Several hypothetical mechanisms have been proposed to explain the associations between autoimmunity and immunodeficiency. Immunologic defects may result in a failure to exclude microbial antigens, resulting in chronic immunologic activation and autoimmune symptoms. There may be shared genetic factors, such as common HLA alleles, which predispose an individual to both autoimmunity and immunodeficiency. Defects within one component of the immune system may alter the way a pathogen induces an immune response and lead to an inflammatory response directed at self-antigens. An understanding of the immunologic defects that contribute to the development of autoimmunity will provide an insight into the pathogenesis of the autoimmune process.

FRI0516 FACTORS ASSOCIATED WITH DECREASED CERVICAL CANCER SCREENING IN WOMEN WITH SYSTEMIC LUPUS ERYTHEMATOSUS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 857.1-857
Author(s):  
S. Bruera ◽  
R. Zogala ◽  
X. Lei ◽  
X. Pundole ◽  
H. Zhao ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Cervical Cancer ◽  
Cancer Screening ◽  
Autoimmune Disease ◽  
Cervical Cancer Screening ◽  
Lupus Erythematosus ◽  
Screening Rate ◽  
Systemic Lupus ◽  
Comorbidity Score ◽  
Increased Risk

Background:Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that carries an increased risk for both viral illnesses and malignancies, including a greater risk for both human papilloma virus (HPV) infection and cervical cancer. Due to this increased risk, the American Society of Colposcopy and Cervical Pathology guidelines for SLE patients recommend more frequent cervical cancer screening. Few studies have examined patient characteristics associated with decreased cervical cancer screening in patients with autoimmune disease, specifically SLE.Objectives:To estimate cervical cancer screening rates in women with recently diagnosed SLE, and to identify characteristics associated with decreased screening.Methods:We identified women with an initial diagnosis of SLE in the United States MarketScan Commercial Claims and Encounter (CCAE, age 18-64) administrative claims database. We included patients with at least three claims with a lupus diagnosis (first and last at least >90 days apart), no lupus claims within the year before initial claim, and who had been on antimalarial drugs for at least 90 days. We excluded all patients with a previous claim for hysterectomy.Cervical cancer screening was ascertained using diagnosis and procedure codes within 1 year before and 2 years after the first SLE claim. Our covariates included the year of first SLE claim (2001-2014), age at first SLE claim, comorbidity score, insurance type, geographical region, and prescriptions for multiple types of corticosteroids. Control patients included age-matched females without autoimmune disease. Univariate comparison and multivariate logistic regression models were built to evaluate determinants of screening.Results:We included 4,316 SLE patients (median age 45) and 86,544 control patients. The screening rate in SLE patients was 73.4% vs 58.5% in the controls (P < 0.001). The screening rate was 71% in 2001, increased to 75% in 2004, then decreased to 70% in 2014 (trend P =0.005). In the multivariate model the following factors were associated with decreased cervical cancer screening: year of first SLE claim 2012-2014 versus 2001-2005 (odds ratio (OR) 0.67, 95% confidence interval (CI) 0.53 – 0.84, P < 0.001); older age 61-64 versus 21-30 (OR 0.27, 95% CI 0.19 – 0.39, P < 0.001); comorbidity score of ≥2 versus <2 (OR 0.71, 95% CI 0.6 – 0.83, P < 0.001); and use of corticosteroids for ≥ 90 days versus <90 days (OR 0.73, 95% CI 0.59 – 0.9, P = 0.003). Insurance type and geographical region were not associated with cervical cancer screening.Conclusion:About three quarters of women with SLE underwent cervical cancer screening within 3 years of their first lupus claim, at higher rates than controls. However, there was a concerning downward trend in screening rates in recent years. In addition, higher risk populations for cervical cancer (older age, increased comorbidities, and longer duration of corticosteroids) had lower screening rates. These findings highlight the need to enhance education for healthcare providers to improve utilization of screening in women with SLE at high risk of cervical cancer.Disclosure of Interests:Sebastian Bruera: None declared, Richard Zogala: None declared, Xiudong Lei: None declared, Xerxes Pundole: None declared, Hui Zhao: None declared, Sharon Giordano: None declared, Jessica Hwang Grant/research support from: MERCK grant funding unrelated to SLE., Maria Suarez-Almazor: None declared

scholarly journals HOMOLOGOUS DISEASE IN THE ADULT RAT, A MODEL FOR AUTOIMMUNE DISEASE

1963 ◽  
Vol 118 (4) ◽  
pp. 635-648 ◽  
Author(s):  
Peter Stastny ◽  
Vernie A. Stembridge ◽  
Morris Ziff
Keyword(s):  
Autoimmune Disease ◽  
Lupus Erythematosus ◽  
Connective Tissue Diseases ◽  
Skin Lesions ◽  
Cutaneous Lesions ◽  
Adult Rats ◽  
Hydropic Degeneration ◽  
Skin Changes ◽  
Adult Rat ◽  
The One

The cutaneous lesions of adult rats with homologous disease are described, and evidence is presented to indicate that they have an immunologic basis. The skin changes included erythema, purpura, edema, and a variety of inflammatory lesions. In the more active lesions, dermal infiltration, hydropic degeneration, acanthosis, and atrophy of the epidermis with hyperkeratosis and follicular plugging were present. In some cases, ulceration and sloughing were also observed. More chronic lesions were characterized by atrophy of the epidermis and collagenization of the dermis with disappearance of the skin appendages. Rejection of autografts was observed simultaneously with acceptance of homografts. The histologic appearance of autografts undergoing rejection was similar to that of the spontaneous skin lesions, suggesting that the latter, too, had an immunologic basis. In favor of this, also, was the specificity of the dermatitis for the skin of the host, with sparing of neighboring homograft tissue. There was a histologic similarity between the spontaneous skin lesions of homologous disease and those of lupus erythematosus on the one hand, and scleroderma on the other, thus supporting the possibility that the cutaneous lesions of these connective tissue diseases of man may also have an immunologic basis. It was concluded that the adult rat with homologous disease may furnish a model for human autoimmune disease.

scholarly journals CARBAMAZEPINE INDUCED SLE-A RARE AND SERIOUS ADR

2016 ◽  
Vol 9 (1) ◽  
pp. 319
Author(s):  
Sai Keerthana P. C. ◽  
Anila K. N.
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Autoimmune Disease ◽  
Lupus Erythematosus ◽  
Low Risk ◽  
Probability Scale ◽  
Systemic Lupus ◽  
Drug Induced ◽  
Rare Phenomenon ◽  
Causality Score

<p style="line-height: 150%; margin-bottom: 0cm;" align="justify">Carbamazepine is a commonly used antiseizure medication. Carbamazepine-induced SLE (Systemic Lupus Erythematosus) is a very rare phenomenon. Drug-induced SLE is an autoimmune disease caused by long-term use of certain drugs. Carbamazepine is a drug with low risk for causing lupus symptoms. The process that leads to drug-induced SLE are not entirely understood. A very few cases are reported with carbamazepine association with SLE. Herein we report a case of 4 y old girl with SLE induced by carbamazepine showing a causality score of 8 by Naranjo ADR probability scale.</p>

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