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14 p.-7 fig.-2 tab., Complement overactivation has been reported in most patients with Barraquer–Simons syndrome (BSS), a rare form of acquired partial lipodystrophy. Complement Factor D (FD) is a serine protease with a crucial role in the activation of the alternative pathway of the complement system, which is mainly synthesized by adipose tissue. However, its role in the pathogenesis of BSS has not been addressed. In this study, plasma FD concentration was measured in 13 patients with BSS, 20 patients with acquired generalized lipodystrophy, 22 patients with C3 glomerulopathy (C3G), and 50 healthy controls. Gene expression and immunohistochemistry studies were assayed using atrophied adipose tissue from a patient with BSS. We found significantly elevated FD levels in BSS cases compared with the remaining cohorts (p < 0.001). There were no significant differences in FD levels between sexes but FD was strongly and directly associated with age in BSS (r = 0.7593, p = 0.0036). A positive correlation between FD and C3 was seen in patients with C3G, characterized by decreased FD levels due to chronic C3 consumption, but no correlation was detected for BSS. Following mRNA quantification in the patient’s adipose tissue, we observed decreased CFD and C3 but elevated C5 transcript levels. In contrast, the increased FD staining detected in the atrophied areas reflects the effects of persistent tissue damage on the adipose tissue, thus providing information on the ongoing pathogenic process. Our results suggest that FD could be a reliable diagnostic biomarker involved in the pathophysiology of BSS by promoting unrestrained local complement system activation in the adipose tissue environment., This study was funded by the Spanish Instituto de Salud Carlos III (ISCIII) and the European Regional Development Fund from the European Union (grant PI15-00255), by the Spanish Autonomous Region of Madrid (Complement II-CM network; S2017/BMD-3673), by the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP), by an intramural grant from the Xunta de Galicia (grant number ED431B 2020/37), and by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases.

Hereditary angioedema due to pathogenic FXII variants (HAE-FXII) is a rare dominant disease caused by increased activation of the plasma contact system. The most prevalent HAE-FXII variant, c.1032C > A p.Thr309Lys (FXII309Lys), results in a smaller FXII protein with increased sensitivity to fluid-phase activation by poorly understood mechanisms. We aimed to investigate the functionality of the FXII309Lys variant in 33 HAE-FXII patients, 25 healthy controls and 46 patients with congenital disorders of glycosylation (CDG). Activation of the plasma contact system was assessed by western blot and amidolytic assay in basal conditions or after treatment with either artificial or physiological activators. Recombinant wild-type and FXII309Lys variants were expressed in S2 insect (Drosophila) cells. Amidolytic and fibrin generation assays were performed in fresh plasma samples. FXII309Lys samples exhibited an increased electrophoretic mobility comparable with N-glycan-deficient FXII from CDG patients and asialo-FXII generated by neuraminidase treatment. They presented increased sensitivity to activation by dextran sulphate and silica which resulted in the generation of an aberrant 37-kDa heavy chain. We did not observe increased susceptibility of FXII309Lys to proteolysis by exogenous or tPA-generated plasmin. However, both exogenous and endogenous thrombin cleaved the FXII309Lys variant, releasing a 37-kDa fragment and resulting in enhanced proteolytic activation on the fluid phase. This model supports a sequential proteolytic activation process involving thrombin priming of FXII309Lys, followed by kallikrein cleavage and generation of active βFXIIa. The present results and the observation that angioedema episodes in HAE-FXII patients occur predominantly during hypercoagulable situations suggest a key role for thrombin.

Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is caused by mutations affecting the SERPING1 gene. Adult patients (≥ 18 years old) diagnosed with C1-INH-HAE were clustered according to a modified SERPING1 gene mutation classification [5]. Demographic, clinical, and laboratory data were studied. Published manuscripts on the genotype/phenotype relationship were reviewed. Eighty-eight patients participated in the study, with 78 having a classifiable mutation. We compared the data in the 3 largest groups: class 0 only (n = 32), class II only (n = 18), class III only (n = 22). Antigenic C4 and C1 inhibitors were higher in class II (p = 0.008 and p = 0.02, respectively), and facial attacks in the last 6 months were more frequent in class III (p = 0.04)). All the other differences were non-significant. Twelve manuscripts on phenotype/genotype correlation were found: missense mutations in SERPING1 gene were associated with delay in disease onset and lower severity score in some studies, whereas the CC F12-C46T/C polymorphism produced earlier disease onset. Our study shows minimal differences regarding clinical phenotype in patients with class 0, II, and III SERPING1 gene mutations, with a tendency to class III having a more severe phenotype. The study should be performed in a larger sample to confirm if they are significant. We propose that larger multicenter, international studies are performed, comparing different SERPING1 gene mutation classifications, combining polymorphisms in other involved genes (kallikrein-kinin system, regulation of vasculature, plasminogen activation) and using different variables and clinical scores to assess C1-INH-HAE disease activity and/or severity in order to study possible genotype/phenotype relationships.

Hereditary angioedema with C1 Inhibitor deficiency (C1-INH-HAE) is caused by a constellation of variants of theSERPING1gene (n= 809; 1,494 pedigrees), accounting for 86.8% of HAE families, showing a pronounced mutagenic liability ofSERPING1and pertaining to 5.6%de novovariants. C1-INH is the major control serpin of the kallikrein–kinin system (KKS). In addition, C1-INH controls complement C1 and plasminogen activation, both systems contributing to inflammation. Recognizing the failed control of C1s protease or KKS provides the diagnosis of C1-INH-HAE.SERPING1variants usually behave in an autosomal-dominant character with an incomplete penetrance and a low prevalence. A great majority of variants (809/893; 90.5%) that were introduced into online database have been considered as pathogenic/likely pathogenic. Haploinsufficiency is a common feature in C1-INH-HAE where a dominant-negative variant product impacts the wild-type allele and renders it inactive. Small (36.2%) and large (8.3%) deletions/duplications are common, with exon 4 as the most affected one. Point substitutions with missense variants (32.2%) are of interest for the serpin structure–function relationship. Canonical splice sites can be affected by variants within introns and exons also (14.3%). For noncanonical sequences, exon skipping has been confirmed by splicing analyses of patients' blood-derived RNAs (n= 25). Exonic variants (n= 6) can affect exon splicing. Rare deep-intron variants (n= 6), putatively acting as pseudo-exon activating mutations, have been characterized as pathogenic. Some variants have been characterized as benign/likely benign/of uncertain significance (n= 74). This category includes some homozygous (n= 10) or compound heterozygous variants (n= 11). They are presenting with minor allele frequency (MAF) below 0.00002 (i.e., lower than C1-INH-HAE frequency), and may be quantitatively unable to cause haploinsufficiency. Rare benign variants could contribute as disease modifiers. Gonadal mosaicism in C1-INH-HAE is rare and must be distinguished from ade novovariant. Situations with paternal or maternal disomy have been recorded (n= 3). Genotypes must be interpreted with biological investigation fitting with C1-INH expression and typing. AnySERPING1variant reminiscent of the dysfunctional phenotype of serpin with multimerization or latency should be identified as serpinopathy.

Barraquer-Simons syndrome (BSS), a form of acquired partial lipodystrophy, is a rare condition characterized by gradual loss of adipose tissue from the upper body, keeping intact the white adipose tissue of the lower extremities. The etiology of BSS is not well understood, and clinical follow-up studies have not been assessed in these patients. Moreover, no histological studies have been conducted during the active phase of the disease, and complement system activation products have not been sought in the affected areas. The objective of this work was to analyze the clinical, immunological and histological events in an 11-year-old girl with BSS over a 5-year follow-up period. Clinical data were collected during six regular visits for a time period of 5 years. The circulating levels of C3, C3adesArg (a product released upon C3 activation), C4 and immunoglobulins (Ig) were quantified in serum while fat tissue from lipoatrophic areas was examined by immunohistochemical and immunofluorescence approaches. In her regular visits, no clinical or laboratory abnormalities had been observed in the patient, except for the progression of lipoatrophy linked to the C3 hypocomplementemia and the occurrence of C3 nephritic factor. Adipose tissue from the patient showed atrophied and dead adipocytes, an abnormal production of extracellular matrix, and a remarkable accumulation of infiltrating CD68 macrophages and adipocyte precursors (marked by c-Kit positiveness). Simultaneous detection of IgG, C3, C5a and C5b-9 proved the ongoing complement activity and complement-directed injury within the adipose tissue. Our results showed the first evidence that the complement system hyperactivation occurs within the adipose tissue and is linked with fat loss in patients with BSS.

Hereditary angioedema (HAE) is becoming much more genetically complex than was initially considered. Thus, the role of HAE genetics is expanding beyond research laboratories, and the genotyping of subjects suffering from HAE has become diagnostically indispensable in clinical practice. The synthesis and interpretation of the clinical and biochemical analyses to facilitate appropriate genetic test selection has thus also become significantly more complex. With this in mind, an international multidisciplinary group of 14 experts in HAE genetics and disease management was convened in October 2018. The objective was to develop clear, actionable, evidence- and consensus-based statements aiming to facilitate the communication between physicians treating patients with HAE and clinical geneticists, and thus promote the effective use of genetics in the management of the disease. Eleven consensus statements were generated, encompassing considerations regarding the clinical indications for genotyping patients with angioedema, the methods of detection of HAE-causative variants, the variant pathogenicity curation, the genotyping of patients with HAE in the clinic, and genetic counseling. These statements are intended both to guide clinicians and to serve as a framework for future educational and further genetic testing developments as the field continues to evolve rapidly.

Background: C3 hypocomplementemia and the presence of C3 nephritic factor (C3NeF), an autoantibody causing complement system over-activation, are common features among most patients affected by Barraquer-Simons syndrome (BSS), an acquired form of partial lipodystrophy. Moreover, BSS is frequently associated with autoimmune diseases. However, the relationship between complement system dysregulation and BSS remains to be fully elucidated. The aim of this study was to provide a comprehensive immunological analysis of the complement system status, autoantibody signatures and HLA profile in BSS. Thirteen subjects with BSS were recruited for the study. The circulating levels of complement components, C3, C4, Factor B (FB) and Properdin (P), as well as an extended autoantibody profile including autoantibodies targeting complement components and regulators were assessed in serum. Additionally, HLA genotyping was carried out using DNA extracted from peripheral blood mononuclear cells. Results: C3, C4 and FB levels were significantly reduced in patients with BSS as compared with healthy subjects. C3NeF was the most frequently found autoantibody (69.2% of cases), followed by anti-C3 (38.5%), and anti-P and anti- FB (30.8% each). Clinical data showed high prevalence of autoimmune diseases (38.5%), the majority of patients (61.5%) being positive for at least one of the autoantibodies tested. The HLA allele DRB1*11 was present in 54% of BSS patients, and the majority of them (31%) were positive for *11:03 (vs 1.3% allelic frequency in the general population). Conclusions: Our results confirmed the association between BSS, autoimmunity and C3 hypocomplementemia. Moreover, the finding of autoantibodies targeting complement system proteins points to complement dysregulation as a central pathological event in the development of BSS., This work was supported by Instituto de Salud Carlos III (Ministerio de Ciencia, Innovación y Universidades, Gobierno de España) and Fondos FEDER (PI15–00255 to M.L-T. and PI08–1449 to D.A-V.), Complemento II-CM network (B2017/BMD3673 to M.L-T), the intramural research program of the Xunta de Galicia (Programa de Consolidación e Estructuración de Unidades de Investigación Competitivas, grant ED341b 2017/19 to D.A-V.), the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP) (to D.A-V., to F.C. and to P.N.)

Summary Acquired angioedema due to C1-inhibitor (C1INH) deficiency (AAE) is caused by secondary C1INH deficiency leading to bradykinin-mediated angioedema episodes. AAE typically presents in adulthood and is associated with B cell lymphoproliferation. Anti-C1INH autoantibodies (antiC1INHAbs) are detectable in a subset of AAE cases and considered a hallmark of the disease. When free antiC1INHAbs and malignant tumors are not detectable, diagnosis relies on the finding of low C1INH levels and/or function, lack of family history and SERPING1 mutations, age at onset and low or undetectable C1q levels, none of which is specific for AAE. We tested the diagnostic value of a novel enzyme-linked immunosorbent assay (ELISA) for the detection of circulating complexes between C1INH and antiC1INHAbs (C1INH–antiC1INHAb) in the serum of 20 European AAE patients characterized on the basis of their complement levels and function. Free antiC1INHAbs were detected in nine of 20 patients [six of immunoglobulin (Ig)G class, two of IgM class and one simultaneously presenting IgG and IgM classes], whereas C1INH–antiC1INHAb complexes were found in 18 of 20 of the AAE cases, regardless of the presence or absence of detectable free anti-C1INHAbs. Of note, nine of 20 patients showed negative free antiC1INHabs, but positive C1INH–antiC1INHAb complexes in their first measurement. In the cohort presented, IgM-class C1INH–antiC1INHAb are specifically and strongly associated with low C1q serum levels. Detection of C1INH–antiC1-INHAbs provides an added value for AAE diagnosis, especially in those cases in whom no free anti-C1INH antibodies are detected. The link between IgM-class C1INH–antiC1INHAb complexes and C1q consumption could have further implications for the development of autoimmune manifestations in AAE.

Hereditary angioedema due to pathogenic FXII variants (HAE-FXII) is a rare dominant disease caused by increased activation of the plasma contact system. The most prevalent HAE-FXII variant, c.1032C A p.Thr309Lys (FXII

49 p.-2 fig.-2 tab., Genetic variability in the complement system and its association with disease has been known for more than 50 years, but only during the last decade have we begun to understand how this complement genetic variability contributes to the development of diseases. A number of reports have described important genotype-phenotype correlations that associate particular diseases with genetic variants altering specific aspects of the activation and regulation of the complement system. The detailed functional characterization of some of these genetic variants provided key insights into the pathogenic mechanisms underlying these pathologies, which is facilitating the design of specific anti-complement therapies. Importantly, these analyses have sometimes revealed unknown features of the complement proteins. As a whole, these advances have delineated the functional implications of genetic variability in the complement system, which supports the implementation of a precision medicine approach based on the complement genetic makeup of the patients. Here we provide an overview of rare complement variants and common polymorphisms associated with disease and discuss what we have learned from them., SRdeC is supported by the Spanish “Ministerio de Economía y Competitividad/FEDER” [SAF2015-66287-R] and the Autonomous Region of Madrid [S2017/BMD-3673]. SRdeC is member of the "CIB Intramural Program “Molecular Machines for Better Life” (MACBET)". MLT is supported by the Spanish “Ministerio de Economía y Competitividad/FEDER” [PI15-00255]. EGdeJ is supported by the Spanish “Ministerio de Economía y Competitividad/FEDER” [SAF2014-52339-P]. SRdeC and EGdeJ are also supported by the “Fundación Inocente Inocente” (Madrid, Spain).

Background Congenital disorders of glycosylation (CDG) are rare diseases with impaired glycosylation and multiorgan disfunction, including hemostatic and inflammatory disorders. Factor XII (FXII), the first element of the contact phase, has an emerging role in hemostasia and inflammation. FXII deficiency protects against thrombosis and the p.Thr309Lys variant is involved in hereditary angioedema through the hyperreactivity caused by the associated defective O-glycosylation. We studied FXII in CDG aiming to supply further information of the glycosylation of this molecule, and its functional and clinical effects. Plasma FXII from 46 PMM2-CDG patients was evaluated by coagulometric and by Western Blot in basal conditions, treated with N-glycosydase F or activated by silica or dextran sulfate. A recombinant FXII expression model was used to validate the secretion and glycosylation of wild-type and variants targeting the two described FXII N-glycosylation sites (p.Asn230Lys; p.Asn414Lys) as well as the p.Thr309Lys variant. Results PMM2-CDG patients had normal FXII levels (117%) but high proportions of a form lacking N-glycosylation at Asn414. Recombinant FXII p.Asn230Lys, and p.Asn230Lys&p.Asn414Lys had impaired secretion and increased intracellular retention compared to wild-type, p.Thr309Lys and p.Asn414Lys variants. The hypoglycosylated form of PMM2-CDG activated similarly than FXII fully glycosylated. Accordingly, no PMM2-CDG had angioedema. FXII levels did not associate to vascular events, but hypoglycosylated FXII, like hypoglycosylated transferrin, antithrombin and FXI levels did it. Conclusions N-glycosylation at Asn230 is essential for FXII secretion. PMM2-CDG have high levels of FXII lacking N-glycosylation at Asn414, but this glycoform displays similar activation than fully glycosylated, explaining the absence of angioedema in CDG.

Background Hereditary angioedema due to the Thr328Lys variant in the coagulation factor XII (HAE-FXII) affects mainly women in whom the symptomatology is dependent on high estrogen levels. Clinical variability and incomplete penetrance are challenging features that hinder the diagnosis and management of HAE-FXII. The c.-4T>C Kozak polymorphism is the only common variation accounting for FXII plasma levels and was previously shown to modify the course of HAE due to C1-Inhibitor deficiency. Objectives To assess the influence of the c.-4T>C polymorphism on disease expression in 39 Spanish HAE-FXII index patients. Methods The c.-4T>C polymorphism was sequenced by the standard Sanger method, and HAE severity was calculated according to the score by Cumming et al. (2003) The activation of the contact system was quantified by the kallikrein-like activity of plasma in chromogenic assays upon activation with high-molecular-weight dextran sulfate. Results The c.-4CC genotype was overrepresented in the studied cohort: 82% were CC-homozygous (expected frequency = 59%) and 18% were CT-heterozygous (expected frequency = 39%) (p = 0.001). Patients with a c.-4CC genotype exhibited higher kallikrein-like activity (0.9659 ± 0.1136) than those with a c.-4TC genotype (0.7645 ± 0.1235) (p = 0.024) or healthy donors. Moreover, the polymorphism influenced HAE-FXII severity score (c.-4CC = 4.43 ± 2.28 vs c.-4TC = 2.0 ± 1.15; p = 0.006) but not the degree of estrogen dependence or time until remission. Conclusion The c.-4T>C polymorphism is overrepresented in a Spanish HAE-FXII cohort and significantly influences the degree of contact system activation and the clinical severity of the disease.

Following the publication of the original article [1], the authors have requested to amend the Abstract and Discussion section as follows.

Additional file 1: Figure S1. The alternative pathway of the complement system and autoantibodies against its proteins. In the alternative pathway (AP), continuous, low-level activation of C3 by spontaneous hydrolysis of the internal C3 thioester, or C3 cleavage by plasma proteases, generates C3(H2O) or C3b. Activation by the AP leads to the generation of C3 convertase complexes (C3bBb) that cleave C3 into C3a and C3b. Additionally, the AP C3 convertase can bind properdin (P), a positive regulator that stabilizes the enzyme, extending its half-life more than 10-fold. The activation of the AP is controlled by two different soluble regulatory proteins, as factor H (FH) and factor I (FI). C3 nephritic factor (C3NeF) is one of the most known autoantibodies which recognized a neo-epitope in the C3 convertase. Other autoantibodies against complement components (C3, FB or P) and regulators (FH or FI), some of them with functional activities, have been shown in the figure. Figure S2. Lack of correlation between complement levels and age. In 20 healthy subjects no correlations were found among age and the levels of (A) C3, (B) C4 (C) factor B (FB) and (D) properdin (P). These data were obtained using the Spearman Rank correlation coefficient. P

Additional file 1: Figure S1. The alternative pathway of the complement system and autoantibodies against its proteins. In the alternative pathway (AP), continuous, low-level activation of C3 by spontaneous hydrolysis of the internal C3 thioester, or C3 cleavage by plasma proteases, generates C3(H2O) or C3b. Activation by the AP leads to the generation of C3 convertase complexes (C3bBb) that cleave C3 into C3a and C3b. Additionally, the AP C3 convertase can bind properdin (P), a positive regulator that stabilizes the enzyme, extending its half-life more than 10-fold. The activation of the AP is controlled by two different soluble regulatory proteins, as factor H (FH) and factor I (FI). C3 nephritic factor (C3NeF) is one of the most known autoantibodies which recognized a neo-epitope in the C3 convertase. Other autoantibodies against complement components (C3, FB or P) and regulators (FH or FI), some of them with functional activities, have been shown in the figure. Figure S2. Lack of correlation between complement levels and age. In 20 healthy subjects no correlations were found among age and the levels of (A) C3, (B) C4 (C) factor B (FB) and (D) properdin (P). These data were obtained using the Spearman Rank correlation coefficient. P

International audience; C1 inhibitor (C1Inh) deficiency is responsible for hereditary angioedema (C1-INH-HAE) and caused by variants of the SERPING1/C1INH/C1NH gene. C1Inh is the major control of kallikrein-kinin system. C1Inh deficiency leads to its uncontrolled activation, with subsequent generation of the vasoactive peptide bradykinin. This update documents 748 different SERPING1 variants, including published variants and additional 120 unpublished ones. They were identified as heterozygous variants (n = 729), as homozygous variants in 10 probands and as compound heterozygous variants (nine combinations). Six probands with heterozygous variants exhibited gonadal mosaicism. Probands with heterozygous (n = 72) and homozygous (n = 1) variants were identified as de novo cases. Overall, 58 variants were found at positions showing high residue conservation among serpins, and have been referred to as a mousetrap function of C1Inh: reactive center loop, gate, shutter, breach, and hinge. C1Inh phenotype analysis identified dysfunctional serpin variants with failed serpin-protease association and a residual 105-kDa species after incubation with target protease. Regarding this characteristic, in conditions with low antigenic C1Inh, 74 C1-INH-HAE probands presented with an additional so-called intermediate C1-INH-HAE phenotype. The present update addresses a comprehensive SERPING1 variant spectrum that facilitates genotype-phenotype correlations, highlighting residues of strategic importance for serpin function and for identification of C1Inh deficiency as serpinopathy.

There is an error in the Acknowledgments statement. The correct name for the funder “Spanish Ministerio de Economia y Competitividad” is “Spanish Instituto de Salud Carlos III.” A correction has been made to the Acknowledgments section: “We appreciate the technical assistance of Lorena Risueno, Cesar Velez, and Alex Otero in the management of biological samples of patients and controls. We thank Rosario Madero (IdiPAZ Biostatistics) for statistical help, and Vega Mauleon and Hoi Tong (IdiPAZ UCICEC) for blood sampling of the healthy Spanish volunteers. This study was funded by the Spanish Instituto de Salud Carlos III and the European Program FEDER (grants PI12/00597 and PI16/00723 to PS-C, and grant SAF2015-66287-R to SR), and by the Complement II-CM network (B2017/BMD-3673). RP and TK received funding from the European Union’s seventh Framework program under ECGA no. 279185 (EUCLIDS; www.euclids-project.eu). AL is supported by the Spanish Center for Biomedical Network Research on Rare Diseases (CIBERER).” The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.

Hereditary angioedema as a result of deficiency of the C1 inhibitor (HAE-C1INH; MIM# 106100) is a rare autosomal disorder and affected individuals are generally heterozygous for dominant negative variants in theSERPING1gene. Homozygosity forSERPING1pathogenic variants was long considered to be embryonically lethal; however, five nonrelated families with a recessive HAE pattern have been described in the last decade. in this report, we functionally characterized two newly reported nonrelated, consanguineous families with a recessive presentation of HAE attributed toSERPING1variants in the reactive center loop (family D; S438F) and gate (family A; I379T) regions. S438F heterozygotes (family D) showed variable levels of intact 105-kDa and cleaved/inactive 96-kDa isoforms of C1INH, whereas their homozygous relative presented only the 96-kDa band. Functional studies showed that S438F reduced C1INH interaction with target proteases in heterozygous (C1s, 32-38% of controls and FXIIa, 28-35% of controls) and homozygous (C1s, 18-24% of controls and FXIIa, 4-8% of controls) carriers, which is consistent with the more severe presentation of HAE in the family and decreased C1q levels in homozygous patients. By contrast, plasma C1INH from I379T heterozygotes (family A) showed normal C1INH/C1s binding (84-94% of controls) and no significant reduction in C1INH/FXIIa complexes (50-70% of controls). However, the homozygote failed to inhibit both C1s (25-42% of controls) and FXIIa (14-18% of controls). This profile is concordant with the less severe presentation of HAE in the family and the conserved C4 and C1q levels in heterozygous and homozygous patients., [ER19P7AC7541/2019], We thank Dr Alper Ozdemir, Arda Kula, Suat Hopanci and Betul Hopanci for obtaining the patient's serum samples. Alberto Lopez Lera is supported by grant ER19P7AC7541/2019 from Centre for Biomedical Network Research or Rare Diseases (CIBERER).