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PubMed2002

Minor role for BRCA2 (exon11) and p53 (exon 5-9) among Sudanese breast cancer patients.

A cohort of 20 breast cancer patients from the Sudan was tested for germ line and somatic mutation in their BRCA2 exon 11 as well as the main conserved area of the p53 tumor suppressor gene. The results indicate that both regions may play a limited role in the pathogenesis of breast cancer in those patients. The fact that there are no somatic mutations detected in p53 was particularly surprising as the expected rate for mutations in breast cancer is 30-50%.

Adult↗
PubMed1998

VH usage and somatic hypermutation in peripheral blood B cells of patients with rheumatoid arthritis (RA).

The human antibody repertoire has been demonstrated to have a marked V-gene-dependent bias that is conserved between individuals. In RA patients, certain heavy chain V genes (VH) have been found to be preferentially used for encoding autoantibodies. To determine if such preferential use of VH genes in autoantibodies is associated with a general distortion of the V gene repertoire in RA patients, the VH composition of peripheral blood B cells was analysed among four RA patients and four age- and sex-matched healthy controls. Usage of individual VH genes (eight VH3 and three VH4 genes tested by hybridization with a set of gene-specific oligonucleotide probes) was highly biased among RA patients, but no evidence of a distortion in the bias was observed compared with healthy controls. However, the occurrence of somatic mutations in these VH genes (estimated by differential hybridization with motif-specific oligonucleotide probes targeted to CDR and FR of the tested genes, and by DNA sequence analysis) was strikingly different between patients and healthy subjects. The number of VH3 rearrangements that had accumulated somatic mutations and the number of mutations per rearrangement were significantly elevated in three of the four RA patients. A slight but not significant elevation in mutations among rearranged VH4 genes was also observed in these patients. These data suggest that although usage of individual VH genes among peripheral blood B cells is not affected by the disease, the autoimmune process may involve a significant fraction of the B cell compartment.

Antibodies↗
PubMed2000

The structural basis of repertoire shift in an immune response to phosphocholine.

The immune response to phosphocholine (PC)-protein is characterized by a shift in antibody repertoire as the response progresses. This change in expressed gene combinations is accompanied by a shift in fine specificity toward the carrier, resulting in high affinity to PC-protein. The somatically mutated memory hybridoma, M3C65, possesses high affinity for PC-protein and the phenyl-hapten analogue, p-nitrophenyl phosphocholine (NPPC). Affinity measurements using related PC-phenyl analogues, including peptides of varying lengths, demonstrate that carrier determinants contribute to binding affinity and that somatic mutations alter this recognition. The crystal structure of an M3C65-NPPC complex at 2.35-A resolution allows evaluation of the three light chain mutations that confer high-affinity binding to NPPC. Only one of the mutations involves a contact residue, whereas the other two have indirect effects on the shape of the combining site. Comparison of the M3C65 structure to that of T15, an antibody dominating the primary response, provides clear structural evidence for the role of carrier determinants in promoting repertoire shift. These two antibodies express unrelated variable region heavy and light chain genes and represent a classic example of the effect of repertoire shift on maturation of the immune response.

Amino Acid Sequence↗
PubMed1980

Lack of heterogeneity in antihapten antibodies of a phylogenetically primitive shark.

Individual mammals have the capacity to express at least one million distinct antigen binding specificities, implying a high degree of structural heterogeneity in the variable heavy and light chain (VH and VL) portions of the antibody molecules. Studies of higher vertebrate species suggest that this heterogeneity is created both through a sizeable repertoire of germ-line VH and VL genes and through random rearrangements of V and joining genes. Additional somatic mechanisms probably also contribute to the ultimate heterogeneity; one-third of murine plasmacytomas producing lambda 1 immunoglobulin carry a somatically mutated Ig1-V gene. The relative contributions of these various mechanisms to the overall imunoglobulin variability are difficult to evaluate. The production of different antibodies to a defined determinant in different individuals of an inbred mouse strain [for example, (3-iodo-4-hydroxy-5-nitrophenyl) acetyl (NIP) in CBA mice] suggests the involvement of somatic mutations or rearrangement but does not rule out the possibility that each individual CBA mouse expresses only a small random fraction from a large germ-line repertoire of V genes determining different anti-NIP binding sites. The opposite finding, that different individuals produce nearly identical antibodies to a defined determinant, would suggest the presence and expression of a limited number of germ-line genes without somatic alterations. Data presented here suggest that primitive sharks (Heterodontus fransisci) produce such antibodies to the hapten furyloxazolone.

Animals↗
PubMed2026

Motif-Centered Analyses Reveal Universal and Tissue-Specific Mutagenic Mechanisms Operating in the Human Body.

Somatic mutations are inevitable in human genomes and can lead to tumorigenesis, yet baseline mutagenesis in non-cancerous normal cells remain poorly understood. Here, we analyzed the mutation profiles of 11,949 normal samples across 25 tissues obtained from whole-genome and whole-exome sequencing datasets. We applied stringent statistical hypothesis for detecting enrichment and enrichment-adjusted Minimal Estimate of Mutation Load (MEML) in trinucleotide motifs preferred by known mutagenic processes. We found several cancer-associated mutational motifs in cancer-free tissues. Samples enriched with C→T mutations in nCg motif associated with clock-like spontaneous meCpG deamination were detected across all tissues. We revealed another clock-like motif, T→C substitutions in aTn motif associated with exposure to small epoxides and other SN2 electrophiles, in several tissues. Donors with several non-cancerous diseases showed significantly higher, age-independent, and concordant accumulation of aTn and nCg motifs compared to healthy donors. Motifs associated with chemical exposures showed sporadic, tissue and disease-specific mutagenesis. APOBEC-induced C→T and C→G mutations in tCw motif were enriched in bladder, lung, small intestine, liver, and breast with preference for APOBEC3A-like mutagenesis in most. Together, our analyses elucidated several ongoing mutagenic processes in normal human tissues and provided a robust analytical framework for identifying mutagenic sources from somatic mutation catalogues.

Journal Article↗
PubMed1996

Inactivation of p16/CDKN2 and p15/MTS2 genes in different histological types and clinical stages of primary ovarian tumors.

To define the involvement of p16/CDKN2 and p15/MTS2 inactivation in ovarian tumorigenesis and the association of these inactivation events with histological types and clinical stages of ovarian tumors, we analyzed homozygous deletion and somatic mutation of p16/CDKN2 and p15/MTS2 genes, as well as hypermethylation of the 5'-CpG island of the p16/CDKN2 gene, in 49 primary ovarian tumors and 6 ovarian carcinoma cell lines. We found homozygous deletions of p16/CDKN2 and p15/MTS2 in 6 (12%) and 5 (10%) primary tumors, respectively. Somatic mutation of p16/CDKN2 was found in only 1 primary tumor, but mutation of p15/MTS2 was not detected in any sample. None of the 28 primary tumors or 6 cell lines was hypermethylated at the 5'-CpG island of p16/CDKN2. The incidence of inactivation of p16/CDKN2 in primary tumors was significantly higher in the advanced stages (7 of 29) than in the early stages (0 of 14). Seven of 9 alterations in p16/CDKN2 and p15/MTS2 were observed in serous (3 of 12), endometrioid (3 of 9) and clear-cell (1 of 4) carcinomas. However, only normal sequences of these genes were detected in mucinous carcinomas. Loss of heterozygosity (LOH) at the IFNA locus was detected in 1 of 19 (5%) tumors, but no change at the D9S171 locus was observed in 17 tumors. These results suggest that: (i) homozygous deletion is the main mechanism of inactivation of p16/CDKN2 and p15/MTS2 in ovarian tumorigenesis; (ii) inactivation of p16/CDKN2 and p15/MTS2 may be the histological type-specific events involved in ovarian tumorigenesis; and (iii) inactivation of p16/CDKN2 is potentially involved in the progression of ovarian tumors in advanced stages.

Carcinoma↗
PubMed2003

Sequence-specific targeting of two bases on both DNA strands by the somatic hypermutation mechanism.

Somatic mutations within antibody genes alter the affinity and selectivity of antibody molecules and largely define the quality of the memory B cell repertoire in many vertebrate species. While some evidence supports the idea that there is a strand bias to the hypermutation mechanism, conflicting data suggest that somatic mutations are initially acquired on both strands of DNA. In this study, we utilized a previously defined trinucleotide target bias of hypermutation to address the question of target strand symmetry during mutation. Mutabilities of specific base positions within all triplets were compared between the two strands of DNA in three divergent databases of hypermutated sequences. Unexpectedly, we consistently observed strong correlations between mutabilities of triplet positions on the two DNA strands only for G and T in the first position of a triplet or for C and A in the last position. The most straightforward interpretation of this result is that the mutation mechanism targets either G and T or C and A on both strands of DNA with a frequency that depends upon the adjacent dinucleotide sequence. In view of published evidence that C is targeted by the hypermutation mechanism, we can extrapolate that C and A are specifically targeted at a frequency that depends upon the preceding 5' dinucleotide.

Animals↗
PubMed1997

Differential rates of somatic hypermutation in V(H) genes among subsets of chronic lymphocytic leukemia defined by chromosomal abnormalities.

Chronic lymphocytic leukemia (CLL) is a B-cell tumor involving small lymphocytes that generally express the CD5 antigen and low levels of surface Ig. Within this definition, there is heterogeneity among cases in cell morphology, karyotypic abnormalities, and clinical course. Trisomy 12, the most frequent karyotypic abnormality, is commonly found in a subset of CLL with atypical morphology. It has also been associated with advanced disease, and possibly with a less favorable prognosis. A further subset of cases with abnormalities involving chromosome 13q14 have typical lymphocyte morphology. Occasionally, the two abnormalities are found together. To assess the clonal history of the cell of origin in disease subsets defined by these two chromosomal abnormalities, we investigated the usage of V(H) genes and the pattern of somatic mutation in 10 cases of trisomy 12 with atypical morphology and eight cases of 13q14 abnormality with typical morphology. In addition, four cases with both chromosomal abnormalities were analyzed. Results confirm a common usage of the V(H)1 family in all subsets. However, the patterns of somatic mutation were distinct, with cases of trisomy 12 showing a minimal level of mutation (mean +/- SD, 0.34% +/- 0.86%) and cases of 13q14 abnormality showing significant levels (6.5% +/- 1.67%). The four cases with both abnormalities showed a mixed pattern. All mutated cases had intraclonal homogeneity, and three of 10 had a pattern indicative of antigen selection. These results suggest that the clonal history of the two subsets of CLL may differ.

Aged↗
PubMed1995

Elevated frequency of glycophorin A mutations in erythrocytes from Chernobyl accident victims.

In 1986, when an explosion accident occurred at the Chernobyl, Ukraine nuclear power plant, a large number of people were exposed to significant amounts of ionizing radiation. During the time between 1986 and 1992, peripheral blood samples were obtained from 102 people who either were on site during the emergency or were brought to Chernobyl shortly thereafter to assist in the cleanup of radioactive contaminants and isolate the damaged reactor from the environment. These blood samples plus samples from 13 unexposed Soviet individuals were analyzed by flow cytometry using the allele-loss somatic mutation assay for glycophorin A. Results of these assays show that the frequency of N/O variant red cells increased in proportion to the estimated radiation exposure of each individual. The radiation dose-response function derived from this population closely resembles that determined previously for atomic bomb survivors whose blood samples were obtained and analyzed 40 years after their exposure. This suggests comparable mutation induction per unit dose for these two populations and long-term persistence of the mutational damage. In addition, measurements on multiple blood samples from each of 10 donors taken over a 7-year period showed no significant changes in N/O variant cell frequencies, confirming the persistence of radiation-induced somatic mutations in long-lived bone marrow stem cells.

Dose-Response Relationship, Radiation↗
PubMed2026

Motif-centered analyses reveal universal and tissue-specific mutagenic mechanisms operating in the human body.

Somatic mutations are inevitable in human genomes and can lead to cancer initiation and tumor progression. Although many mutagenic processes have been linked to cancer, their activities in normal tissues before malignant transformation remain poorly characterized. Here, we analyzed the mutation profiles of 10,625 normal samples across 25 tissues obtained from whole-genome and whole-exome sequencing datasets. We applied stringent statistical hypothesis for detecting enrichment and enrichment-adjusted Minimal Estimate of Mutation Load in trinucleotide motifs preferred by known mutagenic processes. We found several cancer-associated mutational motifs in cancer-free tissues. Samples enriched with C→T mutations in nCg motif associated with clock-like spontaneous meCpG deamination were detected across all tissues. We also identified a second clock-like motif, T→C substitutions in aTn motif associated with exposure to small epoxides and other SN2 electrophiles, in several tissues. Motifs associated with other environmental and chemical mutagens showed sporadic and tissue-specific mutagenesis. APOBEC-induced C→T and C→G mutations in tCw motif were enriched in bladder, lung, small intestine, liver, and breast with preference for APOBEC3A-like mutagenesis in most tissues. Together, our analyses elucidated several cancer-associated mutagenic processes in normal tissues and provided a robust analytical framework for quantifying mutagenic activities from somatic mutation catalogs.

Humans↗
PubMed2006

Mitochondrial DNA sequence variation in single cells from leukemia patients.

A high frequency of mtDNA somatic mutation has been observed in many tumors as well as in aging tissues. In this study, we analyzed the mtDNA control region sequence variation in 3534 single normal cells and individual blasts from 18 patients with leukemia and 10 healthy donors, to address the mutation process in leukemic cells. We found significant differences in mtDNA sequence, as represented by the number of haplotypes and the mean number of cells with each nonaggregate haplotype in a population of cells, in patients compared to controls. Patients with similar clinical leukemia types, particularly acute myeloid leukemia (AML), did not show a uniform pattern of sequence variation in single blasts. Some patients at relapse presented a complex shift of major haplotypes in single cells. Four patients showed high frequencies of cells containing mutations 189, 260, 16150, and 16488, respectively, as a result of clonal expansion and could be considered as potential markers for their respective disease progression. To our knowledge, this is the first large-scale study of mtDNA variation in single malignant cells. Our results suggest that the somatic mutation process in leukemia is complex, leading to diverse levels of genetic alterations due to either intrinsic aspects of leukemia pathophysiology or chemotherapy effects.

Adolescent↗
PubMed1993

Conservation of binding site geometry among p-azophenylarsonate-specific antibodies.

Murine A/J anti-p-azophenylarsonate mAb that express a dominant cross-reactive Id are encoded by a single set of germ-line VH and VL region genes. The crystal structure of the Fab of antibody 36-71, which uses this canonical set of genes but is somatically mutated, was previously determined. An Fab 36-71:phenylarsonate complex was modeled, identifying amino acid side chains that were proposed as contact residues to hapten. The remarkable conservation of these residues among canonical anti-p-azophenylarsonate antibodies suggested that the overall binding site geometry was maintained among somatically mutated antiarsonate monoclonal antibodies. To test this hypothesis, we used the germ-line-encoded antibody 36-65 to construct mutant antibodies, using oligonucleotide-directed mutagenesis, which differed only at the putative H chain hapten-contacting residues, and measured their hapten binding. A framework residue at H chain position 47 involved in a hydrogen bond network with CDR residues was also mutated. Substitution of several amino acids at each position permitted evaluation of the stereochemical requirements for binding. The results indicate the importance of aromatic stacking of two H chain tyrosine residues against the phenyl ring of the hapten in maintaining affinity, as well as strict complementarity at H chain position 35. The results are consistent with the crystal model of the combining site, and provide further evidence for conservation of the three-dimensional binding site motif among antiarsonate antibodies that bear a dominant heritable ld.

Amino Acid Sequence↗
PubMed1991

Different epitope structures select distinct mutant forms of an antibody variable region for expression during the immune response.

Antibody variable (V) regions that initially differ from one another by only single amino acid residues at VH-D and D-JH segment junctions (termed canonical V regions) can be elicited in strain A/J mice by three different haptens. Among such V regions an amino acid substitution due to somatic mutation is recurrently observed at VH CDR2 position 58, regardless of which of these haptens is used for immunization. This substitution confers upon a canonical V region a generic increase in affinity for all the haptens. Conversely, the type of amino acid substitution at VH position 59 resulting from somatic mutation that is recurrently observed among such V regions changes with the eliciting hapten, in a manner that correlates directly with the cognate affinity increases (or decreases) for hapten conferred by the observed substitutions. This small subregion of VH CDR2 therefore plays a major role in determining both affinity and specificity for antigen. The data confirm that affinity for antigen is of pivotal importance in determining the degree of selection of different mutant forms of a V region. Moreover, during an immune response a sufficiently diverse mutant repertoire can be generated from a single canonical V region to allow adaptation to increase affinity for three different epitopes.

Amino Acid Sequence↗
PubMed2001

Role of disease-causing genes in sporadic pancreatic endocrine tumors: MEN1 and VHL.

Pancreatic endocrine tumors (PETs) occur in association with multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau (VHL) syndromes caused by germline alterations in MEN1 and VHL, respectively. It is thus expected that these genes will also be altered in a proportion of sporadic PETs. Indeed, MEN1 is altered in about 25% of nonfamilial PETs, although no mutations have been found in VHL. For all clinical subtypes, the frequency of allelic loss on chromosome arm 11q mirrors observed mutational frequencies, with the exception of nonfunctional tumors (NF-PETs), in which mutations have been reported in only 8% of cases. As allelic loss on 11q is the most frequent event found in these neoplasms, this low frequency is somewhat puzzling, particularly in light of the fact that most MEN1-associated PETs are nonfunctioning. To clarify the role of these genes in sporadic PETs, we analyzed 31 sporadic NF-PETs, nine insulinomas, and one VIPoma for alterations in MEN1 and VHL. As somatic mutations were observed in eight (26%) of the NF tumors and in one insulinoma, it would therefore appear unlikely that an additional tumor suppressor gene related to sporadic PET pathogenesis is located on 11q. One insulinoma also had a somatic mutation in VHL, and thus this gene may also be altered in these neoplasms, albeit in a small proportion of cases.

Genes, Tumor Suppressor↗
PubMed2002

Systematic analysis of sequences of anti-DNA antibodies--relevance to theories of origin and pathogenicity.

Sequence analysis of anti-DNA antibodies is important in determining the molecular features which distinguish potentially pathogenic antibodies from those which are less likely to be pathogenic. Previous analysis of murine anti-DNA antibody sequences suggested that particular murine immunoglobulin genes are used preferentially to encode such antibodies and that somatic mutations to arginine, asparagine and lysine may be important in the creation of DNA binding sites. In this paper, a systematic analysis of published human anti-DNA sequences shows no strong evidence for preferential usage of particular human V(H) or V(L) genes in anti-DNA antibodies. Somatic mutations in IgG and IgA antibodies are clustered in the complementarity determining regions (CDRs) due to the effect of antigen drive. This process contributes to an excess of arginine, asparagine and lysine residues in these CDRs, some of which are likely to play an important role in binding to DNA. Computer modeling and in-vitro expression experiments are likely to help define the roles played by these residues in antigen binding and pathogenicity more clearly.

Amino Acid Sequence↗
PubMed2005

Targeted somatic mutagenesis in the mouse epidermis.

The efficient introduction of somatic mutations in a given gene at a given time and in specific cell types of the skin will greatly facilitate the studies of a number of genes expressed in the skin and the production of animal models for skin diseases. We describe here strategies and techniques to create spatiotemporally controlled somatic mutations of target genes in the skin using a conditional Cre/LoxP system. They are based on cell-specific expression of the chimeric Cre recombinase Cre-ERT2, whose activity is induced by antiestrogens such as Tamoxifen (Tam), and which is obtained by fusing the Cre recombinase with a mutated ligand binding domain of the human estrogen receptor ERalpha. As an example, we present ablation of the retinoid receptor RXRalpha in epidermal basal keratinocytes of adult mice.

Animals↗
PubMed2004

[Preparation of human phage antibodies specific for SSA/Ro antigen and its sequence analysis].

OBJECTIVE: To prepare monoclonal antibodies (mAbs) specific for SSA/Ro antigen from the phage-displayed human single-chain Fv (scFv) antibody library constructed previously, and analyze its gene sequence. METHODS: Frozen strain of Escherichia coli TG1 containing pHEN2-scFv was defrosted and infected by helper phage to produce scFv phage antibody library. 10 random clones from the primary library were checked for the presence of inserts by PCR screening. Four clones containing exogenous gene with correct length were selected randomly to undergo gene sequencing. The diversity of the library was monitored by digesting the PCR products of 8 different phagemids encoding scFv genes. The phage antibody library was biopanned for 3 cycles, using purified SSA/Ro antigen. After biopanning, the binding characterization and the specificity of the enriched library to SSA/Ro antigen was assayed by ELISA. mAbs were obtained from this enriched library and ELISA was used to detect the binding characterization and the specificity of these mAbs, using different purified antigens. The variable region of the monoclonal antibody undergoes sequencing. RESULTS: A phage scFv library with the titer of 1.6 x 10(12) cfu/ml was established. Sample screening showed that eight of the ten clones contained scFv fragments. The insertion and recombination rate of exogenous gene was 80%. These 8 clones were also analyzed by restriction enzyme analysis to assess the diversity of the library. Each of the 8 clones showed a distinct restriction pattern. Sequencing results demonstrated that the genes of scFv were the human antibody genes, and the gene ligating and cloning were correct and successful. The library was subjected to 3 rounds of rescue and panning. A secondary phage antibody library against SSA/Ro was generated and the interest phages were obviously enriched. The 3rd panned library showed good reaction to the SSA/Ro antigen with higher OD value than unenriched library demonstrated by ELISA. The result of ELISA showed that the enriched library reacted specifically to SSA/Ro and had no cross-reactivity to the other autoantigen. 5 mAbs specific for SSA/Ro antigen could be selected from 52 clones, and the gene sequences of their VH and VL were coded by VH1, VH3, VH4, Vkappa1, Vkappa2, and Vkappa3 family genes with somatic mutations. CONCLUSION: The primary scFv phage antibody library fits the need for later operations, and this library was enriched successfully. Enriched scFv phage antibody library is specific for SSA/Ro antigen, from which 5 monoclonal anti-SSA/Ro phage antibodies can be obtained successfully. The sequences of these mAbs show somatic mutations comparing with germline. It may help understand the pathogenesis of some antibody-mediated diseases.

Antibodies, Anti-Idiotypic↗
PubMed2006

Activation of Akt independent of PTEN and CTMP tumor-suppressor gene mutations in epilepsy-associated Taylor-type focal cortical dysplasias.

Focal cortical dysplasias (FCD) with Taylor-type balloon cells (FCD(IIb)) are frequently observed in biopsy specimens of patients with pharmacoresistant focal epilepsies. The molecular pathogenesis of FCD(IIb), which lack familial inheritance, is only poorly understood. Due to their highly differentiated, malformative nature and glioneuronal phenotype, FCD(IIb) share neuropathological characteristics with lesions observed in familial disorders such as cortical tubers present in patients with autosomal dominant tuberous sclerosis complex (TSC), related to mutations in the TSC1 or TSC2 genes, and dysplastic gangliocytomas of the cerebellum found in Cowden disease. Current data have indicated distinct allelic variants of TSC1 to accumulate in FCD(IIb). TSC1 represents a tumor suppressor operating in the phosphatidylinositol 3-kinase (PI3K)/insulin pathway. The tumor-suppressor gene PTEN is mutated in Cowden disease. Like PTEN, also carboxyl-terminal modulator protein (CTMP) modulates PI3K-pathway signaling, both via inhibition of Akt/PKB, a kinase inactivating the TSC1/TSC2 complex. Here, we have analyzed alterations of Akt, PTEN and CTMP relevant for insulin signaling upstream of TSC1/TSC2 in FCD(IIb). Immunohistochemistry with antibodies against phosphorylated Akt (phospho-Akt; Ser 473) in FCD(IIb) (n=23) showed strong phospho-Akt expression in dysplastic FCD(IIb) components. We have further studied sequence alterations of PTEN (n=34 FCD(IIb)) and CTMP (n=20 FCD(IIb)) by laser microdissection/single-strand conformation polymorphism analysis. We observed a somatic mutation in an FCD(IIb), i.e., amino-acid exchange at nucleotide position 834 (PTEN cDNA, GenBank AH007803.1) in exon 8 with replacement of phenylalanine by leucine (F278L). We also found several silent polymorphisms of PTEN in exon 2 and exon 8 as well as silent and coding polymorphisms but no mutations in CTMP. No loss of heterozygosity in FCD(IIb) (n=6) at 10q23 was observed. To our knowledge, we here report on the first somatic mutation of a tumor-suppressor gene, i.e., PTEN, in FCD(IIb). However, our study also demonstrates that mutational alterations of PTEN and CTMP do not play major pathogenetic roles for activation of Akt in FCD(IIb). Future studies need to determine the origin of insulin pathway activation upstream of TSC1/TSC2 in FCD(IIb).

Adaptor Proteins, Signal Transducing↗