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Machine Learning Discoveries of NFκB-X Synergy in ETC-1922159 Treated Colorectal Cancer Cells

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Advances in Colorectal Cancer Therapy

Submitted:

05 September 2024

Posted:

10 September 2024

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Abstract
Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combinations of factors/genes/proteins that might be affecting the pathway under certain conditions. In colorectal cancer (CRC) cells treated with ETC-1922159, many genes were found up and down regulated, individually. A recently developed search engine ranked combinations of Nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB)-X (X, a particular gene/protein) at 2nd order level after drug administration. These rankings reveal which NFκB-X combinations might be working synergistically in CRC. If found true, oncologists can further test the combination of interest in wet lab and determine the mechanism of functioning between the NFκB and X. In this research work, we cover combinations of caspase (CASP) with receptor interacting serine/threonine kinase (RIPK) family, mucin (MUC) family with RIPK, tumor necrosis factor (TNF) with NF-κB family and NF-κB-Inhibitor (NF-κB-I), NFκB-2/I with STAT family, IκB kinase ε (IKBKE) with STAT family, IKBKE with conjugal transfer protein (TRAF), ATP-binding cassette (ABC) domain transporters with NFκB, IKBKE with ubiquitination modifier enzyme and ubiquitination conjugating enzymes (UBA/UBE) and REL-A/B with NFκB .
Keywords: 
Subject: Computer Science and Mathematics  -   Mathematical and Computational Biology

1. Introduction

In the unpublished preprint Sinha [1], a frame work of a search engine was developed which can rank combinations of factors (genes/proteins) in a signaling pathway. Such combinations are of import due to the vast search space in which they exist and the difficulty to find them. The search engine facilitates in prioritizing the combinations as ranked biological hypotheses which the biologists might want to test in wet lab, to know if a synergistic combination is prevalent in a signaling pathway, in a direct or indirect manner. Interested readers are advised to go through unpublished preprints Sinha [1] and Sinha [2] for details regarding the search engine and the discoveries mentioned in there.

2. Materials and Methods

2.1. Combinatorial Search Problem and a Possible Solution

The issue of combinatorial search problem and a possible solution has been addressed in Sinha [3] and Sinha [2]. The details of the methodology of this manuscript have been explained in great detail in Sinha [3] & its application in Sinha [2]. Readers are requested to go through the same for gaining deeper insight into the working of the pipeline and its use of published data set generated after administration of ETC-1922159. In order to understand the significance of the solution proposed to the problem of combinatorial search that the biologists face in revealing unknown biological search problem, these works are of importance.
Briefly, from Sinha [2], the pipleline works by computing sensitivity indicies for each of these unique combinations and then vectorising these indices to connote and form discriminative feature vector for each combination. Since each combination is unique, the training and the test data are same. In the training data, the combinations are arranged and ranks from 1 to n are assigned. The ranking algorithm then learns the patterns from these combinations/sensitivity index vectors. Next the learned model is used to rank the test data by generating the ranking score for each of the unique combination. Sorting these shuffled scores of test data leads to prioritization of the combinations. Joachims [4] show an example of applying learned model to training data (same as the test data) in https://www.cs.cornell.edu/people/tj/svm_light/svm_rank.html. Note that these combinations are now ranked and give the biologists a chance to narrow down their focus on crucial biological hypotheses in the form of combinations which the biologists might want to test. Analogous to the webpage search engine, where the click of a button for a few key-words leads to a ranked list of web links, the pipeline uses sensitivity indices as an indicator of the strength of the influence of factors or their combinations, as a criteria to rank the combinations.

3. Results & Discussion

3.1. NF- κ B Related Synergies

3.1.1. CASP - RIPK Cross Family Analysis

Table 1 and Table 2 show the rankings of CASP family w.r.t RIPK and vice versa, respectively. Followed by this is the derived influences between CASP and RIPK via two way analysis of majority voting of rankings in the two foregoing tables. These influences are tabulated in Table 3. In Table 1, only CASP9 - RIPK3 combination showed up regulation with rankings of 2133 (laplace), 2030 (linear) and 2295 (rbf). In Table 2, RIPK1 showed up regulation with CASP-4/10 with rankings of 2363 (laplace) and 1805 (rbf) for CASP4 - RIPK1; and 2438 (laplace) and 1915 (linear) for CASP10 - RIPK1, respectively. RIPK2 showed up regulation with CASP-5/9/16 with rankings of 1776 (linear) and 2247 (rbf) for CASP5 - RIPK2; 2000 (laplace), 2476 (linear) and 2138 (rbf) for CASP9 - RIPK2; and 2006 (linear) and 2046 (rbf) for CASP16 - RIPK2; Finally, RIPK4 showed up regulation with CASP-16 with rankings of 2273 (laplace) and 2023 (linear) for CASP16 - RIPK4.
The caspase - receptor interacting protein kinases (RIPK) has an intricate mechanism which has not yet been discovered and many views exist about their synergistic interaction. Green et al. [5] presents a review of RIPK-dependent necrosis and its regulation by CASPs. Furthermore, Lin et al. [6] show that cleavage of the death domain RIPK by CASP-8 prompts TNF-induced apoptosis. RIPK1 is known to promote death receptor-independent CASP-8 mediated apoptosis under unresolved ER stress conditions, as shown by Estornes et al. [7]. Weng et al. [8] show that CASP-8 and RIPK regulate bacteria-induced innate immune responses and cell death. Also, Moriwaki et al. [9] show that RIPK3-CASP8 complex mediates atypical pro-IL-1 β processing. Recent work by Declercq et al. [10] shows RIPK importance in cell death and survival along with CASP influence. These interactions point to a definite synergy between the CASP - RIPK. Chaudhary et al. [11] showed activation of NF- κ B pathway via Caspase-8 (CASP-8) and its homologs. Additionally, Caspase-8 was found to interact with Receptor-interacting serine/threonine-protein kinase 1 (RIPK1). Family members belonging to each of the factors like CASP, RIPK etc, might be involved synergistically in pathological case or otherwise. CASP and RIPK members were found to be up regulated after the treatment of ETC-1922159 in colorectal cancer cells.
One can also interpret the results of the Table 3 graphically, with the following influences - • CASP w.r.t RIKP family with CASP9 < − RIPK3 and • RIPK w.r.t CASP family with RIPK1 < − CASP-4/10; RIPK2 < − CASP-5/9/16 and RIPK4 < − CASP16.

3.1.2. MUC - RIPK Cross Family Analysis

In a recent work Sheng et al. [12] show that MUC13 promoted tumor necrosis factro (TNF)-induced NF- κ B activation by interacting with TNFR1 and the E3 ligase, cIAP1, to increase ubiquitination of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1). Family members belonging to each of the factors like MUC, RIPK etc, might be involved synergistically in pathological case or otherwise. MUC and RIPK members were found to be up regulated after the treatment of ETC-1922159 in colorectal cancer cells.
Table 4 and Table 5 show the rankings of MUC family w.r.t RIPK family and vice versa, respectively. Followed by this is the derived influences between MUC and RIPK. In Table 4, MUC1 was found to be highly upregulated with RIPK1. This is reflected in the rankings of 2027 (linear) and 2249 (rbf) for MUC1 - RIPK1. MUC3A was found to be highly upregulated with RIPK3. This is reflected in the rankings of 2208 (laplace) and 2017 (rbf) for MUC3A - RIPK3. MUC12 was found to be highly upregulated with RIPK4. This is reflected in the rankings of 2249 (linear) and 2130 (rbf), for MUC12 - RIPK4. MUC20 was found to be highly upregulated with RIPK3. This is reflected in the rankings of 2192 (laplace), 2288 (linear) and 1796 (rbf) for MUC20 - RIPK3.
In table 5, RIPK-1/2 was found to be highly upregulated with MUC1. This is reflected in the rankings of 1839 (laplace) and 2421 (rbf) for MUC1 - RIPK1; and 1913 (laplace) and 2091 (linear) for MUC1 - RIPK2. RIPK4 was found to be highly upregulated with MUC4. This is reflected in the rankings of 1981 (laplace), 1949 (linear) and 2028 for MUC4 - RIPK4. RIPK4 was found to be highly up regulated with MUC17. This is reflected in the rankings of 2225 (linear) and 2048 (rbf) for MUC17 - RIPK4. RIPK2 was found to be highly up regulated with MUC20. This is reflected in the rankings of 1751 (linear) and 1950 (rbf) for MUC20 - RIPK2.
One can also interpret the results of the table 6 graphically, with the following influences - • MUC w.r.t RIKP family with MUC1 < − RIPK1; MUC3A < − RIPK3; MUC12 < − RIPK4; MUC20 < − RIPK3 and • RIPK w.r.t MUC family with MUC1 − > RIPK-1/2; MUC4 − > RIPK4; MUC17 − > RIPK4; MUC20 − > RIPK2.

3.1.3. TNF - NF- κ B-2/I Cross Family Analysis

The NF- κ B family and NF- κ B-Inhibitor i.e NF- κ B-I play a significant role in immune response to infection. Problems in its functioning leads to cancer, infections, inflammatory and autoimmune diseases. The discovery and seminal work by Sen and Baltimore [13] on NF- κ B lead to range of research on immune responses and study of related pathological cases. Tanaka and Nakano [14] have shown that NF- κ B2 limits TNF- α induced osteoclastogenesis. Recently, in Japanese population, Imamura et al. [15] show that the impaired NF- κ BIE gene function decreases cellular uptake of methotrexate by down-regulating SLC19A1 expression in a human rheumatoid arthritis cell line. They postulate that NF- κ BIE could be closely related to NF- κ B activity. Also, Lee et al. [16] show through deep study of fold-change analysis of the inter-relation between NF- κ B and TNFs. However, the synergy between these members has yet not been explored completely. We found some interesting combinations that were allocated high numerical ranking (in silico) to indicate synergistic up regulation in CRC cells after ETC-1922159 treatment, apart from the individual up regulation that was observed in wet experiements.
Table 7 and Table 8 depict the rankings of TNF family w.r.t to NF- κ B-2/I and vice versa, respectively. Followed by this is table 9 that contains the derived influences via majority voting of the rankings in the tables containing two-way cross family rankings.
In Table 7 we find TNF-RSF10A/RSF12A up regulated with NFkB2. These are reflected in rankings of 2095 (laplace) and 2509 (rbf) for NFkB2 - TNFRSF10A; and 1813 (laplace) and 1893 (rbf) for NFkB2 - TNFRSF12A. TNF-AIP1/RSF10A/RSF10D/RSF14/SF10 were found to be up regulated with NFkBI-A. These are reflected in rankings of 1779 (laplace) and 1904 (linear) for NFkBI-A - TNF-AIP1; 2499 (laplace) and 2191 (rbf) for NFkBI-A - TNFRSF10A; 2498 (laplace), 2344 (linear) and 2501 (rbf) for NFkBI-A - TNFRSF10D; 1974 (laplace) and 2045 (linear) for NFkBI-A - TNFRSF14; and 2185 (laplace) and 2316 (rbf) for NFkBI-A - TNFSF10, respectively. TNF-AIP2/RSF14 were found to be up regulated with NFkBI-E. These are reflected in rankings of 2347 (laplace) and 1863 (linear) for NFkBI-E - TNFAIP2; and 1877 (laplace) and 2282 (linear) for NFkBI-E - TNFRSF14, respectively. Finally, TNF-RSF10B/RSF10D/RSF12A were found to be up regulated with NFkBI-Z. These are reflected in rankings of 2204 (laplace) and 1991 (rbf) for NFkBI-Z - TNFRSF10B; 2214 (laplace), 2033 (linear) and 2514 (rbf) for NFkBI-Z - TNFRSF10D; and 2370 (linear) and 1841 (rbf) for NFkBI-Z - TNFRSF12A, respectively. In Table 8 we find NFkB-2 to be up regulated along with TNF-AIP1/AIP2/AIP3. These are reflected in rankings of 2027 (linear) and 1807 (rbf) for NFkB2 - TNFAIP1; 2077 (laplace) and 2224 (rbf) for NFkB2 - TNFAIP2; and 2336 (linear) and 2130 (rbf) for NFkB2 - TNFAIP3, respectively. Finally, NFkBI-E was found to be up regulated with TNFRSF10D. These are reflected in rankings of 2136 (laplace) and 1811 (rbf) for NFkBI-E - TNFRSF10D.
One can also interpret the results of the table 9 graphically, with the following influences - • TNF w.r.t NFkB family with NFkB2 − > TNF-RSF10A/RSF12A; NFkBI-A − > TNF-AIP1/RSF10A/RSF10D /RSF14/SF10; NFkBI-E − > TNF-AIP2/RSF14; NFkBI-Z − > TNF-RSF10B/RSF10D/RSF12A; and • NFkB w.r.t TNF family with NFkB-2 < − TNF-AIP1/AIP2/AIP3 and NFkBI-E < − TNF-RSF10D.

3.1.4. NF κ B-2/I - STAT Cross Family Analysis

Grivennikov and Karin [17] show the potent collaboration and cross talk of STAT3 and NF- κ B in cancer. In chronic lymphocytic leukemia cells, Liu et al. [18] observe that STAT-3 activates NF- κ B. Co-opertion between STAT3 and NF- κ B pathways has been observed in subtypes of diffuse large B Cell Lymphoma by Lam et al. [19]. Lee et al. [20] also shows a signal network involving coactivated NF- κ B and STAT3 and altered p53 modulates BAX/BCL-XL expression and promotes cell survival of head and neck squamous cell carcinomas. These observations show a definite, concommitent functioning of the two pathways and we further found that some of them were up regulated synergistically in CRC cells after ETC-1922159 treatment, via in silico ranking of the combinations. Table 10 and Table 11 show ranking of STAT family w.r.t NFkB-2/I and vice versa, respectively. Followed by this is the derived influences from majority voting of rankings in the two foregoing tables, which is shown in table 12.
Table 10 and Table 11 show the rankings of STAT family w.r.t NFkB-2/I and vice versa, respectively. Followed by this is the influence between the components in table 12, via majority voting of the rankings. In the drug treated CRC cells, we found members of the STAT family to be up regulated with NFkB-2/I. These are reflected with rankings of 2211 (laplace) and 2402 (rbf) for NFkBIA − > STAT2; 2121 (linear) and 1862 (rbf) for NFkBIZ − > STAT2; and 1969 (linear) and 2485 (rbf) for NFkBIE − > STAT5A, respectively. One can also interpret the results of the table 12 graphically, with the following influences - • STAT w.r.t NFkB-2/I with NFkBIA − > STAT2; NFkBIZ − > STAT2; and NFkBIE − > STAT5A;

3.1.5. IKBKE and STAT Cross Family Analysis

Ng et al. [21] show that phosphorylation of STAT1 by I κ B kinase ε (IKBKE) inhibits STAT1 homodimerization, and thus assembly of GAF, but does not disrupt ISGF3 formation. Furthermore, Guo et al. [22] show that IKBKE is induced by STAT3 and tobacco carcinogen and determines chemosensitivity in non-small cell lung cancer. It has already been established in some cases that IKBKE has a confirmed role with one of the STAT members. Here we found that both IKBKE and STAT were up regulated after ETC-1922159 treatment of CRC cells. Table 13 shows ranking of STAT family vs IKBKE and vice versa. Table 14 shows the dervied influences from majority voting of the rankings. On the left half of Table 13 we find STAT2 to be up regulated w.r.t IKBKE. This is reflected with the rankings of 2033 (linear) and 1892 (rbf) for STAT2 - IKBKE. On the right half of the same table we find IKBKE being up regulated w.r.t STAT-3/5A. These are reflected in rankings of 2179 (linear) and 1976 (rbf) for STAT3 - IKBKE; and 2085 (laplace), 2409 (linear) and 2277 (rbf) for STAT5A - IKBKE, respectively. One can also interpret the results of the Table 14 graphically, with the following influences - • STAT w.r.t IKBKE with STAT2 < − IKBKE; and • IKBKE w.r.t STAT with STAT3 − > IKBKE and STAT5A − > IKBKE;

3.1.6. IKBKE - TRAF Cross Family Analysis

Shen et al. [23] show interaction of IKBKE with TRAF2, by observing that I κ B kinase ε phosphorylates TRAF2 to promote mammary epithelial cell transformation. Zhou et al. [24] observe IKK ε -mediated tumorigenesis requires K63-linked polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex. Also, Nakanishi and Akira [25] show NF- κ B activation through IKK-i-dependent I-TRAF/TANK phosphorylation. These findings suggest interaction between IKBKE - TRAF family members. IKBKE and TRAF members were found to be up regulated in CRC cells treated with ETC-1922159. Their combinations were allocated with high numerical ranks indicating synergistic up regulation. Table 15 rankings between TRAF and IKBKE, both ways. TRAF4 was found to up regulated with IKBKE and the rankings reflect the same with 2158 (linear) and 2416 (rbf). Also IKBKE was found to be up regulated with TRAF6 and the rankings reflect the same with 2105 (laplace) and 1819 (rbf). Table 16 reflects the derived influences graphically for - • TRAF w.r.t IKBKE with TRAF6 < − IKBKE and • IKBKE w.r.t TRAF with TRAF4 − > IKBKE.

3.1.7. ABC Transporters - NF κ B Cross Family Analysis

Gerbod-Giannone et al. [26] observe that TNF α induces ABCA1 through NF- κ B in macrophages and in phagocytes ingesting apoptotic cells. ABCA1 has also been found to be a key regulator in cholesterol related problems. Van Eck et al. [27] report leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues. The macrophage cholesterol exporter ABCA1 functions as an anti-inflammatory receptor, as shown by Tang et al. [28]. Furthermore, macrophage ABCA1 reduces MyD88-dependent Toll-like receptor trafficking to lipid rafts by reduction of lipid raft cholesterol, as shown by Zhu et al. [29]. These findings suggest the intricate role of NF κ B family components play with ABC transporters. Both were up regulated in CRC cells after treatment with ETC-1922159. Our search engine allocated numerically high rank to several of the combinations in silico. These have been tabulated in Table 17 and Table 18, i.e rankings of ABC transporters w.r.t NFkB members and vice versa, respectively. Table 19 shows the un explored hypotheses between the two in the form of the derived influences after majority voting of the two-way cross family the rankings.
In table 17, we find ABC-C13/ABC-D1 to be up regulated w.r.t. NFkBIE. These are reflected in rankings of 2048 (linear) and 1735 (rbf) for ABC-C13 - NFkBIE and 2380 (laplace) and 1795 (linear) for ABC-D1 - NFkBIE, respectively. In Table 18, we find NFkB2 to be up regulated w.r.t ABC-A5/ABC-B11. These are reflected in rankings of 2097 (laplace), 1772 (linear) and 2086 (rbf) for NFkB2 - ABC-A5; and 1916 (linear) and 1955 (rbf) for NFkB2 - ABC-B11, respectively. NFkBIE was up regulated with ABC-C13 and the rankings for the same are reflected in 2318 (laplace) and 2513 (rbf). Also, NFkBIZ was up regulated with ABC-C13 and the rankings for the same are reflected in 1799 (laplace) and 2175 (linear). NFkB2 was up regulated with ABC-G1 and the rankings for the same are reflected in 1951 (laplace), 2240 (linear) and 2215 (rbf).
Finally, 19 shows derived influences which can be represented graphically, with the following influences - • ABC w.r.t NFkB-2/I family with NFkIBE − > ABC-C13/ABC-D1 and • NFkB-2/I w.r.t ABC family with NFkB2 < − ABC-A5/ABC-B11; NFkBIE < − ABC-C13; NFkBIZ < − ABC-C13 and NFkB2 < − ABC-G1;

3.1.8. IKBKE - UBA/UBE Cross Family Analysis

Not much is known about IKBKE and Ubiquitination modifier enzyme and ubiquitination conjugating enzymes interaction. They were found them to be up regulated in CRC cells after ETC-1922159 treatment. Our search engine allocated high ranks to some of the combinations between IKBKE and UBA/UBE family members. These combinations might be worth exploring if it is of interest. Tables 20 shows the rankings of UBE/A w.r.t to IKBKE and vice versa. We find IKBKE to be up regulated w.r.t UBA/E2 family. These are reflected with rankings of 2327 (laplace), 1807 (linear) and 2066 (rbf) for IKBKE - UBA-1; 2326 (linear) and 2456 (rbf) IKBKE - UBA-7; 2162 (laplace) and 1817 (linear) for IKBKE - UBA-P1; 2422 (laplace) and 2328 (rbf) for IKBKE - UBE2-A; 2367 (linear) and 2427 (rbf) for IKBKE - UBE2-B; and finally 2366 (laplace) and 1909 (rbf) for IKBKE - UBE2-Z; We also find UBA/E2 family to be up regulated w.r.t IKBKE also. This is reflected in rankings of 2189 (laplace) and 2271 (linear) for IKBKE - UBA-7; 2262 (laplace), 1901 (linear) and 2341 (rbf) for IKBKE - UBA-P1; 2293 (laplace), 2319 (linear) and 2396 (rbf) for IKBKE - UBE2-A; 2129 (laplace) and 1795 (linear) for IKBKE - UBE2-B; 2494 (laplace), 2233 (linear) and 1896 (rbf) for IKBKE - UBE2-F; 2016 (laplace) and 2103 (linear) for IKBKE - UBE2-Z;
Table 21 shows the derived influences which can be represented graphically, with the following influences - • UBA/E2 w.r.t IKBKE with IKBKE − > UBA-1; IKBKE − > UBA-7; IKBKE − > UBA-P1; and IKBKE − > UBE2-A; IKBKE − > UBE2-B; IKBKE − > UBE2-Z •; IKBKE w.r.t UBE/A2 with IKBKE < − UBA-7; IKBKE < − UBA-P1; IKBKE < − UBA-LD2; and IKBKE < − UBE2-A; IKBKE < − UBE2-B; IKBKE < − UBE2-F; IKBKE < − UBE2-Z;

3.1.9. REL-A/B - NF κ B Cross Family Analysis

REL-A is known to be associated with NF- κ B and most deeply studied member of the NF- κ B. Tian et al. [30] observe that the NFkB subunit RELA is a master transcriptional regulator of the committed epithelial-mesenchymal transition in airway epithelial cells. Ke et al. [31] observe that inactivation of NF- κ B p65 (RelA) in liver improves insulin sensitivity and inhibits cAMP/PKA pathway. Weichert et al. [32] observe that high expression of RelA/p65 is associated with activation of NF- κ B-dependent signaling in pancreatic cancer. These findings and many others not cited here show the deep interaction between REL and NF- κ B members. Table 22 shows rankings of RELA w.r.t NFkB members and vice versa. Table 23 shows rankings of RELB w.r.t NFkB members and vice versa. Finally, Table 24 shows the hypotheses generated from majority voting of the ranks. In Table 22 we find RELA to be up regulated w.r.t NFKB2. This is reflected in rankings of 2454 (laplace) and 2307 (rbf) for NFkB2 - RELA. Similarly, NFKBIA was found to be up regulated w.r.t RELA. This is reflected in rankings of 2106 (laplace) and 2305 (linear) for NFKBIA - RELA. In Table 23 we find NFkB2 to be up regulated RELB. This is reflected in 2146 (laplace) and 1788 (rbf) for NFkB2 - RELB. Similarly, we find NFKBIZ to be 1776 (laplace), 2244 (linear) and 1869 (rbf) for NFKBIZ - RELB. Table 24 shows the derived influences which can be represented graphically, with the following influences - • NFkB-2/I family w.r.t REL-B with NFkB2 < − REL-B and NFKBIZ < − RELB and • REL-A w.r.t NFkB-2/I family with NFkB2 − > RELA and NFKBIA − > RELA.

Conclusion

Presented here are a range of multiple synergistic NF κ B 2nd order combinations that were ranked via a search engine. Later, two way cross family analysis between components of these combinations were conducted. Via majority voting across the ranking methods, it was possible to find plausible unexplored synergistic combinations that might be prevalent in CRC cells after treatment with ETC-1922159 drug. The two-way cross family analysis also assists in deriving influences between components which serve as hypotheses for further tests. If found true, it paves way for biologists/oncologists to further investigate and understand the mechanism behind the synergy through wet experiments.

Author Contributions

Concept, design, in silico implementation - SS. Analysis and interpretation of results - SS. Manuscript writing - SS. Manuscript revision - SS. Approval of manuscript - SS.

Data Availability Statement

Data used in this research work was released in a publication in Madan et al. [33]. The ETC-1922159 was released in Singapore in July 2015 under the flagship of the Agency for Science, Technology and Research (A*STAR) and Duke-National University of Singapore Graduate Medical School (Duke-NUS).

Acknowledgments

Special thanks to Mrs. Rita Sinha and Mr. Prabhat Sinha for supporting the author financially, without which this work could not have been made possible.

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Table 1. 2nd order interaction ranking between CASP w.r.t RIPK family members.
Table 1. 2nd order interaction ranking between CASP w.r.t RIPK family members.
Ranking CASP family w.r.t RIPK family
Ranking of CASP4 w.r.t RIPK family Ranking of CASP5 family w.r.t RIPK
laplace linear rbf laplace linear rbf
CASP4 - RIPK1 1154 1259 147 CASP5 - RIPK1 490 152 1818
CASP4 - RIPK2 559 2147 434 CASP5 - RIPK2 1274 2485 608
CASP4 - RIPK3 111 131 41 CASP5 - RIPK3 523 1047 317
CASP4 - RIPK4 187 1048 1039 CASP5 - RIPK4 7 1176 2361 1292
Ranking of CASP7 w.r.t RIPK family Ranking of CASP9 family w.r.t RIPK
laplace linear rbf laplace linear rbf
CASP7 - RIPK1 2445 1289 1253 CASP9 - RIPK1 1726 1304 1480
CASP7 - RIPK2 1584 406 155 CASP9 - RIPK2 2079 291 1647
CASP7 - RIPK3 1406 1057 2091 CASP9 - RIPK3 2133 2030 2295
CASP7 - RIPK4 1739 231 2332 CASP9 - RIPK4 2037 1627 363
Ranking of CASP10 w.r.t RIPK family Ranking of CASP16 family w.r.t RIPK
laplace linear rbf laplace linear rbf
CASP10 - RIPK1 758 846 1405 CASP16 - RIPK1 73 1046 1887
CASP10 - RIPK2 1535 2312 884 CASP16 - RIPK2 20 932 1189
CASP10 - RIPK3 1530 250 2181 CASP16 - RIPK3 30 359 717
CASP10 - RIPK4 954 415 1547 CASP16 - RIPK4 493 2507 519
Table 2. 2nd order interaction ranking between RIPK w.r.t CASP family members.
Table 2. 2nd order interaction ranking between RIPK w.r.t CASP family members.
Ranking RIPK family w.r.t CASP family
Ranking of RIPK family w.r.t CASP4 Ranking of RIPK family w.r.t CASP5
laplace linear rbf laplace linear rbf
CASP4 - RIPK1 2363 1374 1805 CASP5 - RIPK1 7 82 131
CASP4 - RIPK2 1713 2349 1261 CASP5 - RIPK2 1577 1776 2247
CASP4 - RIPK3 1397 768 1008 CASP5 - RIPK3 574 14 30
CASP4 - RIPK4 2215 1334 1425 CASP5 - RIPK4 2448 1178 810
Ranking of RIPK family w.r.t CASP7 Ranking of RIPK family w.r.t CASP9
laplace linear rbf laplace linear rbf
CASP7 - RIPK1 1341 2005 1131 CASP9 - RIPK1 820 140 611
CASP7 - RIPK2 1287 727 1143 CASP9 - RIPK2 2000 2476 2138
CASP7 - RIPK3 579 595 775 CASP9 - RIPK3 1550 430 97
CASP7 - RIPK4 852 1586 595 CASP9 - RIPK4 1565 862 209
Ranking of RIPK family w.r.t CASP10 Ranking of RIPK family w.r.t CASP16
laplace linear rbf laplace linear rbf
CASP10 - RIPK1 2438 1915 1039 CASP16 - RIPK1 924 686 587
CASP10 - RIPK2 1526 1800 1228 CASP16 - RIPK2 1613 2006 2046
CASP10 - RIPK3 419 1481 2001 CASP16 - RIPK3 827 494 328
CASP10 - RIPK4 1303 947 785 CASP16 - RIPK4 2273 2023 1698
Table 3. 2nd order combinatorial hypotheses between CASP and RIPK.
Table 3. 2nd order combinatorial hypotheses between CASP and RIPK.
Unexplored combinatorial hypotheses
CASP w.r.t RIKP family
CASP9 RIPK3
RIPK w.r.t CASP family
RIPK1 CASP4/CASP10
RIPK2 CASP5/CASP9/CASP16
RIPK4 CASP16
Table 4. 2nd order interaction ranking between MUC w.r.t RIPK family members.
Table 4. 2nd order interaction ranking between MUC w.r.t RIPK family members.
Ranking MUC family w.r.t RIPK family
Ranking of MUC1 w.r.t RIPK family Ranking of MUCA3 w.r.t MUC3A
laplace linear rbf laplace linear rbf
MUC1 - RIPK1 2027 2249 218 MUC3A - RIPK1 945 186 1508
MUC1 - RIPK2 248 1802 389 MUC3A - RIPK2 840 2390 1653
MUC1 - RIPK3 342 410 342 MUC3A - RIPK3 2208 2017 689
MUC1 - RIPK4 176 162 853 MUC3A - RIPK4 714 1494 797
Ranking of MUC4 w.r.t RIPK family Ranking of MUC12 w.r.t RIPK family
laplace linear rbf laplace linear rbf
MUC4 - RIPK1 358 2384 690 MUC12 - RIPK1 317 2437 167
MUC4 - RIPK2 371 500 408 MUC12 - RIPK2 286 2178 76
MUC4 - RIPK3 809 371 1096 MUC12 - RIPK3 747 366 136
MUC4 - RIPK4 652 1863 1248 MUC12 - RIPK4 176 2249 2130
Ranking of MUC13 w.r.t RIPK family Ranking of MUC17 w.r.t RIPK family
laplace linear rbf laplace linear rbf
MUC13 - RIPK1 379 2241 227 MUC17 - RIPK1 858 932 1503
MUC13 - RIPK2 824 2483 227 MUC17 - RIPK2 248 934 37
MUC13 - RIPK3 1687 19 24 MUC17 - RIPK3 342 64 329
MUC13 - RIPK4 562 532 184 MUC17 - RIPK4 209 2335 1080
Ranking of MUC20 w.r.t RIPK family
laplace linear rbf
MUC20 - RIPK1 1419 760 1794
MUC20 - RIPK2 948 2482 137
MUC20 - RIPK3 2192 2288 1796
MUC20 - RIPK4 1564 1619 2179
Table 5. 2nd order interaction ranking between RIPK w.r.t MUC family members.
Table 5. 2nd order interaction ranking between RIPK w.r.t MUC family members.
Ranking RIPK family w.r.t MUC family
Ranking of RIPK family w.r.t MUC1 Ranking of RIPK family w.r.t MUC3A
laplace linear rbf laplace linear rbf
MUC1 - RIPK1 1839 58 2421 MUC3A - RIPK1 783 1668 1842
MUC1 - RIPK2 1913 2091 954 MUC3A - RIPK2 758 2301 459
MUC1 - RIPK3 1038 268 295 MUC3A - RIPK3 268 1595 1893
MUC1 - RIPK4 1385 2246 1298 MUC3A - RIPK4 1770 1109 1461
Ranking of RIPK family w.r.t MUC4 Ranking of RIPK family w.r.t MUC12
laplace linear rbf laplace linear rbf
MUC4 - RIPK1 562 1621 2216 MUC12 - RIPK1 1462 682 2351
MUC4 - RIPK2 383 924 494 MUC12 - RIPK2 989 597 1798
MUC4 - RIPK3 541 43 129 MUC12 - RIPK3 2158 1286 1636
MUC4 - RIPK4 1981 1949 2028 MUC12 - RIPK4 1577 975 976
Ranking of RIPK family w.r.t MUC13 Ranking of RIPK family w.r.t MUC17
laplace linear rbf laplace linear rbf
MUC13 - RIPK1 1961 1535 32 MUC17 - RIPK1 260 446 260
MUC13 - RIPK2 784 494 1467 MUC17 - RIPK2 1021 1114 2355
MUC13 - RIPK3 860 1514 1425 MUC17 - RIPK3 427 223 128
MUC13 - RIPK4 107 1387 1972 MUC17 - RIPK4 1567 2225 2048
Ranking of RIPK family w.r.t MUC20
laplace linear rbf
MUC20 - RIPK1 514 2042 420
MUC20 - RIPK2 1039 1751 1950
MUC20 - RIPK3 303 2504 280
MUC20 - RIPK4 794 1193 989
Table 6. 2nd order combinatorial hypotheses between MUC and RIPK.
Table 6. 2nd order combinatorial hypotheses between MUC and RIPK.
Unexplored combinatorial hypotheses
MUC w.r.t RIKP family
MUC1 RIPK1
MUC3A RIPK3
MUC12 RIPK4
MUC20 RIPK3
RIPK w.r.t MUC family
MUC1 RIPK1/RIPK2
MUC4 RIPK4
MUC17 RIPK4
MUC20 RIPK2
Table 7. 2nd order interaction ranking between TNF w.r.t NFkB-2/I family members.
Table 7. 2nd order interaction ranking between TNF w.r.t NFkB-2/I family members.
Ranking TNF family w.r.t NFkB-2/I family
Ranking of TNF family w.r.t NFkB2 Ranking of TNF family w.r.t NFkBI-A
laplace linear rbf laplace linear rbf
NFkB2 - TNF 1620 615 1897 NFkBI-A - TNF 820 1495 1109
NFkB2 - TNF-AIP1 324 649 1387 NFkBI-A - TNF-AIP1 1779 1904 1400
NFkB2 - TNF-AIP2 1437 715 1986 NFkBI-A - TNF-AIP2 1247 217 766
NFkB2 - TNF-AIP3 1272 1574 441 NFkBI-A - TNF-AIP3 776 981 212
NFkB2 - TNF-RSF1A 30 2465 575 NFkBI-A - TNF-RSF1A 1580 1422 43
NFkB2 - TNF-RSF10A 2095 817 2509 NFkBI-A - TNF-RSF10A 2499 1438 2191
NFkB2 - TNF-RSF10B 37 1411 250 NFkBI-A - TNF-RSF10B 2075 1555 1401
NFkB2 - TNF-RSF10D 2473 12 1499 NFkBI-A - TNF-RSF10D 2498 2344 2501
NFkB2 - TNF-RSF12A 1813 824 1893 NFkBI-A - TNF-RSF12A 2337 1101 1491
NFkB2 - TNF-RSF14 1799 834 302 NFkBI-A - TNF-RSF14 1974 2045 1136
NFkB2 - TNF-RSF21 332 1973 1719 NFkBI-A - TNF-RSF21 1119 951 903
NFkB2 - TNF-SF10 1627 1614 1299 NFkBI-A - TNF-SF10 2185 499 2316
NFkB2 - TNF-SF15 564 2437 1064 NFkBI-A - TNF-SF15 564 1684 1473
Ranking of TNF family w.r.t NFkBI-E Ranking of TNF family w.r.t NFkBI-Z
laplace linear rbf laplace linear rbf
NFkBI-E - TNF 2443 925 228 NFkBI-Z - TNF 851 776 850
NFkBI-E - TNF-AIP1 1720 685 971 NFkBI-Z - TNF-AIP1 153 397 621
NFkBI-E - TNF-AIP2 2347 1863 964 NFkBI-Z - TNF-AIP2 2188 432 566
NFkBI-E - TNF-AIP3 559 1663 280 NFkBI-Z - TNF-AIP3 775 10 2362
NFkBI-E - TNF-RSF1A 846 1624 176 NFkBI-Z - TNF-RSF1A 399 2006 93
NFkBI-E - TNF-RSF10A 840 359 952 NFkBI-Z - TNF-RSF10A 1380 2004 1540
NFkBI-E - TNF-RSF10B 835 2257 1294 NFkBI-Z - TNF-RSF10B 2204 1438 1991
NFkBI-E - TNF-RSF10D 2454 1018 1566 NFkBI-Z - TNF-RSF10D 2214 2033 2514
NFkBI-E - TNF-RSF12A 383 166 1464 NFkBI-Z - TNF-RSF12A 1638 2370 1841
NFkBI-E - TNF-RSF14 1877 2282 1426 NFkBI-Z - TNF-RSF14 1120 1505 1899
NFkBI-E - TNF-RSF21 2129 1293 831 NFkBI-Z - TNF-RSF21 207 804 344
NFkBI-E - TNF-SF10 890 1096 1816 NFkBI-Z - TNF-SF10 609 1088 1344
NFkBI-E - TNF-SF15 523 1957 32 NFkBI-Z - TNF-SF15 1237 1375 2196
Table 8. 2nd order interaction ranking between NFkB-2/I family w.r.t TNF family members.
Table 8. 2nd order interaction ranking between NFkB-2/I family w.r.t TNF family members.
Ranking NFkB-2/I family w.r.t TNF family
Ranking of NFkB-2/I family w.r.t TNF Ranking of NFkB-2/I family w.r.t TNF-AIP1
laplace linear rbf laplace linear rbf
NFkB-2 - TNF 1632 989 1453 NFkB-2 - TNF-AIP1 2027 1807 1140
NFkBI-A - TNF 904 561 658 NFkBI-A - TNF-AIP1 2072 349 1218
NFkBI-E - TNF 2116 1247 803 NFkBI-E - TNF-AIP1 56 420 1551
NFkBI-Z - TNF 691 51 265 NFkBI-Z - TNF-AIP1 499 1648 646
Ranking of NFkB-2/I family w.r.t TNF-AIP2 Ranking of NFkB-2/I family w.r.t TNF-AIP3
laplace linear rbf laplace linear rbf
NFkB-2 - TNF-AIP2 2077 1027 2224 NFkB-2 - TNF-AIP3 1042 2336 2130
NFkBI-A - TNF-AIP2 499 22 1192 NFkBI-A - TNF-AIP3 1452 411 637
NFkBI-E - TNF-AIP2 526 1755 338 NFkBI-E - TNF-AIP3 711 1686 2041
NFkBI-Z - TNF-AIP2 452 988 1617 NFkBI-Z - TNF-AIP3 1979 886 278
Ranking of NFkB-2/I family w.r.t TNF-RSF1A Ranking of NFkB-2/I family w.r.t TNF-RSF10A
laplace linear rbf laplace linear rbf
NFkB-2 - TNF-RSF1A 648 164 990 NFkB-2 - TNF-RSF10A 611 1007 454
NFkBI-A - TNF-RSF1A 435 1454 130 NFkBI-A - TNF-RSF10A 458 190 1412
NFkBI-E - TNF-RSF1A 431 980 1417 NFkBI-E - TNF-RSF10A 1719 263 374
NFkBI-Z - TNF-RSF1A 550 2213 1447 NFkBI-Z - TNF-RSF10A 342 742 732
Ranking of NFkB-2/I w.r.t TNF-RSF10B Ranking of NFkB-2/I w.r.t TNF-RSF10D
laplace linear rbf laplace linear rbf
NFkB-2 - TNF-RSF10B 713 1408 2397 NFkB-2 - TNF-RSF10D 123 1939 543
NFkBI-A - TNF-RSF10B 1237 1054 562 NFkBI-A - TNF-RSF10D 371 948 584
NFkBI-E - TNF-RSF10B 1352 931 2142 NFkBI-E - TNF-RSF10D 2136 621 1811
NFkBI-Z - TNF-RSF10B 165 2407 361 NFkBI-Z - TNF-RSF10D 259 400 1341
Ranking of NFkB-2/I family w.r.t TNF-RSF12A Ranking of NFkB-2/I family w.r.t TNF-RSF14
laplace linear rbf laplace linear rbf
NFkB-2 - TNF-RSF12A 250 341 1232 NFkB-2 - TNF-RSF14 299 1253 543
NFkBI-A - TNF-RSF12A 689 2225 17 NFkBI-A - TNF-RSF14 280 1126 277
NFkBI-E - TNF-RSF12A 1188 1133 765 NFkBI-E - TNF-RSF14 278 2025 1557
NFkBI-Z - TNF-RSF12A 973 1590 2298 NFkBI-Z - TNF-RSF14 131 893 1953
Ranking of NFkB-2/I family w.r.t TNF-RSF21 Ranking of NFkB-2/I family w.r.t TNF-SF10
laplace linear rbf laplace linear rbf
NFkB-2 - TNF-RSF21 250 341 1232 NFkB-2 - TNF-SF10 1643 496 743
NFkBI-A - TNF-RSF21 689 2225 17 NFkBI-A - TNF-SF10 262 1238 1352
NFkBI-E - TNF-RSF21 1188 1133 765 NFkBI-E - TNF-SF10 985 1090 158
NFkBI-Z - TNF-RSF21 973 1590 2298 NFkBI-Z - TNF-SF10 537 1557 2104
Ranking of NFkB-2/I family w.r.t TNF-SF15
laplace linear rbf
NFkB-2 - TNF-SF15 1521 786 1211
NFkBI-A - TNF-SF15 2367 325 1079
NFkBI-E - TNF-SF15 97 1868 1195
NFkBI-Z - TNF-SF15 774 407 372
Table 9. 2nd order combinatorial hypotheses between NFkB-2/I and TNF.
Table 9. 2nd order combinatorial hypotheses between NFkB-2/I and TNF.
Unexplored combinatorial hypotheses
TNF w.r.t NFkB-2/I
NFkB2 TNF-RSF10A/RSF12A
NFkBI-A TNF-AIP1/RSF10A/RSF10D/RSF14/SF10
NFkBI-E TNF-AIP2/RSF14
NFkBI-Z TNF-RSF10B/RSF10D/RSF12A
NFkB-2/I w.r.t TNF
NFkB-2 TNF-AIP1/AIP2/AIP3
NFkBI-E TNF-RSF10D
Table 10. 2nd order interaction ranking between STAT w.r.t NFkB-2/I family members.
Table 10. 2nd order interaction ranking between STAT w.r.t NFkB-2/I family members.
Ranking STAT family w.r.t NFkB-2/I family
Ranking of STAT2 w.r.t NFkB-2/I family Ranking of STAT3 w.r.t NFkB-2/I family
laplace linear rbf laplace linear rbf
NFkB2 - STAT2 2220 1068 1207 NFkB2 - STAT3 2125 252 1453
NFkBIA - STAT2 2211 1253 2402 NFkBIA - STAT3 1614 702 1333
NFkBIE - STAT2 1809 512 1207 NFkBIE - STAT3 1493 211 1850
NFkBIZ - STAT2 802 2121 1862 NFkBIZ - STAT3 1633 1679 2122
Ranking of NFkB-2/I family w.r.t STAT5A
laplace linear rbf
NFkB2 - STAT5A 2034 1321 1502
NFkBIA - STAT5A 490 2215 283
NFkBIE - STAT5A 578 1969 2485
NFkBIZ - STAT5A 2286 473 1409
Table 11. 2nd order interaction ranking between NFkB-2/I family w.r.t STAT members.
Table 11. 2nd order interaction ranking between NFkB-2/I family w.r.t STAT members.
Ranking NFkB-2/I family w.r.t STAT family
Ranking of NFkB-2/I family w.r.t STAT2 Ranking of NFkB-2/I family w.r.t STAT3
laplace linear rbf laplace linear rbf
NFkB2 - STAT2 935 952 86 NFkB2 - STAT3 858 606 162
NFkBIA - STAT2 543 36 1180 NFkBIA - STAT3 1547 88 476
NFkBIE - STAT2 1449 1861 1262 NFkBIE - STAT3 1731 1063 509
NFkBIZ - STAT2 483 1150 262 NFkBIZ - STAT3 1262 489 1145
Ranking of NFkB-2/I family w.r.t STAT3
laplace linear rbf
NFkB2 - STAT5A 558 1070 670
NFkBIA - STAT5A 1509 1020 81
NFkBIE - STAT5A 18 854 1052
NFkBIZ - STAT5A 83 1208 240
Table 12. 2nd order combinatorial hypotheses between NFkB-2/I and TNF
Table 12. 2nd order combinatorial hypotheses between NFkB-2/I and TNF
Unexplored combinatorial hypotheses
STAT w.r.t NFkB-2/I
NFkBIA STAT2
NFkBIZ STAT2
NFkBIE STAT5A
Table 13. 2nd order interaction ranking between STAT family w.r.t IKBKE.
Table 13. 2nd order interaction ranking between STAT family w.r.t IKBKE.
Ranking STAT family vs IKBKE
Ranking of STAT family w.r.t IKBKE family Ranking of IKBKE w.r.t STAT family
laplace linear rbf laplace linear rbf
STAT2 - IKBKE 1267 2033 1892 STAT2 - IKBKE 1604 554 2108
STAT3 - IKBKE 1055 2144 1672 STAT3 - IKBKE 1442 2179 1976
STAT5A - IKBKE 178 1687 1183 STAT5A - IKBKE 2085 2409 2277
Table 14. 2nd order combinatorial hypotheses between NFkB-2/I and TNF
Table 14. 2nd order combinatorial hypotheses between NFkB-2/I and TNF
Unexplored combinatorial hypotheses
STAT w.r.t IKBKE
STAT2 IKBKE
IKBKE w.r.t STAT
STAT3 IKBKE
STAT5A IKBKE
Table 15. 2nd order interaction ranking between STAT family w.r.t IKBKE.
Table 15. 2nd order interaction ranking between STAT family w.r.t IKBKE.
Ranking TRAF family vs IKBKE
Ranking of IKBKE w.r.t TRAF family Ranking of TRAF family w.r.t IKBKE
laplace linear rbf laplace linear rbf
TRAF4 - IKBKE 1235 2158 2416 TRAF4 - IKBKE 1606 461 1330
TRAF6 - IKBKE 1694 389 1554 TRAF6 - IKBKE 2105 1376 1819
TRAFD1 - IKBKE 1687 532 1793 TRAFD1 - IKBKE 866 733 496
TRAF3IP2 - IKBKE 1349 738 1987 TRAF3IP2 - IKBKE 924 1966 334
Table 16. 2nd order combinatorial hypotheses between NFkB-2/I and TNF
Table 16. 2nd order combinatorial hypotheses between NFkB-2/I and TNF
Unexplored combinatorial hypotheses
TRAF w.r.t IKBKE
TRAF6 IKBKE
IKBKE w.r.t TRAF
TRAF4 IKBKE
Table 17. 2nd order interaction ranking between ABC w.r.t NFkB-2/I family members.
Table 17. 2nd order interaction ranking between ABC w.r.t NFkB-2/I family members.
Ranking ABC family w.r.t NFkB-2/I family
Ranking of ABC family w.r.t NFkB2 Ranking of ABC family w.r.t NFkBI-A
laplace linear rbf laplace linear rbf
NFkB2 - ABC-A5 851 1517 350 ABC-A5 - NFkBIA 398 365 1660
ABC-B11 - NFkB2 1684 400 412 ABC-B11 - NFkBIA 1079 566 104
NFkB2 - ABC-C3 127 2031 6 ABC-C3 - NFkBIA 601 1048 1760
NFkB2 - ABC-C5 1035 1431 889 NFkBIA - ABC-C5 1683 2404 1341
NFkB2 - ABC-C13 1399 1951 747 NFkBIA - ABC-C13 200 886 1275
NFkB2 - ABC-D1 1317 1133 1773 ABC-D1 - NFkBIA 1361 1361 1432
NFkB2 - ABC-G1 1983 1343 1140 ABC-G1 - NFkBIA 21 313 461
NFkB2 - ABC-G2 1322 955 1292 ABC-G2 - NFkBIA 809 613 48
Ranking of ABC family w.r.t NFkBI-E Ranking of ABC family w.r.t NFkBI-Z
laplace linear rbf laplace linear rbf
ABC-A5 - NFkBIE 1445 1662 679 ABC-A5 - NFkBIZ 699 1806 1290
ABC-B11 - NFkBIE 2285 1154 54 ABC-B11 - NFkBIZ 1240 37 803
ABC-C3 - NFkBIE 1547 2168 355 ABC-C3 - NFkBIZ 468 1366 1571
NFkBIE - ABC-C5 876 2048 1735 ABC-C5 - NFkBIZ 1278 1714 1065
NFkBIE - ABC-C13 623 1992 2351 ABC-C13 - NFkBIZ 1083 1063 1386
ABC-D1 - NFkBIE 2380 1795 861 ABC-D1 - NFkBIZ 1677 1688 794
ABC-G1 - NFkBIE 2193 251 208 ABC-G1 - NFkBIZ 979 2373 590
ABC-G2 - NFkBIE 2124 383 766 ABC-G2 - NFkBIZ 86 77 845
Table 18. 2nd order interaction ranking between NFkB-2/I w.r.t ABC family members.
Table 18. 2nd order interaction ranking between NFkB-2/I w.r.t ABC family members.
Ranking NFkB-2/I family w.r.t ABC family
Ranking of NFkB-2/I family w.r.t ABC-A5 Ranking of NFkB-2/I family w.r.t ABC-B11
laplace linear rbf laplace linear rbf
ABC-A5 - NFkB2 2097 1772 2086 NFkB2 - ABC-B11 1916 1955 1020
ABC-A5 - NFkBIA 827 1142 379 NFkBIA - ABC-B11 365 1702 602
ABC-A5 - NFkBIE 1276 1749 1795 NFkBIE - ABC-B11 893 1285 1173
ABC-A5 - NFkBIZ 778 272 930 NFkBIZ - ABC-B11 683 254 421
Ranking of NFkB-2/I family w.r.t ABC-C3 Ranking of NFkB-2/I family w.r.t ABC-C5
laplace linear rbf laplace linear rbf
ABC-C3 - NFkB2 1225 936 281 NFkB2 - ABC-C5 1510 1712 939
ABC-C3 - NFkBIA 782 271 1996 NFkBIA - ABC-C5 2017 953 1649
ABC-C3 - NFkBIE 1071 1094 308 NFkBIE - ABC-C5 567 615 1600
ABC-C3 - NFkBIZ 546 653 841 ABC-C5 - NFkBIZ 1978 943 160
Ranking of NFkB-2/I family w.r.t ABC-C13 Ranking of NFkB-2/I family w.r.t TNF-ABC-D1
laplace linear rbf laplace linear rbf
NFkB2 - ABC-C13 618 1423 1550 NFkB2 - ABC-D1 2094 1655 318
NFkBIA - ABC-C13 1499 1092 456 NFkBIA - ABC-D1 613 1812 1581
NFkBIE - ABC-C13 2318 586 2513 NFkBIE - ABC-D1 806 2204 410
NFkBIZ - ABC-C13 1799 2175 1068 NFkBIZ - ABC-D1 16 1723 955
Ranking of NFkB-2/I family w.r.t ABC-G1 Ranking of NFkB-2/I family w.r.t ABC-G2
laplace linear rbf laplace linear rbf
NFkB2 - ABC-G1 1951 2240 2215 NFkB2 - ABC-G2 957 1427 788
NFkBIA - ABC-G1 1155 258 238 NFKBIA - ABC-G2 508 417 686
NFkBIE - ABC-G1 2034 612 490 NFKBIE - ABC-G2 2223 806 685
NFkBIZ - ABC-G1 1146 324 900 NFkBIZ - ABC-G2 229 221 1196
Table 19. 2nd order combinatorial hypotheses between NFkB-2/I and ABC
Table 19. 2nd order combinatorial hypotheses between NFkB-2/I and ABC
Unexplored combinatorial hypotheses
ABC w.r.t NFkB-2/I family
NFkIBE ABC-C13/ABC-D1
NFkB-2/I w.r.t ABC family
NFkB2 ABC-A5/ABC-B11
NFkBIE ABC-C13
NFkBIZ ABC-C13
NFkB2 ABC-G1
Table 20. 2nd order interaction ranking between UBA/E2 family w.r.t IKBKE.
Table 20. 2nd order interaction ranking between UBA/E2 family w.r.t IKBKE.
Ranking UBA/E2 family vs IKBKE
Ranking of UBA/E2 family w.r.t IKBKE Ranking of IKBKE w.r.t UBA/E2 family
laplace linear rbf laplace linear rbf
IKBKE - UBA-1 1752 785 966 UBA-1 - IKBKE 2327 1807 2066
IKBKE - UBA-7 2189 2271 1335 IKBKE - UBA-7 1134 2326 2456
IKBKE - UBA-P1 2262 1901 2341 IKBKE - UBA-P1 2162 1817 1407
IKBKE - UBA-LD2 2034 1773 1409 IKBKE - UBA-LD2 1381 1647 556
IKBKE - UBE2-A 2293 2319 2396 IKBKE - UBE2-A 2422 536 2328
IKBKE - UBE2-B 2129 1516 1795 IKBKE - UBE2-B 680 2367 2427
IKBKE - UBE2-F 2494 2233 1896 IKBKE - UBE2-F 2309 181 24
IKBKE - UBE2-H 1265 1666 1257 IKBKE - UBE2-H 385 710 746
IKBKE - UBE2-J1 905 1936 1046 IKBKE - UBE2-J1 903 1729 2215
IKBKE - UBE2-Z 2016 2103 481 IKBKE - UBE2-Z 783 2366 1909
Table 21. 2nd order combinatorial hypotheses between NFkB-2/I and TNF
Table 21. 2nd order combinatorial hypotheses between NFkB-2/I and TNF
Unexplored combinatorial hypotheses
UBA/E2 w.r.t IKBKE
IKBKE UBA-1/7/P1
IKBKE UBE2-A/B/Z
IKBKE w.r.t UBE/A2
IKBKE UBA-7/P1/LD2
IKBKE UBE2-A/B/F/Z
Table 22. 2nd order interaction ranking between NFkB-2/I VS REL-A family members.
Table 22. 2nd order interaction ranking between NFkB-2/I VS REL-A family members.
Ranking NFkB-2/I VS REL-A
Ranking of NFkB-2/I family w.r.t REL-A Ranking of REL-A w.r.t NFkB-2/I family
laplace linear rbf laplace linear rbf
NFkB2 - RELA 664 420 271 NFkB2 - RELA 2454 794 2307
NFKBIA - RELA 198 205 190 NFKBIA - RELA 2106 2305 1153
NFKBIE - RELA 1503 2321 331 NFKBIE - RELA 1664 456 1926
NFKBIZ - RELA 323 1714 619 NFKBIZ - RELA 1924 1687 1584
Table 23. 2nd order interaction ranking between NFkB-2/I VS REL-B family members.
Table 23. 2nd order interaction ranking between NFkB-2/I VS REL-B family members.
Ranking REL-B VS NFkB-2/I family
Ranking of NFKB-2/I w.r.t REL-B Ranking of REL-B w.r.t NFKB-2/I
laplace linear rbf laplace linear rbf
NFkB2 - RELB 503 2146 1788 NFkB2 - RELB 1156 1346 2184
NFKBIA - RELB 239 1576 924 NFKBIA - RELB 968 424 1725
NFKBIE - RELB 1203 714 2200 NFKBIE - RELB 1414 2228 800
NFKBIZ - RELB 1776 2244 1869 NFKBIZ - RELB 746 1281 1055
Table 24. 2nd order combinatorial hypotheses between NFkB-2/I and ABC
Table 24. 2nd order combinatorial hypotheses between NFkB-2/I and ABC
Unexplored combinatorial hypotheses
NFkB-2/I family w.r.t REL-B
NFkB2 RELB
NFKBIZ RELB
REL-A w.r.t NFkB-2/I family
NFkB2 RELA
NFKBIA RELA
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