The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The literature and database context retrieved here consistently refers to EPYC as epiphycan, also called dermatan sulfate proteoglycan 3 (DSPG3) / proteoglycan-Lb (PG-Lb), in the small leucine-rich proteoglycan (SLRP) family, matching the user-specified UniProt identity (Q99645) and domain family expectations (LRR-containing extracellular proteoglycan). EPYC is described as a dermatan sulfate (DS) SLRP found in epiphyseal cartilage, and it is characterized by a leucine-rich repeat architecture (reported as 7 LRRs in one review). (hayes2018biodiversityofcsproteoglycan pages 7-8, halari2021rolesoftwo pages 4-6)
SLRPs are extracellular matrix (ECM) proteoglycans characterized by a protein core containing leucine-rich repeats (LRRs) and, in many family members, covalently attached glycosaminoglycan (GAG) chains such as dermatan sulfate (DS) or chondroitin sulfate (CS). In a review focused on SLRPs, EPYC is explicitly listed as epiphycan, a DS/CS# SLRP, with chromosomal location 12q21.33*, and SLRPs are described as ECM-resident components involved in tissue structure and collagen organization/fibrillogenesis. (halari2021rolesoftwo pages 4-6)
A second authoritative review focused on CS/DS proteoglycans places epiphycan (EPYC) among DS SLRPs found in epiphyseal cartilage, and it specifies that epiphycan contains 7 LRRs (fewer than the 10–11 LRRs typical of many other SLRPs). (hayes2018biodiversityofcsproteoglycan pages 7-8)
Across the retrieved sources, EPYC is treated as a structural ECM proteoglycan rather than a catalytic enzyme/transport protein. Its repeatedly cited “primary” molecular role is in collagen fibril formation (fibrillogenesis) and cartilage matrix organization, which is consistent with SLRP family biology. (hayes2018biodiversityofcsproteoglycan pages 7-8, halari2021rolesoftwo pages 4-6, yang2024epycfunctionsas pages 1-2)
EPYC is described as an extracellular matrix (ECM) proteoglycan in SLRP reviews. (halari2021rolesoftwo pages 4-6)
More recent mechanistic work in cancer contexts treats EPYC as a secreted/soluble ECM-associated factor that can be supplied as recombinant protein (rhEPYC) and can act on other cells (e.g., endothelial cells), consistent with an extracellular role. Additionally, GO/KEGG enrichment in that laryngeal-cancer study associated EPYC-containing signatures with “extracellular matrix organization,” “extracellular region,” and “ECM-receptor interaction.” (zhou2024epycpromoteslaryngeal pages 1-5, zhou2024epycpromoteslaryngeal pages 5-8)
Evidence spanning cartilage-focused and broader ECM literature supports EPYC as part of cartilage ECM organization:
Together, these sources support a functional annotation in which EPYC/epiphycan is a secreted ECM SLRP that contributes to collagen fibrillogenesis and cartilage ECM assembly, influencing chondrogenesis/matrix maturation. (hayes2018biodiversityofcsproteoglycan pages 7-8, sorrell2018humanmesenchymalstem pages 10-14, yang2024epycfunctionsas pages 1-2)
A 2024 preprint studying growth plate resting-zone biology used Epyc as a marker in scRNAseq-based tissue annotation and reports Epyc specifically expressed in growth plate chondrocytes and absent from articular chondrocytes and perichondrial cells (in the murine tissue analyzed). This supports a strong association with growth plate/epiphyseal chondrocytes, aligning with the epiphyseal cartilage localization reported in the proteoglycan review. (otsuru2024apolipoproteineis pages 1-4, hayes2018biodiversityofcsproteoglycan pages 7-8)
Note: another experimental system (human MSC chondrogenesis) described epiphycan as “characteristic of articular cartilage,” illustrating that EPYC expression can depend on developmental stage/model and that “cartilage” can encompass distinct zones with different gene programs. (sorrell2018humanmesenchymalstem pages 10-14, otsuru2024apolipoproteineis pages 1-4)
Direct 2023–2024 mechanistic studies focused on EPYC in human cartilage biology were limited in the retrieved corpus; however, multiple 2024 studies substantially expand EPYC’s disease-context mechanistic literature, particularly in oncology, while still citing/leveraging EPYC’s ECM/collagen biology.
A 2024 Research Square preprint reports EPYC as an angiogenesis-related hub gene in laryngeal cancer and provides mechanistic evidence that EPYC promotes carcinogenesis and angiogenesis via Wnt/Axin/β-catenin and VEGFR1/VEGF axes:
These findings represent a notable 2024 expansion of EPYC biology into extracellular regulation of growth factor receptor availability and canonical Wnt signaling, albeit in a cancer microenvironment rather than cartilage. (zhou2024epycpromoteslaryngeal pages 10-13, zhou2024epycpromoteslaryngeal pages 1-5, zhou2024epycpromoteslaryngeal media e7b39943)
A peer-reviewed 2024 Scientific Reports paper proposes EPYC as a prognostic biomarker for pancreatic cancer and reports functional assays in which EPYC promotes proliferation “via PI3K-AKT signaling in vivo and in vitro.” The paper also re-states EPYC’s ECM role in regulating fibril formation through collagen/ECM interactions. (yang2024epycfunctionsas pages 1-2)
A 2024 BMC Cancer study identified EPYC among four candidate diagnostic biomarkers derived from integrative bioinformatics and validated via qRT-PCR in 55 breast cancer patients (tumor vs adjacent non-tumor). EPYC mRNA was significantly upregulated (P < 0.0001), but the reported overall survival association for EPYC was weak/non-significant (OS HR = 1.04; log-rank P = 0.72). (golestan2024unveilingpromisingbreast pages 6-8)
Multiple 2024 studies frame EPYC as a candidate diagnostic/prognostic biomarker in distinct cancers (breast, pancreatic, laryngeal). These implementations are currently best characterized as transcript-level biomarkers and hypothesis-generating functional targets, rather than established clinical biomarkers:
In 2024, EPYC/Epyc is used as a marker gene to distinguish growth plate chondrocytes from other cartilage-associated cell types in scRNAseq-based analyses. This is a practical implementation in developmental skeletal biology and spatial annotation workflows. (otsuru2024apolipoproteineis pages 1-4)
Review literature describing EPYC as a DS SLRP localized to epiphyseal cartilage and emphasizing SLRP roles in ECM organization/collagen fibrillogenesis supports a conservative “primary function” annotation: EPYC is likely a structural organizer/modulator of collagen fibrils and cartilage ECM assembly rather than a signaling ligand in the classical sense. (hayes2018biodiversityofcsproteoglycan pages 7-8, halari2021rolesoftwo pages 4-6)
The 2024 laryngeal cancer study suggests EPYC can directly modulate receptor stability (VEGFR1) and Wnt signaling. A plausible integrative interpretation—consistent with known proteoglycan biology—is that an ECM proteoglycan can act as a context-dependent extracellular regulator by binding proteins at the cell surface or in the pericellular milieu, thereby influencing signaling gradients and receptor availability. However, these cancer-context mechanisms should be treated as disease-context expansions of function, not necessarily EPYC’s evolutionarily primary role (which the cartilage-focused and SLRP-focused sources point toward). (hayes2018biodiversityofcsproteoglycan pages 7-8, zhou2024epycpromoteslaryngeal pages 10-13, zhou2024epycpromoteslaryngeal pages 1-5)
Key quantitative values explicitly extractable from 2024 literature in the retrieved corpus include:
Open Targets disease–target association results linked EPYC to several phenotypes/diseases including osteoarthritis, abnormality of the skeletal system, and hip dysplasia (Beukes type) (among others), indicating that human-genetics and curated evidence streams consider EPYC relevant to skeletal/cartilage phenotypes (though the evidence details were not expanded in the retrieved context). (OpenTargets Search: -EPYC)
Cropped figure panels retrieved from the 2024 laryngeal-cancer study show (i) EPYC-associated survival and (ii) mechanistic experiments implicating Axin/β-catenin regulation and VEGFR1 binding/degradation as the basis of pro-angiogenic effects, supporting the textual mechanism summary. (zhou2024epycpromoteslaryngeal media e7b39943, zhou2024epycpromoteslaryngeal media 717e387a, zhou2024epycpromoteslaryngeal media f7ef9b71, zhou2024epycpromoteslaryngeal media c240e33d)
EPYC (epiphycan; UniProt Q99645) is best annotated as a secreted extracellular matrix small leucine-rich proteoglycan (DS/CS SLRP) with LRR architecture (reported 7 LRRs in one review), localized to cartilage (including epiphyseal/growth plate cartilage) and implicated in collagen fibrillogenesis and cartilage matrix maturation. Recent 2024 literature extends EPYC’s known biology into cancer microenvironment signaling, including regulation of PI3K–AKT (pancreatic cancer) and Wnt/Axin/β-catenin plus VEGFR1/VEGF-linked angiogenesis (laryngeal cancer), supporting a model in which an ECM proteoglycan can modulate cell signaling in a context-dependent fashion. (hayes2018biodiversityofcsproteoglycan pages 7-8, yang2024epycfunctionsas pages 1-2, zhou2024epycpromoteslaryngeal pages 10-13, otsuru2024apolipoproteineis pages 1-4)
| Aspect | Summary | Key sources with publication date and URL |
|---|---|---|
| Identity/Family | EPYC encodes epiphycan (human UniProt Q99645), a small leucine-rich proteoglycan (SLRP) carrying dermatan sulfate and/or chondroitin sulfate (DS/CS) chains; reviewed as an ECM proteoglycan at 12q21.33. Open Targets also maps the approved symbol EPYC to disease associations including osteoarthritis and skeletal-system abnormalities, supporting correct human gene identity. (hayes2018biodiversityofcsproteoglycan pages 7-8, halari2021rolesoftwo pages 4-6, OpenTargets Search: -EPYC) | Hayes et al., 2018 — https://doi.org/10.1042/bcj20170820; Halari et al., 2021 — https://doi.org/10.3390/ijms221910584; Open Targets context (OpenTargets Search: -EPYC) |
| Domains/structure | EPYC is an SLRP with leucine-rich repeats (LRRs); the cited review notes epiphycan contains 7 LRRs, fewer than the 10–11 LRRs typical of many other SLRPs. SLRPs share a core LRR-rich protein architecture with extracellular matrix structural roles. (hayes2018biodiversityofcsproteoglycan pages 7-8, halari2021rolesoftwo pages 4-6) | Hayes et al., 2018 — https://doi.org/10.1042/bcj20170820; Halari et al., 2021 — https://doi.org/10.3390/ijms221910584 |
| Localization | Evidence supports EPYC as a secreted/extracellular matrix proteoglycan. Reviews place SLRPs in the ECM, and 2024 laryngeal-cancer work explicitly treats EPYC as a soluble/secreted ECM-associated SLRP acting on endothelial/tumor microenvironment signaling; GO/KEGG enrichment linked EPYC-containing signatures to extracellular matrix organization, extracellular region, and ECM-receptor interaction. (halari2021rolesoftwo pages 4-6, zhou2024epycpromoteslaryngeal pages 1-5, zhou2024epycpromoteslaryngeal pages 5-8) | Halari et al., 2021 — https://doi.org/10.3390/ijms221910584; Zhou et al., 2024 — https://doi.org/10.21203/rs.3.rs-4182627/v1 |
| Core biological role | Current evidence supports a primary structural ECM role in cartilage, especially collagen fibrillogenesis / fibril formation and cartilage matrix maturation. Reviews identify EPYC as a cartilage SLRP; chondrogenic human MSC cultures show EPYC appearing during matrix maturation and being characteristic of a more mature articular-cartilage-like matrix. A 2024 pancreatic-cancer study reiterates that EPYC regulates fibril formation by interacting with collagen fibrils and other ECM proteins. (hayes2018biodiversityofcsproteoglycan pages 7-8, sorrell2018humanmesenchymalstem pages 10-14, yang2024epycfunctionsas pages 1-2) | Hayes et al., 2018 — https://doi.org/10.1042/bcj20170820; Sorrell et al., 2018 — https://doi.org/10.1002/jor.23820; Yang et al., 2024 — https://doi.org/10.1038/s41598-024-51478-w |
| Key tissues/cell types | EPYC is reported in epiphyseal/growth plate cartilage and cartilage-forming cells. Review evidence places epiphycan in epiphyseal cartilage; human MSC chondrogenesis links EPYC to articular-cartilage-type matrix maturation; mouse work found Epyc specifically expressed in growth plate chondrocytes and absent from articular chondrocytes/perichondrial cells in that model; separate cartilage transcriptomics showed strong downregulation in articular cartilage under disease-model conditions. (hayes2018biodiversityofcsproteoglycan pages 7-8, sorrell2018humanmesenchymalstem pages 10-14, otsuru2024apolipoproteineis pages 1-4, westermann2020imbalancedcellularmetabolism pages 9-11) | Hayes et al., 2018 — https://doi.org/10.1042/bcj20170820; Sorrell et al., 2018 — https://doi.org/10.1002/jor.23820; Otsuru et al., 2024 — https://doi.org/10.21203/rs.3.rs-4656728/v1; Westermann et al., 2020 — https://doi.org/10.1242/dmm.046425 |
| Pathways/signaling links | Native/cartilage biology evidence mainly supports ECM assembly roles rather than enzymatic catalysis. In 2024 cancer studies, EPYC was linked to PI3K-AKT signaling in pancreatic cancer and to Wnt/Axin/β-catenin plus VEGFR1/VEGF signaling in laryngeal cancer. The laryngeal study further reported direct EPYC–VEGFR1 binding and VEGFR1 degradation, consistent with extracellular signaling modulation by a secreted matrix proteoglycan. (yang2024epycfunctionsas pages 1-2, zhou2024epycpromoteslaryngeal pages 10-13, zhou2024epycpromoteslaryngeal pages 1-5, zhou2024epycpromoteslaryngeal media e7b39943) | Yang et al., 2024 — https://doi.org/10.1038/s41598-024-51478-w; Zhou et al., 2024 — https://doi.org/10.21203/rs.3.rs-4182627/v1 |
| Disease/biomarker evidence (2023-2024) | Recent studies propose EPYC as a biomarker/functional contributor in several diseases: pancreatic cancer prognostic biomarker with functional proliferation effects; laryngeal cancer angiogenesis/carcinogenesis promoter; breast cancer diagnostic biomarker candidate; Open Targets lists associations with osteoarthritis, abnormality of the skeletal system, and hip dysplasia, Beukes type. These disease links are promising but context-dependent and do not supersede EPYC’s likely core ECM/cartilage function. (yang2024epycfunctionsas pages 1-2, zhou2024epycpromoteslaryngeal pages 1-5, golestan2024unveilingpromisingbreast pages 6-8, OpenTargets Search: -EPYC) | Yang et al., 2024 — https://doi.org/10.1038/s41598-024-51478-w; Zhou et al., 2024 — https://doi.org/10.21203/rs.3.rs-4182627/v1; Golestan et al., 2024 — https://doi.org/10.1186/s12885-024-11913-7; Open Targets context (OpenTargets Search: -EPYC) |
| Quantitative stats (2024) | Reported 2024 quantitative findings include: breast cancer qRT-PCR in 55 paired samples showed EPYC upregulation (P < 0.0001), but overall-survival association was weak/non-significant (HR 1.04, log-rank P = 0.72). Pancreatic-cancer prognostic modeling reported c-index 0.72 (training) and 0.70 (test) in a model retaining EPYC. Laryngeal-cancer work reported EPYC coefficient = 0.25 in its risk score and EPYC–VEGFR1 binding KD ~44.1 µM. In cartilage disease-model tissue, Epyc log2 ratio ~ -4 in hip articular cartilage was reported. (golestan2024unveilingpromisingbreast pages 6-8, yang2024epycfunctionsas pages 8-11, zhou2024epycpromoteslaryngeal pages 5-8, zhou2024epycpromoteslaryngeal pages 10-13, westermann2020imbalancedcellularmetabolism pages 9-11) | Golestan et al., 2024 — https://doi.org/10.1186/s12885-024-11913-7; Yang et al., 2024 — https://doi.org/10.1038/s41598-024-51478-w; Zhou et al., 2024 — https://doi.org/10.21203/rs.3.rs-4182627/v1; Westermann et al., 2020 — https://doi.org/10.1242/dmm.046425 |
Table: This table summarizes the verified identity, structure, localization, biological role, tissue expression, signaling links, and recent disease evidence for human EPYC (epiphycan). It is useful as a compact evidence map for functional annotation grounded in the cited contexts only.
References
(hayes2018biodiversityofcsproteoglycan pages 7-8): Anthony Hayes, Kazuyuki Sugahara, Brooke Farrugia, John M. Whitelock, Bruce Caterson, and James Melrose. Biodiversity of cs-proteoglycan sulphation motifs: chemical messenger recognition modules with roles in information transfer, control of cellular behaviour and tissue morphogenesis. The Biochemical journal, 475 3:587-620, Feb 2018. URL: https://doi.org/10.1042/bcj20170820, doi:10.1042/bcj20170820. This article has 63 citations.
(halari2021rolesoftwo pages 4-6): Chidambra D. Halari, Michael Zheng, and Peeyush K. Lala. Roles of two small leucine-rich proteoglycans decorin and biglycan in pregnancy and pregnancy-associated diseases. International Journal of Molecular Sciences, 22:10584, Sep 2021. URL: https://doi.org/10.3390/ijms221910584, doi:10.3390/ijms221910584. This article has 35 citations.
(yang2024epycfunctionsas pages 1-2): Zhen Yang, Honglin Li, Jie Hao, Hanwei Mei, Minghan Qiu, Huaqing Wang, and Ming Gao. Epyc functions as a novel prognostic biomarker for pancreatic cancer. Scientific Reports, Jan 2024. URL: https://doi.org/10.1038/s41598-024-51478-w, doi:10.1038/s41598-024-51478-w. This article has 15 citations and is from a peer-reviewed journal.
(zhou2024epycpromoteslaryngeal pages 1-5): Dongmei Zhou, Fan Liu, Xiaoqi Li, and Fei Lv. Epyc promotes laryngeal cancer carcinogenesis and angiogenesis via thewnt-axin-β-catenin/vegfr1 pathway. Unknown journal, Apr 2024. URL: https://doi.org/10.21203/rs.3.rs-4182627/v1, doi:10.21203/rs.3.rs-4182627/v1.
(zhou2024epycpromoteslaryngeal pages 5-8): Dongmei Zhou, Fan Liu, Xiaoqi Li, and Fei Lv. Epyc promotes laryngeal cancer carcinogenesis and angiogenesis via thewnt-axin-β-catenin/vegfr1 pathway. Unknown journal, Apr 2024. URL: https://doi.org/10.21203/rs.3.rs-4182627/v1, doi:10.21203/rs.3.rs-4182627/v1.
(sorrell2018humanmesenchymalstem pages 10-14): J. Michael Sorrell, Rodrigo A. Somoza, and Arnold I. Caplan. Human mesenchymal stem cells induced to differentiate as chondrocytes follow a biphasic pattern of extracellular matrix production. Journal of Orthopaedic Research®, 36:1757-1766, Jun 2018. URL: https://doi.org/10.1002/jor.23820, doi:10.1002/jor.23820. This article has 25 citations.
(otsuru2024apolipoproteineis pages 1-4): Satoru Otsuru, Joe Kodama, Takeshi Oichi, Kevin Wilkinson, Joshua Abzug, Takashi Kaito, Motomi Iwamoto-Enomoto, and Masahiro Iwamoto. Apolipoprotein e is a novel marker for chondrocytes in the growth plate resting zone. Research Square, Aug 2024. URL: https://doi.org/10.21203/rs.3.rs-4656728/v1, doi:10.21203/rs.3.rs-4656728/v1. This article has 1 citations.
(zhou2024epycpromoteslaryngeal pages 10-13): Dongmei Zhou, Fan Liu, Xiaoqi Li, and Fei Lv. Epyc promotes laryngeal cancer carcinogenesis and angiogenesis via thewnt-axin-β-catenin/vegfr1 pathway. Unknown journal, Apr 2024. URL: https://doi.org/10.21203/rs.3.rs-4182627/v1, doi:10.21203/rs.3.rs-4182627/v1.
(zhou2024epycpromoteslaryngeal media e7b39943): Dongmei Zhou, Fan Liu, Xiaoqi Li, and Fei Lv. Epyc promotes laryngeal cancer carcinogenesis and angiogenesis via thewnt-axin-β-catenin/vegfr1 pathway. Unknown journal, Apr 2024. URL: https://doi.org/10.21203/rs.3.rs-4182627/v1, doi:10.21203/rs.3.rs-4182627/v1.
(zhou2024epycpromoteslaryngeal media 717e387a): Dongmei Zhou, Fan Liu, Xiaoqi Li, and Fei Lv. Epyc promotes laryngeal cancer carcinogenesis and angiogenesis via thewnt-axin-β-catenin/vegfr1 pathway. Unknown journal, Apr 2024. URL: https://doi.org/10.21203/rs.3.rs-4182627/v1, doi:10.21203/rs.3.rs-4182627/v1.
(golestan2024unveilingpromisingbreast pages 6-8): Ali Golestan, Ahmad Tahmasebi, Nafiseh Maghsoodi, Seyed Nooreddin Faraji, Cambyz Irajie, and Amin Ramezani. Unveiling promising breast cancer biomarkers: an integrative approach combining bioinformatics analysis and experimental verification. BMC Cancer, Jan 2024. URL: https://doi.org/10.1186/s12885-024-11913-7, doi:10.1186/s12885-024-11913-7. This article has 37 citations and is from a peer-reviewed journal.
(yang2024epycfunctionsas pages 8-11): Zhen Yang, Honglin Li, Jie Hao, Hanwei Mei, Minghan Qiu, Huaqing Wang, and Ming Gao. Epyc functions as a novel prognostic biomarker for pancreatic cancer. Scientific Reports, Jan 2024. URL: https://doi.org/10.1038/s41598-024-51478-w, doi:10.1038/s41598-024-51478-w. This article has 15 citations and is from a peer-reviewed journal.
(westermann2020imbalancedcellularmetabolism pages 9-11): Lena Marie Westermann, Lutz Fleischhauer, Jonas Vogel, Zsuzsa Jenei-Lanzl, Nataniel Floriano Ludwig, Lynn Schau, Fabio Morellini, Anke Baranowsky, Timur A. Yorgan, Giorgia Di Lorenzo, Michaela Schweizer, Bruna de Souza Pinheiro, Nicole Ruas Guarany, Fernanda Sperb-Ludwig, Fernanda Visioli, Thiago Oliveira Silva, Jamie Soul, Gretl Hendrickx, J. Simon Wiegert, Ida V. D. Schwartz, Hauke Clausen-Schaumann, Frank Zaucke, Thorsten Schinke, Sandra Pohl, and Tatyana Danyukova. Imbalanced cellular metabolism compromises cartilage homeostasis and joint function in a mouse model of mucolipidosis type iii gamma. Disease Models & Mechanisms, Nov 2020. URL: https://doi.org/10.1242/dmm.046425, doi:10.1242/dmm.046425. This article has 10 citations and is from a domain leading peer-reviewed journal.
(OpenTargets Search: -EPYC): Open Targets Query (-EPYC, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(zhou2024epycpromoteslaryngeal media f7ef9b71): Dongmei Zhou, Fan Liu, Xiaoqi Li, and Fei Lv. Epyc promotes laryngeal cancer carcinogenesis and angiogenesis via thewnt-axin-β-catenin/vegfr1 pathway. Unknown journal, Apr 2024. URL: https://doi.org/10.21203/rs.3.rs-4182627/v1, doi:10.21203/rs.3.rs-4182627/v1.
(zhou2024epycpromoteslaryngeal media c240e33d): Dongmei Zhou, Fan Liu, Xiaoqi Li, and Fei Lv. Epyc promotes laryngeal cancer carcinogenesis and angiogenesis via thewnt-axin-β-catenin/vegfr1 pathway. Unknown journal, Apr 2024. URL: https://doi.org/10.21203/rs.3.rs-4182627/v1, doi:10.21203/rs.3.rs-4182627/v1.