Exploring ChatGPT: Drafting tests

[jvwong]

Hypothesis

A reasonably detailed prompt provided to ChatGPT can enable it to generate a "reasonably" accurate pathway draft from article text.

Methods

Chat GPT

Accessed ChatGPT over the period of June 2 - June 5, 2023.

Prompt

The input text was adapted from that provided by John G. It was modified slightly to correct errors in the Input/Output example JSON, and detail the entity types used in Biofactoid:

You are a helpful biomedical knowledge assistant. Given a full scientific article, extract any novel biological pathways supported by the article. A biological pathway is a series of actions among molecules in a cell that leads to a certain product or a change in the cell. It can trigger the assembly of new molecules, such as a fat or protein, turn genes on and off, or spur a cell to move.

Instructions: Provide your response as minified JSON following the example(s). IMPORTANT: (1) ONLY extract pathways reported as newly discovered. DO NOT include pathways mentioned as previously known (2) ONLY include entities that are directly involved in the pathways that you extract. (3) DO NOT duplicate any entities or relations in your response. (4) Entity types must be one of: "gene or gene product", "dna", "rna" "protein", "complex" or "chemical". Relation types must be one of: "binding", "post-translational modification", "phosphorylation", "dephosphorylation", "methylation", "demethylation", "ubiquitination", "deubiquitination", "transcription-translation" or "other". (5) Provide evidence for each relation by including the sentence from the input that supports it (if possible). (6) Include the name of the organism for each entity, if mentioned in the text.

Example:

Input: SMAD4, a key regulator of transforming growth factor-β (TGF-β) signaling, plays a major role in cell growth, migration, and apoptosis. In particular, TGF-β/SMAD induces growth arrest, and SMAD4 induces the expression of target genes such as p21WAF1 and p15INK4b through its interaction with several cofactors. Thus, inactivating mutations or the homozygous deletion of SMAD4 could be related to tumorigenesis or malignancy progression. However, in some cancer types, SMAD4 is neither mutated nor deleted. In the current study, we demonstrate that TGF-β signaling with a preserved SMAD4 function can contribute to cancer through associations with negative pathway regulators. We found that nuclear respiratory factor-1 (NRF1) is a novel interaction SMAD4 partner that inhibits TGF-β/SMAD4-induced p15INK4b mRNA expression by binding to SMAD4. Furthermore, we confirmed that NRF1 directly binds to the core region of the SMAD4 promoter, thereby decreasing SMAD4 mRNA expression. On the whole, our data suggest that NRF1 is a negative regulator of SMAD4 and can interfere with TGF-β/SMAD-induced tumor suppression. Our findings provide a novel perception into the molecular basis of TGF-β/SMAD4-signaling suppression in tumorigenesis.
Output: {"entities":[{"id":0,"name":"SMAD4","type":"protein","organism":null},{"id":1,"name":"NRF1","type":"protein","organism":null},{"id":2,"name":"p15INK4b","type":"mRNA","organism":null}],"relations":[{"type":"binding","entities":[{"id":0},{"id":1}],"evidence":"we confirmed that NRF1 directly binds to the core region of the SMAD4 promoter"},{"type":"transcription-translation","entities":[{"id":0},{"id":1}],"evidence":"Furthermore, we confirmed that NRF1 directly binds to the core region of the SMAD4 promoter, thereby decreasing SMAD4 mRNA expression."},{"type":"transcription-translation","entities":[{"id":2},{"id":1}],"evidence":"We found that nuclear respiratory factor-1 (NRF1) [...] inhibits TGF-β/SMAD4-induced p15INK4b mRNA expression"}]}

Input: <paste article text here>

Inputs

Originally thought to include a draft a part of an email campaign to authors to promote the inclusion of Biofactoid @elife. Randomly selected 6 eLife articles from 18 published between August 2022 - May 2023 identified by the classifier pipeline (scans Daily PubMed updates).

Input consists of the title appended to the abstract.

Evaluation

For each paper, I read the title and abstract only. I drew out an 'expected' pathway, using only the information in the text. That is, I didn't include my personal background knowledge with respect to the presence of nodes or edges.

The scoring is qualitative, with comments tagged to the relevant entities. I assigned a pass (check) / fail (X) based on whether I would feel confident showing that draft to an author, e.g. whether it was more benefit than cost.

Results

(1) Liu et al. Hypoxia-induced proteasomal degradation of DBC1 by SIAH2 in breast cancer progression. eLife. August 1, 2022. https://doi.org/10.7554/eLife.81247

Input:
Hypoxia-induced proteasomal degradation of DBC1 by SIAH2 in breast cancer progression. DBC1 has been characterized as a key regulator of physiological and pathophysiological activities, such as DNA damage, senescence, and tumorigenesis. However, the mechanism by which the functional stability of DBC1 is regulated has yet to be elucidated. Here, we report that the ubiquitination-mediated degradation of DBC1 is regulated by the E3 ubiquitin ligase SIAH2 and deubiquitinase OTUD5 under hypoxic stress. Mechanistically, hypoxia promoted DBC1 to interact with SIAH2 but not OTUD5, resulting in the ubiquitination and subsequent degradation of DBC1 through the ubiquitin–proteasome pathway. SIAH2 knockout inhibited tumor cell proliferation and migration, which could be rescued by double knockout of SIAH2/CCAR2. Human tissue microarray analysis further revealed that the SIAH2/DBC1 axis was responsible for tumor progression under hypoxic stress. These findings define a key role of the hypoxia-mediated SIAH2-DBC1 pathway in the progression of human breast cancer and provide novel insights into the metastatic mechanism of breast cancer.
Output: {"entities":[{"id":0,"name":"DBC1","type":"protein","organism":null},{"id":1,"name":"SIAH2","type":"protein","organism":null},{"id":2,"name":"OTUD5","type":"protein","organism":null},{"id":3,"name":"CCAR2","type":"protein","organism":null}],"relations":[{"type":"binding","entities":[{"id":0},{"id":1}],"evidence":"hypoxia promoted DBC1 to interact with SIAH2"},{"type":"binding","entities":[{"id":0},{"id":2}],"evidence":"the ubiquitination-mediated degradation of DBC1 is regulated by the E3 ubiquitin ligase SIAH2 and deubiquitinase OTUD5"},{"type":"binding","entities":[{"id":1},{"id":3}],"evidence":"SIAH2 knockout inhibited tumor cell proliferation and migration, which could be rescued by double knockout of SIAH2/CCAR2"}]}

---

(2) Yuan et al. trim-21 promotes proteasomal degradation of CED-1 for apoptotic cell clearance in C. elegans. eLife. August 5, 2022. https://doi.org/10.7554/eLife.76436

Input:
trim-21 promotes proteasomal degradation of CED-1 for apoptotic cell clearance in C. elegans. The phagocytic receptor CED-1 mediates apoptotic cell recognition by phagocytic cells, enabling cell corpse clearance in Caenorhabditis elegans. Whether appropriate levels of CED-1 are maintained for executing the engulfment function remains unknown. Here, we identified the C. elegans E3 ubiquitin ligase tripartite motif containing-21 (TRIM-21) as a component of the CED-1 pathway for apoptotic cell clearance. When the NPXY motif of CED-1 was bound to the adaptor protein CED-6 or the YXXL motif of CED-1 was phosphorylated by tyrosine kinase SRC-1 and subsequently bound to the adaptor protein NCK-1 containing the SH2 domain, TRIM-21 functioned in conjunction with UBC-21 to catalyze K48-linked poly-ubiquitination on CED-1, targeting it for proteasomal degradation. In the absence of TRIM-21, CED-1 accumulated post-translationally and drove cell corpse degradation defects, as evidenced by direct binding to VHA-10. These findings reveal a unique mechanism for the maintenance of appropriate levels of CED-1 to regulate apoptotic cell clearance.
Output:
{"entities":[{"id":0,"name":"trim-21","type":"protein","organism":"C. elegans"},{"id":1,"name":"CED-1","type":"protein","organism":"C. elegans"},{"id":2,"name":"CED-6","type":"protein","organism":"C. elegans"},{"id":3,"name":"SRC-1","type":"protein","organism":"C. elegans"},{"id":4,"name":"NCK-1","type":"protein","organism":"C. elegans"},{"id":5,"name":"UBC-21","type":"protein","organism":"C. elegans"},{"id":6,"name":"VHA-10","type":"protein","organism":"C. elegans"}],"relations":[{"type":"binding","entities":[{"id":1},{"id":2}],"evidence":"When the NPXY motif of CED-1 was bound to the adaptor protein CED-6"},{"type":"phosphorylation","entities":[{"id":1},{"id":3}],"evidence":"the YXXL motif of CED-1 was phosphorylated by tyrosine kinase SRC-1"},{"type":"binding","entities":[{"id":1},{"id":4}],"evidence":"subsequently bound to the adaptor protein NCK-1 containing the SH2 domain"},{"type":"binding","entities":[{"id":0},{"id":5}],"evidence":"TRIM-21 functioned in conjunction with UBC-21"},{"type":"ubiquitination","entities":[{"id":1},{"id":0}],"evidence":"catalyze K48-linked poly-ubiquitination on CED-1"},{"type":"binding","entities":[{"id":1},{"id":6}],"evidence":"direct binding to VHA-10"}]}

---

(3) Wang et al. Tumor elimination by clustered microRNAs miR-306 and miR-79 via noncanonical activation of JNK signaling eLife. October 12, 2022. https://doi.org/10.7554/eLife.77340

Input: Tumor elimination by clustered microRNAs miR-306 and miR-79 via noncanonical activation of JNK signaling. JNK signaling plays a critical role in both tumor promotion and tumor suppression. Here, we identified clustered microRNAs (miRNAs) miR-306 and miR-79 as novel tumor-suppressor miRNAs that specifically eliminate JNK-activated tumors in Drosophila. While showing only a slight effect on normal tissue growth, miR-306 and miR-79 strongly suppressed growth of multiple tumor models, including malignant tumors caused by Ras activation and cell polarity defects. Mechanistically, these miRNAs commonly target the mRNA of an E3 ubiquitin ligase ring finger protein 146 (RNF146). We found that RNF146 promotes degradation of tankyrase (Tnks), an ADP-ribose polymerase that promotes JNK activation in a noncanonical manner. Thus, downregulation of RNF146 by miR-306 and miR-79 leads to hyper-enhancement of JNK activation. Our data show that, while JNK activity is essential for tumor growth, elevation of miR-306 or miR-79 overactivate JNK signaling to the lethal level via noncanonical JNK pathway and thus eliminate tumors, providing a new miRNA-based strategy against cancer.
Output: {"entities":[{"id":0,"name":"miR-306","type":"rna","organism":"Drosophila"},{"id":1,"name":"miR-79","type":"rna","organism":"Drosophila"},{"id":2,"name":"JNK","type":"protein","organism":"Drosophila"},{"id":3,"name":"RNF146","type":"protein","organism":"Drosophila"},{"id":4,"name":"tankyrase (Tnks)","type":"protein","organism":"Drosophila"}],"relations":[{"type":"other","entities":[{"id":0},{"id":2}],"evidence":"miR-306 and miR-79 strongly suppressed growth of multiple tumor models, including malignant tumors caused by Ras activation and cell polarity defects"},{"type":"binding","entities":[{"id":0},{"id":3}],"evidence":"these miRNAs commonly target the mRNA of an E3 ubiquitin ligase ring finger protein 146 (RNF146)"},{"type":"deubiquitination","entities":[{"id":3},{"id":4}],"evidence":"RNF146 promotes degradation of tankyrase (Tnks)"},{"type":"other","entities":[{"id":3},{"id":2}],"evidence":"RNF146 promotes degradation of tankyrase (Tnks), an ADP-ribose polymerase that promotes JNK activation in a noncanonical manner"}]}

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(4) Caligaris et al. Snf1/AMPK fine-tunes TORC1 signaling in response to glucose starvation. eLife. February 7, 2022. https://doi.org/10.7554/eLife.84319

Input: Snf1/AMPK fine-tunes TORC1 signaling in response to glucose starvation. The AMP-activated protein kinase (AMPK) and the target of rapamycin complex 1 (TORC1) are central kinase modules of two opposing signaling pathways that control eukaryotic cell growth and metabolism in response to the availability of energy and nutrients. Accordingly, energy depletion activates AMPK to inhibit growth, while nutrients and high energy levels activate TORC1 to promote growth. Both in mammals and lower eukaryotes such as yeast, the AMPK and TORC1 pathways are wired to each other at different levels, which ensures homeostatic control of growth and metabolism. In this context, a previous study (Hughes Hallett et al., 2015) reported that AMPK in yeast, that is Snf1, prevents the transient TORC1 reactivation during the early phase following acute glucose starvation, but the underlying mechanism has remained elusive. Using a combination of unbiased mass spectrometry (MS)-based phosphoproteomics, genetic, biochemical, and physiological experiments, we show here that Snf1 temporally maintains TORC1 inactive in glucose-starved cells primarily through the TORC1-regulatory protein Pib2. Our data, therefore, extend the function of Pib2 to a hub that integrates both glucose and, as reported earlier, glutamine signals to control TORC1. We further demonstrate that Snf1 phosphorylates the TORC1 effector kinase Sch9 within its N-terminal region and thereby antagonizes the phosphorylation of a C-terminal TORC1-target residue within Sch9 itself that is critical for its activity. The consequences of Snf1-mediated phosphorylation of Pib2 and Sch9 are physiologically additive and sufficient to explain the role of Snf1 in short-term inhibition of TORC1 in acutely glucose-starved cells.
Output: 
{"entities":[{"id":0,"name":"Snf1","type":"protein","organism":"yeast"},{"id":1,"name":"AMPK","type":"protein","organism":null},{"id":2,"name":"TORC1","type":"protein","organism":null},{"id":3,"name":"Pib2","type":"protein","organism":"yeast"},{"id":4,"name":"Sch9","type":"protein","organism":"yeast"}],"relations":[{"type":"phosphorylation","entities":[{"id":0},{"id":2}],"evidence":"we show here that Snf1 temporally maintains TORC1 inactive in glucose-starved cells primarily through the TORC1-regulatory protein Pib2"},{"type":"phosphorylation","entities":[{"id":0},{"id":4}],"evidence":"We further demonstrate that Snf1 phosphorylates the TORC1 effector kinase Sch9 within its N-terminal region"}]}

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(5) Zhang et al. PIMT is a novel and potent suppressor of endothelial activation. eLife. April 18, 2022. https://doi.org/10.7554/eLife.85754

Input: PIMT is a novel and potent suppressor of endothelial activation. Proinflammatory agonists provoke the expression of cell surface adhesion molecules on endothelium in order to facilitate leukocyte infiltration into tissues. Rigorous control over this process is important to prevent unwanted inflammation and organ damage. Protein L-isoaspartyl O-methyltransferase (PIMT) converts isoaspartyl residues to conventional methylated forms in cells undergoing stress-induced protein damage. The purpose of this study was to determine the role of PIMT in vascular homeostasis. PIMT is abundantly expressed in mouse lung endothelium and PIMT deficiency in mice exacerbated pulmonary inflammation and vascular leakage to LPS(lipopolysaccharide). Furthermore, we found that PIMT inhibited LPS-induced toll-like receptor signaling through its interaction with TNF receptor-associated factor 6 (TRAF6) and its ability to methylate asparagine residues in the coiled-coil domain. This interaction was found to inhibit TRAF6 oligomerization and autoubiquitination, which prevented NF-κB transactivation and subsequent expression of endothelial adhesion molecules. Separately, PIMT also suppressed ICAM-1 expression by inhibiting its N-glycosylation, causing effects on protein stability that ultimately translated into reduced EC(endothelial cell)-leukocyte interactions. Our study has identified PIMT as a novel and potent suppressor of endothelial activation. Taken together, these findings suggest that therapeutic targeting of PIMT may be effective in limiting organ injury in inflammatory vascular diseases.
Output: {"entities":[{"id":0,"name":"PIMT","type":"protein","organism":null},{"id":1,"name":"endothelial activation","type":"other","organism":null},{"id":2,"name":"adhesion molecules","type":"protein","organism":null},{"id":3,"name":"isoaspartyl residues","type":"protein","organism":null},{"id":4,"name":"methylated forms","type":"protein","organism":null},{"id":5,"name":"TRAF6","type":"protein","organism":null},{"id":6,"name":"NF-κB","type":"protein","organism":null},{"id":7,"name":"ICAM-1","type":"protein","organism":null},{"id":8,"name":"endothelial cell","type":"cell","organism":null}],"relations":[{"type":"binding","entities":[{"id":0},{"id":5}],"evidence":"we found that PIMT inhibited LPS-induced toll-like receptor signaling through its interaction with TNF receptor-associated factor 6 (TRAF6)"},{"type":"methylation","entities":[{"id":0},{"id":3}],"evidence":"and its ability to methylate asparagine residues in the coiled-coil domain"},{"type":"other","entities":[{"id":5},{"id":6}],"evidence":"This interaction was found to inhibit TRAF6 oligomerization and autoubiquitination, which prevented NF-κB transactivation"},{"type":"other","entities":[{"id":0},{"id":7}],"evidence":"Separately, PIMT also suppressed ICAM-1 expression by inhibiting its N-glycosylation"}]}

---

(6) Yang et al. VPS9D1-AS1 overexpression amplifies intratumoral TGF-β signaling and promotes tumor cell escape from CD8+ T cell killing in colorectal cancer. eLife., 2022. https://doi.org/10.7554/eLife.79811

Input: VPS9D1-AS1 overexpression amplifies intratumoral TGF-β signaling and promotes tumor cell escape from CD8+ T cell killing in colorectal cancer. Efficacy of immunotherapy is limited in patients with colorectal cancer (CRC) because high expression of tumor-derived transforming growth factor (TGF)-β pathway molecules and interferon (IFN)-stimulated genes (ISGs) promotes tumor immune evasion. Here, we identified a long noncoding RNA (lncRNA), VPS9D1-AS1, which was located in ribosomes and amplified TGF-β signaling and ISG expression. We show that high expression of VPS9D1-AS1 was negatively associated with T lymphocyte infiltration in two independent cohorts of CRC. VPS9D1-AS1 served as a scaffolding lncRNA by binding with ribosome protein S3 (RPS3) to increase the translation of TGF-β, TGFBR1, and SMAD1/5/9. VPS9D1-AS1 knockout downregulated OAS1, an ISG gene, which further reduced IFNAR1 levels in tumor cells. Conversely, tumor cells overexpressing VPS9D1-AS1 were resistant to CD8+ T cell killing and lowered IFNAR1 expression in CD8+ T cells. In a conditional overexpression mouse model, VPS9D1-AS1 enhanced tumorigenesis and suppressed the infiltration of CD8+ T cells. Treating tumor-bearing mice with antisense oligonucleotide drugs targeting VPS9D1-AS1 significantly suppressed tumor growth. Our findings indicate that the tumor-derived VPS9D1-AS1/TGF-β/ISG signaling cascade promotes tumor growth and enhances immune evasion and may thus serve as a potential therapeutic target for CRC.
Output: 
{"entities":[{"id":0,"name":"VPS9D1-AS1","type":"rna","organism":null},{"id":1,"name":"TGF-β","type":"protein","organism":null},{"id":2,"name":"ISGs","type":"gene or gene product","organism":null},{"id":3,"name":"lncRNA","type":"rna","organism":null},{"id":4,"name":"ribosome protein S3","type":"protein","organism":null},{"id":5,"name":"TGFBR1","type":"protein","organism":null},{"id":6,"name":"SMAD1/5/9","type":"protein","organism":null},{"id":7,"name":"OAS1","type":"gene or gene product","organism":null},{"id":8,"name":"IFNAR1","type":"protein","organism":null},{"id":9,"name":"CD8+ T cell","type":"cell","organism":null}],"relations":[{"type":"binding","entities":[{"id":0},{"id":4}],"evidence":"VPS9D1-AS1 served as a scaffolding lncRNA by binding with ribosome protein S3 (RPS3) to increase the translation of TGF-β, TGFBR1, and SMAD1/5/9."},{"type":"transcription-translation","entities":[{"id":0},{"id":1}],"evidence":"VPS9D1-AS1 served as a scaffolding lncRNA by binding with ribosome protein S3 (RPS3) to increase the translation of TGF-β, TGFBR1, and SMAD1/5/9."},{"type":"transcription-translation","entities":[{"id":0},{"id":2}],"evidence":"VPS9D1-AS1 served as a scaffolding lncRNA by binding with ribosome protein S3 (RPS3) to increase the translation of TGF-β, TGFBR1, and SMAD1/5/9."},{"type":"transcription-translation","entities":[{"id":3},{"id":4}],"evidence":"VPS9D1-AS1 served as a scaffolding lncRNA by binding with ribosome protein S3 (RPS3) to increase the translation of TGF-β, TGFBR1, and SMAD1/5/9."},{"type":"transcription-translation","entities":[{"id":3},{"id":1}],"evidence":"VPS9D1-AS1 served as a scaffolding lncRNA by binding with ribosome protein S3 (RPS3) to increase the translation of TGF-β, TGFBR1, and SMAD1/5/9."},{"type":"transcription-translation","entities":[{"id":3},{"id":5}],"evidence":"VPS9D1-AS1 served as a scaffolding lncRNA by binding with ribosome protein S3 (RPS3) to increase the translation of TGF-β, TGFBR1, and SMAD1/5/9."},{"type":"transcription-translation","entities":[{"id":3},{"id":6}],"evidence":"VPS9D1-AS1 served as a scaffolding lncRNA by binding with ribosome protein S3 (RPS3) to increase the translation of TGF-β, TGFBR1, and SMAD1/5/9."},{"type":"binding","entities":[{"id":3},{"id":0}],"evidence":"VPS9D1-AS