tooluniverse-literature-deep-research
π―Skillfrom mims-harvard/tooluniverse
|Performs comprehensive literature research with target disambiguation, evidence grading, and structured theme extraction for thorough scientific investigations.
Part of
mims-harvard/tooluniverse(19 items)
Installation
npx skills add mims-harvard/ToolUniversepip install tooluniverseclaude mcp add --transport stdio tooluniverse -- tooluniverse-smcp-stdio --compact-modepip install tooluniverse[client] # Minimal installation{
"mcpServers": {
"tooluniverse": {
"command": "uvx",
"args": ...Skill Details
Conduct comprehensive literature research with target disambiguation, evidence grading, and structured theme extraction. Creates a detailed report with mandatory completeness checklist, biological model synthesis, and testable hypotheses. For biological targets, resolves official IDs (Ensembl/UniProt), synonyms, naming collisions, and gathers expression/pathway context before literature search. Outputs report-only by default; methodology in separate appendix if requested. Use when users need thorough literature reviews, target profiles, or ask "what does the literature say about X?".
Overview
# Literature Deep Research Strategy (Enhanced)
A systematic approach to comprehensive literature research that starts with target disambiguation to prevent missing details, uses evidence grading to separate signal from noise, and produces a content-focused report with mandatory completeness sections.
KEY PRINCIPLES:
- Target disambiguation FIRST - Resolve IDs, synonyms, naming collisions before literature search
- Report-only output - No search process in the report; methodology in separate appendix only if requested
- Evidence grading - Grade every claim by evidence strength (mechanistic paper vs screen hit vs review vs text-mined)
- Mandatory completeness - All checklist sections must exist, even if "unknown/limited evidence"
- Source attribution - Every piece of information traceable to database/tool
---
Workflow Overview
```
User Query
β
Phase 0: CLARIFY (Is this a biological target? What scope?)
β
Phase 1: TARGET DISAMBIGUATION + PROFILE (default ON for biological targets)
ββ Resolve official IDs (Ensembl, UniProt, HGNC)
ββ Gather synonyms/aliases + known naming collisions
ββ Get protein length, isoforms, domain architecture
ββ Get subcellular location, expression, GO terms, pathways
ββ Output: Target Profile section + Collision-aware search plan
β
Phase 2: LITERATURE SEARCH (internal methodology, not shown)
ββ High-precision seed queries (build mechanistic core)
ββ Citation network expansion from seeds
ββ Collision-filtered broader queries
ββ Theme clustering + evidence grading
β
Phase 3: REPORT SYNTHESIS
ββ Progressive writing to [topic]_report.md
ββ Mandatory completeness checklist validation
ββ Biological model + testable hypotheses
β
Optional: methods_appendix.md (only if user requests)
```
---
Phase 0: Initial Clarification
Mandatory Questions
- Target type: Is this a biological target (gene/protein), a general topic, or a disease?
- Scope: Comprehensive review, druggability focus, mechanism focus, or quick overview?
- Known aliases: Any specific gene symbols or protein names you use?
- Constraints: Open access only? Include preprints? Specific organisms?
- Methods appendix: Do you want methodology details in a separate file?
Detect Target Type
| Query Pattern | Type | Action |
|---------------|------|--------|
| Gene symbol (EGFR, TP53, ATP6V1A) | Biological target | Phase 1 required |
| Protein name ("V-ATPase", "kinase") | Biological target | Phase 1 required |
| UniProt ID (P00533, Q93050) | Biological target | Phase 1 required |
| Disease, pathway, method | General topic | Phase 1 optional |
| "Literature on X" | Depends on X | Assess X |
---
Phase 1: Target Disambiguation + Profile (Default ON)
CRITICAL: This phase prevents "missing target details" when literature is sparse or noisy.
1.1 Resolve Official Identifiers
Use these tools to establish canonical identity:
```
UniProt_search β Get UniProt accession for human protein
UniProt_get_entry_by_accession β Full entry with cross-references
UniProt_id_mapping β Map between ID types
ensembl_lookup_gene β Ensembl gene ID, biotype
MyGene_get_gene_annotation β NCBI Gene ID, aliases, summary
```
Output for report:
```markdown
Target Identity
| Identifier | Value | Source |
|------------|-------|--------|
| Official Symbol | ATP6V1A | HGNC |
| UniProt | P38606 | UniProt |
| Ensembl Gene | ENSG00000114573 | Ensembl |
| NCBI Gene ID | 523 | NCBI |
| ChEMBL Target | CHEMBL2364682 | ChEMBL |
Full Name: V-type proton ATPase catalytic subunit A
Synonyms/Aliases: ATP6A1, VPP2, Vma1, VA68
```
1.2 Identify Naming Collisions
CRITICAL: Many gene names have collisions. Examples:
- TRAG: T-cell regulatory gene vs bacterial TraG conjugation protein
- WDR7-7: Could match gene WDR7 vs lncRNA
- JAK: Janus kinase vs Just Another Kinase
- CAT: Catalase vs chloramphenicol acetyltransferase
Detection strategy:
- Search PubMed for
"[SYMBOL]"[Title]- review first 20 titles - If >20% off-topic, identify collision terms
- Build negative filter:
NOT [collision_term1] NOT [collision_term2]
Output for report:
```markdown
Known Naming Collisions
- Symbol "ATP6V1A" is unambiguous (no major collisions detected)
- Related but distinct: ATP6V0A1-4 (V0 subunits vs V1 subunits)
- Search filter applied: Include "vacuolar" OR "V-ATPase", exclude "V0 domain" when V1-specific
```
1.3 Protein Architecture & Domains
Use annotation tools (not literature):
```
InterPro_get_protein_domains β Domain architecture
UniProt_get_ptm_processing_by_accession β PTMs, active sites
proteins_api_get_protein β Additional protein features
```
Output for report:
```markdown
Protein Architecture
| Domain | Position | InterPro ID | Function |
|--------|----------|-------------|----------|
| V-ATPase A subunit, N-terminal | 1-90 | IPR022879 | ATP binding |
| V-ATPase A subunit, catalytic | 91-490 | IPR005725 | Catalysis |
| V-ATPase A subunit, C-terminal | 491-617 | IPR022878 | Complex assembly |
Length: 617 aa | Isoforms: 2 (canonical P38606-1, variant P38606-2 missing aa 1-45)
Active sites: Lys-168 (ATP binding), Glu-261 (catalytic)
Sources: InterPro, UniProt
```
1.4 Subcellular Location
```
HPA_get_subcellular_location β Human Protein Atlas localization
UniProt_get_subcellular_location_by_accession β UniProt annotation
```
Output for report:
```markdown
Subcellular Localization
| Location | Confidence | Source |
|----------|------------|--------|
| Lysosome membrane | High | HPA + UniProt |
| Endosome membrane | High | UniProt |
| Golgi apparatus | Medium | HPA |
| Plasma membrane (subset) | Low | Literature |
Primary location: Lysosomal/endosomal membranes (vacuolar ATPase complex)
Sources: Human Protein Atlas, UniProt
```
1.5 Baseline Expression
```
GTEx_get_median_gene_expression β Tissue expression (TPM)
HPA_get_rna_expression_by_source β HPA expression data
```
Output for report:
```markdown
Baseline Tissue Expression
| Tissue | Expression (TPM) | Specificity |
|--------|------------------|-------------|
| Kidney cortex | 145.3 | Elevated |
| Liver | 98.7 | Medium |
| Brain - Cerebellum | 87.2 | Medium |
| Lung | 76.4 | Medium |
| Ubiquitous baseline | ~50 | Broad |
Tissue Specificity: Low (Ο = 0.28) - broadly expressed housekeeping gene
Source: GTEx v8
```
1.6 GO Terms & Pathway Placement
```
GO_get_annotations_for_gene β GO annotations
Reactome_map_uniprot_to_pathways β Reactome pathways
kegg_get_gene_info β KEGG pathways
OpenTargets_get_target_gene_ontology_by_ensemblID β Open Targets GO
```
Output for report:
```markdown
Functional Annotations (GO)
Molecular Function:
- ATP hydrolysis activity (GO:0016887) [Evidence: IDA]
- Proton-transporting ATPase activity (GO:0046961) [Evidence: IDA]
Biological Process:
- Lysosomal acidification (GO:0007041) [Evidence: IMP]
- Autophagy (GO:0006914) [Evidence: IMP]
- Bone resorption (GO:0045453) [Evidence: IMP]
Cellular Component:
- Vacuolar proton-transporting V-type ATPase, V1 domain (GO:0000221) [Evidence: IDA]
Pathway Involvement
| Pathway | Database | Significance |
|---------|----------|--------------|
| Lysosome | KEGG hsa04142 | Core component |
| Phagosome | KEGG hsa04145 | Acidification |
| Autophagy - animal | Reactome R-HSA-9612973 | mTORC1 regulation |
Sources: GO Consortium, Reactome, KEGG
```
---
Phase 2: Literature Search (Internal Methodology)
NOTE: This methodology is kept internal. The report shows findings, not process.
2.1 Query Strategy: Collision-Aware Synonym Plan
#### Step 1: High-Precision Seed Queries (Build Mechanistic Core)
```
Query 1: "[GENE_SYMBOL]"[Title] AND (mechanism OR function OR structure)
Query 2: "[FULL_PROTEIN_NAME]"[Title]
Query 3: "[UNIPROT_ID]" (catches supplementary materials)
```
Purpose: Get 15-30 high-confidence, mechanistic papers that are definitely on-target.
#### Step 2: Citation Network Expansion (Especially for Sparse Targets)
Once you have 5-15 core PMIDs:
```
PubMed_get_cited_by β Papers citing each seed
PubMed_get_related β Computationally related papers
EuropePMC_get_citations β Alternative citation source
EuropePMC_get_references β Backward citations from seeds
```
Citation-network first option: For older targets with deprecated terminology, citation expansion often outperforms keyword searching.
#### Step 3: Collision-Filtered Broader Queries
```
Broader query: "[GENE_SYMBOL]" AND ([pathway1] OR [pathway2] OR [function])
Apply collision filter: NOT [collision_term1] NOT [collision_term2]
```
Example for bacterial TraG collision:
```
"TRAG" AND (T-cell OR immune OR cancer) NOT plasmid NOT conjugation NOT bacterial
```
2.2 Database Tools
Literature Search (use all relevant):
PubMed_search_articles- Primary biomedicalPMC_search_papers- Full-textEuropePMC_search_articles- European coverageopenalex_literature_search- Broad academicCrossref_search_works- DOI registrySemanticScholar_search_papers- AI-rankedBioRxiv_search_preprints/MedRxiv_search_preprints- Preprints
Citation Tools (with failure handling):
PubMed_get_cited_by- Primary (NCBI elink can be flaky)EuropePMC_get_citations- Fallback when PubMed failsPubMed_get_related- Related articlesEuropePMC_get_references- Reference lists
Annotation Tools (not literature, but fill gaps):
UniProt_*tools - Protein dataInterPro_get_protein_domains- DomainsGTEx_*tools - ExpressionHPA_*tools - Human Protein AtlasOpenTargets_*tools - Target-disease associationsGO_get_annotations_for_gene- GO terms
2.3 Tool Failure Handling
Automatic retry strategy:
```
Attempt 1: Call tool
If timeout/error:
Wait 2 seconds
Attempt 2: Retry
If still fails:
Wait 5 seconds
Attempt 3: Try fallback tool
If fallback fails:
Document "Data unavailable" in report
```
Fallback chains:
| Primary Tool | Fallback 1 | Fallback 2 |
|--------------|------------|------------|
| PubMed_get_cited_by | EuropePMC_get_citations | OpenAlex citations |
| PubMed_get_related | SemanticScholar recommendations | Manual keyword search |
| GTEx_get_median_gene_expression | HPA_get_rna_expression_by_source | Document as unavailable |
| Unpaywall_check_oa_status | Europe PMC OA flags | OpenAlex OA field |
2.4 Open Access Handling (Best-Effort)
If Unpaywall email provided: Check OA status for all papers with DOIs
If no Unpaywall email: Use best-effort OA signals:
- Europe PMC:
isOpenAccessfield - PMC: All PMC papers are OA
- OpenAlex:
is_oafield - DOAJ: All DOAJ papers are OA
Label in report:
```markdown
OA Status: Best-effort (Unpaywall not configured)
```
---
Phase 3: Evidence Grading
CRITICAL: Grade every claim by evidence strength to prevent low-signal mentions from diluting the report.
Evidence Tiers
| Tier | Label | Description | Example |
|------|-------|-------------|---------|
| T1 | β β β Mechanistic | In-target mechanistic study with direct experimental evidence | CRISPR KO + rescue |
| T2 | β β β Functional | Functional study showing role (may be in pathway context) | siRNA knockdown phenotype |
| T3 | β ββ Association | Screen hit, GWAS association, correlation | High-throughput screen |
| T4 | βββ Mention | Review mention, text-mined interaction, peripheral reference | Review article |
How to Apply
In report, label sections and claims:
```markdown
Mechanism of Action
ATP6V1A is the catalytic subunit responsible for ATP hydrolysis in the V-ATPase
complex [β β β Mechanistic: PMID:12345678]. Loss-of-function mutations cause
vacuolar pH dysregulation [β β β : PMID:23456789].
The target has been implicated in mTORC1 signaling through lysosomal amino acid
sensing [β β β Functional: PMID:34567890], though direct interaction data is limited.
A genome-wide screen identified ATP6V1A as essential in cancer cell lines
[β ββ Association: PMID:45678901, DepMap].
```
Theme-Level Grading
For each theme section, summarize evidence quality:
```markdown
3.1 Lysosomal Acidification (12 papers)
Evidence Quality: Strong (8 mechanistic, 3 functional, 1 association)
[Theme content...]
```
---
Report Structure: Mandatory Completeness Checklist
CRITICAL: ALL sections below must exist in the report, even if populated with "Limited evidence available" or "Unknown - no studies identified".
Output Files
[topic]_report.md- Main narrative report (default deliverable)[topic]_bibliography.json- Full deduplicated bibliography (always created)methods_appendix.md- Methodology details (ONLY if user requests)
Report Template
```markdown
# [TARGET/TOPIC]: Comprehensive Research Report
Generated: [Date]
Evidence cutoff: [Date]
Total unique papers: [N]
---
Executive Summary
[2-3 paragraphs synthesizing key findings across all sections]
Bottom Line: [One-sentence actionable conclusion]
---
1. Target Identity & Aliases
[MANDATORY - even for non-target topics, clarify scope]
1.1 Official Identifiers
[Table of IDs or scope definition]
1.2 Synonyms and Aliases
[List all known names - critical for complete literature coverage]
1.3 Known Naming Collisions
[Document collisions and how they were handled]
---
2. Protein Architecture
[MANDATORY for protein targets; state "N/A - not a protein target" otherwise]
2.1 Domain Structure
[Table of domains with positions, InterPro IDs]
2.2 Isoforms
[List isoforms, functional differences if known]
2.3 Key Structural Features
[Active sites, binding sites, PTMs]
2.4 Available Structures
[PDB entries, AlphaFold availability]
---
3. Complexes & Interaction Partners
[MANDATORY]
3.1 Known Complexes
[List complexes the protein participates in]
3.2 Direct Interactors
[Table of top interactors with evidence type and scores]
3.3 Functional Interaction Network
[Describe network context]
---
4. Subcellular Localization
[MANDATORY]
[Table of locations with confidence levels and sources]
---
5. Expression Profile
[MANDATORY]
5.1 Tissue Expression
[Table of top tissues with TPM values]
5.2 Cell-Type Expression
[If single-cell data available]
5.3 Disease-Specific Expression
[Expression changes in disease contexts]
---
6. Core Mechanisms
[MANDATORY - this is the heart of the report]
6.1 Molecular Function
[What the protein does biochemically]
Evidence Quality: [Strong/Moderate/Limited]
6.2 Biological Role
[Role in cellular/organismal context]
Evidence Quality: [Strong/Moderate/Limited]
6.3 Key Pathways
[Pathway involvement with evidence grades]
6.4 Regulation
[How the target is regulated]
---
7. Model Organism Evidence
[MANDATORY]
7.1 Mouse Models
[Knockout/knockin phenotypes, if any]
7.2 Other Model Organisms
[Yeast, fly, zebrafish, worm data if relevant]
7.3 Cross-Species Conservation
[Conservation and functional studies]
---
8. Human Genetics & Variants
[MANDATORY]
8.1 Constraint Scores
[pLI, LOEUF, missense Z - with interpretation]
8.2 Disease-Associated Variants
[ClinVar pathogenic variants]
8.3 Population Variants
[gnomAD notable variants]
8.4 GWAS Associations
[Any GWAS hits for the locus]
---
9. Disease Links
[MANDATORY - include evidence strength]
9.1 Strong Evidence (Genetic + Functional)
[Diseases with causal evidence]
9.2 Moderate Evidence (Association + Mechanism)
[Diseases with supporting evidence]
9.3 Weak Evidence (Association Only)
[Diseases with correlation/association only]
9.4 Evidence Summary Table
| Disease | Evidence Type | Score | Key Papers | Grade |
|---------|---------------|-------|------------|-------|
| [Disease 1] | Genetic + Functional | 0.85 | PMID:xxx | β β β |
| [Disease 2] | GWAS + Expression | 0.45 | PMID:yyy | β β β |
---
10. Pathogen Involvement
[MANDATORY - state "None identified" if not applicable]
10.1 Viral Interactions
[Any viral exploitation or targeting]
10.2 Bacterial Interactions
[Any bacterial relevance]
10.3 Host Defense Role
[Role in immune response if any]
---
11. Key Assays & Readouts
[MANDATORY]
11.1 Biochemical Assays
[Available assays for target activity]
11.2 Cellular Readouts
[Cell-based assays and phenotypes]
11.3 In Vivo Models
[Animal models and endpoints]
---
12. Research Themes
[MANDATORY - structured theme extraction]
12.1 [Theme 1 Name] (N papers)
Evidence Quality: [Strong/Moderate/Limited]
Representative Papers: [β₯3 papers or state "insufficient"]
[Theme description with evidence-graded citations]
12.2 [Theme 2 Name] (N papers)
[Same structure]
[Continue for all themes - require β₯3 representative papers per theme, or state "limited evidence"]
---
13. Open Questions & Research Gaps
[MANDATORY]
13.1 Mechanistic Unknowns
[What we don't understand about the target]
13.2 Therapeutic Unknowns
[What we don't know for drug development]
13.3 Suggested Priority Questions
[Ranked list of important unanswered questions]
---
14. Biological Model & Testable Hypotheses
[MANDATORY - synthesis section]
14.1 Integrated Biological Model
[3-5 paragraph synthesis integrating all evidence into coherent model]
14.2 Testable Hypotheses
| # | Hypothesis | Perturbation | Readout | Expected Result | Priority |
|---|------------|--------------|---------|-----------------|----------|
| 1 | [Hypothesis] | [Experiment] | [Measure] | [Prediction] | HIGH |
| 2 | [Hypothesis] | [Experiment] | [Measure] | [Prediction] | HIGH |
| 3 | [Hypothesis] | [Experiment] | [Measure] | [Prediction] | MEDIUM |
14.3 Suggested Experiments
[Brief description of key experiments to test hypotheses]
---
15. Conclusions & Recommendations
[MANDATORY]
15.1 Key Takeaways
[Bullet points of most important findings]
15.2 Confidence Assessment
[Overall confidence in the findings: High/Medium/Low with justification]
15.3 Recommended Next Steps
[Prioritized action items]
---
References
[Summary reference list in report - full bibliography in separate file]
Key Papers (Must-Read)
- [Citation with PMID] - [Why important] [Grade: β β β ]
- ...
By Theme
[Organized reference lists]
---
Data Limitations
- [Any databases that failed or returned no data]
- [Any known gaps in coverage]
- [OA status method used]
Full methodology available in methods_appendix.md upon request.
```
---
Bibliography File Format
File: [topic]_bibliography.json
```json
{
"metadata": {
"generated": "2026-02-04",
"query": "ATP6V1A",
"total_papers": 342,
"unique_after_dedup": 287
},
"papers": [
{
"pmid": "12345678",
"doi": "10.1038/xxx",
"title": "Paper Title",
"authors": ["Smith A", "Jones B"],
"year": 2024,
"journal": "Nature",
"source_databases": ["PubMed", "OpenAlex"],
"evidence_tier": "T1",
"themes": ["lysosomal_acidification", "autophagy"],
"oa_status": "gold",
"oa_url": "https://...",
"citation_count": 45,
"in_core_set": true
}
]
}
```
Also generate [topic]_bibliography.csv with same data in tabular format.
---
Theme Extraction Protocol
Standardized Theme Clustering
- Extract keywords from titles and abstracts
- Cluster into themes using semantic similarity
- Require minimum N papers per theme (default N=3)
- Label themes with standardized names
Standard Theme Categories (adapt to target)
For V-ATPase target example:
lysosomal_acidification- Core functionautophagy_regulation- mTORC1 signalingbone_resorption- Osteoclast functioncancer_metabolism- Tumor acidificationviral_infection- Viral entry mechanismneurodegenerative- Neuronal dysfunctionkidney_function- Renal acid-basemethodology- Assays/tools papers
Theme Quality Requirements
| Papers | Theme Status |
|--------|--------------|
| β₯10 | Major theme (full section) |
| 3-9 | Minor theme (subsection) |
| <3 | Insufficient (note in "limited evidence" or merge) |
---
Completeness Checklist (Verify Before Delivery)
ALL boxes must be checked or explicitly marked "N/A" or "Limited evidence"
Identity & Context
- [ ] Official identifiers resolved (UniProt, Ensembl, NCBI, ChEMBL)
- [ ] All synonyms/aliases documented
- [ ] Naming collisions identified and handled
- [ ] Protein architecture described (or N/A stated)
- [ ] Subcellular localization documented
- [ ] Baseline expression profile included
Mechanism & Function
- [ ] Core mechanism section with evidence grades
- [ ] Pathway involvement documented
- [ ] Model organism evidence (or "none found")
- [ ] Complexes/interaction partners listed
- [ ] Key assays/readouts described
Disease & Clinical
- [ ] Human genetic variants documented
- [ ] Constraint scores with interpretation
- [ ] Disease links with evidence strength grades
- [ ] Pathogen involvement (or "none identified")
Synthesis
- [ ] Research themes clustered with β₯3 papers each (or noted as limited)
- [ ] Open questions/gaps articulated
- [ ] Biological model synthesized
- [ ] β₯3 testable hypotheses with experiments
- [ ] Conclusions with confidence assessment
Technical
- [ ] All claims have source attribution
- [ ] Evidence grades applied throughout
- [ ] Bibliography file generated
- [ ] Data limitations documented
---
Quick Reference: Tool Categories
Literature Tools
PubMed_search_articles, PMC_search_papers, EuropePMC_search_articles, openalex_literature_search, Crossref_search_works, SemanticScholar_search_papers, BioRxiv_search_preprints, MedRxiv_search_preprints
Citation Tools
PubMed_get_cited_by, PubMed_get_related, EuropePMC_get_citations, EuropePMC_get_references
Protein/Gene Annotation Tools
UniProt_get_entry_by_accession, UniProt_search, UniProt_id_mapping, InterPro_get_protein_domains, proteins_api_get_protein
Expression Tools
GTEx_get_median_gene_expression, GTEx_get_gene_expression, HPA_get_rna_expression_by_source, HPA_get_comprehensive_gene_details_by_ensembl_id, HPA_get_subcellular_location
Variant/Disease Tools
gnomad_get_gene_constraints, gnomad_get_gene, clinvar_search_variants, OpenTargets_get_diseases_phenotypes_by_target_ensembl
Pathway Tools
GO_get_annotations_for_gene, Reactome_map_uniprot_to_pathways, kegg_get_gene_info, OpenTargets_get_target_gene_ontology_by_ensemblID
Interaction Tools
STRING_get_protein_interactions, intact_get_interactions, OpenTargets_get_target_interactions_by_ensemblID
OA Tools
Unpaywall_check_oa_status (if email provided), or use OA flags from Europe PMC/OpenAlex
---
Communication with User
During research (brief updates):
- "Resolving target identifiers and gathering baseline profile..."
- "Building core paper set with high-precision queries..."
- "Expanding via citation network..."
- "Clustering into themes and grading evidence..."
DO NOT expose:
- Raw tool outputs
- Deduplication counts
- Search round details
- Database-by-database results
The report is the deliverable. Methodology stays internal.
---
Summary
This skill produces comprehensive, evidence-graded research reports that:
- Start with disambiguation to prevent naming collisions and missing details
- Use annotation tools to fill gaps when literature is sparse
- Grade all evidence to separate signal from noise
- Require completeness even if stating "limited evidence"
- Synthesize into biological models with testable hypotheses
- Separate narrative from bibliography for scalability
- Keep methodology internal unless explicitly requested
The result is a detailed, actionable research report that reads like an expert synthesis, not a search log.
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