).\n * [ ] Successfully compiled PDF named `_report.pdf`.\n * [ ] ZIP archive (``) < 100 MB containing:\n * [ ] `main.tex`\n * [ ] All supporting `.tex`/`.sty` files (if any were generated/needed beyond standard packages)\n * [ ] `main.bib` (BibLaTeX bibliography file)\n * [ ] Figures as PNG or SVG, named `_Fig###_*.{png|svg}` (e.g., CDK9_Fig001_pathway.png)\n * [ ] Supplementary tables as CSV or JSON, named `_Tab###_*.{csv|json}`\n * [ ] `README.txt` containing:\n * Line 1: Manifest of files included in the ZIP archive.\n * Subsequent lines: `<64-character lowercase SHA-256 checksum> ` for *every* file in the archive (including `main.tex`, `main.bib`, figures, tables, README.txt itself, and the PDF). Generate checksums accurately.\n * [ ] The final, compiled PDF `_report.pdf` **must be inside the ZIP archive**.\n\n3. **LaTeX Compilation Guard-rails**\n * Use TeX Live 2023 distribution compatibility.\n * Only these packages may be explicitly loaded via `\\usepackage{}`:\n `graphicx`, `hyperref`, `xcolor` (with `dvipsnames` or `svgnames` option if needed), `geometry` (use standard margins e.g., `margin=1in`), `microtype`, `siunitx` (for units/numbers), `tabularx`, `booktabs` (for tables), `tcolorbox` (for call-outs), `csquotes` (for quoting), `amsmath`, `textcomp` (for symbols), `biblatex`.\n * *Do not* explicitly load `tikz` (it's included transitively by `tcolorbox` if needed, avoid direct TikZ drawing).\n * Load `biblatex` with options: `style=vancouver, isbn=false, backend=biber`.\n * Include `\\hypersetup{hidelinks}` *after* all package imports to hide citation/link boxes.\n * The document *must* compile successfully using the command:\n ```bash\n latexmk -pdf -interaction=nonstopmode main.tex\n ```\n (This command automatically handles `biber` calls and multiple LaTeX passes).\n * **Error Handling:** If compilation fails *despite* adhering to package constraints:\n 1. Attempt to diagnose the error (e.g., from `.log` file output if accessible). Common issues: undefined control sequences, mismatched brackets/parentheses, invalid characters, missing figure files referenced in `\\includegraphics`.\n 2. Attempt to fix the error(s) directly in the LaTeX source.\n 3. If the error is unresolvable, insert the following comment at the very top of `main.tex`:\n ```tex\n % TODO: LaTeX compilation failed. Reason: [Briefly describe the unresolvable error, e.g., \"Undefined control sequence \\xyz on line 123\", \"Package incompatibility suspected\"]\n ```\n 4. Proceed to generate the ZIP archive with the non-compiling source files and any partial PDF output if generated, but clearly indicate the failure via the TODO comment.\n\n4. **PDF Generation & Naming**\n * After a *successful* compile via `latexmk`, verify `main.pdf` exists.\n * Rename `main.pdf` to `_report.pdf`.\n * Include this renamed PDF in the deliverable ZIP archive.\n\n5. **Style, Citation, and Content Rules**\n * Use standard LaTeX sectioning commands (`\\section`, `\\subsection`, etc.) for structure; allow auto-numbering.\n * Use inline numeric citations via `\\cite{key}` corresponding to entries in `main.bib`. Generate BibTeX keys automatically (e.g., AuthorYear, UniProtID_Source).\n * **Citation Precision:** Cite exact database versions and access dates (e.g., \"AlphaFold DB v4, accessed 2024-05-15\", \"Reactome pathway R-HSA-12345, accessed 2024-05-15\"). For literature, include DOI. Preprints must include DOI, date posted, and the text \"[Preprint]\" in the bibliography entry.\n * **Highlighting Insights:**\n * Identify key single-sentence conclusions or critical data points within paragraphs and make them **bold**.\n * For multi-sentence call-outs summarizing crucial findings or implications, use:\n ```tex\n \\begin{tcolorbox}[colback=gray!10, sharp corners, boxrule=0.5pt]\n [Multi-sentence summary of a key finding or implication.] \\cite{relevant_source_if_specific}\n \\end{tcolorbox}\n ```\n * **Figures:**\n * Generate clear, informative figures (e.g., pathway diagrams, structure representations, data plots). Save as PNG or SVG.\n * Embed using:\n ```tex\n \\begin{figure}[htbp] % Placement preference: here, top, bottom, page\n \\centering\n \\includegraphics[width=0.85\\linewidth]{_Fig###_description.png} % Adjust width as needed\n \\caption{Concise but informative caption describing the figure content. Include data provenance/source. \\cite{source_database_or_paper}}\n \\label{fig:unique_identifier} % e.g., fig:pathway_map\n \\end{figure}\n ```\n * Reference figures in the text using `\\autoref{fig:unique_identifier}` (e.g., \"as shown in \\autoref{fig:pathway_map}\"). Ensure all figures are referenced.\n * **Tables:**\n * Use `booktabs` rules (`\\toprule`, `\\midrule`, `\\bottomrule`) for professional table formatting. Use `tabularx` for tables that need to span text width.\n * For tables with > 20 rows of data: Embed only the header and first 5 representative data rows in the LaTeX document. Provide the full dataset as a supplementary CSV or JSON file (`_Tab###_description.csv`). Add a note below the table in LaTeX: \"Full data available in Supplementary Table X (_Tab###_description.csv).\" Cite this supplementary file.\n * **Report Statistics Precisely:** When reporting quantitative data (e.g., IC50s, expression levels), include number of samples/replicates (*n*), mean ± standard deviation (SD) or 95% confidence interval (CI), and exact *P*-values where available and relevant. Quote CIs and SD exactly as published. Use `siunitx` package for formatting numbers and units (e.g., `\\SI{50}{\\nano\\molar}`, `p = \\num{0.023}`).\n * **Data Provenance:** Append a brief, one-line provenance note to every mention of a specific dataset, figure caption, or table caption. (e.g., \"Source: DepMap 23Q2 public CRISPR screen.\", \"Data from PDB entry 1XYZ.\", \"Expression data from GTEx v8.\").\n * **Handling Missing Information:** If specific information requested for a subsection cannot be located in publicly accessible, reputable sources after a diligent search, explicitly state this using the literal text: `No specific public data located for [detail, e.g., 'quantitative Z-factors for biochemical assays'] as of YYYY-MM-DD.` (Use the date of research). Do *not* invent data or speculate without basis.\n\n6. **File Naming and Hygiene**\n * All generated assets (figures, tables, bib file, tex file, PDF) must begin with `` (e.g., `CDK9_Fig001_pathway.png`, `CDK9_main.tex`).\n * Use three-digit zero-padded indices for figures and tables (001-999).\n * Ensure descriptive suffixes (e.g., `_pathway`, `_SAR_table`, `_expression_heatmap`).\n * The final ZIP archive must *exclude* all intermediate build artifacts (e.g., `.aux`, `.log`, `.bbl`, `.bcf`, `.blg`, `_minted`, `*.synctex.gz`, `__pycache__/`, `.DS_Store`). Check thoroughly.\n\n7. **Length Constraints**\n * Compiled PDF (`_report.pdf`) should ideally be ≤ 30 pages.\n * Prioritize conciseness. Move extensive raw data tables or supplementary figures/details into the supplementary files (CSV/JSON/PNG/SVG) referenced in the main report, rather than embedding excessively long content directly in the LaTeX.\n\n8. **Optional Quality-of-Life Hooks**\n * You *may* use `% TODO: [Reason]` comments within the LaTeX source ONLY for genuine missing context that you couldn't resolve or find (beyond the standard \"No public data located\" statement), or for noting compilation issues as described above.\n * Consider providing a graphical abstract (as a figure) at the beginning of the Executive Summary section if feasible and informative. Omission is allowed if not practical.\n\n######################################################################\n# REPORT TEMPLATE — Fill ALL subsections with synthesized analysis\n######################################################################\n\n# --- Document Preamble (Standard LaTeX setup) ---\n# \\documentclass{article}\n# \\usepackage{[packages listed in Guard-rails]}\n# \\usepackage[backend=biber, style=vancouver, isbn=false]{biblatex}\n# \\addbibresource{main.bib} % Assumes bib file is named main.bib\n# \\hypersetup{hidelinks}\n# \\geometry{margin=1in}\n# \\title{Comprehensive Research Report: ()}\n# \\author{AI Research Agent}\n# \\date{\\today}\n# \\begin{document}\n# \\maketitle\n# --- End Preamble ---\n\n\\section{Target Background \\& Synonyms}\n% Provide the UniProt recommended name, HGNC approved gene symbol.\n% List key historical aliases or alternative names found in literature/databases.\n% Briefly state the protein family/class it belongs to.\n\n\\section{Executive Summary}\n% (Optional: Include graphical abstract figure here if created)\n% Synthesize a concise (1-2 paragraph) overview covering:\n% - Canonical function(s) of .\n% - Primary rationale for therapeutic interest (link to disease).\n% - Brief summary of the current state of drug discovery efforts (e.g., clinical programs, key pre-clinical inhibitors, main challenges). Mention top players if identifiable.\n% - Overall assessment of target druggability and potential.\n\n\\section{Biological Context}\n \\subsection{Function \\& Pathophysiology}\n % Analyze and synthesize findings on the established molecular and cellular functions of .\n % Detail its specific role in relevant disease pathophysiology (specify diseases). Critically evaluate evidence: Is the link causal (e.g., from genetic studies) or correlative?\n % Summarize key knockout/knock-in/knockdown phenotypes reported in model systems (cell lines, animals), citing sources.\n\n \\subsection{Interaction Network \\& Pathway Map}\n % Identify key upstream regulators, downstream effectors, and interacting partners of .\n % Generate/include a schematic diagram (\\autoref{fig:pathway_map}) illustrating these interactions and the pathway(s) operates within.\n % Cite primary sources for interactions and pathway databases (e.g., KEGG, Reactome, WikiPathways, STRING-DB). Ensure figure caption includes provenance.\n\n \\subsection{Expression Profile (Tissue \\& Cellular)}\n % Analyze and summarize quantitative mRNA and protein expression levels across major healthy human tissues (e.g., using data from GTEx, Human Protein Atlas).\n % Report expression patterns in relevant disease tissues vs. healthy controls, if data exists.\n % Include insights from single-cell RNA-seq data if available, highlighting expression in specific cell types relevant to function or disease.\n % Present key findings potentially as a summary table or figure (\\autoref{fig:expression_summary}), citing data sources precisely.\n\n \\subsection{Genetic \\& Multi-Omics Evidence Linking to Disease}\n % Synthesize evidence from human genetics: GWAS associations (report key SNPs, associated traits/diseases, effect sizes, p-values), rare variants linked to Mendelian diseases (cite OMIM/ClinVar), somatic mutations in cancer (cite COSMIC/cBioPortal).\n % Integrate findings from functional genomics: CRISPR/RNAi screens (identify dependencies, report scores like CERES/DEMETER if applicable, cite DepMap/Score), proteomics/phosphoproteomics (PTMs, interaction changes in disease), metabolomics changes linked to target activity/levels.\n % Analyze relevant QTLs (eQTLs, pQTLs) linking genetic variation to target expression/protein levels.\n % **Focus on evidence directly linking the target to human disease states.** Evaluate the strength of evidence.\n\n\\section{Structural \\& Biophysical Characterization}\n % Compile and summarize available experimental structural data from the PDB for (human and key orthologs).\n % For key structures, report PDB ID, resolution, organism, experimental method, and bound ligands/partners. Highlight structures most relevant for drug design (e.g., human protein bound to inhibitor).\n % Include analysis of computational models (e.g., AlphaFold2, RoseTTAFold), noting their confidence scores (pLDDT) especially for key domains or potential binding sites. Discuss model limitations.\n % Describe the protein's domain architecture, identifying key functional domains (e.g., kinase domain, binding domains). Pinpoint known catalytic sites or key interaction interfaces. Map known post-translational modifications (PTMs) onto the structure/sequence if possible.\n % Discuss known conformational dynamics or states based on experimental data (e.g., HDX-MS, NMR) or computational studies (MD simulations), if significant findings exist. Identify any known transient or allosteric pockets.\n % Include representative figures (\\autoref{fig:structure_overview}, \\autoref{fig:ligand_binding_site}) showing domain architecture, key sites, or ligand binding modes.\n\n\\section{Chemistry Landscape}\n \\subsection{Known Ligands & Modulators}\n % Compile a summary of known chemical matter targeting . Include diverse modalities: small molecules, fragments, peptides, biologics (antibodies, etc.).\n % For key representative compounds/series, report binding affinity (K\\textsubscript{d}, K\\textsubscript{i}), functional activity (IC\\textsubscript{50}, EC\\textsubscript{50}), and selectivity data (against key off-targets, especially paralogs) where available. Use a table for concise presentation (\\autoref{tab:known_ligands}, potentially supplementary). Cite primary literature or databases (ChEMBL, DrugBank).\n\n \\subsection{Structure–Activity Relationships (SAR)}\n % Analyze and synthesize publicly available SAR data for key chemical series targeting .\n % Identify key scaffolds, pharmacophores, and structural motifs associated with activity.\n % Highlight any reported \"activity cliffs\" (small structural changes causing large activity changes).\n % Discuss potential vectors for optimization or unexplored chemical space based on published SAR.\n\n \\subsection{Physicochemical & ADME Properties}\n % Analyze trends in physicochemical properties (e.g., MW, logP, TPSA, Fsp\\textsuperscript{3}) for known active compounds. Compare against typical drug-likeness criteria (e.g., Lipinski's Rule of 5).\n % Summarize any reported ADME (Absorption, Distribution, Metabolism, Excretion) or pharmacokinetic (PK) challenges or liabilities associated with known chemotypes targeting .\n\n \\subsection{Patent Landscape Overview}\n % Identify key assignees (companies, institutions) filing patents related to modulators.\n % Summarize the main chemical scaffold types or therapeutic approaches claimed in recent (last 5-7 years) patents.\n % Briefly describe the types of claims being made (e.g., composition of matter, method of use). Cite representative patent families/numbers.\n\n\\section{Assay Toolbox & Technology}\n% Summarize the types of assays commonly used to study and screen for modulators.\n% - *Biochemical/Biophysical Assays:* Describe common formats (e.g., enzyme kinetics, binding assays like SPR, ITC, DSF). Report typical throughput and quality metrics (e.g., Z'-factor) if published.\n% - *Cellular Assays:* Describe relevant cell-based assays measuring target engagement or downstream functional consequences (e.g., reporter assays, proliferation assays, target phosphorylation). Specify cell lines commonly used.\n% - *In Vivo Models:* Summarize established animal models (species, type e.g., xenograft, transgenic) used to evaluate efficacy or pharmacology of modulators.\n% - *Pharmacodynamic (PD) Biomarkers:* Identify any established biomarkers used to measure target engagement or biological response in pre-clinical models or clinical settings.\n\n\\section{Computational Resources & Datasets}\n% Summarize available computational resources relevant to drug discovery.\n% - *Structural Models:* Recap availability of experimental structures (PDB) and computational models (AlphaFold DB, etc.). Mention availability of pre-computed docking grids or pharmacophore models if known.\n% - *Screening Datasets:* Identify publicly available datasets suitable for virtual screening or ML model training (e.g., curated sets of SMILES strings with associated activity data from ChEMBL or PubChem BioAssay). Describe data size and quality if possible.\n% - *Modeling Workflows:* Briefly mention computational methods commonly applied to this target class (e.g., docking protocols, generative chemistry approaches, FEP/MD simulations for binding prediction), citing relevant studies if specific workflows for have been published.\n\n\\section{Safety \\& Liability Profile}\n \\subsection{Target-Related Safety Assessment}\n % Evaluate potential on-target toxicity concerns based on the biological function and expression pattern of .\n % Report essential-gene status from large-scale genetic screens (e.g., DepMap).\n % Summarize findings from in-vivo toxicology studies targeting or highly related proteins, if published.\n\n \\subsection{Off-Target Considerations}\n % Identify key paralogs or structurally related proteins that represent significant selectivity challenges. Report sequence/structural similarity.\n % Summarize known off-target liabilities of existing chemical matter (e.g., cross-reactivity reported in broad panel screens).\n % Mention potential for common promiscuous liabilities like hERG channel inhibition if relevant data exists for known ligands.\n\n \\subsection{Human Genetic Safety Flags}\n % Analyze human genetic data for potential safety signals related to target inhibition/loss-of-function.\n % Report constraint metrics (e.g., pLI, LOEUF from gnomAD) indicating intolerance to loss-of-function variation.\n % Summarize known human Mendelian diseases caused by mutations in the gene encoding (from OMIM/ClinVar), focusing on phenotypes relevant to safety.\n\n\\section{Translational \\& Clinical Considerations}\n% Synthesize information relevant to translating preclinical findings into clinical development.\n% - *Biomarkers:* Summarize potential patient stratification biomarkers (predictive) or pharmacodynamic biomarkers (response monitoring) relevant for clinical trials targeting .\n% - *Companion Diagnostics:* Mention if any companion diagnostics are necessary or in development.\n% - *Mechanisms of Resistance:* Discuss known or potential mechanisms of resistance to inhibitors based on preclinical studies or clinical observations (if available).\n% - *Formulation & Delivery:* Note any known challenges or specific requirements related to formulation or drug delivery for targeting or its associated pathways/locations.\n% - *Clinical Trials:* Summarize ongoing or completed clinical trials involving direct modulation of (list key trial IDs from ClinicalTrials.gov, phases, indications, reported status/outcomes).\n\n\\section*{References}\n% Bibliography section. Ensure `\\printbibliography` command is present here.\n% All citations referenced via \\cite{key} in the text must have a corresponding, fully formatted entry in main.bib, generated by the research process and formatted by biblatex/biber.\n\n# --- Document End ---\n# \\end{document}\n# --- End Document End ---\n\n######################################################################\n# FINAL COMPLETION CHECKLIST (AI agent must ensure ALL are satisfied)\n######################################################################\n\n* [ ] **Research Depth:** All sections and subsections in the template are addressed using synthesized information from reputable, cited sources, reflecting the Research Strategy. Handling of conflicting data and uncertainty is appropriate.\n* [ ] **Content Accuracy:** Factual claims are accurately represented from cited sources. No invented data, structures, or results. \"No public data located...\" used correctly where applicable.\n* [ ] **LaTeX Compilation:** `main.tex` compiles successfully using `latexmk -pdf -interaction=nonstopmode main.tex` with `biber`, producing no errors (unless unavoidable and documented with `% TODO:` at the top).\n* [ ] **PDF Generated:** Final, correctly named PDF (`_report.pdf`) exists and matches the compiled LaTeX source.\n* [ ] **Deliverables Complete:** ZIP archive (``) created, is < 100 MB, and contains *only* the whitelisted files: `main.tex`, `main.bib`, required `.sty` (if any), figures (`*.png`/`*.svg`), supplementary tables (`*.csv`/`*.json`), `README.txt`, and the final compiled PDF. No intermediate build files included.\n* [ ] **Formatting & Style:** Adherence to all specified LaTeX packages, sectioning, citation style (`\\cite{key}`, Vancouver via biblatex), statistical reporting, highlighting (`\\textbf{}`, `tcolorbox`), figure/table formatting (`\\autoref`, captions, provenance), and file naming conventions (`_Fig###_*`, etc.). ASCII source enforced.\n* [ ] **Citations:** Every factual claim, data point, figure, and table derived from external sources is cited inline (`\\cite{key}`). `main.bib` contains complete entries for all keys, including database access dates/versions and preprint details where applicable.\n* [ ] **Cross-referencing:** All figures and tables are referenced in the text using `\\autoref{}`. Labels (`\\label{}`) are unique.\n* [ ] **File Naming & Structure:** All assets follow the `_` naming convention with appropriate indices and descriptions. Directory structure within the ZIP is clean (ideally flat or with simple `figures`/`tables` subdirs if needed).\n* [ ] **README.txt:** Includes a one-line manifest and accurate SHA-256 checksums (64 lowercase hex chars + 2 spaces + filename) for *all* files in the archive.\n* [ ] **Placeholders:** All placeholders (``, ``, ``, ``) have been correctly substituted throughout the prompt instructions *and* the generated LaTeX/filenames.\n* [ ] **Length:** Compiled PDF page count is respected (ideally <= 30 pages). Content prioritized, large datasets moved to supplementary files.\n* [ ] **Self-Correction Applied:** Implicitly or explicitly reviewed the draft for consistency, accuracy, and adherence to all instructions before finalizing.","model_settings":{"top_p":null,"models":[],"max_tokens":null,"temperature":null,"presence_penalty":null,"frequency_penalty":null,"additional_instructions":null},"categories":[],"description":"example","updated_at":"2025-04-24T15:45:29.178625+00:00","rating":0,"fork_count":0,"profiles":{"username":"josepipe0909_66df"},"authorUsername":"josepipe0909_66df"};