@bgicli/bgicli 2.1.1 → 2.2.0

package/data/skills/boltzgen/SKILL.md

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+---
+name: boltzgen
+description: >
+  All-atom protein design using BoltzGen diffusion model. Use this skill when:
+  (1) Need side-chain aware design from the start,
+  (2) Designing around small molecules or ligands,
+  (3) Want all-atom diffusion (not just backbone),
+  (4) Require precise binding geometries,
+  (5) Using YAML-based configuration.
+
+  For backbone-only generation, use rfdiffusion.
+  For sequence-only design, use proteinmpnn.
+  For structure validation, use boltz.
+license: MIT
+category: design-tools
+tags: [structure-design, sequence-design, diffusion, all-atom, binder]
+proteinbase_slug: boltzgen
+proteinbase_url: https://proteinbase.com/design-methods/boltzgen
+biomodals_script: modal_boltzgen.py
+---
+
+# BoltzGen All-Atom Design
+
+## Prerequisites
+
+| Requirement | Minimum | Recommended |
+|-------------|---------|-------------|
+| Python | 3.10+ | 3.11 |
+| CUDA | 12.0+ | 12.1+ |
+| GPU VRAM | 24GB | 48GB (L40S) |
+| RAM | 32GB | 64GB |
+
+## How to run
+
+> **First time?** See [Installation Guide](../../docs/installation.md) to set up Modal and biomodals.
+
+### Option 1: Modal (recommended)
+```bash
+# Clone biomodals
+git clone https://github.com/hgbrian/biomodals && cd biomodals
+
+# Run BoltzGen (requires YAML config file)
+modal run modal_boltzgen.py \
+  --input-yaml binder_config.yaml \
+  --protocol protein-anything \
+  --num-designs 50
+
+# With custom GPU
+GPU=L40S modal run modal_boltzgen.py \
+  --input-yaml binder_config.yaml \
+  --protocol protein-anything \
+  --num-designs 100
+```
+
+**GPU**: L40S (48GB) recommended | **Timeout**: 120min default
+
+**Available protocols**: `protein-anything`, `peptide-anything`, `protein-small_molecule`, `nanobody-anything`, `antibody-anything`
+
+### Option 2: Local installation
+```bash
+git clone https://github.com/HannesStark/boltzgen.git
+cd boltzgen
+pip install -e .
+
+python sample.py config=config.yaml
+```
+
+### Option 3: Python API
+```python
+from boltzgen import BoltzGen
+
+model = BoltzGen.load_pretrained()
+designs = model.sample(
+    target_pdb="target.pdb",
+    num_samples=50,
+    binder_length=80
+)
+```
+
+**GPU**: L40S (48GB) | **Time**: ~30-60s per design
+
+## Key parameters (CLI)
+
+| Parameter | Default | Description |
+|-----------|---------|-------------|
+| `--input-yaml` | required | Path to YAML design specification |
+| `--protocol` | `protein-anything` | Design protocol |
+| `--num-designs` | 10 | Number of designs to generate |
+| `--steps` | all | Pipeline steps to run (e.g., `design inverse_folding`) |
+
+## YAML configuration
+
+BoltzGen uses an **entity-based YAML format** where you specify designed proteins and target structures as entities.
+
+**Important notes:**
+- Residue indices use `label_seq_id` (1-indexed), not author residue numbers
+- File paths are relative to the YAML file location
+- Target files should be in CIF format (PDB also works but CIF preferred)
+- Run `boltzgen check config.yaml` to verify your specification before running
+
+### Basic Binder Config
+```yaml
+entities:
+  # Designed protein (variable length 80-140 residues)
+  - protein:
+      id: B
+      sequence: 80..140
+
+  # Target from structure file
+  - file:
+      path: target.cif
+      include:
+        - chain:
+            id: A
+      # Specify binding site residues (optional but recommended)
+      binding_types:
+        - chain:
+            id: A
+            binding: 45,67,89
+```
+
+### Binder with Specific Binding Site
+```yaml
+entities:
+  - protein:
+      id: G
+      sequence: 60..100
+
+  - file:
+      path: 5cqg.cif
+      include:
+        - chain:
+            id: A
+      binding_types:
+        - chain:
+            id: A
+            binding: 343,344,251
+      structure_groups: "all"
+```
+
+### Peptide Design (Cyclic)
+```yaml
+entities:
+  - protein:
+      id: S
+      sequence: 10..14C6C3  # With cysteines for disulfide
+
+  - file:
+      path: target.cif
+      include:
+        - chain:
+            id: A
+
+constraints:
+  - bond:
+      atom1: [S, 11, SG]
+      atom2: [S, 18, SG]  # Disulfide bond
+```
+
+## Design protocols
+
+| Protocol | Use Case |
+|----------|----------|
+| `protein-anything` | Design proteins to bind proteins or peptides |
+| `peptide-anything` | Design cyclic peptides to bind proteins |
+| `protein-small_molecule` | Design proteins to bind small molecules |
+| `nanobody-anything` | Design nanobody CDRs |
+| `antibody-anything` | Design antibody CDRs |
+
+## Output format
+
+```
+output/
+├── sample_0/
+│   ├── design.cif         # All-atom structure (CIF format)
+│   ├── metrics.json       # Confidence scores
+│   └── sequence.fasta     # Sequence
+├── sample_1/
+│   └── ...
+└── summary.csv
+```
+
+**Note**: BoltzGen outputs CIF format. Convert to PDB if needed:
+```python
+from Bio.PDB import MMCIFParser, PDBIO
+parser = MMCIFParser()
+structure = parser.get_structure("design", "design.cif")
+io = PDBIO()
+io.set_structure(structure)
+io.save("design.pdb")
+```
+
+## Sample output
+
+### Successful run
+```
+$ modal run modal_boltzgen.py --input-yaml binder.yaml --protocol protein-anything --num-designs 10
+Running: boltzgen run binder.yaml --output /tmp/out --protocol protein-anything --num_designs 10
+[INFO] Loading BoltzGen model...
+[INFO] Generating designs...
+[INFO] Running inverse folding...
+[INFO] Running structure prediction...
+[INFO] Filtering and ranking...
+[INFO] Pipeline complete
+
+Results saved to: ./out/boltzgen/2501161234/
+```
+
+**Output directory structure:**
+```
+out/boltzgen/2501161234/
+├── intermediate_designs/           # Raw diffusion outputs
+│   ├── design_0.cif
+│   └── design_0.npz
+├── intermediate_designs_inverse_folded/
+│   ├── refold_cif/                 # Refolded complexes
+│   └── aggregate_metrics_analyze.csv
+└── final_ranked_designs/
+    ├── final_10_designs/           # Top designs
+    └── results_overview.pdf        # Summary plots
+```
+
+**What good output looks like:**
+- Refolding RMSD < 2.0A (design folds as predicted)
+- ipTM > 0.5 (confident interface)
+- All designs complete pipeline without errors
+
+## Decision tree
+
+```
+Should I use BoltzGen?
+│
+├─ What type of design?
+│  ├─ All-atom precision needed → BoltzGen ✓
+│  ├─ Ligand binding pocket → BoltzGen ✓
+│  └─ Standard miniprotein → RFdiffusion (faster)
+│
+├─ What matters most?
+│  ├─ Side-chain packing → BoltzGen ✓
+│  ├─ Speed / diversity → RFdiffusion
+│  ├─ Highest success rate → BindCraft
+│  └─ AF2 optimization → ColabDesign
+│
+└─ Compute resources?
+   ├─ Have L40S/A100 (48GB+) → BoltzGen ✓
+   └─ Only A10G (24GB) → Consider RFdiffusion
+```
+
+## Typical performance
+
+| Campaign Size | Time (L40S) | Cost (Modal) | Notes |
+|---------------|-------------|--------------|-------|
+| 50 designs | 30-45 min | ~$8 | Quick exploration |
+| 100 designs | 1-1.5h | ~$15 | Standard campaign |
+| 500 designs | 5-8h | ~$70 | Large campaign |
+
+**Per-design**: ~30-60s for typical binder.
+
+---
+
+## Verify
+
+```bash
+find output -name "*.cif" | wc -l  # Should match num_samples
+```
+
+---
+
+## Troubleshooting
+
+**Verify config first**: Always run `boltzgen check config.yaml` before running the full pipeline
+**Slow generation**: Use fewer designs for initial testing, then scale up
+**OOM errors**: Use A100-80GB or reduce `--num-designs`
+**Wrong binding site**: Residue indices use `label_seq_id` (1-indexed), check in Molstar viewer
+
+### Error interpretation
+
+| Error | Cause | Fix |
+|-------|-------|-----|
+| `RuntimeError: CUDA out of memory` | Large design or long protein | Use A100-80GB or reduce designs |
+| `FileNotFoundError: *.cif` | Target file not found | File paths are relative to YAML location |
+| `ValueError: invalid chain` | Chain not in target | Verify chain IDs with Molstar or PyMOL |
+| `modal: command not found` | Modal CLI not installed | Run `pip install modal && modal setup` |
+
+---
+
+**Next**: Validate with `boltz` or `chai` → `protein-qc` for filtering.

package/data/skills/bone-marrow-ai-agent/SKILL.md

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+<!--
+# COPYRIGHT NOTICE
+# This file is part of the "Universal Biomedical Skills" project.
+# Copyright (c) 2026 MD BABU MIA, PhD <md.babu.mia@mssm.edu>
+# All Rights Reserved.
+#
+# This code is proprietary and confidential.
+# Unauthorized copying of this file, via any medium is strictly prohibited.
+#
+# Provenance: Authenticated by MD BABU MIA
+
+-->
+
+---
+name: 'bone-marrow-ai-agent'
+description: 'AI-powered bone marrow morphology analysis, cell classification, and hematologic disorder diagnosis using deep learning on aspirate and biopsy images.'
+measurable_outcome: Execute skill workflow successfully with valid output within 15 minutes.
+allowed-tools:
+  - read_file
+  - run_shell_command
+---
+
+
+# Bone Marrow AI Agent
+
+The **Bone Marrow AI Agent** provides comprehensive AI-driven analysis of bone marrow aspirate and biopsy specimens. It performs automated cell identification, differential counting, morphological assessment, and pattern recognition for hematologic disease diagnosis.
+
+## When to Use This Skill
+
+* When performing automated bone marrow differential counts from aspirate smears.
+* To identify morphological abnormalities (dysplasia, blasts, abnormal cells).
+* For pattern recognition in myelodysplastic syndromes (MDS), leukemias, and other disorders.
+* When assessing cellularity, fibrosis, and infiltration in trephine biopsies.
+* To standardize morphological assessment across institutions.
+
+## Core Capabilities
+
+1. **Cell Classification**: Deep learning identification and classification of 15+ bone marrow cell types with >95% accuracy.
+
+2. **Automated Differential**: Rapid 500-cell differential counts from digital aspirate images.
+
+3. **Dysplasia Detection**: AI recognition of dyserythropoiesis, dysgranulopoiesis, and dysmegakaryopoiesis.
+
+4. **Blast Quantification**: Accurate blast percentage enumeration for AML/MDS classification.
+
+5. **Biopsy Analysis**: Cellularity estimation, fibrosis grading, and infiltration pattern recognition.
+
+6. **Quality Assessment**: Automated specimen adequacy and hemodilution detection.
+
+## Cell Types Classified
+
+| Lineage | Cell Types | Key Features |
+|---------|------------|--------------|
+| Erythroid | Pronormoblast, basophilic, polychromatic, orthochromatic | Size, chromatin, cytoplasm color |
+| Myeloid | Myeloblast, promyelocyte, myelocyte, metamyelocyte, band, seg | Granules, nuclear shape |
+| Monocytic | Monoblast, promonocyte, monocyte | Nuclear folding, cytoplasm |
+| Lymphoid | Lymphocyte, plasma cell | Size, chromatin density |
+| Megakaryocytic | Megakaryocytes (all stages) | Size, nuclear lobation |
+| Other | Mast cells, osteoblasts, osteoclasts | Distinctive morphology |
+
+## Workflow
+
+1. **Input**: Bone marrow aspirate images (Wright-Giemsa stained) or biopsy sections (H&E).
+
+2. **Preprocessing**: Color normalization, focus stacking, region of interest selection.
+
+3. **Cell Detection**: Instance segmentation to identify individual cells.
+
+4. **Classification**: CNN/CoAtNet model assigns cell type labels.
+
+5. **Differential**: Aggregate counts and calculate percentages.
+
+6. **Pattern Recognition**: Identify disease-associated morphological patterns.
+
+7. **Output**: Differential count, morphology report, diagnostic suggestions.
+
+## Example Usage
+
+**User**: "Analyze this bone marrow aspirate smear and provide a differential count with morphological assessment."
+
+**Agent Action**:
+```bash
+python3 Skills/Hematology/Bone_Marrow_AI_Agent/bm_analyzer.py \
+    --image aspirate_smear.tiff \
+    --stain wright_giemsa \
+    --target_cells 500 \
+    --assess_dysplasia true \
+    --model coatnet_bm_v2 \
+    --output bm_report.json
+```
+
+## Model Architecture
+
+**CoAtNet Hybrid Model**:
+- Combines CNN (local features) with Transformer (global context)
+- Pre-trained on 100,000+ annotated bone marrow cells
+- Achieves >95% accuracy on cell classification
+- Real-time inference (<1 second per cell)
+
+**Training Data Sources**:
+- Munich AML Morphology Dataset (Matek et al.)
+- Multi-institutional bone marrow collections
+- Expert hematopathologist annotations
+
+## Diagnostic Pattern Recognition
+
+| Pattern | Associated Conditions | AI Features |
+|---------|----------------------|-------------|
+| Increased blasts | AML, MDS, ALL | Blast%, CD34 correlation |
+| Dysplastic features | MDS, AML-MRC | Hypolobation, ring sideroblasts |
+| Left shift | Infection, CML, recovery | Myeloid maturation pyramid |
+| Plasma cell infiltration | Myeloma, MGUS | Plasma cell%, morphology |
+| Lymphoid aggregates | CLL, lymphoma | Pattern, location |
+
+## FDA-Cleared and Research Systems
+
+| System | Approval | Application |
+|--------|----------|-------------|
+| CellaVision | FDA cleared | Peripheral blood and BM |
+| Scopio Labs X100 | FDA cleared | Full-field digital morphology |
+| Techcyte | Research | AI-powered hematology |
+| Morphogo | Research | Deep learning cytology |
+
+## Quality Metrics
+
+**Performance Benchmarks**:
+- Cell classification accuracy: >95%
+- Blast detection sensitivity: >98%
+- Dysplasia recognition: >90% concordance with experts
+- Processing speed: 500-cell differential in <2 minutes
+
+**Quality Flags**:
+- Hemodilution detection
+- Specimen adequacy assessment
+- Staining quality evaluation
+- Artifacts and debris identification
+
+## Prerequisites
+
+* Python 3.10+
+* PyTorch with CoAtNet/ViT models
+* OpenCV for image processing
+* Digital pathology scanner or microscope camera
+
+## Related Skills
+
+* Flow_Cytometry_AI - For immunophenotyping correlation
+* AML_Classification - For WHO/ICC AML subtyping
+* MDS_Diagnosis - For MDS-specific analysis
+
+## Clinical Integration
+
+1. **LIS Interface**: HL7/FHIR export of results
+2. **Quality Assurance**: Flagging for pathologist review
+3. **Documentation**: Automated report generation
+4. **Audit Trail**: All AI decisions logged
+
+## Author
+
+AI Group - Biomedical AI Platform
+
+
+<!-- AUTHOR_SIGNATURE: 9a7f3c2e-MD-BABU-MIA-2026-MSSM-SECURE -->

package/data/skills/brainstorming/SKILL.md

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+---
+name: brainstorming
+description: "You MUST use this before any creative work - creating features, building components, adding functionality, or modifying behavior. Explores user intent, requirements and design before implementation."
+---
+
+# Brainstorming Ideas Into Designs
+
+## Overview
+
+Help turn ideas into fully formed designs and specs through natural collaborative dialogue.
+
+Start by understanding the current project context, then ask questions one at a time to refine the idea. Once you understand what you're building, present the design and get user approval.
+
+<HARD-GATE>
+Do NOT invoke any implementation skill, write any code, scaffold any project, or take any implementation action until you have presented a design and the user has approved it. This applies to EVERY project regardless of perceived simplicity.
+</HARD-GATE>
+
+## Anti-Pattern: "This Is Too Simple To Need A Design"
+
+Every project goes through this process. A todo list, a single-function utility, a config change — all of them. "Simple" projects are where unexamined assumptions cause the most wasted work. The design can be short (a few sentences for truly simple projects), but you MUST present it and get approval.
+
+## Checklist
+
+You MUST create a task for each of these items and complete them in order:
+
+1. **Explore project context** — check files, docs, recent commits
+2. **Ask clarifying questions** — one at a time, understand purpose/constraints/success criteria
+3. **Propose 2-3 approaches** — with trade-offs and your recommendation
+4. **Present design** — in sections scaled to their complexity, get user approval after each section
+5. **Write design doc** — save to `docs/plans/YYYY-MM-DD-<topic>-design.md` and commit
+6. **Transition to implementation** — invoke writing-plans skill to create implementation plan
+
+## Process Flow
+
+```dot
+digraph brainstorming {
+    "Explore project context" [shape=box];
+    "Ask clarifying questions" [shape=box];
+    "Propose 2-3 approaches" [shape=box];
+    "Present design sections" [shape=box];
+    "User approves design?" [shape=diamond];
+    "Write design doc" [shape=box];
+    "Invoke writing-plans skill" [shape=doublecircle];
+
+    "Explore project context" -> "Ask clarifying questions";
+    "Ask clarifying questions" -> "Propose 2-3 approaches";
+    "Propose 2-3 approaches" -> "Present design sections";
+    "Present design sections" -> "User approves design?";
+    "User approves design?" -> "Present design sections" [label="no, revise"];
+    "User approves design?" -> "Write design doc" [label="yes"];
+    "Write design doc" -> "Invoke writing-plans skill";
+}
+```
+
+**The terminal state is invoking writing-plans.** Do NOT invoke frontend-design, mcp-builder, or any other implementation skill. The ONLY skill you invoke after brainstorming is writing-plans.
+
+## The Process
+
+**Understanding the idea:**
+- Check out the current project state first (files, docs, recent commits)
+- Ask questions one at a time to refine the idea
+- Prefer multiple choice questions when possible, but open-ended is fine too
+- Only one question per message - if a topic needs more exploration, break it into multiple questions
+- Focus on understanding: purpose, constraints, success criteria
+
+**Exploring approaches:**
+- Propose 2-3 different approaches with trade-offs
+- Present options conversationally with your recommendation and reasoning
+- Lead with your recommended option and explain why
+
+**Presenting the design:**
+- Once you believe you understand what you're building, present the design
+- Scale each section to its complexity: a few sentences if straightforward, up to 200-300 words if nuanced
+- Ask after each section whether it looks right so far
+- Cover: architecture, components, data flow, error handling, testing
+- Be ready to go back and clarify if something doesn't make sense
+
+## After the Design
+
+**Documentation:**
+- Write the validated design to `docs/plans/YYYY-MM-DD-<topic>-design.md`
+- Use elements-of-style:writing-clearly-and-concisely skill if available
+- Commit the design document to git
+
+**Implementation:**
+- Invoke the writing-plans skill to create a detailed implementation plan
+- Do NOT invoke any other skill. writing-plans is the next step.
+
+## Key Principles
+
+- **One question at a time** - Don't overwhelm with multiple questions
+- **Multiple choice preferred** - Easier to answer than open-ended when possible
+- **YAGNI ruthlessly** - Remove unnecessary features from all designs
+- **Explore alternatives** - Always propose 2-3 approaches before settling
+- **Incremental validation** - Present design, get approval before moving on
+- **Be flexible** - Go back and clarify when something doesn't make sense