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Batch effect correction for CRISPR screens covering ComBat empirical-Bayes, RUV, SVA, control-sgRNA normalization, and the model-based alternative of including batch as a covariate in MAGeCK MLE or Chronos. Covers screen-specific batch sources (passage cohort, library lot, infection day, sequencing run, Cas9 lot, FBS lot), PCA + variance-decomposition diagnostic to decide if correction is needed, when correction harms biology by over-correcting condition into batch, limma removeBatchEffect for visualization-only correction, and relationship to multi-condition design matrices. Use when combining screens for joint analysis, when passage cohort confounds biology, when DepMap-style panels need Chronos with batch covariates, when picking ComBat vs RUV, or when correction harms biology and should be replaced with explicit covariate modeling.

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Quantify homologous recombination deficiency (HRD) from tumor copy number using the three genomic-scar metrics — loss of heterozygosity (LOH), large-scale state transitions (LST), and telomeric allelic imbalance (TAI) — with scarHRD, and via the whole-genome HRDetect and CHORD models. Covers the genomic instability score, the PARP-inhibitor clinical context, whole-genome-doubling correction, and the scar-versus-state distinction. Use when computing an HRD score for PARP-inhibitor eligibility, deriving LOH/LST/TAI scars from allele-specific copy number, deciding between scar-based and mutational-signature HRD methods, or interpreting an HRD result in a BRCA-reverted or low-purity tumor.

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Analyzes base-editing screens for variant function. Covers library design (Hanna 2021 ClinVar-scale CBE screen benchmarked on BRCA1/2, Cuella-Martin 2021 DDR saturation), CBE vs ABE chemistry choice (BE3/BE4 vs ABE7.10/ABE8.20/ABE8e), editing-window math (positions 4-8 from PAM-distal end; 4-7 for ABE7.10), bystander-edit quantification and the variant-call ambiguity it creates, sgRNA-efficiency filtering before hit calling, indel byproduct interpretation, the substitution-vs-indel diagnostic, variant annotation against ClinVar / COSMIC, and the Broad be-validation-pipeline. Use when designing a BE variant screen, choosing CBE vs ABE for a specific edit, interpreting bystander-confounded hits, distinguishing functional signal from indel artifact, integrating CRISPResso2 output with screen scoring, or deciding BE vs PE for SNV installation.

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Quantifies CRISPR editing outcomes with CRISPResso2 (Clement 2019 Nat Biotechnol) across Cas9-nuclease (indels, HDR), CBE and ABE base editors (target conversion + bystander), and prime editor (pegRNA-templated) modes. Covers single-amplicon (CRISPResso), multi-sample batch (CRISPRessoBatch), pooled-amplicon (CRISPRessoPooled), WGS off-target (CRISPRessoWGS), and sample-comparison (CRISPRessoCompare) workflows; quantification-window math that controls what is called edited; substitution-vs-indel diagnostic to distinguish BE from Cas9 contamination; MMEJ deletion pattern interpretation; allele-frequency tables; and failure modes from amplicon misalignment or contamination. Use when quantifying editing from amplicon sequencing, choosing CRISPResso mode by design, distinguishing intended edits from bystanders and indel byproducts, debugging low-alignment runs, or generating publication-grade editing reports.

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Infer orthologous genes and gene families across species using OrthoFinder3 (HOG-based phylogenetic orthology), SonicParanoid2, Broccoli, ProteinOrtho, OMA / FastOMA hierarchical orthologous groups, eggNOG-mapper, JustOrthologs, and TOGA whole-genome-alignment orthology. Use when building single-copy ortholog sets for phylogenomics, classifying co-orthologs and in/out-paralogs after gene duplication, propagating functional annotation via orthology with awareness of the ortholog conjecture, distinguishing speciation from duplication via gene-tree species-tree reconciliation, computing Quest-for-Orthologs benchmark performance, or running synteny-aware ortholog detection in WGD-affected lineages.

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Discover RBP binding motifs from CLIP-seq peaks or single-nucleotide crosslink sites using HOMER, MEME/STREME, kpLogo, mCross (CL-position-registered motifs), PEKA (positional k-mer enrichment), RBPamp (affinity), and RNA Bind-n-Seq (RBNS) cross-validation. Use when characterizing RBP sequence specificity, registering motifs to crosslink positions, validating in vivo CLIP motifs against in vitro RBNS Kd, reconciling motif disagreements across tools, or correcting for the uracil crosslinking bias that contaminates raw CLIP motif logos.

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Analyzes CRISPR drug-modifier (chemogenomic) screens with drugZ (Colic et al. 2019 Genome Med), a bidirectional Z-score method that identifies synthetic-lethal sensitizing genes and resistance-conferring suppressor genes from vehicle vs drug comparisons. Covers vehicle-anchored design (not Day-0), the bidirectional Z math giving greater sensitivity to small-effect hits than MAGeCK / STARS / edgeR / RIGER on drug screens, per-gene sumZ and normZ, synth (sensitizer) vs supp (suppressor) FDR, multi-dose handling, integration with control sgRNAs, and comparison with MAGeCK MLE with dose covariate. Use when running a drug-modifier CRISPR screen, identifying sensitizing or resistance genes for a drug candidate, choosing drugZ vs MAGeCK MLE for chemogenomic analysis, troubleshooting low-effect drug screens where MAGeCK lacks sensitivity, or designing a drug-screen layout (vehicle vs drug arms).

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Designs novel molecules using REINVENT 4 (de novo, scaffold decoration, linker design, R-group, molecular optimization), MolMIM, Diffusion-based generators (DiGress, DiffSMol), and JT-VAE with explicit handling of multi-parameter optimization (MPO), goal-directed scoring functions, transfer/reinforcement/curriculum learning, synthetic accessibility scoring, and chemical space exploration vs exploitation. Use when designing new chemical matter against a target, decorating a scaffold, linking fragments, or optimizing a hit for multiple ADMET / activity properties simultaneously.

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Performs retrosynthetic planning using AiZynthFinder (template-based MCTS), maintained or version-pinned template-free models, ASKCOS, and emerging RetroSynFormer with explicit handling of route scoring, configurable MCTS rewards, building-block availability, and forward-prediction checks. Use when assessing synthetic feasibility of generated or selected molecules, planning multi-step syntheses, building synthesis-aware design pipelines, or screening libraries for retro-route feasibility.

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Designs PROTACs, molecular glues, and bivalent degraders with explicit handling of E3 ligase choice (VHL, CRBN, IAP, MDM2, KEAP1), linker design (length, composition, rigidity), ternary complex prediction (PRosettaC, DeepTernary, AlphaFold3), cooperativity (alpha), DC50 / Dmax characterization, hook effect, and prediction-experiment reconciliation. Use when designing targeted protein degraders, planning linker SAR, predicting ternary complex stability, or building generative degrader workflows.

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Designs covalent inhibitors and warheads targeting cysteine, lysine, serine, threonine, tyrosine, and aspartate residues, with explicit handling of warhead reactivity (acrylamide, chloroacetamide, vinyl sulfone, sulfonyl fluoride, fluorosulfate, aldehyde, boronate, nitrile), reversibility (kinact/Ki, t_residence), glutathione (GSH) stability, intrinsic reactivity assays, and covalent docking (DOCKovalent, GOLD, HCovDock). Use when designing covalent inhibitors for targeted covalent inhibition (TCI), KRAS G12C-style approaches, or rationalizing covalent SAR.

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Predicts whether a DNA variant alters mRNA splicing using sequence-based deep-learning tools — SpliceAI (10kb context dilated CNN, clinical default), Pangolin (multi-tissue), MMSplice (modular per-region CNN with calibrated ΔPSI), SpliceTransformer/TrASPr (tissue-aware transformers), SpliceVault (empirical 300K-RNA lookup of likely mis-splicing outcomes), CADD-Splice (composite score). Applies the ClinGen SVI 2023 framework for ACMG/AMP variant interpretation (PVS1, PP3, BP4 evidence codes), HGVS splicing nomenclature (c.123+1G>A, c.123-3T>G, r.spl?), extended-window scoring for deep-intronic pseudoexons, tissue-specific predictions, branchpoint variant detection (BPHunter, LaBranchoR), and splice-switching ASO design. Use when interpreting splice impact of clinical variants, prioritizing VUS, identifying deep-intronic pathogenic variants, or designing ASOs.

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Design and build a high-converting questionnaire-style onboarding flow for your app, modelled on proven conversion patterns from top subscription apps.

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Review TDesign Flutter 组件的公开 Demo、API 收敛、Flutter 设计模式、主题、测试和 Golden 证据。以小程序公开 Demo 作为可见效果参考，但不机械映射其 props/events；适用于组件对齐和 PR Review。

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TDesign Flutter 通用协作约定，适用于仓库开发和 PR 工作，涵盖 Spec、更新日志、公开契约、生成产物、双版本及 CI 登记。组件对齐由 Review skill 补充，CNB 平台限制见仓库协作说明。

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Use when working with camera, photos, audio, haptics, ShazamKit, on-device music analysis, face grouping and video highlights, screen recording, casting to non-AirPlay routes, SharePlay playback, the user's Apple Music library, lock-screen metadata, or CarPlay app design, templates, and navigation. Covers AVCaptureSession, AVFoundation, Core Haptics, MediaPlayer, MusicKit, NowPlaying, ScreenCaptureKit, DockKit.

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Use when making visual or interaction design decisions for an Apple app — HIG patterns, Liquid Glass, SF Symbols, typography, app entry-point and auth-flow structure.

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Apply Swift API Design Guidelines to name, label, and document Swift APIs. Covers argument label rules (prepositional phrase rule, grammatical phrase rule, first-label omission), mutating/nonmutating pair naming (-ed/-ing participle pattern, form- prefix, sort/sorted, formUnion/union), side-effect naming (noun for pure, verb for mutating), documentation comment structure (summary by declaration kind, O(1) complexity rule), clarity at call site, role-based naming, protocol naming (-able/-ible/-ing), default arguments over method families, casing conventions, and terminology. Use when designing new Swift APIs, reviewing naming and argument labels, writing documentation comments, or refactoring for call site clarity.

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Create media playback experiences using AVKit. Use when adding video players with AVPlayerViewController, enabling Picture-in-Picture, routing media with AirPlay, using SwiftUI VideoPlayer views, configuring transport controls, displaying subtitles and closed captions, or integrating AVFoundation playback with system UI.

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Implement AlarmKit alarms and countdown timers for iOS and iPadOS with Lock Screen, Dynamic Island, StandBy, and paired Apple Watch system UI. Covers AlarmManager scheduling, AlarmAttributes and AlarmPresentation, system Stop and AlarmButton secondary actions, authorization, state observation, countdown widget-extension handoff, and Live Activity integration. Use when building wake-up alarms, countdown timers, or alarm-style alerts that need Apple's system alarm experience.

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Build investor-ready pitch scripts in multiple formats (10-min, 5-min, 2-min, 1-min elevator, investor email). Produces pitch narratives, Q&A preparation, pitch scoring rubric, and optional investor roleplay practice. Use when the user wants to create a pitch, prepare for investor meetings, craft a startup pitch, write a fundraising narrative, or practice their pitch. Triggers for "pitch deck", "investor pitch", "pitch my startup", "fundraising deck", "seed deck", "how to pitch", "investor meeting", "demo day", "prepare pitch", "pitch script", "elevator pitch for investors", "pitch practice", "practice my pitch", "investor roleplay", or any request to present a startup to investors, accelerators, or partners. Works standalone — no prior startup-design session needed, but leverages its output if available.

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Design, validate, and plan a startup from scratch. Covers market research, competitive analysis, business model, brand identity, product definition, financial projections, and validation experiments. Trigger when the user has a startup idea to explore, wants to validate a business concept, needs a business plan or lean canvas, asks for market sizing or competitive landscape, wants brand positioning or go-to-market strategy, or says anything like "I have an idea for..." or "is this idea worth pursuing". Also handles resuming from a previous checkpoint.

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This skill should be used when the user asks to "verify UI changes", "test every screen and action", "run regression QA", "check a deployed UI", or "validate an extension release". Test known web and browser-extension workflows on localhost, staging, or production with action coverage, recovery, localization, accessibility, and real integration evidence. Use dogfood for open-ended bug discovery.

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Guides Metronome usage-based billing integration decisions — event ingestion (single and batch, idempotency, billable metrics), contract design (rate cards, overrides, dimensional pricing, products), invoicing lifecycle (grace periods, finalization, Stripe sync), credit and commit management (prepaid, postpaid, thresholds, auto-recharge), and Stripe integration (arrears invoicing, tax providers, line item limits). Use when building, modifying, or reviewing any Metronome integration — including ingesting usage events, creating customers, contracts, or rate cards, designing billable metric group keys, managing credits and commits, configuring invoicing, syncing invoices with Stripe Billing, billing AI applications for token usage, setting up self-serve (PLG) pricing, reviewing customer health, commit burn, portfolios, or renewals, or migrating from Stripe Billing Meters to Metronome.

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