「signing」の検索結果

画面の設計判断（ナビゲーション・重ね方・通知と空状態と読み込み・外枠とトークンと状態表現）の型を決定表で選び、アプリ内の全画面で揃える。画面・ページ・レイアウト・ナビゲーション・ダイアログ・コンポーネントを新しく作る・作り直す時、モックやダッシュボードを作る時、サイドバー・タブ・モーダル・シート・toast・バナー・空状態のどれを使うか決める時に使用。PJ に components.json があれば shadcn の部品とトークンへの対応も扱う。主要なデザインシステム（Material・HIG・Carbon・Primer・Atlassian・Fluent・GOV.UK・NN/g・WAI-ARIA APG・WCAG）の一致点を規則にし、食い違いの採否を定めてある。境界: 画面の文言は writing-ui-text、画面に何を出すかと提示前の完了基準は context/ui-artifact-standards.md、コードの実装原則は writing-code、shadcn 部品の API と組み立ては shadcn。

Designs donor/repair templates for precise CRISPR knock-ins -- choosing the format (ssODN, long-ssDNA/Easi-CRISPR, dsDNA/plasmid, AAV6), sizing homology arms, placing the cut within ~10 bp of the edit, and adding a mandatory codon-checked blocking (PAM/seed) mutation so the edited allele is not re-cut. Frames the HDR-vs-NHEJ-vs-MMEJ pathway competition, the MMEJ (PITCh) and homology-independent (HITI/HMEJ) alternatives for post-mitotic cells, ssODN strand/asymmetry choice, phosphorothioate end-protection, and ranked HDR enhancers. Use when designing a donor for a point mutation, epitope/fluorophore tag, allele replacement, or knock-in, or when HDR efficiency is low. Guide design and base/prime editing are separate skills.

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Designs pegRNAs and nicking guides for prime editing (PE) -- choosing the nick/strand, tuning the primer-binding site (PBS) and reverse-transcription template (RTT) as a per-locus panel, selecting the PE system (PE2/PE3/PE3b/PE4/PE5/PEmax/PE7), adding MMR-evading and PAM-disrupting silent edits, appending epegRNA 3' motifs (tevopreQ1/mpknot), and ranking with PRIDICT/DeepPrime. Covers twinPE/PASTE for large insertions and the prime-vs-base-editing decision. Use when designing a scarless point mutation, small insertion/deletion, or any of the 12 base conversions without a double-strand break, when efficiency is low and MMR inhibition or pegRNA stabilization is needed, or when routing a large insertion to an integrase method. Generic guide scoring and base editing are separate skills.

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Performs proximity operations on genomic intervals with bedtools (closest, window, flank, slop) and pybedtools - nearest-feature queries with signed/strand-aware distance, fixed-radius window searches, strand-aware promoter construction, and interval extension. Covers the closest -d/-D a/b/ref/-t/-k/-io/-iu/-id flags, the -D ref strand sign-flip, silent chromosome-end clipping in slop/flank, -t all tie double-counting, and the critical distinction between a geometry answer (nearest TSS) and a biology answer (which gene an element regulates). Use when assigning peaks or variants to genes, defining promoters from a gene model, building distance-to-TSS distributions, finding features within a window, or extending intervals - and when deciding whether nearest-gene is a fair prior (GWAS locus) or a trap (distal enhancer).

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Structures biological experiments so inference is valid by construction, covering Fisher's principles (randomization, replication, local control), the experimental-vs-observational unit distinction and pseudoreplication (Hurlbert 1984; Lazic 2018), randomization mechanics (complete, restricted, stratified, rerandomization, run-order), blocking layouts (randomized complete block, Latin square, incomplete block), factorial designs and interactions, and the split-plot/nested error strata hidden inside multi-batch genomics. Use when deciding the experimental unit and what counts as a replicate, planning randomization and run order, choosing a blocked/factorial/split-plot/nested layout, avoiding pseudoreplication in cell-culture or animal studies, or specifying the random-effects structure of the analysis model. For assigning samples to sequencing batches/lanes/plates and batch-effect correction see experimental-design/batch-design; for regulated clinical-trial randomization see clinical-biostatistics.

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Designs genomics experiments so technical nuisance variation (batch, lane, plate, flow cell, operator, reagent lot, processing day) is balanced against the biological variable of interest and therefore estimable rather than confounded, using constrained sample-to-batch assignment (designit, OSAT), the confounder/mediator/collider distinction, and the principle that no post-hoc correction recovers a fully confounded design. Covers detecting hidden batches with surrogate variable analysis, a decision table for downstream correction (ComBat-seq, RUVSeq, SVA) whose execution is deferred to differential-expression/batch-correction, and reproducibility metadata. Use when assigning samples to sequencing batches/lanes/plates, avoiding batch-condition confounding, deciding whether a design is salvageable by correction, choosing a correction method, or estimating the number of hidden batches. For the experimental unit, randomization, and blocking concepts see experimental-design/randomization-blocking.

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Handles batch effects in bulk RNA-seq via design-matrix inclusion (the correct path for DE), ComBat/ComBat-seq for visualization, SVA for unknown latent factors, RUVSeq for negative-control-gene-anchored unwanted variation, and limma::removeBatchEffect for plotting only. Encodes the Nygaard 2016 cardinal sin against testing on a batch-corrected matrix, the choice between SVA/RUVg/RUVs/RUVr, the confounding non-identifiability problem, the single-cell boundary (Harmony/MNN are NOT for bulk), and the Goh 2017 harmonization critique. Use when designing a DE analysis with batch structure, troubleshooting batch-dominated PCA, choosing ComBat vs ComBat-seq, handling unknown batch via SVA, integrating across studies, or deciding when (rarely) to subtract batch.

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Assigns pathogen lineages (SARS-CoV-2 Pangolin via UShER mode; Nextclade clade + QC; pango-designation alias_key.json resolution) and tracks variant frequencies over time using Nextstrain (Augur + Auspice), wastewater deconvolution (Freyja, COJAC, alcov, lineagespot), lineage fitness modelling (Wenseleers / Bedford-Figgins multinomial logistic), and recombinant detection (3SEQ, RDP4, Bolotie). Covers Pangolin pangolin-data version pinning (mandatory for reproducibility), Nextclade dataset versioning (lineage-defining mutations change with dataset), Freyja barcode forward-only date constraint, ARTIC primer scheme version churn (V3 / V4 / V4.1 / V5.3.2 / Midnight 1200) with documented dropout regions, recombinant X-prefix Pango designation lag, GISAID vs INSDC dual-deposition tensions, and the Karthikeyan 2022 wastewater early-detection signal with explicit reproducibility caveats. Use when assigning Pango lineages and Nextclade clades to viral consensus sequences, building Nextstrain Augur surveillance pipelines, deconvolving wastewater pooled samples into lineage frequencies with Freyja, tracking lineage frequencies and growth advantages over time, pinning pangolin-data / Nextclade dataset versions for reproducibility, handling ARTIC primer dropouts (V4.1 amplicons 64 / 76 / 88-90), or running variant surveillance for SARS-CoV-2 / influenza / Mpox / RSV / H5N1 / measles.

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Assigns isolate identity at the right resolution for the question -- ANI / Mash species triage, 7-locus MLST historical comparability, cgMLST / wgMLST outbreak resolution (chewBBACA, BIGSdb, Ridom SeqSphere, EnteroBase HierCC), in-silico serotyping (SISTR, SeqSero2 for Salmonella; SerotypeFinder for E. coli; Kaptive K/O for Klebsiella; SeroBA for pneumococcus; spa + SCCmec for S. aureus), and lineage callers (TB-Profiler / Mykrobe Coll-Napier barcode for MTBC, Pangolin + Nextclade for SARS-CoV-2, PopPUNK GPSC for S. pneumoniae). Use when typing bacterial isolates for surveillance or outbreak investigation, choosing between cgMLST allele distance and core-SNP distance for cluster definition, harmonising calls across schemas / database versions (chewBBACA vs Ridom vs EnteroBase), assigning MTBC lineage with the Napier 2020 90-SNP barcode, calling Salmonella serovar via SISTR with monophasic Typhimurium awareness, running Pangolin UShER mode with explicit pangolin-data version pinning, or selecting a typing resolution to match the surveillance question.

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Analyzes CRISPR drug-modifier (chemogenomic) screens with drugZ (Li & Hart 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 2-3x sensitivity over 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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Download large datasets from NCBI efficiently using EPost, history server, batching, rate limiting, and retry logic. Use when bulk-fetching tens of thousands of sequences, pulling all results of a large ESearch, designing reproducible pipelines, comparing E-utilities to NCBI Datasets v2 CLI, or implementing checksum-validated downloads. Encodes WebEnv TTL (~8h), EPost 200-ID limit, retmax caps, parallelization design, and integrity verification.

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Analyzes base-editing screens for variant function. Covers library design (Sanson 2020 GRACE, Hanna 2021 BRCA1/2 SNV scanning, Cuella-Martin 2021), CBE vs ABE chemistry choice (BE3/BE4 vs ABE7.10/ABE8.20/ABE8e), editing-window math (positions 4-8 from PAM-distal end, wider for ABE8e), 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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Designs and analyzes combinatorial CRISPR screens covering paired-Cas9 (Big Papi, Najm 2018), enhanced AsCas12a multiplex (enCas12a, DeWeirdt 2021), in4mer 4-guide-array Cas12a (Esmaeili Anvar N et al 2024 Nat Commun 15:3577) and the Inzolia paralog-pair library, paralog-buffering detection (Dede 2020 Genome Biol; Thompson 2021 Cell Reports 36:109597), genetic-interaction (GI) scoring as observed_double_LFC minus expected_additive_double_LFC, synthetic-lethal and synthetic-rescue interaction interpretation, the half-of-essentiality buffered by paralogs phenomenon, multiplex screen statistical analysis with MAGeCK MLE interaction terms, and the relationship to single-cell combinatorial Perturb-seq. Use when designing a paralog or pathway-pair screen, choosing between paired-Cas9 (Big Papi) and Cas12a multiplex (Inzolia), interpreting genetic interaction scores, identifying synthetic-lethal targets for drug development, or scaling beyond single-gene CRISPR screens.

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Designs and analyzes pooled prime-editor (PE) screens for installing precise genetic variants without bystander confounding. Covers pegRNA design with PRIDICT and PRIDICT2 (Mathis 2023/2024) for predicting per-pegRNA editing efficiency, pegRNA architecture (spacer + scaffold + PBS + RTT), PE2 / PE3 / PE3b / PEmax / PEAR variants, MOSAIC in situ saturation mutagenesis (Hsu JY et al 2024 bioRxiv), the PRIME pooled-screen methodology (Erwood/Doman 2023 Nat Biotechnol 41:885; ~3,699 ClinVar variant screens), chromatin context as a primary determinant of PE efficiency, scaffold-incorporation and indel byproduct quantification with CRISPResso2, and the cross-modal validation strategy of PE + base-editor screens for variant function. Use when designing a pegRNA library for variant installation, choosing between BE and PE for a specific edit, predicting pegRNA efficiency before library synthesis, analyzing PE screen output, distinguishing intended-edit from scaffold-incorporation, or scaling PE screens to thousands of variants.

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Designs pooled sgRNA libraries for CRISPR knockout, interference (CRISPRi), activation (CRISPRa), Cas12a multiplex, base-editor, and prime-editor screens. Covers on-target scoring (Rule Set 2, Azimuth, DeepSpCas9, CRISPRon), off-target scoring (CFD, MIT), TSS-relative positioning for CRISPRi/a (Horlbeck, Dolcetto, Calabrese), PAM-variant chemistries, control-guide composition, oligo cloning architecture, and library QC. Use when choosing a genome-wide library (GeCKOv2 vs Avana vs Brunello vs TKOv3 vs Inzolia), designing a focused or paralog-focused custom library, picking CRISPRi vs CRISPRa TSS windows, deciding control-guide proportions, or diagnosing library skew and dropout in a freshly cloned pool.

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Designs and analyzes in vivo CRISPR screens in animal tumor models, organoids, and immune-cell adoptive transfers. Covers bottleneck math (250x cells/sgRNA requires ~25M cells implanted; impossible for most syngeneic models, forcing focused libraries), focused library design (Manguso 2017 Nature 547:413 immune screen; Chen 2015 tumor screens), CRISPR-StAR intrinsic-control screening (Uijttewaal 2025 Nat Biotechnol 43:1848), clonal-dynamics-limited detection, tumor-explant DNA recovery, syngeneic vs xenograft vs PDX considerations, and the relationship to downstream MAGeCK / drugZ analysis. Use when designing in vivo CRISPR screens for tumor / immune / metastasis biology, choosing focused vs genome-wide for animal models, addressing bottleneck-induced clonal collapse, picking the syngeneic / xenograft / PDX model, integrating in vivo with in vitro results, or applying CRISPR-StAR for animal experiments.

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Applies ACMG/AMP 2015 framework with ClinGen SVI specifications, Tavtigian 2018/2020 Bayesian point system, Abou Tayoun 2018 PVS1 decision tree, Pejaver 2022 calibrated PP3/BP4 thresholds for REVEL/BayesDel/AlphaMissense, Brnich 2020 PS3/BS3 OddsPath, Walker 2023 SpliceAI splicing framework, and AMP/ASCO/CAP 2017 tumor tiers. Use when classifying germline variants P / LP / VUS / LB / B, applying VCEP-specific CSpec rules, computing Whiffin BS1, or assigning cancer Tier I-IV per Li 2017.

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Identify differentially bound regions across CLIP-seq conditions (knockdown vs control, treatment vs vehicle, disease vs healthy) using DEWSeq (sliding-window DESeq2), Flipper (Skipper-downstream), ASpeak, edgeR, or limma-voom. Use when computing condition-level changes in RBP binding intensity, choosing peak-level vs window-level vs crosslink-level testing, designing replicate experiments, or distinguishing biological binding shifts from technical confounders.

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Classify constitutional (germline) copy number variants for clinical reporting using the 2019 ACMG/ClinGen technical standards points-based framework, with ClassifyCNV and AnnotSV for semi-automated scoring. Covers the separate copy-number-loss and copy-number-gain rubrics, the five-tier classification, ClinGen haploinsufficiency/triplosensitivity and dosage-sensitive regions, de novo and segregation evidence, and population-frequency benign evidence. Use when assigning pathogenic/likely-pathogenic/VUS/likely-benign/benign to a constitutional CNV, scoring a CNV against ACMG/ClinGen criteria, or distinguishing the automatable evidence from the case-specific evidence requiring manual input.

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Reconstruct ancestral states at internal phylogenetic nodes for sequences (PAML codeml, IQ-TREE --ancestral, GRASP, FastML), discrete traits (corHMM hidden-rate Markov, ape::ace, phytools::make.simmap stochastic mapping, BayesTraits), and continuous traits (phytools::fastAnc, geiger Brownian/OU, RPANDA). Use when designing constructs for ancestral protein resurrection, tracing trait evolution along a tree, performing stochastic character mapping, testing models of trait evolution (BM vs OU vs EB), inferring ancestral genome content via Dollo or DTL reconciliation, or quantifying ancestral-state uncertainty for downstream comparative analyses.

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Compute genome-to-genome distances (ANI, AAI, dDDH, k-mer Mash) and assign taxonomic classifications using skani (Shaw 2023), FastANI (Jain 2018), pyani / pyANI ANIb / ANIm, OrthoANI (Lee 2016), AAI (amino-acid identity), dDDH via TYGS / GGDC, GTDB-Tk (Chaumeil 2020 standard prokaryote taxonomy), and Mash MinHash (Ondov 2016). Use when delineating prokaryote species (95% ANI threshold; Jain 2018 Nat Commun 9:5114), assigning genomes to GTDB taxonomy with ANI radius, computing genome similarity matrices for clustering, classifying archaea, evaluating MAG (metagenome-assembled genome) species assignment, applying skani for fast metagenomic ANI screening, or reconciling 16S rRNA-based taxonomy with whole-genome ANI.

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Designs Bayesian clinical trials including Phase I dose-finding (BOIN, CRM, EWOC, mTPI-2), meta-analytic-predictive (MAP) priors with robust mixtures for external data borrowing, EXNEX for basket trials, hierarchical models for safety AE (Berry-Berry), Bayesian platform trials (I-SPY 2, GBM AGILE, REMAP-CAP), and posterior probability stopping rules. Covers FDA Bayesian Devices Guidance (2010), FDA Bayesian Methodology in Drugs Draft (January 2026), BOIN Fit-for-Purpose qualification (December 2021), and Project Optimus dose-optimisation. Use when designing dose-finding studies, platform trials, or sensitivity analyses with informative priors.

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Implements multiplicity control for confirmatory clinical trials using graphical procedures (Bretz-Maurer-Hommel), gatekeeping (parallel, serial, mixed), Hochberg/Hommel/Holm with PRDS, and the closed-testing principle (Marcus-Peritz-Gabriel; Goeman 2021 admissibility). Covers FDA Multiple Endpoints Final Guidance (October 2022), graphical procedures via R gMCP, primary + key-secondary + subgroup hierarchies, and FWER vs FDR distinction. Use when designing the multiplicity strategy for confirmatory trials with multiple primary or key secondary endpoints.

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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 with constraints), 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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