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Chronological records of raw computational observations, literature synopses, code fragments, and unanswered biological questions.

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fn-001|2026-08-14NPC1
TOPIC: NPC1 Transport

Structural Dynamics of NPC1 Luminal Loop 1 in Cholesterol Delivery

RESEARCH QUESTION“How do missense variants in the NTD domain alter cholesterol transfer rates from NPC2?”
WHAT WAS LEARNED

Molecular dynamics simulations indicate that Arg518 and Pro1007 destabilize hydrophobic interactions within the sterol-sensing domain, leading to impaired lysosomal efflux without abolishing protein synthesis.

COMPUTATIONAL SNIPPET
def calculate_binding_energy(trajectory_file, res_ids=[518, 1007]):
    # Compute hydrophobic contact area across trajectory frames
    contacts = analyze_contacts(trajectory_file, res_ids)
    return np.mean(contacts, axis=0)
OPEN QUESTIONS FOR NEXT EXPERIMENT
  • • Can small-molecule chaperones stabilize the mutated NTD interface?
  • • Does pathway feedback trigger compensatory lipid droplet storage?
PRIMARY CITATIONS & PAPERS
  • • Pfeffer SR. NPC1 and NPC2: Lysosomal cholesterol transport mechanisms. J Cell Biol. 2019.
  • • Kwon HJ et al. Structure of Niemann-Pick C1 protein. Cell. 2009.
fn-002|2026-07-28AI
TOPIC: Genomics AI

Deep Generative Models for Pathogenicity Scoring of Rare Coding Variants

RESEARCH QUESTION“Can unsupervised sequence language models outperform conservation metrics on rare missense mutations?”
WHAT WAS LEARNED

Combining ESM-2 evolutionary embeddings with structural contact maps reduced false-positive pathogenic classifications by 18% across ClinVar rare disease benchmark sets.

COMPUTATIONAL SNIPPET
embed = esm_model.encode_sequence("MTARR...")
pathogenicity_score = classifier.predict_proba(embed)
OPEN QUESTIONS FOR NEXT EXPERIMENT
  • • How to evaluate zero-shot models on novel non-coding regulatory elements?
  • • Is multi-species alignment alignment depth adequate for orphan genes?
PRIMARY CITATIONS & PAPERS
  • • Lin Z et al. Evolutionary-scale prediction of atomic-level protein structure. Science. 2023.
fn-003|2026-06-19Computational Biology
TOPIC: Systems Biology

Constraint-Based Metabolic Modeling of Lysosomal Storage Pathways

RESEARCH QUESTION“What metabolic flux rerouting occurs during chronic intracellular cholesterol accumulation?”
WHAT WAS LEARNED

Flux balance analysis suggests upregulated sphingomyelin synthesis compensates for membrane rigidity, providing potential secondary therapeutic targets.

OPEN QUESTIONS FOR NEXT EXPERIMENT
  • • Are perturbed fatty acid oxidation pathways rate-limiting in neural cell models?
PRIMARY CITATIONS & PAPERS
  • • Orth BD et al. What is flux balance analysis? Nat Biotechnol. 2010.
fn-004|2026-05-04Genomics
TOPIC: Genomics

Resolving Complex Genomic Rearrangements in Undiagnosed Rare Disorders

RESEARCH QUESTION“Do long-read Nanopore sequences resolve intronic insertion breakpoints missed by short reads?”
WHAT WAS LEARNED

Long-read phase analysis uncovered a 4.2kb retrotransposon insertion within an unannotated intron of a key lipid transporter gene.

OPEN QUESTIONS FOR NEXT EXPERIMENT
  • • What target coverage is required for reliable somatic mosaicism detection?
PRIMARY CITATIONS & PAPERS
  • • Logsdon GA et al. Long-read sequencing and the future of comparative genomics. Nat Rev Genet. 2020.
Scientific Digest

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