Theory gaps in Biology

Representative open questions

Showing 30 of 368 — one per source paper, highest-quality first.

• Longitudinal localization of leukaemic stem cells between the metaphysis and central marrow governs their behaviour (2026) · doi

  The study demonstrates CXCL12-independent CXCR4 signaling in MLL-AF9 acute myeloid leukemia (reference 49), but the specific downstream mechanisms beyond JAK/STAT5 pathway activation that mediate leukaemic stem cell behavior in the metaphyseal versus central marrow niches remain uncharacterized. Direct mechanistic investigation of alternative CXCR4 effectors in spatially-distinct bone marrow microenvironments is needed.

• Fast analysis and engineering of protein function by microbe-independent deep assembly and screening (2026) · doi

  NanoLuc substrate specificity variants (Fz, FFz, CFz9) were engineered at active-site positions, but the paper does not specify how substrate-facing residue predictions were derived (computational modeling, structural homology, or empirical mapping) or validate whether residues outside the catalytic cleft influence substrate selectivity. Systematic saturation mutagenesis of predicted non-catalytic residues would determine the full active-site architecture governing substrate discrimination.

• Charcoal rot in sesame: infection biology, host resistance mechanism, and genomic-enabled strategies for durable resistance breeding (2026) · doi

  The molecular basis of sesame-M. phaseolina interaction under combined heat and drought stress remains uncharacterized; specifically, how stress signaling, hormone crosstalk, ROS homeostasis, and defense gene activation are coordinated to determine susceptibility or durable resistance requires integrated transcriptomic and physiological investigation.

• From parasite-induced immune activation to neuroinflammation and behavioral dysfunction: convergent mechanisms across protozoa and helminths: a review (2026) · doi

  Biomarkers and host-directed therapies targeting shared neuroinflammatory nodes across protozoan and helminthic infections remain unidentified. The convergent mechanisms linking parasite-induced immune activation to microglia/astrocyte priming and blood–brain barrier disruption lack validated biomarker panels that discriminate between parasitic species and predict neuropsychiatric risk.

• Development and research trends of stay-green biology in legumes: a bibliometric and visual analysis over three decades (2026) · doi

  Basic themes such as stay-green syndrome in the context of geminivirus and hemiptera alydidae pest resistance show foundational importance but lack cohesive conceptual development. The molecular basis linking stay-green phenotypes to disease and pest resistance mechanisms requires integrated transcriptomic and physiological investigation.

• Decoding Rho GTPase signalling networks in directed cell migration (2026) · doi

  Studies show that matrix stiffness modulates tip cell formation through the p-PXN-Rac1-YAP axis and that KIF13A regulates RhoB plasma membrane localization for blebby migration, but how mechanotransduction pathways intersect with Rho GTPase signaling networks to coordinate different migration modes (mesenchymal versus amoeboid) across varying tissue stiffness ranges has not been quantitatively modeled.

• ​​Integrating machine learning and spatial transcriptomics uncovers shared immunomodulatory deubiquitinases in MAFLD and HCC (2026) · doi

  The regulatory role and molecular mechanisms of EIF3F in MAFLD pathogenesis remain undefined. Current mechanistic understanding of EIF3F focuses on HCC and other solid tumors, but its specific contribution to lipid metabolic reprogramming and immune microenvironment remodeling during MAFLD progression has not been elucidated.

• Dietary N-acetylcysteine enhances sperm motility by remodeling the rumen microbiome and its metabolic axis in goats (2026) · doi

  The study identified elevated plasma levels of taurine-conjugated bile acids positively correlated with sperm motility, but the mechanistic pathway by which microbiota-modulated bile acid composition enhances membrane fluidity and sperm physiological function remains incompletely characterized. Direct mechanistic studies examining how taurine-conjugated versus glycine-conjugated bile acids affect sperm mitochondrial membrane potential and ATP synthesis are needed.

• Gut microbiota-driven IL-17/PPAR axis mediates epigallocatechin-induced intestinal repair in weaned lambs (2026) · doi

  The molecular mechanisms by which epigallocatechin (EGC) microbial metabolites (valeric acid and C ring fission products) activate the PPAR signaling pathway to restore FABP1 and SLC2A2 expression have not been elucidated; the direct interaction between postbiotics and PPAR receptors in jejunal epithelial cells requires biochemical and binding assay validation.

• Self-organisation of complex dynamical systems: from synergetics to neuromorphic systems (2026) · doi

  While the paper states that locally-active memristors can amplify signals similar to transistors and that local activity leads to complex pattern emergence from homogeneous brain tissues, it does not provide specific mathematical conditions or circuit design parameters needed to determine when and how local activity in memristive architectures transitions from pattern suppression to pattern generation in cellular neuronal networks.

• Managing Spinal Muscular Atrophy: A Look at the Biology and Treatment Strategies (2025) · doi

  SMN2 gene expression variation has been identified as correlating with SMA severity, but the specific molecular mechanisms regulating SMN2 splicing patterns during cellular differentiation and in different tissue types remain incompletely characterized. Further investigation into tissue-specific transcriptional regulation of SMN genes during neurogenesis and motor neuron development is needed.

• Adaptation of lipid metabolism of the polyextremophilic cyanobacterium Cyanobacterium aponinum PCC 10605 to adverse environmental conditions (2026) · doi

  The differential regulation of TAG, FAPE, and acylated plastoquinol synthesis derived from multifunctional acyltransferase (MFAT) activity under chlorotic growth conditions requires mechanistic investigation. The paper demonstrates differential regulation occurs but does not elucidate which substrate preferences or post-translational modifications of CyanMFAT_2185 govern the allocation of acyl groups to different lipid products during extended cultivation and micronutrient limitation.

• Evaluation of the effects of hydrogel and glycine betaine application on growth, physiological characteristics and yield of peanut under water deficit (2026) · doi

  Although the study found that combined hydrogel and GB application produced more significant increases in peanut growth and yield than either treatment alone, the physiological basis for this synergistic interaction was not mechanistically explored. Research should investigate whether synergistic effects operate through improved osmolyte accumulation, enhanced ion homeostasis regulation, or better soil water availability when both amendments are applied simultaneously to peanut.

• Ethyl methanesulfonate mutagenesis in fungi: genetic mechanisms, applications, and implications for agricultural biotechnology (2026) · doi

  The bidirectional effects of EMS-induced point mutations on virulence phenotypes in fungal pathogens (both attenuation and enhancement) remain mechanistically unclear across different genetic contexts. Systematic characterization of how low-level mutational variation in specific pathogenic pathways shifts infection outcomes is needed through targeted allele mapping and regulatory pathway analysis.

• Comparative genomics identifies small interfering RNA with activity against all five human betacoronaviruses (2026) · doi

  The discrepancy between luciferase reporter assays and replication-competent infection models for HCoV-NL63 revealed that mismatch tolerance differs between assay systems, particularly at the 3' end of siRNA. The mechanistic basis for context-dependent mismatch tolerance in viral RNA targets versus standard mRNA requires investigation through systematic variation of mismatch positions in both reporter and infection model systems.

• What causes self-sterility in Couroupita guianensis (Lecythidaceae)? (2026) · doi

  The paper identifies LSI (late-acting self-incompatibility) as the mechanism in C. guianensis but does not investigate the specific molecular or physiological trigger causing precocious fruit abortion before embryogenesis initiation in selfed seeds. Future research should characterize the biochemical or hormonal signals responsible for fruit abscission timing in selfed versus crossed fruits.

• Kidney angiopoietin-like protein 4 regulates fibrotic responses in diabetic kidney disease (2026) · doi

  The molecular mechanisms by which ANGPTL4 promotes epithelial-to-mesenchymal transition (EMT) in kidney fibrosis have not been fully elucidated—particularly the upstream signaling cascades linking ANGPTL4 to loss of E-cadherin expression and acquisition of mesenchymal markers in renal tubular epithelial cells under diabetic conditions.

• Metabolic reprogramming in intervertebral disc degeneration: mechanisms and therapeutic opportunities (2026) · doi

  HIF1A upregulates autophagy to alleviate compression-induced apoptosis in nucleus pulposus-derived stem cells, but the mechanistic crosstalk between HIF1A-mediated metabolic reprogramming (glycolysis vs. oxidative phosphorylation) and autophagy flux modulation under sustained mechanical loading has not been elucidated.

• Cationic nanoparticles with disrupting neutrophil extracellular traps inhibit the progression of head and neck squamous cell carcinoma (2026) · doi

  The bioinformatics analysis revealed negative correlation between MPO expression and CD8+ T-cell infiltration in HNSCC tissues, but the mechanistic pathway by which MPO copy number amplification suppresses immune cell infiltration and the specific molecular mediators involved remain uncharacterized and require functional validation studies.

• Society for Developmental Biology 70th Annual Meeting (2011) · doi

  Stabilin2 involvement in zebrafish arterial-venous differentiation (B122) has been identified but the specific molecular mechanisms by which Stabilin2 regulates endothelial cell fate decisions and vascular morphogenesis remain uncharacterized.

• Trajectory inference for a branching SDE model of cell differentiation via lineage tracing (2026) · doi

  Whether a drift making the collection of reweighted marginal distributions compatible can be gradient or not with more than two timepoints remains unclear. The paper demonstrates that at each observation timepoint ti the reweighted empirical distribution is associated with a timepoint-specific drift bias −∇Φti, but no single biased SDE can simultaneously interpolate all observed distributions across multiple timepoints in the branching SDE cell differentiation model.

• Pure Time Theory - Application I - From Pure Time to Lived Time - Fundamental chemistry, the living and heritability under axial transport (2026) · doi

  Section 6.12 introduces the concept of 'suppleness' as the necessary balance between rigidity and plasticity for durable living, positioning it as the biological manifestation of the viability corridor, but the specific molecular or organizational mechanisms that maintain this balance—and measurable thresholds for excessive rigidity versus excessive plasticity—are not detailed.

• Evaluating poultry by-product meal, tomato pomace, and azolla with or without Natuzyme supplementation as sustainable alternatives to fish meal for Nile tilapia (Oreochromis niloticus) (2026) · doi

  While the research assessed hemato-biochemical parameters and antioxidant status in Nile tilapia fed alternative diets, the specific mechanisms by which azolla, tomato pomace, and Natuzyme modulate intestinal microbiota composition and immune gene expression remain uncharacterized, limiting understanding of how these ingredients enhance disease resistance.

• Cell type-agnostic transcriptomic signatures enable uniform comparisons of neural maturation (2026) · doi

  The sensitivity analysis of principal component-based age predictions to cell type removal (S5 Fig) demonstrated that removing progenitors or neurons shifts age-correlations across datasets, but the mechanistic basis for why specific cell type compositions drive particular principal components in different studies remains unexplored; this limits interpretability of which developmental processes the model captures.

• Discovery of an Endonuclease G-inhibitory Ku80-peptide protecting against leukemogenic rearrangements at the MLL breakpoint cluster (2026) · doi

  While DNA-PKcs inhibition with NU7441 was tested in co-treatment experiments, the mechanistic interplay between Ku80-mediated endogenous DNA repair pathways and endonuclease G inhibition at the MLL breakpoint cluster during NHEJ versus homologous DSB repair remains incompletely characterized.

• On the potential origin of the zygote-like cancer stem cell with a focus on fusion for cell rescue (2026) · doi

  The mechanisms by which germline genes promote malignancy in cancer stem cells derived from zygote-like fusion events remain incompletely characterized. Specific investigation is needed into how massive expression of germ cell-specific genes in cancer cells relates to the zygote-like cancer stem cell origin hypothesis and fusion-based cell rescue mechanisms.

• Deciphering Trichoderma viride-mediated cadmium stress alleviation in wheat: morphological, physiological and biochemical insights (2026) · doi

  Conflicting results exist regarding the effect of Trichoderma species on proline and glycine betaine accumulation during cadmium stress—T. viride increased these osmoregulatory components in wheat, while T. harzianum reduced proline levels in V. radiata; comparative mechanistic studies across different Trichoderma strains and host plant species are needed to clarify the strain-specific and species-specific responses.

• Hair cell loss – cause or consequence of hearing loss? (2026) · doi

  The mechanisms underlying prestin-dependent outer hair cell survival require investigation of partial rescue in PrestinV499G/Y501H knockin mice to determine whether prestin loss directly causes hair cell degeneration or triggers secondary degeneration pathways, as Cheatham et al. (2015) demonstrate partial rescue but do not elucidate the molecular cascade linking prestin function to cell viability.

• Immune molecular mechanisms of PANoptosis in sepsis-induced acute kidney injury (2026) · doi

  While reverse electron transfer-mediated mitochondrial DNA oxidation has been identified as a therapeutic target in PANoptosis, the specific molecular mechanisms linking mitochondria-derived reactive oxygen species production to GSDMD activation in sepsis-induced AKI tubular epithelial cells require mechanistic elucidation through direct inhibition studies.

• Tissue maturation and development of mechanical properties in hyaluronic acid bioink-based cartilaginous constructs (2026) · doi

  The interaction effects between synthesized ECM components (collagen, GAG) and smaller linker proteins on mechanical behavior in bioprinted HA constructs have not been systematically characterized, limiting mechanistic understanding of how multiple matrix components collectively influence construct stiffness.