Application gaps in Biology

Representative open questions

Showing 30 of 216 — one per source paper, highest-quality first.

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

  High-throughput phenotyping and AI-based analytics platforms for scaling charcoal rot screening in sesame require development and validation; integration of automated image analysis with disease severity assessment under controlled and field conditions has not been demonstrated in sesame breeding pipelines.

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

  Marker-assisted breeding for persistent green color in common bean and cowpea has demonstrated practical applications, but integration of stay-green traits with yield components and seed quality parameters lacks field validation across diverse agronomic environments. The trade-offs between chlorophyll retention and reproductive stage physiology remain unquantified.

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

  The regulation of LARG/ARHGEF12 in leukemia and ARHGEF15 overexpression in pancreatic cancer show enhanced cell motility, but direct comparison of how different GEF families (ARHGEF, DBL, TIAM families) compete for or collaborate in activating Rho GTPases during invasion specifically in three-dimensional extracellular matrix environments has not been systematically investigated.

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

  The protective effects of EGC have been validated only in weaned lambs; the generalizability of the gut microbiota-driven IL-17/PPAR axis mechanism to other ruminant species (calves, goats) and different weaning ages/feed transition protocols remains unexplored and requires species-comparative and age-dependent studies.

• PRONIOSOMAL DRUG DELIVERY SYSTEMS: FABRICATION APPROACHES, MECHANISTIC INSIGHTS, AND MULTIFUNCTIONAL THERAPEUTIC APPLICATIONS (2026) · doi

  Gene delivery via proniosomal niosomes has only been demonstrated with plasmid DNA (pCMSEGFP) in retinal tissue and siRNA/miRNA in mesenchymal stem cells; systematic comparative studies are needed to evaluate proniosomal gene delivery efficacy across different cell types, tissues, and genetic cargo (mRNA, lncRNA, CRISPR components) to establish optimal surface charge and lipid composition parameters.

• Jellyfish bioactive compounds fueling marine biotechnology in blue economy and biomedicine (2026) · doi

  Proteomic investigations of Nemopilema nomurai jellyfish venom identified cardiotoxic and anticancer targets in HepG2 hepatocarcinoma cells, but the mechanism of action and selectivity of these venom components against other cancer cell lines (breast, lung, colon) and their therapeutic window have not been established.

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

  Mutation stability and phenotypic reversion rates in EMS-derived fungal strains are inadequately characterized beyond laboratory conditions. Field-level performance testing and long-term stability assessments are required to evaluate whether mutations remain stable across multiple generations and diverse agricultural environments before strain deployment.

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

  The chemical modification pattern of the siRNAs is based on clinically validated designs and showed in vivo protection against SARS-CoV-2 for up to four weeks after single dose. In vivo pharmacokinetics and protective efficacy of si117m, si123m, and si128m must be evaluated in animal models following respiratory tract delivery to support clinical translation.

• 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

  Long-term feeding trials (beyond the typical 8-12 week experimental period) are needed to evaluate the sustained effects of Natuzyme-supplemented diets containing azolla, poultry by-product meal, and tomato pomace on organ development, lipid metabolism, and reproductive performance in Nile tilapia broodstock.

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

  The compositional versus cell-autonomous age prediction analysis was conducted only across three tissue types (mouse brain, organoid, and fetal human brain); the generalizability of compositional age predictions driven by astrocyte-progenitor dynamics to other neural tissue contexts (e.g., postnatal brain, adult neural stem cell niches, or brain tumors with altered cellular composition) has not been evaluated.

• The Bounded Corridor_Life as Persistence Under Joint Constraint (2026) · doi

  The framework explains microbiome tolerance as organismal-scale identity enforcement but does not specify whether boundary drift during inflammaging alters the composition of tolerated commensal species or their spatial distribution within tissues. Longitudinal 16S rRNA and metagenomic analyses paired with immune phenotyping in aging organisms would test whether the tolerated microbiome shifts as the identity corridor contracts.

• Engineered exosome biomedical technologies for precision diagnosis and therapy in orthopedic diseases (2026) · doi

  Engineered exosomes with controlled release of pro-mineralization factors (BMP2 mRNA, hypoxia-specific gene delivery) have been integrated into hydrogel scaffolds for craniofacial bone healing without cell transplantation, but comparative efficacy against standard bone regeneration approaches in large-animal models and human clinical trials is absent.

• Elovanoid neuroprotection targets cell transcriptomics and proteomics to sustain synaptic integrity after brain injury (2026) · doi

  The translation of elovanoid neuroprotection from rodent traumatic brain injury models to larger animal models (primates, swine) and clinical application requires validation of species-specific differences in ELOVL4 expression, elovanoid biosynthesis capacity, and brain injury response pathways. Studies in these models are needed before human clinical trials.

• A Mathematical Model for Smooth Muscle Cell Phenotype Switching In Atherosclerotic Plaque (2026) · doi

  The model incorporates SMC population initiation from progenitor cells after 5-6 weeks based on the Misra et al. (2018) murine lineage tracing study, but the generalizability of this temporal dynamics to human atherosclerotic plaque development remains unexplored. The study does not address whether SMC recruitment and proliferation kinetics differ between murine models and human plaques of varying ages and stages.

• SARS-CoV-2 pseudoparticles preferentially infect ectoderm in human embryonic tissues (2026) · doi

  Although aprotinin and Dyngo4a showed variable efficacy across different cell types tested, future studies must test drug combinations over a range of doses to assess synergy, additivity, and antagonism while establishing in vivo pharmacokinetics and placental transfer rates of these endocytosis and serine protease inhibitors in the context of preventing SARS-CoV-2 vertical transmission.

• An animal component-free bioprocess for synthesizing 3D human matrix scaffolds using mesenchymal stromal cells (2026) · doi

  While Chen et al. (2025) demonstrated in vivo efficacy of MSC spheroid-derived 3D decellularized ECM in traumatic brain injury models, the present paper does not include in vivo functional validation of the animal component-free synthesized scaffolds or tissue regeneration capacity in relevant disease models.

• Clonal Signatures of Telomere Biology Disorders (2026) · doi

  The shared genetic predisposition between rheumatoid arthritis-interstitial lung disease and familial pulmonary fibrosis (reference 77) linked to telomere biology genes requires investigation into how telomerase-associated protein mutations (NHP2, NOP10) and poly(A)-specific ribonuclease deficiency contribute to autoimmune manifestations in addition to pulmonary fibrosis phenotypes.

• In silico molecular docking, molecular dynamics, and ADMET analysis of metabolites from Strychnos cocculoides as potential therapeutics for erectile dysfunction: a comparative study with sildenafil (2026) · doi

  L4 exhibits comparatively lower LD₅₀ values and multiple toxicity alerts despite favorable binding affinity to PDE5/PDE6; structure–activity relationship (SAR) and derivative optimization studies are required to systematically reduce the moderate hepatotoxic tendencies while maintaining potency comparable to sildenafil.

• Non-coding RNA delivery via lipid nanoparticles: a novel strategy for cancer immunotherapy (2026) · doi

  The POST modular platform for organ-specific LNP surface modification has been proposed theoretically but lacks comprehensive experimental validation across multiple cancer types; specific studies comparing targeting efficacy of different surface modifications (ligands, antibodies, peptides) for selective accumulation in pancreatic cancer, colorectal cancer, and cholangiocarcinoma tissues are needed.

• Fine-tuned GPT-based foundation models effectively reconstruct bacterial transcriptional regulatory networks from literature (2026) · doi

  While the authors propose applying the BERN2-based algorithm with species-specific transcription factor and regulated element dictionaries to reconstruct TRNs in diverse bacterial species, no evaluation has been performed on non-Salmonella bacteria. The scalability and accuracy of the fine-tuned GPT approach across clinically and biologically relevant bacteria with different regulatory mechanisms, genetic organization, and literature coverage patterns requires empirical validation.

• Harnessing climate-adaptive breeding to accelerate tolerance to extreme temperatures in rice (2026) · doi

  Natural variation in cold tolerance genes (CTF1) and high-temperature tolerance genes (HTH5) from wild rice species Oryza rufipogon has been documented, but systematic screening and introgression of these alleles into elite breeding lines using genome-wide association studies and genomic selection remains incomplete. Precision characterization of gene-by-environment interactions for temperature tolerance across diverse germplasm collections is needed.

• Phytochemical profiling and multi-target pharmacological evaluation of Symphyotrichum squamatum unveils its potential as a source of antidiabetic and anti-inflammatory agents (2026) · doi

  While kaempferol 3-O-glucoside (K3G) from related species showed MAPK and Nrf2/HO-1 pathway activation in microglial cells, the anti-inflammatory mechanism of S. squamatum's kaempferol glycosides in neuroinflammatory models has not been tested, limiting assessment of potential neuroprotective applications.

• GlyT1 (SLC6A9) inhibition in neurological and psychiatric disorders (2026) · doi

  Off-target interactions of GlyT1 inhibitors with GlyT2 could interfere with inhibitory glycinergic signaling, while residual affinity for SLC6A7 may alter L-proline homeostasis and glutamatergic tone in limbic regions. Functional consequences of these cross-reactivity effects have not been systematically characterized in region-specific and cell type–specific contexts.

• Ethnobotanical study of wild edible plants in Dabat District, Ethiopia (2026) · doi

  The inverse relationship between literacy status and wild edible plant knowledge (illiterate 4.1±1.9 vs. literate 1.9±1.3) indicates a need to experimentally design and test integration frameworks that embed ethnobotanical content into formal education curricula, field-based learning modules, and community training programs to measure knowledge retention outcomes.

• Exosomes and extracellular vesicles: Rethinking the essential values in cancer biology (2021) · doi

  The reciprocal cell competition mechanisms between cancer cells and normal cells mediated by secretory microRNAs and extracellular vesicles have been identified; systematic investigation of how EV-mediated competitive interactions influence cancer prevention and suppression of preneoplastic cell populations in intact mammary and prostate tissue is needed.

• Aquaporin membrane channels in the hepatobiliary tract: a model of complexity and clinical implications in health and disease (2026) · doi

  Aquaporin-8's involvement in hepatocyte lipid synthesis and cholesterol biosynthesis through SREBP signaling has been shown in isolated cell studies, but the functional significance of AQP8-SREBP interactions in non-alcoholic fatty liver disease (NAFLD) progression, particularly in high-fat diet models or in genetically obese animal strains beyond db/db mice, requires investigation.

• Cytoskeletal Remodeling in Cancer (2020) · doi

  Villin's role in F-actin severing and enterocyte polarity maintenance (reference 87) has been established in gut epithelium, but whether site-specific phosphorylation of villin (reference 90) similarly regulates cytoskeletal organization and cell polarity in epithelial cancers requires investigation.

• The regulatory world of tRNA fragments beyond canonical tRNA biology (2020) · doi

  The therapeutic potential of specific tdRs in treating human diseases (particularly in immunity and carcinogenesis contexts) has been proposed, but the development of stable tdR-based therapeutics requires comprehensive characterization of tdR half-life, cellular uptake mechanisms, and off-target effects across disease models.

• Structural Biology and Structure–Function Relationships of Membrane Proteins (2021) · doi

  ABC transporter investigation in Mycobacterium tuberculosis has identified roles in virulence and antibiotic resistance, as well as two novel ABC-like proteins important for mammalian cell entry. Structure-function studies are needed that directly link ABC transporter atomic structures to their specific roles in M. tuberculosis pathogenesis and drug resistance mechanisms.

• Recovery continues for developmental biology community in Puerto Rico (2018) · doi

  Garcia-Arrarás notes that his sea cucumber experimental research cannot be conducted outside Puerto Rico, but the paper does not systematically document which specific developmental biology experimental systems are geographically dependent or why replication at mainland institutions fails for particular research methodologies in sea cucumber biology.