AND-gating is a mechanism capable of generating nonlinear biological responses because a productive output requires the joint satisfaction of several necessary molecular events. AND gates are considered here in the context of gene expression. Three minimal architectures are discussed, parallel AND gates, kinetic AND gates, and a serial arrangement of AND gates. In a parallel AND gate, output depends on the simultaneous engagement of several modules. In a kinetic AND gate, output requires the completion of several events within a finite time window. In a serial arrangement, the output of one gate becomes the input of the next. These architectures can generate S-shaped responses even when the elementary processes are non-cooperative. Although transcription is our main focus, the same logic applies to other processes. The sigmoidal responses produced by these AND gates provide a phenomenological explanation for how a reduction in the abundance or activity of a dosage-sensitive molecule can generate more-than-proportional downstream effects, a hallmark of haploinsufficiency (HI), a form of dominance. The same AND-gate logic also sheds light on dominant-negative effects, where a mutant protein interferes with its wild-type counterpart. These models illustrate how AND gate architectures can contribute to biological threshold generation and to nonlinear genotype-phenotype relationships, which underlie dominance.
ABSTRACT Aging and diabetes, risk factors for cancer, are characterized by high tissue levels of several dicarbonyl species; understanding their relative toxicity can help design targeted strategies. We hypothesize that contextual effects of distinct dicarbonyls on extracellular matrices (ECM) differentially tweak the homeostasis of transformed and untransformed cell niches within intravasative tumor microenvironments consisting of ECM, endothelia, and cancer cells. We show how glycation by three best‐studied dicarbonyls: the C2‐α‐dicarbonyls methylglyoxal (MGO) and glyoxal (GO), and the C6‐α‐dicarbonyl 3‐deoxyglucosone (3‐DG), of two ECMs: Collagen I and laminin‐rich basement membrane (lrBM), differentially alters their morphodynamic interactions with untransformed human endothelia TeloHAEC and aggressive triple negative breast cancer MDA‐MB‐231 cells. We identify disruption in endothelial morphogenesis and adhesion, an increase in cancer cell de‐adhesion, and motility dynamics upon exposure of lrBM to C2‐α‐dicarbonyls, but not 3‐DG. This is due to dissolution of the migration‐inhibitive ECM by glycation. Similar effects are observed on Collagen I substrata due to matrix hyperpolymerization through picrosirius staining. Decreased adhesion not only ensures relative viability of cancer cells over endothelia; the latter exposed to C2‐α‐dicarbonyl‐glycated ECM exhibit even greater cell death. In summary, C2‐α‐dicarbonyls specifically can privilege the survival of cancer cells over endothelia through altering ECM adhesion.
ABSTRACT Alopecia areata (AA) is a common autoimmune hair‐loss disorder driven by cytotoxic T cells, interferon‐γ (IFN‐γ) signaling, and dysregulated JAK‐STAT activation. Current systemic treatments, including JAK inhibitors, are limited by safety considerations and frequent relapse after treatment discontinuation. Local nucleic acid delivery is promising but faces challenges in stability, tissue retention, and controlled release. Luo et al. recently developed a reactive oxygen species (ROS)‐responsive injectable hydrogel based on polyvinyl alcohol crosslinked with N 1 ,N 3 ‐bis(4‐boronobenzyl)‐N 1 ,N 1 ,N 3 ,N 3 ‐tetramethylpropane‐1,3‐diaminium bromide (PVA‐TSPBA) for delivery of miR‐665, a microRNA targeting STAT3. This Commentary evaluates the mechanistic rationale of the miR‐665/STAT3 axis, the advantages of ROS‐responsive hydrogels for lesion‐specific release, and key translational barriers. Specific testable mechanisms are proposed for the dissociation between reduced STAT3 mRNA and stable total protein, including upstream kinases (JAK2/SRC), phosphatases (SHP‐1/PTEN), and indirect pathways. Although the system shows prolonged local retention, attenuated inflammation, and enhanced hair follicle regeneration in preclinical models, critical issues remain unresolved, including the cellular targeting spectrum of miR‐665, in vivo ROS‐dependent release kinetics, miRNA stability under oxidative conditions, and potential systemic immune effects. Single‐cell omics, spatial imaging, in vivo imaging, humanized models, and toxicological evaluation will be key to clinical translation.
ABSTRACT AND‐gating is a mechanism capable of generating nonlinear biological responses because a productive output requires the joint satisfaction of several necessary molecular events. AND gates are considered here in the context of gene expression. Three minimal architectures are discussed, parallel AND gates, kinetic AND gates, and a serial arrangement of AND gates. In a parallel AND gate, output depends on the simultaneous engagement of several modules. In a kinetic AND gate, output requires the completion of several events within a finite time window. In a serial arrangement, the output of one gate becomes the input of the next. These architectures can generate S‐shaped responses even when the elementary processes are non‐cooperative. Although transcription is our main focus, the same logic applies to other processes. The sigmoidal responses produced by these AND gates provide a phenomenological explanation for how a reduction in the abundance or activity of a dosage‐sensitive molecule can generate more‐than‐proportional downstream effects, a hallmark of haploinsufficiency (HI), a form of dominance. The same AND‐gate logic also sheds light on dominant‐negative effects, where a mutant protein interferes with its wild‐type counterpart. These models illustrate how AND gate architectures can contribute to biological threshold generation and to nonlinear genotype–phenotype relationships, which underlie dominance.
Alveolar epithelial cell (AEC) inflammation is a key driver of infectious pneumonia pathology. Toll-like receptor 4 (TLR4) is a central mediator in this response, but its specific regulatory mechanisms at the cellular level remain unclear. TLR4 was identified as a candidate target gene for childhood infectious pneumonia (CIP) using the GeneCards database, and analyzed in a lipopolysaccharide (LPS)-induced A549 AEC injury model. Cell viability, apoptosis, and inflammatory cytokine levels were examined using the cell counting kit-8 (CCK-8) assay, flow cytometry, lactate dehydrogenase (LDH) assay, and inflammatory factor detection kits, respectively. Upstream miR-21-5p of TLR4 and its upstream lncRNA OTUD6B-AS1 were predicted using bioinformatics databases, and binding interactions were confirmed by luciferase reporter assays. The functional role of the OTUD6B-AS1-miR-21-5p-TLR4 axis was investigated by transfecting oe-OTUD6B-AS1 and miR-21-5p mimics. LPS upregulated TLR4 in A549 cells. TLR4 knockdown attenuated LPS-induced reductions in viability, cytotoxicity, and apoptosis. Further studies revealed binding of miR-21-5p to both TLR4 and OTUD6B-AS1. OTUD6B-AS1 sponged miR-21-5p to reduce miR-21-5p-mediated repression of TLR4, thereby promoting TLR4 expression and exacerbating the inflammatory response. The OTUD6B-AS1/miR-21-5p/TLR4 axis plays a pivotal role in AEC inflammation and represents a promising therapeutic target for CIP.
