Open Access Publications
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Open access publications by faculty, postdocs, and graduate students in the Department of Biological Sciences
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- ItemMucopolysaccharidoses: Cellular Consequences of Glycosaminoglycans Accumulation and Potential Targets(International Journal of Molecular Sciences, 2022-12-28) Leal, Andrés Felipe; Benincore-Flórez, Eliana; Rintz, Estera; Herreño-Pachón, Angélica María; Celik, Betul; Ago, Yasuhiko; Alméciga-Díaz, Carlos Javier; Tomatsu, ShunjiMucopolysaccharidoses (MPSs) constitute a heterogeneous group of lysosomal storage disorders characterized by the lysosomal accumulation of glycosaminoglycans (GAGs). Although lysosomal dysfunction is mainly affected, several cellular organelles such as mitochondria, endoplasmic reticulum, Golgi apparatus, and their related process are also impaired, leading to the activation of pathophysiological cascades. While supplying missing enzymes is the mainstream for the treatment of MPS, including enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), or gene therapy (GT), the use of modulators available to restore affected organelles for recovering cell homeostasis may be a simultaneous approach. This review summarizes the current knowledge about the cellular consequences of the lysosomal GAGs accumulation and discusses the use of potential modulators that can reestablish normal cell function beyond ERT-, HSCT-, or GT-based alternatives.
- ItemSelf-Assembly, Self-Folding, and Origami: Comparative Design Principles(Biomimetics, 2022-12-27) Jungck, John R.; Brittain, Stephen; Plante, Donald; Flynn, JamesSelf-assembly is usually considered a parallel process while self-folding and origami are usually considered to be serial processes. We believe that these distinctions do not hold in actual experiments. Based upon our experience with 4D printing, we have developed three additional hybrid classes: (1) templated-assisted (tethered) self-assembly: e.g., when RNA is bound to viral capsomeres, the subunits are constricted in their interactions to have aspects of self-folding as well; (2) self-folding can depend upon interactions with the environment; for example, a protein synthesized on a ribosome will fold as soon as peptides enter the intracellular environment in a serial process whereas if denatured complete proteins are put into solution, parallel folding can occur simultaneously; and, (3) in turbulent environments, chaotic conditions continuously alternate processes. We have examined the 43,380 Dürer nets of dodecahedra and 43,380 Dürer nets of icosahedra and their corresponding duals: Schlegel diagrams. In order to better understand models of self-assembly of viral capsids, we have used both geometric (radius of gyration, convex hulls, angles) and topological (vertex connections, leaves, spanning trees, cutting trees, and degree distributions) perspectives to develop design principles for 4D printing experiments. Which configurations fold most rapidly? Which configurations lead to complete polyhedra most of the time? By using Hamiltonian circuits of the vertices of Dürer nets and Eulerian paths of cutting trees of polyhedra unto Schlegel diagrams, we have been able to develop a systematic sampling procedure to explore the 86,760 configurations, models of a T1 viral capsid with 60 subunits and to test alternatives with 4D printing experiments, use of MagformsTM, and origami models to demonstrate via movies the five processes described above.
- ItemNeuroD1 localizes to the presumptive ganglia and gut of the sea urchin larvae(microPublication Biology, 2022-11-15) Konrad, Kalin D.; Song, Jia L.NeuroD1 is a transcription factor (TF) that plays a dual role in vertebrate neurogenesis and glucose homeostasis in the pancreas. We identified a NeuroD1 antibody developed against human that cross-reacts with the sea urchin NeuroD1. NeuroD1 protein localizes to the presumptive ganglia and neurofilament structures in the ciliary band of the sea urchin larvae. In addition, we also observed NeuroD1 in the perinuclear region in the sea urchin gut which is analogous to the mammalian pancreas. These results suggest that NeuroD1 may play an evolutionarily conserved role in the invertebrate sea urchin.
- ItemMegakaryocyte membrane-wrapped nanoparticles for targeted cargo delivery to hematopoietic stem and progenitor cells(Bioengineering and Translational Medicine, 2022-11-29) Das, Samik; Harris, Jenna C.; Winter, Erica J.; Kao, Chen-Yuan; Day, Emily S.; Papoutsakis, Eleftherios TerryHematopoietic stem and progenitor cells (HSPCs) are desirable targets for gene therapy but are notoriously difficult to target and transfect. Existing viral vector-based delivery methods are not effective in HSPCs due to their cytotoxicity, limited HSPC uptake and lack of target specificity (tropism). Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) are attractive, nontoxic carriers that can encapsulate various cargo and enable its controlled release. To engineer PLGA NP tropism for HSPCs, megakaryocyte (Mk) membranes, which possess HSPC-targeting moieties, were extracted and wrapped around PLGA NPs, producing MkNPs. In vitro, fluorophore-labeled MkNPs are internalized by HSPCs within 24 h and were selectively taken up by HSPCs versus other physiologically related cell types. Using membranes from megakaryoblastic CHRF-288 cells containing the same HSPC-targeting moieties as Mks, CHRF-wrapped NPs (CHNPs) loaded with small interfering RNA facilitated efficient RNA interference upon delivery to HSPCs in vitro. HSPC targeting was conserved in vivo, as poly(ethylene glycol)–PLGA NPs wrapped in CHRF membranes specifically targeted and were taken up by murine bone marrow HSPCs following intravenous administration. These findings suggest that MkNPs and CHNPs are effective and promising vehicles for targeted cargo delivery to HSPCs.
- ItemStress deprivation of tendon explants or Tpm3.1 inhibition in tendon cells reduces F-actin to promote a tendinosis-like phenotype(Molecular Biology of the Cell, 2022-12-01) Inguito, Kameron L.; Schofield, Mandy M.; Faghri, Arya D.; Bloom, Ellen T.; Heino, Marissa; West, Valerie C.; Ebron, Karl Matthew M.; Elliot, Dawn M.; Parreno, JustinActin is a central mediator between mechanical force and cellular phenotype. In tendons, it is speculated that mechanical stress deprivation regulates gene expression by reducing filamentous (F)-actin. However, the mechanisms regulating tenocyte F-actin remain unclear. Tropomyosins (Tpms) are master regulators of F-actin. There are more than 40 Tpm isoforms, each having the unique capability to stabilize F-actin subpopulations. We investigated F-actin polymerization in stress-deprived tendons and tested the hypothesis that stress fiber–associated Tpm(s) stabilize F-actin to regulate cellular phenotype. Stress deprivation of mouse tail tendon down-regulated tenogenic and up-regulated protease (matrix metalloproteinase-3) mRNA levels. Concomitant with mRNA modulation were increases in G/F-actin, confirming reduced F-actin by tendon stress deprivation. To investigate the molecular regulation of F-actin, we identified that tail, Achilles, and plantaris tendons express three isoforms in common: Tpm1.6, 3.1, and 4.2. Tpm3.1 associates with F-actin in native and primary tenocytes. Tpm3.1 inhibition reduces F-actin, leading to decreases in tenogenic expression, increases in chondrogenic expression, and enhancement of protease expression in mouse and human tenocytes. These expression changes by Tpm3.1 inhibition are consistent with tendinosis progression. A further understanding of F-actin regulation in musculoskeletal cells could lead to new therapeutic interventions to prevent alterations in cellular phenotype during disease progression.