Cell penetrating peptides (CPPs), also known as protein transduction domains (PTDs), first identified ~25 years ago, are small, 6-30 amino acid long, synthetic, or naturally occurring peptides, able ...to carry variety of cargoes across the cellular membranes in an intact, functional form. Since their initial description and characterization, the field of cell penetrating peptides as vectors has exploded. The cargoes they can deliver range from other small peptides, full-length proteins, nucleic acids including RNA and DNA, liposomes, nanoparticles, and viral particles as well as radioisotopes and other fluorescent probes for imaging purposes. In this review, we will focus briefly on their history, classification system, and mechanism of transduction followed by a summary of the existing literature on use of CPPs as gene delivery vectors either in the form of modified viruses, plasmid DNA, small interfering RNA, oligonucleotides, full-length genes, DNA origami or peptide nucleic acids.
Objectives
To summarize and critically evaluate research on the effects of Tai Chi on cognitive function in older adults.
Design
Systematic review with meta‐analysis.
Setting
Community and ...residential care.
Participants
Individuals aged 60 and older (with the exception of one study) with and without cognitive impairment.
Measurements
Cognitive ability using a variety of neuropsychological testing.
Results
Twenty eligible studies with a total of 2,553 participants were identified that met inclusion criteria for the systematic review; 11 of the 20 eligible studies were randomized controlled trials (RCTs), one was a prospective nonrandomized controlled study, four were prospective noncontrolled observational studies, and four were cross‐sectional studies. Overall quality of RCTs was modest, with three of 11 trials categorized as high risk of bias. Meta‐analyses of outcomes related to executive function in RCTs of cognitively healthy adults indicated a large effect size when Tai Chi participants were compared with nonintervention controls (Hedges' g = 0.90; P = .04) and a moderate effect size when compared with exercise controls (Hedges' g = 0.51; P = .003). Meta‐analyses of outcomes related to global cognitive function in RCTs of cognitively impaired adults, ranging from mild cognitive impairment to dementia, showed smaller but statistically significant effects when Tai Chi was compared with nonintervention controls (Hedges' g = 0.35; P = .004) and other active interventions (Hedges' g = 0.30; P = .002). Findings from nonrandomized studies add further evidence that Tai Chi may positively affect these and other domains of cognitive function.
Conclusion
Tai Chi shows potential to enhance cognitive function in older adults, particularly in the realm of executive functioning and in individuals without significant impairment. Larger and methodologically sound trials with longer follow‐up periods are needed before more‐definitive conclusions can be drawn.
Nucleic acid-based materials enable sub-nanometer precision in self-assembly for fields including biophysics, diagnostics, therapeutics, photonics, and nanofabrication. However, structural DNA ...nanotechnology has been limited to substantially hydrated media. Transfer to organic solvents commonly used in polymer and peptide synthesis results in the alteration of DNA helical structure or reduced thermal stabilities. Here we demonstrate that gamma-modified peptide nucleic acids (γPNA) can be used to enable formation of complex, self-assembling nanostructures in select polar aprotic organic solvent mixtures. However, unlike the diameter-monodisperse populations of nanofibers formed using analogous DNA approaches, γPNA structures appear to form bundles of nanofibers. A tight distribution of the nanofiber diameters could, however, be achieved in the presence of the surfactant SDS during self-assembly. We further demonstrate nanostructure morphology can be tuned by means of solvent solution and by strand substitution with DNA and unmodified PNA. This work thereby introduces a science of γPNA nanotechnology.
Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. Here, we undertake genome-wide ...association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (408,786 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detect 21 genome-wide significant associations independent of previously reported results. Investigations of pleiotropy identify 12 cancer pairs exhibiting either positive or negative genetic correlations; 25 pleiotropic loci; and 100 independent pleiotropic variants, many of which are regulatory elements and/or influence cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.
The bioengineering applications of cells, such as cell printing and multicellular assembly, are directly limited by cell damage and death due to a harsh environment. Improved cellular robustness thus ...motivates investigations into cell encapsulation, which provides essential protection. Here we target the cell-surface glycocalyx and cross-link two layers of DNA nanorods on the cellular plasma membrane to form a modular and programmable nanoshell. We show that the DNA origami nanoshell modulates the biophysical properties of cell membranes by enhancing the membrane stiffness and lowering the lipid fluidity. The nanoshell also serves as armor to protect cells and improve their viability against mechanical stress from osmotic imbalance, centrifugal forces, and fluid shear stress. Moreover, it enables mediated cell–cell interactions for effective and robust multicellular assembly. Our results demonstrate the potential of the nanoshell, not only as a cellular protection strategy but also as a platform for cell and cell membrane manipulation.
Chemical modifications that regulate protein expression at the translational level are emerging as vital components of the cellular stress response. Transfer RNAs (tRNAs) are significant targets for ...methyl-based modifications, which are catalyzed by tRNA methyltransferases (Trms). Here, Saccharomyces cerevisiae served as a model eukaryote system to investigate the role of 2'-O-ribose tRNA methylation in the cell's response to oxidative stress. Using 2'-O-ribose deletion mutants for trms 3, 7, 13, and 44, in acute and chronic exposure settings, we demonstrate a broad cell sensitivity to oxidative stress-inducing toxicants (i.e., hydrogen peroxide, rotenone, and acetic acid). A global analysis of hydrogen peroxide-induced tRNA modifications shows a complex profile of decreased, or undetectable, 2'-O-ribose modification events in 2'-O-ribose trm mutant strains, providing a critical link between this type of modification event and Trm status post-exposure. Based on the pronounced oxidative stress sensitivity observed for trm7 mutants, we used a bioinformatic tool to identify transcripts as candidates for regulation by Trm7-catalyzed modifications (i.e., enriched in UUC codons decoded by tRNAPheGmAA). This screen identified transcripts linked to diverse biological processes that promote cellular recovery after oxidative stress exposure, including DNA repair, chromatin remodeling, and nutrient acquisition (i.e., CRT10, HIR3, HXT2, and GNP1); moreover, these mutants were also oxidative stress-sensitive. Together, these results solidify a role for TRM3, 7, 13, and 44, in the cellular response to oxidative stress, and implicate 2'-O-ribose tRNA modification as an epitranscriptomic strategy for oxidative stress recovery.
The aquaporin family of integral membrane proteins is composed of channels that mediate cellular water flow. Aquaporin 4 (AQP4) is highly expressed in the glial cells of the central nervous system ...and facilitates the osmotically driven pathological brain swelling associated with stroke and traumatic brain injury. Here we show that AQP4 cell surface expression can be rapidly and reversibly regulated in response to changes of tonicity in primary cortical rat astrocytes and in transfected HEK293 cells. The translocation mechanism involves PKA activation, influx of extracellular calcium, and activation of calmodulin. We identify five putative PKA phosphorylation sites and use site-directed mutagenesis to show that only phosphorylation at one of these sites, serine 276, is necessary for the translocation response. We discuss our findings in the context of the identification of new therapeutic approaches to treating brain edema.
Background: The water channel protein aquaporin 4 (AQP4) controls water permeability of the blood-brain barrier.
Results: Hypotonicity induces rapid relocalization of AQP4 in a calcium-, calmodulin-, and kinase-dependent manner.
Conclusion: AQP4 can be relocalized between the cell membrane and intracellular compartments.
Significance: Pharmacological modulation of AQP4 membrane localization could provide a new approach to treating brain edema.
Through targeted binding to the cell membrane, structural DNA nanotechnology has the potential to guide and affix biomolecules such as drugs, growth factors and nanobiosensors to the surfaces of ...cells. In this study, we investigated the targeted binding efficiency of three distinct DNA origami shapes to cultured endothelial cells via cholesterol anchors. Our results showed that the labeling efficiency is highly dependent on the shape of the origami as well as the number and the location of the binding overhangs. With a uniform surface spacing of binding overhangs, 3D isotropic nanospheres and 1D anisotropic nanorods labeled cells effectively, and the isotropic nanosphere labeling fit well with an independent binding model. Face-decoration and edge-decoration of the anisotropic nanotile were performed to investigate the effects of binding overhang location on cell labeling, and only the edge-decorated nanotiles were successful at labeling cells. Edge proximity studies demonstrated that the labeling efficiency can be modulated in both nanotiles and nanorods by moving the binding overhangs towards the edges and vertices, respectively. Furthermore, we demonstrated that while double-stranded DNA (dsDNA) bridge tethers can rescue the labeling efficiency of the face-decorated rectangular plate, this effect is also dependent on the proximity of bridge tethers to the edges or vertices of the nanostructures. A final comparison of all three nanoshapes revealed that the end-labeled nanorod and the nanosphere achieved the highest absolute labeling intensities, but the highest signal-to-noise ratio, calculated as the ratio of overall labeling to initiator-free background labeling, was achieved by the end-labeled nanorod, with the edge-labeled nanotile coming in second place slightly ahead of the nanosphere. The findings from this study can help us further understand the factors that affect membrane attachment using cholesterol anchors, thus providing guidelines for the rational design of future functional DNA nanostructures.
Nanoscale extracellular vesicles (EVs) represent a unique cellular derivative that reflect the therapeutic potential of mesenchymal stem cells (MSCs) toward tissue engineering and injury repair ...without the logistical and safety concerns of utilizing living cells. However, upon systemic administration in vivo,EVs undergo rapid clearance and typically lack controlled targeted delivery, thus reducing their effectiveness in therapeutic regenerative therapies. Here, we describe a strategy that enables long-term in vivo spatial EV retention by chemoselective immobilization of metabolically incoporated azido ligand-bearing EVs (azido-EVs) within a dibenzocyclooctyne-modified collagen hydrogel. MSC-derived azido-EVs exhibit comparable morphological and functional properties as their non-labeled EV counterparts and, when immobilized within collagen hydrogel implants via click chemistry, they elicited more robust host cell infiltration, angiogenic and immunoregulatory responses including vascular ingrowth and macrophage recruitment compared to ten times the higher dose required by non-immobilized EVs. We envision this technology will enable a wide range of applications to spatially promote vascularization and host integration relevant to tissue engineering and regenerative medicine applications.
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Summary
Root‐associated fungi (RAF) and root traits regulate plant acquisition of nitrogen (N), which is limiting to growth in Arctic ecosystems. With anthropogenic warming, a new N source from ...thawing permafrost has the potential to change vegetation composition and increase productivity, influencing climate feedbacks. Yet, the impact of warming on tundra plant root traits, RAF, and access to permafrost N is uncertain.
We investigated the relationships between RAF, species‐specific root traits, and uptake of N from the permafrost boundary by tundra plants experimentally warmed for nearly three decades at Toolik Lake, Alaska.
Warming increased acquisitive root traits of nonmycorrhizal and mycorrhizal plants. RAF community composition of ericoid (ERM) but not ectomycorrhizal (ECM) shrubs was impacted by warming and correlated with root traits. RAF taxa in the dark septate endophyte, ERM, and ECM guilds strongly correlated with permafrost N uptake for ECM and ERM shrubs. Overall, a greater proportion of variation in permafrost N uptake was related to root traits than RAF.
Our findings suggest that warming Arctic ecosystems will result in interactions between roots, RAF, and newly thawed permafrost that may strongly impact feedbacks to the climate system through mechanisms of carbon and N cycling.
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