In the skin, Merkel cells connect with keratinocytes and Aβ nerve fibers to form a touch receptor that functions as a slow adapting mechanoreceptor (slow adapting type 1). In human and mouse Merkel cells, we observed an increased concentration of intracellular Ca ions in response to cold temperature and transient receptor potential melastatine 8 (TRPM8) ion channel agonists. A reduction in the response to cooling and TRPM8 agonists occurred after the addition of TRPM8 antagonists, as well as in TRPM8 knockout mice. Cold temperature and TRPM8 agonists also induced a current that was inhibited by a TRPM8 antagonist. Our results indicate that Merkel cells sense cooling through TRPM8 channels. We hypothesized that cooling modulates the slow adapting type 1 receptor response. Cooling mouse skin to 22°C reduced the slow adapting type 1 receptor discharge frequency. Interestingly, we observed no such reduction in TRPM8 knockout mice. Similarly, in human skin, a temperature of 22°C applied to the slow adapting type 1 receptive field reduced the spiking discharge. Altogether, our results indicate that Merkel cells are polymodal sensory cells that respond to mild cold stimuli through the activation of TRPM8 channels. Thermal activation of Merkel cells, and possibly other TRPM8-expressing non-neuronal cells, such as keratinocytes, potentially adapts the discharge of slow adapting type 1 receptors during cooling.
Polymeric carriers have long been recognized as some of the most effective and promising systems for nucleic acid delivery. In this study, we utilized an anionic di-block co-polymer, PEG-PLE, to enhance the performance of lipid-modified PEI (C14-PEI) nanoplexes for delivering Cas9 mRNA and sgRNA targeting KRAS G12S mutations in lung cancer cells. Our results demonstrated that PEG-PLE, when combined with C14-PEI at a weight-to-weight ratio of 0.
Merkel cells are perceived as tactile receptors within skin and oral mucosa containing abundant intermediate filaments but lacking characteristic condensation of tonofilaments, hence are also referred to as non-keratinocytes. Merkel cell carcinomas (MCCs) are primary aggressive neuroendocrine neoplasms occurring in elderly individuals. Toker in 1972 reported MCC of skin pointing towards sweat glands as the source of origin which was later rectified by Tang with the aid of ultrastructural studies as Merkel cells to be a lineage of such tumours.
Lab of Biocompatible Polymers, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, Palermo 90123, Italy.
Here, a pulmonary formulation based on lipid-polymer hybrid nanoparticles carrying small interfering RNA (siRNA) was developed to realize a RNA interference-based therapy to treat respiratory diseases. Toward this aim, a new copolymer was synthesized, by functionalization of the α,β-poly(-2-hydroxyethyl)-d,l-aspartamide with 35 mol % of 1,2-bis(3-aminopropylamino)ethane, 0.4 mol % of fluorescent dye, and 4.
Cationic polymers are known to efficiently deliver nucleic acids to target cells by encapsulating the cargo into nanoparticles. However, the molecular organization of these nanoparticles is often not fully explored. Yet, this information is crucial to understand complex particle systems and the role influencing factors play at later stages of drug development.
Lewis Katz School of Medicine at Temple University, Department of Microbiology, Immunology and Inflammation, Center for Neurovirology and Gene Editing, 3500 N. Broad Street, Philadelphia, PA, 19140, USA. Electronic address:
- The JC virus (JCV) encodes multiple regulatory proteins, including large T antigen (LT-Ag) and small t antigen (Sm t-Ag), through alternative splicing of its pre-mRNA, with LT-Ag known for its role in cell transformation.
- The study found that Sm t-Ag aids cell cycle progression by facilitating the transition from G0/G1 to S phase, which involves early expression of important cyclins and cyclin-dependent kinases (like cyclin B and Cdk2).
- Sm t-Ag is shown to enhance growth-promoting pathways such as the PI3K/Akt/mTOR axis, leading to increased levels of active proteins like phosphorylated-Akt, suggesting
