30988 research outputs found
Sort by
The association of maternal caffeine intake with maternal and infant sleep at three months postpartum
No full textThe Use of Power and Intimate Terrorism in Stephanie Garber’s Once Upon a Broken Heart Trilogy
No full textActivation of cGAS-STING signaling in senescent cells promotes the aging process by remodeling the functions of the immune system
No full textAn accumulation of senescent cells within tissues is a hallmark of the aging process. Cellular senescence is associated with an increased level of cytosolic dsDNA which primarily originates from a leakage of mitochondrial DNA (mtDNA) and a loss of genomic DNA integrity. Cytosolic dsDNA is an important alarming factor for cytosolic dsDNA sensors which trigger the remodeling of the immune system through diverse signaling pathways. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) (cGAS-STING) signaling is a major defence mechanism induced by an accumulation of cytosolic dsDNA in senescent cells. The cGAS-STING pathway stimulates immune responses via the interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB)-driven pathways. The activation of cGAS-STING signaling in senescent cells generates pleiotropic immune responses in a context-dependent manner. For instance, cGAS-STING signaling induces proinflammatory responses by enhancing the secretion of cytokines, chemokines, and colony-stimulating factors. The secretion of many chemokines and colony-stimulating factors can remodel hematopoiesis and enhance thymic involution with aging. Moreover, cGAS-STING signaling promotes proinflammatory responses by stimulating the NLRP3 inflammasomes. On the other hand, cGAS-STING signaling aids in the resolution of inflammation by recruiting immunosuppressive cells into tissues and suppressing the pathogenic activity of T helper 17 cells. In addition, an increased cGAS-STING signaling in senescent cells stimulates the expression of inhibitory immune checkpoint ligands, such as PD-L1, and thus prevents their elimination by immune cells. Recent studies have clearly revealed that cGAS-STING signaling not only induces cellular senescence but it can also promote the aging process
The Impact of an AI Tool on Application Developers’ Perceived Productivity, Well-being, and Flow Experiences
No full textAn in vitro approach to explore molecular characteristics supporting LAT1-mediated transport
No full textBrain-targeted Jedi1 and Jedi2 derivatives as potent enhancers of Piezo1 ion channel activity
No full textMechanosensitive Piezo1 channel is highly expressed in the eukaryotic central nervous system and involved in many important physiological functions that maintain cell homeostasis. This membrane ion channel is opened by different forms of mechanical and chemical stimulation. However, pharmacological tools for Piezo1 channel manipulations and in vivo application are limited. In the present study, to address this need, 12 L-type amino acid transporter 1 (LAT1)-utilizing brain-targeted conjugates of Piezo1 activators, Jedi1 and Jedi2, were synthesized and evaluated for their physicochemical and pharmaceutical properties. As a result, the novel compounds were more effectively transported via LAT1 into mouse BV2 microglia cells. Moreover, compared to their parent compounds, they had a higher ability to activate Piezo1 measured by a fluorescent live calcium imaging assay. Furthermore, the pharmacokinetic study revealed that the compounds were delivered into the mouse brain and were distributed to other peripheral tissues to a lesser extent than their parent compound, Jedi2. Therefore, these novel conjugates can be considered as potential compounds to achieve brain- and microglia-targeted delivery and potential neuroprotective effects via Piezo1 ion channel activation, being beneficial in the treatment of neurodegenerative disorders
