Zobrazení zdroje stránky Hayessandoval1999

Nicotine is an addictive substance historically consumed through smoking and more recently through the use of electronic vapor devices. The increasing prevalence and popularity of vaping prompts the need for preclinical rodent models of nicotine vapor exposure and an improved understanding of the impact of vaping on specific brain regions, bodily functions, and behaviors. We used a rodent model of electronic nicotine vapor exposure to examine the cellular and behavioral consequences of acute and repeated vapor exposure. Adult male C57BL/6J mice were exposed to a single 3-h session (acute exposure) or five daily sessions (repeated exposure) of intermittent vapes of 120 mg/ml nicotine in propylene glycolvegetable glycerol (PG/VG) or PG/VG control. Acute and repeated nicotine vapor exposure did not alter body weight, and both exposure paradigms produced pharmacologically significant serum nicotine and cotinine levels in the 120 mg/ml nicotine group compared with PG/VG controls. Acute exposure to electronic nicotine vapor increased central amygdala (CeA) activity in individual neuronal firing and in expression of the molecular activity marker, cFos. The changes in neuronal activity following acute exposure were not observed following repeated exposure. Acute and repeated nicotine vapor exposure decreased core body temperature, however acute exposure decreased locomotion while repeated exposure increased locomotion. Collectively, these studies provide validation of a mouse model of nicotine vapor exposure and important evidence for how exposure to electronic nicotine vapor produces differential effects on CeA neuronal activity and on specific body functions and behaviors like thermoregulation and locomotion.<br /><br /> The virtual glaucoma clinic (VGC) is a well-established diagnostic pathway for delivery of glaucoma care. Current UK national guidance recommends VGCs for patients with ocular hypertension, glaucoma suspects or early glaucoma. This study evaluates whether expanded eligibility criteria, including other glaucoma phenotypes and disease stages, can deliver safe and effective care with a positive patient experience.<br /><br /> Records of over 8000 patients were reviewed in order to determine suitability for VGC attendance using expanded eligibility criteria. Patients with three prior consecutive visits within the glaucoma service were included. Follow-up interval, clinic type, visual acuity (VA), intraocular pressure (IOP) and visual field performance were recorded. Patient satisfaction was recorded for a sample of 118 patients.<br /><br /> 2017 patients over 31 months were included. Two-thirds of eyes had ocular comorbidities, a fifth of eyes had undergone prior cataract surgery and 10% of eyes had undergone a prior laser treatment for glaucoma. [https://www.selleckchem.com/products/pfi-3.html PFI-3 Epigenetic Reader Do inhibitor] After three visits, 32% of patients remained in the VGC, 42% were seen in face-to-face clinics and 25% were discharged. There were no clinically significant changes in VA, IOP and visual field performance during follow-up. 72% of patients expressed a preference to continue their care within VGCs.<br /><br /> This study demonstrates that VGCs with expanded patient eligibility criteria can deliver high-quality glaucoma care that is safe, effective and with high levels of patient satisfaction. This approach provides a long-term solution to adapt delivery of glaucoma care to our expanding and ageing population.<br /><br />This study demonstrates that VGCs with expanded patient eligibility criteria can deliver high-quality glaucoma care that is safe, effective and with high levels of patient satisfaction. This approach provides a long-term solution to adapt delivery of glaucoma care to our expanding and ageing population.The role of RNA methylation on N 6-adenosine (m6A) in cancer has been acknowledged, but the underlying mechanisms remain obscure. Here, we identified homeobox containing 1 (HMBOX1) as an authentic target mRNA of m6A machinery, which is highly methylated in malignant cells compared to the normal counterparts and subject to expedited degradation upon the modification. m6A-mediated down-regulation of HMBOX1 causes telomere dysfunction and inactivation of p53 signaling, which leads to chromosome abnormalities and aggressive phenotypes. CRISPR-based, m6A-editing tools further prove that the methyl groups on HMBOX1 per se contribute to the generation of altered cancer genome. In multiple types of human cancers, expression of the RNA methyltransferase METTL3 is negatively correlated with the telomere length but favorably with fractions of altered cancer genome, whereas HMBOX1 mRNA levels show the opposite patterns. Our work suggests that the cancer-driving genomic alterations may potentially be fixed by rectifying particular epitranscriptomic program.For nonequilibrium systems, how to define temperature is one of the key and difficult issues to solve. Although effective temperatures have been proposed and studied to this end, it still remains elusive what they actually are. Here, we focus on the fluctuation-dissipation temperatures and report that such effective temperatures of slow-evolving systems represent characteristic temperatures of their equilibrium counterparts. By calculating the fluctuation-dissipation relation of inherent structures, we obtain a temperature-like quantity T IS For monocomponent crystal-formers, T IS agrees well with the crystallization temperature T c, while it matches with the onset temperature T on for glass-formers. It also agrees with effective temperatures of typical nonequilibrium systems, such as aging glasses, quasi-static shear flows, and quasi-static self-propelled flows. From the unique perspective of inherent structures, our study reveals the nature of effective temperatures and the underlying connections between nonequilibrium and equilibrium systems and confirms the equivalence between T on and T c.The cargo-binding capabilities of cytoskeletal motor proteins have expanded during evolution through both gene duplication and alternative splicing. For the light chains of the kinesin-1 family of microtubule motors, this has resulted in an array of carboxyl-terminal domain sequences of unknown molecular function. Here, combining phylogenetic analyses with biophysical, biochemical, and cell biology approaches, we identify a highly conserved membrane-induced curvature-sensitive amphipathic helix within this region of a subset of long kinesin light-chain paralogs and splice isoforms. This helix mediates the direct binding of kinesin-1 to lipid membranes. Membrane binding requires specific anionic phospholipids, and it contributes to kinesin-1-dependent lysosome positioning, a canonical activity that, until now, has been attributed exclusively the recognition of organelle-associated cargo adaptor proteins. This leads us to propose a protein-lipid coincidence detection framework for kinesin-1-mediated organelle transport.Biomaterials without exogenous cells or therapeutic agents often fail to achieve rapid endogenous bone regeneration with high quality. link2 Here, we reported a class of three-dimensional (3D) nanofiber scaffolds with hierarchical structure and controlled alignment for effective endogenous cranial bone regeneration. 3D scaffolds consisting of radially aligned nanofibers guided and promoted the migration of bone marrow stem cells from the surrounding region to the center in vitro. These scaffolds showed the highest new bone volume, surface coverage, and mineral density among the tested groups in vivo. The regenerated bone exhibited a radially aligned fashion, closely recapitulating the scaffold's architecture. The organic phase in regenerated bone showed an aligned, layered, and densely packed structure, while the inorganic mineral phase showed a uniform distribution with smaller pore size and an even distribution of stress upon the simulated compression. link3 We expect that this study will inspire the design of next-generation biomaterials for effective endogenous bone regeneration with desired quality.Integrating signals is essential for cell survival, leading to the concept of synthetic lethality. However, how signaling is integrated to control cell migration remains unclear. By conducting a "two-hit" screen, we revealed the synergistic reduction of cell migration when serine-threonine kinase 40 (STK40) and mitogen-activated protein kinase (MAPK) were simultaneously suppressed. Single-cell analyses showed that STK40 knockdown reduced cell motility and coordination by strengthening focal adhesion (FA) complexes. Furthermore, STK40 knockdown reduced the stability of yes-associated protein (YAP) and subsequently decreased YAP transported into the nucleus, while MAPK inhibition further weakened YAP activities in the nucleus to disturb FA remodeling. Together, we unveiled an integrated STK40-YAP-MAPK system regulating cell migration and introduced "synthetic dysmobility" as a novel strategy to collaboratively control cell migration.Intermetallic nanocrystals are a large family of emerging materials with extensive applications in many fields. Yet, a generalized synthetic method for intermetallic nanocrystals is lacking. Here, we report the development of a colloidal synthesis method based on amalgamation of monometallic nanocrystal seeds with low-melting point metals. We use this approach to achieve crystalline and compositionally uniform intermetallic nanocrystals of Au-Ga, Ag-Ga, Cu-Ga, Ni-Ga, Pd-Ga, Pd-In, and Pd-Zn compounds. We demonstrate both compositional tunability across the phase spaces (e.g., AuGa2, AuGa, Au7Ga2, and Ga-doped Au), size tunability (e.g., 14.0-, 7.6-, and 3.8-nm AuGa2), and size uniformity (e.g., 5.4% size deviations). This approach makes it possible to systematically achieve size- and composition-controlled intermetallic nanocrystals, opening up a multitude of possibilities for these materials.Harm avoidance is critical for survival, yet little is known regarding the neural mechanisms supporting avoidance in the absence of trial-and-error experience. Flexible avoidance may be supported by a mental model (i.e., model-based), a process for which neural reactivation and sequential replay have emerged as candidate mechanisms. During an aversive learning task, combined with magnetoencephalography, we show prospective and retrospective reactivation during planning and learning, respectively, coupled to evidence for sequential replay. Specifically, when individuals plan in an aversive context, we find preferential reactivation of subsequently chosen goal states. Stronger reactivation is associated with greater hippocampal theta power. At outcome receipt, unchosen goal states are reactivated regardless of outcome valence. Replay of paths leading to goal states was modulated by outcome valence, with aversive outcomes associated with stronger reverse replay than safe outcomes. Our findings are suggestive of avoidance involving simulation of unexperienced states through hippocampally mediated reactivation and replay.Men with more advantaged socioeconomic position (SEP) have been observed to have higher levels of testosterone. It is unclear whether these associations arise because testosterone has a causal impact on SEP. In 306,248 participants of UK Biobank, we performed sex-stratified genome-wide association analysis to identify genetic variants associated with testosterone. Using the identified variants, we performed Mendelian randomization analysis of the influence of testosterone on socioeconomic position, including income, employment status, neighborhood-level deprivation, and educational qualifications; on health, including self-rated health and body mass index; and on risk-taking behavior. We found little evidence that testosterone affected socioeconomic position, health, or risk-taking. Our results therefore suggest that it is unlikely that testosterone meaningfully affects these outcomes in men or women. Differences between Mendelian randomization and multivariable-adjusted estimates suggest that previously reported associations with socioeconomic position and health may be due to residual confounding or reverse causation.