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0001, except C1 vs. C2P > 0.99 and C4 vs. C5P = 0.11). The deep vascular complex displayed diffusely decreased VP, greater at the FAZ (P < 0.0001).

High-density en face OCTA cluster analysis suggests relative sparing of the radial peripapillary capillary plexus and impairment of underlying retinal vasculature, supporting potential anterograde transsynaptic degeneration in iAMD. These location-specific data may better guide future diagnostic and management protocol of iAMD.

High-density en face OCTA cluster analysis suggests relative sparing of the radial peripapillary capillary plexus and impairment of underlying retinal vasculature, supporting potential anterograde transsynaptic degeneration in iAMD. These location-specific data may better guide future diagnostic and management protocol of iAMD.In 1970, Masahiro Mori proposed the uncanny valley (UV), a region in a human-likeness continuum where an entity risks eliciting a cold, eerie, repellent feeling. Recent studies have shown that this feeling can be elicited by entities modeled not only on humans but also nonhuman animals. The perceptual and cognitive mechanisms underlying the UV effect are not well understood, although many theories have been proposed to explain them. To test the predictions of nine classes of theories, a within-subjects experiment was conducted with 136 participants. The theories' predictions were compared with ratings of 10 classes of stimuli on eeriness and coldness indices. One type of theory, configural processing, predicted eight out of nine significant effects. Atypicality, in its extended form, in which the uncanny valley effect is amplified by the stimulus appearing more human, also predicted eight. Threat avoidance predicted seven; atypicality, perceptual mismatch, and mismatch+ predicted six; category+, novelty avoidance, mate selection, and psychopathy avoidance predicted five; and category uncertainty predicted three. Empathy's main prediction was not supported. Given that the number of significant effects predicted depends partly on our choice of hypotheses, a detailed consideration of each result is advised. We do, however, note the methodological value of examining many competing theories in the same experiment.We address two questions concerning eye guidance during visual search in naturalistic scenes. First, search has been described as a task in which visual salience is unimportant. Here, we revisit this question by using a letter-in-scene search task that minimizes any confounding effects that may arise from scene guidance. Second, we investigate how important the different regions of the visual field are for different subprocesses of search (target localization, verification). In Experiment 1, we manipulated both the salience (low vs. high) and the size (small vs. large) of the target letter (a "T"), and we implemented a foveal scotoma (radius 1°) in half of the trials. In Experiment 2, observers searched for high- and low-salience targets either with full vision or with a central or peripheral scotoma (radius 2.5°). In both experiments, we found main effects of salience with better performance for high-salience targets. In Experiment 1, search was faster for large than for small targets, and high-salience helped more for small targets. When searching with a foveal scotoma, performance was relatively unimpaired regardless of the target's salience and size. In Experiment 2, both visual-field manipulations led to search time costs, but the peripheral scotoma was much more detrimental than the central scotoma. Peripheral vision proved to be important for target localization, and central vision for target verification. Salience affected eye movement guidance to the target in both central and peripheral vision. Collectively, the results lend support for search models that incorporate salience for predicting eye-movement behavior.Numerous proteins that have hydrophobic transmembrane domains (TMDs) traverse the cytosol and posttranslationally insert into cellular membranes. Epacadostat cell line It is unclear how these hydrophobic membrane proteins evade recognition by the cytosolic protein quality control (PQC), which typically recognizes exposed hydrophobicity in misfolded proteins and marks them for proteasomal degradation by adding ubiquitin chains. Here, we find that tail-anchored (TA) proteins, a vital class of membrane proteins, are recognized by cytosolic PQC and are ubiquitinated as soon as they are synthesized in cells. Surprisingly, the ubiquitinated TA proteins are not routed for proteasomal degradation but instead are handed over to the targeting factor, TRC40, and delivered to the ER for insertion. The ER-associated deubiquitinases, USP20 and USP33, remove ubiquitin chains from TA proteins after their insertion into the ER. Thus, our data suggest that deubiquitinases rescue posttranslationally targeted membrane proteins that are inappropriately ubiquitinated by PQC in the cytosol.Hepatic ischemia and reperfusion (IR) injury contributes to the morbidity and mortality associated with liver transplantation. microRNAs (miRNAs) constitute a family of noncoding RNAs that regulate gene expression at the posttranslational level through the repression of specific target genes. Here, we hypothesized that miRNAs could be targeted to enhance hepatic ischemia tolerance. A miRNA screen in a murine model of hepatic IR injury pointed us toward the liver-specific miRNA miR122. Subsequent studies in mice with hepatocyte-specific deletion of miR122 (miR122loxP/loxP Alb-Cre+ mice) during hepatic ischemia and reperfusion revealed exacerbated liver injury. Transcriptional studies implicated hypoxia-inducible factor-1α (HIF1α) in the induction of miR122 and identified the oxygen-sensing prolyl hydroxylase domain 1 (PHD1) as a miR122 target. Further studies indicated that HIF1α-dependent induction of miR122 participated in a feed-forward pathway for liver protection via the enhancement of hepatic HIF responses through PHD1 repression. Moreover, pharmacologic studies utilizing nanoparticle-mediated miR122 overexpression demonstrated attenuated liver injury. Finally, proof-of-principle studies in patients undergoing orthotopic liver transplantation showed elevated miR122 levels in conjunction with the repression of PHD1 in post-ischemic liver biopsies. Taken together, the present findings provide molecular insight into the functional role of miR122 in enhancing hepatic ischemia tolerance and suggest the potential utility of pharmacologic interventions targeting miR122 to dampen hepatic injury during liver transplantation.Allergic asthma is a chronic inflammatory airway disease characterized by dysregulated type 2 immune responses, including degranulating airway eosinophils that induce tissue damage and airway hyperresponsiveness (AHR). The type 2 cytokines interleukin 5 (IL-5) and IL-13 and the eosinophil-specific chemokine CCL11/CCL24/CCL26 axis recruit, activate, and regulate eosinophils in the airways. In this issue of the JCI, Karcz et al. identified a mechanism involving the nucleotide sugar UDP-glucose (UDP-G) and the purinergic receptor P2Y14R in amplifying eosinophil accumulation in the lung. During type 2 inflammation, UDP-G activates P2Y14R on eosinophils, inducing the cells to move and migrate into the lung. Pharmacologically or genetically inhibiting P2Y14R on eosinophils attenuated eosinophil infiltration and AHR. Future experiments, including identifying additional type 2 factors regulating P2Y14R expression on lung eosinophils, are necessary to ascertain the impact of targeting P2Y14R as an alternative or adjunctive therapy to current type 2 biologics for the treatment of asthma.Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass.Airway eosinophilia is a hallmark of allergic asthma and is associated with mucus production, airway hyperresponsiveness, and shortness of breath. Although glucocorticoids are widely used to treat asthma, their prolonged use is associated with several side effects. Furthermore, many individuals with eosinophilic asthma are resistant to glucocorticoid treatment, and they have an unmet need for novel therapies. Here, we show that UDP-glucose (UDP-G), a nucleotide sugar, is selectively released into the airways of allergen-sensitized mice upon their subsequent challenge with that same allergen. Mice lacking P2Y14R, the receptor for UDP-G, had decreased airway eosinophilia and airway hyperresponsiveness compared with wild-type mice in a protease-mediated model of asthma. P2Y14R was dispensable for allergic sensitization and for the production of type 2 cytokines in the lung after challenge. However, UDP-G increased chemokinesis in eosinophils and enhanced their response to the eosinophil chemoattractant, CCL24. In turn, eosinophils triggered the release of UDP-G into the airway, thereby amplifying eosinophilic recruitment. This positive feedback loop was sensitive to therapeutic intervention, as a small molecule antagonist of P2Y14R inhibited airway eosinophilia. These findings thus reveal a pathway that can be therapeutically targeted to treat asthma exacerbations and glucocorticoid-resistant forms of this disease.Adoptive T cell therapies (ACTs) hold great promise in cancer treatment, but low overall response rates in patients with solid tumors underscore remaining challenges in realizing the potential of this cellular immunotherapy approach. Promoting CD8+ T cell adaptation to tissue residency represents an underutilized but promising strategy to improve tumor-infiltrating lymphocyte (TIL) function. Here, we report that deletion of the HIF negative regulator von Hippel-Lindau (VHL) in CD8+ T cells induced HIF-1α/HIF-2α-dependent differentiation of tissue-resident memory-like (Trm-like) TILs in mouse models of malignancy. VHL-deficient TILs accumulated in tumors and exhibited a core Trm signature despite an exhaustion-associated phenotype, which led to retained polyfunctionality and response to αPD-1 immunotherapy, resulting in tumor eradication and protective tissue-resident memory. VHL deficiency similarly facilitated enhanced accumulation of chimeric antigen receptor (CAR) T cells with a Trm-like phenotype in tumors.