Effects of aging and noncanonical form presentation on idiom processing: Evidence from eye tracking

Comprehending idioms (e.g., bite the bullet) requires that people appreciate their figurative meanings while suppressing literal interpretations of the phrase. While much is known about idioms, an open question is how healthy aging and noncanonical form presentation affect idiom comprehension when the task is to read sentences silently for comprehension. Here, younger and older adults read sentences containing idioms or literal phrases, while we monitored their eye movements. Idioms were presented in a canonical or a noncanonical form (e.g., bite the iron bullet). To assess whether people integrate figurative or literal interpretations of idioms, a disambiguating region that was figuratively or literally biased followed the idiom in each sentence. During early stages of reading, older adults showed facilitation for canonical idioms, suggesting a greater sensitivity to stored idiomatic forms. During later stages of reading, older adults showed slower reading times when canonical idioms were biased toward their literal interpretation, suggesting they were more likely to interpret idioms figuratively on the first pass. In contrast, noncanonical form presentation slowed comprehension of figurative meanings comparably in younger and older participants. We conclude that idioms may be more strongly entrenched in older adults, and that noncanonical form presentation slows comprehension of figurative meanings.

Molecular mechanisms of LC3-associated phagocytosis in the macrophage response to Paracoccidioides spp

Paracoccidiomycosis is a systemic fungal infection that is endemic in Latin America. The etiologic agents are thermodimorphic fungi from the Paracoccidiodes genus, which are facultative intracellular parasites of macrophages. LC3-associated phagocytosis (LAP), a noncanonical form of autophagy, is important in the immune response to similar pathogens, so we sought to determine the role LAP plays in the macrophage response to Paracoccidioides spp. By immunofluorescence, we found that LC3 was recruited to phagosomes containing Paracoccidioides spp. in both RAW264.7 and J774.16 cell lines and in bone marrow-derived macrophages. Interference with autophagy using RNAi against ATG5 reduced the antifungal activity of J774.16 cells, showing that LC3 recrutiment is important for proper control of the fungus by macrophages. Finally, we used pharmacological Syk kinase and NAPH oxidase inhibitors, which inhibit signalling pathways necessary for macrophage LAP against Aspergillus fumigatus and Candida albicans, to dissect part of the signaling pathways that trigger LAP agains Paracoccidioides spp. Interestingly, these inhibitors did not decrease LAP against P. brasiliensis, possibly due to differences in the fungal cell surface compositions. These observations suggest a potential role for autophagy as target for host-directed paracoccidioidomycosis therapies.

Microglial autophagy–associated phagocytosis is essential for recovery from neuroinflammation

Multiple sclerosis (MS) is a leading cause of incurable progressive disability in young adults caused by inflammation and neurodegeneration in the central nervous system (CNS). The capacity of microglia to clear tissue debris is essential for maintaining and restoring CNS homeostasis. This capacity diminishes with age, and age strongly associates with MS disease progression, although the underlying mechanisms are still largely elusive. Here, we demonstrate that the recovery from CNS inflammation in a murine model of MS is dependent on the ability of microglia to clear tissue debris. Microglia-specific deletion of the autophagy regulator Atg7, but not the canonical macroautophagy protein Ulk1, led to increased intracellular accumulation of phagocytosed myelin and progressive MS-like disease. This impairment correlated with a microglial phenotype previously associated with neurodegenerative pathologies. Moreover, Atg7-deficient microglia showed notable transcriptional and functional similarities to microglia from aged wild-type mice that were also unable to clear myelin and recover from disease. In contrast, induction of autophagy in aged mice using the disaccharide trehalose found in plants and fungi led to functional myelin clearance and disease remission. Our results demonstrate that a noncanonical form of autophagy in microglia is responsible for myelin degradation and clearance leading to recovery from MS-like disease and that boosting this process has a therapeutic potential for age-related neuroinflammatory conditions.

Inflammatory and mitogenic signals drive interleukin 23 subunit alpha (IL23A) secretion independent of IL12B in intestinal epithelial cells

The heterodimeric cytokine interleukin-23 (IL-23 or IL23A/IL12B) is produced by dendritic cells and macrophages and promotes the proinflammatory and regenerative activities of T helper 17 (Th17) and innate lymphoid cells. A recent study has reported that IL-23 is also secreted by lung adenoma cells and generates an inflammatory and immune-suppressed stroma. Here, we observed that proinflammatory tumor necrosis factor (TNF)/NF-κB and mitogen-activated protein kinase (MAPK) signaling strongly induce IL23A expression in intestinal epithelial cells. Moreover, we identified a strong crosstalk between the NF-κB and MAPK/ERK kinase (MEK) pathways, involving the formation of a transcriptional enhancer complex consisting of proto-oncogene c-Jun (c-Jun), RELA proto-oncogene NF-κB subunit (RelA), RUNX family transcription factor 1 (RUNX1), and RUNX3. Collectively, these proteins induced IL23A secretion, confirmed by immunoprecipitation of endogenous IL23A from activated human colorectal cancer (CRC) cell culture supernatants. Interestingly, IL23A was likely secreted in a noncanonical form, as it was not detected by an ELISA specific for heterodimeric IL-23 likely because IL12B expression is absent in CRC cells. Given recent evidence that IL23A promotes tumor formation, we evaluated the efficacy of MAPK/NF-κB inhibitors in attenuating IL23A expression and found that the MEK inhibitor trametinib and BAY 11–7082 (an IKKα/IκB inhibitor) effectively inhibited IL23A in a subset of human CRC lines with mutant KRAS or BRAFV600E mutations. Together, these results indicate that proinflammatory and mitogenic signals dynamically regulate IL23A in epithelial cells. They further reveal its secretion in a noncanonical form independent of IL12B and that small-molecule inhibitors can attenuate IL23A secretion.

New Oscillation Conditions for Second Order Half-Linear Advanced Difference Equations

This paper aims to establish adequate conditions that are intended for the oscillation of every solution of the second order advanced type half-linear difference equations with noncanonical form. Initially, we derive a sufficient condition that ensures all solutions of the studied equation are either oscillatory or tending to zero. Secondly, we obtain a criteria for the oscillation of all solutions of the studied equation. These criteria are obtained by using Riccati transformation and summation averaging method. The results established in this paper in essence complement, extend and enhance the existing outcomes recorded in the literature. The improvement of our main results are illustrated through three examples.

Synthetic Tyrosine tRNA Molecules with Noncanonical Secondary Structures

The L-shape form of tRNA is maintained by tertiary interactions occurring in the core. Base changes in this domain can cause structural defects and impair tRNA activity. Here, we report on a method to safely engineer structural variations in this domain utilizing the noncanonical scaffold of tRNAPyl. First, we constructed a naïve hybrid between archaeal tRNAPyl and tRNATyr, which consisted of the acceptor and T stems of tRNATyr and the other parts of tRNAPyl. This hybrid tRNA efficiently translated the UAG codon to 3-iodotyrosine in Escherichia coli cells, when paired with a variant of the archaeal tyrosyl-tRNA synthetase. The amber suppression efficiency was slightly lower than that of the “bench-mark” archaeal tRNATyr suppressor assuming the canonical structure. After a series of modifications to this hybrid tRNA, we obtained two artificial types of tRNATyr: ZtRNA had an augmented D (auD) helix in a noncanonical form and the D and T loops bound by the standard tertiary base pairs, and YtRNA had a canonical auD helix and non-standard interloop interactions. It was then suggested that the ZtRNA scaffold could also support the glycylation and glutaminylation of tRNA. The synthetic diversity of tRNA would help create new tRNA–aminoacyl-tRNA synthetase pairs for reprogramming the genetic code.

Canonical word order and interference-based integration costs during sentence comprehension: The case of Spanish subject- and object-relative clauses

Object-relative clauses are generally harder to process than subject-relative clauses. Increased processing costs for object-relatives have been attributed either to working memory demands for the establishment of long-distance dependencies or to difficulties processing unexpected, noncanonical structures. The current study uses self-paced reading to contrast the impact of both kinds of factors in Spanish object-relative clauses, manipulating the interposition of the subject of the relative clause between object and verb. In addition, object-relatives were unambiguously marked at their onset with the Spanish preposition “ a”. Reading times increased at the onset and final regions of object-relative clauses, regardless of interference-based working memory costs, although interference costs may affect the processing of post-relative-clause regions. These results suggest that, beyond interference-related working memory costs, end-of-clause integration processes may be affected by a preference for canonical structures, thus increasing processing difficulties when confronted with a noncanonical form.