The Role of Medial Temporal Lobe Regions in Incidental and Intentional Retrieval of Item and Relational Information in Aging: Medial Temporal Lobes in Aging and Memory

Considerable neuropsychological and neuroimaging work indicates that the medial temporal lobes are critical for both item and relational memory retrieval. However, there remain outstanding issues in the literature, namely the extent to which medial temporal lobe regions are differentially recruited during incidental and intentional retrieval of item and relational information, and the extent to which aging may affect these neural substrates. The current fMRI study sought to address these questions; participants incidentally encoded word pairs embedded in sentences and incidental item and relational retrieval were assessed through speeded reading of intact, rearranged, and new word-pair sentences, while intentional item and relational retrieval were assessed through old/new associative recognition of a separate set of intact, rearranged, and new word pairs. Results indicated that, in both younger and older adults, anterior hippocampus and perirhinal cortex indexed incidental and intentional item retrieval in the same manner. In contrast, posterior hippocampus supported incidental and intentional relational retrieval in both age groups and an adjacent cluster in posterior hippocampus was recruited during both forms of relational retrieval for older, but not younger, adults. Our findings suggest that while medial temporal lobe regions do not differentiate between incidental and intentional forms of retrieval, there are distinct roles for anterior and posterior medial temporal lobe regions during retrieval of item and relational information, respectively, and further indicate that posterior regions may, under certain conditions, be over-recruited in healthy aging

Radiation-induced Assembly of Rad51 and Rad52 Recombination Complex Requires ATM and c-Abl

Cells from individuals with the recessive cancer-prone disorder ataxia telangiectasia (A-T) are hypersensitive to ionizing radiation (I-R). ATM (mutated in A-T) is a protein kinase whose activity is stimulated by I-R. c-Abl, a nonreceptor tyrosine kinase, interacts with ATM and is activated by ATM following I-R. Rad51 is a homologue of bacterial RecA protein required for DNA recombination and repair. Here we demonstrate that there is an I-R-induced Rad51 tyrosine phosphorylation, and this induction is dependent on both ATM and c-Abl. ATM, c-Abl, and Rad51 can be co-immunoprecipitated from cell extracts. Consistent with the physical interaction, c-Abl phosphorylates Rad51 in vitro and in vivo. In assays using purified components, phosphorylation of Rad51 by c-Abl enhances complex formation between Rad51 and Rad52, which cooperates with Rad51 in recombination and repair. After I-R, an increase in association between Rad51 and Rad52 occurs in wild-type cells but not in cells with mutations that compromise ATM or c-Abl. Our data suggest signaling mediated through ATM, and c-Abl is required for the correct post-translational modification of Rad51, which is critical for the assembly of Rad51 repair protein complex following I-R

Effects of aging and prospective memory on recognition of item and associative information.

Older adults typically perform worse than young adults on tasks of associative, relative to item, memory. One account of this deficit is that older adults have fewer attentional resources to encode associative information. Previous studies investigating this issue have divided attention at encoding and then examined whether associative and item recognition were differentially affected. The current study utilized a different cognitive task shown to tax attentional resources: event-based prospective memory. Although older adults demonstrated worse associative, relative to item, memory, the presence of the prospective memory task at encoding decreased item and associative memory accuracy to the same extent in both age groups. These results do not support the resource account of age-related associative deficits

Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry

© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90) + HLA-DRA hi sublining fibroblasts, IL1B + pro-inflammatory monocytes, ITGAX + TBX21 + autoimmune-associated B cells and PDCD1 + peripheral helper T (T PH ) cells and follicular helper T (T FH ) cells. We defined distinct subsets of CD8 + T cells characterized by GZMK + , GZMB + , and GNLY + phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1 + HLA-DRA hi fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis

Structure and Function of Bacillus subtilis YphP, a Prokaryotic Disulfide Isomerase with a CXC Catalytic Motif†,‡

ABSTRACT: The DUF1094 family contains over 100 bacterial proteins, all containing a conserved CXCmotif, with unknown function. We solved the crystal structure of the Bacillus subtilis representative, the product of the yphP gene. The protein shows remarkable structural similarity to thioredoxins, with a canonical RβRβRββR topology, despite low amino acid sequence identity to thioredoxin. The CXC motif is found in the loop immediately downstream of the first β-strand, in a location equivalent to the CXXC motif of thioredoxins, with the first Cys occupying a position equivalent to the first Cys in canonical thioredoxin. The experimentally determined reduction potential of YphP is E0 =-130 mV, significantly higher than that of thioredoxin and consistent with disulfide isomerase activity. Functional assays confirmed that the protein displays a level of isomerase activity that might be biologically significant.We propose a mechanism by which the members of this family catalyze isomerization using the CXC catalytic site. The Bacillus subtilis yphP gene codes for a member of a superfamily of over 100 prokaryotic, highly conserved proteins (DUF1094), found predominantly in Firmicutes such as Staphy

Language attitudes and use in a transplanted setting: Greek Cypriots in London

In this paper we explore language attitudes and use in the Greek Cypriot community in London, England. Our study is based on an earlier survey carried out in Nicosia, Cyprus and we compare attitudes to language and reported language use in the two communities. We thereby highlight the significance of sociolinguistic variables on similar groups of speakers. We further extend our investigation to include codeswitching practices in the London community. \ud Analysis of language attitudes and use within the Greek-Cypriot population of London, and comparisons with findings in Nicosia, reflect symbolic forces operating in the two contexts. Despite obvious differences between the two communities, (most obviously the official languages and distinct cultural backgrounds of the two nations), the Greek Cypriot Dialect continues to play an active role in both. English is however the ‘default choice‘ for young Cypriots in the UK and Standard Modern Greek occupies a much more limited role than in Cyprus. It is argued that differences in language attitudes and use can be interpreted in light of different market forces operating in the nation (i.e. Cyprus) and the Diaspora (i.e. UK)

MDM2 Antagonist Improves Therapeutic Activity of Azacitidine in Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

Failure of hypomethylation agent (HMA) treatments is an important issue in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Recent studies indicated that function of wildtype TP53 positively impacts outcome of HMA treatments. We investigated the combination of the HMA azacitidine (AZA) with DS-3032b and DS-5272, novel antagonists of the TP53 negative regulator MDM2, in cellular and animal models of MDS and CMML. In TP53 wildtype myeloid cell line, combinational effects of DS-3032b or DS-5272 with AZA were observed. In Tet2-knockout mouse model of MDS and CMML, DS-5272 and AZA combination ameliorated disease-like phenotype. RNA-Seq analysis in mouse bone marrow hematopoietic stem and progenitors indicated that DS-5272 and AZA combination caused down-regulation of leukemia stem cell marker genes and activation of pathways of TP53 function and stability. These findings demonstrate that combining an MDM2 antagonist with AZA has potential to improve AZA treatment in TP53 wildtype MDS and CMML