Impaired metacognition and reduced neural signals of decision confidence in adults with traumatic brain injury.

OBJECTIVE: Metacognition reflects our capacity to monitor or evaluate other cognitive states as they unfold during task performance, for example, our level of confidence in the veracity of a memory. Impaired metacognition is seen in patients with traumatic brain injury (TBI) and substantially impacts their ability to manage functional difficulties during recovery. Recent evidence suggests that metacognitive representations reflect domain-specific processes (e.g., memory vs. perception) acting jointly with generic confidence signals mediated by widespread frontoparietal networks. The impact of neurological insult on metacognitive processes across different cognitive domains following TBI remains unknown. METHOD: To assess metacognitive accuracy, we measured decision confidence across both a perceptual and memory task in patients with TBI (n = 27) and controls (n = 28). During the metacognitive tasks, continuous electroencephalography was recorded, and event-related potentials (ERP) were analyzed. RESULTS: First, we observed a deficit in metacognitive efficiency across both tasks suggesting that patients show a loss of perceptual and memorial evidence available for confidence judgments despite equivalent accuracy levels to controls. Second, a late positive-going ERP waveform (500-700 ms) was greater in amplitude for high versus low-confidence judgements for controls across both task domains. By contrast, in patients with TBI, the same ERP waveform did not vary by confidence level suggesting a deficient or attenuated neural marker of decision confidence postinjury. CONCLUSIONS: These findings suggest that diffuse damage to putative frontoparietal regions in patients disrupts domain-general metacognitive accuracy and electrophysiological signals that accumulate evidence of decision confidence. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Domain-specific and domain-general processes underlying metacognitive judgments.

Metacognition and self-awareness are commonly assumed to operate as global capacities. However, there have been few attempts to test this assumption across multiple cognitive domains and metacognitive evaluations. Here, we assessed the covariance between "online" metacognitive processes, as measured by decision confidence judgments in the domains of perception and memory, and error awareness in the domain of attention to action. Previous research investigating metacognition across task domains have not matched stimulus characteristics across tasks raising the possibility that any differences in metacognitive accuracy may be influenced by local task properties. The current experiment measured metacognition in perceptual, memorial and attention tasks that were closely matched for stimulus characteristics. We found that metacognitive accuracy across the three tasks was dissociated suggesting that domain specific networks support an individual's capacity for accurate metacognition. This finding was independent of objective performance, which was controlled using a staircase procedure. However, response times for metacognitive judgments and error awareness were associated suggesting that shared mechanisms determining how these meta-level evaluations unfold in time may underlie these different types of decision. In addition, the relationship between these laboratory measures of metacognition and reports of everyday functioning from participants and their significant others (informants) was investigated. We found that informant reports, but not self reports, predicted metacognitive accuracy on the perceptual task and participants who underreported cognitive difficulties relative to their informants also showed poorer metacognitive accuracy on the perceptual task. These results are discussed in the context of models of metacognitive regulation and neuropsychological evidence for dissociable metacognitive systems. The potential for the refinement of metacognitive assessment in clinical populations is also discussed.

Cytotoxicity associated with electrospun polyvinyl alcohol.

Polyvinyl alcohol (PVA) is a synthetic, water-soluble polymer, with applications in industries ranging from textiles to biomedical devices. Research on electrospinning of PVA has been targeted toward optimizing or finding novel applications in the biomedical field. However, the effects of electrospinning on PVA biocompatibility have not been thoroughly evaluated. In this study, the cytotoxicity of electrospun PVA (nPVA) which was not crosslinked after electrospinning was assessed. PVA polymers of several molecular weights were dissolved in distilled water and electrospun using the same parameters. Electrospun PVA materials with varying molecular weights were then dissolved in tissue culture medium and directly compared against solutions of nonelectrospun PVA polymer in human coronary artery smooth muscle cells and human coronary artery endothelial cells cultures. All nPVA solutions were cytotoxic at a threshold molar concentration that correlated with the molecular weight of the starting PVA polymer. In contrast, none of the nonelectrospun PVA solutions caused any cytotoxicity, regardless of their concentration in the cell culture. Evaluation of the nPVA material by differential scanning calorimetry confirmed that polymer degradation had occurred after electrospinning. To elucidate the identity of the nPVA component that caused cytotoxicity, nPVA materials were dissolved, fractionated using size exclusion columns, and the different fractions were added to HCASMC and human coronary artery endothelial cells cultures. These studies indicated that the cytotoxic component of the different nPVA solutions were present in the low-molecular-weight fraction. Additionally, the amount of PVA present in the 3-10 kg/mol fraction was approximately sixfold greater than that in the nonelectrospun samples. In conclusion, electrospinning of PVA resulted in small-molecular-weight fractions that were cytotoxic to cells. This result demonstrates that biocompatibility of electrospun biodegradable polymers should not be assumed on the basis of success of their nonelectrospun predecessors.

A T cell gene expression panel for the diagnosis and monitoring of disease activity in patients with systemic lupus erythematosus.

Systemic Lupus Erythematosus (SLE) remains a challenging disease to diagnose and follow, as no reliable biomarkers are known to date. We designed a gene expression panel with 40 genes known to play a role in SLE pathogenesis. We found that the combined expression of these genes in SLE T cells can accurately differentiate SLE from healthy individuals and patients with other autoimmune diseases. The accuracy of the test increased further (83%) when only three out of the initial genes (OAS2, CD70 and IL10) were used. A T cell score, calculated from the combined expression levels of these genes, correlated positively with various SLE activity markers in a cross-sectional cohort and in a few patients that were followed prospectively. These data showcase the usefulness of measuring mRNA levels of key molecules in diagnosing and following patients with SLE.

The catalytic subunit of protein phosphatase 2A (PP2Ac) promotes DNA hypomethylation by suppressing the phosphorylated mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/phosphorylated ERK/DNMT1 protein pathway in T-cells from controls and systemic lupus erythematosus patients.

DNA hypomethylation is a characteristic feature of systemic lupus erythematosus (SLE) immune cells. Numerous reports have implicated the involvement of the MEK/ERK pathway in the reduction of DNA methyltransferase (DNMT) expression, hence inducing the transcription of methylation-sensitive genes in SLE patients. However, the molecular mechanisms involved remain unclear. Here, we investigated whether the catalytic subunit of protein phosphatase 2A (PP2Ac), which is overexpressed in SLE T-cells, contributes to reduced DNA methylation. We show that both chemical suppression and siRNA silencing of PP2Ac in T-cells resulted in sustained phosphorylation of MEK and ERK following stimulation with phorbol 12-myristate 13-acetate and ionomycin. Furthermore, PP2Ac suppression resulted in increased DNMT enzyme activity, DNA hypermethylation, and decreased expression of methylation-sensitive genes. Similarly, in SLE T-cells, suppression of PP2Ac resulted in increased MEK/ERK phosphorylation, enhanced DNMT1 expression and suppressed expression of the methylation-sensitive CD70 gene. Our results demonstrate that PP2A regulates DNA methylation by influencing the phosphorylation of MEK/ERK. We propose that enhanced PP2Ac in SLE T-cells may dephosphorylate and activate the signaling pathway upstream of DNMT1, thus disturbing the tight control of methylation-sensitive genes, which are involved in SLE pathogenesis.

Splicing factor SF2/ASF rescues IL-2 production in T cells from systemic lupus erythematosus patients by activating IL-2 transcription.

T cells from patients with systemic lupus erythematosus (SLE) produce insufficient amounts of the vital cytokine IL-2. We previously showed that SLE T cells express decreased levels of the T-cell receptor-CD3ζ chain and forced expression of CD3ζ into SLE T cells restores IL-2 production. We recently showed that the serine arginine protein splicing factor 2/alternative splicing factor (SF2/ASF) enhances the expression of CD3ζ chain by limiting the production of an unstable splice variant. Here we demonstrate that SF2/ASF levels are decreased in patients with SLE and more so in those with active disease. More importantly, we reveal a function of SF2/ASF, independent of T-cell receptor/CD3 signaling, whereby it is recruited to the IL-2 promoter, increases transcriptional activity, and enhances IL-2 production in SLE T cells. Our results demonstrate that SF2/ASF regulates IL-2 production and that decreased SF2/ASF expression in SLE T cells contributes to deficient IL-2 production.

The genome of the domesticated apple (Malus × domestica Borkh.).

We report a high-quality draft genome sequence of the domesticated apple (Malus × domestica). We show that a relatively recent (>50 million years ago) genome-wide duplication (GWD) has resulted in the transition from nine ancestral chromosomes to 17 chromosomes in the Pyreae. Traces of older GWDs partly support the monophyly of the ancestral paleohexaploidy of eudicots. Phylogenetic reconstruction of Pyreae and the genus Malus, relative to major Rosaceae taxa, identified the progenitor of the cultivated apple as M. sieversii. Expansion of gene families reported to be involved in fruit development may explain formation of the pome, a Pyreae-specific false fruit that develops by proliferation of the basal part of the sepals, the receptacle. In apple, a subclade of MADS-box genes, normally involved in flower and fruit development, is expanded to include 15 members, as are other gene families involved in Rosaceae-specific metabolism, such as transport and assimilation of sorbitol.

Expression of CD44 variant isoforms CD44v3 and CD44v6 is increased on T cells from patients with systemic lupus erythematosus and is correlated with disease activity.

OBJECTIVE: To quantify the expression of CD44 and variant isoforms CD44v3 and CD44v6 on T cells from patients with systemic lupus erythematosus (SLE), and to assess correlations of the level of expression of these molecules with disease manifestations. METHODS: Information on clinical and demographic characteristics was collected, and blood samples were obtained from 72 patients with SLE and 32 healthy control subjects matched to the patients by sex, race, and age. Expression of CD44 and variants CD44v3 and v6 on T cell subsets was determined by flow cytometry, and Pearson's correlations of their expression levels with clinical variables, SLE Disease Activity Index (SLEDAI) scores, and presence of lupus nephritis were determined. Wilcoxon's rank sum tests and conditional multivariable regression analyses were applied to identify differences in the expression of CD44 between patients with SLE and healthy controls. RESULTS: Expression of CD44 was higher on CD4+ and CD8+ T cells from SLE patients compared with controls (P

A high quality draft consensus sequence of the genome of a heterozygous grapevine variety.

BACKGROUND: Worldwide, grapes and their derived products have a large market. The cultivated grape species Vitis vinifera has potential to become a model for fruit trees genetics. Like many plant species, it is highly heterozygous, which is an additional challenge to modern whole genome shotgun sequencing. In this paper a high quality draft genome sequence of a cultivated clone of V. vinifera Pinot Noir is presented. PRINCIPAL FINDINGS: We estimate the genome size of V. vinifera to be 504.6 Mb. Genomic sequences corresponding to 477.1 Mb were assembled in 2,093 metacontigs and 435.1 Mb were anchored to the 19 linkage groups (LGs). The number of predicted genes is 29,585, of which 96.1% were assigned to LGs. This assembly of the grape genome provides candidate genes implicated in traits relevant to grapevine cultivation, such as those influencing wine quality, via secondary metabolites, and those connected with the extreme susceptibility of grape to pathogens. Single nucleotide polymorphism (SNP) distribution was consistent with a diffuse haplotype structure across the genome. Of around 2,000,000 SNPs, 1,751,176 were mapped to chromosomes and one or more of them were identified in 86.7% of anchored genes. The relative age of grape duplicated genes was estimated and this made possible to reveal a relatively recent Vitis-specific large scale duplication event concerning at least 10 chromosomes (duplication not reported before). CONCLUSIONS: Sanger shotgun sequencing and highly efficient sequencing by synthesis (SBS), together with dedicated assembly programs, resolved a complex heterozygous genome. A consensus sequence of the genome and a set of mapped marker loci were generated. Homologous chromosomes of Pinot Noir differ by 11.2% of their DNA (hemizygous DNA plus chromosomal gaps). SNP markers are offered as a tool with the potential of introducing a new era in the molecular breeding of grape.

Effect of glutathione S-transferase polymorphisms and proximity to hazardous waste sites on time to systemic lupus erythematosus diagnosis: results from the Roxbury lupus project.

OBJECTIVE: The high prevalence of systemic lupus erythematosus (SLE) among African American women may be due to environmental exposures, genetic factors, or a combination of factors. Our goal was to assess association of residential proximity to hazardous waste sites and genetic variation in 3 glutathione Stransferase (GST) genes (GSTM1, GSTT1, and GSTP1) with age at diagnosis of SLE. METHODS: Residential histories were obtained by interviewing 93 SLE patients from 3 predominantly African American neighborhoods in Boston. Residential addresses and locations of 416 hazardous waste sites in the study area were geocoded using ArcView software. Time-varying Cox models were used to study the effect of residential proximity to hazardous sites, GST genotype, and interaction between genotype and exposure in determining age at diagnosis. RESULTS: The prevalence of SLE among African American women in these neighborhoods was 3.56 SLE cases per 1,000. Homozygosity for GSTM1-null and GSTP1 Ile105Val in combination was associated with earlier SLE diagnosis (P = 0.03), but there was no association with proximity to 416 hazardous sites. Available data on specific site contaminants suggested that, at a subset of 67 sites, there was higher potential risk for exposure to volatile organic compounds (P < 0.05 with Bonferroni correction). GST genotypes had a significant interaction with proximity (P = 0.03) in analyses limited to these sites. CONCLUSION: There was no independent association between residential proximity to hazardous waste sites and the risk of earlier SLE diagnosis in this urban population. However, analysis of a limited number of sites indicated that the risk of earlier SLE associated with proximity to hazardous sites might be modulated by GST polymorphisms.