A Cross-National Investigation of Hallucination-Like Experiences in 10 Countries: The E-CLECTIC Study

Hallucination-like experiences (HLEs) are typically defined as sensory perceptions in the absence of external stimuli. Multidimensional tools, able to assess different facets of HLEs, are helpful for a better characterization of hallucination proneness and to investigate the cross-national variation in the frequencies of HLEs. The current study set out to establish the validity, factor structure, and measurement invariance of the Launay-Slade Hallucinations Scale-Extended (LSHS-E), a tool to assess HLEs. A total of 4419 respondents from 10 countries were enrolled. Network analyses between the LSHS-E and the 3 dimensions of the Community Assessment of Psychic Experiences (CAPE) were performed to assess convergent and divergent validity of the LSHS-E. Confirmatory factor analysis was used to test its measurement invariance. The best fit was a 4-factor model, which proved invariant by country and clinical status, indicating cross-national stability of the hallucination-proneness construct. Among the different components of hallucination-proneness, auditory-visual HLEs had the strongest association with the positive dimension of the CAPE, compared with the depression and negative dimensions. Participants who reported a diagnosis of a mental disorder scored higher on the 4 LSHS-E factors. Small effect size differences by country were found in the scores of the 4 LSHS-E factors even after taking into account the role of socio-demographic and clinical variables. Due to its good psychometric properties, the LSHS-E is a strong candidate tool for large investigations of HLEs

Type-I interferon pathway and DNA damage accumulation in peripheral blood of patients with psoriatic arthritis

ObjectivesThe abnormal DNA damage response is associated with upregulation of the type-1 interferon (IFN-I) pathway in certain rheumatic diseases. We investigated whether such aberrant mechanisms operate in psoriatic arthritis (PsA).MethodsDNA damage levels were measured by alkaline comet assay in peripheral blood mononuclear cells from 52 PsA patients and age-sex-matched healthy individuals. RNA expression of IFIT1, MX1 and IFI44, which are selectively induced by IFN-I, was quantitated by real-time polymerase chain reaction and their composite normalized expression resulted in IFN-I score calculation. RNA expression of IL1β, IL6, TNF, IL17A and IL23A was also assessed in PsA and control subgroups.ResultsIn PsA, DNA damage accumulation was increased by almost two-fold compared to healthy individuals (olive tail moment arbitrary units, mean ± SD; 9.42 ± 2.71 vs 4.88 ± 1.98, p<0.0001). DNA damage levels significantly correlated with serum C-Reactive-protein and IL6 RNA expression in PBMCs. Despite increased DNA damage, the IFN-I score was strikingly lower in PsA patients compared to controls (-0.49 ± 6.99 vs 4.24 ± 4.26; p<0.0001). No correlation was found between IFN-I pathway downregulation and DNA damage. However, the IFN-I score in a PsA subgroup was lower in those patients with higher IL1β expression, as well as in those with higher TNF/IL23A PBMCs expression.ConclusionDNA damage in PsA correlates with measures of inflammation but is not associated with the IFN-I pathway induction. The unexpected IFN-I downregulation, albeit reminiscent to findings in experimental models of spondyloarthritis, may be implicated in PsA pathogenesis and explained by operation of other cytokines

Oxidative stress and endogenous DNA damage in blood mononuclear cells may predict anti-SARS-CoV-2 antibody titers after vaccination in older adults

Immune senescence in the elderly has been associated with chronic oxidative stress and DNA damage accumulation. Herein we tested the hypothesis that increased endogenous DNA damage and oxidative stress in peripheral blood mononuclear cells of older adults associate with diminished humoral immune response to SARS-CoV-2 vaccination. Increased oxidative stress and DNA double-strand breaks (DSBs) were detected in 9 non-immunocompromised individuals aged 80–96 years compared to 11 adults aged 27–44 years, before, as well as on days 1 and 14 after the first dose, and on day 14 after the second dose of the BNT162B2-mRNA vaccine (all p < 0.05). SARS-CoV-2 vaccination induced a resolvable increase in oxidative stress and DNA damage, but individual DSB-repair efficiency was unaffected by vaccination irrespective of age, confirming vaccination safety. Individual titers of anti-Spike-Receptor Binding Domain (S-RBD)-IgG antibodies, and the neutralizing capacity of circulating anti-SARS-CoV-2 antibodies, measured on day 14 after the second dose in all participants, correlated inversely with the corresponding pre-vaccination endogenous oxidative stress and DSB levels (all p < 0.05). In particular, a strong inverse correlation of individual pre-vaccination DSB levels with both the respective anti-S-RBD-IgG antibodies titers (r = −0.867) and neutralizing capacity of circulating anti-SARS-CoV-2 antibodies (r = −0.983) among the 9 older adults was evident. These findings suggest that humoral responses to SARS-CoV-2 vaccination may be weaker when immune cells are under oxidative and/or genomic stress. Whether such measurements may serve as biomarkers of vaccine efficacy in older adults warrants further studies. © 202

Adenosine-to-inosine RNA editing contributes to type I interferon responses in systemic sclerosis

Objective: Adenosine deaminase acting on RNA-1 (ADAR1) enzyme is a type I interferon (IFN)-stimulated gene (ISG) catalyzing the deamination of adenosine-to-inosine, a process called A-to-I RNA editing. A-to-I RNA editing takes place mainly in Alu elements comprising a primate-specific level of post-transcriptional gene regulation. Whether RNA editing is involved in type I IFN responses in systemic sclerosis (SSc) patients remains unknown. Methods: ISG expression was quantified in skin biopsies and peripheral blood mononuclear cells derived from SSc patients and healthy subjects. A-to-I RNA editing was examined in the ADAR1-target cathepsin S (CTSS) by an RNA editing assay. The effect of ADAR1 on interferon-α/β-induced CTSS expression was assessed in human endothelial cells in vitro. Results: Increased expression levels of the RNA editor ADAR1, and specifically the long ADAR1p150 isoform, and its target CTSS are strongly associated with type I IFN signature in skin biopsies and peripheral blood derived from SSc patients. Notably, IFN-α/β-treated human endothelial cells show 8-10-fold increased ADAR1p150 and 23-35-fold increased CTSS expression, while silencing of ADAR1 reduces CTSS expression by 60-70%. In SSc patients, increased RNA editing rate of individual adenosines located in CTSS 3′ UTR Alu elements is associated with higher CTSS expression (r = 0.36–0.6, P < 0.05 for all). Similar findings were obtained in subjects with activated type I IFN responses including SLE patients or healthy subjects after influenza vaccination. Conclusion: ADAR1p150-mediated A-to-I RNA editing is critically involved in type I IFN responses highlighting the importance of post-transcriptional regulation of proinflammatory gene expression in systemic autoimmunity, including SSc. © 2021 The Author

Adenosine-to-inosine RNA editing contributes to type I interferon responses in systemic sclerosis

Parallelism in processor architecture and design imposes a verification challenge as the exponential growth in the number of execution combinations becomes unwieldy. In this paper we report on the verification of a Very Large Instruction Word processor. The verification team used a sophisticated test program generator that modeled the parallel aspects as sequential constraints, and augmented the tool with manually written test templates. The system created large numbers of legal stimuli, however the quality of the tests was proved insufficient by several post silicon bugs. We analyze this experience and suggest an alternative, parallel generation technique. We show through experiments the feasibility of the new technique and its superior quality along several dimensions. We claim that the results apply to other parallel architectures and verification environments

Chronological Age and DNA Damage Accumulation in Blood Mononuclear Cells: A Linear Association in Healthy Humans after 50 Years of Age

Aging is characterized by the progressive deregulation of homeostatic mechanisms causing the accumulation of macromolecular damage, including DNA damage, progressive decline in organ function and chronic diseases. Since several features of the aging phenotype are closely related to defects in the DNA damage response (DDR) network, we have herein investigated the relationship between chronological age and DDR signals in peripheral blood mononuclear cells (PBMCs) from healthy individuals. DDR-associated parameters, including endogenous DNA damage (single-strand breaks and double-strand breaks (DSBs) measured by the alkaline comet assay (Olive Tail Moment (OTM); DSBs-only by γH2AX immunofluorescence staining), DSBs repair capacity, oxidative stress, and apurinic/apyrimidinic sites were evaluated in PBMCs of 243 individuals aged 18–75 years, free of any major comorbidity. While OTM values showed marginal correlation with age until 50 years (rs = 0.41, p = 0.11), a linear relationship was observed after 50 years (r = 0.95, p p < 0.001). Results were reproduced when we examined men and women separately. Prospective studies confirming the value of DNA damage accumulation as a biomarker of aging, as well as the presence of a relevant agethreshold, are warranted