Perceived ethnic discrimination and persecutory paranoia in individuals at ultra-high risk for psychosis

Despite a consensus that psychosocial adversity plays a role in the onset of psychosis, the nature of this role in relation to persecutory paranoia remains unclear. This study examined the complex relationship between perceived ethnic discrimination and paranoid ideation in individuals at Ultra High Risk (UHR) for psychosis using a virtual reality paradigm to objectively measure paranoia. Data from 64 UHR participants and 43 healthy volunteers were analysed to investigate the relationship between perceived ethnic discrimination and persecutory ideation in a virtual reality environment. Perceived ethnic discrimination was higher in young adults at UHR in comparison to healthy controls. A positive correlation was observed between perceived ethnic discrimination and paranoid persecutory ideation in the whole sample. Perceived ethnic discrimination was not a significant predictor of paranoid persecutory ideation in the VR environment. Elevated levels of perceived ethnic discrimination are present in individuals at UHR and are consistent with current biopsychosocial models in which psychosocial adversity plays a key role in the development of psychosis and attenuated symptomatology

ADP-ribosylation of arginine

Arginine adenosine-5′-diphosphoribosylation (ADP-ribosylation) is an enzyme-catalyzed, potentially reversible posttranslational modification, in which the ADP-ribose moiety is transferred from NAD+ to the guanidino moiety of arginine. At 540 Da, ADP-ribose has the size of approximately five amino acid residues. In contrast to arginine, which, at neutral pH, is positively charged, ADP-ribose carries two negatively charged phosphate moieties. Arginine ADP-ribosylation, thus, causes a notable change in size and chemical property at the ADP-ribosylation site of the target protein. Often, this causes steric interference of the interaction of the target protein with binding partners, e.g. toxin-catalyzed ADP-ribosylation of actin at R177 sterically blocks actin polymerization. In case of the nucleotide-gated P2X7 ion channel, ADP-ribosylation at R125 in the vicinity of the ligand-binding site causes channel gating. Arginine-specific ADP-ribosyltransferases (ARTs) carry a characteristic R-S-EXE motif that distinguishes these enzymes from structurally related enzymes which catalyze ADP-ribosylation of other amino acid side chains, DNA, or small molecules. Arginine-specific ADP-ribosylation can be inhibited by small molecule arginine analogues such as agmatine or meta-iodobenzylguanidine (MIBG), which themselves can serve as targets for arginine-specific ARTs. ADP-ribosylarginine specific hydrolases (ARHs) can restore target protein function by hydrolytic removal of the entire ADP-ribose moiety. In some cases, ADP-ribosylarginine is processed into secondary posttranslational modifications, e.g. phosphoribosylarginine or ornithine. This review summarizes current knowledge on arginine-specific ADP-ribosylation, focussing on the methods available for its detection, its biological consequences, and the enzymes responsible for this modification and its reversal, and discusses future perspectives for research in this field

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Performance and Acceptability of a New Dexpanthenol-Containing Hand Cream in Subjects with Sensitive and Very Dry Skin: A Randomized Controlled Study

A new dexpanthenol-containing hand cream (ND-HC) was developed for people with dry, sensitive, and/or environmentally stressed hands. To explore the performance and acceptability of ND-HC, we conducted a randomized, intraindividual comparison study in 40 healthy adult subjects with sensitive and very dry skin on the hands. Instrumental measurements determined the effects on stratum corneum (SC) hydration and transepidermal water loss (TEWL) after single and/or 4 weeks’ use of ND-HC. Single and continued at least four times daily applications of ND-HC to very dry skin of the hand for 4 weeks triggered significant increases in SC hydration. On day 29, the mean change in skin capacitance from baseline was significantly greater when ND-HC was applied to the test area compared with the untreated area on the contralateral hand (12.41 vs. 4.46 a.u.; p 2/h; p = 0.003), indicating an improvement in SC barrier function. A reduction in dry hand symptoms was observed over the study course. ND-HC was well tolerated and achieved a high level of acceptance and satisfaction. Our findings suggest that ND-HC complies with the required features of a state-of-the-art hand cream

Performance and Acceptability of a New Dexpanthenol-Containing Hand Cream in Subjects with Sensitive and Very Dry Skin: A Randomized Controlled Study

A new dexpanthenol-containing hand cream (ND-HC) was developed for people with dry, sensitive, and/or environmentally stressed hands. To explore the performance and acceptability of ND-HC, we conducted a randomized, intraindividual comparison study in 40 healthy adult subjects with sensitive and very dry skin on the hands. Instrumental measurements determined the effects on stratum corneum (SC) hydration and transepidermal water loss (TEWL) after single and/or 4 weeks’ use of ND-HC. Single and continued at least four times daily applications of ND-HC to very dry skin of the hand for 4 weeks triggered significant increases in SC hydration. On day 29, the mean change in skin capacitance from baseline was significantly greater when ND-HC was applied to the test area compared with the untreated area on the contralateral hand (12.41 vs. 4.46 a.u.; p < 0.001). Upon use of ND-HC over 4 weeks, mean TEWL decreased significantly (bilateral difference: −1.8 vs. 1.0 g/m2/h; p = 0.003), indicating an improvement in SC barrier function. A reduction in dry hand symptoms was observed over the study course. ND-HC was well tolerated and achieved a high level of acceptance and satisfaction. Our findings suggest that ND-HC complies with the required features of a state-of-the-art hand cream

New methods for assessing secondary performance attributes of sunscreens suitable for professional outdoor work

Abstract Background Outdoor workers (OW) are highly exposed to solar ultraviolet radiation (UVR) and thus at increased risk for developing skin cancer. An essential part of an overall strategy to reduce workplace UVR-exposure to OW’s skin is the usage of sunscreens. However, compliance with regular sunscreen usage seems to be low, as products are usually designed for recreational sun exposure and thus do not meet the requirements of physically active OW. To date, no standardized test procedures assess the suitability of sunscreens for professional use. The aim of this pilot study was to develop standardized methods of testing secondary performance attributes (PA) to represent real-life working conditions of outdoor work. Methods Ten sunscreen products, carefully selected after a detailed market survey of all relevant producers available on the German market, were evaluated regarding their suitability for professional outdoor work on 24 healthy volunteers in a newly designed test procedure. In addition to three standardized efficacy characteristics, i.e., sun protection factor, water-resistance, and UVA protection, we evaluated each PA involving parameters typically associated with outdoor workplaces. Results We developed standardized methods for objectifying the suitability of sunscreen products for professional outdoor work. The test procedures used are well feasible and appropriate for testing the PA because they represent practical working conditions in detail – although the degree of discriminability of single test methods varied. The claimed sun protection factor (SPF) of the products was confirmed; bio-stability of the SPF after physical activity was achieved in most cases. While most products hardly irritate the eyes and are quickly absorbed, the evaluation of the subjective skin feeling and non-slip grip is inconsistent. Conclusions In this pilot study, for the first time secondary PA are defined and examined. Although further objectification of the PA assessment as well as the establishment of minimum standards should be sought, the new methods could already complement the so far mandatory labels and in this way provide a significant impetus for the current scientific and political focus on the improvement of occupational health in highly UVR-exposed OW

Design, synthesis, and bioactivity of novel inhibitors of E. coli aspartate transcarbamoylase

A series of inhibitors of the aspartate transcarbamoylase, an enzyme involved in pyrimidine nucleotide biosynthesis, has been synthesized. These inhibits are analogues of a highly potent inhibitor of this enzyme, N-phosphonacetyl-L-aspartate (PALA). Analogues have been synthesized with modifications at the α and β carboxylates as well as at the aspartate moiety. The ability of these compounds to inhibit the enzyme was evaluated. These studies, with functional group modified PALA derivatives, showed that amide groups can be a useful substitute of the carboxylate in order to reduced the charge on the molecule, and indicate that the relative position of the functional group in the β-position is more critical than the nature of the functional group. Some of the molecules synthesized here are potent inhibitors of the enzyme.Joby Eldo, Sabrina Heng, and Evan R. Kantrowit