Moment-to-moment associations between negative affect,aberrant salience,and paranoia

Introduction: There is an ongoing debate about whether negative affect are consequences or triggers of paranoid thinking. It has also been suggested that aberrant salience is central to the development of delusions. This study modelled the moment-to-moment relationships between negative affect, aberrant salience, and paranoia in acute inpatients with psychosis.

Methods: Participants with active paranoid delusions were assessed using clinical rating scales and experience sampling method (ESM) over 14 days. ESM data were analysed using time-lagged multilevel regression modelling.

Results: Both negative affect and aberrant salience predicted an increase in paranoia at the next time point. Conversely, the level of paranoia did not predict subsequent changes in negative affect or aberrant salience. Negative affect predicted an increase in aberrant salience at the next time point, and vice versa.

Conclusions: Negative affect and aberrant salience appear to drive and exacerbate paranoia, rather than being merely the sequelae of the symptom. Our results suggest both direct and indirect (via aberrant salience) pathways from negative affect to paranoia.     

Regulation of the specialized DNA polymerase eta: Revisiting the biological relevance of its PCNA‐ and ubiquitin‐binding motifs

During translesion synthesis (TLS), low‐fidelity polymerases of the Y‐family polymerases bypass DNA damages that block the progression of conventional processive DNA polymerases, thereby allowing the completion of DNA replication. Among the TLS polymerases, DNA polymerase eta (polη) performs nucleotide incorporation past ultraviolet (UV) photoproducts and is deficient in cancer‐prone xeroderma pigmentosum variant (XPV) syndrome. Upon UV irradiation, the DNA sliding clamp PCNA is monoubiquitylated on its conserved Lys‐164. This event is considered to facilitate the TLS process in vivo since polη preferentially interacts with monoubiquitylated PCNA through its ubiquitin‐binding domain (UBZ) as well as its PCNA interacting peptide (PIP)‐box. However, recent observations questioned this model. Therefore, in this study, we re‐examined the relative contribution of the regulatory UBZ and PIP domains of polη in response to UVC. We show that simultaneous invalidation of both motifs confers sensitivity to UVC, sensitization by low concentrations of caffeine, prolonged inhibition of DNA synthesis and persistent S phase checkpoint activation, all characteristic features of XPV cells. While each domain is essential for efficient accumulation of polη in replication factories, mutational inactivation of UBZ or PIP motif only confers a slight sensitivity to UVC indicating that, although informative, polη focus analysis is not a reliable tool to assess the polη's ability to function in TLS in vivo. Taken together, these data indicate that PIP and UBZ motifs are not required for recruitment but for retention of polη at sites of stalled replication forks. We propose that this is a way to ensure that a sufficient amount of the protein is available for its bypass function. Environ. Mol. Mutagen., 2012. © 2012 Wiley Periodicals, Inc.     

HIV-1 Nef protein expression in human CD34+ progenitors impairs the differentiation of an early T/NK cell precursor

HIV-1 impairs the production of T cells, through mechanisms that are still unknown. Here, we investigated the effect of the expression of HIV-1 Nef on the T-cell potential of human hematopoietic CD34(+) precursors. Those progenitors were transduced by using lentiviral vectors expressing Nef and cultured on OP9-DL1 cells allowing the differentiation of T cell from human hematopoietic precursors. We demonstrate that Nef impairs the generation of a CD3epsilon(+)CD5(+) CD1a(+) precursor stage that has initiated a D-J rearrangement of the TCRbeta locus. Onward stages of T-cell development were also affected with a quantitative reduction of CD4(+) intraCD3epsilon(+) Immature single positive cells (ISP), Double Positive (DP) CD4(+)CD8(+) TCRalphabeta T cells and CD56(+) NK cells. But B cell production was not affected. Limiting dilution analyses demonstrated a significant reduction in the frequency of T/NK progenitors among Nef-expressing CD34(+) cells. Altogether, these data demonstrate that Nef interferes with the differentiation of a primitive lymphoid human precursor with a T/NK potential.     

CRTAP and LEPRE1 mutations in recessive osteogenesis imperfecta

Autosomal dominant osteogenesis imperfecta (OI) is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Recently, dysregulation of hydroxylation of a single proline residue at position 986 of both the triple-helical domains of type I collagen alpha1(I) and type II collagen alpha1(II) chains has been implicated in the pathogenesis of recessive forms of OI. Two proteins, cartilage-associated protein (CRTAP) and prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene) form a complex that performs the hydroxylation and brings the prolyl cis-trans isomerase cyclophilin-B (CYPB) to the unfolded collagen. In our screen of 78 subjects diagnosed with OI type II or III, we identified three probands with mutations in CRTAP and 16 with mutations in LEPRE1. The latter group includes a mutation in patients from the Irish Traveller population, a genetically isolated community with increased incidence of OI. The clinical features resulting from CRTAP or LEPRE1 loss of function mutations were difficult to distinguish at birth. Infants in both groups had multiple fractures, decreased bone modeling (affecting especially the femurs), and extremely low bone mineral density. Interestingly, "popcorn" epiphyses may reflect underlying cartilaginous and bone dysplasia in this form of OI. These results expand the range of CRTAP/LEPRE1 mutations that result in recessive OI and emphasize the importance of distinguishing recurrence of severe OI of recessive inheritance from those that result from parental germline mosaicism for COL1A1 or COL1A2 mutations.     

Somatostatin,Alzheimer's disease and cognition: An old story coming of age?

In mammalian brain, the somatostatin (SRIF: somatotropin release-inhibiting factor) family is composed of two peptides: SRIF and cortistatin (CST), which interact with five different receptor subtypes, sst_1–5. This review summarizes the properties of these receptors, the involvement of somatostatinergic systems in Alzheimer's disease (SRIF/acetylcholine (Ach), SRIF/amyloid β peptides, and SRIF/tau interactions) and their role in cognition from early studies using cysteamine as an SRIF depleting substance to the use of subtype selective analogues and knockout mice, and modulation of synaptic plasticity. The current SRIF story illustrates how cognition and emotion are intimately integrated in brain function.     

Cis variants identified in F508del complex alleles modulate CFTR channel rescue by small molecules

Molecules correcting the trafficking (correctors) and gating defects (potentiators) of the cystic fibrosis causing mutation c.1521_1523delCTT (p.Phe508del) begin to be a useful treatment for CF patients bearing p.Phe508del. This mutation has been identified in different genetic contexts, alone or in combination with variants in cis. Until now, 21 exonic variants in cis of p.Phe508del have been identified, albeit at a low frequency. The aim of this study was to evaluate their impact on the efficacy of CFTR‐directed corrector/potentiator therapy (Orkambi). The analysis by minigene showed that two out of 15 cis variants tested increased exon skipping (c.609C > T and c.2770G > A). Four cis variants were studied functionally in the absence of p.Phe508del, one of which was found to be deleterious for protein maturation c.1399C > T (p.Leu467Phe). In the presence of p.Phe508del, this variant was the only to prevent the response to Orkambi treatment. This study showed that some patients carrying p.Phe508del complex alleles are predicted to poorly respond to corrector/potentiator treatments. Our results underline the importance to validate treatment efficacy in the context of complex alleles.     

Correlation of Phenotype/Genotype in a Cohort of 23 Xeroderma Pigmentosum‐Variant Patients Reveals 12 New Disease‐Causing POLH Mutations

Xeroderma pigmentosum variant (XP‐V) is a rare genetic disease, characterized by some sunlight sensitivity and predisposition to cutaneous malignancies. We described clinical and genetic features of the largest collection ever published of 23 XP‐V patients (ages between 21 and 86) from 20 unrelated families. Primary fibroblasts from patients showed normal nucleotide excision repair but UV‐hypersensitivity in the presence of caffeine, a signature of the XP‐V syndrome. 87% of patients developed skin tumors with a median age of 21 for the first occurrence. The median numbers of basal‐cell carcinoma was 13 per patient, six for squamous‐cell carcinoma, and five for melanoma. XP‐V is due to defects in the translesion‐synthesis DNA polymerase Polη coded by the POLH gene. DNA sequencing of POLH revealed 29 mutations, where 12 have not been previously identified, leading to truncated polymerases in 69% of patients. Four missense mutations are correlated with the protein stability by structural modeling of the Polη polymerase domain. There is a clear relationship between the types of missense mutations and clinical severity. For truncating mutations, which lead to an absence of or to inactive proteins, the life‐cumulated UV exposure is probably the best predictor of cancer incidence, reinforcing the necessity to protect XP‐Vs from sun exposure.     

Classification Algorithm for Subspecies Identification within the Mycobacterium abscessus Species,Based on Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry

Mycobacterium abscessus, as a species, has been increasingly implicated in respiratory infections, notably in cystic fibrosis patients. The species comprises 3 subspecies, which can be difficult to identify. Since they differ in antibiotic susceptibility and clinical relevance, developing a routine diagnostic tool discriminating Mycobacterium abscessus at the subspecies level is a real challenge. Forty-three Mycobacterium abscessus species isolates, previously identified by multilocus sequence typing, were analyzed by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS). A subspecies identification algorithm, based on five discriminating peaks, was drawn up and validated by blind identification of a further 49 strains, 94% of which (n = 46) were correctly identified. Two M. abscessus subsp. massiliense strains were misidentified as M. abscessus subsp. abscessus, and for 1 other strain identification failed. Inter- and intralaboratory reproducibility tests were conclusive. This study presents, for the first time, a classification algorithm for MALDI-TOF MS identification of the 3 M. abscessus subspecies. MALDI-TOF MS proved effective in discriminating within the M. abscessus species and might be easily integrated into the workflow of microbiology labs.     

Motives for Participating in a Web-Based Nutrition Cohort According to Sociodemographic,Lifestyle, and Health Characteristics: The NutriNet-Santé Cohort Study

Background

In traditional epidemiological studies, participants are likely motivated by perceived benefits, feelings of accomplishment, and belonging. No study has explored motives for participation in a Web-based cohort and the associated participant characteristics, although such information is useful for enhancing recruitment and improving cohort retention.

Objective

We aimed to evaluate the relationships between motives for participation and sociodemographic, health, and lifestyle characteristics of participants in the NutriNet-Santé Web-based cohort, designed to identify nutritional risk or protective factors for chronic diseases.

Methods

The motives for participation were assessed using a specifically developed questionnaire administered approximately 2 years after baseline. A total of 6352 completed the motives questionnaire (43.34%, 6352/15,000 randomly invited cohort participants). We studied the associations between motives (dependent variables) and individual characteristics with multivariate multinomial logistic regression models providing odds ratios and 95% confidence intervals.

Results

In total, 46.45% (2951/6352) of participants reported that they would not have enrolled if the study had not been conducted on the Internet, whereas 28.75% (1826/6352) were not sure. Men (OR 1.21, 95% CI 1.04-1.42), individuals aged 26-35 years (OR 1.51, 95% CI 1.20-1.91), and obese participants (OR 1.30, 95% CI 1.02-1.65) were more inclined to be motivated by the Internet aspect. Compared with younger adults and managerial staff, individuals >55 years (OR 0.60, 95% CI 0.48-0.45) and employees/manual workers were less likely motivated by the Internet aspect (OR 0.77, 95% CI 0.63-0.92). Regarding reasons for participation, 61.37% (3898/6352) reported participating to help advance public health research on chronic disease prevention; 22.24% (1413/6352) to help advance nutrition-focused research; 6.89% (438/6352) in response to the call from the media, after being encouraged by a close friend/associate, or a medical provider. Individuals >45 years (vs younger participants) were more likely (OR 1.62, 95% CI 1.07-2.47), whereas overweight and obese participants (vs nonobese participants) were less likely to participate in the study for reasons related to helping public health research on chronic disease prevention (OR 0.72, 95% CI 0.58-0.89; OR 0.62, 95% CI 0.46-0.84; respectively). Exclusive public funding of the study was important for 67.02% (4257/6352) of the participants. Men (OR 1.37, 95% CI 1.17-1.61) and persons >55 years (OR 1.97, 95% CI 1.57-2.47) were more likely to consider the exclusive public funding as very important.

Conclusions

The use of the Internet, the willingness to help advance public health research, and the study being publicly funded were key motives for participating in the Web-based NutriNet-Santé cohort. These motives differed by sociodemographic profile and obesity, yet were not associated with lifestyle or health status. These findings can help improve the retention strategies in Web-based cohorts, particularly during decisive study periods when principal exposure information is collected.     

<Emphasis Type="Italic">TCF7L2</Emphasis> rs7903146 variant does not associate with smallness for gestational age in the French population

Background  

In adults, the TCF7L2 rs7903146 T allele, commonly associated with type 2 diabetes (T2D), has been also associated with a lower body mass index (BMI) in T2D individuals and with a smaller waist circumference in subjects with impaired glucose tolerance.