Murine model of autosomal dominant retinitis pigmentosa generated by targeted deletion at codon 307 of the rds-peripherin gene

We introduced a targeted single base deletion at codon 307 of the rds-peripherin gene in mice, similar mutations being known to cause autosomal dominant retinitis pigmentosa (RP) in man. Histopathological and electroretinographic analysis indicate that the retinopathy in mice homozygous for the codon 307 mutation appears more rapid than that in the naturally occurring null mutant, the rds(-/-) mouse, suggesting that the rds-307 mutation displays a dominant negative phenotype in combination with that due to haplosufficiency. RP is the most prevalent cause of registered visual handicap in those of working age in developed countries, the 50 or so mutations so far identified within the RDS-peripherin gene accounting for up to 10% of dominant cases of the disease. Given the sequence homologies that exist between the murine rds-peripherin and the human RDS-peripherin gene, this disease model, the first to be generated for peripherin-based RP using gene targeting techniques, should in principle be of value in the work-up in mice of therapeutics capable of targeting transcripts derived from the human gene.

Recruitment bias and clinical characterstics of participants with severe cerebral palsy in a cross-sectional survey

Aim.  This article is a report of recruitment bias in a sample of 5–25-year-old patients with severe cerebral palsy.

Background.  The way in which study participants are recruited into research can be a source of bias.

Method.  A cross-sectional survey of 5–25-year-old patients with severe cerebral palsy using standardized questionnaires with parents/carers was undertaken in 2007/2008. A case register was used as the sampling frame, and 260 families were approached: 178/260 (68%) responded and 82/260 families never replied (non-respondents). Among responders: 127/178 (71%) opted in to the study, but only 123/127 were assessed, and 82/178 were opted out (or refused). Multivariable logistic regression giving odds ratios was used to study the association between participant characteristics and study outcomes (responders vs. non-responders; opting in vs. opting out; assessed vs. eligible, but not assessed).

Results.  Responders (compared with non-responders) were significantly more likely to have a family member with cerebral palsy who was male and resident in more affluent areas. Families who opted in (compared with those opting out and refusing) were more likely to have a family member with cerebral palsy and intellectual impairment and to reside in certain geographical areas. Families who were actually assessed (compared with all eligible, but not assessed) were more likely to have a family member with cerebral palsy and intellectual impairment.

Conclusion.  Several sources of bias were identified during recruitment for this study. This has implications for the interpretation and conclusions of surveys of people with disabilities and complex needs.

Explaining the relationship between ingroup identification and intergroup bias following recategorization: A self-regulation theory analysis

We tested the hypothesis that regulation of discrepancies between perceived actual and ideal differentiation between the ingroup and outgroup could help to explain the relationship between ingroup identification and intergroup bias when participants are recategorized into a superordinate group. Replicating previous findings, we found that following recategorization, identification was positively related to intergroup bias. No such differences emerged in a control condition. However, we also, in the recategorization condition only, observed a positive association between ingroup identification and the perceived discrepancy between actual and ideal degree of differentiation from the outgroup: at higher levels of identification, participants increasingly perceived the ingroup to be less differentiated from the outgroup than they would ideally like. This tendency mediated the relationship between identification and bias. We discuss the theoretical, methodological and practical implications of these findings.

Common Ingroups and Complex Identities: Routes to Reducing Bias in Multiple Category Contexts

We tested the hypothesis that evaluative bias in common ingroup contexts versus crossed categorization contexts can be associated with two distinct underlying processes. We reasoned that in common ingroup contexts, self-categorization, but not perceived complexity, would be positively related to intergroup bias. In contrast, in crossed categorization contexts, perceived complexity, but not self-categorization, would be negatively related to intergroup bias. In two studies, and in line with predictions, we found that while self-categorization and intergroup bias were related in common ingroup contexts, this was not the case in crossed categorization contexts. Moreover, we found that perceived category complexity, and not self-categorization, predicted bias in crossed categorization contexts. We discuss the implications of these findings for models of social categorization and intergroup bias.

Using sketch-map coordinates to analyze and bias molecular dynamics simulations

When examining complex problems, such as the folding of proteins, coarse grained descriptions of the system drive our investigation and help us to rationalize the results. Oftentimes collective variables (CVs), derived through some chemical intuition about the process of interest, serve this purpose. Because finding these CVs is the most difficult part of any investigation, we recently developed a dimensionality reduction algorithm, sketch-map, that can be used to build a low-dimensional map of a phase space of high-dimensionality. In this paper we discuss how these machine-generated CVs can be used to accelerate the exploration of phase space and to reconstruct free-energy landscapes. To do so, we develop a formalism in which high-dimensional configurations are no longer represented by low-dimensional position vectors. Instead, for each configuration we calculate a probability distribution, which has a domain that encompasses the entirety of the low-dimensional space. To construct a biasing potential, we exploit an analogy with metadynamics and use the trajectory to adaptively construct a repulsive, history-dependent bias from the distributions that correspond to the previously visited configurations. This potential forces the system to explore more of phase space by making it desirable to adopt configurations whose distributions do not overlap with the bias. We apply this algorithm to a small model protein and succeed in reproducing the free-energy surface that we obtain from a parallel tempering calculation.