Temperature-Sensitive RB Mutations Linked to Incomplete Penetrance of Familial Retinoblastoma in 12 Families

SummaryThe tumor-suppressor activity of the retinoblastoma protein (RB) is encoded within a protein-binding (“pocket”) domain that is targeted for mutations in all cases of familial retinoblastoma and in many common adult cancers. Although familial retinoblastoma is a paradigm for a highly penetrant, recessive model of tumorigenesis, the molecular basis for the phenotype of incomplete penetrance of familial retinoblastoma is undefined. We studied the RB pocket-binding properties of three independent, mutant RB alleles that are present in the germline of 12 kindreds with the phenotype of incomplete penetrance of familial retinoblastoma. Each arises from alterations of single codons within the RB pocket domain (designated “Δ480,” “661W,” or “712R”). Under the same conditions, we studied the properties of wild-type (WT) RB, an RB point mutant isolated from a lung carcinoma sample (706F) and an adjacent, in vitro–generated point mutant (707W). The Δ480, 661W, and 712R mutants lack pocket protein-binding activity in vitro but retain the WT ability to undergo cyclin-mediated phosphorylation in vivo. Each of the low-penetrant RB mutants exhibits marked enhancement of pocket protein binding when the cells are grown at reduced temperature. In contrast, in this temperature range, no change in binding activity is seen with WT RB, the 706F mutant, or the 707W mutant. We have demonstrated that many families with incomplete penetrance of familial retinoblastoma carry unstable, mutant RB alleles with temperature-sensitive pocket protein-binding activity. The variable frequency for tumor development in these families may result from reversible fluctuations in a threshold level of RB pocket-binding activity

Pregnancy and neonatal outcomes of COVID-19: The PAN-COVID study

Objective To assess perinatal outcomes for pregnancies affected by suspected or confirmed SARS-CoV-2 infection. Methods Prospective, web-based registry. Pregnant women were invited to participate if they had suspected or confirmed SARS-CoV-2 infection between 1st January 2020 and 31st March 2021 to assess the impact of infection on maternal and perinatal outcomes including miscarriage, stillbirth, fetal growth restriction, pre-term birth and transmission to the infant. Results Between April 2020 and March 2021, the study recruited 8239 participants who had suspected or confirmed SARs-CoV-2 infection episodes in pregnancy between January 2020 and March 2021. Maternal death affected 14/8197 (0.2%) participants, 176/8187 (2.2%) of participants required ventilatory support. Pre-eclampsia affected 389/8189 (4.8%) participants, eclampsia was reported in 40/ 8024 (0.5%) of all participants. Stillbirth affected 35/8187 (0.4 %) participants. In participants delivering within 2 weeks of delivery 21/2686 (0.8 %) were affected by stillbirth compared with 8/4596 (0.2 %) delivering ≥ 2 weeks after infection (95 % CI 0.3–1.0). SGA affected 744/7696 (9.3 %) of livebirths, FGR affected 360/8175 (4.4 %) of all pregnancies. Pre-term birth occurred in 922/8066 (11.5%), the majority of these were indicated pre-term births, 220/7987 (2.8%) participants experienced spontaneous pre-term births. Early neonatal deaths affected 11/8050 livebirths. Of all neonates, 80/7993 (1.0%) tested positive for SARS-CoV-2. Conclusions Infection was associated with indicated pre-term birth, most commonly for fetal compromise. The overall proportions of women affected by SGA and FGR were not higher than expected, however there was the proportion affected by stillbirth in participants delivering within 2 weeks of infection was significantly higher than those delivering ≥ 2 weeks after infection. We suggest that clinicians’ threshold for delivery should be low if there are concerns with fetal movements or fetal heart rate monitoring in the time around infection

Using Normalisation Process Theory to understand the likely success of implementing a short educational film within routine antenatal care to reduce the risk of cytomegalovirus infection in pregnancy: An exploratory qualitative study

Background: Congenital cytomegalovirus (CMV) infection is a leading cause of sensorineural hearing loss and neuro-disability in childhood. In the absence of a licensed vaccine, adoption of hygiene-based measures may reduce the risk of CMV infection in pregnancy, however these measures are not routinely discussed with pregnant women as part of National Health Service (NHS) antenatal care in the United Kingdom (UK). Methods: An exploratory qualitative study was conducted, underpinned by Normalization Process Theory (NPT), to investigate how an educational intervention comprising of a short film about CMV may best be implemented, sustained, and enhanced in real-world routine antenatal care settings. Video, semi-structured interviews were conducted with participants who were recruited using a purposive sample that comprised of midwives providing antenatal care from three NHS hospitals (n=15) and participants from professional colleges and from organisations or charities providing, or with an interest in, antenatal education or health information in the UK (n=15). Findings: Midwives were reluctant to include CMV as part of early pregnancy discussions about reducing the risk of other infections due to lack of time, knowledge and absence of guidance or policies relating to CMV in antenatal education. However, the educational intervention was perceived to be a useful tool to encourage conversations and empower women to manage risk by all stakeholders, which would overcome some identified barriers. Macro-level challenges such as screening policies and lack of official guidelines to legitimise dissemination were identified. Discussion: Successful implementation of education about CMV as part of routine NHS care in the UK will require an increase in awareness and knowledge about CMV amongst midwives. NPT revealed that ‘coherence’ and ‘cognitive participation’ between service members are vital to imbed CMV education in routine practice. ‘Collective action’ in and ‘reflexive monitoring’ is required to sustain service changes

Effort reinforces learning

Humans routinely learn the value of actions by updating their expectations based on past outcomes – a process driven by reward prediction errors (RPEs). Importantly, however, implementing a course of action also requires the investment of effort. Recent work has revealed a close link between the neural signals involved in effort exertion and those underpinning reward-based learning, but the behavioural relationship between these two functions remains unclear. Across two experiments, we tested healthy participants (N=140) on a reinforcement learning task in which they registered their responses by applying physical force to a pair of hand-held dynamometers. We examined the effect of effort on learning by systematically manipulating the amount of force required to register a response during the task. Our key finding, replicated across both experiments, was that greater effort increased learning rates following positive outcomes and decreased them following negative outcomes, which corresponded to a differential effect of effort in boosting positive RPEs and blunting negative RPEs. Interestingly, this effect was most pronounced in individuals who were more averse to effort in the first place, raising the possibility that the investment of effort may have an adaptive effect on learning in those less motivated to exert it. By integrating principles of reinforcement learning with neuroeconomic approaches to value-based decision making, we show that the very act of investing effort modulates one’s capacity to learn, and demonstrate how these functions may operate within a common computational framework

Investigation of copper(II) tetrafluoroborate catalysed epoxide opening

We report the extension of the copper(II) tetrafluoroborate catalysed opening of epoxides with alcohols to include a wider variety of alcohols, a range of solvents and a method to purify the products from the reaction