SummaryThe myristoylated, alanine-rich C kinase substrate (MARCKS) is a prominent substrate for protein kinase C (PKC) in a variety of cells, and has been implicated in diverse cellular processes including neurosecretion, fibroblast mitogenesis, and macrophage activation . In macrophages that have spread on the substratum, MARCKS has a punctate distribution at the cell-substratum interface of pseudopodia and filopodia . At these points, MARCKS co-localizes with vinculin and talin . Activation of PKC with phorbol esters results in the rapid disappearance of punctate staining of MARCKS, but not vinculin or talin, and is accompanied by cell spreading and loss of filopodia . The morphological changes and disappearance of punctate staining follow a time-course that closely approximates both the PKC-dependent phosphorylation of MARCKS, and its phosphorylation-dependent release from the plasma membrane. Our results suggest a role for PKCdependent phosphorylation of MARCKS in the regulation of the membrane cytoskeleton .T he protein kinases C (PKC)t are a family of diacylglycerol-activated, calcium-dependent protein kinases that play a central role in transducing signals that regulate diverse cellular events. Little is known about the functions of the major cellular substrates for PKC, and the role of their phosphorylation in mediating biological responses . One of the most prominent substrates for PKC is an acidic protein with an apparent molecular mass of 68-87K. Phosphorylation of 68-87K is synonymous with the activation of PKC during neurosecretion (1), fibroblast mitogenesis (2, 3), and macrophage activation (4) . The protein was first shown to be myristoylated in macrophages (4) and this observation has been confirmed in a variety of cell types (5) . This modification, together with its high proportion of alanine (6, 7), led to the suggestion that the protein be referred to by the acronym MARCKS (for myristoylated, alanine-rich C kinase substrate) (7) . Despite extensive biochemical and biophysical characterization of MARCKS (6-9), the precise biological role of this protein remains unknown . We have attempted to gain insight into the function of MARCKS by immuno-localization studies . We report here that in unstimulated cells, MARCKS stains in a punctate distribution at the substrate-adherent surface of macrophage pseudopodia and filopodia, where it colocalizes with vinculin and talin . MARCKS is displaced from 'Abbreviations used in this paper. MARCKS, myristoylated alanine-rich C kinase substrate; PKC, protein kinase C. this location upon PKC-mediated phosphorylation. This event is accompanied by morphological alteration in the macrophage. Materials and MethodsImmunofluorescence. Mouse brain MARCKS (68K) was purified to homogeneity, and a polyclonal rabbit antibody to mouse MARCKS was generated (10) . This antiserum, affinity-purified (11) against a second preparation of purified murine brain protein, immunoblotted a single species in mouse macrophage lysates that had a molecular mass of 68K, and isoelectric po...

With advances in the 'new genetics', an increasing number of people will have access to genetic information and predictive or susceptibility testing. Genetic knowledge has implications for individuals themselves, as well as other family members. In general, health professionals encourage people to pass on genetic risk information to their relatives. However, the disclosure of such information is not always straightforward and, consequently, some people may not be aware of their risk. If risk information is actively withheld, genetic counsellors may need to determine whether they have a duty to pass this on, particularly when preventive action can be taken. To date, little research has explored the barriers and facilitators in family communication about genetic risk. This paper draws on empirical data from a qualitative study exploring communication in families with late-onset familial disease. Interviews were conducted with participants who received genetic counselling for risk of Huntington's disease and hereditary breast or ovarian cancer. Participants' experiences of who was responsible for (not) telling relatives in their families is studied. A number of themes were identified. These were: (1) 'whose place is it to tell', (2) the gendering of disclosure, and (3) who is 'family'. The implications of these findings are considered.

Previous research and clinical experience suggest that Huntington's disease (HD) can considerably affect family life, particularly for young people (YP) at risk. The goal of this study was to describe the experiences of YP from families affected by HD. YP were identified through the regional genetics clinic and the Scottish Huntington's Association. In-depth interviews were used to explore YP's experiences of finding out about HD in the family; perceptions of their own risk; caring activities; protective or risk factors; and the impact of HD on relationships with siblings, parents, extended family members, and the wider community. Thirty-three YP between the ages of 9 and 28 years were interviewed. A qualitative thematic analysis was undertaken. The analysis revealed four main themes: YP as carers, the worried well, those who cope, and those at risk/in need. These themes highlight the varied experience of growing up in a family affected by HD. Whilst some YP successfully coped, others experienced considerable problems and were at risk of physical and/or emotional harm. In understanding why some cope better than others, our findings suggest protective and risk factors within these themes. In particular, participants who grew up knowing about HD from an early age seemed to cope better.

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Objective To quantify the change in quality of life, disease-specific indicators, health, and lifestyle before and during the COVID19 pandemic amongst people with musculoskeletal diagnoses and symptoms. Methods We undertook an additional follow-up of two existing UK registers involving people with axial spondyloarthritis (axSpA) or psoriatic arthritis (PsA) and participants in a trial in the UK who had regional pain and were identified at high risk of developing chronic widespread pain. Participants completed the study questionnaire between July and December 2020, throughout which time there were public health restrictions in place. Results 1054 people took part in the study (596 axSpA, 162 PsA, 296 regional pain). In comparison to their previous (pre-pandemic) assessment, there was an age-adjusted significant, small, decrease in quality of life measured by EQ-5D (-0.020 95% CI (-0.030, -0.009)) overall and across all population groups examined. This was primarily related to poorer mental health and pain. There was a small increase in fibromyalgia symptoms, but a small decrease in sleep problems. There was a small deterioration in axSpA disease activity, and disease-specific quality of life and anxiety in PsA participants. Predictors of poor quality of life were similar pre- and during the pandemic. The effect of lockdown on activity differed according to age, gender, and deprivation. Conclusion Important lessons include focussing on addressing anxiety and providing enhanced support for self-management in the absence of normal health care being available, and awareness that all population groups are likely to be affected.

A growing number of young people (YP) are requesting predictive testing (PT) for Huntington's disease (HD), yet there is little research in this area. The aim of this study was to explore YP's experiences of PT for HD, the impact of their result and any gaps in information or support. In‐depth interviews were conducted with YP who sought PT for HD from nationally funded Genetics Services. Participants were recruited through the Grampian Genetics Service or Scottish Huntington's Association. Twelve female participants aged 17–26 years were recruited (seven below 20 years). Pre‐ and post‐test interviews were conducted where possible. A qualitative thematic analysis suggests three main testing experiences, regardless of test result. Testing may be: (i) a journey of empowerment, (ii) an ambivalent process or (iii) a poor experience. In pre‐test counselling, gaps in emotional support were highlighted. The post‐test period was particularly difficult if there were unanticipated changes in family dynamics or an individual's result contradicted what they expected ‘deep down’. YP's experiences of PT for HD are generally similar to those of adults, but testing may help or interfere with key issues related to this age and stage. Implications for clinical practice are outlined.

Familial hypercholesterolemia (FH) is a serious inherited disorder, which greatly increases individuals' risk of cardiovascular disease (CVD) in adult life. However, medical treatment and lifestyle adjustments can fully restore life expectancy. Whilst European guidance advises that where there is a known family mutation genetic testing is undertaken in early childhood, the majority of the at-risk population remain untested and undiagnosed. To date, only a small number of studies have explored parents' and children's experiences of testing and treatment for FH, and little is known about interactions between health professionals, parents, and children in clinic settings. In this study, in-depth interviews were undertaken with parents who had attended a genetics and/or lipid clinic for FH with their children (n = 17). A thematic analysis revealed four main themes: undertaking early prevention, postponing treatment, parental concerns, and the importance of the wider family context. The majority of parents supported genetic testing for FH in childhood. However, although some were very supportive of following early treatment recommendations, others expressed reluctance. Importantly, some parents were concerned that inappropriate information had been shared with their children and wished that more time had been given to discuss how, when, and what to tell in advance. Future research is needed to explore the long-term outcomes for children who undertake genetic testing and early treatment for FH and to trial interventions to improve the engagement, follow-up, and support of children who are at risk, or diagnosed, with this disorder.