Identification of novel bile acids as biomarkers for the early diagnosis of Niemann-Pick C disease

This article describes a rapid UPLC-MS/MS method to quantitate novel bile acids in biological fluids and the evaluation of their diagnostic potential in Niemann-Pick C (NPC). Two new compounds, NPCBA1 (3β-hydroxy,7β-N-acetylglucosaminyl-5-cholenoic acid) and NPCBA2 (probably 3β,5α,6β-trihydroxycholanoyl-glycine), were observed to accumulate preferentially in NPC patients: median plasma concentrations of NPCBA1 and NPCBA2 were 40- and 10-fold higher in patients than in controls. However, NPCBA1 concentrations were normal in some patients because they carried a common mutation inactivating the GlcNAc transferase required for the synthesis of this bile acid. NPCBA2, not containing a GlcNAc moiety, is thus a better NPC biomarker

Towards memory supporting personal information management tools

In this article we discuss re-retrieving personal information objects and relate the task to recovering from lapse(s) in memory. We propose that fundamentally it is lapses in memory that impede users from successfully re-finding the information they need. Our hypothesis is that by learning more about memory lapses in non-computing contexts and how people cope and recover from these lapses, we can better inform the design of PIM tools and improve the user's ability to re-access and re-use objects. We describe a diary study that investigates the everyday memory problems of 25 people from a wide range of backgrounds. Based on the findings, we present a series of principles that we hypothesize will improve the design of personal information management tools. This hypothesis is validated by an evaluation of a tool for managing personal photographs, which was designed with respect to our findings. The evaluation suggests that users' performance when re-finding objects can be improved by building personal information management tools to support characteristics of human memory

AtHMA4 drives natural variation in leaf Zn concentration of Arabidopsis thaliana

Zinc (Zn) is an essential element for plant growth and development, and Zn derived from crop plants in the diet is also important for human health. Here, we report that genetic variation in Heavy Metal-ATPase 4 (HMA4) controls natural variation in leaf Zn content. Investigation of the natural variation in leaf Zn content in a world-wide collection of 349 Arabidopsis thaliana wild collected accessions identified two accessions, Van-0 and Fab-2, which accumulate significantly lower Zn when compared with Col-0. Both quantitative trait loci (QTL) analysis and bulked segregant analysis (BSA) identified HMA4 as a strong candidate accounting for this variation in leaf Zn concentration. Genetic complementation experiments confirmed this hypothesis. Sequence analysis revealed that a 1-bp deletion in the third exon of HMA4 from Fab-2 is responsible for the lose of function of HMA4 driving the low Zn observed in Fab-2. Unlike in Fab-2 polymorphisms in the promoter region were found to be responsible for the weak function of HMA4 in Van-0. This is supported by both an expression analysis of HMA4 in Van-0 and through a series of T-DNA insertion mutants which generate truncated HMA4 promoters in the Col-0 background. In addition, we also observed that Fab-2, Van-0 and the hma4-2 null mutant in the Col-0 background show enhanced resistance to a combination of high Zn and high Cd in the growth medium, raising the possibility that variation at HMA4 may play a role in environmental adaptation

Assessing the impact and cost-effectiveness of needle and syringe provision and opioid substitution therapy on hepatitis C transmission among people who inject drugs in the UK: an analysis of pooled data sets and economic modelling

Background There is limited evidence of the impact of needle and syringe programmes (NSPs) and opioid substitution therapy (OST) on hepatitis C virus (HCV) incidence among people who inject drugs (PWID), nor have there been any economic evaluations. Objective(s) To measure (1) the impact of NSP and OST, (2) changes in the extent of provision of both interventions, and (3) costs and cost-effectiveness of NSPs on HCV infection transmission. Design We conducted (1) a systematic review; (2) an analysis of existing data sets, including collating costs of NSPs; and (3) a dynamic deterministic model to estimate the impact of differing OST/NSP intervention coverage levels for reducing HCV infection prevalence, incidence and disease burden, and incremental cost-effectiveness ratios to measure the cost-effectiveness of current NSP provision versus no provision. Setting Cost-effectiveness analysis and impact modelling in three UK sites. The pooled analysis drew on data from the UK and Australia. The review was international. Participants PWID. Interventions NSP coverage (proportion of injections covered by clean needles) and OST. Outcome New cases of HCV infection. Results The review suggested that OST reduced the risk of HCV infection acquisition by 50% [rate ratio (RR) 0.50, 95% confidence interval (CI) 0.40 to 0.63]. Weaker evidence was found in areas of high (≥ 100%) NSP coverage (RR 0.77, 95% CI 0.38 to 1.54) internationally. There was moderate evidence for combined high coverage of NSPs and OST (RR 0.29, 95% CI 0.13 to 0.65). The pooled analysis showed that combined high coverage of NSPs and OST reduced the risk of HCV infection acquisition by 29–71% compared with those on minimal harm reduction (no OST, ≤ 100% NSP coverage). NSPs are likely to be cost-effective and are cost-saving in some settings. The impact modelling suggest that removing OST (current coverage 81%) and NSPs (coverage 54%) in one site would increase HCV infection incidence by 329% [95% credible interval (CrI) 110% to 953%] in 2031 and at least double (132% increase; 95% CrI 51% to 306%) the number of new infections over 15 years. Increasing NSP coverage to 80% has the largest impact in the site with the lowest current NSP coverage (35%), resulting in a 27% (95% CrI 7% to 43%) decrease in new infections and 41% (95% CrI 11% to 72%) decrease in incidence by 2031 compared with 2016. Addressing homelessness and reducing the harm associated with the injection of crack cocaine could avert approximately 60% of HCV infections over the next 15 years. Limitations Findings are limited by the misclassification of NSP coverage and the simplified intervention definition that fails to capture the integrated services that address other social and health needs as part of this. Conclusions There is moderate evidence of the effectiveness of OST and NSPs, especially in combination, on HCV infection acquisition risk. Policies to ensure that NSPs can be accessed alongside OST are needed. NSPs are cost-saving in some sites and cost-effective in others. NSPs and OST are likely to prevent considerable rates of HCV infection in the UK. Increasing NSP coverage will have most impact in settings with low coverage. Scaling up other interventions such as HCV infection treatment are needed to decrease epidemics to low levels in higher prevalence settings. Future work To understand the mechanisms through which NSPs and OST achieve their effect and the optimum contexts to support implementation. Funding The National Institute for Health Research Public Health Research programme. </jats:sec

Apoptotic Cleavage of Cytoplasmic Dynein Intermediate Chain and P150GluedStops Dynein-Dependent Membrane Motility

Cytoplasmic dynein is the major minus end–directed microtubule motor in animal cells, and associates with many of its cargoes in conjunction with the dynactin complex. Interaction between cytoplasmic dynein and dynactin is mediated by the binding of cytoplasmic dynein intermediate chains (CD-IC) to the dynactin subunit, p150Glued. We have found that both CD-IC and p150Glued are cleaved by caspases during apoptosis in cultured mammalian cells and in Xenopus egg extracts. Xenopus CD-IC is rapidly cleaved at a conserved aspartic acid residue adjacent to its NH2-terminal p150Glued binding domain, resulting in loss of the otherwise intact cytoplasmic dynein complex from membranes. Cleavage of CD-IC and p150Glued in apoptotic Xenopus egg extracts causes the cessation of cytoplasmic dynein–driven endoplasmic reticulum movement. Motility of apoptotic membranes is restored by recruitment of intact cytoplasmic dynein and dynactin from control cytosol, or from apoptotic cytosol supplemented with purified cytoplasmic dynein–dynactin, demonstrating the dynamic nature of the association of cytoplasmic dynein and dynactin with their membrane cargo

Modelling the impact of a national scale-up of interventions on hepatitis C virus transmission among people who inject drugs in Scotland

BACKGROUND AND AIMS: To reduce hepatitis C virus (HCV) transmission among people who inject drugs (PWID), Scottish Government-funded national strategies, launched in 2008, promoted scaling-up opioid substitution therapy (OST) and needle and syringe provision (NSP), with some increases in HCV treatment. We test whether observed decreases in HCV incidence post-2008 can be attributed to this intervention scale-up. DESIGN: A dynamic HCV transmission model among PWID incorporating intervention scale-up and observed decreases in behavioural risk, calibrated to Scottish HCV prevalence and incidence data for 2008/09. SETTING: Scotland, UK. PARTICIPANTS: PWID. MEASUREMENTS: Model projections from 2008 to 2015 were compared with data to test whether they were consistent with observed decreases in HCV incidence among PWID while incorporating the observed intervention scale-up, and to determine the impact of scaling-up interventions on incidence. FINDINGS: Without fitting to epidemiological data post-2008/09, the model incorporating observed intervention scale-up agreed with observed decreases in HCV incidence among PWID between 2008 and 2015, suggesting that HCV incidence decreased by 61.3% [95% credibility interval (CrI) = 45.1-75.3%] from 14.2/100 person-years (py) (9.0-20.7) to 5.5/100 py (2.9-9.2). On average, each model fit lay within 84% (10.1/12) of the confidence bounds for the 12 incidence data points against which the model was compared. We estimate that scale-up of interventions (OST + NSP + HCV treatment) and decreases in high-risk behaviour from 2008 to 2015 resulted in a 33.9% (23.8-44.6%) decrease in incidence, with the remainder [27.4% (17.6-37.0%)] explained by historical changes in OST + NSP coverage and risk pre-2008. Projections suggest that scaling-up of all interventions post-2008 averted 1492 (657-2646) infections over 7 years, with 1016 (308-1996), 404 (150-836) and 72 (27-137) due to scale-up of OST + NSP, decreases in high-risk behaviour and HCV treatment, respectively. CONCLUSIONS: Most of the decline in hepatitis C virus (HCV) incidence in Scotland between 2008 and 2015 appears to be attributable to intervention scale-up (opioid substitution therapy and needle and syringe provision) due to government strategies on HCV and drugs

Impact of current and scaled up levels of Hepatitis C (HCV) prevention and treatment interventions for people who inject drugs in three UK settings – what is required to achieve the WHO’s HCV elimination targets?

Aims: We estimate the impact of existing high coverage needle and syringe provision (HCNSP, defined as obtaining more than one sterile needle and syringe per injection reported) and opioid substitution therapy (OST) on hepatitis C virus (HCV) transmission among people who inject drugs (PWID) in three United Kingdom (UK) settings. We determine required scale-up of interventions, including HCV treatment, needed to reach the World Health Organisation (WHO) target of reducing HCV incidence by 90% by 2030. Design HCV transmission modelling utilising UK empirical estimates for effect of OST and/or HCNSP on individual risk of HCV acquisition Setting Three UK cities with varying HCV antibody prevalence (Bristol 60%, Dundee 46%, Walsall 32%), OST (72-81%), and HCNSP coverage (28-56%). Measurements Relative change in new HCV infections over 2016-2030 if current interventions were stopped. Scale-up of HCNSP, OST and HCV treatment required to achieve the WHO elimination target. Findings Removing HCNSP or OST would increase the number of new HCV infections over 2016-2030 by 23-64% and 92-483%, respectively. Conversely, scaling-up these interventions to 80% coverage could achieve a 29% or 49% reduction in Bristol and Walsall, respectively, whereas Dundee achieves a 90% decrease in incidence with current levels of intervention because of existing high levels of HCV treatment (47-58 treatments per 1000 PWID). If OST and HCNSP are scaled-up, Walsall and Bristol can achieve the same impact by treating 14 or 40 per 1000 PWID annually, respectively (currently 1-3 and 6-12 treatments per 1000 PWID), while 18 and 43 treatments per 1000 PWID would be required if OST and HCNSP are not scaled-up. Conclusions Current opioid substitution therapy and high coverage needle and syringe provision coverage is averting substantial Hepatitis C transmission in the United Kingdom. Maintaining this coverage while initiating current injectors on treatment can reduce incidence by 90% by 2030

Neurocognitive bases of emotion regulation development in adolescence

Emotion regulation is the ability to recruit processes to influence emotion generation. In recent years there has been mounting interest in how emotions are regulated at behavioural and neural levels, as well as in the relevance of emotional dysregulation to psychopathology. During adolescence, brain regions involved in affect generation and regulation, including the limbic system and prefrontal cortex, undergo protracted structural and functional development. Adolescence is also a time of increasing vulnerability to internalising and externalising psychopathologies associated with poor emotion regulation, including depression, anxiety and antisocial behaviour. It is therefore of particular interest to understand how emotion regulation develops over this time, and how this relates to ongoing brain development. However, to date relatively little research has addressed these questions directly. This review will discuss existing research in these areas in both typical adolescence and in adolescent psychopathology, and will highlight opportunities for future research. In particular, it is important to consider the social context in which adolescent emotion regulation develops. It is possible that while adolescence may be a time of vulnerability to emotional dysregulation, scaffolding the development of emotion regulation during this time may be a fruitful preventative target for psychopathology

Ilya Neustadt, Norbert Elias, and the Leicester Department: personal correspondence and the history of sociology in Britain

The central aims of this paper are: (1) to explore the utility of using personal correspondence as a source of data for sociological investigations into the history of sociology in the UK; (2) in relation to this undertaking, to advance the beginnings of a figurational analysis of epistolary forms; and (3), to provide an empirically-grounded discussion of the historical significance of the Department of Sociology at the University of Leicester (a University largely ignored in 'standard histories' of the subject) at a formative phase in the development of the discipline within the UK. The correspondence drawn upon in the paper is between Norbert Elias and Ilya Neustadt between 1962 and 1964 when Elias was Professor of Sociology at the University of Ghana and Ilya Neustadt was Professor of Sociology and Head of the Sociology Department at the University of Leicester. From an analysis of this correspondence, we elucidate an emergent dynamic to the relationship between Neustadt and Elias, one which, we argue, undergirds the development of sociology at Leicester and the distinctive character of the intellectual climate that prevailed there during the 1960s. The paper concludes with a consideration of whether it was a collapse of this dynamic that led to a total breakdown in the relationship between Neustadt and Elias, and by extension, an important phase in the expansion of sociology at Leicester