Mathematical modeling accurately predicts the dynamics and scaling of nuclear growth in discrete cytoplasmic volumes

Scaling of nuclear size with cell size has been observed in many species and cell types. In this work we formulate a modeling framework based on the limiting component hypothesis. We derive a family of spatio-temporal mathematical models for nuclear size determination based on different transport and growth mechanisms. We analyse model properties and use in vitro experimental data to identify the most probable mechanism. This suggests that nuclear volume scales with cell volume and that a nucleus controls its import rate as it grows. We further test the model by comparing to data of early frog development, where rapid cell divisions set the relevant time scales

Long-term outcome of partial P450 side-chain cleavage enzyme deficiency in three brothers: the importance of early diagnosis.

Objective: CYP11A1 mutations cause P450 side-chain cleavage (scc) deficiency, a rare form of congenital adrenal hyperplasia with a wide clinical spectrum. We detail the phenotype and evolution in a male sibship identified by HaloPlex targeted capture array. Family study: The youngest of three brothers from a non-consanguineous Scottish family presented with hyperpigmentation at 3.7 years. Investigation showed grossly impaired glucocorticoid function with ACTH elevation, moderately impaired mineralocorticoid function, and normal external genitalia. The older brothers were found to be pigmented also, with glucocorticoid impairment but normal electrolytes. Linkage studies in 2002 showed that all three brothers had inherited the same critical regions of the maternal X chromosome suggesting an X-linked disorder, but analysis of NR0B1 (DAX-1, adrenal hypoplasia) and ABCD1 (adrenoleukodystrophy) were negative. In 2016, next-generation sequencing revealed compound heterozygosity for the rs6161 variant in CYP11A1 (c.940G>A, p.Glu314Lys), together with a severely disruptive frameshift mutation (c.790_802del, K264Lfs*5). The brothers were stable on hydrocortisone and fludrocortisone replacement, testicular volumes (15-20 mL), and serum testosterone levels (24.7, 33.3, and 27.2 nmol/L) were normal, but FSH (41.2 µ/L) was elevated in the proband. The latter had undergone left orchidectomy for suspected malignancy at the age of 25 years and was attending a fertility clinic for oligospermia. Initial histology was reported as showing nodular Leydig cell hyperplasia. However, histological review using CD56 staining confirmed testicular adrenal rest cell tumour (TART). Conclusion: This kinship with partial P450scc deficiency demonstrates the importance of precise diagnosis in primary adrenal insufficiency to ensure appropriate counselling and management, particularly of TART

Damage function for historic paper. Part I: Fitness for use

Background In heritage science literature and in preventive conservation practice, damage functions are used to model material behaviour and specifically damage (unacceptable change), as a result of the presence of a stressor over time. For such functions to be of use in the context of collection management, it is important to define a range of parameters, such as who the stakeholders are (e.g. the public, curators, researchers), the mode of use (e.g. display, storage, manual handling), the long-term planning horizon (i.e. when in the future it is deemed acceptable for an item to become damaged or unfit for use), and what the threshold of damage is, i.e. extent of physical change assessed as damage. Results In this paper, we explore the threshold of fitness for use for archival and library paper documents used for display or reading in the context of access in reading rooms by the general public. Change is considered in the context of discolouration and mechanical deterioration such as tears and missing pieces: forms of physical deterioration that accumulate with time in libraries and archives. We also explore whether the threshold fitness for use is defined differently for objects perceived to be of different value, and for different modes of use. The data were collected in a series of fitness-for-use workshops carried out with readers/visitors in heritage institutions using principles of Design of Experiments. Conclusions The results show that when no particular value is pre-assigned to an archival or library document, missing pieces influenced readers/visitors’ subjective judgements of fitness-for-use to a greater extent than did discolouration and tears (which had little or no influence). This finding was most apparent in the display context in comparison to the reading room context. The finding also best applied when readers/visitors were not given a value scenario (in comparison to when they were asked to think about the document having personal or historic value). It can be estimated that, in general, items become unfit when text is evidently missing. However, if the visitor/reader is prompted to think of a document in terms of its historic value, then change in a document has little impact on fitness for use

Nonsteroidal anti-inflammatory drug use and Alzheimer's disease risk: the MIRAGE Study

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAID) use may protect against Alzheimer's disease (AD) risk. We sought examine the association between NSAID use and risk of AD, and potential effect modification by APOE-ε4 carrier status and ethnicity. METHODS: The MIRAGE Study is a multi-center family study of genetic and environmental risk factors for AD. Subjects comprised 691 AD patients (probands) and 973 family members enrolled at 15 research centers between 1996 and 2002. The primary independent and dependent variables were prior NSAID use and AD case status, respectively. We stratified the dataset in order to evaluate whether the association between NSAID use and AD was similar in APOE-ε4 carriers and non-carriers. Ethnicity was similarly examined as an effect modifier. RESULTS: NSAID use was less frequent in cases compared to controls in the overall sample (adjusted OR = 0.64; 95% CI = 0.38–1.05). The benefit of NSAID use appeared more pronounced among APOE-ε4 carriers (adjusted OR = 0.49; 95% CI = 0.24–0.98) compared to non-carriers, although this association was not statistically significant. The pattern of association was similar in Caucasian and African Americans. CONCLUSIONS: NSAID use is inversely associated with AD and may be modified by APOE genotype. Prospective studies and clinical trials of sufficient power to detect effect modification by APOE-ε4 carrier status are needed

P-rex1 cooperates with PDGFRβ to drive cellular migration in 3D microenvironments

Expression of the Rac-guanine nucleotide exchange factor (RacGEF), P-Rex1 is a key determinant of progression to metastasis in a number of human cancers. In accordance with this proposed role in cancer cell invasion and metastasis, we find that ectopic expression of P-Rex1 in an immortalised human fibroblast cell line is sufficient to drive multiple migratory and invasive phenotypes. The invasive phenotype is greatly enhanced by the presence of a gradient of serum or platelet-derived growth factor, and is dependent upon the expression of functional PDGF receptor β. Consistently, the invasiveness of WM852 melanoma cells, which endogenously express P-Rex1 and PDGFRβ, is opposed by siRNA of either of these proteins. Furthermore, the current model of P-Rex1 activation is advanced through demonstration of P-Rex1 and PDGFRβ as components of the same macromolecular complex. These data suggest that P-Rex1 has an influence on physiological migratory processes, such as invasion of cancer cells, both through effects upon classical Rac1-driven motility and a novel association with RTK signalling complexes

Inconsistent strategies to spin up models in CMIP5: Implications for ocean biogeochemical model performance assessment

This is the final version of the article. Available from EGU via the DOI in this record.During the fifth phase of the Coupled Model Intercomparison Project (CMIP5) substantial efforts were made to systematically assess the skill of Earth system models. One goal was to check how realistically representative marine biogeochemical tracer distributions could be reproduced by models. In routine assessments model historical hindcasts were compared with available modern biogeochemical observations. However, these assessments considered neither how close modeled biogeochemical reservoirs were to equilibrium nor the sensitivity of model performance to initial conditions or to the spin-up protocols. Here, we explore how the large diversity in spin-up protocols used for marine biogeochemistry in CMIP5 Earth system models (ESMs) contributes to model-to-model differences in the simulated fields. We take advantage of a 500-year spin-up simulation of IPSL-CM5A-LR to quantify the influence of the spin-up protocol on model ability to reproduce relevant data fields. Amplification of biases in selected biogeochemical fields (O2, NO3, Alk-DIC) is assessed as a function of spin-up duration. We demonstrate that a relationship between spin-up duration and assessment metrics emerges from our model results and holds when confronted with a larger ensemble of CMIP5 models. This shows that drift has implications for performance assessment in addition to possibly aliasing estimates of climate change impact. Our study suggests that differences in spin-up protocols could explain a substantial part of model disparities, constituting a source of model-to-model uncertainty. This requires more attention in future model intercomparison exercises in order to provide quantitatively more correct ESM results on marine biogeochemistry and carbon cycle feedbacks.We sincerely thank I. Kriest, F. Joos, the anonymous reviewer and A. Yool for their useful comments on this paper. This work was supported by H2020 project CRESCENDO “Coordinated Research in Earth Systems and Climate: Experiments, kNowledge, Dissemination and Outreach”, which received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 641816 and by the EU FP7 project CARBOCHANGE “Changes in carbon uptake and emissions by oceans in a changing climate” which received funding from the European community’s Seventh Framework Programme under grant agreement no. 264879. Supercomputing time was provided by GENCI (Grand Equipement National de Calcul Intensif) at CCRT (Centre de Calcul Recherche et Technologie), allocation 016178. Finally, we are grateful to the ESGF project which makes data available for all the community. Roland Séférian is grateful to Aurélien Ribes for his kind advices on statistics. Jerry Tjiputra acknowledges ORGANIC project (239965/F20) funded by the Research Council of Norway. Christoph Heinze and Jerry Tjiputra are grateful for support through project EVA – Earth system modelling of climate variations in the Anthropocene (229771/E10) funded by the Research Council of Norway, as well as CPU-time and mass storage provided through NOTUR project NN2345K as well as NorStore project NS2345K. Keith Lindsay and Scott C. Doney acknowledge support from the National Science Foundation

Identifying enablers and barriers to individually tailored prescribing: a survey of healthcare professionals in the UK.

BACKGROUND: Many people now take multiple medications on a long-term basis to manage health conditions. Optimising the benefit of such polypharmacy requires tailoring of medicines use to the needs and circumstances of individuals. However, professionals report barriers to achieving this in practice. In this study, we examined health professionals' perceptions of enablers and barriers to delivering individually tailored prescribing. METHODS: Normalisation Process Theory (NPT) informed an on-line survey of health professionals' views of enablers and barriers to implementation of Individually Tailored Prescribing (ITP) of medicines. Links to the survey were sent out through known professional networks using a convenience/snowball sampling approach. Survey questions sought to identify perceptions of supports/barriers for ITP within the four domains of work described by NPT: sense making, engagement, action and monitoring. Analysis followed the framework approach developed in our previous work. RESULTS: Four hundred and nineteen responses were included in the final analysis (67.3% female, 32.7% male; 52.7% nurse prescribers, 19.8% pharmacists and 21.8% GPs). Almost half (44.9%) were experienced practitioners (16+ years in practice); around one third reported already routinely offering ITP to their patients. GPs were the group least likely to recognise this as consistent usual practice. Findings revealed general support for the principles of ITP but significant variation and inconsistency in understanding and implementation in practice. Our findings reveal four key implications for practice: the need to raise understanding of ITP as a legitimate part of professional practice; to prioritise the work of ITP within the range of individual professional activity; to improve the consistency of training and support for interpretive practice; and to review the impact of formal and informal monitoring processes on practice. CONCLUSION: The findings will inform the ongoing development of our new complex intervention (PRIME Prescribing) to support the individual tailoring of medicines needed to address problematic polypharmacy

Protecting eyewitness evidence: Examining the efficacy of a self-administered interview tool

Given the crucial role of eyewitness evidence, statements should be obtained as soon as possible after an incident. This is not always achieved due to demands on police resources. Two studies trace the development of a new tool, the Self-Administered Interview (SAI), designed to elicit a comprehensive initial statement. In Study 1, SAI participants reported more correct details than participants who provided a free recall account, and performed at the same level as participants given a Cognitive Interview. In Study 2, participants viewed a simulated crime and half recorded their statement using the SAI. After a delay of 1 week, all participants completed a free recall test. SAI participants recalled more correct details in the delayed recall task than control participants

Do emotional difficulties and peer problems hew together from childhood to adolescence? The case of children with a history of developmental language disorder (DLD)

Children and adolescents with developmental language disorder (DLD) are, overall, vulnerable to difficulties in emotional adjustment and in peer relations. However, previous research has shown that different subgroups follow different trajectories in respect of quality of peer relations. Less is known of the trajectories of emotional development. We consider here the possibility that development in these two domains is interrelated: that is, the trajectories of emotional and peer problems will proceed in parallel. We conducted longitudinal joint trajectories analyses of emotional and peer relations in a sample of young people identified as having DLD at age 7 years and seen at intervals up to 16 years. Potential influences on joint trajectory group membership were examined. Findings revealed five distinct joint trajectories. Emotional and peer difficulties do hew together from childhood to adolescence for just over half of the sample, but not all. The variables most clearly associated with group membership were pragmatic language ability, prosociality and parental mental health. This is the first study to examine joint longitudinal trajectories of emotional and peer difficulties in individuals with DLD. We demonstrate that development in individuals with DLD is heterogeneous and identify three key variables associated with personal and social adjustment from childhood to adolescence. Theoretical and clinical implications of these findings are discussed