Intellectual ability in tuberous sclerosis complex correlates with predicted effects of mutations on TSC1 and TSC2 proteins.

BACKGROUND: Tuberous sclerosis complex is a multisystem genetic disease, caused by mutation in the TSC1 or TSC2 genes, associated with many features, including intellectual disability (ID). We examined psychometric profiles of patients with TSC1 or TSC2 mutations and tested whether different mutation types were associated with different degrees of intellectual ability. METHODS: One hundred subjects with known TSC1/TSC2 mutations were assessed using a range of IQ or developmental quotient (DQ) measures. Effects of mutations on TSC1/TSC2 proteins were inferred from sequence data and published biochemical studies. RESULTS: Most individuals with TSC1 mutations fell on a normal distribution identical to the general population, with ∼10% showing profound ID. Of individuals with TSC2 mutations, 34% showed profound ID, and the remainder a pattern of IQ/DQ more variable and shifted to the left than in TSC1 or the general population. Truncating TSC1 mutations were all predicted to be subject to nonsense-mediated mRNA decay. Mutations predicted to result in unstable protein were associated with less severe effects on IQ/DQ. There was a statistically significant negative correlation between length of predicted aberrant C-terminal tails arising from frameshift mutations in TSC1 and IQ/DQ; for TSC2 a positive but not statistically significant correlation was observed. CONCLUSION: We propose a model where (i) IQ/DQ correlates inversely with predicted levels and/or deleterious biochemical effects of mutant TSC1 or TSC2 protein, and (ii) longer aberrant C-terminal tails arising from frameshift mutations are more detrimental for TSC1 and less for TSC2. Predictions of the model require replication and biochemical testing.We thank the Tuberous Sclerosis Association, the Wales Gene Park, the National Research Foundation of South Africa and the Struengmann Fund for financial support. We thank Prof Chris Smith for helpful comments on the manuscript.This is the author accepted manuscript. The final version is available from the British Medical Journal via http://dx.doi.org/10.1136/jmedgenet-2015-10315

Quantification of High-Resolution Lattice Images and Electron Holograms

Progress towards the quantification of high-resolution electron microscopy and electron holograms has been achieved using digital acquisition with a slow-scan charge-coupled device (CCD) camera. Two applications are described: the precise measurement of lattice-fringe spacings and the determination of the mean inner potential. Lattice images can be characterized by a finite sum of two-dimensional sinusoids. A new method for measurement of the frequency, amplitude and phase of each sinusoid, based on an interpolation technique in reciprocal space, is presented. The method offers considerably higher precision for measurement of lattice fringes than the optical bench and is applicable to images recorded with an electron dose of less than 1 el / Å2 and specimen areas as small as 8 Å across. The attainable precision is dependent on specimen characteristics, electron dose and the size of the measured area, and ranges from 0.001 Å to 0.05 Å. An improved method has also been developed for measurement of mean inner potential using digital off-axis electron holograms from 90° crystal wedges. The value of (-14.21 ± 0.16) V obtained for GaAs represents the most accurate measurement yet reported for the mean inner potential

C-reactive protein and neutrophil count laboratory test requests from primary care:what is the demand and would substitution by point of care technology be viable?

Aims: C-reactive protein (CRP) and neutrophil count (NC) are important diagnostic indicators of inflammation. Point-of-care (POC) technologies for these markers are available but rarely used in community settings in the UK. To inform the potential for POC tests, it is necessary to understand the demand for testing. We aimed to describe the frequency of CRP and NC test requests from primary care to central laboratory services, describe variability between practices and assess the relationship between the tests.Methods: We described the number of patients with either or both laboratory tests, and the volume of testing per individual and per practice, in a retrospective cohort of all adults in general practices in Oxfordshire, 2014–2016.Results: 372 017 CRP and 776 581 NC tests in 160 883 and 275 093 patients, respectively, were requested from 69 practices. CRP was tested mainly in combination with NC, while the latter was more often tested alone. The median (IQR) of CRP and NC tests/person tested was 1 (1–2) and 2 (1–3), respectively. The median (IQR) tests/ practice/week was 36 (22–52) and 72 (50–108), and per 1000 persons registered/practice/week was 4 (3–5) and 8 (7–9), respectively. The median (IQR) CRP and NC concentrations were 2.7 (0.9–7.9)mg/dL and 4.1 (3.1–5.5)×109/L, respectively.Conclusions: The high demand for CRP and NC testing in the community, and the range of results falling within the reportable range for current POC technologies highlight the opportunity for laboratory testing to be supplemented by POC testing in general practice

Tunneling magnetoresistance in diluted magnetic semiconductor tunnel junctions

Using the spin-polarized tunneling model and taking into account the basic physics of ferromagnetic semiconductors, we study the temperature dependence of the tunneling magnetoresistance (TMR) in the diluted magnetic semiconductor (DMS) trilayer heterostructure system (Ga,Mn)As/AlAs/(Ga,Mn)As. The experimentally observed TMR ratio is in reasonable agreement with our result based on the typical material parameters. It is also shown that the TMR ratio has a strong dependence on both the itinerant-carrier density and the magnetic ion density in the DMS electrodes. This can provide a potential way to achieve larger TMR ratio by optimally adjusting the material parameters.Comment: 5 pages (RevTex), 3 figures (eps), submitted to PR

Using neutral cline decay to estimate contemporary dispersal: a generic tool and its application to a major crop pathogen

Dispersal is a key parameter of adaptation, invasion and persistence. Yet standard population genetics inference methods hardly distinguish it from drift and many species cannot be studied by direct mark-recapture methods. Here, we introduce a method using rates of change in cline shapes for neutral markers to estimate contemporary dispersal. We apply it to the devastating banana pest Mycosphaerella fijiensis, a wind-dispersed fungus for which a secondary contact zone had previously been detected using landscape genetics tools. By tracking the spatio-temporal frequency change of 15 microsatellite markers, we find that σ, the standard deviation of parent–offspring dispersal distances, is 1.2 km/generation1/2. The analysis is further shown robust to a large range of dispersal kernels. We conclude that combining landscape genetics approaches to detect breaks in allelic frequencies with analyses of changes in neutral genetic clines offers a powerful way to obtain ecologically relevant estimates of dispersal in many species

Psychophysical responses to a speech stressor: Correlation of plasma beta-endorphin levels at rest and after psychological stress with thermally measured pain threshold in patients with coronary artery disease

OBJECTIVES: We tested the hypothesis that psychological stress alters plasma levels of opioid peptides and that these plasma levels are related to pain perception in patients with coronary artery disease. BACKGROUND: Public speaking psychological stress has previously been shown to be associated with silent ischemia. METHODS: After instrumentation and a 30-min rest period, venous blood samples for beta-endorphin were obtained before and immediately after psychological stress in 20 patients with coronary artery disease. Pain threshold was then assessed using a thermal probe technique at baseline and immediately after stress. Patients gave three brief speeches lasting a total of 15 min about real-life hassle situations. RESULTS: Psychological stress significantly increases plasma beta-endorphin levels (4.3 +/- 0.9 pmol/liter [mean +/- SE] at rest to 8.3 +/- 2 pmol/liter after stress, p < 0.05). There was a significant positive correlation between pain threshold and beta-endorphin levels after stress (r = 0.577, p = 0.008). This significant positive correlation was still present while rest blood pressure and change in blood pressure during stress were controlled for by analysis of covariance techniques. CONCLUSIONS: In patients with coronary artery disease and exercise-induced ischemia, public speaking produces psychological stress manifested by increased cardiovascular reactivity and causes an increase in plasma beta-endorphin levels that is significantly correlated with pain thresholds. These findings may explain the predominance of silent ischemia during psychological stress in patients with coronary artery disease

The Epicurean Parasite: Horace, Satires 1.1-3

We have learned a great deal in recent years about reading Horace\u27s satires; there is now widespread agreement that the speaker of the satires is himself a character within them, a persona. Such a persona may be most effective when it has obvious connections with its creator, but that fact does not preclude the exaggeration of reality, or even its complete inversion. For Horace the implications of this approach are exciting: instead of a poet discoursing with cheerful earnestness on morality, on poetry and on his daily life, we have a fictional character, whom we do not have to take seriously at all.The three diatribe satires present us with a character so absurd that they have been taken, I think rightly, as parodies. Although the poems were once appreciated as effective moralising sermons, even their admirers found it hard to justify the lack of intellectual coherence, to say nothing of the astonishing vulgarity of the second satire. As parodies, however, the poems are wonderfully successful. The speaker trots out a series of banalities: ‘people should be content with who they are’; ‘people should not go to extremes’; ‘people should be consistent’. But he invariably gets distracted, goes off on tangential rants, and makes a fool of himself. The moralist of the first three satires is, to put it bluntly, a jerk

Transformation and time-out: the role of alcohol in identity construction among Scottish women in early midlife

Despite the increase in drinking by women in early midlife, little alcohol research has focused on this group. We explore how alcohol is associated with the construction of gender identities among women aged 30 to 50 years in the west of Scotland, United Kingdom. We draw on qualitative data from 11 focus groups (five all-female, six mixed-sex) with pre-existing groups of friends and work colleagues in which women and men discuss their drinking behaviours. Analysis demonstrated how alcohol represented a time and space away from paid and unpaid work for women in a range of domestic circumstances, allowing them to relax and unwind. While women used alcohol to construct a range of identities, traditional notions of femininity remained salient (e.g. attention to appearance, drinking ‘girly’ drinks). Drinking enabled women to assert their identity beyond the roles and responsibilities often associated with being a woman in early midlife. For example, some respondents with young children described the transformative effects of excessive drinking which allowed them to return temporarily to a younger, carefree version of themselves. Thus, our data suggest that women's drinking in early midlife revolves around notions of ‘idealised’ femininity but simultaneously represents a way of achieving ‘time out’ from traditional female responsibilities such as caring for others. We consider these findings within a broader social and cultural context including alcohol marketing, domestic roles and motherhood and their implications for health promotion

Social capital theory: a cross-cutting analytic for teacher/therapist work in integrating children's services?

Reviewing relevant policy, this article argues that the current 'integration interlude' is concerned with reformation of work relations to create new forms of 'social capital'. The conceptual framework of social capital has been used by government policy-makers and academic researchers to examine different types, configurations and qualities of relationships, including professional relations, and how these may function as resources. Focusing on the co-work of teachers and speech and language therapists, this analysis introduces social capital as a means of understanding the impact of integrating children's services on professional practitioner groups and across agencies. Social capital theory is compared to alternative theoretical perspectives such as systems and discourse theories and explored as an analytic offering a multi-level typology and conceptual framework for understanding the effects of policy and governance on interprofessional working and relationships. A previous application of social capital theory in a literature review is introduced and analysed, and instances of the additionality provided by a social capital analysis is offered. The article concludes that amongst the effects of current policy to re-design children's services are the reconstruction of professionals' knowledge/s and practices, so it is essential that such policy processes that have complex and far-reaching effects are transparent and coherent. It is also important that new social capital relations in children's services are produced by groups representative of all involved, importantly including those practitioner groups charged in policy to work differently together in future integrated services

The effect of laser transformation notching on the controlled fracture of a high carbon (C70S6 ) steel

A high carbon (C70S6) steel has been laser surface treated using CO2 and Diode lasers in order to produce an embrittled region to act as a fracture notch. Such a process has been investigated as a precursor to the fracture splitting of automotive engine connecting rods. Microstructures of the treated regions have been examined and the fracture behaviour of notched samples has been quantified. Depending on the laser processing parameters used, the laser transformation notch (LTN) undergoes either solid state transformations or a mixture of melting and solid state transformations. The effect of LTN depth on the peak impact force, the crack initiation energy and Charpy fracture energy was investigated on a C70S6 carbon steel using an instrumented Charpy impact facility. It was reduced to a value < 3.5 J by a LTN of ~ 0.5 mm in depth. Fracture mechanics models indicate that such a LTN can behave in a similar way to a fatigue created crack used in fracture toughness testing ie the LTN behaves as a sharp crack. Obtaining a sharp crack effect from a LTN is attributable to a combination of: a) the presence of brittle martensite, b) intergranular cracking of favourably oriented columnar grains after melting with inclusions and defects at their boundaries, c) intergranular cracking of coarse grains produced by a high austenitising temperatures and d) minor or major cracks sometimes resulting in centre – line cracking which arises during solidification. LTN was thus shown to have the potential to lead to an effective means of obtaining consistent fracture splitting of connecting rods