Genetics update: monogenetics, polygene disorders and the quest for modifying genes

The genetic channelopathies are a broad collection of diseases. Many ion channel genes demonstrate wide phenotypic pleiotropy, but nonetheless concerted efforts have been made to characterise genotype-phenotype relationships. In this review we give an overview of the factors that influence genotype-phenotype relationships across this group of diseases as a whole, using specific individual channelopathies as examples. We suggest reasons for the limitations observed in these relationships. We discuss the role of ion channel variation in polygenic disease and highlight research that has contributed to unravelling the complex aetiological nature of these conditions. We focus specifically on the quest for modifying genes in inherited channelopathies, using the voltage-gated sodium channels as an example. Epilepsy related to genetic channelopathy is one area in which precision medicine is showing promise. We will discuss the successes and limitations of precision medicine in these conditions

Does measurement technique explain the mismatch between European head size and WHO charts?

Objective To test whether different measuring techniques produce systematic differences in head size that could explain the large head circumferences found in Northern European children compared with the WHO standard. Design: Cross-sectional observational study. Setting: Scotland, UK. Patients: Study 1: 68 healthy children aged 0.4–18 months from mother and baby groups and a medical students teaching session. Study 2: 81 children aged 0.4 to 25 months from hospital wards and neonatal follow-up clinics. Interventions: Study 1: heads measured with plastic tape using both the WHO tight and UK loose technique. Study 2: heads measured using WHO research technique and a metal measuring tape and compared with routinely acquired measurements. Main outcome measures: Mean difference in head z-scores using WHO standard between the two methods. Results: The tight technique resulted in a mean (95% CI) z-score difference of 0.41 (0.27 to 0.54, p<0.001) in study 1 and 0.44 (0.36 to 0.53, p<0.001) in study 2. However, the mean WHO measurements in the healthy infants still produced a mean z-score that was two-third of a centile space (0.54 SD (0.28 to 0.79) p<0.001) above the 50th centile. Conclusion: The WHO measurement techniques produced significantly lower measures of head size, but average healthy Scottish children still had larger heads than the WHO standard using this method

Contingent Reinforcement Modeled Consequences

Abstract Children with autism who have deficits in social and communication skills are often limited in their capacity to learn play skills. Video modeling has been used to teach scripted play skills to children with autism and many variations have been used to determine which techniques are most important. Children have been observed to readily imitate behaviors exhibited by a model in the presence of a model and have generalized those responses to a new setting in the absence of a model. The purpose of this study was to determine whether observing consequences provided to the model (positive reinforcement or no observed positive reinforcement) influenced skill acquisition of video modeled play skills. An A-B-A-C-A-X experimental design counterbalanced for order of presentation, and X representing the most effective treatment condition was utilized with four children diagnosed with autism. The results of the study indicated that neither contingent reinforcement (CR) nor no reinforcement (NR) conditions were more effective than the other for teaching modeled actions and scripted verbalizations during play. Decreases in unscripted verbalizations were observed during both CR and NR video modeling conditions

Origin of seismic reflectors within carbonate-rich sediments from northeastern Australian margin

Journal ArticleWe use continuous velocity records from 12 sites and continuous density records from 9 sites from Ocean Drilling Program (ODP) Leg 133 to examine both direct and indirect controls on seismic reflectors and depth-to-time conversion for the northeastern Australian margin. In these carbonate-rich sediments, the character of both velocity and density appears to be responding primarily to porosity variations and indirectly to lithologic or diagenetic variations. However, we find no consistent empirical relationship between velocity and porosity because of intrasite and intersite variations in style of cementation. Impedance, the product of velocity and density, is dominated by porosity change throughout the depth range studied, but the mechanism of this control changes: porosity influence on density is an important impedance control in the top 100 meters below seafloor (mbsf). while porosity influence on velocity is most important to deeper impedance variations. This difference arises from the relative insensitivity of velocity to porosity change at the high porosities of the uppermost 50 to 100 mbsf. Because velocity dominates most impedance variations and because velocity and density are locally well correlated, density can be omitted entirely from the calculation of most ODP synthetic seismograms without adverse effects. Depth-to-lime conversion can be based either on matching a synthetic seismogram to the seismic section or on a plot of two-way time vs. depth. Synthetic seismogram character is sensitive not only to the character of velocity variations caused by changes in porosity and diagenesis, but also to wavelet uncertainties and impedance interference patterns. Plots of two-way time vs. depth for these carbonate-dominated sediments are remarkably similar down to 250 mbsf and moderately predictable down to at least 450 mbsf

The effect of sampling techniques used in the multiconfigurational Ehrenfest method

In this paper, we compare and contrast basis set sampling techniques recently developed for use in the ab initio multiple cloning method, a direct dynamics extension to the multiconfigurational Ehrenfest approach, used recently for the quantum simulation of ultrafast photochemistry. We demonstrate that simultaneous use of basis set cloning and basis function trains can produce results which are converged to the exact quantum result. To demonstrate this, we employ these sampling methods in simulations of quantum dynamics in the spin boson model with a broad range of parameters and compare the results to accurate benchmarks

Surveying the upper Ocean with the Ocean Surveyor - a new Phased Array Doppler Current Profiler

A new shipboard current profiler, a 75-kHz ocean surveyor, was operationally used during two research cruises in the tropical Atlantic and the subpolar North Atlantic, respectively. Here, a report is presented on the first experience with this instrument in two very different current regimes, in the Tropics with large vertical shears, and in the subpolar regime with mainly barotropic flow. The ocean surveyor continuously measured currents in the upper ocean from near the surface to about 500–700-m depth. The measurement range showed a dependence on the regional and temporal variations of scattering particles and on the intensity of swell and wind waves. Statistical comparisons are performed with on-station lowered acoustic Doppler current profiler (LADCP) profiles and underway measurements by classic shipboard acoustic Doppler current profiler (ADCP) measurements. Accuracy estimates for hourly averaged ocean surveyor currents result in errors of about 1 cm s–1 for on-station data and of 2–4 cm s–1 for underway measurements, depending on the regional abundance of scatterers and on the weather conditions encountered

Maternal parity and its effect on adipose tissue deposition and endocrine sensitivity in the postnatal sheep

Maternal parity influences size at birth, postnatal growth and body composition with firstborn infants being more likely to be smaller with increased fat mass, suggesting that adiposity is set in early life. The precise effect of parity on fat mass and its endocrine sensitivity remains unclear and was, therefore, investigated in the present study. We utilised an established sheep model in which perirenal–abdominal fat mass (the major fat depot in the neonatal sheep) increases ∼10-fold over the first month of life and focussed on the impact of parity on glucocorticoid sensitivity and adipokine expression in the adipocyte. Twin-bearing sheep of similar body weight and adiposity that consumed identical diets were utilised, and maternal blood samples were taken at 130 days of gestation. One offspring from each twin pair was sampled at 1 day of age, coincident with the time of maximal recruitment of uncoupling protein 1 (UCP1), whilst its sibling was sampled at 1 month, when UCP1 had disappeared. Plasma leptin was lower in nulliparous mothers than in multiparous mothers, and offspring of nulliparous mothers possessed more adipose tissue with increased mRNA abundance of leptin, glucocorticoid receptor and UCP2, adaptations that persisted up to 1 month of age when gene expression for interleukin-6 and adiponectin was also raised. The increase in fat mass associated with firstborn status is therefore accompanied by a resetting of the leptin and glucocorticoid axis within the adipocyte. Our findings emphasise the importance of parity in determining adipose tissue development and that firstborn offspring have an increased capacity for adipogenesis which may be critical in determining later adiposity

Advanced-stage cervix cancer: rapid tumour growth rather than late diagnosis

Either diagnostic delay or tumour biology are possible factors governing the degree of spread at diagnosis of cervical cancer. To try to identify the most important parameter contributing to advanced stage, the duration of symptoms were recorded from patients scheduled for radiotherapy (n = 141) or radical hysterectomy (n = 36). In 146 cases tumour proliferation rates were evaluated following in vivo labelling with the DNA precursor BrdUrd. For symptomatic patients there was no association between duration of symptoms and stage at presentation. There was a significant trend for patients with increasing tumour stage to have more rapidly proliferating tumours with higher mean labelling index (LI) measurements (P = 0.001) and a shorter mean potential doubling time (Tpot) (P = 0.023). Socio economic deprivation may be associated with shorter Tpot values. The conclusion from this data is that stage at diagnosis is more dependent on the biological behaviour of the tumour, as expressed by proliferation rates, than delay in presentation. © 2000 Cancer Research Campaig

Identification of pathogenic Leptospira species by conventional or real-time PCR and sequencing of the DNA gyrase subunit B encoding gene

BACKGROUND: Leptospira is the causative genus of the disease, leptospirosis. Species identification of pathogenic Leptospira in the past was generally performed by either DNA-DNA hybridisation or 16s rRNA gene sequencing. Both methods have inherent disadvantages such as the need for radio-labelled isotopes or significant homology between species. A conventional and real-time PCR amplification and sequencing method was developed for an alternate gene target: DNA gyrase subunit B (gyrB). Phylogenetic comparisons were undertaken between pathogenic Leptospira 16srRNA and gyrB genes using clustering and minimum evolution analysis. In addition 50 unidentified Leptospira isolates were characterised by gyrB sequencing and compared with conventional 16s rRNA sequencing. RESULTS: A conventional and real-time PCR methodology was developed and optimised for the amplification of the gyrB from pathogenic Leptospira species. Non pathogenic and opportunistic Leptospira species such as L. fainei and L. broomi were not amplified. The gyrB gene shows greater nucleotide divergence (3.5% to 16.1%) than the 16s rRNA gene (0.1% to 1.4%). Minimum evolution analysis reveals that the gyrB has a different evolution topology for L. kirschneri and L. interrogans. When the two genes were compared for the identification of the 50 unknown isolates there was 100% agreement in the results. CONCLUSION: This research has successfully developed a methodology for the identification of pathogenic Leptospira using an alternate gene to 16s rRNA. The gyrB encoding gene shows higher nucleotide/evolutionary divergence allowing for superior identification and also the potential for the development of DNA probe based identification