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

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

Reduced selenium concentrations and glutathione peroxidase activity in preeclamptic pregnancies

Preeclampsia is a pregnancy-specific condition affecting 2-7% of women and a leading cause of perinatal and maternal morbidity and mortality. Preeclampsia may also predispose the fetus to increased risks of adult cardiovascular disease. Selenium, acting through the selenoprotein glutathione peroxidases, has critical roles in regulating antioxidant status. Recent reports implicate poor maternal selenium status as a nutritional factor predisposing the mother to preeclampsia but the fetus and placenta have not been studied in tandem. Measurement of selenium concentrations, expression and activity levels of glutathione peroxidase and markers of oxidative stress were performed on maternal and umbilical venous blood samples or the placenta from 27 normal pregnant, 25 preeclamptic and 22 healthy age-matched non-pregnant women. The results of this study revealed highly significant reductions in serum selenium concentrations and plasma glutathione peroxidase activity in pregnancy per se compared to non-pregnant controls. Moreover, these levels were further decreased in the preeclamptic mothers and babies compared to normal pregnancies. Umbilical venous selenium was particularly low (42.1±11.8 and 29.0 ± 9.9 mug/L; mean ±s.d.; P<0.05). Both mother and baby had significantly increased levels of markers for oxidative stress in the preeclamptic group. The placental glutathione peroxidase activity and immunohistochemical staining were also reduced in the preeclampsia placentae. Oxidative stress associated with preeclampsia may be a consequence of reduced antioxidant defence pathways specifically involving glutathione peroxidases, perhaps linked to reduced selenium availability. Reduced glutathione peroxidases could be associated with increased generation of toxic lipid peroxides contributing to the endothelial dysfunction and hypertension of preeclampsia

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

Investment in sensory structures, testis size, and wing coloration in males of a diurnal moth species: trade-offs or correlated growth?

For dioecious animals, reproductive success typically involves an exchange between the sexes of signals that provide information about mate location and quality. Typically, the elaborate, secondary sexual ornaments of males signal their quality, while females may signal their location and receptivity. In theory, the receptor structures that receive the latter signals may also become elaborate or enlarged in a way that ultimately functions to enhance mating success through improved mate location. The large, elaborate antennae of many male moths are one such sensory structure, and eye size may also be important in diurnal moths. Investment in these traits may be costly, resulting in trade-offs among different traits associated with mate location. For polyandrous species, such trade-offs may also include traits associated with paternity success, such as larger testes. Conversely, we would not expect this to be the case for monandrous species, where sperm competition is unlikely. We investigated these ideas by evaluating the relationship between investment in sensory structures (antennae, eye), testis, and a putative warning signal (orange hindwing patch) in field-caught males of the monandrous diurnal painted apple moth Teia anartoides (Lepidoptera: Lymantriidae) in southeastern Australia. As predicted for a monandrous species, we found no evidence that male moths with larger sensory structures had reduced investment in testis size. However, contrary to expectation, investment in sensory structures was correlated: males with relatively larger antennae also had relatively larger eyes. Intriguingly, also, the size of male orange hindwing patches was positively correlated with testis size

Sofosbuvir and Daclatasvir Combination Therapy in a Liver Transplant Recipient With Severe Recurrent Cholestatic Hepatitis C

Recurrent HCV infection following liver transplantation can lead to accelerated allograft injury that is difficult to treat with interferon. The aim of this study is to describe the first ever use of an interferon‐free, all oral regimen in a liver transplant recipient with severe recurrent HCV. A 54‐year‐old male with HCV genotype 1b developed severe cholestatic HCV at 6 months posttransplant with ascites, AST 503 IU/mL, alkaline phosphatase of 298 IU/mL, HCV RNA of 12 000 000 IU/mL, and histological cholestasis with pericellular fibrosis. Sofosbuvir, an HCV polymerase inhibitor (400 mg/day), and daclatasvir, an HCV NS5A replication complex inhibitor (60 mg/day), were co‐administered for 24 weeks. Within 4 weeks of initiating treatment, serum HCV RNA levels became undetectable and liver biochemistries normalized with concomitant resolution of ascites. The patient achieved a sustained virological response with undetectable HCV RNA at 9 months posttreatment. During and following treatment, the daily dose and blood level of tacrolimus remained stable and unchanged. The rapid and sustained suppression of HCV replication in this liver transplant recipient provides great promise for the use of combination oral antiviral regimens in other immunosuppressed and interferon refractory HCV patients. A patient with severe cholestatic hepatitis C virus genotype 1b infection at nine months after liver transplantation was successfully treated with a six‐month course of oral sofosbuvir in combination with daclatasvir and remains HCV RNA negative during posttreatment follow‐up with improved liver biochemistries and health.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98302/1/ajt12209.pd

Sex differences in metabolic and adipose tissue responses to juvenile-onset obesity in sheep

Sex is a major factor determining adipose tissue distribution and the subsequent adverse effects of obesity-related disease including type 2 diabetes. The role of gender on juvenile obesity and the accompanying metabolic and inflammatory responses is not well established. Using an ovine model of juvenile onset obesity induced by reduced physical activity, we examined the effect of gender on metabolic, circulatory, and related inflammatory and energy-sensing profiles of the major adipose tissue depots. Despite a similar increase in fat mass with obesity between genders, males demonstrated a higher storage capacity of lipids within perirenal-abdominal adipocytes and exhibited raised insulin. In contrast, obese females became hypercortisolemic, a response that was positively correlated with central fat mass. Analysis of gene expression in perirenal-abdominal adipose tissue demonstrated the stimulation of inflammatory markers in males, but not females, with obesity. Obese females displayed increased expression of genes involved in the glucocorticoid axis and energy sensing in perirenal-abdominal, but not omental, adipose tissue, indicating a depot-specific mechanism that may be protective from the adverse effects of metabolic dysfunction and inflammation. In conclusion, young males are at a greater risk than females to the onset of comorbidities associated with juvenile-onset obesity. These sex-specific differences in cortisol and adipose tissue could explain the earlier onset of the metabolic-related diseases in males compared with females after obesity

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

Measurement of the [Formula: see text] production cross section using events in the [Formula: see text] final state in pp collisions at [Formula: see text].

The cross section of top quark-antiquark pair production in proton-proton collisions at [Formula: see text] is measured by the CMS experiment at the LHC, using data corresponding to an integrated luminosity of 2.2[Formula: see text]. The measurement is performed by analyzing events in which the final state includes one electron, one muon, and two or more jets, at least one of which is identified as originating from hadronization of a b quark. The measured cross section is [Formula: see text], in agreement with the expectation from the standard model