Adeno-Associated Virus-Mediated Rescue of the Cognitive Defects in a Mouse Model for Angelman Syndrome

Angelman syndrome (AS), a genetic disorder occurring in approximately one in every 15,000 births, is characterized by severe mental retardation, seizures, difficulty speaking and ataxia. The gene responsible for AS was discovered to be UBE3A and encodes for E6-AP, an ubiquitin ligase. A unique feature of this gene is that it undergoes maternal imprinting in a neuron-specific manner. In the majority of AS cases, there is a mutation or deletion in the maternally inherited UBE3A gene, although other cases are the result of uniparental disomy or mismethylation of the maternal gene. While most human disorders characterized by severe mental retardation involve abnormalities in brain structure, no gross anatomical changes are associated with AS. However, we have determined that abnormal calcium/calmodulin-dependent protein kinase II (CaMKII) regulation is seen in the maternal UBE3A deletion AS mouse model and is responsible for the major phenotypes. Specifically, there is an increased αCaMKII phosphorylation at the autophosphorylation sites Thr286 and Thr305/306, resulting in an overall decrease in CaMKII activity. CaMKII is not produced until after birth, indicating that the deficits associated with AS are not the result of developmental abnormalities. The present studies are focused on exploring the potential to rescue the learning and memory deficits in the adult AS mouse model through the use of an adeno-associated virus (AAV) vector to increase neuronal UBE3A expression. These studies show that increasing the levels of E6-AP in the brain using an exogenous vector can improve the cognitive deficits associated with AS. Specifically, the associative learning deficit was ameliorated in the treated AS mice compared to the control AS mice, indicating that therapeutic intervention may be possible in older AS patients

A comparison of spectroscopic methods for detecting starlight scattered by transiting hot Jupiters, with application to Subaru data for HD 209458b and HD 189733b

The measurement of the light scattered from extrasolar planets informs atmospheric and formation models. With the discovery of many hot Jupiter planets orbiting nearby stars, this motivates the development of robust methods of characterisation from follow up observations. In this paper we discuss two methods for determining the planetary albedo in transiting systems. First, the most widely used method for measuring the light scattered by hot Jupiters (Collier Cameron et al.) is investigated for application for typical echelle spectra of a transiting planet system, showing that detection requires high signal-to-noise ratio data of bright planets. Secondly a new Fourier analysis method is also presented, which is model-independent and utilises the benefits of the reduced number of unknown parameters in transiting systems. This approach involves solving for the planet and stellar spectra in Fourier space by least-squares. The sensitivities of the methods are determined via Monte Carlo simulations for a range of planet-to-star fluxes. We find the Fourier analysis method to be better suited to the ideal case of typical observations of a well constrained transiting system than the Collier Cameron et al. method. We apply the Fourier analysis method for extracting the light scattered by transiting hot Jupiters from high resolution spectra to echelle spectra of HD 209458 and HD 189733. Unfortunately we are unable to improve on the previous upper limit of the planet-to-star flux for HD 209458b set by space-based observations. A 1{\sigma}upper limit on the planet-to-star flux of HD 189733b is measured in the wavelength range of 558.83-599.56 nm yielding {\epsilon} < 4.5 \times 10-4. Improvement in the measurement of the upper limit of the planet-to-star flux of this system, with ground-based capabilities, requires data with a higher signal-to-noise ratio, and increased stability of the telescope.Comment: 15 pages, 8 figures, 2 tables. Monthly Notices of the Royal Astronomical Society, in press. Accepted 2011 March 17. Received 2011 March 17; in original form 2010 June 2

Pliocene and Pleistocene geologic and climatic evolution in the San Luis Valley of south-central Colorado

Sediments of the Alamosa Formation spanning the upper part of the Gauss and most of the Matuyama Chrons were recovered by coring in the high (2300 m) San Luis Valley of south-central Colorado. The study site is located at the northern end of the Rio Grande rift. Lithologic changes in the core sediments provide evidence of events leading to integration of the San Luis drainage basin into the Rio Grande. The section, which includes the Huckleberry Ridge Ash (2.02 Ma) and spans the entire Matuyama Chron, contains pollen, and invertebrate and vertebrate fossils. Stable isotope analyses of inorganic and biogenic carbonate taken over most of the core indicate substantially warmer temperatures than occur today in the San Luis Valley. At the end of the Olduvai Subchron, summer precipitation decreased, summer pan evaporation increased, and temperatures increased slightly compared to the earlier climate represented in the core. By the end of the Jaramillo Subchron, however, cold/wet and warm/dry cycles become evident and continue into the cold/wet regime associated with the deep-sea oxygen-isotope Stage 22 glaciation previously determined from outcrops at the same locality. Correspondence between the Hansen Bluff climatic record and the deep-sea oxygen-isotope record (oxygen-isotope stages from about 110-18) is apparent, indicating that climate at Hansen Bluff was responding to global climatic changes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29956/1/0000316.pd

`Whose Shoes?` Can an educational board game engage Ugandan men in pregnancy and childbirth?

Background Men can play a significant role in reducing maternal morbidity and mortality in low-income countries. Maternal health programmes are increasingly looking for innovative interventions to engage men to help improve health outcomes for pregnant women. Educational board games offer a unique approach to present health information where learning is reinforced through group discussions supporting peer-to-peer interactions. Methods A qualitative study with men from Uganda currently living in the UK on their views of an educational board game. Men were purposively sampled to play a board game and participate in a focus group discussion. The pilot study explored perceptions on whether a board game was relevant as a health promotional tool in maternal health prior to implementation in Uganda. Results The results of the pilot study were promising; participants reported the use of visual aids and messages were easy to understand and enhanced change in perspective. Men in this study were receptive on the use of board games as a health promotional tool and recommended its use in rural Uganda. Conclusions This study provides preliminary data on the relevancy and efficacy of using board games in maternal health. Key messages from the focus group appeared to be that the board game is more than acceptable to fathers and that it needs to be adapted to the local context to make it suitable for men in rural Uganda

Clustered mutations in the <i>GRIK2</i> kainate receptor subunit gene underlie diverse neurodevelopmental disorders

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G&gt;A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.</p

Clustered mutations in the <i>GRIK2</i> kainate receptor subunit gene underlie diverse neurodevelopmental disorders

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development

Predicting the Current and Future Potential Distributions of Lymphatic Filariasis in Africa Using Maximum Entropy Ecological Niche Modelling

Modelling the spatial distributions of human parasite species is crucial to understanding the environmental determinants of infection as well as for guiding the planning of control programmes. Here, we use ecological niche modelling to map the current potential distribution of the macroparasitic disease, lymphatic filariasis (LF), in Africa, and to estimate how future changes in climate and population could affect its spread and burden across the continent. We used 508 community-specific infection presence data collated from the published literature in conjunction with five predictive environmental/climatic and demographic variables, and a maximum entropy niche modelling method to construct the first ecological niche maps describing potential distribution and burden of LF in Africa. We also ran the best-fit model against climate projections made by the HADCM3 and CCCMA models for 2050 under A2a and B2a scenarios to simulate the likely distribution of LF under future climate and population changes. We predict a broad geographic distribution of LF in Africa extending from the west to the east across the middle region of the continent, with high probabilities of occurrence in the Western Africa compared to large areas of medium probability interspersed with smaller areas of high probability in Central and Eastern Africa and in Madagascar. We uncovered complex relationships between predictor ecological niche variables and the probability of LF occurrence. We show for the first time that predicted climate change and population growth will expand both the range and risk of LF infection (and ultimately disease) in an endemic region. We estimate that populations at risk to LF may range from 543 and 804 million currently, and that this could rise to between 1.65 to 1.86 billion in the future depending on the climate scenario used and thresholds applied to signify infection presence