Novel loss-of-function mutation in HERC2 is associated with severe developmental delay and paediatric lethality

Background: The HERC2 gene encodes a 527 kDa E3 ubiquitin protein ligase that has key roles in cell cycle regulation, spindle formation during mitosis, mitochondrial functions and DNA damage responses. It has essential roles during embryonic development, particularly for neuronal and muscular functions. To date, missense mutations in HERC2 have been associated with an autosomal recessive neurodevelopmental disorder with some phenotypical similarities to Angelman syndrome, and a homozygous deletion spanning HERC2 and OCA2 causing a more severe neurodevelopmental phenotype. Methods and results: We ascertained a consanguineous family with a presumed autosomal recessive severe neurodevelopmental disorder that leads to paediatric lethality. In affected individuals, we identified a homozygous HERC2 frameshift variant that results in a premature stop codon and complete loss of HERC2 protein. Functional characterisation of this variant in fibroblasts, from one living affected individual, revealed impaired mitochondrial network and function as well as disrupted levels of known interacting proteins such as XPA. Conclusion: This study extends the genotype–phenotype correlation for HERC2 variants to include a distinct lethal neurodevelopmental disorder, highlighting the importance of further characterisation for HERC2-related disorders

A "superstorm": When moral panic and new risk discourses converge in the media

This is an Author's Accepted Manuscript of an article published in Health, Risk and Society, 15(6), 681-698, 2013, copyright Taylor & Francis, available online at: http://www.tandfonline.com/10.1080/13698575.2013.851180.There has been a proliferation of risk discourses in recent decades but studies of these have been polarised, drawing either on moral panic or new risk frameworks to analyse journalistic discourses. This article opens the theoretical possibility that the two may co-exist and converge in the same scare. I do this by bringing together more recent developments in moral panic thesis, with new risk theory and the concept of media logic. I then apply this theoretical approach to an empirical analysis of how and with what consequences moral panic and new risk type discourses converged in the editorials of four newspaper campaigns against GM food policy in Britain in the late 1990s. The article analyses 112 editorials published between January 1998 and December 2000, supplemented with news stories where these were needed for contextual clarity. This analysis shows that not only did this novel food generate intense media and public reactions; these developed in the absence of the type of concrete details journalists usually look for in risk stories. Media logic is important in understanding how journalists were able to engage and hence how a major scare could be constructed around convergent moral panic and new risk type discourses. The result was a media ‘superstorm’ of sustained coverage in which both types of discourse converged in highly emotive mutually reinforcing ways that resonated in a highly sensitised context. The consequence was acute anxiety, social volatility and the potential for the disruption of policy and social change

Liraglutide and renal outcomes in type 2 diabetes

In a randomized, controlled trial that compared liraglutide, a glucagon-like peptide 1 analogue, with placebo in patients with type 2 diabetes and high cardiovascular risk who were receiving usual care, we found that liraglutide resulted in lower risks of the primary end point (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) and death. However, the long-term effects of liraglutide on renal outcomes in patients with type 2 diabetes are unknown

Is it time to reappraise blood pressure thresholds and targets? Statement from the international society of hypertension - a global perspective

No abstract available

Science Diplomacy Through Cities: Applying NASA Earth Observations at the Urban Scale

NASA's scientific expertise and data products are enhancing cities' environmental monitoring activities by pioneering applications of remote sensing and model-based Earth Observations at the urban scale. The above activities have greatly benefitted from engaging stakeholders and city practitioners from the start. Further, NASA's collaborations with cities have: Advanced NASA science, in testing new products and validating of satellite datasets, while meeting the needs of city governments. Broadened Rio de Janeiro's regional viewpoint and strengthened its relationships with neighboring cities. Scientific collaborations with cities benefit from: Selecting city partners with a high level of technical capacity and willing to make strong investments in joint projects. Sustained communication and face-to-face interactions. Well-defined deliverables, with dedicated resources and personnel. Pairing global datasets and projections with in situ measurements and local knowledgeSensitivity to local working culture and politics

MegaTevs: Single-Chain Dual Nucleases for Efficient Gene Disruption

Targeting gene disruptions in complex genomes relies on imprecise repair by the non-homologous end-joining DNA pathway, creating mutagenic insertions or deletions (indels) at the break point. DNA end-processing enzymes are often co-expressed with genome-editing nucleases to enhance the frequency of indels, as the compatible cohesive ends generated by the nucleases can be precisely repaired, leading to a cycle of cleavage and non-mutagenic repair. Here, we present an alternative strategy to bias repair toward gene disruption by fusing two different nuclease active sites from I-TevI (a GIY-YIG enzyme) and I-OnuI E2 (an engineered meganuclease) into a single polypeptide chain. In vitro, the MegaTev enzyme generates two double-strand breaks to excise an intervening 30-bp fragment. In HEK 293 cells, we observe a high frequency of gene disruption without co-expression of DNA end-processing enzymes. Deep sequencing of disrupted target sites revealed minimal processing, consistent with the MegaTev sequestering the double-strand breaks from the DNA repair machinery. Off-target profiling revealed no detectable cleavage at sites where the I-TevI CNNNG cleavage motif is not appropriately spaced from the I-OnuI binding site. The MegaTev enzyme represents a small, programmable nuclease platform for extremely specific genome-engineering applications

Improving lipid profiles and increasing use of lipid-lowering therapy in England: results from a national cross-sectional survey-2006

Objective To evaluate blood lipid levels in the adult English population in 2006 and to report change in the use and efficacy of lipid-lowering treatment since 2003 after which time the general practitioner contract introduced a 'pay-per-performance' approach.Design Cross-sectional surveys.Participants Nationally representative sample of 14 142 noninstitutionalized adults (>16 years) living in England, partaking in the Health Survey for England 2006.Measurements Mean levels of total, HDL, non-HDL and total/HDL cholesterol ratio, prevalence of hypercholesterolaemia, use of lipid lowering agents and lipid levels and control rates among those on treatment.Results Age-standardized mean cholesterol levels fell from 5.49 mm in men and 5.56 mm in women in 2003 to 5.26 and 5.37 mm, respectively, in 2006. In 2006, 59% of adults had a total cholesterol >= 5.0 mm and 11% reported lipid-lowering treatment, of whom 66% had a total cholesterol <5.0 mm and 22% were <4.0 mm. The majority of those with established coronary heart disease, stroke or diabetes but fewer than one quarter of those with hypertension or 20% estimated 10-year cardiovascular risk and no established CVD took lipid-lowering drugs. Lipid lowering treatment rates increased fivefold and control rates among the treated (to <5.0 mm) more than doubled between 1998 and 2006. About one-third of those with established CVD or diabetes had cholesterol levels of <4.0 mm.Conclusions Previously reported improvements in treatment and control rates between 1998 and 2003 continued between 2003 and 2006, with the biggest increases among those with established CVD and diabetes

Replica Cluster Variational Method: the Replica Symmetric solution for the 2D random bond Ising model

We present and solve the Replica Symmetric equations in the context of the Replica Cluster Variational Method for the 2D random bond Ising model (including the 2D Edwards-Anderson spin glass model). First we solve a linearized version of these equations to obtain the phase diagrams of the model on the square and triangular lattices. In both cases the spin-glass transition temperatures and the tricritical point estimations improve largely over the Bethe predictions. Moreover, we show that this phase diagram is consistent with the behavior of inference algorithms on single instances of the problem. Finally, we present a method to consistently find approximate solutions to the equations in the glassy phase. The method is applied to the triangular lattice down to T=0, also in the presence of an external field.Comment: 22 pages, 11 figure

Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series

The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers