Functional Analysis of Missense Mutations in Kv8.2 Causing Cone Dystrophy with Supernormal Rod Electroretinogram

Mutations in KCNV2 have been proposed as the molecular basis for cone dystrophy with supernormal rod electroretinogram. KCNV2 codes for the modulatory voltage-gated potassium channel α-subunit, Kv8.2, which is incapable of forming functional channels on its own. Functional heteromeric channels are however formed with Kv2.1 in heterologous expression systems, with both α-subunit genes expressed in rod and cone photoreceptors. Of the 30 mutations identified in the KCNV2 gene, we have selected three missense mutations localized in the potassium channel pore and two missense mutations localized in the tetramerization domain for analysis. We characterized the differences between homomeric Kv2.1 and heteromeric Kv2.1/Kv8.2 channels and investigated the influence of the selected mutations on the function of heteromeric channels. We found that two pore mutations (W467G and G478R) led to the formation of nonconducting heteromeric Kv2.1/Kv8.2 channels, whereas the mutations localized in the tetramerization domain prevented heteromer generation and resulted in the formation of homomeric Kv2.1 channels only. Consequently, our study suggests the existence of two distinct molecular mechanisms involved in the disease pathology

Briefing: Resource scarcity and resource security – a suppressed civil engineering challenge

While natural and manufactured resources provide the raw materials with which civil engineers work, the term ‘resources’ should always be considered in its wider interpretation and then in the context that resources are in many cases limited. That they should be used wisely (resource efficiency) is beyond contention – we do this as a matter of course – yet considerations of where and how resources are obtained and refined for use are far less likely to feature in a civil engineer's psyche. Similarly, considerations of resource availability for others now, and importantly in the future, and the vulnerability of these resources to future supply disruption (e.g. for geopolitical reasons) are likely not to be in the forefront of our thinking when conducting our routine business. The ICE Research, Development & Innovation towards Engineering Excellence panel has chosen this topic as one of pressing importance across all the sectors that comprise civil engineering. Accordingly, the panel is promoting this topic for Research & Development Enabling Fund (R&DEF) proposals. This briefing note describes the prior work of the panel in exploring the extent of this issue, along with insights from current research, to raise awareness, encourage R&DEF proposals and prime debates on this topic

Stimulation of translation by human Unr requires cold shock domains 2 and 4, and correlates with poly(A) binding protein interaction

The RNA binding protein Unr, which contains five cold shock domains, has several specific roles in post-transcriptional control of gene expression. It can act as an activator or inhibitor of translation initiation, promote mRNA turnover, or stabilise mRNA. Its role depends on the mRNA and other proteins to which it binds, which includes cytoplasmic poly(A) binding protein 1 (PABP1). Since PABP1 binds to all polyadenylated mRNAs, and is involved in translation initiation by interaction with eukaryotic translation initiation factor 4G (eIF4G), we investigated whether Unr has a general role in translational control. We found that Unr strongly stimulates translation in vitro, and mutation of cold shock domains 2 or 4 inhibited its translation activity. The ability of Unr and its mutants to stimulate translation correlated with its ability to bind RNA, and to interact with PABP1. We found that Unr stimulated the binding of PABP1 to mRNA, and that Unr was required for the stable interaction of PABP1 and eIF4G in cells. siRNA-mediated knockdown of Unr reduced the overall level of cellular translation in cells, as well as that of cap-dependent and IRES-dependent reporters. These data describe a novel role for Unr in regulating cellular gene expression

Role of Esrrg in the Fibrate-Mediated Regulation of Lipid Metabolism Genes in Human ApoA-I Transgenic Mice

We have used a new ApoA-I transgenic mouse model to identify by global gene expression profiling, candidate genes that affect lipid and lipoprotein metabolism in response to fenofibrate treatment. Multilevel bioinformatical analysis and stringent selection criteria (2-fold change, 0% false discovery rate) identified 267 significantly changed genes involved in several molecular pathways. The fenofibrate-treated group did not have significantly altered levels of hepatic human APOA-I mRNA and plasma ApoA-I compared with the control group. However, the treatment increased cholesterol levels to 1.95-fold mainly due to the increase in high-density lipoprotein (HDL) cholesterol. The observed changes in HDL are associated with the upregulation of genes involved in phospholipid biosynthesis and lipid hydrolysis, as well as phospholipid transfer protein. Significant upregulation was observed in genes involved in fatty acid transport and β-oxidation, but not in those of fatty acid and cholesterol biosynthesis, Krebs cycle and gluconeogenesis. Fenofibrate changed significantly the expression of seven transcription factors. The estrogen receptor-related gamma gene was upregulated 2.36-fold and had a significant positive correlation with genes of lipid and lipoprotein metabolism and mitochondrial functions, indicating an important role of this orphan receptor in mediating the fenofibrate-induced activation of a specific subset of its target genes.National Institutes of Health (HL48739 and HL68216); European Union (LSHM-CT-2006-0376331, LSHG-CT-2006-037277); the Biomedical Research Foundation of the Academy of Athens; the Hellenic Cardiological Society; the John F Kostopoulos Foundatio

Identification of strontium in the merger of two neutron stars.

Half of all of the elements in the Universe that are heavier than iron were created by rapid neutron capture. The theory underlying this astrophysical r-process was worked out six decades ago, and requires an enormous neutron flux to make the bulk of the elements1. Where this happens is still debated2. A key piece of evidence would be the discovery of freshly synthesized r-process elements in an astrophysical site. Existing models3-5 and circumstantial evidence6 point to neutron-star mergers as a probable r-process site; the optical/infrared transient known as a 'kilonova' that emerges in the days after a merger is a likely place to detect the spectral signatures of newly created neutron-capture elements7-9. The kilonova AT2017gfo-which was found following the discovery of the neutron-star merger GW170817 by gravitational-wave detectors10-was the first kilonova for which detailed spectra were recorded. When these spectra were first reported11,12, it was argued that they were broadly consistent with an outflow of radioactive heavy elements; however, there was no robust identification of any one element. Here we report the identification of the neutron-capture element strontium in a reanalysis of these spectra. The detection of a neutron-capture element associated with the collision of two extreme-density stars establishes the origin of r-process elements in neutron-star mergers, and shows that neutron stars are made of neutron-rich matter13

Rethinking the patient: using Burden of Treatment Theory to understand the changing dynamics of illness

<b>Background</b> In this article we outline Burden of Treatment Theory, a new model of the relationship between sick people, their social networks, and healthcare services. Health services face the challenge of growing populations with long-term and life-limiting conditions, they have responded to this by delegating to sick people and their networks routine work aimed at managing symptoms, and at retarding - and sometimes preventing - disease progression. This is the new proactive work of patient-hood for which patients are increasingly accountable: founded on ideas about self-care, self-empowerment, and self-actualization, and on new technologies and treatment modalities which can be shifted from the clinic into the community. These place new demands on sick people, which they may experience as burdens of treatment.<p></p> <b>Discussion</b> As the burdens accumulate some patients are overwhelmed, and the consequences are likely to be poor healthcare outcomes for individual patients, increasing strain on caregivers, and rising demand and costs of healthcare services. In the face of these challenges we need to better understand the resources that patients draw upon as they respond to the demands of both burdens of illness and burdens of treatment, and the ways that resources interact with healthcare utilization.<p></p> <b>Summary</b> Burden of Treatment Theory is oriented to understanding how capacity for action interacts with the work that stems from healthcare. Burden of Treatment Theory is a structural model that focuses on the work that patients and their networks do. It thus helps us understand variations in healthcare utilization and adherence in different healthcare settings and clinical contexts

Solutions to cultural, organizational, and technical challenges in developing PECAS models for the cities of Shanghai, Wuhan, and Guangzhou

Massive construction of transportation infrastructure and fast growth of private car ownership have brought unprecedented changes in land use and transportation systems to cities and regions in many developing countries. Traditional “four-step” travel demand models, which are not designed to assess transport policies under the case of rapid land-use change, cannot be used to achieve coordinated planning of transport and land use. Therefore, there is a pressing need to develop and use integrated land-use transport models (ILUTMs), which consider interactions among socioeconomic activities, urban land use, and transportation development, for policy analysis and for guiding the progressive urbanization process taking place in many parts of these countries. In light of this, efforts have been invested in developing production, exchange, and consumption allocation system (PECAS) models for the cities of Shanghai, Wuhan, and Guangzhou in mainland China. This paper presents the cultural, organizational, and technical challenges encountered in the development of PECAS models for the cities of Shanghai, Wuhan, and Guangzhou and the mitigating solutions from the development teams for taking up or working around them. The solutions and discussions presented in this paper should be interesting to researchers and practitioners for developing ILUTMs in the context of a developing country like China

Incubation of ovine scrapie with environmental matrix results in biological and biochemical changes of PrPSc over time

Ovine scrapie can be transmitted via environmental reservoirs. A pool of ovine scrapie isolates were incubated on soil for one day or thirteen months and eluted prion was used to challenge tg338 mice transgenic for ovine PrP. After one-day incubation on soil, two PrPSc phenotypes were present: G338 or Apl338ii. Thirteen months later some divergent PrPSc phenotypes were seen: a mixture of Apl338ii with either G338 or P338, and a completely novel PrPSc deposition, designated Cag338. The data show that prolonged ageing of scrapie prions within an environmental matrix may result in changes in the dominant PrPSc biological/biochemical properties