Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities

Huntington disease (HD) is a neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT) and involves a complex web of pathogenic mechanisms. Mutant HTT (mHTT) disrupts transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences the disease course. Genome-wide association studies have identified DNA repair pathways as modifiers of somatic instability and disease course in HD and other repeat expansion diseases. In animal models of HD, nucleocytoplasmic transport is disrupted and its restoration is neuroprotective. Novel cerebrospinal fluid (CSF) and plasma biomarkers are among the earliest detectable changes in individuals with premanifest HD and have the sensitivity to detect therapeutic benefit. Therapeutically, the first human trial of an HTT-lowering antisense oligonucleotide successfully, and safely, reduced the CSF concentration of mHTT in individuals with HD. A larger trial, powered to detect clinical efficacy, is underway, along with trials of other HTT-lowering approaches. In this Review, we discuss new insights into the molecular pathogenesis of HD and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself

Protocol for an HTA report: Does therapeutic writing help people with long-term conditions? Systematic review, realist synthesis and economic modelling

This article is made available through the Brunel Open Access Publishing Fund. This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/Introduction: Long-term medical conditions (LTCs) cause reduced health-related quality of life and considerable health service expenditure. Writing therapy has potential to improve physical and mental health in people with LTCs, but its effectiveness is not established. This project aims to establish the clinical and cost-effectiveness of therapeutic writing in LTCs by systematic review and economic evaluation, and to evaluate context and mechanisms by which it might work, through realist synthesis. Methods: Included are any comparative study of therapeutic writing compared with no writing, waiting list, attention control or placebo writing in patients with any diagnosed LTCs that report at least one of the following: relevant clinical outcomes; quality of life; health service use; psychological, behavioural or social functioning; adherence or adverse events. Searches will be conducted in the main medical databases including MEDLINE, EMBASE, PsycINFO, The Cochrane Library and Science Citation Index. For the realist review, further purposive and iterative searches through snowballing techniques will be undertaken. Inclusions, data extraction and quality assessment will be in duplicate with disagreements resolved through discussion. Quality assessment will include using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Data synthesis will be narrative and tabular with meta-analysis where appropriate. De novo economic modelling will be attempted in one clinical area if sufficient evidence is available and performed according to the National Institute for Health and Care Excellence (NICE) reference case.National Institute for Health Research Health Technology Assessment (NIHR HTA) Programm

HEREFORD AND WORCESTER (Reino Unido). Canales (1785?). 1:49100

Escala gráfica de 5 millas [= 16,4 cm]. Orientado con lis en rosa de ocho vientosOrografía a trazosRelación de las parroquias adyacentes al recorrido del canal, indicadas por clave numéricaFigura una tabla con datos sobre la longitud, elevación y caida de los diversos tramos del canalForma parte de la Colección Mendoz

Aesthetic Worlds: Rimbaud, Williams and Baroque Form

The sense of form that provides the modern poet with a unique experience of the literary object has been crucial to various attempts to compare poetry to other cultural activities. In maintaining similar conceptions of the relationship between poetry and painting, Arthur Rimbaud and W. C. Williams establish a common basis for interpreting their creative work. And yet their poetry is more crucially concerned with the sudden emergence of visible "worlds" containing verbal objects that integrate a new kind of literary text. This paper discusses the emergence of "aesthetic worlds" in the work of both poets and then examines how a common concern with Baroque form unites them in the phenomenological task of overcoming Cartesian dualism

Development and validation of a risk score for chronic kidney disease in HIV infection using prospective cohort data from the D:A:D study.

Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice

Biomass-derived carbonaceous adsorbents for trapping ammonia

The preparation of low-cost carbonaceous adsorbents for nitrogen recovery is of interest from agricultural and waste management perspectives. In this study, the gaseous ammonia (NH3) and aqueous ammonium (NH4+) sorption capacities have been measured for different types of carbonaceous chars produced under different conditions. The study includes a comparison of an oak-based hydrochar produced from hydrothermal carbonisation (HTC) at 250◦ C with two biochars produced from slow pyrolysis at 450◦ C and 650◦ C, respectively. The chars were also chemically modified with H2 SO4, H3 PO4, H2 O2, and KOH to investigate the potential for sorption enhancement. The highest sorption capacities for NH3 were observed for the hydrochars with typical uptake capacities ranging from 18–28 mg g−1 NH3. Sorption capacity for oak biochars is significantly lower and ranges from 4–8 mg g−1 for biochars produced at 450◦ C and 650◦ C, respectively. Hydrochar showed a substantially higher sorption capacity for NH3 despite its lower surface area. The CaCl2 extractable NH4+ following ammonia adsorption is incomplete. Typically, only 30–40% of the N is released upon washing with CaCl2 in form of NH4+. Post chemical modification of the chars resulted in only limited enhancement of char NH3 and NH4+ sorption. H3 PO4 treatment showed the greatest potential for increasing NH3 /NH4+ sorption in biochars, while KOH and H2 O2 treatment increased NH3 sorption in the hydrochar. As only marginal increases to char surface area were observed following char treatment, these findings suggest that char surface functionality is more influential than surface area in terms of char NH3 /NH4+ sorption

The long and the short of it: long-styled florets are associated with higher outcrossing rate in Senecio vulgaris and result from delayed selfpollen germination

The research reported in this article was funded in part by the Natural Environment Research Council under grants: GR3/6203A - Male competition and outcrossing rate in a hermaphrodite plant. GR9/1782A – Genomic analysis of wild hybrid derivatives of Senecio squalidus x S. vulgaris using in situ hybridization.Background: It has been reported that some plants of the self-compatible species, Senecio vulgaris, produce capitula containing long-styled florets which fail to set seed when left to self-pollinate, although readily set seed when self-pollinated by hand. Aims: To determine if production of long-styled florets is associated with higher outcrossing rate in S. vulgaris, and whether long-styles occur in non-pollinated florets, whereas short-styles are present in self-pollinated florets. Methods: The frequency of long-styled florets was compared in the radiate and non-radiate variants of S. vulgaris, known to exhibit higher and lower outcrossing rates, respectively. In addition, style length was compared in emasculated florets that were either self-pollinated or left non-pollinated. Results: Long-styled florets were more frequent in the higher outcrossing radiate variant. Following emasculation, long styles occurred in non-pollinated florets, while short styles were present in self-pollinated florets. The two variants did not differ in style length within the non-pollinated or within the self-pollinated floret categories. Conclusions: A high frequency of long-styled florets is associated with higher outcrossing rate in S. vulgaris and results from delayed self-pollination and pollen germination on stigmas.Publisher PDFPublisher PDFPeer reviewe

Renal Impairment and Cardiovascular Disease in HIV-positive Individuals; The D:A:D Study

BACKGROUND: While the association between renal impairment and cardiovascular disease (CVD) is well established in the general population, the association remains poorly understood in HIV-positive individuals. METHODS: Individuals with >2 estimated glomerular filtration rate (eGFRs) after 1/2/2004 were followed until CVD, death, last visit plus six months or 1/2/2015. CVD was defined as centrally validated myocardial infarction, stroke, invasive cardiovascular procedures or sudden cardiac death. RESULTS: During 8.0 years median follow-up (Interquartile range 5.4-8.9) 1,357 of 35,357 developed CVD (incidence 5.2/1000 person-years [95%confidence interval, CI [5.0-5.5]). Confirmed baseline eGFR and CVD were closely related with 1.8% [95%CI 1.6-2.0%] estimated to develop CVD at five years at eGFR>90 ml/min/1.73m(2), increasing to 21.1% [95%CI 6.6-35.6%] at eGFR<30 ml/min/1.73m(2) The strong univariate relationship between low current eGFR and CVD was primarily explained by increasing age in adjusted analyses, although all eGFRs<80 ml/min/1.73m(2) remained associated with 30-40% increased CVD rates and particular high rates at eGFR<30 ml/min/1.73m(2) (3.08 [95%CI 2.04-4.65]). CONCLUSIONS: Among HIV-positive individuals in a large contemporary cohort a strong relation between confirmed impaired eGFR and CVD was observed. This finding highlights the need for renal preventive measures and intensified monitoring for emerging CVD, in particular in older individuals with continuously low eGFR

Recovering from failure by asking for help

Robots inevitably fail, often without the ability to recover autonomously. We demonstrate an approach for enabling a robot to recover from failures by communicating its need for specific help to a human partner using natural language. Our approach automatically detects failures, then generates targeted spoken-language requests for help such as “Please give me the white table leg that is on the black table.” Once the human partner has repaired the failure condition, the system resumes full autonomy. We present a novel inverse semantics algorithm for generating effective help requests. In contrast to forward semantic models that interpret natural language in terms of robot actions and perception, our inverse semantics algorithm generates requests by emulating the human’s ability to interpret a request using the Generalized Grounding Graph (G[superscript 3]) framework. To assess the effectiveness of our approach, we present a corpus-based online evaluation, as well as an end-to-end user study, demonstrating that our approach increases the effectiveness of human interventions compared to static requests for help.Boeing CompanyU.S. Army Research Laboratory (Robotics Collaborative Technology Alliance