Abandoning clinical trial safeguards won\u27t boost local industry

CLINICAL TRIALS - Human clinical trials are an important last hurdle in the development of new drugs and therapies. Today, The Conversation takes a closer look at this vital scientific endeavour with three articles that look at different aspects of the process

Contact-induced apical asymmetry drives the thigmotropic responses of Candida albicans hyphae

Acknowledgements We thank Marco Thiel for assistance with data interpretation, Peter Sudbery for the provision of strains and Jeremy Craven for useful discussions. This work was supported by a BBSRC-DTG to D. D. T., NIH award DK083592 to F. J. B. and P. A. J., and a Royal Society URF UF080611 and MRC NIRG 90671 to A. C. B.Non peer reviewedPublisher PD

A SQUAMOSA MADS-box gene involved in the regulation of anthocyanin accumulation in bilberry fruits

Anthocyanins are important health promoting phytochemicals that are abundant in many fleshy fruits. Bilberry (Vaccinium myrtillus L.) is one of the best sources of these compounds. Here we report on the expression pattern and functional analysis of a SQUAMOSA (SQUA) class MADS-box transcription factor, VmTDR4, associated with anthocyanin biosynthesis in bilberry. Levels of VmTDR4 expression were spatially and temporally linked with colour development and anthocyanin-related gene expression. Virus induced gene silencing (VIGS) was used to suppress VmTDR4 expression in bilberry resulting in substantial reduction in anthocyanin levels in fully ripe fruits. Chalcone synthase was used a positive control in the VIGS experiments. Additionally, in sectors of fruit tissue in which the expression of the VmTDR4 gene was silenced, the expression of R2R3 MYB family transcription factors related to the biosynthesis of flavonoids were also altered. We conclude that VmTDR4 plays an important role in the accumulation of anthocyanins during normal ripening in bilberry; probably through direct or indirect control of transcription factors belonging to the R2R3 MYB family

Meningococcal disease in children in Merseyside, England:a 31 year descriptive study

Meningococcal disease (MCD) is the leading infectious cause of death in early childhood in the United Kingdom, making it a public health priority. MCD most commonly presents as meningococcal meningitis (MM), septicaemia (MS), or as a combination of the two syndromes (MM/MS). We describe the changing epidemiology and clinical presentation of MCD, and explore associations with socioeconomic status and other risk factors. A hospital-based study of children admitted to a tertiary children's centre, Alder Hey Children's Foundation Trust, with MCD, was undertaken between 1977 to 2007 (n = 1157). Demographics, clinical presentations, microbiological confirmation and measures of deprivation were described. The majority of cases occurred in the 1-4 year age group and there was a dramatic fall in serogroup C cases observed with the introduction of the meningococcal C conjugate (MCC) vaccine. The proportion of MS cases increased over the study period, from 11% in the first quarter to 35% in the final quarter. Presentation with MS (compared to MM) and serogroup C disease (compared to serogroup B) were demonstrated to be independent risk factors for mortality, with odds ratios of 3.5 (95% CI 1.18 to 10.08) and 2.18 (95% CI 1.26 to 3.80) respectively. Cases admitted to Alder Hey were from a relatively more deprived population (mean Townsend score 1.25, 95% CI 1.09 to 1.41) than the Merseyside reference population. Our findings represent one of the largest single-centre studies of MCD. The presentation of MS is confirmed to be a risk factor of mortality from MCD. Our study supports the association between social deprivation and MCD

Quantitative analysis of regulatory flexibility under changing environmental conditions

The circadian clock controls 24-h rhythms in many biological processes, allowing appropriate timing of biological rhythms relative to dawn and dusk. Known clock circuits include multiple, interlocked feedback loops. Theory suggested that multiple loops contribute the flexibility for molecular rhythms to track multiple phases of the external cycle. Clear dawn- and dusk-tracking rhythms illustrate the flexibility of timing in Ipomoea nil. Molecular clock components in Arabidopsis thaliana showed complex, photoperiod-dependent regulation, which was analysed by comparison with three contrasting models. A simple, quantitative measure, Dusk Sensitivity, was introduced to compare the behaviour of clock models with varying loop complexity. Evening-expressed clock genes showed photoperiod-dependent dusk sensitivity, as predicted by the three-loop model, whereas the one- and two-loop models tracked dawn and dusk, respectively. Output genes for starch degradation achieved dusk-tracking expression through light regulation, rather than a dusk-tracking rhythm. Model analysis predicted which biochemical processes could be manipulated to extend dusk tracking. Our results reveal how an operating principle of biological regulators applies specifically to the plant circadian clock

Objective cough frequency, airway inflammation, and disease control in asthma

Background Cough is recognized as an important troublesome symptom in the diagnosis and monitoring of asthma. Asthma control is thought to be determined by the degree of airway inflammation and hyperresponsiveness but how these factors relate to cough frequency is unclear. The goal of this study was to investigate the relationships between objective cough frequency, disease control, airflow obstruction, and airway inflammation in asthma. Methods Participants with asthma underwent 24-h ambulatory cough monitoring and assessment of exhaled nitric oxide, spirometry, methacholine challenge, and sputum induction (cell counts and inflammatory mediator levels). Asthma control was assessed by using the Global Initiative for Asthma (GINA) classification and the Asthma Control Questionnaire (ACQ). The number of cough sounds was manually counted and expressed as coughs per hour (c/h). Results Eighty-nine subjects with asthma (mean ± SD age, 57 ± 12 years; 57% female) were recruited. According to GINA criteria, 18 (20.2%) patients were classified as controlled, 39 (43.8%) partly controlled, and 32 (36%) uncontrolled; the median ACQ score was 1 (range, 0.0-4.4). The 6-item ACQ correlated with 24-h cough frequency (r = 0.40; P < .001), and patients with uncontrolled asthma (per GINA criteria) had higher median 24-h cough frequency (4.2 c/h; range, 0.3-27.6) compared with partially controlled asthma (1.8 c/h; range, 0.2-25.3; P = .01) and controlled asthma (1.7 c/h; range, 0.3-6.7; P = .002). Measures of airway inflammation were not significantly different between GINA categories and were not correlated with ACQ. In multivariate analyses, increasing cough frequency and worsening FEV1 independently predicted measures of asthma control. Conclusions Ambulatory cough frequency monitoring provides an objective assessment of asthma symptoms that correlates with standard measures of asthma control but not airflow obstruction or airway inflammation. Moreover, cough frequency and airflow obstruction represent independent dimensions of asthma control

Some old movies become classics - a case study determining the scientific value of ROV inspection footage on a platform on Australia's North West Shelf

© 2018 Thomson, Fowler, Davis, Pattiaratchi and Booth. The global oil and gas industry holds a vast archive of Remotely Operated Vehicle (ROV) inspection footage potentially containing useful long-term data on marine biological communities. With the upcoming era of decommissioning of oil and gas structures, it is timely to assess the usefulness of this footage for researching these communities. We used ROV inspection footage to characterize the sessile invertebrates and fishes associated with the Goodwyn Alpha Production Platform (GWA) on the North West Shelf of Australia between depths of 10 and 125 m during 2006 and 2008. Depth was a major driver of invertebrate assemblages, most likely due to specific requirements such as light, and differences between years were most likely from the physical detachment of species by cyclones and internal waves. Phototrophic species were mostly limited to the upper 50 m of the platform, including the hard coral Pocillopora sp. and the soft corals Nephthea sp. and Scleronephthya sp. In contrast, heterotrophic species including sponges, anemones, bryozoans, hydroids, bivalves such as Lopha folium and the hard coral Tubastrea spp., were distributed across all depths. We observed 1791 fish from at least 10 families and 19 species, including commercial species such as crimson seaperch (Lutjanus erythropterus), red emperor (L. sebae), saddle-tailed seaperch (L. malabaricus), mangrove jack (L. argentimaculatus) and trevally (Caranx spp.). Fish density increased significantly with depth during 2008, from a mean of 23 fish/50 m2 between 10 and 25 m to 3373 fish/50 m2 at 125 m, where small unidentified baitfish were abundant. The highest densities of commercial species occurred between 25 and 75 m depth, suggesting that mid-depth platform sections had high habitat value, a consideration when selecting decommissioning options. The greatest difficulties using the video were the poor lighting and resolution that inhibited our ability to identify sessile species with high taxonomic precision. However, the footage was useful for evaluating high-level biodiversity of the platform, understanding how fish and invertebrate communities changed with depth and comprehending the dynamic nature of the invertebrate community over time. Understanding the habitat value of structures will be necessary for making environmentally sound decommissioning decisions in the future

Case report: Severe mercuric sulphate poisoning treated with 2,3-dimercaptopropane-1-sulphonate and haemodiafiltration

INTRODUCTION: Inorganic mercury poisoning is uncommon, but when it occurs it can result in severe, life-threatening features and acute renal failure. Previous reports on the use of extracorporeal procedures such as haemodialysis and haemoperfusion have shown no significant removal of mercury. We report here the successful use of the chelating agent 2,3-dimercaptopropane-1-sulphonate (DMPS), together with continuous veno-venous haemodiafiltration (CVVHDF), in a patient with severe inorganic mercury poisoning. CASE REPORT: A 40-year-old man presented with haematemesis after ingestion of 1 g mercuric sulphate and rapidly deteriorated in the emergency department, requiring intubation and ventilation. His initial blood mercury was 15 580 μg/l. At 4.5 hours after ingestion he was started on DMPS. He rapidly developed acute renal failure and so he was started on CVVHDF for renal support and in an attempt to improve mercury clearance; CVVHDF was continued for 14 days. METHODS: Regular ultradialysate and pre- and post-filtrate blood samples were taken and in addition all ultradialysate generated was collected to determine its mercury content. RESULTS: The total amount of mercury in the ultrafiltrate was 127 mg (12.7% of the ingested dose). The sieving coefficient ranged from 0.13 at 30-hours to 0.02 at 210-hours after ingestion. He developed no neurological features and was discharged from hospital on day 50. Five months after discharge from hospital he remained asymptomatic, with normal creatinine clearance. DISCUSSION: We describe a patient with severe inorganic mercury poisoning in whom full recovery occurred with the early use of the chelating agent DMPS and CVVHDF. There was removal of a significant amount of mercury by CVVHDF. CONCLUSION: We feel that CVVHDF should be considered in patients with inorganic mercury poisoning, particularly those who develop acute renal failure, together with meticulous supportive care and adequate doses of chelation therapy with DMPS

Iterative focused screening with biological fingerprints identifies selective Asc-1 inhibitors distinct from traditional high throughput screening

N-methyl-d-aspartate receptors (NMDARs) mediate glutamatergic signaling that is critical to cognitive processes in the central nervous system, and NMDAR hypofunction is thought to contribute to cognitive impairment observed in both schizophrenia and Alzheimer’s disease. One approach to enhance the function of NMDAR is to increase the concentration of an NMDAR coagonist, such as glycine or d-serine, in the synaptic cleft. Inhibition of alanine–serine–cysteine transporter-1 (Asc-1), the primary transporter of d-serine, is attractive because the transporter is localized to neurons in brain regions critical to cognitive function, including the hippocampus and cortical layers III and IV, and is colocalized with d-serine and NMDARs. To identify novel Asc-1 inhibitors, two different screening approaches were performed with whole-cell amino acid uptake in heterologous cells stably expressing human Asc-1: (1) a high-throughput screen (HTS) of 3 M compounds measuring 35S l-cysteine uptake into cells attached to scintillation proximity assay beads in a 1536 well format and (2) an iterative focused screen (IFS) of a 45 000 compound diversity set using a 3H d-serine uptake assay with a liquid scintillation plate reader in a 384 well format. Critically important for both screening approaches was the implementation of counter screens to remove nonspecific inhibitors of radioactive amino acid uptake. Furthermore, a 15 000 compound expansion step incorporating both on- and off-target data into chemical and biological fingerprint-based models for selection of additional hits enabled the identification of novel Asc-1-selective chemical matter from the IFS that was not identified in the full-collection HTS

Effects of a museum-based social-prescription intervention on quantitative measures of psychological wellbeing in older adults

Aims: To assess psychological wellbeing in a novel social prescription intervention for older adults called Museums on Prescription, and to explore the extent of change over time in six self-rated emotions (‘absorbed, ‘active’, ‘cheerful’, ‘encouraged’, ‘enlightened’ and ‘inspired’). Methods: Participants (n=115) aged 65-94 were referred to museum-based programmes comprising 10, weekly sessions, by healthcare and third sector organisations using inclusion criteria (e.g. socially isolated; able to give informed consent; not in employment; not regularly attending social or cultural activities) and exclusion criteria (e.g. unable to travel to the museum; unable to function in a group situation; unlikely to be able to attend all sessions; unable to take part in interviews and complete questionnaires). In a within-participants design, the Museum Wellbeing Measure for Older Adults (MWM-OA) was administered pre-post session at start- mid- and end-programme. Twelve programmes, facilitated by museum staff and volunteers, were conducted in seven museums in central London and across Kent. In addition to the quantitative measures, participants, carers where present, museum staff and researchers kept weekly diaries following guideline questions, and took part in end programme in-depth interviews. Results: Multivariate analyses of variance showed significant participant improvements in all six MWM-OA emotions, pre-post session at start- mid- and end-programme. Two emotions, ‘absorbed’ and ‘enlightened’, increased pre-post session disproportionately to the others; ‘cheerful’ attained the highest pre-post session scores whereas ‘active’ was consistently lowest. Conclusions: Museums can be instrumental in offering museum-based programmes for older adults to improve psychological wellbeing over time. Participants in the study experienced a sense of privilege, valued the opportunity to liaise with curators, visit parts of the museum closed to the public, and handle objects normally behind glass. Participants appreciated opportunities afforded by creative and co-productive activities to acquire learning and skills, and get to know new people in a different context