Selecting RNA aptamers for synthetic biology: investigating magnesium dependence and predicting binding affinity.

The ability to generate RNA aptamers for synthetic biology using in vitro selection depends on the informational complexity (IC) needed to specify functional structures that bind target ligands with desired affinities in physiological concentrations of magnesium. We investigate how selection for high-affinity aptamers is constrained by chemical properties of the ligand and the need to bind in low magnesium. We select two sets of RNA aptamers that bind planar ligands with dissociation constants (K(d)s) ranging from 65 nM to 100 microM in physiological buffer conditions. Aptamers selected to bind the non-proteinogenic amino acid, p-amino phenylalanine (pAF), are larger and more informationally complex (i.e., rarer in a pool of random sequences) than aptamers selected to bind a larger fluorescent dye, tetramethylrhodamine (TMR). Interestingly, tighter binding aptamers show less dependence on magnesium than weaker-binding aptamers. Thus, selection for high-affinity binding may automatically lead to structures that are functional in physiological conditions (1-2.5 mM Mg(2+)). We hypothesize that selection for high-affinity binding in physiological conditions is primarily constrained by ligand characteristics such as molecular weight (MW) and the number of rotatable bonds. We suggest that it may be possible to estimate aptamer-ligand affinities and predict whether a particular aptamer-based design goal is achievable before performing the selection

Geospatial mapping and data linkage uncovers variability in outcomes of foot disease according to multiple deprivation: a population cohort study of people with diabetes

Aims/hypothesis: Our aim was to investigate the geospatial distribution of diabetic foot ulceration (DFU), lower extremity amputation (LEA) and mortality rates in people with diabetes in small geographical areas with varying levels of multiple deprivation. Methods: We undertook a population cohort study to extract the health records of 112,231 people with diabetes from the Scottish Care Information – Diabetes Collaboration (SCI-Diabetes) database. We linked this to health records to identify death, LEA and DFU events. These events were geospatially mapped using multiple deprivation maps for the geographical area of National Health Service (NHS) Greater Glasgow and Clyde. Tests of spatial autocorrelation and association were conducted to evaluate geographical variation and patterning, and the association between prevalence-adjusted outcome rates and multiple deprivation by quintile. Results: Within our health board region, people with diabetes had crude prevalence-adjusted rates for DFU of 4.6% and for LEA of 1.3%, and an incidence rate of mortality preceded by either a DFU or LEA of 10.5 per 10,000 per year. Spatial autocorrelation identified statistically significant hot spot (high prevalence) and cold spot (low prevalence) clusters for all outcomes. Small-area maps effectively displayed near neighbour clustering across the health board geography. Disproportionately high numbers of hot spots within the most deprived quintile for DFU (p < 0.001), LEA (p < 0.001) and mortality (p < 0.001) rates were found. Conversely, a disproportionately higher number of cold spots was found within the least deprived quintile for LEA (p < 0.001). Conclusions/interpretation: In people with diabetes, DFU, LEA and mortality rates are associated with multiple deprivation and form geographical neighbourhood clusters

Spin polarized transport current in n-type co-doped ZnO thin films measured by Andreev spectroscopy

We use point contact Andreev reflection measurements to determine the spin polarization of the transport current in pulse laser deposited thin films of ZnO with 1% Al and with and without 2%Mn. Only films with Mn are ferromagnetic and show spin polarization of the transport current of up to 55 $\pm$ 0.5% at 4.2 K, in sharp contrast to measurements of the nonmagnetic films without Mn where the polarization is consistent with zero. Our results imply strongly that ferromagnetism in these Al doped ZnO films requires the presence of Mn.Comment: Published versio

Osteoarthritis Disease Severity in the Temporomandibular Joint and the Knee Joint: A Comparative Cadaveric Study

OBJECTIVE: The objective of this study was to determine the level of disease severity in a pilot cohort of temporomandibular joints (TMJs) and compare them to the pathology findings previously characterized in cadaveric knee joints. DESIGN: Thirty-one intact TMJs from 17 cadaveric donors were harvested and arthritic lesioning seen in the knee joint was investigated on the condyle and the fossa of the TMJ. Prevalence of gross alterations was equated and disease severity was determined for sex- and age-based donor pools using a validated, osteoarthritis (OA) disease severity scale (DSS). Knee joint DSS scores were also compared to the TMJ condyle and fossa DSS scores and a case study was carried out on a male donor that demonstrated severe OA in the both joints. RESULTS: The mandibular fossa demonstrated an increase in disease severity compared to the mandibular condyle in a mixed sex donor pool ( CONCLUSIONS: This study demonstrates that gross signs of OA in the TMJs of cadavers are comparable to pathology found in the knee. The mandibular fossa appears to be the site of more profound disease, implying translational movements may be more likely to induce biomechanically abnormal movement, loading, and OA

Genome Characterization of a Novel Wastewater Bacteroides fragilis Bacteriophage (vB_BfrS_23) and its Host GB124

Bacteroides spp. are part of the human intestinal microbiota but can under some circumstances become clinical pathogens. Phages are a potentially valuable therapeutic treatment option for many pathogens, but phage therapy for pathogenic Bacteroides spp. including Bacteroides fragilis is currently limited to three genome-sequenced phages. Here we describe the isolation from sewage wastewater and genome of a lytic phage, vB_BfrS_23, that infects and kills B. fragilis strain GB124. Transmission electron microscopy identified this phage as a member of the Siphoviridae family. The phage is stable when held at temperatures of 4 and 60°C for 1 h. It has a very narrow host range, only infecting one host from a panel of B. fragilis strains (n = 8). Whole-genome sequence analyses of vB_BfrS_23 determined it is double-stranded DNA phage and is circularly permuted, with a genome of 48,011 bp. The genome encodes 73 putative open reading frames. We also sequenced the host bacterium, B. fragilis GB124 (5.1 Mb), which has two plasmids of 43,923 and 4,138 bp. Although this phage is host specific, its isolation together with the detailed characterization of the host B. fragilis GB124 featured in this study represent a useful starting point from which to facilitate the future development of highly specific therapeutic agents. Furthermore, the phage could be a novel tool in determining water (and water reuse) treatment efficacy, and for identifying human fecal transmission pathways within contaminated environmental waters and foodstuffs

Effectiveness of community-links practitioners in areas of high socioeconomic deprivation

PURPOSE: To assess the effect of a primary care–based community-links practitioner (CLP) intervention on patients’ quality of life and well-being. METHODS: Quasi-experimental cluster-randomized controlled trial in socioeconomically deprived areas of Glasgow, Scotland. Adult patients (aged 18 years or older) referred to CLPs in 7 intervention practices were compared with a random sample of adult patients from 8 comparison practices at baseline and 9 months. Primary outcome: health-related quality of life (EQ-5D-5L, a standardized measure of self-reported health-related quality of life that assesses 5 dimensions at 5 levels of severity). Secondary outcomes: well-being (Investigating Choice Experiments for the Preferences of Older People Capability Measure for Adults [ICECAP-A]), depression (Hospital Anxiety and Depression Scale, Depression [HADS-D]), anxiety (Hospital Anxiety and Depression Scale, Anxiety [HADS-A]), and self-reported exercise. Multilevel, multiregression analyses adjusted for baseline differences. Patients were not blinded to the intervention, but outcome analysis was masked. RESULTS: Data were collected on 288 and 214 (74.3%) patients in the intervention practices at baseline and follow-up, respectively, and on 612 and 561 (92%) patients in the comparison practices. Intention-to-treat analysis found no differences between the 2 groups for any outcome. In subgroup analyses, patients who saw the CLP on 3 or more occasions (45% of those referred) had significant improvements in EQ-5D-5L, HADS-D, HADS-A, and exercise levels. There was a high positive correlation between CLP consultation rates and patient uptake of suggested community resources. CONCLUSIONS: We were unable to prove the effectiveness of referral to CLPs based in primary care in deprived areas for improving patient outcomes. Future efforts to boost uptake and engagement could improve overall outcomes, although the apparent improvements in those who regularly saw the CLPs may be due to reverse causality. Further research is needed before wide-scale deployment of this approach

Facilitators and barriers to help-seeking for breast and cervical cancer symptoms: a qualitative study with an ethnically diverse sample in London

Objective Earlier diagnosis of cancer has become a policy priority. There is evidence that minority ethnic groups are more likely to delay help‐seeking for cancer symptoms, but few studies have explored reasons for delay in these groups. The present study explored facilitators and barriers to help‐seeking for breast and cervical cancer in an ethnically diverse sample of women. Methods Semi‐structured interviews were carried out with 54 healthy women from a range of ethnic backgrounds; Indian, Pakistani, Bangladeshi, Caribbean, African, Black British, Black other, White British and White other. Framework analysis was used to identify themes. Results Appraising a symptom as possibly due to cancer was an important facilitator of help‐seeking, although for some the prospect of a cancer diagnosis was a deterrent. Women believed that earlier diagnosis improved the chance of survival, and this facilitated prompt help‐seeking. A sympathetic GP facilitated help‐seeking, and an unsympathetic GP was a deterrent. Some ethnic minority women described the use of alternative medicine and prayer as a first‐line strategy that might delay help‐seeking. Language barriers, racism and a tendency to ‘soldier on’ were also mentioned by these women. Conclusions Models of delay in presentation for early cancer symptoms are likely to transfer across different ethnic groups. Encouraging open discussion about cancer among minority communities could help raise awareness about the importance of early detection and promote help‐seeking as a priority response to a possible cancer symptom

Regional climate impacts of a possible future grand solar minimum.

This is the final published version. It first appeared at http://www.nature.com/ncomms/2015/150623/ncomms8535/full/ncomms8535.html.Any reduction in global mean near-surface temperature due to a future decline in solar activity is likely to be a small fraction of projected anthropogenic warming. However, variability in ultraviolet solar irradiance is linked to modulation of the Arctic and North Atlantic Oscillations, suggesting the potential for larger regional surface climate effects. Here, we explore possible impacts through two experiments designed to bracket uncertainty in ultraviolet irradiance in a scenario in which future solar activity decreases to Maunder Minimum-like conditions by 2050. Both experiments show regional structure in the wintertime response, resembling the North Atlantic Oscillation, with enhanced relative cooling over northern Eurasia and the eastern United States. For a high-end decline in solar ultraviolet irradiance, the impact on winter northern European surface temperatures over the late twenty-first century could be a significant fraction of the difference in climate change between plausible AR5 scenarios of greenhouse gas concentrations.This work was supported by the Joint DECC/Defra Met Office Hadley Centre Climate Programme (GA01101) and also by the EU project SPECS funded by the European Commission’s Seventh Framework Research Programme under the grant agreement 308378 (Met Office Hadley Centre authors), by the NERC National Centre for Atmospheric Science (NCAS) Climate directorate (L.J.G. and A.C.M.), an ERC ACCI grant (A.C.M) and an AXA Postdoctoral Fellowship (A.C.M.)

Elite mountain bike enduro competition: a study of rider hand-arm vibration exposure

Limited information is currently available regarding the hand-arm vibration (HAV) exposure 5 for professional off-road cyclists. Previous reports have suggested that commuting and 6 recreational cyclists are at risk of exceeding exposure limit values (ELV) in a single ride. 7 Therefore, further investigation of HAV exposure in competitive mountain biking is 8 warranted. Partial and total eight hour exposure data (Ai(8), A(8), ms⁻²) were computed for a 9 national level mountain bike enduro competitions. Hand-arm vibrations were measured using 10 a tri-axial accelerometer recording at a frequency of 3.2 kHz mounted on the handlebar and 11 accelerations were quantified after frequency weighting filters were applied (Wh). The data 12 presented shows that HAV exposure during one day of competitive enduro mountain bike 13 racing exceeds ELV (mean race exposure = 5.84 ms⁻² , minimum = 5.47ms⁻² , maximum = 14 6.61ms⁻²) and is greater than the HAV exposure observed in recreational cycling. This 15 suggests that further work is required to determine the exposure associated with changes in 16 equipment, technique and international racing events in professional athletes