Cyclic pyrrole-imidazole polyamides targeted to the androgen response element

Hairpin pyrrole−imidazole (Py-Im) polyamides are a class of cell-permeable DNA-binding small molecules that can disrupt transcription factor−DNA binding and regulate endogenous gene expression. The covalent linkage of antiparallel Py-Im ring pairs with an γ-amino acid turn unit affords the classical hairpin Py-Im polyamide structure. Closing the hairpin with a second turn unit yields a cyclic polyamide, a lesser-studied architecture mainly attributable to synthetic inaccessibility. We have applied our methodology for solution-phase polyamide synthesis to cyclic polyamides with an improved high-yield cyclization step. Cyclic 8-ring Py-Im polyamides 1−3 target the DNA sequence 5′-WGWWCW-3′, which corresponds to the androgen response element (ARE) bound by the androgen receptor transcription factor to modulate gene expression. We find that cyclic Py-Im polyamides 1−3 bind DNA with exceptionally high affinities and regulate the expression of AR target genes in cell culture studies, from which we infer that the cycle is cell permeable

The Effect of Body Region on Hair Cortisol Concentration in Common Marmosets (\u3cem\u3eCallithrix jacchus\u3c/em\u3e)

Common marmosets (Callithrix jacchus) are a valuable research model for the study of neuroscience and the biologic impact of aging due to their adaptivity, physiologic characteristics, and ease of handling for experimental manipulations. Quantification of cortisol in hair provides a noninvasive, retrospective biomarker of hypothalamics-pituitary-adrenal (HPA) axis activity and information on animal wellbeing, including responses to environmental and social stimuli. To obtain valid and reliable measurements of long-term HPA activity, we investigated the variability of cortisol concentration in the hair depending on the body region of marmosets. Hair was collected from the back and tail of 9 adult common marmosets during annual health screenings (male n = 3; female n = 6) and these samples were analyzed for cortisol via methanol extraction and enzyme immunoassay. We found that hair cortisol concentration differed between the tail and back regions, with the tail samples having a significantly higher cortisol concentration. These results indicate intraindividual and interindividual comparisons of hair cortisol concentration should use hair obtained from the same body region in marmosets

Randomised, controlled trial of alternating pressure mattresses compared with alternating pressure overlays for the prevention of pressure ulcers : PRESSURE (pressure relieving support surfaces) trial

Objective To compare whether differences exist between alternating pressure overlays and alternating pressure mattresses in the development of new pressure ulcers, healing of existing pressure ulcers, and patient acceptability. Design Pragmatic, open, multicentre, randomised controlled trial. Setting 11 hospitals in six NHS trusts. Participants 1972 people admitted to hospital as acute or elective patients. Interventions Participants were randomised to an alternating pressure mattress (n = 982) of- an alternating pressure overlay (n = 990). Main outcome measures The proportion of participants developing a new pressure ulcer of grade 2 or worse; time to development of new pressure ulcers; proportions of participants developing a new ulcer within 30 days; healing of existing pressure ulcers; and patient acceptability Results Intention to treat analysis found no difference in the proportions of participants developing a new pressure ulcer of grade 2 or worse (10.7% overlay patients, 10.3% mattress patients; difference 0.4%, 95% confidence interval - 23% to 3.1%, P = 0.75). More overlay patients requested change owing to dissatisfaction (23.3%) than mattress patients (18.9%, P = 0.02). Conclusion No difference was found between alternating pressure mattresses and alternating pressure overlays in the proportion of people who develop a pressure ulcer

Numerical methods for the TSD equation in conservation law form

The Transonic Small Disturbance (TSD) Equation is a common model equation for describing subsonic and supersonic flow close to the local speed of sound (transonic). In transonic flow there is an embedded region of locally supersonic flow inside an otherwise subsonic flow. The supersonic region is usually terminated by a shock discontinuity. The success of a numerical scheme for transonic flow prediction depends on its capability of capturing all the flow details and non-linearities including sharp shock profiles without oscillations near the shock. Most of the important phenomena in the TSD equation occur in the stream-wise direction. The nonlinearity and changes in the region of influence depend only on the stream-wise derivation. A suitable one-dimensional model equation derived from the TSD Equation is used. The one-dimensional equation is written in conservation law form. This nonlinear system of equations models the transition from supersonic to subsonic flow. In the numerical calculations the discretised problem is treated as a series of Riemann problems. We will investigate various techniques for solving these Riemann problems. It will be shown that the techniques do not allow non-physical expansion shocks to develop and that the techniques smooth out expansion shocks when these non-physical shocks are present in the initial velocity profile. A comparison will be made between the schemes based on the sharpness of the resulting shock profiles