Effect of Alkyl Chain Length and Linker Atom on the Crystal Packing in 6,12-Dialkoxy- And 6,12-Dialkylsulfanyl-Benzo[1,2- b:4,5- b′]bis[ b]benzothiophenes

The effect of varying the chain length on the solid state conformation and packing of 6,12-dialkoxy- and 6,12-dialkylsulfanyl-benzo[1,2-b:4,5-b′]bis[b]benzothiophenes has been studied. The compounds were prepared by SNAr reaction of 6,12-difluorbenzo[1,2-b:4,5-b′]bis[b]benzothiophene with alkoxides or alkanethiolates derived from C7-C10 alcohols and alkanethiols. Single crystal X-ray diffraction analysis revealed that all but two compounds crystallize in the triclinic space group P1. Two compounds were obtained as monoclinic crystals with space group P21/c. The alkoxy substituted compounds adopted a molecular conformation with a step from the core and a gauche conformation about the C1′-C2′ bond placing the alkyl chains close to parallel with the pentacyclic arene ring system, whereas in the alkylsufanyl derivatives, the alkyl chains were arranged strongly deviated from the plane of the ring, with the sulfur atom antiperiplanar to C3′ of the alkyl chain. NMR measurement of T1 relaxation in CDCl3 showed both the alkoxy and alkylsulfanyl substituents to be freely rotating at ambient temperature in solution, indicating the orientation of the chains in the solid state was due to packing interactions during crystallization

Restoration of oligodendrocyte pools in a mouse model of chronic cerebral hypoperfusion

Chronic cerebral hypoperfusion, a sustained modest reduction in cerebral blood flow, is associated with damage to myelinated axons and cognitive decline with ageing. Oligodendrocytes (the myelin producing cells) and their precursor cells (OPCs) may be vulnerable to the effects of hypoperfusion and in some forms of injury OPCs have the potential to respond and repair damage by increased proliferation and differentiation. Using a mouse model of cerebral hypoperfusion we have characterised the acute and long term responses of oligodendrocytes and OPCs to hypoperfusion in the corpus callosum. Following 3 days of hypoperfusion, numbers of OPCs and mature oligodendrocytes were significantly decreased compared to controls. However following 1 month of hypoperfusion, the OPC pool was restored and increased numbers of oligodendrocytes were observed. Assessment of proliferation using PCNA showed no significant differences between groups at either time point but showed reduced numbers of proliferating oligodendroglia at 3 days consistent with the loss of OPCs. Cumulative BrdU labelling experiments revealed higher numbers of proliferating cells in hypoperfused animals compared to controls and showed a proportion of these newly generated cells had differentiated into oligodendrocytes in a subset of animals. Expression of GPR17, a receptor important for the regulation of OPC differentiation following injury, was decreased following short term hypoperfusion. Despite changes to oligodendrocyte numbers there were no changes to the myelin sheath as revealed by ultrastructural assessment and fluoromyelin however axon-glial integrity was disrupted after both 3 days and 1 month hypoperfusion. Taken together, our results demonstrate the initial vulnerability of oligodendroglial pools to modest reductions in blood flow and highlight the regenerative capacity of these cells

Why do people choose nephrology? Identifying positive motivators to aid recruitment and retention

Increasing concerns about recruitment and retention of junior doctors have led to renewed interest in how and when trainees choose their specialties. To our knowledge, no study has yet reported what attracts UK applicants to nephrology nor how clinicians develop vocational interests or make occupational choices. With this in mind, we sought to explore the motivation behind current nephrologist's career choices in the UK. We interviewed 11 nephrologists using a semi-structured face-to-face approach and used interpretative phenomenological analysis to conduct and analyse the interviews. We found role models were pivotal in encouraging specialization in nephrology, particularly those encountered in early postgraduate training. The diversity, diagnostic challenge and cross-specialty knowledge was highlighted as well as the ability to 'make a difference to patients' lives'. Nephrologists enjoyed the challenge of managing very sick, acutely unwell patients as well as the holistic continuity of long-term care offered to dialysis patients and their families. Academic and procedural components were attractive motivators to the specialty and the flexibility to have multiple interests was noted, with many nephrologists having 'portfolio' careers. Based on these results, we suggest strategies the specialty can use to aid policy decision making, promote recruitment and improve educational experiences within current training programmes

Randomized clinical trials to identify optimal antibiotic treatment duration

Background Antibiotic resistance is a major barrier to the continued success of antibiotic treatment. Such resistance is often generated by overly long durations of antibiotic treatment. A barrier to identifying the shortest effective treatment duration is the cost of the sequence of clinical trials needed to determine shortest optimal duration. We propose a new method to identify the optimal treatment duration of an antibiotic treatment regimen. Methods Subjects are randomized to varying treatment durations and the cure proportions of these durations are linked using a logistic regression model, making effective use of information across all treatment duration groups. In this paper, Monte Carlo simulation is used to evaluate performance of such a model. Results Using a hypothetical dataset, the logistic regression model is seen to provide increased precision in defining the point estimate and confidence interval (CI) of the cure proportion at each treatment duration. When applied to the determination of non-inferiority, the regression model allows identification of the shortest duration meeting the predefined non-inferiority margin. Conclusions This analytic strategy represents a practical way to develop shortened regimens for tuberculosis and other infectious diseases. Application of this strategy to clinical trials of antibiotic therapy could facilitate decreased antibiotic usage, reduce cost, minimize toxicity, and decrease the emergence of antibiotic resistance

Translational Recoding Induced by G-Rich mRNA Sequences That Form Unusual Structures

AbstractWe investigated a herpesvirus mutant that contains a single base insertion in its thymidine kinase (tk) gene yet expresses low levels of TK via a net +1 translational recoding event. Within this mutant gene, we defined a G-rich signal that is sufficient to induce recoding. Unlike other translational recoding events, downstream RNA structures or termination codons did not stimulate recoding, and paused ribosomes were not detected. Mutational analysis indicated that specific tRNAs or codon–anticodon slippage were unlikely to account for recoding. Rather, recoding efficiency correlated with the G-richness of the signal and its ability to form unusual structures. These findings identify a mechanism of translational recoding with unique features and potential implications for clinical drug resistance and other biological systems

Evaluation of exposure-specific risks from two independent samples: A simulation study

<p>Abstract</p> <p>Background</p> <p>Previous studies have proposed a simple product-based estimator for calculating exposure-specific risks (ESR), but the methodology has not been rigorously evaluated. The goal of our study was to evaluate the existing methodology for calculating the ESR, propose an improved point estimator, and propose variance estimates that will allow the calculation of confidence intervals (CIs).</p> <p>Methods</p> <p>We conducted a simulation study to test the performance of two estimators and their associated confidence intervals: 1) current (simple product-based estimator) and 2) proposed revision (revised product-based estimator). The first method for ESR estimation was based on multiplying a relative risk (RR) of disease given a certain exposure by an overall risk of disease. The second method, which is proposed in this paper, was based on estimates of the risk of disease in the unexposed. We then multiply the updated risk by the RR to get the revised product-based estimator. A log-based variance was calculated for both estimators. Also, a binomial-based variance was calculated for the revised product-based estimator. 95% CIs were calculated based on these variance estimates. Accuracy of point estimators was evaluated by comparing observed relative bias (percent deviation from the true estimate). Interval estimators were evaluated by coverage probabilities and expected length of the 95% CI, given coverage. We evaluated these estimators across a wide range of exposure probabilities, disease probabilities, relative risks, and sample sizes.</p> <p>Results</p> <p>We observed more bias and lower coverage probability when using the existing methodology. The revised product-based point estimator exhibited little observed relative bias (max: 4.0%) compared to the simple product-based estimator (max: 93.9%). Because the simple product-based estimator was biased, 95% CIs around this estimate exhibited small coverage probabilities. The 95% CI around the revised product-based estimator from the log-based variance provided better coverage in most situations.</p> <p>Conclusion</p> <p>The currently accepted simple product-based method was only a reasonable approach when the exposure probability is small (< 0.05) and the RR is ≤ 3.0. The revised product-based estimator provides much improved accuracy.</p

The impact of future sea-level rise on the global tides

Tides are a key component in coastal extreme water levels. Possible changes in the tides caused by mean sea-level rise (SLR) are therefore of importance in the analysis of coastal flooding, as well as many other applications. We investigate the effect of future SLR on the tides globally using a fully global forward tidal model: OTISmpi. Statistical comparisons of the modelled and observed tidal solutions demonstrate the skill of the refined model setup with no reliance on data assimilation. We simulate the response of the four primary tidal constituents to various SLR scenarios. Particular attention is paid to future changes at the largest 136 coastal cities, where changes in water level would have the greatest impact. Spatially uniform SLR scenarios ranging from 0.5 to 10 m with fixed coastlines show that the tidal amplitudes in shelf seas globally respond strongly to SLR with spatially coherent areas of increase and decrease. Changes in the M2 and S2 constituents occur globally in most shelf seas, whereas changes in K1 and O1 are confined to Asian shelves. With higher SLR tidal changes are often not proportional to the SLR imposed and larger portions of mean high water (MHW) changes are above proportional. Changes in MHW exceed ±10% of the SLR at ~10% of coastal cities. SLR scenarios allowing for coastal recession tend increasingly to result in a reduction in tidal range. The fact that the fixed and recession shoreline scenarios result mainly in changes of opposing sign is explained by the effect of the perturbations on the natural period of oscillation of the basin. Our results suggest that coastal management strategies could influence the sign of the tidal amplitude change. The effect of a spatially varying SLR, in this case fingerprints of the initial elastic response to ice mass loss, modestly alters the tidal response with the largest differences at high latitudes

Proudman resonance with tides, bathymetry and variable atmospheric forcings

Proudman resonance is a primary amplification mechanism for meteotsunamis, which are shallow-water waves generated by atmospheric forcings. The effect of tides, sloping bathymetry and the speed, amplitude and aspect ratio of the atmospheric forcing on Proudman resonant wave growth are investigated using analytical approximations and numerical models. With tides included, maximum wave growth through Proudman resonance occurred when the atmospheric-forcing speed matched the tidal-wave speed. Growth greater than Proudman resonance occurred with a positive tidal elevation together with a tidal current in the opposite direction to wave propagation, due to linear growth combined with further amplification from wave-flux conservation. Near-Proudman resonant growth occurred when the forced-wave speed or free-wave speed varied by either a small amount, or varied rapidly, around a speed appropriate for Proudman resonance. For a forcing moving at Proudman resonant speed, resultant wave growth was proportional to the total, time-integrated forcing amplitude. Finally, Proudman resonant wave growth was lower for forcings with lower aspect ratios (AP), partly because forced-wave heights are proportional to 1 + A 2P , but also because free waves could spread in two dimensions. Whilst the assumptions of strict Proudman resonance are never met, near-Proudman resonant growth may occur over hundreds of kilometres if the effective Froude number is near 1 and the resultant wave propagates predominantly in one dimension