Prevalence of HCV NS3 pre-treatment resistance associated amino acid variants within a Scottish cohort

Background: Protease inhibitors (PI) including boceprevir, telaprevir and simeprevir have revolutionised HCV genotype 1 treatment since their introduction. A number of pre-treatment resistance associated amino acid variants (RAVs) and polymorphisms have been associated with reduced response to treatment. Objectives: We measured the prevalence of RAVs/polymorphisms in a PI treatment-naïve HCV genotype 1 Scottish cohort using Sanger sequencing. Study design: Chronically infected, treatment-naïve, HCV genotype 1 patients (n = 146) attending NHS Greater Glasgow and Clyde clinics were investigated for RAVs/polymorphisms to the PIs boceprevir, telaprevir and simeprevir. The NS3/4A region was amplified by nested polymerase chain reaction. The 1.4 kb amplified product was sequenced using an ABI 3710XL DNA sequencer. Sequence analysis was performed using web-based ReCall (beta 2.10). Amino acid positions 36, 41, 43, 54, 55, 80, 109, 122, 155, 156, 168 and 170 were analysed for RAVs/polymorphisms. Results: Overall, 23.29% (34/146) of patients had an RAV or polymorphism detected. Overall, 13.69% (20/146) of patients had HCV virus that contained the Q8 K polymorphism. Other RAVs detected were: V36 M 0.70% (1/146), V36L 0.70% (1/146), T54S 6.85% (10/146), V55A 3.42% (5/146) and V/I170A 0.68% (1/146). Four patients had dual combinations of mutations (T54S + V36L; T54S + V55A and 2 patients with T54S + Q80K). Conclusions: Q80K was the most prevalent baseline polymorphism detected in the Scottish cohort. Simeprevir treatment is not recommended in patients infected with the Q80K genotype 1a variant. This highlights the need for baseline sequencing prior to administration of this drug in this population

Serotonin signaling through the 5-HT1B receptor and NADPH oxidase 1 in pulmonary arterial hypertension

Objective: Serotonin can induce human pulmonary artery smooth muscle cell (hPASMC) proliferation through reactive oxygen species (ROS), influencing the development of pulmonary arterial hypertension (PAH). We hypothesise that in PASMCs, serotonin induces oxidative stress through NADPH-oxidase-derived ROS generation and reduced Nrf-2 anti-oxidant systems, promoting vascular injury. Approach and Results: HPASMCs from controls and PAH patients, and PASMCs from Nox1-/- mice, were stimulated with serotonin in the absence/presence of inhibitors of Src kinase, the 5-HT1B receptor and NADPH oxidase 1 (Nox1). Markers of fibrosis were also determined. The pathophysiological significance of our findings was examined in vivo in serotonin transporter overexpressing (SERT+) female mice, a model of pulmonary hypertension (PH). We confirmed serotonin increased superoxide and H2O2 production in these cells. For the first time, we show that serotonin increased oxidized protein tyrosine phosphatases and peroxiredoxin-SO3H and decreased Nrf-2 and catalase activity in hPASMCs. ROS generation was exaggerated, and dependent on c-Src, 5-HT1B receptor and the serotonin transporter in PAH-hPASMCs. Proliferation and extracellular matrix remodeling were exaggerated in PAH-hPASMCs and dependent on 5-HT1B receptor signaling and Nox1, confirmed in PASMCs from Nox1-/- mice. In SERT+ mice, SB216641, a 5-HT1B receptor antagonist, prevented development of PH in a ROS-dependent manner. Conclusions: Serotonin can induce c-Src-regulated Nox1-induced ROS and Nrf-2 dysregulation, contributing to increased post-translational oxidative modification of proteins, activation of redox-sensitive signaling pathways in hPASMCs; associated with mitogenic responses. 5-HT1B receptors contribute to experimental PH by inducing lung ROS production. Our results suggest 5-HT1B receptor-dependent c-Src-Nox1-pathways contribute to vascular remodeling in PAH

Multi-temporality and the ghostly: How communing with times past informs organizational futures

Despite growing interest in time, history, and memory, we lack an understanding of the multi-temporal reality of organizations - how past, present and future intersect to inform organizational life. In assuming that legacies are conveyed from past to present, there has been little theorization on how this works practically. We propose that the lexicon of the ghostly can help. We contribute a theory of ghostly influence from past to future by offering a framework focusing on core moments of organizational existence: foundation, strategic change, and longevity commemoration, and illustrate this use a case study of the consumer goods multinational Procter & Gamble (1930-2010). In showing that organizational ghosts, absent members whose presence is consequential to the actions of living members, are active and dialogical, we illuminate a dialogical interaction missing from other non-linear conceptions of temporality. This emphasizes the performative force of a dynamic past that provides an inference to action in the present and future

Notch3 signaling and vascular remodeling in pulmonary arterial hypertension

Notch signalling is critically involved in vascular morphogenesis and function. Four Notch isoforms (Notch1–4) regulating diverse cellular processes have been identified. Of these, Notch3 is expressed almost exclusively in vascular smooth muscle cells (VSMCs), where it is critically involved in vascular development and differentiation. Under pathological conditions, Notch3 regulates VSMC switching between the contractile and synthetic phenotypes. Abnormal Notch3 signalling plays an important role in vascular remodelling, a hallmark of several cardiovascular diseases, including pulmonary arterial hypertension (PAH). Because of the importance of Notch3 in VSMC (de)differentiation, Notch3 has been implicated in the pathophysiology of pulmonary vascular remodelling in PAH. Here we review the current literature on the role of Notch in VSMC function with a focus on Notch3 signalling in pulmonary artery VSMCs, and discuss potential implications in pulmonary artery remodelling in PAH

Spectroscopy of 50^{50}Sc and ab initio calculations of B(M3)B(M3) strengths

The GRIFFIN spectrometer at TRIUMF-ISAC has been used to study excited states and transitions in $^{50}$Sc following the $\beta$-decay of $^{50}$Ca. Branching ratios were determined from the measured $\gamma$-ray intensities, and angular correlations of $\gamma$ rays have been used to firmly assign the spins of excited states. The presence of an isomeric state that decays by an $M3$ transition with a $B(M3)$ strength of 13.6(7)\,W.u. has been confirmed. We compare with the first {\it ab initio} calculations of $B(M3$) strengths in light and medium-mass nuclei from the valence-space in-medium similarity renormalization group approach, using consistently derived effective Hamiltonians and $M3$ operator. The experimental data are well reproduced for isoscalar $M3$ transitions when using bare $g$-factors, but the strength of isovector $M3$ transitions are found to be underestimated by an order of magnitude

Including Limited Partners in the Diversity Jurisdiction Analysis

This paper presents the results of the Dynamic Pricing Challenge, held on the occasion of the 17th INFORMS Revenue Management and Pricing Section Conference on June 29–30, 2017 in Amsterdam, The Netherlands. For this challenge, participants submitted algorithms for pricing and demand learning of which the numerical performance was analyzed in simulated market environments. This allows consideration of market dynamics that are not analytically tractable or can not be empirically analyzed due to practical complications. Our findings implicate that the relative performance of algorithms varies substantially across different market dynamics, which confirms the intrinsic complexity of pricing and learning in the presence of competition

Regulatory fine-tuning of mcr-1 increases bacterial fitness and stabilises antibiotic resistance in agricultural settings

Antibiotic resistance tends to carry fitness costs, making it difficult to understand how resistance can be maintained in the absence of continual antibiotic exposure. Here we investigate this problem in the context of mcr-1, a globally disseminated gene that confers resistance to colistin, an agricultural antibiotic that is used as a last resort for the treatment of multi-drug resistant infections. Here we show that regulatory evolution has fine-tuned the expression of mcr-1, allowing E. coli to reduce the fitness cost of mcr-1 while simultaneously increasing colistin resistance. Conjugative plasmids have transferred low-cost/high-resistance mcr-1 alleles across an incredible diversity of E. coli strains, further stabilising mcr-1 at the species level. Regulatory mutations were associated with increased mcr-1 stability in pig farms following a ban on the use of colistin as a growth promoter that decreased colistin consumption by 90%. Our study shows how regulatory evolution and plasmid transfer can combine to stabilise resistance and limit the impact of reducing antibiotic consumption

The Intrinsic Origin of Spin Echoes in Dipolar Solids Generated by Strong Pi Pulses

In spectroscopy, it is conventional to treat pulses much stronger than the linewidth as delta-functions. In NMR, this assumption leads to the prediction that pi pulses do not refocus the dipolar coupling. However, NMR spin echo measurements in dipolar solids defy these conventional expectations when more than one pi pulse is used. Observed effects include a long tail in the CPMG echo train for short delays between pi pulses, an even-odd asymmetry in the echo amplitudes for long delays, an unusual fingerprint pattern for intermediate delays, and a strong sensitivity to pi-pulse phase. Experiments that set limits on possible extrinsic causes for the phenomena are reported. We find that the action of the system's internal Hamiltonian during any real pulse is sufficient to cause the effects. Exact numerical calculations, combined with average Hamiltonian theory, identify novel terms that are sensitive to parameters such as pulse phase, dipolar coupling, and system size. Visualization of the entire density matrix shows a unique flow of quantum coherence from non-observable to observable channels when applying repeated pi pulses.Comment: 24 pages, 27 figures. Revised from helpful referee comments. Added new Table IV, new paragraphs on pages 3 and 1