Silver resistance in Gram-negative bacteria: a dissection of endogenous and exogenous mechanisms

Objectives: To gain a more detailed understanding of endogenous (mutational) and exogenous (horizontally acquired) resistance to silver in Gram-negative pathogens, with an emphasis on clarifying the genetic bases for resistance. Methods: A suite of microbiological and molecular genetic techniques was employed to select and characterize endogenous and exogenous silver resistance in several Gram-negative species. Results: In Escherichia coli, endogenous resistance arose after 6 days of exposure to silver, a consequence of two point mutations that were both necessary and sufficient for the phenotype. These mutations, in ompR and cusS, respectively conferred loss of the OmpC/F porins and derepression of the CusCFBA efflux transporter, both phenotypic changes previously linked to reduced intracellular accumulation of silver. Exogenous resistance involved derepression of the SilCFBA efflux transporter as a consequence of mutation in silS, but was additionally contingent on expression of the periplasmic silver-sequestration protein SilE. Silver resistance could be selected at high frequency (>10(-9)) from Enterobacteriaceae lacking OmpC/F porins or harbouring the sil operon and both endogenous and exogenous resistance were associated with modest fitness costs in vitro. Conclusions: Both endogenous and exogenous silver resistance are dependent on the derepressed expression of closely related efflux transporters and are therefore mechanistically similar phenotypes. The ease with which silver resistance can become selected in some bacterial pathogens in vitro suggests that there would be benefit in improved surveillance for silver-resistant isolates in the clinic, along with greater control over use of silver-containing products, in order to best preserve the clinical utility of silver

Virological efficacy of PI monotherapy for HIV-1 in clinical practice.

BACKGROUND: Clinical trials of PI monotherapy indicate that most participants maintain viral suppression and emergent protease resistance is rare. However, outcomes among patients receiving PI monotherapy for clinical reasons, such as toxicity or adherence issues, are less well studied. METHODS: An observational study of patients attending an HIV treatment centre in London, UK, who had received PI monotherapy between 2004 and 2013, was conducted using prospectively collected clinical data and genotypic resistance reports. Survival analysis techniques were used to examine the times to virological failure and treatment discontinuation. RESULTS: Ninety-five patients had PI monotherapy treatment for a median duration of 126 weeks. Virological failure occurred during 64% of episodes and 8% of patients developed emergent protease mutations. We estimate failure occurs in half of episodes within 2 years following initiation. Where PI monotherapy was continued following virological failure, 68% of patients achieved viral re-suppression. Despite a high incidence of virological failure, many patients continued PI monotherapy and 79% of episodes were ongoing at the end of the study. The type of PI used, the presence of baseline protease mutations and the plasma HIV RNA at initiation did not have a significant impact on treatment outcomes. CONCLUSIONS: There was a higher incidence of virological failure and emerging resistance in our UK clinical setting than described in PI monotherapy clinical trials and other European observational studies. Despite this, many patients continued PI monotherapy and regained viral suppression, indicating this strategy remains a viable option in certain individuals following careful clinical evaluation

Zone center phonons of the orthorhombic RMnO3 (R = Pr, Eu, Tb, Dy, Ho) perovskites

A short range force constant model (SRFCM) has been applied for the first time to investigate the phonons in RMnO3 (R = Pr, Eu, Tb, Dy, Ho) perovskites in their orthorhombic phase. The calculations with 17 stretching and bending force constants provide good agreement for the observed Raman frequencies. The infrared frequencies have been assigned for the first time. PACS Codes: 36.20.Ng, 33.20.Fb, 34.20.CfComment: 8 pages, 1 figur

Constraining General Two Higgs Doublet Models by the Evolution of Yukawa Couplings

We study how general two Higgs doublet models can be constrained by considering their properties under renormalization group evolution of the Yukawa couplings. We take into account both the appearance of a Landau pole as well as off-diagonal Yukawa couplings leading to flavour changing neutral currents in violation with experimental constraints at the electroweak scale. We find that the latter condition can be used to limit the amount of Z2 symmetry breaking allowed in a given model.Comment: 28 pages, 10 figures, added discussion of evolution from high to low scales, to be published in JHE

Hypothalamic-pituitary-adrenal stress axis function and the relationship with chronic widespread pain and its antecedents

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.In clinic studies, altered hypothalamic-pituitary-adrenal (HPA) axis function has been associated with fibromyalgia, a syndrome characterised by chronic widespread body pain. These results may be explained by the associated high rates of psychological distress and somatisation. We address the hypothesis that the latter, rather than the pain, might explain the HPA results. A population study ascertained pain and psychological status in subjects aged 25 to 65 years. Random samples were selected from the following three groups: satisfying criteria for chronic widespread pain; free of chronic widespread pain but with strong evidence of somatisation ('at risk'); and a reference group. HPA axis function was assessed from measuring early morning and evening salivary cortisol levels, and serum cortisol after physical (pain pressure threshold exam) and chemical (overnight 0.25 mg dexamethasone suppression test) stressors. The relationship between HPA function with pain and the various psychosocial scales assessed was modelled using appropriate regression analyses, adjusted for age and gender. In all 131 persons with chronic widespread pain (participation rate 74%), 267 'at risk' (58%) and 56 controls (70%) were studied. Those in the chronic widespread pain and 'at risk' groups were, respectively, 3.1 (95% CI (1.3, 7.3)) and 1.8 (0.8, 4.0) times more likely to have a saliva cortisol score in the lowest third. None of the psychosocial factors measured were, however, associated with saliva cortisol scores. Further, those in the chronic widespread pain (1.9 (0.8, 4.7)) and 'at risk' (1.6 (0.7, 3.6)) groups were also more likely to have the highest serum cortisol scores. High post-stress serum cortisol was related to high levels of psychological distress (p = 0.05, 95% CI (0.02, 0.08)). After adjusting for levels of psychological distress, the association between chronic widespread pain and post-stress cortisol scores remained, albeit slightly attenuated. This is the first population study to demonstrate that those with established, and those psychologically at risk of, chronic widespread pain demonstrate abnormalities of HPA axis function, which are more marked in the former group. Although some aspects of the altered function are related to the psychosocial factors measured, we conclude that the occurrence of HPA abnormality in persons with chronic widespread pain is not fully explained by the accompanying psychological stress

A spin triplet supercurrent through the half-metallic ferromagnet CrO2

In general, conventional superconductivity should not occur in a ferromagnet, though it has been seen in iron under pressure. Moreover, theory predicts that the current is always carried by pairs of electrons in a spin singlet state, so conventional superconductivity decays very rapidly when in contact with a ferromagnet, which normally prohibits the existence of singlet pairs. It has been predicted that this rapid spatial decay would not occur when spin triplet superconductivity could be induced in the ferromagnet. Here we report a Josephson supercurrent through the strong ferromagnet CrO2, from which we infer that it is a spin triplet supercurrent. Our experimental setup is different from those envisaged in the earlier predictions, but we conclude that the underlying physical explanation for our result is a conversion from spin singlet to spin triplets at the interface. The supercurrent can be switched with the direction of the magnetization, analogous to spin valve transistors, and therefore could enable magnetization-controlled Josephson junctions.Comment: 14 pages, including 3 figure

The RN/CFT Correspondence Revisited

We reconsidered the quantum gravity description of the near horizon extremal Reissner-Nordstr{\o}m black hole in the viewpoint of the AdS$_2$/CFT$_1$ correspondence. We found that, for pure electric case, the right moving central charge of dual 1D CFT is $6 Q^2$ which is different from the previous result $6 Q^3$ of left moving sector obtained by warped AdS$_3$/CFT$_2$ description. We discussed the discrepancy in these two approaches and examined novel properties of our result.Comment: revtex4, 16 pages, sign mistakes corrected, references include

Transmit Power Minimization for MIMO Systems of Exponential Average BER with Fixed Outage Probability

This document is the Accepted Manuscript version of the following article: Dian-Wu Yue, and Yichuang Sun, ‘Transmit Power Minimization for MIMO Systems of Exponential Average BER with Fixed Outage Probability’, Wireless Personal Communications, Vol. 90 (4): 1951-1970, first available online on 20 June 2016. Under embargo. Embargo end date: 20 June 2017. The final publication is available at Springer via https://link.springer.com/article/10.1007%2Fs11277-016-3432-4This paper is concerned with a wireless multiple-antenna system operating in multiple-input multiple-output (MIMO) fading channels with channel state information being known at both transmitter and receiver. By spatiotemporal subchannel selection and power control, it aims to minimize the average transmit power (ATP) of the MIMO system while achieving an exponential type of average bit error rate (BER) for each data stream. Under the constraints on each subchannel that individual outage probability and average BER are given, based on a traditional upper bound and a dynamic upper bound of Q function, two closed-form ATP expressions are derived, respectively, which can result in two different power allocation schemes. Numerical results are provided to validate the theoretical analysis, and show that the power allocation scheme with the dynamic upper bound can achieve more power savings than the one with the traditional upper bound.Peer reviewe

Charged-Higgs phenomenology in the Aligned two-Higgs-doublet model

The alignment in flavour space of the Yukawa matrices of a general two-Higgs-doublet model results in the absence of tree-level flavour-changing neutral currents. In addition to the usual fermion masses and mixings, the aligned Yukawa structure only contains three complex parameters, which are potential new sources of CP violation. For particular values of these three parameters all known specific implementations of the model based on discrete Z_2 symmetries are recovered. One of the most distinctive features of the two-Higgs-doublet model is the presence of a charged scalar. In this work, we discuss its main phenomenological consequences in flavour-changing processes at low energies and derive the corresponding constraints on the parameters of the aligned two-Higgs-doublet model.Comment: 46 pages, 19 figures. Version accepted for publication in JHEP. References added. Discussion slightly extended. Conclusions unchange

Higgs-mediated FCNCs: Natural Flavour Conservation vs. Minimal Flavour Violation

We compare the effectiveness of two hypotheses, Natural Flavour Conservation (NFC) and Minimal Flavour Violation (MFV), in suppressing the strength of flavour-changing neutral-currents (FCNCs) in models with more than one Higgs doublet. We show that the MFV hypothesis, in its general formulation, is more stable in suppressing FCNCs than the hypothesis of NFC alone when quantum corrections are taken into account. The phenomenological implications of the two scenarios are discussed analysing meson-antimeson mixing observables and the rare decays B -> mu+ mu-. We demonstrate that, introducing flavour-blind CP phases, two-Higgs doublet models respecting the MFV hypothesis can accommodate a large CP-violating phase in Bs mixing, as hinted by CDF and D0 data and, without extra free parameters, soften significantly in a correlated manner the observed anomaly in the relation between epsilon_K and S_psi_K.Comment: 27 pages, 4 figures. v3: minor modifications (typos corrected and few refs. added), conclusions unchanged; journal versio